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.
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 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.
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).
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 did not produce systemic signs of hypoperfusion, such as a decrease in base excess or altered hemodynamic and oxygen-related variables (65). Also, subsequent 40%, 70%, and 100% occlusion of the superior mesenteric arterial blood flow for 1 h each did not result in increased mixed-venous arterial Pco2 gradients despite intramucosal acidosis, increased splanchnic oxygen extraction, and increased portal venous-arterial lactate gradients (66).
We have measured the HABR under conditions of selectively, severely reduced mesenteric blood flow in pigs (67). The absolute increase in hepatic arterial blood flow in response to portal vein occlusion decreased significantly during 2 h of ischemia. In control animals, the HABR became less effective but was not exhausted. Reperfusion restored the HABR partially. Possibly, repeated ischemia/reperfusion events caused by testing the buffer response interfered with hepatic adenosine production or transport. Alternatively, the effects of surgery, anesthesia, or both may have contributed to the observed changes in both groups of animals.
In summary, isolated mesenteric hypoperfusion, e.g., as a consequence of mesenteric embolism or portal venous thrombosis, may not become clinically apparent because of regional blood flow redistribution and local regulatory mechanisms. The exhaustion of the HABR in conditions in which splanchnic blood flow is low also has important clinical implications. If the hepatic arterial blood flow has already increased in response to a decreasing mesenteric blood flow, it may not compensate for an acute further impairment of mesenteric flow.
In experimental circulatory shock, a decrease in blood flow to vital organs may be attenuated by a concomitant disproportionate decrease in perfusion of visceral organs (16,38–41). In patients with low cardiac output after cardiac surgery (57,58), and during experimental, euvolemic cardiac tamponade (22), splanchnic blood flow is reduced in proportion to cardiac output. Moreover, mesenteric lactate production occurs late during tamponade (22). It is important to realize that in the carefully designed and conducted experiments by Bailey et al. and Bulkley et al. (16,38–41), low systemic blood flow was achieved by a combination of hemorrhage and cardiac tamponade, and blood flow was measured from single regional splanchnic vessels, i.e., from the inferior mesenteric artery (16,40), the celiac trunk (38), the superior mesenteric artery (39), or the hepatic artery or portal vein (41). The authors combined hemorrhage and cardiac tamponade because they realized that prior hemorrhage sensitized the animals to subsequent tamponade. In these experiments, cardiac output was reduced to <40% of baseline levels. Fractional regional splanchnic blood flow decreased only at the lowest level of cardiac output (40).
We have measured regional splanchnic perfusion (blood flow from the superior mesenteric artery, celiac trunk, hepatic artery, and portal vein) and the HABR during moderate and more severe cardiac tamponade (decreases in cardiac output by 20% and 55%, respectively) in euvolemic pigs (22). During severe tamponade, all regional blood flows decreased. While fractional superior mesenteric blood flow remained constant, fractional hepatic arterial blood flow increased during moderate tamponade and remained unchanged thereafter. The acute compensation of hepatic arterial blood flow for a decrease in portal venous flow—the HABR—disappeared during tamponade. These data demonstrate that the liver is only initially protected during low systemic perfusion. Later, the HABR is exhausted. Because fractional splanchnic blood flow was preserved in these euvolemic animals, the splanchnic organs were not among the first to produce lactate during tamponade (unlike the lungs, where lactate production occurred early) (22). In contrast, the capacity of the liver to increase lactate uptake was exhausted early (22).
There are different forms of acute circulatory failure, and their effect on hepatosplanchnic perfusion may vary. For example, right ventricular failure with increased central venous pressure is associated with hepatic ischemia (68,69). This is in contrast to shock without cardiac insufficiency (68). In this recent retrospective analysis, 31 patients with ischemic hepatitis not related to trauma were identified. Ischemic hepatitis was defined as an acute, reversible increase in either serum alanine or aspartate aminotransferase of at least 20 times the upper limit of normal, excluding known causes of acute hepatitis or hepatocellular injury, in patients with documented systolic blood pressures <75 mm Hg for at least 15 min. These patients were compared with a cohort of another 31 previously healthy patients who sustained major nonhepatic trauma and in whom similar hypotensive episodes were documented. Despite the marked reduction in blood pressure, no patient in the control group developed ischemic hepatitis. All 31 patients with ischemic hepatitis had evidence of underlying organic heart disease, and 29 of these (94%) had right-sided heart failure. Hence, right-sided heart failure, with resultant hepatic venous congestion, seems to predispose the liver to hepatic injury during periods with low blood pressure.
In conclusion, depending on the pathophysiology of acute circulatory failure, splanchnic blood flow may be reduced proportionately or disproportionately to systemic perfusion. Although in the presence of both low systemic blood flow and hypovolemia, splanchnic blood flow is preferentially reduced, patients in shock with concomitant right ventricular failure are at high risk of developing severe liver dysfunction. In these patients, preservation of a certain perfusion pressure across the hepatosplanchnic region may become a therapeutic target to achieve rather than the absolute systemic blood pressure.
To eliminate systemic effects such as congestion on hepatosplanchnic perfusion, we have recently developed a new model for isolated visceral hypoperfusion (70,71). Blood flow to the abdominal organs was selectively reduced by using an extracorporeal circuit between the proximal abdominal aorta (inflow limb just below the diaphragm) and the distal abdominal aorta (outflow limb beyond the kidney arteries) (70,71). Twenty-four pigs were randomized to a control group and a low-flow group (12 in each group). Ultrasound flowprobes were placed around the celiac trunk, the superior mesenteric artery, the portal vein, the hepatic artery, and the left kidney artery. Laser Doppler flowprobes were fixed on the surface of the liver, the left kidney, and the gastric and jejunal mucosa. The induction of the shunt was associated with a proportional decrease in all visceral blood flows, whereas the changes in the mucosal perfusion were heterogeneous. The overall correlation between the regional and the respective mucosal and surface blood flows was weak. These data demonstrate that local splanchnic mucosal and serosal blood flow distribution occur independently of regional blood flow changes. The heterogeneity of local splanchnic blood flow distribution is a phenomenon that seems to occur independently of the underlying mechanism for impaired splanchnic perfusion (54,72). It may provide a basis for maintenance of splanchnic oxygenation in local splanchnic tissues.
CPB and the subsequent rewarming phase are therefore other conditions with impaired hepatosplanchnic perfusion. Especially gastric and gut mucosal blood flow are reduced, and increased permeability and endotoxemia are common (77). Although no drug is available that selectively improves splanchnic perfusion in a clinically significant way, perioperative volume loading seems to prevent or ameliorate mucosal acidosis and outcome (11). In addition, enteral nutrition after cardiac surgery is associated with increased systemic and splanchnic blood flow, even in patients requiring hemodynamic support (84). This indicates an adequate hemodynamic response to early enteral feeding.
During infection and severe systemic inflammation, splanchnic metabolic demands increase (85–89). Because splanchnic oxygen consumption increases to a greater extent than splanchnic blood flow in hyperdynamic septic states, oxygen extraction increases. In septic shock, in which early myocardial depression is common, splanchnic tissue perfusion is at risk. Sepsis and endotoxemia are associated with major changes in systemic and regional blood flows and blood flow regulation (87,90–92). Early in endotoxemia, lung, intestinal, hepatic arterial, celiac trunk, and portal venous vascular resistances increase, and the HABR is abolished (52,90–93). Later, the regional vascular resistances decrease, but not uniformly (52), and the HABR recovers with an increased hepatic arterial resistance for a given portal flow (91). Endotoxic shock is associated with early (after 30 min) and late (after 240 min) impairment of portal venous blood flow, increased splanchnic blood pooling, and a subsequent decrease in cardiac output (91).
Splanchnic microcirculatory blood flows are heterogeneously distributed in septic shock, and the changes cannot be predicted from changes in systemic or regional hemodynamics (72). During endotoxemia, superficial hepatic blood flow decreases, whereas jejunal mucosal blood flow increases (94). When blood flow is reduced by cardiac tamponade, endotoxin-treated animals have a greater whole-body and regional critical oxygen delivery and a lower whole-body, liver, and intestinal critical oxygen extraction ratio than control animals (94). This emphasizes impaired oxygen extraction capabilities, possibly due to maldistribution in microcirculation, in septic states. Hepatic perfusion and oxygenation are therefore especially at risk in septic shock because of a combination of diminished portal blood flow, impaired or exhausted HABR, and decreased oxygen extraction capability.
Several direct and indirect consequences of trauma may impair splanchnic blood flow, including direct abdominal injury, hemorrhage, increased intrathoracic pressure, or cardiac tamponade, with resulting impaired venous return and increased intraabdominal pressure. There is some evidence that angiotensin-converting enzyme inhibitors may improve the adequacy of gastric mucosal perfusion in patients after trauma (95). However, the lack of a control group in this study makes the interpretation of the results difficult.
Once splanchnic ischemia is detected, treatment is not straightforward. No drugs are available that can selectively and completely restore impaired splanchnic blood flow. However, a number of drugs may actually worsen splanchnic perfusion, decrease metabolism, or both (96,97). Because dopamine and β2 receptors are expressed to a great extent on mesenteric vessels, drugs with affinity to these receptors have been predominantly studied in trials of hepatosplanchnic perfusion. Recently, systemic and splanchnic hemodynamic effects of fenoldopam, a dopamine-1 receptor agonist, were studied during hemorrhage (98). Fenoldopam restored portal vein blood flow to near baseline, maintained fractional splanchnic blood flow, and attenuated the increase in ileal mucosal Pco2. In addition, fenoldopam redistributed the blood flow away from the serosal to the mucosal layer, both at baseline and during hemorrhage. Whether fenoldopam improves splanchnic perfusion in patients with low systemic blood flow originating from conditions other than hemorrhage has not yet been demonstrated.
The effects of dobutamine and enoximone, a phosphodiesterase inhibitor, were compared in patients with intravascularly fluid-resuscitated septic shock (99). Liver blood flow was estimated by using the continuous indocyanine green infusion technique and hepatic venous catheterization. Liver function was assessed by using monoethylglycinexylidide formation after lidocaine injection, and inflammation was quantified as the release of hepatic tumor necrosis factor-α. Cardiac output and splanchnic blood flow increased in both groups after 12 and 48 h of the respective drug infusion. In dobutamine-treated patients, the fractional hepatosplanchnic blood flow decreased slightly, whereas it remained unchanged in the enoximone group. Hepatosplanchnic oxygen consumption and release of tumor necrosis factor-α were increased in both groups after 12 h of vasoactive drug infusion, but arterial monoethylglycinexylidide (MEGX) concentrations increased only in the enoximone group. Methodological problems in this study, such as a lack of control patients and incomplete assessment of MEGX kinetics, make it difficult to draw conclusions as to the superiority of one of the drugs in terms of better preservation of liver function or attenuation of inflammation.
Dopamine is used to support cardiac output and blood pressure in patients with cardiac failure and septic shock (102,103). We measured the effects of dopamine on systemic and splanchnic blood flow and metabolism in septic and cardiac surgery patients (97). Dopamine infusion was started at a dose of 1 μg · kg−1 · min−1 and then gradually increased until the thermodilution cardiac output was 25% higher than at baseline. Dopamine infusion was associated with a parallel increase in systemic and splanchnic blood flow. Although systemic oxygen consumption did not change in either group of patients, splanchnic oxygen consumption decreased in septic patients and increased in cardiac surgery patients. A decrease in splanchnic oxygen consumption during dopamine infusion has also been reported in patients with acute hepatic failure (104). Blood flow redistribution could explain a reduction of hepatosplanchnic oxygen uptake despite an increase in regional perfusion. Alternatively, some metabolic functions of the hepatosplanchnic region may have been impaired. Dopamine may directly inhibit isoenzymes of the cytochrome P450 complex (105). Different baseline activities of P450 isoenzymes may account for the inverse effects of dopamine infusion on splanchnic oxygen consumption in the two patient groups. The indications and safety of dopamine in sepsis should therefore be reevaluated.
Dopexamine may improve splanchnic tissue oxygenation during major abdominal surgery (106). However, the beneficial effects seem to be restricted to certain sites of the gut. Whereas the Po2 on the serosal side of the small bowel increased during dopexamine infusion, the gastric mucosal-arterial Pco2 gradient as a measure of the adequacy of local perfusion did not improve (106). In addition, severe tachycardia associated with dopexamine may limit its usefulness.
Because endothelin is a potent splanchnic vasoconstrictor, inhibition of endothelin-1 receptors may be useful to increase splanchnic blood flow. In experimental acute cardiac failure, endothelin-1 blockade improved mesenteric but not renal perfusion (107). Endothelin-1 blockade also restored mucosal blood flow and oxygenation. These results illustrate the regional importance of endothelin-1-induced vasoconstriction. Considering the implications of improved mucosal perfusion in terms of maintenance of mucosal barrier integrity, endothelin blockade may be helpful in low-output states. However, the usefulness of endothelin blockade has yet to be demonstrated in clinical studies. These trials suggest that some drugs may be beneficial for the perfusion of certain areas within the visceral circulation. However, there may also be adverse effects, such as depressed metabolism, and the overall benefits of such drugs have not been evaluated properly thus far.
The goals of drug infusion in patients with hypotension are to increase preload, myocardial contractility, heart rate, and vascular resistance or to achieve a combination of any of these. If blood pressure increases as a result of an increased vascular resistance, splanchnic blood flow may be at risk. In a trial, titrating norepinephrine (to a mean arterial blood pressure of 65, 75, and 85 mm Hg) in patients with septic shock did not affect splanchnic blood flow, and cardiac output increased by 15%–20%(108). Similarly, a reduction of norepinephrine dose and fluid administration did not alter absolute or fractional splanchnic blood flow in septic shock (12). In patients with acute hepatic failure, increasing systemic blood pressure from 68 to 85 mm Hg with dopamine (5 μg · kg−1 · min−1) resulted in a similar increase in cardiac output and splanchnic blood flow (104). Vasopressin has been recommended in the treatment of adult patients with ventricular fibrillation. The effect of vasopressin on total hepatosplanchnic blood flow has not yet been studied in humans. In a pig model of cardiopulmonary resuscitation, vasopressin-treated animals survived, whereas all animals that received epinephrine died (109). During and after resuscitation from cardiac arrest in animals, both renal and splanchnic blood flow may be critically impaired, especially when vasopressin is used (110–112). A reduction in portal and total hepatosplanchnic blood flow, respectively, has also been described with the use of terlipressin in animals (113) and in patients with liver cirrhosis (114).
It is not known whether the vasopressin-induced shift in blood flow during cardiopulmonary resuscitation from the muscle, skin, and gut towards the brain and myocardium has deleterious effects for the splanchnic region and whether this may lead to multiple organ failure once spontaneous circulation has been reestablished. Hence, the liberal use of vasopressin or one of its analogs is not recommended at the moment. In contrast, dopamine and norepinephrine at doses sufficient to achieve arterial blood pressure of 65 to 85 mm Hg in septic shock do not seem to impair total hepatosplanchnic blood flow.
Inadequate splanchnic perfusion in critically ill patients is associated with increased morbidity and mortality. The underlying pathophysiological mechanisms are still not well understood. Insufficient splanchnic blood flow may result from a multitude of different diseases, treatment modalities, and their interplay. It is therefore important to realize under which experimental or clinical conditions the effects of vasoactive drugs on splanchnic blood flow are assessed. Unfortunately, many of the available monitoring tools for hepatosplanchnic perfusion and metabolism are difficult to apply in the clinical setting, and the interpretation of the obtained results is not straightforward. Hence, splanchnic resuscitation concepts have not been established. Future research projects should focus on the interplay among the physiological regulatory mechanisms in splanchnic organs, disease, and treatment.
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