Chapter 88

Shock

David A. Turner, Ira M. Cheifetz

Shock is an acute process characterized by the body's inability to deliver adequate oxygen to meet the metabolic demands of vital organs and tissues. Insufficient oxygen at the tissue level is unable to support normal aerobic cellular metabolism, resulting in a shift to less efficient anaerobic metabolism. As shock progresses, increases in tissue oxygen extraction are unable to compensate for this deficiency in oxygen delivery, leading to progressive clinical deterioration and lactic acidosis. If inadequate tissue perfusion persists, adverse vascular, inflammatory, metabolic, cellular, endocrine, and systemic responses worsen 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). Of importance, the brain is especially sensitive to periods of poor oxygen supply given its lack of capacity for anaerobic metabolism. Initially, shock is often well compensated, but it may rapidly progress to an uncompensated state requiring more aggressive therapies to achieve clinical recovery. The combination of a continued presence of an inciting trigger and the body's exaggerated and potentially harmful neurohumoral, inflammatory, and cellular responses lead to the progression of shock. Irrespective of the underlying cause of shock, the specific pattern of response, pathophysiology, clinical manifestations, and treatment 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. Untreated shock causes irreversible tissue and organ injury (i.e., irreversible shock ) and, ultimately, death.

Epidemiology

Shock occurs in approximately 2% of all hospitalized infants, children, and adults in developed countries, and the mortality rate varies substantially depending on the etiology and clinical circumstances. Of patients who do not survive, most do not die in the acute hypotensive phase of shock, but rather as a result of associated complications and multiple-organ dysfunction syndrome (MODS). MODS is defined as any alteration of organ function that requires medical support for maintenance, and the presence of MODS in patients with shock substantially increases the probability of death. In pediatrics, educational efforts and the utilization of standardized management guidelines that emphasize early recognition and intervention along with the rapid transfer of critically ill patients to a pediatric intensive care unit (PICU) have led to decreases in the mortality rate for shock (Figs. 88.1 and 88.2 ).

Fig. 88.1 American College of Critical Care Medicine algorithm for time-sensitive, goal-directed stepwise management of hemodynamic support in newborns . Proceed to next step if shock persists. (1) First-hour goals—restore and maintain heart rate thresholds, capillary refill ≤ 2 sec, and normal blood pressure in the 1st hr. (2) Subsequent ICU goals—restore normal perfusion pressure (mean arterial pressure – central venous pressure), preductal and postductal oxygen saturation difference < 5%, and either ScvO ₂ > 70% (*except congenital heart patients with mixing lesions), superior vena cava flow > 40 mL/kg/min, or cardiac index > 3.3 L/min/m² in NICU. (From Davis AL, Carcillo JA, Aneja RK, et al: American College of Critical Care Medicine clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock, Crit Care Med 45:1061–1093, 2017, Fig 4.)

Fig. 88.2 American College of Critical Care Medicine algorithm for time-sensitive, goal-directed stepwise management of hemodynamic support in infants and children . Proceed to next step if shock persists. (1) First-hour goals—restore and maintain heart rate thresholds, capillary refill ≤ 2 sec, and normal blood pressure in the 1st hr/emergency department. (2) Subsequent ICU goals—if shock not reversed, proceed to restore and maintain normal perfusion pressure (MAP – CVP) for age, ScvO ₂ > 70% (*except congenital heart patients with mixing lesions), and cardiac index > 3.3 and < 6.0 L/min/m² in PICU. (From Davis AL, Carcillo JA, Aneja RK, et al: American College of Critical Care Medicine clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock, Crit Care Med 45:1061–1093, 2017, Fig 2.)

Types of Shock

Shock classification systems generally define 5 major types of shock: hypovolemic, cardiogenic, distributive, obstructive, and septic (Table 88.1 ). Hypovolemic shock , the most common cause of shock in children worldwide, is most frequently caused by diarrhea, vomiting, or hemorrhage. Cardiogenic shock is seen in patients with congenital heart disease (before or after surgery, including heart transplantation) or those with congenital or acquired cardiomyopathies, including acute myocarditis. Obstructive shock stems from any lesion that creates a mechanical barrier that impedes adequate cardiac output, which includes pericardial tamponade, tension pneumothorax, pulmonary embolism, and ductus-dependent congenital heart lesions. Distributive shock is caused by inadequate vasomotor tone, which leads to capillary leak and maldistribution of fluid into the interstitium. Septic shock is often discussed synonymously with distributive shock, but the septic process usually involves a more complex interaction of distributive, hypovolemic, and cardiogenic shock.

Table 88.1

Types of Shock

HYPOVOLEMIC	CARDIOGENIC	DISTRIBUTIVE	SEPTIC	OBSTRUCTIVE
Decreased preload secondary to internal or external losses	Cardiac pump failure secondary to poor myocardial function	Abnormalities of vasomotor tone from loss of venous and arterial capacitance	Encompasses multiple forms of shock Hypovolemic: third spacing of fluids into the extracellular, interstitial space Distributive: early shock with decreased afterload Cardiogenic: depression of myocardial function by endotoxins	Decreased cardiac output secondary to direct impediment to right- or left-sided heart outflow or restriction of all cardiac chambers
POTENTIAL ETIOLOGIES
Blood loss: hemorrhage Plasma loss: burns, nephrotic syndrome Water/electrolyte loss: vomiting, diarrhea	Congenital heart disease Cardiomyopathies: infectious or acquired, dilated or restrictive Ischemia Arrhythmias	Anaphylaxis Neurologic: loss of sympathetic vascular tone secondary to spinal cord or brainstem injury Drugs	Bacterial Viral Fungal (immunocompromised patients are at increased risk)	Tension pneumothorax Pericardial tamponade Pulmonary embolism Anterior mediastinal masses Critical coarctation of aorta

Pathophysiology

An initial insult triggers shock, leading to inadequate oxygen delivery to organs and tissues. Compensatory mechanisms attempt to maintain blood pressure (BP) by increasing cardiac output and systemic vascular resistance (SVR). The 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 (GI) tract. These responses lead to an initial state of compensated shock in which BP 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, death (Tables 88.2 and 88.3 ).

Table 88.2

Criteria for Organ Dysfunction

ORGAN SYSTEM	CRITERIA FOR DYSFUNCTION
Cardiovascular	Despite administration of isotonic intravenous fluid bolus ≥60 mL/kg in 1 hr: decrease in BP (hypotension) systolic BP <90 mm Hg, mean arterial pressure <70 mm Hg, <5th percentile for age, or systolic BP <2 SD below normal for age or Need for vasoactive drug to maintain BP in normal range (dopamine >5 µg/kg/min or dobutamine, epinephrine, or norepinephrine at any dose) or Two of the following: Unexplained metabolic acidosis: base deficit >5.0 mEq/L Increased arterial lactate: >1 mmol/L or >2× upper limit of normal Oliguria: urine output <0.5 mL/kg/hr Prolonged capillary refill: >5 sec Core-to-peripheral temperature gap: >3°C (5.4°F)
Respiratory	PaO 2 /FIO 2 ratio <300 in absence of cyanotic heart disease or preexisting lung disease or PaCO 2 >65 torr or 20 mm Hg over baseline PaCO 2 or Need for >50% FIO 2 to maintain saturation ≥92% or Need for nonelective invasive or noninvasive mechanical ventilation
Neurologic	GCS score ≤11 or Acute change in mental status with decrease in GCS score ≥3 points from abnormal baseline
Hematologic	Platelet count <100,000/mm3 or decline of 50% in platelet count from highest value recorded over last 3 days (for patients with chronic hematologic or oncologic disorders) or INR >1.5 or Activated prothrombin time >60 sec
Renal	Serum creatinine >0.5 mg/dL, ≥2× upper limit of normal for age, or 2-fold increase in baseline creatinine value
Hepatic	Total bilirubin ≥4 mg/dL (not applicable for newborn) Alanine transaminase level 2× upper limit of normal for age

BP, Blood pressure; FIO ₂ , fraction of inspired oxygen; GCS, Glasgow Coma Scale; INR, international normalized ratio; PaCO ₂ , arterial partial pressure of carbon dioxide; PaO ₂ , partial pressure arterial oxygen; SD, standard deviations.

Table 88.3

Signs of Decreased Perfusion

ORGAN SYSTEM	↓ PERFUSION	↓↓ PERFUSION	↓↓↓ PERFUSION
Central nervous system	—	Restless, apathetic, anxious	Agitated/confused, stuporous, coma
Respiration	—	↑ Ventilation	↑↑ Ventilation
Metabolism	—	Compensated metabolic acidemia	Uncompensated metabolic acidemia
Gut	—	↓ Motility	Ileus
Kidney	↓ Urine volume	Oliguria (<0.5 mL/kg/hr)	Oliguria/anuria
	↑ Urinary specific gravity
Skin	Delayed capillary refill	Cool extremities	Mottled, cyanotic, cold extremities
Cardiovascular system	↑ Heart rate	↑↑ Heart rate	↑↑ Heart rate
		↓ Peripheral pulses	↓ Blood pressure, central pulses only

In the early phases of shock, multiple compensatory physiologic mechanisms act to maintain BP and preserve tissue perfusion and oxygen delivery. Cardiovascular effects include increases in heart rate (HR), stroke volume, and vascular smooth muscle tone, which are regulated through sympathetic nervous system activation and neurohormonal responses. Respiratory compensation involves greater carbon dioxide (CO₂ ) elimination in response to the metabolic acidosis and increased CO₂ production from poor tissue perfusion. Renal excretion of hydrogen ions (H⁺ ) and retention of bicarbonate (HCO₃ ⁻ ) also increase in an effort to maintain normal body pH (see Chapter 68.7 ). Maintenance of intravascular volume is facilitated via sodium regulation through the renin-angiotensin-aldosterone and atrial natriuretic factor axes, cortisol and catecholamine synthesis and release, and 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.

Another important aspect of the initial pathophysiology of shock is the impact on cardiac output. All forms of shock affect cardiac output through several mechanisms, with changes in HR, preload, afterload, and myocardial contractility occurring separately or in combination (Table 88.4 ). Hypovolemic shock is characterized primarily by fluid loss and decreased preload. Tachycardia and an increase in SVR are the initial compensatory responses to maintain cardiac output and systemic BP. Without adequate volume replacement, hypotension develops, followed by tissue ischemia and further clinical deterioration. When there is preexisting low plasma oncotic pressure (caused by nephrotic syndrome, malnutrition, hepatic dysfunction, acute severe burns, etc.), even further volume loss and exacerbation of shock may result from endothelial breakdown and worsening capillary leak.

Table 88.4

Pathophysiology of Shock

Extracorporeal Fluid Loss

• Hypovolemic shock may be a result of direct blood loss through hemorrhage or abnormal loss of body fluids (diarrhea, vomiting, burns, diabetes mellitus or insipidus, nephrosis).

Lowering Plasma Oncotic Forces

• Hypovolemic shock may also result from hypoproteinemia (liver injury, or as a progressive complication of increased capillary permeability).

Abnormal Vasodilation

• Distributive shock (neurogenic, anaphylaxis, or septic shock) occurs when there is loss of vascular tone—venous, arterial, or both (sympathetic blockade, local substances affecting permeability, acidosis, drug effects, spinal cord transection).

Increased Vascular Permeability

• Sepsis may change the capillary permeability in the absence of any change in capillary hydrostatic pressure (endotoxins from sepsis, excess histamine release in anaphylaxis).

Cardiac Dysfunction

• Peripheral hypoperfusion may result from any condition that affects the heart's ability to pump blood efficiently (ischemia, acidosis, drugs, constrictive pericarditis, pancreatitis, sepsis).

In contrast, the underlying pathophysiologic mechanism leading to distributive shock is a state of abnormal vasodilation and decreased SVR. Sepsis, hypoxia, poisoning, anaphylaxis, spinal cord injury, or mitochondrial dysfunction can cause vasodilatory shock (Fig. 88.3 ). The 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 these problems simultaneously.

Fig. 88.3 Mechanisms of vasodilatory shock. Septic shock and states of prolonged shock causing tissue hypoxia with lactic acidosis increase nitric oxide synthesis, activate the adenosine triphosphate (ATP)–sensitive and calcium-regulated potassium channels (K_ATP and K_Ca , respectively) in vascular smooth muscle, and lead to depletion of vasopressin. cGMP, Cyclic guanosine monophosphate. (From Landry DW, Oliver JA: The pathogenesis of vasodilatory shock, N Engl J Med 345:588.595, 2001.)

Cardiogenic shock may be seen in patients with myocarditis, cardiomyopathy, arrhythmias and congenital heart disease (generally following cardiac surgery) (see Chapter 461 ). In these patients, myocardial contractility is affected, leading to systolic and/or diastolic dysfunction. The later phases of all forms of shock frequently have a negative impact on the myocardium, leading to development of a cardiogenic component to the initial shock state.

Septic shock is generally a unique combination of distributive, hypovolemic, and cardiogenic shock. Hypovolemia from intravascular fluid losses occurs through capillary leak. Cardiogenic shock results from the myocardial-depressant effects of sepsis, and 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 through activation of the reticular endothelial system along with the cellular and humoral immune systems. This host immune response produces an inflammatory cascade of toxic mediators, including hormones, cytokines, and enzymes. If this inflammatory cascade is uncontrolled, derangement of the microcirculatory system leads to subsequent organ and cellular dysfunction.

The systemic inflammatory response syndrome (SIRS ) is an inflammatory cascade that is initiated by the host response to an infectious or noninfectious trigger (Table 88.5 ). This inflammatory cascade is triggered when the host defense system does not adequately recognize and/or eliminate the triggering event. The inflammatory cascade initiated by shock can lead to hypovolemia, cardiac and vascular failure, acute respiratory distress syndrome (ARDS), insulin resistance, decreased cytochrome P450 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 (IL)-1 stimulate the release of proinflammatory and antiinflammatory mediators, causing fever and vasodilation. Proinflammatory mediators include IL-6, IL-12, interferon-γ, and macrophage migration inhibitory factor; antiinflammatory cytokines include IL-10, transforming growth factor-β, and IL-4. Arachidonic acid metabolites lead to the development of fever, tachypnea, ventilation-perfusion abnormalities, and lactic acidosis. Nitric oxide (NO), released from the endothelium or inflammatory cells, is a major contributor to hypotension. Myocardial depression is caused directly by myocardial-depressant factors, TNF, and some interleukins and is further depressed by depleted catecholamines, increased β-endorphin, and production of myocardial NO.

Table 88.5

Differential Diagnosis of Systemic Inflammatory Response Syndrome (SIRS)

Infection

• Bacteremia or meningitis (Streptococcus pneumoniae, Haemophilus influenzae type b, Neisseria meningitidis, group A streptococcus, Staphylococcus aureus )
• Viral illness (influenza, enteroviruses, hemorrhagic fever group, herpes simplex virus, respiratory syncytial virus, cytomegalovirus, Epstein-Barr virus)
• Encephalitis (arboviruses, enteroviruses, herpes simplex virus)
• Rickettsiae (Rocky Mountain spotted fever, Ehrlichia, Q fever)
• Syphilis
• Vaccine reaction (pertussis, influenza, measles)
• Toxin-mediated reaction (toxic shock, staphylococcal scalded skin syndrome)

Cardiopulmonary

• Pneumonia (bacteria, virus, mycobacteria, fungi, allergic reaction)
• Pulmonary emboli
• Heart failure
• Arrhythmia
• Pericarditis
• Myocarditis

Metabolic-Endocrine

• Adrenal insufficiency (adrenogenital syndrome, Addison disease, corticosteroid withdrawal)
• Electrolyte disturbances (hypo- or hypernatremia; hypo- or hypercalcemia)
• Diabetes insipidus
• Diabetes mellitus
• Inborn errors of metabolism (organic acidosis, urea cycle, carnitine deficiency, mitochondrial disorders)
• Hypoglycemia
• Reye syndrome

Gastrointestinal

• Gastroenteritis with dehydration
• Volvulus
• Intussusception
• Appendicitis
• Peritonitis (spontaneous, associated with perforation or peritoneal dialysis)
• Necrotizing enterocolitis
• Hepatitis
• Hemorrhage
• Pancreatitis

Hematologic

• Anemia (sickle cell disease, blood loss, nutritional)
• Methemoglobinemia
• Splenic sequestration crisis
• Leukemia or lymphoma
• Hemophagocytic syndromes

Neurologic

• Intoxication (drugs, carbon monoxide, intentional or accidental overdose)
• Intracranial hemorrhage
• Infant botulism
• Trauma (child abuse, accidental)
• Guillain-Barré syndrome
• Myasthenia gravis

Other

• Anaphylaxis (food, drug, insect sting)
• Hemolytic-uremic syndrome
• Kawasaki disease
• Erythema multiforme
• Hemorrhagic shock–encephalopathy syndrome
• Poisoning
• Toxic envenomation
• Macrophage activation syndrome
• Idiopathic systemic capillary leak (Clarkson) syndrome

The inflammatory cascade is initiated by toxins or superantigens through macrophage binding or lymphocyte activation (Fig. 88.4 ). The 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 and endogenous opiates, activation of the complement system, and production and release of other mediators, which may be proinflammatory or antiinflammatory. The balance among these mediator groups for an individual patient contributes to the progression (and resolution) of disease and affects the prognosis.

Fig. 88.4 Hypothetical pathophysiology of the septic process.

Clinical Manifestations

Table 88.1 shows a classification system for shock. Categorization is important, but there may be significant overlap among these groups, especially in septic shock. The clinical presentation of shock depends in part on the underlying etiology, but 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 organ injury and death.

Shock may initially manifest as only tachycardia, with or without tachypnea. Progression leads to decreased urine output, poor peripheral perfusion, respiratory distress or failure, alteration of mental status, and low BP (see Table 88.3 ). A significant misconception is that shock occurs only with low BP; hypotension is often a late finding and is not a criterion for the diagnosis of shock because of a complex set of compensatory mechanisms that attempt to preserve BP and peripheral perfusion. Hypotension reflects an advanced state of decompensated shock and is associated with increased morbidity and mortality.

Hypovolemic shock often manifests initially as orthostatic hypotension and is associated with dry mucous membranes, dry axillae, poor skin turgor, and decreased urine output. Depending on the degree of dehydration, the patient with hypovolemic shock may present with either normal or slightly cool distal extremities, and pulses may be normal, decreased, or absent depending on disease severity. The 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 caused by the combination of decreased cardiac output and compensatory peripheral vasoconstriction (see Chapter 469.1 ). Obstructive shock often also manifests as inadequate cardiac output because of a physical restriction of forward blood flow, and the 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 cardiac output, respiratory failure, obtundation, and oliguria, occurs late in the progression of disease. Table 88.6 lists the hemodynamic findings in various shock states. 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.

Table 88.6

Hemodynamic Variables in Different Shock States

TYPE OF SHOCK	CARDIAC OUTPUT	SYSTEMIC VASCULAR RESISTANCE	MEAN ARTERIAL PRESSURE	CAPILLARY WEDGE PRESSURE	CENTRAL VENOUS PRESSURE
Hypovolemic	↓	↑	↔ or ↓	↓↓↓	↓↓↓
Cardiogenic*
Systolic	↓↓	↑↑↑	↔ or ↓	↑↑	↑↑
Diastolic	↔	↑↑	↔	↑↑	↑
Obstructive	↓	↑	↔ or ↓	↑↑ †	↑↑ †
Distributive	↑↑	↓↓↓	↔ or ↓	↔ or ↓	↔ or ↓
Septic
Early	↑↑↑	↓↓↓	↔ or ↓ ‡	↓	↓
Late	↓↓	↓↓	↓↓	↑	↑ or ↔

^* Systolic or diastolic dysfunction.

^† Wedge pressure, central venous pressure, and pulmonary artery diastolic pressures are equal.

^‡ Wide pulse pressure.

Sepsis is defined as SIRS resulting from a suspected or proven infectious etiology. The clinical spectrum of sepsis begins when a systemic (e.g., bacteremia, rickettsial disease, fungemia, viremia) or localized (e.g., meningitis, pneumonia, pyelonephritis, peritonitis, necrotizing fasciitis) infection progresses from sepsis to severe sepsis (i.e., presence of sepsis combined with organ dysfunction). Further clinical 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, and possibly death (Table 88.7 ). This is a complex spectrum of clinical problems that is a leading cause of mortality in children worldwide. Mortality can be mitigated and outcomes improved with early recognition and treatment.

Table 88.7

International Consensus Definitions for Pediatric Sepsis

Infection

• Suspected or proven infection or a clinical syndrome associated with high probability of infection.

Systemic Inflammatory Response Syndrome (SIRS)

1. Two of 4 criteria, 1 of which must be abnormal temperature or abnormal leukocyte count:
2. 1. Core temperature >38.5°C (101.3°F) or <36°C (96.8°F) (rectal, bladder, oral, or central catheter)
3. 2. Tachycardia:
   • Mean heart rate >2 SD above normal for age in absence of external stimuli, chronic drugs or painful stimuli
   • or
   • Unexplained persistent elevation over 0.5-4 hr
   • or
   • In children <1 yr old, persistent bradycardia over 0.5 hr (mean heart rate <10th percentile for age in absence of vagal stimuli, β-blocker drugs, or congenital heart disease)
4. 3. Respiratory rate >2 SD above normal for age or acute need for mechanical ventilation not related to neuromuscular disease or general anesthesia
5. 4. Leukocyte count elevated or depressed for age (not secondary to chemotherapy) or >10% immature neutrophils

Sepsis

• SIRS plus a suspected or proven infection

Severe Sepsis

1. Sepsis plus 1 of the following:
2. 1. Cardiovascular organ dysfunction, defined as:
   • Despite >40 mL/kg of isotonic intravenous fluid in 1 hr:
   • • Hypotension <5th percentile for age or systolic blood pressure <2 SD below normal for age
   • or
   • • Need for vasoactive drug to maintain blood pressure
   • or
   • Two of the following:
   • • Unexplained metabolic acidosis: base deficit >5 mEq/L
   • • Increased arterial lactate: >2 times upper limit of normal
   • • Oliguria: urine output <0.5 mL/kg/hr
   • • Prolonged capillary refill: >5 sec
   • • Core-to-peripheral temperature gap: >3°C (5.4°F)
3. 2. Acute respiratory distress syndrome (ARDS), as defined by the presence of a PaO ₂ /FIO ₂ ratio ≤300 mm Hg, bilateral infiltrates on chest radiograph, and no evidence of left-sided heart failure.
   • or
   • Sepsis plus ≥2 organ dysfunctions (respiratory, renal, neurologic, hematologic, or hepatic).

Septic Shock

• Sepsis plus cardiovascular organ dysfunction as defined above.

Multiple-Organ Dysfunction Syndrome (MODS)

• Presence of altered organ function such that homeostasis cannot be maintained without medical intervention.

FIO ₂ , Fraction of inspired oxygen; PaO ₂ , partial pressure of arterial oxygen; SD, standard deviations.

Although septic shock is primarily distributive in nature, multiple other elements of pathophysiology are represented in this disease process. The initial signs and symptoms of sepsis include alterations in temperature regulation (hyperthermia or hypothermia), tachycardia, and tachypnea. In the early stages (hyperdynamic phase, low SVR, or warm shock), cardiac output increases 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 SVR and the development of cold shock.

Diagnosis

Shock is a clinical diagnosis based on a thorough history and physical examination (see Tables 88.2 and 88.3 ). Septic shock has a specific consensus conference definition (see Table 88.7 ). In cases of suspected septic shock, an infectious etiology should be sought through culture of clinically appropriate specimens and prompt initiation of empirical antimicrobial therapy based on patient age, underlying disease, and geographic location, recognizing that time is necessary for incubation of cultures, and results often are not positive. Additional evidence for identifying an infectious etiology as the cause of SIRS includes physical examination findings, imaging, presence of white blood cells in normally sterile body fluids, and suggestive rashes such as petechiae and purpura. Affected children should be admitted to a PICU or other highly monitored environment as indicated by clinical status and the resources of the medical facility. These patients necessitate continuous monitoring, with a combination of noninvasive (e.g., pulse oximetry, capnography, near-infrared spectroscopy) and invasive (e.g., central venous pressure, arterial BP) techniques as clinically indicated.

Laboratory Findings

Laboratory findings often include evidence of hematologic abnormalities and electrolyte disturbances. Hematologic abnormalities may include thrombocytopenia, prolonged prothrombin and partial thromboplastin times, reduced serum fibrinogen level, elevation of fibrin split products, and anemia. Elevated neutrophil counts and increased immature forms (i.e., bands, myelocytes, promyelocytes), vacuolation of neutrophils, toxic granulations, and Döhle bodies can be seen with infection. Neutropenia or leukopenia may be an 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 partial pressure of arterial oxygen [PaO ₂ ]) as well as of ventilation (increased arterial partial pressure of carbon dioxide [PaCO ₂ ]) in the later stages of lung injury (see Chapter 89 ).

The hallmark of uncompensated shock is an imbalance between oxygen delivery (DO ₂ ) and oxygen consumption (VO ₂ ). Oxygen delivery normally exceeds oxygen consumption by threefold. The oxygen extraction ratio is approximately 25%, thus producing a normal mixed venous oxygen saturation (SvO ₂ ) of approximately 75%. A falling SvO ₂ value, as measured by cooximetry, reflects an increasing oxygen extraction ratio and documents a decrease in oxygen delivery relative to consumption. This increase in oxygen extraction by the end organs is an attempt to maintain adequate oxygen delivery at the cellular level. This state is manifested clinically by increased lactic acid production (e.g., high anion gap, metabolic acidosis) caused by anaerobic metabolism and a compensatory increase in tissue oxygen extraction. The gold standard measurement of SvO ₂ is from a pulmonary arterial catheter, but measurements from this location are often not clinically feasible. Sites such as the right ventricle, right atrium, superior vena cava (SvCO ₂ ), or inferior vena cava can be as surrogate measures of mixed venous blood to follow the adequacy of oxygen delivery and effectiveness of therapeutic interventions. Elevated blood lactate levels reflect poor tissue oxygen delivery noted in all forms of shock.

Treatment

Initial Management

Early recognition and prompt intervention are extremely important in the management of all forms of shock (Tables 88.8 to 88.12 ; see Figs. 88.1 and 88.2 ). The vital sign targets and dose recommendations in Tables 88.9 to 88.12 should be adjusted to pediatric-size patients. Baseline mortality is much lower in pediatric shock than in adult shock, and further improvements in mortality are associated with early interventions (see Fig. 81.1 ). The initial assessment and treatment of the pediatric shock patient should include stabilization of airway, breathing, and circulation as established by the American Heart Association's pediatric advanced life support and neonatal advanced life support guidelines (see Chapter 81 ). Depending on the severity of shock, further airway intervention, including intubation and mechanical ventilation, may be necessary to lessen the work of breathing and decrease the body's overall metabolic demands.

Table 88.8

Goal-Directed Therapy of Organ System Dysfunction in Shock

SYSTEM	DISORDERS	GOALS	THERAPIES
Respiratory	Acute respiratory distress syndrome	Prevent/treat: hypoxia and respiratory acidosis	Oxygen Noninvasive ventilation
	Respiratory muscle fatigue Central apnea	Prevent barotrauma Decrease work of breathing	Early endotracheal intubation and mechanical ventilation
			Positive end-expiratory pressure (PEEP) Permissive hypercapnia High-frequency ventilation Extracorporeal membrane oxygenation (ECMO)
Renal	Prerenal failure Renal failure	Prevent/treat: hypovolemia, hypervolemia, hyperkalemia, metabolic acidosis, hypernatremia/hyponatremia, and hypertension Monitor serum electrolytes	Judicious fluid resuscitation Establishment of normal urine output and blood pressure for age Furosemide (Lasix) Dialysis, ultrafiltration, hemofiltration
Hematologic	Coagulopathy (disseminated intravascular coagulation)	Prevent/treat: bleeding	Vitamin K Fresh-frozen plasma Platelets
	Thrombosis	Prevent/treat: abnormal clotting	Heparinization
Gastrointestinal	Stress ulcers Ileus	Prevent/treat: gastric bleeding Avoid aspiration, abdominal distention	Histamine H2 -receptor–blocking agents or proton pump inhibitors Nasogastric tube
	Bacterial translocation	Avoid mucosal atrophy	Early enteral feedings
Endocrine	Adrenal insufficiency, primary or secondary to chronic steroid therapy	Prevent/treat: adrenal crisis	Stress-dose steroids in patients previously given steroids Physiologic dose for presumed primary insufficiency in sepsis
Metabolic	Metabolic acidosis	Correct etiology Normalize pH	Treatment of hypovolemia (fluids), poor cardiac function (fluids, inotropic agents) Improvement of renal acid excretion Low-dose (0.5-2.0 mEq/kg) sodium bicarbonate if patient is not showing response, pH <7.1, and ventilation (CO2 elimination) is adequate

Table 88.9

Recommendations for Shock: Initial Resuscitation and Infection Issues—Adults

Initial Resuscitation

1. 1. Protocolized, quantitative resuscitation of patients with sepsis-induced tissue hypoperfusion (defined as hypotension persisting after initial fluid challenge or blood lactate concentration ≥4 mmol/L). Goals during the 1st 6 hr of resuscitation:
   • a. Central venous pressure 8-12 mm Hg
   • b. Mean arterial pressure (MAP) ≥65 mm Hg
   • c. Urine output ≥0.5 mL kg⁻¹ hr
   • d. Central venous (superior vena cava) or mixed venous oxygen saturation: 70% or 65%, respectively
2. 2. In patients with elevated lactate levels, targeting resuscitation to normalize lactate as rapidly as possible.

Screening for Sepsis and Performance Improvement

1. 1. Routine screening of potentially infected seriously ill patients for severe sepsis to allow earlier implementation of therapy.
2. 2. Hospital-based performance improvement efforts in severe sepsis.

Diagnosis

1. 1. Cultures as clinically appropriate before antimicrobial therapy if no significant delay (>45 min) in the start of antimicrobial(s). At least 2 sets of blood cultures (both aerobic and anaerobic bottles) should be obtained before antimicrobial therapy with at least 1 drawn percutaneously and 1 drawn through each vascular access device, unless the device was recently (<48 hr) inserted.
2. 2. Use of the 1,3 β-D -glucan assay, mannan and antimannan antibody assays, if available, and invasive candidiasis is in differential diagnosis of cause of infection.
3. 3. Imaging studies performed promptly to confirm a potential source of infection.

Antimicrobial Therapy

• 1. Administration of effective intravenous antimicrobials within the 1st hr of recognition of septic shock and severe sepsis without septic shock as the goal of therapy.
• 2a. Initial empirical antiinfective therapy of 1 or more drugs that have activity against all likely pathogens (bacterial and/or fungal or viral) and that penetrate in adequate concentrations into tissues presumed to be the source of sepsis.
• 2b. Antimicrobial regimen should be reassessed daily for potential deescalation.
• 3. Use of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empirical antibiotics in patients who initially appeared septic, but have no subsequent evidence of infection.
• 4a. Combination empirical therapy for neutropenic patients with severe sepsis and for patients with difficult-to-treat, multidrug-resistant bacterial pathogens such as Acinetobacter and Pseudomonas spp.
  • For patients with severe infections associated with respiratory failure and septic shock, combination therapy with an extended-spectrum β-lactam and either an aminoglycoside or a fluoroquinolone is for Pseudomonas aeruginosa bacteremia. A combination of β-lactam and macrolide for patients with septic shock from bacteremic Streptococcus pneumoniae infections.
• 4b. Empirical combination therapy should not be administered for more than 3-5 days. Deescalation to the most appropriate single therapy should be performed as soon as the susceptibility profile is known.
• 5. Duration of therapy typically 7-10 days; longer courses may be appropriate in patients who have a slow clinical response, undrainable foci of infection, bacteremia with Staphylococcus aureus , some fungal and viral infections, or immunodeficiencies (e.g., neutropenia).
• 6. Antiviral therapy initiated as early as possible in patients with severe sepsis or septic shock of viral origin.
• 7. Antimicrobial agents should not be used in patients with severe inflammatory states determined to be of noninfectious cause.

Source Control

1. 1. A specific anatomic diagnosis of infection requiring consideration for emergent source control should be sought and diagnosed or excluded as rapidly as possible, and intervention undertaken for source control within the 1st 12 hr after the diagnosis is made, if feasible.
2. 2. When infected peripancreatic necrosis is identified as a potential source of infection, definitive intervention is best delayed until adequate demarcation of viable and nonviable tissues has occurred.
3. 3. When source control in a severely septic patient is required, the effective intervention associated with the least physiologic insult should be used (e.g., percutaneous rather than surgical drainage of an abscess).
4. 4. If intravascular access devices are a possible source of severe sepsis or septic shock, these should be removed promptly after other vascular access has been established.

Infection Prevention

• 1a. Selective oral decontamination and selective digestive decontamination should be introduced and investigated as a method to reduce the incidence of ventilator-associated pneumonia; this infection control measure can then be instituted in healthcare settings and regions where this methodology is found to be effective.
• 1b. Oral chlorhexidine gluconate be used as a form of oropharyngeal decontamination to reduce the risk of ventilator-associated pneumonia in ICU patients with severe sepsis.

Adapted from Dellinger PR, Levy MM, Rhodes A, et al: Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2012, Crit Care Med 41(2):580–637, 2013 (Table 5, p 589).

Table 88.10

Surviving Sepsis Campaign: Care Bundles

1. To be completed within 3 hr:
2. 1. Measure lactate level.
3. 2. Obtain blood cultures before administration of antibiotics.
4. 3. Administer broad-spectrum antibiotics.
5. 4. Administer 30 mL/kg crystalloid for hypotension or lactate ≥4 mmol/L.
6. To completed within 6 hr:
7. 5. Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain a mean arterial pressure (MAP) ≥65 mm Hg.
8. 6. In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or initial lactate ≥4 mmol/L (36 mg/dL):
   • Measure central venous pressure (CVP).*
   • Measure central venous oxygen saturation (ScvO ₂ ).*
9. 7. Remeasure lactate if initial lactate was elevated.*

---

^* Targets for quantitative resuscitation included in the guidelines are CVP of ≥8 mm Hg, ScvO₂ of ≥70%, and normalization of lactate.

Adapted from Dellinger PR, Levy MM, Rhodes A, et al: Surviving Sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 41(2):580–637, 2013 (Fig 1, p 591).

Table 88.11

Recommendations for Shock: Hemodynamic Support and Adjunctive Therapy—Adults

Fluid Therapy of Severe Sepsis

1. 1. Crystalloids as the initial fluid of choice in the resuscitation of severe sepsis and septic shock.
2. 2. Against the use of hydroxyethyl starches for fluid resuscitation of severe sepsis and septic shock.
3. 3. Albumin in the fluid resuscitation of severe sepsis and septic shock when patients require substantial amounts of crystalloids.
4. 4. Initial fluid challenge in patients with sepsis-induced tissue hypoperfusion with suspicion of hypovolemia, to achieve a minimum of 30 mL/kg of crystalloids (a portion of this may be albumin equivalent). More rapid administration and greater amounts of fluid may be needed in some patients.
5. 5. Fluid challenge technique be applied in which fluid administration is continued as long as there is hemodynamic improvement either based on dynamic (e.g., change in pulse pressure, stroke volume variation) or static (e.g., arterial pressure, heart rate) variables.

Vasopressors

1. 1. Vasopressor therapy initially to target a mean arterial pressure (MAP) of 65 mm Hg.
2. 2. Norepinephrine as the first-choice vasopressor.
3. 3. Epinephrine (added to and potentially substituted for norepinephrine) when an additional agent is needed to maintain adequate blood pressure.
4. 4. Vasopressin 0.03 units/min can be added to norepinephrine (NE) with intent of either raising MAP or decreasing NE dosage.
5. 5. Low-dose vasopressin is not recommended as the single initial vasopressor for treatment of sepsis-induced hypotension, and vasopressin doses >0.03-0.04 units/min should be reserved for salvage therapy (failure to achieve adequate MAP with other vasopressor agents).
6. 6. Dopamine as an alternative vasopressor agent to NE only in highly selected patients (e.g., with low risk of tachyarrhythmias and absolute or relative bradycardia).
7. 7. Phenylephrine is not recommended in the treatment of septic shock except in circumstances where (a) NE is associated with serious arrhythmias, (b) cardiac output is known to be high and blood pressure persistently low, or (c) as salvage therapy when combined inotrope/vasopressor drugs and low-dose vasopressin have failed to achieve MAP target.
8. 8. Low-dose dopamine should not be used for renal protection.
9. 9. All patients requiring vasopressors have an arterial catheter placed as soon as practical if resources are available.

Inotropic Therapy

1. 1. A trial of dobutamine infusion up to 20 µg/kg/min be administered or added to vasopressor (if in use) in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion, despite achieving adequate intravascular volume and adequate MAP.
2. 2. Not using a strategy to increase cardiac index to predetermined supranormal levels.

Corticosteroids

1. 1. Not using intravenous hydrocortisone to treat adult septic shock patients, if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (see goals for Initial Resuscitation). In the event this is not achievable, we suggest IV hydrocortisone alone at a dose of 200 mg/day.
2. 2. Not using the ACTH stimulation test to identify adults with septic shock who should receive hydrocortisone.
3. 3. In treated patients, hydrocortisone tapered when vasopressors are no longer required.
4. 4. Corticosteroids should not be administered for the treatment of sepsis in the absence of shock.
5. 5. When hydrocortisone is given, use continuous flow.

Adapted from Dellinger PR, Levy MM, Rhodes A, et al: Surviving Sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012, Crit Care Med 41(2):580–637, 2013 (Table 6, p 596).

Table 88.12

Recommendations for Shock: Special Considerations in Pediatric Patients

Initial Resuscitation

1. 1. For respiratory distress and hypoxemia, start with face mask oxygen or, if needed and available, high-flow nasal cannula oxygen or nasopharyngeal CPAP (NP CPAP). For improved circulation, peripheral intravenous access or intraosseous access can be used for fluid resuscitation and inotrope infusion when a central line is not available. If mechanical ventilation is required, cardiovascular instability during intubation is less likely after appropriate cardiovascular resuscitation.
2. 2. Initial therapeutic end-points of resuscitation of septic shock: capillary refill of ≤2 sec, normal blood pressure for age, normal pulses with no differential between peripheral and central pulses, warm extremities, urine output >1 mL kg⁻¹ hr⁻¹ , and normal mental status. ScvO ₂ saturation ≥70% and cardiac index between 3.3 and 6.0 L/min/m² should be targeted thereafter.
3. 3. Follow American College of Critical Care Medicine–Pediatric Advanced Life Support (ACCM-PALS) guidelines for the management of septic shock.
4. 4. Evaluate for and reverse pneumothorax, pericardial tamponade, or endocrine emergencies in patients with refractory shock.

Antibiotics and Source Control

1. 1. Empirical antibiotics should be administered within 1 hr of the identification of severe sepsis. Blood cultures should be obtained before administering antibiotics when possible, but this should not delay administration of antibiotics. The empirical drug choice should be changed as epidemic and endemic ecologies dictate (e.g., H1N1, methicillin-resistant Staphylococcus aureus [MRSA], chloroquine-resistant malaria, penicillin-resistant pneumococci, recent ICU stay, neutropenia).
2. 2. Clindamycin and antitoxin therapies for toxic shock syndromes with refractory hypotension.
3. 3. Early and aggressive source control.
4. 4. Clostridium difficile colitis should be treated with enteral antibiotics if tolerated. Oral vancomycin is preferred for severe disease.

Fluid Resuscitation

1. 1. In the industrialized world with access to inotropes and mechanical ventilation, initial resuscitation of hypovolemic shock begins with infusion of isotonic crystalloids or albumin with boluses of up to 20 mL/kg crystalloids (or albumin equivalent) over 5-10 min, titrated to reversing hypotension, increasing urine output, and attaining normal capillary refill, peripheral pulses, and level of consciousness without inducing hepatomegaly or rales. If hepatomegaly or rales present, inotropic support should be implemented, not fluid resuscitation. In nonhypotensive children with severe hemolytic anemia (severe malaria or sickle cell crises), blood transfusion is considered superior to crystalloid or albumin bolus.

Inotropes, Vasopressors, and Vasodilators

1. 1. Begin peripheral inotropic support until central venous access can be attained in children who are not responsive to fluid resuscitation.
2. 2. Patients with low cardiac output and elevated systemic vascular resistance states with normal blood pressure should be given vasodilator therapies in addition to inotropes.

Extracorporeal Membrane Oxygenation

1. 1. Consider ECMO for refractory pediatric septic shock and respiratory failure.

Corticosteroids

1. 1. Timely hydrocortisone therapy in children with fluid-refractory, catecholamine-resistant shock and suspected or proven absolute (classic) adrenal insufficiency.

Protein C and Activated Protein Concentrate

• No recommendations (no longer available).

Blood Products and Plasma Therapies

1. 1. Similar hemoglobin targets in children as in adults. During resuscitation of low superior vena cava oxygen saturation shock (<70%), hemoglobin levels of 10 g/dL are targeted. After stabilization and recovery from shock and hypoxemia, a lower target (>7.0 g/dL) can be considered reasonable.
2. 2. Similar platelet transfusion targets in children as in adults.
3. 3. Use plasma therapies in children to correct sepsis-induced thrombotic purpura disorders, including progressive disseminated intravascular coagulation, secondary thrombotic microangiopathy, and thrombotic thrombocytopenic purpura.

Mechanical Ventilation

1. 1. Lung-protective strategies during mechanical ventilation.

Sedation, Analgesia, and Drug Toxicities

1. 1. We recommend use of sedation with a sedation goal in critically ill, mechanically ventilated patients with sepsis.
2. 2. Monitor drug toxicity lab results because drug metabolism is reduced during severe sepsis, putting children at greater risk of adverse drug-related events.

Glycemic Control

1. 1. Control hyperglycemia using a similar target as in adults (≤180 mg/dL). Glucose infusion should accompany insulin therapy in newborns and children because some hyperglycemic children make no insulin whereas others are insulin resistant.

Diuretics and Renal Replacement Therapy

1. 1. Use diuretics to reverse fluid overload when shock has resolved, and if unsuccessful, use continuous venovenous hemofiltration (CVVH) or intermittent dialysis to prevent >10% total body weight fluid overload.

Deep Vein Thrombosis (DVT) Prophylaxis

• No recommendation on the use of DVT prophylaxis in prepubertal children with severe sepsis.

Stress Ulcer (SU) Prophylaxis

• No recommendation on the use of SU prophylaxis in prepubertal children with severe sepsis.

Nutrition

1. 1. Enteral nutrition given to children who can be fed enterally, and parenteral feeding in those who cannot (grade 2C).

CPAP, Continuous positive airway pressure.

Adapted from Dellinger PR, Levy MM, Rhodes A, et al: Surviving Sepsis campaign: I nternational guidelines for management of severe sepsis and septic shock: 2012, Crit Care Med 41(2):580–637, 2013 (Table 9, p 614).

Given the predominance of sepsis and hypovolemia as the most common causes of shock in the pediatric population, most therapeutic regimens are based on guidelines established in these settings. Immediately following establishment of intravenous (IV) or intraosseous (IO) access, aggressive, early goal-directed therapy should be initiated unless there are significant concerns for cardiogenic shock as an underlying pathophysiology. Rapid IV administration of 20 mL/kg isotonic fluid should be initiated to reverse the shock state. This bolus should be repeated quickly up to 60-80 mL/kg; it is not unusual for severely affected patients to require this volume within the 1st 3 hr of treatment.

Rapid fluid resuscitation totaling 60-80 mL/kg or more is associated with improved survival without an increased incidence of pulmonary edema. Fluid resuscitation in increments of 20 mL/kg should be titrated to normalize HR (according to age-based HRs), urine output (to 1 mL/kg/hr), capillary refill time (to <2 sec), and mental status. If shock remains refractory following 60-80 mL/kg of volume resuscitation, vasopressor therapy (e.g., norepinephrine, epinephrine) should be instituted while additional fluids are administered. Pediatric guidelines for septic shock unresponsive to fluid resuscitation suggest epinephrine (Fig. 88.2 ) or dopamine (Fig. 88.1 ), whereas adult guidelines recommend norepinephrine.

Fluid resuscitation may sometimes require as much as 200 mL/kg or greater. It must be stressed that hypotension is often a late and ominous finding, and BP normalization alone is not a reliable end-point for assessing the effectiveness of resuscitation. Although the type of fluid (crystalloid vs colloid) is an area of ongoing debate, fluid resuscitation (usually crystalloid) in the 1st hr is unquestionably essential to survival in septic shock, regardless of the fluid type administered.

Additional Early Considerations

In septic shock specifically, early (within 1 hr ) administration of broad-spectrum antimicrobial agents is associated with a reduction in mortality. The choice of antimicrobial agents depends on the predisposing risk factors and the clinical situation. Bacterial resistance patterns in the community and/or hospital should be considered in the selection of optimal antimicrobial therapy. Neonates should be treated with ampicillin plus cefepime and/or gentamicin. Acyclovir should be added if herpes simplex virus is suspected clinically. In infants and children, community-acquired infections with Neisseria meningitidis can initially be treated empirically with a third-generation cephalosporin (e.g., ceftriaxone, cefepime), as can Haemophilus influenzae infections. The prevalence of resistant Streptococcus pneumoniae requires the addition of vancomycin. Suspicion of community- or hospital-acquired, methicillin-resistant Staphylococcus aureus (MRSA) infection warrants coverage with vancomycin, depending on local resistance patterns. If an intraabdominal process is suspected, anaerobic coverage should be included with an agent such as metronidazole, clindamycin, or piperacillin-tazobactam.

Nosocomial sepsis should generally be treated with at least a third- or fourth-generation cephalosporin or a penicillin with an extended 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 patient has an indwelling medical device (see Chapter 206 ), if gram-positive cocci are isolated from the blood, if MRSA infection is suspected, or as empirical coverage for S. pneumoniae in a patient with meningitis. Empirical coverage for fungal infections should be considered for selected immunocompromised patients (see Chapter 205 ). It should be noted that these are broad, generalized recommendations that must be tailored to the individual clinical scenario and to the local resistance patterns of the community and hospital.

Distributive shock that is not secondary to sepsis is caused by a primary abnormality in vascular tone. Cardiac output in affected patients is usually maintained and may initially be supranormal. These patients may benefit temporarily from volume resuscitation, but the early initiation of a vasoconstrictive agent to increase SVR is an important element of clinical care. Patients with spinal cord injury and spinal shock may benefit from either phenylephrine or vasopressin to increase SVR; epinephrine is the treatment of choice for patients with anaphylaxis (Table 88.13 ). Epinephrine has peripheral α-adrenergic as well as inotropic effects that may improve the myocardial depression seen with anaphylaxis and its associated inflammatory response (see Chapter 174 ).

Table 88.13

Cardiovascular Drug Treatment of Shock

DRUG	EFFECT(S)	DOSING RANGE	COMMENT(S)
Dopamine	↑ Cardiac contractility	3-20 µg/kg/min	↑ Risk of arrhythmias at high doses
	Significant peripheral vasoconstriction at >10 µg/kg/min
Epinephrine	↑ Heart rate and ↑ cardiac contractility	0.05-3.0 µg/kg/min	May ↓ renal perfusion at high doses
	Potent vasoconstrictor		↑ Myocardial O2 consumption
			Risk of arrhythmia at high doses
Dobutamine	↑ Cardiac contractility	1-10 µg/kg/min	—
	Peripheral vasodilator
Norepinephrine	Potent vasoconstriction	0.05-1.5 µg/kg/min	↑ Blood pressure secondary to ↑ systemic vascular resistance
	No significant effect on cardiac contractility		↑ Left ventricular afterload
Phenylephrine	Potent vasoconstriction	0.5-2.0 µg/kg/min	Can cause sudden hypertension
			↑ O2 consumption

Patients with cardiogenic shock have poor cardiac output secondary to systolic and/or diastolic myocardial depression, often with a compensatory elevation in SVR. These patients may show poor response to fluid resuscitation and may decompensate quickly when fluids are administered. Smaller boluses of fluid (5-10 mL/kg) should be given in cardiogenic shock to replace deficits and maintain preload. In any patient with shock whose clinical status deteriorates with fluid resuscitation, a cardiogenic etiology should be considered, and further administration of IV fluids should be provided judiciously. Early initiation of myocardial support with epinephrine or dopamine to improve cardiac output is important in this context, and early consideration should be given to administration of an inodilator, such as milrinone.

Despite adequate cardiac output with the support of inotropic agents, a high SVR with poor peripheral perfusion and acidosis may persist in cardiogenic shock. Therefore, if not already started, milrinone therapy may improve systolic function and decrease SVR without causing a significant increase in HR. Furthermore, this agent has the added benefit of enhancing diastolic relaxation. Dobutamine or other vasodilating agents, such as nitroprusside, may also be considered in this setting (Table 88.14 ). Titration of these agents should target clinical end-points, including increased urine output, improved peripheral perfusion, resolution of acidosis, and normalization of mental status. Even though they may be beneficial in other forms of shock, agents that improve BP by increasing SVR, such as norepinephrine and vasopressin, should generally be avoided in patients with cardiogenic shock. These agents may cause further decompensation and potentially precipitate cardiac arrest as a result of the increased afterload and additional work imposed on the myocardium. The combination of inotropic and vasoactive agents must be tailored to the pathophysiology of the individual patient with close and frequent reassessment of the patient's cardiovascular status.

Table 88.14

Vasodilators/Afterload Reducers in Treatment of Shock

DRUG	EFFECT(S)	DOSING RANGE	COMMENT(S)
Nitroprusside	Vasodilator (mainly arterial)	0.5-4.0 µg/kg/min	Rapid effect
			Risk of cyanide toxicity with prolonged use (>96 hr)
Nitroglycerin	Vasodilator (mainly venous)	1-20 µg/kg/min	Rapid effect
			Risk of increased intracranial pressure
Prostaglandin E1	Vasodilator	0.01-0.2 µg/kg/min	Can lead to hypotension
	Maintains an open ductus arteriosus in the newborn with ductal-dependent congenital heart disease		Risk of apnea
Milrinone	Increased cardiac contractility	Load 50 µg/kg over 15 min	Phosphodiesterase inhibitor—slows cyclic adenosine monophosphate breakdown
	Improves cardiac diastolic function	0.5-1.0 µg/kg/min
	Peripheral vasodilation

For patients with obstructive shock , fluid resuscitation may be briefly temporizing in maintaining cardiac output, but the primary insult must be immediately addressed. Examples of lifesaving therapeutic interventions for such patients are pericardiocentesis for pericardial effusion, pleurocentesis or chest tube placement for pneumothorax, thrombectomy/thrombolysis for pulmonary embolism, and the initiation of a prostaglandin infusion for ductus-dependent cardiac lesions. There is often a last-drop phenomenon associated with some obstructive lesions, in that small additional amounts of intravascular volume depletion may lead to a rapid deterioration, including cardiac arrest, if the obstructive lesion is not corrected.

Regardless of the etiology of shock, metabolic status should be meticulously maintained (see Table 88.8 ). Electrolyte levels should be monitored closely and corrected as needed. Hypoglycemia is common and should be promptly treated. Neonates and infants in particular may have profound glucose dysregulation in association with shock. Glucose levels should be checked routinely and treated appropriately, especially early in the course of illness. Hypocalcemia, which may contribute to myocardial dysfunction, should be treated with a goal of normalizing the ionized calcium concentration. There is no evidence that supranormal calcium levels benefit the myocardium, and hypercalcemia may be associated with increased myocardial toxicity.

Adrenal function is another important consideration in shock, and hydrocortisone replacement may be beneficial. Up to 50% of critically ill patients may have absolute or relative adrenal insufficiency. Patients at risk for adrenal insufficiency include those with congenial adrenal hypoplasia, abnormalities of the hypothalamic-pituitary axis, and recent therapy with corticosteroids (including those with asthma, rheumatic diseases, malignancies, and inflammatory bowel disease). These patients are at high risk for adrenal dysfunction and should receive stress doses of hydrocortisone. Corticosteroids may also be considered in patients with shock that is unresponsive to fluid resuscitation and catecholamines. Although a subset of pediatric septic shock patients may benefit from treatment with hydrocortisone, currently available pediatric data do not demonstrate an overall survival benefit in patients with shock treated with hydrocortisone. Determination of baseline cortisol levels before corticosteroid administration may be beneficial in guiding therapy, although this approach remains controversial.

Considerations for Continued Therapy

After the 1st hr of therapy and attempts at early reversal of shock, focus on goal-directed end-points should continue in an intensive care setting (see Figs. 88.1 and 88.2 and Table 88.8 ). Clinical end-points serve as global markers for organ perfusion and oxygenation. Laboratory parameters such as SvO ₂ (or ScvO₂ ), serum lactate concentration, cardiac index, and hemoglobin serve as adjunctive measures of tissue oxygen delivery. Hemoglobin should be generally maintained at 10 g/dL, SvO ₂ (or ScvO₂ ) >70%, and cardiac index at 3.3-6.0 L/min/m² to optimize oxygen delivery in the acute phase of shock. It is important to note that cardiac index is rarely monitored in the clinical setting because of the limited use of pulmonary artery catheters and lack of accurate noninvasive cardiac output monitors for infants and children. Blood lactate levels and calculation of base deficit from arterial blood gas values are very useful markers for the adequacy of oxygen delivery. These traditional markers are indicators of global oxygen utilization and delivery. There is increasing use of measures of local tissue oxygenation, including near-infrared spectroscopy of the cerebrum, flank, or abdomen.

Respiratory support should be used as clinically appropriate. When shock leads to ARDS requiring mechanical ventilation, lung-protective strategies to keep plateau pressure <30 cm H₂ O and maintain tidal volume at 6 mL/kg have been shown to improve mortality in adult patients (see Chapter 89 ). These data are extrapolated to pediatric patients because of the lack of definitive pediatric studies in this area. Additionally, after the initial shock state has been reversed, data demonstrate that judicious fluid administration, renal replacement therapy, and fluid removal may also be useful in children with anuria or oliguria and fluid overload (see Chapter 550 ). Other interventions include correction of coagulopathy with fresh-frozen plasma or cryoprecipitate and platelet transfusions as necessary, especially in the presence of active bleeding.

If shock remains refractory despite maximal therapeutic interventions, mechanical support with extracorporeal membrane oxygenation (ECMO) or a ventricular assist device (VAD) may be indicated. ECMO may be lifesaving in cases of refractory shock regardless of underlying etiology. Similarly, a VAD may be indicated for refractory cardiogenic shock in the setting of cardiomyopathy or recent cardiac surgery. Systemic anticoagulation, which is required while patients are receiving mechanical support, may be difficult, given the significant coagulopathy often encountered in refractory shock, especially when the underlying etiology is sepsis. Mechanical support in refractory shock poses substantial risks but can improve survival in specific populations of patients.

Prognosis

In septic shock, mortality rates are as low as 3% in previously healthy children and 6–9% in children with chronic illness (compared with 25–30% in adults). With early recognition and therapy, the mortality rate for pediatric shock continues to improve, but shock and MODS remain one of the leading causes of death in infants and children. The risk of death involves a complex interaction of factors, including the underlying etiology, presence of chronic illness, host immune response, and timing of recognition and therapy.

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