Splanchnic Blood Flow in Low-Flow States

Since the establishment of the pathophysiologic concept that low splanchnic blood flow leads to increased mucosal permeability, endotoxemia, and local and distant organ failure (1–6), the adequacy of splanchnic perfusion has become a major concern in the most critically ill patients, such as trauma victims or patients in septic or circulatory shock. However, recent trials have shown that hepatosplanchnic perfusion and oxygenation are at risk even during routine interventions in the intensive care unit (7) and during established surgical procedures such as cardiac surgery (8,9). In these patients, hepatosplanchnic cellular damage can occur (8,9). Although the administration of crystalloids may improve hepatosplanchnic perfusion in preoperative cardiac surgical patients (10,11), this seems not to be true for patients with other forms of circulatory failure (12). Moreover, the administration of crystalloid and colloid solutions based on saline can actually result in metabolic acidosis and impaired gastric mucosal perfusion (13). The effects of drugs on hepatosplanchnic blood flow may differ from their effects on the systemic circulation (14). In addition, drugs may also interfere with hepatosplanchnic metabolism (15). The aim of this review is to alert the anesthesiologist to the consequences of both impaired systemic blood flow and its treatment on splanchnic perfusion and metabolism. The review discusses pathophysiological aspects of blood flow regulation under different clinical and experimental conditions associated with impaired splanchnic blood flow. Recently published trials on the effects of various drugs with the potential to alter hepatosplanchnic perfusion are briefly reviewed. Hepatosplanchnic Circulation and Function Under Low-Flow Conditions Under various conditions of low systemic perfusion—e.g., hypovolemia, hemorrhage, and circulatory shock—blood flow to vital organs is maintained at the expense of the perfusion of visceral organs (16–21). However, the findings are conflicting: we (22) and others (23) have provided evidence that blood flow to the splanchnic region is reduced in proportion to systemic blood flow under different conditions of low systemic blood flow. Moreover, the splanchnic organs are not among the first to produce lactate when systemic blood flow decreases (22). Varying study conditions and consequent pathophysiological reactions can explain such inconsistent findings. The splanchnic region has a large capacity to increase oxygen extraction (24). At least over the short term, the metabolic processes can be maintained at a high level of oxygen extraction in low-flow states. Prolonged impaired perfusion of the splanchnic organs results in ischemia, tissue damage, and necrosis. As a result of splanchnic ischemia, mucosal permeability increases (25), and endotoxin and other bacterial products can pass through the gut wall into lymph nodes and blood vessels (26–28) and thereby cause injury to local and distant organs (6,29). In addition, leukocyte-activating factors are released during both splanchnic ischemia and reperfusion (30). Multiple organ failure and death have been associated with such changes (3,5). However, studies have failed to demonstrate the complete sequence of events in patients. Nevertheless, there is a strong association between low gastric mucosal pH and increased morbidity and mortality in critically ill patients (5,31–33). Regulation of Hepatosplanchnic Blood Flow Both intrinsic and extrinsic mechanisms regulate the intestinal blood flow (34). Intrinsic factors include local myogenic and metabolic control, locally produced vasoactive substances, and local reflexes. The intrinsic factors are responsible for phenomena such as pressure/flow autoregulation, reactive hyperemia, and hypoxic vasodilation (34). Extrinsic factors are circulating vasoactive substances, sympathetic innervation, and systemic hemodynamic changes. Infusion of drugs acting on α-adrenergic receptors results in intestinal vasoconstriction, whereas pharmacological stimulation of β-adrenergic receptors is associated with intestinal vasodilation. Angiotensin, vasopressin, and endothelin are potent intestinal vasoconstrictors (35–37). In low-flow states, activation of the renin-angiotensin axis is a predominant feature of splanchnic vasoconstriction (38–42). Mesenteric angiotensin II-mediated vasoconstriction can be inhibited by pharmacological maintenance of perfusion pressure with sodium nitroprusside (43). In this study, incremental doses of angiotensin II in pigs caused a strong dose-dependent vasoconstriction (increases in vascular resistance of up to of 90% and 110% in the mesenteric and renal vascular beds, respectively). When sodium nitroprusside was infused at doses titrated to keep the mean arterial blood pressure constant during concurrent angiotensin II administration, angiotensin II-induced vasoconstriction was inhibited in the mesenteric but not in the renal circulation. As the authors of the article state (43), this can be explained by differences between the vascular beds in the relative regional balance between nitric oxide-mediated vasodilation and angiotensin II-induced vasoconstriction. Alternatively, coexisting local myogenic pressure-dependent vasoconstriction may be different in the renal and mesenteric regions. Despite the theoretical benefit of angiotensin-converting enzyme inhibition and/or infusion of sodium nitroprusside in conditions in which mesenteric blood flow is low, the systemic effects of these drugs often prohibit their administration in cardiogenic shock and hypovolemia. The Hepatic Arterial Buffer Response It is believed that the liver is relatively protected in states of low gut blood flow. The hepatic arterial buffer response (HABR)—a dynamic interaction between hepatic arterial and portal venous blood flow (44–46) —tends to maintain total hepatic blood flow when portal blood flow decreases (Fig. 1). The compensation of hepatic arterial blood flow for the decreased portal venous blood flow is roughly 20%–30%(44–46). The compensation in terms of oxygen delivery is substantially higher because of the higher oxygen content in the hepatic artery as compared with the portal vein. Adenosine is involved in the underlying physiological mechanism of the HABR (Fig. 2) (48). It is hypothesized that the adenosine in Mall’s space is washed out when portal venous blood flow is normal, but not when it is low. Under these circumstances, accumulating adenosine causes hepatic arterial vasodilation (44).Figure 1: Hepatic arterial buffer response. When portal venous blood flow is acutely reduced by local vascular occlusion, hepatic arterial blood flow increases to compensate partially for the reduced blood flow to the liver.Figure 2: Adenosine washout hypothesis. Portal triad with terminal branches of the hepatic arteriole, portal venule, and bile ductule, surrounded by parenchymal cells. The space enclosed by the cells is called the space of Mall. Adenosine is proposed to be continuously secreted in the space of Mall, and the local concentration of adenosine determines the hepatic arterial tone. Reprinted with permission from Lautt WW, Can J Physiol Pharmacol 1996;74:223–33 (47).Most of the experiments for the assessment of the HABR have been performed in splenectomized animals (44,46,48–51). Splenectomy is performed to avoid an increase in circulating splanchnic blood volume when the spleen is contracted in response to decreasing mesenteric perfusion. Hence, splenectomy would be most useful in animals with large spleens and contractile splenic capsules (such as dogs). For easier assessment of blood flow changes, branches from the celiac trunk other than the hepatic arteries are often ligated, and branches to the portal vein are excluded from the circulation. This procedure has a major effect on blood flow distribution and probably also on blood flow regulation during decreasing portal venous blood flow. The HABR has been evaluated mainly during acute mesenteric artery occlusion in animals with normal cardiac output (44,46,49,50). This model represents clinical syndromes such as mesenteric embolism or mesenteric or portal venous thrombosis. However, systemic hemodynamics may have an effect on the HABR (22). We have recently demonstrated that the hepatic arterial blood flow compensation disappears during cardiac tamponade (22). The HABR is also exhausted during continuous endotoxin infusion (52) and in CO2 pneumoperitoneum (53). Hence, it appears that the protection of liver oxygenation and perfusion is lost during low systemic blood flow and other conditions of reduced visceral organ blood flow. This may explain the early appearance of hepatic failure under these conditions. Effects of Underlying Mechanisms of Impaired Splanchnic Blood Flow on Hepatosplanchnic Blood Flow Regulation Hypovolemia and Hemorrhage. During hemorrhage in humans, total splanchnic blood flow decreases in proportion to cardiac output (23). In contrast, local microcirculatory blood flow in the gastrointestinal region is heterogeneously distributed during acute hemorrhage (54): in this animal study, the microcirculatory flow in the jejunal mucosa was better preserved than in the gastric mucosa, whereas the microcirculation of the pancreas was disproportionately impaired, indicating the presence of particularly vulnerable splanchnic organs. There is evidence that total splanchnic blood flow, if once decreased, may remain low for an extended period: in volunteers, simulated transient hypovolemia by prolonged application of lower-body negative pressure caused a parallel decrease in systemic, splanchnic, and musculocutaneous blood flow (55). Each cardiovascular and biological variable had returned to baseline values after 60 min of recovery except splanchnic blood flow, which remained below baseline values. In contrast, transiently decreased splanchnic blood flow during hemodialysis with ultrafiltration returned rapidly to baseline values (7). In these patients, the transient, threefold increase in renin concentration during hemodialysis likely indicates hypovolemia-induced impairment of renal perfusion. Differences in the effective circulating blood volume and renal function between the volunteers and the patients, and changes in serum osmolality during and after hemodialysis, may explain the discrepancies. During hemorrhage (10 mL/kg body weight), the HABR is maintained (48). Liver oxygen supply does not decrease until the blood loss exceeds 30%(56), suggesting blood flow redistribution within the splanchnic region, with impaired perfusion of extrahepatic branches of the celiac trunk. It is speculative whether similar pathophysiological effects explain the coexistence of low cardiac output, low splanchnic blood flow, maintained splanchnic oxygen consumption, and gastric mucosal acidosis in patients after cardiac surgery (57–59). During hypovolemia, total hepatosplanchnic perfusion can therefore be estimated from systemic blood flow, but one has to bear in mind that splanchnic blood flow may remain decreased when systemic hemodynamics have been restored. In addition, on a local level, visceral perfusion may be disproportionately diminished. Hemodilution. Isovolemic hemodilution is another mechanism by which blood flow is redistributed within the splanchnic region: in one experiment, acute isovolemic hemodilution with hydroxyethyl starch to a hematocrit of 20% resulted in an 86% increase in hepatic arterial blood flow and a 28% increase in portal venous blood flow (60). In the same experiment, small-intestine mucosal perfusion increased by 68%, whereas blood flow to the nonmucosal tissue compartment of the gut wall increased by 32%. Different rheological properties in the respective microcirculation can explain these discrepancies. Redistribution of blood flow during isovolemic anemia may form the basis for preservation of tissue oxygenation and function in certain organs (61). Mesenteric Occlusion. Ischemia of abdominal visceral organs is associated with the activation of visceral afferent sympathetic C fibers and a concomitant reflex increase in arterial blood pressure, heart rate, and cardiac contractility (62). The afferent sympathetic nerve endings respond to severe hypoxia, as well as to bradykinin and prostaglandins (63). Celiac and superior mesenteric ganglionectomy diminish the cardiovascular reflexes (62). Occlusion of both the celiac trunk and the superior mesenteric artery produces additive effects, but the occlusion of the latter artery is associated with a more profound cardiovascular reflex (64). This occurs despite the fact that the celiac trunk supplies a larger organ mass as compared with the superior mesenteric artery and is possibly related to the greater reduction in tissue pH and the increase in venous lactate concentration from the ischemic vascular bed in the superior mesenteric artery-supplied organs (64). Local regulatory mechanisms compensate for an acute reduction in regional splanchnic perfusion, and the reduction in blood flow is therefore less than would be proportional to the reduction in perfusion pressure (62). In animals, up to 5 h of intestinal ischemia not produce systemic of such as a decrease in or hemodynamic and and occlusion of the superior mesenteric arterial blood flow for h not result in increased arterial despite increased splanchnic oxygen and increased portal lactate We have the HABR under conditions of reduced mesenteric blood flow in pigs The increase in hepatic arterial blood flow in response to portal vein occlusion decreased during h of In animals, the HABR less effective but was not the HABR events caused by the buffer response with hepatic adenosine or Alternatively, the effects of or both may have to the changes in both of In mesenteric as a of mesenteric embolism or portal venous may not become because of regional blood flow redistribution and local regulatory The of the HABR in conditions in which splanchnic blood flow is low also has clinical the hepatic arterial blood flow has increased in response to a decreasing mesenteric blood flow, it may not compensate for an acute impairment of mesenteric flow. In experimental circulatory a decrease in blood flow to vital organs may be by a concomitant decrease in perfusion of visceral organs In patients with low cardiac output after cardiac surgery and during cardiac tamponade splanchnic blood flow is reduced in proportion to cardiac Moreover, mesenteric lactate occurs during tamponade (22). It is to that in the and experiments by and low systemic blood flow was by a of hemorrhage and cardiac and blood flow was from regional splanchnic from the mesenteric artery the celiac trunk the superior mesenteric artery or the hepatic artery or portal vein The authors hemorrhage and cardiac tamponade because that hemorrhage the animals to In these cardiac output was reduced to of baseline regional splanchnic blood flow decreased at the level of cardiac output We have regional splanchnic perfusion flow from the superior mesenteric celiac hepatic and portal and the HABR during and more severe cardiac tamponade in cardiac output by 20% and in pigs (22). During severe regional blood superior mesenteric blood flow remained hepatic arterial blood flow increased during tamponade and remained The acute compensation of hepatic arterial blood flow for a decrease in portal venous during demonstrate that the liver is protected during low systemic perfusion. the HABR is splanchnic blood flow was preserved in these animals, the splanchnic organs not among the first to produce lactate during tamponade the lactate (22). In contrast, the capacity of the liver to increase lactate was exhausted early (22). There are different forms of acute circulatory and their effect on hepatosplanchnic perfusion may For failure with increased venous pressure is associated with hepatic ischemia This is in to shock cardiac In this recent patients with ischemic not related to trauma was as an increase in serum or of at least the of normal, causes of acute or in patients with blood for at least patients compared with a of another patients major trauma and in similar Despite the reduction in blood pressure, in the ischemic patients with ischemic had evidence of underlying heart and of these had heart Hence, heart with hepatic venous seems to the liver to hepatic injury during with low blood In on the of acute circulatory splanchnic blood flow may be reduced or disproportionately to systemic perfusion. Although in the presence of both low systemic blood flow and hypovolemia, splanchnic blood flow is patients in shock with concomitant failure are at high risk of severe liver In these patients, preservation of a certain perfusion pressure the hepatosplanchnic region may become a to than the systemic blood systemic effects such as on hepatosplanchnic perfusion, we have recently a model for visceral Blood flow to the abdominal organs was reduced by an between the abdominal below the and the abdominal the pigs to a and a low-flow in the celiac the superior mesenteric the portal the hepatic and the on the of the the and the gastric and jejunal The of the was associated with a proportional decrease in visceral blood whereas the changes in the mucosal perfusion The between the regional and the respective mucosal and blood was demonstrate that local splanchnic mucosal and blood flow distribution occur of regional blood flow changes. The of local splanchnic blood flow distribution is a that seems to occur of the underlying mechanism for impaired splanchnic perfusion It may a basis for maintenance of splanchnic oxygenation in local splanchnic is associated with a systemic response and with increased gastrointestinal permeability of the intestinal wall as a of may be related to a certain of or both and the associated and changes a increase in systemic vascular resistance that into the early organ perfusion and increased are potential During flow in humans, total hepatic blood flow decreases by an of In to hepatic blood flow, gastrointestinal blood flow not decrease in animals during or However, changes in blood vessels not hemodynamic changes in beds mucosal blood flow may decrease by both during and despite or even superior mesenteric arterial blood flow gastric mucosal acidosis has also been during the and the are therefore other conditions with impaired hepatosplanchnic perfusion. gastric and gut mucosal blood flow are and increased permeability and are Although is that splanchnic perfusion in a volume seems to or mucosal acidosis and In addition, after cardiac surgery is associated with increased systemic and splanchnic blood flow, even in patients hemodynamic This indicates an hemodynamic response to early During and severe systemic splanchnic metabolic increase splanchnic oxygen increases to a greater than splanchnic blood flow in septic states, oxygen extraction In septic in which early is splanchnic tissue perfusion is at and are associated with major changes in systemic and regional blood and blood flow regulation in endotoxemia, hepatic celiac and portal venous vascular and the HABR is the regional vascular but not and the HABR with an increased hepatic arterial resistance for a portal flow shock is associated with early and impairment of portal venous blood flow, increased splanchnic blood and a decrease in cardiac output Splanchnic microcirculatory blood are heterogeneously distributed in septic and the changes be from changes in systemic or regional hemodynamics During endotoxemia, hepatic blood flow whereas jejunal mucosal blood flow increases When blood flow is reduced by cardiac animals have a greater and regional oxygen delivery and a and intestinal oxygen extraction than animals This impaired oxygen extraction possibly to in in septic states. Hepatic perfusion and oxygenation are therefore at risk in septic shock because of a of portal blood flow, impaired or exhausted and decreased oxygen extraction and and consequences of trauma may splanchnic blood flow, abdominal hemorrhage, increased pressure, or cardiac with impaired venous and increased There is evidence that angiotensin-converting enzyme may improve the adequacy of gastric mucosal perfusion in patients after trauma However, the of a in this study the of the results Effects of in Splanchnic Blood Flow splanchnic ischemia is treatment is not drugs are that can and impaired splanchnic blood flow. However, a of drugs may actually splanchnic perfusion, decrease or both and receptors are to a on mesenteric drugs with to these receptors have been in trials of hepatosplanchnic perfusion. systemic and splanchnic hemodynamic effects of a during hemorrhage portal vein blood flow to maintained splanchnic blood flow, and the increase in mucosal In addition, redistributed the blood flow from the to the mucosal both at baseline and during splanchnic perfusion in patients with low systemic blood flow from conditions other than hemorrhage has not been The effects of and a compared in patients with septic shock Liver blood flow was estimated by the continuous infusion and hepatic venous Liver function was by after and was as the of hepatic output and splanchnic blood flow increased in both after and h of the respective In patients, the hepatosplanchnic blood flow decreased whereas it remained in the Hepatosplanchnic oxygen and of increased in both after h of vasoactive but arterial increased in the in this study, such as a of patients and assessment of it to as to the of one of the drugs in terms of better preservation of liver function or of The effects of and compared during CO2 with increased pressure In increases in pressure not to However, is performed in and patients, in the procedure may Under circumstances, clinical in renal and hepatic function have been Despite of gut mucosal perfusion and hepatic arterial blood flow with doses of total hepatosplanchnic blood flow not be maintained with or is to cardiac output and blood pressure in patients with cardiac failure and septic shock We the effects of on systemic and splanchnic blood flow and metabolism in septic and cardiac surgery patients infusion was at a of and increased until the cardiac output was higher than at infusion was associated with a parallel increase in systemic and splanchnic blood flow. Although systemic oxygen not in of patients, splanchnic oxygen decreased in septic patients and increased in cardiac surgery patients. decrease in splanchnic oxygen during infusion has also been in patients with acute hepatic failure Blood flow redistribution explain a reduction of hepatosplanchnic oxygen despite an increase in regional perfusion. Alternatively, metabolic of the hepatosplanchnic region may have been may of the Different baseline of may for the effects of infusion on splanchnic oxygen in the The and of in therefore be may improve splanchnic tissue oxygenation during major abdominal surgery However, the effects to be to certain of the the on the of the increased during the gastric as a of the adequacy of local perfusion not improve In addition, severe associated with may its endothelin is a potent splanchnic inhibition of receptors may be useful to increase splanchnic blood flow. In experimental acute cardiac mesenteric but not renal perfusion also mucosal blood flow and results the regional of vasoconstriction. the of mucosal perfusion in terms of maintenance of mucosal endothelin may be in states. However, the of endothelin has to be demonstrated in clinical trials that drugs may be for the perfusion of certain within the visceral circulation. However, there may also be effects, such as and the of such drugs have not been evaluated Effects of for of Blood on Splanchnic Blood Flow The of infusion in patients with are to increase heart rate, and vascular resistance or to a of of blood pressure increases as a result of an increased vascular splanchnic blood flow may be at In a a mean arterial blood pressure of and in patients with septic shock not splanchnic blood flow, and cardiac output increased by a reduction of and administration not alter or splanchnic blood flow in septic shock (12). In patients with acute hepatic systemic blood pressure from to with resulted in a similar increase in cardiac output and splanchnic blood flow has been in the treatment of patients with The effect of on total hepatosplanchnic blood flow has not been in In a model of animals whereas animals that During and after from cardiac in animals, both renal and splanchnic blood flow may be critically impaired, when is reduction in portal and total hepatosplanchnic blood flow, has also been with the of in animals and in patients with liver It is not whether the in blood flow during from the and gut the and has effects for the splanchnic region and whether this may to organ failure once circulation has been Hence, the of or one of its is not at the In contrast, and at doses to arterial blood pressure of to in septic shock not to total hepatosplanchnic blood flow. splanchnic perfusion in critically ill patients is associated with increased morbidity and The underlying pathophysiological mechanisms are not well splanchnic blood flow may result from a of different treatment and their It is therefore to under which experimental or clinical conditions the effects of vasoactive drugs on splanchnic blood flow are of the for hepatosplanchnic perfusion and metabolism are to in the clinical and the of the results is not Hence, splanchnic have not been on the among the physiological regulatory mechanisms in splanchnic and