Chapter 64: Shock

Shock Acute syndrome characterized by the body’s inability to deliver adequate oxygen

to meet the metabolic demands of vital organs and tissues. Patients have insufficient oxygen at the tissue level to support normal aerobic

cellular metabolism, resulting in a shift to less efficient anaerobic metabolism. Increases in tissue oxygen extraction are unable to compensate for this

deficiency in oxygen delivery, leading to progressive lactic acidosis and possible clinical deterioration.

If inadequate tissue perfusion persists, adverse vascular, inflammatory, metabolic, cellular, endocrine, and systemic responses worsen the physiologic instability.

Compensation for inadequate oxygen delivery involves a complex set of responses that attempt to preserve oxygenation of the vital organs (i.e., brain, heart, kidneys, liver) at the expense of other organs (i.e., skin, gastrointestinal tract, muscles)

Brain is especially sensitive to periods of poor oxygen supply, given its lack of capacity for anaerobic metabolism.

Initially, shock may be well compensated, but it may rapidly progress to an uncompensated state requiring more aggressive therapies to achieve clinical recovery or improvement.

Combination of a continued presence of an inciting trigger and a body’s exaggerated and potentially harmful neurohumoral, inflammatory, and cellular responses leads to the progression of shock.

Untreated shock causes irreversible tissue and organ injury (i.e., irreversible shock) and, ultimately, death.

Irrespective of the underlying cause of shock, the specific pattern of response, pathophysiology, clinical manifestations, and treatments may vary significantly, depending on the specific etiology (which may be unknown), the clinical circumstances, and an individual patient’s

Biologic response to the shock state.

EPIDEMIOLOGY Shock occurs in approximately 2% of all hospitalized infants, children, and

adults in the USA (≈400,000 cases/yr) Most patients who die do so not in the acute hypotensive phase of shock, but

rather as a result of associated complications. Multiple Organ Dysfunction Syndromes (MODS)

Defined as any alteration of organ function that requires medical support for maintenance

Presence of MODS in patients with shock substantially increases the probability of death.

In pediatrics, the mortality rate for shock is decreasing as a consequence of educational efforts and the utilization of standardized management guidelines, which emphasize early recognition and intervention along with the rapid transfer of critically ill patients to a pediatric intensive care unit

DEFINITION Shock classification systems generally define 5 major types of shock:

1. Hypovolemic2. Cardiogenic3. Distributive4. Obstructive5. Septic

Hypovolemic Shock Most common cause of shock in children worldwide Most frequently caused by diarrhea, vomiting, or hemorrhage.

Cardiogenic shock Seen in patients with congenital heart disease (before or after surgery, including

heart transplantation) or with congenital or acquired cardiomyopathies, including acute myocarditis.

Obstructive Shock Stems from any lesion that creates a mechanical barrier that impedes adequate

cardiac output Examples are pericardial tamponade, tension pneumothorax, pulmonary

embolism, and ductus-dependent congenital heart lesions when systemic blood flow decreases as the ductus arteriosus closes.

Distributive Shock Caused by inadequate vasomotor tone which leads to capillary leak and

maldistribution of fluid into the interstitium.

Septic shock Often discussed synonymously with distributive shock, but the septic process

usually involves a more complex interaction of distributive, hypovolemic, and cardiogenic shock.

PATHOPHYSIOLOGY An initial insult triggers shock, leading to inadequate oxygen delivery to organs

and tissues. Compensatory mechanisms attempt to maintain blood pressure

By increasing CO and SVR Body also attempts to optimize oxygen delivery to the tissues by

increasing oxygen extraction and redistributing blood flow to the brain, heart, and kidneys (at the expense of the skin and gastrointestinal tract).

These responses lead to an initial state of compensated shock, in which blood pressure is maintained.

If treatment is not initiated or is inadequate during this period, decompensated shock develops, with hypotension and tissue damage that may lead to multisystem organ dysfunction and ultimately to death

In the early phases of shock, multiple compensatory physiologic mechanisms act to maintain blood pressure and preserve tissue perfusion and oxygen delivery These responses include increases in HR, SV, and vascular smooth

muscle tone Regulated through sympathetic nervous system activation and

neurohormonal responses. Increased RR with greater CO2 elimination is a compensatory response to

the metabolic acidosis Increased CO2 production from poor tissue perfusion. Renal excretion of hydrogen ions and retention of bicarbonate also

increase in an effort to maintain normal body pH Maintenance of intravascular volume is facilitated via sodium regulation

through Renin angiotensin-aldosterone and atrial natriuretic factor axes Cortisol and catecholamine synthesis and release Antidiuretic hormone secretion

Despite these compensatory mechanisms, the underlying shock and host response lead to vascular endothelial cell injury and significant leakage of intravascular fluids into the interstitial extracellular space.

All forms of shock affect cardiac output via several mechanisms. Changes in heart rate, preload, afterload, and myocardial contractility may

occur separately or in combination

Hypovolemic shock Characterized primarily by fluid loss and decreased preload. Tachycardia and an increase in systemic vascular resistance are the initial compensatory responses to maintain cardiac output and systemic blood pressure. Without adequate volume replacement, hypotension develops, followed

by tissue ischemia and further clinical deterioration. When there is pre-existing low plasma oncotic pressure (nephrotic

syndrome, malnutrition, hepatic dysfunction, acute severe burns, etc.) Even further volume loss and exacerbation of shock may occur because

of endothelial breakdown and worsening capillary leak. Underlying pathophysiologic mechanism leading to Distributive Shock is a

state of abnormal vasodilation. Sepsis, hypoxia, poisonings, anaphylaxis, spinal cord injury, or mitochondrial

dysfunction can cause Vasodilatory Shock Lowering of SVR is accompanied initially by a maldistribution of blood flow

away from vital organs and a compensatory increase in cardiac output. This process leads to significant decreases in both preload and afterload. Therapies for distributive shock must address both of these problems

simultaneously. Cardiogenic Shock may be seen in patients with myocarditis, cardiomyopathy,

congenital heart disease, or arrhythmias, or following cardiac surgery Myocardial contractility is affected, leading to systolic and/or diastolic

dysfunction Later phases of all forms of shock frequently have a negative impact on the

myocardium, leading to development of a cardiogenic component to the shock state.

Septic shock is often a unique combination of distributive, hypovolemic, and cardiogenic shock. Hypovolemia from intravascular fluid losses occurs through capillary leak. Cardiogenic shock results from the myocardium-depressant effects of

sepsis Distributive shock is the result of decreased SVR

The degree to which a patient exhibits each of these responses varies, but there are frequently alterations in preload, afterload, and myocardial contractility.

In septic shock, it is important to distinguish between the inciting infection and the host inflammatory response. Normally, host immunity prevents the development of sepsis via activation

of the reticular endothelial system along with the cellular and humoral immune systems

If this inflammatory cascade is uncontrolled, derangement of the microcirculatory system leads to subsequent organ and cellular dysfunction.

Systemic Inflammatory Response Syndrome (SIRS)

An inflammatory cascade that is initiated by the host response to an infectious or noninfectious trigger

Inflammatory cascade is triggered when the host defense system does not adequately recognize and/or clear the triggering event. Inflammatory cascade initiated by shock can lead to hypovolemia, cardiac

and vascular failure, acute respiratory distress syndrome (ARDS), insulin resistance, decreased cytochrome P450 (CYP450), activity (decreased steroid synthesis), coagulopathy, and unresolved or secondary infection.

Tumor necrosis factor (TNF) and other inflammatory mediators increase vascular permeability, causing diffuse capillary leak, decreased vascular tone, and an imbalance between perfusion and metabolic demands of the tissues.

TNF and interleukin-1 (IL-1) stimulate the release of pro-inflammatory and anti-inflammatory mediators, causing fever and vasodilatation.

Arachidonic acid metabolites lead to the development of fever, tachypnea, ventilation-perfusion abnormalities, and lactic acidosis.

Nitric oxide, released from the endothelium or inflammatory cells, is a major contributor to hypotension.

Myocardial depression is caused by myocardium-depressant factors, TNF, and some interleukins through direct myocardial injury, depleted catecholamines, increased β-endorphin, and production of myocardial nitric oxide.

Inflammatory cascade is initiated by toxins or super antigens via macrophage binding or lymphocyte activation.

Vascular endothelium is both a target of tissue injury and a source of mediators that may cause further injury.

Biochemical responses include the production of arachidonic acid metabolites, release of myocardial depressant factors, release of endogenous opiates, activation of the complement system, as well as the production and release of many other mediators, which may be either pro-inflammatory or anti-inflammatory Balance between these mediator groups for an individual patient

contributes to the progression of disease and affects the chance for survival.

CLINICAL MANIFESTATIONS Categorization of shock is important, but there may be significant overlap among

these groups, especially in septic shock Clinical presentation of shock depends in part on the underlying etiology. If unrecognized and untreated, all forms of shock follow a common and

untoward progression of clinical signs and pathophysiologic changes that may ultimately lead to irreversible shock and death

Shock may initially manifest as only tachycardia or tachypnea. Progression leads to decreased urine output, poor peripheral perfusion,

respiratory distress or failure, alteration of mental status, and low blood pressure Significant misconception is that shock occurs only with low blood pressure.

Because of compensatory mechanisms, hypotension is often a late finding and is not a criterion for the diagnosis of shock.

Tachycardia, with or without tachypnea, may be the first or only sign of early compensated shock.

Hypotension reflects an advanced state of decompensated shock Associated with increased mortality.

Hypovolemic shock often manifests initially as orthostatic hypotension Associated with dry mucous membranes, dry axillae, poor skin turgor, and

decreased urine output. Depending on the degree of dehydration, patient may present with either normal

or slightly cool distal extremities, and peripheral or even central (femoral) pulses may be normal, decreased, or absent.

Because of decreased CO and compensatory peripheral vasoconstriction, presenting signs of cardiogenic shock are tachypnea, cool extremities, delayed capillary filling time, poor peripheral and/or central pulses, declining mental status, and decreased urine output

Obstructive shock often also manifests as inadequate cardiac output due to a physical restriction of forward blood flow Acute presentation may quickly progress to cardiac arrest.

Distributive shock manifests initially as peripheral vasodilation and increased but inadequate cardiac output.

Regardless of etiology, Uncompensated Shock, with hypotension, high SVR, decreased CO, respiratory failure, obtundation, and oliguria, occurs late in the progression of disease.

Additional clinical findings in shock include cutaneous lesions such as petechiae, diffuse erythema, ecchymoses, ecthyma gangrenosum, and peripheral gangrene.

Jaundice can be present either as a sign of infection or as a result of MODS. Sepsis

Defined as SIRS resulting from a suspected or proven infectious etiology Clinical spectrum of sepsis begins when a systemic (e.g., bacteremia,

rickettsial disease, fungemia, viremia) or localized (e.g., meningitis, pneumonia, pyelonephritis)

Infection progresses from sepsis to Severe Sepsis Presence of sepsis combined with organ dysfunction

Further deterioration leads to Septic Shock

Severe sepsis plus the persistence of hypoperfusion or hypotension despite adequate fluid resuscitation or a requirement for vasoactive agents

MODS possibly death

Outcomes improve with early recognition and treatment. Initial signs and symptoms of sepsis include

Alterations in temperature regulation (hyperthermia or hypothermia) Tachycardia Tachypnea

In the early stages (Hyperdynamic phase or “warm” shock), the cardiac output increases in an attempt to maintain adequate oxygen delivery and meet the greater metabolic demands of the organs and tissues.

As septic shock progresses, cardiac output falls in response to the effects of numerous inflammatory mediators, leading to a compensatory elevation in systemic vascular resistance and the development of “cold” shock.

DIAGNOSIS Shock is diagnosed clinically on the basis of a thorough history and physical

exam In cases of suspected septic shock, an infectious etiology should be sought

through culture of clinically appropriate specimens and prompt initiation of empiric antimicrobial therapy based on patient age, underlying disease, and geographic location.

Cultures take time for incubation and their results may not always be positive. Additional evidence for identifying an infectious etiology as the cause of SIRS

includes Physical examination findings Imaging findings Presence of white blood cells in normally sterile body fluids Suggestive rashes such as petechiae and purpura.

Affected children should be admitted to an intensive care unit or other highly monitored environment, as indicated by clinical status and the resources of the medical facility, where continuous, close invasive monitoring can be performed, including central venous pressure and arterial blood pressure monitoring as clinically indicated.

LABORATORY FINDINGS Laboratory findings often include evidence of hematologic abnormalities and

electrolyte disturbances. Hematologic abnormalities may include thrombocytopenia, prolonged PT and

PTT, reduced serum fibrinogen level, elevations of fibrin split products, and anemia.

Elevated neutrophil counts and increased immature forms can be seen with infection

Bands, myelocytes, promyelocytes, vacuolation of neutrophils, toxic granulations, and Döhle bodies.

Neutropenia or leukopenia: ominous sign of overwhelming sepsis. Glucose dysregulation, a common stress response, may manifest as

hyperglycemia or hypoglycemia. Other electrolyte abnormalities are hypocalcemia, hypoalbuminemia, and

metabolic acidosis. Renal and/or hepatic function may also be abnormal.

Patients with ARDS or pneumonia have impairment of oxygenation (decreased PaO2) as well as of ventilation (increased Paco2) in the later stages of lung injury

Hallmark of uncompensated shock is an imbalance between oxygen delivery (DO2) and oxygen consumption (VO2)

Metabolic acidosis state is manifested clinically by increased lactic acid production (high anion gap, metabolic acidosis) due to anaerobic metabolism

Low mixed venous oxygen saturation (SVO2) due to the compensatory increase in tissue oxygen extraction

Gold standard measurement of SVO2 is from a Pulmonary Arterial Catheter Measurements from this location are often not clinically feasible. Sites such as the right ventricle, right atrium, superior vena cava (Svco2),

or inferior vena cava are often used as for surrogate measures of mixed venous blood.

Oxygen delivery normally exceeds oxygen consumption by threefold Oxygen extraction ratio is approximately 25%, thus producing a normal SVO2 of

75-80% Falling SvO2 value, as measured by Co-Oximetry, reflects an increasing

oxygen extraction ratio and documents a decrease in oxygen delivery relative to consumption. Increase in oxygen extraction by the end organs is an attempt to

maintain adequate oxygen delivery at the cellular level. Along with SVO2, serum lactate measurements may be used as a marker for the

adequacy of oxygen delivery and the effectiveness of therapeutic interventions.

TREATMENTInitial Management Early recognition and prompt intervention are extremely important in the

management of all forms of shock Baseline mortality is much lower in pediatric shock than in adult shock, and

further improvements in mortality may occur with early interventions Initial assessment and treatment of the pediatric shock patient should include

Stabilization of airway Breathing Circulation (the ABCs) established by the American Heart Association’s pediatric advanced life

support (PALS) and neonatal advanced life support (NALS) guidelineDepending on the severity of shock, further airway intervention, including intubation and mechanicalventilation, may be necessary to lessen the workload of breathingand decrease the body’s overall metabolic demands. Neonatesand infants in particular may have profound glucose dysregulationin association with shock. Glucose levels should be checkedroutinely and treated appropriately, especially early in the courseof illness.Given the predominance of sepsis and hypovolemia as themost common causes of shock in the pediatric population, mosttherapeutic regimens are based on guidelines established in thesesettings. Immediately following establishment of intravenous (IV)or intraosseous (IO) access, aggressive, early goal-directed therapy(EGDT) should be initiated unless there are significant concernsfor cardiogenic shock as an underlying pathophysiology. RapidIV administration of 20 mL/kg isotonic saline or, less often,colloid should be initiated in an attempt to reverse the shockstate. This bolus should be repeated quickly up to 60-80 mL/kg;it is not unusual for severely affected patients to require thisvolume within the first hour.If shock remains refractory following 60-80 mL/kg of volumeresuscitation, inotropic therapy (dopamine, norepinephrine, orepinephrine) should be instituted while additional fluids areadministered. Current guidelines recommend administration ofthese inotropic agents via peripheral intravenous (PIV) lines, withvery close monitoring of the PIV sites while central venous accessis being obtained, because a delay in the initiation of inotropesin shock has been associated with increased mortality.Rapid fluid resuscitation using 60-80 mL/kg or more is associatedwith improved survival without an increased incidence ofpulmonary edema. Fluid resuscitation in increments of 20 mL/kgshould be titrated to normalize heart rate (according to age-basedheart rates), urine output (to 1 mL/kg/hr), capillary refill time (to<2 sec), and mental status. Fluid resuscitation may sometimesrequire as much as 200 mL/kg. It must be stressed that hypotensionis often a late and ominous finding, and normalization ofblood pressure alone is not a reliable endpoint for assessing theeffectiveness of resuscitation. Although the type of fluid (crystalloidvs colloid) is an area of ongoing debate, fluid resuscitationin the first hour is unquestionably essential to survival in septicshock, regardless of the fluid type administered.Additional Early ConsiderationsIn septic shock specifically, early administration of broad-spectrumantimicrobial agents is associated with a reduction in mortality.

The choice of antimicrobial agents depends on thepredisposing risk factors and the clinical situation. Bacterial resistancepatterns in the community and/or hospital should be consideredin the selection of optimal antimicrobial therapy. Neonatesshould be treated with ampicillin plus cefotaxime and/or gentamicin.Acyclovir should be added if herpes simplex virus is suspectedclinically. In infants and children, community-acquiredinfections with Neisseria meningitidis can be treated empiricallywith a 3rd-generation cephalosporin (ceftriaxone or cefotaxime)or high-dose penicillin. Haemophilus influenzae infections can betreated empirically with a 3rd-generation cephalosporin (ceftriaxoneor cefotaxime). The prevalence of resistant Streptococcuspneumoniae often requires the addition of vancomycin, dependingon the specific clinical scenario. Suspicion of community- orhospital-acquired, methicillin-resistant Staphylococcus aureusinfection warrants coverage with vancomycin, depending on localresistance patterns. If an intra-abdominal process is suspected,anaerobic coverage should be included with an agent such asmetronidazole, clindamycin, or piperacillin-tazobactam.Nosocomial sepsis should generally be treated with at least a3rd- or 4th-generation cephalosporin or a penicillin with anextended gram-negative spectrum (e.g., piperacillin-tazobactam).An aminoglycoside should be added as the clinical situation warrants.Vancomycin should be added to the regimen if the patienthas an indwelling medical device (Chapter 172), gram-positivecocci are isolated from the blood, or methicillin-resistant S.aureus infection is suspected, or as empiric coverage for S. pneumoniaein a patient with meningitis. Empirical coverage forfungal infections should be considered for selected immunocompromisedpatients (Chapter 171). It should be noted that theseare broad, generalized recommendations that must be tailored tothe individual clinical scenario and to the local resistance patternsof the community and/or hospital.Distributive shock that is not secondary to sepsis is caused bya primary abnormality in vascular tone. Cardiac output inaffected patients is usually maintained and may initially be supranormal.These patients may benefit temporarily from volumeresuscitation, but the early initiation of a vasoconstrictive agentto increase SVR is an important element of clinical care. Patientswith spinal cord injury and spinal shock may benefit from eitherphenylephrine or vasopressin to increase SVR. Epinephrine is thetreatment of choice for patients with anaphylaxis (Table 64-9).This agent has peripheral α-adrenergic as well as inotropic effectsthat may improve the myocardial depression seen with anaphylaxisand its associated inflammatory response (Chapter 143).Patients with cardiogenic shock have poor cardiac outputsecondary to systolic and/or diastolic myocardial depression,often with a compensatory elevation in SVR. These patients mayshow poor response to aggressive fluid resuscitation and, in fact,may demonstrate decompensation quickly when fluids are administered.Smaller boluses of fluid (5-10 mL/kg) should be given incardiogenic shock. In any patient with shock whose clinical statusdeteriorates with fluid resuscitation, a cardiogenic etiology shouldbe considered, and further administration of intravenous fluidsshould be performed cautiously. Early initiation of myocardialsupport with dopamine or epinephrine to improve cardiac outputis important in this context. Consideration should be given toadministering an inodilator, such as milrinone, early in the process.Despite adequate cardiac output with the support of inotropicagents, a high SVR with poor peripheral perfusion and acidosismay persist in cardiogenic shock. Therefore, if not already started,milrinone therapy may improve systolic function and decreaseSVR without causing a significant increase in heart rate. Furthermore,this agent has the added benefit of enhancing diastolicrelaxation. Dobutamine or other vasodilating agents, such asnitroprusside, may also be considered in this setting (Table64-10). Dosage titration of these agents should target clinicalendpoints, including increased urine output, improved peripheralperfusion, resolution of acidosis, and normalization of mentalstatus. Agents that improve blood pressure by increasing SVR,such as norepinephrine and vasopressin, should generally beavoided in patients with cardiogenic shock (although they maybe helpful for other causes of shock). These agents may causefurther decompensation and potentially precipitate cardiac arrestas a result of the increased afterload and additional work imposedon the myocardium. The combination of inotropic and vasoactiveagents administered must be tailored to the pathophysiology ofthe individual patient. Close and frequent reassessment of thepatient’s cardiovascular status is essential.For patients with obstructive shock, fluid resuscitation may be

briefly temporizing in maintaining cardiac output, but the primaryinsult must be immediately addressed. Examples of lifesavingtherapeutic interventions for such patients are pericardiocentesisfor pericardial effusion, pleurocentesis or chest tube placementfor pneumothorax, thrombectomy/thrombolysis for pulmonaryembolism, and the initiation of a prostaglandin infusion forductus-dependent cardiac lesions. There is often a “last drop”or “last straw” phenomenon associated with some obstructivelesions, in that further small amounts of intravascular volumedepletion may lead to a rapid deterioration, including cardiacarrest, if the obstructive lesion is not corrected.Regardless of the etiology of shock, metabolic status shouldbe meticulously maintained (see Table 64-8). Electrolyte levelsshould be monitored closely and corrected as needed. Hypoglycemiais common and should be promptly treated. Hypocalcemia,which may contribute to myocardial dysfunction, should betreated with a goal of normalizing the ionized calcium concentration.There is no evidence that supranormal calcium levels benefitthe myocardium, and hypercalcemia may actually be associatedwith increased myocardial toxicity.Hydrocortisone replacement may be beneficial in pediatricshock. Up to 50% of critically ill patients may have absolute orrelative adrenal insufficiency. Patients at risk for adrenal insufficiencyinclude those with congenial adrenal hypoplasia, abnormalitiesof the hypothalamic-pituitary axis, and recent therapywith corticosteroids (including patients with asthma, rheumaticdiseases, malignancies, and inflammatory bowel disease). Thesepatients are at high risk for adrenal dysfunction and shouldreceive stress doses of hydrocortisone. Steroids may also be consideredin patients with shock that is unresponsive to fluid resuscitationand catecholamines. Determination of baseline cortisollevels prior to steroid administration may be beneficial in guidingtherapy, although this idea remains controversial.Considerations for Continued TherapyAfter the first hour of therapy and attempts at early reversal ofshock, focusing of therapies on goal-directed endpoints shouldcontinue in an intensive care setting (see Fig. 64-1 and Table64-8). These clinical endpoints serve as global markers for organperfusion and oxygenation. Laboratory parameters such as SvO2(or Scvo2), serum lactate concentration, cardiac index, andhemoglobin level serve as adjunctive measures of tissue oxygendelivery. On the basis of guidelines published in 2009, hemoglobinshould be maintained >10 g/dL, SvO2 (or ScvO2) >70%, andcardiac index at 3.3-6 L/min/m2 to optimize oxygen delivery inthe acute phase of shock (although it should be noted that cardiacindex is rarely monitored in the clinical setting owing to thelimited use of pulmonary artery catheters and the lack of accuratenoninvasive cardiac output monitors for infants and children).Blood lactate levels and calculation of base deficit from arterialblood gas values are very useful markers for the adequacy ofoxygen delivery. It is important to note that these parameters areall indicators of global oxygen delivery and utilization, but thereare no currently available clear indicators for adequate measurementof local tissue oxygenation.Respiratory support should be used as clinically appropriate.When shock leads to ARDS or acute lung injury (ALI) requiringmechanical ventilation, lung-protective strategies to keep plateaupressure below 30 cm H2O and maintain tidal volume at 6 mL/kg have been shown to improve mortality in adult patients(Chapter 65). These data are extrapolated to pediatric patientsbecause of the lack of definitive pediatric studies in this area.Additionally, after the initial shock state has been reversed, renalreplacement therapy and fluid removal may also be useful inchildren with anuria or oliguria and resultant severe fluid overload(Chapter 529). Intravenous immunoglobulin infusion orplasmapheresis may also be considered in certain circumstancesas therapeutic adjuncts for shock. Other interventions includecorrection of coagulopathy with fresh frozen plasma or cryoprecipitateand platelet transfusions as necessary, especially in thepresence of active bleeding.In addition to symptomatic care and treatment of any underlyinginfectious causes, therapies to augment host defense, blocktrigger events, prevent leukocyte-endothelium interaction, andinhibit vasoactive substances, cytokines, or lipid mediators arebeing investigated. To date, the results of clinical trials investigatingdrugs targeting the mediators of SIRS have been disappointing.Trials have been conducted with anti-endotoxin antibodies,antioxidant compounds, an IL-1 receptor antagonist, IL-1 antibodies,bradykinin receptor antibodies, cyclooxygenase inhibitors,thromboxane antagonists, platelet-activating factor (PAF)

antagonists, inhibitors of leukocyte adhesion molecules, nitricoxide antagonists, anti-TNF antibody, bactericidal permeability–increasing protein, and recombinant human activated protein C(drotrecogin-α). Studies of drotrecogin-α have shown improvementin the 28-day survival rate in adults, but enrollment in thepediatric trial was closed early because of an increased risk ofintracranial bleeding and an unfavorable risk : benefit ratio, particularlyin neonates. The best treatment for shock consists ofearly recognition, early antimicrobial therapy (for suspectedseptic shock), aggressive fluid resuscitation (except in cardiogenicshock), and early goal-directed therapy.If shock remains refractory despite maximal therapeutic interventions,mechanical support with extracorporeal membraneoxygenation (ECMO) or a ventricular assist device (VAD) maybe indicated. ECMO may be lifesaving in cases of refractoryshock regardless of underlying etiology. Similarly, a VAD may beindicated for refractory cardiogenic shock in the setting of cardiomyopathyor recent cardiac surgery. Systemic anticoagulation,which is required while patients are receiving mechanical support,may be difficult, given the significant coagulopathy often encounteredin refractory shock, especially when the underlying etiologyis sepsis. Mechanical support in refractory shock poses substantialrisks but can improve survival in specific populations ofpatients.PROGNOSISIn septic shock, mortality rates are as low as 3% in previouslyhealthy children and 6-9% in children with chronic illness(compared with 25-30% in adults). With early recognition andtherapy, the mortality rate for pediatric shock continues toimprove, but shock and MODS remain one of the leading causesof death in infants and children. The risk of death involves acomplex interaction of factors, including the underlying etiology,presence of chronic illness, host immune response, and timing ofrecognition and therapy.