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Algorithm 9-1. Neurohormonal response to hypovolemia. CNS, central nervous system; ACTH, adrenocorticotropic hormone; AVP,

arginine vasopressin.

Adrenergic-mediated vasoconstriction affects arterioles, pre- and postcapillary sphincters, and small

veins and venules. Due to this specific vasoconstriction, decreased hydrostatic pressure distal to the

precapillary sphincter occurs that leads to reabsorption of interstitial fluid (water, sodium [Na+], and

chloride [Cl−]) into the vascular space. This functions to restore circulating blood volume and is known

as transcapillary refill.42

Sustained Response

Sustained compensatory responses include the release of vasoactive hormones and fluid shifts from the

interstitium and the intracellular space to the intravascular compartment. Decreased renal blood flow,

increased adrenergic activity, and compositional changes in tubular fluid lead to the secretion of renin

from the juxtaglomerular complex. Renin results in increased formation and release of angiotensin I by

the liver. Circulating angiotensin I is rapidly converted to angiotensin II by the lungs and is the most

potent known arterial and arteriolar vasoconstrictor. Angiotensin II also stimulates the release of

pituitary ACTH. Increased circulating levels of both angiotensin II and ACTH result in increased

secretion of aldosterone. As a result, reabsorption of Na+ in the distal renal tubules in exchange for

potassium (K+) and hydrogen ions occurs.

Additionally, due to hypovolemia and increased serum osmolarity, reduced stimulation of arterial

baroreceptors occurs, leading to the release of arginine vasopressin (AVP), also known as antidiuretic

hormone (ADH). This hormone not only functions as a potent vasoconstrictor but also causes increased

reabsorption of water by increasing water permeability and passive Na+ transport in the distal renal

tubule. The overall net effect of aldosterone and AVP is to decrease glomerular filtration and increase

salt and water tubular reabsorption in an effort to replace circulating intravascular volume deficits.

Finally, the increased release of the stress hormones (epinephrine, ACTH, cortisol, and glucagon)

leads to glycogenolysis, lipolysis, and protein catabolism, causing a negative nitrogen balance and high

extracellular concentration of glucose due to decreased insulin release and resistance. This leads to

increased glucose utilization by insulin-independent tissues such as the brain and heart. In addition to

glucose, products of anaerobic metabolism from hypoperfused cells accumulate in the extracellular

compartment, inducing hyperosmolarity. This extracellular hyperosmolarity draws water from the

intracellular space, increasing interstitial osmotic pressure, which in turn drives water, Na+, and Cl−

across the capillary endothelium into the vascular space.

ORGAN-SPECIFIC COMPENSATORY RESPONSES TO SHOCK

Cardiac and Microvascular Response

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Cardiovascular physiology is profoundly affected by shock (Table 9-3). Reduced stroke volume is caused

by an absolute or relative loss of preload. Intrinsic neuroendocrine and renal compensatory responses,

along with additional intravenous fluid, are needed to increase ventricular end-diastolic volume.

Restoration of adequate preload alone is often sufficient to return cardiac output to levels required to

overcome peripheral perfusion deficits. However, some cases are complicated by acquired myocardial

contractility derangements. Contractile function under these conditions is less a function of preload and

more related to intrinsic myocardial dysfunction.

A defining characteristic of shock is compromise of microvascular perfusion. Far from being a passive

conduit, the microvasculature actively participates in the response to shock. Arteriolar vessels are

innervated by sympathetic nerves, as are small veins and venules. The vasoconstriction of hypovolemic

shock and the vasodilation of septic and neurogenic shock are a result of these autonomic responses.

The majority of the circulating blood volume resides in the venous system, and normal physiologic

compensation mechanisms rely on this venous blood pool as an autotransfusion reservoir. Collapse of

underperfused veins passively propels blood toward the heart, while α-adrenergic venoconstriction

actively mobilizes the venous pool. Profound peripheral vasoconstriction via α-adrenergic, vasopressin,

angiotensin II, and endothelin-1 stimulation of arteriolar and precapillary smooth muscle sphincters

selectively diminishes perfusion to dermal, renal, muscle, and, significantly, splanchnic vascular beds to

preserve perfusion of critical central organs, primarily the central nervous system (CNS) and

myocardium.43

The capillary endothelial monolayer maintains a semipermeable barrier between the intra- and

extraluminal spaces and is compromised by shock.44 Circulating inflammatory mediators and byproducts

of infection (LPS, thrombin, tumor necrosis factor alpha [TNF-α], interleukin [IL]-1, nitric oxide, and

endothelin-1) generated in response to traumatic or septic shock have been shown to induce and sustain

endothelial capillary leak. Although the exact mechanisms of endothelial monolayer dysfunction are

unclear, the only available therapies to reverse microvascular decompensation are timely restoration of

peripheral perfusion, rapid elimination of infectious and necrotic tissue, and pharmacologic and

mechanical support of cardiopulmonary function.45–46

Neuroendocrine Response

The neuroendocrine reaction to shock consists of involuntary responses by the hypothalamus, autonomic

nervous system, and secretory endocrine glands and is directed toward restoration of tissue perfusion

and a redirected utilization of metabolic substrates. The autonomic response is initially triggered by

hypoxia, hypotension, or hypovolemia detected by aortic and carotid baroreceptors and chemoreceptors

(Algorithm 9-2). Subsequently, sympathetic vasoconstriction of specific vascular beds, induced by direct

synaptic release of norepinephrine, results in redistribution of circulating blood volume from tissue of

low metabolic activity to more metabolically demanding organs. Cardiac output, diminished by loss of

preload, is augmented by inhibition of cardiac vagal activity and a resulting reflex tachycardia.

Circulating epinephrine and norepinephrine alter several aspects of glucose utilization, availability,

and metabolism. The hyperglycemia of stress results from catecholamine-induced glycogenolysis,

gluconeogenesis, and decreased pancreatic insulin release. Simultaneously, hypothalamic stimulation of

the anterior pituitary induces release of ACTH, which in turn prompts cortisol and aldosterone release

by the adrenal cortex. Elevated serum cortisol contributes to postinjury hyperglycemia by increasing

gluconeogenesis, enhancing lipolysis, and diminishing peripheral utilization of glucose and amino acids.

The pancreatic response is characterized by a decrease in insulin release and an increase in glucagon

secretion, which further stimulates hepatic gluconeogenesis. The combined actions of catecholamines,

cortisol, and glucagon are synergistic and create a shock-related hyperglycemia that is often refractory

to insulin treatment.

Renal juxtaglomerular secretion of renin in response toadrenergic stimulation and renal

hypoperfusion triggers the formation of angiotensin I in the liver, which is subsequently converted to

angiotensin II by the lungs. Angiotensin II, a potent vasoconstrictor, augments shock-induced

catecholamine-mediated peripheral and splanchnic vasoconstriction and stimulates aldosterone release

from the adrenal cortex. Renal tubular reabsorption of sodium in response to elevated circulating

aldosterone creates highly concentrated, low-volume urine. Vasopressin secretion by the posterior

pituitary similarly contributes to compensatory restoration and maintenance of intravascular volume by

promoting water reabsorption by the renal distal tubules and by causing peripheral and splanchnic

vasoconstriction. A major result is a prolonged severe hypoperfusion of the splanchnic vascular bed,

further augmenting the deleterious host response.

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Algorithm 9-2. Shock resuscitation algorithm. ATLS, advanced trauma life support; ACLS, advanced cardiac life support; SBP,

systolic blood pressure; CVP, central venous pressure; HCT, hematocrit; VS, vital signs; TTE, transthoracic echocardiography; PAC,

pulmonary artery catheter; CI, cardiac index; MAP, mean arterial pressure.

Immunoinflammatory Response

Many shock-inducing events, particularly those associated with septic or traumatic shock,

simultaneously trigger a massive systemic inflammatory response. Although inflammatory mediators

(TNF-α, ILs, chemokines, etc.) play an integral role in the recovery of local tissue to trauma and

infection, an uncontrolled systemic inflammatory response contributes to organ failure.

Immunologically active cells involved in the systemic inflammatory response include nucleated blood

cells (monocytes, polymorphonuclear leukocytes [PMNs]) and platelets, microvascular endothelial cells,

and tissue macrophages. These cells generate and secrete scores of signal-amplifying inflammatory

mediators ranging in complexity from individual molecules (nitric oxide) to large multisubunit,

extensively modified proteins (TNF-α, IL-1, etc.). Even transient systemic elevation of any of these

mediators has profound physiologic consequences.

Local tissue destruction, microbial contamination, and infection similarly activate the coagulation

cascade and induce platelet aggregation and release of numerous platelet-, endothelial-, and clot-derived

vasoactive mediators. Persistent, profound, and recurring microvascular hypoperfusion of the splanchnic

and other organs likewise causes local tissue ischemia, parenchymal cell injury, microvascular

coagulation, activation of inflammatory cells, and release of inflammatory mediators. Circulating

monocyte, lymphocyte, and PMN adherence to activated endothelium results in extraluminal

transmigration of these inflammatory cells into tissues remote from the area of injury. This

hyperdynamic immunologic response, with continued generation of proinflammatory mediators, is

responsible for the progression of SIRS toward MODS.47–50

Regulation of the systemic inflammatory response has been an active area of shock research for

several decades. Elimination of particular inflammatory mediators from the systemic circulation, or

inhibition of particular cell–cell interactions in experimental animal systems, has been shown to

improve outcomes after shock resuscitation.51–55 However, to date, all efforts to regulate the SIRS

response with therapeutic elimination or supplementation of specific proinflammatory and antiinflammatory mediators have proven ineffective or even harmful in humans. This lack of efficacy may

relate to inadequacy of current animal models of shock, sepsis, and organ failure or to inadequate

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understanding of the full spectrum and interactive nature of key elements that regulate this syndrome.

Unfortunately, the network of inflammatory mediators and affected cells is so complex and redundant

that no single agent is likely to be effective at interrupting this response. As a result, there is probably

no single common pathway likely to respond to a “silver bullet” approach.

Pulmonary Response

The lung is the organ system most sensitive to systemic insult and injury and is frequently the first

organ to fail in the progression to MODS. ARDS represents a high-mortality form of pulmonary

insufficiency that is often precipitated by sepsis or traumatic shock. It is triggered and perpetuated by

the numerous inflammatory mediators created in the hypoperfused microvasculature elsewhere in the

body.51–56

Interstitial edema and subsequent reduced compliance result in diminished tidal volume and

tachypnea, compromising gas exchange. Surfactant abnormalities contribute to alveolar collapse,

resulting in loss of functional residual capacity (FRC) and the onset of pulmonary insufficiency. The

pulmonary microvascular response mirrors the systemic response, with angiotensin and α-adrenergic–

induced vasoconstriction creating significant elevations of pulmonary vascular resistance, further

straining the heart. Pulmonary parenchymal injury may be propagated by excessive positive-pressure

ventilation generated by alveolar overdistention in particular, further contributing to alveolar damage.

No specific measures are available to reverse the ARDS process; therefore, aggressive management of

predisposing conditions is most appropriate. Once ARDS has become fully developed, treatment

involves intensive supportive care while minimizing iatrogenic insults. As a result, early utilization of

lung-protective strategies may diminish progressive ventilator-induced lung injury and improve

outcome.57

Renal Response

Direct sympathetic-induced renal vasoconstriction increases afferent arteriole resistance in response to

shock. This effect is reinforced by elevated circulating angiotensin II and catecholamines. The resulting

decrease in renal blood flow and glomerular filtration rate (GFR), along with elevated circulating

aldosterone and vasopressin (ADH), produce oliguria and prerenal azotemia. Acute tubular necrosis

(ATN) may result from prolonged decreases in renal cortical blood flow, as well as from toxins

generated during sepsis. Oliguric renal failure, like the pulmonary insufficiency of ARDS, is a common

component of MODS.

Distinguishing low urine output due to oliguric renal failure from the oliguria of decreased renal

perfusion pressure can be aided by analyzing urine sodium and osmolality. Renal hypoperfusion usually

results in urine sodium of less than 20 mEq/L with an osmolality of greater than 400 mOsm/kg,

whereas acute tubular injury impairs sodium reabsorption and is associated with a low urinary

osmolality. A fractional excretion of sodium of less than 1% may also help determine whether the cause

is renal or prerenal.

Early detection of abnormal kidney function is critical to prevent progression to renal injury.

Abnormal renal function can be detected as a decline in creatinine clearance. The correlation between a

creatinine clearance based on a 24-hour collection and a sample collected over a shorter interval is poor.

However, the 24-hour value represents an average value over that time. A sample obtained over a

shorter period may reflect the time in question and allow timely recognition and treatment of renal

dysfunction.

Hepatic Response

Ischemic injury to liver is not apparent early during shock. However, the liver plays an important role

in the regulation of shock and subsequent tissue injury through both the release of acute-phase reactants

and lack of clearance of potential toxic agents. As shock continues, hepatic necrosis occurs, leading to

the release of aspartate aminotransferase and alanine aminotransferase. Continued shock results in

attenuated synthesis of coagulation factors, albumin and prealbumin. Although progressive ischemia can

occur, leading to complete loss of glycogen stores and marked hypoglycemia, this condition is rare

without pre-existing liver disease, significant direct liver injury, or hepatic artery occlusion.

Genetic Regulation of the Response to Shock

Individuals vary considerably in their susceptibility to shock and in their ability to recover from its

consequences. Recently, unique host-specific responses have been identified as important determinants

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