Mechanisms Underlying Impaired Cardiovascular Performance

The development of shock is related to alterations in one or more components of the circulatory system that regulate cardiovascular performance. The first component is intravascular volume, which regulates mean circulatory pressures and venous return to the heart. Decreases in intravascular volume limit venous return to the heart and cardiac output. The heart is the second component. Cardiac output is determined by heart rate, contractility, and loading conditions. Abnormalities in rhythm and heart rate may limit cardiac output. Impaired cardiac contractility decreases effective ventricular ejection and compromises stroke volume. Abnormalities in valvular function may also limit cardiac output. The third component is the resistance circuit and consists of the arteriolar bed, where the major decreases in vascular resistance occur. Arteriolar tone plays an important role in ventricular loading conditions, arterial pressure, and the distribution of systemic blood flow. Excessive decreases in arteriolar tone produce hypotension and limit effective organ perfusion, whereas excessive increases in arteriolar tone impede cardiac ejection by increasing ventricular afterload. Differences in arteriolar tone between organs can result in maldistribution of blood flow and mismatching of blood supply with tissue metabolic demands. The capillaries are the fourth component. They are the site of nutrient exchange and fluid flux between the intravascular and extravascular spaces. Increases in capillary permeability result in tissue edema and loss of intravascular volume. Decreases in capillary cross-sectional area, due to either obstruction or impairment in endothelial cell function, compromise nutrient blood flow. The opening of arteriovenous connections which bypass the capillary network may play a role in tissue hypoperfusion. The venules are the fifth component. They are the site of lowest shear stress in the circulatory system, and thus the site most prone to occlusion from alterations in cell rheology. Venular resistance contributes 10% to 15% of total vascular resistance. Increases in venular tone increase capillary hydrostatic pressures, thereby promoting the extravascular movement of fluid. The sixth component is the venous capacitance circuit. More than 80% of the total blood volume resides in the large-capacitance vessels. Increases in venous tone decrease venous capacitance, redistributing blood volume centrally and thereby increasing venous return to the heart. Decreases in venous tone increase venous capacitance and decrease effective arterial blood volume and venous return. The seventh component is mainstream patency. Obstruction of the systemic or pulmonary circuit impedes ventricular ejection, while venous obstruction limits venous return to the ventricles.

Hemodynamic Assessment

Circulatory performance can be assessed from hemodynamic parameters. A low heart rate may limit cardiac output, whereas increased heart rates can compromise stroke volumes by limiting ventricular filling times. Bradyarrhythmias indicate structural abnormalities, the effects of drugs, hypoxia, or other metabolic stimuli. Severe bradyarrhythmias can also represent reflex-mediated responses, as occurs in cases of severe hemorrhagic shock, acute inferior wall myocardial infarction, and neurocardiogenic syncope (although not a true shock state). Tachyarrhythmias may be due to underlying cardiac disease and pharmacologic or environmental stimuli. Alternatively, increases in heart rate may reflect compensatory responses to maintain cardiac output.

In patients with circulatory shock, blood pressure should be monitored using intravascular measurements. Vasoconstriction due to compensatory mechanisms to maintain arterial pressure and the use of pharmacologic agents limits the accuracy of noninvasive measurements. This is particularly true in hypodynamic forms of circulatory failure.³

For most vital organs, autoregulatory and neuronal mechanisms maintain blood flow independent of blood pressure at a mean arterial pressure of 60 to 130 mm Hg.⁴ At either higher or lower levels of pressure, blood flow becomes linearly dependent on blood pressure. Diseases such as hypertension can shift this relationship and increase the critical level of arterial pressure required for organ perfusion. Similarly, impaired autoregulatory mechanisms present in a variety of pathologic states expand the range of pressure-dependent blood flow.

The level of arterial pressure is not a reliable indicator of circulatory performance and tissue perfusion.^5,6 In states of hypodynamic circulatory shock, hypotension is a late marker of critical hypoperfusion. As cardiac output falls, blood pressure is initially maintained by increases in peripheral vascular resistance largely mediated by the sympathoadrenal system, and it is only after these mechanisms have been exhausted that hypotension develops. In this setting, tissue hypoperfusion may be present despite normal levels of blood pressure as blood flow is redirected toward more vital organs.^7,8 Conversely, hypotension may exist without evidence of organ hypoperfusion. In some vasodilated states, increases in cardiac output maintain vital organ blood flow despite decreased levels of arterial pressure.

Pulmonary artery wedge pressure and central venous pressure are indirect measures of ventricular preload. These measurements correlate poorly with blood volume, end-diastolic volumes, and fluid responsiveness.^9,10 Filling pressures are determined by ventricular compliance, venous return, and systolic function. Factors such as ventricular interactions, positive airway pressure, and intrinsic cardiac disease may decrease ventricular compliance and lead to an overestimation of ventricular preload.⁹ Echocardiographic techniques can provide a more accurate assessment of ventricular loading conditions, while dynamic indicators such as pulse pressure variation or stroke volume variation may provide greater insight as to fluid responsiveness.^11,12

Cardiac output can be measured by multiple techniques. Pulmonary artery thermodilution has been augmented by less invasive techniques including transpulmonary thermodilution and lithium dilution, echocardiography, esophageal Doppler, and arterial pulse contour analysis. End-systolic pressure-volume measurements are independent of loading conditions and are the most reliable measurement of cardiac contractility. Echocardiographic measurements and esophageal Doppler can be used to assess ventricular ejection. The response of stroke volume to changes in ventricular loading during fluid infusion is also useful to assess cardiac contractility. However, the adequacy of cardiac output in meeting tissue metabolic demands must be assessed independently by monitoring indices of tissue perfusion and oxygen metabolism. A low cardiac output may be adequate when metabolic requirements are decreased—for example, deep sedation or hypothermia. In contrast, an increased cardiac output may not be adequate when metabolic requirements are increased or maldistribution of blood flow exists, such as in septic shock.

Systemic vascular resistance is an indicator of arterial tone and is calculated from cardiac output and arterial pressure. Increases in systemic vascular resistance are due to vasoconstriction and represent compensatory mechanisms directed at maintaining blood pressure in the setting of decreased cardiac output. Excessive increases in vascular resistance increase ventricular afterload and the impedance to ejection. Decreases in vascular resistance are due to vasodilation, decreases in blood viscosity, or the presence of arteriovenous connections. Vasodilation may be pathologic, as occurs in septic shock and liver disease, or it may be adaptive, as occurs in hyperdynamic stress following major surgery and traumatic injury. Venous tone is much harder to assess clinically. In most cases, changes in venous tone will parallel changes in arterial tone. Modest increases in central venous pressures in the setting of large-volume infusion and the absence of intravascular volume loss suggest decreased venous tone.

Progression of Shock

Critical reductions in tissue perfusion elicit a complex set of reflexes that are directed at maintaining cardiac output and arterial pressure.⁴ Activation of the sympathetic system increases heart rate and contractility. The release of catecholamines, angiotensin, vasopressin, and endothelins increases arteriolar and venous tone, thereby increasing arterial blood pressure and shifting blood volume from the capacitance vessels to the central circulation. In addition, blood flow is redirected from skeletal muscle, subcutaneous tissue, and the splanchnic circulation to the heart and brain. Vasopressin and activation of the renin-angiotensin system serve to enhance water and sodium retention, thereby protecting intravascular blood volume.

Progression of the shock state is marked by further declines in blood pressure that compromise coronary perfusion and cardiac performance. Increases in peripheral vascular resistance impede left ventricular ejection by increasing left ventricular afterload. Terminal phases of shock are marked by vasomotor dysfunction characterized by loss of arteriolar tone with paradoxical increased venular resistance. The resulting increase in capillary hydrostatic pressure coupled with increased microvascular permeability leads to a loss of intravascular volume and worsening of the shock state. Leukostasis and changes in erythrocyte rheology further impair microvascular blood flow. In animal models of hemorrhagic shock, a state of irreversible shock evolves from which the animals cannot be successfully resuscitated.¹⁹

This pathophysiology is altered in patients with hyperdynamic forms of circulatory failure such as septic shock, where inflammatory mediators play a prominent role.²⁰ These patients are characterized by arterial and venous dilation and increased cardiac output. The influence of vasodilatory substances such as nitric oxide predominates over the effects of endogenous and exogenous vasopressor substances. In some forms of vasodilatory shock, inappropriately low levels of vasopressin and cortisol may contribute to vasodilation and refractoriness to catecholamines.^21,22 Decreases in capillary cross-sectional area due to the interactions of activated leukocytes, platelets, endothelial cells, and the clotting cascade limit effective nutrient blood flow despite the increase in cardiac output.^23,24 Progressive hypotension refractory to fluid infusion and vasopressors results in worsening tissue hypoperfusion, acidosis, and organ failure. A hypodynamic circulation develops as a terminal event.

Oxidative Metabolism in Shock

The primary metabolic defect in circulatory shock is impaired oxidative metabolism with resulting cellular and organ failure. This impairment is most commonly due to decreases in tissue oxygen supply caused by either global decreases in blood flow or maldistribution of blood flow on a regional or microcirculatory level. Systemic oxygen consumption may initially be increased yet inadequate to meet tissue metabolic requirements; however, the terminal phases of all forms of shock are characterized by decreases in oxygen consumption. In experimental studies, the risk of mortality is directly related to the total amount of accumulated oxygen debt.²⁵

Oxygen delivery is determined by cardiac output, hemoglobin concentration, and the arterial oxygen saturation. Under normal circumstances, oxygen consumption is independent of oxygen delivery and cardiac output (Figure 90-1). Increases in cellular oxygen extraction from a normal level of 25% to a maximum of level of 80% maintain oxygen consumption as blood flow is reduced. When oxygen extraction is maximized, a critical level of oxygen delivery (DO₂crit) is reached below which oxygen consumption decreases and anaerobic metabolism ensues. Alterations in vasomotor reflexes due to sepsis or drugs limit maximal oxygen extraction, resulting in critical tissue hypoxia and anaerobic metabolism at higher levels of oxygen delivery.^26,27

Figure 90-1 Oxygen consumption/oxygen delivery relationships.

Oxygen consumption (VO₂) is independent of oxygen delivery (DO₂) until a critical level of DO₂ is reached at which oxygen extraction has been maximized. At that level of oxygen delivery (DO₂crit), VO₂ becomes linearly dependant on DO₂, and anaerobic metabolism manifested by lactic acidosis ensues. This relationship shifts upward and to the right when the ability of the tissues to extract oxygen is impaired due to alterations in the distribution of blood flow.

Aerobic adenosine triphosphate (ATP) generation is dependent on glycolysis occurring in the cytoplasm and oxidative phosphorylation occurring in the mitochondria (Figure 90-2). Under anaerobic conditions, ATP generation is limited to the two ATP generated in the cytoplasm, as compared to the 38 ATP generated aerobically. The decreased entry of pyruvate into the citric acid cycle results in the accumulation of lactic acid and the generation of additional hydrogen ions from the hydrolysis of ATP. Accordingly, the presence of lactic acidosis serves as an indicator of critical cellular deficits in high-energy phosphate metabolism. The normal level of lactate is 0.4 mEq/L to 1.2 mEq/L; levels greater than 2 mEq/L are associated with an increased mortality rate.²⁸

Figure 90-2 Cellular oxidative metabolism.

Glucose is metabolized anaerobically in the cytoplasm and aerobically in the mitochondria under conditions of normal tissue perfusion. In conditions of shock, high-energy phosphate generation (ATP) is limited to anaerobic pathways. Nitric oxide (NO), peroxynitrite (ONOO⁻), and superoxide (O₂⁻) are potential inhibitors of the electron transfer chain.

Oxidative metabolism may also be impaired by mechanisms independent of tissue hypoperfusion. A number of inflammatory mediators including nitric oxide, endotoxin, oxygen radicals, calcium, and tumor necrosis factor impair mitochondrial function. Mitochondrial abnormalities have been observed in animal models of septic shock and in cases of reperfusion injury.²⁹ Serum from patients with septic shock inhibits mitochondrial respiration and decreases cellular ATP concentration in vitro.³⁰ A potential pathway of direct mitochondrial impairment involves nitric oxide and its metabolite, peroxynitrite. Both of these substances can directly impair mitochondrial electron chain complexes.³¹

Accumulation of tissue carbon dioxide (CO₂) parallels the development of oxygen debt in circulatory shock.³² Clinically, increases in tissue CO₂ levels are manifested by venous hypercapnia and decreases in venous pH. The result is a widening of the arterial-venous CO₂ gradient proportional to the degree of circulatory failure. The normal gradient is less than 5 mm Hg, and it can increase to 40 mm Hg during cardiac arrest.³³ Decreased clearance of CO₂ generated by oxidative processes is responsible for the initial increase in tissue CO₂ levels. With the onset of anaerobic metabolism, tissue CO₂ excess is largely generated from titration of anaerobically derived acids by bicarbonate. The increase in tissue CO₂ levels may have physiologic significance and has been associated with impaired myocardial performance in vitro.

Monitoring Perfusion Failure

Controversy exists over the optimal manner in which to monitor tissue perfusion in patients with circulatory shock. Commonly utilized parameters such as heart rate, arterial pressure, and cardiac output correlate poorly with survival in critically ill patients.^5,6 This is particularly true in patients with septic shock and traumatic injury, in whom underlying deficits in tissue perfusion may exist despite initial resuscitative efforts.^5,34 These observations have led to the use of indices of tissue oxygen metabolism as markers of tissue perfusion and the adequacy of resuscitative efforts.

Mixed venous oxygen saturation (SvO₂) measured on blood taken from the pulmonary artery is used as an index of tissue oxygenation. Venous blood is in equilibrium with the tissues. Mixed venous blood, representing a weighted mean of all the venous effluents, reflects overall tissue oxygenation. Since increased oxygen extraction is the primary compensatory mechanism to maintain oxygen consumption, decreases in SvO₂ are an early marker of compromised tissue perfusion. In cardiogenic shock, SvO₂ tracks cardiac function and systemic perfusion.³⁵ The same is not true in septic shock and other settings where the relationship between venous blood and tissue oxygenation is altered by maldistribution of blood flow.¹⁵ In these circumstances, the ability of the tissues to extract oxygen is limited by decreases in effective nutrient flow such that SvO₂ may be increased or normal despite the presence of tissue hypoxia and anaerobic metabolism. Accordingly, while mixed venous desaturation is indicative of tissue hypoxia, normal levels do not preclude tissue hypoperfusion.

Central venous oxygen saturation (ScvO₂) measured on samples taken from the superior vena cava and right atrium serves as an alternative to SvO₂.^36,37 In critically ill patients, the ScvO₂ is generally 5% higher than SvO₂; however, their correlation is inconsistent, depending in part on the location of the tip of the central venous catheter. In one study, patients with septic shock demonstrated improved survival when therapy was titrated to ScvO₂ ≥ 70%.³⁶

Lactate concentration is a useful marker of critical hypoperfusion. Increases in lactate levels indicate the presence of anaerobic metabolism and tissue energy deficits.²⁸ Although the initial blood level of lactate has prognostic significance, the inability to clear lactate over time is more discriminating.^38,39 In patients with septic shock, factors other than hypoperfusion may contribute to lactate accumulation. These factors include increased muscle ATPase activity, increased hepatic flux of alanine from skeletal muscle, decreased pyruvate dehydrogenase activity, decreased hepatic clearance of lactate, and dysfunctional mitochondrial respiration. Despite these concerns, increases in lactate concentration are associated with decreases in the intracellular redox potential in patients with septic shock, suggesting that it is a useful marker of cellular energy metabolism.⁴⁰ When titration of therapy to ScvO₂ above 70% was compared to achieving a lactate clearance of 10% over 6 hours in patients with septic shock, the outcome was similar.⁴¹

Oxygen consumption and oxygen delivery are global markers of systemic oxygen metabolism. Oxygen consumption, a measure of overall metabolic requirements, is calculated from cardiac index, hemoglobin, and arterial and venous oxygen saturation. It can also be measured directly from expired gases. Oxygen delivery is calculated from cardiac output, hemoglobin, and arterial saturation and is a measure of the total amount of oxygen being delivered to the tissues. Although increased values of oxygen consumption and oxygen delivery have been observed in survivors compared with non-survivors, considerable overlap exists between the two groups. Efforts to titrate therapy to values associated with survival—“optimal goals”—have produced mixed results.^42,43 These differences may in part reflect the varying metabolic requirements of individual patients.

The decrease in CO₂ clearance in circulatory shock is the basis for end-tidal CO₂ and tissue CO₂ measurements. End-tidal CO₂ measurements are useful in monitoring perfusion during cardiopulmonary resuscitation.⁴⁴ Cardiac arrest results in marked decreases in pulmonary blood flow and accompanying decreases in CO₂ excretion. Consequently, end-tidal CO₂ values move toward zero during arrest and increase with successful resuscitation.

There have been multiple attempts to use measures of local or regional perfusion as indices of overall systemic perfusion. Toe temperature, subcutaneous oxygen tensions, transcutaneous oxygen tension, and laser Doppler are some examples of regional measures previously studied. Gastric tonometry, and more recently sublingual tonometry, have been used to assess those vascular beds for CO₂ excess as a marker of systemic hypoperfusion. Current attention has focused on two measures of microvascular blood flow. One approach is the use of near-infrared spectroscopy (NIRS) to assess the level of oxygenated hemoglobin in thenar skeletal muscle. Both the actual value and the response of tissue hemoglobin saturation to reactive hyperemia have been reported to predict survival.^45,46 The other techniques, orthogonal polarization spectral (OPS) imaging and sidestream dark-field (SDF) imaging, have been used to directly visualize microcirculatory flow. Decreases in capillary blood flow have been observed in patients with septic shock and cardiogenic shock which correlated with survival.^24,47 Evidence of persistent hypoperfusion using these measurements has been reported in patients with septic shock, despite improvement in systemic indices of perfusion.⁴⁸ Whether titration of therapy to these measures of local perfusion will impact on outcome remains to be determined.

Organ Failure

The primary causes of organ dysfunction in circulatory shock are ischemic injury, mediator-related organ dysfunction, and reperfusion injury. Ischemic injury occurs when anaerobic metabolism ensues and high-energy phosphate production falls below the level required for cellular function and membrane integrity. It is the major factor contributing to organ failure in patients with cardiogenic and hypovolemic shock. The direct effect of inflammatory mediators, coupled with an ischemic injury, plays a major role in organ dysfunction in septic shock. Tumor necrosis factor, nitric oxide, and superoxide radicals are examples of mediators directly affecting cellular and organ function. Reperfusion injury occurs upon restoration of tissue perfusion following an absence of blood flow (Figure 90-3). Activated neutrophils, oxygen radicals, endothelial cell dysfunction and apoptosis play important roles in this process.⁴⁹ Reperfusion injury may be important in hemorrhagic and traumatic shock; its role in cardiogenic shock and septic shock is less clear.

Figure 90-3 Reperfusion injury.

Under ischemic conditions, ATP is metabolized to hypoxanthine and xanthine dehydrogenase is converted to xanthine oxidase. During reperfusion, superoxide is produced from hypoxanthine and oxygen by xanthine oxidase. Superoxide and its metabolites produce cellular injury and membrane disruption, resulting in the release of prostanoids and leukotrienes. The lipid mediators and oxygen radicals act as chemoattractants for neutrophils, which injure tissues through the release of elastases, proteases, and additional oxygen radicals.

In cases of acute myocardial infarction shock, cardiac dysfunction is related to ischemia and myocardial necrosis. Reperfusion injury may also play a role in patients following acute coronary revascularization. Cardiac dysfunction is frequently observed in patients in shock. Myocardial depressant substances cause myocardial depression in patients in septic shock and may also play a role in cases of hemorrhagic shock.⁵⁰ Down-regulation of β-receptor density and affinity contribute to myocardial failure in sepsis and other syndromes. Increases in pulmonary vascular resistance are the cause of acute right ventricular failure in patients with pulmonary embolism and may also be important in septic shock, particularly when it is complicated by the acute respiratory distress syndrome.

Minute ventilation and respiratory rate increase in patients with shock. Overt respiratory failure may result from pulmonary edema or acute lung injury and leads to additional increases in the work of breathing. Decreased respiratory muscle perfusion coupled with hypoxia contributes to respiratory muscle failure. In patients with septic shock, inflammatory mediators may also directly impair respiratory muscle activity.⁵¹

Renal dysfunction in shock is related to ischemic and reperfusion injury. Initially, as cardiac output decreases, glomerular filtration is maintained by increases in efferent arteriolar tone. Release of atrial natriuretic peptide due to increased atrial pressures may help protect renal blood flow in patients with cardiogenic shock. However, as shock progresses, the increases in afferent arteriolar tone result in renal ischemia and acute tubular necrosis. Activation of neutrophils, dendritic cells, and lymphocytes during reperfusion all play an important role in renal injury associated with shock.⁵² In septic shock, alterations in intrarenal blood flow may also impair effective glomerular filtration.

A characteristic pattern that involves centrilobar necrosis and marked transaminase elevation is observed in patients with ischemic hepatic injury associated with hypodynamic circulatory states.⁵³ Activation of Kupffer cells and the release of inflammatory mediators exacerbate ischemic injury in patients in septic shock and traumatic shock. In septic shock, canalicular cell function is impaired, resulting in intrahepatic cholestasis. Hepatic metabolic failure and impaired amino acid clearance are also features of septic shock.

Splanchnic mucosal blood flow is compromised early in shock. Intestinal injury may result from hypoperfusion and/or the release of oxygen radicals and activation of neutrophils during reperfusion. Loss of the integrity of the intestinal barrier can lead to translocation of bacteria and toxins, which in turn contributes to organ failure.⁵⁴ Splanchnic hypoperfusion related either to shock or to the use of vasopressors also contributes to the development of stress ulceration, acalculous cholecystitis, intestinal necrosis, and pancreatitis. Pancreatic hypoperfusion may also predispose to the release of myocardial depressant factors.

Thrombocytopenia is observed in a majority of patients with septic shock. The coagulation cascade is activated in septic and traumatic shock by the cytokines, tissue factors, and bacterial toxins. Disseminated intravascular coagulation is marked by impaired fibrinolysis and increased consumption of clotting factors. Clinical manifestations are bleeding and microvascular thrombosis. Large-volume asanguineous fluid resuscitation may exacerbate these tendencies by additional hemodilution of clotting factors and platelets. The development of hypothermia will exacerbate coagulopathies in patients with circulatory shock.

Disorientation and delirium are common in patients in shock. Hypotension, metabolic abnormalities, and hypoxia all contribute to neurologic dysfunction. Alterations in cerebral vascular reactivity and direct toxic effects of inflammatory mediators may also play a role in cerebral injury.⁵⁵ Severe hypotension, mean arterial pressure well below 60 mm Hg, can result in ischemic injury of the arterial border zones in the cortex and spinal cord.

Microvascular blood flow is impaired in all forms of circulatory failure.^24,47,56 The microcirculation is characterized by heterogeneous blood flow and decreased capillary perfusion. Rheologic abnormalities of neutrophils and erythrocytes impede microvascular blood flow. Increased expression of the neutrophil integrins, platelet P-selectin, and the endothelial cell adhesion molecules result in cellular aggregation and microvascular obstruction. Platelet-fibrin interactions mediated through platelet expression of glycoprotein IIB/IIIA receptors accentuate this process.²³ Decreased endothelial cell nitric oxide synthetase activity impairs normal vasodilatory reflexes and decreases the microvascular response to hypoxia. Increased microvascular permeability and tissue edema may also impede the diffusion of oxygen from the capillaries into the cells.

Shock is associated with down-regulation of immunologic function. Immunosuppressive substances including interleukin (IL)-10, prostaglandin E₂, and adenosine are released and decrease cellular and humoral immunity. Dendritic cell– and monocyte-mediated antigen processing is impaired, as is neutrophil function. Apoptosis of lymphocytes, dendritic cells, and monocytes is increased. An immunologic profile of decreased monocyte HLA-DR expression and impaired monocyte responsiveness to inflammatory stimuli has been associated with an increased risk of secondary infection and mortality.^57,58

Initial Approach to Circulatory Shock

The approach to patients with circulatory shock involves a rapid assessment of the underlying disease process and restoration of cardiopulmonary stability. The patient should be assessed for the cause of the shock syndrome and for evidence of end-organ hypoperfusion. A complete blood cell count, coagulation studies, blood gases, and electrolytes measurement should be performed. Blood lactate measurement is helpful to confirm the severity of perfusion failure. An electrocardiogram and chest radiograph should also be obtained. The need for additional studies such as cultures, cardiac enzymes, and other tests depends on the suspected cause of the shock state. Efforts to achieve cardiopulmonary stability should occur simultaneously. The VIP approach can be used to prioritize these efforts by focusing on ventilation, infusion, and pump activity.⁵⁹ A systematic approach that incorporates physiologic endpoints for resuscitation with monitoring indices of systemic perfusion and an algorithm for therapeutic interventions based on the pathophysiology of the underlying shock state results in the best outcomes.⁶⁰

Oxygenation and adequate ventilation must be ensured. High-flow oxygen systems can be employed initially; however, evidence of respiratory muscle fatigue, refractory hypoxia, or severe acidosis should prompt intubation and the initiation of mechanical ventilation. Reduction in the work of breathing may reduce physiologic stress and allow for redistribution of blood flow away from the respiratory muscles to other hypoperfused areas of the body.

Multiple studies have failed to demonstrate a benefit in mortality associated with the use of the pulmonary artery catheter. Less invasive techniques are being utilized to assess cardiac output and function, including transpulmonary thermodilution and lithium dilution, echocardiography, esophageal Doppler, and arterial pulse contour analysis. Nonetheless, information gained from a pulmonary artery catheter can be extremely helpful in guiding management in treating more complicated shock patients, particularly those with combined renal failure and respiratory failure.

Critical hypovolemia is present in the majority of patients presenting with circulatory shock in the medical-surgical setting and a significant portion of patients presenting with shock and acute myocardial infarction. Fluids should be infused in boluses and titrated to specific endpoints of heart rate, blood pressure, urine output, central venous or mixed venous saturation, and clearance of blood lactate. Determining the adequacy of fluid infusion based on intracavitary measurements such as central venous pressure may be difficult and should be guided by dynamic measurements when possible.^10–12 Attention should be given to the hemoglobin level, which will decrease with significant asanguineous fluid resuscitation. Although many patients tolerate a hemoglobin level of 7 g/dL to 10 g/dL, higher levels may be required in patients with cardiac dysfunction.

Disturbances of cardiac rhythm should be addressed rapidly. Bradycardia associated with hypotension may require a pacemaker or pharmacologic therapy to increase the heart rate. Tachyarrhythmias that are not compensatory may require cardioversion. In the appropriate clinical setting, consideration should always be given to possible cardiac tamponade and tension pneumothorax, since these are rapidly reversible causes of shock.

Continued evidence of hypoperfusion despite initial resuscitation efforts requires the initiation of vasoactive drugs. The choice of agents should be predicated on the goal of therapy. Persistent hypotension requires the use of a pressor agent such as norepinephrine to restore blood pressure to a level of mean arterial pressure associated with adequate end-organ perfusion. For many patients, this will be a mean arterial pressure from 60 to 70 mm Hg, which is within the autoregulatory range for most organs; however, this level may vary in individual patients. When hypotension is accompanied by impaired cardiac performance, an inotropic agent such as dobutamine should be added.

The treatment of lactic acidosis with alkali solutions is controversial. Sodium bicarbonate solutions increase serum osmolality and potentially worsen intracellular acidosis as bicarbonate is titrated to CO₂ and water. Prospective randomized trials have not demonstrated any benefit in either oxygen metabolism or circulatory function after alkali infusion for severe lactic acidosis.⁶¹

Definitive therapy depends on the cause of the shock state and may require additional diagnostic and therapeutic interventions. These efforts should be pursued in a timely manner. Endoscopic or surgical interventions may be required for patients in hemorrhagic and traumatic shock. Circulatory assist devices coupled with prompt efforts at revascularization enhance outcome in patients with cardiogenic shock.¹ Antibiotics and drainage procedures are required for septic shock. Steroids and activated protein C may also benefit patients with septic shock.^22,62 Acute pulmonary embolism and shock can be treated with thrombolysis, catheter embolectomy, or, in more extreme circumstances, surgical embolectomy.

Newer Therapies

There is continuing interest in modulating the activity of inflammatory mediators in septic shock, hemorrhagic shock, and even cardiogenic shock.¹ Similarly there is an ongoing focus on attenuating reperfusion injury through interventions directed at neutrophils, reactive oxygen species, and reactive nitrogen species in multiple settings.⁴⁹ Efforts to avoid the adverse sequelae of resuscitation including the use of excessive fluids and the use of fluids that may exacerbate the inflammatory response are being examined. Newer fluids are being developed which, in addition to their volume-expanding capacity, have antiinflammatory activity. The role of the cholinergic antiinflammatory pathway and its manipulation is being elucidated. Hydrogen sulfide is being studied for its antiinflammatory and metabolic effects. Mitochondrial targeted therapies are being investigated in an effort to enhance mitochondrial function and recovery in shock. The role of apoptosis in the development of immune dysfunction and organ failure is being examined, with possible interventions directed at altering this process. Finally, the genetic underpinning of the immune response and its role in circulatory shock is another area of active interest.⁶³ Progress in this important area will ultimately allow for the development of more focused interventions that have the greatest likelihood of benefiting individual patients.

Key Points