Pathomechanism of Shock and Disseminated intravascular coagulation DIC

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Pathomechanism of Shock and Disseminated
intravascular coagulation (DIC)

• Nicole Meissner-Pearson

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• 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 (lt60 mmHG)
• Tachycardia
• Oliguria
• Altered mental status
• Peripheral hypoperfusion and hypoxia

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Mechanisms of blood pressure regulationBlood
pressure is proportionate to cardiac output and
peripheral vascular resistance
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Mechanisms of blood pressure regulation
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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)

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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

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Stages of hypovolemic shock

• Mild (loss of lt 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 gt100 beats/min (sympathetic response)
• oliguria
• blood pressure may be maintained in supine
  patient
• Severe (loss of lt 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

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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)

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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

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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)
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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

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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)

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NEJM 2004, Vol. 3512 pp 159-169
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Most septic shocks are caused by
endotoxin-producing gram negative bacilli
Endotoxins are bacterial cell wall Lipopolysacchar
ides (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.
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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)

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Sepsis From hyper inflammatory response to
immunosuppression
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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 lt 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)

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Cellular and tissue changes induced by shock
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Inflammatory response to Sepsis
Inflammatory Responses to Sepsis
NEJM 35516 Oct. 19th 2006 pp. 1699-1713
Russell J. N Engl J Med 20063551699-1713
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Endotoxemia during sepsis stimulates the
induction of NO synthase, which leads to
NO-mediated arterial vasodilation
NEJM, 2004, Vol.3512,pp. 159-169
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.
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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.
NEJM, 1998,VOl. 338, pp 671-675
Muddy brown urine cast are typical for ATN
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Pathomechanism of ischemic tubular necrosis
See Robbins p. 994
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Effects of systemic arterial vasodilation in
patients with sepsis and acute renal failure
NEJM, 2004, Vol.3512,pp. 159-169
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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

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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
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Virtually all patients with sepsis have
coagulation abnormalities. 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)
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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

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Levi, M. et al. N Engl J Med 1999341586-592
NEJM 1999 August 19, pp 586-592
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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
NEJM 2006 Oct 19
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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 (gt 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.

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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