Shock: Classification, Pathophysiology, and Approach To Management

22
Shock: Classification, Pathophysiology,

and Approach to Management
ANAND KUMAR, VICTOR TREMBLAY, GLORIA VAZQUEZ-GRANDE,
AND JOSEPH E. PARRILLO
CHAPTER OUTLINE cases annually).1,2 Finally, despite improving medical and surgical
History
therapy, the ranking of septicemia as a cause of death has increased
over the past two decades from the 13th to the 11th most frequent
Definitions and Categorization of Shock cause of death in the United States.1,3,4 Most current estimates
Classification suggest more than 100,000 cases of septic shock annually in the
Hypovolemic Shock United States alone.5,6 In addition, all forms of shock increase the
Cardiogenic Shock probability of other major comorbidities, such as serious infection,
Obstructive Shock adult respiratory distress syndrome (ARDS), and multiple organ
Distributive Shock dysfunction syndrome (MODS).
This chapter provides an overview of circulatory shock with an
Pathogenesis and Pathophysiology of Shock
emphasis on the common elements and important differences in
Hemodynamic Basis of Shock
the pathophysiology and pathogenesis of the various forms of the
Microvascular Function in Shock
syndrome. This focus on common elements of different forms of
Mechanisms of Cellular Injury in Shock
shock continues through sections on systemic shock hemodynamics,
Compensatory Responses to Shock
microvascular dysfunction, mechanisms of cellular injury, oxygen
Organ System Dysfunction Owing to Shock supply dependency, compensatory responses, diagnostic approach/
Diagnostic Approach and Evaluation evaluation, and management/therapy.
Clinical Evaluation
Laboratory Studies History
Imaging
Invasive Hemodynamic Monitoring Despite recognition of a posttraumatic syndrome by Greek physi-
Ancillary Monitoring Techniques cians such as Hippocrates and Galen, the origin of the term shock
is generally credited to the French surgeon Henri François Le
Management and Therapy Dran, who in his 1737 A Treatise of Reflections Drawn from Experience
Aims with Gunshot Wounds, coined the term choc to indicate a severe
Resuscitation impact or jolt.7 An inappropriate translation by the English physician
Conclusion Clarke, in 1743, led to the introduction of the word shock to the
English language to indicate the sudden deterioration of a patient’s
condition with major trauma.7 It was Edwin A. Moses,8 however,
who began to popularize the term, using it in his 1867 A Practical
Treatise on Shock After Operations and Injuries. He defined it as “a
T
he syndrome of shock in humans is often the final pathway peculiar effect on the animal system, produced by violent injuries
through which a variety of pathologic processes lead to from any cause, or from violent mental emotions.” Before this
cardiovascular failure and death. As such, it is perhaps the definition, the rarely used term shock referred in a nonspecific
most common and important problem with which critical care sense to the immediate and devastating effects of trauma, not a
physicians contend. The importance of shock as a medical problem specific posttrauma syndrome. Although not entirely accurate by
can be appreciated by the prominence of its three dominant forms. today’s standards, his definition was one of the first to separate
Cardiogenic shock, related to pump failure, is a major component the syndrome involving the body’s response to massive trauma
of the mortality associated with cardiovascular disease, the leading from the immediate, direct manifestations of trauma itself.
cause of death in the United States with almost 800,000 deaths By the late 1800s, two theories of traumatic shock physiology
annually.1 Similarly, hypovolemic shock remains a major contributor dominated. The first, based on observations by Bernard, Charcot,
to early mortality from trauma, the most common cause of death Goltz, and others, was proposed by Fischer in 1870.9–11 He suggested
in those between the ages of 1 and 45 years (approximately 200,000 that traumatic shock was caused by generalized “vasomotor paralysis”
288
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CHAPTER 22 Shock: Classification, Pathophysiology, and Approach to Management 289
resulting in splanchnic blood pooling. The corollary was that total standardized animal model which showed that prolonged hypo-
circulating blood volume is preserved in shock. The second dominant volemic shock resulted in a resuscitation-resistant state that he
theory, articulated by Mapother in 1879, suggested that decreased termed irreversible shock. He defined it as condition resulting from
cardiac output (CO) in traumatic shock is caused by intravascular “a depression of many functions but in which reduction of the
volume loss owing to extrusion of plasma through the vessel wall effective circulating blood volume is of basic importance and in
from the intravascular space to the interstitium.12 He proposed which impairment of the circulation steadily progresses until it
that this was a consequence of the failure of “vasodilator nerves” eventuates in a state of irreversible circulatory failure.” Aggressive
in traumatic shock and subsequent generalized arteriolar vasocon- fluid support became the standard of resuscitation for trauma and
striction. With the 1899 publication of An Experimental Research shock.
into Surgical Shock (perhaps the first experimental studies of shock), Subsequently, the Korean War fueled the research demonstrating
George W. Crile provided scientific data supporting a variation of the relationship of acute tubular necrosis (ATN) and acute renal
the vasomotor paralysis theory.13 After documenting the importance failure (ARF) to circulatory shock.22 In addition, studies of battlefield
of decreased central venous pressure (CVP) and venous return in casualties clearly demonstrated the relationship between early
experimental shock as the result of hemorrhage and demonstrating resuscitation and survival.22 During the Vietnamese conflict, with
the potential for intravascular volume replacement as therapy, he the widespread use of ventilator technology, the dominant research
proposed that traumatic shock was caused by exhaustion of the concern became postshock infection and “shock lung” (ARDS),
overstimulated “vasomotor center” and subsequent generalized a concern that has evolved to the present interest in shock-related
relaxation of large vessels (veins), leading to decreased ventricular MODS.
filling and CO.
Further advances in shock research were substantially driven Definitions and Categorization of Shock
by military concerns. During World War I, Walter B. Cannon
and other physiologists/physicians studied the early clinical response The definition of shock has evolved in parallel with our understand-
to battlefield trauma. Their work eventually led to the publication ing of the phenomenon. As noted, until the late 1800s, the term
of the classic monograph Traumatic Shock in 1923.14 Cannon and shock was used to indicate the immediate response to massive
his colleagues were the first to relate trauma-associated hypotension trauma, without regard to a specific posttrauma syndrome. The
in a large group of patients to a fall in blood volume, loss of definition consisted of descriptions of its obvious clinical signs. In
bicarbonate, and accumulation of organic acids. Others, using dye 1895, John Collins Warren23 referred to shock as “a momentary
dilution techniques, demonstrated that severity of shock was directly pause in the act of death” that was characterized by an “imper-
related to the decrease in intravascular volume.15 Clinical data ceptible” or “weak, thread-like” peripheral pulse and a “cold, clammy
from war casualties also suggested the importance of reduced blood sweat.”
flow (independent of blood pressure) in shock.16 The observation Subsequently, with the introduction of noninvasive blood
that blood in the capillaries of victims of massive trauma was pressure monitoring devices, most clinical definitions of shock
hemoconcentrated compared to venous blood was to lead to the added the requirement for arterial hypotension. In 1930 Blalock9
practice of resuscitating trauma patients with dried pooled plasma included arterial hypotension as one of the required manifestations
rather than whole blood in the early part of World War II.17 of shock when he defined it as “peripheral circulatory failure resulting
Although work originating from the battlefields of World War from a discrepancy in the size of the vascular bed and the volume
I clearly linked traumatic shock associated with substantial, obvious of the intravascular fluid.” Simeone,24 as recently as 1964, suggested
bleeding to a loss of circulating blood volume, the origin of traumatic that shock exists when “the cardiac output is insufficient to fill the
shock in the absence of defined hemorrhage was unclear. The arterial tree with blood under sufficient pressure to provide organs
accepted explanation for this phenomenon remained a variation and tissues with adequate blood flow.”
of the vasomotor paralysis theory of shock. It was postulated that Current technology, which allows assessment of perfusion
nonhemorrhagic, posttraumatic shock (“wound shock”) was caused independent of arterial pressure, has shown that hypotension does
by the liberation of “wound toxins” (histamine and/or other not define shock. The emphasis in defining shock is now on tissue
substances), which resulted in “neurogenic” vasodilation and perfusion in relation to cellular function. According to Fink,25
peripheral blood pooling. However, after the war, Blalock and shock is “a syndrome precipitated by a systemic derangement of
others demonstrated in animal models that nonhemorrhagic perfusion leading to widespread cellular dysoxia and vital organ
traumatic shock was due to the loss of blood and fluids into injured dysfunction.” Cerra26 has emphasized supply/demand mismatch
tissue rather than circulating toxins resulting in stasis of blood in his definition: “a disordered response of organisms to an inap-
within the circulation.18 propriate balance of substrate supply and demand at a cellular
Additional advances occurred during World War II. Using injured level.”
subjects from the European front, Henry Beecher confirmed that The appropriate definition of shock varies with the context of
hemorrhage and fluid loss leading to metabolic acidosis was a its use. For paramedical personnel, a definition that incorporates
major cause of shock.19 In the first use of indicator dye techniques the typical clinical signs of shock (arterial hypotension, tachypnea,
in humans for studying blood flow, Cournand and Riely, in 1943, tachycardia, altered mental status, and decreased urine output)
demonstrated that CO was typically reduced in shock.20 They also may suffice. For the physiologist, shock may be defined by specific
reinforced Blalock’s findings regarding non-hemorrhagic “wound hemodynamic criteria involving alterations of ventricular filling
shock” in trauma patients by demonstrating that circulating blood pressures, venous pressures, arterial pressures, CO, and systemic
volume was reduced in such patients through loss of fluid into vascular resistance (SVR). Similarly, in the appropriate context,
damaged tissues. The importance of maintaining intravascular shock could also be defined by alterations of biochemical/
volume in traumatic and hemorrhagic shock was supported by bioenergetic pathways or intracellular gene expression. For the
the well-known cardiovascular physiologist, Carl J. Wiggers, who physician, however, we find the most appropriate definition to be
published a landmark series of studies21 in the 1940s using a “the state in which profound and widespread reduction of effective
290 Pa rt 2 Critical Care Cardiovascular Disease
• BOX 22.1 Determinants of Effective Tissue (i.e., anaphylactic), bacteremic (i.e., septic), obstructive, and
Perfusion in Shock endocrinologic shock.31 However, as the hemodynamic profiles of
the different forms of shock were uncovered, a classification based
1. Cardiovascular performance (total systemic perfusion/cardiac output) on cardiovascular characteristics (initially proposed in 1972 by
Cardiac function Hinshaw and Cox32) came to be accepted by most clinicians. The
Preload categories include the following:
Afterload 1. Hypovolemic shock, caused by a decreased circulating blood
Contractility volume in relation to the total vascular capacity and characterized
Heart rate
by a reduction of diastolic filling pressures and volumes;
Venous return
Right atrial pressure (dependent on cardiac function)
2. Cardiogenic shock related to cardiac pump failure as the result
Mean circulatory pressure of loss of myocardial contractility/functional myocardium or
Stressed vascular volume structural/mechanical failure of the cardiac anatomy and
Mean vascular compliance characterized by elevations of diastolic filling pressures and
Venous vascular resistance volumes;
Distribution of blood flow 3. Extracardiac obstructive shock involving obstruction to flow
2. Distribution of cardiac output in the cardiovascular circuit and characterized by either impair-
Intrinsic regulatory systems (local tissue factors) ment of diastolic filling or excessive afterload;
Extrinsic regulatory systems (sympathetic/adrenal activity) 4. Distributive shock caused by loss of vasomotor control resulting
Anatomic vascular disease
in arteriolar and venular dilation and (after resuscitation with
Exogenous vasoactive agents (inotropes, vasopressors, vasodilators)
3. Microvascular function
fluids) characterized by increased CO with decreased SVR.
Precapillary and postcapillary sphincter function We have adapted these categories into an etiologic/physiologic
Capillary endothelial integrity classification of shock that is summarized in Fig. 22.1 and Box 22.2.
Microvascular obstruction (fibrin, platelets, WBC, RBC) This figure and table represent our current understanding of the
4. Local oxygen unloading and diffusion causes and typical hemodynamic features of different forms of shock.
Oxyhemoglobin affinity Despite this hemodynamic-based categorization system, it is
RBC 2,3-DPG important to note the mixed nature of most forms of clinical shock.
Blood pH Septic shock is nominally considered a form of distributive shock.
Temperature However, before resuscitation with fluids, a substantial hypovolemic
5. Cellular energy generation/utilization capability
component may exist as the result of venodilatation and third spacing.
Citric acid (Kreb) cycle
Oxidative phosphorylation pathway
In addition, depression of the myocardium in human septic shock
Other energy metabolism pathways (e.g., ATP utilization) is well documented (see Fig. 22.1).33–35 Similarly, hemorrhagic shock
in experimental models has been linked to both myocardial depres-
2,3-DPG, 2,3-diphosphoglycerate; ATP, adenosine triphosphate; RBC, red blood cell; WBC, white sion36,37 and vascular dysfunction (Fig. 22.1).38,39 Cardiogenic shock
blood cell.
typically presents with increased ventricular filling pressures. However,
many patients have undergone aggressive diuresis before the onset
of shock and may have a relative hypovolemic component. In addition,
SVR is only inconsistently increased in cardiogenic shock, suggesting
tissue perfusion leads first to reversible, and then, if prolonged, to that an inflammatory element may exist under some circumstances.
irreversible cellular injury.” Finally, shock from any cause may cause a deterioration of the coro-
“Effective” tissue perfusion, as opposed to tissue perfusion per nary perfusion pressure, the difference between mean arterial pressure
se, is an important issue. Effective tissue perfusion may be reduced (MAP) and the higher of left ventricular diastolic pressure or the
by either a global reduction of systemic perfusion (CO) or by right atrial pressure, resulting in some degree of myocardial ischemia
increased ineffective tissue perfusion owing to a maldistribution and myocardial dysfunction.40 Although four categories of shock
of blood flow or a defect of substrate utilization at the subcellular exist based on hemodynamic profile, clinical shock states tend to
level (see Box 22.1). combine components of each (Fig. 22.1).33–40
Classification Hypovolemic Shock

Although hypovolemic shock associated with trauma was the first Hypovolemic may be related to dehydration, internal or external
form of shock to be recognized and studied, by the early 1900s it hemorrhage, gastrointestinal fluid losses (diarrhea or vomiting),
became broadly recognized that other clinical conditions could urinary losses resulting from either diuretics or kidney dysfunction,
result in a similar constellation of signs and symptoms. Sepsis as or loss of intravascular volume to the interstitium owing to increased
a distinct cause of shock was initially proposed by Laennec in vascular permeability (in response to sepsis or trauma). Alternately,
1831 and subsequently supported by Boise in 1897.27,28 In 1934, venodilation secondary to sepsis, spinal injury, various drugs, and
Fishberg and colleagues introduced the concept of primary car- toxins can result in a relative hypovolemic condition that contributes
diogenic shock caused by myocardial infarction (MI).29 Later the to shock (Box 22.2, see Fig. 22.1).
same year, Blalock developed the precursor of the most commonly Hemodynamically, hypovolemic shock is characterized by a fall
used classification systems of the present.30 He subdivided shock in ventricular preload resulting in decreased ventricular diastolic
into four etiologic categories: hematogenic or oligemic (hypovo- pressures and volumes (Table 22.1). Cardiac index (CI) and stroke
lemic), cardiogenic, neurogenic (e.g., shock after spinal injury), volume index (SVI) are typically reduced. In addition to hypoten-
and vasogenic (primarily septic shock). Shubin and Weil, in 1967, sion, a decreased pulse pressure may be noted. Because of a decreased
proposed the additional etiologic categories of hypersensitivity output and unchanged or increased metabolic demand, mixed
EXTRACARDIAC OBSTRUCTIVE CARDIOGENIC HYPOVOLEMIC DISTRIBUTIVE

(e.g., myocardial (e.g., hemorrhage) (e.g., septic)
infarction)
Preload
Diastolic filling Ventricular afterload Myocardial damage Myocardial depression
(e.g., tension pneumothorax or (e.g., massive pulmonary ( systolic and
pericardial tamponade) embolus) Diastolic filling diastolic function)
Systolic and diastolic
function
Diastolic function Systolic function
CO SVR
( SVR) ( CO)
MAP
Maldistribution
of flow
Shock
MODS
• Fig. 22.1 The interrelationships between different forms of shock. For cardiogenic, hypovolemic, and

obstructive shock, hypotension is primarily due to decreased cardiac output with systemic vascular
resistance rising secondarily. With distributive (and particularly, septic) shock, hypotension is primarily due
to a decrease in systemic vascular resistance with a secondary increase of cardiac output. In many forms
of shock, the hemodynamic characteristics are influenced by elements of hypovolemia, myocardial
depression (ischemic or otherwise), and vascular dysfunction (which may affect afterload). Dominant
pathophysiologic pathways are denoted by heavier lines. CO, Cardiac output; MAP, mean arterial blood
pressure; MODS, multiple organ dysfunction syndrome; SVR, systemic vascular resistance.
venous oxygen saturation (MvO2) may be decreased and the 2,3-diphosphoglycerate (2,3-DPG), and increased fluid retention.
arteriovenous oxygen content difference widened. Clinical char- On the other hand, a similar slow loss may lead to substantial
acteristics include pale, cool, clammy skin (often mottled); hemodynamic compromise in a person with a limited cardiac
tachycardia (or if severe shock, bradycardia8,41); tachypnea; flat, reserve even while their PAOP and CVP remain elevated.
nondistended peripheral veins; decreased jugular venous pulse; Hypovolemic shock represents more than a simple mechanical
decreased urine output; and altered mental status. response to loss of circulating volume. It is a dynamic process
Several factors can influence the development and hemodynamic involving competing adaptive (compensatory) and maladaptive
characteristics of hypovolemic shock in humans. Studies in animals responses at each stage of development. Thus although intravascular
and humans have demonstrated a clear relationship between the volume replacement is always a necessary component of resuscitation
degree of circulating blood volume loss and clinical response.42–45 from hypovolemia or hypovolemic shock, the biologic responses
Acute loss of 10% of the circulating blood volume is well tolerated to the insult may progress to the point where such resuscitation
and compensated by tachycardia. CI may be minimally decreased is insufficient to reverse the progression of the shock syndrome.
despite a compensatory increase in myocardial contractility. SVR Patients who have sustained a greater than 40% loss of blood
typically increases slightly, particularly if sympathetic stimulation volume for 2 hours or more may be unable to be effectively
augments MAP. Compensatory mechanisms begin to fail with a resuscitated.38,42,45 A series of inflammatory mediator, cardiovascular,
20% to 25% volume loss. Mild to moderate hypotension and and organ responses to shock are initiated that supersede the
decreased CI may be present. Orthostasis (with a blood pressure importance of the initial insult in driving further injury.
decrease of 10 mm Hg and increased heart rate [HR] of 20 to 30
beats/min) may become apparent. There is a marked increase in Cardiogenic Shock
SVR and serum lactate may begin to rise. With decreases of the
circulating volume of 40% or more, marked hypotension with Cardiogenic shock results from the failure of the heart as a pump
clinical signs of shock is noted. CI and tissue perfusion may fall (see Box 22.2 and Fig. 22.1). It is the most common cause of
to less than half normal. Lactic acidosis is usually present at this in-hospital mortality in patients with Q-wave MI.49,50 Hemodynami-
stage and predicts a poor outcome.46,47 The case fatality rate can cally, cardiogenic shock is characterized by increased ventricular
exceed 50% in hemorrhagic shock associated with trauma.48 preload (increased ventricular volumes, pulmonary wedge pressure
The rate of loss of intravascular volume and the preexisting and CVP) (see Table 22.1). Otherwise hemodynamic characteristics
cardiac reserve is of substantial importance in the development are similar to those for hypovolemic shock (see Table 22.1). In
of hypovolemic shock. As an example, although an acute blood particular, both involve reduced CI, SVI, and ventricular stroke
loss of 1 L in a healthy adult may result in mild to moderate work indices with increased SVR. As the result of inadequate tissue
hypotension with a reduced pulmonary artery occlusion pressure perfusion, the MvO2 is substantially reduced and the arteriovenous
(PAOP) and CVP,43 the same loss over a longer period may be oxygen content difference increased. The degree of lactic acidosis
well tolerated owing to compensatory responses, such as tachycardia, may predict mortality.51 Clinically, the specific signs of shock are
increased myocardial contractility, increased red blood cell similar. However, signs of congestive heart failure (CHF, volume
• BOX 22.2 Classification of Shock

1. Hypovolemic (Oligemic) Tachycardia
Hemorrhagic Supraventricular
Trauma Ventricular
Gastrointestinal 3. Extracardiac Obstructive
Retroperitoneal Impaired diastolic filling (decreased ventricular preload)
Intravascular fluid depletion (nonhemorrhagic) Direct venous obstruction (vena cava)
External fluid loss Intrathoracic obstructive tumors
Dehydration Increased intrathoracic pressure (decreased transmural pressure
Vomiting gradient)
Diarrhea Tension pneumothorax
Polyurea Mechanical ventilation (with positive end-expiratory pressure [PEEP]
Interstitial fluid redistribution or volume depletion)
Thermal injury Decreased cardiac compliance
Trauma Constrictive pericarditis
Anaphylaxis Cardiac tamponade
Increased vascular capacitance (venodilatation) Acute
Sepsis Post MI free wall rupture
Anaphylaxis Traumatic
Toxins/Drugs Hemorrhagic (anticoagulation)
2. Cardiogenic Chronic
Myopathic Malignant
Myocardial infarction Uremic
Left ventricle Idiopathic
Right ventricle Impaired systolic contraction (increased ventricular afterload)
Myocardial contusion (trauma) Right ventricle
Myocarditis Pulmonary embolus (massive)
Cardiomyopathy Acute pulmonary hypertension
Post-ischemic myocardial stunning Left ventricle
Septic myocardial depression Saddle embolus
Drug toxicity Aortic dissection
Anthracycline cardiotoxicity 4. Distributive
Calcium channel blockers Septic (bacterial, fungal, viral, rickettsial)
Mechanical Toxic shock syndrome
Valvular failure (stenotic or regurgitant) Anaphylactic, anaphylactoid
Hypertropic cardiomyopathy Neurogenic (spinal shock)
Ventricular septal defect Endocrinologic
Arrhythmic Adrenal crisis
Bradycardia Thyroid storm
Sinus (e.g., vagal syncope) Toxic (e.g., nitroprusside, bretyllium)
Atrioventricular blocks
overload) are typically present in cardiogenic shock. The jugular several major studies suggest that mortality of infarction-related
and peripheral veins may be distended. An S3 and evidence of cardiogenic shock may be improved by emergent angioplasty.63–65
pulmonary edema are usually found. Accordingly, recent data suggest a reduction in incidence of acute
Cardiogenic shock is most commonly due to ischemic myocardial infarction-related cardiogenic shock to less than 2% in 2003 in
injury with a total of 40% of the myocardium nonfunctional.50,52–54 association with widespread use of emergent percutaneous coronary
Such damage may involve a single large myocardial infarction (MI) intervention.63 This intervention has also been associated with a
or may involve accumulation of damage from multiple infarctions. reduction of cardiogenic shock mortality risk from 60% to 84%
In addition, viable but dysfunctional “stunned” myocardium may to 43% to 47% in two large analyses.63,66,67
temporarily contribute to cardiogenic shock after infarction. Mortality is better for cardiogenic shock resulting from surgically
Cardiogenic shock usually involves an anterior MI with left main remediable cardiac lesions. Mitral valve failure may be associated
or proximal left anterior descending artery occlusion. Historically, with rupture or dysfunction of chordae or papillary muscles owing
the incidence of cardiogenic shock caused by Q-wave infarction to myocardial ischemia or infarction, endocarditis, blunt chest
has ranged from 8% to 20%.49,55–57 Although several large studies trauma, or prosthetic valve deterioration and is characterized by
demonstrate lower incidence rates (4%–7%) when patients receive “v” waves of greater than 10 mm Hg on a PAOP tracing. Ischemic
thrombolytic interventions,56,58–61 retrospective community studies papillary muscle rupture frequently occurs 3 to 7 days after an
suggest no overall decrease in incidence of postinfarction cardiogenic infarct in left anterior descending coronary artery territory and
shock or cardiogenic shock mortality (70%–90%) in the first may be preceded by the onset of a mitral regurgitant murmur.68
decades after the introduction of this therapy.49 Further, no trials Mortality is high in the absence of surgical therapy.68 Acute aortic
have demonstrated that thrombolytic therapy reduces mortality valve failure is most commonly the result of endocarditis but may
rates in patients with established cardiogenic shock.58,62 In contrast, involve mechanical failure of prosthetic valves, or aortic dissection.
TABLE a
22.1 Hemodynamic Profiles of Shock
Diagnosis CO SVR PWP CVP SVO2 Comments

Cardiogenic Shock
Caused by myocardial ↓↓ ↑ ↑↑ ↑↑ ↓ Usually occurs with evidence of extensive myocardial
dysfunction infarction (>40% of left ventricular myocardium
nonfunctional), severe cardiomyopathy, or myocarditis
Caused by a mechanical
defect
Acute ventricular septal LVCO ↓↓ ↑ nl or ↑ ↑↑ ↑ or ↑↑ If shunt is left to right, pulmonary blood flow is greater
defect RVCO > LVCO than systemic blood flow; oxygen saturation “step-up”
(≥5%) occurs at right ventricular level; ↑ SVO2 is
caused by left to right shunt
Acute mitral regurgitation Forward CO ↓↓ ↑ ↑↑ ↑ or ↑↑ ↓ Large V waves (≥10 mm Hg) in pulmonary wedge
pressure tracing
Right ventricular ↓↓ ↑ nl or ↑ ↑↑ ↓ Elevated right atrial and right ventricular filling pressures
infarction with low or normal pulmonary wedge pressures
Extracardiac Obstructive Shock
Pericardial tamponade ↓ or ↓↓ ↑ ↑↑ ↑↑ ↓ Dip and plateau in right and left ventricular pressure
tracings. The right atrial mean, right ventricular
end-diastolic, pulmonary artery end-diastolic, and
pulmonary wedge pressures are within 5 mm Hg of
each other.
Massive pulmonary ↓↓ ↑ nl or ↓ ↑↑ ↓ Usual finding is elevated right-sided heart pressures with
emboli low or normal pulmonary wedge pressure
Hypovolemic Shock
↓↓ ↑ ↓↓ ↓↓ ↓ Filling pressures may appear normal if hypovolemia
occurs in the setting of baseline myocardial
compromise
Distributive Shock
Septic shock ↑↑ or nl, rarely ↓ ↓ or ↓↓ ↓ or nl ↓ or nl ↑ or ↑↑ The hyperdynamic circulatory state (↑CO, ↓SVR)
associated with distributive forms of shock usually
depends on resuscitation with fluids; before such
resuscitation, a hypodynamic circulation is typical
Anaphylaxis ↑↑ or nl, rarely ↓ ↓ or ↓↓ ↓ or nl ↓ or nl ↑ or ↑↑
a
The hemodynamic profiles summarized in this table refer to patients with the diagnosis listed in the left column who are also in shock (mean arterial blood pressure <60–65 mm Hg).
CO, Cardiac output; CVP, central venous pressure; LV, left ventricular; nl, normal; PWP, pulmonary wedge pressure; SVR, systemic vascular resistance; SVO2 , mixed venous oxygen saturation; ↑↑ or
↓, mild to moderate increase or decrease; ↑↑ or ↓, moderate to severe increase or decrease.
Modified from Parrillo JE. Septic shock: clinical manifestations, pathogenesis, hemodynamics, and management in a critical care unit. In: Parrillo JE, Ayers SM, eds. Major Issues in Critical Care Medicine.
Baltimore: Williams & Wilkins; 1984.
Ventricular septal defects caused by MI may also result in the inotropes (rather than vasopressors), differentiation from other
abrupt onset of cardiogenic shock and can be diagnosed by a 5% causes of cardiogenic shock is crucial. Conditions compromising
step-up in hemoglobin oxygen saturation between the right atrium right ventricular function, such as cardiac tamponade, restrictive
and the pulmonary artery (owing to left to right shunting of blood cardiomyopathy, constrictive pericarditis, and pulmonary embolus,
through the septum).69 As with ischemic papillary muscle rupture, are also included in the differential diagnosis. Each of these condi-
rupture of the intraventricular septum is most frequently seen with tions may present with some of the typical clinical and hemodynamic
occlusions of the left anterior descending artery a few days after findings of right ventricular infarction, including Kussmaul sign,
infarction.69 pulsus paradoxus with elevation and equalization of CVP, right
The pathophysiology of cardiogenic shock caused by a right ventricular systolic pressure, pulmonary artery diastolic pressure,
ventricular infarction and failure is different than other forms of and PAOP. Prognosis in this form of cardiogenic shock is distinctly
cardiogenic shock. Although some degree of right ventricular better than that of cardiogenic shock owing to left ventricular
involvement is seen in half of inferior MIs, only the largest 10% infarction72,73; however, an inferior infarction with right ventricular
to 20% result in right ventricular failure and cardiogenic shock.70 injury has a substantially worse prognosis than such an infarction
These infarctions usually involve part of the left ventricular wall without significant right-sided involvement.74
as well. Isolated infractions of the right ventricle are rare.70,71 Because As with hypovolemic shock, a number of interactions may
therapy for this form of shock requires fluid resuscitation and complicate the development of cardiogenic shock. Optimal cardiac
performance in patients with impaired myocardial contractility with bleeding into the pericardium after blunt chest trauma or
may occur at substantially higher than normal PAOP (i.e., thrombolytic therapy. Pericardial tamponade owing to malignant
20–24 mm Hg). Yet patients in whom cardiogenic shock develops or inflammatory pericardial effusions usually develops much more
are frequently initially treated with diuretics and may have a degree slowly. Although shock may still develop, it usually requires
of hypovolemia (relative to their optimal requirements). Thus substantially more pericardial fluid (1–2 L) to cause critical failure
patients should not be diagnosed with cardiogenic shock unless of right ventricular diastolic filling.76 No large reliable studies
hypotension (MAP < 65 mm Hg) and reduced CO (CI < 2.2 L/ examining mortality rates with and without therapy in these
min per m2) coexist with an elevated ventricular filling pressure.75 conditions are available because of the small numbers of cases.
Cautious fluid challenge may be required (in the absence of overt A similar time course–dependent risk is seen with major pul-
pulmonary edema) to increase the filling pressures to an optimal monary emboli. In those without preexisting cardiopulmonary
range. Other interactions include increased right ventricular ischemia disease, a massive embolus involving two or more lobar arteries
owing to decreased right coronary perfusion pressure (MAP and 50% to 60% of the vascular bed79,80 may result in obstructive
decreased while right ventricular end-diastolic pressure is increased) shock. However, if recurrent smaller pulmonary emboli result in
and increased right ventricular afterload owing to pulmonary right ventricular hypertrophy, a substantially larger total occlusion
hypertension. Right ventricular ischemia may also lead to right of the pulmonary vascular bed may be required to cause right
ventricular dilatation, septal shift, and impairment of left ventricular ventricular decompensation. Recent analyses have suggested that
function. the presence of shock owing to pulmonary embolus (regardless of
Other causes of cardiogenic shock include acute myocarditis, underlying chronic cardiopulmonary dysfunction) indicates a
end-stage cardiomyopathy, bradyarrhythmias or tachyarrhythmias, three- to sevenfold increase in mortality risk with the majority of
hypertrophic cardiomyopathy with obstruction, and traumatic deaths occurring within an hour of presentation.81,82 An analysis
myocardial contusion (see Box 22.2). of more than 70,000 unstable (hemodynamic instability or
ventilator-requiring) patients with pulmonary embolus in the
National Inpatient Sample shows that mortality in untreated patients
Obstructive Shock is approximately 47%.83 Systemic thrombolysis is associated with
Extracardiac obstructive shock results from an obstruction to flow a substantial reduction in mortality to 15%. Where available,
in the cardiovascular circuit (see Box 22.2 and Fig. 22.1). Pericardial catheter-directed therapy may be even more efficacious with lower
tamponade and constrictive pericarditis directly impair diastolic risk of serious hemorrhage.84 Shock resulting from pulmonary
filling of the right ventricle. Tension pneumothorax and intrathoracic embolism is an indication for urgent thrombolytic or catheter-
tumors indirectly impair right ventricular filling by obstructing directed intervention.
venous return. Massive pulmonary emboli (two or more lobar
arteries with >50% of the vascular bed occluded), nonembolic Distributive Shock
acute pulmonary hypertension, large systemic emboli (e.g., saddle
embolus), and aortic dissection may result in shock owing to The defining feature of distributive shock is loss of peripheral
increased ventricular afterload. resistance. Septic shock is the most common form and has the
The characteristic hemodynamic/metabolic patterns are, in most greatest impact on intensive care unit (ICU) morbidity and
ways, similar to other low-output shock states (see Table 22.1). mortality.
CI, SVI, and stroke work indices are usually decreased. Because Hemodynamically, distributive shock is characterized by an
tissue perfusion is decreased, the MvO2 is low, the arteriovenous overall decrease in SVR (see Table 22.1). However, resistance in
oxygen content difference increased, and serum lactate frequently any specific organ bed or tissue may be decreased, increased, or
elevated. Other hemodynamic parameters are dependent on the unchanged. Initially, CI may be depressed and ventricular filling
site of the obstruction. Tension pneumothorax and mediastinal pressures decreased. After fluid resuscitation, when filling pressures
tumors may obstruct the great thoracic veins, resulting in a are normalized or increased, CI is usually elevated. Owing to
hemodynamic pattern (decreased CI and elevated SVR) similar to hypotension, left and right ventricular stroke work indices are
hypovolemia (although distended jugular and peripheral veins may normally decreased. MvO2 is increased above normal. Concomitantly,
be seen). Cardiac tamponade typically causes increased and equalized the arteriovenous oxygen content difference is narrowed despite
right and left heart ventricular diastolic pressures, pulmonary artery the fact that oxygen demand is usually increased (particularly in
diastolic pressure, CVP, and PAOP. In constrictive pericarditis, sepsis). The basis of this phenomenon may be that while total
right and left ventricular diastolic pressures are elevated and within body perfusion (CI) is increased, perfusion is not effective in that
5 mm Hg of each other. Mean right and left atrial pressures may either it does not reach the necessary tissues or the tissues cannot
or may not be equal as well. Massive pulmonary embolus results use the substrates presented. As a reflection of this inadequate
in right ventricular failure with elevated pulmonary artery and “effective” tissue perfusion, lactic acidosis may ensue. Clinical
right heart pressures, whereas PAOP remains normal. A systemic characteristics of resuscitated distributive shock include, in contrast
saddle embolus or aortic occlusion owing to dissection cause to the other forms of shock, warm, well-perfused extremities, a
peripheral hypotension and signs of left ventricular failure including decreased diastolic blood pressure, and an increased pulse pressure.
an elevated PAOP. Clinical signs are similarly dependent on the Nonspecific signs of shock include tachycardia, tachypnea, decreased
site of the obstruction. urine output, and altered mentation. In addition, evidence of the
As with other forms of shock, the time course of development primary insult may exist (urticaria for anaphylaxis, spinal injury
of the insult has a substantial impact on the clinical response. for neurogenic shock, and evidence of infection in septic shock).
Ischemic rupture of the left ventricular free wall (usually 3 to 7 Septic shock (shock caused by infection) and sepsis-associated
days after MI) leads to immediate cardiac tamponade and shock multiple organ failure are the most common cause of death in
with as little as 150 mL blood in the pericardium.76–78 Survival ICUs of the industrialized world. As many as 800,000 patients
requires emergency surgery.77,78 Similar situations may develop with sepsis are admitted every year to American hospitals
(comparable to the incidence of first MIs), half of whom develop Septic shock is caused by the systemic activation of the inflam-
septic shock and about half (200,000) who die.85 The past four matory cascade. Numerous mediators, including cytokines, kinins,
decades have seen a progressive increase in the incidence of and complement, coagulation factors, and eicosanoids, are activated
total deaths from sepsis and septic shock.86 The total toll of septic or systemically released, resulting in profound disturbances of
deaths is comparable to deaths from MI and far exceeds the impact cardiovascular and organ system function88 (see Table 22.2). These
of illnesses such as AIDS or breast cancer together.85,87 mediators, particularly tumor necrosis factor α (TNF-α), interleukin
TABLE
22.2 Inflammatory Mediators in Sepsis and Septic Shock
Mediator Major Reported Effects

Proinflammatory Cytokines
TNF-α Stimulates release of IL-1, IL-6, IL-8, platelet-activating factor, leukotrienes, thromboxane A2, prostaglandins; may
be able to stimulate macrophages directly to promote its own release
Stimulates production of polymorphonuclear cells by bone marrow; enhances phagocytic activity of
polymorphonuclear cells
Promotes adhesion of endothelial cells, polymorphonuclear cells, eosinophils, basophils, monocytes, and,
occasionally, lymphocytes by inducing increased expression of adhesion molecules
Activates common pathway of coagulation and complement system
Directly toxic to vascular endothelial cells; increases microvascular permeability
Acts directly on hypothalamus to produce fever
Reduces transmembrane potential of muscle cells and depresses myocardial contractility
Decreases arterial pressure, systemic vascular resistance, and ventricular ejection fraction; increases cardiac output
IL-1β Stimulates release of TNF, IL-6, IL-8, platelet-activating factor, leukotrienes, thromboxane A2, prostaglandins; may
also be capable of stimulating its own production
Activates resting T cells to produce lymphocytes and other products; supports B-cell proliferation and antibody
production; is cytotoxic for insulin-producing B cells
Promotes adhesion of endothelial cells, polymorphonuclear cells, eosinophils, basophils, monocytes, and
occasionally, lymphocytes by inducing increased expression of adhesion molecules
Promotes polymorphonuclear cell activation and accumulation
Increases endothelial procoagulant activity
Acts synergistically with TNF; enhances tissue cell sensitivity to TNF
Depresses myocardial contractility
Acts directly on hypothalamus to produce fever
IL-2 May promote release of TNF and INF-γ
Decreases arterial pressure, systemic vascular resistance, and ejection fraction; increases cardiac output
IL-4 Enhances lymphocyte adhesion to endothelial cells
Induces antigen expression on macrophages
Synergistically increases TNF- or IL-1–induced antigen expression on endothelial cells, but inhibits the increased
expression of adhesion molecules by TNF, IL-1, or INF-γ
IL-6 Induction of hepatic acute-phase protein response
Induces myelomonocytic and terminal B lymphocyte differentiation; activates T cells/thymocytes
May contribute to septic myocardial depression
Inhibits TNF production
IL-8 Chemotactic for both neutrophils and lymphocytes; induces tissue infiltration of both
Inhibits endothelial-leukocyte adhesion; decreases the hyperadhesion induced by those molecules
IL-17 Induces synthesis of TNF-α, IL-1β, IL-6, G-CSF, GM-CSF, TGF-β, and other chemokines
IL-18 Initiates cell-mediated immune response
Increases secretion of interferon-γ
INF-γ Promotes release of TNF, IL-1, IL-6 (possibly because of its ability to augment effects of endotoxin on
macrophages); augments production of adhesion molecules
May act synergistically with TNF to produce cytotoxic and cytostatic activity; interacts with other cytokines in
variable ways
Encourages polymorphonuclear cell activation and accumulation; enhances the phagocytic activity of
polymorphonuclear cells
Promotes macrophage activation, macrophage microbicidal function, and expression of cellular receptors for TNF-α
Macrophage migration inhibitory Increases TNF-α and Toll-like receptor 4 expression
factor Activates T lymphocytes
Increases mortality in experimental peritonitis
High-mobility group box protein 1 Possesses both cytokine and intracellular signaling activity
May generate late organ failure of sepsis
Impairs vascular endothelial integrity
Continued
TABLE
22.2 Inflammatory Mediators in Sepsis and Septic Shock—cont'd
Mediator Major Reported Effects

Antiinflammatory Cytokines
IL-4 Induction of differentiation of naïve helper T cells to T helper type 2 cells
IL-10 Downregulation of macrophage function, leading to decreased TNF-α release
IL-1 receptor antagonist Antagonistic blockade of IL-1β
Transforming growth factor β1 Broad immunomodulatory activity (protective in endotoxic shock)
Inhibition of effect of proinflammatory cytokines on a variety of tissues
Suppression of macrophage proinflammatory responses
Interference with phagocytic activation
Endothelial Factors
Endothelin 1 Strongly promotes vasoconstriction
Nitric oxide Mediates vascular smooth muscle relaxation and arteriovenular dilatation in septic shock
May be responsible for septic myocardial depression
Involved in leukocyte/macrophage antimicrobial activity
Arachidonic Acid Pathway Factors and Metabolites
Phospholipase A2 Releases arachidonic acid (the precursor of eicosanoids such as leukotrienes, prostaglandins, and thromboxanes)
Decreases arterial pressure, systemic vascular resistance, and ventricular ejection fraction; increases cardiac output
Leukotrienes Promote neutrophil chemotaxis and adhesion of neutrophils to endothelium (neutrophils have specific receptors for
leukotriene B4)
Increase vascular permeability, either directly or through interaction of neutrophils and endothelial cells
Decrease coronary blood flow and myocardial contractility
Thromboxane A2 Produces vasoconstriction of vascular beds; secondarily promotes release of endothelium-derived relaxing factor
and may stimulate prostacyclin production
Causes platelet aggregation and neutrophil accumulation
Increases vascular permeability; enhances permeability of both single- and double-unit membranes
Produces pulmonary bronchoconstriction
Prostaglandin E2 Inhibits IL-1 production
Low concentrations stimulate TNF release; higher concentrations suppress TNF production at a dose-dependent
level
Causes vasodilation and increased blood flow
Has a beneficial effect on tissue perfusion and may thereby decrease the severity of tissue damage
Acts synergistically with prostacyclin to increase the effects of serotonin and bradykinin on vascular permeability
Prostacyclin (prostaglandin I2) Inhibits platelet aggregation and adhesion
Causes vasodilation and increased blood flow; in early sepsis, exerts a beneficial effect on tissue perfusion
Produces smooth muscle relaxation
Others
Platelet-activating factor Stimulates release of TNF, leukotrienes, thromboxane A2
Promotes leukocyte activation and subsequent free radical formation
Encourages platelet aggregation, leading to thrombosis
Markedly alters microvascular permeability, thereby promoting microvascular fluid loss
Exerts a negative inotropic effect on the heart; lowers arterial blood pressure
Complement fragment C3a Causes mast cell degranulation and vasodilatory mediator release
Fragment C5a Causes smooth muscle contraction and mucous secretion
Causes mast cells to degranulate and release vasodilatory mediators
Promotes TNF release
Enhances polymorphonuclear cell activation, migration, adherence, and aggregation
Induces capillary leakage
May decrease systemic vascular resistance and produce hypotension
IL, Interleukin; INF-γ, interferon γ; TNF, tumor necrosis factor.

Adapted from Bone RC. The pathogenesis of sepsis. Ann Intern Med. 1991;115:457–459.
(IL) 1β (IL-1β), platelet-activating factor (PAF), and prostaglandins cause as much as 50% of septic shock cases with an identified
are thought to mediate reduced peripheral vascular resistance seen pathogen), other major initiators of the systemic inflammatory
in septic shock. response characteristic of sepsis include various exotoxins (all
The triggers for systemic activation of the inflammatory cascade bacteria), peptidoglycans (streptococci), and techioic acid (Staphy-
include a large number of constitutive and/or inducible elements lococcus aureus); lipoarabinomannan of mycobacteria; bacterial
of invasive microorganisms. Beyond endotoxin (lipopolysaccharide), DNA and ribonucleic (RNA); and mannoproteins and β-glucan
which represents a major trigger in gram-negative bacilli (that of fungi.89–95 Recent investigations suggest a surprising commonality
of signaling mechanisms in septic shock via Toll-like receptors of shock in spinal injury appears to be loss of venous tone resulting
from a broad range of etiologic agents.90,96–99 in increased venous capacitance. Arteriolar tone may also be affected,
More than any other form of shock, distributive and, particularly, resulting in increased CO after fluid resuscitation.
septic shock involves substantial elements of the hemodynamic Adrenal crisis is an uncommon cause of shock which can be
characteristics of other shock categories (see Fig. 22.1 and Table difficult to diagnose since it occurs in patients with other active
22.1). As noted, all forms of distributive shock involve decreased disease processes and the clinical features may mimic infection. It
mean peripheral vascular resistance. Before fluid resuscitation, is a life-threatening emergency which requires prompt diagnosis
distributive shock also involves a relative hypovolemic component. and management.
The first element of this relative hypovolemia is an increase of the Adrenal crisis is caused by a deficiency of adrenal production
vascular capacitance as the result of venodilatation. This phenom- of mineralocorticoids and glucocorticoids. It may occur de novo
enon has been directly supported in animal models of sepsis100–104 in patients with critical illness or against a background of occult
and is reinforced by the fact that clinical hypodynamic septic shock adrenal insufficiency. In the critical care setting, the most common
(low CO) can usually be converted to hyperdynamic shock (high cause of de novo acute adrenal insufficiency is bilateral adrenal
CO) with adequate fluid resuscitation.105–107 Relaxation of vascular hemorrhage in association with overwhelming infections (classically
smooth muscle is attributed to a number of the mediators known meningococcal, but frequently gram-negative bacteria), human
to circulate during sepsis. These same mediators also contribute immunodeficiency virus infection, or anticoagulation.123,124 In
to the second cause of hypovolemia in sepsis: third-spacing of addition, fungal infections such as histoplasmosis, blastomycosis,
fluid to the interstitium owing to loss of endothelial integrity. In and coccidioidomycosis and malignant infiltration of the adrenal
addition, a number of studies have demonstrated that human glands may cause acute adrenal insufficiency in ICU patients.123
septic shock is characterized by myocardial depression (biventricular In some patients, steroid production remains adequate for the
dilatation and decreased ejection fraction).33–35 Circulating substances baseline state despite adrenal disease. Once stressed, however, adrenal
such as TNF-α, IL-1β, PAF, leukotrienes, and most recently, IL-6 response is inadequate, leading to decompensation and adrenal
have been implicated in this process.108–115 crisis. Stressors may be relatively innocuous or may be severe. A
Anaphylactic shock is a form of distributive shock caused by febrile illness, infection, trauma, surgery, dehydration, or any other
release of mediators from tissue mast cells and circulating basophils. intercurrent illness may trigger the crisis. Abrupt cessation of
Anaphylaxis, an immediate hypersensitivity reaction, is mediated glucocorticoid therapy or replacement may also result in adrenal
by the interaction of immunoglobulin (Ig) E (IgE) antibodies on crisis.
the surface of mast cells and basophils with the appropriate antigen. Symptoms are generally nonspecific and may include anorexia,
Antigen binding results in release of the primary mediators of nausea, vomiting, diarrhea, abdominal pain, myalgia, joint pains,
anaphylaxis contained in the basophilic granules of mast cells and headache, weakness, confusion, and agitation or delirium.123,125
basophils. These include histamine, serotonin, eosinophil chemo- Fever (often out of proportion to any minor infection) is almost
tactic factor, and various proteolytic enzymes.116 Subsequently, a always present, and hypotension, initially caused by hypovolemia,
number of secondary lipid mediators are synthesized and released, is frequent.123 The initial hemodynamic pattern may resemble
including PAF, bradykinin prostaglandins, and leukotrienes (slow- hypovolemic shock (if shock is due only to adrenal crisis). With
reacting substance of anaphylaxis).116 An anaphylactoid reaction volume resuscitation, a high-output, vasopressor-refractory shock
(clinically indistinguishable from anaphylaxis) results from direct, may become apparent.126,127
nonimmunologic release of mediators from mast cells and basophils Shock owing to adrenal crisis may be masked by or contribute
and can also result in shock. to shock owing to other concomitant critical illness, particularly
Anaphylaxis is triggered by insect envenomations (Hymenoptera septic shock. Thus if vasopressor-refractory shock occurs in patients
bees, hornets, and wasps), foods (including eggs and nuts, especially potentially predisposed to adrenal insufficiency, a cortisol level and
peanuts) and certain drugs, particularly antibiotics (β-lactams, rapid adrenocorticotropic hormone stimulation test must be
cephalosporins, sulfonamides, and vancomycin).116 In addition, performed and the patient given glucocorticoids and other therapy.
less frequently, heterologous serum (e.g., tetanus antitoxin, snake An unrecognized “relative” adrenal insufficiency has been impli-
antitoxin, antilymphocyte antisera), blood transfusion, immuno- cated in the pathogenesis of human septic shock.128–135 In this cir-
globulin (particularly in IgA-deficient patients) and egg-based cumstance, sepsis is associated with a suboptimal adrenal response
vaccine products have been implicated.116 Anaphylactoid reactions with an improvement in cardiovascular parameters and/or outcome
can be caused by a wide range of medical agents, including ionic with “stress” dose corticosteroid administration.128,129,132–137 One
contrast media, protamine, opiates, polysaccharide volume expand- randomized controlled trial suggested that prospective “stress dose”
ers, such as dextran and hydroxyethyl starch, muscle relaxants, therapy with a combination of hydrocortisone (50 mg intravenous
and anesthetics.116 [IV] every 6 hours) and fludrocortisone (50 µg oral/nasogastric
The hemodynamic features of anaphylactic shock are very similar daily) for 7 days improved outcome in nonresponders to corticotropin
to septic shock and include elements of hypovolemia (owing to challenge.138 Confirmatory randomized trials have failed to reproduce
interstitial edema and venodilatation) and myocardial this finding.139,140 However, given solid data suggesting a vasopressor-
depression.117–121 CO and ventricular filling pressures may be reduced sparing effect,136,137 the current recommendation is to consider
until patients are fluid resuscitated.117,122 In addition to typical administration of hydrocortisone only in refractory septic shock
findings of shock, patients may demonstrate urticaria, angioedema, (when there is a suboptimal response to appropriate fluid resuscitation
laryngeal edema, and severe bronchospasm. and vasopressors).141–143
Neurogenic shock involves loss of peripheral vasomotor control
as the result of dysfunction or injury of the nervous system. The Pathogenesis and Pathophysiology of Shock
classic example is shock associated with spinal injury. A similar
phenomenon is active in vasovagal syncope and spinal anesthesia, The inability of cells to obtain and/or use oxygen in sufficient
but such conditions are self-limited and transient. The major cause quantity to optimally meet their metabolic requirements has
Hypovolemia Sepsis Myocardial dysfunction

(e.g., myocardial infarction)
Intravascular Venous Cardiovascular obstruction
volume capacitance (e.g., massive pulmonary embolus)
Venous pressure Cardiovascular stress Renal perfusion
Circulatory shock
( MAP)
Stretch receptors Baroreceptors Renal juxtaglomerular

Right atrial Aortic arch apparatus
pulmonary artery Carotid body
Splanchnic vessels
Vascular chemoreceptors
Carotid
Aorta
Medullary chemoreceptor
CNS
Sympathetic response Pituitary response
Hormonal Neural ACTH

ADH
Epinephrine Cardiac contractility
Norepinephrine Vasoconstriction Cortisol
Renin/angiotensin flow redistribution Aldosterone
Aldosterone
Na retention
Na/H2O retention Maintain cardiovascular
Cardiac contractility catecholamine responsiveness
Vasoconstriction
Flow redistribution
• Fig. 22.2 Neurohormonal response to shock. During early cardiovascular stress, the neurohormonal
response may be limited to increased activity of the juxtaglomerular apparatus and stimulation of right
atrial and pulmonary artery low-pressure mechanoreceptors. With further hypotension, high-pressure
vascular baroreceptors, vascular chemoreceptors, and the medullary chemoreceptor are sequentially
stimulated resulting in augmented neurohormonal activity with increased pituitary hormone (adrenocorti-
cotropic hormone [ACTH] and antidiuretic hormone [ADH]) release and increased sympathetic outflow
from the central nervous system (CNS). Volume retention, increased venous tone, increased cardiac
contractility, and blood flow redistribution to vital organs results. MAP, Mean arterial pressure; Na, sodium;
H2O, water.
classically been considered to be the pathophysiologic basis of all but overt evidence of shock (hypotension, altered sensorium,
forms of shock. In the first half of the 20th century, the study of metabolic acidosis) may not. Therapeutic interventions have a high
shock focused on the relatively distinct hemodynamic physiology probability of preventing ischemic tissue injury and initiation of
that characterizes the different forms of shock. Since then evidence progressive systemic inflammatory cascades during this early
has accumulated that the various types of clinical shock have compensated stage. Adaptive compensatory mechanisms fail and
significant overlap in their hemodynamic characteristics. In parallel, organ damage/failure ensues if the injury that initiates shock is
shock of most causes has been shown to involve similar biochemical too extensive or progresses despite therapy.284 As the duration of
and metabolic pathways. In the following section, the pathophysiol- established shock increases, therapy is less likely to be effective in
ogy and pathogenesis of shock are reviewed from the hemodynamic preventing organ failure and death.
to the molecular level. (See the online supplement for discussion Various sensing mechanisms involved in physiologic compensa-
on the “Hemodynamic Basis of Shock,” “Microvascular Function tory responses exist to recognize hemodynamic and metabolic
in Shock,” and “Mechanisms of Cellular Injury in Shock.”) dyshomeostasis (Fig. 22.2). Low-pressure right atrial and pulmonary
artery stretch receptors sense volume changes. A decrease in circulat-
ing volume (or increase of venous capacitance) results in an increase
Compensatory Responses to Shock in sympathetic discharge from the medullary vasomotor
Shock is usually not a discrete condition occurring abruptly after center.144,285,286 Aortic arch, carotid, and splanchnic high-pressure
injury or infection. With the onset of hemodynamic stress, baroreceptors sense early blood pressure changes close to the
homeostatic compensatory mechanisms engage to maintain effective physiologic range.144,285,286 An increase of sympathetic discharge
tissue perfusion. At this time, subtle clinical evidence of hemody- from the medullary vasomotor center results from a small to
namic stress may be apparent (tachycardia, decreased urine output) moderate decrease in blood pressure associated with early shock.
CHAPTER 22 Shock: Classification, Pathophysiology, and Approach to Management
298.e1
Hemodynamic Basis of Shock Cardiac Output

From a hemodynamic perspective, shock is the failure of cardio- The fact that total systemic perfusion is defined by CO underlies its
vascular adaptation to systemic dyshomeostasis induced by trauma, importance in shock. The product of HR and stroke volume (SV)
infection, or other insult such that CO and/or blood pressure are determines CO (CO = HR × SV). SV (a measure of myocardial
compromised. This failure is manifested by inadequate organ and performance) is dependent on preload, afterload, and contractility.
tissue perfusion. Although effective perfusion is also dependent Preload represents the extent of precontraction myocardial fiber
on microcirculatory and intracellular factors (see Box 22.1), the (or sarcomere) stretch. In vivo, preload is the end-diastolic ven-
hemodynamic aspects of shock can be described, in part, by the tricular volume. Because measurement of such volumes in the
contributions of cardiac and arterial vascular function to blood clinical context is difficult, intracardiac pressures, which can be
pressure and CO. determined more easily, are frequently substituted. There are
difficulties with this approach. The relationship of ventricular
Arterial Pressure end-diastolic volume (preload) to end-diastolic pressure is nonlinear.
Although CO may be expressed as a function of MAP and vascular Further, alterations of myocardial compliance render CVP and
resistance [CO = (MAP − CVP)/SVR], CO is not directly dependent PAOP unreliable as estimates of preload in critically ill patients.146
on MAP in most physiologic states. Instead, blood pressure is Preload is dependent on circulating volume, venous tone, atrial
typically dependent on CO and vascular resistance. Blood pressure, contraction, and intrathoracic pressure among other factors.144,147
however, does provide a mechanism to indirectly sense CO and Atrial contraction is particularly important in those with impaired
global perfusion perturbations for autoregulatory purposes. ventricular function. Although accounting for only 5% to 10%
The ability of all organ vascular beds to support normal blood of CO in healthy humans, synchronized atrial contraction con-
flow is dependent on maintenance of blood pressure within the tributes as much as 40% to 50% of the CO in patients with severe
defined range for that organ (eFig. 22.1).144 Vital organs, such as left ventricular dysfunction.147 Increased intrathoracic pressure or
the brain and heart, in particular, are able to autoregulate blood increased venous capacitance affect preload by reducing venous
flow over a wide range of blood pressure. Failure to maintain the return.144,148 Nitrovasodilators such as nitroglycerin may decrease
minimal MAP and perfusion pressure required for autoregulation CO despite arteriolar vasodilation owing to their venodilatory
during hypodynamic circulatory shock indicates a severe reduction (decreased preload) effects. Conversely, the earliest increases in
in CO. Pharmacologic support of blood pressure in such situations CO seen with sympathetic stimulation and exogenous catecholamine
(with α-adrenergic agonists) usually results in decreased total infusion are related to venoconstriction-induced increases of venous
systemic perfusion as sensitive vascular beds constrict and overall return and preload.149 Cardiogenic and some forms of obstructive
vascular resistance increases. However, because of their strong shock are typically characterized by increased preload. Preresuscita-
autoregulatory capacity, vital organs will maintain increased perfu- tion distributive shock and hypovolemic shock are uniformly
sion under these conditions. associated with decreased preload.144
In addition to sufficient CO, effective perfusion requires Afterload refers to the total resistance to ejection of blood from
appropriate distribution of blood flow. Failure to maintain blood the ventricle during contraction. Increasing afterload results in
pressure within the autoregulatory range results in distribution of decreased extent and velocity of myocardial contraction.144 Excessive
blood flow which is strictly dependent on the passive mechanical afterload (aortic dissection, pulmonary embolus) causes some forms
properties of the vasculature.145 This may result in inappropriate of obstructive shock. Ex vivo, afterload can be easily defined as a
distribution of perfusion between and within tissues and organs. resistive force applied to an isolated papillary muscle. Because the
Late hemorrhagic shock has been shown to be characterized by heart does not displace a fixed mass but rather rhythmically moves
abnormal microvascular flow with dilatation of precapillary a viscous, non-Newtonian fluid through branching viscoelastic
sphincters.38 conduits, the definition of afterload in vivo is difficult.
Afterload has been suggested to be equivalent to systolic
myocardial wall stress. This definition suggests that afterload is
substantially dependent on intrinsic cardiac mechanical and
functional properties.150 An alternative approach equates left
Perfusion (blood flow) (¥ normal)
2.0 ventricular afterload with the mechanical properties of the arterial

side of the circulatory system. Aortic input impedance, which
represents the total resistance to flow from outside the left ventricle,
1.5
is determined by the inertial and viscous properties of blood, and
Autoregulation
the resistive and viscoelastic properties of the arterial system. The
1.0 term is inclusive of SVR, HR effects, and pulse wave reflections
in the arterial tree.150 Although an accurate measure of afterload
0.5
in pulsatile systems, assessment of impedance is technically difficult,
requiring continuous harmonic analysis of rhythmic variations of
aortic pressure and flow. SVR is a limited approximation of aortic
0 input impedance based on a model that assumes nonpulsatile flow.
0 50 100 150 200 At an HR of 0, SVR and aortic input impedance are equivalent.
Mean arterial pressure (mm Hg) From a clinical point of view, SVR is the most practical way of
• eFig. 22.1 Idealized representation of blood flow autoregulation. Within

assessing afterload.
the autoregulatory range of blood pressure for a tissue or organ, perfusion Afterload is increased in pathologic conditions such as aortic
can be held relatively constant. Outside this range, autoregulation fails and stenosis, systemic embolism, and hypertension. Vasopressors
perfusion becomes a function of mean arterial pressure. including α-agonists (e.g., phenylephrine, norepinephrine) and

298.e2 Pa rt 2 Critical Care Cardiovascular Disease
Contractility
vascular volume that contributes to venous pressure) divided by
Afterload the mean vascular compliance (C):
Normal Pmc = Vs C (2)
Vs is dependent on total vascular volume (Vt) and the state of
Cardiac output
venous tone (i.e., venoconstriction). It is defined as the difference

between Vt and the unstressed vascular volume (V0), the intravas-
cular volume that remains when the vascular circuit is equalized
to atmospheric pressure (i.e., the volume remaining after passive
exsanguination). Vs volume is approximately 30% of total blood
Contractility volume in both humans and in experimental animals.154–156 Compli-
Afterload ance refers to the total elastic properties of the entire cardiovascular
circuit inclusive of the heart and vasculature.
As Eq. (1) shows, the only direct role the heart plays on venous
Atrial pressure return is by altering right atrial pressure (Pa). MAP has no direct
• eFig. 22.2
Cardiac function curve demonstrating the effect of variations
effect at all despite the fact that it is closely related to CO in the
of preload (atrial pressure), contractility, and afterload on cardiac systemic circulation (MAP − CVP = CO × SVR).
performance. Rapid alterations of venous return are typically mediated by
changes of Pmc or Rv. Pmc is acutely influenced by changes of
Vs, either directly through alterations of venous capacitance, which
primarily involves changes of small vein and venular tone (exogenous
vasopressors or vasodilators, sympathetic stimulation); or indirectly
vasopressin also increase afterload, whereas nitrates and other by changes of Vt (volume depletion or infusion). Compliance is
vasodilator agents decrease it. Increased intrathoracic pressure owing substantially a passive mechanical property of the vasculature and
to mechanical ventilation and positive end-expiratory pressure does not cause acute alterations of Pmc or venous return. Rv to
decrease left ventricular afterload while increasing right ventricular flow is acutely altered by changes of the caliber of large-diameter
afterload. Hypodynamic and hyperdynamic shock are usually veins, particularly the vena cava and great veins of the thorax.
characterized by increased and decreased afterload, respectively. However, although resistance resides primarily in large veins and
Contractility refers to the intrinsic ability of myocardial fibers the vena cava, and venous capacitance resides primarily in small
to shorten under given loading conditions. Under normal conditions veins and venules, all veins contribute to resistance and capacitance
determinants of contractility include myocardial mass and sym- to some extent. Alterations of venous tone (either pharmacologic
pathoadrenal activation state. In pathologic states (e.g., shock), or physiologic) therefore tend to induce opposing changes in Pmc
hypoperfusion/ischemia, myocardial cell injury (e.g., reperfusion and Rv with respect to venous return. Vasodilatation decreases
injury, myocarditis), acidosis, and circulating myocardial depressant Pmc by decreasing Vs but it also decreases Rv. Vasoconstriction
substances (such as seen in sepsis) depress cardiac contractility results in increases of both Pmc and Rv. Only alterations in Vt
(eFig. 22.2). alter Pmc without affecting Rv.
As with preload and afterload, the ex vivo/in vitro assessment The venous return relationship is shown in eFig. 22.3.144,157–159
of contractility is straightforward. Assessment of in vivo contractility Because the systemic venous bed constitutes the bulk of venous
(even in experimental animals) is substantially more difficult owing capacitance, the systemic venous vasculature dominates the physiol-
to intrinsic lability of preload and afterload. Relatively load- ogy of venous return. Venous return is linearly related to Pa down
independent variables, such as the peak systolic pressure/end-systolic to 0 cm H2O (= atmospheric pressure), at which point intermittent
volume ratio, may be the most clinically useful measures of collapse of the great veins results in limitation of return producing
contractility. 151 Many of these variables can be obtained the plateau.144,159,160 The slope of the line representing venous return
echocardiographically.152,153 is the inverse of the resistance (1/Rv). The ordinate intercept denotes
the Pa at which venous return is zero. But according to Eq. (1),
Venous Function in Shock venous return is zero only when Pa equals the Pmc. Thus the
Given that the cardiovascular circuit is a closed system and CO intercept of the atrial pressure axis represents Pmc. Changes of
cannot exceed the rate of return of blood to the right ventricle, Pmc shift the curve to the left or right without changing the slope
venous return can be considered a fundamental determinant of of the line (Fig. 22.3, line a to lines b and c). Changes of Rv
cardiac performance. Although preload is a related variable, it change the slope of the line without changing the Pmc (eFig. 22.3,
primarily reflects ventricular properties related to compliance and line a to lines d and e).
HR, whereas venous return is substantially dependent on the
extracardiac properties of the systemic venous circulation. Maximum Graphic Analysis of Venous-Cardiac
venous return is described by the following equation: Interactions During Shock
(Pmc − Pa ) Rv, (1) In a closed system, CO as determined by HR, preload, afterload,

and contractility must equal venous return as determined by mean
where Pmc is the mean circulatory pressure (the upstream driving circulatory pressure, right atrial pressure, and Rv. CO therefore is
pressure of the systemic venous circulation—i.e., the intravascular not strictly a product of cardiac or vascular function but is dependent
pressure measured when the heart is stopped), Pa is the right atrial on their interaction. Because venous return and CO are equal and
pressure (the downstream pressure that opposes flow to the right are dependent on atrial pressure, the right heart Starling function
ventricle), and Rv is the venous resistance (resistance of the conduit curves can be superimposed on the systemic venous return curves
to flow). Pmc equals the stressed volume or Vs (the portion of the using the same graphic parameters. The intersection of the two
298.e3
Cardiac output and venous return

Normal
Pmc Pmc
Contractility
b Normal or Afterload
Rv Venous Pmc – Pa
return = Rv A
+ Dobutamine
d E
Venous return
Normal D
a Slope = 1/Rv
Contractility
Rv C or Afterload
e B
Pmc Pmc = Vs/C
c
0
Atrial pressure
• eFig. 22.4
Graphic representation of systemic venous return–right heart
0 performance interactions during cardiogenic shock (point A to B) and
Atrial pressure therapy (see text for details). Pmc, Mean circulatory pressure.
• eFig. 22.3 Graphic representation of venous return with varying atrial
pressures, mean circulatory pressures and venous resistance. Altering

mean circulatory pressure displaces the line representing venous return
(line a to line b or c) without changing the slope (which represents venous

resistance to flow). Altering venous resistance changes the slope of the
Moderate-dose
venous return curve (line a to line d or e) without changing the intercept Normal catecholamines
point of the venous return line with the ordinate (which defines mean
circulatory pressure). C, Mean vascular compliance; Pa, right atrial pres-
Normal
sure; Pmc, mean circulatory pressure; Rv, venous resistance; Vs, stressed Fluids
volume. See text for details.
D
Pmc ( Vt) A
C
curves defines CO and venous return for any given set of conditions B
involving the right heart and the systemic venous circulation. The
circulatory physiology of shock can be described by the interaction
of cardiac function and venous return curves.
Cardiogenic shock and obstructive shock owing to increased
0
afterload of the right or left ventricle (e.g., massive pulmonary Atrial pressure
embolus) result in a common change of the right ventricular Starling
function curves. In the case of primary left ventricular loading or • eFig. 22.5 Graphic representation of systemic venous return–right heart

performance interactions during hypovolemic shock (point A to B) and

damage, this occurs because increased left ventricular filling pressures
therapy (see text for details). Pmc, Mean circulatory pressure; Vt, total
are passively transmitted to the right ventricle. The Starling curves vascular volume.
are shifted downward and to the right (flatter) (eFig. 22.4, point
A to B), resulting in decreased CO at increased atrial pressures.
Therapy can consist of fluid resuscitation (increased Vt and Pmc),
which may result in only modest augmentation of CO despite contractility with shift of the Starling function curve downward
significant increases of atrial pressures and ventricular filling pressures and to the right (analogous to myocardial depression during
(point C); dobutamine, a β1- and β2-agonist that increases CO cardiogenic shock) has been noted in experimental hemorrhagic
by increasing contractility (point D); and both fluids and dobu- shock,36,37 this phenomenon is not considered here. Volume therapy,
tamine (point E). Other catecholamines such as dopamine and whether with crystalloid or colloid, tends to correct Pmc and
norepinephrine, which both increase myocardial contractility and venous return toward the original value (point C). Although optimal
reduce venous capacitance, also increase afterload and have variable therapy of hypovolemic shock involves volume resuscitation, low-
effects on CO and venous return depending on which effect is dose catecholamines exert similar hemodynamic effects; Pmc (and
dominant. Resistance to therapy may be noted if myocardial damage venous return) are augmented by an increase of the Vs while the
is sufficiently severe to flatten the Starling function curve to the total (reduced from baseline) circulating volume (Vt) is unchanged
point that increasing Pmc has little effect on increasing venous (also point C).158,161,162 These changes outweigh any deleterious
return/CO and insufficient functional myocardium remains to effect on increasing Rv. Cardiac contractility and vascular resistance
respond to inotropes with increased contractility (a steeper Starling are minimally affected at these doses. At moderate infusion rates
relationship). (and with sympathetic stimulation), cardiac contractility is also
Hypovolemic shock results from decreased Vt, Vs, and Pmc augmented (point D). With higher catecholamine infusion rates,
(eFig. 22.5, point A to B). The venous return curve is shifted Vr and afterload may increase resulting to the point of decreasing
downward and to the left, resulting in a reduced venous return CO and venous return (not shown). For that reason, vasopressors
and CO at lower Pas. Although late depression of myocardial may be used only with great caution in hypovolemic shock.163

N Pmc Rv that both vascular and myocardial responsiveness to sympathomimet-

ics may be reduced. In addition, they may also affect vascular
compliance, similar to the potential compensatory neurohumoral
effects described earlier.
Obstructive forms of shock such as those caused by pericardial
tamponade and tension pneumothorax can also be analyzed in the
Normal context of venous/cardiac interactions. For a detailed review of

this subject matter, the reader is referred to several excellent reviews
of this subject.149,168,169
Ventricular function of each distinct form of shock can also be
examined by using end-systolic and end-diastolic pressure-volume
D Contractility analysis. Such analysis can be demonstrated graphically using
Normal ventricular pressure-volume loops. Changes in SV and ventricular
E contractility can be examined with respect to ventricular volume
Pmc Rv A and pressure alterations in circulatory shock states. Although this
represents a useful approach to the study of circulatory shock
C physiology, a review of the subject is beyond the scope of this
Pmc N Rv
F chapter. The interested reader is referred to a number of cogent
B
Contractility reviews.170–172
Microvascular Function in Shock

Preserved microvascular (vessels <100–150 µM in diameter) func-
0 tion is a critical determinant of appropriate tissue perfusion during
Atrial pressure shock. Although adequate CO at sufficient blood pressure is required
• eFig. 22.6Graphic representation of systemic venous return–right heart
for appropriate global perfusion and systemic hemodynamics,
performance interactions during septic shock (point A to B) and therapy effective tissue perfusion also requires intact local and systemic
(see text for details). Pmc, Mean circulatory pressure; Rv, venous microvascular function.
resistance.
Distribution of CO is a complicated process involving local
intrinsic autoregulation and extrinsic regulation mediated by
autonomic tone and humoral factors. Blood flow to individual
Septic shock is especially complicated. Sepsis may involve organs may be affected by system-wide changes in microarteriolar
elements of hypovolemia, myocardial depression, and altered tone or by local alterations in metabolic activity. Blood flow within
distribution of CO. Vt and Vs are decreased owing to loss of fluids organs also requires microvascular regulation to match blood flow
to the interstitium (third-spacing) and insensible losses. Vs is further to areas of highest metabolic activity.
decreased as the result of active dilation of small venules/veins, Intrinsic control (autoregulation) of blood flow is thought to
resulting in increased venous capacitance. This increase in Vt and occur through two mechanisms. Rapid alterations of microvascular
decrease in Vs has been confirmed in experimental animal models tone are mediated through endothelial stretch receptors so that
of canine and porcine endotoxemia.101,164 Thus in unresuscitated sudden changes in perfusion pressure can be compensated by
septic shock, Pmc is almost universally decreased, resulting in opposing changes in vascular resistance to maintain perfusion.173
reduced venous return and CO (eFig. 22.6, point A to B). Sepsis In addition, increases in metabolic activity within tissues and organs
is also associated with dilatation of large veins and shunting of are thought to cause local elevation of various metabolites (carbon
arterial blood flow to low-resistance (fast time constant) vascular dioxide [CO2], hydrogen ion [H+], and so on), resulting in
beds, both of which decrease Vr and tend to augment venous vasodilation and increased perfusion to match substrate demand.173
return. Decreased Vr, however, does not fully compensate for Extrinsic control of vascular tone is primarily exerted through
decreased Pmc in unresuscitated septic shock. CO remains depressed the autonomic nervous system. Parasympathetic release of acetyl-
(point B to C). With fluid resuscitation Pmc may be corrected choline to blood vessels results in nitric oxide (NO) and cyclic
back toward normal, allowing the decreased Rv to be manifested guanosine monophosphate (cGMP) generation in endothelial cells
by supernormal CO and venous return (point D).101 Patients with and vascular smooth muscle, leading to vascular relaxation. Increases
septic shock also develop myocardial depression, which is typically of sympathetic tone cause local norepinephrine release, activation
masked by the overall increase in CO (point E). In about a fifth of vascular α-adrenoreceptors, and increased vascular tone
of patients, however, myocardial depression is sufficiently severe (eFig. 22.7). Under stress, epinephrine and norepinephrine can
that venous return and, therefore, CO remains depressed even be systemically released by sympathetic stimulation of the adrenal
after resuscitation (point F). medulla. Basal control of blood pressure and flow resides in the
Human data suggest that sepsis is associated with a decrease of activity of the renin-angiotensin system.
total vascular compliance.165,166 However, it is unclear whether this Alterations in microvascular function are effected through
represents a primary septic phenomenon or a neurohumorally precapillary and postcapillary sphincters that are sensitive to both
mediated compensatory response.149,165,167 After fluid resuscitation, intrinsic and extrinsic control mechanisms. Because exchange of
therapy of septic shock primarily involves catecholamines such as CO2, oxygen, and other substrates/metabolites and compartmental
norepinephrine and dopamine. These affect the venous and cardiac regulation of fluids occur at the capillary level, alteration of tone
function curves as specified earlier, although some data suggest of either sphincter may have varying effects. Opening of either
298.e5
Vasodilating factors Vasoconstricting factors

Renin
Stretch
Al All
O–2
H+ ADH
CO2
Acetylcholine Platelets O–2
Intravascular TNF Bradykinin
PAF LTE4
space IL-1 PGE2 PGH2 TXA2 Endothelin EDCF1
NO PG1
Endothelium
Vascular iNOS
smooth cGMP
NO ONOO–
muscle
TNF PGI1 Histamine
Extravascular IL-1 PGE2 PGI1
space PGE2 Norepinephrine
PAF (sympathetic innervation)
PAF
Macrophage
Mast cell
• eFig. 22.7 Physiologic and pathophysiologic vasoactive factors. AI, Angiotensin I; AII, angiotensin II;
ADH, antidiuretic hormone (vasopressin); cGMP, cyclic guanosine monophosphate; CO2, carbon monox-
ide; EDCF, endothelium-derived contracting factor; H+, hydrogen ion; IL-1, interleukin 1β; iNOS, inducible
nitric oxide synthetase; LTE4, leukotriene E4; NO, nitric oxide; O2−, superoxide anion; ONOO−, peroxynitritel;
PAF, platelet-activating factor; PGE2, prostaglandin E2; PGH2, prostaglandin H2; PGI2, prostacyclin; TNF,
tumor necrosis factor-α; TXA2, thromboxane A2.
nonnutrient capillary sphincters (microanatomic shunts)174 or of flow. Blood flow to other organs is reduced relative to the
increased flow to hypometabolic tissues (functional shunts)175 results decrease in total CO as organ vascular resistance increases to
in suboptimal distribution of substrate supply with increased MvO2. maintain blood pressure.176 This effect is mediated in part by both
Failure to dilate sphincters supplying metabolically active tissues sympathetic neural activity and adrenal release of catechol-
may result in ischemia and anaerobic metabolism with lactate amines.145,176 This adaptive mechanism maintains perfusion to vital
production. Increased precapillary tone as seen with sympathetic organs at mild to moderate levels of reduced CO. If the insult is
stimulation results in increased blood pressure systemically and sufficiently severe or prolonged, organ ischemia and subsequent
decreased hydrostatic pressure locally. This decreased hydrostatic organ failure may develop. Even if resuscitation restores systemic
pressure favors redistribution of volume from the interstitium to circulatory hemodynamics, microvascular perfusion abnormalities
the circulation. Increased postcapillary tone (relative to precapillary) persist for days.177 Experimental data suggest that perfusion of
results in vascular pooling of blood and loss of fluid to interstitium brain, kidneys, liver, and other splanchnic organs remains impaired
(owing to increased hydrostatic pressure). after resuscitation from hemorrhagic shock.177 Persistence of
Organ blood flow changes are well characterized in shock states. inadequate matching of tissue substrate demand and delivery after
Autoregulation of blood flow is dependent on maintenance of resuscitation of shock can lead to continued ischemia/hypoxia of
blood pressure within a defined range that varies among organs. some tissues. This may explain why hemorrhagic shock-related
The autoregulatory capacity of various organs can be determined tissue injury can be irreversible if the duration and severity of is
by mechanically altering blood pressure in the organ vascular bed. excessive. Animal models suggest this irreversible phase of severe
With isolated local hypotension, the brain exhibits dominant hemorrhagic shock is characterized by vasodilatation of precapillary
autoregulatory capability with the ability to maintain blood flow sphincters.178
over a wide range of pressures (30–200 mm Hg in dogs).145 Coro- During sepsis and septic shock, organ blood flow is disturbed
nary perfusion is also substantially autoregulated between 40 and at higher MAP, suggesting a primary defect of microvascular
100 mm Hg. In contrast, mesenteric and renal blood flow becomes function. Cerebral blood flow to the brain in humans has been
pressure dependent below about 60 mm Hg, whereas the vascular shown to be depressed even before the onset of septic shock in
bed of skeletal muscle behaves in a passive manner at pressures patients with systemic inflammatory response syndrome.179 This
outside 50 and 100 mm Hg. Human data suggest that, overall, pathologic vasoconstriction (apparently a unique response of the
good autoregulation of blood flow exists in humans between cerebral circulation to sepsis) does not appear to be the cause of
pressures of 60 and 100 mm Hg.145 In the context of normal septic encephalopathy. Cerebral autoregulation remains intact during
physiology, blood flow is not effectively autoregulated outside this sepsis.180 The greater decrease in coronary than SVR during human
range. Without local adaptation, this would result in mismatching septic shock may suggest that myocardial autoregulation also remains
of blood flow and metabolic demands, producing organ failure intact despite the fact that, in contrast to the brain, myocardial
and the metabolic correlates of shock. However, extrinsic adaptive perfusion is often increased during septic shock.181,182
mechanisms to protect the most vital organs come into play. Animal models demonstrate that all other vascular beds
During hypovolemia and other hypodynamic forms of shock, (splanchnic, renal, skeletal, cutaneous) exhibit decreased vascular
extrinsic blood flow regulatory mechanisms overwhelm the auto- resistance, with flow in these beds becoming increasingly dependent
regulatory response of most vascular beds. Blood flow to the heart on CO. This suggests both an active vasodilatory process and
and brain are well preserved owing to dominant local autoregulation failure of extrinsic control of blood flow.145 Inappropriate levels

of splanchnic and skeletal muscle perfusion are also observed in The metabolic pathways involved in shock, like all cellular
humans during sepsis.183 Other experimental data suggest that pathways, involve multiple levels of feedback. Some pathways have
sepsis and septic shock are also associated with aberrant distribution positive feedback mechanisms, where an initial small signal results
of flow within organs.175 In sepsis, vasodilatation and autoregulatory in accelerating downstream effects, and negative feedback mecha-
failure of the microvasculature may be responsible for mismatches nisms, where downstream effects results in downregulation of
of oxygen delivery and results in anaerobic glycolysis with lactate upstream processes. Because cellular mechanisms from different
production despite increased mixed venous oxygen saturation. signal transduction pathways often share common elements, different
During both irreversible hemorrhagic shock and septic shock, pathways have positive and negative feedback effects on each other;
peripheral vascular failure results in worsened matching of tissue this is termed crosstalk.
demand and substrate supply leading to failure of all organs and In all forms of shock, the hemodynamic changes involved
death. The following are among the potential responsible eventually result in decreased oxygen delivery to target organs,
mechanisms: with resultant cellular ischemia. The degree to which this is
1. Tissue acidosis184 important in the development of organ damage and death in the
2. Catecholamine depletion and mediator-related vascular resistance different shock forms may vary, but it clearly is the major factor
to catecholamines185 in hypodynamic forms of shock, and it also plays a large role in
3. Release of vasodilating and vasoconstricting arachidonic acid the ultimate mortality of hyperdynamic, hypermetabolic shock.
metabolites186 In the stressed preshock phase, physiologic adaptive mechanisms
4. Decreased sympathetic tone as the result of altered central attempt to compensate and perfusion to vital organs is maintained.
nervous system (CNS) perfusion187 With the onset of shock, these mechanisms fail, and thus oxygen
5. Pathologic generation of NO by vascular smooth muscle cells39,188 delivery to tissues is not maintained. At the cellular level, a lack
In addition to vasomotor dysfunction, shock is associated with of oxygen prevents the mitochondrial citric acid cycle from function-
other microvascular pathology recently referred to as shock-induced ing and pyruvate accumulates (eFig. 22.9). The failure of aerobic
endotheliopathy.189,190 Prime among these is disruption of endothelial respiration requires shunting of pyruvate into the lactic acid pathway
cell barrier integrity. The endothelial layer is responsible for to recycle nicotinamide adenine dinucleotide (NAD) and allow
maintaining oncotic proteins (mostly albumin) within the circulatory glycolysis to continue. However, the loss of the aerobic citric acid
space. During shock capillary permeability is increased, resulting cycle results in a large decrease in adenosine triphosphate (ATP)
in loss of plasma proteins into the interstitium. Endothelial injury, production (net 2 molecules of ATP per molecule of glucose versus
through the action of neutrophil-generated free radicals191 and a theoretical net of 38 molecules of ATP per glucose molecule in
NO/peroxynitrite generation,192,193 may account for this phenom- the entire aerobic pathway). In addition, shunting to the lactic
enon. Release of vasoactive intermediaries such as histamine, acid pathway results in the accumulation of hydrogen ions. Thus
bradykinin, PAF, leukotrienes, and TNF-α appear to drive this loss of perfusion results in a rapid decrease in cellular energy stores,
pathologic process. Injury is initiated by leukocyte-endothelial cell with inadequate ATP regeneration rates. As ATP is the primary
interactions via adhesion molecules (integrins, selectins) that allow source of energy in the cell, energy-dependent cellular systems
emigration of neutrophils to the tissues. Blockade of such activity cease functioning. This includes energy-dependent enzymes,
or depletion of neutrophils attenuates tissue injury in animal models maintenance of transmembrane gradients including electrical
of shock.194 With the loss of plasma proteins, the plasma oncotic potential,197 mitochondrial function,198 carbohydrate metabolism,199
pressure drops, interstitial edema develops, and circulating volume and even the glycolysis pathway itself, which requires two ATP
falls. molecules to prime each glucose molecule at the entry point into
There is also evidence of intravascular hemagglutination of red the pathway. Some cell types are more sensitive than others to
blood cells, white blood cells, and platelets in almost all shock depletion of energy stores, such as in the liver and kidney, but
syndromes.175,189,195 This may be due to primary microvascular eventually all organs are affected.197,200–203 With the loss of energy-
clotting leading to microthrombi. Alternately, clotting may occur dependent cell maintenance functions, ultrastructural breakdown,
as a consequence of primary endothelial damage owing to circulating including mitochondria, occurs.204 Systemically, the combination
cytokines, free radicals produced by reperfusion and neutrophils, of worsening acidosis and loss of energy stores results in a positive
or complement activation.189 In any case, the result may be further feedback loop of worsening shock, organ failure, and eventual
endothelial cell injury, microvascular abnormalities, and inadequate death.
distribution of perfusion within tissues. Decreased deformability Ischemia is felt to play a minor role in early sepsis, with high
of erythrocytes caused by membrane free radical injury may also COs maintaining perfusion to more sensitive, higher energy-
play a role in microcirculatory alterations in hemorrhagic and consuming tissues, and that ATP levels remain normal in these
septic shock.196 tissues, with mitochondrial function preserved. Instead, early septic
organ dysfunction results from other causes.205–207 However, localized
areas of ischemia are not ruled out. Potentially, microthrombi may
Mechanisms of Cellular Injury in Shock result in small areas of decreased microcirculatory flow, resulting
in localized ischemia. Evidence to support a role for ischemia in
Although different forms of shock have their different precipitants, cellular dysfunction in sepsis includes oxygen supply–dependent
they do share common mechanisms of cellular dysfunction and oxygen consumption, washout of organic acids from ischemic areas
injury. Eventually, events at the cellular level result in organ dysfunc- in patients in septic shock receiving vasodilators, and elevated ATP
tion and death. The pathogenesis of the cellular dysfunction is a degradation products. In any case, the role of ischemia in septic
combination of the interrelated precipitants and consequences of shock remains a question. For example, alterations of liver and
shock, including (1) ischemia, (2) inflammation, and (3) free radical skeletal muscle transmembrane potential occur early in shock before
injury (eFig. 22.8). Genetic factors are also felt to play a role in the decrease in levels of high-energy phosphates and onset of
an individual’s susceptibility and response to shock. hypotension. Further, this membrane defect is not prevented by
298.e7
Mediators
Plasma membrane
Membrane ? Synthesis
receptor NOS Nucleus
NO Programmed Lysozome
Free radicals autolysis?
membrane
channel Ca2+
K+ Na+ cGMP
Na+Ca2+ pH
K+ cAMP
Ca2+
Mediators AC
GP Contractility
AR Proteolytic
ATP
Actin/myosin enzymes
(muscle fiber)
Mitochondria
Membrane injury
Mediators Ischemia Free radicals and loss of integrity
• eFig. 22.8 Mechanisms of cellular dysfunction and injury in shock. Cell injury is mediated by multiple
mechanisms during shock. Tissue ischemia may result in limitation of aerobic adenosine triphosphate
(ATP) generation. This results in further mitochondrial impairment owing to deficits of mitochondrial mem-
brane function, altered signal transduction including decreased muscle contractility (ATP is the precursor
of cyclic adenosine monophosphate [AMP]), impaired energy-dependent maintenance of transmembrane
potential and ion gradients, increased intracellular pH owing to anaerobic metabolism, and possible initia-
tion of autolytic mechanisms. Free radicals may result in broad injury to cellular membranes, resulting in
impaired maintenance of transmembrane potential and ion gradients, mitochondrial generation of ATP,
and activation of autolytic pathways involving DNA degradation and lysosomal rupture (apoptosis). Various
circulating mediators (including cytokines, kinins, eicosanoids, and complement components) may result
in mitochondrial dysfunction, signal transduction abnormalities, membrane protein channel alterations,
and possibly alterations of gene expression. Any of these may lead to cell death through metabolic failure
and lysosomal enzyme release. AC, adenylate cyclase; Ca2+, calcium ion; cAMP, cyclic adenosine mono-
phosphate; cGMP, cyclic guanosine monophosphate; GP, G proteins; K+, potassium; Na+, sodium ion;
NO, nitric oxide; NOS, nitric oxide synthetase; βAR, β-adrenergic receptor.
Anaerobic glycolysis Aerobic glycolysis of the inflammatory cascade—for example, in hemorrhagic shock
(Cytoplasm) (Mitochondria) with tissue trauma.211 Indeed, shock is associated with systemic
activation of the inflammatory cascade. The resulting cellular and
Glycogen Glucose Pyruvic acid O2
CO2 tissue dysfunction and hypermetabolic state contribute to organ
2ATP H2O dysfunction and failure. The inflammatory cascade in sepsis can
Citric 36ATP be roughly broken down into initiation, transduction, and release
acid of inflammatory mediators.
cycle
Lactate Initiation of the inflammatory cascade in sepsis is thought to
rely largely on the innate immune response.212–214 This ancient
immune pathway evolved to recognize nonself molecular signatures,
• eFig. 22.9 Aerobic and anaerobic glucose metabolism. Under anaerobic produced by pathogens including bacteria, yeast, and viruses, which
conditions, pyruvic acid cannot enter the citric acid cycle in the mitochon- have remained invariant over time. These signatures are called
dria (to optimally produce adenosine triphosphate [ATP]) and is shunted pathogen-associated molecular patterns (PAMPs), and they are
to lactate in the cytoplasm. This produces less high-energy phosphates recognized by a series of receptors known as pattern recognition
per mole of glucose metabolized. Hydrolysis of ATP molecules in an receptors (PRRs). In addition, signature host proteins can also be
anaerobic environment results in production of hydrogen ions that cannot released extracellularly in response to cellular damage, and these
be metabolized or cleared resulting in intracellular acidosis. ATP, Adenos- proteins, also called alarmins, are known as damage-associated
ine triphosphate; CO2, carbon dioxide; H2O, water; O2, oxygen. Adapted molecular patterns (DAMPs), and these too may be recognized
with permission.401
by PRRs. Thus both nonself PAMPs and self-expressed DAMPs
may lead to initiation of the inflammatory cascade via the PRRs.
Known PRRs include the following:
administration of membrane-permeable forms of high-energy 1. Toll-like receptors (TLRs)
phosphates such as ATP-magnesium chloride (MgCl2).208 2. C-type lectin receptors (CLRs)
Inflammation, on the other hand, is a major contributor to the 3. Nucleotide oligomerization domain (NOD)-like receptors
development of septic shock and its effects on cellular and organ (NLRs)
dysfunction.209,210 Other forms of shock also result in activation 4. Retinoic acid–inducible gene I–like receptors (RLRs)

The TLRs and CLRs, as transmembrane receptors, are presented NF-κB sits at the end of many of these cascades and plays a crucial
on the cell surface or within the lumens of endosomes or lyso- role in the regulation of expression of many of these factors.209,215,218
somes.209,214,215 Currently 10 families of TLRs have been identified NF-κB is present in an inactive form in the cytoplasm, in complex
in humans. Different TLR families on the cell surface recognize with repressor proteins.219 When the repressors, known as IκB
various bacterial lipoproteins, lipopolysaccharides, or flagellins, proteins, are phosphorylated and subsequently degraded, NF-κB
with sources that may be bacterial, viral, or protozoan. In contrast, is released and transported into the nucleus, where it can act on
those TLR families located in endosomal lumens recognize single- its target sequences. By being stored in inactive form in the
stranded RNA, double-stranded RNA, and modified oligodeoxy- cytoplasm, no new NF-κB need be expressed, allowing for rapid
nucleotide-DNA, which may be of viral or bacterial origin. response to the signals received by the PRRs. Inflammatory media-
Interestingly, different individual families of TLRs can form both tors under the control of NF-κB include cytokines such as TNF-α,
homodimers and heterodimers on the cell surface, increasing their IL-1β, and IL-6, enzymes involved in inflammation, such as
range of ligand recognition. Meanwhile, the CLRs are presented inducible NO synthase and others.209
on the cell surface, and as lectins, recognize polysaccharides present Inflammatory mediator effects on cellular metabolism are
in yeast and fungi, mycobacteria, and viruses. of prime importance in organ dysfunction owing to sepsis and
In contrast, the NLRs and RLRs are intracellular, and require septic shock. Circulating inflammatory mediators may also play
that their ligands be present in the cytoplasm of the cell.215 NLRs a substantial role in other forms of shock, including hemorrhagic
recognize bacterial peptidoglycans; the RLR ligands consist primarily shock associated with extensive tissue trauma.220,221 Both sepsis and
of double-stranded RNA, cytoplasmically produced either by dsRNA trauma are associated with generalized, systemic activation of the
viruses or as an intermediate step in the replication of single-stranded inflammatory response. Resulting cell injury and hypermetabolism
RNA viruses. may culminate in organ failure. A number of triggers can result
Once initiated by recognition of PAMPs or DAMPs, the inflam- in activation of the inflammatory cascade. The best studied is
matory cascade involves a large number of protein, kinase, and endotoxin from gram-negative bacteria, but other bacterial antigens
second-messenger cascades. These cascades can lead to activation and cell injury itself can also initiate the cascade. Macrophage
of transcription factors or to posttranscriptional or posttranslational production of cytokines such as TNF-α, IL-1β, and IL-6 appears to
activation of inflammatory mediators. be central.
The TLRs have been shown to use two primary pathways.215 All TNF-α is a 51-kD trimeric peptide produced by macrophages
the TLRs, with the exception of TLR3, use a pathway dependent in response to a variety of inflammatory stimuli, including bacterial
on the myeloid differentiation adaptor protein (MyD88), which antigens and other cytokines. Circulating levels of TNF-α are
binds to the intracellular sections of the TLRs; for some of the transiently elevated soon after the onset of shock (particularly
TLRs, another adaptor protein is required to bind MyD88. Upon septic shock).222 Administration of TNF-α to animals or humans
activation of the TLR, MyD88 recruits a serine/threonine kinase, results in a hyperdynamic circulatory state (± dose-dependent
IRAK-4 (IL-1 receptor–associated kinase 4), in turn recruiting further hypotension) similar to untreated sepsis and septic shock.111
kinases such as IRAK-1 and IRAK-2. Ultimately, the cytoplasmic Although clinical trials to date have yielded disappointing results,
cascade results in phosphorylation and degradation of IκB, an anti–TNF-α strategies protect animals from experimental endotoxic
inhibitor of the transcription factor nuclear factor κ light-chain and septic shock.223 Among the many effects of TNF-α are release
enhancer of activated B cells (NF-κB). This allows NF-κB to enter of IL-1β, IL-6, IL-8, PAF, leukotrienes, thromboxanes, and
the nucleus, resulting in the activation of transcription of a suite of prostaglandins; stimulation of production and activity of poly-
inflammatory mediators and modulators. In contrast, TLR3 uses a morphonuclear leukocytes; promotion of immune cell adhesion
pathway dependent on the TRIF adaptor protein, which also to endothelium; activation of coagulation and complement systems;
ultimately results in NF-κB activation. In both pathways, other direct endothelial cell cytotoxicity; depression of myocardial
adaptor proteins may be required for individual TLRs to activate contractility; and fever production by the hypothalamus.111,224
these cascades; for example, TLR4 can also use the TRIF-dependent Notably, TNF-α causes alterations of skeletal transmembrane
pathway but is dependent on the TRAM adaptor protein to do this. electrical potential similar to those described in hemorrhagic and
Different cell types may express different adaptor proteins, resulting septic shock.225 These membrane effects precede hemodynamic
in intertissue variation in the cascades. In addition, protein inhibitors alterations, suggesting that TNF-α exerts a primary effect on cell
of the cascades can be expressed variably in different cell types. metabolism independent of perfusion alterations. Although TNF-α
In contrast, the NLRs act via formation of a multiprotein appears to be of central importance in the pathogenesis of septic
complex, termed the inflammasome.209,215,216 The caspases,217 a family shock, it is also known to be elevated in CHF226 and hemorrhagic
of cysteine proteases, are central to this cascade. Upon activation, shock.220
the NLR recruits a pro-caspase, along with an adaptor protein Other substances involved in the inflammatory process include
ASC, which recruits a second pro-caspase. This complex allows the following:
the pro-caspase pair to autoactivate, resulting in active caspase. IL-1β, which can potentiate the in vivo effects of TNF-α
The best studied of these is caspase-1, although other caspases may IL-2, which can cause hemodynamic abnormalities in humans
be involved. Once activated, caspase-1 in turn activates the inflam- IL-6, which is involved in the acute-phase response and has recently
matory cytokine IL-1β, allowing its release from the cell. Similarly, been implicated in septic myocardial depression
caspase-1 is also responsible for the activation and release of other Interferon (INF)-γ, which promotes the release of other cytokines,
cytokines, including IL-18. In this way, the NLR’s prime function enhances adhesion of immune cells, and promotes macrophage
is to regulate inflammatory mediator release through a posttransla- activation
tion system. Crosstalk from the TLR cascades may also activate IL-10, which is an antiinflammatory cytokine that limits macrophage
some NLRs and result in inflammasome formation. generation of proinflammatory cytokines;
At the center of these cascades is transcriptional regulation of TGF-β, which is another antiinflammatory cytokine that, in
inflammatory cytokines and mediators. The transcription factor addition to limiting macrophage proinflammatory responses,
298.e9
also blocks the effects of proinflammatory cytokines on target may, in part, explain irreversible vascular collapse seen late in
cells hemorrhagic shock.39 A potential role for NO in inflammation-
Endothelin-1, a cytokine which strongly promotes vasoconstriction, associated edema and third-spacing during shock has also been
particularly in the renal vascular bed, possibly resulting in renal suggested.192 The in vitro myocardial depressant effects of TNF-α,
hypoperfusion and decreased glomerular filtration rate IL-1β, and serum from septic humans may be mediated by a
PAF, which stimulates TNF-α, thromboxane, and leukotriene similar NO- and cGMP-dependent pathway.111,238
release; stimulates free radical formation; and alters microvascular An alternative pathway by which NO may play a role in the
permeability cardiovascular pathophysiology of shock and sepsis was described
Leukotrienes, which release other arachidonic acid metabolites, by Beckman and colleagues in 1990.245 Peroxynitrite (ONOO−),
alter vascular endothelial permeability, and may mediate vascular a highly reactive oxidant, is produced from the interaction of
and myocardial depression in shock superoxide (OH−) and NO (NO−). It is known to react rapidly
Thromboxanes, which may contribute to altered microvascular with proteins, lipids, and DNA during sepsis and shock states.246–249
vasomotor and permeability function Lipids may be peroxidized and although proteins may be oxidized,
Prostaglandins, which produce fever, induce vasodilatation, and nitrated, or nitrosated, the last resulting in nitrotyrosine resi-
inhibit thrombus formation dues.245,250,251 Peroxynitrite inactivates mitochondrial aconitase
Complement fragments C3a and C5a, which constrict vascular smooth disrupting the Kreb cycle and otherwise interferes with ATP produc-
muscle, release histamine, and promote chemotaxis.115,227,228 tion and utilization,252–257 an activity similar to that described for
Several newly recognized mediators/mediator groups have been NO.258–260 It also generates DNA strand breaks, leading to poly-
shown to have important roles in shock, particularly septic shock. adenosine diphosphate (ADP) ribose synthetase activation that
These include high-mobility group 1 protein (HMG-1), myocardial may itself have significant pathophysiologic effects.261,262 Peroxyni-
depressant substances, and NO/peroxynitrites. HMG-1 appears trite, like NO, also activates guanylate cyclase in vascular tissues.263,264
to have a key role in the late pathogenesis of sepsis229,230 and may In the periphery, the result may be cellular energetic failure, vascular
also have a role in traumatic/hemorrhagic shock.224,231,232 HMG-1 contractile dysfunction (vasodilation), and reperfusion injury.261,265–267
is a late mediator of inflammation. Mice show increased levels of Many other molecular targets of NO relevant to the cardiovascular
HMG-1 in serum 8 to 32 hours after endotoxin administration. system exist and are well reviewed elsewhere.250,268
Patients succumbing to septic shock also demonstrate increased It is of note that as part of the release of inflammatory mediators,
serum HMG-1 levels.229 Administration of HMG-1 to normal immune cells, including macrophages, polymorphonuclear leuko-
and endotoxin-resistant mice induces dose-dependent mortality cytes, and lymphocytes, may also be activated in some forms of
with signs consistent with endotoxic shock.229,230 Several anti– hypodynamic shock (e.g., hemorrhagic shock), resulting in a
HMG-1 therapies are in development.232 self-perpetuating, systemic inflammatory response (similar to that
A circulating myocardial-depressant substance is present in the seen in sepsis). This response can contribute to vascular and
blood of patients with septic shock who exhibit myocardial depres- parenchymal injury and culminate in MODS.
sion with biventricular dilatation and reduced ventricular ejection Free radical injury induced by reperfusion or neutrophil activity
fractions.233 Similar substances have been shown to be present in is another mechanism of organ injury during hemorrhagic and
animal models of hemorrhagic shock.234 Other data suggest canine septic shock as well as burns and MI.269 During tissue ischemia,
MI235 and human cardiogenic shock236 may also be associated with oxygen deficiency leads to accumulation of ATP degradation
a circulating myocardial-depressant substances. Serum from products, including adenosine, inosine, and hypoxanthine (eFig.
appropriate septic patients or animal models depresses myocardial 22.10).270 With resuscitation and reperfusion of ischemic areas,
tissue in vitro.144,233 Myocardial depressant substances from both oxygen drives the generation of superoxide (O2−), the most common
septic and hemorrhagic shock appear to be dependent on calcium.237 precursor of reactive oxidants, by xanthine oxidase in endothelial
The substance implicated in human sepsis may represents a syn- cells. Most of the superoxide is converted, either spontaneously
ergistic combination of TNF-α and IL-1β that produce depression or through superoxide dismutase to hydrogen peroxide (H2O2−).
by inducing myocardial NO production.233,238,239 TNF-α and IL-1β This further reacts to produce tissue-damaging hydroxyl radicals
are both elevated in shock and cause similar depression of myocardial (or other highly reactive free radicals).269 These radicals interact
tissue.238,240 Other data suggest that IL-6 may have a central with critical cell targets, such as the plasma membrane, lipid
role.115,227,241 membranes of organelles, and various enzymes, resulting in cell
Another important mediator, NO, has a vital role in normal lysis and tissue injury. Oxidant activity, directly and through
intracellular signal transduction.242 Of particular importance to endothelial damage, attracts and activates neutrophils, resulting
shock, NO is the mediator through which endothelial cells normally in amplification of superoxide generation by a neutrophil dihy-
cause relaxation of adjacent smooth muscle.242 Endothelial cells, dronicotinamide adenine dinucleotide phosphate (NADPH)-oxidase
through a constitutive NO synthetase, produce picomolar quantities and in further tissue damage owing to neutrophil protease release.269
of NO in response to a number of vasodilatory mediators such as Injured tissue may release xanthine oxidase into the circulation
acetylcholine and bradykinin. This NO diffuses to adjacent smooth resulting in systemic microvascular injury.271
muscle and activates guanylate cyclase to produce cGMP, which A parallel process is found during reperfusion of ischemic
affects vascular relaxation. Nitrovasodilators bypass NO synthetase myocardium after MI.272 Thrombolytic therapy or balloon angioplasty
to relax smooth muscle directly though the guanylate cyclase results in sudden delivery of oxygen to ischemic myocardium.
pathway. During septic shock, an inducible NO synthetase capable Although substantial salvage of myocardial function results, free
of producing nanomolar quantities of NO is generated in vascular oxygen radical–mediated reperfusion injury can contribute to
smooth muscle.242,243 Studies have also implicated NO in late myocardial “stunning.”273 Cardiogenic shock during this phase may
vascular dysfunction seen in hemorrhagic shock.39 NO-mediated resolve as the reperfusion injury settles. Free radical damage likely
generation of cGMP may explain the profound loss of arterial also plays a role in tissue damage during sepsis and septic shock.
vascular tone and venodilatation seen in septic shock243,244 and After activation by inflammatory mediators and during phagocytosis,

ATP
ADP
AMP
Ischemia
Adenosine
Inosine
XO XO
Hypoxanthine Xanthine Uric acid
Reperfusion
O2 O2–• SOD H2O2

Catalase
H2O
OH• Tissue injury

NADPH
2° Radicals
oxidase
Neutrophil Tissue
chemotaxis proteases
Tissue
neutrophils
• eFig. 22.10 Free radical–mediated tissue injury. Superoxide (O2−) is primarily produced in shock from

hypoxanthine (a metabolite of adenosine triphosphate [ATP] degradation) by xanthine oxidase (XO) during
reperfusion after ischemia. Superoxide can be converted to hydrogen peroxide (H2O2) by superoxide
dismutase (SOD) and then to water (H2O) or may be converted to the highly reactive hydroxyl (OH−) that
mediates tissue injury. Free radical tissue injury may be amplified by superoxide recruitment of neutrophils
that secondarily produce additional superoxide through NADPH oxidase. 2°, Second degree; NADPH,
reduced nicotinamide adenine dinucleotide phosphate. (Adapted with permission from Girardin E, Grau
GE, Dayer JM, et al. Plasma tumor necrosis factor and interleukin-1 in the serum of children with severe
infectious purpura. N Engl J Med. 1989;319:397–400.)
polymorphonuclear leukocytes undergo a respiratory burst during receptor antagonist gene polymorphism has been linked to increased
which they consume oxygen and generate both superoxide and susceptibility to sepsis.279 Several additional linked polymorphisms
hydrogen peroxide through a membrane-associated NADPH- have been described in recent years. 280 It appears likely that
oxidase.269 Macrophages similarly produce oxygen radicals upon gene polymorphisms may also play similar roles in other forms of
activation. Activation also enhances adhesion and tissue migration shock.
of leukocytes so that both vascular endothelial and parenchymal Beyond the role of gene alleles in the development and clinical
tissue damage may result. Free radical injury may play an important response to shock, the progression of irreversible circulatory shock
role in the development of organ failure after shock.274 and MODS may have its basis in genetically driven vascular or
Variations in stress response genes between individuals and parenchymal responses. Production of cytokines by macrophages
alteration of gene expression in immune, endothelial, muscle, and during shock requires acute expression of the genes coding for
organ parenchymal cells are other important aspects of cellular TNF-α, IL-1β, and other proinflammatory cytokines. The produc-
dysfunction/injury in circulatory shock. Although shock can be tion of adhesion molecules by endothelial cells and inducible NO
present immediately after injury (massive trauma, hemorrhage, or synthetase by vascular smooth muscle during shock requires active
endotoxin infusion) before the onset of substantial alterations of upregulation of gene expression. Both events are thought to be
gene expression, its evolution is dependent on a combination of key to the development of MODS after shock in humans. In
the ongoing nature of the insult, the genetically passive compensa- addition, human and animal research indicate that apoptosis, a
tory physiologic/metabolic response, the underlying genotype with genetically programmed process of cell autolysis, occurs in a variety
respect to stress response elements, and stress-related modulation of organs during shock and subsequent organ failure.281,282 Recent
of gene expression in a variety of cells. data suggest that a variety of transcription factors may be activated
The clinical presentation of shock, progression of the syndrome, in models of sepsis in association with the process.283 Further
and final outcome may be substantially controlled by genetic research should elucidate the important link between irreversible/
factors.275 Genetic factors have been best studied in septic shock. refractory shock/shock-associated MODS and genetically pro-
Studies have demonstrated that the human TNF-α promoter grammed cell responses to inflammatory stimulation and/or
polymorphism, TNF-2, imparts an increased susceptibility to and injury.
mortality from septic shock.276 Other studies suggest increased Whatever the initiating event or events, progressive cell metabolic
TNF-α generation, severity of sepsis, and mortality with another failure occurs. Mitochondrial activity continues to deteriorate,
human TNF-α gene polymorphism.277 A specific locus on chromo- subcellular organelles are damaged, and intracellular (and possibly,
some 12 in mice has been shown to be associated with resistance systemic) release of lysosome hydrolytic enzymes occurs, accelerating
to mortality owing to TNF-α–induced shock.278 A human IL-1β cell death and organ failure.
However, once MAP falls below about 80 to 90 mm Hg, aortic • BOX 22.3 Cardiovascular/Metabolic Compensatory
baroreceptor activity is absent. Subsequently, carotid baroreceptor Responses to Shock
response is eliminated as mean pressure falls below 60 mm Hg.
As blood pressure falls further, carotid and aortic chemoreceptors, 1. Maintain mean circulatory pressure (venous pressure)
sensitive to decreased partial pressure of oxygen (PO2), increased Volume
partial pressure of arterial carbon dioxide (PCO2), and increased Fluid redistribution to vascular space (increased total vascular volume)
H+ concentrations (decreased pH), dominate the response. These from interstitium (Starling effect) from intracellular space (osmotic)
receptor complexes, active only when mean blood pressure is less Decreased renal fluid losses
Decreased glomerular filtration rate
than approximately 80 mm Hg, are of minimal relevance during
Increased aldosterone
physiologic states.144 During shock, they make a substantial contribu- Increased vasopressin
tion to increases of sympathetic tone. Pressure
During severe shock, the most powerful stimulus to sympathetic Decreased venous capacitance (increased stressed volume) increased
tone is the CNS ischemic response.144 The lower medullary che- sympathetic activity
moreceptors for this response (thought to be sensitive to increased Increased circulating (adrenal) epinephrine
CO2 associated with decreased cerebral perfusion) become active Increased angiotensin
when mean blood pressure falls below 60 mm Hg. Sympathetic Increased vasopressin
stimulation provided by these receptors peaks at mean pressures 2. Maximize cardiac performance
of 15 to 20 mm Hg and results in maximal stimulation of the Increase contractility
Sympathetic stimulation
cardiovascular system.144 The Cushing response to increased intra-
Adrenal stimulation
cranial pressure is an example of activation of this reflex under 3. Redistribute perfusion
different circumstances. Extrinsic regulation of systemic arterial tone
Other mechanisms also play a role in the compensatory response Dominant autoregulation of vital organs (heart, brain)
to shock. Vasopressin release is regulated by alterations of serum 4. Optimize oxygen unloading
osmolality. During effective hypovolemia owing to intravascular Increased RBC 2,3-DPG
volume loss or increased vascular capacitance, low-pressure, right Tissue acidosis
atrial stretch receptors can override osmolar control of vasopressin Pyrexia
response to effect retention of body water.144,287 Similarly, during Decreased tissue PO2
hypovolemia and shock, the juxtaglomerular apparatus in the 2,3-DPG, 2,3-Diphosphoglycerate; PO2, partial pressure of oxygen.
kidneys respond to decreased perfusion pressure by renin release.144
All compensatory responses to shock, whether hemodynamic,
metabolic or biochemical, support oxygen delivery to vital organs.
These responses are similar (to varying extents) for different classes
of shock and can be broken down into four components: (1) angiotensin II), which increases sodium reabsorption in the distal
maintenance of mean circulatory pressure (a measure of venous tubules of the kidney in exchange for potassium or hydrogen ion.144
pressure) by either maintaining total intravascular volume, or Angiotensin II also exerts a powerful direct vasoconstricting effect
increasing stressed volume (i.e., increasing venous tone); (2) (particularly on mesenteric vessels) while increasing sympathetic
optimizing cardiac performance; (3) redistributing perfusion to outflow and adrenal epinephrine release.290 As noted, vasopressin
vital organs; and (4) optimizing unloading of oxygen at the tissues (antidiuretic hormone) release occurs through activation of right
(Box 22.3, see eFig. 22.3). atrial low pressure. Angiotensin II augments this release by increasing
Mean circulatory pressure (and venous return) are sustained in sympathetic outflow. The release of vasopressin from the posterior
early shock by a number of mechanisms. Acutely, total intravascular pituitary results in water retention at the expense of osmolarity.
volume is supported by alterations of capillary hydrostatic pressure Hyponatremia can result. Vasopressin, like angiotensin II, also
as described by Starling.288 Sympathetic activation results in precapil- results in vasoconstriction, particularly of the splanchnic
lary vasoconstriction. In combination with initial hypotension, circulation.290
this results in decreased capillary hydrostatic pressure.288 A decrease Finally, increased sympathetic activity and release of adrenal
in capillary hydrostatic pressure enhances intravascular fluid shift epinephrine results in systemic venoconstriction, particularly of
owing to maintained plasma oncotic pressures. Transcapillary fluid the venous capacitance vessels of the splanchnic circulation. This
influx after removal of 500 to 1000 mL blood volumes in humans supports mean circulatory pressure and venous return by increasing
can be as high as 2 mL/min with full correction of intravascular stressed volume.
volume by 24 to 48 hours.289 The intravascular volume may also Increased sympathetic nervous system activity accounts for most
be supported by the osmotic activity of glucose generated by of the enhancement of cardiac performance during shock. Local
glycogenolysis. Increased extracellular osmolarity results in fluid release of norepinephrine by sympathetic nerves and systemic release
redistribution from the intracellular to the extracellular space. of epinephrine result in stimulation of cardiac α- and β-adrenergic
Intravascular volume is also conserved by decreasing renal fluid receptors, resulting in increases of HR and contractility that optimize
losses. Renal compensatory mechanisms are of limited value in CO and support blood pressure. Angiotensin II may also exert
acute shock but can have more impact in the subacute phase. direct as well as indirect (sympathetic stimulation) inotropic effects
Decreased renal perfusion associated with reduced CO and afferent on myocardium. Improved cardiac function also results in decreased
arteriolar constriction results in a fall in glomerular filtration rate right atrial pressure, which tends to increase venous return.
and urine output. In addition, decreased renal perfusion pressure, Redistribution of blood flow during shock has already been
sympathetic stimulation, and compositional changes in tubular discussed. Increased sympathetic vasoconstrictor tone, systemic
fluid144 result in renin release from the juxtaglomerular apparatus. release of epinephrine from the adrenals, vasopressin, endothelin,
Renin release leads to adrenal cortical release of aldosterone (via and angiotensin II cause vasoconstriction in all sensitive vascular
beds, including skin, skeletal muscle, kidneys, and splanchnic TABLE

organs.145 Dominant autoregulatory control of blood flow spares 22.3 Organ System Dysfunction in Shock
brain and heart blood work from these effects. Redistribution of
flow to these vital organs is the effective result. Central nervous Encephalopathy (ischemic or septic)
The effects of decreased delivery of oxygen to the tissues during system Cortical necrosis
shock can be attenuated by local adaptive responses. Hypoperfusion Heart Tachycardia, bradycardia
and tissue ischemia result in local acidosis as the result of decreased Supraventricular tachycardia
clearance of CO2 and anaerobic metabolism. Local acidosis results Ventricular ectopy
in decreased affinity between oxygen and hemoglobin at the capillary Myocardial ischemia
level.144 The resultant rightward shift of the oxyhemoglobin dis- Myocardial depression
sociation curve allows greater unloading of oxygen from hemoglobin Pulmonary system Acute respiratory failure
for a given PO2. Tissue ischemia is also accompanied by decreased Acute respiratory distress syndrome
tissue PO2 (relative to normal), which further augments unloading
of oxygen. Pyrexia associated with sepsis may also contribute to a Kidney Prerenal failure
rightward shift of the oxyhemoglobin dissociation curve, whereas Acute tubular necrosis
hypothermia is associated with a leftward shift. For that reason, Gastrointestinal Ileus
maintenance of normothermia during resuscitation from shock is system Erosive gastritis
helpful in optimizing oxygen unloading. Pancreatitis
Acalculous cholecystitis
Colonic submucosal hemorrhage
Organ System Dysfunction Owing Transluminal translocation of bacteria/antigens
to Shock (Table 22.3) Liver Ischemic hepatitis
“Shock” liver
Central Nervous System Intrahepatic cholestasis
CNS neurons are extremely sensitive to ischemia. Fortunately, the Hematologic Disseminated intravascular coagulation
CNS vascular supply is highly resistant to extrinsic regulatory system Dilutional thrombocytopenia
mechanisms. Although cerebral perfusion is clearly impaired in
shock, flow remains relatively well preserved until the later Metabolic Hyperglycemia
Glycogenolysis
stages.291,292 Absent primary cerebrovascular impairment, cerebral
Gluconeogenesis
function is well supported until MAP fall below approximately Hypoglycemia (late)
50 and 60 mm Hg.293 Eventually, irreversible ischemic injury may Hypertriglyceridemia
occur to the most sensitive areas of the brain (cerebral cortex).
Before this fixed injury, an altered level of consciousness, varying Immune system Gut barrier function depression
from confusion to unconsciousness, may be seen depending on Cellular immune depression
Humoral immune depression
the degree of perfusion deficit. Disturbances of acid/base/electrolytes
may also contribute. Electroencephalographic recordings demon-
strate nonspecific changes compatible with encephalopathy.
Sepsis-related encephalopathy may occur at higher blood pressures
(owing in part to the effects of circulating inflammatory mediators)
and is associated with increased mortality.294 ischemia. Further, circulating myocardial-depressant substances
contribute to myocardial depression in septic233 and hemorrhagic234
Heart shock. This has been linked to decreased β-adrenoreceptor affinity
The major clinically apparent manifestations of shock on the heart and density as well as potential defects of intracellular signal
are due to sympathoadrenal stimulation. Increased HR, in the transduction involving NO, G proteins, cyclic adenosine mono-
absence of disturbances of cardiac conduction, is almost universally phosphate (cAMP), and cGMP.111 Circulating depressant substances
present. Vagally mediated paradoxical bradycardia may be seen on may also be present during cardiogenic shock.236
occasion in severe hemorrhage.41 In patients predisposed to
myocardial ischemia or irritability, catecholamine-driven supra- Respiratory System
ventricular tachycardias and ventricular ectopy with ischemic Early alterations of pulmonary function seen during acute circulatory
electrocardiographic (ECG) changes are not common. Like the shock are primary related to changes in central drive or muscle
brain, the blood supply to the heart is autoregulated. This, in fatigue. Increased minute volume occurs as a result of augmented
combination with the resilient nature of myocardial tissue, renders respiratory drive owing to peripheral stimulation of pulmonary J
it resistant to sympathetically driven vasoconstriction and shock- receptors and carotid body chemoreceptors as well as hypoperfusion
related hypoperfusion injury. Overt necrosis does not typically of the medullary respiratory center. This results in hypocapnia and
occur, although evidence of cellular injury may be present. primary respiratory alkalosis.144,295 With increased minute volume
Most forms of shock are associated with increased contractility and decreased CO, the ventilation-perfusion (V̇ /Q̇ ) ratio is increased.
of healthy myocardium. Despite this, shock can have substantial Unless arterial hypoxemia complicates shock, pulmonary resistance
impact on myocardial contractility and compliance. Hypotension is initially unchanged or minimally increased. Coupled with an
during cardiogenic (and other forms of shock) is associated with increased workload, respiratory and diaphragmatic muscle impair-
decreased coronary artery perfusion pressure. In patients with ment related to hypoperfusion (manifested by decreased trans-
coronary artery disease (CAD) and/or increased filling pressures, membrane electrical potential) may lead to early respiratory failure.296
decreased coronary artery perfusion pressure may lead to overt ARDS owing to inflammatory or free radical injury to the
alveocapillary cell layers after established shock may develop as a case, early increases in bilirubin and alkaline phosphatase are modest.
late cause of respiratory failure. Despite the production of acute-phase reactants in early circulatory
shock, synthetic functions may be impaired with decreased genera-
Kidney tion of prealbumin, albumin, and hepatic coagulation factors. After
ARF is a major complication of circulatory shock with associated hemodynamic resolution of shock, evidence of biliary stasis with
mortality rates between 35% and 80%.297 Although initial injury increased bilirubin and alkaline phosphatase can develop even
manifested by decreased urine output occurs, other clinical mani- though the patient is otherwise improving. Postshock MODS
festations of renal dysfunction (increased creatinine, urea, and involves similar hepatic pathology.
potassium) may not be noted for 1 to 3 days. Once hemodynamic
stabilization has been achieved, it becomes apparent that urine Hematologic System
output does not immediately improve and both serum creatinine Hemotologic manifestations of circulatory shock tend to be
and urea continue to rise. The single most common cause of ARF dependent on the nature of shock. Disseminated intravascular
is renal hypoperfusion resulting in ATN. The most frequent cause coagulation (DIC), characterized by microangiopathic hemolysis,
of renal hypoperfusion is hemodynamic compromise from septic consumptive thrombocytopenia, consumptive coagulopathy, and
shock, hemorrhage, hypovolemia, trauma, and major operative microthrombi with tissue injury, is most commonly seen in associa-
procedures. ATN that occurs in the setting of circulatory shock tion with septic shock. Because it is due to simultaneous systemic
is associated with a higher mortality than in other situations. activation of coagulation and fibrinolysis cascades, it can be dif-
Part of the reason for the kidney’s sensitivity to hypoperfusion ferentiated from the coagulopathy of liver failure by determination
relates to the nature of its vascular supply. The renal vascular bed of endothelial cell–produced factor 8 (normal or increased with
is moderately autoregulated. Increases of efferent arteriolar tone hepatic dysfunction). In the absence of extensive tissue injury/
can initially maintain glomerular perfusion despite compromise trauma, hemorrhagic shock is rarely associated with DIC.304
of renal flow.298 Renal hypoperfusion does not become critical Dilutional thrombocytopenia is the most common cause of coagula-
until relatively late in shock when maximal vasoconstriction of tion deficits after resuscitation for hemorrhage.305
renal preglomerular arterioles298 results in cortical, then medullary,
ischemic injury. Metabolic Alterations
Decreased urine output in shock can pose a diagnostic dilemma Metabolic alterations associated with shock occur in a predictable
because it can be associated with both oliguric ATN and pattern. Early in shock, when hemodynamic instability triggers
hypoperfusion-related prerenal failure without ATN. Indices sug- compensatory responses, sympathoadrenal activity is enhanced.
gestive of the latter include a benign urine sediment; urine sodium Increased release of adrenocorticotropic hormone, glucocorticoids,
concentration less than 20 mEq/L; fractional urine sodium excretion and glucagon and decreased release of insulin results in glycogenolysis,
less than 1%; urine osmolality greater than 450 mOsm/L; and gluconeogenesis, and hyperglycemia.287,306 Increased release of
urine/plasma creatinine ratio greater than 40. Useful markers of epinephrine results in skeletal muscle insulin resistance, sparing
ARF owing to ATN include hematuria and heme granular casts; glucose for use by glucose dependent organs (heart and brain).
urine sodium concentration to more than 40 mEq/mL; fractional Late in shock, hypoglycemia may develop, possibly owing to
excretion of urine sodium to more than 2%; urine osmolarity less glycogen depletion or failure of hepatic glucose synthesis. Fatty
than 350 mOsm/L; and urine:plasma creatinine ratio less than acids are increased early in shock but fall later as hypoperfusion
20.299 Of note, ATN caused by circulatory shock may be associated of adipose-containing peripheral tissue progresses. Hypertriglyc-
with urine sodium less than 20 mEq/L and fractional excretion eridemia is often seen during shock as a consequence of catecholamine
less than 1% if the acute renal injury is superimposed on chronic stimulation and reduced lipoprotein lipase expression induced by
effective volume depletion as may be seen with cirrhosis and CHF.300 circulating TNFα.306 Increased catecholamines, glucocorticoids,
and glucagon also increase protein catabolism resulting in a negative
Gastrointestinal System nitrogen balance.306
The gut is relatively sensitive to circulatory failure. The splanchnic
vasculature is highly responsive to sympathetic vasoconstriction. Immune System
Typical clinical gut manifestations of hypoperfusion, sympathetic Immune dysfunction, frequent during and after circulatory shock
stimulation, and inflammatory injury associated with shock include and trauma, rarely has immediate adverse effects but likely con-
ileus, erosive gastritis, pancreatitis, acalculous cholecystitis, and tributes to late mortality. Underlying mechanisms of immune
colonic submucosal hemorrhage. Enteric ischemia produced by dysfunction that induce dysfunction of the cellular and humoral
circulatory shock and free radical injury with resuscitation may immune system include ischemic injury to barrier mucosa (par-
breach gut barrier integrity with translocation of enteric bacteria ticularly of the gut), leading to anatomical breaches (colonic
and antigens (notably endotoxin) from the gut lumen to the systemic ulceration) and potential mucosal translocation of bacteria and
circulation, resulting in propogation and amplification of shock bacterial products; parenchymal tissue injury owing to associated
and MODS.301,302 trauma, inflammation, ischemia or free radical injury; and direct
ischemic or mediator (immunosuppressant cytokines, corticosteroids,
Liver prostaglandins, catecholamines, endorphins).307,308 In particular,
Like the gut, the liver is highly sensitive to hypotension and macrophage function is adversely affected during trauma and circula-
hypoperfusion injury. “Shock liver,” associated with massive ischemic tory shock. A decrease in antigen presenting ability impairs the
necrosis and major elevations of transaminases, is atypical in the activation of T and B lymphocytes. Associated with this defect are
absence of extensive hepatocellular disease on very severe insult.303 a decrease in Ia antigen expression, decrease in membrane IL-1β
Centrilobular injury with mild increases of transaminases and lactate receptors, and the presence of suppressor T lymphocytes. Phagocytic
dehydrogenase is more typical. Transaminases usually peak within activity of the reticuloendothelial system is also compromised,
1 to 3 days of the insult and resolve over 3 to 10 days. In either partially because of an acute decrease in fibronectin levels.
Suppression of T-lymphocyte immune function is manifested by • BOX 22.4 General Approach to Shock: Initial
decreased responsiveness to antigenic stimulation and a decreased Diagnosis and Evaluation
helper:suppressor ratio. Decreased production of IgG and IgM
suggests B-cell suppression. Nonspecific immune suppression is Clinical (primary diagnosis)
expressed as decreased neutrophil bactericidal function, chemotaxis, Tachycardia, hypotension (systolic blood pressure <90 mm Hg) tachypnea,
opsonization, and phagocytosis. oliguria, encephalopathy (confusion), peripheral hypoperfusion (mottled
Resuscitation agents used in shock may also substantially depress extremities), cyanosis
immune function. For example, red blood cell transfusion used Laboratory (confirmatory)
Hemoglobin, WBC, platelets
in traumatic hemorrhagic shock and in support of oxygen transport
Prothrombin time/partial thromboplastin time
in septic shock309 has been shown to suppress immune function, Electrolytes, arterial blood gases, Ca, Mg, BUN, creatinine, serum lactate
leading to increased infections (and improved allograft survival).310,311 ECG
Similarly, dopamine, used for hemodynamic support in shock, has Monitoring (continuous ECG and respiratory monitors)
been shown to suppress pituitary production of prolactin (required Pulse oximetry
for optimal immune function), resulting in suppression of T-cell Urinary catheter (urine output)
proliferative responses.312 Thus dopamine may contribute, along Point-of-care ultrasonography (heart, lung, abdominal, and major vessels)
with stress-induced increases in immunosuppressive glucocorticoids, Arterial pressure catheter
to T-cell anergy seen in critically ill patients. Central venous pressure monitor (uncomplicated shock)
These factors may contribute to the propensity of critically ill Pulmonary artery flotation catheter
Cardiac output
patients to develop ongoing organ system dysfunction as well as
Pulmonary artery occlusion pressure
a variety of infections during the postshock phase. It is notable Central and/or mixed venous oxygen saturation (intermittent or
that one-third to one-half of patients with shock die late in their continuous)
course after resolution of the acute-shock phase. Oximetrya
Imaging (chest x-ray)
Diagnostic Approach and Evaluation X-ray views of abdomena
Computed tomographic scan: abdomen or chesta
Shock is always a life-threatening emergency. Diagnosis, evaluation, Formal transthoracic and/or transesophageal echocardiograma
and management must often occur virtually simultaneously. The a
Optional.
diagnosis must be made as early as possible while shock is well BUN, Blood urea nitrogen; Ca, calcium; ECG, electrocardiogram; Mg, magnesium; WBC, white
compensated. Once marked hypotension and hypoperfusion are blood cell.
present, mortality is increased. Because early recognition and
treatment are key to survival, the diagnosis is primarily a clinical
one. Laboratory and imaging studies are useful for confirmation
of the diagnosis and determination of the specific shock etiology.
Elevated lactate might help identify patients for whom the diagnosis shock may evidence elevated jugular venous pressure with hepa-
of shock is not obvious clinically. However, therapy of shock should tojugular reflux, an S3, an S4, and regurgitant heart murmurs.
never be delayed to accommodate these studies. The initial diagnosis Obstructive shock signs are usually dependent on the nature of
of shock can and should be made strictly on clinical signs and the obstruction. Pulmonary embolus may be characterized by
symptoms. Because shock is the common endpoint of a variety dyspnea and right-sided evidence of heart failure. Cardiac tamponade
of insults, evaluation and management for all forms of shock involves may demonstrate the Kussmaul sign, a pulsus paradoxus, and distant
a common approach (Box 22.4). heart sounds. Septic shock in the absence of neutropenia usually
exhibits a focus of infection along with fever, chills, and warm
extremities. Patients with septic shock and neutropenia often have
Clinical Evaluation no clinically apparent focus. Elderly patients may present with
Impending shock is characterized by the typical compensatory little more than unexplained hyperventilation and hypotension.
response to cardiovascular stress. Tachycardia, tachypnea, and oliguria
(<0.5 mL/kg per hour) are usually present. Cool extremities are Laboratory Studies
seen in hypovolemic, cardiogenic, and obstructive shock. The blood
pressure may be elevated or normal with maximal sympathetic Laboratory data are used to confirm the diagnosis of shock and
stimulation. With progression, however, blood pressure falls while to help clarify the etiology. Leukocyte count is frequently elevated
pulse pressure narrows (except in the case of distributive shock). early in shock owing to demargination of neutrophils. Leukopenia
Frank hypotension (MAP <60–65 mm Hg in adults) may ensue. may be found in sepsis and late shock. Hemoglobin concentration
The chronic level of blood pressure must be considered. Normoten- is variably affected depending on the etiology of shock. For example,
sion in a normally hypertensive patient may denote a critical degree nonhemorrhagic hypovolemic shock and septic shock with extravasa-
of hypoperfusion. With further progression anuria may develop, tion of intravascular water to the interstitium may result in an
extremities may become mottled and dusky (except in distributive apparent erythrocytosis. Platelet count increases acutely with the
shock), and the sensorium may become clouded. It is important stress of circulatory shock, but with progression of sepsis or
to note that clinical parameters can underestimate initial resuscitative resuscitation of massive hemorrhage, thrombocytopenia may occur.
requirements in critically ill subjects including those with septic Arterial blood gases and electrolytes may demonstrate a nonanion
shock.313–316 gap acidosis if hypovolemic shock is associated with excessive
Other clinical manifestations of shock are useful in attempting diarrhea and metabolic alkalosis if associated with vomiting. An
to attempt to differentiate the etiology. Hypovolemic shock is anion gap acidosis, often caused by elevated levels of lactic acid,
characterized by decreased jugular venous pressure. Cardiogenic usually reflects prolonged inadequate tissue perfusion. Serum
creatinine and blood urea nitrogen are rarely changed after the Invasive Hemodynamic Monitoring
acute onset of shock even if renal injury is present. With slower
onset of shock—for example, in sepsis—increased creatinine is All patients suspected of having circulatory shock should have an
common and early resolution is an excellent marker of effective indwelling arterial pressure catheter placed. Although there are
resuscitation and survival. Markers of renal function can also be no randomized controlled trials showing benefit of arterial pressure
helpful diagnostically. An isolated increased blood urea nitrogen catheters, we believe there are reasonable grounds to use them
with anemia and normal creatinine may suggest gastrointestinal in shock.332 Blood pressure assessment by manual sphygmoma-
bleeding. An arterial blood gas analysis will help to determine nometry or automated noninvasive oscillometric techniques may
adequacy of oxygenation and give evidence of acid-base disturbances. be inaccurate during shock owing to marked peripheral vasoconstric-
An ECG is critical for diagnosis of ischemic cardiac injury either tion.333 In addition, neither technique supplies continuous monitor-
as a primary cause of cardiogenic shock or secondary to hypotension ing of the rapidly changing hemodynamic status of unstable patients.
associated with shock of another etiology. Further, an arterial catheter allows ready access for arterial
Lactate levels (particularly serial determinations) are useful in blood gas samples and other laboratory tests. In most cases, a
assessment of prognosis. Substantial data suggest that lactate levels, peripheral site, such as the radial artery, is used. However, given
as a marker of tissue oxygen debt, can predict outcome in the potential for disparity of pressures between central and peripheral
shock.46,47,317–321 The utility of lactate assessment is limited by the sites,334 if marked peripheral vasoconstriction caused by either
fact that it is a relatively late marker of tissue hypoperfusion.322,323 sympathetic stimulation or exogenous catecholamines obscures
Significant tissue ischemia and injury are present by the time it is the peripheral pulses, a central site such as the femoral artery may
elevated. In addition, lactate is cleared primarily by the liver. Liver be preferred.
failure may markedly increase elevated lactate levels during CVP monitoring is frequently used during the perioperative
hypoperfusion. Conversely, normal hepatic clearance may obscure period for assessment of intravascular volume status in patients
limited lactate production by ischemic tissues. Glycolysis and without critical illness. Because of the relatively stable hemodynamic
alkalosis will also nonspecifically increase lactate levels.324,325 status of these patients and the questionable benefit of pulmonary
However, because in the appropriate setting, arterial lactate levels artery catheterization in such patients, such an approach is adequate.
beyond 2 mEq/L are associated with increased mortality,47,51,319,320,326 Similarly, CVP monitoring for otherwise healthy patients being
such levels should be considered to represent tissue ischemia in resuscitated for hypovolemic shock may provide useful data. In
the absence of another clearly defined etiology. The adequacy of the appropriate clinical context, CVP monitoring may also occasion-
resuscitation of shock can also be assessed using serial changes of ally be useful in differentiating between different forms of shock
systemic lactate.321,326,327 A protocol of resuscitation using a goal (e.g., low CVP in hypovolemic shock, high CVP in cardiac
of lactate clearance greater than or equal to 10% versus a target tamponade). As a rule, though, CVP monitoring is inadequate
of central venous oxygen saturation (cSvO2) greater than or equal for the hemodynamic assessment of critically ill patients, particularly
to 70% was found to be noninferior.328 Therefore reduction in those with shock. A number of studies have conclusively shown
lactate concentration after initial management is a reassuring that CVP does not accurately estimate left ventricular preload in
indicator of adequacy of resuscitation and serial lactate measurement critically ill patients.335,336 In fact, data suggest that static measures
can replace more invasive monitoring for certain cases. of CVP do not correlate with right or left ventricular volumes in
cSvO2 can also be used to assess prognosis and efficacy of normal volunteers.337
resuscitation in shock states including septic shock.309,316,329,330 The use of the flow-directed balloon-tipped pulmonary artery
However, central venous saturation, which has been suggested to catheters (PACs) with thermodilution CO determination capability
represent a reliable marker of resuscitation efficacy in sepsis,309 has been the standard of practice for the hemodynamic assessment
does not appear to correlate well with lactate clearance in some of circulatory shock. Their use is supported by a number of studies
sepsis studies, perhaps reflecting elements other than oxygen debt that demonstrate that experienced physicians cannot accurately
in those conditions.327 Poor correlation with mixed venous oxygen determine cardiac filling pressures or CO based on clinical evaluation
saturation has also been noted in septic shock.331 Achievement of alone.338,339 In addition to CO determination, PACs provide
central venous saturation of 70% or higher was less predictive of continuous monitoring of central venous and pulmonary artery
good outcome in septic shock compared with lactate clearance of waveforms and pressures. Pulmonary artery occlusion pressure (as
10% or higher. an estimate of left ventricular end-diastolic pressure and volume)
and waveform can be obtained intermittently. Although substantially
supplanted by the increased availability of bedside echocardiography
Imaging in developed nations, waveform analysis may be useful in cardio-
A chest radiograph is useful in ruling out pneumonia as a source vascular diagnoses of cardiac tamponade, restrictive cardiomyopathy,
of septic shock, pulmonary edema as a manifestation of cardiogenic CHF, ventricular hypertrophy, and mitral or tricuspid regurgitation
shock, tension pneumothorax, pericardial tamponade, and so on. if echocardiography access is limited. In addition, PACs can
Although abdominal views may be helpful on occasion, intra- demonstrate evidence of right heart and pulmonary artery oxygen
abdominal processes resulting in shock are usually clinically apparent. saturation step-ups for the diagnosis of left-to-right shunts associated
Computed axial tomograms may be helpful in directing management with cardiac anatomic abnormalities such as ventricular septal
in specific instances (occult internal hemorrhage, aortic dissection, defect. These devices also allow withdrawal of blood from the
pulmonary embolus). Similarly, transthoracic and transesophageal pulmonary artery enabling determination of MvO2 to verify sufficient
echocardiography can diagnose specific repairable cardiac or aortic oxygen delivery during hypodynamic shock. In shock, the flow-
lesions associated with shock with great accuracy and can be highly directed balloon-tipped PAC is useful for etiologic classification,
suggestive of other important diagnoses, including hemodynamically determination of optimal management, and to follow the response
significant pulmonary embolus. Other imaging modalities have to therapy. Typical hemodynamic profiles of different forms of
less of a role in the evaluation of acute shock. shock have been described in Table 22.1.
The utility of pulmonary artery catheterization has been

questioned over the past decade. A case-matched study suggested
increased resource utilization and mortality associated with the
use of PACs in the ICU.340 A series of randomized studies performed O2
since then have reported on the role of the PAC in the setting of consumption
. Physiologic O2 supply/
major non-cardiac surgery,341 CHF,342 sepsis and ARDS,343 acute (VO2) consumption relationship
lung injury,344 and in the general ICU setting.345,346 In the periopera- Pathologic O2 supply/
tive management of patients undergoing major noncardiac surgery, consumption relationship
the use of a PAC did not impact mortality and was associated
with a greater incidence of pulmonary embolism.341 In critically
O2
ill patients diagnosed with CHF, management directed with the extraction
use of a PAC did not influence mortality but resulted in more ratio
in-hospital adverse events.342 Another study comparing the use of
PAC versus central venous monitoring in acute lung injury found
no difference in organ failure or mortality.344 A large trial evaluating
the role of the PAC in the management of patients with ARDS
Serum
secondary to sepsis also found no significant differences in mortality lactate
if a PAC was used or not.343 Two randomized studies of general
ICU patients similarly concluded that the use of PACs among
critically ill patients neither increased nor decreased mortality.345,346
Most, although not all, meta-analyses have shown no consistent
benefit with PACs.347–350 These studies failing to show a lack of
clinical benefit have been paralleled by other studies questioning Physiologic
. Pathologic
.
some of the basic premises of PAC utility. Several studies have DO2 Crit DO2 Crit
.
shown a lack of correlation between PAOP/CVP and ventricular O2 delivery (DO2)
volumes in the critically ill.351,352 One study has even demonstrated • Fig. 22.3 Oxygen supply–dependent oxygen (O2) consumption in shock.
that PAOP and CVP fail to predict ventricular filling volume, Physiologic supply-dependent oxygen consumption is characterized by a
cardiac performance, or the response to volume infusion in normal biphasic relationship between oxygen delivery (Ḋ O2) and oxygen consump-
volunteer subjects.337 Despite these data, no studies have examined tion (V̇ O2). The inflection point defines the physiologic critical oxygen
the use of PACs in cases of shock specifically. Nonetheless, the use delivery (Ḋ O2crit). Below this Ḋ O2crit, V̇ O2 is linearly dependent on Ḋ O2, the
of PACs in the United States has decreased dramatically over the oxygen extraction ratio is maximal, and lactate (indicating anaerobic
metabolism) is produced. Above the physiologic Ḋ O2crit, V̇ O2 is independent
past 20 years.353
of Ḋ o2, the oxygen extraction ratio varies to maintain a constant V̇ O2, and
Given the lack of evidence of benefit of PACs and alternative lactate is not produced.
diagnostic and monitoring tools such as bedside ultrasonography,
we believe that PACs should not be routinely inserted in shock.
However, there is still room for PACs in cases of mixed shock,
right ventricular failure, or in instances when the diagnostic evalu- Oxygen delivery and oxygen consumption variables can also
ation including bedside ultrasonography cannot reveal the cause be determined using PAC-derived data. Although such global
of the shock. perfusion data appear to have prognostic significance for large
Another parameter provided by a PAC is mixed venous oxygen groups of the critically ill, their utility is limited when applied to
saturation. Compared with cSvO2, which reflects mixed oxygen individual patients.
saturation from the superior vena cava, MvO2 reflects a global Recent modifications to the standard pulmonary artery flotation
picture of oxygen extraction. This measure may provide an assess- catheter allow continuous monitoring of MvO2 or determination
ment of adequacy of resuscitation of low output states before the of right ventricular ejection fractions and volumes. Although both
presence of anaerobic metabolism (as signified by increased lactate). innovations have been used for clinical research purposes and each
MvO2 rises with increases of perfusion above requirements and theoretically offers unique insights into shock, they have no defined
falls, with increasing oxygen extraction ratio, as perfusion becomes role at this time in clinical shock management.
inadequate (see Fig. 22.3). Normal MvO2 falls within the 65% to
75% range. During MI saturations of less than 60% are found Ancillary Monitoring Techniques
with CHF and less than 40% with cardiogenic shock.330 Lactate
accumulation and supply-dependent oxygen consumption begin Oximetry
to appear as saturation levels fall below 30% to 40%.354,355 MvO2 Because oxygen delivery is dependent on arterial oxygen saturation,
is especially useful in determining whether low COs indicate pulse oximetry should, in theory, provide useful data during circula-
supply-dependent oxygen consumption (MvO2 low) or normally tory shock. However, limitations of the technique include the fact
depressed metabolic demands (normal MvO2). Owing to the that ambient light sources, dyhemoglobinemias (methemoglobin,
maldistribution of perfusion in distributive shock (or substrate carboxyhemoglobin), lipemia, and hypothermia can affect results.356
utilization defect in septic shock) and left-to-right shunting in Motion artifact may generate a false signal.357 Shock-associated
cardiogenic shock associated with ventricular septal defects, MvO2 vasoconstriction also impairs signal acquisition. One study has
is not useful in assessment in those conditions. Recently cSv O2 shown that a CI less than 2.4 L/min per m2 is associated with
has been proposed as an alternate method to examine adequacy signal loss.358 Although these problems limit the utility of pulse
of resuscitation, although correlation with MvO2 is imperfect in oximetry in the acute management of circulatory shock, the
septic shock.309,316,331 technique may be more helpful during postresuscitation monitoring.
At this time, sequential arterial blood gases provide more reliable ultrasound, such as valvular abnormalities or intracardiac shunt,
data during acute shock. formal transthoracic or transesophageal echocardiography should
be obtained.
Ultrasound/Echocardiography
The application of point-of-care (POC) ultrasound in the ICU Management and Therapy
environment as diagnostic and intermittent monitoring tools may
represent one of the most exciting developments in critical care Patients in whom circulatory shock is suspected should be managed
management. A number of factors have hastened this development. in an ICU with continuous ECG monitoring and close nursing
These include questions regarding the safety and efficacy of routine support. Those whose etiologic diagnosis is in doubt, whose
PAC utilization; the availability of relatively inexpensive, portable hemodynamic instability does not quickly resolve with IV fluids,
echocardiography systems; the application of advanced software or whose conditions are medically complicated should undergo
algorithms to analysis of data; and the development of new, high- invasive hemodynamic monitoring with arterial and central venous
resolution echocardiographic techniques, including transesophageal catheters or PACs. POC ultrasonography should generally be
and contrast echocardiography. The confluence of these factors performed. Laboratory tests as mentioned earlier should be per-
has resulted in a substantial increase in use of echocardiography formed at or before admission.
in the ICU for assessment of hemodynamic instability and shock. Management of shock can be divided into specific therapy for
In addition to its long-recognized ability to detect anatomic lesions the triggering injury and general therapy of the shock syndrome.
(pericardial tamponade, pericardial effusion, septal defects, valvular Examples of specific therapy include antibiotics for infections
disease, aortic dissection), new techniques allow assessment of CO, causing septic shock, blood transfusion for hemorrhagic shock,
SV, preload (ventricular volumes), intravascular volume status thrombolysis for acute MI or massive pulmonary embolus, and
(inspiratory inferior caval collapse), pulmonary artery pressures, pericardial aspiration for pericardial tamponade. Specific therapy
systolic contractility (ejection fraction), diastolic function, and for different etiologies of shock is discussed in Chapters 23
regional motion abnormalities at baseline and under stressed and 26.
conditions.359 Utility for diagnosis of hemodynamically significant
pulmonary embolism has also been established.360 The widespread Aims
dissemination of echocardiographic skills among the next generation
of intensivists has allowed for a substantial reduction in use of Because the shock syndrome shares many characteristics across
invasive monitoring techniques including pulmonary artery different etiologies, the general management of shock is similar in
catheterization. Multiple different algorithms have been developed all cases. The basic goal of circulatory shock therapy is the rapid
for the use of POC ultrasound in shock, including Rapid Ultrasound restoration of effective perfusion to vital organs and tissues before
for Shock and Hypotension (RUSH) and Abdominal and Cardiac the onset of cellular injury. Effective tissue perfusion is dependent
Evaluation with Sonography in Shock (ACES).361,362 on both sufficient CO and adequate driving pressure. Consequently,
As part of these algorithms, heart, lungs, abdomen, and large ideal therapy of shock requires early reestablishment of both an
vessels are usually examined. Views of the heart are examined to appropriate CI and mean blood pressure (Box 22.5). However,
look for signs of pericardial effusion and tamponade. The overall because for brief periods marked hypoperfusion is better tolerated
size and contractility of the right and left ventricles are appreciated. than severe hypotension, the first specific resuscitative aim—support
Left ventricle hypokinesis is suggestive of cardiogenic shock, and of blood pressure (>60–65 mm Hg in a baseline normotensive
the presence of regional wall motion abnormalities should raise
the suspicion of a coronary artery lesion. Right ventricular dilatation
and hypokinesis may suggest pulmonary embolism or right ven- • BOX 22.5 General Approach to Shock:
tricular infarction. The size of the inferior vena cava as well as Immediate Goals
respiratory variation can give an estimation of CVP as well as fluid
responsiveness. Lung ultrasound can be used to identify pneumo- General
thorax with the absence of lung sliding and lung pulse and presence Find cause of shock and apply specific treatment (examples: antibiotics for
of a lung point. It is also useful to identify B-lines that represent sepsis or pericardiocentesis for tamponade)
interstitial fluid, which could represent pulmonary edema or Hemodynamic
pneumonia. Evaluation of the pleural space is more accurate with MAP >65 mm Hg (higher in the presence of coronary artery disease or
ultrasound than with standard chest radiography. Abdominal chronic hypertension)
CVP = 8–12 mm Hg/PAOP = 12–15 mm Hg (may be higher for cardiogenic
ultrasound is useful to identify free fluid in the peritoneum that shock)a
might be the source of hypovolemic shock, for example, in trauma. CI >2.1 L/min per m2a
Evaluation of the abdominal aorta is very accurate to identify Optimization of oxygen delivery
abdominal aortic aneurysm. Finally, compression ultrasonography Hemoglobin >7–9 g/dL; >7 g/L after shock is sufficient
of the femoral veins can quickly identify proximal deep venous Arterial saturation > 92%
thrombus. MvO2 > 60%, sCV02 > 70%*
A POC ultrasonography examination of heart, lung, abdomen Normalization of serum lactate (to <2.2 mM/L)
and great vessels should take only a few minutes and can often Reverse organ system dysfunction
quickly diagnose the cause of shock. It can be repeated after Reverse encephalopathy
therapeutic interventions (fluid bolus, inotropes). It should be Maintain urine output >0.5 mL/kg per hour
remembered that ultrasonography is very operator dependent. Thus a
Optional.
clinicians should ensure they are competent in POC ultrasound CI, Cardiac index; CVP, central venous pressure; MAP, mean arterial pressure; MvO2, mixed venous
oxygen saturation; PAOP, pulmonary artery occlusion pressure.
before basing their clinical decision on their ultrasound findings.363
If there is a suspicion of a diagnosis not easily seen on POC
patient)—may initially take priority over the second specific oxygen demand. Given that pulmonary infiltrates (aspiration,
aim—maintenance of CI. The blood pressure goal target has pneumonia, or ARDS) are common, positive end-expiratory pressure
traditionally been MAP greater than 65 mm Hg. A recent random- may be necessary to ensure adequate oxygenation. Potential adverse
ized controlled trial in septic shock failed to show benefit for a hemodynamic effects from positive-pressure ventilation (related
MAP goal of 80 to 85 mm Hg versus 65 to 70 mm Hg with more primarily to decreased venous return) may be seen but can be
atrial fibrillation in the higher MAP goal. For patients with chronic minimized by fluid loading so that the patient is euvolemic or
hypertension, a higher MAP goal was associated with less renal modestly hypervolemic.
replacement therapy but similar mortality.364 Based on these data, Depending on the clinical situation, pain management may be
a MAP greater than 65 mm Hg for most patients is reasonable. necessary. Again, potential adverse hemodynamic effects may be
Finally, maintaining perfusion sufficiently high that arterial lactate seen if intravascular volume is inadequate because all measures
concentration remains below 2.2 mmol/L is a generally accepted result in some degree of venodilation either directly or by decreasing
approach to avoiding anaerobic metabolism and ischemic tissue sympathetic tone. Two- to 4-mg boluses of IV morphine are recom-
injury (Box 22.5). mended. During circulatory shock clearance of morphine by the
The practice of targeting oxygen delivery to specified supranormal liver may be impaired owing to hepatic hypoperfusion. In addition
oxygen delivery goals or to evidence of supply-independent oxygen to relieving pain, analgesia should also decrease systemic oxygen
consumption in the ICU has been substantially discredited by consumption.
clinical studies.365–368 In an earlier study, early targeting (<6 hours Management of lactic acidosis that develops during circulatory
after presentation) to a cSvO2 of greater than 70% using a defined shock is problematic. Bicarbonate therapy may have adverse effects
protocol with fluids, blood transfusion, and dobutamine support on intracellular pH even while improving the pH of the extracellular
has been shown to improve outcome in severe sepsis and fluid. Further, even when pH is extremely low, bicarbonate therapy
septic shock.309 However, three more recent randomized controlled does not improve systemic hemodynamics in shock associated with
trials have shown that this protocol is not superior to standard acidosis.383 In addition, increasing serum pH may adversely affect
treatment.369–371 the oxyhemoglobin dissociation relationship. The optimal approach
The reasons for the discrepancy between the initial study by to the management of lactic acidosis is to improve organ and
Rivers and the latest three randomized controlled trials are not systemic perfusion so that anaerobic metabolism is limited and
totally clear.309 However, it appears that the standard of care for the liver and, to a lesser extent, kidneys can clear the accumulated
septic shock has shifted in recent years to earlier recognition and lactate. If this is not effective, restricting the use of sodium bicarbon-
aggressive early management, which might have decreased the ate to situations in which pH is less than 7.1 to 7.15 may be
relative benefit of the early goal-directed therapy protocol. appropriate.
One of the major achievements in shock therapy in the past Initial management of circulatory shock should almost always
decade has been the recognition that speed of implementation of include a crystalloid fluid challenge. In the absence of invasive
supportive and specific therapies may be critical to improvement monitoring with a PAC, the only practical exception is if clinical
in outcomes. This concept of a “golden hour” has long been evidence strongly suggests ventricular filling pressures are already
recognized in the context of specific and resuscitative therapy of elevated. This is usually limited to clinical situations involving
trauma-induced hypovolemic shock with blood products and surgical cardiogenic shock and marked pulmonary edema. Even then, if
management372,373 and then cardiogenic shock owing to MI with pulmonary edema is manageable, crystalloid challenge may be
emergent primary angioplasty or thrombolysis.374 In recent years, appropriate. The volume of the challenge is variable. Large volumes,
a similar rapid treatment paradigm has been established for on the order of 1 to 2 L given rapidly (0.5–1.0 L every 10–15
thrombolytic therapy for obstructive shock caused by a massive minutes) are frequently used in hemorrhagic and septic shock.
pulmonary embolus.81,82,375 Similarly, rapid fluid resuscitation Boluses of 100 to 200 mL may be used during cardiogenic shock.
(<6 hours)309 and antimicrobial therapy (<1 hours)376–378 have been If shock does not resolve promptly after the initial fluid challenge,
shown to be key to maximizing survival in severe sepsis and septic patients should undergo more detailed invasive (central venous
shock. Accelerated provision of effective therapy probably accounts catheter) and/or noninvasive (echocardiographic) assessment. As
for reports of improved clinical outcomes with medical emergency previously discussed, a central role for pulmonary artery catheteriza-
response teams.379–381 The variation in baseline provision of effective tion in shock is now highly questionable.
therapy likely accounts for the inconsistent results seen with such Although aggressive fluid resuscitation is well accepted in the
teams.382 The importance of early aggressive resuscitative and specific therapy of shock, emerging data support more limited resuscitation
therapy of all shock states cannot be sufficiently emphasized. in some contexts. Resuscitation to the lower limit of normal targets
(target systolic blood pressure 90–100 mm Hg) has been recom-
mended in hemorrhagic shock resulting from penetrating trauma
Resuscitation based on data showing improved survival using this approach.378,384
The universal basics of resuscitation underlie the initial management In addition, a limited fluid resuscitation protocol for 7 days has
of circulatory shock. Because many patients with circulatory shock been shown to improve the number of ventilator- and ICU-free
may have accompanying trauma and/or decreased level of conscious- days in acute lung injury without increasing the prevalence of
ness, the ventilatory status of the patient must be secured. This shock or the mortality rate.385 A more limited early fluid resuscitation
may involve tracheal intubation and/or mechanical ventilation, if has also been shown to be associated with improved survival in
necessary. Oxygen should be provided at a sufficiently high con- children with shock associated with infection in underresourced
centration to provide an arterial oxygen saturation of greater than settings.386
90% to 92%. Unintubated patients may require high-flow (30–45 L/ Although fluid is generally given as the first treatment, reas-
min) or rebreathing oxygen delivery systems because many patients sessment of fluid is needed throughout the resuscitation. Multiple
have unusually high minute ventilation volumes. Intubated patients static and dynamic predictors of fluid responsiveness have been
should initially receive full ventilatory support to decrease systemic used. CVP of 8 to 12 mm Hg has traditionally been a target in
shock management, but CVP is not a great predictor of fluid ratio of platelets:plasma:packed red blood cells showed no significant
responsiveness and many factors influence the CVP value. Response differences in mortality at 30 days. However, more patients achieved
to rapid infusion of fluid or passive leg raise seems to predict fluid hemostasis and fewer died of exsanguination in the 1:1:1 group.400
responsiveness better than CVP, but the sensitivity of the test is With respect to hemoglobin, one randomized trial has suggested
better if CO is monitored rather than simply blood pressure or that a hemoglobin level of 70 g/L is sufficient for most patients
pulse pressure. In passive mechanically ventilated patients, pulse in the ICU (other than those with high severity of illness or acute
pressure variation and systolic pressure variation can be used. POC coronary syndrome401,402). Although several other studies have noted
measurement of inferior vena cava (IVC) can be helpful with IVC the potential risks associated with blood transfusion in the ICU
variation of 50% or greater in unintubated patients and 12% to setting,311,403–405 no study has directly examined hemoglobin
18% and more in intubated patients associated with fluid requirements during shock. The only study to (indirectly) examine
responsiveness.387,388 blood transfusion in shock suggested that early augmentation of
In addition, substantial controversy exists regarding the appropri- hematocrit to more than 30% during septic shock as part of a
ate use of crystalloid and colloid fluids after initial resuscitation protocol to drive cSvO2 to more than 70% was associated with
attempts. The basis of this controversy lies with the differing oncotic improved survival.309 For that reason, it is reasonable to recommend
properties of the fluids. Crystalloid fluids (such as normal saline that a hemoglobin level of 90 to 100 g/L be maintained during
solution and lactated Ringer solution) contain sodium chloride in acute shock.
a quantity that closely matches extracellular fluid. No large molecules Once intravascular volume is optimized, the next line of therapy
are present. Thus such fluids distribute into the extracellular space. of circulatory shock usually involves inotropes and vasopressors.
Colloids, in addition, contain albumin or large osmotically active Alternately, vasopressors may be occasionally required for brief
carbohydrates (hydroxyethylstarch, dextran) that may be held within periods of blood pressure support in extremely hypotensive patients
the intravascular space, resulting in an increase of the plasma oncotic before initiation of fluid infusion.
pressure. It has been suggested that in shock associated with Three major classes of agents are used clinically for inotropic
microvascular changes of permeability (such as sepsis), colloid fluids or vasopressor support in critically ill patients: sympathomimetics,
remain in the intravascular space, leading to decreased tissue edema phosphodiesterase inhibitors, and vasopressin (antidiuretic hormone)
and noncardiogenic pulmonary edema.389 However, the limited (Table 22.4). Sympathomimetics (catecholamines) may activate
human studies available suggest that although radiographic infiltrates cardiac β1- and α-adrenoreceptors, peripheral vascular α- or β2-
may appear more severe with crystalloid resuscitation of sepsis, receptors, and vascular dopaminergic receptors. Cardiac β1-
gas exchange is comparable to colloid resuscitation.42 adrenoreceptors augment HR and myocardial contractility by
More importantly, it has been proposed that colloids may provide increasing activity of adenylate cyclase, resulting in increased
better outcomes in the resuscitation of shock because of the rapidity generation of c AMP.406 α-Receptors act through phospholipase
and persistence of volume expansion compared with crystalloid C production of inositol triphosphate and diacylglycerol.407–409
infusion.42,390 However, clinical studies for the most part have not Peripheral vascular α-receptors cause vasoconstriction, whereas
supported this contention. For the most part, meta-analyses have peripheral β2-adrenoreceptors induce a mild vasodilatation. Cardiac
failed to demonstrate clinical outcome superiority of crystalloids α-adrenoreceptors contribute to increased contractility (but not
compared to either albumin or synthetic colloids.391 In fact, one HR) when stimulated.407,409 Dopaminergic adrenoreceptors, mediat-
meta-analysis of randomized controlled studies examining the effect ing dilatation, are found in the arterial vessels supplying vital
of fluid administration in critically ill patients with burn injury, organs (including the heart, brain, kidneys, and splanchnic
hypovolemia, or hypoalbuminemia suggested increased mortality organs).410 Phosphodiesterase inhibitors such as amrinone and
in patients treated with colloids.392 In one large randomized study milrinone augment cardiac contractility by inhibition of cAMP
of albumin versus normal saline solution, there was no benefit to degradation. They also relax vascular smooth muscle.411 Despite a
albumin. A trend toward improved outcomes with albumin in severe long history of digitalis use in the management of CHF and older
sepsis and saline solution in trauma failed to reach significance in data suggesting potential hemodynamic benefit in sepsis,412 cardiac
that study.393 A more recent study of albumin versus crystalloid in glycosides are rarely used for the acute management of circulatory
severe sepsis also failed to show any benefits to albumin. More shock because of their narrow therapeutic index and long half-life.
recently, a substantial body of literature has shown that synthetic Recent uncontrolled studies have shown that endogenous vasopressin
colloids increase the risk of renal injury and death, particularly in concentrations may be relatively deficient in shock states and that
sepsis and septic shock.394–396 An increased risk of renal injury/dialysis infusion of vasopressin (which has little effect in healthy, normo-
requirement and risk of death was shown for hydroxyethylstarch tensive subjects), can have a profound pressor effect during vasodila-
versus Ringer solution therapy in two large randomized trials of tory shock.413–416
sepsis.394,395 Some data, however, suggest colloid resuscitation may Norepinephrine, an endogenous catecholamine, exerts both
clear lactate more quickly and result in less renal injury than crystalloid powerful inotropic (cardiac alpha and β1-adrenoreceptors) and
in penetrating trauma.397 Given the much higher costs of colloids peripheral vasoconstriction effects (α-adrenoreceptors). It is currently
and higher risk of renal injury and death with synthetic colloids, the favored catecholamine for initial management of shock. It can
resuscitation of shock should generally focus on crystalloid solutions. be used for persistent hypotension despite high-dose dopamine
Albumin can be considered in septic shock for volume replacement during septic and obstructive shock. It should generally be used
in patients who need substantial amount of crystalloid.398 only transiently in cardiogenic shock because it may drastically
During hemorrhagic shock, fluid resuscitation should consist reduce forward flow. Similarly, it should not be required during
mostly of blood products. Crystalloids are only acceptable if blood hemorrhagic shock except for extremely brief periods of blood
products are unavailable. Controversy exists on the exact ratio of pressure support pending volume infusion. Infusion rates of 2 to
packed red blood cells, fresh frozen plasma, and platelets. Obser- 20 µg/min are commonly used, but if necessary higher rates may
vational studies suggested that a ratio of 1:1:1 was superior.399 A be tried. Suggestions that there is clinical utility in the concomitant
recent randomized controlled trial of a 1:1:1 versus 1:1:2 transfusion use of “low”-dose dopamine with norepinephrine to generate
TABLE a
22.4 Relative Potency of Intravenously Administered Vasopressors/Inotropes Used in Shock
CARDIAC PERIPHERAL VASCULATURE

Drug Dose Heart Rate Contractility Vasoconstriction Vasodilation Dopaminergic Typical Clinical Use
Dopamine 1–4 µg/kg/min 1+ 1–2+ 0 1+ 4+ All shock
5–10 µg/kg/min 2+ 2+ 1–2+ 1+ 4+
11–20 µg/kg/min 2+ 2+ 2–3+ 1+ 4+
Norepinephrine 0.01–0.3 µg/kg/min 2+ 2+ 4+ 0 0 Refractory shock
Dobutamine 1–20 µg/kg/min 1–2+ 3+ 1+ 2+ 0 CHF; cardiogenic, obstructive
and septic shock
Dopexamineb 0.5–6 µg/kg/min 2+ 1+ 0 3–4+ 4+ CHF; cardiogenic shock
Epinephrine 0.05–0.2 µg/kg/min 4+ 4+ 4+ 3+ 0 Refractory shock or
anaphylactic shock
Phenylephrine 0.1–1 µg/kg/min 0 1+ 4+ 0 0 Neurogenic or septic shock
Isoproterenol 1–8 µg/min 4+ 4+ 0 4+ 0 Cardiogenic shock
(bradyarrhythmia),
torsades de pointes,
ventricular tachycardia
Vasopressin 0.02–0.04 U/min 0 0 4+ 0 0 Vasodilatory (e.g., septic)
shock
Milrinone 37.5–75 µg/kg bolus 1+ 3+ 0 2+ 0 CHF; cardiogenic shock
over 10 min;
0.375–0.75 µg/kg/
min infusion
a
The 1 to 4+ scoring system represents an arbitrary quantitation of the comparative potency of different vasopressors/inotropes.
b
Not clinically released in the United States.
CHF, Congestive heart failure.
sparing of pressor and shock-associated renal injury has been substantial interindividual variation in response, with some showing
refuted.417–419 substantial vasopressor or inotropic responses at low infusion
Dopamine has fallen out of favor as the initial vasopressor used rates. For management of circulatory shock, dopamine is often
for circulatory shock. A central and peripheral nervous system started at 5 µg/kg per minute and increased rapidly (5 µg/kg
neurotransmitter and the biologic precursor of norepinephrine, per minute every 2 or 3 minutes) to a maximum of 20 µg/kg
dopamine stimulates three different receptors; vascular dopaminergic, per minute until the target blood pressure is reached. If vasopressor
cardiac β1, and vascular α. In addition, part of dopamine’s effects are inadequate at these infusion rates, norepinephrine
myocardial effects are mediated by release of endogenous norepi- infusion is begun. In a randomized controlled trial in patients
nephrine. Dose-dependent maximal stimulation of each of each with shock, norepinephrine and dopamine were similar in
of dopamine’s target receptors has been suggested to result in regard to mortality. Dopamine was associated with more
different typical hemodynamic responses at different infusion rates. adverse effects including tachyarrhythmias and subgroup analysis
At infusion rates of less than 4 to 5 µg/kg per minute, dopaminergic suggested higher mortality for dopamine in the cardiogenic shock
effects have been said to dominate, but studies suggest this has subgroup.421
little clinical relevance (although in the past it was the theoretical Dobutamine, which is structurally derived from isoproterenol,
basis for use of low-dose dopamine for renal protection).417,418 is a racemic mixture of two synthetic stereoisomers. In combination,
Vascular dopamine 2 receptors vasodilate the renal, mesenteric, the stereoisomers result in increased myocardial contractility through
myocardial, and cerebral vascular beds. In addition, renal dopamine α and β1 cardiac adrenoreceptors.422,423 Weak arteriolar vasodilatory
1 receptors mediate a mild natriuresis.420 β-Adrenoreceptor–mediated effects are mediated through dominance of β1-adrenoreceptor–
cardiac inotropic effects have been suggested to dominate at doses mediated vascular relaxation over α-adrenoreceptor–mediated
below approximately 10 µg/kg per minute with α-adrenoreceptor vasoconstriction in the arterial circulation. Evidence suggesting
vasopressor effects more prominent at doses above 10 µg/kg that dobutamine induces vasoconstriction in the systemic venous
per minute.410 It is important to note, however, that dopaminergic bed (resulting in increased mean circulatory pressure and augmenta-
and cardiac adrenergic effects are not suppressed at higher doses tion of venous return/CO) implies that α-adrenoreceptor–mediated
but rather that additional effects are seen. In addition, there is effects may be dominant in small capacitance vessels.162,422,423
Although its hemodynamic effects are otherwise similar to are intraoperatively to counteract the vasodilatory effects of anesthet-
isoproterenol, dobutamine has been reputed to exert minimal ics and in septic shock, in which its lack of β-adrenergic activity
chronotropic effects.422,424 This attribute has been questioned in may help limit deleterious increases in HR seen with other agents.
recent studies425 and may have been based on the selection of Isoproterenol is another synthetic catecholamine with dominant
CHF patients with β-adrenoreceptor downregulation and other β1 and β2 activity. Its previous indications for use have largely been
potential alterations of adrenoreceptor signal transduction.424,426 supplanted by dobutamine. Because of its powerful chronotropic
Dobutamine’s powerful inotropic effect is due to a combination of effects, it can be useful in the management of bradyarrhythmias
its direct effect on myocardial contractility, its afterload reducing and torsades de pointes ventricular tachycardia (for overdrive pacing),
effect, and α-adrenoreceptor–mediated venoconstriction.422,424 In but otherwise it has no specific role in the management of circulatory
contrast to dopamine, it causes a reduction in filling pressures and shock.
a greater increase in CO at equivalent doses.427,428 In addition, In recent years, vasopressin levels in septic shock have been
although it increases myocardial oxygen demand (like dopamine), shown to be significantly suppressed.416 Studies have shown that
myocardial perfusion is also augmented (in contrast to dopamine).429 IV infusion of vasopressin into patients with septic shock results
The most well-accepted use of dobutamine in circulatory shock in a profound pressor response.415 This profound pressor response
relates to cardiac etiologies.422,424 Once blood pressure is corrected, occurs despite the absence of such an effect with even larger amounts
dobutamine may be used to increase cardiac performance and of vasopressin in normotensive patients. Investigators have also
decrease elevated ventricular filling pressures associated with documented efficacy in other vasodilatory shock states with refrac-
cardiogenic pulmonary edema. In this setting dobutamine may tory hypotension, including milrinone-induced shock in severe
in fact increase blood pressure. Alternatively, if myocardial damage heart failure,437 postcardiotomy vasodilatory shock,438 unstable
is extensive, vasodilatory properties may dominate, resulting in brain-dead organ donors,439 and late-phase hemorrhagic shock.413
hypotension. Dobutamine may also be of use in obstructive shock Vasopressin (0.1–1.0 U/mL in normal saline solution or 5% dextrose
pending definitive intervention and can be used for augmentation in water) may be initiated at 0.02 to 0.04 U/min. Few patients
of low CI occasionally seen in fluid-resuscitated septic shock. Our respond with higher doses and the dose should rarely, if ever, be
own experience suggests that a somewhat hypervolemic state higher than 0.04 U/min for an extended period of time. In large
(a PAOP of at least 15 mm Hg if a PAC is used) is required doses, vasopressin may produce bradycardia, minor arrhythmias,
during dobutamine infusion to avoid hypotension in patients premature atrial contraction, heart block, peripheral vascular
with septic shock. The use of dobutamine for routine augmenta- constriction or collapse, coronary insufficiency, decreased CO,
tion of oxygen delivery in septic shock has been substantially myocardial ischemia, and MI. In patients with CAD, even small
rejected.430,431 doses of the drug can precipitate angina. At the upper end of
Epinephrine is occasionally used when other inotrope/vasopressors dosing, a significant subset of patients may develop digital, mes-
have failed to support blood pressure and/or CO in circulatory enteric, or myocardial ischemia; thus it is imperative to use the
shock. It is the first-line agent for management of anaphylactic minimal amount of vasopressin possible to achieve desired blood
shock. In addition, it is used to support myocardial contractility pressure goals. Published data suggest vasopressin can be used for
after cardiopulmonary bypass.432 Epinephrine stimulation of α, up to 4 to 6 days if necessary. A randomized, blinded study of
β1-, and β2-receptors results in increases of myocardial contractility vasopressin treatment of septic shock has shown that the addition
that are more pronounced than with any other inotrope. Infusion of low-dose vasopressin (vs. norepinephrine) to open-label vasopres-
rates in nanograms per kilogram per minute result in significant sors offered no overall advantage.440 A recent randomized controlled
increases in CO.432 Epinephrine is also frequently used in septic trial showed that vasopressin as a first-line vasopressor was safe
shock refractory to other inotropes/vasopressors. Effects attributable but did not provide any advantages over norepinephrine.441 Because
to impaired myocardial perfusion (chest pain, arrhythmias, ST of the limited experience with this compound and the relatively
depression) in patients with known CAD are usually limited to longer half-life of the drug, vasopressin should be used only after
patients receiving more than 0.1 µg/kg/min.433 Although the usual hemodynamic stabilization with standard agents (catecholamines)
infusion rate is 0.05–0.2 µg/kg/min higher rates can be used with has been attempted.
the potential for increasing toxicity. Another agent in a totally different class that could be used as
Milrinone, a bipyridine phosphodiesterase inhibitor, increases vasopressor is angiotensin II. In a recent randomized controlled
intracellular concentrations of cAMP by blocking cAMP break- trial, angiotensin II as an add-on to norepinephrine showed that
down.411 Although some controversy has existed regarding the relative it could increase MAP compared with placebo without significant
contributions of increased myocardial contractility and decreased adverse effects. The role of this agent in management of shock is
vascular tone with respect to the apparent inotropic properties of still to be defined.290
phosphodiesterase inhibitors, recent data confirm the presence of
substantial increases of myocardial contractility434; these agents also Conclusion
produce substantial vasodilatation. The most accepted use for
milrinone in the ICU is in the management of CHF, cardiogenic Although the syndrome of shock ultimately involves common late
shock, and postcardiopulmonary bypass myocardial dysfunction.411 pathologic elements, the early pathophysiologic processes underlying
Experimental animal studies suggest phosphodiesterase inhibitors different conditions resulting in circulatory shock are both diverse
may exert beneficial hemodynamic effects in sepsis by augmenting and complex. Our concepts of shock, which once focused on broad
CO and increasing oxygen delivery without increasing consump- cardiovascular physiologic mechanisms, have more recently centered
tion.435 Occasional clinical reports suggest a potential management on issues of microvascular function and cellular metabolism. In
role in catecholamine-refractory septic shock.436 the future, this focus may evolve toward questions of altered cellular
Phenylephrine is a synthetic catecholamine that is unique in gene expression and metabolomics in a variety of tissues. Advances
its almost pure α-adrenergic agonist effects. Its most common uses in therapy have developed in parallel to these changes in our
understanding of shock pathophysiology. Early work on therapy experimental therapies being examined today involve direct
of shock concentrated on correction of hemodynamic derangements manipulation of gene expression via antisense oligonucleotides
through the use of vasopressors and inotropes. Clinical trials over and transcription factor inhibitors. Despite these advances, many
decades have centered on anticytokines such as anti–TNF-α and questions remain. Only ongoing basic research and clinical trials
various novel resuscitative compounds. The most advanced will answer them.
Key Points
• Shock is the final pathway through which a variety of pathologic • During distributive shock, particularly septic shock, organ blood
processes lead to cardiovascular failure and death. flow is disturbed at higher MAPs, suggesting a primary defect
• Shock is the state in which profound and widespread reduction of microvascular function.
of effective tissue perfusion leads to cellular injury. The inability • Cellular dysfunction and organ failure in shock involves the
of cells to obtain and/or use oxygen in sufficient quantity to interactions of cellular ischemia, circulating or local inflammatory
optimally meet their metabolic requirements is common to all mediators, and free radical injury.
forms of shock. Hypotension alone does not define shock. • All compensatory responses to shock support oxygen delivery
• Based on hemodynamic characteristics, shock is categorized to vital tissues. The mechanisms include support of venous
as hypovolemic, cardiogenic, extracardiac obstructive, or pressure, maximization of cardiac function, redistribution of
distributive. perfusion to vital organs, and optimization of oxygen unloading.
• Although one hemodynamic categorization dominates, most • Circulatory shock may be associated with encephalopathy, ARDS,
forms of clinical shock involve some cardiovascular characteristics ATN, ischemic hepatitis or intrahepatic cholestasis, thrombo-
of several categories. cytopenia, immunosuppression, and MODS.
• The clinical picture of shock is dependent on the etiology, the • Because early recognition and treatment is key to improved
magnitude of the injury or insult, and the degree of physiologic survival, the diagnosis of shock is primarily based on clinical
compensation. Physiologic compensation is determined by the criteria. Laboratory and radiologic data are used to confirm the
time course of development of shock and the preexisting car- diagnosis and to help clarify etiology.
diovascular reserve. • Clinically, shock is characterized by physiologic compensatory
• The systemic hemodynamic aspects of shock can be described responses, including tachycardia, tachypnea, oliguria, and by
by the interactive contributions of cardiac and vascular function signs of physiologic decompensation, particularly hypotension.
to blood pressure and CO. • Shock should be managed in an ICU with continuous monitoring
• Physiologically, blood pressure is dependent on CO and vascular and close nursing support. Those patients whose etiologic
resistance; CO is not dependent on blood pressure. diagnosis is in doubt, whose hemodynamic instability does not
• Failure to maintain the blood pressure required for autoregulation quickly resolve with IV fluids, or whose conditions are medically
during hypodynamic circulatory shock indicates a severe reduc- complicated should undergo noninvasive (echocardiographic)
tion in CO. and/or invasive hemodynamic monitoring with arterial and
• In a closed cardiovascular circuit, CO (as determined by HR, centrally placed catheters. PACs remain a reasonable option in
preload, afterload, and contractility) equals venous return (as some cases.
determined by venous pressure [mean circulatory pressure]), • The basic goal of therapy of circulatory shock is the restoration
right atrial pressure, and venous resistance. Total systemic of effective perfusion to vital organs and tissues before the onset
perfusion is therefore dependent on cardiac and vascular of cellular injury.
interactions. • The speed with which effective perfusion is established and the
• In addition to sufficient CO at sufficient pressure, effective underlying cause of hemodynamic instability is definitively
perfusion requires normal local and systemic microvascular addressed are critical determinants of survival in shock.
function, resulting in appropriate distribution of CO. • The specific aims of resuscitation of shock include support of
• During hypovolemic and other forms of hypodynamic shock, mean blood pressure above 60 to 65 mm Hg, maintenance of
extrinsic blood flow regulatory mechanisms overwhelm the CI greater than 2.1 L/min per m2, and restriction of arterial
autoregulatory response of most vascular beds. Blood flow to lactate concentrations to less than 2.2 mmol/L.
vital organs such as the heart and brain is relatively well preserved
owing to dominant autoregulatory control.
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310.e11
Review Questions
1. A 33-year-old woman is brought to the intensive care unit represents another way to define oxygen consumption. Simply
(ICU) for dyspnea and acute hepatic dysfunction. Her symp- put, this is the ratio of oxygen consumption to oxygen delivery,
toms began 2 weeks ago with an apparent upper respiratory or SaO2 − SvO2/SvO2. The normal extraction ratio is approxi-
tract infection, cough, and fever. She subsequently developed mately 0.25:0.33, which reflects a mixed venous saturation of
complaints of progressive fatigue, weakness, and dyspnea. 65% to 70%.
Overnight decompensation continues with increasing dyspnea 3. Match each of the following clinical scenarios with the best
and hypoxemia, requiring endotracheal intubation. She choice of vasoactive medication (a–d) listed below.
becomes hypotensive and oliguric despite repeated intravenous Scenario 1: A 58-year-old man with a history of hypertension
fluid boluses. The electrocardiogram (ECG) shows sinus tachy- and diabetes is brought to the ICU after successful angioplasty
cardia, with nonspecific ST-segment changes. Transaminase in the setting of acute myocardial infarction. The cardiac
levels are elevated: aspartate aminotransferase, 689 U/L; index is markedly low (1.5 L/min/m2). His blood pressure
alanine aminotransferase, 580 U/L. Pulmonary artery (PA) is 120/70 mm Hg and his heart rate is 115 beats/min.
catheterization is performed; right atrial (RA) pressure is Scenario 2: A 24-year-old woman without medical history
14 mm Hg; PA pressure is 43/26 mm Hg; pulmonary capil- presents with septic shock and is still hypotensive despite
lary wedge pressure is 22 mm Hg; cardiac index 1.3 L/min/ adequate cardiac filling pressures and a high rate of dopamine
m2; and systemic vascular resistance is 1250 dyne/sec/cm−5. infusion.
What is her likely diagnosis? Scenario 3: A 67-year-old man presents in shock after a motor
a. Pulmonary embolism vehicle collision in which he has spinal cord impingement
b. Septic shock at the C4-C5 vertebrae.
c. Acute myocardial infarction a. Dopamine
d. Acute myocarditis b. Norepinephrine
e. Anaphylactic shock c. Milrinone
Answer: d. This patient experienced a viral infection that d. Phenylephrine
progressed to acute viral myocarditis with cardiogenic shock. Answers: Scenario 1: c; Scenario 2: b; Scenario 3: d. Dopa-
Her mild transaminase elevation was secondary to a low cardiac mine stimulates dopaminergic, β-adrenergic, and α-adrenergic
output state. PA catheter findings in pulmonary embolism (PE) receptors. At low doses, dopamine receptor stimulation leads
include a depressed cardiac output/index, with elevated RA to improved renal perfusion. At moderate doses (5–10 μg/kg/
pressures, and an elevated PA diastolic to pulmonary capillary min), β1-adrenergic stimulation augments cardiac function. At
wedge pressure (PCWP) gradient (classically >10 mm Hg). In high doses (10–20 μg/kg/min) α-adrenergic receptor stimulation
PE-induced shock, the PCWP would be decreased because it causes peripheral vascular constriction. The β1 effects of dopamine
only produces hypotension by decreasing left ventricular (LV) can cause significant tachycardia. Therefore norepinephrine,
filling. Anaphylaxis and sepsis are both forms of distributive which strongly stimulates α-adrenergic receptors (with lesser
shock. These “hyperdynamic” forms of shock typically present β-adrenergic receptor stimulation), may increase blood pressure
with an elevated cardiac output/index. Central venous pressure without the chronotropic effects of dopamine. Phenylephrine,
(CVPs) and PCWPs are often low because of the intravascular which exclusively stimulates α-adrenergic receptors, can be
volume depletion resulting from profound capillary leak, and used as a venous and arterial vasoconstrictor for pure vasodila-
systemic vascular resistance (SVR) is markedly reduced from tory shock states such as neurogenic or anaphylactic shock.
arteriolar vasodilatation. Hypovolemic shock usually presents Milrinone inhibits cyclic adenosine monophosphate (cAMP)
with reduced cardiac index (CI), reduced CVP and PCWP, degradation. The overall effects of milrinone include increased
and very high SVR. Cardiogenic shock presents with reduced cardiac contractility and peripheral and pulmonary vasodilation.
cardiac indices, elevated CVP and PCWP, and elevated SVR Similar to dobutamine, the vasodilation associated with mil-
as seen in this patient. However, there is no ST-segment elevation rinone may precipitate arterial hypotension; thus this agent
or Q-wave suggesting an acute infarct in this case. must be used with caution in patients with marginal blood
2. Which of the following correctly defines oxygen consumption pressure.
(Q = cardiac output; CaO2 = arterial oxygen content; CvO2 = The first scenario is low cardiac output state with normal
mixed venous oxygen content; Hb = hemoglobin concentra- blood pressure and thus milrinone is the correct choice as the
tion; PaO2 = arterial partial pressure of oxygen; SaO2 = arterial use of dopamine may exacerbate tachycardia. In the second
oxygen consumption; SvO2 = venous oxygen saturation)? scenario, norepinephrine would be the best choice to achieve
a. Q × CaO2 an acceptable mean arterial pressure. The third scenario is “spinal
b. SaO2 − SvO2/SvO2 shock”; a pure vasoconstrictor (phenylephrine) is the best choice.
c. Q × (CaO2 − CvO2) 4. Which of the following is most correct regarding issues of
d. (1.34 × Hb × SaO2) + (0.0031 × PaO2) invasive hemodynamic monitoring?
Answer: c. Systemic oxygen delivery is defined as the product a. Many studies have proven that PA catheters improve
of cardiac output and the total oxygen content of arterial blood mortality.
(Q × CaO2). Oxygen content can be defined as the oxygen b. Manual sphygmomanometry or automated blood pressure
bound to arterial or venous hemoglobin (1.34 × Hb × S[a or cuffs are relatively accurate in shock states.
v]O2 plus the amount of oxygen dissolved in blood (0.0031 × c. Monitoring CVP can be helpful to accurately estimate left
P[a or v]O2). Oxygen consumption therefore can be defined as ventricle preload in the critically ill.
a difference between oxygen delivery and oxygen demand (Q d. Serum lactate will be elevated at mixed oxygen saturation
× [CaO2 − CvO2]). Calculating the oxygen extraction ratio levels below 30% to 40%.

Answer: d. Invasive hemodynamic monitoring may provide the techniques. Data from the PA catheter can be diagnostic (dif-
clinician with a great deal of important physiologic information. ferentiating shock states) or used to guide therapy. However,
Arterial catheters should be used for blood pressure measure- no study has linked PA catheter utilization with improved
ment in shock states. Manual and automated blood pressure outcomes. PA blood can be obtained to measure SvO2. In
measurement techniques have been found to be inaccurate in assessing oxygen supply dependency in shock, an SvO2 of 65%
hypotensive patients. CVP can be used to monitor volume to 70% suggests that global tissue oxygen supply is meeting
status. A markedly low CVP correctly identifies a hypovolemic tissue oxygen demands. Tissue oxygen extraction would be
state. However, a normal or high CVP value does not necessarily increased in this condition. Lactate accumulation and supply-
ensure adequate cardiac filling, because the value for CVP can dependent oxygen consumption reliably occur at SvO2 levels
be influenced by valvular heart disease or intrathoracic pressure. below 30% to 40%. However, lactate levels may be elevated at
PA catheters can provide data reflecting left venctricular preload higher levels of SvO2 if regional (rather than global) hypo-
(PCWP) and can measure cardiac output via thermodilution perfusion is occurring.

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Shock: Classification, Pathophysiology,

Classification Hypovolemic Shock

EXTRACARDIAC OBSTRUCTIVE CARDIOGENIC HYPOVOLEMIC DISTRIBUTIVE

• BOX 22.2 Classification of Shock

Diagnosis CO SVR PWP CVP SVO2 Comments

Mediator Major Reported Effects

Mediator Major Reported Effects

IL, Interleukin; INF-γ, interferon γ; TNF, tumor necrosis factor.

Hypovolemia Sepsis Myocardial dysfunction

Venous pressure Cardiovascular stress Renal perfusion

Stretch receptors Baroreceptors Renal juxtaglomerular

Hormonal Neural ACTH

Hemodynamic Basis of Shock Cardiac Output

2.0 ventricular afterload with the mechanical properties of the arterial

venous tone (i.e., venoconstriction). It is defined as the difference

Cardiac output and venous return

pressures, mean circulatory pressures and venous resistance. Altering

Cardiac output and venous return

performance interactions during hypovolemic shock (point A to B) and

N Pmc Rv that both vascular and myocardial responsiveness to sympathomimet-

Normal context of venous/cardiac interactions. For a detailed review of

Microvascular Function in Shock

Vasodilating factors Vasoconstricting factors

O2 O2–• SOD H2O2

OH• Tissue injury

beds, including skin, skeletal muscle, kidneys, and splanchnic TABLE

The utility of pulmonary artery catheterization has been

CARDIAC PERIPHERAL VASCULATURE

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