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.