Pathomechanism of Shock and

Disseminated intravascular coagulation (DIC)

Nicole Meissner-Pearson

• Shock occurs when the rate of arterial blood flow is inadequate

to meet metabolic tissue needs and is the consequence of cardio-vascular collapse

• Essentials of diagnosis are– Hypotension (<60 mmHG)– Tachycardia– Oliguria– Altered mental status– Peripheral hypoperfusion and hypoxia

Mechanisms of blood pressure regulation:Blood pressure is proportionate to cardiac output and

peripheral vascular resistance

Mechanisms of blood pressure regulation

Three major types of shock

• Hypovolemic shock– Decreased intravascular volume resulting form loss

of blood, plasma, or fluids and electrolytes • Cardiogenic shock

– Pump failure due to myocardial damage or massive obstruction of outflow tracts

• Distributive shock– Reduction of vascular resistance form

• Sepsis• Anaphylaxis• Systemic inflammatory response syndrome

(SIRS)

Hypovolemic shock (most common type of shock)

• Loss of blood (hemorrhagic)– External bleeding (wound to the outside or

gastrointestinal)– Internal bleeding (hematoma, hemothorax,

hemopertitoneum)

• Loss of plasma– Burns– Exfoliative dermatitis

• Loss of fluids and electrolytes– External (vomiting, diarrhea, excessive sweating)– Internal ( “third spacing” = pancreatitis, ascitis, bowl

obstruction– Excessive sweating

Stages of hypovolemic shock• Mild (loss of < 20% blood volume)

– Few external signs in supine young patients but• Increased capillary refill time ( longer 3 sec. = 10% volume loss)

• Moderate (loss of 20-40% blood volume)– Patient becomes increasingly anxious and tachycardic >100

beats/min (sympathetic response)– oliguria – blood pressure may be maintained in supine patient

• Severe (loss of < 40% blood volume)– Classic signs of shock appear with hemodynamic instability

(Cave: if mental confusion occurs is an ominous clinical sign)

Only very short time frame may separate mild and severe shock symptoms that lead, when left untreated, to progressive and irreversible cell injury and death

Cardiogenic shock• Pump failure

– Secondary to myocardial infarction (most common)– Cardio-myophathy– Acute valvular dysfunction (regurgitations)– Rupture of the ventricular septum

• Arrhythmia– Tachyarrhythmia – Bradyarrhythmia

• Obstructions– Tension pneumothorax– Pericardial diseases (tamponade or constrictive pericarditis)– Pulmonary hypertension (emboli or other vascular diseases)

Characteristics of Cardiogenic Shock

• Low cardiac output

• Peripheral vasoconstriction

• Left sided heart failure leads to pulmonary venous congestion and pulmonary edema

• Right sided heart failure leads to systemic venous congestion and peripheral edema

It is essential to distinguish a cardiogenic from a hypovolemic shock!Both forms are associated with reduced cardiac out put, and increased peripheral vascular resistance, however:

Cardiogenic shock: jugular venous distention (high CVP)

Hypovolemic shock: collapsed capacitance veins (low CVP)

Distributive Shock

• Sepsis– Due to gram negative or gram positive

bacteria

• Anaphylaxis – Due to previous sensitization to an allergen

• Neurogenic– Due to traumatic spinal cord injury– Effects of epidural or spinal anesthetics– Reflex parasymapthetic stimulation

Pathogenesis of Septic Shock(vasodilatory shock)

• Sepsis is defined as a systemic inflammatory response to a bacterial infection with bacteriemia (though blood cultures can be negative)

• Severe sepsis is defined by additional end-organ dysfunction (mortality rate: 25-30%)

• Septic shock is defined as sepsis with hypotension despite fluid resuscitation and evidence of inadequate tissue perfusion (40-70%)

NEJM 2004, Vol. 351;2 pp 159-169

Most septic shocks are caused by endotoxin-producing gram negative bacilli

Endotoxins are bacterial cell wallLipopolysaccharides (LPS) that are released when the cell wall is degraded.

LPS consists of a toxic fatty acid (Lipid A) and a polysaccharide coat.LPS complexes with a circulatory LPS-binding protein and binds to its receptor CD14 on macrophages and signaling molecules (Toll-like receptor = TLR-4).

At lower dosages LPS serves to activate monocytes and macrophages and enhance clearance of a pathogen.

At higher dosages the systemic inflammatory response becomes overwhelming and affects organ functions.

The syndrome of septic shock is characterized by

• Systemic vasodilation (hypotension)

• Diminished myocardial contractility

• Widespread endothelial injury and activation leading to fluid leakage (capillary leak) resulting in acute respiratory distress syndrome (ARDS)

• Activation of the coagulation cascade (DIC)

Sepsis: From hyper inflammatory response to immunosuppression

Stages of Shock

• Initial non-progressive stage– Baro-receptor reflexes– Release of catecholamine– Activation of renin-angiotensin-aldosteron system– ADH release

results in tachycardia, peripheral vasoconstriction (cool skin) and renal fluid conservation

• Progressive stage– Widespread tissue hypoxia results in anaerobic glycolysis and– Lactate acidosis (pH < 7.35)– Vasodilation with blood pooling in microcirculation– Declined cardiac output– Oligouria– Widespread tissue hypoxia

• Irreversible stage– Widespread cell injury leading to– Further decreased myocardial contractility– Anuria with tubular necrosis– Ischemic bowl may lead to leakage of bacterial flora– Fluid lung (ARDS)

Cellular and tissue changes induced by shock

Russell J. N Engl J Med 2006;355:1699-1713

Inflammatory Responses to Sepsis

NEJM 355;16 Oct. 19th 2006 pp. 1699-1713

Inflammatory response to Sepsis

Endotoxemia during sepsis stimulates the induction of NO synthase, which leads to NO-mediated arterial vasodilation

Arterial under-filling will result in increased renal sympathetic and angiotensin activities resulting in renal vasoconstriction with sodium and

water retention and predisposition to acute renal failure.

NEJM, 2004, Vol.351;2,pp. 159-169

Shock kidney resulting in Acute Tubular Necrosis (ATN)

Typical is a pale swollen kidney with congested medullary parenchyma and tubular obstruction due to cell cast formation

ATN is the consequence of acute renal failure due to hypo-perfusion of the organ. The mortality rate is approximately 50% depending on underlying illnesses. Hypo-perfusion initiates cell injury and death. Injury of tubular epithelial cells is most prominent in in the straight portion of the proximal tubules and the thick ascending limb of the loop of Henle. The reduction of GFR is the result of hypo-perfusion and tubule lumen obstruction with cell casts and debris.

Muddy brown urine cast are typical for ATN

NEJM, 1998,VOl. 338, pp 671-675

Pathomechanism of ischemic tubular necrosis

See: Robbins p. 994

Effects of systemic arterial vasodilation in patients with sepsis and acute renal failure

NEJM, 2004, Vol.351;2,pp. 159-169

Adult Respiratory Distress Syndrome (ARDS) = Shock lung

• diffuse pulmonary parenchymal injury associated with non-cardiogenic

pulmonary edema resulting in severe respiratory distress

• pathological hallmark: diffuse alveolar damage (DAD)

• loss of the integrity of the alveolar-capillary barrier

• alveolar walls become lined with hyaline membranes (fibrin deposition)

• overall mortality rate is 60%

Mechanisms of acute lung injury resulting in ARDS and resolution

NEJM. Vol. 342, May 4 2000; pp 1334-1349

Importantly, the exudate and diffuse tissue destruction that occurs with ARDS can not be easily resolved and generally results in scaring (fibrosis). This is in contrast to the transudate of cardiogenic pulmonary edema which usually resolves completely

Virtually all patients with sepsis have coagulationabnormalities. The extreme form of it is called:

Acute disseminated intravascular coagulation (DIC)

Severe cutaneous bleeding as a result of fulminant Meningococcal septicemia due to activation and consumption

of all coagulation factors (consumption coagulopathy)

Disseminated intravascular coagulation (DIC)

• is characterized by widespread activation of coagulation resulting in the intravascular formation of fibrin and ultimately thrombotic occlusion of small and midsize vessels

• leads to compromise of blood supply to organs and may therefore contribute to multiple organ failure

• subsequent depletion of platelets and coagulation factors can result in severe bleeding and may be the presenting symptom

Levi, M. et al. N Engl J Med 1999;341:586-592

NEJM 1999; August 19, pp 586-592

NEJM 2006; Oct 19

The principal initiator of inflammation-induced

thrombin generation is tissue factor (TF)

Tissue factor expression can be induced by pro-inflammatory cytokines such as IL-1 and TNF-a

on tissue and blood cells

Symptoms and Diagnosis of DIC

• There is no single laboratory test that can establish or rule out the diagnosis of DIC. However, in the clinical practice the disorder can be diagnosed on the basis of the following findings:– Presence of an underlying disease known to be associated

with DIC– Platelet count less than 100,000/ul – Rapid decline of the platelet count– Prolongation of clotting time (> PTT, PT)– Manifestation of thrombembolic diseases and/or diffuse

bleeding leading to multi-organ failure – Presence of fibrin split products (D-Dimers)– Low levels of coagulation inhibitors (Antithrombin III,

Protein C)low and progressive drop in platelet count are sensitive, though not specific, signs of DIC.

Treatment of DIC

• Cornerstone of management is the treatment of the underlying illness

• Supportive management with– Disruption of coagulation cascade using

• “lower dose” heparin-treatment,

• administration of ATIII and/or activated protein C (protein C infusion has shown to be the first intervention proven to be effective in reducing the mortality in septic patients

– If bleeding is the predominant symptom • Platelet infusion

• Coagulation factor substitution with fresh frozen plasma