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SHOCK
Shock is the final common pathway for a number of potentially lethal clinical events,
including severe hemorrhage, extensive trauma or burns, large myocardial infarction,
massive pulmonary embolism, and microbial sepsis. Regardless of the underlying
pathology, shock gives rise to systemic hypoperfusion; it can be caused either by
reduced cardiac output or by reduced effective circulating blood volume. The end
results are hypotension, impaired tissue perfusion, and cellular hypoxia. Although the
hypoxic and metabolic effects of hypoperfusion initially cause only reversible cellular
injury, persistence of shock eventually causes irreversible tissue injury and can culminate
in the death of the patient.
There are three general categories of shock: cardiogenic, hypovolemic, and septic (Table
4-3). The mechanisms underlying cardiogenic and hypovolemic shock are fairly
straightforward; septic shock is substantially more complicated and is discussed in further
detail below.
Cardiogenic shock results from failure of the cardiac pump. This may be caused by
myocardial damage (infarction), ventricular arrhythmias, extrinsic compression (cardiac
tamponade, Chapter 11), or outflow obstruction (e.g., pulmonary
embolism).Hypovolemic shock results from loss of blood or plasma volume. This may be
caused by hemorrhage, fluid loss from severe burns, or trauma. Septic shock is caused by
microbial infection. Most commonly this occurs in the setting of gram-negative infections
(endotoxic shock), but it can also occur with gram-positive and fungal infections.
Notably, there need not be systemic bacteremia to induce septic shock; host inflammatory
responses to local extravascular infections may be sufficient (see below).
Table 4-3. Three Major Types of Shock
Type of Shock
Cardiogenic
Clinical Examples
Principal Mechanisms
Myocardial infarction
Ventricular rupture
Arrhythmia
Cardiac tamponade
Pulmonary embolism
Failure of myocardial pump
resulting from intrinsic
myocardial damage,
extrinsic pressure, or
obstruction to outflow
Hemorrhage
Fluid loss (e.g., vomiting,
diarrhea, burns, or trauma)
Inadequate blood or plasma
volume
Overwhelming microbial
infections
Endotoxic shock
Peripheral vasodilation and
pooling of blood;
endothelial
Hypovolemic
Septic
Gram-positive septicemia
Fungal sepsis
Superantigens (e.g. toxic
shock syndrome)
activation/injury; leukocyteinduced damage;
disseminated intravascular
coagulation; activation of
cytokine cascades
Less commonly, shock may occur in the setting of an anesthetic accident or a spinal cord
injury (neurogenic shock), as a result of loss of vascular tone and peripheral pooling of
blood. Anaphylactic shock represents systemic vasodilation and increased vascular
permeability caused by an immunoglobulin E hypersensitivity reaction (Chapter 5). In
these situations, acute severe widespread vasodilation results in tissue hypoperfusion and
cellular anoxia.
Pathogenesis of Septic Shock
With a 25% to 50% mortality rate, septic shock ranks first among the causes of death in
intensive care units and accounts for more than 200,000 deaths annually in the United
States. Moreover, the continuing increase in the incidence of sepsis syndromes is
attributable to improved life support for high-risk patients, an increase in invasive
procedures, and the growing numbers of immunocompromised hosts (secondary to
chemotherapy, immunosuppression, or infection with the human immunodeficiency
virus). Septic shock results from the host innate immune response to infectious organisms
that may be blood borne or localized to a particular site.
Most cases of septic shock (approximately 70%) are caused by endotoxin-producing
gram-negative bacilli (Chapter 9)-hence the term endotoxic shock. Endotoxins are
bacterial wall lipopolysaccharides (LPS) consisting of a toxic fatty acid (lipid A) core
common to all gram-negative bacteria, and a complex polysaccharide coat (including O
antigen) unique for each species. Analogous molecules in the walls of gram-positive
bacteria and fungi can also elicit septic shock.
All of the cellular and hemodynamic effects of septic shock can be reproduced by LPS
injection alone. Free LPS attaches to a circulating LPS-binding protein, and the complex
then binds to a specific receptor (CD14) on monocytes, macrophages, and neutrophils.
Engagement of CD14 (even at doses as minute as 10 pg/mL) results in intracellular
signaling via an associated "Toll-like receptor" protein 4 (TLR-4), resulting in profound
activation of mononuclear cells and production of potent effector cytokines such as IL-1
and TNF (Chapter 2). These cytokines act on endothelial cells and have a variety of
effects including reduced synthesis of anticoagulation factors such as tissue factor
pathway inhibitor and thrombomodulin (see Fig. 4-7). The effects of the cytokines may
be amplified by TLR-4 engagement on endothelial cells.
TLR-mediated activation helps to trigger the innate immune system to efficiently
eradicate invading microbes (Chapter 5). Unfortunately, depending on the dosage and the
extent of immune and vascular activation, the secondary effects of LPS release can also
cause severe pathologic changes, including fatal shock.
At low doses, LPS predominantly activates monocytes, macrophages, and neutrophils; it
can also directly activate complement, thereby contributing to local eradication of
bacteria. Mononuclear phagocytes respond to LPS by producing TNF, which in turn
induces IL-1 synthesis. Both TNF and IL-1 act on endothelial cells (and other cell types)
to produce additional cytokines (e.g., IL-6 and IL-8) and induce adhesion molecules
(Chapter 2). Thus, the initial release of LPS results in a circumscribed cytokine cascade
(Fig. 4-20 and Fig. 4-21) that enhances the local acute inflammatory response and
improves clearance of the infection.
With moderately severe infections, and therefore with higher levels of LPS (and a
consequent augmentation of the cytokine cascade), cytokine-induced secondary effectors
(e.g., nitric oxide and platelet-activating factor; Chapter 2) become significant. In
addition, systemic effects of TNF and IL-1 may begin to be seen, including fever,
increased synthesis of acute-phase reactants, and increased production of circulating
neutrophils (see Fig. 4-21). Higher LPS levels tip the endothelium toward a net
procoagulant phenotype.
Finally, at still higher levels of LPS, the syndrome of septic shock supervenes (see Fig. 421); the same cytokine and secondary mediators, now at high levels, result in
Systemic vasodilation (hypotension)Diminished myocardial contractilityWidespread
endothelial injury and activation, causing systemic leukocyte adhesion and diffuse
alveolar capillary damage in the lung (Chapter 13)Activation of the coagulation system,
culminating in disseminated intravascular coagulation (DIC) (Chapter 12)
Figure 4-20 Cytokine cascade in sepsis. After lipopolysaccharide (LPS) release there are
successive waves of tumor necrosis factor (TNF), interleukin 1 (IL-1), and IL-6 secretion.
(Modified from Abbas AK, et al: Cellular and Molecular Immunology, 4th ed.
Philadelphia, WB Saunders, 2000.)
The hypoperfusion resulting from the combined effects of widespread vasodilation,
myocardial pump failure, and DIC causes multiorgan system failure that affects the liver,
kidneys, and central nervous system, among others. Unless the underlying infection (and
LPS overload) is rapidly brought under control, the patient usually dies. In some
experimental animal models, soluble CD14, antibodies to LPS-binding proteins, or
pharmacologic inhibitors of the secondary mediators (e.g., nitric oxide synthesis) have
demonstrated some efficacy in protecting against septic shock. Unfortunately, these
interventions have not yet proved of significant clinical benefit in patients, perhaps
because many different pathways and mediators are activated by LPS.
An interesting group of bacterial proteins called superantigens also causes a syndrome
similar to septic shock (e.g., toxic shock syndrome toxin 1, responsible for the toxic
shock syndrome). Superantigens are polyclonal T-lymphocyte activators that induce
systemic inflammatory cytokine cascades similar to those that occur in response to LPS.
Their actions can result in a variety of clinical manifestations ranging from a diffuse rash
to vasodilation, hypotension, and death.
Stages of Shock
Figure 4-21 Effects of lipopolysaccharide (LPS) and secondarily induced effector
molecules. LPS initiates the cytokine cascade described in Fig. 4-21. In addition, LPS
and the secondary mediators can also directly stimulate downstream cytokine production,
as indicated. Secondary effectors that become important include nitric oxide (NO) and
platelet-activating factor (PAF). At low levels, only local inflammatory effects are seen.
With moderate levels, more systemic events occur in addition to the local vascular
effects. At high concentrations, the syndrome of septic shock supervenes. ARDS, adult
respiratory distress syndrome; DIC, disseminated intravascular coagulation; IL-1,
interleukin 1; IL-6, interleukin 6; IL-8, interleukin 8; TNF, tumor necrosis factor.
(Modified from Abbas AK, et al: Cellular and Molecular Immunology, 4th ed.
Philadelphia, WB Saunders, 2000.)
Shock is a progressive disorder that if uncorrected leads to death. Unless the insult is
massive and rapidly lethal (e.g., a massive hemorrhage from a ruptured aortic aneurysm),
shock tends to evolve through three general (albeit somewhat artificial) stages. These
stages have been documented most clearly in hypovolemic shock but are common to
other forms as well:
An initial nonprogressive stage during which reflex compensatory mechanisms are
activated and perfusion of vital organs is maintained. A progressive stage characterized
by tissue hypoperfusion and onset of worsening circulatory and metabolic imbalances.
An irreversible stage that sets in after the body has incurred cellular and tissue injury so
severe that even if the hemodynamic defects are corrected, survival is not possible
In the early, nonprogressive phase of shock, various neurohumoral mechanisms help
maintain cardiac output and blood pressure. These include baroreceptor reflexes, release
of catecholamines, activation of the renin-angiotensin axis, antidiuretic hormone release,
and generalized sympathetic stimulation. The net effect is tachycardia, peripheral
vasoconstriction, and renal conservation of fluid. Cutaneous vasoconstriction, for
example, is responsible for the characteristic coolness and pallor of skin in shock
(although septic shock may initially cause cutaneous vasodilation and thus present with
warm, flushed skin). Coronary and cerebral vessels are less sensitive to the sympathetic
response and thus maintain relatively normal caliber, blood flow, and oxygen delivery to
their respective vital organs.
If the underlying causes are not corrected, shock passes imperceptibly to the progressive
phase, during which there is widespread tissue hypoxia. In the setting of persistent
oxygen deficit, intracellular aerobic respiration is replaced by anaerobic glycolysis, with
excessive production of lactic acid. The resultant metabolic lactic acidosis lowers the
tissue pH and blunts the vasomotor response; arterioles dilate, and blood begins to pool
in the microcirculation. Peripheral pooling not only worsens the cardiac output but also
puts endothelial cells at risk of developing anoxic injury with subsequent DIC. With
widespread tissue hypoxia, vital organs are affected and begin to fail.
Unless there is intervention, the process eventually enters an irreversible stage.
Widespread cell injury is reflected in lysosomal enzyme leakage, further aggravating the
shock state. Myocardial contractile function worsens, in part because of nitric oxide
synthesis. If ischemic bowel allows intestinal flora to enter the circulation, endotoxic
shock may also be superimposed. At this point, the patient has complete renal shutdown
due to ischemic acute tubular necrosis (Chapter 14), and, despite heroic measures, the
downward clinical spiral almost inevitably culminates in death.
Morphology
The cellular and tissue changes induced by shock are essentially those of hypoxic injury
(Chapter 1), due to some combination of hypoperfusion and microvascular thrombosis.
Since shock is characterized by failure of many organ systems, the cellular changes may
appear in any tissue. Nevertheless, they are particularly evident in the brain, heart,
kidneys, adrenal glands, and gastrointestinal tract. Fibrin thrombi may be identified in
virtually any tissue, although they are usually most readily visualized in kidney
glomeruli. The adrenal changes in shock are those seen in all forms of stress; essentially
there is cortical cell lipid depletion. This reflects not adrenal exhaustion but instead
conversion of the relatively inactive vacuolated cells to metabolically active cells that use
stored lipids for the synthesis of steroids. The kidneys typically reveal acute tubular
necrosis (Chapter 14) so that oliguria, anuria, and electrolyte disturbances dominate the
clinical picture. The gastrointestinal tract may mainfest focal mucosal hemorrhage and
necrosis. The lungs are seldom affected in pure hypovolemic shock, because they are
somewhat resistant to hypoxic injury. However, when shock is caused by bacterial sepsis
or trauma, changes of diffuse alveolar damage (Chapter 13) may develop, the so-called
shock lung.
With the exception of neuronal and myocyte ischemic loss, virtually all tissues may
revert to normal if the patient survives. Unfortunately, most patients with irreversible
changes due to severe shock die before the tissues can recover.
Clinical Course
The clinical manifestations of shock depend on the precipitating insult. In hypovolemic
and cardiogenic shock, the patient presents with hypotension; a weak, rapid pulse;
tachypnea; and cool, clammy, cyanotic skin. In septic shock, however, the skin may be
warm and flushed as a result of peripheral vasodilation. The initial threat to life stems
from the underlying catastrophe that precipitated the shock state (e.g., a myocardial
infarct, severe hemorrhage, or bacterial infection). Rapidly, however, the cardiac,
cerebral, and pulmonary changes that occur secondary to the shock state materially
worsen the problem. If patients survive the initial complications, they enter a second
phase, dominated by renal insufficiency and marked by a progressive fall in urine output
as well as acidosis, and severe fluid and electrolyte imbalances.
The prognosis varies with the origin of shock and its duration. Thus, 80% to 90% of
young, otherwise healthy patients with hypovolemic shock survive with appropriate
management, whereas cardiogenic shock associated with extensive myocardial infarction,
or gram-negative sepsis carries a mortality rate of 75%, even with care that is state of the
art.
SUMMARY
Shock
Shock causes systemic hypoperfusion due to either reduced cardiac output or reduced
circulating blood volume.The most common causes of shock are cardiogenic (cardiac
pump failure due, for example, to myocardial infarction), hypovolemic (due, for example,
to blood loss), and sepsis (due to infections).Septic shock results from the host innate
immune response to bacterial or fungal cell molecules (most commonly endotoxin), with
systemic production of cytokines, such as TNF and IL-1, that affect endothelial and
inflammatory cell activation.Hypotension, DIC, and metabolic disturbances constitute the
clinical triad of septic shock.Shock of any form causes pathology by inducing prolonged
tissue hypoxic injury.