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Division
*d’Hépatologie et de Gastroentérologie and
de Soins Intensifs Chirurgicaux, Hôpital Cantonal Universitaire de Genève, Geneva, Switzerland
Address correspondence and reprint requests to C. M. Pastor, MD, PhD, Division d’hépatologie et de gastroentérologie, Hôpital Cantonal Universitaire de Genève, Rue Micheli-du-Crest 24, 1211 Geneva 14, Switzerland. Address e-mail to Catherine.Pastor{at}medecine.unige.ch
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Introduction |
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 Top Introduction Modifications of Hepatic...Hepatic Cell Functions in...ConclusionReferences |
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Modifications of hepatic blood flow have been extensively studied in experimental sepsis, but these findings are difficult to extrapolate to humans. In human sepsis, hepatic dysfunction is usually mild and is defined by modifications of biochemical tests. However, there is no consensus on the most appropriate criteria to define and quantify hepatic dysfunction, and these criteria do not reflect the full spectrum of alterations in hepatic cell functions encountered in experimental sepsis. Although several articles have reviewed the numerous alterations of hepatic cell functions encountered in these experimental models, none has addressed the modifications of hepatic blood flow and hepatic function observed in humans sepsis. We review these alterations as reported in both clinical and experimental studies. Although all published clinical studies are included in the text, because of the large number of experimental studies, only the most illustrative experimental data are discussed. We hope that this text will contribute to a better understanding of the role of the liver in human sepsis.
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Modifications of Hepatic Hemodynamics in Sepsis |
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TopIntroductionModifications of Hepatic...Hepatic Cell Functions in...ConclusionReferences |
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-actin. Thus, during sepsis, stellate cells undergo contractile properties and, similar to endothelial cells, participate to the modifications of hepatic blood flow. Kupffer cells are hepatic macrophages and represent 80%–90% of all resident macrophages of the body. They play a major role in the uptake and destruction of bacteria and endotoxin. After activation by endotoxin, they secrete cytokines, lipid mediators such as leukotrienesand prostaglandins, O2-derived radicals, and lysosomal enzymes. Hepatocytes, which represents 60% of hepatic cells, have numerous metabolic functions, including gluconeogenesis and glycogenolysis, protein synthesis (albumin, fibrinogen), urea synthesis, bile formation, and drug biotransformation by cytochrome P-450 enzymes.
Estimation of Hepatic Blood Flow in Human Studies
Hepatic blood flow in humans has been assessed in septic patients or healthy volunteers injected with endotoxin by clearance methods using indicators injected into the blood and cleared by the liver. The disappearance rate of these indicators is usually used to estimate hepatic blood flow. These methods require the insertion of a catheter into the right hepatic vein under fluoroscopic visualization. Indocyanine green (ICG) is the most commonly used indicator and is injected as a single bolus or infused over a longer period.
The continuous ICG infusion method was first described by Bradley et al. (7) and is based on the Fick principle. Under conditions of constant flow, the volume of blood moving through an organ per time (Q) can be calculated by determining the amount of ICG extracted (R) over that time and the difference between ICG concentrations entering (Ci) and leaving (C0) the organ (8). The equation for this relationship is Q = R/(Ci - C0). Under steady-state conditions, the IV infusion rate (I) of ICG removed exclusively by the liver equals the rate of hepatic removal (R = I). Ci is determined from blood collected from a peripheral vein or artery (because the ICG concentrations are similar), and C0 is measured from blood collected in the hepatic vein. Because ICG is distributed only in the plasma, the calculated plasma flow must be converted to blood flow by knowing the hematocrit (Hct): Q (blood flow) = Q (plasma flow) x 1/(1 - Hct). ICG is the preferred dye indicator because it typically has a high hepatic extraction ratio, no extrahepatic uptake, and low toxicity, and it is easily measured by spectrophotometry. The procedure requires that the catheter be positioned correctly in the hepatic vein, deep enough but not wedged. Otherwise, blood from the inferior vena cava can backflow during sampling; such dilution of the hepatic venous sample introduces error. During experimental endotoxemia, a back-diffusion of ICG from hepatocytes into the hepatic vein has also been described (9). Although the hepatic extraction ratio (ER) estimated by (Ci - C0)/Ci is usually >90% in control patients (8), it is as low as 30% in septic patients (10). Low extraction and back-diffusion narrow the difference between ICG concentrations in arterial and hepatic vein samples, leading to an overestimation of hepatic blood flow. Moreover, although extrahepatic ICG extraction is small in normal conditions, it is not known whether it is modified in sepsis. Clearance of a single bolus of ICG is also used, allowing repeated tests. Hepatic blood flow obtained by using this technique correlates well with values obtained with the continuous-injection ICG method in patients with liver disease (11).
Estimation of Hepatic Blood Flow in Human Septic Shock
Several studies have attempted to determine the consequences of sepsis on hepatosplanchnic blood flow. In volunteers injected with endotoxin (20 U/kg over 5 min), hepatosplanchnic blood flow increases within 1 h, peaks by 3 h, and finally returns to baseline by 6 h (12). In intensive care units, septic patients are usually ventilated mechanically. To prevent feeding from modifying hepatic blood flow, enteral feeding is withdrawn and septic patients are infused with various electrolyte solutions. These patients have various sources of infection, including intraperitoneal infections. Ruokonen et al. (13) found that hepatosplanchnic blood flow is higher in hyperdynamic septic patients than in patients after uncomplicated cardiac surgery. Because the cardiac index is also higher in these patients, the ratio between hepatosplanchnic blood flow and cardiac output remains constant (approximately 25%). Dahn et al. (14) compared the hepatosplanchnic blood flow in critically ill patients with or without sepsis and found similar results. These studies suggest that hepatosplanchnic blood flow increases proportionately to the cardiac index in patients with sepsis and that the fractional hepatosplanchnic blood flow remains constant. Whether the relationship between hepatosplanchnic blood flow and cardiac output remains constant throughout the evolution of the disease remains to be determined.
O2 Delivery and O2 Consumption in the Hepatosplanchnic Region
Hepatosplanchnic O2 delivery (·DO2) and O2 consumption (
O2) were also measured in clinical studies. However, the contribution of the liver to the whole hepatosplanchnic O2 is impossible to determine because no sample can be collected from the portal vein (15). Hepatosplanchnic O2 is significantly higher in septic patients (1.9 ± 0.5 mL · min-1 · kg-1) than in nonseptic patients (1.3 ± 0.4 mL · min-1 · kg-1), whereas systemic O2 is similar in both groups (14). Both hepatosplanchnic O2 and systemic O2 are significantly increased in septic patients and postoperative patients (13). In healthy volunteers, hepatosplanchnic O2 is 66 ± 5 mL/min before endotoxin administration and increases 120 min (100 ± 13 mL/min) and 240 min (90 ± 12 mL/min) after endotoxin administration. Hepatosplanchnic O2 returns to baseline by 360 min (12). Moreover, ·DO2 is higher in septic shock patients treated with norepinephrine than in patients with severe sepsis who do not receive noradrenaline (16). This finding contrasts with the common knowledge that norepinephrine infusion decreases hepatosplanchnic blood flow (15). It is likely that the vascular hyporesponsiveness to norepinephrine observed in the mesenteric circulation during experimental sepsis is an explanation for this finding (17). Thus, hepatosplanchnic O2 is increased during sepsis, but the contribution of the liver to the hepatosplanchnic O2 remains unknown. Hepatic ·DO2 and O2 have been measured in large animals. In anesthetized pigs continuously infused with endotoxin, hepatic ·DO2 and O2 did not change over a 24-h experimental period (18). In a similar experimental model, hepatic O2 was maintained over 6 h, whereas ·DO2 decreased (19). However, these experimental findings cannot be extrapolated to clinical studies.
In septic patients, most of the increased hepatosplanchnic O2 is attributed to an increased hepatic glucose production resulting from increased substrate delivery (12,20). Hepatic amino acid uptake (20) and other hepatic pathways, such as tumor necrosis factor- (TNF-) and free fatty acid production, are also increased in volunteers injected with endotoxin (12).
Relationship Between O2 and ·DO2 in the Hepatosplanchnic Region
In critically ill patients, the relationship between O2 and ·DO2 is used to assess the O2 deficiency leading to organ dysfunction (21). Over a wide range of ·DO2 values, O2 remains constant as ·DO2 varies. Organs extract only as much O2 from the blood as needed to maintain cellular metabolism, and O2 and ·DO2 are independent. However, when ·DO2 decreases below a critical threshold value, O2 decreases in direct proportion to ·DO2, and O2 becomes dependent on ·DO2. This O2/·DO2 dependency may be responsible for organ dysfunction. To determine whether the increased hepatosplanchnic O2 is limited by the regional ·DO2 in septic patients, both hepatosplanchnic O2 and ·DO2 were measured before and after therapeutic interventions, such as the infusion of packed red blood cells (22) or dobutamine infusion (10,23) (13), to study the evolution of the hepatosplanchnic O2 while increasing the regional ·DO2. Ruokonen et al. (13) first reported an increase in hepatosplanchnic O2 after the administration of dopamine, dobutamine, or norepinephrine. After the infusion of 2 U of packed red blood cells, the hepatosplanchnic O2 moderately increased by 9%, whereas hepatosplanchnic ·DO2 increased by 26% (22). These two studies demonstrate a flow-dependent O2 consumption in hepatosplanchnic organs. In contrast, when hepatosplanchnic O2 and ·DO2 were measured before and after the infusion of dobutamine, hepatosplanchnic O2 remained constant, whereas hepatosplanchnic ·DO2 increased by 29% (10). These contradictory results may be explained by a recent study (23) showing that, in septic patients with a gradient between mixed venous and hepatic vein saturation >10%, both hepatosplanchnic ·DO2 and O2 increased during dobutamine perfusion, demonstrating O2/·DO2 dependency. In contrast, in patients with a gradient <10%, hepatosplanchnic O2 remained constant and the regional ·DO2 increased with the dobutamine perfusion (23). Consequently, hepatosplanchnic ·DO2 seems sufficient to fulfill the regional O2 demand in most septic patients, but not in those with a high gradient between mixed venous and hepatic vein saturation.
Lactate Flux in the Hepatosplanchnic Region
The evolution of hepatosplanchnic lactate flux has also been determined while the regional ·DO2 is increased. In a study by Steffes et al. (22), regional lactate uptake did not change in response to the increased hepatosplanchnic ·DO2. In contrast, lactate uptake increased by 38% in septic patients infused with dobutamine, and the increased lactate uptake was similar for patients who had a O2/·DO2 dependency and for those in whom O2 did not increase in response to the dobutamine perfusion (23). However, interpreting the evolution of lactate flux while hepatosplanchnic ·DO2 increases is difficult. During O2/·DO2 dependency, an increase in O2 after ·DO2 increase is not always associated with an increased lactate uptake because lactate uptake is influenced not only by the amount of O2 available for the conversion of lactate to pyruvate, but also by the total amount of lactate delivered to the liver. Consequently, lactate uptake can increase when blood flow is increased, even in the absence of hypoxia. Moreover, hepatosplanchnic lactate uptake represents the net lactate flux through both the gut and the liver. Because lactate is produced by the gut and taken up by the liver, and because lactate concentrations in portal vein are not available in clinical studies, it is difficult to interpret hepatosplanchnic lactate flux in humans.
In summary, sepsis increases hepatosplanchnic blood flow and O2. Besides an increased production of TNF- and free fatty acids, hepatic glucose production is likely responsible for the increased hepatosplanchnic O2. The increased hepatosplanchnic blood flow, however, may not be sufficient to meet the hepatosplanchnic O2 in patients with a high gradient between mixed venous and hepatic vein O2 saturation.
Hepatic Blood Flow in Experimental Studies
In contrast to human studies, both hepatic artery and portal vein blood flows can be measured in animals. Various models of septic shock have been described, including the injection of endotoxin or bacteria (IV or intraperitoneal injection or perfusion) and cecal ligation and puncture (CLP). These experimental models of sepsis induce either a hypodynamic syndrome (defined mainly by a low cardiac output) or a hyperdynamic syndrome (associated with an increased cardiac output). The type of animals used (for example, pigs do not often develop hyperdynamic syndrome), the treatment (fluid challenge), and the model of sepsis determine whether the syndrome will be hypodynamic or hyperdynamic (24–26). In septic models associated with hypotension and low cardiac output, hepatic perfusion is compromised by a decrease in both portal vein and hepatic artery flows (27–28). In rabbits anesthetized with pentobarbital after endotoxin injection, portal vein blood flow decreased, whereas hepatic artery blood flow increased (29). However, the type of shock induced in these experimental models differs from the classically described hyperdynamic shock observed in humans. In experimental models in which the increased cardiac output is similar to that observed in patients, both hepatic flows increased by 24 h (30). Moreover, the two hepatic flows also interact to maintain a constant blood flow to the liver. The "hepatic arterial buffer response" (31) is defined as the inverse changes in hepatic artery blood flow in response to the changes in portal flow. For example, an increase in hepatic artery flow compensates for a decrease in portal vein flow, maintaining a constant blood flow to the liver. This hepatic arterial buffer response is preserved in hemorrhagic shock (32) but is altered during sepsis (33). During endotoxemia, a decrease of portal blood flow is not buffered by an increased of hepatic artery blood flow, and the increased NO production observed in this model is not the cause for the loss of the hepatic arterial buffer response (33). The isolated perfused liver is also an interesting model for studying the direct effects of endotoxin administration without the interference of cardiac output and other organs. After endotoxin administration, intrahepatic resistances increase. The effect is similar when endotoxin is injected through either the portal vein or the hepatic artery (34). Thus, both hepatic blood flows increase in experimental septic shock associated with a high cardiac output, but the regulation between the two hepatic flows is altered.
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Hepatic Cell Functions in Sepsis |
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Besides the role of hepatic injury on the mortality rate in septic patients, the importance of preexisting normal hepatic function for the survival rate of these patients is emphasized by the fact that underlying hepatic dysfunction is an important risk factor for prognosis (43). For example, the mortality rate was 100% in a group of cirrhotic patients requiring mechanical ventilation for septic shock (44).
Additionally, the alteration of hepatic tests observed in humans do not reflect the full spectrum of alterations in hepatic functions encountered in experimental models of sepsis (45–48). In these experimental models, the modifications of hepatic function during sepsis may be either beneficial (acute-phase protein response, clearance of endotoxin, bacteria, and cytokines) or deleterious (release of oxygen-derived radicals and decrease in cytochrome P-450 activity) and may, in this way, modify the prognosis of the disease.
Modifications of Hepatic Function in Experimental Models of Sepsis
During experimental sepsis, hepatic plasma concentrations of proteins such as C reactive protein, 1-antitrypsin, and fibrinogen increase (5). These acute-phase proteins modulate the immunologic functions, repair tissue injury, and have a protective effect on endotoxin- and TNF-–induced injury (4). An increased transport of amino acids in hepatocytes is necessary to increase the synthesis of these proteins, and endotoxin has been shown to increase hepatic glutamine (49) and arginine (50) transport. In contrast, concentrations of albumin and transferrin decrease. Hepatic production of urea is also activated in experimental sepsis by the increased uptake of amino acids after the catabolism of proteins in peripheral tissues (51). Numerous alterations of glucose metabolism have been described. Glycogenolysis is increased during sepsis by catecholamines, prostaglandins, and glucagon (52). Gluconeogenesis initially upregulated by the increased availability of amino acid and lactate is soon reduced because the activity of the limiting enzyme of the pathway (phosphoenolpyruvate carboxykinase) is down-regulated by endotoxin (53). In rats with peritonitis, the phosphofructo-kinase activity is stimulated due to a rapid accumulation of fructose 2,6 biphosphate, which is the most potent regulator of gluconeogenesis, and hexoses are preferentially channeled through glycolysis rather than toward gluconeogenesis (54). Consequently, as glucose becomes limited, severe hypoglycemia may occur. Glucose availability may also modify the inflammatory response of the liver because, in Kupffer cells, the release of interleukin-1 (IL-1) is lower when cells are incubated in a glucose-deficient medium than in a normal medium (55). The reduction of drug biotransformation is another modification encountered during sepsis (56,57). Cytokines (56) and NO (57) have been shown to decrease the activity of most cytochrome P-450 enzymes. Decreased bile flow and diminished bile excretion impair the elimination of various compounds (58) (Table 3).
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production (61). Besides TNF-, endotoxin injection increases the production of IL-1 in Kupffer cells (62). In rats subjected to CLP, plasma concentrations of TNF- and IL-6 increased 1.5 h after CLP, whereas the mRNA concentrations of the two cytokines in isolated Kupffer cells increased as early as 1 h after CLP (63). In the intact liver, IL-1/ß mRNA significantly increases 1–2 h after endotoxin injection, whereas the IL-1 receptor antagonist (IL-1ra) mRNA peaks 2–4 h later (64). Thus, Kupffer cells produce both proinflammatory and antiinflammatory cytokines. The liver also participates in cytokine clearance (6). Thus, this organ plays a key role in the inflammatory response during sepsis by both producing and clearing cytokines. During sepsis, oxygen-derived radicals are released by the hepatic macrophages. These radicals are involved in microbial killing but may also induce tissue injury. Superoxide anion (O2-) release by the liver is enhanced after the IV administration of endotoxin (65). Thus, numerous hepatic cell functions are modified in experimental sepsis. Whether these modifications are beneficial or deleterious on outcome is speculative. On one hand, acute-phase protein response, bacteria and endotoxin scavenging, and cytokine clearance might be beneficial by decreasing systemic inflammation. On the other hand, decreased biotransformation and hypoglycemia might have deleterious consequences. Extrapolating these experimental findings to human sepsis is premature.
Hepatic Injury in Experimental Models
Sequestration of polymorphonuclear neutrophils (PMNs) into the liver is responsible for hepatic injury in experimental models (66). The endotoxin-mediated migration of PMNs follows the release of chemotactic agents (complement, leukotriene B4, and TNF-) by Kupffer cells (67). After the up-regulation of adhesion molecules on neutrophils, the activation of adhesion molecules in endothelial cells promotes PMN migration. TNF- and IL-1 are responsible for transcriptional activation of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and P-selectin (68). The increased expression of intercellular adhesion molecule-1 is detected in all hepatic cells, whereas the increased expression of vascular cell adhesion molecule-1 and selectins is detected on endothelial cells and Kupffer cells (68–69). After the activation of these molecules, transendothelial migration and extravasation of neutrophils occur in sinusoids, but not in postcapillary venules, as observed in extrahepatic organs (70). These PMNs secrete potent mediators, destructive enzymes, and O2-derived radicals. Both activated PMNs and Kupffer cells represent a potential hazard to the integrity of tissue and seem to be important contributors to hepatic injury (67,71). Elimination of neutrophils from the circulation by monoclonal or polyclonal antibodies against neutrophils minimizes the deleterious effects of PMNs (72).
Besides the sequestration of PMNs, other mechanisms have been involved in hepatic injury in experimental models of sepsis. Although several authors (73–74) found a protective effect of NO on liver cell damage, Bohlinger et al. (75), Thiermermann et al. (76), and Ruetten et al. (77) published opposite results. The role of Kupffer cells in mediating hepatic damage is underscored by the protective effect of macrophage inactivation. The inactivation of Kupffer cells by methyl palmitate reduces the hepatic injury induced by CLP in mice (78). Experiments blocking Kupffer cell activation with gadolinium chloride have yielded similar results (79–81). Similarly, acute-phase proteins (4,82–83) and IL-10 (84) can protect the liver from sepsis-induced liver damage. However, these effects observed in experimental studies have not been investigated in humans.
Flow-Dependent Cellular Dysfunction?
Because clinical studies found an increased hepatosplanchnic blood flow associated with mild hepatic injury during sepsis, either the high hepatosplanchnic blood flow is insufficient for the regional O2 demand or hepatic dysfunction is not flow-dependent. Using colloidal carbon infusion and laser Doppler flowmetry, Wang et al. (85) showed that, after endotoxin and TNF- perfusion, hepatic cellular dysfunction occurred despite the preservation of the microcirculation. This early dysfunction persisted after fluid administration, but its precise mechanism is unknown. In contrast, using galactose clearance to assess the hepatic microcirculation, Machiedo et al. (86) noted that alterations in the intracellular concentrations of Na+ and K+, which are considered earlier indicators of cell dysfunction in sepsis, followed hepatic hypoperfusion. They argued that cellular damage is a flow-related phenomenon rather than a direct injury induced by circulating toxins. Thus, modifications of hepatic function may be the consequence of the direct effect of endotoxin and/or cytokines. Additionally, hepatic injury may occur after hepatic hypoperfusion, with cell damage and enzyme release. Whether increasing hepatosplanchnic ·DO2 might improve hepatic function and outcome has not been demonstrated.
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Conclusion |
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TopIntroductionModifications of Hepatic...Hepatic Cell Functions in...ConclusionReferences |
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O2 is increased. Although the criteria for hepatic dysfunction and its severity must be better defined, clinical studies show that hepatic injury is frequent, often moderate, and influences the outcome. Thus, because increased hepatosplanchnic blood flow is associated with mild hepatic injury, either the hepatic blood flow is insufficient for the regional O2 demand or hepatic dysfunction is not flow-dependent. Whether increasing hepatosplanchnic ·DO2 might improve hepatic function and outcome has not been demonstrated. Limitations of clinical studies are important. First, hepatic arterial and portal vein blood flows are not measured separately. Second, the hepatic O2 is not measured independently from splanchnic O2 because it is not possible to collect samples from the portal vein. Finally, hepatic tests measure cellular injury, but there are few data on the alterations of hepatic functions. In contrast, animal models of sepsis are numerous but do not always reflect clinical situations. Many hepatic function modifications have been described in these models. These changes may be the consequence of the direct effects of endotoxin and/or cytokines. They also represent a combination of deleterious consequences on outcome and a protective adaptation with beneficial effects. Hepatic hypoperfusion may also occur and increase hepatic injury. According to experimental findings, further clinical investigations are required for a better understanding of the role of the liver in human sepsis. |
Acknowledgments |
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References |
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TopIntroductionModifications of Hepatic...Hepatic Cell Functions in...ConclusionReferences |
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. Hepatology 1992;15:122–9.[ISI][Medline]
/ß and interleukin-1 receptor antagonist mRNA during endotoxemia and during endotoxin-initiated local acute inflammation. Am J Pathol 1992;141:61–8.[Abstract]
-monomethyl-L-arginine inhibits endotoxin-induced nitrite/nitrate biosynthesis while promoting hepatic damage. J Leukoc Biol 1990;48:565–9.[Abstract]
-induced liver injury through distinct pathways. Hepatology 1995;22:1829–37.[ISI][Medline]
1-acid glycoprotein against tumor necrosis factor-induced lethality. J Exp Med 1994;180:1571–5.1-antitrypsin inhibits the lethal response to TNF in mice. J Immunol 1996;157:5126–9.[Abstract]
produces hepatocellular dysfunction despite normal cardiac output and hepatic microcirculation. Am J Physiol 1993;265:G126–32.This article has been cited by other articles:
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  N. Okano, H. Hiraoka, R. Owada, N. Fujita, Y. Kadoi, S. Saito, F. Goto, and T. Morita Hepatosplanchnic oxygenation is better preserved during mild hypothermic than during normothermic cardiopulmonary bypass : [L'oxygenation hepatosplanchnique est mieux preservee pendant la circulation extracorporelle sous legere hypothermie que sous normothermie] Can J Anesth, November 1, 2001; 48(10): 1011 - 1014. [Abstract] [Full Text] [PDF]
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