Septic shock: Pathogenesis and treatment

S Y M P O S I U M : P E D I A T R I C I N T E N S I V E C A R E - I I

Indian J Pediatr 1993; 60 : 367-379

Septic Shock : Pathogenesis and Treatment

Leticia Castillo and Melchor Sanchez*

Pediatric and Neonatal Intensive Care Units, Children's Service, Massachusetts General Hospital Boston, U.S.A. and *Department of Pediatrics, Harvard Medical School

Massachusetts General Hospital Boston, U.S.A.

Abstract, Septic shock is the host's inflammatory response to infection. There are multiple endogenous mediators responsible for the pathogenesis of septic shock. Cytokines, nitric oxide and prostaglandins are some of the major mediators. The term sepsis syndrome allows for an earlier diagnosis and treatment. Management of septic shock is focused in maintaining heine- dynamic stability and an adequate oxygen delivery and utilization. Careful attention to each organ-system is of paramount importance to prevent complications and improve outcome. Experimental therapies to modulate the inflammatory response are promising. (Indian J Pedlatr 1993; 60 : 367-379 )

Keyworda : Septic shock; Sepsis syndrome; Critical~, ill.

S eptic shock is a complex syndrome that has become increasingly impor-

tant as a cause of morbidity and mortality in the Intensive Care Unit? Sepsis is the host's inflammatory response to infection and it is a continuous progression from a localized infection without systemic manifestations such as otitis media or gastroenteritis, to an infection with systemic manifestations such as fever, tachycarrdia, leukocytosis, chills and bacteremia; to an infection with systemic manifestations and hemodynamic instability such as hypotension, poor perfusion and cardiorrespiratory arrest. Septic shock is the final stage of the dynamic Process of sepsis. 2

In order to identify a population of Patients at risk for developing sepsis

Reprint requests : Dr. Leticia Castillo, Pediat- tic and Neonatal Intensive Care Unit, Ellison 317, Massachusetts General Hospital, Boston, MA 02114, U.S.A.

early, the term Clinical Sepsis Syndrome was first used by Bone in 1987. 3 Sixty- four percent of 191 patients identified with this criteria subsequently developed shock, and only 45% of the patients had a positive blood culture. Clinical Sepsis Syndrome relies on clinical criteria to facilitate diagnosis of sepsis; such as a high suspicion of infection, (confir- mation by blood culture is not required), fever, tachypnea, tachycardia and impaired organ system function as indicated by oliguria, abnormal mentation, hypoxemia or increased plasma lactate. When we apply this concept to the pediatric population, a large proportion of our patients, many with uncomplicated viral infections may meet the sepsis syndrome criteria without necessarily pro- gressing towards septic shock. This deft- nition is significant, however, because it is an effective warning to carefully as- sess, treat and follow patients at risk for

368 THE INDIAN JOURNAL OF PEDIATRICS 1993; Vol. 60. No. 3

TASLE 1. Clinical Sepsis S y n d r o m e in Children

Fever Bounding pulses

Irritability Oliguria

Tachycardia Capillary refill > 3 sec

Flushed, warm skin

developing septic shock. The mortality for those patients who will progress to shock is about 60 to 90%, 4~ despite current antibiotic therapy and sophisticated techniques of file support. Under these circumstances the early diagnosis and aggressive management of septic patients is of utmost importance in the outcome of septic shock, s Table 1 shows the characteristics of sepsis syndrome in children.

PATHOGENESIS

Traditionally, it has been believed that septic shock occurs as the result of re- leased lipopolysaccharide (LPS) by gram negative bacteria; nonetheless, exotoxin from gram positive bacteria, and fungal and viral products are able to produce the same clinical picture. 67 It is now known that these bacterial, viral and fungal products possess no profound toxicity of their own, but rather, they elicit the production of highly toxic endogenous mediators by the host. s01~ LPS for in- stance, activates leukocytes, macrophages, endothelial cells, and possibly other cells. The activated leukocytes release peptides known as cytokines. These cytokines, particularly tumor necrosis factor (TNF)2and interleuikin-1 (IL-1) are responsible for the physiologic changes observed in septic shock. ~u2 TNF and IL-1 elicit the release of nitric

oxide (NO), an oxygen radical product of arginine metabolism synthesized by macrophages, neutrophils, central nerv- ous system (CNS) cells, and endothelial cells. NO is a signal transducer, it has cy- totoxic activity, and is a potent endogenous vasodilator responsible for the hypotension observed in septic shock. 13,~4 TNF induces fever, lactic acidosis, hypotension and suppresses lipoprotein li- pase resulting in hypertryglyceridemia. If TNF is administered in sublethal doses, it induces fever, anorexia, cachexia, anemia, and leukocytosis. 11,~s IL-1 also has widespread systemic effects. 16.17 At the CNS level it induces lethargy, release of ACTH, neuropeptides and decreases appetite. IL-1 has profound metabolic effects; it increases the synthesis of acute phase reactant proteins such as C reactive protein and fibrinogen, and decreases the synthesis of structural proteins mainly albumin and transferrin; a fragment of IL-1 known as proteinolysis inducing factor is responsible for the protein breakdown observed in septic patients, also known as septic autocannibalism. IL-1 elicits the release of glucagon, catecholamines, and other counteregulatory hormones resulting in hyperglycemia? 7 The vascular effects of IL-1 are of great significance in septic shock; it increases leukocyte ad- herence, degranulation, and release of proteases and free radicals. These ele- ments will cause lipid peroxidation of the phospholipid layer in the cellular membrances, resulting in widespread tissue and organ injury, is During this process both pathways of arachidoniC acid metabolism also become activated. The lipooxygenase pathway results in the production of leukotrienes, which

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induce enhanced capillary permeability, vasoconstriction, bronchoconstriction, and leukocyte aggregation. Activation of the cyclooxygenase pathway leads to production of prostaglandin (PG) and thromboxane. Some prostaglandins such as PGE and PGI or prostacyclin are synthesized primarily by vascular endothe- lium and induce vasodilation and inhibit platelet aggregation. Thromboxane is mainly produced by platelets and results in vosoconstriction and platelet aggregation. 19 The main pathophysiologic events

THE INDIAN JOURNAL OF PEDIATRICS 369

of septic shock are summarized in Figure 1.

There are many other mediators of the inflammatory process of sepsis such as platelet activating factor, fibronectin, complement, proteases, and endogenous opioids (Table 2). It is likely that some others have not been discovered yet. Hence, the pathogenesis of sepsis is multifactorial and once the inflammatory cascade is activated, no single "magic bullet" will prevent it from pro- gressing, thus, a wide comprehensive

ACTIVATION �9 Bradykinines �9 Clotting Factors �9 Plasmin �9 Complement

,( Release of Proteases

Vascular Leakage

\ Tissue lniury

INFECTION

LPS, TSST-1, etc. , ---.. MACROPHAGES ENDOTHELIAL CELLS

CYTOKINs Nitric Oxide �9 / \ �9 IL-1 - IL-6

Cytotoxicity Vasodilation

PMN

~ ~ - ~ " ~ " ~ Release of Release Oxygen Radicals

,t Lipid Peroxidatiun

1 ORGAN DYSFUNCTION

Arachidonic Acid Metabolites

Lypooxygenase Cyclooxygenase

Leukotrienes Thromboxane, PGI, PGE

Vasoconstriction Platelet Aggregation

Tissue Injury

/

FThe major pathophysiologic events in sepsis are depicted. Endotoxin or exotoxin activa !Land endothelial cells leaaing to release of endogenous mediators and organ dysfunction

or exotoxin activates factors and cells, mainly macrophages

Fig. 1. Pathophysiologic events of septic shock

370 THE INDIAN JOURNAL OF PEDIATRICS

TASLE 2. Mediators of Septic Shock

Cytokines Tumor necrosis factor Interleukins

Eicosanoids Leukotrienes Thromboxane A2 Prostaglandins

Other Platelet activa~g factor Nitric oxide Complement fragments C3a, CSa Toxic oxygen radicals Proteases Fibrin Thrombin Bradykinism Plasminogen activator inhibitors Beta-endorphins Myocardial depressant factor

approach is necessarily aimed to reduce the morbidity and mortality of septic shock.

CLINICAL MANIFESTATIONS

The clinical manifestations of sepsis are widespread, involving multiple organs and systems.

CNS

At the CNS level, sepsis induces a vari- ety of mental changes, coma, seizures, and focal neurologic alterations. The septic encephalopathy may be caused by toxic and metabolic changes, or diffuse impairment of cerebral perfusion. 2~ A severe peripheral neuropathy characterized by axonal degeneration of motor and sensory nerves is found in 50% of septic patients. The peripheral neuropathy contributes to failure to successfully wean patients from the ventilators. 21

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Cardiovascular

Sepsis is manifested by hemodynamic instability. Children, however, have re- markable compensatory mechanisms and hypotension is often a late sign. Di- agnosis of septic shock in children should not be based on hypotension, but rather on early hemodynamic changes such as persistent tachycardia, flushed, warm skin, bounding pulses and wide pulse pressure. This has been known as the "early" hyperdynamic or "warm" phase of septic shock, l~oor capillary refill, metabolic acidosis and evidence of organ hypoperfusion such as oliguria or lethargy supervene later. Initially cardiac output is increased several fold and the systemic vascular resistance is low. If hypovolemia is not aggressively corrected, the patient will progress towards the late, hypodynamic or "cold" phase of septic shock, characterized by hypotension and cold "clammy" skin; in this situation the cardiac output is decreased and the systemic vascular resistance is high.

Hypotension is the result of multifactorial events affecting pre-load (circulat- ing volume) afterload (systemic vascular resistance), and myocardial contractility. 2~ Some mediators such as nitric oxide, leukotrienes, activated complement, prostacyclin, etc. play a role in the vasodilation of sepsisP Down regulation of cz adrenergic receptors resulting in a decrease capacity for vasoconstriction has also been described with sepsis. In addition, despite the initial increase in cardiac output, there is myocardial de- pression manifested by a decreased left ventricular ejection fraction, u Myocar- dial dysfunction is secondary to dov,~

1993; Vol. 60. No. 3 THE INDIAN JOURNAL OF PEDIATRICS 371

2 a o

0 ~0

0- 39-

- o? 06

o5 oc

o3 ~2 oL

20 30 ~'0

b

lO 20 30 40 Oxygen del;ver~ [mt/mlnlkg)

Fig. 2a.Oxygen consumption remains steady, independently of higher or lower oxygen delivery until a critical point; below this point oxygen consumption falls. Fi 8 2b. Oxygen extraction increases when oxygen delivery falls. (From Schumacker PT, Cain SM. In- tensive Care Med 1987; 13 : 223; with permission).

regulation of I~ receptors. Possibly some ~ mediators such as TNF may be also re- ~

• o , sponsible for the depressed cardiac func-

tion. ~ ~ A controversial hemodynamic event

in septic shock is the development of flow dependent oxygen consumption 0 (VO2).~-~ Oxygen delivery is the product of cardiac output and the arterial oxygen content (DO 2 = CO x CaO2). Cardiac out- Fi 8. 3. put is dependent on preload, afterload, and contractility. Arterial oxygen content is the sum of the oxygen chemically bound by hemoglobin and the oxygen physically dissolved in the plasma; CaO 2 = Hb x 1.34 x SaO~ + PaO 2 x 0.003, where 1.34 is the volume of oxygen (ml) that binds to lg of hemoglobin when it is

fully saturated, 0.003 is the solubility co- efficient of oxygen in human plasma, Hb is hemoglobin concentration and SaO 2 is the percentage o f oxygen saturation. In healthy individuals, the oxygen uptake is independent of oxygen supply. As shown in Figure 2, if DO t is acutely re- duced, oxygen extraction ratio (VO2/ DOt) increases, so the VO 2 can be maintained. It is only when DO 2 values fall below a critical point (8 ml /kg/min) , that the oxygen extraction capabilities are overwhelmed and VO 2 falls; at this point, lactic acidosis develops. ~

During sepsis, the ability of tissues to extract oxygen is impaired by microvascular and cellular abnormalities, and oxygen del ivery is decreased due to myocardial depressant factors a n d / o r abnormal CaO 2 (hypoxemia, anemia, etc.). 26 DO 2 may need to be increased in order to achieve adequate oxygen up-

104 | ENDOTOXIN: QO2c= 128 +_ 1 9 ERc=O 54~0 10

s . . . . . . . . . . . . . . . . . . . . . . . . j z

CONTROL: QO2c = 68 -+ I 1 ERe : 078 = 004

i 2~) 4O

SYSTEMtC OXYGEN DELIVERY (mP/min - kg body wt)

Relationship between oxygen delivery and consumption in control animals and after administration of endotoxin. In the endotoxin challenged animals the oxgyen requirement is increased, and oxygen extraction is decreased at the critical oxygen delivery. (From Nelson DP, Samsel RW, Wood LDH. J App Physiol. 1988; 64; 2410, with permission)


take by the tissues. This is known as an atmormal dependency, of VO~ on DO Z. Figure 3 shows the relationship between VO 2 and DO 2 under physiological conditions and after endotoxin administration. ~

Respiratory System

Initially, hyperventilation and respiratory alkalosis are present during the early stages of septic shock; later, hypoxemia may develop as a result of pulmonary shunts. Adult respiratory distress syndrome is a dreaded complication of septic shock. Persistent hypoxemia, low pressure pulmonary edema, and pulmonary hypertension are important features of ARDS. ~

Gastrointestinal

There is some degree of liver dysfunction induced by sepsis, Abnormal plasma amino acid patterns characterized by increased in aromatic amino acids such as phenyhlanine and tyrosine, and decreased branched chain amino acids are seen in later stages of septic shock. 3~ Re-distribution of blood flow may result in gastrointestinal ischemia with translocation of bacteria and/or endotoxin that will set the stage for chronic inflammation and multiorgan failure. 31 Stress ulcers occasionally com- plicate the clinical course of critically ill septic children. Hypoperfusion and oxygen radical injury are major factors in the development of stress ulcers, and gastrointestinal bleeding under these conditions. 32

Metabolic

Energy expenditure is greatly increased in septic shock. Oxygen consumption

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may be high, normal or low depending on the hemodynamic state. Metabolic acidosis due to excessive production of lactic acid carries a poor prognosis.

Gluconeogenesis is also increased and does not respond to exogenous administration of glucose. There is some degree of insulin resistance and increased prote- olysis that supplies amino acids for gluconeogenesis, these events frequently lead to glucose intolerance. 33 Hypergly- cemia is an early manifestation of sepsis in infants; hypoglycemia will present in later stages of septic shock, if metabolic support is not provided. Hypertryglyc- eridemia is often present as a result of increased lipolysis.

Septic patients exhibit massive weight loss due to increased protein breakdown, which supplies amino acid sub- strate for gluconeogenesis. Nitrogen balance under this circumstances becomes negative. 33

Disseminated Intravascular Coagula- tion (DIC)

DIC is a common manifestation of sepsis and is characterized by coexistent hem- orrhage and microvascular thrombosis. Clinically it presents with persistent gastrointestinal bleeding, hematuria, bleeding at previous puncture sites and mu- cus membrances. If DIC is severe, areas of necrosis may occur. A prolonged prothrombin and partial thromboplastin time (PT, PTr), thrombocytopenia, increased fibrin degradation products and microangiopathic hemolytic anemia is frequently found in DIC. u

Renal

Sepsis often manifests with hypoperfu-


sion and oliguria, if the hypovolemic state is not promptly corrected, mor- phologic and functional disturbances of the kidneys may occur. Pre-renal disease due to hypovolemia and poor perfusion is the most frequent cause of the renal dysfunction. Activation of mediators and local inflammatory response in the kidneys may lead to tubular necrosis. Drug toxicity such as aminoglycoside antiboifics will contribute to tubulointer- sfifial disease. Decreased urine output to less than 1 m l / k g / h r in children or 30 ml /hr in adolescents should alert the cli- nician. Rising blood urea nitrogen and creafinine, metabolic acidosis, and hy- perkalemia will appear later. Fractional excretion of sodium is less than 1% during pre-renal states, due to an appropri- ate sodium retention. In the presence of tubular damage, the kidneys fail to re- tain sodium and high urinary sodium excretion results in a fractional excretion greater than 1%. 35

TREATMENT

In view of the multiple pathophysiologic events in septic shock, its treatment must be focused in every organ-system and therefore a broad approach isnecessary. In any critically ill patient, basic prin- ciples of resuscitation (airway, breathing, and circulation) are vital in the initial management of these patients. If the patient is diagnosed early and successfully fluid resuscitated, endotracheal in- tubation and mechanical ventilation may not be necessary. In contrast, if the patient appears to have an increased work of breathing, regardless of normal arterial blood gases; or presents with hemodynamic instability such as persistent

tachycardia, poor capillary refill, mottled skin or hypotension, endotracheal intu- bation is necessary. 'l-he use of mechanical ventilation, sedation and muscle relaxation will avoid "wasting" cardiac output and oxygen delivery to respiratory muscles and preventing respiratory arrest. ~s

Endotracheal intubafion, if elective, should always be performed under controlled conditions, the patient should re- ceive pre-oxygenation, sedation, and, if necessary, muscle relaxation. Some seda- fives such as morphine or its derivatives may aggravate hypotension. Careful consideration to the side effects of any drugs used, should always be given. Benzodiazepines such as diazepam .2 mg/kg, or midazolam .1 mg/kg, or syn- thetic narcotics such as fentanyl 1-3 mcg/kg W will provide adequate sedation with a lesser risk of hemodynamic instability.

Once the patient is intubated and muscle relaxed, optimal ventilation should be achieved, by using the necessary tidal volume to appropriately ex- pand the chest. High Positive End Expi- ratory Pressure (PEEP) may be necessary to achieve an adequate arterial oxygenation, as assessed by the patient's color, PaO 2, or by pulse oximeter SaO 2. Con- comitant to management of airway and ventilation, support of the circulation is mandatory. Immediate venous access via peripheral or central lines should be gained for fluid resuscitation. If venous access becomes difficult due to hypotension, intraosseous access should be initi- ated. In addition to airway, breathing, and circulation, antibiotic treatment is of paramount importance in the treatment of septic shock. Blood cultures should be

374 THE INDIAN JOURNAL OF PEDIATRICS 1993; Vol. 60. No. 3

promptly obtained and antibiotic cover- age started according to the clinical situation. After the ABC's of resuscitation have been established, individual organ- systems should be considered.

CNS

Critically ill patients should be ade- quately sedated. Anxiety or pain leads to catecholamine release and increased metabolic rate under conditions of al- ready precarious oxygen delivery. Con- tinuous intravenous infusion of seda- fives achieve better sedation than spor- dic IV boluses. Morphine .05 mg/kg/hr , fentanyl 3-5 mcg/kg/hr or midazolam 0.1 mg/kg /hr can be used. Sedatives should be titrated to achieve the desired effect. Some patients may require larger amounts or even combinations of two drugs, particularly those patients with longer clinical course in whom tolerance has developed. ~7 If the patient remains muscle relaxed, the neurologic exam with exception of pupillary reflexes, will be lost. At our institution, we use phenobarbital to achieve a prophylactic anti- convulsivant effect, particularly on those patients with severe hypoxemic-ischemic events, or meningitis that may predis- pose to seizure activity. In the critically ill muscle relaxed patient, seizure activity may manifest only as episodes of hypertension, tachycardia or desatura- tion. A therapeutic level of phenobarbital of about 20-40 mg/dL should be maintained under these circumstances.

Cardiovascular

Cardiovascular support will depend on the clinical stage of septic shock that the patient presents with. Early and aggres-

sive fluid resuscitation is paramount for survival achieving increased cardiac output, DO 2 and VO 2, An initial bolus of crystalloid solution (lactated Ringer's or normal saline) at 20 m l / k g should be administered as an intravenous push or as a bolus over 20-30 minutes, depending on the clinical status of the patient. Continuous reassessment of the patient's perfusion status (capillary refill time, pulses, heart rate, mentation, blood pressure) is mandatory. If there is no im- provement, IV fluid boluses should be repeated up to about 60 ml/kg in the first hour. This amount is only a guide- line and should suffice to restore the cir- culating volume in most patients. Some other patients, however, mainly those with meningococcemia will require larger amounts of fluid resuscitation. Garcillo and coworkers, 5 recently re- ported that a more aggressive fluid resuscitation approach in the first hours of management is associated with an im- provement in survival and does not increase the risk of cardiogenic pulmonary edema or Adult Respiratory Distress Syndrome. If after adequate fluid resuscitation the patient remains hypotensive, invasive monitoring with a pulmonary artery catheter is required. Assessment of central venous pressure, cardiac output, pulmonary wedge pressure, systemic and pulmonary vascular resis- tances. DOz, VO 2 and oxygen extraction is imFoctant to guide fnrther management. If pulmonary artery catheteriza- tion is unavailable, determination of CVP, urine output, perfusion, metabolic acidosis and response to therapeutic ma- neuvers will provide the physician with clues about the pathophysiologic state of the patient. Sophisticated monitoring,

1993; VoL 60. No. 3 THE INDIAN JOURNAL OF PEDIATRICS 375

however, will never replace dedicatiorL to the patient and good clinical judge- ment.

When maintenance of an adequate perfusion cannot be achieved with fluid administration, the use of inotropic and / or vasopressor agents should be considered. 3s'4~ Dopamine at starting doses of 5 mcg /kg /min and titrated to response, is a useful agent for hemod3nlamic support. If doses greater than 20 mcg /kg / rain are reached without a satisfactory response, re-assessment of the hemodynamic state is necessary. Addition of an cx adrenergic agent such as epinephrine or norepinephrine, or a second intropic agent such as dobutamine, or further fluid boluses may be necessary. Restor- ing and sustaining hemodynamic stability is a primary goal in the management of septic shock. Hematocrit should be maintained about 40 in order to improve DO 2 in these patients. Hemodynamic stability should be achieved for at least 24 hours before weaning inotropic support is considered.

Respiratory

The goal of respirator,/, management is to maximize DO 2. If hypoxemia secondary to ARDS develops, higher PEEP may be required. It is important to keep in mind that high PEEP will decrease cardiac output by : (i) reducing preload due to higher intrathoracic pressure, (ii) increasing right ventricular afterload due to increase in pulmonary vascular resistance, and (iii) decreasing left ventricular end diastolic volume (LVEDV) due to ventricular interdependence. If right ventricle becomes enlarged, it will dis-

place the ventricular septum and decrease the LVEDV. Therefore, further fluid resuscitation or increasing inotropic support may be necessary when using high PEEP. 36-4~

Supplemental oxygen should be weaned as soon as possible. Tolerance for relatively lower PaO 2 (50-60 torr), hypercapnea (50-60 torr) and some respiratory acidosis (PH 7.28-7.30) will allow for survivors with lesser morbidity. 42

Gastrointestinal

Early enteral feedings are of major importance in preventing multiorgan failure. The enteral route can provide larger amount of calories, avoids gut atrophy and may prevent bacterial translocation. 31 Bronchoaspiration may be a risk, even fore those patients with cuffed en- dotrachealtubes. Use of nasojejunal feedings should prevent this complication. Continuous diluted feeding in small volume should be started as soon ss possible, often within 24-36 hours of the initial septic episode.Although muscle relaxation is not a contraindication for en- ternal feedings, narcotic sedatives may decrease intestinal motility, a change in sedative drugs may be necessary. Gastric PH should be monitored; of PH<4.5, ant- acid medications, H 2 blockers agents or sucralfate should be used.

Renal and Metabolic

Preservation of renal function in the management of the shock states is important. This is done by maintaining an adequate intravascular volume with the administration of fluids and the use of

376 THE INDIAN JOURNAL OF PEDIATRICS 1993; VoL 60. ~ 3

dopamine at low doses (3 mcg/kg/min) to maintain renal blood flow. A Foley catheter should be placed to obtain an accurate estimation of renal function. In the presence of persistent oliguria, it is mmtdatory to rule out decreased cardiac output or hypovolemia before diuretics are used. Despite multiple fluid boluses, septic patients are often hypovolemic due to capillary leak syndrome, so that the infused fluids escape to the intersti- tial space with resultant oliguria. If fluid challenge does not resolve oliguria and there is hemodynamic evidence of adequate volume, diuretics such as furosem- ide euld/or mannitol are indicated. 3s

Fluids and Electrolytes

Once the acute episode of sepsis is controlled, these patients should be given two thirds to full maintenance fluids. In view of their requirement for blood products, multiple medications and fluid boluses, it is likely that over 24 hours the patients will have an excessively positive fluid balance. The objective of fluid therapy is to achieve an envolemic state while avoiding fluid overload. Electro- lyte abnormalities should be promptly corrected. Hypocalcemia often develops in patients with metabolic acidosis corrected with sodium bicarbonate. Hypo- phosphatemia and hypomagnesemia is often encountered. The latter particularly occurs in patients that have re- ceived aminoglycoside therapy. Hyper- glycemia and glucose intolerance is often seen early in the course of the disease, usually resolved by lowering the amount of glucose provided. ~ The use of insulin in septic hyperglycemic patients is controversial; although it will decrease the

blood glucose, insulin does not increase glucose oxidation and utilization in the septic patient. ~ Metabolic acidosis is a sign of poor perfusion and impaired DO r Under these conditions; fluid challenge and improving cardiac output may prove beneficial. If metabolic acidosis persists despite adequate cardiac output and DO 2, sodium bicarbonate may be used. Parenteral nutrition should be ini- tiated whenever internal nutrition is not possible.

Disseminated Intravascular Coagula- tion (DIC)

Rapid recognition and treatment of the primary underlying disease continues to be the most important aspect of success- ful management of DIC, Replacement therapy with fresh frozen plasma (factors II, V, VII, VIII, IX, X, XI, XII, an- tithrombin III, etc.), cryoprecipitate (Fac- tors VIII, yon Willibrand factor, fibronectin, fibrinogen), red blood cells, and platelets is necessary. 34 Heparin is not used to treat DIC unless there is evidence of thrombosis, and severe ischemia that may lead to necrosis of the affected area. This is often seen in patients with severe meningococcemia. In- hibitors of fibrinolysis such as e- aminocaproic acid may foster the ap- pearance of thrombosis and are not row tinely used.

Experimental Contmvemial Therapy

During the past years, there has been an explosion of potential therapies for septic shock. When corticosteroids are give~ to animals before a challenge injection of a lethal endotoxin dose, septic shock


does not develop. 44 Nevertheless, in human studies, high dose corticosteroid therapy failed to improve survival and increased morbidity and mortality from injection. 3 Corticosteroids are used oIfly in those septic patients with established or suspected adrenal insufficiency.

Nonsteroidal ant i - inf lammatory (NSAID) drugs have proved to be useful in different animal models of septic shock and lung injury. Preliminary studies in human sepsis indicate possible benefits. An NIH sponsored multicenter trial is in progress to determine the effi- cacy of NSAID in the treatment of patients with septic shock. Currently these drugs are still considered experimental. *s

Controlled studies using naloxone, an endrophin inhibitor, have failed to prove a beneficial effect and the therapeutic value is controversial. 46'.7

Pharmacological inhibition of nitric oxide synthesis has restored blood pressure in patients with septic shock.** Nev- ertheless, in view of the complex phar- macodynamic effects of drugs that inhibit NO synthesis, this potential therapy will need to be carefully evaluated before it can be widely applied to the clini- ca] setting. 49

Therapeutic use of human (HA-1A) monoclonal anti-lipid A ant ibody or murine-derived Ig M monoclonal antibody has shown beneficial effects in se- lected populations of septic patients. The cost of this therapy is excessive and patient selection is still controversia]? ~

Monoclonal ant ibodies to TNF (x proved to be efficacious in experimental animals, s2 Preliminary results in human studies are encouraging, s3 Receptor an- tagonists to IL 1 (ILt-a),S* or to PAF, ss are also potential beneficial therapies. Other

inhibitors of infammafion, such as complement C 1 and C s inhibitors, neutrophil and protease inhibitors (pentoxifylline, adenosine, etc.) antioxidants and oxygen radical scavengers may play a role in the management of complex pathophysiologic events of sepsis, la Further studies are necessary to confirm their benefit, and determine proper clinical use.

The t reatment of septic shock no longer is limited to support ive care and anffbiotic adminis t ra t ion. Better understanding of the concepts of oxygen delivery and uptake from the tissues, and of the mechanisms of tissue and cellular injury has opened new opportunities to an earlier diagnosis and better treatment of this disease.

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Septic shock: Pathogenesis and treatment