Catecholamine-induced Changes in the Splanchnic Circulation Affecting Systemic Hemodynamics

The splanchnic system receives nearly 25% of the cardiac output through three large arteries (fig. 1): the celiac artery (which typically has three major branches: hepatic, splenic, and gastric) and the superior and inferior mesenteric arteries. Roughly one fourth of the splanchnic arterial flow goes directly to the liver via  the hepatic artery; the remaining three fourths reaches the liver after perfusing the preportal organs. The preportal veins anastomose to form the portal vein. The portal vein and hepatic artery enter the liver at its hilum and ramify into progressively smaller vessels before emptying into the hepatic sinusoids. Postsinusoidal blood flows through venules, sublobular and lobular veins, and the hepatic veins, which drain into the inferior vena cava.

The hepatic artery and the arteries of the preportal splanchnic organs have mean pressures of approximately 90 mmHg. The portal venous pressure is 7–10 mmHg, which is only slightly higher than the pressure in the sinusoids (fig. 2). Most of the intrahepatic vascular resistance is distal to the sinusoids 1,2; possible locations of this resistance include one or more of the following sites: the sublobular veins, upstream to the larger veins, or at the junction of the hepatic veins and inferior vena cava. 2 

Although knowledge of the various adrenoceptor subtypes has expanded dramatically during the past decade, much uncertainty remains about the distribution and functional importance of these receptors in the splanchnic vasculature. 3Pure α-adrenergic agonists (e.g. , phenylephrine) constrict hepatic arterial smooth muscle, increase arterial resistance, and reduce hepatic arterial blood flow (table 1). Pure β-adrenergic agonists (e.g. , isoproterenol) dilate hepatic arterioles, decrease vascular resistance, and increase flow through the hepatic artery; these effects are blocked by nonselective β-adrenergic antagonists (e.g. , propranolol) but not by selective β¹-antagonists (e.g. , atenolol). Therefore, the hepatic artery contains α-adrenergic and β²-adrenergic receptors. 4The arterial supply of the preportal splanchnic organs is densely populated with α¹-, α²-, and β²-adrenergic receptors. 4 

Preportal (intestinal) capacitance vasculatures have both α¹- and α²-adrenergic receptors but lack β²receptors. 5The portal vein contains α-adrenergic but not β²-adrenergic receptors. 4Capacitance vessels of the liver (including sinusoids) have α-adrenergic receptors, and hepatic veins contain both α- and β²-adrenergic receptors. 4In the splanchnic venous system overall, α¹- and α²-adrenergic receptor stimulation leads to venoconstriction, which decreases venous capacitance and increases venous resistance, whereas β²receptor activation decreases hepatic venous resistance. It seems that the density of α-adrenergic receptors is the highest in the splanchnic (preportal) arteries.

Normovolemic healthy male adults have a blood volume of approximately 70 ml/kg body weight. Splanchnic organs constitute 10% of the body weight, but they contain 25% of the total blood volume. 1,6Nearly two thirds of the splanchnic blood (i.e. , > 800 ml) can be autotransfused into the systemic circulation within seconds (table 2). The liver and intestines each provide between 300 and 400 ml of the blood; the spleen only contributes approximately 100 ml, but the hematocrit of this blood often approaches 75%. Therefore, the splanchnic vasculature serves as an important blood reservoir for the circulatory system.

The capacity of catecholamines to increase cardiac output is dependent, in part, on the compliance, capacitance, and blood volume of the splanchnic vasculature. With normovolemia, the volume of blood in the splanchnic capacitance vessels varies in a manner that is approximately linearly related to the transmural pressure in this vasculature. 7–9That is, under physiologic conditions, a change in splanchnic arterial flow leads to a proportional change in the pressure within splanchnic capacitance vessels. 7When arterial flow decreases, the blood volume and therefore the pressure within the veins decrease. These veins recoil around the decreasing pressure, mitigating the reduction in pressure. This phenomenon, referred to as elastic recoil , maintains the intramural pressure at a level sufficient to provide a driving force for expulsion of intravenous volume to the systemic circulation.

Sympathoadrenal stimulation causes sympathetic nerve terminals and the adrenal medulla to release catecholamines, which play a major role in regulating the tone of the arterial resistance vessels and venous capacitance vessels (fig. 3). Catecholamines can cause splanchnic arterial constriction or relaxation; the net effect depends on the specific catecholamines involved, their concentrations at adrenergic receptors, and the densities of the adrenoceptor subtypes within the vasculature. The major effect of catecholamines on splanchnic capacitance vessels is venoconstriction, which increases the pressure in capacitance vessels. This mechanism can actively expel splanchnic blood into the systemic circulation, even when splanchnic arterial flow has been markedly reduced.

Active (venoconstriction) and passive (elastic recoil) mechanisms work in concert to shift splanchnic blood volume to the systemic circulation. Both mechanisms make equal contributions to the volume shift during activation of the sympathetic nervous system. 10These processes account for the 35% decrease in splanchnic blood volume associated with mild exercise in humans. 11In animals subjected to moderate hemorrhage (8–9 ml/kg), the splanchnic vessels deliver 5 ml/kg to the systemic circulation, effectively compensating for 60% of the withdrawn blood. 12Studies in dogs indicate that electrical stimulation of the splanchnic (sympathetic) nerves can rapidly decrease splanchnic arterial flow while triggering a brief but substantial outflow of blood from the splanchnic vasculature. 13The maximum volume expelled (15 ml/kg) was nearly 66% of the total splanchnic blood volume, and occurred in 12–15 s. 13 

Intrahepatic vascular resistance can affect the volume of the splanchnic blood reservoir. By decreasing or increasing this resistance, catecholamines may either facilitate or impede the shift of blood from splanchnic capacitance vessels to the systemic circulation. 14Alterations in hepatic venous resistance usually contribute less to such shifts than the degree of venoconstriction and venous recoil within the splanchnic organs. However, large increases in hepatic venous resistance can cause blood to pool within the splanchnic system and can lead to systemic hypovolemia. Histamine-related anaphylactic reactions in animal experiments provide a dramatic example of this phenomenon. 15Clearly, the mechanism of the severe arterial hypotension that occurs during anaphylactic shock is complex; pathophysiologic events include profound vasodilation as well as increased capillary permeability and massive transudation of fluid into the interstitial space. Epinephrine is the drug of choice for the treatment of anaphylaxis, primarily because of its efficacy to maintain arterial blood pressure; conceivably, it supports the systemic circulation in part by constricting splanchnic capacitance vessels and relaxing hepatic venous resistance vessels. Such effects would maximize the translocation of splanchnic blood to the central circulation, helping to restore venous return and cardiac output.

Cardiac output is regulated by preload, contractility, heart rate, and afterload. Unless heart failure exists, the heart (in accordance with the Frank-Starling law) pumps out all of the blood that returns to it, leaving a small residual end-systolic volume. An increase in contractility per se  increases stroke volume to a limited extent by increasing ejection fraction and reducing end-systolic left ventricular volume. The ability of a catecholamine to increase cardiac output is related in part to its capacity to shift splanchnic blood into the systemic circulation and to increase venous return. An increase in flow through other organs and tissues also plays a role in the increase in venous return and cardiac output. Experimental data confirm that the mobilization of splanchnic blood volume is almost entirely the result of β²- and α-adrenergic receptor activation because selective β¹blockade does not alter the associated increase in cardiac output. 16 

The capacity of any particular catecholamine to affect the systemic circulation through an alteration of the splanchnic circulation is determined by numerous factors, including (1) relative densities of α¹-, α²-, and β²-adrenoceptors throughout the splanchnic vasculature; (2) affinities of the catecholamine for the adrenoceptor subtypes; (3) plasma concentration of the catecholamine; (4) preexisting tone of the splanchnic vessels; and (5) blood volume in the splanchnic vasculature.

Many years ago, Imai et al. , 17using various adrenergic antagonists, found that stimulation of β²-adrenergic receptors decreased venous resistance (including splanchnic venous resistance) and increased venous return, whereas activation of α-adrenergic receptors increased venous resistance and decreased venous return. Activation of β²adrenoceptors almost invariably enhances venous return (by increasing arterial flow and decreasing hepatic venous resistance); the situation with α adrenoceptors is more complex—an increase or a decrease may occur. Generally, α agonists increase venous return under normovolemic conditions, but they decrease it when used at high doses or in the presence of severe hypovolemia. Although the decrease could result from an α-adrenoceptor–mediated increase in hepatic venous resistance, it is more likely the result of removing a portion of the vasculature from the systemic circulation by arterial vasoconstriction. The initial response to an α agonist is usually an increase in venous return. However, if the splanchnic reservoir is depleted, further α-adrenergic stimulation will no longer increase venous return and may indeed decrease it.

Epinephrine has a high affinity for all splanchnic adrenergic receptors, but it seems to exert greater effects on α¹- and β²-adrenergic receptors than on α²-adrenergic receptors. In the splanchnic system, norepinephrine exerts pronounced effects on both α¹and α²receptors but has very little if any effect on β²-adrenergic receptors. Selective β²-adrenergic agonists can increase venous return by one third, entirely by increasing splanchnic blood flow and decreasing splanchnic venous resistance by more than 40%. 18 

The effect of dopamine on splanchnic circulation is complex, and the information in the literature is controversial. Dopamine, at low doses, stimulates dopaminergic-1 and dopaminergic-2 receptors and produces vasodilation. At higher doses, dopamine (directly and via  conversion to norepinephrine) activates both α¹and α²adrenoceptors. Infused at relatively low doses, dopamine consistently causes an increase in portal blood flow; this effect may be related to the stimulation of β²-adrenergic receptors within the preportal arteries because phenoxybenzamine (an α-adrenergic antagonist) augments the increase, whereas propranolol (a β-adrenergic antagonist) abolishes it. 19 

Dopamine can cause hepatic arterial blood flow to decrease, increase, or remain constant. 20,21The mechanism of the decrease is unclear; it may result from the effect of dopamine on α-adrenergic receptors, particularly at relatively high doses, or from the hepatic arterial buffer response, 22which mediates the reciprocal relation between portal flow and hepatic arterial blood flow (i.e. , an increase in the former causes the latter to decrease) when lower doses are used.

The dose-related effects of dopamine on the hepatic oxygen supply–demand relation have been studied in animals. At the low end of the dose range, dopamine causes a parallel increase in hepatic oxygen supply and consumption; however, higher doses of dopamine decrease the ratio of oxygen supply to consumption. 20Dopamine-induced increases in mesenteric blood flow have been associated with decreases in oxygen extraction, 23nutritive blood flow, and capillary density in the intestines. 24Therefore, dopamine may divert blood flow away from splanchnic mucosa and predispose to mucosal ischemia. 25,26 

More than 25 yr ago, Marino et al. , 27using a cardiopulmonary bypass model, noted that phenylephrine and dopamine increased the blood volume in the bypass reservoir, indicating that both drugs decrease venous capacitance. In such experiments, changes in bypass reservoir volume are inversely related to the changes in venous capacitance. Studies in the cardiopulmonary bypass model have also shown that dopamine produces dose-dependent decreases in venous capacitance during spinal anesthesia. 28Experiments using selective receptor antagonists have demonstrated that both α- and β-adrenergic receptor stimulation contribute to dopamine- and norepinephrine-induced increases in venous return. 29Epinephrine and norepinephrine can produce equivalent reductions of splanchnic (including hepatic) blood volume. 30 

Hypovolemia leads to an activation of sympathetic nervous system and an increase in circulating catecholamines. As a result, blood is translocated from blood reservoirs (primarily splanchnic capacitance vessels) of the body into the systemic circulation, which partially compensates for the decreases in circulating blood volume. In a recent study in dogs, hemorrhage sufficient to decrease mean aortic pressure by 50% was associated with a 50% reduction in cardiac output and nearly a 90% reduction in intestinal blood volume. 31Although the induction of moderate hypervolemia or hypovolemia did not substantially affect cardiac output, it markedly altered the intestinal blood volume. 31When intestinal blood volumes ranged between 95% and 135% of the baseline values, cardiac output remained constant. Outside this range, constriction or dilation of intestinal vessels caused large increases or decreases in venous pressure and cardiac output. 31Therefore, these observations confirm the notion that splanchnic venous vasculature moderates changes in cardiac output during acute volume loading and hemorrhage, thereby maintaining cardiac output relatively constant over a wide range of total vascular blood volume. 6,12,31,32 

The effects of catecholamines administered during hypovolemia depend on the volume of blood in the splanchnic reservoir. When hypovolemia is severe, the homeostatic mechanisms involved in blood pressure and cardiac output regulation have already emptied the splanchnic reservoir. That is, the capacity of exogenous catecholamines to improve systemic hemodynamics by modulating the splanchnic circulation decreases progressively in the setting of increasing sympathoadrenal outflow and increases in the plasma concentrations of endogenous catecholamines and other vasoconstrictors (e.g. , angiotensin II, vasopressin/antidiuretic hormone, endothelin-1). After depletion of the splanchnic reservoir, large doses of catecholamines may still be able to increase blood pressure by further elevating arterial resistance in splanchnic and other vascular beds. Such effects might be essential for maintaining perfusion pressure and blood flow to the heart and brain. However, the intense vasoconstriction can be detrimental to the splanchnic organs by producing severe ischemic injury, which could subsequently lead to multiorgan failure. Therefore, when treating hypovolemia-induced hypotension, the use of exogenous catecholamines should be limited to a brief period and should not be viewed as a substitute for the immediate replacement of blood volume.

Nearly 25% of the total blood volume in humans resides within the splanchnic venous vasculature. In healthy normovolemic adults, sympathoadrenal stimulation can almost instantaneously transfuse approximately 2 units of whole blood from the splanchnic to the systemic circulation (table 2). α-Adrenoceptor stimulation actively expels blood from splanchnic capacitance vessels, producing a rapid increase in venous return. 33–35This volume mobilization occurs because of active venoconstriction as well as passive elastic recoil of the splanchnic veins secondary to decreased arterial inflow. The initial increase in venous return may be counteracted by other α-adrenergic effects, such as an increase in hepatic venous resistance (which impedes expulsion of blood from the splanchnic to the central circulation) and a significant decrease in splanchnic arterial flow (which pharmacologically removes a portion of the systemic circulation). The degree to which an α-adrenergic agonist affects venous return and cardiac output is therefore dependent on many factors, including baseline myocardial contractility, blood volume, and sympathetic tone.

Pure β-adrenergic agonists (e.g. , isoproterenol) augment cardiac output primarily by increasing venous return, which results from increases in splanchnic blood flow due to lowered resistances in splanchnic arterial vessels and hepatic veins. In general, a drug that stimulates both α- and β-adrenergic receptors would be expected to more effectively maintain systemic hemodynamics than one that activates either α- or β-adrenergic receptors. When simultaneously stimulated, α- and β-adrenergic receptors act in concert to maximally shift blood from the splanchnic vasculature into the systemic circulation by producing vasoconstriction, decreasing splanchnic vascular capacitance, and decreasing (or minimizing the increase in) intrahepatic vascular resistance.