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PHASE 3 NOTES: ACUTE DYSPNOEA AND HAEMOPTYSIS
CONTENTS:
Page
Definition and clinical assessment of dyspnoea (history, physical
exam key points, differential diagnosis) 2
Clinical assessment of haemoptysis and pathogenetic mechanisms 9
Surface anatomy of the thorax and lungs 14
Examination of the Respiratory system 16
Deep venous thrombosis, pulmonary embolism and case protocol 3 26
Haematology review- Haemostasis and coagulation pathways 42
Pharmacology- Drugs to treat thrombosis and embolism 49
Heart failure 54
Asthma and case protocol 39 80
Acute Respiratory Distress Syndrome 97
Arterial Blood gas analysis for acute dyspnoea (laboratory visit) 102
Smoking prevention and lung cancer 109
Lung cancer and case protocol 19 118
Pneumonia
Bronchiectasis
Lung abscess
Tuberculosis
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Clinical Assessment & Management of Dyspnoea
History/initial assessment of the presenting problem: dyspnoea:
Dyspnoea is the subjective experience or perception of uncomfortable breathing or „short of breath‟.
However, the relationship between the level of dyspnoea and the severity of disease varies widely.
Conditions that cause dyspnoea affect the mechanical effort of breathing (e.g. asthma, COPD), or may
arise from conditions that necessitate compensatory tachypnoea (e.g. acidosis, hypoxaemia), or from
psychogenic causes (e.g. anxiety).
When evaluating a patient with shortness of breath, one should first determine the time course over which
the symptom has become manifest. Patients who were well previously and developed acute shortness of
breath (over a period of minutes to days) may have acute disease affecting either the upper or the
intrathoracic airways (e.g., laryngeal edema or acute asthma, respectively), the pulmonary parenchyma
(acute cardiogenic or noncardiogenic pulmonary edema or an acute infectious process such as a bacterial
pneumonia), the pleural space (a pneumothorax), or the pulmonary vasculature (a pulmonary embolus). A
subacute presentation (over days to weeks) can suggest an exacerbation of preexisting airways disease
(asthma or chronic bronchitis), an indolent parenchymal infection (Pneumocystis jiroveci pneumonia in a
patient with AIDS, mycobacterial or fungal pneumonia), a noninfectious inflammatory process that
proceeds at a relatively slow pace (Wegener‟s granulomatosis, eosinophilic pneumonia, cryptogenic
organizing pneumonia, and many others), neuromuscular disease (Guillain-Barre syndrome, myasthenia
gravis), pleural disease (pleural effusion from a variety of possible causes), or chronic cardiac disease
(congestive heart failure). A chronic presentation (over months to years) often indicates chronic
obstructive lung disease, chronic interstitial lung disease, or chronic cardiac disease. Chronic diseases of
airways (not only chronic obstructive lung disease but also asthma) are characterized by exacerbations
and remissions. Patients often have periods when they are severely limited by shortness of breath, but
these may be interspersed with periods in which symptoms are minimal or absent. In contrast, many of
the diseases of the pulmonary parenchyma are characterized by slow but inexorable progression. Chronic
respiratory symptoms may also be multifactorial in nature, as patients with chronic obstructive pulmonary
disease may also have concomitant heart disease. As with all other presenting symptoms, know how to
ask relevant questions.
Importantly, it is necessary to establish how long the patient has been dyspnoeic. Was the onset of
shortness of breath acute or gradual? (i.e. timing of dyspnoea) This is important as the differential
diagnosis for acute (e.g. paroxysmal) dyspnoea is different to subacute or chronic progressive dyspnoea.
Some causes of acute dyspnoea include bronchospasm, pulmonary embolism (PE), pneumothorax,
pulmonary infection, acute respiratory distress syndrome (ARDS), diaphragmatic paralysis, myocardial
ischaemia, acute cardiogenic pulmonary oedema, and anxiety/panic attacks. Note that chronic dyspnea
can present with an acute exacerbation.
Are there any associated symptoms? The patient may focus on the shortness of breath and fail to
disclose chest pain, pressure, or discomfort unless specifically asked. Qualify the chest pain; for example,
chest pain of a pleuritic nature characterises pneumothorax or PE with infarction. Bear in mind that
dyspnoea rather than angina may be the primary or the only symptom of acute myocardial ischaemia.
Determination of the effect of positional changes of dyspnoea (i.e. what makes the shortness of breath
better or worse? Is the shortness of breath better or worse when you are lying down or sitting up,
etc?) is important. Orthopnea (difficulty breathing when lying flat) suggests congestive heart failure, or
diaphragmatic dysfunction. Platypnea (difficulty breathing when sitting upright) invokes intrapulmonary
or intracardiac shunting. Trepopnea (an inability to lie on one‟s side) implies pleural effusion or
congestive heart failure. Assessment for precipitants, including dyspnoea on exertion (How far can you
walk after you feel breathless?) and exposure to chemicals, and other irritants is also helpful (thus a
thorough occupational health history, smoking history, and history of drugs & medications and
allergies is important). It may also be helpful to ask for other important presenting symptoms including
haemoptysis, cough, wheeze, chest pain, fever.
Is the patient cyanotic? Hypoxemia is a potentially lethal condition. If there is obvious cyanosis (or
evidence of hypoxia, such as by pulse oximetry) noted, then immediate oxygen therapy is indicated.
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Breathlessness: How long have you been short of breath? Important to ask about timing and onset
(see below) Was onset of breathlessness gradual, or all of a sudden? What are alleviating
and aggravating factors- i.e. what makes it better or worse? Is there a particular time
during the day that breathlessness is worse? Are there any other associated symptoms, for
example chest pain, discomfort, cough, sputum expectoration, wheeze, haemoptysis? Have you
coughed up blood? (80% of cases of haemoptysis may be due to either: bronchitis, bronchial
carcinoma, pneumonia and bronchiectasis). Important causes of dyspnoea include airways disease
(asthma, chronic bronchitis, Cystic Fibrosis (CF)), parenchymal disease (pneumonia, allergic
alveolitis, emphysema, sarcoidosis), Pulmonary circulation (PE), Chest wall & pleura (effusion,
massive ascites, tumour). See below for details on dyspnoea.
Cough & Sputum production: How long has the cough lasted for and what brought it about,
i.e. what do you think caused it? Are you bringing up any sputum with the cough? What is
the smell (foul-smelling brown sputum occurs with lung abscess with anaerobic organisms),
colour and volume? (i.e. how much sputum- a large volume of purulent yellow to green sputum
occurs with bronchiectasis or lobar pneumonia). What makes the cough better or worse; e.g. is
the coughing worse or better after drinking or eating? (May be useful to indicate laryngeal
pathology or may indicate a tracheo-oesophageal fistula). Have you had a recent fever with the
cough (for acute bronchitis & other upper respiratory tract infections, pneumonia?) Have you
had a wheeze associated with the cough? (A chronic cough with wheeze could indicate chronic
asthma). Is it a dry, chronic cough? (Occurs with oesophageal reflux and laryngeal irritation,
late interstitial pulmonary fibrosis with interstitial lung disease, or with use of ACE inhibitors).
Do you find that the cough wakes you from sleep, or when do you find that it is worst? (may
indicate anything, but specifically it could also point towards cardiac failure or gastro-
oesophageal reflux disease with laryngeal/tracheobronchial irritation). Have you noticed a
change in the character of the cough? (could occur with lung cancer). Can you give me a
cough to show me what it is like; is it a productive, dry or barking cough? (Barking cough
can occur with pertussis, laryngitis, or epiglottitis; a loud, brassy cough can occur with tracheal
obstruction, e.g. due to tumour compression; a “hollow sounding cough” can be due to recurrent
laryngeal nerve palsy). What time of the day do you cough most? With respiratory system
questions, time during the day is useful. Cough may indicate the presence of lung disease, but
cough per se is not useful for differential diagnosis. The presence of sputum accompanying the
cough often suggests airway disease and may be seen in asthma, chronic bronchitis, or
bronchiectasis. Haemoptysis can originate from disease of the airways, the pulmonary
parenchyma, or the vasculature. Diseases of the airways can be inflammatory (acute or chronic
bronchitis, bronchiectasis, or cystic fibrosis) or neoplastic (bronchogenic carcinoma or bronchial
carcinoid tumours). Parenchymal diseases causing haemoptysis may be either localized
(pneumonia, lung abscess, tuberculosis, or infection with Aspergillus) or diffuse (Goodpasture‟s
syndrome, idiopathic pulmonary hemosiderosis). Vascular diseases potentially associated with
haemoptysis include pulmonary thromboembolic disease and pulmonary arteriovenous
malformations.
Chest pain: Use SOCRATES mnemonic, for pain as always. With chest pain associated with the
respiratory system, it is pleuritic in nature, which is sharp, stabbing pain that is well localised (to
the area of the parietal pleura which has been involved by inflammation or local injury) and is
worse on inspiration. Important causes of pleuritic chest pain include Pulmonary Embolism with
infarction & pleural involvement, pneumonia with pleural involvement and Pneumothorax.
What are relieving factors? Important relieving factors that may give the diagnosis include: rest
(most lung diseases), shallow breathing (e.g. with pneumothorax). What are aggravating
factors? important aggravating factors to note include: exercise, deep breaths and coughing. Just
remember other major types of chest pain including pain from cardiovascular causes including
myocardial ischaemia, aortic dissection, musculoskeletal pain, or neuropathic, e.g. herpes zoster
shingles. Chest pain caused by diseases of the respiratory system usually originates from
involvement of the parietal pleura. As a result, the pain is accentuated by respiratory motion and
is often referred to as pleuritic. Common examples include primary pleural disorders, such as
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neoplasm or inflammatory disorders involving the pleura, or pulmonary parenchymal disorders
that extend to the pleural surface, such as pneumonia or pulmonary infarction.
Wheeze: An important presenting problem, that may be associated with dyspnoea, e.g. in the case of
asthma or COPD. Again use the SOCRATES mnemonic to ask relevant questions. Note that not
just asthma or COPD cause wheeze and other important causes of wheeze include tumours and
foreign bodies.
Nasal symptoms: An important cause of coughing is a post-nasal drip, in which case the patient has
a cough although they have no lower respiratory tract infections, and this is usually worse at night
or when they have a runny nose, as in the case with allergies. Other important nasal problems
that can cause nasal symptoms include nasal polyps as well as septum deviation.
Hoarseness: Many causes, including laryngitis, vocal cord tumours, vocal cord paralysis, recurrent
laryngeal nerve palsy.
Sleep apnoea symptoms: Importantly, because the patient with sleep apnoea has poor quality
sleep, they usually have chronic fatigue syndrome, morning headaches, daytime somnolence
(feeling sleepy and having a tendency to sleep), as well as falling asleep- daytime micro-sleep,
witness apnoeas (a person such as the wife notices that patient is loudly snoring during the night
and suddenly they stop breathing- may cause them to wake up and restart breathing). Usually
these patients are overweight/obese.
Fever, night sweats: These constitutional symptoms are non-specific, but usually in the case of
respiratory system diseases they point-towards infections. Night sweats are an important
systemic feature of certain diseases, including haematological malignancies and very importantly
tuberculosis.
Never forget for a Respiratory System presenting problem other critical components of the medical
history, including: Family History (important for many conditions, as diverse as α1-antitrypsin
deficiency in COPD to Cystic Fibrosis CFTR mutations), Social history (e.g. ask about how the disease
has impacted them and their ADLs, how far they can walk before they become breathless, how many
stairs they can climb, do they have any stairs at home, travel history, do they have any pets- specifically
birds- as some birds can transmit Chlamydia psittacosis or may be a cause of hypersensitivity
pneumonitis), Occupational history is very important with the respiratory system, and obviously a
comprehensive smoking history.
Family History: Important conditions to ask for include cystic fibrosis, tuberculosis, COPD (α1-
antitrypsin deficiency), pulmonary hypertension, interstitial lung diseases including familial
idiopathic pulmonary fibrosis, sarcoidosis and other respiratory diseases including asthma.
Interestingly, for patients whose both parents had asthma, they have a 60% risk of acquiring asthma.
Social History:
Smoking history: how much they have smoked cigarettes and for how long and report this as pack
years. Ask if they smoke anything other than tobacco cigarettes, e.g. marijuana. Also if they have
ceased smoking, how long it has been since they quit. Exposure to significant second-hand (passive)
smoke at home or in the work-place should also be identified with a full respiratory history.
Occupational history (e.g. including asbestos exposure, exposure to dusts, e.g. western red cedar for
asthma, volatile chemicals, aerosols, dusts in factories etc) This includes both past and current work.
Go back ~20 years when asking for occupational history and ask about all work the person has been
involved with. Important to ask about construction or insulation work (e.g. electricians, plumbers)
and exposure to asbestos, boiler makers (involved with insulation cladding with asbestos) and ship
builders and destructors. Also important to assess silicate exposure, important to ask about mining
work (hard rocks, minerals/metals including zinc mining, copper, coal (if coal is in a salicaceous
deposit- however this causes coal workers pneumoconioses rather than silicosis), tunnelers-
(underground miners), jack-pick operators, exposure to sandstone and sand-blasting. Also ask for
occupations that are risk factors for hypersensitivity pneumonitis (animals, moulds- protein deposits
usually in the upper lobes, which infiltrates, causing granulomas with giant cells, pulmonary
infiltrates, fever, lung fibrosis with prolonged exposure) including farmers (“farmer‟s lung”), malt-
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workers lung, bird/poultry farmers. For occupational asthma, ask about exposure to paints, spray
paints, (asthma induced by di-isocyanates which are volatile chemicals found in 2-pack paints),
animal exposure with furs (e.g. lab workers experimenting with mice), aluminium smelters (involves
electrolytic production with Bauxite, which uses hydrofluoric acid (HF) and this as well as aluminium
metal fumes can cause “pot room asthma”), exposure to chlorine gas as well as carpenters (red cedar
or elm exposure; these woods contain plicatic acid and abietic acids).
Travel history & what they did during travel, ask about risk factors for respiratory disease you may
be suspecting. Importantly, endemic areas for tuberculosis or geographic locations for certain fungi
(e.g. histoplasma, coccidioidomycosis, blastomycosis).
Pets and especially birds: Important as they can transmit Coxiella burnetii (Q-fever), Chlamydia
psittacosis (Psittacosis), and may cause interstitial lung diseases including hypersensitivity
pneumonitis (Type 1 hypersensitivity to avian allergens).
Hobbies: May include work that may be contributing to their presenting problem, e.g. wood
work/carpentry with extensive dust exposure, spray painting, hence hobbies are also important
together with occupational history.
Risk factors for HIV/TB: A sexual history may be necessary if HIV is being considered. Travel
history to TB endemic areas, exposure to TB, previous TB infection and HIV infection are also
important for TB.
Home environment & ADLs: Especially in patients with advanced lung disease, it is important to
make an assessment of their home and functional status and how well they manage their ADLs. How
many stairs do they have in their house; how do they cope with stairs, do they become breathless?
How long can they walk before they need to rest? Do they need home oxygen therapy?
Obviously a comprehensive drug history is needed and outside the social history, a comprehensive
medication and allergies history.
Important sites of respiratory diseases include obviously from the nose to the distal airways; the nose,
nasopharynx, larynx, trachea, bronchi and smaller airways, alveoli, as well as the pleura, chest
wall/respiratory muscles, diaphragm, and the CNS for respiratory regulation (respiratory centres).
Allergy history important; do not forget to ask about skin-prick tests (important for asthma & some
other conditions). Importantly, dust-mite, cockroach pollen, pet or di-isocyanate allergies.
Don‟t forget past medical history! Especially for rheumatological diseases associated with pleural/lung
parenchymal disease. History of previous cancers indicating metastatic disease, HIV/AIDS risk factors,
secondary immunoglobulin deficiencies. The lungs are the most common-site for AIDS defining illness.
Medications: chemotherapy/radiotherapy, amiodarone, ACE inhibitors, beta-blockers etc.
Physical examination key points:
Vital signs: Fever may signify infection, but can also occur with PE and MI. Tachypnoea occurs most
often in cases of dyspnoea; however, dyspnoea can occur with a normal respiratory rate. Hypotension
may result from a tension pneumothorax, anaphylaxis, pericardial tamponade, acute MI, or anaemia from
haemorrhage. Tachycardia is also seen in the above conditions. Pulsus paradoxus (inspiratory
diminution in systolic blood pressure exceeding 10 mmHg) may occur with acute exacerbation of asthma,
COPD, constrictive pericarditis, or pericardial tamponade and its significance is established only during
normal cardiac rhythm and with respirations of normal tidal rhythm and depth (tidal breathing). Bedside
pulse oximetry is a valuable bedside measurement.
Lungs: Observe the patient for signs of respiratory distress, including accessory muscle use. Paradoxical
abdominal movement during respiration suggests diaphragmatic and respiratory muscle fatigue. Palpate
for tracheal deviation, which may be encountered in pneumothorax, large pleural effusion, or pulmonary
mass. Percuss the lung fields to survey for asymmetry of resonance as found in pneumothorax.
Auscultate for wheezes, stridor, crackles, friction rubs, and absent breath sounds.
Heart: Check for elevated jugular venous pressure, displaced apex beat, or an S3 gallop suggests
decompensated heart failure. Jugular venous distension on inspiration, a non-palpable apical impulse and
muffled heart tones occur with pericardial tamponade. Irregular heart beat and murmurs are also
important signs.
Extremities: Examine for peripheral oedema or other evidence of deep venous thrombosis, which
predisposes to pulmonary embolus. Also, evaluate for pallor and peripheral cyanosis. Clubbing may
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be seen in a dyspnoeic patient with chronic suppurative lung disease (e.g. Cystic fibrosis), bronchial
carcinoma, cyanotic heart disease, bacterial endocarditis, cirrhosis or Grave‟s hyperthyroidism.
Neurologic exam: Confusion and impaired mentation may signify severe hypoxemia or may elucidate the
cause of dyspnoea, such as infection.
Differential Diagnosis:
Dyspnoea is the subjective sensation of difficult, laboured, uncomfortable breathing. It may occur through
increased respiratory muscle work, stimulation of neuroreceptors throughout the respiratory tract, or
stimulation of peripheral or central chemoreceptors. Although many diseases produce dyspnoea, two-
thirds are caused by pulmonary or cardiac disorders.
A. Pulmonary causes:
1) Pulmonary embolism: This diagnosis must be considered in any patient presenting with acute
dyspnoea. Also recurrent pulmonary emboli can cause intermittent dyspnoea at rest. This diagnosis
should be considered especially in the presence of risk factors such as prolonged immobilisation, recent
operative procedure, obesity, malignancy (especially adenocarcinomas which cause migratory
thrombophlebitis or Trousseau‟s syndrome), venous trauma, known venous thrombosis,
hypercoagulable risk factors (protein C and protein S deficiencies, Factor V Leiden mutation,
prothrombin gene mutation, antithrombin III deficiency- e.g. pregnancy) or hypercoagulable state (such
as antiphospholipid antibody syndrome) or high-dose oestrogen therapy, especially in women over 35
years age who take oral contraceptive pills and smoke.
2) Pneumothorax: This can occur after trauma, or spontaneously in patients with bullous emphysema, or
in young people- especially males with a tall, thin body habitus. Patients on ventilators are at increased
risk. Iatrogenic pneumothoraces may occur after central line insertion, bronchoscopy, positive-pressure
ventilation or thoracentesis.
3) Obstructive lung diseases: asthma/Chronic Obstructive Pulmonary Disease (COPD): Sometimes
patients with asthma primarily have chest hyperinflation and increased work of breathing before actual
wheezing occurs. A careful examination and review of history are important. However, anaphylaxis
can also produce wheezing. In addition to bronchospasm, these patients demonstrate other evidence of
anaphylaxis such as stridor, wheezing, pruritus, hypotension and urticaria.
4) Asthma: The patient may have developed acute asthma, it is important to ascertain whether they have
had asthma in their past medical history. If suspecting asthma, how often do they have symptoms (i.e.
what is the frequency of their symptoms)? Do they know what triggers their asthma and have they
had exposure to any allergens, such as grass or flower pollens, recent viral infection, exercise induced
asthma etc?
5) Aspiration: An altered mental status or advanced age or comorbidities (e.g. neurological deficit in a
stroke patient) is often present (e.g. from intoxication, psychosis, delirium); also ask about dysphagia
and muscle weakness suggesting an acute cerebral vascular accident.
6) Pneumonia: It is characterised by fever, productive cough, radiographic infiltrates, and either
leukocytosis or leukopenia.
7) Interstitial lung disease: This usually produces progressive dyspnoea and is caused by diseases such as
sarcoidosis, idiopathic pulmonary fibrosis, collagen vascular disease and occupational lung disease.
8) Pleural effusion: This is more likely to cause chronic or subchronic dyspnoea rather than acute
dyspnoea, except in the setting of significant parapneumonic effusion or in association with congestive
heart failure, renal failure, or pulmonary haemorrhage.
9) Acute respiratory distress syndrome: This is defined as acute bilateral lung injury with severe
hypoxemia and is commonly associated with pneumonia, aspiration, sepsis, trauma, pancreatitis or
receiving multiple transfusions.
B. Cardiac causes:
Acute Myocardial Infarction (MI): Myocardial ischaemia can present primarily with dyspnoea rather
than chest pain, which is important to remember. In addition, patients with acute MI can develop acute
PE or congestive heart failure with pulmonary oedema as a complication of MI.
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Congestive heart failure: Accumulation of fluid in the interstitial spaces of the lung stimulates neuro-
receptors, which produce a sensation of dyspnoea often causing orthopnea and paroxysmal nocturnal
dyspnoea. Common causes of Ischaemic heart disease/heart failure include myocardial ischaemia,
hypertension, dilated cardiomyopathy and valvular heart disease.
Pericarditis/pericardial effusion causing pericardial tamponade: Dyspnoea and fatigue, as well as
chest discomfort are frequently significant complaints. Suspect pericardial effusion in a patient with
pulmonary malignancy.
Cardiac dysrhythmias: Dyspnoea may accompany cardiac tachyarrhythmias (e.g. atrial fibrillation,
supraventricular tachycardia, ventricular tachycardia) or bradyarrhythmias (e.g. complete atrioventricular
block or sinus bradycardia).
Valvular or other cardiac disease: Aortic stenosis, aortic insufficiency, mitral stenosis and mitral
insufficiency as well as intracardiac shunt and atrial myxoma can cause dyspnoea.
C. Neuromuscular diseases:
Dyspnoea can be caused by central nervous system disorders, proximal myopathies, neuropathies, phrenic
nerve or diaphragmatic disorders, spinal cord disorders or systemic neuromuscular diseases for example
myasthenia gravis, Guillain-Barré syndrome.
D. Other organic diseases:
Anaemia, gastro-oesophageal reflux, thyrotoxicosis, hypothyroidism, metabolic acidosis (particularly
diabetic ketoacidosis), renal failure (with concomitant pulmonary oedema and/or uremic pericarditis),
carbon monoxide poisoning, massive ascites (effectively resulting in restrictive lung disease), and
deconditioning may all cause dyspnoea.
E. Psychogenic breathlessness:
Dyspnoea associated with hyperventilation can be difficult to separate from dyspnoea due to organic
causes. Typically anxiety, acral paraesthesias and light-headedness are present. The dyspnoea is worse at
rest and improves during exercise. A diagnosis of psychogenic breathlessness should not be made until
organic diseases have been excluded. These patients often have an increased frequency of sighing.
Relevant investigations for dyspnoea:
Full blood count and blood film: Leukocytosis with an increase in banded neutrophils occurs with
pneumonia. Anaemia can cause dyspnoea on exertion and may precipitate myocardial
ischaemia in patients with established coronary heart disease.
Arterial blood gases (ABGs): These values should be obtained in any patient with significant dyspnoea
or when hypoxemia is suspected based on a decreased percentage of oxygen saturation as
measured by pulse oximetry. Assess for elevation of the alveolar-arterial (A-a) pO2
gradient. See below for basic ABG interpretation.
Sputum gram stain, microscopy, culture and sensitivity: Obtain if pneumonia is suspected.
Electrolytes, and renal function tests: Metabolic acidosis or renal failure may be discovered. Potential
metabolic causes of cardiac arrhythmias (e.g. hypocalcemia, hypokalemia/hyperkalemia,
hypomagnesemia) or diaphragmatic dysfunction (hypophosphatemia) can be uncovered.
Thyroid function tests: Obtain if Thyroid disease is suspected.
Markers of cardiac disease: Elevations of creatinine kinase (particularly MB fraction) and troponin are
supportive of myocardial ischaemia or infarction. Brain natriuretic peptide (BNP) increases in
acute ventricular dysfunction, but also may be elevated in chronic heart failure, PE or cor-
pulmonale.
Chest x-ray: Obtain a stat portable upright chest x-ray if there is obvious distress. If the patient is unable
to sit for an adequate film, obtain lateral decubitus films to rule out the possibility of basilar
pneumothorax. A clear chest x-ray raises the possibility of airway obstruction or PE. An increased
cardiac silhouette (implies wither cardiomegaly from heart disease or pericardial effusion),
pulmonary vascular congestion, infiltrates, pleural effusion, elevated diaphragm (seen in
neuromuscular disorders), or pneumothorax may be discovered. See below for chest x-ray basic
interpretation.
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ECG: Should always be obtained in evaluating acute dyspnoea to rule out myocardial ischaemia or
infarction (ST depression, ST elevation-complex upwards; T-wave inversion; new Q waves);
arrhythmias; pericarditis (PR depression, ST elevation-diffuse and concave upward, T-wave
inversion), pericardial effusion (low QRS amplitude, electrical alternans); or PE (S1Q3T3, right-axis
deviation, right-bundle branch block; T wave inversion).
Pulmonary function tests: These are not applicable to the acute situation, but can assist in the evaluation
of patients with obstructive or restrictive lung disease. (See below for interpretation of these tests).
Bronchial provocation testing, may help increase yield of pulmonary function testing when
looking for causes of chronic dyspnoea or cough.
Ventilation-perfusion ( V Q ) scan: To evaluate for PE (although PE diagnosis is now made more
accurately with CT pulmonary angiography). With underlying cardiopulmonary disease, spiral CT
of the chest may be preferred because of the higher rate of ventilation defects, thus lowering the
number of high-probability scans. Remember that spiral CT is an excellent rule-in test, but a
negative result does not rule out PE and hence CT reader expertise is essential.
Pulmonary angiogram: In patients with low or moderate probability V/Q scan, or negative spiral CT in
whom there exists a suspicion for PE, this test is the gold standard for diagnosing PE. A venogram
or impedance plethysmography and Doppler ultrasound scan of lower extremities may be helpful,
potentially obviating the need for pulmonary angiogram if results demonstrate thrombosis.
Echocardiography: Should be obtained emergently if there is a strong clinical suspicion for cardiac
tamponade/pericardial effusion. Otherwise, echocardiography can be useful for assessing left
ventricular function and valvular function and whether or not cardiac disease is responsible for the
dyspnoea.
Cardiopulmonary exercise testing: Useful if the diagnosis is unclear. It can help determine whether a
cardiac or pulmonary abnormality exists.
Summary of some important causes of dyspnoea:
Type of dyspnoea Cause Pathology in dyspnoea
Mechanical
Asthma Bronchospasm → airway constriction and obstruction
Increased mucous secretion → obstruction
Smooth muscle hypertrophy → airway constriction
COPD Shunting (bronchitis component) and dead-spacing
(emphysema component) leading to ventilation-perfusion
mismatch → hypoxemia → dyspnoea
Pneumonia Destruction of lung tissue & inflammation leading to
exudation and oedema in small airways → decreased
effectiveness of gas exchange
Pulmonary oedema Alveolar oedema → decreased gas exchange
Pneumothorax Air in pleural space displacing lung tissue → dead-spacing
Pulmonary embolism Pulmonary arterial obstruction→ hypoxaemia/dead-spacing
Acute Respiratory
Distress Syndrome
(ARDS)
Diffuse alveolar damage and hyaline membrane formation
→ decreased effectiveness of gas exchange → hypoxemia
→ dyspnoea
Pleural effusion Displaced lung tissue → dead-spacing plus underlying
cause of effusion causing dyspnoea (e.g. infection, cancer)
Aspiration Foreign object obstruction and associated pneumonitis
Secondary
Cardiac
Metabolic
Psychiatric
Myocardial infarction Decreased effectiveness of cardiac output → hypoxia
CCF Pulmonary oedema
Arrhythmia Decreased effectiveness of cardiac output → hypoxia
Cardiac tamponade Obstruction to cardiac output → hypoxia
Acidosis/hypercapnea Respiratory compensation → tachypnoea & dyspnoea
Sepsis Metabolic (lactic) acidosis → respiratory compensation
Anxiety/Panic Psychogenic (SpaO2 does not decrease despite perception)
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Clinical assessment of presenting problem: Haemoptysis
A 60-year old male smoker comes to the emergency department complaining of “spitting up blood”
for 1 week.
Immediate questions:
Is the patient truly experiencing haemoptysis? Haemoptysis is defined as the expectoration of blood
from the respiratory tract- a spectrum that varies from blood-streaked sputum to large amounts of pure
blood. Blood from the nasal, oral or upper GI (i.e. gastro-oesophageal) source may be aspirated to the
larynx and then expectorated- don‟t confuse with epistaxis or haematemesis. Usually, sputum is inter-
mixed with blood in the haemoptysis and is frothy, alkaline and bright red. Haematemesis is acidic and
dark. Note: Melaena may occur if blood is swallowed.
What is the volume of the haemoptysis? Massive haemoptysis (>100-600ml/24 hours) connotes a life-
threatening problem that demands immediate ICU admission as well as rapid diagnostic evaluation.
Although the patient‟s estimates may be notoriously unreliable, but life-threatening nonetheless.
Has this happened before? If so, how frequently? Patients with recurrent acute bronchitis or with
mitral stenosis may have had multiple episodes or minor haemoptysis.
What is the smoking history? The higher the pack years, the more likely the patient has chronic
bronchitis or bronchogenic carcinoma.
Is there a history of productive cough preceding the haemoptysis? If the answer is yes, then the
problem may be an infection, such as acute bronchitis or bronchiectasis.
Has there been any history of accompanying chest pain? Pleuritic chest pain may be a symptom of
pneumonia, or a pulmonary embolism with infarction. Haemoptysis may accompany pulmonary oedema
from any number of causes.
Differential diagnosis:
A. Pulmonary causes:
1) Infection
a) Acute or chronic bronchitis- one of the most common causes of bronchitis, blood-streaks in sputum
b) Pneumonia- A necrotising gram negative or staphylococcal pneumonia can cause haemoptysis.
Symptoms are acute.
c) Lung abscess- Often produces foul-smelling sputum.
d) Bronchiectasis- Seen in patients with recurrent episodes of respiratory infections, voluminous foul-
smelling sputum production, and intermittent haemoptysis.
e) Tuberculosis- Usually apical infiltrates are observed on chest x-ray. Symptoms are often chronic or
subacute.
f) Parasitic- Paragonimiasis and Hydatid cysts (echinococcosis) (both rare).
g) Mycetoma- A ball of Aspergillus fungus may form in a previously formed cavity, blastomycosis.
Look for the crescent sign on chest x-ray. Below: PA chest radiograph of a 14-year-old girl with a thin-
walled cavity in the right upper lobe (long arrows) containing a fungus ball (short arrows). B: PA chest
radiograph after change in patient position shows movement of the mobile fungus ball.
10
B. Neoplastic causes: a) Bronchogenic carcinoma- Usually, the chest x-ray is abnormal, but it may be normal in up to
13% of patients with early lung cancer and haemoptysis.
b) Bronchial adenoma- Carcinoid tumours are notorious for brisk haemoptysis and suspect
in a young patient. Chest radiograph may be normal.
c) Metastatic disease- A history of cancer should be uncovered during the history. The chest x-
ray will be abnormal, usually with multiple lesions and there may be endobronchial infiltration,
causing haemoptysis.
d) Kaposi sarcoma- consider in a HIV patient with poorly controlled HIV or AIDS.
C. Vascular causes:
a) Pulmonary embolism (PE) with infarction- Only 10% of patients with PE present with
haemoptysis, but pulmonary emboli are very common and should not be missed.
b) Mitral stenosis-May arise from rupture of the pulmonary veins or from frank pulmonary
oedema.
c) Cardiogenic pulmonary oedema- Surprisingly common, especially now that most cardiac
patients are on some form of anticoagulant therapy.
d) Pulmonary arteriovenous malformation e) Osler-Weber-Rendu disease (hereditary haemorrhagic telangiectasis)
D. Trauma:
a) Pulmonary contusion- direct lung injury.
b) Bronchial or vascular tear- wounds, post-intubation or thoracic surgery, lung biopsies.
c) Retained/aspirated foreign body- Teeth and fillings sometimes find their way down into the
bronchi.
E. Systemic diseases:
1) Anticoagulation/bleeding diatheses
a) Drugs- Warfarin (Coumadin), heparin, aspirin, streptokinase (Streptase), urokinase (abbokinase),
tissue plasminogen activator, and APSAC (anisoylated plasminogen streptokinase activator
complex) or antistreplase (Eminase). Cocaine is an important drug to remember as it can cause
nasal bleeding with intranasal cocaine use (snorting/snuffing).
b) Uraemia c) Thrombocytopenia- drugs, idiopathic thrombocytopenic purpura, cancer
d) Disseminated intravascular coagulation (DIC)
e) Liver disease- Severe liver disease can result in thrombocytopenia and also decrease production
of coagulation factors.
2) Autoimmune diseases/genetic/other
a) Wegener’s granulomatosis- Look for renal changes of glomerulonephritis (red cell casts,
haematuria, proteinuria) and upper and lower respiratory tract and sinus disease. The chest x-ray
and chest CT is often abnormal. Bilateral nodular densities and cavitation are common.
Haemoptysis from small vessel granulomatous vasculitis with necrosis.
b) Goodpasture’s syndrome- This disease often involves the kidney. Proteinuria, haematuria and
red cell casts may be present. Diffuse alveolar infiltrates are often present.
c) Systemic lupus erythematosis (SLE)- Lupus more frequently involves the pleura, but patients
may develop life-threatening haemoptysis from lupus pneumonitis. Pulmonary pathology can
include haemorrhage, pleural effusions, pleuritis and interstitial fibrosis. ANA serology positive
and often abnormalities are seen on chest imaging (effusions, interstitial infiltrates).
d) Cystic fibrosis (CF)- although not an autoimmune condition, haemoptysis can occur in CF.
e) Idiopathic pulmonary haemosiderosis- Consider with haemoptysis in children (also
predominace in males), exclude all other causes and this requires a tissue biopsy.
f) Polyarteritis nodosa- if the vasculitis involves the bronchial arteries and erodes into the airways.
g) Sarcoidosis- if there is active granulomatous vasculitis (rare).
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Physical examination key points:
1) Vital signs: Look particularly for fever and signs of impending respiratory failure: tachypnoea with
respiratory rate >30 per minute, abdominal paradox with inspiration (Hoover‟s sign), and accessory
muscle use.
2) HEENT: Look carefully for a nasal or oropharyngeal source of bleeding.
3) Chest: Inspect and palpate for signs of trauma such as rib or clavicle fractures. Listen for a pleural friction
rub, localised rales, or signs of consolidation.
4) Heart: An irregularly irregular pulse signifies atrial fibrillation and suggests mitral stenosis as a possible
cause. Pulmonary embolus can also cause atrial fibrillation. An S3 and jugular venous distension suggest
congestive heart failure as a possible cause. Always listen carefully for the low diastolic rumble of mitral
stenosis at the cardiac apex with the bell.
5) Abdomen: Palpate the epigastrium, liver and spleen. Peptic ulcer disease or alcoholic liver disease could
certainly cause GI bleeding which might be believed to be haemoptysis.
6) Extremities: Examine the lower extremities for signs of deep venous thrombosis or oedema. Look for
cyanosis or clubbing. Clubbed fingers associated with haemoptysis generally imply bronchiectasis or
pulmonary neoplasm.
7) Skin: Inspect the skin for petechiae, ecchymoses, purpura, angiomata, and rashes.
Relevant investigations for a patient with haemoptysis:
It is very important to obtain an adequate history and examination to identify the cause and direct
investigations.
Full blood count and blood film: May reveal anaemia that could be caused by haemoptysis or, more likely,
is related to haemoptysis. A normocytic anaemia, with a normal or low reticulocyte count may
be secondary to anaemia of chronic disease (e.g. cancer). An elevated reticulocyte count
indicates haemolytic anaemia possibly secondary to an autoimmune disease process, consider
SLE. An iron deficiency can indicate Goodpasture‟s syndrome.
Platelet count, prothrombin time, INR and activated partial thromboplastin time: All are indicated to
rule out a coagulopathy as a cause. If platelet dysfunction is suspected, bleeding time will be
prolonged in the presence of a normal platelet count.
D-dimer: in cases of suspected PE or if the patient is believed to be developing DIC.
Group and hold and crossmatch- important if transfusion is needed.
Urea, creatinine and electrolytes (UECs): For rapid evaluation of “pulmonary-renal” syndromes
(Goodpasture‟s syndrome, Wegener‟s granulomatosis, SLE and other forms of vasculitis).
Antineutrophil cytoplasmic antibodies (ANCA) and anti-glomerular basement antibody (anti-GBM):
May indicate Wegener‟s granulomatosis (especially cytoplasmic-staining ANCA (C-ANCA))
and anti-GBM Ab is positive in 85% of patients with Goodpasture‟s syndrome.
Arterial Blood gases: Check for adequate ventilation and oxygenation. If the patient has underlying
pulmonary disease, respiratory failure may be precipitated by haemoptysis.
Sputum examination including cytology: If the sputum is purulent, Gram stain and culture and antibiotic
sensitivity are helpful. For patients with upper lobe infiltrates or HIV, check sputum samples
for acid fast bacilli smear and culture. Sputum cytology is useful in detecting lung cancer, and
can be further used with staining techniques including immunohistochemistry, silver or acid-
fast stains. If blood is mixed with sputum and purulent and the patient is febrile- consider
bronchitis or pneumonia. If it is foul-smelling also consider bronchiectasis (especially if
chronic and copious) or lung abscess. Blood not mixed with sputum suggests trauma or
infarction (sudden pleuritic chest pain with dyspnoea).
PPD (tuberculin) skin test: To help rule out tuberculosis.
Other autoimmune blood tests: Anti-nuclear antibodies (ANA) for SLE and serum complement levels
including C3 and C4, which may also be decreased in Goodpasture‟s syndrome with
glomerulonephritis.
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.Chest x-ray: First and most important radiological test after the history and physical examination. The
pattern and location of any infiltrate, combined with the history and physical examination
findings will dictate the remainder of the work-up.
Ventilation/perfusion ( V Q ) scan: If pulmonary embolism is suspected, a scan must be done.
Alternatively a spiral CT may be done or a CT pulmonary angiogram (more sensitive for PE
diagnosis). With underlying cardiopulmonary disease, spiral CT/CTPA of the chest may be
preferred because of the higher rate of ventilation defects, thus lowering the number of high-
probability scans. Remember that spiral CT is an excellent rule-in test, but a negative result
does not rule out PE and hence CT reader expertise is essential.
Angiography: If PE is suspected and scans are not clearly positive or negative (indeterminate), then
pulmonary angiography is indicated. Angiography may also be indicated for the diagnosis of
pulmonary arteriovenous malformations.
Chest CT including CT angiography: This provides much better anatomic view of pulmonary pathology
compared with chest radiographs and also reveals lesions not seen previously. However, the
CT pulmonary angiogram is only indicated acutely if looking for an aortic dissection or PE. CT
angiography (helical or spiral and electron-beam) are about 90% sensitive and 90% specific for
detecting proximal (main, lobar and segmental) pulmonary artery emboli. CT angiography is
not good at detecting subsegemental emboli.
ECG: May show atrial fibrillation. A right axis shift and/or right bundle branch block may suggest a PE.
Classically, a large PE produces an S wave in lead I, and a Q wave and inverted T wave in lead
III (S1Q3T3).
Bronchoscopy: Patients with unclear sources of haemoptysis, massive haemoptysis, or the suspicion or a
neoplasm require fibreoptic bronchoscopy. The earlier it is done, the more likely the source of
bleeding will be identified.
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Basic plan for a patient with haemoptysis:
1) ICU admission may be necessary if
a. There is massive haemoptysis.
b. There is present or impending hypoxemic or hypercarbic respiratory failure.
2) Establish IV access: Death results from asphyxia rather than haemorrhage, but IV access is important for
administration of medications.
3) Always protect the airway: This may require early intubation.
4) Correct any coagulopathy 5) Arrange a bronchoscopy: arrange early especially if the diagnosis is unclear or if haemoptysis continues.
6) Consult: Obtain a cardiothoracic surgery consult if the patient has massive or continuous haemoptysis.
Medical management of massive haemoptysis is associated with a high mortality rate.
7) Cough suppression: Retard the cough reflex with codeine-based drugs, and place the patient on quiet bed
rest.
8) Treat the underlying disease state:
a. Lung cancer: Can be treated surgically if there are no metastases present and there is
adequate pulmonary reserve. Otherwise, radiation, or laser therapy can control bleeding.
b. Infections: Treat with antibiotics as dictated by Gram‟s stain and clinical picture. If a
necrotising pneumonia is present, consider methicillin resistant Staphylococcus aureus or
Pseudomonas infection and treat accordingly.
c. Pulmonary emboli: Treat acutely with heparin or enoxaparin.
d. Diffuse alveolar haemorrhage or pulmonary-renal syndrome: 1000mg methyl-
prednisolone (Solu-Medrol) IV may control bleeding, pending definite workup.
e. Nonsurgical patients with localised bleeding: Bronchial arteriography followed by
embolism may be life-saving. However, collateral circulation to the spinal arteries or carotids
must be excluded before embolisation.
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Surface anatomy of the Thorax and lungs
1. Apertures of the Thorax: The superior or thoracic inlet (5 cm anteroposteriorly and 10-11 cm
transversely) is bounded by the body of the 1st thoracic vertebra, the medial border of the first ribs and
their costal cartilages, and the superior part of the manubrium of the sternum. The inferior or thoracic
outlet is bounded by the TV12, 12th pair of ribs, costal margins and the xiphisternal joint. Palpate the
superior and inferior apertures.
2. Thoracic vertebrae (TV): Palpate and count the thoracic spines starting from the 7th cervical
vertebra (vertebra prominens) which usually is the first prominent lump when palpating from above
downward. Make it prominent by having the patient flex their neck. Spinous processes of TV1 to
TV4 are easy to feel and see, those of TV5 – TV12 are much more difficult to palpate. Also the
vertebral border of the scapula can be felt (TV2-TV7 level).
3. Sternum: In the midline, palpate the jugular notch at the upper end of the manubrium and between the
sternal ends of the clavicle. The notch is usually at the level of TV2 or TV3. Slide your finger down
the midline for ~5cm and this prominence is the site of the sternal angle (of Louis) (at TV4 or a disc
between TV4-TV5). It is an important landmark for the lower border of the superior mediastinum
and for the level of the 2nd
costal cartilage, the starting point from which the ribs should be counted.
Palpate the xiphoid process lying at the bottom of the infrasternal fossa (epigastric fossa or „pit of the
stomach‟).
4. Ribs: The first rib can be felt below and above the medial 1/3 of the clavicle. The other ribs can be
palpated by placing the fingertips in the axilla and slowly drawing them back inferomedially over the
ribcage. Note that the spine of the scapula lies over the 3rd
rib or 3rd
intercostal space and the inferior
angle of the scapula is at the level of the 7th rib and it is a good guide to the 7
th intercostal space. The
costal margins are palpable with ease. The highest part of the costal margin is formed by the 7th
costal cartilage and the lowest part by the 10th costal cartilage. Anteriorly, the ribs can be counted,
starting from the sternal angle (which is the 2nd
costal cartilages), below which is the 2nd
intercostal
space. This is important for finding the location of the apex cardiac beat & check for its displacement.
5. Diaphragm: The level of the diaphragm on both sides varies in relation to the ribs and to the vertebrae
according to the phase of respiration, posture and degree of distension of the abdominal viscera. The
diaphragm is highest when the person is supine, lowest when the person is sitting or in an erect
position (this explains why patients with difficulties in inspiration prefer to sit up/stand rather than
lying down). In an erect position, the right dome of the diaphragm should be at the level of the 5th
intercostal space midclavicular line, the central tendon at the xiphisternal junction, and the left dome
at the level of the 6th costal cartilage.
6. Trachea, lungs and Pleurae: The bifurcation of the trachea is at or below the sternal angle (TV5 or
TV6) and slightly to the right. The bifurcation is not fixed and moves downward with respiration.
The main bronchi move obliquely for 2.5 cm.
The pleural cavity on each side surrounds a lung and is lined by parietal pleura. These two
pleural cavities represent separate and closed potential spaces. The parietal pleura which cover the
different parts of the thoracic wall and thoracic content can be divided into: (1) costal pleura, (2)
mediastinal pleura, (3) diaphragmatic pleura and (4) cervical pleura. The apex of the lung is covered
by cervical pleura (dome or cupola) which extends through the inlet of the thorax upwards to the neck
of the 1st rib (level of the spinous process of CV7). Because the 1
st rib slopes downward, the lungs
and the pleura rise about 3 cm above the anterior end of the 1st rib and 1 to 2 cm above the middle
third of the clavicle, behind the sternomastoid muscle.
The lines of pleural reflection are sites at which the costal pleura becomes continuous with the
mediastinal pleura anteriorly and posteriorly and with the diaphragmatic pleura inferiorly.
The sternal or anterior reflection: a line from the sternoclavicular joint to the median line at the
level of the sternal angle. Then the right margin continues down to the xiphisternal joint, the left
margin curves out from the 4th costal cartilage along the margin of the sternum to the 6
th costal
cartilage.
The costal or inferior reflection is where the costal pleura is continuous with the diaphragmatic
pleura near the costal margin. It passes obliquely across the 8th rib in the midclavicular line , the 10
th
rib in the midaxillary line and the 12th rib towards the spinous process of TV12 (mnemonic Pleura 8,
10, 12).
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The Lungs: The apex of the lung rises above the clavicle, filling the cupola of the pleural sac.
The anterior border of the lung follows the lines of pleural reflection, except for the anterior border
of the left lung which deviates ~2.5 cm laterally from the left margin of the sternum to form the
cardiac notch. The inferior border of both lungs crosses the 6th rib in the midclavicular line, the 8
th
rib at the midaxillary line, 10th rib in the midscapular line and ends ~2.5cm lateral to the spinous
process of TV10 (mnemonic: Lungs 6, 8, 10). During deep inspiration, the apparent level of the lung
descends at least two intercostal spaces. The oblique fissure of the lung can be drawn on the surface
of the thorax from a point ~2.5cm lateral to the spinous process of the TV2 to the 6th costochondral
junction (~5cm from the anterior median line). When the arm is abducted and the hand on the back
of the head, the medial border of the scapula approximately indicates the oblique fissure.
The horizontal fissure of the right lung is indicated by a longitudinal line that runs from the
anterior border of the lung along the 4th costal cartilage to the oblique fissure.
For the right lung:
For the left lung:
7. Important points for physical examination of the chest:
a. By inspection: General contours of the chest, the respiratory movements, the apex beat which
may be visible or other pulsations.
b. By palpation: The position of the mediastinum can be assessed by determining the position of the
cardiac apex beat and the trachea.
c. By percussion: By percussion the boundaries between contiguous organs can be determined, and
it should be performed from the resonant (e.g. lung) towards less resonant (e.g. heart or liver)
organ. Normally lungs are resonant to percussion and there are areas of dullness over the liver
and heart. Impaired resonance is found over consolidated or collapsed lungs. The inferior, left
and right borders of the heart may be determined by percussion and by this means the cardiac
area (area of cardiac dullness) can be outlined.
d. By auscultation: The breath sounds are characterised by long inspiratory phase followed by the
expiratory phase, which can be heard over the lungs. „Bronchial breathing‟ (harsher quality) is
heard by listening with a stethoscope over the larynx or trachea.
16
Heart sounds: are produced by valve closure, the first heart sound is produced by closure of
the atrioventricular valves (tricuspid and mitral valves), the second heart sound is produced by closure
of the semilunar aortic and pulmonary valves. The first heart sound is best heard at the cardiac apex
(mitral valve area) and over the lower part of the body of the sternum (tricuspid valve area). The
second heart sound is best heard at the 2nd
right (aortic valve) and 2nd
left (pulmonary valve)
intercostal space. The first sound corresponds with the beginning of ventricular systole, the second
sound is sharper and shorter than the first and marks the beginning of ventricular diastole. In some
abnormal conditions abnormal heart sounds can be heard. They may be caused by pathological
narrowing of the valves (e.g. mitral stenosis), incompetence of the valves or by distension of the
channels.
Examination of the Respiratory system
I. General Inspection: Stand back, inspect for a sputum cup (purulent sputum indicates respiratory
infection or bronchiectasis, haemoptysis important), can the patient talk? Dyspnoea, count
respiratory rate, check use of accessory muscles of respiration, intercostal in-drawing of lower
ribs, cachexia. Inspect for Obvious chest wall abnormalities including thoracic kyphosis, ankylosing
spondylitis, increased anteroposterior diameter of chest wall (Barrel chest that occurs in patients with
emphysema), Tripod position.
II. Hands: Pick up the patient‟s hands, look for clubbing, peripheral cyanosis, tar staining, palmar
erythema, anaemia. Note small muscle wasting of the hands (check for asymmetry, unilateral
wasting can occur with a Pancoast‟s tumour) and weakness of finger abduction (lung cancer
involving the brachial plexus, get patient to abduct fingers and then the examiner should try to adduct
them against patient resistance). Palpate wrists for tenderness (hypertrophic pulmonary
osteoarthropathy). Palpate radial pulse for obvious tachycardia, AF or pulsus paradoxus (a bounding
pulse, an exaggeration of the normal variation in the systemic arterial pulse volume with respiration,
becoming weaker with inspiration and stronger with expiration; characteristic of cardiac tamponade,
rare in constrictive pericarditis; so called because these changes are independent of changes in the
cardiac rate as measured directly or by electrocardiogram. In respiratory disease it indicates CO2
retention, there is an increase in pulse pressure as CO2 is a good vasodilator. It can be measured
clinically with >10 mmHg difference in systolic pressure). Also make the patient extend their arms at
the elbow, with flexed wrists and abducted fingers to check for a flapping tremor (asterixis) of
Carbon dioxide narcosis with severe COPD. Also palpate the axillary lymph nodes.
Peripheral cyanosis (look at thumbs) Nicotine tar stains
Fingernail clubbing (can also occur with toenails) is the exaggerated curvature of nails in all directions, and there is
a loss of the angle between the nail and the nail fold and the nail fold feels boggy, these are due to changes in blood
flow but exact mechanism is not known. Remember the most important causes of according to different systems: (1)
Thoracic causes: Bronchial carcinoma (usually not small cell), chronic lung suppuration including:
empyema/abscesses, bronchiectasis, cystic fibrosis, fibrosing alveolitis and mesothelioma. (2) GI causes: IBD
(especially Crohn‟s disease), cirrhosis, GI lymphoma, malabsorption disease, e.g. coeliac disease. (3) Cardiac
17
causes: Cyanotic congenital heart diseases, Endocarditis, Atrial myxoma. (4) Rare causes include: familial, thyroid
acropachy, unilateral clubbing from axillary artery aneurysm or brachial arteriovenous malformations (AVMs).
This image of a patient with emphysema in the Tripod position; where they are leaning forward to increase their
ventilatory capacity and this promotes use of accessory muscles. The patient appears cachectic and almost „typical‟
appearance of a patient who is a “pink puffer”. Also when observing, inspect the whole patient and their
surroundings, are they sitting up/standing, do they appear comfortable/in distress, do they have ventilatory aids such
as a ventilatory mask/Nebuliser (what type is it, e.g. Venturi mask, Hudson mask) attached to an oxygen source, or a
metered nose inhaler, nasal prongs, walking aids etc.
III. Face: Look for pupil constriction and ptosis (occurs unilaterally from decreased sympathetic
activity with Horner‟s syndrome due to n apical Pancoast‟s lung cancer compressing the
cervicothoracic/stellate ganglion). Look at the eyes for conjunctival pallor which may suggest
anaemia. Inspect tongue for central cyanosis and the oropharynx to check the tonsils. Examine the
inside of the nose and check for visible nasal polyps (if patient has a blocked nose), a deviated nasal
septum (have they had nasal surgery?). Does the patient have a hoarse voice (e.g. with recurrent
laryngeal nerve palsy)?
IV. Trachea: Palpate the position of the trachea. If the trachea is displaced, you must concentrate on the
upper lobes for physical signs. Tracheal tug (indicates severe airflow obstruction) and feel for the
use of the accessory muscles. Ask the patient to speak (hoarseness) and then cough and note whether
this is a loose cough, a dry cough or a bovine cough. Measure the forced expiratory time (FET).
Tell the patient to take a maximal inspiration and blow out as rapidly and forcefully as possible while
you listen. Note audible wheeze and prolongation of the time beyond 3 seconds as evidence of
chronic obstructive pulmonary disease. Similarly, peak expiratory flow can be measured using a
Peak Flow device, where the patient must be standing and with maximal inspiration they must expire
rapidly and forcefully and the best of 3 measurements should be recorded; also make sure that you do
not touch the patient‟s mouthpiece (before and after use).
V. Back of the chest: This is when the patient should be undressed. 1) Inspection: Look for
kyphoscoliosis. Do not miss ankylosing spondylitis, which causes decreased chest expansion and
upper lobe fibrosis and watch out for any chest wall abnormalities (e.g. pectus excavatum, pectus
carinatum). Look for thoracotomy scars and prominent veins. Also note any skin changes for
18
radiotherapy markers or radiotherapy scars. 2) Palpation: Palpate first from behind for the
cervical and supraclavicular lymph nodes. Then examine for expansion-first upper lobe expansion,
which is best seen by looking over the patient's shoulders at clavicular movement during moderate
respiration. The affected side will show a delay or decreased movement. Then examine lower lobe
expansion by palpation. Note asymmetry and reduction of movement. 3) Percussion: ask the patient
to bring his or her elbows together in the front to move the scapulae out of the way. Examine for
tactile vocal fremitus first then percuss the back of the chest. Percussion is quite useful for detecting
pleural effusions, but it is essential to have appropriate technique, make sure you have flowing,
floppy wrists & make sure the finger being struck is placed firmly on the patient‟s chest wall 4)
Auscultation usually with the diaphragm in respiratory examination: Note breath sounds (whether
vesical or bronchial) and their intensity (normal or reduced). Listen for adventitious (added) sounds
(crackles and wheezes). Finally examine for vocal resonance. If a localised abnormality is found,
try to determine the abnormal lobe and segment.
(It is essential that for a complete respiratory examination, both the anterior and posterior chest wall is
examined, importantly because the upper lung lobes are mainly located anteriorly, whilst the lower
lobes are mainly located posteriorly- see surface anatomy.)
Note that sometimes chest wall deformities may be subtle, e.g. scoliosis here, so look for it!!
VI. Front of the chest: 1) Inspection: Inspect again for chest deformity, distended veins, radiotherapy
markers and changes (skin may appear erythematous after a course of radiotherapy) and scars. 2)
Palpation: Chest wall expansion can be checked, note that it is best to check both upper and lower
chest wall expansion. Palpate the supraclavicular and axillary nodes (leave till last if patient sweaty).
3) Percussion: as for back 4) Auscultation: as for back:
19
VII. The heart: In order to examine the heart and JVP, the patient MUST be laying down at 45 degrees.
Measure JVP. Examine the praecordium and lower limbs for signs of cor pulmonale. Alternatively,
the JVP can be measured after examining the face, just remember to have the patient at the right angle
for JVP!
VIII. The abdomen: Palpate the liver for liver ptosis (due to emphysema, or for enlargement from
secondary deposits of tumour in cases of lung carcinoma).
IX. Other: Pemberton’s sign (ask patient to lift arms over head & wait for 1 minute. In superior vena
caval obstruction, patient with have facial plethora, cyanosis, inspiratory stridor & non-pulsatile
elevation of JVP). Inspect calves and feet for oedema or cyanosis (cor pulmonale) and DVTs.
Measure temperature (infection) & respiratory rate with exercise.
Important physical signs related to the respiratory system
Signs of respiratory disease:
The following are important signs of respiratory disease to be aware of:
o Dyspnoea and obvious shortness of breath
o Tachypnoea (respiratory rate >25 breaths per minute), Bradypnoea with respiratory rate <8
breaths per minute. Count the respiratory rate surreptitiously as respiration is also under
voluntary control and the patient may consciously try to reduce their respiratory rate, or anxiety
may increase respiratory rate. Normal range is between 12-20 breaths per minute. Tachypnoea
should hence be >20 breaths per minute, but >25 breaths per minute is definite tachypnoea.
Note that the respiratory rate in paediatrics is different in adults, as babies have a faster
respiratory rate that reduces to the normal adult value over time.
o Use of accessory muscles of respiration, including nasal flaring, use of the
sternocleidomastoid, scalenus muscles, costal in-drawing; the Tripod position.
o Pursed-lip breathing, e.g. in patients with emphysema or any other lung disease.
o Cyanosis- central and peripheral cyanosis.
o Clubbing of the fingernails.
o Wheeze or stridor.
o Prolongation of the expiratory phase.
Signs of Chest wall hyperinflation:
Be able to identify signs of chest wall hyperinflation.
This includes a „barrel-shaped’ chest with an increased anteroposterior diameter.
20
Pursed-lip breathing occurs in COPD that is predominantly emphysema (but not in predominantly
chronic bronchitis) and this is the expiration through partly closed lips which increases the end-
expiratory pressure and helps keep the airways open, which helps minimise air trapping.
Use of accessory muscles of respiration and in-drawing of the lower intercostal muscles with
inspiration.
With palpation one can measure chest wall expansion, and if the chest wall is already expanded, then
there will be reduced chest wall expansion and a hyper-inflated chest wall.
With percussion, one should classically hear a hyper-resonant note, with decreased liver dullness.
Although this is a poor test and hard to discern.
Breath sounds: decreased breath sounds (due to less expansion of airways) as well as possibly early
inspiratory crackles.
In a hyper-inflated chest radiograph, more than six ribs can be seen above the diaphragm in the mid-
clavicular line. There are also flat hemidiaphragms, increased transverse diameters, and a small contour
of the heart, as seen below:
Demonstrate signs of abnormalities in chest wall expansion:
Place the hands firmly on the chest wall with the fingers extending around the sides of the chest. The
thumbs should almost meet in the middle line and should be lifted slightly off the chest so that they are
free to move with respiration. As the patient takes a big breath in, the thumbs should move
symmetrically apart at least 5 cm. Reduced expansion on one side indicates a lesion on that side.
Reduced unilateral chest wall movement (i.e. on one side) may be due to localised pulmonary
fibrosis, consolidation, lung collapse/atelectasis, pleural effusion or pneumothorax.
Bilateral reduction of chest wall movement indicates a diffuse abnormality such as COPD or diffuse
pulmonary fibrosis.
Detect abnormalities in the percussion note:
The percussion note is affected by the thickness of the chest wall, as well as by underlying structures:
Percussion over a solid structure, such as the liver or a consolidated area of lung,
produces a dull note.
Percussion over a fluid-filled area, such as a pleural effusion, produces an extremely dull
(stony dull) note.
Percussion over the normal lung produces a resonant note.
Percussion over hollow structures, such as the bowel or a pneumothorax, produces a
hyper-resonant note.
21
Chest Auscultation:
Listen to Lung sounds recordings for revision & practice on patients!
Be able to understand normal breath sounds. Using the diaphragm of the stethoscope, one should listen
to the breath sounds in all zones of the lung. It is important to compare each side with the other.
Remember to listen high up into the axillae and, using the bell of the stethoscope applied above the
clavicles, to listen to the lung apices. A number of observations must be made while auscultating and,
as with auscultation of the heart, different parts of the cycle must be considered. Listen for the quality
of the breath sounds, the intensity of the breath sounds, and the presence of additional
(adventitious) sounds.
Quality of breath sounds: Normal breath sounds are heard with the stethoscope over nearly all parts
of the chest. The patient should be asked to breathe through the mouth so that added sounds from the
nasopharynx do not interfere. These sounds are produced in the airways rather than the alveoli. They
had once been thought to arise in the alveoli (vesicles) of the lungs and are therefore called vesicular
sounds. Their intensity is related to total airflow at the mouth (hence patient must take a deep breath in
and out through the mouth) and to regional airflow. Normal (vesicular) breath sounds are louder and
longer on inspiration than on expiration and there is no gap between the inspiratory and expiratory
sound phases. They are due to the transmission of air turbulence in the large airways filtered through
the normal lung to the chest wall. The diagram below compares normal vesicular breath sounds with
harsh bronchial sounds and where these sounds are normally heard. The numbers suggest an order of
where the lungs should be auscultated on the anterior chest, note importantly that each lung should be
compared at the same level:
With bronchial breath sounds turbulence in the large airways is heard without being filtered by
the alveoli, producing a different quality. Bronchial breath sounds have a hollow, blowing quality.
They are audible throughout expiration and there is often a gap between inspiration and expiration. The
expiratory sound has a higher intensity and pitch than the inspiratory sound. Bronchial breath sounds
are more easily remembered than described. They are audible in normal people, posteriorly over the
right upper chest where the trachea is contiguous with the right upper bronchus. Very importantly,
bronchial breathing sounds are heard over areas of consolidation, as solid lung conducts the sound of
turbulence in main airways to peripheral areas without filtering. Causes of bronchial sounds include:
commonly areas of consolidated lung from pneumonia (especially lobar pneumonia) and uncommonly:
localised pulmonary fibrosis, above areas of pleural effusion and collapsed lung (adjacent to a pleural
effusion). Bronchial breath sounds are also heard in atelectasis and have a high pitched, hollow quality,
clearly audible during expiration & inspiration. In pulmonary fibrosis, bronchial breathing is heard
usually in the lower lung zones, having a similar quality as in atelectasis and are usually due to
interstitial pulmonary fibrosis.
Intensity of the breath sounds. It is better to describe breath sounds as being of normal or reduced
intensity than to speak about air entry. The entry of air into parts of the lung cannot be directly gauged
from the breath sounds. Causes of reduced breath sounds include chronic obstructive pulmonary disease
22
(especially emphysema), pleural effusion, pneumothorax, pneumonia, a large neoplasm and pulmonary
collapse. Added (adventitious) sounds. There are two types of added sounds-continuous (wheezes) and
interrupted (crackles).
Crackles are interrupted non-musical sounds. Crackles are probably the result of loss of stability of
peripheral airways that collapse on expiration, created when alveoli and small airways open and close
with respiration. Typically associated with interstitial lung disease, microatelectasis or filling of alveoli
by liquid. Early inspiratory crackles (cease before the middle of inspiration) suggest disease of the
small airways, and are characteristic of COPD. The crackles are heard only in early inspiration and are
of medium coarseness. They are different from those heard in left ventricular failure, which occur later
in the respiratory cycle.
Late or pan-inspiratory crackles suggest disease confined to the alveoli. They may be fine,
medium or coarse in quality. Fine crackles have been likened to the sound of hair rubbed between the
fingers, or to the sound Velcro makes when pulled apart-they are typically caused by pulmonary
fibrosis. Characteristically, more crackles are heard in each inspiration when they are due to fibrosis- up
to 14 compared with 1 to 4 for COPD and 4 to 9 for cardiac failure. As fibrosis becomes more severe
the crackles extend earlier into inspiration and are heard further up the chest. Basal fine crackles are
commonly found with pulmonary fibrosis and left ventricular failure and associated pulmonary oedema.
Medium crackles are usually due to left ventricular failure. Here the presence of alveolar fluid disrupts
the function of the normally secreted surfactant. Coarse crackles are characteristic of pools of retained
secretions and have an unpleasant gurgling quality. They tend to change with coughing, which also has
an unpleasant gurgling quality. Bronchiectasis is a common cause as well as atelectasis, but any disease
that leads to retention of secretions such as infection may produce these features.
Pleural friction rub: when thickened, roughened pleural surfaces rub together as the lungs expand
and contract, a continuous or intermittent grating sound may be audible (similar to bits of leather
rubbing over each other). A pleural rub indicates pleurisy, which may be secondary to pulmonary
infarction or pneumonia. Rarely, malignant involvement of the pleura, a spontaneous pneumothorax or
pleurodynia may cause a rub.
Wheezes are continuous sounds. They are abnormal findings and have a musical quality. Wheezes
reflect oscillation of the airway walls as occurs when there is airflow limitation. The wheezes must be
timed in relation to the respiratory cycle. They may be heard in expiration or inspiration, or both.
Wheezes are due to continuous oscillation of opposing airway walls and imply significant airway
narrowing. Wheezes tend to be louder on expiration. This is because the airways normally dilate during
inspiration and are narrower during expiration. An inspiratory wheeze implies severe airway narrowing.
Inspiratory wheezes are common to have in upper respiratory tract abnormalities, such as in a patient
with a large goitre that is obstructing the trachea.
The pitch (frequency) of wheezes varies. It is determined only by the velocity of the air jet and is
not related to the length of the airway. High-pitched wheezes are produced in the smaller bronchi and
have a whistling quality, whereas low-pitched wheezes arise from the larger bronchi.
Wheezes are usually the result of acute or chronic airflow obstruction due to asthma (often high
pitched) or chronic obstructive pulmonary disease (often low pitched), secondary to a combination of
bronchial muscle spasm, mucosal oedema and excessive secretions. Wheezes are a poor guide to the
severity of airflow obstruction. In severe airways obstruction, wheeze can be absent because ventilation
is so reduced that the velocity of the air jet is reduced below a critical level necessary to produce the
sound.
A fixed bronchial obstruction, usually due to a carcinoma of the lung (or a foreign body such as a
peanut), tends to cause a localised wheeze, which has a single musical note (monophonic) and does not
clear with coughing.
Wheezes must be distinguished from stridor, which sounds very similar to wheeze but is louder
over the trachea and is always inspiratory (wheezes usually occur in expiration-the majority-but can
occur in both inspiration and expiration).
23
Egophony is a peculiar broken quality of voice sounds like the bleating of a goat, heard about the upper
level of fluid in the case of effusion, or in consolidation or a tumour.
Describe patterns of physical signs with consolidation, effusion & pneumothorax:
Signs of lung consolidation:
Pneumonia is defined as inflammation of the lung which is characterised by exudation into the alveoli.
Pneumonia may be classified on an anatomical basis into lobar, segmental or lobular pneumonia (i.e.
bronchopneumonia). The signs of lobar pneumonia are characteristic and are referred to clinically as
consolidation.
Signs of consolidation include as follows:
o Reduced chest expansion on affected side.
o Vocal fremitus increased on affected side (this is an important examination in pneumonia,
in other diseases it is a fairly useless test).
o Percussion note dull, but not „stony‟ dull.
o Breath sounds: bronchial over affected lobe. Bronchial breath sounds are associated with
conditions that increase lung tissue density, (e.g. because of consolidation, fluid accumulation,
lung collapse or fibrotic scarring.) One of the most common causes of bronchial breath
sounds from consolidation is pneumonia and in pneumonia bronchial breath sounds have a
hollow or „tubular quality‟, are high pitched and they remain audible during inspiration and
expiration.
o Vocal resonance: Increased on the affected zones of lung. This is also known as increased
bronchophony (or a nasal egophony sound) and the words “ninety nine” are hence more
clearly heard in consolidation.
o Pleural friction rub may be present.
Important causes of consolidation include:
o Lobar pneumonia: pneumococcal (90% of cases), H. influenzae, staphylococcal.
o Bronchopneumonia (lobular): bacteria-H. influenzae and S. pneumoniae (commonest), viruses
such as influenza virus, adenovirus, measles virus, cytomegalovirus. In bronchopneumonia,
crackles are often the only chest sign.
o Primary atypical pneumonia: Mycoplasma pneumoniae (majority), Chlamydia psittaci,
Legionella spp, Coxiella burnetii (Q fever).
Signs of pleural effusion:
This is a collection of fluid in the pleural space. Note that pleural collections consisting of blood
(haemothorax), chyle (chylothorax) or pus (empyema) have specific names, and are not called pleural
effusions, although the physical signs are similar.
Important signs of a pleural effusion include:
o Trachea and apex beat: displaced away from a massive effusion.
o Chest Expansion: reduced on the affected side.
o Percussion: Stony dull over the fluid.
o Breath sounds: reduced or absent (unlike with a consolidation, in an effusion presence of fluid
means there is no net movement of air over the fluid due to acoustical mismatch- hence reduced
or no transmission of breath sounds). There may be an area of bronchial breathing audible
above the effusion due to compression of overlying lung.
o Vocal resonance: reduced.
Important causes of pleural effusions include:
o Transudate (<30 g protein per litre of fluid): (i) cardiac failure; (ii) hypoalbuminaemia from the
nephrotic syndrome or chronic liver disease; (iii) hypothyroidism; (iv) Meigs syndrome (ovarian
fibroma causing pleural effusion and ascites).
o Exudate: (>30 g of protein per litre of fluid): (i) pneumonia; (ii) neoplasm: bronchial carcinoma,
metastatic carcinoma, mesothelioma; (iii) tuberculosis; (iv) pulmonary infarction; (v) subphrenic
24
abscess; (vi) acute pancreatitis; (vii) connective tissue disease such as rheumatoid arthritis, systemic
lupus erythematosus; (viii) drugs such as methysergide, cytotoxics; (ix) irradiation; (x) trauma.
o Empyema (pus in the pleural space): (i) pneumonia; (ii) lung abscess; (iii) bronchiectasis; (iv)
tuberculosis; (v) penetrating chest wound.
o Haemothorax (blood in the pleural space): (i) severe trauma to the chest; (ii) rupture of a pleural
adhesion containing a blood vessel.
o Chylothorax (milky-appearing pleural fluid due to leakage of lymph): (i) trauma or surgery to the
thoracic duct; (ii) carcinoma or lymphoma involving the thoracic duct.
Signs of pneumothorax:
Leakage of air from the lung or a chest wall puncture into the pleural space causes a pneumothorax
Important signs observed with a pneumothorax include:
o Chest expansion: Reduced on the affected side.
o Percussion: Hyperresonance over affected are if pneumothorax is large.
o Breath sounds: Greatly reduced or absent over affected area.
o There may be subcutaneous emphysema. This occurs due to entry of air bubbles in the fascial
planes under the skin and it feels like „bubble wrap‟.
o There may be no signs if the pneumothorax is small (30% of cases).
Important causes include:
o 'Spontaneous': (i) subpleural bullae rupture, usually in tall, healthy young males; (ii)
emphysema with rupture of bullae, usually in middle-aged or elderly patients with generalised
emphysema/COPD; (iii) rarely in asthma, lung abscess, bronchial carcinoma, eosinophilic
granuloma, end-stage fibrosis or Marfan's syndrome; (iv) iatrogenic (caused by medical
intervention), following the insertion of a central venous catheter.
o Traumatic: rib fracture, penetrating chest wall injury, or during pleural or pericardial
aspiration
Signs of tension pneumothorax:
This occurs when there is a communication between the lung and the pleural space, with a flap of tissue
acting as a valve, allowing air to enter the pleural space during inspiration and preventing it from
leaving during expiration. A tension pneumothorax results from air accumulating under increasing
pressure in the pleural space; it causes considerable displacement of the mediastinum with obstruction
and kinking of the great vessels, and represents a medical emergency.
Important signs to remember include (similar to a normal pneumothorax, however, there may be signs
of shock with hypotension, as well as tachypnoea & cyanosis due to impingement/kinking of great
vessels in the thorax):
o The patient is often tachypnoeic and cyanosed, and may be hypotensive.
o Trachea and apex beat: displaced away from the affected side.
o Chest Expansion: reduced or absent on affected side.
o Percussion: hyperresonance over the affected side.
o Breath sounds: absent.
o Vocal resonance: absent.
Important causes of tension pneumothorax include:
o Trauma.
o Mechanical ventilation at high positive pressure.
o Spontaneous is very rare.
25
The following summarised table indicates the typical chest examination findings in selected clinical
conditions, with the detailed table below from Harrison‟s. TV/VR refers to tactile vocal fremitus and
VR to vocal resonance:
Condition Percussion note TV/VR Breath sounds Pleural Effusion Dull (stony) Decreased Reduced
Consolidation Dull Increased Increased, crackles present Collapse of lung lobe
(e.g. lower lobe collapse
secondary to
pneumonia)
Dull Reduced (little air in
collapsed lung,
prevents sound
transmission)
Reduced
Pneumothorax Resonant Decreased Reduced/absent
Types of patients to watch out for that may come up in a station may include (although not limited to) a
patient with a pleural effusion, bronchiectasis, lung removal- surgically removed in a patient with lung
cancer (patient would obviously have a large sternotomy or thoracotomy scars, with chest wall
asymmetry, diaphragm higher up, smaller chest on affected side, abnormal- possibly absent breath
sounds).
Major categories of respiratory diseases to remember include:
1) Airways disease: Increase in size (bronchiectasis); decrease in size (asthma, chronic bronchitis,
local obstruction from: foreign body, carcinoma, mucous plug), disappeared
airways (bronchiolitis, small airways disease).
2) Airspace disease: Increased airspaces (emphysema); decreased airspaces (lung fibrosis:
rheumatoid disease, cryptogenic fibrosing alveolitis, systemic sclerosis/
scleroderma); airspace disappearance (consolidation/atelectasis: transient- for
example pneumonia, infarction; or permanent- e.g. obstruction large infarcts)
3) Pulmonary vascular disease: Increased pulmonary arterial pressure (various lung diseases,
hypoxia, „primary‟), decreased pulmonary venous drainage (left ventricular
failure), destruction of vessels/lumen (vasculitis, pulmonary emboli).
4) Ventilatory diseases: Pleural disease (pleural effusions, pleural thickening, pneumothorax),
chest-wall disease-mechanical defects (skeletal deformities, muscle diseases),
diaphragm weakness.
5) Control of ventilation: CNS causes: Efferent pathways (Medulla lesions, cervical spine,
neuropathies/poliomyelitis); afferent pathways (hypoxic: carotid or aortic
body disease; or hypercapnic: medulla lesions).
26
Deep Vein Thrombosis and Pulmonary Embolism Case protocol 3: Pulmonary thromboembolism
A 52 year old woman suddenly developed breathlessness
the day after laparascopic cholecystectomy. The patient,
who was previously otherwise well, had a strong family
history of ischaemic heart disease and smoked 20
cigarettes per day. Examination revealed an obese,
distressed woman with obvious tachypnoea and a
productive cough. Auscultation of her chest revealed
decreased air entry at the right base.
Vital signs also indicate tachycardia and relative hypotension (indicating she is haemodynamically
unstable) along with tachypnoea and mild fever. Based on the history and physical examination, there
must be some underlying cardiovascular or respiratory complication following her cholecystectomy.
As the patient appears haemodynamically unstable and may have developed shock, it is important to
identify and exclude serious conditions. She may have developed hypovolemic shock (haemorrhage,
dehydration), cardiogenic shock (which may explain some of her symptoms), distributive shock
including sepsis (although she is only mildly febrile at this stage, other very unlikely causes of
distributive shock: anaphylaxis, neurogenic) and obstructive shock (including pulmonary embolism,
other very unlikely causes of obstructive shock include pericardial tamponade and tension
pneumothorax).
The patient also has developed acute dyspnoea and cough with a mild grade fever after the procedure,
along with haemodynamic instability which are more consistent with pulmonary embolism. The
decreased air entry at the right base on auscultation is also consistent with a pleural effusion,
pneumothorax, atelectasis or pulmonary infarction and/or embolism (due to ventilation-perfusion
mismatch).
The provisional diagnosis in this case for acute dyspnoea, cough, low-grade fever, haemodynamic
instability post-cholecystectomy is pulmonary embolism, secondary to deep venous thrombosis.
Other important differential diagnoses include:
o COPD exacerbation: Given her history of smoking she may have underlying COPD, and
which could be exacerbated by her hospital stay (infections), anaesthesia, intubation and
mechanical ventilation and the procedure.
o Pneumothorax/tension pneumothorax- this would cause acute dyspnoea and decreased
air entry on auscultation and could happen after such a procedure. A tension
pneumothorax is very unlikely, given there are no obvious precipitating factors (trauma
etc) and it may lead to death very rapidly. These conditions do not explain her cough.
o Pneumonia/bronchitis/pleural effusion- this would explain her cough, fever and
dyspnoea. But her fever is mild and she is very tachypnoeic at rest, the timeframe for
infection is too short following the procedure. Also her fever would be much higher if she
had septic shock.
o Acute asthmatic attack: Although it was not noted in the history, she may have asthma
which was not noted. This could also explain some of her symptoms and would be
exacerbated by the anaesthesia/procedure, although she does not have a wheeze or other
signs of asthma.
o Inhaled foreign body/laryngeal oedema: Would explain sudden shortness of breath,
cough, low-grade fever and decreased air-entry. However, if she had aspirated a foreign
body or if she had other risk factors for aspiration, it may have been noted on history.
Laryngeal oedema usually occurs in the setting of anaphylaxis- does she have any
allergies to any medications?
27
o Myocardial ischaemia/infarction/heart failure: Would explain her acute shortness of
breath, haemodynamic instability and low-grade fever. Also she has cardiovascular risk
factors (smoking) and family history. However, there is no note of chest pain etc.
o Pericarditis and cardiac tamponade: Important to consider with tachycardia,
hypotension and haemodynamic instability (also indicating obstructive shock).
o Aortic dissection: Can also present with sudden hypotension but also with severe chest
pain.
o Post-operative atelectasis: Especially important post-procedure and intubation/
ventilation. Although would not explain why she has unilaterally decreased air-entry on
auscultation, and she has no crepitations/crackles. Does not explain cough,
haemodynamic instability, fever.
o Obesity sleep-apnoea hypoventilation syndrome: A differential to consider given she is
obese, but would not explain most of her presentation, and she is currently
hyperventilating, not hypoventilating.
If the patient has pulmonary embolism, important risk factors predisposing to her condition can be
derived from Virchow‟s triad (see below). In her case, importantly:
o Immobility/stasis: obesity, pain related to gallstones and the operation.
o Hypercoagulability: smoking, oestrogen (being female and she may be on hormone
replacement therapy if she is peri-menopausal), genetic factors-
family history of IHD, increasing thrombosis related to surgery
(related to surgical trauma/haemorrhage leading to increased
production of coagulation factors) and she may possibly be
dehydrated.
o Endothelial damage: surgical trauma
Important investigations in this case include:
o ECG: Important bedside investigation to quickly check for signs of myocardial
ischaemia/infarction, cardiac rhythm abnormalities, and signs of pulmonary embolism.
Important ECG changes related to pulmonary embolism to remember include usually a
normal ECG or one that shows sinus tachycardia. Sometimes, it may indicate right-
ventricular strain with a pattern similar to right-ventricular hypertrophy. Look at the
following waves and leads: right-axis deviation (S waves in lead I), tall R waves in lead
V1, inverted T waves in V1 (normal) spreading across to V2 and V3 and a „Q‟ wave in
lead III resembling inferior infarction (also known as the S1Q3T3 rhythm), also in some
cases you can see right-bundle branch block. This may occur with larger emboli causing
strain to the right ventricle. However, an ECG alone is NOT diagnostic for pulmonary
embolism.
o Full blood count: to check for signs of infection with high white cell count, and
importantly to check for thrombocytosis or anaemia.
o Urea, electrolytes and creatinine (UECs), calcium, magnesium phosphate and liver
function tests: to check post-operatively and compare to baseline, and check if the
patient is fluid overloaded or dehydrated, to check if the patient requires IV fluids or
diuretics.
o Arterial blood gases: to check if the patient is hypoxemic, or if there are acid-base
abnormalities.
o D-dimer: sensitive test for identification of pulmonary embolism.
o Other potentially useful blood tests include Troponin to exclude MI and coagulation
studies (PT, APTT and INR) to check for risks of coagulation. Some other predisposing
causes of hypercoagulability include Protein C or S deficiency, Antithrombin III
deficiency, presence of antiphospholipid antibodies/lupus anticoagulant or Factor V
Leiden‟s mutations. This is especially important if the patient is younger and has had a
28
history of repeated miscarriages (20-30 year old female). Blood cholesterol, glucose,
HbA1c can be checked as risk factors for IHD, the most common cause for heart failure.
Add on Thyroid function tests as hyperthyroidism may lead to high output cardiac failure
leading to such a clinical presentation.
o Chest x-ray (see image below)- a wedge shaped opacity is uncommon. A normal or near
normal chest x-ray in a dyspnoeic patient suggests PE. Well established abnormalities
include focal oligemia (Westermark’s sign), peripheral wedge-shaped density above the
diaphragm (Hampton’s hump) (or peripheral opacities) or an enlarged right descending
pulmonary artery. Also may see pleural effusion or atelectasis.
o V/Q scan: the main value of this technique is in the detection of pulmonary
thromboemboli, as it shows reduction of segmental perfusion and normal ventilation-
ventilation-perfusion mismatch (atelectasis: no ventilation, PE: no perfusion). In
pneumonia there may be good perfusion, lobar area of poor ventilation. A high
probability scan is diagnostic if the clinical suspicion is also high (i.e. a classic story for
PE in a patient with risk factors). A low-probability scan can rule out PE only in the low
clinical suspicion patient, whilst an indeterminate-probability scan is indeterminate.
o Pulmonary angiography or CT pulmonary angiogram: CTPA is now the gold
standard for diagnosis of pulmonary emboli, particularly in the acutely ill and shocked
patient or when ventilation-perfusion scans are equivocal (it shows filling defects
corresponding to thromboemboli). A pulmonary angiogram is the gold standard for
diagnosis. This procedure is generally safe (0.3% mortality) and indicated if the diagnosis
remains uncertain after non-invasive testing.
o Doppler and ultrasound scan: to check for DVT, and venous Doppler to exclude
venous flow occlusion.
o Bedside pulmonary function tests: If the patient is asthmatic, check peak expiratory
flow rate. Spirometry is also useful to check underlying airways disease to discriminate
between obstructive and restrictive disease.
A chest x-ray was performed which showed an area of opacification at the right base, together with a
small right pleural effusion.
Important causes of the chest x-ray features together with her clinical presentation include pulmonary
embolism and infarction, which can cause opacification and pleural effusion. With infarction, red
infarction occurs at the initial stages of embolic impaction in the lungs, as the embolus obstructs the
pulmonary circulation to that zone in the lung, but because of the lungs dual blood supply from the
bronchial arteries, blood can extravasate to that area. A pale infarct occurs when there is no secondary
blood supply to an affected zone. With PE, chest x-ray most often shows atelectasis, seen in 60-70% of
patients. Other less common signs include (also see image on pages below): increased lung lucency in
the area of the embolus (Westermark sign), abrupt cutoff of vessel, wedge-shaped pleural based
infiltrate (Hampton‟s hump) and pleural effusion which can appear bloodstained if sampled with
thoracentesis. Pleural effusion and wedge-shaped areas of infarction usually occur 12-36 hours after
symptoms begin and usually indicate pulmonary infarction. An area of confluent consolidation or
atelectasis can also cause the chest x-ray features.
29
Arterial blood gas was performed:
The patient appears to have uncompensatory respiratory alkalosis (high pH and hypocapnia) due to
her hyperventilation. She is also hypoxemic due to the ventilation-perfusion mismatch and shunting.
The ABG abnormalities of hypoxemia can be explained due to the pulmonary infarction and pleural
effusion and pulmonary arterial obstruction. The hypocapnia is due to her hyperventilation which was
the result of increased respiratory drive because of the hypoxemia leading her to blow off excess CO2.
ABGs typically show hypoxemia, hypocarbia and a respiratory alkalosis. However, a normal ABG
does NOT conclusively rule out pulmonary embolus.
Because of the diagnosis of pulmonary embolism, the patient obviously requires urgent anticoagulation
therapy, with either
o Fibrinolytic agents: Tissue plasminogen activator (alteplase, duteplase), streptokinase.
o IV Unfractionated Heparin: use a loading dose of 60U/kg bolus, a maintenance dose of
12U/kg/hr IV infusion. But must monitor APTT levels every 4-6hours, ensure that it is 1.5-2
times the patient‟s baseline, normal is ~30 seconds). Mechanism of action: potentiates the
activity of the endogenous anticoagulant antithrombin III. This in turn inactivates thrombin
(factor IIa) and other clotting factors (IX, X, XI, XII) and plasmin. Be aware of the heparin
induced thrombocytopenia syndrome (HITS) or other signs of bleeding, reversal is with
protamine sulphate. Other contraindications include undiagnosed or active bleeding,
haemorrhagic stroke or allergies.
o SC low molecular weight heparin (Enoxaparin (Clexane))- use 1mg/kg bd or 1.5mg/kg
once daily. No monitoring is required. Mechanism of action: inactivates thrombin to a lesser
extent than unfractionated heparin because smaller molecules (2000-6000 molecular weight vs.
5000-30 000) cannot bind to both antithrombin and thrombin simeoultaneously.Enoxaparin has
a better bioavailability compared to unfractionated heparin, so one does not have to monitor
levels and there is less bleeding than warfarin.
o PO warfarin (Coumadin): dose varies with individual, but start with 5-10mg dose and titrate
to INR 2-3 as needed (INR for AF, DVT, PE is 2-3; mechanical prosthetic heart valve 3-4.5).
Monitor until the patient has 2 theapeutic INRs, then check 2-3 times/week for 1-2 weeks,
once the patient is stable can decrease monitoring to every 4-6 weeks. Also monitor for signs
of bleeding. Reversal is with vitamin K (INR > 6.0). Initially monitor INR and PT levels 4-5
days after starting (half-life is 36 hours), so cover with heparin as initially prothrombotic and
to prevent further PE. PT should be 1.3-1.5 times the control. INR = (PTobs/PTcontrol) ISI of
thromboplastin agent being used in the lab. ISI = International sensitivity index. Mechanism of
action: vitamin K reductase inhibitor, inhibits synthesis of vitamin K dependent factors II, VII,
IX, X) and antagonises protein C and S. Contraindications: undiagnosed bleed, haemorrhagic
episode over last 6 months, haemorrhagic stroke (most thrombotic), allergy or drug
interactions.
o Surgical management: Insertion of IVC filter for patients with high risk of developing PE
from DVTs and bilateral DVTs (e.g. cancer patients) and in which anticoagulation is
contraindicated. Also can operate- and remove thrombosis, for example with pulmonary
embolectomy or thrombectomies.
o Prophylaxis: Mobilise, prevent dehydration, use of compression stockings (TEDS).
Also refer to old Phase 2 notes from HM3 week 7on GI bleeding for more information on disorders of
haemostasis and treatment.
30
The patient was sent for a ventilation-perfusion lung scan, but during transport she developed central
chest pain, increasing dyspnoea and cyanosis. Her blood pressure fell to 70/40 mmHg and her JVP
was elevated to 7cm. Despite attempting resuscitation, the patient died in ICU four hours later.
Clinical signs of massive pulmonary embolism include intense chest pain, acute/worsening dyspnoea,
cyanosis and circulatory collapse. Note that pulmonary embolism can have the following effects:
o Increased pulmonary vascular resistance due to vascular obstruction.
o Impaired gas exchange due to ventilation-perfusion mismatch
o Alveolar hyperventilation due to reflex stimulation of irritant receptors, and
hypoxemic drive.
o Increased airways resistance due to bronchoconstriction.
o Decreased pulmonary compliance due to lung oedema, haemorrhage, and loss of
surfactant.
o Right ventricular dysfunction- which can manifest as ECG changes and chest x-ray
features.
Sequence of events:
o Thrombosis: Usually arises from a vein (DVT) in the deep venous muscular plexus of the leg.
The thrombus may be attached to the endothelial wall and there may be partial or complete
occlusion.
o Embolism occurs when a mobile segment of the thrombus dislodges and passes up to the
lungs via the IVC and right-side of the heart.
o Depending on the size of the embolism, degree of collateral blood supply several outcomes can
occur. In this case massive pulmonary saddle embolism may have occurred, leading to acute
obstruction of right cardiac outflow (acute cor pulmonale) leading to obstructive shock (she
was very hypotensive) and rapid death. Before this, she would have had smaller emboli, which
caused pulmonary infarction, which was evident on chest x-ray.
Small pulmonary thromboemboli occur in 60-80% of cases and are asymptomatic, and they can cause
chronic right heart strain, chronic thromboemboli and pulmonary arterial hypertension.
Medium-sized emboli occur in 20-30% of cases, which can be a primary presentation which leads to
sudden-onset shortness of breath, pleuritic chest pain, can develop into chronic pulmonary arterial
hypertension and the patient may have many risk factors.
Large-sized emboli occur in 5-10% of cases and can lead to sudden death (saddle embolus), the release
of vasoactive amines and pro-inflammatory cytokines can also lead to circulatory collapse and
uncorrected shock and low-grade fever.
Progressive right heart failure is the usual immediate cause of death from PE. As pulmonary vascular
resistance increases, right ventricular wall tension rises and perpetuates further right ventricular
dilatation and dysfunction. Consequently, the interventricular septum bulges into and compresses an
intrinsically normal left ventricle. Increased right ventricular wall tension also compresses the right
coronary artery and may precipitate myocardial ischaemia and right ventricular infarction. Decreased
filling of the left ventricle may lead to a fall in left ventricular output and systemic arterial pressure,
thereby provoking myocardial ischaemia due to compromised coronary artery perfusion. Eventually,
circulatory collapse and death may ensue (In this case the patient died from saddle embolus, not RHF).
In this case of death a post-mortem examination is mandatory. Importantly this is because the patient
was <24 hours post-op (<24 hours of admission to hospital, nursing home, post-surgery or major
procedure) and was relatively young (52 years old). However, the death in this case was not
unexpected (given she developed acute PE) and the death was not unexplained. A post-mortem
examination in this case would provide a definite diagnosis of the cause of death in this patient.
Important major pathological findings one would expect at autopsy would include:
o DVTs: on inspection there may be unilateral/bilateral oedema in the lower limbs and on
autopsy there may be propagating deep venous thrombosis in the lower limb.
31
o Lungs: There may be a large saddle embolus obstructing the pulmonary artery. There
may also be smaller pulmonary emboli (as opposed to a post-mortem clot) in the smaller
branches of the pulmonary arteries. As this was acute on onset there may not be any other
major pathological changes. However, there may be wedge-shaped infarction in the lower
lobes, (as seen on chest x-ray) with apex pointing towards the lung hila with haemorrhage
and fibrinous exudation or fibrosis (long-standing) from previous PE. If the patient also
had pulmonary arterial hypertension, there may be atherosclerosis in the pulmonary
arteries. There may also be changes in the lungs related to COPD if the patient was a
long-standing smoker and the pleural effusion may also be noted.
o Heart: There may be evidence of right heart failure and right heart strain (increased
thickness of the right heart muscle wall). There may also be atherosclerotic changes in
the coronary arteries (related to smoking).
Pulmonary wedge-shaped haemorrhagic infarction on pleural surface of lung (left), which is hard and elevated
above adjacent lung surface. Right, pulmonary embolus in supplying artery (black arrow) at the apex of a distal
wedge-shaped haemorrhagic infarct.
Pulmonary thromboemboli at autopsy (arrow)
If the patient had survived, important long-term complications that may have developed would include:
o Pulmonary arterial hypertension, this could lead to right heart strain and development
of cor pulmonale (right heart disease which is a sequelae of chronic pulmonary disease).
o Other important long-term complications could include repeated thromboemboli if the
patient is not adequately given anticoagulants.
o Unilateral peripheral oedema (from recurrent DVT)
o If emboli do not resolve, smooth muscle proliferation and intimal thickening associated
with other possible outcomes will cause decreased vessel compliance. This results in
decreased flow in the affected vessel and predisposes to thrombus formation on top of
emboli.
o Ventilation-perfusion mismatching alters the function of Type 2 pneumocytes, which subsequently
produce less surfactant and this decreases lung compliance.
32
Case: Pulmonary thromboembolism
A 73 year old woman with long-standing congestive cardiac failure presented to her GP with sudden
onset of dyspnoea at rest, associated with haemoptysis and pleuritic chest pain. In the preceding week,
she had experienced several short-lived episodes of dyspnoea at rest. Her GP organised admission to
hospital, concerned about the possibility of pulmonary thromboemboli.
A provisional diagnosis of pulmonary embolus (PE) is reasonable, based on all the clinical features and
the timing onset of the dyspnoea. Pleuritic chest pain and haemoptysis indicate the possibility of
pulmonary infarction from PE. The episodic shortness of breath over the preceding week indicates
possible showers of emboli to the lungs and hence persistence of pleurisy and dyspnoea.
Her risk factors include: her long-standing congestive cardiac failure which predisposes to venous stasis
from poor systemic circulation & venous return; which can cause deep-vein thrombosis formation and
hence PE. This is one element of Virchow’s triad (which includes changes in blood flow:
stasis/turbulence in aneurysms or vessel branch points), vessel/endothelial injury (ruptured
atherosclerotic plaques, trauma, vasculitis) and changes in blood constituents (hypercoagulable states-
hyperviscosity of blood from erythrocytosis/polycythemia, dehydration, impaired synthesis of
coagulation factors by the liver- with systemic inflammation, oral contraceptive pills/hyper-oestrogenic
states, cancer, inherited deficiencies of anti-clotting agents such as antithrombin III, protein C, protein S;
Factor V Leiden‟s genetic mutations). Another important risk factor is potential hypercoagulability due
to reduced mobility from cardiac failure and drugs to treat her condition such as diuretics causing
hyperviscosity of her blood.
Note that in 50% of cases of DVT, patients are asymptomatic; whilst 36-84% of patients may have
dyspnoea, pleuritic chest pain or cough (most common features), leg pain is present in 25%; and
haemoptysis, palpitations, wheezing and anginal pain in <25%. Also importantly, syncope and sudden
death and worsening of underlying heart failure or lung disease. Important signs to identify include
tachypnoea (very common), crackles and tachycardia (very common) including supraventricular
tachycardia (40-90%), S4 accentuated S2P (pulmonary component of second heart sound) (~25%), low-
grade fever (variable), Homan’s sign (pain in the calf or popliteal region with abrupt dorsiflexion of the
patient‟s foot at the ankle, while the knee is flexed to 90 degrees), pleural rub, third heart sound (S3)
and cyanosis.
Investigations which might assist in establishing the diagnosis include:
o AP chest x-ray: With PE a chest x-ray is not diagnostic or very helpful as the film may be normal or
may have subtle changes, some signs of possible PE include linear collapse lines from atelectasis, and
pleural effusions. A chest x-ray is helpful to rule out other causes of chest pain differential diagnoses
such as pneumonia, pneumothorax or exacerbations of cardiac failure.
o ECG: a relatively simple investigation, usually ECG is normal or shows sinus tachycardia in PE.
Sometimes, it may indicate right-ventricular strain with a pattern similar to right-ventricular
hypertrophy. Look at the following waves and leads: right-axis deviation (S waves in lead I), tall R
waves in lead V1, inverted T waves in V1 (normal) spreading across to V2 and V3 and a „Q‟ wave in
lead III resembling inferior infarction. However, an ECG is NOT diagnostic for pulmonary embolism.
o D-dimer (Fibrin degradation product), a small protein product present in the blood after a thrombus
has been degraded by fibrinolysis, and a positive result is useful in the diagnosis of thrombosis and
DIC. If a D-dimer reading is high, then further imaging with venous ultrasonography, or lung
scintigraphy or CT pulmonary angiography is indicated.
o CT pulmonary angiogram (or helical CT with contrast): this is performed with contrast and is now the
gold-standard for diagnosing PE, the path of contrast is followed with the scanner to look for pulmonary
emboli and wedge shaped areas of haemorrhagic infarction. This is now more commonly used
(contraindicated in pregnancy) rather than a V Q nuclear lung scan, which reports the probability of
the patient having a PE as either low, medium or high probability- this modality also requires a high
index of clinical suspicion as well as looking for ventilation-perfusion ( V Q ) mismatch on this scan. In
a V Q lung scan radio-labelled particles are inhaled and segmental areas where there is ventilation but
33
no perfusion of the particles are observed for and this calculates a low, moderate or high probability of
PE.
o DVT venogram: In a DVT venogram look for filling defects in the lower limb veins, and this
requires IV radio-contrast. Also a simple Venous Doppler study is also very useful for visualising
thrombosis in the lower limb veins.
o Pulmonary angiography: These are very invasive procedures but can very accurately diagnose PE,
they are usually performed when surgery is required, e.g. surgical embolectomy to treat a PE.
Pulmonary angiography is very invasive as it requires cardiac catheterisation, to check for a cut-off of
perfusion blood supply to a lung segment, it is only used in patients where other investigations were
not helpful in diagnosing PE when a strong clinical suspicion of PE still remains.
If PE is the cause of her symptoms, she could have still potentially experienced multiple episodes of
painless dyspnoea, which could have been the result of smaller showers of emboli that did not cause
pulmonary infarction and pleural involvement. Hence pleuritic chest pain is significant in pulmonary
thromboembolism as it indicates pulmonary haemorrhagic infarction which very often involves the
pleura, causing inflammation and irritation of the parietal pleura.
The following specimens are taken from another patient that died from PE. On the left-hand side, there
is recognisable alveolar tissue, the right-hand side is haemorrhagic (it has jitter artefact with a banding
wavy pattern), it also has a ghost pattern of alveoli with a loss of nuclei- indicating coagulative necrosis
and hence haemorrhagic pulmonary infarction. An example of thromboembolism is seen with a
fragment impacting in a pulmonary artery on the right-side of the field. The actual embolus that caused
infarction, however, would have impacted proximally in the supplying branch of the pulmonary artery.
In the left-hand side there are areas of necrotic alveoli and red material (hemosiderin) in macrophages
from long-standing congestion of the vessels from chronic congestive cardiac failure and increased
pulmonary vascular resistance indicating pulmonary artery congestion. On the pleural surface, there is
evidence of inflammation, in most cases one would expect to have a fibrinous pleural exudate, although
fibrin is not present in the pleura in this slide. There may be insufficient time (less than a few hours) or
insufficient stimulus to cause a fibrinous exudate not observed here:
The possible outcomes of DVT‟s and pulmonary thromboembolism include:
34
o Saddle embolism: occurs in ~10% of cases, causing sudden death, as it causes sudden obstruction
to right-ventricular outflow, (also known as acute cor pulmonale), hence there is no venous return
to the left ventricle and hence sudden loss of cardiac output, loss of perfusion to the heart and
brain and sudden death. Saddle emboli are associated with recurrent multiple emboli that precede
the massive embolus. A large saddle embolus impacts into the pulmonary trunk, where >60%
obstruction results in acute hypotension & breathlessness causing sudden death.
o Paradoxical embolism: this is rare, but is due to left-right shunting of the heart, e.g. in patients
with atrioventricular septal defects (“hole in the heart”) this can mean that an embolus from a
DVT can cause systemic embolic phenomena, such as TIA/stroke, splenic, renal or bowel
ischaemia/infarction, or embolisation to the lower limbs.
o ~65% of pulmonary embolism is asymptomatic, or has subtle signs such as mild-shortness of
breath. These are due to small-sized emboli.
o Pulmonary infarction: this occurs as a result of mild-moderate sized emboli, e.g. in the case of
this patient with congestive cardiac failure. However, in young people with good bronchial
collateral circulation, infarction would not be likely to occur.
o Pulmonary arterial hypertension: this can occur as a result of permanent narrowing of the
vessel wall due to embolus organisation and recanalisation, which can predispose to PE. The
permanent narrowing of the pulmonary vessel wall increases vessel resistance and hence causes
chronic pulmonary arterial hypertension.
o Most emboli go to the bases of the lungs due to the effects of gravity.
Thus pulmonary embolism requires fast treatment & management, as well as prevention as soon as
possible, which is what the GP did in this case to prevent massive PE.
In venous thrombosis, the majority of DVT‟s form in the deep veins of the calf, that extend in length
(propagate) in direction of blood flow to the heart. On microscopy (see below) it is seen to be mainly
made up of laminations of red blood cells with small amounts of fibrin & platelets- hence known as a
red thrombus. Note that not all microemboli cause pulmonary infarction, as the lungs have a dual blood
supply via the bronchial arteries, which may not allow gas exchange but allows appropriate pulmonary
perfusion.
~50-65% of DVT‟s are silent, hence in such immobilised, dehydrated & post-operative hospitalised
patients, must have high suspicion for DVT‟s. The rest of patients with DVT‟s may have swelling &
pain in their legs (unilaterally generally).
The following specimens display a lung at autopsy, which shows a massive recent infarct in the lower
lobe and embolus can be seen in branches of the pulmonary artery.
35
The following specimen displays a circumscribed area of infarction in the mid-zone of the right upper
lobe, dark red in the centre, with pale areas at the margin. Thrombus is present in small vessels, and on
the pleural surface there is quite marked fibrinous pleurisy- a frequent reaction to infarction.
Massive pulmonary thromboembolism:
A 68 year old man was diagnosed with primary pancreatic cancer, which was found to be inoperable. He
underwent a course of chemotherapy, but developed sudden severe dyspnoea and collapsed in a
cardiorespiratory arrest, from which he could not be resuscitated. The following specimens were
obtained at autopsy:
The patient‟s pancreatic cancer diagnosis is important, as he would have most-likely had Trousseau
syndrome of migratory thrombophlebitis (or Trousseau sign of malignancy). Pancreatic cancers and some
visceral adenocarcinomas/GI cancers produce mucin, which predisposes to coagulation and hence
thromboembolic phenomena. All other cancers that cause loss of mobility also predispose to hemostasis,
DVT formation and pulmonary embolism. Furthermore, cancers produce a hypercoagulable state.
36
The specimen shows the left and right lungs, with the pulmonary valve, pulmonary trunk and
bifurcation. There is a pulmonary embolus straddling the pulmonary artery bifurcation- a "saddle" of
embolus, extending into the intrapulmonary portion of both right and left pulmonary arteries. The upper
lobes of both lungs are pale, but there are no localised areas of infarction in this specimen, indicating it
is a saddle embolus with no evidence of lung infarction. Also on the left, there is an image of a large
DVT, which grows in the direction of venous flow towards the inferior vena cava & right ventricle.
The slide below displays embolus in a pulmonary artery, an embolus is different to a post-mortem clot
as emboli contain laminations of fibrin/platelets and red cells. The presence of a semilunar valve
indicates that this specimen is from a large vein (e.g. femoral or iliac vein). There are bands of
eosinophilic red cells with darker bands indicating laminations so this is a thrombus rather than a post-
mortem clot, particularly in conditions of stasis.
Thrombus organisation is occurring, with granulation tissue occurring around the sides of the valves
indicating this thrombus is a few days old, this also indicates that this process occurred during life and
is not a post-mortem clot (which would consist of two separated distinct layers of “red currant jelly”
with red-cells and a supernatant of plasma and fibrin overlying it, known as “chicken fat”).
An old infarct is shrunken in appearance, fibrotic/scarred; a new infarct is haemorrhagic and hard.
Remember that ~50% of DVTs are asymptomatic; others may cause localised heat, swelling and pain
due to venous congestion or thrombophlebitis. One must be very vigilant to investigate for DVTs when
these signs are seen.
Virchow‟s triad of changes in the vessel wall, changes in the constituency of blood and endothelial
injury describes factors that contribute in the formation of thrombosis. Thrombosis in the deep venous
37
plexus of the calf increases risk of embolism into the pulmonary circulation. Clinically this is results in
a ventilation/perfusion mismatch, due to the blockage of blood to the pulmonary circulation via the
pulmonary arteries. It is often clinically asymptomatic (50%) and is an important cause of mortality.
Other symptoms include chest pain, dyspnoea, haemoptysis, faintness + collapse and signs of right
heart failure. Signs reveal circulatory collapse – tachycardia, hypotension, elevated JVP, decreased
urinary output and gallop rhythm and loud P2.
Confirmation is firstly based on history and examination, and investigation using arterial blood gas,
with addition of D-dimer, ECG, lower-limb Doppler studies, V/Q scan, CTPA [and pulmonary
angiography] as required.
Mechanisms of Thrombosis and pathogenesis of PE
Virchow‟s triad
Endothelial damage is an important factor causing thrombosis; important causes include post-MI mural
thrombus, valve inflammation, endothelial injury leading to exposure of subendothelial collagen (vessel
wall damage- infections/sepsis, trauma, burns, systemic vasculitides), atherosclerosis, smoking.
Hypercoagulability is the imbalance between anticoagulant (e.g. PGI2 and plasminogen activator) and
pro-coagulant (tissue factor, plasminogen activator inhibitor and adhesion molecules binding to
platelets (e.g. vWF and subendothelial collagen)) factors. These can be affected by certain disorders, e.g.
consumption of factors that occurs in DIC, hypercoagulable states in certain cancers, pregnancy,
hyperviscosity syndromes, e.g. polycythemia, sickle cell anaemia etc.
Normal blood flow is laminar; abnormal blood flow results from turbulence from stasis, vessel branch
points, aneurysms, MI – mural thrombus, atrial fibrillation, mitral valve stenosis (e.g. after rheumatic
heart disease).
Some important causes and risk factors of hypercoagulability include:
Primary
Factor V Leiden
Prothrombin mutation (G20210A), hyperhomocystinemia
Antithrombin III deficiency
Protein C or S deficiency
Secondary
Venous stasis: prolonged bed rest, immobilisation, dehydration
Myocardial infarction, heart failure
Tissue damage (fractures, surgery, burns, major trauma)
Cancer
DIC
Prosthetic valves
Heparin-induced thrombocytopenia syndrome (HITS)
SLE (lupus anticoagulant, anti-cardiolipin antibodies)
Atrial fibrillation
Nephrotic syndrome
Cardiomyopathy
Hyperoestrogenic states (e.g. pregnancy, oral contraceptive pill)
Sickle cell anaemia
Smoking
38
Risk factors predispose to the formation of a DVT and this can then lead to one of the four paths:
o DVT propagation- thrombus grows proximally, obstructing a critical vessel
o Embolisation- impacts the lung vasculature, resulting in infarction, right to left shunting and
obstructive shock
o Dissolution of thrombus- fibrinolysis
o Organisation and recanalisation and incorporation of thrombus into the vessel wall
DVT leasing to PE accounts for 75-90% of all PE. Also consider other emboli- amniotic fluid, fat,
foreign bodies, air, parasites, septic emboli, cholesterol emboli or tumour emboli.
Important risk factors for DVT formation include:
Surgery
Major abdominal/pelvic surgery
Hip/knee surgery
Post-operative care/intensive care
Cardiorespiratory disease
COPD
Congestive cardiac failure
Obstetric Pregnancy/peurperium
Lower limb disorders Varicose veins
Fracture
Stroke/spinal cord injury
Malignant disease Abdominal/pelvic
Advanced metastatic
Concurrent with chemotherapy
Other Previous proven venous thromboembolism
Immobility
Thrombotic disorders
Trauma
Increasing age
Some chest radiograph changes to note (although not commonly present) in pulmonary embolism and
infarction include:
39
Management of pulmonary embolism
Anticoagulant therapy is required in the treatment of pulmonary thromboembolism. Heparin, both
unfractionated and low-molecular weight heparin may be used, fibrinolytics and warfarin are
indicated. Fibrinolytics include alteplase and streptokinase, and in the scenario of heparin
complications, lepirudin or danaparoid may be used. Warfarin is a standard for long-term therapy if
indicated. Heparin potentiates antithrombin III and antagonises factors II, IX, X, XI and XII in the
coagulation pathway. Fibrinolytics are analogues of tissue plasminogen activator or have similar
activity such that plasminogen is activated into plasmin, which catalyses the degradation of fibrin fibres.
Warfarin is a vitamin K reductase inhibitor which inhibits the formation of factors II, VII, IX and X
(vitamin K-dependent factors) in the coagulation cascade.
Heparin/warfarin treatment:
1) Enoxaparin 1.5mg/kg SC daily or 1mg/kg SC BD for 5 days
2) Start warfarin 5 mg PO daily, titrate to INR 2-3.
3) Maintain enoxaparin for at least 5 days, and for two days of stable INR with warfarin.
Use compression stockings as an adjunct. Also an inferior vena caval (IVC) filter may be used in
patients with confirmed DVTs who are at high risk of developing massive or significant PE, this
requires ultrasound or CT guidance for insertion via a femoral venous catheter.
Consider DVT in the axillosubclavian veins, mesenteric veins and cerebral sinuses.
The following is a guide for the management of DVT/PE depending on clinical circumstances:
40
The molecular mechanisms of the common anti-coagulant medications are highlighted below:
41
Summary of important features to remember about the pathogenesis and complications of DVT/PE:
42
Haematology: Haemostasis & coagulation pathways
Haemostasis:
Haemostasis is the normal physiological response to stop bleeding after rupture in blood vessel walls. It consists
of three parts: 1) Vasoconstriction of the damaged vessel, 2) Platelet activation that forms a plug around the site
of vessel damage, which leads to 3) formation of an insoluble fibrin clot. These processes together help to prevent
bleeding. It is most effective in controlling small vessel injuries.
Since veins contain blood at lower pressures, hence venous bleeding is less rapid and more easily controlled.
Sometimes venous bleeding can be controlled simply by lifting the limb involved, i.e. above heart level. Also
internal venous bleeding can be controlled by the accumulation of pressure from accumulated blood in the tissues.
A collection of blood in tissues is known as a haematoma.
The following describes haemostasis in more detail: It is actually a five-stage procedure, involving the following
processes:
Vascular spasm & vasoconstriction.
Formation of a platelet plug
Formation of a blood clot through coagulation
Clot retraction
Replacement of the clot with fibrous tissue
Immediately after trauma (i.e. cut or rupture) to a blood vessel, the trauma to the vessel wall causes
vasoconstriction or spasm, which will instantly reduce blood flow (and hence blood loss) to that vessel. Vascular
contraction usually results from a combination of local smooth muscle spasm, nervous reflexes initiated by pain
nociceptive fibres and local chemical factors produced by traumatised tissues to cause vasoconstriction. In smaller
vessels, platelets are responsible for most of vasoconstriction, as they release the vasoconstrictor substances with
the main vasoconstrictor being Thromboxane A2. Note that the greater the damage, the greater the degree of
vascular spasm. Hence a cut vessel will bleed greater than a crushing injury, as the crushing injury has a greater
deal of damage, to surrounding tissue and hence greater vascular spasm preventing (further) bleeding, cuts have
relatively less damage. Local vascular spasm can last for many minutes or even hours during which time the
wound can be sealed by a blood clot.
Platelets generally have a lifetime of ~8 days and are then eliminated from the circulation by tissue macrophages.
Cell membranes of platelets are important, for clotting as they have a glycoprotein coat, which allows platelets to
slide past vessel walls, but adhere to tissue factor in injured areas. Platelets have secretory vesicles containing
adrenaline, serotonin, ADP and Thromboxane A2. If the hole in the damaged vessel wall is relatively small, it can
be sealed by the platelet plug. The glycoprotein coat is hence important in the formation of a platelet plug for
adhesion to the damaged vessel wall. Processes involved in formation of the platelet plug include:
The damaged vessel disrupts the endothelium and exposes subendothelial connective tissue and
collagen.
When platelets encounter the defect in the blood vessel and collagen, platelets swell, forming
irregular shapes with numerous pseudopods and attach to exposed collagen- “platelet adhesion”.
Once attached, contractile proteins in the platelet contract forcefully, releasing multiple active
factors from storage granules.
Platelet substances released from the granules include Thromboxane A2, adrenaline and serotonin
which cause vasoconstriction and minimise blood loss.
ADP is released from platelets causing the platelets to become „sticky‟ and adhesive which causes
another layer of platelets to adhere to the first layer of platelets. These platelets also release ADP
causing a platelet adhesion/pile-up through receptor/ligand interaction via GPIb/IX and vWF or
GPIIb/GPIIIa receptors and further platelet aggregation, until a platelet plug is formed. Hence
platelet adhesion to the vessel wall occurs first, then followed by platelet aggregation & plug
formation.
Platelets also release Thromboxane A2, which also directly causes vasoconstriction but also directly
promotes platelet aggregation and triggers the release of more ADP from platelet granules.
Thromboxane A2 and ADP hence promotes platelets plug formation to stop bleeding.
Note that the platelet plug is limited to the site of vessel injury; the normal endothelium releases
prostacyclin (PGI2), which profoundly inhibits platelet aggregation, which limits platelet plug
formation to the area of the defect. Hence it prevents the extension of the plug out into areas of
43
normal endothelium. Prostacyclin hence prevents clotting from occurring. The body is hence in a
balance whereby procoagulant and anticoagulant factors and states are normally balanced.
Note that however, Prostacyclin and Thromboxane A2 are related as they are both Eicosanoids
derived from Arachidonic acid. Nevertheless thromboxane A2 causes vasoconstriction and platelet
aggregation, whilst prostacyclin causes vasodilatation and inhibits platelet aggregation.
If a defect in the vessel wall is small enough, then the platelet plug by itself can stop blood loss. If the hole in the
vessel wall is large, then a blood clot rather than a platelet plug is required.
Transformation of blood into a solid gel or clot/thrombus occurs mainly through the formation of the polymer
protein fibrin. Blood coagulation occurs around the formed platelet plug, it serves to reinforce the plug and
solidify the blood that remains in the wound channel. This process involves several stages and is known as the
coagulation pathway.
Platelets contain actin and myosin contractile proteins, which allows platelets to pull the edges of the damaged
vessel wall back together once the platelet plug has been formed. This process is known as clot retraction. As a
result serum (plasma minus fibrinogen) is exuded out of the bloodstream at the damage site, this is the fluid
exuded in this shrinking process.
Following this there is a process of replacing the clot with fibrous tissue. Platelets secrete growth factor proteins
stimulating the growth of arterial smooth muscle and skin fibroblasts; this begins after the first few hours of clot
formation. Serotonin stimulates fibroblasts to secrete collagen. As a result the blood clot is converted to fibrous
tissue. This process takes about 1-2 weeks.
There are three major stages in blood coagulation; 1) injury to the vessel wall leads to a chemical reaction cascade
that leads to the formation of prothrombin activator. 2) prothrombin is then converted to thrombin, catalysed by
prothrombin activator. 3) Thrombin acts as an enzyme which converts fibrinogen to fibrin fibres which trap
platelets, blood cells and plasma to form a clot. There are ~50 substances in blood which affect coagulation; some
are procoagulants, others are anticoagulants. There is a balance between these to determine clotting. In the normal
state anticoagulants are more active, preventing blood clotting, with damaged vessels there is procoagulability.
Prothrombin activator is the rate-limiting step in blood-coagulation. Prothrombin activator can be formed in two
ways; by an extrinsic pathway involving factors present in damaged tissue and by an intrinsic pathway
involving coagulation factors already present in plasma. In both pathways of prothrombin activator formation,
plasma proteins known as blood clotting factors, play major roles. Most are inactive forms of proteolytic enzymes.
When active, their enzymatic actions cause the next cascading reactions of the clotting process. Most clotting
factors are designated by roman numerals, i.e. Factor VIII (complexes with von Willebrand‟s factor), factor X, etc.
A small „a‟ is written after the number to indicate the active form of the factor, e.g. Factor Xa.
The following image displays the intrinsic clotting pathway. It is initiated by inactive Factor XII (Hageman factor)
coming into contact with a foreign surface, i.e. collagen for example from a damaged blood vessel. This pathway
finishes off with prothrombin activator being activated. Ionic calcium, Ca2+
and platelet factor (a phospholipid)
are needed for this clotting pathway to occur, hence in hypocalcaemia, patients may also have blood clotting
abnormalities. If no anticoagulants are used and blood is taken into a glass tube, for example, due to Factor XII
coming into contact with this foreign surface, blood then quickly coagulates via this intrinsic clotting pathway:
44
The extrinsic clotting pathway begins with a damaged vascular wall or extravascular tissue that comes into
contact with blood. The damaged tissue releases several factors into the blood, which include Factor III (also
known as tissue factor or tissue thromboplastin) which complexes with Factor V and Factor VII to form
extrinsic thromboplastin catalysed by Ca2+
. Hence the extrinsic clotting pathway starts with tissue damage and
ends with prothrombin activator activation and requires Ca2+
in several steps.
With the formation of prothrombin activator, the intrinsic and extrinsic pathways converge and afterwards it is a
common coagulation pathway. Thus after a blood vessel ruptures, blood starts to clot via both the intrinsic &
extrinsic pathways. An important difference in both pathways is that the extrinsic clotting pathway is much
shorter, taking ~15 seconds. The intrinsic clotting pathway is much slower, requiring 1-6 minutes to cause clotting.
Hence both occur simultaneously but one occurs much more faster than the other.
The common coagulation pathway is depicted as follows, after prothrombin activator has been formed:
Fibrin is the end-product of the common clotting pathway and it is important in forming the framework of the clot.
Fibrinogen is the precursor, a high molecular weight protein synthesised by the liver.
Thrombin changes fibrinogen into a smaller monomer which then polymerises with other fibrin monomers to
form long fibrin fibres that form the reticulum (meshwork) of the clot. Initially fibrin fibres are held together by
weak hydrogen bonding that is easily broken.
Thrombin activates platelets to release a fibrin stabilising factor; that causes covalent bonding between fibrin
monomers; adding strength and cross-linkages between the fibres to form the fibrin meshwork.
The final clot consists of fibrin fibres running in all directions, entrapping blood cells, platelets and plasma. The
fibrin fibres adhere to the damaged areas of the blood vessels therefore the clot adheres to any vascular opening,
preventing further blood loss.
Most procoagulant molecules are synthesised in the liver and some are vitamin K dependant, including Factors II,
VII, IX, X; anticoagulants protein S and protein C (vitamin K γ-carboxylation is vital for biological activity).
von Willebrand‟s factor (factor VIIIR) is complexed with factor VIII and is synthesised by megakaryocytes and
endothelial cells. Factor VIII circulates complexed with vWF, as vWF protects it from proteolytic degradation.
Anticoagulation:
Dissolving the clot: The fibrin meshwork is not meant to last forever and is broken down after a certain time,
where new skin and blood vessel growth occurs and hence is a temporary measure to allow blood vessel
regeneration and healing.
45
In a system analogous to the clotting pathways, the anti-clotting system dissolves the clot. This occurs when
plasminogen is converted to the active enzyme plasmin, which digests fibrin and other clotting factors to dissolve
the clot.
Note other inhibitors of blood coagulation include dilution of procoagulants (e.g. with liver disease, haemophilia
& other coagulopathies), secretion of prostacyclin and nitric oxide by neighbouring endothelial cells
(vasodilators); removal of particulate matter and activated factors by the reticuloendothelial system. There are
also specific inhibitors to coagulation pathways including tissue factor pathway inhibitor; protein C and protein S
and antithrombins. (Remember Protein C and S deficiencies predispose to thrombosis). Antithrombin, Protein C
and protein S are formed by the liver as well; hence the liver is important in forming both coagulant &
anticoagulant molecules.
Heparin is an important anticoagulant used clinically but also occurs as an endogenous molecule on the surface of
endothelial cells, which functions physiologically by binding to antithrombin III thus forming an antithrombin III-
heparin complex that inactivates factors XI, IXa, Xa or IIa). The drug form of heparin exists as a free molecule
that also binds to circulating antithrombin III and the resultant complex inhibits the same clotting factors.
The tissue factor pathway inhibitor (TFPI) is also an important endogenous molecule that inhibits coagulation by
binding to factor Xa inhibiting it and subsequently also inhibiting the tissue factor-factor VIIa complex:
Also do not forget fibrinolysis via the activation of plasminogen to plasmin, which breaks down/dissolves fibrin
strands in a clot.
Investigations for Coagulation:
Activated Partial Thromboplastin Time (APTT): this test is performed by adding kaolin to patient plasma to
provide surface activation of factors XII and XI. Platelet lipid surrogate is then added and the time taken to
produce fibrin is recorded. In other words, it measures the clotting time after the addition of contact factors (e.g.
factors V, VIII, IX, X, XI, XII, prothrombin and fibrinogen), but without added tissue thromboplastin. APTT is
affected by deficiencies of factors which precede to the activation of Factor X (i.e. it measures the intrinsic
pathway coagulation time); i.e. it is sensitive to the action of heparin, and it is used to monitor heparin therapy.
APTT is also prolonged in the haemophilias.
Prothrombin time (PT): In this test a tissue extract such as thromboplastin/tissue factor (Factor III) is added to
patient plasma and the time taken to produce fibrin is recorded, hence measuring clotting time of the extrinsic
46
coagulation pathway. It is then reported as a corrected prothrombin ratio (PR), expressed as the INR
(International Normalised Ratio) which is corrected to take account of the differences in the thromboplastins. It
is hence sensitive to abnormalities of the extrinsic coagulation pathway (e.g. abnormalities with Factors I, II, V,
VII and X) and hence INR is used to monitor patient warfarin therapy.
D-Dimer (Fibrin/fibrinogen Degradation Products): This is a latex agglutination test, which detects the cross-
linked fibrin degradation fragment, D-dimer. Elevations in this fragment are seen in primary and secondary
fibrinolysis; during thrombolytic or defibrination therapy with tissue plasminogen activator (tPA); as a result of
thrombotic disease, such as deep-vein thrombosis, pulmonary embolism or DIC; in vaso-occlusive crisis of sickle
cell anaemia; in malignancies; and in surgery.
Platelet function tests: Tests for platelet function include checking the platelet count in the FBC, checking blood
films, checking patient bleeding time and aggregometry.
Factor assays can be done if there are unexplained reasons why a patient has abnormalities with blood
coagulation based on other tests. It can be useful for bleeding disorders, e.g. Factor VII deficiency and testing
other factors.
Disorders of too little coagulation:
Important disorders of too little clotting include Thrombocytopenia, platelet function defects, coagulation
factor deficiencies (of these, they are inherited, and they involve either failure to synthesise factors or failure to
consume factors) and vascular purpura (e.g. due to endothelial defects, for example in Ehlers Danlos syndrome
or acquired conditions, e.g. corticosteroid excess, senile purpura, leukocytoclastic vasculitis).
Thrombocytopenia:
This is abnormally low platelet numbers and hence a tendency to bleed, usually bleeding from capillaries and
venules.
Clinically, the skin may develop small purplish patches which is venule bleeding into the skin and is known as
purpura (lower limbs or upper limbs), or ecchymoses (bruising). It may also present with petechiae- capillary
bleeding usually in the lower limbs, buccal mucosa, or with abrasions. The patient may also have menorrhagia, or
mucosal bleeding, e.g. bleeding gums. The cause of platelet disorders should be categorised into either
quantitative platelet disorders (thrombocytopenia) or qualitative platelet defects.
Thrombocytopenia occurs mostly as a result of formation of antibodies which react against platelets to destroy
them, hence most commonly it has an autoimmune cause; other times it is due to blood transfusions and formation
of antibodies against donor platelets.
Important ways of classifying causes of thrombocytopenia includes:
Platelet production defects: -Due to bone marrow ablation from radiation or cytotoxic drugs.
- Bone marrow infiltration (due to infection or malignancy)
- Selectively impaired platelet production from drugs (e.g. gold, ethanol,
sulphonamides, thiazides etc)
- Ineffective megakaryopoiesis (due to B12 or folic acid deficiency or
myeloproliferative disease).
- Congenital defects of platelet production (Fanconi‟s anaemia).
Accelerated platelet removal: - Immunological causes (e.g. Idiopathic Thrombocytopenic Purpura, SLE,
Non-Hodgkin Lymphoma, drug induced immune reactions, heparin,
infections, HIV, sepsis)
-Non-immune causes, e.g. Disseminated Intravascular Coagulation,
Haemolytic-uraemic syndrome, transfusion induced platelet destruction.
Platelet sequestration: Hypersplenism & any causes of hypersplenism, e.g. Malaria, portal hypertension.
Idiopathic thrombocytopenic purpura (ITP) is caused by platelet associate-IgG (this is often directed against the
platelet surface glycoprotein molecules GP-IX or GPIIb-GPIIIa complexes). These platelets are tagged by these
IgG antibodies for destruction in the spleen by the reticuloendothelial cells. It is often a self-limiting disorder
(„acute‟) with remission in <3 months, it usually occurs in children/young adults and follows Epstein-Barr virus &
other viral infections. Chronic ITP however, can occur and when it does it is in adults. Management of ITP
involves anti-inflammatory drugs including corticosteroids, intravenous γ-globulin and in severe chronic cases
splenectomy may be necessary.
47
Platelet functional disorders: These can be separated into either 1) Hereditary diseases that involve genetic
mutations in platelet membranes, platelet granules and von Willebrand‟s disease (failure of platelet adhesion via
GPIb-IX glycoproteins); or 2) Acquired platelet disorders including bone marrow disorders such as
Myelodysplasia, Uraemia or drug induced such as through NSAIDs and aspirin.
Vascular Purpuras:
This occurs as a result of leakage of blood from terminal arterioles, capillaries and post-capillary venules. For
example this can occur with Scurvy, as vitamin C is needed for normal collagen metabolism (formation of
hydroxylysine/hydroxyproline for collagen) and hence smaller blood vessels are weak & susceptible to bleeding.
Vascular Purpuras can also occur with corticosteroid excess (see House season 1 Cushing syndrome episode.)
Also caused by senile purpura and leukocytoclastic vasculitis (immune complex deposition in smaller blood
vessels).
Vitamin K deficiency:
Vitamin K is important for the formation of 5 blood clotting factors. It is required by the liver to synthesis these
clotting factors including prothrombin. Hence Vitamin K deficiency can lead to serious bleeding disorders.
Vitamin K is fat soluble, continuously synthesised in the GI tract by gut flora. Hence it requires bile salts for
absorption in the small intestine. Vitamin K deficiency can hence occur with cholestasis, which prevents the liver
releasing bile into the gut preventing vitamin K (and other fat soluble vitamins A, D and E) being absorbed.
Warfarin is a competitive inhibitor of Vitamin K hence preventing blood clots. It competes with vitamin K for
active sites in the enzymatic process of prothrombin and other clotting factor synthesis. It is hence a competitive
antagonist of vitamin K and has anticoagulant effects.
Von Willebrand’s Disease:
This is caused by a deficiency of vWF, the carrier of Factor VIII. vWF is needed for platelet adhesion via the
GPIb receptor. This is usually an autosomal dominant disorder.
Patients with this disease have a lifelong history of mucosal bleeding, severe bleeding during surgery or trauma.
Relevant investigations to diagnose this condition include prolonged bleeding time, increased APTT, decreased
antigenic vWF, decreased Factor VIII to protein C ratio and abnormal ristocetin-induced platelet aggregation.
Haemophilia:
This is a hereditary disease characterised by uncontrolled bleeding, even with minor injuries. In ~80% of
haemophiliacs, it is due to Factor VIII deficiency. Haemophilia A is caused by defective/deficient Factor VIII to
protein C ratios. Haemophilia B is caused by Factor IX deficiency.
It is inherited as sex-linked recessive, carried by the mother on the X-chromosome, hence predominantly males
are affected and females are carriers. There are over 600 genetic mutations identified with Haemophilia A,
including insertions, deletions and point mutations.
The severity of haemophilia is very variable, it can range from excessive bruising, persistent bleeding after a
simple cut to haemorrhage into joints or muscles, which can be painful and disabling, causing arthropathy.
Relevant investigations that provide diagnosis of a suspected Haemophilia patient include increased APTT (as
mentioned previously), decreased Factor VIII to protein C ratio but normal vWF levels (unlike von Willebrand‟s
disease).
Haemophiliacs used to require frequent blood transfusions, nowadays it is treated by synthetic factor VIII, which
is synthesised by genetic engineering. With diagnosis patients also require genetic counselling. It is also important
to prevent and manage possible complications of Haemophilia, including arthropathy/myopathy from intra-
articular or intramuscular bleeding; analgesic dependence and prevention of blood-borne infections (e.g. Hepatitis
C, HIV etc) in patients requiring regular transfusions.
48
Other acquired disorders of coagulation:
Again this may be due to decreased production of clotting factors, as can occur with:
i. Vitamin K deficiency (affects Factors II, VII, IX, X) as a result of low dietary vitamin K or with Warfarin
therapy.
ii. Hepatic disease causing decreased Factor II, V, VII, IX, X and protein C.
iii. Disseminated intravascular coagulopathy, e.g. either as a result of massive tissue damage, burns, tumours,
amniotic fluid embolus, sepsis etc. With investigations there will is usually thrombocytopenia, prolonged
APTT, elevated INR, decreased fibrinogen levels, elevated D-Dimer.
iv. Inhibition of clotting factor production: for example with antibodies to clotting factors, or with
Antiphospholipid antibody syndrome.
Hypercoagulable states:
Important hypercoagulable states occur with Antiphospholipid antibody syndrome; or deficiencies of
anticoagulant molecules:
o An important deficiency of an anticoagulant molecule is antithrombin III deficiency (also
known as heparin resistance).
o Protein C or protein S deficiency (hence the loss of the ability to inactivate Factor VIIIa or Va).
Activated Protein C (APC) resistance (resistance of factor Va to activated Protein X)- also known as Factor V
(Leiden) mutations, an important cause of hypercoagulable states to be aware of, that for example is associated
with cerebrovascular accidents.
Prothrombin gene variants can also cause hypercoagulability.
Trousseau’s syndrome an important eponymous syndrome which included migratory thrombophlebitis
associated with malignancy, especially pancreatic cancer and other glandular mucin/tissue factor producing
adenocarcinomas.
Obesity, immobility, pregnancy and other hyper-oestrogenic states are other important causes of a
hypercoagulable state.
49
Pharmacology: Treatment of Thrombosis
Arterial thrombosis mainly occurs as a result of atherosclerotic disease, for example in the coronary arteries
which leads to myocardial infarction; or in the cerebral circulation causing cerebral infarction & stroke, this is
usually a „white thrombus‟ that consists predominantly of fibrin and platelets. Venous thrombosis is mainly the
result of stasis of blood flow & hypercoagulable states, for example, deep vein thrombosis and subsequently
pulmonary embolism, in cases of venous thrombosis there is usually a „red thrombus‟.
Thrombosis can be treated with either: anti-platelet, anti-coagulant or thrombolytic drugs.
Anti-platelet drugs:
Many factors released by platelets and some clotting factors act on platelet G-protein coupled receptors, e.g. P2Y,
Thromboxane A2 receptor, PAR-1 etc. Platelet adhesion contributes to thrombus formation. Activation of platelet
surface G-protein coupled receptors (e.g. the Adenosine diphosphate activated P2Y receptor) activate intracellular
platelet-signalling pathways, that up-regulates the dimeric platelet glycoprotein IIb/IIIa receptor complex binding
to the platelet surface. This causes the platelets to form pseudopodia on their surface, which can help platelet
clumping or binding to vWF or fibrinogen. The GPIIb/IIIa is the platelet receptor for fibrinogen or vWF and can
hence bind to fibrinogen and hence other platelet GPIIb/IIIa complexes causing platelet adhesion, as shown below:
Protease-activated receptor-1 (PAR-1) does not have a circulating ligand; however, thrombin can cleave part of its
end-terminus, causing PAR-1 activation.
Note that platelets produce Thromboxane A2 via break-down of arachidonic acid (AA) to prostaglandins via
cyclooxygenase. This formed Thromboxane A2 can activate the Thromboxane A2 receptors usually found on
platelets. Note that intra-platelet AA is modulated by levels of cyclic AMP; where high levels of cAMP decreases
AA levels. cAMP levels are regulated by conversion of AMP to cAMP via phosphodiesterases.
The following diagram indicates where the major anti-platelet drugs act on these biochemical platelet pathways:
50
Aspirin is an oral anticoagulant drug, which inhibits the formation of Thromboxane A2 by inhibiting
cyclooxygenase (but not prostacyclin), low doses of 300mg/day prevents thrombus formation and
embolisation. Aspirin is rapidly absorbed from the GIT with a peak concentration achieved after 30-40
minutes. It takes about one week for platelet function to come back after ceasing aspirin.
Contraindications for aspirin use include NSAID hypersensitivity/allergies, peptic ulcer disease, severe
hepatic/renal disease. Adverse effects of aspirin are obviously (like any anticoagulant) haemorrhage and
also upper GI toxicity/gastritis/ulceration.
Dipyridamole: mainly inhibits platelet cAMP formation and hence decreases the formation of Thromboxane A2,
furthermore, it can also inhibit platelet adenosine binding. Dipyridamole is mainly used in the
clinical use in combination with aspirin in patients with transient ischaemic attacks (TIA) and
also patients with thrombotic strokes. Dipyridamole can be administered orally or IV. It is
contraindicated in patients with hypertension, angina, asthma and syncope. Adverse effects of
dipyridamole include headache, dizziness, hypotension (hence can cause syncope).
Clopidogrel: inhibits the action of the ADP activated P2Y receptor, hence preventing GPIIb/IIIa upregulation and
hence prevents platelet activation and adhesion. Clopidogrel is used in combination with aspirin in
patients with unstable coronary syndromes (e.g. unstable angina pectoris) to prevent platelet
aggregation & coronary thrombus formation. It is actually a pro-drug and hence is given orally to
be converted to active form. Contraindications of Clopidogrel include bleeding and adverse effects
include rash and diarrhoea.
Abciximab: This is a synthetic antibody that is used to bind to the GPIIb/IIIa receptor complex, thus blocking
fibrinogen or vWF binding and hence preventing platelet adhesion & aggregation. A similar drug is
Eptifibatide, which is derived from snake venom and also inhibits this receptor. Abciximab is
clinically used in coronary artery angioplasty/stenting to prevent coronary thrombosis. It is
administered as an IV bolus followed by continual infusion up to 72 hours. Platelet function
recovers after 2 days of infusion cessation. Contraindications of Abciximab include active bleeding,
concurrent warfarin use and previous thrombocytopenia with use of GPIIb/IIIa antagonists.
Adverse effects include thrombocytopenia, bleeding, nausea, fever, headache, rash.
Anticoagulant drugs:
Refer to the coagulation cascade described previously. There are many different anticoagulant drugs which inhibit
clotting factors in both the intrinsic and extrinsic coagulation pathways. Major drugs in this category include
Warfarin, Heparin, Hirudin, Rivaroxaban and Dabigatran etexilate.
Warfarin has many effects on the coagulation cascade, but mainly inhibits the extrinsic pathway (hence affects
PT and thus INR monitoring is required). The following displays coagulation cascade factors that are inhibited by
warfarin:
Warfarin can be taken orally and is a competitive inhibitor of vitamin K, it lowers levels of prothrombin and other
clotting factors, reduces clotting by 20% in 24 hours. Note that warfarin was discovered after the use of Coumarin
as a rat poison (very similar to warfarin) and subsequently side chains were added to make it safer for humans and
51
hence Coumadin (also known as warfarin) was made. Vitamin K is needed by the liver for the production of the
active forms of: prothrombin, Factor VII, IX and X. Since warfarin inhibits the enzymes synthesised from vitamin
K; it is thus a competitive inhibitor of vitamin K and thus inhibits formation of prothrombin, Factor VII, IX and X
as described earlier. The following depicts the vitamin K cycle, importantly warfarin inhibits formation of vitamin
K hydroquinone; as well as inhibiting the Quinone reductase and Vitamin K epoxide reductase enzymes. The
vitamin K cycle is needed to form circulating clotting factors from precursors:
There are MANY drugs which can interact with warfarin and affect warfarin activity; thus affecting patient INR.
Important agents which can increase warfarin INR response include: SSRIs, MAOIs, NSAIDs, analgesics,
penicillins, Quinolones, Tetracyclines, Sulfonamides and beta-blockers. Drugs which can decrease warfarin INR
response include: foods high in vitamin K (i.e. green leafy vegetables), antacids, antihistamines, oral
contraceptives, immunosuppressive drugs.
Heparin mainly inhibits the intrinsic coagulation pathway, inhibiting Factor IXa, Xa and thrombin and thus it has
its major effects in increasing APTT. Large molecular-weight Heparin inhibits thrombin binding via long
chains needs to bind to BOTH thrombin and Antithrombin III, which once bound to antithrombin III can then
inhibit thrombin. Large molecular-heparin can also after binding to antithrombin III bind to Factor Xa, thus
inhibiting coagulation via that pathway. However, the risk associated with Large molecular-weight heparin is that
by inhibiting thrombin and Factor Xa, it can cause a tendency to bleed and the syndrome (Heparin-induced
thrombocytopenia) HITS:
Low molecular-weight heparins are relatively safer in that they do not cause HITS as often, since the low
molecular weight heparin binds only to antithrombin III, but as it does not have a long chain, it cannot bind to &
inhibit thrombin. However, its action of factor Xa is unaffected, as shown below. The incidence of HITS is much
less with low molecular-weight heparin as there is less thrombin activity:
Heparin-induced thrombocytopenia initially causes thrombosis that is then followed by bleeding and
thrombocytopenia. HITS usually manifests as a dramatic drop in platelets 1-20 days after initiation of therapy and
is believed to be an autoimmune destruction mediated through IgG. An immune thrombocytopenia also occurs
with GPIIb/IIIa antagonists such as Abciximab also causing thrombocytopenia. Heparin must be given IV, it is a
naturally occurring chemical; produced by Basophils and Mast cells, inhibiting thrombin formation and reduces
52
platelet function. Heparin injection can increase blood clotting time almost 5 times, hence has a fast & immediate
effect, slowing the process of embolisation. Heparin can also be used as an in-vitro anticoagulant, preventing
blood coagulation outside the body as well, also it is useful in surgery, i.e. cannulas and heart lung machines
storing blood.
The ideal anticoagulant should be a medication that can be administered orally (unlike heparin), one tablet once
daily (unlike warfarin). It should be highly effective in reducing thromboembolic events, with predictable dose
response and kinetics and a low incidence of bleeding events. It should also not need routine monitoring of
coagulation (unlike warfarin) or platelet count required. It must also have a wide therapeutic window, with no
dose adjustment required and little interaction with other drugs (again a problem with warfarin); it should also
have low, non-specific plasma protein binding (problem with heparin only binding to antithrombin III) and
inhibition of both free and clot-bound activated coagulation factors. It can be seen how difficult it is to produce
such an ideal drug.
Direct thrombin inhibitors include (large molecular-weight heparins are indirect thrombin inhibitors); include
Dabigatran etexilate and Melagatran which inhibit thrombin at its catalytic site; and also Hirudin which binds
to the thrombin substrate recognition site. Hirudin is a peptide molecule derived from medicinal leaches. Hirudin
is not available orally and it is used as the replacement anticoagulant in patients with HITS. Dabigatran is used
mainly in patients with major orthopaedic surgery of the lower limb, for example, total hip or knee replacement
surgery. Unlike Hirudin, Dabigatran is given orally, and contraindicated in patients with active bleeding, renal
impairment (due to renal clearance), and has adverse effects including haemorrhage, anaemia and abnormal liver
function tests. Melagatran and Ximelagatran are both derived from Naja Naja cobra venom, but have both been
withdrawn due to hepatotoxicity.
Direct Factor Xa inhibitors include Rivaroxaban and Apixaban. Major clinical use of Rivaroxaban include
major orthopaedic surgery of the knee or lower limbs, e.g. total hip replacement surgery or knee replacement
surgery. It is administered orally, and contraindicated in patients with active bleeding and other drugs which are
inhibitors of CYP3A4 inducers. Rivaroxaban can cause GI upsets, haemorrhage, anaemia, cramping, syncope and
jaundice.
The following compares warfarin with new oral anticoagulants:
There are also some new experimental drugs that are being tested that are thrombin-like enzymes. These are
basically competitive antagonists of thrombin, which hence causes a decrease in formation of fibrin strands.
Thrombolytic drugs:
Refer to the fibrinolytic pathway described previously, where fibrin strands are broken down by plasmin. Tissue
Plasminogen activator (tPA): Unlike warfarin & heparin, tPA is a thrombolytic, when delivered directly to an
area of thrombosis, it activates plasminogen to plasmin, dissolving clots. Heparin & warfarin prevent clot
formation. tPA is naturally occurring, but is produced synthetically by genetic engineering, directly dissolving a
thrombus hence can be rapidly used to treat acute Ischaemic Heart Disease. With ischaemic stroke, tPA must be
53
prescribed within the first three hours of stroke, since it rapidly causes thrombolysis and hence even in thrombotic
stroke if end-organ vessels have become ischaemic and necrotic, tPA could rapidly cause bleeding into the stroke
penumbra zone causing neuronal excito-toxicity. Furthermore, it is very important to establish that the cause of
the patient‟s stroke was not due to a haemorrhagic stroke; thus an early head CT within 3 hours is required to
exclude haemorrhage. Hence even though this is a very effective drug in preventing damage from thrombotic
stroke, it must be administered carefully to prevent further neurological damage. It is hence is not given as
commonly as it should with thrombotic stroke due to the short timeframe that it should be administered; so only
1-5% of patients with ischaemic stroke receive tPA due to delayed hospital presentation. There are many
contraindications for tPA in this setting, including subarachnoid haemorrhage or intracerebral haemorrhage, raised
PT, hypertension, seizures (as tPA also acts on excitable NMDA receptors in the brain), haematuria,
thrombocytopenia, GI bleeding etc.
Streptokinase: Has the same action as tPA, removing clots once they have formed, it is produced by
Streptococcal bacteria. Similarly urokinase can also be used which is also a plasminogen activator.
Desmotoplase is a new drug, which can also be used in ischaemic stroke and unlike tPA has a larger window of
opportunity, allowing up to six hours after stroke onset. This is because it has similar mode of action as tPA,
however, it does not cause NMDA excito-toxicity. It is derived from vampire-bat saliva, but still is under trials.
In-vitro clotting agents include tubes coated with silicon, which also prevents Factor XII activation and the
intrinsic clotting pathway. Ca2+
binding substances include chelating substances, which prevent Ca2+
activating
reactions in the clotting pathways, these include oxalate, citrate and EDTA. These chemicals bind Ca2+
to test-
tubes preventing blood coagulation.
54
Physiology of oedema and cardiac failure
Oedema is basically caused by water & salt loss from capillaries. Capillaries are exchange vessels, containing
diameters of between 5-10μm and re important in controlling nutrient and waste exchange. Capillaries contain a
single endothelial layer on a basement membrane. The number of pores varies between tissues, with the liver and
kidneys containing many fenestrations in their capillaries, whist the brain contains low numbers.
Fluid enters and leaves the capillaries from the bloodstream via filtration. This is determined by the rate and
direction of water passage through pores/fenestrations. Filtration is in turn, determined by various forces acting on
fluid within the capillary, these are known as Starling forces.
Starling forces and equation in trans-capillary exchange: „outward‟ forces driving filtration include: hydrostatic
pressure of blood in capillary (Pc), interstitial fluid colloid osmotic pressure (πif). „Inward‟ forces driving
absorption of fluid back into the capillary bloodstream include: hydrostatic pressure of interstitial fluid (Pif) and
colloid plasma osmotic pressure (πc). The net movement of fluid is given by the following equation:
Using this equation, it can be found that at the arteriole end of a capillary there is net filtration of 13mmHg; this is
then collected by lymphatic vessels; whilst at the venule end there is a net absorption of fluid of -8mmHg. The
fluid flux/filtration equation takes into account the capillary filtration coefficient, hydrostatic forces and colloid
osmotic forces.
Capillaries are exchange vessels, and hydrostatic forces pull water out, lymphatics drain this excess interstitial
fluid and proteins. Plasma colloid osmotic forces from plasma proteins pushes water back into the capillaries,
preventing leakage of fluid. As plasma proteins are not exchanged out of capillaries, that is why they tend to keep
water with them and prevent it leaking. Only some low molecular weight proteins may leak out, however, these
would be removed by the lymphatics. Thus the amount of water moving in and out of capillaries is balanced,
otherwise oedema occurs.
The hydrostatic pressure in the capillary is a key factor for this equation, which is why when capillary fluid
overload occurs in heart failure that causes increased hydrostatic pressure, which leads to oedema.
Capillary hydrostatic pressure may be increased by:
o Increased arteriole pressure, as in hypertension.
o Increased venous pressure, such as in heart failure.
o Increased blood volume, such as in heart failure.
Congestive heart failure:
Heart failure definition: “The situation when the heart is incapable of maintaining a cardiac output adequate
to accommodate the metabolic requirements and the venous return.” Basically, the heart fails to maintain a
cardiac output of 5L/minute.
Heart failure is a complex clinical syndrome with typical symptoms that can occur at rest or with exertion,
including fatigue, dyspnoea, orthopnoea and paroxysmal nocturnal dyspnoea and fluid retention. The main
physiological consequences of LV failure is low cardiac output and elevated pulmonary venous pressure
(dyspnoea), whereas RV failure there is low pulmonary artery output and thus elevated systemic venous pressures
(↑JVP, hepatojugular reflux, hepatic congestion, ascites, peripheral pitting oedema). Radiographic appearances
are related to the dominant sided pathology which includes pulmonary oedema (left-sided) and primary
pathologies in right-sided heart failure. Heart failure is characterised by objective evidence of underlying
structural abnormality or cardiac dysfunction that impairs the ability of the ventricle to fill with or eject blood
(particularly during physical activity). A diagnosis of heart failure can be strengthened by improvement in
symptoms in response to treatment.
Heart failure with preserved systolic function (diastolic heart failure) (i.e. impaired relaxation of the ventricle with
inability to fill with blood, leading to cardiac dysfunction is associated with LVEF > 40%
~300 000 Australians have heart failure, causing ~90 000 annual hospitalisations, with ~75% of admissions being
in those aged over 70. The average length of hospital stay from heart failure is ~10 days and there is a readmission
rate of 30% within 28 days. The 1 year mortality is very high at ~30%. This is the only cardiovascular disorder
that is increasing in prevalence.
55
The aetiology of cardiac failure (impaired ability to eject blood, LVEF≤40%) includes:
o Coronary artery disease with prior MI (ischaemic heart disease) in 2/3 cases, patients may have had
prior MI; this is the most common cause. IHD is present in over 50% of new cases.
o Valvular heart disease/Endocarditis- aortic/mitral incompetence/stenosis.
o Hypertension- present in about 2/3 cases.
o Cardiomyopathy- restrictive (sarcoidosis, amyloidosis), dilated (cytotoxic agents- (doxorubicin,
cyclophosphamide, paclitaxel), viral myocarditis- HIV, CMV, Coxsackie virus, pregnancy-related),
hypertrophic (HOCM, autosomal dominant genetic causes, familial especially in those with younger
age)
o Alcoholic dilated cardiomyopathy- also associated with wet beriberi from thiamine (B1) deficiency.
o Chronic cardiac arrhythmias e.g. AF
o Thyroid disease (hyper-/hypothyroidism)
o Myocarditis
o Living at high altitudes increases intrathoracic pressure & can cause heart failure.
o Idiopathic causes.
Important symptoms and signs of decreased ventricular pump function include:
Symptoms Signs of congestion Dyspnoea Fatigue (these are signs of left ventricular
failure).
Oedema (RHF) Weight gain (RHF) Ascites (RHF) Increased JVP (RHF) Pulmonary congestion (LHF)
The New York Heart Association (NYHA) classification of dyspnoea is useful to know for classifying
differing degrees of dyspnoea:
Relevant physical examination in a patient with congestive cardiac failure includes:
o Appearance: distressed patient, exhaustion, tachypnoea, cyanosis, Cheyne-Stokes breathing (end-
stage heart failure breathing, near time of death).
o Pulse: weak, tachycardia, atrial fibrillation, pulsus alternans.
o BP: low, possibly hypotensive
o Face: cyanosis, look for myxoedema, malar flush of mitral stenosis.
o JVP: elevated, large v waves suggest tricuspid regurgitation.
o Carotids: low volume in character.
o Praecordium: apex beat displaced and dyskinetic, right ventricular parasternal lift.
o Auscultation: Third heart sound (sign of heart failure in those aged over >30 years), gallop rhythm,
functional mitral regurgitation due to mitral annular dilatation.
o Lung fields: Pleural effusions, bilateral basal crackles, check for sacral oedema.
o Legs: Peripheral pitting oedema, establish the level.
o Abdomen: Hepatomegaly, ascites.
The acute response to cardiac failure is:
o Strong sympathetic stimulation (baroreceptors/chemoreceptors) to increase heart rate and contractile
force, in order to improve systemic perfusion.
56
o Thus the heart rate and contractile force increase, and peripheral vasoconstriction occurs.
o Overall, the capillary pressure falls (peripheral pressure falls overall).
The delayed response to heart failure (>1 day) is:
o An attempt to conserve volume to maintain pressure.
o This leads to a fluid overload and hence peripheral oedema.
The following diagram displays the forces driving peripheral oedema in ongoing heart failure:
When left-ventricular failure occurs, the heart does not pump sufficient blood as it should and this could be due to
several reasons as mentioned above, such as cardiomyopathy, which results in a drop in cardiac output and hence
a drop in BP. This would lead to a drop in renal blood flow. This activates the renin-angiotensin-aldosterone
system, which hence leads to renal reabsorption of salt and water, subsequently, this results in an increase in
blood volume.
As a result of this increase in blood volume, the venous system becomes congested, and engorged with a greater
blood volume.
Also as the left ventricle is not sufficiently pumping blood away, this leads to pressure build-up in the pulmonary
veins and pulmonary capillary beds, as there is now a greater end-diastolic volume of blood in the left-heart. This
subsequently leads to increased pulmonary venous pressure.
Increased pulmonary venous pressure will lead to pulmonary oedema, which can be heard as crackles on
auscultation of the lung bases. Pulmonary oedema makes gas-exchange much more difficult and hence this will
lead to the symptom of dyspnoea. The gases would diffuse through liquid before entering the alveoli, hence
compromising oxygenation and carbon dioxide removal.
Preload or end-diastolic volume (EDV) is determined by the extent of ventricular filling (end-diastolic volume).
The Frank-Starling mechanism or relationship relates the increased force of myocardial contraction with
increased stretch on the fibres, which occurs with increased pre-load; “energy of contraction of the ventricle is a
function of the initial length of fibres in its walls”. In other words, the ventricle automatically adjusts to increased
pre-load with increased force of contraction, so that blood in = blood out. Note that however, there is a limit to
how much the cardiac muscle fibres can be stretched, after which the contractile force decreases. This is shown
below (see curve on right for instance) and is seen as an upside down parabola curve. For example, end-diastolic
volume is normally ~120mL, however, it could be increased to 300ml, and the ventricular output, or stroke
volume also increases proportionally. However, after 300ml end-diastolic volume, the stroke volume decreases, as
the cardiac muscle fibres are over-stretched, from the Frank-Starling mechanism.
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In an attempt to maintain cardiac output and myocyte contractility, this leads to hypertrophy of the existing
myocyte mass, leading to increased oxygen requirements and increased energy usage, acute ischaemia is more
likely (large mass for coronary arterial perfusion) and ventricular enlargement can lead to mitral regurgitation,
which further facilitates heart failure
End-diastolic volume is determined primarily by venous return. Factors influencing venous return include:
o Pressure at the end of capillaries
o (Right) atrial pressure
o Blood volume, since ~60-70% of blood volume is stored in the venous system
o Venous tone
o Muscle, respiratory and abdominal pumps to help venous return
The following pressure-volume curve displays the effects of increased pre-load on left ventricular pressure:
The following diagram displays the distribution of blood volumes in the circulation and the relative mean
pressures at different sites in a normal circulation with normal cardiac function:
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However, when congestive cardiac failure occurs, with right-heart failure there is an increase in RAP, which
forces more blood into the ventricle but also increases blood pooling in the veins, this increases mean capillary
pressure, Pc. The following is again the same diagram, but with cardiac output 50% of normal:
The following chart displays the effects of acute cardiac failure and how increasing right atrial pressure is related
to cardiac output, with increasingly severe degrees of heart-failure and different compensatory mechanisms:
One of the compensatory responses to oedema includes increased lymphatic drainage, although lymphatics have
limited ability to cope with excess fluid. Late-stage heart-failure may cause death by acute pulmonary oedema.
Some important processes in heart-failure include: there may be a temporary cardiac overload, through exercise,
stress/anxiety, or severe cold, this puts increased stress on the heart and blood pools in capillaries (pulmonary),
pulmonary oedema occurs as fluid accumulates in the lung tissues and alveoli. There is hence decreased ability for
gas-exchange and hypoxemia develops. Decreased oxygen absorption leads to peripheral vasodilation, lowered
BP and thus more blood pools in the capillaries and hence oedema becomes worse and progressive.
A summary of heart failure from Phase 1 medicine notes:
In heart failure, the left-ventricle is not clearing blood that is collecting in the lungs. Hence the veins develop
venous congestion in the lungs, as a result of back-pressure from the heart.
In the microcirculation and veins, the increased blood and congestion in veins leads to failure of venous valves
and this causes an increased blood pressure back to the capillaries. As capillaries are not resistance vessels, this
venous congestion results in a dramatic increase in capillary pressure. As a result of this venous congestion,
hydrostatic driving forces are increased. However, as plasma protein levels remain the same, osmotic driving
forces are approximately the same. This increased hydrostatic pressure leads to a greater amount of fluid diffusing
out of capillaries and into the interstitium. Some fluid enters the lymphatics, which removes it. The excess fluid
remains in the tissues, causing it to swell and become oedematous.
Oedema may also result from increased vascular permeability, i.e. if the endothelium is damaged or as a result of
exudation in inflammation, for example. This leads to leakage of plasma proteins. As there will be fewer plasma
proteins in the blood, this would mean that they would not be able to exert their capillary plasma colloid osmotic
pressure and thus there would be little driving force opposing outward hydrostatic force. Increased capillary
permeability may be the result of, for example:
o A bee sting, or insect bites, which causes increased histamine release, which increases vascular
permeability and exudation of inflammatory proteins/molecules and inflammation occurs.
o Severe burns, a state with increased vascular permeability, which leads to severe exudation into the
skin and low protein and dehydration/hypovolemia, as a complication of severe burns.
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Another cause may be a low protein oedema, i.e. protein deficiency from chronic liver failure or Kwashiorkor or
protein losing enteropathy, where there is hence lowered osmotic pressure and the patient is more prone to
oedema.
Lymphatic obstructions- can severely cause lymphoedema and tissue oedema (non-pitting gross oedema) as
excess fluid is not drained out of tissues and remains in tissues causing swelling. Lymphatic obstruction can be
caused by surgical damage to lymphatics, parasitic infections (e.g. lymphatic filariasis from Wuchereria bancrofti
infection) or congenital lymphatic disorders, such as Milroy‟s syndrome.
Pathology of Ischaemic Heart Disease & Congestive Cardiac Failure
Case: Paroxysmal nocturnal dyspnoea and heart failure
A 75 year old man with a history of long-standing ischemic heart disease with a MI severeal years ago, was brought
to ED by ambulance at 3 am because of acute shortness of breath, which had woken him from his sleep.
A chest x-ray was taken in the ED and is shown below.
New S-T segment depression was seen in the anterior leads of his ECG, which reverted following sublingual
glyceryl-trinitrate therapy. He was also treated with oxygen by mask and diuretics, and recovered rapidly. Serial
ECGs and measurements of serum Troponin levels excluded acute MI.
The acute shortness of breath which suddenly woke him from sleep, was most likely paroxysmal nocturnal
dyspnoea from pulmonary oedema, due to left-sided ventricular failure, which causes upper lobe blood
diversion, which can be seen on the chest x-ray below. These vessels appear more dilated than vessels at the
hilum of the lungs.
This is a case of unstable angina, stable angina normally occurs with exertion and is relieved by rest. On the
other hand, unstable angina occurs in patients that are at rest. In this case, unstable angina indicates possible
plaque rupture that has not completely occluded the coronary arteries, although there is a very high risk of
myocardial infarction and this is an important sign that the patient may develop MI.
The chest x-ray appearances show upper lobe blood
diversion, interstitial alveolar oedema with a „spider-like
appearance’ of the lung fields- Kerley B lines indicate
interstitial oedema, cardiomegaly (on a PA chest x-ray
view, there is >50% maximal cardiac diameter relative to
the transthoracic diameter). With severe pulmonary oedema,
alveolar oedema may also be seen –patchy shadows
around hila, may be unilateral, that is high in the upper
lobes, with a “bat’s wings” appearance and also keep an
eye out for pleural effusions which usually occur on the
right side in heart failure, remember the features as A, B, C, D, E. Note that it is however, difficult to comment on
cardiac size on an AP film. In right failure, signs of pulmonary hypertension and respiratory causes (COPD, other
lung pathologies such as interstitial lung disease) may be present.
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Apart from ischaemic heart disease, which is the most common cause of left-ventricular failure, other causes
include the following list. These can either cause concentric hypertrophy (this usually occurs with increased
pressure load, without chamber dilation) or eccentric hypertrophy (usually occurs with volume overload with
chamber dilation) to compensate for loss of heart muscle.
o With a pressure overload- hypertension, or aortic stenosis, mitral stenosis.
o With a volume overload- mitral and aortic regurgitation, patent ductus arteriosus.
o Intrinsic disease of heart muscle:
Dilated cardiomyopathy- with impaired systole for example, caused by viral myocarditis such
as from HIV, CMV, enteroviruses such as Coxsackie virus, influenza or genetic causes,
pregnancy (dilated cardiomyopathy), alcohol, cytotoxic agents.
Restrictive cardiomyopathy- from toxic conditions such as sarcoidosis, amyloidosis, or
haemochromatosis.
Hypertrophic cardiomyopathy: HOCM, autosomal dominant genetic diseases of heart muscle.
Important causes of right ventricular failure include cases of volume overload (atrial septal defects, tricuspid
regurgitation), pressure overload (pulmonary stenosis, pulmonary hypertension), myocardial disease
(secondary to LV failure, or RV infarction (uncommon)).
The important short and long-term complications of left-sided cardiac failure includes those of eccentric or
concentric hypertrophy; or in the long-term it can also cause right-ventricular failure, due to interventricular
interdependence. Since both ventricles lie in a common pericardial sac, ventricular interdependence means that
the right-ventricle will fail from long-standing left-ventricular failure.
Case: Complications of right ventricular failure
A 73 year old man with a long-history of hypertension had suffered from repeated episodes of shortness of breath
over many years. These episodes had increased in severity following a myocardial infarction three years previously.
Prior to his death he had also suffered from significant swelling of his ankles. The following specimens were
obtained at autopsy:
The history indicates that he had congestive cardiac failure due to progressively worsening shortness of breath,
and peripheral oedema on a background history of myocardial infarction and a long-standing hypertension. He
may also have had a raised JVP, hepatosplenomegaly, as well as ascites, sacral & peripheral oedema.
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The macroscopic specimens consist of slices of liver and heart. The liver weighed 1350g, and the heart, 837g. The
heart shows areas of greyish-white fibrous tissue on the interventricular septum, and the posterolateral wall of the
left ventricle. The anterior part of the left ventricle shows almost complete replacement of the myocardium by
greyish-white fibrous tissue, with the formation of an aneurysm of the wall. The heart shows eccentric
hypertrophy on the posterior left ventricle, thinned anteriorly due to aneurysmal dilatation, with white-silvery
areas of scar tissue.
The liver shows the typical appearances of chronic passive venous congestion ("nutmeg liver"), the small red foci
representing the central areas of congestion of the lobule, surrounded by a yellow zone representing the peripheral
zone of each lobule. This is the appearance of cardiac hepatomegaly or nutmeg liver, and on close inspection the
liver has a mottled, tanned, yellowish appearance and is plumpish in some areas.
On microscopic examination of the heart, there are collagenous bands of connective tissue, which may represent
fibrosis/scar tissue which is evidence of old infarction and organisation, with patchy areas of fibrosis- focal bands
of connective tissue. The surviving myocytes have undergone hypertrophy- they have larger bore-like nuclei, this
is a subtle appearance, not seen on the magnification below (need higher magnification of individual cells), this is
compensatory hypertrophy of remaining cardiac myocytes.
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On microscopic examination of the liver, the portal tracts appear abnormal, there is mild centrilobular hepatic
steatosis from intracellular hepatocyte triglyceride accumulation that is secondary to vascular congestion from
heart failure. Steatosis is the response to chronic hepatocyte hypoxia, due to a chronic lack of venous return from
venous congestion; there is poor hepatic oxygenation and thus impaired β-oxidation of triglycerides which hence
accumulate in hepatocytes. Thus chronic heart-failure or passive venous congestion of the liver leads to mild to
moderate hepatic steatosis.
A summary of the main clinical features of left-ventricular cardiac failure are summarised below:
Pulmonary oedema: Left heart failure
Symptoms - Exertional dyspnoea
- Fatigue
- Othopnoea
- Paroxysmal nocturnal dyspnoea
- Wheeze („cardiac asthma‟)
- Cough (pink froth)
- Haemoptysis (pink coloured)
Signs - Tachypnoea (due to raised pulmonary
pressures
- Tachycardia (increased sympathetic tone)
- End-inspiratory basal crackles
- LV S3 heart sound
- Functional mitral regurgitation (secondary
to valve ring dilatation)
- Pulsus alternans (alternating large and
small pulse pressures – rare)
- Cardiomegaly
- Displaced apex beat with LV dilation
(dyskinetic in anterior MI or dilated
cardiomyopathy)
- Palpable gallop rhythm
- Central cyanosis (pulmonary oedema)
- Hypotension (low cardiac output)
- Cardiac cachexia
- Pleural effusion
- Peak expiratory flow rate may be low, but
if it is <150L/min, suspect COPD or
asthma
-
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Important signs and symptoms of right-ventricular failure are summarised below:
Pulmonary oedema: Right heart failure Symptoms - Peripheral pitting oedema (ankle/sacral/scrotal/ascites)
- Dyspnoea
- Abdominal discomfort
- Nausea
- Fatigue
- Wasting and often weight gain
Signs - Raised JVP
- Due to raised venous pressure (right heart preload)
- Large v waves (functional tricuspid regurgitation secondary to valve ring dilation.
- Kussmaul‟s sign
- JVP rises with inspiration (normally falls)
- Due to poor RV compliance (e.g. RV MI)
- RV heave, S3, pansystolic murmur of functional TR (murmur absence does not exclude TR)
- Tender hepatomegaly
- Due to raised venous pressure transmitted by hepatic veins
- Pulsatile if TR is present
- Oedema
- Due to sodium and water retention plus raised venous pressure
- Pitting ankle and sacral oedema or pleural effusions (small)
- Low volume arterial pulse (due to low cardiac output), reduced peripheral pulses
Important investigations to perform in clinically suspected cardiac failure includes:
o Full blood count: (anaemia is an adverse prognostic marker)
o UECs: (check renal function for cardiorenal syndrome, responses to and maintenance of therapy, especially
diuretics and ACE inhibitors)
o LFTs: Check for cardiac hepatomegaly/cardiac cirrhosis
o Thyroid function tests (TFTs): check thyroid function as an underlying treatable cause
o Atrial or brain natriuretic peptide (ANP/BNP): quantification may be of prognostic value.
o ECG: check for conduction abnormalities, arrhythmias, MI
o CXR: exclude pulmonary oedema, look for other signs of cardiac failure
o Trans thoracic or trans-oesophageal Echocardiography: must perform to characterise cardiac failure,
calculate LV ejection fractions (%) as a marker for degree of heart failure and for prognosis. May also be able
to identify underlying cause or anatomical anomalies.
o Coronary angiography: consider if the patient has IHD.
o Nuclear medicine scan: May also be useful to perform a Sestamibi nuclear medicine scan with/without
dipyradimole stress or if not contraindicated other physical stress, to evaluate degree of ischaemia.
Spirometry: Exclude concurrent respiratory causes for airflow limitation.
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Pharmacology for treatment of hypertension
Hypertension is defined clinically as a blood pressure greater than 140 mmHg systolic or greater than 90 mmHg
diastolic pressure. There are in fact only few recognisable, treatable causes for hypertension, and most cases have a
multifactorial aetiology. 90% of hypertension is essential (i.e. of unknown aetiology). The remainder of causes are
secondary causes, e.g. endocrine (such as hyperaldosteronism- Conn syndrome) or renal causes (e.g. renal artery
stenosis or a renin producing tumour, for example). The diagnosis of hypertension is very important, as
hypertension can lead to microcirculatory damage (i.e. hyaline arteriolosclerosis) and hence this can lead to chronic
vascular and end-organ damage.
The following are WHO-ISH definitions and classifications of BP levels for adults aged 18 years and older:
Apparently the lower the BP is reduced, the better the prognosis and hence BP is now aggressively attempted to be
reduced to 120/80 mmHg by most primary health care physicians.
Indications for ambulatory blood pressure monitoring include:
1) Possible white coat hypertension- i.e. hypertension in clinic only.
2) Patient‟s with variable blood pressure.
3) Evaluation of the efficacy of treatment over 24 hours.
4) Evaluation of drug resistant hypertension.
5) Evaluation of patients with nocturnal hypertension.
Before proceeding with exploration of pharmacology, it is essential to explore non-pharmacological treatment of
hypertension, which may greatly help reduce BP to normotensive levels, however, mainly involve life-style changes
which are hard to sustain:
1) Weight loss may lead to a 5-10mmHg drop in BP/10kg weight loss, although this may be difficult to
sustain.
2) Limit alcohol, reduces BP by 2-4mmHg.
3) Diet- DASH diet, high in complex carbohydrates (e.g. fruits & vegetables) and potassium, can reduce
BP by 6mmHg.
4) Physical activity of at least 30 minutes/day, can reduce BP by 4-9 mmHg.
5) Reduce sodium to <100 milliequivalents/day reduces BP by 2-8mmHg.
However, drugs are consistently better than lifestyle changes in head to head comparisons.
Remember that blood pressure is actually the product of the person‟s cardiac output (cardiac output itself is the
product of heart rate & stroke volume) and total peripheral resistance.
Blood pressure regulation involves different mechanisms, including short term controllers (such as the
baroreceptors, autonomic nervous system, catecholamines etc.) and long-term controllers (i.e. the kidneys- renin-
angiotensin-aldosterone system). This also involves various adrenergic receptors as shown below:
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The most important classes of antihypertensive agents include the following:
1) Diuretics (osmotic diuretics, carbonic anhydrase inhibitors, loop-diuretics, thiazides, potassium-
sparing diuretics(subdivided into aldosterone antagonists and sodium-channel blockers)
2) β-adrenergic antagonists
3) α-adrenoreceptor antagonists, calcium channel blockers
4) Drugs acting on the renin-angiotensin system
5) Centrally acting drugs, methyl-dopa, clonidine
6) Renin inhibitors
7) Osmotic diuretics, mannitol
8) Other anti-hypertensives- e.g. hydralazine, nitrates.
Diuretics:
(Refer to the chapter 31 in Guyton & Hall‟s Physiology for a more detailed discussion on diuretics) These drugs
increase the rate of urine flow. Most diuretics actually increase Na+ excretion.
There are several different groups of diuretics with different mechanisms and sites of action.
A diuretic is a substance that increases the rate of urine volume output, as the name implies. Most diuretics also
increase urinary excretion of solutes, especially sodium and chloride. In fact, most diuretics that are used clinically
act by decreasing the rate of sodium reabsorption from the tubules, which causes natriuresis (increased sodium
output), which in turn causes diuresis (increased water output). That is, in most cases, increased water output occurs
secondary to inhibition of tubular sodium reabsorption, because sodium remaining in the tubules acts osmotically to
decrease water reabsorption. Because the renal tubular reabsorption of many solutes, such as potassium, chloride,
magnesium, and calcium, is also influenced secondarily by sodium reabsorption, many diuretics raise renal output
of these solutes as well.
The most common clinical use of diuretics is to reduce extracellular fluid volume, especially in diseases associated
with oedema and hypertension. A loss of sodium from the body mainly decreases extracellular fluid volume;
therefore, diuretics are most often administered in clinical conditions in which extracellular fluid volume is
expanded. Some diuretics can increase urine output more than 20-fold within a few minutes after they are
administered. However, the effect of most diuretics on renal output of salt and water subsides within a few days.
This is due to activation of other compensatory mechanisms initiated by decreased extracellular fluid volume. For
example, a decrease in extracellular fluid volume often reduces arterial pressure and glomerular filtration rate (GFR)
and increases renin secretion and angiotensin II formation; all these responses, together, eventually override the
chronic effects of the diuretic on urine output. Thus, in the steady state, urine output becomes equal to intake, but
only after reductions in arterial pressure and extracellular fluid volume have occurred, relieving the hypertension or
oedema that prompted the use of diuretics in the first place.
The many diuretics available for clinical use have different mechanisms of action and, therefore, inhibit tubular
reabsorption at different sites along the renal nephron. The general classes of diuretics and their mechanisms of
action are shown below:
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The diuretics used to treat hypertension include loop diuretics, thiazides and potassium sparing diuretics.
Loop diuretics: The mechanism of action of loop diuretics is that they inhibit Na
+ and Cl
- reabsorption in the thick ascending limb
of the loop of Henle, via the Na+/2Cl
-/K
+ cotransporter. The main examples include furosemide (Lasix),
ethacrynic acid and bumetanide.
Furosemide, ethacrynic acid, and bumetanide are powerful diuretics that decrease active reabsorption in the thick
ascending limb of the loop of Henle by blocking the 1-sodium, 2-chloride, 1-potassium co-transporter located in the
luminal membrane of the epithelial cells. These diuretics are among the most powerful of the clinically used
diuretics. Illustrated below are the electrolytes that are reabsorbed in the loop of Henle and also the mechanism of
action of the loop diuretics:
By blocking active sodium-chloride-potassium co-transport in the luminal membrane of the loop of Henle, the loop
diuretics raise urine output of sodium, chloride, potassium, and other electrolytes, as well as water, for two reasons:
(1) they greatly increase the quantities of solutes delivered to the distal parts of the nephrons, and these act as
osmotic agents to prevent water reabsorption as well; and (2) they disrupt the counter-current multiplier system by
decreasing absorption of ions from the loop of Henle into the medullary interstitium, thereby decreasing the
osmolarity of the medullary interstitial fluid. Because of this effect, loop diuretics impair the ability of the kidneys
to either concentrate or dilute the urine. Urinary dilution is impaired because the inhibition of sodium and chloride
reabsorption in the loop of Henle causes more of these ions to be excreted along with increased water excretion.
Urinary concentration is impaired because the renal medullary interstitial fluid concentration of these ions, and
therefore renal medullary osmolarity, is reduced. Consequently, reabsorption of fluid from the collecting ducts is
decreased, so that the maximal concentrating ability of the kidneys is also greatly reduced. In addition, decreased
renal medullary interstitial fluid osmolarity reduces absorption of water from the descending loop of Henle. Because
of these multiple effects, 20 to 30 per cent of the glomerular filtrate may be delivered into the urine, causing, under
acute conditions, urine output to be as great as 25 times normal for at least a few minutes.
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As a result important side effects to be aware of include hypokalemia and thus metabolic alkalosis (as hydrogen ions
tend to „follow‟ potassium). As with all other drugs, patients may have allergies to loop diuretics. Loop diuretics also
cause hearing loss and there are drug interactions.
Thiazide diuretics:
The Thiazide diuretics inhibit Na+ and Cl
- reabsorption in the early distal convoluted tubule via inhibition of the
Na+/Cl
- co-transporter at the basolateral membrane of these epithelial cells. An important example is chlorothiazide.
The Thiazide derivatives, such as chlorothiazide, act mainly on the early distal tubules to block the sodium chloride
co-transporter in the luminal membrane of the tubular cells. Under favourable conditions, these agents cause 5 to 10
per cent of the glomerular filtrate to pass into the urine. This is about the same amount of sodium normally
reabsorbed by the distal tubules. Thiazides are also useful in hypertension as they cause vasodilation.
The following is an image of the electrolytes that are reabsorbed in the early distal convoluted tubule and the
mechanism of action of Thiazide diuretics:
Important adverse effects of Thiazide diuretics include hypokalemia, hyponatremia (more so than the loop
diuretics), hyperlipidemia, hyperglycaemia (with ~1% risk of developing Diabetes Mellitus with Thiazide diuretic
use), uric acid retention and obviously allergic reactions may occur.
Potassium-sparing diuretics:
Note that there are two major subtypes, which are the aldosterone antagonists (such as spironolactone) and the
sodium-channel blockers (such as amiloride).
Spironolactone, Aldactone and eplerenone are aldosterone antagonists that compete with aldosterone for receptor
sites in the cortical collecting tubule epithelial cells and, therefore, can decrease the reabsorption of sodium and
secretion of potassium in this tubular segment. As a consequence, sodium remains in the tubules and acts as an
osmotic diuretic, causing increased excretion of water as well as sodium. Because these drugs also block the effect
of aldosterone to promote potassium secretion in the tubules, they decrease the excretion of potassium. Aldosterone
antagonists also cause movement of potassium from the cells to the extracellular fluid. In some instances, this
causes extracellular fluid potassium concentration to increase excessively. For this reason, spironolactone and other
aldosterone inhibitors are referred to as potassium-sparing diuretics. Many of the other diuretics cause loss of
potassium in the urine, in contrast to the aldosterone antagonists, which “spare” the loss of potassium.
Spironolactone could also be used effectively to treat Conn syndrome, as it is an aldosterone antagonist, perfect for
hyperaldosteronism. Aldosterone antagonists have been shown to improve survival in randomised controlled trials,
with up to 30% reduction in the risk of death and hospitalisation in patients with heart failure.
Amiloride and triamterene also inhibit sodium reabsorption and potassium secretion in the collecting tubules,
similar to the effects of spironolactone. However, at the cellular level, these drugs act directly to block the entry of
sodium into the sodium channels of the luminal membrane of the collecting tubule epithelial cells. Because of this
decreased sodium entry into the epithelial cells, there is also decreased sodium transport across the cells‟ basolateral
membranes and, therefore, decreased activity of the sodium-potassium adenosine triphosphatase pump. This
decreased activity reduces the transport of potassium into the cells and ultimately decreases the secretion of
potassium into the tubular fluid. For this reason, the sodium channel blockers are also potassium-sparing diuretics
and decrease the urinary excretion rate of potassium.
Amiloride blocks Na+ channels and hence spares K
+ in the late distal convoluted tubules or collecting tubules.
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The following image displays the mechanism of action of the potassium sparing diuretics- the aldosterone receptor
antagonists (spironolactone and eplerenone) and the sodium channel blockers (amiloride and triamterene). There is
also an image of the electrolytes that are reabsorbed/secreted at the level of the late distal convoluted tubules and
collecting tubules (note the intercalated cells reabsorb potassium and exchange this with hydrogen and the principal
cells reabsorb sodium and chloride but secrete potassium and reabsorb water under the influence of ADH):
β-adrenoreceptor antagonists:
β-blockers inhibit the sympathetic activity of noradrenaline/adrenaline on β-adrenoreceptors. They reduce cardiac
output by decreasing the heart rate and force of contraction. It also affects heart activity even during exercise.
Furthermore, they also act on β-adrenoreceptors in the kidneys, reducing renin release thus decreasing blood volume
and vascular tone. The juxtaglomerular cells of the kidney have β1-adrenoreceptors, which stimulates the release of
renin under sympathetic control.
β-blockers also have some effect on the central nervous system, possibly relevant to BP reduction. These drugs are
useful to circumvent sympathetic response (i.e. if a 1st line antihypertensive does not work in reducing BP in the
long-term).
However, there is variation, with β1 and β2-selective adrenoreceptor antagonism. There is also variation between
these drugs in their intrinsic sympathomimetic activity and their lipid solubility.
Non-selective β1 and β2 receptor antagonists include propranolol, pindolol and timolol. It is very important to
avoid these drugs and not to prescribe in asthmatics, as they cause β2-receptor antagonism which could lead to
bronchospasm in asthmatics. Furthermore, these non-selective β-blockers can also cause effects on the liver. β2-
adrenoreceptors are found in the lung, the liver and peripheral vessels.
β1-selective receptor antagonists include atenolol, bisoprolol and metoprolol, which are more useful for treating
hypertension (effects on cardiac output and renal renin release) compared with the non-selective β-blockers.
For treatment of hypertension, it is thus preferred to have β-blockers that are more β1-selective and have less β2-
receptor activity. Note that in the human heart the ratio of β-adrenoreceptors in cardiac muscle is (β1: β2 75:25).
The kidney predominantly contains β1 adrenoreceptors. However, the bronchi, peripheral vessels and some other
tissues predominantly have β2 adrenoreceptors. β2-receptors are similar to β1 and hence β2-selective drugs may have
slight β1-affinity. Thus even with a β1-selective antagonist, such as atenolol, there is a risk of
bronchoconstriction/spasm for asthmatics.
Important adverse effects from β-blockers to remember include those from β-adrenoreceptor blockade, such as cold
hands and feet, bronchospasm, increased triglycerides (effects on the liver), CNS effects: dreams, insomnia,
syncope and fatigue.
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α/β-adrenoreceptor antagonists:
Carvedilol and labetolol are examples of non-selective adrenoreceptor blockers, so it has effects on both α and β
adrenoreceptors, and it has no intrinsic sympathomimetic activity. Carvedilol is used for the treatment of mild to
moderate congestive cardiac failure. Labetolol is frequently used for pregnancy-induced hypertension and pre-
eclampsia and also for acute hypertensive crisis or pheochromocytoma.
The effects of blocking α1 receptors include vasodilatation, β1-antagonism as mentioned before blocks reflex
tachycardia (through reduced heart rate & force of contractility) and reduced renin release.
α-adrenoreceptor antagonists:
Important drugs include Prazosin and terazosin, which are α1-selective adrenoreceptor antagonists, which „blocks‟
post-synaptic α1-receptors, so noradrenaline cannot bind. The mechanism of action includes peripheral
vasodilatation (just like calcium channel blockers), both arterial and venodilation, due to blockade of postsynaptic
α1 receptors.
These are however, NOT 1st line antihypertensives. They are also used for benign prostatic hyperplasia.
They have side effects including postural hypotension, and this is a 1st-dose effect; it is not a good idea to prescribe
in the elderly geriatric population, due to risks of orthostatic hypotension and syncope.
These drugs can also cause weakness and drowsiness/dizziness/presyncope.
Calcium channel blockers:
Calcium has a pivotal role as an intracellular 2nd
messenger. Transient increases in calcium concentration can be
initiated by:
1) Increased release from intracellular storage sites
2) Increased Ca2+
permeability of the plasma membrane- opening of channels.
Note that many cells have voltage sensitive Ca2+
channels (VOCC). Calcium concentrations are also very important
in controlling smooth muscle tone and there is a 1000 times gradient from extracellular to intracellular Ca2+
concentration (being highest in the extracellular compartment). Note that in arterial smooth muscle a special type of
calcium channel the L-type exists (different from cardiac muscle T-type). All L-type Ca channel blockers relax
arterial smooth muscle by preventing Ca2+
entry into smooth muscle cells, thus causing vasodilation and decreasing
blood pressure.
The site specificity varies, and important drugs include:
The dihydropyridines, such as nifedipine and amlodipine (Norvasc) which are vascular smooth muscle Ca2+
channel-selective (L-type channel-selective).
Diltiazem is a calcium channel blocker of the benzothiazepine class which is both vascular and cardiac muscle
selective. However, verapamil is completely cardiac muscle selective. For a patient with cardiac failure and
hypertension, you should NOT give verapamil or diltiazem as it can further compromise cardiac function (due to
negative inotropic effects), instead nifedipine or amlodipine may be given.
Verapamil is a calcium channel blocker of the phenylalkylamine class and also a Class IV anti-arrhythmic agent
that acts on cardiac L-type calcium channels, which slows conduction in the SA and AV nodes where action
potential propagation depends on slow inward Ca2+
slowing the heart and terminating SVT rhythms by causing
partial AV block. They shorten the plateau of the action potential and thus reduce the force of contraction. Reduced
Ca2+
entry reduces after-depolarisation and thus suppresses premature ectopic beats. The main clinical indication for
verapamil is for treatment of dysrhythmias, in particular to slow ventricular rate in rapid atrial fibrillation, to prevent
recurrence of supraventricular tachyarrhythmias (SVT) (given IV to terminate SVT, although now largely replaced
by adenosine).
The main clinical use for dihydropyridines is for treatment of hypertension, and according to the National Heart
Foundation guidelines, it is considered a first-line anti-hypertensive together with either an ACE inhibitor or AT II
antagonist.
Dihydropyridines may also be used to prevent angina, which is also the main clinical indication for diltiazem.
Clinical uses:
1) Hypertension (mainly dihydropyridines)
2) Angina (mainly diltiazem, some use for dihydropyridines)
3) Dysrhythmias (rapid AF and SVTs, mainly verapamil)
Important adverse effects of the dihydropyridines include: oedema, flushing, headaches, and reflex increase in
sympathetic activity.
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Important adverse effects of diltiazem and verapamil include cardiac bradyarrhythmias. Side effects of the
dihydropyridines include oedema, flushing, headaches, constipation (with verapamil) and reflex increase in
sympathetic activity- as the baroreceptors return BP to previous levels- dihydropyridines would not be effective in
this case.
Drugs affecting the Renin-Angiotensin system:
Remember the basics of the renin-angiotensin-aldosterone system, highlighted below:
Note that angiotensin II has two ways of increasing BP, it can act as a powerful vasoconstrictor, or it can lead to
increased adrenal production of aldosterone, which causes water and salt retention thus also increasing BP.
The following highlights the mode of action of angiotensin converting enzyme (ACE) inhibitors, note that they are
also involved blocking the in breakdown of bradykinins (bradykinin breakdown is an important role of ACE).
The ACE inhibitors:
Enalapril and perindopril are important ACE inhibitors (ACEI) that block the conversion of angiotensin I to
angiotensin II, therefore it causes a decrease in vascular tone and BP and also decreases aldosterone production.
However, the adverse effects of the ACE inhibitors include severe hypotension, acute renal failure, hyperkalemia,
cough (associated with decreased break down of bradykinins, ACE is commonly found in the lungs and on
endothelium), loss of taste (dysgeusia), rash and fetal malformations (highly teratogenic). ACE inhibitors hence
contraindicated in pregnancy and in people with pre-existing renal disease.
Angiotensin II antagonists:
Angiotensin receptors are widely distributed; in vascular smooth muscle, adrenal cortex, kidney and brain.
There are two types of angiotensin II receptors identified, AT1 and AT2 receptors. AT2 receptors are found in
blood vessels.
However, most known actions of angiotensin II are mediated through the AT1 receptor, which are involved in
increasing adrenal aldosterone secretion and causing vasoconstriction via angiotensin II. Angiotensin II is ~40 times
more potent than noradrenaline.
In the near future renin inhibitors will hopefully be a new future possibility for treatment of hypertension.
The following image summarises the mechanism of action of the Angiotensin II receptor antagonists:
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Important angiotensin II receptor antagonists include losartan (Cozaar), candesartan (Atacand) and irbesartan
(Avapro), which are all selective for AT1 receptors, and inhibit the cardiovascular effects of angiotensin II, and
have similar efficacy as ACE inhibitors. Note that these drugs have the same adverse effects as ACEI, however,
unlike ACEI they are not involved in the break-down of bradykinins, and so they do not produce a cough.
So, adverse effects include: hyperkalemia, headaches, dizziness, etc. It is important just like with ACEI to avoid
angiotensin II receptor antagonists in pregnancy (due to teratogenicity) and also in patients with renal impairment.
Note however, that diabetics may in fact benefit from use of ACE inhibitors/angiotensin II receptor antagonists.
Centrally acting antihypertensives:
Note that it is the baroreflex that increases BP when the BP is detected as being low in the carotid sinus. This then
causes increased descending sympathetic outflow from the medulla oblongata that then acts on the heart, blood
vessels & kidneys to increase blood pressure.
Centrally acting antihypertensives act by decreasing sympathetic outflow from brain centres and thus decreasing
vascular tone. Important drugs to remember include α-methyldopa which is converted to α-methyl noradrenaline
(which is an α2-receptor agonist) in the brain that then decreases sympathetic outflow and also clonidine- an α2-
receptor agonist. These drugs hence act at the brainstem level on α2-receptors (agonists). The following reactions
display the conversion of α-methyldopa to α-methyl noradrenaline:
However, adverse effects of centrally acting antihypertensives include sedation, sleep disturbance, dreams,
depression, xerostomia. Also α-methyldopa side effects include hepatotoxicity and haemolytic anaemia. Clonidine
is also associated with a withdrawal syndrome which is a detrimental rebound increase in sympathetic activity.
Overview of treatment for hypertension: benefits are unequivocal with reducing BP. Lifestyle measurements may be
useful, although there are a diverse range of drugs that aim to normalise BP. However, adverse effects of these
drugs may preclude use. Note also that 50-75% of patients will not respond adequately to monotherapy, so
combination therapy is used.
Note that a larger reduction in BP produces a larger reduction in risk of end-organ and vascular diseases. From
randomised controlled trials, there was no significant differences in outcome in the total number of major
cardiovascular events between ACEI, calcium antagonists, diuretics or beta blockers.
Hypertension is a common cause of morbidity, but too few patients are adequately treated. A reduction in
cardiovascular disease mortality and morbidity can be achieved through improved treatment and control of
hypertension. A choice of drugs is available for hypertension, systematic trial and error may be necessary for each
individual.
An estimated 50-75% of patients with hypertension will not achieve BP targets with monotherapy. For most patients,
a combination of anti-hypertensive drugs from two or more pharmacological classes is needed. Occasionally a
combination of three or more may be required to achieve adequate BP control.
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With combination therapy, it is important to use drugs from different groups. Based on current evidence, the use of
an ACE inhibitor or AT II antagonist in conjunction with a calcium channel blocker is the most effective
combination in most people and has particularly beneficial effects for diabetics and those with lipid abnormalities.
Aim for at least additive effects, for example, use one of the following:
1) ACEI or ARA & calcium channel blocker
2) ACEI or angiotensin II receptor antagonist (ARA) & a Thiazide diuretic (effective for heart failure or
post-stroke)
3) ACEI or ARA & beta blocker (useful in the setting of heart failure)
4) Beta blocker & Ca channel blocker (DHP)
5) Thiazide diuretic & Ca channel blocker
6) However AVOID: ACEI and K+ sparing diuretic (as it would cause hyperkalemia), and beta
blocker with either verapamil or diltiazem (causes severe bradycardia/bradyarrhythmia).
7) Also large-scale trials have shown that combination therapy with ACE inhibitors in
conjunction with AT II receptor antagonists are not more effective in reducing
cardiovascular death or morbidity in patients with vascular disease or diabetes, however,
increased the risks of hypotensive symptoms, syncope and renal dysfunction.
The following table gives the advantages & disadvantages of different drugs:
AE refers to adverse effects, adv- advantages, TG- triglycerides, C/I-contraindicated
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Pharmacological management of heart failure
ACE inhibitors and AT II receptor antagonists, β-blockers and diuretics are the mainstay of therapy. Nitrates are
useful if the cause is MI (for coronary artery vasodilation and prophylaxis), and while digoxin improves
symptoms and reduces hospitalisation, they have yet to be shown to improve mortality. Other medication such as
direct vasodilators (hydralazine) and calcium channel blockers may be used but have yet to be shown to improve
mortality.
β-blockers are used in the treatment of cardiac failure to decrease cardiac work, pre-load and after-load to
decrease heart contractility. However, in late stages of cardiac failure, there must be an increase in contractility to
keep the patient alive and then this would involve use of inotropic agents to increase heart contractility and
includes the cardiac glycosides and catecholamines.
Important non-pharmacological management includes physical activity and rehabilitation, nutrition (optimise
weight), saturated fat intake, fibre intake, malnutrition (cardiac cachexia, anaemia), reduce sodium intake, refer to
specialised dietician.
With fluid management, be aware of weight gain (>2kg over 2 days prompts medical attention). Also
avoid >2Lfluid intake/day, with restrictions liberalised with warmer weather. Abstain from alcohol if alcoholic
cardiomyopathy, otherwise limit to 1-2 standard drinks/day. Reduce caffeine intake, limit to 1-2 beverages/day.
Smoking cessation important and education regarding condition, monitoring, beneficial lifestyle changes,
medication side-effects, signs of deterioration, importance of adherence to therapy and psychosocial support.
Sleep apnoea, vaccination (influenza and pneumococcal) and counselling in travel (DVTs) and in pregnancy (high
morbidity and mortality).
Heart failure aims of treatment include:
To improve cardiac function
Reduce symptoms and improve quality of life, including fatigue, dyspnoea and oedema.
Prevent progression and increase survival rate by ~10% even with mild or moderate heart
failure.
Inotropic agents are used last, as they are administered intravenously for acute exacerbations of heart failure or for
advanced chronic heart failure.
Heart failure is defined as insufficient cardiac output from the heart to meet the perfusion requirements of the body.
It has multiple causes:
Ischaemic heart disease/coronary heart disease
Long-standing hypertension
Valvular heart disease/endocarditis
Cardiomyopathy- think in terms of hypertrophic, restrictive or dilated, but other important
categories of causes include infectious, inflammatory, familial, metabolic,
toxin-related, idiopathic.
Myocarditis- inflammatory
In a normal heart, as ventricular end-diastolic volume (pre-load) increases, stroke-volume also increases to
compensate, as the heart pumps more forcefully to remove the blood. In cardiac failure, despite increasing end-
diastolic volume (because of volume overload), stroke volume does not increase and the heart compensates by
trying to work harder as a result of stretching of the fibres (Frank-Starling mechanism), which eventually leads to
cardiac hypertrophy (and/or dilation also ensues as a result of higher end-diastolic volume). Hence treatment must
also include decreasing pre-load (load placed on myocardium due to venous return- the end diastolic volume), or
reducing after-load (the pressure at which the heart has to contract) in accordance with Laplace‟s law. By
decreasing pre-load and after-load, pressure on the myocardium is reduced and this decreases symptoms of
congestive cardiac failure (CCF).
In cardiac failure there is increased sympathetic overdrive due to low BP stimulating baroreceptors (low BP from
low cardiac output). This leads to increased sympathetic drive with chronic over-action of β1-adrenoreceptors. This
74
leads to impaired β1-adrenoreceptor coupling and reduced β1-adrenoreceptor expression that can lead to reduced
sensitivity to β1-receptor antagonists.
Disease/damage to the myocardium leads to decreased cardiac output and hence cardiac failure. Then
compensatory mechanisms are activated; e.g.:
Increased sympathetic activity
Activation of the renin-angiotensin-aldosterone system
Cardiac hypertrophy to try to increase cardiac output
In the long-term, these compensatory mechanisms are disadvantageous, i.e.:
It leads to sodium and water retention leading to oedema
Cardiac hypertrophy due to increased cardiac muscle work, this increased cardiac muscle mass also
has greater requirements for oxygenation
Treatment strategies thus are aimed at these compensatory responses, i.e. to remove salt and water with diuretics,
reduce pre-load and after-load by vasodilators and improvement of cardiac muscle work/contraction with
inotropic agents. Also a number of non-pharmacological strategies may be employed such as salt and water
restriction.
Thus drugs for heart failure include:
Diuretics as discussed above
ACE inhibitors/Angiotensin II AT1 receptor antagonists
Vasodilators
β-blockers
Cardiac glycosides
Phosphodiesterase inhibitors
Sympathetic stimulants- sympathomimetics
Some of the previous discussion is repeated for diuretics, β-blockers, ACE inhibitors/AT II antagonists but now
for the context of heart failure.
Diuretics in heart failure:
Loop diuretics are particularly useful for removing excess fluids and these include furosemide (Lasix), bumetanide
and ethacrynic acid. They are particularly useful for removing excess extracellular fluids, such as in peripheral
oedema, ascites, pleural effusions and pulmonary oedema which occurs in heart failure.
Loop diuretics act on the thick ascending limb of the loop of Henle, by inhibiting the Na+/K
+/2Cl
- co-transporter,
which leads to natriuresis and diuresis but may lead to hypokalemia and metabolic alkalosis, hearing impairment as
an adverse-effect. This can be controlled by giving the patient IV fluids supplemented with potassium or also using
a potassium-sparing diuretic.
Thiazides such as chlorothiazide act on the luminal side of the distal convoluted tubules, and inhibit the Na+/Cl
- co-
transporter and thus decreasing NaCl reabsorption. Again, hyponatremia, hypokalemia are important side effects.
Many people taking diuretics will need supplements due to electrolyte imbalances. Also, many patients with
chronic heart failure will need chronic loop diuretics.
Potassium sparing diuretics such as spironolactone act on the collecting ducts and tubules and is an aldosterone
antagonist, it has been shown that aldactone has similarly reduced mortality in cardiac failure by up to 30%. These
diuretics spare potassium excretion and hence there are no side-effects of hypokalemia, however, it can induce life-
threatening hyperkalemia. Spironolactone antagonises the action of aldosterone on the aldosterone nuclear receptor,
which inhibits its transcription of the ENaC channels (epithelial Na+ channels) as well as luminal Na
+/K
+
transporters. It thus leads to sodium and chloride excretion, but spares potassium excretion. This is a weak diuretic,
that blocks aldosterone and hence prevents K+ loss but enhances Na
+ removal.
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ACE inhibitors in heart failure:
Inhibition of ACE leads to inhibition of angiotensin II production, leading to decreased aldosterone release, which
leads to decreased fluid retention (thus reducing preload); and it also inhibits the vasoconstriction from angiotensin
II, which leads to decreased arteriolar tone and constriction (thus reducing afterload).
Examples include enalapril and perindopril, which inhibits conversion of angiotensin I to angiotensin II,
suppressing aldosterone production by the adrenal medulla which dilates arteries and thus reduces afterload.
Some ACE inhibitors may cause venodilation and are used for early and moderate cardiac failure, but may also
decrease cardiac hypertrophy due to decreased preload and afterload.
Hence ACE inhibitors may improve survival, but have the side-effects of hyperkalemia, first-dose hypotension,
renal impairment, dry cough, and teratogenicity.
Renal impairment may be an important co-morbidity to consider especially if the patient has cardio-renal
syndrome with renal failure secondary to heart failure.
Angiotensin II AT1 receptor antagonists in heart failure:
Common examples include losartan and candesartan. These drugs block the action of angiotensin II on vessels,
and avoids some of the side-effects of ACE inhibitors.
These drugs are useful for mild to moderate heart failure.
They may also decrease cardiac hypertrophy by decreasing heart preload and afterload.
Important side effects however, to remember include hypotension, teratogenicity, hyperkalemia and renal
impairment.
Renal impairment may be an important co-morbidity to consider especially if the patient has cardio-renal
syndrome with renal failure secondary to heart failure.
Vasodilators in heart failure and angina:
These drugs act by decreasing peripheral resistance and hence decreasing BP.
In the setting of heart failure, they decreased preload by venous dilatation and afterload by arterial dilatation. This
leads to decreased cardiac workload.
Important examples include nitrates, hydralazine, ACE inhibitors and angiotensin II AT1 receptor antagonists.
These drugs have been shown to improve survival in heart failure.
Nitrates: Nitric oxide donors stimulate guanyl cyclase, which leads to calcium being held in smooth muscle
cells in the blood vessel wall and leads to vasodilation. Examples include nitroglycerin (glyceryl-
trinitrate) and isosorbide dinitrate.
Nitrates predominantly lead to venous dilatation, thus reducing pre-load.
Glyceryl trinitrate (GTN) is used to treat acute cardiac failure and myocardial ischaemia (angina) and
it is given sublingually or with a translingual spray. It leads to relaxation of vascular smooth muscle
and dilation of coronary arteries.
Isosorbide dinitrate is used more for the treatment of longer term cardiac failure as well as angina.
Important side effects of nitrates include flushing, headaches, hypotension and reflex sympathetic
tachycardia. They may be contraindicated in postural hypotension, head trauma and cerebral
haemorrhage. Importantly, tolerance may develop to nitrates within 1-2 weeks of chronic use, which
can be avoided with a nitrate-free period each day, using shorter acting nitrates and removing long-
acting patches.
Hydralazines: an example being apresoline. These are direct vasodilators, which increase guanosine
monophosphate levels, thus decreasing the action of the secondary messenger IP3, which limits calcium
release from smooth muscle sarcoplasmic reticulum and tis hence leads to blood vessel relaxation and
dilation. It has also been identified as a nitric oxide donor.
Hydralazines can be used in combination with isosorbide dinitrate to reduce the mortality of cardiac
failure.
Side-effects include hypotension, reflex tachycardia, but it is a useful vasodilator to give in conjunction
with β-blockers, as the compensatory sinus tachycardia can be eliminated with a β-blocker. They may
also induce an SLE-like syndrome, SVT and peripheral neuropathy and may lead to hepatic impairment
in pre-existing liver disease.
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β-blockers in heart failure and angina:
Important examples include carvedilol- a non-selective adrenoreceptor antagonist, which blocks α1, β1 and β2
adrenoreceptors.
These drugs have no intrinsic sympathomimetic activity.
Carvedilol blocks α1, receptors, which leads to peripheral vasodilatation (and decreased preload), β1 receptors,
which leads to decreased heart rate and cardiac output and the reflex sympathetic tachycardia response is also
blocked and additionally, it inhibits renin release by the juxtaglomerular apparatus cells of the kidney. With
inhibition of α1, β1 and β2 receptors stroke volume is reduced.
The important side effect of carvedilol is that it causes hypotension, dizziness and fatigue.
Inotropic agents:
Inotropic agents act by increasing the force of cardiac contraction and thus increasing cardiac output. This
includes:
The cardiac glycosides
Phosphodiesterase inhibitors
Adrenoreceptor agonists with (sympathomimetic activity)
Some of these drugs work by increasing sympathetic activity, which in an acutely failing heart can improve
contractility.
The cardiac glycosides: include digoxin, or digitalis and ouabain, which is derived from the Foxglove plant and
has been used for many years, and can also be used in conjunction with diuretics and ACE
inhibitors. In addition to contractility, it decreases sympathetic drive, which enhances
parasympathetic activity causing vasodilation and reduces resting heart rate along with
increasing force of contraction.
Thus it has a POSITIVE inotropic effect, but a NEGATIVE chronotropic effect.
Cardiac glycosides inhibit the Na+/K
+ ATPase pump; hence Na
+ build up occurs inside
myocytes; this then reduces Ca2+
efflux as it then INCREASES activity of the Na+/Ca
2+
symport exchanger. The diagram on the left shows in a cardiac myocyte that digitalis
inhibits the Na+/K
+ ATPase pump and hence Na
+ builds up in the myocyte. This
subsequently increases Na+/Ca
2+ re-entry via a Na
+/Ca
2+ exchanger, keeping Ca
2+ with it,
this leads to increased contractility. Digoxin,
however, has a small safety margin and increased
toxicity with lowered plasma K+ in cardiac failure
and atrial fibrillation (thus one must NOT use
digoxin in conjunction with most diuretics in these
situations).
A severe adverse effect is that it could cause
ventricular arrhythmias and hence digoxin is used
for advanced heart failure. As almost all cells in
the body have a Na+/K
+ ATPase pump and hence
digoxin has many widespread adverse effects,
including diarrhoea, drowsiness, confusion,
psychosis and arrhythmias.
Phosphodiesterase inhibitors: Phosphodiesterase inhibitors prevent cyclic AMP breakdown (as
phosphodiesterase breaks down cAMP), which increases Ca2+
entering into the cell.
Intravenous milronone is used for acute cardiac failure, and in cardiogenic shock. These
drugs may cause GIT symptoms, hepatotoxicity and ventricular arrhythmias. Hence these
drugs cannot be used chronically due to their toxic effects and increased mortality.
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β-adrenoreceptor STIMULANTS in heart failure:
These drugs are catecholamines with sympathomimetic activity, which also cause cardiac myocyte cAMP increase,
which increases Ca2+
entry into cells leading to increased contractility, along with increased rate of contraction
and can be used to treat acute heart failure and cardiogenic shock.
Intravenous dobutamine (low dose dobutamine) is one example, which causes direct stimulation of β1-
adrenoreceptors (cardiac contractility effects are hence similar to specific β1 receptor stimulation.
These drugs, including dopamine (a sympathomimetic) can also increase renal perfusion, as they act on
dopaminergic DA receptors.
β1-adrenoreceptor agonists are only used in the acute care setting (e.g. coronary care units), as these drugs may
cause arrhythmias, they can down-regulate β1-receptors and can lead to an increased rate of cardiac work and need
for oxygen consumptions (can predispose to myocardial ischaemia).
The following table summarises the main forms of treatment in cardiac failure:
Drug class Mechanism Effects Diuretics Decrease oedema Decreased preload
Spironolactone Aldosterone antagonist Decreases preload, reduces
heart failure-related cardiac
fibrosis
ACE inhibitors/AT II receptor
antagonists
Vasodilation, and decreases
extracellular fluid volume
Decreased preload
Decreased afterload
Non-selective α/β blockers Vasodilation, no reflex increases
in heart rate
Increased stroke volume,
decreased preload
Inotropic drugs Increased contractility Increased cardiac output
Hence these drugs help to decrease mortality associated with heart failure.
Heart failure treatment involves many drugs, which may not improve disease progression; but can improve
symptoms and morbidity.
Other measures (discussed earlier) such as salt and water retention are also required. Compliance with medications
and fluid/salt restrictions is very important.
Other important treatment strategies include pacing with a pacemaker, or with a left or bi-ventricular assist
device, use of implanted cardioverters (expensive) and surgery (LV excisions, aneurysmectomy, and heart
transplantation).
There are many flowcharts/guidelines for the pharmacological treatment of CCF, based on the New York Heart
Association functional status score.
In short, if there is no functional limitation from diagnosed heart failure (LVEF<40%) then use
ACE inhibitors and β-blocker.
78
If there is functional limitation, start ACE inhibitors and diuretic, add a β-blocker and consider
adding spironolactone, digoxin and AT II inhibitors to achieve symptomatic improvement.
Summary of the mechanisms of heart failure and sites of target for pharmacological agents:
79
The following is a related-aside topic that is very important to understand for management of acute pulmonary
oedema: in the emergency situation:
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Asthma Case protocol 39: Asthma
A 35 year old woman was seen by her local doctor because of
increasing dyspnoea over the previous 12 hours. She had suffered
from asthma since childhood, requiring numerous hospital admissions,
and consequently was reluctant to consult doctors or to go to hospital.
Her only medication was a salbutamol puffer, used as required. She
had been suffering from an upper respiratory tract infection for the
past three days and had a cough productive of yellow sputum.
On examination, the woman was dyspnoeic at rest, having difficulty in
carrying out a conversation. She was pale but not cyanosed, the chest was hyperinflated with prominent tracheal
tug, and she was using accessory muscles of respiration. Bilateral inspiratory and expiratory wheezes were heard
on auscultation. She was commenced on antibiotics, nebulised salbutamol and prednisone tablets, but refused
admission to hospital.
On examination, the patient is also tachycardic and tachypnoeic. Also importantly, she is afebrile, with an
elevated systolic blood pressure.
Based on the history and physical examination findings, the provisional diagnosis is an acute exacerbation of
asthma or an „asthma attack‟ and possibly development of status asthmaticus, secondary to a recent upper
respiratory tract infection (likely viral) along with poor compliance with medical treatment.
Respiratory infections are the most common of the stimuli that evoke acute exacerbation of asthma. It has been
shown that viruses (Influenza, parainfluenza, coronaviruses, respiratory-syncytial virus, rhinovirus, adenovirus etc)
are a major aetiological factor. In older children and adults, rhinoviruses and influenza viruses predominate as
pathogens.
Differentials to consider (although asthma is very likely the cause in her presentation) include lower respiratory
tract infection including bronchitis, bronchiolitis or pneumonia (although she is afebrile) secondary to the upper
respiratory tract infection or bronchiolitis obliterans organising pneumonia (BOOP) (idiopathic and rare). Given
her young age, it would be extremely unlikely for her to have cardiac failure and acute pulmonary oedema, or
upper airway obstruction from a tumour. She may also have laryngeal oedema, recurrent pulmonary embolism, or
a large pulmonary embolus (she may be a smoker on the oestrogen contraceptive pill) carcinoid tumour or even
eosinophilic pneumonia, or diffuse vasculitic lung disease (e.g. Churg-Strauss syndrome).
Appropriate pharmacotherapy must be given (see discussion on following pages), basically with reliever
medications (bronchodilators) and preventers (e.g. steroids). Antibiotics may not be necessary as it appears that
she is now recovering from a viral infection.
Her treatment should be monitored in terms of her lung function: pulmonary function tests should be performed
along with a challenge test with a bronchodilator response (>15% increase in FEV1 in asthma after
bronchodilators). This can be followed-up as an outpatient and she can also do peak-expiratory flow
measurements at home using a peak flow meter to assess the severity of her asthma as well as response to
medications. Her compliance to medications needs to be checked along with adequate education regarding her
puffer use and how to take it properly. Other inhaler devices can be used as necessary (puffers/metered dose
inhalers, turbuhalers, spacers, nebulisers etc).
This woman exhibited features indicative of severe asthma, including dyspnoea at rest, tachypnoea (RR 26) with
tracheal tug and hyperinflated chest (indicating air trapping from severe airways obstruction leading to increased
anteroposterior diameter), bilateral inspiratory and expiratory wheezes.
Important investigations to assess the nature of her disease would include:
i. Peak expiratory flow rates
ii. Pulmonary function tests- spirometry to check lung volumes and flow rates
iii. Chest x-ray (showing hyperinflation, air trapping, mucous plugging)
iv. Arterial blood gases
v. Sputum sample to check for microscopy (Gram stain), culture and sensitivity and to check for sputum and
blood eosinophil count.
vi. Serum IgE levels
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Twelve hours after her initial consultation she was admitted to hospital following a respiratory arrest at home.
Examination in the Emergency Department revealed a drowsy, cyanosed woman in severe distress and unable
to talk. Respiratory effort was poor, the pulse rate was 180 beats per minute, the blood pressure 140/60 mm Hg
with 30 mm Hg of paradox (pulsus paradoxus), and the chest was silent.
Important questions to ask the carer/family would be the progression of what happened after she returned home.
It is also important to ask about her medication use: compliance, how much she takes and how often. This is to
check the effectiveness of her medications (in terms of reversibility) because if she took too much salbutamol
often previously it may have induced tachyphylaxis and thus now there could have been a poor response to the
bronchodilators, which is why she did not get better after her first ED admission.
Otherwise, there may also have been worsening of infection with sepsis, development of ARDS, progression of
asthma with a delayed asthma attack, a cardiac tachyarrhythmia or a rapid progression of some other
unknown/rare condition such as Churg-Strauss syndrome etc.
Important investigations would be to:
i. recheck her vital signs (also check for fever, check oxygen saturation with pulse oximetry and check her
arousal with Glasgow Coma Scale).
ii. Also do an urgent arterial blood gas analysis
iii. Urgent chest x-ray.
iv. Collect blood cultures if she is febrile
v. Also obtain IV access with a cannula to start her on IV medications if indicated and check her FBC, CRP.
vi. She will also require urgent ventilation with oxygenation and if she is not breathing may need intubation
with positive pressure ventilation and ICU admission.
Arterial blood gases were obtained and they show obvious respiratory acidosis, with severe hypoxemia,
hypercarbia, and there may be some degree of metabolic compensation (positive numbers for base excess
indicates excess base and negative indicates a deficit- a high base excess usually involves a high level of
bicarbonate and can be caused by metabolic compensation for respiratory acidosis). This is due to her asthma and
hypoventilation.
Refer to the discussion on the following pages for detailed description of the aetiology and pathogenesis of
asthma. Asthma is a very common condition. Bronchial asthma occurs at all ages, but predominantly early in life.
Half of all cases develop before age 10, one-third before age 40.
Asthma is a heterogeneous disease, it would be useful to classify asthma by principal stimuli that incite or are
associated with acute episodes.
Atopy is the largest risk factor for development of asthma but a significant number suffer from idiosyncratic
asthma.
Asthma that has its onset in early life tends to have a strong allergic component. Asthma that develops late tends
to have a non-allergic or mixed aetiology.
The hallmark pathological features of asthma to note include reduction in airway diameter brought about by
contraction of smooth muscle, vascular congestion, oedema of bronchial wall, thick tenacious secretions and
mucous plugging.
These pathological changes result in increased airways resistance, with decreased forced expiratory volume and
flow rates. This can lead in respiratory muscle function to air-trapping in the lungs and hence hyperinflation of the
lungs and thorax, increased work of breathing and alterations in respiratory muscle function and changes in elastic
lung recoil. There can also be impaired distribution of both ventilation and pulmonary blood flow with V/Q
mismatch and hence altered blood gas concentrations.
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In acutely ill patients:
Residual volume can reach 400% of normal
Findings of metabolic acidosis signifies severe airways obstruction.
Hypoxemia is a universal finding during acute exacerbations, but frank ventilatory failure
such as in this case is relatively uncommon (10-15%).
Despite all attempts at resuscitation, the patient‟s condition continued to deteriorate, and six hours later she had
a cardiac arrest and died.
Important macroscopic pathological findings would include obvious gross distension of the lungs, the lungs
may also fail to collapse after the pleural cavities are opened due to air-trapping with airways obstruction and
mucous plugging.
When the lungs are cut, gelatinous plugs of exudates and mucous plugs in the bronchial tree down to the
terminal bronchus may be observed. Below: The following image is of a lung at autopsy from a woman who had
chronic asthma, but who died from an acute asthmatic attack. The lung specimen shows complete occlusion of some of the
respiratory passages in the lungs by thick, tenacious mucous (arrows).
Important histopathological changes that could be observed (see detailed description and images below) would
include:
Bronchial smooth muscle hypertrophy
Hyperplasia of mucosal and submucosal vessels (angiogenesis).
Mucosal oedema due to exudation
Thickening of the basement membrane
Mucous plugs in airways
Eosinophillic infiltrates in bronchial wall, along with lymphocytes and plasma cells.
Absence of any well-recognised forms of destructive emphysema.
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Asthma case 2::
A 42 year old man who had a long history of intermittent dyspnoea associated with expiratory wheezing and chest
tightness presented to the emergency room of his local hospital. He had developed a cold 3 days earlier and
during the night he had become very short of breath. His regular medications did not seem to have any effect. The
man had never smoked. On examination, his respiratory rate was 30/min and widespread wheezing was audible
in both lung fields. The following investigation results were obtained:
Spirometry (after usual medications) FEV1 0.9L Expected FEV1 4.0L FVC 4.2 L Expected FVC 5.0L
Arterial blood gases (on room air) pH 7.38 (7.36-7.44) pO2 (mmHg) 55* (80-100) pCO2 (mmHg) 45 (35-45) Bicarbonate (mmol/L) 24 (24-32) O2 saturation 85* (95-100)
Since his shortness of breath is noticeable, this is evidence of respiratory distress. Other signs of respiratory
distress may include costal in-drawing and subcostal recession, use of accessory muscles of respiration,
tachypnoea, tachycardia and cyanosis.
The spirometry illustrates an obstructive pattern of lung disease. The FEV1 is severely reduced, the FEV1/FVC
ratio is ~20% which is very seriously reduced, even after he has taken his regular medication, which indicates
he is not responding to his medications. Spirometry is the way that lung air volumes & lung capacity can be
measured. The normal Forced Vital Capacity (FVC) is 5.0L, i.e. the lungs can hold (on average) a maximum
volume of ~5.0L. Forced Expiration Volume in 1 second (FEV1) is used to identify how much air one can
expire in one second. In people with normal lung function, forced expiration leads to an exponential decrease of
air over time, with ~4.0L of FVC expired within 1 second. The normal ratio of FEV1/FVC should hence be
~80%. In asthmatics FEV1/FVC ratio is however <40%, although this is not necessarily diagnostic of asthma.
This ratio can be increased (hence reversing bronchoconstriction) with the use of bronchodilator drugs,
particularly β2-adrenergic agonist such as Salbutamol, which acts on bronchiolar smooth muscle, relaxing this
smooth muscle & hence dilating airways. In this patient the FEV1/FVC ratio is ~0.21, which seems to be a grim
outlook for the patient.
The cold was most likely the result of a viral infection, which is a major trigger for exacerbating asthma. This
led to seriously impaired air flow, & low oxygen status. This leads to the central nervous system respiratory
centres increasing respiration rate to 30/min, compared to a normal 12-20/min. The viral infection was possibly
complicated by spreading & causing a lower respiratory infection that triggered serious asthma. The
bronchoconstriction, increased mucous output & airway oedema would have caused the audible wheezing
sounds to be heard on both lung fields.
Arterial blood gas is an invasive method of measuring arterial oxygen saturation levels. A less invasive method
to monitor oxygen saturation would be with a pulse oximetry. The results of his ABGs indicates that he is
hypoxemic, his O2 saturation is markedly reduced, since a normal O2 saturation should be ~98%. His pCO2 is in
the upper range of normal, which is a bad sign of decompensated lung disease, since he is hyperventilating but
not able to blow-off excess CO2. His bicarbonate is in the lower range of normal, he is not acidotic, as his pH is
still in the normal range.
The possible provisional diagnosis in this case is that (although we have not ascertained that he has a previous
diagnosis of asthma in his medical history), this is a severe case of asthma; based on his history and physical
examination findings, his ABGs and spirometry, and his unresponsiveness to his (asthma) medications.
The differential diagnosis of a wheeze in this case is as follows:
o The provisional diagnosis is severe asthma, secondary to a recent viral infection. The viral upper
respiratory tract infection precipitated acute asthma.
o Acute exacerbation of COPD, in a patient that has a background history of chronic bronchitis or
emphysema, although he has never smoked.
o Other obstructive lung diseases: small airways lung disease/bronchiolitis, bronchiectasis (irreversible
ectasis or enlargement of the larger airways).
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o If there is a localised wheeze, rather than a diffuse bilateral pattern, consider the possibility of lung
cancer. If there is a unilateral/localised wheeze consider foreign bodies, such as coins, toys, food etc.
The man was commenced on salbutamol, a β2-adrenergic agonist, by nebuliser & given an intravenous dose of
hydrocortisone, a corticosteroid
The pathogenesis of asthma includes acute inflammation (from an irritant agent leading to acute
bronchoconstriction), non-specific hyperactivity of chronic inflammation & airway remodelling (with
metaplasia & hyperplasia of goblet cells, hypertrophy of bronchial smooth muscle, increased vascularity &
subepithelial fibrosis). Hence asthma has an acute on chronic pattern of pathogenesis. Treatment is thus targeted
at both arms of this pattern of inflammation.
Some triggers for asthma include house dust mite, pollens, animal fur & feathers, some chemical,
insects (i.e. cockroaches), dust, fungal spores, some drugs (e.g. aspirin), exercise, cold weather,
tobacco smoke, viruses. This leads to an acute inflammatory response initiated by Helper-T cells that
sample the presented antigen from epithelial antigen presenting (dendritic) cells. These cells then
release TH2 cytokines (namely IL-4, IL-5 and IL-13), which activate IgE secreting B lymphocytes
(which could be formed at any stage of antigenic exposure), they secrete IgE, which activates Mast
cells. Mast cells then secrete IL-3 & IL-5 which activates & recruits epithelial eosinophils (which are
also activated by other pro-inflammatory factors from T helper cells). Eosinophilic major basic
protein and Eosinophilic cationic proteins then lead to epithelial damage and acute inflammation. This
also contributes to the chronic process of airway remodelling.
The β2-adrenergic agonist (Salbutamol, note also Terbutaline can be given) given to the patient is an important
reliever medication, that relieves symptoms; by causing bronchodilatation. These drugs function via
physiological antagonism, whereby these β2-receptor agonists oppose the parasympathetic effects of muscarinic
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M1, 2 & 3 receptors stimulated by acetylcholine from the parasympathetic vagus nerve branches. Salbutamol &
Terbutaline, are β2-adrenergic agonists, short-acting bronchodilators (hence relievers), acting on smooth
muscle cells in the airways to cause bronchodilatation. In this case it was given by nebuliser, as this gives better
respiratory absorption (with vapour) of the drugs. The vapour allows mucous plugs to become softened and
hence expectorated. Note that the nebuliser increases deposition of anti-asthmatic drugs into the bronchi &
lungs. However, note that with puffers/inhalers only ~10% of the drug enters the lungs, the rest is deposited into
the stomach. IV β2-adrenergic agonists are given in status asthmaticus- severe prolonged asthma episodes.
Note that salbutamol/terbutaline are short acting (4-6 hours) and relieve the symptoms of bronchoconstriction &
hence decrease hypoxemia. Tremors & tachycardia are a side effect, as these drugs have partial effects on other
types of β-adrenergic receptors in other sites of the body (i.e. β1 receptors). However, overuse, which may have
been the case in this patient leads to development of tolerance. Hence a higher dose would be needed to reach a
therapeutic effect. A β2-adrenergic agonist with longer lasting activity that could be used includes salmetrol.
Asthma has an acute/early phase characterised with bronchospasm (acute inflammation), and a late
inflammatory phase 5-8 hours after contact with initial stimuli.
It is important to characterise the pathological changes observed in the acute and chronic phases of asthma.
Important changes in the early phase include:
o Initiation of an acute inflammatory response with symptoms, 30-60 minutes after inhalation of antigen.
o Initial triggering of Mast cells, which release mediators such as histamine, which increases cell-junction
permeability, which leads to more exposure of antigen to mucosal mast cells, histamine also affects
Mast cell degranulation.
o Parasympathetic stimulation also occurs leading to bronchoconstriction.
o Mast cells release:
o Leukotrienes C4, D4 and E4: bronchoconstriction, mucin secretion
o Prostaglandin D2, E2, F2α: bronchoconstriction, vasodilation, increased vascular permeability
o Histamine: bronchospasm, increased vascular permeability
o Platelet activating factor: recruits platelets to release histamine
o Mast cell tryptases: inactivation of normal bronchodilatory peptide (VIP)
Important changes in the late-phase of asthma include:
o Usually occurs 4-8 hours after inhalation of antigen/allergen
o It is dominated by leukocytes: basophils, neutrophils and eosinophils
o Late-phase cells release:
o Eosinophilic and neutrophilic chemotactic factors and leukotriene B4
o IL-4, IL-5, which augment the TH2 response, increases IgE synthesis and chemotaxis and
proliferation.
o Platelet activating factor and IL-5: recruits platelets for chemotaxis
o TNF-α up-regulates adhesion molecules on vascular endothelium and on inflammatory cells.
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IV hydrocortisone was also given to the patient, which is the most potent naturally occurring anti-inflammatory
drug. The intended action of this corticosteroid is to reduce the general inflammation in the lungs. The action of
the hydrocortisone is to improve airway wall function, decrease airway hyper-reactivity by reducing
inflammation, mainly by reducing oedema, mast cell degranulation and eosinophil recruitment. This functions
by reducing cytokines & pro-inflammatory interleukins & inhibits leukocyte influx into lungs. A good method
of administration would be inhaled glucocorticoids (i.e. budesonide, beclomethasone, fluticasone) for quick
deposition of steroids into the lungs.
Other possible potent anti-inflammatory drugs that could be used include leukotriene receptor antagonists, as
the pathogenesis of asthma is also mediated by leukotrienes.
Also apart from these treatments, it is important to give the patient O2 ventilation to improve their hypoxemia
and give them IV rehydration. Also for management, it is important to do physiotherapy (e.g. breathing
exercises with a bag) to allow expectoration of mucous plugs, preventing secondary infection & relieving
airways obstruction.
In severe cases of asthma, adrenaline is given, and one can try to reassure the patient.
Adrenaline is very rarely used as a treatment nowadays; it is given for patients in the
case of either anaphylaxis or croup/epiglottitis in children.
Asthma has a: 1 in 6 prevalence in children, and a lower 1 in 10 prevalence in adults in
Australia. However, importantly, asthma nowadays has a low mortality rate.
The man did not respond to these medications & was transferred to the ICU. He died
several hours later with respiratory failure. The following on the right is from tissues
prepared at autopsy:
This macroscopic specimen is from a lung in a patient that died from severe asthma. The
lung appears collapsed, hyperaemic and congested, consistent with asthma. The
segmental large and medium-sized bronchioles are thick-walled & their lumina are
occluded by greyish-white, opalescent, jelly-like mucous plugs. It is these plugs, rather
than bronchospasm that have caused lung collapse (due to air trapping- air is absorbed
by alveoli and then there is atelectasis, with hyperinflation in other areas),
unconsciousness, hypoxemia, acidosis & death in this patient. The pulmonary vessels in
the vicinity of the bronchi contain post-mortem clot. A histological specimens below
displayed the following:
The main features seen in this slide which are suggestive of long-standing asthma includes smaller
bronchiole lumens, eosinophil influx- characteristic of asthma, with intraepithelial eosinophils; mucous
plug obstruction of airways (which could have led to respiratory failure from status asthmaticus). Also
seen is subepithelial fibrosis & hypertrophy of bronchiole smooth muscle both indicative of a chronic
asthma.
Furthermore, goblet cell metaplasia & hyperplasia is observed in the bronchiole lumen. Also significant
lymphocytic infiltrate is observed indicating chronic inflammation of asthma.
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Note that the reduced lumen size is due to the mucous plugs. The lumen is highly folded, due to increased
number of goblet cells being accommodated by the bronchi, i.e. goblet cell hyperplasia which is abnormal.
The subepithelial fibrosis indicates a chronic inflammatory process. Also lymphoid aggregates present with
prominent germinal centres, these are CD4+ T lymphocytes and activated B cells, Plasma cells.
Vascular changes from inflammation & oedema are also observed; as well as compensatory hyperinflation of
the alveolar acini.
Note that mast cell proteases (e.g. tryptases) on immunohistochemistry stain can be used to detect mast cells in
asthma.
Asthma assessment & management
Asthma is chronic airway inflammation, with increased airway responsiveness. This results in the symptoms of
wheeze, cough, „chest tightness‟ and dyspnoea. Asthma is airways obstruction which is variable over short
periods of time or reversible with treatment.
Asthma is a common condition, affecting many Australians. It has a multifactorial complex aetiology, with
genetic and environmental factors causing the disease. Indoor environmental agents that can predispose or
induce asthma include house dust mite pellets (dust), pet derived allergens, fungal spores, pollutants and
cigarette smoke. In the outdoor environment, the role of agents in initiating asthma is small, although these
agents/allergens have an important role in triggering exacerbations of existing asthma; including grasses and
flower pollens as well as air pollution gases (e.g. Oxides of Nitrogen etc). Occupational asthma is also
important, with major work environments that can predispose/induce asthma including people who are spray
painters (exposure to diisothiocyanates), hard wood dusts (e.g. carpenters working with red cedar woods),
laboratory-workers working with animals. In these cases, the patient is characteristically only affected when at
work (e.g. not on weekends) or if the agent is removed within the first six months of symptoms there is usually
no persistent pathology. More persistent symptoms can lead to irreversible airways changes. In some patients,
chronic inflammatory stimuli cannot be identified, yet they have severe airway inflammation. These patients
have intrinsic asthma (non-allergic), which separates them from allergic asthma, but they have all the classic
features of airway hyper-responsiveness and obstruction.
A number of other factors influence the development of asthma. For example, infections, e.g. viral,
Mycoplasma and bacterial infection provoke a transient increase in airway responsiveness in normal people and
in asthmatics, as well as cigarette smoke, cold air, exercise (induced asthma) etc. Breastfeeding may offer some
protection against development of asthma.
For asthma pathogenesis, a series of factors combined lead to asthma, including: increasing airway
inflammation and responsiveness, followed by bronchoconstriction and symptoms of asthma. With inhalation of
an allergen, this leads to a sensitised atopic individual. In acute asthma, there is then a two-phase response; 1)
and early asthmatic response maximum of 20 minutes after allergen exposure, followed by 2) a late asthmatic
reaction from ongoing/late inflammation- about 6-12 hours later.
Clinical features of asthma include that of:
o Episodic asthma: which is the pattern observed in children and young adults; patients are generally
asymptomatic between episodes, they then suffer an „asthma attack‟- e.g. during a viral upper
respiratory tract infection or exposure to allergens, such as pets, pollen.
o Persistent asthma: this is “adult onset asthma”, which is characterised by a chronic wheeze and
dyspnoea. It is more common in older patients.
There is a variable nature of symptoms, which is characteristic in asthma, e.g. there may be a diurnal pattern
(symptoms and peak flow measurements being worse in the early morning, improving during day); some
patients may have nocturnal symptoms, some patients have a cough variant asthma, some patients have an
exercise-induced asthma.
The pattern of asthma is important to ask for: what is the frequency of symptoms, i.e. how often and when do
you have these symptoms (daily, monthly)? What triggers your asthma? Important trigger factors include
upper respiratory tract infections, cold air, dusts/dust mites (dermatophagoides)/vacuuming, allergen exposure
such as cockroaches, cats, furs, feathers/birds, “stress-induced”, seasonal triggers such as grasses and pollen,
exercise-induced asthma, drugs such as β-blockers (systemic or topical or selective β2-blockers), aspirin
(aspirin-sensitive asthma), ACE inhibitors (associated with inhibited break-down of kinins, which are
bronchoconstrictors), gastro-oesophageal reflux, premenstrual asthma (related to a fall in progesterone levels,
also associated with thyrotoxicosis or hypothyroidism). Exercise-induced asthma is common in children and
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typically begins after exercise has ended and normally recovers spontaneously after 30 minutes. Exercise-
induced asthma is worse in cold and dry climates more than hot and humid climates. Exercise-induced asthma
can be inhibited by β-blockers, anti-leukotrienes and glucocorticoids. Exercise leads to hyperventilation, which
leads to increasing osmolarity in airway lining fluids and mast cell mediator release and bronchoconstriction.
Other similar mechanisms in asthma include cold-air and hyperventilation, laughter (hyperventilation), weather
changes, strong smells and perfumes. Mechanisms of food-induced asthma may be related with
anaphylactic/anaphylactoid reactions leading to wheezing, rather than foods that genuinely increase asthma
symptoms, some examples include: aspirin-induced, shellfish, nuts, food preservatives and colouring agents.
Air-pollution may also induce asthma, related to increased levels of sulphur-dioxides, ozone, nitrogen oxides
and dusts. Also importantly, occupational-asthma.
It is important to ask: do you have pets? Also have you had any allergy or skin-prick tests? What were the
results of the skin-prick tests and what are your allergies?
Another important clinical feature to ask about is their response to treatments, which should be asked with their
medications history. What is your response to treatment, or how well do you respond to treatment? This is
important as it provides clues to the reversibility of the disease, and is important to ask in elderly people who
have had chronic asthma. Other important questions to ask for in the history include a comprehensive
occupational history (remember occupational risk factors), what was your age when you first developed
asthma? This is important, as generally most children with childhood asthma become better and their asthma
gradually improves becoming milder or disappears during the teens; at least in one-thirds of patients the asthma
will go away, although some people develop asthma in their 20s. It is also important to ask about past
hospitalisations and past asthma history, especially important are any ICU visits that may have been the result
of severe asthma and these patients are at higher risk of dying from asthma. Have you been admitted to
hospital before for asthma, when was this etc?
It is important to ask about what medications the patient uses for asthma and how they respond to treatment,
what do you take for your asthma and do medications/inhalers/nebulisers improve their symptoms? Take
a good detailed medications history; ask about preventers, relievers (SABA, LABA, muscarinic receptor
antagonists etc.).
What investigations/tests have you had done? Important tests to ask for and check results include Peak flow
charts documenting changes in Peak Expiratory flow, lung-function tests (has there been any improvement in
obstructive lung patterns, FEV1/FVC with medications?), chest x-rays, bronchial challenge tests (nebulised
histamine, hypertonic saline or methacholine) and was there any changes/fall in FEV1 with bronchial challenge?
Have they done an exhaled Nitrous oxide test?
Also important to ask in patients is their family history, have they had a family history of asthma or lung
diseases?
Physical examination key points: Typically with asthma, there is a diffuse, bilateral polyphonic
wheeze heard on auscultation. Furthermore, as asthma is an obstructive lung disease, one would expect a
prolonged forced expiratory volume in one second (FEV1) which would result in a low peak expiratory flow
measurement. These are important signs of severity of asthma.
Important investigations for asthma: Spirometry is a good test for checking lung function and
degree of obstruction. Typically with asthma, there is a reduced peak expiratory flow rate
measurement, a reduced FEV1, which thus causes a reduced FEV1/FVC ratio. Note that the patient‟s
lung function test results may be normal in between attacks in patients with episodic asthma. Also note
that it is important to demonstrate disease reversibility with administration of bronchodilators. A
methacholine, hypertonic saline or histamine challenge test (bronchial provocation tests) is also
useful for investigating the patient‟s acute asthma. It is very important that bronchial provocation tests are
performed with careful supervision and available medications as this test may involve precipitating
bronchospasm. Skin prick tests are very useful in determining if the patient has hypersensitivity
reactions to certain allergens and identifying which allergens they should try to stay away from.
Acute severe asthma: In acute severe asthma, the patient may be significantly short of breath that they
may be unable to complete a normal sentence (speaking in short sentences, increased work of breathing). The
patient is usually tachypnoeic with respiratory rate >25/minute and with other signs of respiratory distress. The
patient may also be tachycardic, with a pulse rate >110/minute. Reduced peak flow measurements are
usually <50% of the predicted value for their gender, age and height. The patient with severe asthma may also
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have pulsus paradoxus, which is a fall in the systolic blood pressure of ~10mm Hg during inspiration, although
it can disappear with respiratory muscle fatigue, as the patient can no longer generate intrapleural pressure. It is
very important to recognise life threatening signs of severe acute asthma including:
1) Peak flow <33% of predicted
2) A silent chest with reduced or absent breath sounds
3) PaO2 <60 mm Hg
4) (Normal) or high PaCO2
5) pH decreased, patient acidotic
6) Patient hypotensive and possibly in shock
7) A decreased heart rate.
8) Patient comatose or with other signs of respiratory failure.
Treatment of acute asthma: basic principles: Oxygen therapy is very important, to prevent hypoxemia.
Bronchodilators especially the use of salbutamol (or salmetrol in severe asthma) is important to reverse the
symptoms of acute respiratory distress. Steroids such as prednisolone, or IV hydrocortisone are necessary to
reduce airway inflammation and prevent a late-phase inflammatory response. Xanthines: Theophylline.
Treatment of chronic asthma: basic principles:
1) Reliever medications useful with asthma episodes/acute attacks which are basically
bronchodilators- Short acting bronchodilators (SABA) (salbutamol (Ventolin), albuterol,
terbutaline (Bricanyl or Terbulin)). Muscarinic receptor antagonists (ipratropium bromide,
terpatropium).
2) Preventer medications: are important, as they stabilise the airways, preventing inflammation;
these are inhaled corticosteroids including fluticasone (Flixotide and Seretide: fluticasone/salmetrol),
budesonide (Pulmicort and Symbicort: budesonide/formoterol) and beclamethasone.
3) Long acting bronchodilators (LABA) (Salmetrol, Formoterol).
4) Combined preparations: a combination of inhaled corticosteroids together with long-acting
bronchodilators is useful in controlling asthma, e.g. Seretide (salmetrol & fluticasone) and Symbicort
(budesonide & formoterol).
See below for pharmacology of medications used to treat asthma & COPD.
Pharmacology: Drugs to treat COPD & asthma
COPD or also known as Chronic airways limitation (CAL) is a disease state characterised by airflow limitation
that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal
inflammatory response of the lungs to noxious gases or particles such as cigarette smoke.
Clinical features may include a productive cough, dyspnoea, recurrent low grade infective exacerbations.
Respiratory failure is the leading cause of death.
COPD aetiology is complex, involving bronchoconstriction, inflammation, airway structural changes, that all
contribute to causing airflow limitation. Other factors that can contribute to development of CAL include
occupational dust and fume exposure, air pollution, alpha-1 antitrypsin deficiency (which is involved in
inhibiting neutrophil elastase), genetic predisposition, recurrent respiratory infections in childhood and
bronchial hyper-responsiveness.
The following diagram summarises the very basic pathogenesis of COPD:
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Note that proteinase inhibitors are a potential new drug class being investigated for treatment of COPD.
Bronchoconstriction in CAL may be partially reversible in many patients, however, not all patients respond to
pharmacotherapies.
Airway hyper-responsiveness may develop after exposure to tobacco smoke or environmental irritants. Chronic
inflammation is associated with an increase in the amount of smooth muscle in the airway wall.
Note that there is some overlap between asthma and CAL (asthmatic bronchitis or chronic asthma), otherwise
they are almost two separate obstructive lung diseases.
o COPD usually affects the elderly, it is slowly progressive, it has an inflammatory component that is
mediated by CD8+ T cells, macrophages and neutrophils, and is usually only partially reversible.
o Asthma can affect all ages, especially children, it has an episodic course with triggering factors, the
inflammatory component comprises of CD4+ lymphocytes, eosinophils and mast cells and it can be
fully reversible although there are exceptions in some patients (such as decreased responsiveness to
medications).
The efferent pathways or receptors present in the smooth muscle of the airways includes:
1) β2 adrenergic receptors which respond to circulating adrenaline.
2) Muscarinic receptors (M1, 2, 3), the M2 receptor is a presynaptic inhibitory auto-receptor.
Muscarinic receptors have parasympathetic effects and respond to Acetylcholine.
3) Non-adrenergic non-cholinergic nerves (NANC): inhibitory nerves (relaxant) which are acted on
by nitrous oxides, and stimulant nerves which increase vascular permeability acted on by Substance P
and bradykinins/neurokinin A (a potent spasmogen).
Treatment of COPD
It is important to help the patient to stop smoking and help them on the path to quitting. This has been definitely
shown to improve survival, as there is prolonged life expectancy after stopping smoking, it is never too late to
stop smoking. Smoking impairs mucociliary transport and contributes to mucous gland hypertrophy and altering
the structure of alveolar macrophages in COPD.
Pharmacological management of COPD involves three main types of treatment:
o Bronchodilators these are reliever medications, including β2 adrenergic agonists, xanthines
(which tend to be used when other drugs do not work, due to xanthine side-effects), muscarinic
receptor antagonists.
o Symptom controllers: namely Long-acting β2 adrenergic agonists
o Anti-inflammatory drugs: glucocorticoids/oral steroids, leukotriene receptor antagonists.
Other important therapies for management not discussed here include antibiotics for treating recurrent
infections, vaccinations as prophylaxis against influenza and pneumococcal infection to prevent a major
exacerbation of COPD and also in patients with COPD exacerbation that require oxygen therapy.
β2 adrenergic agonists: reliever medication
β2 adrenergic agonists dilate bronchial smooth muscle by a direct action on β2 adrenergic receptors. These
drugs help antagonise bronchoconstriction of the smooth muscle irrespective of the spasmogen involved, they
are a form of physiological antagonism.
β2 adrenergic agonists also inhibit the release of inflammatory mediators by mast cells.
Common β2 adrenergic agonists that are short acting include salbutamol and terbutaline, which have a
duration of action of 4-6 hours and a maximum effect after 30 minutes (by inhalation). These drugs are resistant
to enzymatic degradation; they are excreted largely unchanged in the urine.
Long-acting β2 adrenergic agonists include salmetrol, which is more effective in treating COPD, but it is more
expensive and has duration of action of ~12 hours, useful for the late-inflammatory stage of acute asthma.
Side-effects and problems of β2 adrenergic agonists include those of increased sympathetic responses, such as
tremor and tachycardia. Another important problem is that patient overuse leads to tolerance and desensitisation.
Hence bronchodilator drugs should be used on an „as need basis‟ during the early stages of disease. Also very
importantly, they should be used with caution in patients with cardiovascular disease and one must be aware of
potential drug interactions, e.g. they should not be used in patients that are taking β1-antagonists for
hypertension/heart failure.
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Muscarinic receptor antagonists:
Ipratropium bromide (Atrovent) antagonises bronchial constriction and mucous production caused by
parasympathetic stimulation from acetylcholine acting on muscarinic M2 and M3 receptors. It is more effective
in treating patients with CAL than for asthma, as it also inhibits mucous secretion (feature of chronic bronchitis).
The onset of duration is often slow, with maximum effect after 30-60 minutes and duration of action 3-5 hours.
They can be used in combination with a short-acting β2 adrenergic agonist. Side-effects are those that cause
inhibition of the parasympathetic nervous system, including nervousness, nausea and vomiting, dry mouth and
tachycardia.
Another important muscarinic receptor antagonist used to treat COPD is tiotropium bromide (Spiriva).
Xanthines:
Theophylline (Nuelin-SR) or aminophylline are examples of a xanthine, which can act as a bronchodilator;
xanthines are used when β2 adrenergic agonists are ineffective.
These drugs are well absorbed, given orally, using slow-release preparations. A sustained blood level is
achieved in up to 12 hours.
The mechanism of action of Theophylline is by inhibiting phosphodiesterase (which metabolises cAMP) thus
increased intracellular cAMP which could inhibit the activation of inflammatory cells and cause
bronchodilatation. However, an effective concentration is needed which exceeds the therapeutic dose.
The side effects of theophylline includes that it has a poor therapeutic index and hence blood plasma levels
should be monitored. Theophylline has many side-effects and many drug interactions.
There is a need for individual monitoring of blood levels because of side effects and the narrow therapeutic
window.
Theophylline causes CNS stimulation (think of side effects of caffeine!); causing reduced fatigue, improvement
in mental and motor tasks, tremor, seizures, nervousness and sleep interference, diuresis, dry throat.
It can also cause cardiac stimulation; with a positive inotropic effect (i.e. increases the force of contraction) and
positive chronotropic effect (increase in heart rate) due to its action on phosphodiesterase inhibitors.
Gastrointestinal symptoms include: nausea, vomiting and anorexia.
Major drug interactions include with oral contraceptives, erythromycin, calcium channel blockers and
cimetidine (a histamine receptor antagonist) and these interactions are all because these drugs reduce CYP450
activity, which is needed to metabolise theophylline.
Glucocorticoids:
Glucocorticoids have an anti-inflammatory and by similar mechanisms immunosuppressant activity.
These drugs are NOT bronchodilators, but they may reduce bronchial hyper-reactivity. They can result in a
significant increase in FEV1, in responsive CAL patients, but non-responsive CAL patients can also benefit by
reducing exacerbations of CAL through reducing inflammation.
Important inhaled glucocorticoids used for treatment of asthma and COPD include budesonide,
beclomethasone and fluticasone.
Immunosuppressant activity of glucocorticoids is via inhibition of the influx of inflammatory cells into the lung.
This involves inhibition of the activation of macrophages and inhibition of the release of inflammatory
mediators from leukocyte including eosinophil major basic protein and major cationic proteins. Glucocorticoids
also reduce the formation of pro-inflammatory cytokines and reduction in the synthesis of IL-3.
Glucocorticoids also have anti-inflammatory actions by inhibiting the induction of cyclooxygenase (COX),
specifically COX-2 (inhibition of pain and inflammatory pathways, as opposed to COX-1 which is responsible
for maintaining and protection of the gastrointestinal tract). Remember that cyclooxygenase is responsible for
catalysing the conversion of arachidonic acid to prostaglandin H2. Three main isoenzymes of COX exists, COX-1, COX-2
and COX-3. (Note that the -coxib drugs are COX-2 selective inhibitors). This is as opposed to non-selective COX-
inhibitors (the classical NSAIDs), which inhibit prostoglanding and thromboxane synthesis and they thus have reduced
inflammation, antipyretic effects, antithrombotic and analgesic effects. The most frequent effect of NSAIDs however, is
irritation of the gastric mucosa/gastritis and gastric bleeding due to the inhibition of prostaglandins which normally have a
protective role in the GI tract. Selectivity for COX-2 is the main feature of celecoxib and rofecoxib and as COX-2 is
usually specific to inflamed tissue there is much less gastric irritation associated with COX-2 inhibitors. The selectivity for
COX-2 inhibitors however, does not negate other side effects including increased risk of renal failure, and also increased
risks associated with thrombosis including thrombosis, myocardial infarcts and strokes through an increase in thromboxane
A2 unbalanced by prostacyclin (which is reduced by COX-2 inhibitors).
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Glucocorticoids also inhibit the formation of arachidonic acid by inducing the synthesis of Lipocortin.
Lipocortin inhibits phospholipase A2 and the subsequent formation of both prostaglandins and leukotrienes.
Refer to the Eicosanoid biosynthesis diagram:
Important side-effects of glucocorticoids to remember include immunosuppression; causing vaginal or oral
thrush that causes hoarseness and they can also precipitate infections that could potentially exacerbate COPD.
They also have systemic effects such as bruising, dermal thinning, adrenal suppression and altered bone
metabolism (causes catabolism that can cause osteoporosis), impaired wound healing, development of diabetes
(causes gluconeogenesis and glycogenolysis and decreases insulin resistance) and peptic ulcers (from effects on
cyclooxygenase on prostaglandin synthesis and hence disrupts gastric mucosa), and can cause iatrogenic
Cushing‟s syndrome. The side effects are more likely to occur with the oral glucocorticoids such as prednisone,
hence inhalation is the preferred method of administration to transfer medication directly to sites of
inflammation in the lung.
Sodium chromoglycate and nedocromil are two related non-steroidal anti-inflammatory agents that are able to
blunt the effect of inflammatory inducers and certain bronchospastic triggers (especially cold air and exercise).
They are particularly effective in patients with a significant allergic component to their asthma. The precise
mechanism of action of these drugs is not clear.
Leukotriene-receptor & synthesis antagonists:
Leukotriene receptor antagonists: leukotrienes are potent bronchoconstrictors that amplify the inflammatory
processes, competitive antagonists of the cysteinyl-leukotrienes LTC4, LTD4 and LTE4 include Montelukast
and Zafirlukast.
Leukotriene synthesis inhibitors: block the formation of LTB4 as well as LTC4, LTD4, LTE4. These drugs also
inhibit 5-lipoxygenase (refer to diagram above) and includes Zileuton.
Monoclonal antibodies:
Omalizumab is a humanised monoclonal antibody that selectively binds to the Fc portion of human IgE and
designed for those with moderate to severe or very severe asthma which is triggered by hypersensitivity
reactions to harmless environmental substances.
Like other biological, the cost can be extremely high and as a result is reserved for patients with severe asthma
whose disease cannot be controlled by high-dose glucocorticoids and other simple medications.
A major risk side-effect of Omalizumab is anaphylaxis or the development of cancer in very few cases.
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Summary of important medications to treat asthma:
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Acute Respiratory Distress Syndrome
Case: ARDS:
A 63 year old woman developed Gram-negative sepsis following a urinary tract infection. She was admitted to the
ICU, but developed rapidly worsening dyspnoea. Arterial blood gases were as shown:
Arterial blood gases pH 7.30* (7.36-7.44) PaO2 (mmHg) 45* (80-100) PaCO2 (mmHg) 48* (35-45) Bicarbonate (mmol/L) 18* (24-32) O2 saturation (%) 75* (95-100)
The ABGs display mixed acidosis, that is both respiratory and metabolic in origin, i.e. she is hypercapnic
indicating a respiratory component to the acidosis (although not severely hypercapnic), together with a
metabolic component with decreased bicarbonate (note if this were respiratory acidosis with metabolic
compensation, one would expect bicarbonate to be elevated (not decreased) with low pH). The whole ABG
pattern indicates respiratory failure, with hypoxemia and hypercapnia one would expect more ventilation-
increased ventilatory drive to blow-off CO2 which is not occurring in this case. Hence the primary problem in
this case is hypoventilation. Furthermore, sepsis causes shock and loss of ventilation-perfusion to tissues and
hence peripheral tissues begin to utilise anaerobic metabolic pathways, and hence there is a build-up of lactic
acid, with lactic metabolic acidosis which hence decreases bicarbonate buffering. Thus this metabolic acidosis
together with the respiratory acidosis indicates mixed acidosis from respiratory failure.
This patient has obvious severe hypoxia from possible acute-respiratory distress syndrome (ARDS); and her
survival probability is very poor. Also even in those who survive the prognosis is still poor, with persistent
morbidity/disability from pulmonary fibrosis.
If this really is ARDS, then a chest x-ray would demonstrate diffuse bilateral oedema, with an acute onset. It
must be distinguished from acute cardiogenic pulmonary oedema from CCF, which is done by inserting a
Swan-Ganz catheter, which is inserted into a major vessel and a balloon is blown to measure capillary wedge
pressure to exclude acute congestive cardiac failure causing pulmonary oedema.
The patient‟s chest x-ray is displayed below.
The chest x-ray appears to have a classical pattern indicating diffuse bilateral pulmonary oedema and together
with her acute progression to respiratory failure may indicate that this is ARDS. This is life-threatening,
associated with complications and is caused by hyaline glassy membranes which form in the alveoli that prevent
gas-exchange.
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She was intubated and ventilated with 100% oxygen, but her arterial oxygen saturation remained dangerously
low. A diagnosis of acute respiratory distress syndrome (ARDS) was made. Treatment was ineffective and she
died in the Intensive Care Unit several days later. The following tissues were obtained from autopsy.
Interstitial inflammation and interstitial oedema is observed, with neutrophil and lymphocytic infiltrate. There is
obvious diffuse eosinophilic material in the lung alveoli, which are hyaline membranes that have replaced
alveolar epithelium. Hyaline membranes are created from epithelial cell necrotic debris, surfactant and fibrin.
There is a diffuse pattern of alveolar pneumocyte and endothelial damage, indicating ARDS. On higher
magnification:
She would have had a very poor lung compliance and hence poor lung expansion. The loss of surfactant would
cause lung collapse and hence would make lung expansion difficult, causing excessively hard work needed for
breathing.
Hyaline membranes and interstitial oedema would have caused hypoxia due to poor gas exchange.
This explains her respiratory failure; the grossly decreased compliance of the lungs and lack of surfactant
causing atelectasis would mean that she cannot hyperventilate to blow-off CO2.
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ARDS is due to primary epithelial/endothelial injury causing inflammation and alveolar & interstitial
oedema. ARDS is defined as a clinical syndrome characterised by severe dyspnoea of rapid onset, with
hypoxemia, diffuse bilateral pulmonary infiltrates leading to respiratory failure. It is characterised as an
interstitial lung disease of acute origin, with „acute lung injury‟. The other form of acute interstitial lung disease
is of less severity than ARDS but may evolve to become ARDS.
ARDS is also characterised by a ratio of PaO2/FiO2 ≤ 200 mmHg, and a PaO2/FiO2 between 200-300mmHg
identifies patients with acute lung injury.
Causes of ARDS can be divided into environmental & non-environmental (or direct and indirect lung injury).
Non-environmental causes include:
1) Burns and severe trauma including pulmonary contusions and near drowning
2) Aspiration of gastric contents
3) Endothelial injury from Gram-negative septicaemia, the bacterial lipopolysaccharide binds to
neutrophils and macrophages increasing TNF-α, and pro-inflammatory mediators; these cells injure
alveolar epithelial and endothelial cells and thus cause ARDS
4) Diffuse pulmonary infections, such as with pneumonia
5) Obstetric complications such as DIC and endothelial injury as a result of amniotic fluid emboli.
6) Acute pancreatitis
7) Uraemia
Environmental causes of ARDS include:
1) Inhalation of smoke, toxic noxious gases
2) Ingested toxic chemicals
3) Heroin or methadone overdose
4) Acetylsalicylic acid injury
5) Amiodarone induced lung injury
Management of ARDS is to recognise and treat the underlying cause, with supportive care through mechanical
ventilation, nutritional support and preventing complications.
Based on the case above, it can be note that important diagnostic criteria for ARDS includes:
o An acute clinical onset
o With PaO2/FiO2 ≤ 200mmHg (as opposed to acute lung injury (ALI) which has PaO2/FiO2 ≤ 300mmHg)
o A chest x-ray indicating bilateral alveolar or interstitial infiltrates.
o Also importantly, with a pulmonary capillary wedge pressure ≤ 18mmHg or no clinical evidence of
increased left atrial pressure.
o The underlying pathology is diffuse alveolar damage, with three characteristic phases: Exudative,
proliferative and fibrotic:
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The exudative phase is characterised by:
o Capillary endothelium and alveolar type I pneumocyte (alveolar epithelial cell) injury
o Loss of cellular junctions/alveolar barrier
o Exudation and development of alveolar and interstitial oedema
o Production of pro-inflammatory cytokines, chemokines and arachidonic acid derivatives by cells in the
local milieu in the zone of active inflammation, including IL-1, IL-6, IL-8/CXCL-8, TNF-α and
leukotriene B4, to increase the inflammatory response in response to the inciting agent and also to
recruit more inflammatory cells.
o This leads to a chemotactic, inflammatory response, with associated vascular obliteration and this leads
to microthrombi formation.
o The chemotactic signals lead to neutrophil infiltration and exudation of acute-phase proteins into the
alveolar spaces and interstitium. Neutrophils secrete proteases, reactive oxygen species (oxidants) and
platelet activating factor, which leads to more local tissue destruction and necrosis.
o The accumulation of proteinaceous exudates including fibrin, necrotic pneumocyte and endothelial cell
debris together with surfactant leads to the development of hyaline glass membranes.
o Dependent alveolar oedema also leads to atelectasis, which together with interstitial oedema decreases
lung compliance. As a result, there is also shunting and hypoxemia worsens.
During the proliferative phase:
o Patients clinically recover rapidly and usually do not require mechanical ventilation, but still experience
dyspnoea, tachypnoea and hypoxemia.
o Histologically, there is resolution of inflammation and initiation of lung repair, organisation of alveolar
exudates.
o There is a transition from acute inflammation mediated predominantly by neutrophil infiltration to more
of a chronic inflammatory picture, with increasing numbers of lymphocytes infiltrating the lungs.
o As part of the healing response, there is a compensatory proliferation of Type II pneumocytes, which
produce new pulmonary surfactant.
o There is also an increase of alveolar Type III pro-collagen peptide, which is produced in response to
increased levels of TGF-β1 and other pro-fibrotic cytokines including Fibroblast growth factor (FGF),
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platelet-derived growth factor (PDGF), fibronectin, insulin-like growth factor etc. Note that type III
pro-collagen peptide is a marker of increased mortality.
In the fibrotic phase:
o A small percentage of patients progress and become more dependent on mechanical ventilation or
supplemental oxygen.
o Histologically, the alveolar oedema and inflammatory exudates become organised and at this stage it is
converted into alveolar and interstitial fibrosis. The acinar architecture becomes markedly disrupted,
with emphysema-like changes with large bullae. There is also fibrous proliferation in the
microcirculation which leads to vascular occlusion and development of pulmonary hypertension.
o These patients are at increased risk of developing pneumothorax (increased rates of positive-pressure
ventilation with background lung injury and bullae which can rupture), decreased lung compliance and
increased pulmonary dead space volume.
o If the patient survives, this can hence progress to chronic interstitial lung disease with pulmonary
fibrosis. Other important complications after survival include psychiatric disorders such as depression,
post-traumatic stress disorder.
Management of ARDS is individualised depending on the patient‟s underlying condition, along with ICU
supportive care, with the following principles in mind:
1) Recognise and treat the underlying medical/surgical disorder
2) Important fluid management: Increased pulmonary vascular permeability leading to interstitial and
alveolar oedema rich in proteins is characteristic of ARDS. In addition, impaired vascular integrity
augments the normal increase in extravascular lung water that occurs with increasing left atrial pressure.
Maintaining a normal or low left atrial filling pressure minimizes pulmonary oedema and prevents
further decrements in arterial oxygenation and lung compliance, improves pulmonary mechanics,
shortens ICU stay and the duration of mechanical ventilation, and is associated with a lower mortality.
Thus, aggressive attempts to reduce left atrial filling pressures with fluid restriction and diuretics should
be an important aspect of ARDS management, limited only by hypotension and hypoperfusion of
critical organs, such as the kidneys.
3) Glucocorticoids: Inflammatory mediators and leukocytes are abundant in the lungs of patients with
ARDS. Many attempts have been made to treat both early and late ARDS with glucocorticoids to
reduce this potentially deleterious pulmonary inflammation. Few studies have shown any benefit.
Current evidence (2009) does not support the use of glucocorticoids in the care of ARDS patients.
4) Minimise invasive procedures and complications
5) Prophylaxis against venous thromboembolism, gastrointestinal bleeding and catheter/cannula-related
infections.
6) Recognition of hospital-acquired infections, with multi-drug resistant organisms, hospital acquired
pneumonia, or central venous access related.
7) Provision of adequate nutrition, use total parenteral nutrition if required.
8) Manage mechanical ventilation:
o Prevent ventilator-induced injury: barotrauma/volutrauma
o Prevention of alveolar collapse, use judicious positive end expiratory pressure (PEEP),
inspiratory-time and expiratory-time.
o Use novel therapies, including nitric oxide and sildenafil etc.
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Role of arterial blood gas analysis in dyspnoea (laboratory visit)
Some revision: Composition of dry air is ~218% oxygen; 78% nitrogen and 0.04% carbon dioxide, atmospheric pressure at STP
is 760mmHg and the partial pressure of water vapour is 47mmHg at body temperature.
Normal respiratory rate is 12-20 breaths per minute, tidal volume is 0.5L, minute volume is 6-8L/min
depending on sex, height & chest size etc.
The normal anatomical dead space volume is 150mL. Thus with each tidal volume, only ~350mL are
exchanged at the alveoli and hence alveolar volume is 4.2L/min. Rapid, shallow breaths can rapidly reduce
alveolar minute volume.
Oxygen reduction, hypoxemia is rapidly detected by the aortic and carotid bodies and this increases respiratory
drive. However, reduction of carbon dioxide with hypocapnia can limit the hypoxemic respiratory drive.
Decreased pH (i.e. increased H+ concentration) and increased carbon dioxide in hypercapnia also stimulates the
respiratory centre to change respiratory rate. In general alveolar minute volume is inversely proportional to
carbon dioxide levels and hypercapnic drive is important for control of respiration.
Remember the haemoglobin-oxygen dissociation curve; which is recorded when pH = 7.4, Pco2 = 40 mmHg,
temperature 37°C and Haemoglobin concentration 15g/100mL.
Useful points to remember from the graph include:
Po2 (mmHg) %Sat 0 0 20 35 27 50 40 75 100 97.5
This can be used to solve the alveolar gas equation, A 2 I 2 a 2P O P O P CO respiratory quotient . The
respiratory quotient is averaged to ~0.8. Hence for example, 100 = 150 – 40mm/0.8, which determines the A-a
gradient, is important to know and should normally be less than 25.
The effects of oxygen therapy are as follows; 30% FiO2 is equivalent to PiO2 = 214 mmHg; 40% FiO2 is
equivalent to PiO2 = 285 mmHg (e.g. calculate the PiO2 from 760mm – 47mm (H20) × 0.4).
With arterial blood gases, the PaO2 must be compared with PAO2 in order to determine the A-a gradient. The
ABG must also be assessed firstly for acidosis or alkalosis. Base excess is useful to determine if there is a
metabolic or respiratory problem.
Some examples for ABGs: in a patient with narcotic overdose; this patient will have a depressed respiratory
drive from opioids and as such their minute volume will be reduced. Hence their PaCO2 is reduced and PAO2
reduces as per the alveolar gas equation.
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In atelectasis there is collapse of the lower lung alveoli, however, perfusion still occurs in the unventilated lung
(causes a ventilation-perfusion mismatch). The degree of hypoxemia is proportional to the amount of lung
collapse. The patient hence becomes short of breath, but the PaCO2 remains the same or slightly reduced.
In pulmonary embolism, there is reflex shallow rapid respiration. A V/Q mismatch occurs because of poor
perfusion to well ventilated lung. Hence PaO2 is reduced, although PaCO2 is normal or slightly reduced from
rapid respiration.
In ARDS, ventilation & perfusion is uneven in the lungs; there is alveolar-capillary block and hence perfusion-
ventilation mismatch, PaO2 is low and PaCO2 may be normal. However, if the lungs become very stiff, as
occurs with hyaline membrane formation, then the PaCO2 can rise.
In a patient with emphysema, the lungs lose their elastic tissue and alveoli breakdown forming large air sacs and
as a result the dead space volume is greatly increased. The alveolar ventilation is poor and uneven, resulting in
perfusion to unventilated areas. As a result severe hypoxia occurs. Hypercarbia develops due to poor ventilation
mechanics. Hypoxia in the lungs also causes pulmonary vasoconstriction, leading to development of pulmonary
hypertension, which can lead also contribute to V/Q mismatch.
The following displays the characteristics of primary acid-base disorders:
The clinical causes of acid-base abnormalities are described below. The major cause of respiratory acidosis is
decreased rate of pulmonary ventilation, which increases PCO2, which causes increased H2CO3 and thus
increased H+ concentrations. Respiratory acidosis can occur from pathological conditions that damage the
respiratory centres (damage to the medulla oblongata) or that decreases the ability of the lungs to eliminate CO2,
such as with airway obstruction with pneumonia, emphysema, or decreased pulmonary membrane surface area;
or any other factor that interferes with gas exchange between blood & alveolar air. In respiratory acidosis, the
compensatory responses include (1) body fluid buffers and (2) the kidneys, which require several days to
compensate by increasing acid secretion & an increase in bicarbonate.
Respiratory alkalosis results from increased ventilation and decreased PCO2. The causes include over-
ventilation by the lungs. This rarely occurs because of organic pathological conditions, however,
psychoneurosis (anxiety- panic attacks) can occasionally cause hyperventilation to the extent that the person
becomes alkalotic. Physiologic type respiratory alkalosis can occur with ascent to high altitude. The low
atmospheric oxygen stimulates respiration (hypoxic drive), which causes excess loss of CO2, and development
of mild respiratory alkalosis. The major means of compensation are chemical body fluid buffers, and the ability
of the kidneys to increase excretion of bicarbonate.
Metabolic acidosis results from decreased extracellular fluid bicarbonate concentration. This refers to all other
types of acidosis besides those caused by excess CO2 in the body fluids. Metabolic acidosis can result from
several causes: 1) failure of the kidneys to excrete metabolic acids from the body, 2) formation of excess
quantities of metabolic acids in the body, 3) addition of acids to the body by ingestion or infusion, 4) or loss of
base from the body, which has the same effect as addition of acid. Some specific conditions are described as
follows;
1) Renal tubular acidosis results from a defect in renal secretion of acid or reabsorption of
bicarbonate, or both. Some causes include chronic renal failure, insufficient aldosterone secretion
(Addison’s disease), and several inherited or acquired disorders that impair tubular function, such as
Fanconi’s syndrome.
2) Severe diarrhoea is probably the most common cause of metabolic acidosis, caused by the
elimination of large quantities of sodium bicarbonate into the faeces (see diarrhoea notes). As the
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gastrointestinal secretions normally contain large amounts of bicarbonate, this results in a loss of
bicarbonate & hence acidosis. This is especially serious and is a cause of death in young children.
3) Vomiting of intestinal contents: as intestinal secretions are basic, this leads to a net loss of base
from the body & hence acidosis, similar to diarrhoea.
4) Diabetes mellitus: this is caused by a lack of pancreatic insulin secretion (type I) or insufficient
secretion of insulin to compensate for decreased sensitivity to the effects of insulin (type II). In the
absence of sufficient insulin, normal glucose metabolism is prevented. Instead some fats are split to
acetoacetic acids (ketone bodies) and this is metabolised in tissues for metabolic fuel rather than
glucose. With severe diabetes, blood acetoacetic acid levels can rise significantly, causing metabolic
acidosis. In an attempt to compensate for this acidosis, large amounts of acid are excreted in the urine,
sometimes as much as 500ml/day.
5) Chronic renal failure: When kidney function declines significantly, there is a build-up of the
anions of weak acids in the body fluids that are not being excreted by the kidneys. In addition
decreased glomerular filtration rate reduces the excretion of phosphates and ammonium, which
reduces the amount of bicarbonate added back to the body fluids. Thus, chronic renal failure can be
associated with severe metabolic acidosis.
6) Ingestion of acids: rarely large amounts of acids are ingested in the diet, although severe metabolic
acidosis can result from ingestion of certain acidic poisons such as acetylsalicylic acid (aspirin) and
methyl alcohol (forms formic acid when metabolised).
Metabolic alkalosis is caused by increased extracellular fluid bicarbonate concentration. This is not nearly as
common as metabolic acidosis but can occur in the following conditions:
1) Administration of diuretics (except carbonic anhydrase inhibitors); all diuretics lead to increased
flow of fluid along the tubules, usually causing increased flow in the distal and collecting tubules. This
leads to increased reabsorption of Na+ from these parts of the nephrons. Because sodium reabsorption here
is coupled with H+ secretion, enhanced sodium reabsorption also increases hydrogen secretion and an
increase in bicarbonate reabsorption. These changes lead to the development of alkalosis, characterised by
increased extracellular fluid bicarbonate concentration.
2) Excess aldosterone (Conn syndrome): When large amounts of aldosterone are secreted, mild
metabolic alkalosis occurs as aldosterone promotes extensive reabsorption of sodium from the distal and
collecting tubules and at the same time stimulates secretion of hydrogen (and potassium) by the intercalated
cells of the collecting tubules. This increased hydrogen secretion leads to its increased excretion by the
kidneys and therefore metabolic alkalosis.
3) Vomiting of gastric contents: causes loss of HCl secreted by the stomach mucosa and hence
development of metabolic alkalosis. This type metabolic alkalosis occurs especially in neonates who have
pyloric stenosis caused by hypertrophied pyloric sphincter muscles.
4) Ingestion of alkaline drugs: A common cause of metabolic alkalosis is ingestion of alkaline drugs
such as sodium bicarbonate for the treatment of gastritis or peptic ulcers.
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In some instances, acid-base disorders are not accompanied by appropriate compensatory responses. When this
occurs, the abnormality is referred to as a mixed acid-base disorder. This means that there are two or more
underlying causes for the acid-base disturbance. For example, a patient with a low pH would be categorised as
acidotic, and if they had low plasma HCO3- concentration associated with elevated PCO2, one would suspect a
metabolic and respiratory component to the acidosis, which could occur for example in a patient with acute
bicarbonate loss from the GI tract because of diarrhoea who also had emphysema. A convenient way to
diagnose acid-base disorders is to use an acid-base nomogram. When using this diagram, one must assume that
sufficient time has elapsed for a full compensatory response, which is 6-12 hours for a respiratory compensation
in primary metabolic disorders and 3-5 days for metabolic compensations in primary respiratory disorders.
A mnemonic to remember causes of metabolic acidosis is LUSK: Lactic acidosis, Uraemia, Salicylates/Severe
diarrhoea, Ketoacidosis.
Ketoacidosis can be the result of starvation, diabetes mellitus or excess alcohol intake.
Laboratory visit notes: Arterial blood gas (ABG) analysis
Measurement of ABG tensions will detect a disturbance of gas exchange and indicate likely mechanisms, if
hypercapnia is present (PaCO2> 45 mmHg), then alveolar ventilation is inadequate for the body‟s metabolic rate.
If hypoxemia is present and it cannot be accounted for solely by hypoventilation then there is disease of the
lung (i.e. airways, parenchyma, and/or pulmonary vasculature).
Measurement of ABG tensions allows assessment of the severity of the patient‟s gas exchange disturbance. For
example, for any given metabolic production of carbon dioxide, a halving of alveolar ventilation will double
PaCO2.
ABGs also indicate the presence of an acid-base disturbance of the blood and allow assessment of the metabolic
component of the disturbance.
However, ABGs cannot:
o Diagnose the patient‟s underlying disease, nor differentiate between different lung diseases.
o ABGs cannot indicate the severity of the patient‟s underlying disease. For example, spirometry should
be used to assess the mechanical disturbance of the lungs in asthma.
o The decision to administer oxygen to a sick patient is a clinical decision and should not be delayed until
the PaO2 is available. Conversely, some patients with low PaO2, e.g. those with Type II respiratory
failure from stable COPD do not require oxygen therapy.
Interpreting ABGs, for alveolar ventilation:
Is a disturbance of gas exchange present , and if so, what is its type?
o First look at arterial PaCO2 (gives indication of respiratory component is primary or secondary). If
PaCO2 is high (>45mmHg hypercapnia), the alveolar ventilation is inadequate to excrete carbon dioxide
produced by metabolism. Normally ventilation is driven by arterial PaCO2. Therefore, a rise in metabolic
CO2 production, e.g. by exercise is followed by a compensatory rise in ventilation. Thus elevations of
PaCO2 marginally above normal are significant and usually indicate severe disease of the brain (e.g.
medulla), respiratory muscles, chest wall or lungs.
Now look at arterial PaO2:
o Is it normal (assuming PaCO2 is normal)? PO2 = 100 – (age × 0.25). If the arterial PO2 is lower than
expected for the patient‟s age, hypoxemia is said to be present and the mechanism needs to be
elucidated. If the alveolar ventilation is adequate (i.e. arterial PaCO2 is normal or low) hypoxemia is
almost certainly due to a disturbance of ventilation/perfusion ratio in the lungs.
o Is it normal (assuming PaCO2 is elevated)? Alveolar ventilation is not adequate and so it is necessary to
assess whether: i) hypoventilation accounts for the hypoxemia, or whether ii) there is also a disturbance
of the ventilation/perfusion ratio. This is done by estimating the difference between alveolar PaO2 and
the arterial PaO2 (A-a gradient) using the alveolar air equation:
= FiO2 × [Patm - 47] – 1.25[PaO2]
Where Patm is atmospheric pressure (760mmHg), Partial pressure of water vapour is 47mmHg).
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Example:
PaCO2 = 62mmHg (hypercapnia)
PaO2 = 69mmHg (borderline hypoxemia)
FiO2 = 0.28 (on 28% oxygen)
= 0.28 × [760 - 47] – 1.25(62) = 122
Therefore the A-a gradient is 122 -69 = 53mmHg.
A value >15-20mmHg means there is a ventilation-perfusion mismatch and consequently there is disease of the
airways, lung parenchyma or vasculature (nonspecific).
N.B. This alveolar-arterial gradient cannot be used to assess the size of ventilation perfusion inequality.
pCO2 is the partial pressure of carbon dioxide that is being carried in the blood stream to the lungs for excretion
by respiration. This hence represents the respiratory component of ABGs, with normal levels being 35-
45mmHg. Most CO2 is carried as carbonic acid (H2CO3) which is converted back to CO2 for excretion in the
lungs. Any excess is excreted through the kidneys via the bicarbonate buffer system. Respiratory excretion of
carbon dioxide assists us in maintaining a normal pH by eliminating the body of the vast amounts of CO2
produced daily as a result of normal cellular metabolism.
pO2 is the partial pressure of oxygen dissolved in the blood, which normally is 80-100mmHg. This only
represents ~2-3% of the oxygen actually in the body, but it is an important indicator of potential tissue
oxygenation. Without sufficient partial pressure, oxygen is unable to bind to Haemoglobin where the majority
of the oxygen is carried to the body tissues.
Bicarbonate plays a role as the metabolic component of acid-base regulation, with normal levels being 22-
28mmol/l. In acidosis, bicarbonate acts as a buffer throughout the body, while the kidney excretes hydrogen
ions and reabsorbs the bicarbonate. In alkalosis, bicarbonate is excreted while hydrogen ions are retained to
maintain balance.
Acid-base status:
ABGs are also used to evaluate pH, which gives an indication of the primary process- acidosis or alkalosis-
since compensation is never complete.
An abnormal pH indicates the presence of an acidosis or alkalosis and the extent of the acid-base disorder. It
may suggest that compensation has occurred. However, pH alone does not indicate whether a mixed disorder is
present. For example:
o pH 7.20 indicates that a severe acidosis is present and that compensation is either not present or has not
controlled the acidosis. Further investigation is needed to determine the origin of the acidosis and
whether more than one acidotic process is present.
o pH 7.48 indicates a mild alkalosis is present. Further investigation is needed to determine the cause of
the alkalosis, whether it is in its early stages, has been nearly compensated or is part of a mixed disorder.
A normal pH may indicate that a patient has no acid-base disorder. On the other hand, the patient may have a
mix of acidotic or alkalotic events (primary or compensatory) that have offset each other. In addition to the
patient‟s history, HCO3- and PaCO2 must be considered. For example:
o pH 7.45 with elevated HCO3- and PaCO2 suggests that a primary metabolic alkalosis has been
compensated by an appropriate respiratory acidotic response. Similarly, a pH of 7.45 with decreased
HCO3- and PaCO2 suggests a primary respiratory alkalosis has been compensated by a metabolic acidotic
response.
o pH 7.40 with both HCO3- and PaCO2 abnormal indicates that a mixed acidosis and alkalosis are present
that are offsetting each other to give a normal pH.
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Graphical presentation of the acid-base status of blood:
Evaluation of acid-base data is often difficult because of the presence of mixed respiratory and metabolic acid-
base disturbances. Hence the graphical diagram (nomogram) on the following page may prove helpful in
identifying the type of disturbance in a particular patient.
The chart refers to the acid-base status determined in arterial blood or arterialised capillary blood. Each point in
the chart is characterised by four different coordinates representing the acid-base values in a given blood sample:
o The acid-base nomogram shows arterial blood pH, arterial plasma HCO3- and PCO2 values. The central
open circle shows approximate limits for acid-base status in normal people. The shaded areas in the
nomogram show the approximate limits for the normal compensations caused by simple metabolic
disorders. For values lying outside the shaded areas, one should suspect a mixed acid-base disorder.
Why is the test performed?
An ABG may be requested to evaluate symptoms of lung disease, such as a chronic cough or dyspnoea. It is
also used to monitor the effectiveness of oxygen therapy. The acid-base component also gives information on
how well the kidneys are functioning.
Blood gases are important in determining the oxygen status of patients who present with conditions such as
chronic emphysema, pneumonia and asthma. Symptoms of hypoxemia include cyanosis and visual
hallucinations. Oxygen therapy is usually given to correct a low pO2.
Symptoms of hypercarbia include drowsiness, bounding pulse, headaches and tremors (carbon dioxide narcosis).
A low pCO2 may suggest a metabolic condition such as acute and/or chronic renal failure, or diabetes mellitus.
Congestive cardiac failure also causes a low pCO2.
How is the test performed?
Pulse oximeters are used to monitor the oxygen saturation of the blood and pulse rate in patients undergoing
surgery. An oximetry device is usually placed on the patient‟s finger and measures the transmission of light
through the tissues as a marker of oxygen saturation.
A blood sample is required for analysis on a blood gas analyser.
Using a small needle, the sample is usually collected from the radial artery in the wrist, after performing Allen‟s
test to check for vascular insufficiency of the hand. The blood is collected in a heparisinised tube and excess air
is removed from the syringe with an air cube. OR this can be performed from sampling blood via syringe from a
site of patient vascular access, such as a central or peripheral arterial line.
At least 500μl of blood is needed to be analysed in the reader and thus collection requires a special syringe.
After collecting blood, it should be well mixed in its heparisinised tube, and any air bubbles fully expelled to
remove any excess oxygen (as air bubbles may falsely elevate the pO2 measurement). Remove the needle to
prevent a needle-stick injury, remove excess air with the air cube and then attach the syringe cap.
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Note that an arterial blood sample for an ABG measurement is stable for ~10 minutes at room temperature,
and hence it must be sent to the lab immediately (via a carrier, as the hospital vacuum pathology tube transport
system may also decrease pO2), or placed on ice (which can increase viability to 30 minutes- although this can
lyse cells and this can hence falsely elevate serum potassium readings for example).
The requesting medical officer must make sure that they have checked the following:
o Correctly labelled the sample, with the patient‟s details and medical record number, check patient labels.
o Appropriately fill in any pathology request forms, with brief history of clinical case.
o Provide your own contact details (pager etc.)
The sample is then introduced to the analyser where specific electrodes measure the partial pressures of gases,
pH and concentrations of other analytes in the blood. The syringe is placed in a specific part of the machine and
a small lever draws up a blood sample by suctioning.
There is then protein removal/washout of the analyser after the sample has been analysed and after these
washing and calibrator reagents are finished, the analyser‟s calibrator reagents must be replaced.
Results take about 2 minutes to obtain after placing the sample in the analyser.
Some of the important measurements obtained include pH, pO2, pCO2, lactate, glucose, total creatinine,
Haemoglobin (Hb), carboxy-Hb, met-Hb, total Hb, sodium, potassium, chloride, bicarbonate and calcium.
One important source of pre-analytical error is leaving the patient tourniquet on for too long (falsely elevates
potassium and some other ions), sample clotting due to poor heparin mixing and not analysing the sample
immediately/efficiently.
The role of ABGs in investigating acute dyspnoea
A patient presenting with acute dyspnoea can be due to several major mechanisms: decreased inspired PO2,
hypoventilation, shunting and V/Q mismatch (*decreased diffusion is also a cause). Through
history/examination and use of the A-a gradient, you can determine the nature of acute dyspnoea.
The clinical situation contributes greatly in decreased inspired PO2 and hypoventilation – since there is no
intrinsic pulmonary defect, there is no dysfunction in gas exchange. In a patient with raised A-a gradient,
organic causes of shunting and V/Q mismatch should be considered and further investigated. These may include
airways disease, ILD, alveolar collapse amongst others. ABG (+A-a gradient) should not be considered
diagnostic, rather, guides clinical thinking and directs further investigations (e.g. PE: (?)D-dimer, ECG, lower-
limb Doppler study, V/Q scan, CTPA)
Acute dyspnoea has many causes:
o Asthma
o Pneumonia (with or without aspiration)
o Pulmonary oedema
o Pneumothorax
o Pulmonary embolism
o Metabolic acidosis
o Acute respiratory distress syndrome
o Panic attack
Other causes include:
o Pulmonary: obstructive (asthma, COPD, foreign body); restrictive (ILD, pleural effusion, respiratory
muscle weakness, obesity); aspiration
o Cardiac: MI, CCF (orthopnoea, paroxysmal nocturnal dyspnoea), arrhythmia, cardiac tamponade
o Neuromuscular: diaphragm dysfunction, phrenic nerve palsy, Guillain-Barre syndrome, Myasthenia
gravis, brainstem and upper spinal cord segment injuries.
o Metabolic: acidosis, hypercapnea, sepsis
o Haematological: anaemia, methaemoglobinaemia
o Psychiatric: anxiety
The Clinical presentation gives many clues, ABG (and A-a gradient) guides further investigations. The alveolar-
arterial oxygen gradient (A-a gradient) is useful in determining the type of respiratory failure. Determined by
the equation:
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Using the A-a gradient equation, one can determine whether hypoxia is due to a problem at the pulmonary or
the extrapulmonary level (760 mmHg is atmospheric pressure at the sea level, 47 mmHg is the pressure
displaced by water vapour, 0.8 is the respiratory quotient). The normal A-a gradient is around 10 mmHg
(Normal PAO2 = 105 mmHg, normal PaO2 = 95 mmHg).
This figure increases with age and should increase with an increasing FiO2 (because you are increasing the
PAO2). This figure stays the same in an extrapulmonary event (e.g. hypoventilation: there is no issue with the
lungs). This figure increases in a pulmonary event (e.g. ventilation/perfusion mismatch, PaO2 drops, PaCO2 stays
roughly the same: CO2 diffusion is 20× better than oxygen, hence PAO2 stays the same, A-a gradient increases).
Defects in diffusion, ventilation-perfusion, and left-to-right shunting is suggested by an increased A-a gradient.
You can differentiate V/Q mismatch with shunting by increasing FiO2, and in V/Q mismatch there should be an
improvement in PaO2 (increase in FiO2 increases PAO2, and in mismatch improves the diffusion across the areas
which are exchanging: the exchange cannot be further improved when it is a left-to-right shunting problem,
such as in congenital cyanotic heart disease- e.g. atrioventricular/ventricular septal defects or patent ductus
arteriosus).
There are various ways to estimate an age-adjusted A-a gradient (to determine an actual rather than background
increase): use ≈15 mm Hg for <30 yo and +3 mm Hg per decade beyond 30 (Harrison‟s).
Below is a flow diagram from Harrison‟s which is useful in determined the causes of acute dyspnoea with
hypoxemia:
Pathology of Lung Cancer:
Lung cancers can basically be divided into either small-cell lung cancers or non-small cell lung cancers. The
main treatment for small cell lung cancers is chemotherapy, which includes Etoposide. Non-small cell lung
cancers basically represent all other types of lung cancer besides small-cell and are broadly divided into the
following three categories:
1) Adenocarcinomas.
2) Squamous cell carcinomas.
3) Large cell/undifferentiated lung cancers.
Other important but less common forms of lung neoplasms include bronchoalveolar cancers (usually
encountered in non-smokers), mesotheliomas and carcinoid tumours.
As with all other cancers, it is important firstly to diagnose and identify what the type of cancer is and identify
grade, and then stage. Basic staging involves: A CT scan of the chest and abdomen, PET scan with 18-
fluorodeoxyglucose is also very important for staging and identifying other areas of metastatic disease that may
not be seen on other scans. It is also perform lung-function tests and check cardiovascular health/coronary
arteries for atherosclerotic disease & check for myocardial ischaemia, which is important to identify
cardiopulmonary reserve to see if the patient may be suitable for surgery, if the cancer is not advanced or is a
well localised. Note that of all lung cancers, only ~5% require surgery. After staging and checking patient lung
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and cardiac function, one must then decide for surgery, or if this is not suitable, appropriate chemotherapy or
radiotherapy or both.
Smoking is the most important epidemiological risk factor by far for the development of lung neoplasms. 10
pack years of smoking increases risk of lung cancer 10-fold. With a >40 pack year history, ~20-30% develop
COPD, but also have a higher risk of developing lung cancer.
Also note that 80-90% of lung cancers occur among smokers, but there is only a 10% mortality of lung
cancer from smoking (i.e. only 10% of smokers die from lung cancer, whereas the mortality amongst non-
smokers is 1%). In non-smokers, this is usually amongst women and may be related to hormonal factors
causing cancer.
The major determinants of risk among smokers are the number of cigarettes smoked per day as well as the total
number of years smoked (usually expressed in pack years, that is the number of packs of cigarettes smoked per
day multiplied by the number of years smoked).
The risk of lung cancer, however, falls progressively in the decade following discontinuation of smoking, and
loss of lung function above the expected age-related decline ceases with the discontinuation of smoking.
However, the risk of developing lung cancer is still present and is just slightly above the risk for the normal
non-smoker population. If a person quits smoking, risk thus declines and by 10 years the lung cancer risk is
only slightly above that of someone who has never smoked, but the risk never returns to baseline.
Other important carcinogenic exposures that can lead to lung cancer includes:
o Radon gas or uranium exposure (Radon is a naturally occurring radioactive gas)
o Asbestos (increases risks of lung cancer and mesothelioma, apart from asbestosis).
o Environmental pollutants (e.g. airway pollution, vehicle exhaust fumes).
o Second hand (passive) smoke o Silica and silicosis
o Heavy metal exposure- Arsenic, beryllium, cadmium, chromium, haematitie, nickel, tin mining.
o Man-made mineral fibres- polycyclic aromatic hydrocarbons, diesel exhaust fumes, cooking oil
vapours.
o Adenomatous hyperplasia of the lung is a precursor for lung adenocarcinoma.
These other carcinogens may be involved with some of the non-smoking related lung cancers that are
encountered.
Even though COPD and neoplasia are the most important respiratory complications of smoking, other
respiratory disorders, e.g. spontaneous pneumothorax, bronchiolitis-interstitial lung disease, pulmonary
Langerhan‟s cell histiocytosis and pulmonary haemorrhage with Goodpasture‟s syndrome are also associated
with smoking.
Evidence on a biological and molecular level as well as an epidemiological level confirms pathogenesis of lung
cancer from cigarette smoking. From the biological perspective– activation of dominant oncogenes and
inactivation of tumour-suppressor genes in cells leads to dysplasia and neoplasia. Activation of autocrine
growth factors and increased cell turnover related to chronic inflammation and irritation increases the likelihood
of neoplastic transformation. From the epidemiological perspective cigarette smoking, first- or second-hand,
exposure duration and intensity are all linked to increased risk for developing lung cancer.
Basic biology of lung cancers and pathogenesis
Lung cancer cells have multiple gene mutations (perhaps ≥ 20)
Once cells have acquired necessary mutations to have acquired malignant behaviour leading to cancer stem cell
and then this leads to clonal proliferation.
The bulk of a lung cancer is likely to contain a large proportion of sub-malignant cells. Cancer stem cells must
be eradicated to „cure‟ disease, but cancer stem cells likely to be more resistant to chemotherapy.
Lung cancer pathogenesis is associated with activation of many oncogenes:
o RAS family of oncogenes leads to formation of the onco-protein KRAS in adenocarcinoma (KRAS
causes increased GTPase siganalling related cell growth, differentiation and survival; and unregulated
increase in cell function).
o Tyrosine kinase domain of the epidermal growth factor receptor (EGFR) in adenocarcinoma from non-
smokers) leads to unregulated increase in growth. In lung cancer other EGFR family members
including Her2/neu and ERB3 may also be upregulated.
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o The BRAF, PIK3CA, PIK3CA/AKT/mTor pathway may also increase in amplification, with
rearrangement and loss of transcriptional control of myc family of oncogenes. There are C-myc changes
found in non-small cell lung cancer and N-, L-myc changes found in small cell lung cancer.
o Some cancers also have Bcl-2 over-expression (oncogene) which has anti-apoptoic functions (also has a
role in granuloma survival in sarcoidosis).
o There may also be an increase in telomerase activation, which increases telomere repair of DNA,
leading to “immortality” of DNA.
o Important tumour suppressor genes involved include TP53 (p53- the „protector‟ or „guardian‟ of the
genome, which can be due to an inherited loss of one copy of the gene, and predisposing to
carcinogenesis with mutations in the second copy (e.g. p53 mutations or RB in retinoblastoma). There
may be tumour-acquired inactivation via DNA methylation, or both. The normal function of the p53
protein is indicated below and indicates how p53 functions when DNA damage or cell cycle
abnormalities occurs. p53 can induce to apoptosis, or cell cycle arrest:
o There are also tumour suppressor genes on chromosome 3p, which can also be mutated.
o Autocrine growth factors: Theory holds that lung cancer arises from a progressive, multistep process
that involves carcinogens causing mutation (initiating the neoplastic process), and promoters of the
neoplastic process. Lung cancer cells produce many peptide hormones and express receptors for
hormones which leads to autocrine stimulation; nicotine is an extrinsic example. Cigarette smoke has
carcinogenic derivatives of nicotine which leads to lung cancer cells expressing nicotinic acetylcholine
receptors that are responsible for promotion of tumour formation and reduction in apoptosis.
Inherited/genetic syndromes associated with lung cancer include: p53: Li-Fraumeni syndrome which
causes lung and breast cancer. Chromosome 6p23 mutations, polymorphisms of cytochrome P450
enzymes which cause decreased metabolism of carcinogens and chromosome fragility (mutagen
sensitivity) which increases potential for chromosomal changes.
Targeted therapy is thus directed against VEGF (Avastin), EGFR (ERBB/Her family) ligands :
Her2/neu (Herceptin- trastuzumab), Her3, Her4, tyrosine kinase inhibitors etc., which specifically
antagonise oncogene associated proteins.
Old Phase 1 revision notes for molecular biology:
Oncogenes are formed from proto-oncogenes either by deletions (in-dels) or point mutations of DNA coding
sequence leading to a hyperactive protein being formed, or gene amplification whereby a normal proto-
oncogene protein is overproduced. Another mechanism of oncogene formation is that chromosomal
rearrangement occurs (i.e. translocations, deletions, duplications, inversions) that affects a nearby promoter
region of the DNA segment that causes transcription to become overactive & hence proteins overproduced; or
fusion occurs of the proto-oncogene segment to a gene that is actively transcribed (house-keeping genes) that
hence causes the proto-oncogene to also be actively transcribed, which leads to formation of a fusion protein
which is hyperactive (see image below).
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Oncogenes that are formed as a result of genetic mutations include genes that code for growth factors, growth
factor receptors, intracellular signal transduction proteins & transcription proteins. Hence these mutations
ultimately affect gene expression. Note that mutation in only ONE COPY of a proto-oncogene can have
disastrous effects that lead to the oncogene to abnormally cause cell proliferation. Hence most oncogenes
behave as dominant alleles.
Examples of proto-oncogene mutations that lead to abnormal onco-proteins includes dimerising cell surface
receptors. For example, Her2/neu receptors (in some breast cancers) are growth factor receptors on the cell
surface, which are encoded by proto-oncogenes. A single point mutation leads to the formation of an abnormal
Neu onco-protein receptor that dimerises without the need for external growth factors (see below). This leads to
a receptor that is always active and when it is normally activated, it is a kinase that phosphorylates signal
transduction proteins that leads to a response by the cell nucleus to cause transcription. Since it is now always
active & dimerised, it can readily phosphorylate signal transduction proteins & hence cause the cell to
abnormally produce proteins. Another example is epidermal growth factor receptors, that when mutated become
ErbB onco-protein receptors that also causes abnormal signal transduction; the beginning of cancer development.
Ras is a G-protein that is involved in the signal transduction pathway for epidermal growth factor receptors
(tyrosine kinase dimerising receptors) by activating downstream proteins with GTP (it is a GTPase switch
protein- hence G protein). It is also a proto-oncogene protein that when a single point-mutation occurs at a
particular codon (glycine at position 12) leads to formation of the mutant K-Ras oncogene that is involved in
continual stimulation of the growth signalling pathways regulated by Ras & hence continual cell growth. K-Ras
is also involved in colorectal carcinomas & involved in ~30% of all cancers. It is possible to detect Ras proto-
oncogene mutations by PCR using primers which will only anneal to the gene if the correct sequence is present.
Following detection of mutant genes by PCR, it is possible to perform DNA sequencing to confirm this finding.
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Diagnostic techniques are being developed to identify mutant K-Ras in both patient stool samples & serum for
colorectal adenocarcinoma, although no. of cancer cells are very low & hence detection methods must be
extremely sensitive.
Tumour suppressor genes are genes that have a normal role in producing inhibitory proteins that inhibit cell
division & the cell cycle, in response to DNA damage. This inhibition allows the cell to repair DNA damage via
ligases & DNA polymerases. Other tumour suppressor gene proteins are involved in directly repairing damaged
DNA, preventing the cell from accumulating cancer causing mutations. Other tumour suppressor genes are
involved in detecting cell DNA damage at restriction points of the cell cycle (i.e. between G1 & S phases) & if
there is significant damage it leads to formation of death activators & proteins that induce apoptosis.
However, cancer predisposition occurs if tumour suppressor genes are mutated, since the cell will continue
proliferating despite accumulated mutations which are thus not repaired; initiating cancer development. Unlike
oncogenes, tumour suppressor alleles behave recessively; hence mutation in both tumour-suppressor genes is
required to block tumour suppression, as one functioning allele has the capacity to repair cell damage.
One of the most important of tumour-suppressor genes in the p53 gene, which is involved in stopping the cell
cycle (by activating cyclin-dependent kinase inhibitors) if there exists DNA damage & activating repair
mechanisms to repair DNA. Also if DNA damage is irreparable, then the p53 protein is involved in activating
apoptosis. p53 is one of the most important of tumour suppressors as it is mutated in ~50% of cancers & when
damaged (TP53) it can lead to more aggressive, metastatic cancers with worse prognosis.
Some hereditary cancer syndromes are the result of inheritance of one defective tumour suppressor allele; hence
these people are thus one step closer to accumulating the necessary mutations for cancer development.
Examples include children that have inherited one abnormal Rb tumour-suppressor gene, whose protein is
involved in inhibiting a transcription factor for cell proliferation. Upon acquiring another mutation in the second
Rb allele, these children are thus prone to retinoblastoma (as well as some other cancers, such as osteosarcoma)
at a younger age compared to normal individuals.
Other hereditary cancer syndromes include certain pancreatic cancers, ~1-5% of breast cancers (& some ovarian
cancers) that involve BRCA1 & BRCA2 tumour suppressor gene mutations, which also explains incidence of
male breast cancers. Other acquired mutations include tumour suppressor genes involved in nucleotide excision
repair, repairing DNA strand breakage from UV light. These people with Xeroderma Pigmentosum & who are
at great risk with minimal UV radiation & hence acquire melanomas & other skin cancers at a young age &
most die by age 20.
DNA mismatch repair is employed by cells to maintain the fidelity of DNA replication by correcting
nucleotide mispairing & small insertions or deletions caused by errors from DNA polymerase during replication.
In the mismatch repair system, a protein called MutS scans the DNA for mismatches by recognising them due to
the distortion they cause to the DNA backbone (e.g. pyrimidines paired with pyrimidines). A second protein,
MutL searches for the damage & triggers degradation of the damaged area, removing strands from the vicinity
of the damage. Then DNA polymerases can repair this segment of DNA by synthesising the correct DNA
sequences. Because of their importance in DNA repair, mutations in mismatch repair genes lead to over a
hundred fold elevation in mutation rate & hence genetic instability leading to cancer.
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Inherited loss of the gene mismatch repair system hence predisposes to colorectal cancer, particularly
hereditary non-polyposis colon cancer (HNPCC). HNPCC is an autosomal dominant disorder, which
accounts for ~3-5% of all colorectal cancers, with most cases occurring as a result of mutations to the MutL &
MutS genes. Individuals with HNPCC hence have a high 70-80% lifetime risk of developing colorectal
carcinomas as well as ovarian cancers (known as the Lynch syndrome) & hence must be screened often for
development of malignancy. Note that MMR gene mutations may be sporadically acquired that predispose to
bowel cancer.
Detection of mismatch repair defects can be performed by assays for protein or also by instability of
microsatellite DNA. Microsatellite DNA is found in the DNA of colorectal cancers in individuals with
mismatch repair gene mutations, as mismatch repair mutations leads to accumulation of nucleotide repeats &
hence abnormal microsatellite DNA.
The Adenomatous Polyposis Coli tumour suppressor gene APC, is a tumour suppressor gene involved in APC
is involved in the Wnt signalling transduction pathway. Binding of Wnt proteins by a cell is a signal for cell
cycle progression. β-catenin is a protein that mediates Wnt protein signalling. When β-catenin is in the
cytoplasm, it however, becomes bound to the APC protein, which targets it for destruction, hence APC inhibits
cell proliferation. Wnt signalling however, causes APC to release β-catenin, which then moves to activate Wnt
proteins to increase transcription factors of growth promoting genes. Thus if APC is mutated, β-catenin is free to
activate Wnt proteins that continuously promotes cell growth.
APC mutations have a very important role in colorectal carcinomas, as mutations occur in over 60% of tumours.
There is also an autosomal dominant syndrome called Familial adenomatous Polyposis (FAP), where a
mutation in APC is inherited. This is uncommon, but like HNPCC it is important in predisposing to colorectal
cancers & accounts for <1% of all colorectal neoplasms. FAP is characterised by the development of hundreds
of intestinal adenomatous polyps (unlike HNPCC) & extra-colonic tumours.
Sporadic APC mutations are also involved in the adenoma-carcinoma sequence, which can lead to a hyper-
proliferative epithelium with increased genetic instability & activation of K-Ras, loss of Smad4 (another tumour
suppressor) & other tumour suppressors (i.e. mismatch repair etc.), loss of p53 & telomerase activation, which
leads to carcinoma formation. It is important to note that the accumulation of mutations, rather than their
occurrence in a specific order is more significant.
The adenoma-carcinoma sequence (in colorectal cancer) was discovered by analysis of intermediate stages-
including polyps, benign adenomas & carcinomas isolated by surgeons, allowing major mutations within each
stage to be identified.
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Smoking, and its link to lung cancer
There is a decreasing trend amongst all smoking populations. Males smoke more than females in most age groups.
There are a substantial proportion of secondary school students smoking. Like other developed countries,
prevalence of smoking is inversely proportional to educational qualification and occupational status. Aboriginal
and Torres Strait Islander populations smoke more in total (>50%) and as age-adjusted populations.
Nicotine replacement therapy serves to replace the cravings of smoking and combat nicotine withdrawal. There
are currently many methods for delivery; including gum, patches, lozenge, inhaler and sublingual tablets.
Currently, about 19% of the Australian adult population are smokers, according to the 2007 data. There is a
significant proportion of adult smokers leading to a high burden of disease (prevalence in males is 21%, females
18%). The following figure indicates that smoking has become a decreasing trend in all age groups, however,
the peak smoking rate is in the 25-29 year old age group:
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Tobacco companies target 18-24 year olds, indicating “smoking is fashionable” and this has led to a rise in
smoking prevalence especially in developing countries.
The prevalence of smoking is inversely related to occupational and socioeconomic status.
Also there is a greater number of smokers amongst those with mental illness and people with substance abuse
disorders.
Smoking cessation is critical in preventing lung cancer and other cancers (oropharyngeal, gastro-oesophageal,
renal, urothelial, gynaecological etc). reducing risks of aggravating other respiratory diseases (COPD, asthma,
infections etc) and increasing cardiovascular disease risk (myocardial infarcts, ischaemic strokes, deep venous
thrombosis & pulmonary embolus, peripheral vascular disease in conjunction with other cardiovascular disease
risk factors). Apart from the numerous health benefits, there are also many economic benefits for the patient.
The major benefits according to timeframe after quitting si summarised below:
Smoking and smoking-related harm prevention is practiced at 3 levels:
o Primary (preventing initiation of tobacco use)
o Secondary (identifying disease related to tobacco use early, and treating it)
o Tertiary (rehabilitation after a tobacco-related disease sets in)
The strategies used include (1) government/community legislation (e.g. taxation, pricing, advertising laws,
restrictions on tobacco companies), (2) community actions (e.g. no-smoking laws at public places etc,
community perceptions), (3) education (community and individual level, advertising of smoking related harms
etc.), (2) treatment (individual smoking cessation)
Many of the prevention strategies are employed in Australia‟s target „at-risk‟ groups:
o Taxation: increasing price has a stronger effect on younger smokers who are „less addicted‟, may
inhibit tobacco sales if expensive
o Laws: regarding age at which one can buy, laws preventing tobacco smoking advertising.
o Introduction of community programs: (Quitline) aimed at encouraging smokers to quit.
o Smoking cessation clinics: with smoking cessation counsellors, multi-language resources are available,
e.g. brochures, advertisements, interpreters for non-English speaking background patients.
o Anti-smoking campaigns: promoted in a variety of media sources.
Smoking cessation should be managed with the 5A’s approach:
o Ask: about and document tobacco use at every opportunity
o Assess: the willingness and motivation to change and confidence to quit- “are you interested in
quitting?”
o Advise: the smoker to stop
o Assist: the smoker to stop (education; Quit-line, counselling, smoking cessation counsellor, nicotine
replacement therapy)
o Arrange follow-up: to maintain smoking cessation and prevent relapse
Pharmacological management of smoking cessation:
Smoking cessation essentially requires providing a gradual reduction to nicotine intake rather than „cold turkey‟
and this leads to reversal of neurological changes in the dopaminergic reward pathways of the brain: which has
shown to improve quit rates.
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From eTG: Dependence on cigarettes has both ritual and addictive components. If judged by quit rates in
motivated individuals, nicotine seems to be one of the most addictive substances yet discovered. Nicotine
replacement therapy (NRT) approximately doubles quit rates compared with controls, irrespective of the
intensity of other support and non-pharmacological intervention- in primary care, quit rates are doubled from
approximately 5% to 10%, and in more intensive settings from approximately 10% to 20%. All patients with
high or moderate nicotine dependency, or whose previous attempts to quit have failed because of nicotine
withdrawal symptoms, should be offered NRT. Consider the level of nicotine dependence when selecting NRT
for those who smoke at least 10 cigarettes daily:
o High: waking at night to smoke, or within the first 5 minutes after waking; usually smokes more than
30 cigarettes daily.
o Moderate: smoking within 30 minutes of waking; usually smokes 20 to 30 cigarettes daily.
o Low-to-moderate: not needing to smoke within the first 30 minutes of waking; usually smokes 10 to 20
cigarettes daily
o Low: not needing to smoke in the first hour after waking; usually smokes fewer than 10 cigarettes daily
*NRT for quitting should start at the quit date, not while the patient is still smoking.
Important methods in NRT include:
o Nicotine patches: which are easy to use, contain half the nicotine concentration of normal cigarettes,
no need to taper dose. However, can be associated with itching/scratching.
o Nicotine gum: 1/3rd
to 2/3rd
nicotine concentration of cigarettes. Should be used for 3 months before
tapering. Possible adverse effects include GIT disturbances, dyspepsia, nausea.
o Nicotine inhaler: Plastic cylinder with cartridge containing 10mg nicotine. 1/3rd
nicotine concentration
of cigarettes, good for smokers who miss the hand-to-mouth action.
o Nicotine lozenge: Absorbed from oral mucosa, good for smokers who like the „quick onset‟ form of
nicotine.
o Sublingual tablets: Tablet is placed under the tongue & disintegrates over 30 minutes. Nicotine
concentration is comparable to gum & lozenges.
o Combination therapy; patches are probably easiest but choice is a personal one.
o Must start after smoking cessation; cannot start while still smoking.
The aim of NRT is to reduce withdrawal symptoms, by providing some of the nicotine from cigarettes but
without the harmful components of tobacco smoke.
NRT is available over-the-counter and can be used in all groups of smokers, including children/adolescents,
pregnant women and patients with cardiovascular disease.
As above, evidence shows that:
o All forms of NRT are equally effective for long-term smoking cessation
o NRT helps smokers unwilling or unable to stop smoking to decrease smoking consumption
o There are no real risks of use, using NRT to quit is always safer than continuing to smoke
Other important pharmacotherapies include:
o Varenicline (Champix): Nicotinic acetylcholine receptor partial agonist, which decreases cravings and
withdrawal symptoms.
o Bupropion (Zyban): Selective catecholamine (noradrenaline/dopamine) reuptake inhibitor with
minimal indolamine (serotonin) reuptake and no inhibitory effect on monoamine oxidase (MAO) and
hence avoids side-effects of other SSRIs including weight gain and loss of libido and has a role in
smoking cessation, by decreasing the urge to smoke and nicotine withdrawal symptoms.
o Nortriptyline: Tricyclic anti-depressant, normally for major or worsening depression, also has some
role in smoking cessation.
o These other pharmacotherapies may be of adjunct use with NRT.
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Case Protocol 19: lung cancer
A 61 year old woman presented to her LMO with a three-week
history of cough and chest pain. She had coughed up a small
amount of blood-stained sputum. There was no history of fever or
night sweats.
Examination revealed a thin woman with dyspnoea on mild
exertion. There was decreased expansion of the left side of the
chest and the percussion note at the left base was stony dull.
Auscultation revealed expiratory rhonchi, and there was no
friction rub.
Further information from history would include asking about:
o Ask questions based on the differential diagnosis: infective (sputum colour, fever, infectious contacts
(e.g. TB), COPD. Neoplastic: (systemic symptoms, smoking history, family history, past medical
history, asbestos); pulmonary thromboembolism: recent surgery/trauma, acute onset, unilateral
calf/leg swelling, leg pain.
o The nature of her cough, presence of mucous, how many previous episodes of haemoptysis, has she had
a cough previously or previously diagnosed CAL/bronchitis/asthma/tuberculosis? How long has she
had the cough? (acute<3 weeks, or chronic>8 weeks?) Is there a constant (intrinsic) or intermittent
(extrinsic) cough? Blood streaked sputum: infection, bronchiectasis, lung cancer, pink & frothy: APO,
frank haemoptysis: TB, lung cancer, PE, bronchiectasis, Wegener‟s, Goodpasure‟s (rare). Timing of
cough: asthma worst at night, APO or GORD worse at night whilst lying supine, special triggers, e.g.
pets, cold, exercise, indicates asthma. Character: wheezy, if airway obstruction, bovine vocal cord
paralysis, dry if pulmonary fibrosis, gurgling if bronchiectasis, „whooping‟.
o Also need to ask about the chest pain- characterise the type and locate the site of pain, location- is it a
visceral or more somatic type of pain? Has she had any other associated symptoms, for example the
dyspnoea- severity of dyspnoea on exertion, does she take any regular medications for her dyspnoea,
orthopnoea, trepopnea (together with the stony dullness on percussion & reduced chest wall expansion
may suggest a pleural effusion), paroxysmal nocturnal dyspnoea (does she have underlying heart
failure?), what relives/aggravates her dyspnoea and chest pain, has she required any medications for the
chest pain, any radiation of the pain.
o Ask about any other systemic symptoms- fever, night sweats, fatigue, weight loss, anorexia,
lymphadenopathy, malaise, any other aches/pains. Weight loss of >10% over 3 months is an important
sign that may indicate a neoplastic, a chronic infectious or inflammatory state or associated malnutrition.
Associated with the weight loss should ask about anorexia with decreased appetite being due to
infection/inflammation, malignancy, or a metabolic/endocrine condition such as poorly controlled
advanced diabetes with ketosis, thyroid or adrenal dysfunction.
o It is also important to ask about similar past episodes, past medical history (may suggest previous
history of cancer, tuberculosis etc), current medications.
o Obviously with any respiratory disease process, a smoking history is critical, quantify pack years
smoked and if currently smoking.
o A family history is also very important, particularly to ask about previous cancers indicating genetic
predisposition.
o Occupational history- asbestos, dust/silica, radiation exposures, exposure to tuberculosis, any pets
such as birds.
o Travel history: where and how recent, travel to TB endemic countries, and any infectious contacts.
The full blood count appears relatively normal, except with haemoglobin/haematocrit in the lower range of
normal. ESR is elevated, indicated a chronic inflammatory/infectious/neoplastic process- it is non-specific.
Anything that causes inflammation and an increase in serum acute-phase proteins or proteins related to
inflammation can cause red cells to stick and hence sedimentation rate is faster.
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Provisional diagnosis appears to be lung cancer. Differential diagnosis includes:
o Lung metastases (secondary tumours in lung)
o Lower respiratory tract infection (pneumonia, bronchitis)
o Acute exacerbation of COPD
o Bronchiectasis
o Pulmonary embolism
o Tuberculosis o Ischaemic heart disease with angina and related haemoptysis, (e.g. acute pulmonary oedema)
o Systemic inflammatory disorder- sarcoidosis, other interstitial lung disease, Wegener‟s,
Goodpasture‟s etc.
Important investigations to perform-
o Initially obtain the patient‟s vital signs- haemodynamic status, respiratory rate, oxygen saturation.
o ECG- should be performed in any case of chest pain and even if the pain is atypical for coronary heart
disease it is worthwhile as the patient may have multiple risk factors including age.
o Other bedside tests: spirometry may be performed to identify if there is an obstructive or restrictive
cause for her dyspnoea, peak flow for asthma.
o Full blood count (performed) – check for elevated white cell count, especially neutrophilia if bacterial.
o Inflammatory markers- (ESR performed, could also check for elevated CRP)
o EUC- check for signs of dehydration and third-space volume loss (related to the pleural effusion, and
check baseline renal function if she may require a procedure such as a bronchoscopy or surgery or if she
requires contrast injection for a CT scan). May also check baseline calcium, magnesium phosphate
later.
o Liver function tests: not particularly indicated but may be useful to obtain a baseline in case she
requires medications or requires a procedure with anaesthetics.
o Arterial blood gas- may be required if the patient is dyspnoeic, cyanotic or in respiratory distress.
o Sputum microscopy, culture, sensitivity, cytology and special acid-fast stains- check for signs of
infection including TB and malignancy. Also may require special fungal stains if the patient is
immunocompromised.
o Imaging- chest radiograph (check for signs of a pleural effusion, consolidation, cardiomegaly,
masses/lesions (e.g. coin lesions, cavitations) suggestive of cancer, enlarged hilar nodes (lung cancer,
infection, sarcoidosis); atelectasis (obstructive lesions, basal if fluid is from below), wedge-shaped
consolidation/opacification- Hampton‟s hump suggestive of PE with infarction. May later require a CT
scan of the thorax if a mass is found for staging and high resolution images of the mediastinum and
lymph nodes, assess severity of COPD, bronchiectasis, pleural effusions. Although not indicated here, if
there was as greater clinical suspicion of PE she may require a lower limb Doppler, CTPA or V/Q scan.
Further enquiry revealed that the patient had lost 6 kg in weight during the preceding 3 months. She had smoked
40-50 cigarettes a day since she was 18 years old. A chest x-ray revealed a left pleural effusion. Sputum culture
was negative, as was microscopy for AFB‟s.
Important further investigations to now consider would include firstly identifying the cause of the pleural
effusion. Hence a thoracentesis could be performed to obtain a pleural aspirate- and check again for
microscopy, culture, sensitivity and importantly cytology. Depending on the clinical suspicion for TB, a acid-
fast stains may also be performed. If suspecting a neoplastic process, a pleural biopsy may also be obtained.
Note that the thoracentesis and drainage of effusion may be therapeutic, as it may also relieve her symptoms.
A CT scan of the thorax may be performed to identify the extent of the effusion, and identify a possible cause
for the effusion.
Depending on the results of the previous investigations, a bronchoscopy may also be performed, and any
lesions identified with endobronchial biopsy excision, brushings or washings for cytology. If considering
interstitial lung diseases such as sarcoidosis or even atypical forms of lung cancer, a bronchoalveolar lavage
may be required. Bronchoscopy has the benefit of also allowing sampling of underlying nodes with a
transbronchial biopsy or even use of the new technique of endobronchial ultrasound (EBUS) for biopsy.
Further basic imaging, such as a chest x-ray may be needed after draining the effusion- to check position of
chest tube and identify if an underlying lesion can now be seen on chest x-ray.
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These investigations may allow for a definitive diagnosis of lung cancer, TB, other infection, abscess, vascular
causes etc.
The patient was admitted to hospital for aspiration of the effusion. Cytological analysis of the aspirated pleural
fluid revealed malignant cells. A subsequent chest x-ray revealed a 2cm coin lesion in the left lower lobe near the
hilum. Bronchoscopy and biopsy were performed.
The lesion is very likely a lung cancer, and it is important to note general patterns of where these lesions arise
from. Small cell cancers are mainly found in the upper lobes and can be multiple lesions, at an advanced stage
when first diagnosed. Squamous cell cancers are often found in the peripheries, or also on the surfaces of the
respiratory tract (e.g. oropharynx, larynx, trachea, bronchi etc.). Adenocarcinoma is often peripheral. Large
cell/undifferentiated cancers can arise anywhere.
Bronchial carcinoma: is by definition, a malignant epithelial tumour arising from the bronchi or lung
parenchyma. It is the leading cause of death due to cancer in Australia and is the 5th most common cancer.
Cigarette smoking is the most important factor. On macroscopic examination, it appears as a firm, grey/white
mass arising close to the origin of the main bronchi, presenting as a stenotic ulcerating mass, an infiltrating
peribronchial mass, or a cauliflower like intra-parenchymal tumour growing from the bronchus. A few (mainly
adenocarcinomas) arise peripherally, and are often associated with areas of scarring; one variant
(bronchoalveolar) grows along the alveolar walls with mucin secretion producing a mucoid grey cut surface.
There are 4 principal histological types of lung cancer:
o Squamous cell carcinoma (30%): composed of malignant epithelial cells showing keratinisation, with
keratin pearl formation and/or intracellular bridges (desmosomes/hemidesmosomes).
o Adenocarcinoma (30%): takes two forms, either acinar adenocarcinoma, with a predominance of
glandular structures, or bronchoalveolar carcinoma in which the cylindrical malignant epithelial cells
grow on the walls of pre-existing alveoli. Both principal types produce variable amounts of mucin.
o Small cell carcinoma (25%): composed of loosely aggregated round or oval cells about 2 times the size
of lymphocytes with scanty indistinct cytoplasm (oat cell carcinoma). Usually centrally located, and
widely disseminated when diagnosed, the primary tumour is often small and inconspicuous, but may
produce systemic effects from inappropriate hormone production (paraneoplastic syndromes). These
cancers are usually only responsive to chemotherapy (and may relapse quickly after which they are
resistant to chemotherapy) and are usually not resectable (due to spread at presentation).
o Large cell carcinoma (15%): constitute a group of neoplasms that lack cytologic differentiation. The
cells are large, usually anaplastic and have large vesicular nuclei. Usually centrally located, and
metastasise early in their course so have a poor prognosis.
Clinically it is important to make the distinction between small cell and non-small cell tumours. Non-small cell
cancers are potentially curable if localised with no evidence of metastases (in which they are surgically
resectable, and such localised stage I tumours may be curable with 30-50% 5 year survival).
Carcinoid tumours are rare, neuroendocrine tumours, and may present with serotonin syndrome, which may
present with personality changes, diarrhoea and flushing.
The natural history of lung cancer is a typically early metastases to local nodes (with increased hilar shadows),
and this may be spread by either the lymphatic or haematogenous route. Some cancers may cause
paraneoplastic effects (effects of a neoplasm not related to either the primary tumour mass or metastatic tumour
deposits, e.g. abnormal hormone production, cachexia etc.), for example hypercalcaemia due to Parathyroid-
hormone-related peptide, Cushing’s syndrome due to a ectopic ACTH producing small cell tumour, syndrome
of inappropriate ADH secretion (SIADH) which can cause hyponatremia. Important causes of hyponatremia
include: low volume (diuretics, Addison‟s, vomiting/diarrhoea), normal volume (SIADH, e.g. chest malignancy,
head infection, head trauma (including neurosurgery), high volume (renal failure, CCF, liver failure);
cachexia/wasting due to systemic inflammatory effects. Neuromuscular effects- e.g. Lambert-Eaton
Myasthenia syndrome, increased risk of DVTs and PE, e.g. migratory thrombophlebitis with Trousseau’s
syndrome.
In lung cancer the overall outlook is generally poor. Surgical resection offers the best hope of cure, but the
majority are inoperable. Survival rates for the following includes:
o Non-small cell: 50% 2 year survival without spread, 10% with spread.
o Small cell: median survival is 3 months if untreated, 1-1.5 years if treated.
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Two weeks later she complained of further left-sided pleuritic chest pain and fever.
Important causes for her fever and pleuritic chest pain would include pneumonia (with pleural involvement), or
pulmonary abscess (with pleural involvement) or empyema secondary to abscess/pneumonia.
Pneumonia or lung abscess may be secondary to bronchial obstruction. This usually results from impaired
fluid/lymphatic drainage, distal atelectasis (from radiotherapy, surgery), and aspiration of blood, tumour
fragments or even food from broncho-oesophageal fistula all contribute to the development of pneumonia or
lung abscess.
Lateral confluence pneumonia may be due to obstructive lesion setting off pleural inflammatory response
(lesion centrally, which produced obstruction distally, and because of the atelectasis, a fertile ground for
developing secondary pneumonia).
This presentation may also have developed secondary to a pulmonary thromboembolism, due to her
immobility, hypercoagulable state (increased risk with adenocarcinomas, large cell), post-surgical (or with
trauma).
There may also be progression or extension of the tumour.
Other important complications of lung cancer include:
o Local: recurrent laryngeal nerve palsy (causing hoarseness of the voice), phrenic nerve palsy
(leading to dyspnoea, chest pain/shoulder pain or sensory loss of C3-C5 dermatomal distribution),
Superior Vena Cava obstruction (check with Pemberton‟s sign), Horner’s syndrome (due to an
apical Pancoast’s tumour impinging on the superior cervical ganglion), rib erosion due to local spread
and tissue breakdown as well as PTH-related peptide effects, pericarditis and atrial fibrillation.
o Metastatic: brain (neurological deficits, headaches, seizures), bone (bone pain, anaemia,
hypercalcaemia, pathological fractures spinal cord compression), liver (hepatomegaly), adrenals
(Addison‟s disease), local satellite spread within the lungs, lymph nodes (ulcerating masses from lymph
nodes).
o Endocrine: ectopic hormone secretion, e.g. SIADH (hyponatremia, and increased ADH), ACTH
(Cushing‟s) by small cell tumours, PTH-related peptide (hypercalcaemia) by squamous cell tumours
and adenocarcinoma.
The patient's condition deteriorated over the following three months and she eventually died at home.
Likely causes of death in this patient includes:
o Pneumonia: if she had pneumonia in the previous episode it may have worsened, and the infection may
have spread causing severe infection including an acute respiratory distress syndrome and sepsis. She
may also develop febrile neutropenia if she is on chemotherapy, which can lead to sepsis.
o Pulmonary thromboembolism: again due to her risk factors, which could have led to acute respiratory
failure.
o Disseminated Intravascular Coagulation (DIC): due to Hypercoagulability, leading to widespread
micro-emboli within the circulation.
o Progression/expansion of tumour: metastases to the central nervous system, leading to raised
intracranial pressure and herniation syndromes. Extensive metastases to the liver (>90% involvement)
may lead to liver failure which can lead to death including hepatic encephalopathy (due to ammonia and
toxic nitrogenous waste metabolite build-up).
o Phrenic nerve impingement: May lead to diaphragm paralysis and hence the patient would not be able
to breathe unassisted.
o Spinal cord compression: An emergency situation in oncology, if there are metastases and
pathological fractures, may lead to spinal cord compression and hence can lead to neurogenic shock.
o Cachexia: malnutrition, dehydration or electrolyte imbalances, may predispose to dysrhythmias, and
can occur with hyperkalemia or hyponatremia.
o Pericarditis (dysrhythmias): Patient may die from fatal abnormal heart rhythms such as VT and VF.
Important findings on autopsy include:
o Brain- metastases, oedema with flattened gyri and sulci.
o Lungs- evidence of pneumonia, PTE, bony changes in underlying ribs, identify the primary lesion
if still present (if has not been removed).
o Abdomen: metastases to the liver, renal and adrenals. Also consider spinal metastases.
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Case: Bronchial squamous cell carcinoma:
A 65 year old man presented to his local doctor complaining of worsening dyspnoea, cough and haemoptysis over
the past 6 weeks. He had smoked a packet of cigarettes per day for over 40 years.
The patient has presented with a long smoking history and is at major risk for lung cancer development; it is
also important to know his past medical history/background including pulmonary comorbidities, as he may have
developed emphysematous changes after smoking for so long. Furthermore, if he has COPD he may have
predominantly chronic bronchitis (develops in smokers) and they may present with a productive blood-stained
cough. What is really important in these patients is if they have noticed a change in the character of their
sputum (colour, smell, volume etc.). If the haemoptysis is more frequent & copious with a larger amount of
blood-stained mucous it is important to have it investigated as it may no longer be just bronchitis. Based on the
history given, a differential diagnosis can be formulated for what appears to be a sinister underlying cause:
o Lung cancer (Bronchial neoplasms): The time-frame at which his symptoms have occurred as well as
the constellation of symptoms is highly suggestive of lung cancer. Also he has risk factors including
his age, and his long, >40 pack year smoking history.
o Pulmonary Embolism: Although he has had these symptoms over 6 weeks, it does not exclude medium
to small-sized pulmonary thromboemboli. Worsening pain, cough and haemoptysis can all occur with
PE, however, he may also have pleuritic chest pain, which is important to ask for.
o Pneumonia complicated by an abscess: Worsening symptoms of shortness of breath and cough can
occur with a lower respiratory tract infection such as pneumonia. If the pneumonia was complicated,
such as with abscess formation, this could explain the haemoptysis and chronicity of his symptoms.
However, he may have a putrid smelling purulent yellow-brown, blood-stained sputum on
expectoration. Common causes of haemoptysis include bronchitis or lower respiratory tract infection, as
well as PE, bronchiectasis and lung carcinoma.
o Bronchiectasis: Bronchiectasis would explain the chronic symptoms of dyspnoea and often the cough is
blood stained, this is because there is necrosis of airway walls which occurs with dilatation of the
airways often secondary to airway obstruction.
o Cardiac causes: Mitral stenosis/left ventricular failure: In cases of pulmonary oedema and pooling of
fluid in the lungs, there may be a pink tinge in the patient‟s sputum.
o Other infections such as Tuberculosis. Uncommon, but must never simply rule out TB until certain.
This clinical picture does not necessarily indicate tuberculosis but it is low in the differential diagnosis.
Also with TB there would be other constitutional symptoms, such as possible fever, night-sweats,
lymphadenopathy, unexplained weight-loss etc.
o It is important to exclude haematemesis or haematemesis with aspiration as a cause of the patient‟s
“haemoptysis”. Have the patient cough and check if they expectorate any blood in the sputum.
Important features to look for in the patient‟s physical examination re outlined as follows:
o Start at the hands: look for clubbing (occurs in lung cancer, bronchiectasis), wrist tenderness from
hypertrophic pulmonary osteoarthropathy, check for signs of anaemia, signs of brachial plexus
involvement if there is cancer. Check the head for central cyanosis, the face for pallor, jaundice etc. If
there is a known apical lung cancer check for signs of Horner‟s syndrome (ptosis, miosis, anhidrosis)
due to compression of nerves of the sympathetic trunk or compression of the stellate ganglion.
o Examine the lymph nodes of the head and neck region, including the supraclavicular lymph nodes.
o If worried about mitral stenosis check for a Diastolic murmur.
o Important signs to note for the rest of the examination with respect to lung cancer includes: pleural
effusion (stony dullness to percussion, reduced breath sounds, reduced vocal resonance), consolidation
(may also indicate pneumonia developing). Yield in physical examination may not be that high in the
lungs.
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The GP organised a chest x-ray, which is shown below:
This x-ray appearance is typical of a pleural effusion. Mitral stenosis/heart failure will give bilateral pleural
effusion, so some other underlying pathology would have caused this unilateral pleural effusion, such as lung
cancer. If TB is suspected one may see apical cavitation. Unusual to see one lung completely unaffected.
Would have to proceed with further investigations as this does not .indicate any specific underlying pathology.
Further investigations to be organised include:
o A Full blood count (anticipating an elevated WCC and PMN leukocytosis in pulmonary infection,
lymphocyte count in possible Tuberculosis, RBC erythrocytosis in COPD, check for anaemia of chronic
disease).
o Check the patient‟s clinical chemistry including urea, creatinine & electrolytes, to check renal
function, as well as liver function tests.
o Since the patient is coughing, it is important to obtain a sputum sample for sputum
microscopy/cytology, culture and sensitivity. Multiple samples are required, to check cytology for
possible neoplastic cells, similar to a Pap smear for cervical cancer screening, this can be useful for
ruling in lung cancer, and can identify malignant cells. A separate specimen could be used for gram
stain microscopy, culture & sensitivity to check for possible pneumonia/lower respiratory tract infection.
Similarly, if Tuberculosis is suspected, then it is important to perform an acid-fast stain (Ziehl-Neelson
stain) to check for presence of mycobacteria, as well as mycobacterial Lowenstein-Jenson culture &
sensitivity (although results take many weeks to obtain). A special fluorescent stain may also be used.
o Since the patient also has a large left pleural effusion, it is important to assess and manage this; a
pleural aspirate/thoracentesis should be performed. Cytology should be performed on the aspirate to
check for malignant cells, e.g. in the case of mesothelioma, as well as gram-stain microscopy, culture
and sensitivity testing for the possibility of infections such as in empyema thoracis.
o If there is a strong index of suspicion of lung cancer, it is important to organise a bronchoscopy, with
bronchial lavage and excision biopsy if a tumour is identified. Bronchoscopy is important, as it allows
the identification of any exophytic bronchial lesions that may have caused the patient‟s cough &
haemoptysis. It also allows the sampling of cells either for cytology in the case of lavage, or
histopathology with excision biopsy.
o Further imaging can be performed, with a chest CT scan, if one is suspecting malignancy; also apart
from diagnosis, it is important for staging cancers. The greater anatomical detail of a CT scan allows
the observation of airways and identifying which airways are involved in cancer, lymphadenopathy
from spread to lymph nodes (hilar, mediastinal etc.). One may be able to see metastases in the liver, in
scans involving the abdomen.
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The following table summarises the patient‟s clinical chemistry results:
Clinical Chemistry Sodium (mmol/L) 141 135-145 Potassium (mmol/L) 3.7 3.5-5.0 Chloride (mmol/L) 105 95-110 Bicarbonate (mmol/L) 27 24-32 Calcium (mmol/L) 3.2* 2.10-2.55 Phosphate (mmol/L) 0.57* 0.8-1.50 Urea (mmol/L) 3.8 3.0-8.0 Creatinine (μmol/L) 90 60-110 Bilirubin (mmol/L) 15 2-20 Alkaline phosphatase (U/L) 85 38-126 γ-glutamyltransferase (U/L) 25 <30 AST (U/L) 31 <45 ALT (U/L) 26 <45 Total protein (g/L) 64 62-80 Albumin (g/L) 43 33-48
The clinical chemistry displays that the patient has hypercalcemia and hypophosphatemia. The causes of these
electrolyte abnormalities usually include:
o Hyperparathyroidism, which increases excretion of phosphate by the renal tubules and increases
calcium absorption from intestine, bone calcium resorption. or something behaving like parathyroid
hormone. This can also occur with any peptide that acts similar to parathyroid hormone (PTH); such as
PTH-related peptide, which is secreted by some cancer cells and causes this paraneoplastic effect.
Bronchial carcinoma may also be releasing PTH -related peptide– classically produced by squamous
cell lung carcinoma.
o Calcium may also be elevated in malignancy and could possibly be the result of bony metastases, which
may stimulate local destruction of bone by osteoclasts (causing osteolytic bony metastases), releasing
calcium and phosphate. Sometimes in the absence of bony metastases, tumours secrete IL-1 and TNF-
alpha which stimulates osteoclasts and causes this paraneoplastic effect.
The results of sputum cytology and an aspirate of pleural fluid are displayed below. Following this, bronchoscopy
and biopsy of a lesion in the left main bronchus was also performed. On the basis of all the investigations
undertaken it was decided the patient should have a pneumonectomy:
Cytology report: Papanicolaou stain used for sputum cytology. Large, irregular cells with eosinophilic
cytoplasm observed, these are cancer cells. They are a little pleomorphic, with central nuclei. These are
carcinoma cells (malignant tumour of epithelial origin). Different forms of epithelial differentiation can be
picked up on sputum cytology. Although no architecture is preserved here. The redness in the cells with this
stain is keratin. Hence these malignant cells are showing squamous cell differentiation. Not all are accumulating
keratin. Small cells appear to be neutrophils.
Malignant cell,
keratinising
Non- keratinising
normal epithelium
PMNs
125
The pleural aspirate above displays epithelial cells, which display a high nuclear to cytoplasmic ratio, the cells
have irregular nuclear membranes, indicating nuclear pleomorphism. The cells have not accumulated keratin &
are quite convincingly malignant cancer cells.
The patient underwent bronchoscopy with a biopsy and following staging, it was decided that a
pneumonectomy would be performed for curative intent: The following slide displays a histopathological
section from the neoplasm removed after pneumonectomy:
The histological section contains all sectioned borders, and has been taken from bronchi, as there is cartilage
evident. The lesion appears ulcerated, haemorrhagic and the tumour appears to be invading from the epithelial
layer to the lung parenchyma, characteristic of a bronchial squamous cell carcinoma.
The section on the following page displays higher magnifications of the specimen:
The slide above shows a higher magnification displaying normal respiratory (pseudo-stratified ciliated columnar
epithelium) and a section of cartilage is seen, there is no evidence of neoplasia observed here.
The rest of the specimen does not display this normal pattern of differentiation, the slide below displays
abnormal epithelial proliferation in one of the large airways:
126
The slide above displays (with arrow) abnormal epithelial proliferation; squamous metaplasia. It is stratified
squamous, and this metaplastic change occurs to protect against smoke. The epithelial cells lose cilia, and this
interferes with mucus clearance, causing mucous build-up and the “smokers cough”. Smokers are thus at
increased risk of lung infection due to mucous build-up. The next step along for metaplasia may then be to turn
to dysplasia (cytological features of malignancy). The cells become darker staining, larger, with a higher
nuclear to cytoplasmic ratio etc. It may just be that the lower lung lobes are affected, or all areas in the lungs etc.
If dysplasia is full-thickness- this is a bad sign, but if it has not appeared to have invaded then by definition this
is carcinoma in situ. This is not carcinoma in situ because there is invasion. Evidence of invasion can be seen in
the following higher magnification.
On this higher magnification, it is very obvious that the bronchial cartilage is being invaded by malignant
epithelial cells (which are normally very resistant to tumour invasion, it requires tumour cells to have matrix
metalloproteinases and collagenases to degrade and invade the cartilage matrix), which display squamous cell
differentiation. The darker malignant epithelial cells are invading in sheets/nests and cords of cells and the local
invasion suggests malignancy. In order to determine the cell type of the cancer, to distinguish it from other lung
cancers, in this case it is useful to find extracellular keratin blobs, not necessarily small keratin whorls.
127
The specimen has an eosinophilic surface, indicating keratin accumulating on the surface of lesion (this was an
exophytic lesion growing into the lumen of the airway). Malignant cells can be observed underneath the surface
keratin (there is fair amounts of stroma underneath it, which indicates the tumour has stimulated a desmoplastic
fibroblast response). The section below also shows this and indicates a substantial amount of material occluding
an airway lumen (hence causing the patient to cough up mucus with inflammatory cells and blood).
Hence the histopathological diagnosis in this case is an ulcerating squamous cell carcinoma of the bronchus that
is moderately well differentiated. There is evidence of intracellular bridging (a feature of squamous cell
differentiation) and hence this is moderately well differentiated. After histological typing it is very important to
comment on any local invasion or the presence of tumour adjacent or near lymphatics & blood vessels, or if
tumour cells are present near surgical margins, which can affect patient management. There appears to be some
lymphatic infiltration (difficult to see). There is obvious formation of an invasive carcinoma around the lumen
of this bronchus.
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Case 10: Metastatic small cell carcinoma:
A 59 year old woman presented with unproductive cough and chest pain. Bronchoscopy and biopsy revealed small
cell (also known as „oat cell‟) carcinoma of the bronchus. It was decided that an operation was not appropriate and
the woman was treated with chemotherapy. In spite of this treatment she gradually deteriorated over the following 3
months. The following biochemical profile was obtained. Unfortunately, she died 1 week after this investigation.
Clinical Chemistry
Sodium (mmol/L) 144 135-145
Potassium (mmol/L) 2.9* 3.5-5.0
Chloride (mmol/L) 108 95-110
Bicarbonate (mmol/L) 37* 24-32
Calcium (mmol/L) 2.4 2.10-2.55
Phosphate (mmol/L) 1.2 0.8-1.50
Urea (mmol/L) 4.6 3.0-8.0
Creatinine (μmol/L) 90 60-110
Bilirubin (mmol/L) 35* 2-20
Alkaline phosphatase (U/L) 156* 38-126
γ-glutamyltransferase (U/L) 78* <30
AST (U/L) 70* <45
ALT (U/L) 68* <45
Total protein (g/L) 65 62-80
Albumin (g/L) 43 33-48
Glucose (mmol/L) 10.3* 3.0-6.5
Based on her known metastatic disease that was unresponsive to chemotherapy, some abnormalities that would
be expected at autopsy and the basis of the biochemical abnormalities shown above are as follows:
o The biochemical profile displays the patient had hypokalemia and metabolic alkalosis (Hypercarbia)
(although it does not indicate if metabolic acidosis was the original insult or if there was compensation for
it) as well as hyperglycaemia.
o In the liver function tests it should be noted that protein and albumin are in the normal range (as albumin
has a half-life of ~3weeks, this short time span is a marker of chronic liver damage, indicating that
chronic liver damage has not occurred). Note that AST and ALT are mildly elevated, indicating
hepatocellular damage or dysfunction (not in the 1000s as in acute hepatitis).
o These tests also indicate biliary duct obstruction- a cholestatic picture. Intrahepatic biliary duct
obstruction is most likely to have been caused by liver metastases. ALP and γ-GT are also raised which is
also consistent with liver metastases.
o Is there a possibility that the patient may have had excess glucocorticoids in the bloodstream? This could
explain her hyperglycaemia and other possible metabolic abnormalities. Furthermore, it is important to
remember that she has small cell carcinoma. Small cell cancers sometimes do produce excess ACTH and
more commonly they secrete ADH. Hence in small cell cancers abnormalities observed include Syndrome
of Inappropriate ADH secretion (SIADH) and adrenal cortex hyper-stimulation with ACTH. Excess
ACTH can stimulate the adrenal cortex to produce both glucocorticoids and mineralocorticoids, which
could cause mixed features of Cushing‟s and Conn syndrome. In particular, ACTH can cause
hypercortisolism (especially in stress situations) and this can elevate blood glucose. Hypercortisolism can
also cause mineralocorticoid effects, such as those caused by aldosterone. Hence hypercortisolism (and
possible hyperaldosteronism) explains why the patient‟s sodium is in the upper-range of normal and with
there is hypokalemia.
o Metabolic acidosis can be explained by the fact that the patient has low serum and extracellular fluid
potassium levels.This causes movement of large amounts of reserve potassium from the intracellular fluid,
and this requires exchange with hydrogen ions (remember from physiology, hypokalemia leads to
movement of hydrogen ions into the cell). As a result, the extracellular fluid hydrogen ion concentration
decreases, pH increases and this leads to a metabolic alkalosis as a compensation for hypokalemia. Note
that this can occur the opposite way with hypoaldosteronism in Addison‟s disease & the patient develops
metabolic acidosis. Thus there is hypokalemic metabolic alkalosis from paraneoplastic effects of the small
cell lung cancer.
129
Based on her histopathological findings, the reason why she was not treated surgically is explained as follows.
There is a clinical division of lung carcinomas into either small cell or non-small cell carcinomas. Surgical
treatment is not usually used in patients with small cell carcinoma as it is usually a very aggressive cancer that
metastases early. The usual anatomical distribution of lung cancers is that cancers originating in the lung hila
are commonly small cell, squamous cell or large cell carcinomas. Carcinomas originating from the lung
periphery are commonly adenocarcinomas. Hence with small cell carcinomas, there is usually no point in
attempting surgical resection. Patients are thus likely to be treated palliatively, with chemotherapy or adjuvant
radiotherapy with metastatic disease or to relieve symptoms. Palliative chemo-radiotherapy may increase
patient survival time and rarely in some cases may lead to a cure.
Abnormalities that can be found at autopsy are outlined as follows:
o In the lungs: one would most likely find neoplastic lesions in the larger airways (e.g. in the lung hila). The
primary lesion may be either reasonably large or small. Proximal to the primary tumour, the hilar lymph
nodes may be engulfed by local invasion or the nodes may be affected by metastatic disease. The hilar
lymph nodes are usually not the only nodes affected, and other mediastinal nodes may be affected.
o On the lungs: Small cell carcinoma may also spread along the lung surface as a result of intrapleural
spread on the visceral and parietal pleural surface. Cancer at the pleural surface may stimulate pleural
effusion. Inside the lung the tumour may protrude into airways, causing collapse/atelectasis and prevent
drainage of secretions and lymph from the airways, which would predispose to bronchopneumonia. Most
patients would have this once died from cancer, and this will be in both lungs, not just the lung with the
primary lesion. Also one may find on autopsy deposits of metastatic lung cancer in both lungs.
o Metastases: Cancer spread may be identified in lymph nodes, liver, brain, bone and adrenals. Though
small cell carcinoma is not aggressive as melanoma this is still a very aggressive cancer.
The following specimens display sections of lung and liver in a patient who had small cell carcinoma. There is a
small, greyish neoplasm arising from a large bronchus in the upper lobe. Note that even though the primary
cancer is small, it has metastasised extensively. Scattered nodules of metastatic carcinoma are seen on the
pleural surface and multiple metastases are seen throughout the liver:
The following histological sections were taken from the patient at autopsy. It can be seen that there is a large
malignant tumour with irregular borders that appears to be spreading on the lung pleural surface and into the
parenchyma.
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On higher magnification; the neoplastic cells are highly basophilic, with very little cytoplasm
(hyperchromasia- increased chromatin), these are small cell carcinoma cells, which do not display much
pleomorphism (they mostly appear similar). They differentiate to be of the neuroendocrine type (and are hence
associated with ACTH and ADH secretion).
The lung is the only significant site of small cell carcinomas.
The following was also taken from the patient‟s liver indicating distant metastases. It can be seen that on the left
there are normal liver sinusoids, however, invading the liver is small cell lung cancer on the right of the field.
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Case 11: Lung adenocarcinoma:
The following lung neoplasm was identified as a “coin-lesion” on chest x-ray in the peripheral lung of a
different patient. The differential diagnosis of lung coin lesions on chest x-ray includes tuberculosis cavitations,
lung abscess where the pus has not been drained, lung metastases (canon-ball metastases), pulmonary infarction,
patchy pneumonic consolidation, hamartomas, granulomatous inflammation of the lung (e.g. sarcoidosis), and
may even be a primary cavitating lung cancer.
This is a section from the lung, since on the top-right hand corner normal lung tissue can be seen. This is a
neoplastic lesion, since clusters of cells can be seen with loss of differentiation; it is malignant because it is
invading lung tissue. This is an example of small cell carcinoma, which when very poorly differentiated is
termed „anaplastic‟. Athough not well differentiated, this is not anaplastic small cell lung cancer, as seen below
on higher magnification:
On higher magnification, this does not appear to be small cell carcinoma, as there is nuclear pleomorphism
(unlike previous slides), and cells are obviously apparent here. There is also attempt at lumen formation by
some neoplastic cells.
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The cells are not hyperchromatic, although there is only a slightly higher nuclear to cytoplasmic ratio but there
are prominent nucleoli. These cells are still trying to make lumens. There is some wispy material in the lumen
of these glands, this represents mucin. The malignant tumour is actually an adenocarcinoma. There are sheets
of epithelial-type cells making lumens, hence this has glandular differentiation and is thus adenocarcinoma. It is
invasive. One would expect to see this in periphery of lung, as was seen on the chest x-ray, although they can
occur at the lung hila. Note that there is a lot of connective tissue surrounding the tumour, which is a
desmoplastic reaction (stroma induced by carcinoma). Also quite a common host response seen with
malignancy and observed here is lymphocytic infiltration.
Epidemiologically, smoking is the most important risk factor for bronchial squamous cell and small-cell
carcinomas. It is also a risk factor in adenocarcinomas, however, adenocarcinomas also arise in patients who
have never smoked before and this usually occurs in women, so smoking is not as much of a significant risk
factor for adenocarcinomas.
Case 12: Disseminated malignancy of unknown primary:
In this case tissue was prepared from a 56 year old woman who died from disseminated malignancy, with the
primary tumour unknown. The following lung specimen shows malignancy, with an unknown primary.
On autopsy, a pathologist can search for the primary, although this may take several days of searching. If the
patient is alive, histological samples are the best specimens that can be used to identify tumour differentiation.
Special stains, such as immunohistochemical tests can then be used to identify where the tumour cells
originated from. With epithelial tumours, use cytokeratins, mucin stains are useful for adenocarcinomas, breast
cancer may be positive for oestrogen or progesterone receptors. For mesenchymal tumours use special proteins.
Receptors can narrow down certain types of adenocarcinomas to primary sites. Usually melanomas may be a
cause of unknown primaries, although it may be possible to use special stains for melanoma (e.g. cytokeratins
etc). Tumour markers may also be helpful.
This specimen is taken from lung tissue. There appears to be abnormalities in the blood vessels of the lung.
There are islands of cells which are well adherent to each other, and may be trying to form lumens (rounded
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spaces as opposed to artefacts) and are hence possibly epithelial cells. These appear to be metastatic tumour
emboli that have lodged/arrested in the blood vessels of the lung. They may try to extravasate, like little tongues
trying to push through vessels walls to set up secondary metastatic deposits, these usually do not survive for
long but can kill the person. These tumour emboli can sit there for quite a while in the vessels in a dormant state
(e.g. a breast carcinoma, which may arise many years later. These tumour emboli will not kill a patient
immediately. Hence treatment is with chemotherapy, aimed at destroying micro-metastatic lung deposits. The
following is a higher magnification of a tumour embolus in the lung:
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Case 7: Bronchopneumonia:
A 78 year old woman, debilitated by congestive cardiac failure, was admitted to hospital with a 4 day history of
cough and fever. The cough had become productive of yellow sputum over the last 2 days. She also complained
of increasing weakness and lassitude. Examination revealed signs of patchy lower lobe consolidation.
The yellow sputum indicates purulent sputum containing inflammatory cells, predominantly neutrophils.
Important signs not to miss of a patchy lower lobe consolidation include reduced/asymmetric chest expansion
on affected lobe, dullness to percussion, decreased breath sounds, harsh bronchial breath sounds in areas of
consolidation and increased vocal resonance as solid material conducts sound better and additional sounds
would include crackles due to the presence of exudate in the alveoli with pneumonitis.
The following investigations were performed:
Full Blood Count
Haemoglobin (g/L) 118 115-165
RCC (×1012
/L) 4.0 4.5-6.5
Platelet Corpuscle Volume (PCV) 0.38 0.40-0.54
Mean Corpuscle Volume (fl) (MCV) 86 80-100
MCH (pg) 28 27-32
MCHC (g/L) 308 300-350
WCC (×109/L) 20.8* 4.0-11
Neutrophils 18.5* 2.0-7.5
Lymphocytes 1.5 1.5-4.0
Monocytes 0.2 0.2-0.8
Eosinophils 0.1 0.04-0.4
Platelets (×109/L) 270 150-400
ESR (mm/hr) 63* 2-15
C0reactive protein (mg/L) 1200* <5
Arterial blood gases pH 7.49* (7.36-7.44) PaO2 (mmHg) 58* (80-100) PaCO2 (mmHg) 33* (35-45) Bicarbonate (mmol/L) 24 (24-32) O2 saturation (%) 80* (95-100)
Sputum culture results:
Gram stain: Polymorphs +++, Gram positive diplococci in chains
Culture: Pure growth of Streptococcus pneumoniae
Blood culture: Pure growth of Streptococcus pneumoniae in 2 of 2 bottles.
The full blood count displays a neutrophil leukocytosis which is consistent with a systemic inflammatory
response that could have occurred due to infection such as in pneumonia. Also consistent with this is the
increase in acute-phase inflammatory markers such as ESR and C-RP.
The arterial blood gases indicate that the patient has alkalosis. Also importantly, she is hypoxemic and
hypocapnic and this indicates a picture of respiratory alkalosis due to decreased PaCO2, and as the bicarbonate
is normal, there is no metabolic compensation. This pattern of ABGs is consistent with systemic hypoxemia
due to lobar pneumonia. There is thus increased ventilatory drive (which causes her to blow-off CO2 which
causes hypocapnia) due to hypoxia sensed by the central chemoreceptors. Hypoxia occurs due to a V Q
mismatch in the lungs from reduced gas-exchange in consolidated alveoli, which causes hypoxia.
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It is difficult to obtain a good sputum culture, for example if the patient has difficulty expectorating or if they
contaminate the specimen by holding sputum in their mouth, they must expectorate directly into the sputum
sample cup. The patient‟s blood culture is consistent with bacteremia and sepsis, and as there is a pure growth
of Streptococcus pneumoniae in sputum culture and blood culture, she most likely has a community-acquired
pneumococcal pneumonia.
Based on the history, examination and investigation results the provisional diagnosis would be pneumonia. She
also has risk factors for developing community-acquired pneumonia. Congestive cardiac failure produces a
good culture medium for bacterial growth if the patient has pulmonary oedema. Also oedema causes impaired
function of alveolar macrophages; they have impaired phagocytic ability in a fluid-medium. There is also an
increased risk of pneumonia in patients with disseminated malignancy.
A chest x-ray was requested to investigate for possible pneumonia:
An examination of the chest x-ray displays an abnormally shaped mediastinum, with a boot-shaped heart from
congestive cardiac failure. Also in both lung fields there are multifocal areas of patchy consolidation, consistent
with bronchopneumonia.
The woman died the next day due to sepsis and hypoxemia; the combination causing septic shock. The following
specimens were obtained from tissues removed at autopsy:
The specimen consists of a section of the left lung and shows extensive consolidation of most of the upper lobe.
The lesions are confluent, and the specimen shows something of the appearance of "lobar" pneumonia. The
lower lobe shows the typical patchy appearance of bronchopneumonia. The middle part of the lobe displays
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confluence pneumonia, which is a poor prognostic marker, as it indicates that the patches of
bronchopneumonia have become confluent as there is spread of inflammation between the patches, which is
hard to distinguish from lobar pneumonia. This is a poor host response to bronchopneumonia.
The following slides were also obtained:
On higher magnification:
On low magnification, the alveoli appear like pieces of „popcorn‟, indicating areas of alveoli that are not
consolidated and expanded with air. The „popcorn alveoli‟ mean that increased oxygen saturation occurs in the
well-ventilated areas, but there is not enough to obtain an oxygen concentration any higher in these areas as
there is saturation (from the Hb-O2 saturation curve) and this compensation is not enough to overcome poor
ventilation in the consolidated areas. The net effect is hence hypoxemia.
The bronchioles are filled with neutrophils, necrotic debris and exudate, which is pus.
Surrounding the pus filled bronchioles, there are areas of marked consolidation in the surrounding alveoli, due
to spread of a fibrinosuppurative exudate meshwork (causing consolidation of airspaces and bronchopneumonia)
and spread of necrotic material into the smaller distal airways. Hence there is a spread of inflammation out
from the small airways or a bronchocentric inflammation, which causes patchy consolidation which is in
differing stages in different parts of the lung in this specimen.
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Some of the non-consolidated alveoli have oedema, possibly from congestive cardiac failure. In other parts of
the lung haemorrhage can be observed.
Classically in a lung with bronchopneumonia, the histological appearances are as follows: the bronchioles are
filled with pus caused by inflammation from pyogenic bacteria, so-called suppurative bronchiolitis with
neutrophil infiltrate, necrotic tissue and exudation. In acute bronchopneumonia the significant features that are
seen include vasodilatation, congestion of blood vessels, exudation of fluid and proteins, infiltration of
inflammatory cells and epithelial damage. The alveolar structure remains, however, there are suppurative
collections- abscesses. Consolidation of alveoli in acute bacterial pneumonia occurs due to accumulation of
fibrinosuppurative exudate, along with vascular changes of acute inflammation in alveolar blood vessels.
In acute bronchopneumonia, the alveoli are consolidated by fibrinosuppurative exudate, hence expectorated
sputum will be purulent (yellow-green) not mucoid (white). Of the other features: fever is a systemic response
(mediated by the hypothalamic synthesis of Prostaglandin E2, from systemic release of cytokines including
Interleukin-1 and TNF-α from inflamed lung tissue. Bronchial breath sounds are heard on auscultation over
areas of consolidated alveoli. A neutrophil leukocytosis is caused by the release of a reserve pool of neutrophils
from the bone marrow, in response to a systemic increase in IL-1 and TNF-α, from the inflamed lung tissue.
Consolidation is also evident on chest x-ray, which is the most important investigative finding in establishing
the diagnosis of bacterial pneumonia (sputum culture is required to determine causative agent(s)).
However, one must distinguish between different types of pneumonia; alveolar pneumonitis or interstitial
pneumonitis. They cause reduced lung compliance and hence interference with gaseous diffusion.
Some extra information of pneumonia:
Pneumonia is the most common cause of infection-related death, with ~50% of cases and the majority of deaths
due to bacteria. It is the 6th leading cause of death in western countries and occurs in patients with CCF or
cancer. Transmission of organisms occurs due to inhalation, aspiration, haematogenous spread, direct infection
extension into the lungs or exogenous penetration and contamination (i.e. foreign bodies). Remember the
common clinical features including cough with purulent sputum, shortness of breath, fever, chest pain,
respiratory distress namely tachypnoea. Diagnosis of pneumonia is based on history, examination and
diagnostic investigations- where chest x-ray and sputum culture being very important in identifying the
organism. Common aetiological agents of pneumonia include:
o Bacterial:
1) Gram positive bacteria: Streptococcus pneumonia & Staphylococcus aureus
2) Gram negative bacteria: Haemophilus influenzae, Pseudomonas
aeruginosa (e.g. in patients with cystic fibrosis), Klebsiella pneumoniae,
Legionella pneumophila, E. coli, Enterobacter sp.
3) Moraxella catarrhalis
o Bacterial-like agents:
1) Mycoplasma pneumoniae
2) Chlamydia pneumoniae; Chlamydia psittaci
3) Coxiella burnetti (the cause of Q-Fever in farmers)
o Mycobacteria: e.g. Mycobacterium tuberculosis or Mycobacterium avium
o Viral (viral infection is usually complicated by bacterial pneumonia):
1) Respiratory syncytial virus (RSV), parainfluenza virus, influenza virus, adenovirus.
o Fungal: Aspergillus species (common in neutropenic patients such as those with leukaemia),
Cryptococcus neoformans or Pneumocystis jirovecii (e.g. in HIV patients).
o Protozoal
There is also a pattern of „typical‟ and „atypical‟ pneumonia. Typical pneumonia has an abrupt onset of
productive cough with purulent sputum, pleuritic chest pain, impressive physical findings, leukocytosis or
leukopenia. Atypical pneumonia has a gradual onset, non-productive cough, substernal chest pain,
unimpressive physical examination, white blood cell count normal.
Other important classification schemes for pneumonia include either acute or chronic pneumonia (chronic e.g.
in atypical pneumonias), Community acquired or nosocomial pneumonia (also known as health-care associated
pneumonia as occurs in hospital settings, dialysis centres, nursing homes etc) (which is a good classification
system as it can distinguish between organisms and hence the treatment varies with community or nosocomial
pneumonia). Also pneumonia can occur in a normal or immunocompromised host, or it can be classified
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according to microbiological agent (although this is not easy to identify), and radiological/pathological features
(lobar or bronchopneumonia).
Aspiration pneumonia: this usually involves aspiration of oropharyngeal contents. The organisms involved
usually include oropharyngeal flora, anaerobes (from non oropharyngeal secretions), enteric bacteria. Chest x-
rays show consolidation dependent at the time of aspiration. Sputum culture in these cases is unreliable, with
growth of oral anaerobes, hence it is also important to do blood cultures or cultures of pleural fluid.
Pneumonia can be either classified as community-acquired or hospital acquired (nosocomial) pneumonia.
Community Acquired pneumonia:
The most common causative agents, such as in this lady‟s case is Streptococcus pneumoniae. Other important
major causes include in terms of most-common to less-common: Mycoplasma pneumoniae, Chlamydia
pneumoniae, Haemophilus influenzae, Legionella pneumophila and other organisms.
Community acquired pneumonia usually occurs with certain age groups (e.g. increased risk at extremes of age
although all ages can be affected), environmental factors (mid-winter, or such as transmission via air-
conditioning towers or cooling towers as in the case of Legionella pneumophila which like aquatic
environments) or with certain lifestyles/diseases (such as alcoholics, with aspiration pneumonia, who develop
Klebsiella pneumonia). The following table displays the most-likely organisms with community-acquired
pneumonia in different age-groups:
Age Most likely organisms Neonatal (0-1 month) E. coli (faecal contamination), Group B streptococcus
(intrapartum infection, part of vaginal flora in a mother that is
GBS positive, they need prophylactic antibiotics before delivery) Infants (1-6 months) Chlamydia trachomatis, Respiratory Syncytial virus (once they
develop RSV antibodies, they acquire life-long immunity to RSV) Children (6months to 5 years) Respiratory Syncytial virus, Parainfluenza viruses Children (5-15 years) Mycoplasma pneumoniae, Influenza type A Young adults (16-30) Mycoplasma pneumoniae, Streptococcus pneumoniae Older adults Streptococcus pneumoniae, Haemophilus influenzae
Important symptoms include: chills, rigors, productive cough and pleuritic chest pain. Signs include: fever,
tachypnoea, dullness to percussion, bronchial breathing an/or crackles, pleural friction rubs.
Laboratory findings may include: neutrophil leukocytosis, hypoxemia, sputum with PMN and causative
organism found on Gram stain.
With bacterial pneumonia, anatomically it can cause either lobar or bronchopneumonia patterns, suppurative
inflammation and the classical stages of 1) lung congestion, 2) red hepatisation, 3) grey hepatisation and finally
4) resolution. In initial congestion, there is exudation of acute-phase proteins into the alveolar spaces, with few
inflammatory cells and one would hear crackles/crepitations as a result of fluid filling the alveoli. With red
hepatisation, a fibrin meshwork forms and solidifies the exudate, which makes the lung appear red, also
suppuration occurs with neutrophil infiltrate; the redness is from the dilatation of the alveoli and some
exudation of red blood cells which makes the lung red „liver-like‟. With grey hepatisation, the red blood cells
degrade and hence the lung appears grey; macrophages remove the exudate and debris and are also removed via
the lymphatics or the patient coughs this up as sputum; no ventilation occurs at this stage or in the earlier stages.
With resolution the lung finally returns to normal.
Microscopically in early bacterial pneumonia, the alveolar capillaries become dilated and hence alveolar walls
are more prominent and congested with blood. There are also neutrophils in the alveolar spaces, also red cells
and proteinaceous exudate which forms a fibrin meshwork that helps consolidate the alveoli.
As a result of this pathology, virulence of causative agents and their ability to spread and also depending on the
host response, this leads to either lobar or bronchopneumonia. Bronchopneumonia appears as patchy areas of
consolidation, with other areas of lung being unaffected and is usually caused by less virulent organisms.
Streptococcus pneumoniae causes a brisk exudative response and spreads quickly, resisting phagocytosis due to
its polysaccharide capsule and hence this agent commonly causes lobar pneumonia.
Clinicopathological correlation in community acquired pneumonia, the cause of symptoms is explained below:
o Cough: is caused by the stimulation of the cough reflex by the inflammatory process in the airways.
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o Dyspnoea: hypoxemia due to ventilation/perfusion mismatch and subsequent blood shunting. This can be
life-threatening in pneumonia and it can cause cyanosis. In the affected bronchi, dyspnoea is caused by
low PaO2, due to a combination of ventilation/perfusion mismatch and shunting of blood- due to a lack of
ventilation in the consolidated alveoli blood shunting occurs to other alveoli.
o Pleuritic chest-pain: stimulation of somatic sensory nerve endings in the parietal pleura by the
inflammatory products on the visceral pleura.
The cause of important signs in pneumonia are explained below:
o Tachypnoea: this is the result of increased ventilatory drive from a chemoreceptor mediated response
to hypoxemia. There is increased saturation of O2 in the well ventilated areas, but not enough to obtain
a O2 concentration that is any higher in these areas due to saturation (from the Haemoglobin-oxygen
saturation curve) and this is not enough to overcome the poor ventilation in the poorly ventilated areas
thus resulting in hypoxemia.
o Fever: due to resetting of the hypothalamic thermostat by IL-1, TNF-α.
o Crepitations/crackles: this is due to opening of fluid/pus filled alveoli.
o Dullness to percussion: loss of resonance in the consolidated alveoli.
Important investigations to perform in a patient with suspected community-acquired pneumonia include:
o Imaging: chest x-ray is the most important diagnostic investigation. Without a chest x-ray one cannot
make a diagnosis that the infection is in the lung parenchyma or in the bronchi etc. Check for lobar or
bronchopneumonia, an air bronchogram suggests consolidation rather than effusion or collapse. The
following is a chest x-ray of middle lobe consolidation (check for silhouette sign at right cardiac border)
in a patient with lobar pneumonia:
o Cultures: Sputum Gram stain, culture, antibiotic sensitivities; and blood culture (which is positive
in 20-30% cases). With microbiology, Streptococcus pneumoniae is the most common, Haemophilus
influenzae is commonly found in patients with COPD or with previous viral infections, Staphylococcus
aureus is common after viral infections such as influenza. Legionella pneumophila typically occurs in
epidemic settings.
o Ancillary tests: full-blood count: look for neutrophil leukocytosis; inflammatory markers: check
CRP & other acute-phase proteins; arterial blood gases/pulse oximetry: check for hypoxemia, if
hypoxemic use ventilatory oxygen.
Bronchopneumonia occurs more commonly in debilitated people such as those with cancer or CCF, it more
commonly occurs in the lung bases, due to static secretions and impaired cough reflexes; it is typically bilateral
and caused by low virulence organisms.
Certain features which suggest certain causative agents include with lung consolidation (either lobular,
segmental or lobar) this is most likely Streptococcus pneumoniae, or diffuse/bronchopneumonia is commonly
due to Mycoplasma pneumoniae, Chlamydia pneumoniae, Staphylococcus aureus.
Important microbiological investigations for pneumonia include: sputum direct gram stain, culture (enables
antibiotic sensitivity testing, although difficult to interpret if contaminated & many cannot produce sputum),
blood cultures (High specificity with bacteremia/sepsis, although it has a low sensitivity of 20-30%). A urine
sample may be useful for detecting microbial antigens filtered in the kidneys such as streptococcus pneumoniae
urinary antigen and Legionella urinary antigen. Serology tests may also be useful for certain organisms such as
Legionella, Chlamydia and Mycoplasma.
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Important ways to prevent pneumonia include with influenza vaccination: pneumonia is a common
complication of influenza. Pneumococcal vaccination: is important for patients who are at risk who have
chronic illnesses such as COPD, are recovering from severe illnesses, are in nursing homes or other chronic
care facilities and are aged 65 years and older.
Hospital Acquired pneumonia:
This usually occurs in patients that have underlying respiratory disease, such as COPD or bronchiectasis, or in
the elderly and unwell. It occurs in hospitals, nursing homes, patients with recent surgery, intubation (gram-
negatives common cause of ventilator-associated pneumonia, they are good colonisers of ventilatory equipment)
and with broad-spectrum antibiotic use causing resistance organisms.
Symptoms include fever and deterioration in clinical course. Signs include tachypnoea and basal crackles.
Laboratory findings include leukocytosis and hypoxemia and there is chest x-ray evidence of consolidation, or
variable, often patchy, widespread bronchopneumonia. Drug-resistant organisms may be cultured, such as
MRSA.
Usual infective agents include aerobic gram negative bacilli in 60% of cases including Klebsiella pneumoniae,
E. coli, Serratia species, Enterobacter species and pseudomonas aeruginosa. Other organisms include
Streptococcus pneumoniae, Staphylococcus aureus and Haemophilus influenzae.
Neonatal hospital acquired pneumonia infective agents commonly include Group-B streptococcus, Chlamydia
trachomatis, both from intrapartum vertical transmission.
Other causes of hospital acquires pneumonia include transmission from medical equipment, such as in those
requiring assisted ventilation, common causative agents include Klebsiella pneumoniae, Staphylococcus aureus
(a very common nosocomial infection, also don‟t forget MRSA).
Pneumococcal pneumonia:
Clinical features include an abrupt onset of symptoms, with fever, rigor and chills, productive cough with
purulent sputum, pleuritic chest pain, dyspnoea, tachypnoea and hypoxemia.
Risk factors for pneumococcal pneumonia include patients that have chronic illnesses such as lung disease,
heart disease, kidney disorders, diabetes, or sickle-cell anaemia. Also in patients recovering from serious
illnesses. Some patients developing pneumococcal-pneumonia are living in nursing homes or other chronic
care facilities, and are usually aged 65 years and older.
Mycoplasma pneumoniae:
This organism lacks a true cell wall and hence does not gram stain. It is a fastidious organism, that is slow
growing and may take >7 days to grow in culture. Also since this organism does not have a cell-wall, beta
lactam antibiotics are ineffective, hence specific antibiotics are needed, and thus there is slow eradication.
Mycoplasma pneumoniae are the smallest self-replicating organisms which grow on special media and are never
found freely in nature. They can not be seen by simple light-microscopy.
Infection usually occurs in children >5 years of age and young adults, Mycoplasma pneumonia is the most
common cause of pneumonia in school children, contributing to 15-20% of community acquired pneumonias,
with an incubation period of 1-3 weeks and symptoms developing over 2-4 days. The symptoms may persist
for a few days to more than a month.
Laboratory diagnosis of Mycoplasma pneumoniae pneumonia is with serology, Mycoplasma PCR and a
sputum culture.
Atypical pneumonia:
Atypical pneumonia is more common in children, adolescents, young adults; institutions as a year round
occurrence, and it has specific risk factors. Atypical pneumonia or interstitial pneumonia, is more commonly
caused by intracellular organisms e.g. Chlamydia, viruses, Toxoplasma.
Symptoms of atypical pneumonia include a 3-4 day prodrome of malaise, then headache, fever and dry cough.
Signs are typically sparse. Hence atypical pneumonia may be mistaken for non-specific viral bronchitis or other
viral illnesses.
Laboratory findings are typically limited. Inflammatory products are in the lung interstitium rather than in the
alveolar air spaces. There is limited or no lung signs, cultures are negative.
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Atypical pneumonia pathology: It is an interstitial pneumonia, where inflammation predominantly occurs within
the alveolar septa, there is mononuclear leukocyte infiltrate including macrophages, lymphocytes, plasma cells
rather than neutrophils observed with typical pneumonias, as this is predominantly a cell-mediated immune
response, needed to overcome intracellular organisms that have infected alveolar macrophages and alveolar
pneumocytes. There is usually an intraalveolar proteinaceous exudate in many cases, leading to signs of
crackles, although this is not consistent. As a result of intraalveolar proteinaceous exudation and inflammation,
there is hyaline membrane formation, which reflects alveolar damage.
The following displays a microscopic image of atypical pneumonia, indicating thickening of the alveolar septa
and epithelial debris, which can form hyaline membranes from surfactant and exudate. The hyaline membranes
form barriers to gaseous diffusion:
In atypical pneumonia, ~70% of cases are due to Mycoplasma pneumoniae, Chlamydia (Chlamydophila)
pneumoniae, viral causes: Influenza A and B, Coxiella burnetii (Q fever), Chlamydia (Chlamydophila) psittaci.
On radiology there is typically a diffuse, interstitial pattern:
Pneumonia pathogenesis:
Pneumonia occurs as a result of failure of host defences, such as humidification and filtration of inspired air,
epiglottic or cough reflexes, mucociliary transport, innate immunity (alveolar macrophages, neutrophils and
complement), humoral immunity (B lymphocytes, immunoglobulin and complement all from the Bronchial-
associated lymphoid tissue) and cellular immunity (T lymphocytes).
Pathogenesis also depends on the virulence factors of the organism and sufficient inoculum.
Remember important lung defences such as mucociliary transport in large airways, IgA secretion by mucosal
plasma cells, regional lymph nodes and alveolar macrophages in smaller airways and alveoli.
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Impaired defences include: extremes of age (paediatric & geriatric populations- who have the inability to mount
adequate responses), impaired drainage of secretions (cystic fibrosis, bronchiectasis, obstructive neoplasm,
foreign body); impaired mucociliary transport (congenital immotile cilia, cigarette smoking and post-viral)
impaired consciousness (suppression of the cough reflex with anaesthesia, coma, narcotic drugs, alcohol), static
fluid in alveoli, e.g. pulmonary oedema, which impairs macrophage phagocytosis and immunodeficiency
(innate, humoral or cell-mediated).
Pneumonia syndromes include: acute, community acquired pneumonia; atypical pneumonia, nosocomial
(health-care associated) pneumonia and pneumonia in the immunocompromised.
Pneumonia in the immunocompromised:
Features are closely related to the immunodeficiency;
o HIV: there is diffuse, interstitial pneumonia, of insidious onset, commonly due to Pneumocystis
jirovecii (usually with CD4 T cell count <400) or Cryptococcus neoformans.
o Acute leukaemia: there is focal pneumonia also of insidious onset with fever and productive cough,
often due to Aspergillus fumigatus.
o Bone marrow transplantation: severe, diffuse interstitial pneumonia, often due to Cytomegalovirus.
Pneumonia complications:
Abscess formation. This most commonly occurs due to aspiration of infective material, such as oropharyngeal
material, commonly in people that have lost consciousness such as patients on anaesthetics, alcoholics, people
taking narcotics, etc or can occur from sepsis from teeth or gum infections. Certain bacteria are associated with
bronchopneumonia, especially Staphylococcus aureus, Klebsiella pneumoniae and type 3 pneumococcus. Lung
abscesses can also cause septic embolism. It can be caused by airways obstruction, penetrating injury to the
lungs, spread from adjacent organs or it can lead to haematogenous spread to the lungs.
Signs and symptoms of lung abscesses include high spiking fevers, copious amounts of purulent sputum when
the lung abscess communicates with the airways, and this may lead to resultant haemoptysis due to erosion into
blood vessels and this may lead to sinus formation to the pleural surface, leading to spread of
infection/inflammation into the pleural sac, causing empyema thoracis.
The following chest x-ray depicts a lung abscess, which appears as a cavitating lung lesion. There is an area of
cavitation, surrounded by opacification:
Empyema (thoracis) formation. The following chest x-ray is from a patient with empyema thoracis:
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Disseminated infection, particularly with bacterial infections, including meningitis, septic arthritis, infective
endocarditis, septic shock and multiple organ failure- the inflammatory response to sepsis can cause multi-
system failure.
Respiratory failure and the ARDS.
Organisation of exudate: Permanent loss of lung-function due to organisation of granulation tissue, rather than
resolution. If the exudate is not coughed-up, or phagocytosed by macrophages or drained by lymphatics, then
the exudate may organise into granulation tissue. This granulation tissue can permanently impair gas exchange.
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Principles of O2 therapy & basic respiratory physiology (revisited)
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Bronchiectasis
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Arterial Blood Gas interpretation
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Oxygen therapy clinical tutorial & Revise respiratory physiology and include arterial blood gas
tutorial & importantly clinical interpretation of ABGs based on respiratory physiology
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Pathology of tuberculosis infection
Case : Tuberculosis
A 48 year old man, who had recently emigrated from Cambodia, presented with a three month history of fever,
night sweats and 6kg weight loss. He spoke little English and used his 16 year old son as an interpreter. He had
a chronic cough, productive of mucoid sputum. On occasion he had noticed haemoptysis and more recently
complained of right sided pleuritic chest pain. He smoked 40 cigarettes and consumed 50g of alcohol per day.
Abnormalities on examination included fever (38.3°C), obvious wasting, and reduced expansion of the right
lung with bronchial breath sounds over the right apex. A chest x-ray taken at the time is shown below (left).
The projected x-ray on the left shows opacification in the apex of the right lung, with radiolucent areas in the
centre of the lung indicating cavitation. The chest radiograph on the right also shows a right upper lobe infiltrate
with the appearance of apical cavitation with an air-fluid level in a patient with active tuberculosis. The x-ray on
the right also shows small scattered nodules in the upper zone of the left lung which appear calcified (and a
calcified nodule behind the heart on the left side).
Mucoid sputum indicates a clear coloured of sputum. Note that pleuritic chest pain is characterised as a sharp,
stabbing type of chest pain that is worse on inspiration/coughing, that is indicative of pleural irritation, as the
parietal pleura is supplied by somatic sensory nerve fibres.
3 common lesions that could present with these chest x-ray appearances could include:
1) Tuberculosis: Chronic inflammation associated with TB; this would be high on the differential
diagnosis in this case, based on most of the clinical features in the history. Opacification may be
associated with concurrent fibrosis, granulomatous tissue and caseous necrosis.
2) Pulmonary abscess: Acute inflammation from a lung abscess could also produce a cavitating lesion,
in this case possibly a communicating lung abscess that has been drained into a bronchus via a draining
sinus. This could produce a similar chest x-ray image, although the duration of illness would not be 3
months.
3) Lung cancer: An apical lung cancer could also cause similar opacification in the lungs, with central
necrosis causing cavitation. Such a tumour could also cause airway obstruction leading to secondary
destruction of lung tissue from pneumonia.
One should always suspect tuberculosis in such a clinical presentation with signs/symptoms of fatigue, night-
sweats, chest pain, dyspnoea, weight loss, cough/haemoptysis and this type of x-ray appearance.‟
Other important clinical factors to note in a patient with suspected tuberculosis include if they are
immunosuppressed (for example, HIV positive patients), and also patients from certain endemic regions (or with
significant travel history) including China, South-East Asia, South Asia/subcontinent and Central-West Africa.
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The patient‟s full blood count results were as follows:
Full Blood Count
Haemoglobin (g/L) 112* 130-180
RCC (×1012
/L) 4.0** 4.5-6.5
Packed Corpuscle Volume (PCV)
(Haematocrit)
0.35** 0.40-0.54
Mean Corpuscle Volume (fl) (MCV) 88 80-100
MCH (pg) 28 27-32
MCHC (g/L) 317 300-350
WCC (×109/L) 13.7* 4.0-11
Neutrophils 6.8 2.0-7.5
Lymphocytes 6.5* 1.5-4.0
Monocytes 0.3 0.2-0.8
Eosinophils 0.1 0.04-0.4
Blood Film Normochromic, normocytic
Platelets (×109/L) 346 150-400
ESR (mm/hr) 52* 1-10
The full blood count indicates a normocytic, normochromic pattern of anaemia; commonly caused by anaemia of
chronic disease due to impaired haematopoiesis from chronically elevated levels of circulating TNF-α. Again,
this could be due to a chronic pulmonary abscess, tuberculosis/chronic inflammation or cancer- it does not help
with the differential diagnosis.
However, the elevated lymphocyte count (lymphocytosis) is significant, as it indicates that the patient‟s disease
is most likely not due an acute inflammation due to a pyogenic bacteria (i.e. most likely not abscess). ESR is also
elevated indicating chronic inflammation.
Other investigations that may now be performed:
1) Sputum cytology to rule out tuberculosis or cancer. Cytology is important to identify dysplastic or
neoplastic changes in the airway epithelial cells.
2) Rapid Mycobacterium tuberculosis PCR can also be performed to identify mycobacterium tuberculosis
DNA either in a lung biopsy sample or on sputum.
3) Mycobacterium tuberculosis culture on Lowenstein-Jenson medium; this takes ~6 weeks to grow,
while the more modern BacTec culture takes about 2 weeks to culture. Culture is important to perform if
a diagnosis of TB is to be made since it also allows for determination of organism antibiotic sensitivities.
4) Ziehl-Neelson acid-fast stain of sputum or lung biopsy specimen; a stain to identify acid-fast
organisms (i.e. Mycobacteria). An auramine-rhodamine fluorescent stain is also used to visualise
Mycobacteria and although cheaper and more sensitive, is not as specific as the ZN stain for
mycobacteria. Below is a ZN stain from sputum, showing red-coloured acid-fast mycobacteria, and a
auramine-rhodamine fluorescent stain of sputum, indicating yellow fluorescent mycobacteria.
5) Gram stain, microscopy and culture of sputum to identify organisms that may cause acute
inflammation and abscess formation. However, this would not be useful for detection of mycobacteria.
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6) Repeat chest x-rays, or thoracic CT scan may be indicated following treatment to assess for clinical
improvement. A CT scan may be performed if the diagnosis was initially unclear.
7) QuantiFERON TB Gold or other interferon-γ release assays may also be performed in cases of
patients with suspected TB, and this is more sensitive than a Mantoux test, and this involves mixing a
patient‟s blood sample overnight with Mycobacterium tuberculosis antigenic proteins including
purified-protein derivative (PPD), early-antigenic target-6 (ESAT-6) and culture-filtrate-protein-10
(CFP-10) and then measuring the amount of interferon- produced by the patient‟s lymphocytes and
comparing to non-stimulated and control patient blood.
Unfortunately, before the diagnosis could be confirmed, the man discharged himself from hospital. The man
returned by ambulance two weeks later, having collapsed after a massive haemoptysis. Unfortunately, he could
not be resuscitated. The following slides were prepared from tissues removed at autopsy.
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The patient may have died as a result of aspiration of blood (and hence hypoxia) or as a result of massive
haemorrhage that could have caused hypovolemic/haemorrhagic shock and hence death.
The slides display multifocal abnormalities due to the presence of chronic granulomatous inflammation, with
some granulomas exhibiting central foci of caseation. Most granulomas in the slide are necrotising (indicating it
is most likely caused by tuberculosis; i.e. as non-caseating granulomas in the lung have other causes such as
chronic beryllium disease, hypersensitivity pneumonitis, some fungal infections and sarcoidosis).
A granuloma is a focal aggregate of macrophage derivatives. Giant epithelioid cells make up most of the
granuloma, due to shrinkage of tissue they appear stringy and “oedematous.” They are formed due to activation
of macrophages (from interferon-γ activation) fusing together to form a syncytium. They “wall-off” spherical
areas of M. tuberculosis infection. There are also Langhan‟s multinucleated giant cells that have „horseshoe
shaped‟ nuclei located peripherally and these are morphologically different from the foreign body type of giant
cells.
Note that caseous (“cheese-like”) necrosis is a type of necrosis that is intermediate between the liquefactive and
coagulative types. Casseous necrosis undergoes liquefaction if it erodes into the airways and if neutrophil
infiltration enters leading to tissue liquefaction. This pattern of granuloma formation is the manifestation of a
cell-mediated response to a poorly removed pathogen (M. tuberculosis) and is an example of a type IV or
delayed hypersensitivity reaction.
Cell-mediated immune response by T cells leads to macrophage activation and granuloma formation. When cell
mediated immunity wanes, e.g. due to HIV/AIDS, alcoholism, diabetes, age etc., granulomatous inflammation
can spread to the airways via bronchogenic spread. Latent tuberculosis infection usually remains in the lung apex
due to higher oxygen tension in the upper lungs.
The pathogenesis of granuloma formation in response to a poorly solubilised antigen is summarised in the
diagram below:
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Within each tuberculous granuloma, there is a zone of casseous necrosis, surrounded by a syncytium of
epithelioid cells interspersed with Langhan’s-type multinucleated giant cells. Surrounding the granuloma is a
cuff of T-lymphocytes, which are driving the TH1 immune response to Mycobacterium tuberculosis, as well as a
peripheral zone of granulation tissue. The granulation tissue (mature scar tissue) is composed of fibroblasts, new
blood vessel formation and macrophages.
The slide below also shows the presence of an acute fibrinous pleuritis (which would have caused the patient‟s
pleurisy, i.e. pleuritic chest pain), representing the pleura‟s reaction to the chronic inflammatory response in the
underlying lung parenchyma. Characteristic microscopic features include:
1) Vasodilatation and vascular congestion.
2) Fluid exudation (indicated by clear spaces within tissue) and protein (fibrin) deposition.
3) Infiltration by inflammatory cells.
This would have undergone reorganisation and thickening of the pleura. However, it could also be associated
with tuberculous empyema and spread of granulomas over the pleural surface. Acute inflammation is also seen in
the pleura (hence this is an acute-on-chronic inflammation) due to increased vascular permeability with oedema,
proteinaceous exudates; neutrophil infiltration; increased vascularity; some angiogenesis and early granulation
tissue formation. This is a non-specific response in the pleura to inflammatory mediators from the lung
parenchyma:
A granuloma is a focal lesion, consisting of an aggregate of chronic inflammatory cells, principally macrophages,
epithelioid cells, giant cells and lymphocytes. It exhibits the following classic features of chronic inflammation:
1) Ongoing tissue injury (necrosis)
2) Concurrent attempts at healing by repair (i.e. organisation and formation of granulation tissue).
3) Mononuclear cell (i.e. monocyte/macrophage & lymphocyte) infiltration.
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The slides above display a lymph node, it is identified as a lymph node by the high concentration of lymphocytes
and the lymph node capsule.
Casseous necrosis in granulomas is present with a rim of giant epithelioid cells and some multinucleate giant
cells. TB spread to lymph nodes occurs due to macrophages transporting mycobacteria to lymph nodes for T-cell
presentation.
Lymph nodes are the most common extra-pulmonary site of infection, although it can spread to other tissues.
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Tuberculosis is a major health problem, ~1/3 or the world‟s population has been infected with Mycobacterium
tuberculosis, with ~2million deaths/year worldwide. That does not mean that 1/3 of the world population have
the disease, and fortunately there is a big difference in being infected with M. tuberculosis and actually having
the disease, however, once infected, one is at higher risk of developing disease. Thus there are many people at
high risk of disease worldwide.
~1.5 million people worldwide have active tuberculosis at any one time. In Australia, tuberculosis is not a health
problem as much as it is in other regions of the world. In Australia, the case rate declined from ~50
patients/100000 population in the 1950s to ~5cases/100 000 currently. Australia has also very much survived the
surge of tuberculosis that has been associated with the HIV epidemic. HIV AIDS is substantially related to the
development of tuberculosis, as tuberculosis is an interaction between the organism and the host immune
response. Since HIV-AIDS destroys the host immune response, this provides a good environment for
tuberculosis to cause disease. Australia is very lucky to have low rates of incidence of tuberculosis/HIV co-
infection.
Hence in Australia, tuberculosis is not always considered in a differential diagnosis, when it is considered likely
in other parts of the world. Hence this may be a problem, as the right diagnosis may not be achieved on time in
Australia, although it is fortunate that tuberculosis does not occur commonly in Australia.
In Australia, there is ~8 times higher incidence of tuberculosis in indigenous Australians and certain migrants
compared with non-indigenous Australians, illustrating that even still the same level of healthcare and health
outcomes are not achieved in Australia, in indigenous communities.
Mycobacterium tuberculosis is a remarkable organism in two main ways: 1) it does not produce any real toxins,
2) it is extraordinarily difficult to destroy this organism, at least by normal immune cells, although it is
susceptible to dessication and UV radiation and this is also a fastidious organism, growing in oxygen-rich
environments- it is a strict aerobe. However, due to its outer waxy coat; it can survive phagocytosis and reside
within macrophages.
Natural history of tuberculosis:
The natural history of tuberculosis illustrates the relationship of Mycobacterium tuberculosis and the host
immunological response. Tuberculosis is always about the balance between organism and host.
In a typical tuberculosis reaction, the pattern of disease is a function of time and level of immune response.
When the immune reaction is really good, there is effective localisation of the infection, perhaps so effective that
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infection is „wiped out‟ although not necessarily so, and the process of removing the organism results in tissue
destruction- resulting from immunologically driven granulomatous responses, complete with necrosis. The
necrotising granulomas have a pattern of caseous necrosis. Hence there is a trade-off; a good immune response to
tuberculosis will be localised although it results in tissue destruction. Whereas, in a poor immune response there
is little tissue destruction and caseation, and also spreading of infection. A good immune response damages the
host tissue (resulting in caseation) but also destroys the organisms within the cells and hence infection becomes
localised. Tissue destruction is a price to pay to eliminate M. tuberculosis. At the bottom end of the y-axis of the
graph above, the poor immune response means that there are many macrophages infected by the organism,
however, these are ineffective and the organism is not eliminated and there is infection spread and no tissue
damage.
Even with a slowly replicating organism, such as M. tuberculosis, in a poor immune response and given enough
time, the organism can spread and disseminate within the body.
Referring to the previous chart, a person with a PRIMARY INFECTION is a naïve host that is exposed to M.
tuberculosis for the first time and has not developed an adaptive immune response. The infection usually occurs
via inhalation of the organism with dust particles or respiratory droplets containing the organism- hence primary
infection is mainly a pulmonary infection.
Hence primary infection results in an initial innate immune response- although it does NOT trigger a neutrophil-
mediated response, hence this organism is a low intensity irritant, as there is no significant inflammatory
response occurring at all. Then macrophages resident in local tissues phagocytose the mycobacteria, but these are
only internalised and not killed by the macrophages, as mycobacteria are normally resistant to being killed by
macrophages, as the organism has an outer waxy-coat that resists normal macrophage lysosomal enzymes.
To kill a Mycobacterium tuberculosis inside a phagolysosome, it must essentially be „nuked‟, by high-energy,
highly reactive molecular species, that combine with the bacterial lipid coat and destroy it. These include
reactive oxygen species or free radicals, to kill the organism within the phagolysosomes. Whereas neutrophils
produce oxygen-free radicals, macrophages when activated can produce both oxygen and nitrogen free radicals
that can destroy the mycobacteria. However, unlike neutrophils, macrophages must be activated to kill
effectively. Therefore as the macrophages are not initially activated, the mycobacteria acquire a new „mobile
home‟, by preventing fusion of the phagosome and lysosome, allowing mycobacterial migration elsewhere.
Hence after primary infection, in a naïve host, there is a period when mycobacteria can proliferate both
intracellularly and extracellularly and even though numbers may be small and it is slow dividing, it will find its
way into the bloodstream, causing a pre-immune low-level bacteraemia. This first stage of infection is a
completely asymptomatic initial period of infection, but the organisms are slowly dividing and disseminate.
After a few weeks, the immune response is activated, as this occurs the destructive process also occurs. In an
„ideal word‟ the immune response should move up vertically in the chart to remove the organism. What occurs
with the initial immune activation is a TYPICAL PRIMARY COMPLEX- a focal localisation of organisms in
the site where they were first lodged, or a focal proliferation of organisms in a draining lymph node. There is
hence an inflammatory response in this primary site of focal proliferation- there is thus a granulomatous lesion
with caseous necrosis at this site of primary proliferation and this typical primary complex is also referred to as a
Gohn complex. This indicates that an immune response has kicked-in and the organism is being destroyed, if no
problems/complications occur, this primary gohn complex progresses towards healing- with healed lesions and
the organisms may hence lose viability.
However, as not all cases are ideal, some organisms may evade the immune response and the organisms may
remain dormant in the latent pulmonary or extra-pulmonary lesions. The organism can remain in a dormant state
in these sites for decades, non-replicating after the primary immune response. The organism is „waiting‟…in
latent lesions.
The immune response may then decline for various reasons (old age, HIV infection etc.) and the organism is then
reactivated.
However, the vast majority, or ~95% of people develop an effective primary response against the organism and
will progress towards healing. However, ~5% of people may not have an effective primary response and they
may develop PROGRESSIVE PRIMARY TUBERCULOSIS.
To develop progressive primary tuberculosis means that the host immune response is not very effective. A good
immune response will develop highly localised lesions, with marked caseation, a poor response will not be
limited, with organism spread and less caseation developing primary progressive tuberculosis during the primary
response.
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With a very poor immune response, this can then lead to massive haematogenous dissemination of the
organism- the slowly replicating organisms keep spreading but given time this leads to infection spread
massively throughout the body via the bloodstream. Massive haematogenous dissemination is also referred to as
MILIARY TUBERCULOSIS. Development of primary progressive tuberculosis and then miliary tuberculosis
may be the outcome of <5% of infections.
For most people ~90-95%, there is a good immune response that progresses to healing and a loss of viable
organisms, and that is where the story ends. However, for some people, the organisms remain dormant and the
proportion is not well known. It appears that most people with primary infection are at risk, as there are some
residual viable organisms remaining. In these people with latent lesions, there may be reactivation of tuberculosis
and re-infection. This may occur from a decreased host-immune response due to HIV, or from impaired
macrophage function, e.g. in the case of diabetes. The organisms make a comeback and this reactivation and re-
infection results in POST-PRIMARY TUBERCULOSIS. The attenuated immune response results in what
appears to be the same as in a failed primary response to tuberculosis. This hence results in some localisation of
the lesions with caseation. Post-primary tuberculosis is the most common clinical form of tuberculosis,
which results from a drop in the host immune response.
A more severe drop in the host immune response e.g. with AIDS leads to PROGRESSIVE POST-PRIMARY
TUBERCULOSIS; similar to progressive primary tuberculosis that results from primary infection. Just like in
progressive primary tuberculosis, there is also the possibility of massive haematogenous dissemination/miliary
tuberculosis during post-primary tuberculosis. Note that post-primary tuberculosis should not be called
„secondary tuberculosis‟ (see the same graph from Robbins Pathology below, note that they refer to post-primary
tuberculosis as „secondary‟) as this confuses it with secondary spread to extra-pulmonary sites (e.g. like with
secondary cancer spread). Also primary tuberculosis occurs at a much different timescale to post-primary
tuberculosis, which can occur years to decades after primary infection. It is NOT „secondary‟ spread from the
primary infection, hence avoid calling this „secondary TB‟. Note the y-axis in the graph below is the same as in
the previous chart (represents the host immune response).
Also note that over time, there may be increased tuberculin reactivity, against M. tuberculosis antigenic proteins
(heightened Type IV delayed-type hypersensitivity reactions); this can also occur in some cases with BCG
vaccination and is generally measured with a Mantoux test.
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Tuberculosis: Sites of primary lesions:
In a normal tidal inspiration, there is not much ventilation of the apex and base
of the lungs, most ventilation occurs in the middle 2/3rds or more of the lung.
Thus with primary pulmonary tuberculosis infections, they mostly occur in the
middle 2/3rds of the lungs (as shown in the diagram on the right), as a result of
multiple exposures with the organism and inhalation of the organisms through
dust particles or respiratory droplets. Hence a typical Gohn focus of caseation
occurs in the middle 2/3rds of the lung, spreading out to the pleura with
associated hilar/paratracheal adenopathy and caseation in these draining lymph
nodes (together these two features is referred to as a Gohn complex).
The organisms replicate at these primary foci within macrophages and can
spread to draining lymph nodes- pulmonary, hilar, tracheobronchial and
paratracheal lymph nodes. As a result of the host immune response, there is
resulting caseation in the lung periphery and caseation in the draining lymph
nodes (forming the primary complex).
By observing the gohn complex primary focus of caseation, under high magnification, it can be observed that
there would be numerous macrophages. Using special stains that identify acid-fast mycobacteria (ZN and
auramine-rhodamine), it can be seen that these macrophages are laden with intracellular bacilli. The image below
is an acid-fast stain, which demonstrates foamy histiocytes (tissue macrophages) laden with hundreds of acid-fast
mycobacterial organisms:
As mycobacteria have a waxy lipid coat; the special stains, e.g. Ziehl-Neelson stain binds to this lipid coat, but
after treatment of the histological section with acid, the dye is removed from all tissue except the mycobacteria-
resulting in observable residing mycobacteria within the macrophages, as above. Acid-fast organisms retain dye
even after treatment with acid and alcohol. M. tuberculosis is weakly gram positive.
The image below is from primary pulmonary tuberculosis, with a Gohn-complex. The gray-white parenchymal
focus is under the pleura in the lower part of the upper lobe. Hilar lymph nodes with caseation are shown on the
left. During primary infection, there is also caseation necrosis in the primary local site of infection and in a
draining lymph node- indicating immune activation/responsiveness. The primary infection is usually subclinical,
similar to an upper respiratory tract infection.
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If all goes well, that primary lesion heals and scars and what occurs is that a small area of scar tissue that is
observed years on, with no viable organisms, this area may become calcified as a Ranke complex, which is
radiographically observable and appears white on gross-examination. There would be scar-tissue deposition, with
abundant collagen fibres and as there might be lymphatic obstruction, there may also be peripheral aggregates of
carbon around the scar, where the carbon is not removed by the lymphatics (patchy areas of anthracosis, which
may be observed on histology) and there may be central areas of necrosis. However, within such a scar in some
cases there may be remnant necrotic debris, which would provide evidence of mycobacterial DNA from PCR
analysis. With culture of this sample of tissue, it may be possible to demonstrate that there may be viable
organisms present. Given the right circumstances, these could cause post-primary TB. Hence, what appears to be
calcified scar tissue may contain viable organisms present- hence these lesions are referred to as latent lesions.
Progressive-primary tuberculosis
If the individual does not mount an adequate immune response to primary infection, this could lead to
progressive primary tuberculosis. Instead of nice localisation in a typical primary complex lesion, there would be
progressive spread and enlargement of the pulmonary lesion, as shown in the section of lung below:
As there may be some host immune responses occurring, there would be caseation necrosis present, as it is not a
„runaway lesion.‟ However, the host immune response may not be effective, leading to development of
pulmonary satellite lesions. There could be poor outcomes for such individuals.
One poor outcome would result from spread of the caseating lesions and hence mycobacteria into the circulation,
which could lead to massive haematogenous dissemination.
Massive haematogenous dissemination
Despite slow growth of mycobacteria, spread of caseation into vascular tissues may lead to tremendous
haematogenous spread and dissemination.
The dissemination could spread tuberculosis lesions locally and the pulmonary tissue-forming small foci of
granulomatous lesions, which do not have much caseation, as there is a poor host immune response. Within these
granulomatous lesions, there are many macrophages that are full of hundreds to thousands of mycobacteria,
however, as there is no significant host immune response, there is not much caseation.
Massive haematogenous dissemination of TB lesions is what kills people, as it can spread to distant sites,
such as the central nervous system and meninges- the most dangerous site of spread of massive haematogenous
dissemination. It is also an overwhelming infection that can kill in part because of the systemic inflammatory
consequences. The following shows disseminated TB in the lung (miliary TB- with appearance of millet seeds):
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Post-primary tuberculosis
For most people, primary infection is a terminating event, with a host immune response; localisation of the lesion,
with caseation and then progression to healing and repair (with calcification). For some people, this is not the
case.
In some people, their immune response drops over the course of their life for various reasons, e.g. age may be a
predisposing factor, malnutrition (especially in chronic alcoholics in Australia), which impairs cell-mediated
immune responses and diabetes mellitus, which impairs phagocyte function are major predisposing factors.
These are all predisposing factors as CD4+ T-cells are involved in producing cytokines (hence HIV which
destroys these cells leads to poor TB outcomes), such as IFN-γ and macrophage activating factors
(macrophage inflammatory proteins (MIPs), and macrophage inflammatory activating factors (MIFs)) that cause
macrophages to produce reactive oxygen and nitrogen species. The TH1 CD4+ cells drive macrophage activation
in response to M. tuberculosis, this TH1 activation results in activated epithelioid giant cells and
multinucleated giant cells that are designed to kill mycobacterial organisms. Epithelioid giant cells are
mycobacterial killers, as they upregulate reactive oxygen and nitrogen species and multinucleated giant cells also
have a higher capability for phagocytosis and mycobacterial destruction.
The following diagram highlights the important sequence of immunopathologic events in primary pulmonary
tuberculosis, commencing with inhalation of virulent M. tuberculosis and culminating with the development of
cell mediated immunity to the organism. A. events occurring within the first 3 weeks after exposure B. events
thereafter. The development of resistance to the organism is accompanied by appearance of a positive tuberculin
(Mantoux) skin test. Cells and bacteria are not drawn to scale, iNOS (inducible nitric oxide synthase);
NRAMP1, natural resistance-associated macrophage protein.
Note the important roles of IL-2, IL-12, IFN-γ and TNF-α in mediating this inflammatory pathway. iNOS
induction is also very important, to counteract mycobacterial phagocytosis evasion, and leads to increased
intracellular nitric oxide and reactive oxygen species to destroy the bacilli.
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Thus in a person with an impaired immune response, e.g. in HIV AIDS, there is no or limited cytokine
production and hence the macrophages are not activated. But in a diabetic, it would not matter what signals are
given to the macrophages, their phagocytic capability would be compromised. The end result is that the latent
organisms are no longer held under control.
When reactivation occurs, this leads to bacterial colonisation at sites that suit them best- this means that
mycobacterial colonisation occurs most often at the lung apices (below)- this is because the lungs are an oxygen
rich environment, but most enter the bloodstream due to gas exchange. At the apices, there is not much gas
exchange as there is lower blood-flow perfusion due to gravitational effects on blood flow (pulmonary blood
flow is greatest at lung bases). As Mycobacterium tuberculosis is a strict aerobe, it hence grows more readily in
the lung apices when reactivation occurs in post-primary TB lesions, as there is higher oxygen tension than
compared with the lung bases.
On microscopic examination of post-primary TB lesions, there is caseation present, with a lot of necrotic debris,
surrounded by granulomatous inflammation with numerous epithelioid giant cells, multinucleate giant cells that
in TB have a characteristic appearance with apically located nuclei arranged in a horse-shoe shape, which are
referred to as Langhan‟s giant cells. It is possibly the driving cytokines that causes a different morphological
appearance as that of foreign-body type giant cells. There are also lymphocytes, indicating cell-mediated immune
responses activating the macrophages (these lymphocytes are located more peripherally in the granuloma).
Peripherally, fibroblasts may also be prominent and a major feature of granulation tissue, which can also
contribute to development of pulmonary fibrosis if there is extensive attempt at healing.
An area of caseous necrosis is NOT an abscess, as there is no suppuration and neutrophils present. But a strange
phenomenon can occur with apical post-primary TB lesions in that a secondary wave of neutrophil infiltration
can occur, the trigger for this is not well known. However, when the neutrophils appear, they can liquefy the
necrotic material, that does not mean it became an abscess, as the neutrophils did not appear first.
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Nevertheless, like an abscess, the liquefied material can be discharged elsewhere and in the case of the lung, the
liquefied necrotic debris can discharge into the airways, such as a bronchus. If that occurs, i.e. the area of
necrosis has gained access to an airway and then this can lead to:
1) Dispersal of organisms, e.g. with coughing there is dispersal of organisms, and hence there is
high potential of spread of organisms into the environment.
2) The necrotic debris may drain out of the airways forming cavities- cavitating lesions, which are
remnants of caseous TB lesions. Apical cavitations are a classical presentation of post-primary
TB, in someone whose immune response has dropped modestly.
Apical cavitations may then heal and then scar. As carbon deposition may occur around these areas of healing,
this leads to the appearance of fibrocaseous tuberculosis.
However, in someone who had a poor immune response, or whose immune response dropped significantly, there
would be worse outcomes. The apical cavitation may lead to progressive post-primary TB, this progression may
not only involve massive haematogenous spread, but also bronchogenic spread, where the TB lesions spread
via the small airways- the bronchioles and some smaller divisions of bronchi. This would form patchy areas of
caseation and TB lesions that appear larger than those of miliary tuberculosis. Note that on top of bronchogenic
spread, in post-primary tuberculosis, there may also be massive haematogenous spread. The following CT scan
displays the appearance of miliary and bronchogenic tuberculosis.
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Extra-pulmonary tuberculosis
Extra-pulmonary TB can result from massive haematogenous dissemination of pulmonary TB, or it may occur
without evidence of pulmonary TB, although it is fairly uncommon. It may be the case that pulmonary TB leads
to healing and was subclinical, whilst the extra-pulmonary TB was not.
In Australia, ~40% of cases of reported TB are now extra-pulmonary. Common sites of extra-pulmonary TB
include:
1) Lymph nodes 40%
2) Pleura 14% (not part of lung parenchyma)
3) Skeletal 9%
4) Genitourinary tract 7%
5) Central nervous system 5% (meningitis or tuberculoma)
6) Miliary spread 2% (massive haematogenous dissemination)
Lymph node involvement is common, usually presents with lymphadenopathy that is often discrete and non-
tender, rarely inflammatory with fistula formation. Typically the cervical lymphadenopathy (scrofula),
supraclavicular and axillary nodes and is associated with HIV.
Many people with post-primary TB reactivation who develop extra-pulmonary TB occur as a result of the pre-
immune bacteraemia from primary infection, or seeding of infection, the organisms which spread via the
bloodstream are not eliminated at distant sites and hence remain latent until reactivation of post-primary TB.
In pleural TB spread, as it is a mesothelial surface, the vascular response of inflammation leads to exudation (not
commonly seen in TB chronic inflammation), causing tuberculous pleurisy (with or without pain) and can lead
to pleural effusions, tuberculous empyema and fever. There is a mixed acute and chronic inflammatory
response in the pleura, whilst in the lung parenchyma there is a chronic granulomatous inflammatory response.
Aspiration reveals straw-coloured aspirate, may be haemorrhagic exudates (protein > 50% than that of serum),
low glucose, pH ≈ 7.3, detectable WBC (neutrophils and mononuclear cells). Pleural biopsy reveals granulomas,
acid-fast bacilli. Fistulae may form with tuberculous emphysema.
The upper airways may be involved in advanced disease, with involvement of the larynx, pharynx and epiglottis.
This may have a mass effect: altered phonation, hoarseness, dysphagia, due to spread of organisms by lymphatics
or expectoration of infective matrial. Smear masses for AFBs.
Caseous necrosis can also spread to the urinary tract, effacing the kidneys for example below. Important features
include renal impairment, frequency, dysuria, pyuria, haematuria, obstruction, calcifications, strictures, mass
effect and tissue destruction:
With CNS tuberculosis, typically TB spreads to the grey-white junctions, forming caseous necrotic granulomas
in this area of the cerebral cortex. It can also lead to tuberculous meningitis with leptomeningeal involvement.
(Important differentials to consider: neurosarcoidosis, multiple sclerosis, CNS abscesses, lymphoma/malignancy).
It is this involvement of critical organs and the difficulty of organism elimination that makes TB such a
worrisome and deadly disease. Diagnosis is with obtaining a biopsy specimen from necrotic tissue, or identifying
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AFB on lumbar puncture. Can present with meningism and mass-occupying lesions. Neurological deficits may
persist in 25% of cases.
Skeletal tuberculosis often involves weight bearing joints and forms joint/bony abscesses and osteomyelitis.
Spinal tuberculosis is referred to as Pott’s disease, shown here to involve the right pedicle of a vertebra:
Gastrointestinal/tuberculous peritonitis is not very common (~3.5%), but can present with terminal ileal, caecal
masses, appendicitis, with intestinal wall involvement, ulcerations and fistulae likened to Crohn‟s disease. It
causes abdominal pain (similar to appendicitis) and swelling, obstruction, haematochezia and a palpable mass,
which are common findings on presentation. Fever, weight loss, anorexia, night sweats are common. TB
peritonitis may also occur via rupture of lymph nodes, abdominal organs and haematogenous spread. Confirm
with peritoneal biopsy. Oropharyngeal and intestinal tuberculosis contracted by drinking contaminated milk
containing M. bovis is now rare in developed countries, but is still seen in countries that have tuberculous dairy
cows and unpasteurised milk. The organisms may also be transmitted by swallowing coughed sputum and
organisms may accumulate in Peyer‟s patches in the GI tract, undergo caseating necrosis and ulcerate.
Pericardial: rare, but can lead to pericardial effusions and cardiac tamponade, diagnosed on pericardial biopsy.
Others: chorioretinitis, uveitis, otitis, congenital, dissemination in organs in miliary, e.g. with
hepatosplenomegaly. Splenic involvement (below) in miliary disease, cut-surface shows numerous grey-white
tubercles:
Miliary TB is most prominent in the liver, kidneys, spleen, adrenals (formerly an important cause of Addison’s
disease), bone marrow and bone (tuberculous osteomyelitis), meninges (tuberculous meningitis), fallopian
tubes (tuberculous salpingitis) and epididymis and can spread to the skin (lichen scrofulosorum).
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Summary of tuberculosis pathogenesis:
1) Primary infection is seeding of the organism (common organisms include: Mycobacterium hominis
tuberculosis, M. bovis tuberculosis, M. avium tuberculosis, M. intracellulare tuberculosis.
2) Organism lodges in the alveoli (seeding in the lungs) and divides in alveolar macrophages, enters
lymphatics and causes a low-level bacteraemia (as opposed to sepsis). There may be seeding to: lymph
nodes, bone, urinary tract, genital tract.
3) A T-cell mediated response develops against TB organisms, which leads to delayed-type hypersensitivity
reactions (Type IV DTH). This can lead to control of the organisms with a chronic granulomatous
inflammatory response, in lung parenchyma and hilar/tracheobronchial lymph nodes. Fibrosis occurs to
wall off immune response and gohn complex formation.
4) Reactivation of the organism after many years and with reduction of immune response.
5) Organism causes caseating post-primary TB in lung apices. This may lead to either:
a. drainage via the airways with liquefaction; hence cavitations form; a poor immune response
may lead to bronchogenic spread.
b. Or it may erode into blood vessels, leading to massive haematogenous spread (which may
present as haemoptysis. This may lead to death from haemoptysis.
6) Massive haematogenous spread leads to miliary TB, which can lead to extra-pulmonary TB spread to vital
organs and this can lead to death.
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Microbiology, diagnosis and management of tuberculosis
Summary: Investigation of tuberculosis is dependent on the stage or extent of the disease. In primary pulmonary
tuberculosis, investigations include sputum microscopy, culture and sensitivities, acid-fast stains, PCR
amplification, chest x-ray, Mantoux test and, QuantiFERON TB Gold. Rarely does post-primary tuberculosis
present with only extrapulmonary signs. In this setting, the particular system should be investigated with
tuberculosis in mind (e.g. lymph node, pleural etc.). Treatment of tuberculosis is based on the Direct Observed
Treatment Short-course (DOTS) with the four mainstay drugs of rifampicin, isoniazid, pyrazinamide and
ethambutol. Under the Therapeutic Guidelines, this is recommended for 6 months, either once daily or three
times weekly (at different doses).
Important symptoms of tuberculosis include:
1) Coughing- may be associated with haemoptysis in cavitatory TB
2) Chest pain: may be pleuritic due to pleural involvement
3) Weight loss: effects of chronic inflammation, cachexia
4) Fever/Night sweats: effect of inflammation, pro-inflammatory cytokines (TNF-α, IL-1) increases
PGE2 in hypothalamus, increasing thermoregulatory set-point and hence causes fever.
5) Malaise: General feeling of being unwell due to inflammation
6) Signs are variable and may also depend on extra-pulmonary features noted previously.
Mycobacterium genus contains >70 known species:
Mycobacterium tuberculosis complex (M. TB complex):
Mycobacterium tuberculosis hominis- causes human TB
M. africanum- also causes TB, limited to Africa, less common
M. canettii- also found in Africa, causes human TB, less common
M. bovis- Causes TB in cows and humans
M. microti- TB in rodents, rare in humans, only immunocompromised
Mycobacterium avium complex (MAC) includes:
M. avium species Immunocompromised patients (e.g. HIV AIDS)
M. avium intracellulare Immunocompromised patients (e.g. HIV AIDS)
M. avium paratuberculosis species- affects cattle
Mycobacterium leprae (Hansen‟s bacillus) causes leprosy
Properties of M. tuberculosis
Mycobacteria are strict aerobes, and they must require oxygen for growth. They are slightly curved or rod shaped
bacilli.
Mycobacteria are very slow growing, e.g. M. tuberculosis doubling time is ~15-20 hours, M. leprae is a few
weeks. This is in comparison to E. coli, which has a doubling time of 20-40 minutes. The mycobacterial cell wall
is complex, composed of many lipids, mycolic acid, which causes acid-fast staining, plasma membrane and
polysaccharides. The outer waxy coat of mycobacteria is what gives them their special properties.
The mycobacterial cell wall is complex; waxy, with a high lipid content, which is why it is resistant to chemical
agents and desiccation- organisms can hence survive for weeks in dry sputum. Cell wall components of
mycobacteria powerfully stimulate the immune system, e.g. Mannan and lipopolysaccharide. The cell wall is also
resistant to decolourisation with acid and ethanol.
Diagnosis of M. tuberculosis
It is important to obtain the appropriate specimens for investigation. For pulmonary tuberculosis, a sputum
sample is taken. This is usually digested with enzymes first to break down the mucous and then examined for
mycobacteria.
Extra-pulmonary tuberculosis requires lymph node and tissue biopsies, CSF and blood samples.
Sputum/tissue microscopy: Direct microscopy is useful for rapid diagnosis, because it allows rapid diagnosis
and also detection of AFBs with a Ziehl-Neelson stain is diagnostic, as this stain does not stain other organisms.
An acid-fast stain- Zhiel-Neelson staining of the tissue/sputum sample involves initial staining with carbol-
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fuschin (the primary stain, red colour), while heating tissues/sputum with steam. The sample is then decolourised
with a mixture of hydrochloric acid and ethanol. Then there is counter-staining with methylene blue (blue colour).
Standard protocols may call for examination of 100 fields of view. The identification of a single acid-fast
bacillus is diagnostic of infection. Despite the identification of only one acid-fast bacillus, to obtain smear
positivity, high bacterial numbers are required (with ~104 organisms/ml). Hence care must be taken with the
reporting of negative results, it should be stated that “NO acid-fast bacilli were observed on microscopy”. Also
note that all mycobacteria are acid-fast bacilli, not just M. tuberculosis complex, as other bacilli, such as nocardia
are also weakly acid-fast.
Fluorescent staining involves the use of mycobacterial antibodies that have fluorescent proteins attached. This
type of stain is much more efficient and more sensitive to identify organisms than conventional acid-fast staining.
This includes auramine-rhodamine or auramine-o stains, and fluorochrome smears with a fluorescent
microscope (expensive) are needed.
Mycobacterial cultures and sensitivity: A sample must be cultured to properly identify the organism and also
to obtain antibiotic sensitivity results. This involves the use of either a solid media or liquid media. With solid
media, commonly Lowenstein-Jensen medium is used and growth occurs in 2-6 weeks. An additional 2-6
weeks afterwards is needed for species identification. With liquid media, the BACTEC radiometric system
allows faster, more rapid detection of ~2 weeks. With solid cultures, malachite green is added to inhibit growth
of other organisms yet assists in isolation of mycobacterial species. M. tuberculosis is grown on a capped bottle
and not on an agar plate as there is a risk of infection via the air, aerosol spread to prevent infection spread. Also
it allows aerobic growths of culture media or contamination.
Molecular methods: Polymerase chain reaction (PCR) amplification of mycobacterial DNA is performed
using patient tissue samples, sputum or cultures. PCR then involves 1) denaturing of DNA, 2) primer annealing
to relevant DNA sequence sites, then 3) amplification of DNA sequences and extension. Then the amplified
DNA is separated using gel electrophoresis with ethidium bromide gel and staining to identify electrophoretic
bands that correspond to M. tuberculosis DNA sequences. Nucleic acid probes may also be used, which
involves hybridisation using specific mycobacterial DNA probes, similar to fluorescent in-situ hybridisation.
Sputum should be obtained if the patient is competent, otherwise use nebulised hypertonic saline to obtain
induced sputum, or seek physiotherapy aid, or can investigate bronchoalveolar lavage samples.
A Mantoux test, also referred to as the tuberculin test or purified protein derivative (PPD) test can be used.
PPD is a crude extract of M. tuberculosis antigens. In the Mantoux test there is intradermal injection of PPD. As
tuberculosis results in a delayed-type (IV) hypersensitivity reaction, hence measurement of the size of induration
occurs 48-72 hours later, to determine if a delayed-type hypersensitivity response has been elicited, as it
stimulates specific CD4+ TH1 cells. A positive test signals previous TB organism or M. avium complex exposure,
latent disease or BCG vaccination, not necessarily an active TB case. Exposure to mycobacterium species other
than M. tuberculosis can be (weakly) skin positive. Note that it takes ~4 weeks to convert to test positive, so
Mantoux test may be negative with a recent infection. Also false negatives can occur in immunocompromised
patients with TB infection, or those with active disease with peripheral anergy.
With the Mantoux test, if the subject has circulating mycobacteria-specific memory T-cells, these cells are
activated at the site of intradermal injection and release cytokines, including interferon-γ. The cytokines attract
and activate macrophages. The resulting inflammation is slow in onset and persists for several days (delayed).
Mantoux tests are assessed 48-72 hours after injection, when the reactions peak and other types of
hypersensitivity have subsided.
Events that occur with the Mantoux test include increased adhesiveness of the local endothelium (within 12
hours after injection) and then influx of leukocytes into the skin. There is then activation of specific T-cells by
local dendritic cells or infiltrating macrophages. This leads to release of factors including IFN-γ by T-cells. There
is then a further influx and activation of macrophages (peaking at 48 hours).
Interferon-γ release assays: such as the QuantiFERON TB Gold are also useful diagnostic tests. Whole blood
is incubated with TB antigens (synthetic recombinant TB peptides including ESAT-6, PPD and CFP-10).
Dendritic cells or macrophages in the blood activate specific T-cells and this leads to release of IFN-γ ~24 hours
later. The plasma is then separated and collected and the amount of released IFN-γ is later measured by ELISA;
the presence of IFN-γ is indicative of latent and active disease. This is a useful test compared to Mantoux, as it
eliminates false-positive results by non-tuberculous mycobacterial infections and cross-reactivity to previous
BCG vaccination.
Similarities of the Mantoux and IFN-γ release assays includes that they both assess for whether antigen-specific
memory T-cells are present. Therefore the tests are useful to assess whether the patient has latent TB infection,
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but they do not distinguish between latent and active TB infection. They may also be negative in advanced TB or
in immunocompromised patients (for example, patients with HIV and TB).
The advantages of Mantoux over IFN-γ release assays is that Mantoux is inexpensive and there is no need for a
sophisticated laboratory for investigation.
Advantages of IFN-γ release assays includes that it is much more specific for M. tuberculosis; IFN-γ release
assays are negative after BCG vaccination and in most other mycobacterial infections, whereas Mantoux may be
positive. IFN-γ release assays are probably more sensitive than Mantoux, especially in the immunocompromised
and it does not require the patient to be injected or to return for assessment
Chest x-ray: Some important features to note include a calcified/fibrotic Gohn complex: check hilar/paratracheal
lymphadenopathy with a calcified focus in the lung periphery. Atelectasis secondary to lymphadenopathy may be
found in children. Fibrocaseous cavitating lesion in the apical region is found in post-primary tuberculosis. If a
patient has no respiratory symptoms, a normal chest x-ray almost excludes pulmonary tuberculosis. Chest x-rays
are valuable for detecting pulmonary lesions of tuberculosis, however, activity of disease cannot be judged with
certainty. Classic upper-zone changes can be due to other pathology, and pulmonary tuberculosis can have many
other non-classic presentations with broad differential diagnoses. Unusual chest x-ray appearances (including
normal chest x-ray) are more common in people with immune deficiencies and other comorbidities. Once
pulmonary TB is suspected, the most appropriate initial investigation is sputum analysis and not further imaging,
even if chest x-ray shows fibrosis which appears to be radiologically inactive.
Investigations for post-primary (secondary) TB:
Lymph nodes: Fine needle aspirate and/or biopsy. Biopsy obviously more sensitive
Pleural: Thoracentesis: microscopy, culture, sensitivities, acid-fast stain and check appearance, protein, glucose
concentration, LDH, white blood cells. Also obtain a pleural biopsy
Upper airways: Sputum acid-fast stain, laryngoscopy and biopsy
Genitourinary: IV pyelogram, abdominal CT/MRI may show deformities, obstructions, calcifications and
ureteral strictures. Culture 3 morning specimens of urine.
Skeletal: Obtain a synovial aspirate, microscopy, culture and sensitivities, acid-fast stain, check appearance,
protein, glucose concentration, white blood cells. Relevant imaging (x-rays, CT/MRI, bone scans).
Rarely arthroscopy and synovial biopsy.
Meningitis/tuberculoma: LP microscopy, culture and sensitivities, acid-fast stains and appearance, protein,
glucose concentration, white blood cell count; PCR. CT/MRI may show hydrocephalus or space-
occupying lesions.
Gastrointestinal: Paracentesis, microscopy, culture, sensitivities, acid-fast stain and appearance, protein, glucose
concentration, white cell count and peritoneal biopsies with laparoscopy. Biopsy as part of surgery,
endoscopy; anal fistula, inflammation and ulceration.
Pericardial: Pericardiocentesis, microscopy, culture and sensitivities, acid-fast stain, appearance, protein, glucose
concentration, white cell count.
Miliary: Chest x-ray, sputum and bronchoalveolar lavage. Haematology: anaemia with leukopenia, lymphopenia,
neutrophilic leukocytosis and polycythemia, DIC. Blood culture for mycobacteria. LFT abnormalities:
liver and bone marrow biopsies may be needed. CD4+ T-cell count.
Other: chorioretinitis, uveitis, otitis (congenital), investigate as required. ENT/ophthalmology referral.
Key factors in Tuberculosis management
Requires at least 6 months of treatment, the first- line drugs used include isoniazid, rifampin/rifampicin,
pyrazinamide, ethambutol and occasionally streptomycin.
The second-line of drugs are less effective and have more toxic/side-effects.
Also non-compliance is a major problem with TB prevention/treatment. WHO advocates the DOTS programme;
which is Directly Observed Therapy Short Course; to ensure a full course is taken by the patient and to avoid
relapse and discourage emergence of drug-resistance.
Prevention: vaccination? The BCG vaccine was developed from M. bovis, when administered it enters
macrophages, elicits a response and is killed. It is a safe and cheap vaccine but is it effective? This is
controversial, as it has a wide range of efficacy, 0-80%; it does not prevent reactivation of pre-existing
infections. Patients become Mantoux skin test positive, hence BCG vaccines are not routinely used in USA and
Australia (since 1950s).
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Multi-drug resistant TB (MDR-TB) is resistant to at least isoniazid and rifampicin. Extensively drug
resistant TB (XDR-TB) is MDR-TB that is resistant to quinolones and also to any one of kanamycin,
capreomycin or amikacin. XDR-TB is almost untreatable and a serious public health threat. There was an
outbreak in South Africa in 2006 with 53 cases of XDR-TB. The average time to death was 16 days after
sputum sample was taken and all cases were HIV positive.
HIV and TB: HIV infection is a potent risk factor for TB, not only does HIV increase risk of reactivating latent
TB, it also increases risks of rapid TB progression soon after infection or re-infection with M. tuberculosis. In
persons infected with M. tuberculosis only, lifetime risk of developing TB ranges from 10-20%. In persons co-
infected with HIV and M. tuberculosis, however, the annual risk can exceed >10%, i.e. 10% risk/year. The TB
burden in countries with a generalised HIV epidemic has therefore increased rapidly over the past decade,
especially in severely affected regions of Eastern and Southern Africa. TB is one of the most common causes of
morbidity ad most common cause of death in HIV-positive adults living in less-developed countries.
Also in HIV patients, M. Avium Complex (MAC) can occur, which is similar to M. tuberculosis in many ways,
but resistant to conventional drugs used to treat TB.
There is a large link between poverty, overcrowding, poor health services and other social/cultural factors that
affect rates in countries; as well as factors such as migration, air travel, access to treatment, preventative public
health measures, vaccination rate, compliance to treatment (DOTS), patients follow-up, housing, employment
and education, environmental factors etc.
Treatment of Tuberculosis:
TB was regarded as a treatable disease from the 1960s after introduction of rifampicin and ethambutol. However,
there was a TB re-emergence in the late 1980s, with increased virulent strains, multi-drug resistant strains are
now common.
Primary TB is mostly asymptomatic, and may be similar to a respiratory tract infection. TB disease is associated
with: persistent cough, haemoptysis, lethargy/fatigue & malaise, anorexia and weight loss, low grade fever and
night sweats.
Mycobacterial cell walls are impenetrable to antibacterial agents due to presence of a waxy coat. Also as some
mycobacteria reside within macrophages, this aids in protection of the organism from anti-bacterial agents.
These organisms easily develop resistance against single antibiotic agents. Thus effective therapy requires a
prolonged course of multiple drugs with different mechanisms.
Problems arising from combination therapy include: compliance, drug toxicity/side effects and drug
interactions- particularly in patients who are also being treated for HIV at the same time.
First-line therapy: Includes four drugs; isoniazid, rifampicin, ethambutol and pyrazinamide given for two
months. In HIV patients there is substitution of rifampicin with rifambutin, which minimises drug interactions
with HIV protease inhibitors and HIV non-nucleotide reverse transcriptase inhibitors. Then rifampicin and
isoniazid are continued for another 3-6 months. This regimen has the greatest level of efficacy, with acceptable
levels of toxicity. It is assuring to find that the majority of patients can be treated successfully with these drugs.
Total treatment course for non-resistant TB is 6 months; but this is extended to 9 months in patients who are
HIV infected or have meningitis. Therapy may depend on whether drug-resistance is found, “second-line” drugs
may then be added.
Principles of pharmacological therapy includes that successful treatment of any infection relies on the principle
of selective toxicity:
Ideally drugs would be toxic to the invading organism and not harmful to the host-
selective toxicity, but in reality this is only relative. Hence generally, selective toxicity
relies on some process that is essential to the organism but not the host.
Common mechanisms of action of antibacterial agents include: inhibition of cell wall synthesis, cell wall
permeability, protein synthesis, nucleotide synthesis, and also anti-metabolites which interfere with metabolic
processes.
Important pre-treatment screening includes checking baseline weight, liver & renal function tests, visual acuity
and colour vision testing and recording, full blood examination, testing for HIV (after appropriate counselling),
and contraceptive advise for fertile female patients.
Isoniazid: the activity of this drug is limited to mycobacteria and it was discovered in 1945 and used in clinical
practice later, it is a hydrazide of isonicotinic acid. Its mechanism of action is unclear, there is evidence of
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inhibition of cell wall constituents- a glycopeptide-like action. Isoniazid is special in acting as a bacteriostatic
for resting bacteria and a bacteriocidal for growing bacteria. Allergic skin reactions can occur as well as
hepatitis.
Ethambutol: is a tuberculostatic drug that inhibits cell wall synthesis by inhibiting cell wall arabinosyl
transferase of M. tuberculosis. Important adverse effects include optic neuritis causing visual disturbances,
colour blindness and also peripheral neuropathy. Resistance occurs as a result of bacterial modification of target
arabinosyl transferase, resulting from genetic mutations.
Rifampicin: Is also known as rifampin the USA and its mechanism of action is that it inhibits bacterial DNA
dependent RNA polymerase activity (present in prokaryotic cells only), which suppresses chain formation in
RNA synthesis. It is active against most gram positive bacteria. It is absorbed well from the gut after oral
administration, it has a wide distribution and it is excreted via the liver into bile. Adverse effects include: nausea,
vomiting, diarrhoea; rash, fever, red tears & urine, drug interactions. Bacterial resistance occurs via
modification of the antibiotic target, resulting from bacterial gene mutations.
Pyrazinamide: Is a nicotinamide analogue; which affects fatty acid synthase; thus affecting mycobacterial cell
wall synthesis and ATP synthesis. However, pyrazinamide is ineffective at neutral pH and kills bacteria in
acidic conditions, thus it is effective against intracellular mycobacteria within macrophages. It is well absorbed
in the gut, with wide distribution. Adverse effects include: liver damage (with high doses), gout and GI upsets.
The mechanism of action of the main first-line drugs for tuberculosis are shown below:
Streptomycin: was the first available drug used for TB (used rarely now). It is bactericidal in-vitro, but
bacteriostatic in-vivo. Its mechanism of action is that it inhibits protein synthesis by binding to the ribosomal
30S subunit (it is an aminoglycoside). It is poorly absorbed in the gut and hence needs to be administered IV or
IM and has renal excretion. Adverse effects include those of aminoglycosides: ototoxicity, tinnitus, vertigo and
renal impairment. Resistance occurs via many different mechanisms including failure of permeation, reduced
ribosomal affinity and drug interactions.
Pharmacological prophylaxis: is usually with isoniazid, as this is specific for mycobacteria and is used in high
risk groups only, including household exposure in family members of those infected, those with infection with
evidence from a Mantoux test (10mm induration, or 5mm induration in immune suppressed or HIV infected) or
in whom disease is latent/inactive.
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Important public health issues include those of treat, trace, educate and notify. Public heath detention is only
applicable to those who are not complaint with therapy. Screen people at high risk (e.g. from TB endemic areas)
and liaise with national/international groups to improve surveillance and control.
Summary of TB drugs:
1) Rifamipicin: inhibits DNA dependent RNA polymerase activity
2) Isoniazid: inhibits cell-wall synthesis
3) Pyrazinamide: impairs cell-wall and ATP synthesis, has activity in acidic pH (important for
intracellular macrophage penetration)
4) Ethambutol: inhibits cell wall synthesis
5) No difference in treatment of pulmonary and extra-pulmonary disease
6) Precautions to adverse reactions, epilepsy (isoniazid), renal and hepatic impairment (all),
pregnancy (rifampicin), diabetes (rifampicin), optic neuritis (ethambutol), gout (ethambutol),
monitor changes in colour vision, check Snellen chart every 3 months (ethambutol).
Some doses to remember: