The reason for impaired oxygen utilization by cells differs with the various types of shock, but the outcomes are similar. A continuous supply of oxygen is needed by cells to allow sufficient production of energy in the form of adenosine triphosphate (ATP). Inadequate oxygen availability at the cellular level quickly impairs aerobic metabolism of glucose, fatty acids, and amino acids and causes the cells to rely on the relatively inefficient processes of glycolysis to produce cellular ATP. (A review of ATP synthesis can be found in Chapter 3.) Glycolysis is the enzymatic process of converting glucose to pyruvate, with the net production of two ATP molecules per glucose molecule. If oxygen were available, pyruvate would normally enter the mitochondria and proceed through the citric acid cycle. In the absence of cellular oxygen, the citric acid cycle is inhibited and pyruvate accumulates in the cytoplasm. Pyruvate accumulation would quickly inhibit further glycolysis and shut down ATP production entirely if not for the conversion of pyruvate to lactate. Lactate diffuses from the cell and into the extracellular fluid, and accumulation of lactate in the bloodstream (more than 5 to 6 mmol/L) is considered a sign of significant tissue hypoxia.^4,5

An inadequate supply of cellular ATP inhibits energy-requiring cellular functions, including maintenance of ion concentrations across the plasma membrane. Because of their steep electrochemical gradients, extracellular sodium and calcium ions tend to leak into the cell. ATP-dependent pumps in the cell membrane are needed to continuously pump these ions back out. Failure of ion pumps leads to sodium and water accumulation in the cell (hydropic swelling) and an excess of intracellular free calcium. Intracellular calcium ions trigger a cascade of cellular events that further impair energy production and plasma membrane integrity. Cell death from oxygen deprivation takes from minutes to several hours, depending on the rate of cellular metabolic activity. However, even a short period of oxygen deprivation often sets in motion a complex cascade of events that lead to further cell damage (Figure 20-1). Two important aspects of this cascade are (1) formation of oxygen free radicals, and (2) induction of inflammatory cytokines.

The role that immune cytokines play in shock has been studied extensively in septic shock. The roles of these cytokines are thought to be similar in the late stages of other types of shock as well. Macrophages and tissue cells are stimulated to release inflammatory cytokines in response to hypoxic tissue injury and, in the case of septic shock, in response to endotoxin or other microorganism antigens.6 The levels of tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) cytokines in particular have been shown to increase in the bloodstream of patients with septic shock, and these cytokines are thought to be important mediators of vascular failure and progressive organ damage.⁶ Numerous other immune cytokines and neurohormonal mediators have been implicated in the pathogenesis of shock (Table 20-2). These mediators represent potential therapeutic targets for a disorder that is notoriously difficult to manage effectively.

A hallmark of shock is failure of the microcirculation to appropriately autoregulate blood flow. Normal tissues are able to match blood flow with metabolic needs across a wide range of blood pressures. This property ensures that blood flow is evenly distributed to tissues according to metabolic needs. In shock, autoregulation fails, leading to an abnormal distribution of blood flow.7 Some capillary beds receive inadequate flow and become progressively more hypoxic, whereas other vascular routes are excessively dilated and receive too much flow. Advances in technology have allowed direct visualization of capillary flow through tissue beds and confirmed the presence of perfusion abnormalities in the microcirculation. These abnormalities differ depending on the primary cause of shock.⁷ In cases of reduced cardiac output resulting from hypovolemic or cardiogenic shock, there is a homogeneous reduction in blood flow through a given tissue’s arterioles, capillaries, and venules that is directly related to the severity of cardiac output reduction. In distributive shock states, such as septic shock, the degree of microcirculatory flow is heterogeneous within a tissue, with some capillaries being closed and others open. Often there is high flow rate through some of the venules and the degree of microcirculatory dysfunction is poorly correlated with systemic hemodynamics. Overall, this imbalance leads to a so-called oxygen debt in the tissues. It has been suggested that the overall oxygen debt can be estimated clinically by the serum lactate level and degree of metabolic acidosis, both of which imply a switch to anaerobic metabolism by oxygen-deprived tissues.⁵

In septic shock, immune cytokines are believed to be at the root of the microcirculatory maldistribution problem. TNF-α, IL-1, and other inflammatory mediators induce vascular cells to produce excessive amounts of the vasodilator nitric oxide.⁶ Nitric oxide in normal quantity is thought to be protective for tissues during shock, whereas excessive production is detrimental. Nitric oxide is produced in endothelial cells and vascular smooth muscle by two enzymes: nitric oxide synthase (NOS) and inducible nitric oxide synthase (iNOS). TNF-α and IL-1 increase the activity of iNOS and thereby cause excessive production of nitric oxide (Figure 20-2). Efforts to minimize the microcirculatory oxygen debt in early shock and to quickly restore adequate microcirculatory blood flow distribution, as evidenced by normalized serum lactate concentration and acid-base balance, are an important focus of therapy for all types of shock.

Insufficient cardiac output and decreased effective tissue perfusion are early defects in all types of shock. Insufficient cardiac output may be a consequence of an ineffective cardiac pump (cardiogenic, obstructive) or insufficient blood volume to fill the vascular space (hypovolemic, distributive). A number of compensatory mechanisms are triggered in response to inadequate cardiac output in an attempt to restore adequate perfusion pressure (Figure 20-3). Baroreceptors located in the aorta and carotid arteries quickly sense the decrease in pressure and transmit signals to the vasomotor center in the brainstem medulla. Stimulation of the sympathetic nervous system (SNS) results in increased cardiac output and vascular resistance. Because blood pressure is determined by the product of cardiac output and vascular resistance, an increase in one or both of these factors will help restore blood pressure. The SNS increases cardiac output through several mechanisms. The adrenal medulla is stimulated to release increased amounts of the catecholamines epinephrine and norepinephrine (NE), which circulate to the heart and stimulate β₁ receptors. The β₁ receptors respond by increasing the heart rate and force of contraction in an attempt to increase cardiac output. The SNS also enhances venous return to the heart by constricting systemic arterioles and venules. Arterial vasoconstriction reduces flow through the capillary bed, which causes hydrostatic pressure in the capillaries to fall. Fluid reabsorption from interstitial spaces helps increase blood volume and improve preload. Blood vessels in the skin, kidneys, and gastrointestinal tract constrict and shunt blood to the heart and brain.

These compensatory mechanisms work well in the early stage of hypovolemic shock and may maintain blood pressure within the normal range until the volume of blood loss becomes too great (Figure 20-4). In other forms of shock, compensatory mechanisms are less effective in restoring cardiac output. In cardiogenic shock, the compensatory responses may worsen the already high preload and impose a greater workload on the failing heart. In distributive shock, the vasculature is not responsive to SNS signals to constrict. Blood pools in the peripheral tissues, which makes it difficult for the heart to maintain cardiac output despite sympathetic stimulation to increase the heart rate and contractility.

The early, compensated stage of shock may be difficult to detect clinically (Figure 20-5). A high index of suspicion is needed in patients with heart failure, trauma, blood loss, and severe infection. In addition, the following clinical findings may be present:

At some point, which is highly variable and differs among individuals depending on age, comorbidities, and specific etiology, the compensatory mechanisms can no longer sustain adequate perfusion to tissues and cells begin to suffer significant hypoxic injury. This condition is sometimes called the progressive stage of shock. Active therapeutic intervention is required at this stage or the patient will probably not survive. As previously described, reduced delivery of oxygen to tissues results in hypoxic injury, free radical damage, and stimulation of the inflammatory response. Lactic acidosis may occur during the progressive stage of shock. In addition to being a marker of anaerobic metabolism, lactate can alter the acid-base balance of the blood and create metabolic acidosis. Metabolic acidosis places a greater burden on the respiratory and renal systems and may contribute to further dysfunction. Metabolic acidosis can affect electrolyte balance and contribute to cardiac dysrhythmias and conduction disturbances. In addition, myocardial depressant factors are released that impair myocardial contractility.8 These factors contribute to reduced cardiac output and a progressive cycle of worsening tissue hypoxia.

As shock continues to progress, the vascular system begins to fail. Arterioles become unresponsive to catecholamines and previously constricted vascular beds begin to dilate. Widespread dilation and low cardiac output combine to produce severe hypotension. The low blood pressure is not sufficient for organ perfusion. At this stage the effects of shock produce more shock processes. Tissue damage often activates the clotting cascade, which contributes to sluggish blood flow, vascular thrombosis, and more severe tissue ischemia. Release of inflammatory mediators, along with vascular occlusion, may precipitate organ failure. The kidney, liver, and lung are particularly susceptible. At some point, the stage of refractory shock occurs and the patient becomes unresponsive to therapeutic interventions.

The progressive stage of shock is characterized by the following clinical manifestations: