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Anesth Analg 1999;89:344
© 1999 International Anesthesia Research Society

CRITICAL CARE AND TRAUMA

Hepatic Hemodynamics and Cell Functions in Human and Experimental Sepsis

Catherine M. Pastor, MD, PhD*, and Peter M. Suter, MD{dagger}

Division *d’Hépatologie et de Gastroentérologie and {dagger}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


   Introduction
Top
 Introduction
Modifications of Hepatic...
 Hepatic Cell Functions in...
 Conclusion
 References
 
The liver plays a major role in modulating the systemic response in severe sepsis because it contains most of the macrophages of the body (Kupffer cells) able to clear the endotoxin and bacteria that may stimulate the systemic inflammatory response (1–3). Hepatocytes synthesize the acute phase proteins and the enzymes required to modulate the inflammatory response (4–5). Additionally, during bacterial translocation from the gut, the liver limits the access of proinflammatory substances into the systemic circulation (6).

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.


   Modifications of Hepatic Hemodynamics in Sepsis
Top
 Introduction
 Modifications of Hepatic...
Hepatic Cell Functions in...
 Conclusion
 References
 
Hepatic Vessels and Cells
The liver has a dual blood supply. Approximately two thirds of the blood perfusing the liver is venous and is supplied by the portal vein draining the splanchnic vascular bed, which collects the blood coming from the digestive tract below the diaphragm, the spleen, and the pancreas. One third of the blood perfusing the liver is arterial and is provided through the hepatic artery. Within the liver, the portal vein and the hepatic artery branch in parallel. After a number of divisions, terminal branches of these vessels supply blood to the hepatic capillaries or sinusoids, which are organized in a dense network. In sinusoids, several types of cells have been identified: endothelial cells, Kupffer cells, and stellate cells. Endothelial cells are perforated by large fenestrae and are not surrounded by a basal lamina. Thus, the porosity of the sinusoids enable the dispersion of plasma into the space of Disse (which separates sinusoids and hepatocytes). Endothelial cells have a high endocytic activity and produce various mediators, such as thromboxane and prostaglandins. Stellate cells store intracytoplasmic fat droplets containing vitamin A and synthesize collagen and other constituents of the extracellular matrix. After acute or chronic hepatic injury, stellate cells undergo activation, a process characterized by the conversion to a myofibroblastic phenotype with de novo expression of the cytoskeletal protein smooth muscle {alpha}-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 ({image}O2) were also measured in clinical studies. However, the contribution of the liver to the whole hepatosplanchnic {image}O2 is impossible to determine because no sample can be collected from the portal vein (15). Hepatosplanchnic {image}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 {image}O2 is similar in both groups (14). Both hepatosplanchnic {image}O2 and systemic {image}O2 are significantly increased in septic patients and postoperative patients (13). In healthy volunteers, hepatosplanchnic {image}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 {image}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 {image}O2 is increased during sepsis, but the contribution of the liver to the hepatosplanchnic {image}O2 remains unknown. Hepatic ·DO2 and {image}O2 have been measured in large animals. In anesthetized pigs continuously infused with endotoxin, hepatic ·DO2 and {image}O2 did not change over a 24-h experimental period (18). In a similar experimental model, hepatic {image}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 {image}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-{alpha} (TNF-{alpha}) and free fatty acid production, are also increased in volunteers injected with endotoxin (12).

Relationship Between {image}O2 and ·DO2 in the Hepatosplanchnic Region
In critically ill patients, the relationship between {image}O2 and ·DO2 is used to assess the O2 deficiency leading to organ dysfunction (21). Over a wide range of ·DO2 values, {image}O2 remains constant as ·DO2 varies. Organs extract only as much O2 from the blood as needed to maintain cellular metabolism, and {image}O2 and ·DO2 are independent. However, when ·DO2 decreases below a critical threshold value, {image}O2 decreases in direct proportion to ·DO2, and {image}O2 becomes dependent on ·DO2. This {image}O2/·DO2 dependency may be responsible for organ dysfunction. To determine whether the increased hepatosplanchnic {image}O2 is limited by the regional ·DO2 in septic patients, both hepatosplanchnic {image}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 {image}O2 while increasing the regional ·DO2. Ruokonen et al. (13) first reported an increase in hepatosplanchnic {image}O2 after the administration of dopamine, dobutamine, or norepinephrine. After the infusion of 2 U of packed red blood cells, the hepatosplanchnic {image}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 {image}O2 and ·DO2 were measured before and after the infusion of dobutamine, hepatosplanchnic {image}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 {image}O2 increased during dobutamine perfusion, demonstrating {image}O2/·DO2 dependency. In contrast, in patients with a gradient <10%, hepatosplanchnic {image}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 {image}O2/·DO2 dependency and for those in whom {image}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 {image}O2/·DO2 dependency, an increase in {image}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 {image}O2. Besides an increased production of TNF-{alpha} and free fatty acids, hepatic glucose production is likely responsible for the increased hepatosplanchnic {image}O2. The increased hepatosplanchnic blood flow, however, may not be sufficient to meet the hepatosplanchnic {image}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.


   Hepatic Cell Functions in Sepsis
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 Introduction
 Modifications of Hepatic...
 Hepatic Cell Functions in...
Conclusion
 References
 
Hepatic Injury in Clinical Studies
Hepatic injury has been investigated mainly in critically ill patients, but few studies have included only septic patients. Criteria used to define hepatic injury are jaundice; hyperbilirubinemia; increase of plasma concentrations of transaminases, alkaline phosphatase, or lactate dehydrogenase; and decrease of serum albumin concentration. These criteria vary among studies (Table 1). A disproportionate increase in plasma concentration of total bilirubin, compared with that in alanine transaminase and aspartate transaminase, is found in septic patients (35). Prothrombin time has been proposed by Le Gall et al. (36) and Smail et al. (37) as an early criterion of hepatic injury. They suggest that prothrombin time may be abnormal even when the plasma concentration of bilirubin remains within normal limits. To quantify the degree of hepatic injury, scores with a severity grading have also been proposed (Table 2). These scores measure the worst values observed during the disease. An important limitation is that they do not take into consideration the duration of hepatic injury. These scores are similar to those measured in chronic hepatic diseases. Besides the systemic release of various substances by hepatic cells, hepatic injury may also be assessed by the inability of hepatic cells to metabolize exogenous compounds. Maynard et al. (38) used the monethylglycinexylidide formation test to assess hepatic function in critically ill septic patients. After a subtherapeutic injection of lidocaine (1 mg/kg), monethylglycinexylidide (an hepatic metabolite of lidocaine) was measured over the first 3 days after admission. The authors found that the arterial concentration of monethylglycinexylidide was higher in patients who survived than in patients who died. Thus, this test could be an interesting method to assess hepatic dysfunction in critically ill septic patients.


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  		Table 1. Criteria for hepatic dysfunction in multiple organ dysfunction syndrome
 

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  		Table 2. Criteria for Hepatic Dysfunction in Multiple Organ Dysfunction Syndrome: Severity Grading Score
 
The occurrence of hepatic injury varies markedly among studies. One reason might be that low-grade hyperbilirubinemia and increased hepatic enzyme go unnoticed in many patients without clinical jaundice. When defined by low-grade hyperbilirubinemia and mild hepatic enzyme increase, hepatic injury is as common as pulmonary and renal failure (39). Hepatic dysfunction is usually mild during septic shock (Tables 1 and 2). It can occur 5.7 ± 7.6 days after surgery (39), after pulmonary failure but before cardiovascular failure (35). In septic patients without preexisting hepatic disease, the plasma bilirubin concentration may become abnormally increased >1 wk after the initial injury (35). Compared with other organ dysfunction, the effect of hepatic injury on mortality rate in intensive care unit patients is controversial. It can be lower (36,39) or higher (35,40–42) than the mortality rate associated with other organ failure.

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, {alpha}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-{alpha}–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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  		Table 3. Modifications of Hepatic Functions in Experimental Models of Sepsis
 
The liver is a potent scavenger for endotoxin, bacteria, and cytokines. After an IV injection, most of the endotoxin is ingested by Kupffer cells (1). Hepatocytes can clear and directly eliminate endotoxin in the bile (2). The liver also removes bacteria from blood (3), and bacterial clearance is modified by the site of injection and by preexisting liver disease (59). Acute liver failure after partial hepatectomy results in a decreased ability to clear bacteria, which is compensated for by increased phagocytic function in the spleen and lungs (60). The liver is also a site of cytokine release, as well as a potent scavenger for extrahepatic cytokines (6). In conscious dogs injected with endotoxin, the liver is a major site of TNF-{alpha} production (61). Besides TNF-{alpha}, endotoxin injection increases the production of IL-1 in Kupffer cells (62). In rats subjected to CLP, plasma concentrations of TNF-{alpha} 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{alpha}/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-{alpha}) 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-{alpha} 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-{alpha} 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.


   Conclusion
Top
 Introduction
 Modifications of Hepatic...
 Hepatic Cell Functions in...
 Conclusion
References
 
In patients with sepsis, hepatosplanchnic blood flow increases proportionately to cardiac output, and the fractional hepatosplanchnic blood flow remains constant. Hepatosplanchnic {image}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 {image}O2 is not measured independently from splanchnic {image}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
 
This work was supported by the Fond National Suisse de la Recherche Scientifique 3200.045985.95/1 (to CMP).


   References
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 Introduction
 Modifications of Hepatic...
 Hepatic Cell Functions in...
 Conclusion
 References
 

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Accepted for publication April 16, 1999.





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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press