If a person rapidly loses <10% or 20% of total blood volume from a large vein, the inadequate intravascular volume causes sequential decreases in central blood volume, venous return, ventricular filling, stroke volume, cardiac output, and thus mean arterial pressure. However, if the blood loss comes from a large peripheral artery, the mean arterial pressure in central arteries does not fall until cardiac output falls secondary to decreased venous return. Of course, if the blood loss occurs from a blown aortic aneurysm, mean arterial pressure falls immediately.
Large hemorrhages, in which one loses 30% or more of total blood volume, produce hypovolemic shock. Shock is a state of peripheral circulatory failure that is characterized by inadequate perfusion of the peripheral tissues. During shock, the systolic arterial pressure is usually <90 mm Hg, and the mean arterial pressure is <70 mm Hg. For reasons that will become clear, by the time one records a significant fall in mean arterial pressure, other signs of shock are evident. The first signs may be narrowing of the pulse pressure and a sensation of faintness when sitting or standing. The subject in hypovolemic shock has cold and moist (i.e., “clammy”) skin as well as a rapid and weak pulse. Moreover, urine output drops to <25 mL/hr, even if fluid intake had been normal.
After its abrupt initial fall, arterial pressure tends to return to normal (Fig. 25-8, red curve), although blood pressure falls irreversibly (blue dashed curve) in some cases. Under favorable circumstances, the body restores blood pressure toward normal values by mobilizing two lines of defense. First, circulatory control mechanisms act on the heart and blood vessels to restore cardiac output and to increase peripheral resistance. Second, mechanisms of capillary exchange and fluid conservation restore the intravascular volume.
FIGURE 25-8 Changes in blood pressure with hemorrhage. At time zero, the investigator removes enough blood from the experimental animal to lower mean arterial pressure to 45 mm Hg.
After hemorrhage, cardiovascular reflexes restore mean arterial pressure
Several cardiovascular reflexes cooperate to compensate for the fall in mean arterial pressure. These reflexes originate from four major groups of receptors (numbered 1 to 4 in Fig. 25-9):
1. High-pressure baroreceptors. The fall in arterial pressure leads to a decrease in the firing rate of afferents from the carotid and aortic baroreceptors (see p. 534). The resulting enhanced sympathetic output and diminished vagal output increase heart rate and cardiac contractility and also produce venoconstriction and selective arteriolar constriction. These responses cooperate to re-establish the arterial pressure.
2. Low-pressure baroreceptors. Reduced blood volume directly decreases effective circulating volume, which in turn lessens the activity of low-pressure stretch receptors (see p. 547). The resulting increased sympathetic outflow causes vasoconstriction in a number of vascular beds, particularly the kidney, reducing glomerular filtration rate and urine output. In response to decreased stretch, low-pressure receptors at various sites in the circulation ultimately have divergent effects on heart rate. The atrial stretch receptors also instruct the hypothalamus to enhance release of AVP, which reduces renal water excretion (see pp. 817–818). During shock, the vasoconstrictor effects of AVP appear to be important for maintaining peripheral vascular resistance. Reduced atrial stretch also lowers the level of circulating atrial natriuretic peptide (ANP; see p. 547), thereby reducing salt and water loss by the kidneys (see p. 843).
3. Peripheral chemoreceptors. As blood pressure drops, perfusion of the carotid and aortic bodies declines, causing local hypoxia near the glomus cells and an increase in the firing rate of the chemoreceptor afferents (see pp. 710–712), a response enhanced by increased sympathetic tone to the peripheral chemoreceptor vessels (see pp. 711–712). Increased chemoreceptor discharge leads to increased firing of the sympathetic vasoconstrictor fibers and ventilatory changes that indirectly increase heart rate (see p. 544).
4. Central chemoreceptors. Severe hypotension results in brain ischemia, which leads to a fall in the of brain ECF as well as a rise in and a fall in pH. The acidosis has a profound effect on the central chemoreceptors in the medulla (see p. 713, leading to a sympathetic output (see p. 546) several-fold more powerful than that caused by baroreceptor reflexes (see p. 546).
FIGURE 25-9 Integrated response to hemorrhage. Blood loss triggers four kinds of receptors (numbered 1 to 4) to produce an integrated response orchestrated by the medulla.
These four reflex pathways have in common the activation of a massive sympathetic response that results in the release of norepinephrine from postganglionic sympathetic neurons. In addition, the sympathetic response triggers the adrenal medulla to release epinephrine and norepinephrine roughly in proportion to the severity of the hemorrhage. Lowering of the mean arterial pressure to 40 mm Hg causes circulating levels of epinephrine to rise 50-fold and those of norepinephrine, 10-fold. The consequences of the four combined reflex actions are the following responses (see Fig. 25-9).
Tachycardia and Increased Contractility
Increased sympathetic activity increases heart rate roughly in proportion to the volume of shed blood. Thus, the degree of tachycardia is an index of the severity of the hemorrhage. Increased sympathetic tone increases myocardial contractility but can increase stroke volume only after venous return also improves.
Sympathetic constriction of the resistance vessels is most pronounced in the blood vessels of the extremities, skin, skeletal muscle, and abdominal viscera. Although both precapillary and postcapillary resistance vessels constrict, the precapillary response initially dominates. As a result, capillary pressure falls precipitously, leading to the transcapillary refill discussed in the next section. Renal blood flow falls rapidly after hemorrhage as a result of the fall in blood pressure but recovers after a few minutes because of autoregulation (see p. 750). The responses of both high- and low-pressure stretch receptors lead to enhanced sympathetic vasoconstrictor traffic to the kidney. Although renal blood flow has a high threshold for this sympathetic traffic, the sympathetic vasoconstriction eventually overrides renal autoregulation if arterial pressure remains low or continues to fall. In hypovolemic shock, renal blood flow falls to a proportionately greater extent than does cardiac output, which explains why severe hemorrhage often results in acute renal failure. Blood flow in the medulla of the kidney is less compromised than in the cortex, leading to “medullary washout” of the hypertonic interstitial fluid in the renal medulla (see pp. 813–815) and an inability to produce a concentrated urine. Both coronary blood flow and cerebral blood flow initially fall after hemorrhage, but autoregulation can largely restore blood flow to normal.
The fall in blood volume with hemorrhage occurs primarily in the large-capacitance vessels, especially those that contain the central blood volume. These vessels are very sensitive to sympathetic stimulation (which causes constriction) and less so to local metabolites (which causes dilation). The sympathetic venous constriction decreases both the capacity and the compliance of the large veins, thereby tending to restore central venous pressure. In addition, sympathetic venous constriction increases postcapillary resistance, which is important for transcapillary refill (see below).
Circulating Vasoactive Agonists
As already discussed, sympathetic stimulation of the adrenal medulla causes circulating epinephrine levels to rise (see p. 585). In addition, sympathetic stimulation of the granular cells in the juxtaglomerular apparatus of the kidney leads to an increased release of renin and, ultimately, increased plasma levels of angiotensin II (ANG II) (see p. 553). In hemorrhagic shock, ANG II rises to concentrations that are vasoconstrictive. Activation of the sympathetic system also triggers sympathetic cholinergic stimulation of the sweat glands (see p. 571), causing the patient's extremities to become clammy.
With moderate blood losses (10% to 20%), these four responses can increase total peripheral resistance sufficiently to keep arterial pressure at about normal levels. However, cardiac output remains depressed.
After hemorrhage, transcapillary refill, fluid conservation, and thirst restore the blood volume
The reflexes discussed in the preceding section compensate for the principal consequences of blood loss—decreased blood pressure and reduced cardiac output. The responses discussed here compensate for the primary disturbance, the loss of blood volume.
The movement of fluid from the interstitium to the blood plasma is the major defense against reduced blood volume. Starling forces (see pp. 467–468) are critically important during hemorrhage and hypovolemic shock. Immediately after hemorrhage, a phase of hemodilution develops, as was first observed during World War I, when medics noted that injured soldiers arrived at the first-aid station with diluted blood (i.e., low hematocrit). Within an hour, interstitial fluid replaces ~75% of the shed blood volume. Studies performed around World War II showed that the dilution of hemoglobin is more pronounced than the dilution of plasma proteins after hemorrhage. Therefore, not only do fluid and electrolytes move from the interstitium to the blood, but proteins also enter the vascular compartment.
Transcapillary refill involves two steps. The first is fluid movement from the interstitium to the vasculature. Capillary hydrostatic pressure (Pc) (Fig. 25-10A) depends on arteriolar and venular pressures as well as on the relation of the precapillary to the postcapillary resistance (see pp. 451–452). Immediately after the hemorrhage, the upstream arteriolar pressure and the downstream venular pressure both fall, causing Pc to fall (see Fig. 25-10B). The Starling forces thus produce a large net movement of fluid and small electrolytes from the interstitium into the capillaries. As compensation occurs, total peripheral resistance increases, in part restoring arteriolar pressure (see Fig. 25-10C). However, because precapillary resistance increases more than does postcapillary resistance, Pc remains relatively low, sustaining the net movement of fluid into the capillaries. Normally, little protein would enter with the fluid because nonfenestrated capillary walls reflect proteins very effectively (see p. 468). The entry of protein-free fluid into the capillary gradually modifies the three other Starling forces. First, the interstitial fluid volume decreases, lowering interstitial hydrostatic pressure (Pif). Second, the plasma proteins become diluted, so that capillary colloid osmotic pressure (πc) falls. Finally, the removal of a protein-free solution from the interstitium raises colloid osmotic pressure in the bulk interstitium (πif) and in the subglycocalyx fluid (πsg; see pp. 471–472). The result of these dissipating Starling forces is that transcapillary refill gradually wanes and eventually ceases.
FIGURE 25-10 Effect of hemorrhage on capillary hydrostatic pressure. A, In this figure (which is similar to Fig. 19-4A), Rpre and Rpost are the precapillary and postcapillary resistances, respectively. Here, the ratio Rpost/Rpre = 0.35. B, The fall in capillary hydrostatic pressure reverses the Starling forces, causing net movement of fluid from the interstitium to the capillary lumen. C, Sympathetic stimulation increases total peripheral resistance (Rpost/Rpre = 0.25 in this example). D, Capillary pressure rises (Rpost/Rpre = 0.45 in this example).
The second step in transcapillary refill is the appearance of plasma proteins in the blood. These proteins probably enter the blood across fenestrae of the mesenteric and hepatic capillaries, two regions in which the interstitium has a very high interstitial colloid osmotic pressure. In addition, hemorrhage rapidly stimulates albumin synthesis by the liver. Plasmapheresis, the artificial removal of plasma proteins from the blood, has the same effect on albumin synthesis, suggesting that a reduction in the concentration of plasma proteins per se stimulates the liver to make albumin.
Water from the intracellular compartments ultimately replaces the lost interstitial fluid. What the driving force is for water to leave the cells and to enter the interstitium is somewhat controversial. The blood osmolality often rises after hemorrhage, which presumably reflects interstitial hyperosmolality. The additional interstitial osmoles come from ischemic tissues that release the products of proteolysis, glycolysis, and lipolysis. Therefore, interstitial hyperosmolality may provide the osmotic drive for the movement of water from the intracellular to the interstitial compartment.
Renal Conservation of Salt and Water
Arterial hypotension and lowered renal blood flow reduce the glomerular filtration rate (see p. 739) and therefore diminish the urinary excretion of salt and water. In addition to the direct hemodynamic effects, the reduced effective circulating volume promotes the renal retention of Na+ by four mechanisms, which are discussed more fully in Chapter 40. First, reduced effective circulating volume activates the renin-angiotensin cascade (see pp. 841–842), increasing aldosterone release and thus enhancing salt and water reabsorption by the distal nephron. Second, increased sympathetic nerve activity (see p. 842) promotes Na+ retention by altering renal hemodynamics, enhancing renin release, and stimulating Na+ reabsorption by renal tubule cells. Third, the release of AVP reduces water excretion (see p. 843). Finally, reduced effective circulating volume inhibits release of ANP (see p. 843) and thus promotes renal Na+ retention. Therefore, the overall response of the kidney to blood loss is to reduce the excretion of water and salt, thereby contributing to the conservation of ECF. However, the renal response only conserves fluid; by itself, it does not add any water to the ECF.
The blood hyperosmolality caused by hemorrhage (discussed two paragraphs above) stimulates thirst osmoreceptors (see pp. 845–846). A far more potent stimulus for thirst (see p. 849)—as well as salt appetite—is the reduced effective circulating volume and blood pressure caused by severe hemorrhage. These urges, if fulfilled, actually provide some of the raw materials for replacement of the blood lost in hemorrhage.
Positive-feedback mechanisms cause irreversible hemorrhagic shock
In some cases, hemorrhagic shock can be irreversible. After an initial fall in arterial pressure and perhaps some recovery, arterial pressure and the perfusion of peripheral tissues may inexorably deteriorate (see Fig. 25-8, blue dashed curve). Moreover, in these cases, the fall in arterial pressure does not reverse even if the physician intervenes at this time and replaces the volume of blood lost as the result of hemorrhage.
The best experimental model for irreversible hemorrhagic shock is prolonged hypotension. Typically, the researcher acutely removes blood from an experimental animal—thereby reducing blood pressure to some low target value—and then clamps the mean arterial pressure at this low target by either removing or infusing blood as the normal physiological responses evolve. Studies of this kind reveal that hemorrhagic shock can become irreversible as a result of the failure of multiple response components: (1) the vasoconstrictor response, (2) the capillary refill response, (3) the cardiac response, and (4) the CNS response.
Failure of the Vasoconstrictor Response
With prolonged hemorrhagic hypotension, the total peripheral resistance—which first increases in response to sympathetic stimulation—tends to return to prehemorrhage levels. This failure to maintain vasoconstriction has several origins. First, desensitization of the vascular adrenoceptors or depletion of neurotransmitters in the nerve terminals close to the blood vessels may cause “sympathetic escape.” Second, the ischemic tissues release metabolites and other vasodilator compounds that act on local blood vessels, thereby counteracting the vasoconstricting stimuli. In the late phases of irreversible shock, humans may become completely unresponsive to a range of vasoconstrictor drugs. Third, plasma AVP levels may have fallen substantially from the peak value during the early phase of hemorrhage—which perhaps reflects a decreased ability of the low-pressure baroreceptor reflex to trigger hypothalamic neurons to release AVP or a depletion of AVP stores. Under these conditions, restoration of AVP levels to their initial peak can markedly increase blood pressure.
Failure of the Capillary Refill
Some blood vessels are able to sustain the initial increase in resistance better than others are. Over time, precapillary sphincters fail first, followed by the precapillary resistance vessels (i.e., arterioles), the postcapillary resistance vessels, and the capacitance vessels. Figure 25-10D shows an example in which, after prolonged hypotension, the precapillary constrictor response has fully faded, whereas the postcapillary response is partially maintained. Because the ratio Rpost/Rpre has risen, the midcapillary pressure (see pp. 451–452) increases from 16 mm Hg (see Fig. 25-10C) to 21 mm Hg (see Fig. 25-10D). You will recall that early during hemorrhage, the net Starling forces reverse, favoring the movement of fluid from the interstitium to the blood. The gradual increase of Rpost/Rpre (see Fig. 25-10D) reverses this reversal, so that fluid once again leaves the capillary, even though the blood volume has not yet been restored. Thus, after the initial large influx of water and electrolytes into the capillary lumen, not only does transcapillary refill decline, but a net loss occurs. This phenomenon contributes to the hemoconcentration that occasionally occurs in prolonged hemorrhagic states.
Failure of the Heart
Several factors may contribute to the weakening of the heart. Acidosis reduces [Ca2+]i in the myocardium and thus reduces contractility. In severe cases, subendocardial hemorrhage and necrosis of the heart muscle render the myocardium nonfunctional. Various organs may also release cardiotoxic shock factors, which exert a negative inotropic effect on the heart (see pp. 530–532). Ultimately hypovolemic shock converts to cardiogenic shock.
Moderate ischemia, by its effects on the central chemoreceptors, stimulates the cardiovascular control centers in the brain (see p. 585). However, prolonged cerebral ischemia depresses neural activity throughout the brain, thereby weakening the sympathetic output and in turn causing a decay in both vascular and cardiac responses. A progressive fall in the circulating levels of catecholamines of adrenal origin further worsens the outcome.