Chinese Medical Journal 2011;124(10):1458-1464
Alternatives to albumin administration in hepatocellular carcinoma patients undergoing hepatectomy: an open, randomized clinical trial of efficacy and safety

YANG Jian,  WANG Wen-tao,  YAN Lü-nan,  XU Ming-qing,  YANG Jia-yin

YANG Jian (Division of Liver Transplantation, West China Hospital, West China Medical School of Sichuan University, Chengdu, Sichuan 610041, China)

WANG Wen-tao (Division of Liver Transplantation, West China Hospital, West China Medical School of Sichuan University, Chengdu, Sichuan 610041, China)

YAN Lü-nan (Division of Liver Transplantation, West China Hospital, West China Medical School of Sichuan University, Chengdu, Sichuan 610041, China)

XU Ming-qing (Division of Liver Transplantation, West China Hospital, West China Medical School of Sichuan University, Chengdu, Sichuan 610041, China)

YANG Jia-yin (Division of Liver Transplantation, West China Hospital, West China Medical School of Sichuan University, Chengdu, Sichuan 610041, China)

Correspondence to:WANG Wen-tao,Division of Liver Transplantation, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan 610041, China (Tel: 86-28-85422476. Fax:86-28-85423724. E-mail:wtzyy2002@163.com)
Keywords
artificial colloids; hepatectomy; hepatocellular carcinoma; inflammatory response; volume replacement
Abstract
Background  The value of artificial colloids in treating patients with liver disease is controversial. The effects of intravascular volume replacement regimens on liver function secondary to alteration of the postoperative inflammatory response are not known. In this study, we evaluated the effects of different volume replacement regimens in hepatocellular carcinoma patients undergoing hepatectomy to clarify whether albumin administration can be replaced by other volume replacement products. 
Methods  Ninety consecutive hepatocellular carcinoma patients scheduled for hepatectomy were prospectively randomized to receive 20% human albumin (HA), 6% hydroxyethyl starch (HES) or lactated Ringer’s solution (LR) for postoperative volume replacement. Hemodynamic, liver function and inflammatory response parameters were recorded on postoperative days one, three, and five throughout the investigation period.
Results  Significantly less volume was required in the HA and the HES groups. Although patients in all groups had similar baseline values, the plasma osmolality was significantly higher in the HA and HES groups. Total bilirubin (TB), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) increased from baseline in all groups, and did not differ significantly between groups. C-reactive protein (CRP) was significantly lower in the HES group compared with the other groups.
Conclusions  In hepatocellular carcinoma patients undergoing hepatectomy, HA can be replaced by HES or LR in well selected patients. Hemodynamic stability, liver function, and postoperative clinical outcomes could be equivalently achieved in the HES group; also, HES may exert more favorable effects on the acute phase response. (Registered in the Chinese Clinical Trial Registry, ChiCTR-TRC-10000790)
Hemodynamic stability is a prerequisite for adequate tissue perfusion and energy metabolism and is essential in the management of patients undergoing major surgery. Different intravascular volume replacement regimens have been proposed for volume replacement therapy. A novel 6% hydroxyethyl starch (HES) with an intermediate molecular weight (MW, 130 000 Dalton) and a very low degree of substitution (Ds 0.4) (HES 130/0.4; Voluven®, Fresenius AG, Bad Homburg, Germany) has been approved in several countries for routine volume replacement. HES 130/0.4 has been reported to have significant pharmacokinetic and pharmacodynamic advantages such as a stable volume effect, decreased tissue storage, rapid plasma elimination and a low impact on coagulation.1,2 In addition to the effect on maintenance and stability of hemodynamic parameters, some studies in vitro and in vivo have shown that HES may even exert anti-inflammatory effects.3,4 The effects may result in less endothelial cell damage and an improved microcirculation.
 
In patients undergoing major hepatic resection, intravascular volume depletion is often seen after surgery for several reasons. The consequence of hypovolemia is the inexorable development of complex pathophysio- logical processes including progressive liver failure, which is a major contributor to postoperative mortality. Following liver resection, the disturbance of the balance between immediate and ongoing loss of hepatocytes and liver regeneration explains the nature of evolving liver failure. We know that in liver resection, inflow occlusion and subsequent restoration of blood supply causes reperfusion injury, termed ischemia-reperfusion injury (IRI). This can lead to ongoing loss of hepatocytes and postoperative liver insufficiency, particularly in patients with cirrhosis. However, the remnant liver has a strong ability to regenerate after partial hepatectomy. It is well known that some inflammatory mediators are important in the mechanisms of both IRI and liver regeneration. During liver resection, the liver is exposed to variable periods of interruption of portal vascular flow and systemic hypotension. After the onset of reperfusion, the liver is subjected to a further insult caused by the introduction of oxygenated blood. This, in turn, is followed by the activation of Kupffer cells, which produce inflammatory cytokines and oxygen-derived free radicals (ODFR);5,6 consequently, failure of the microcirculation is followed by a deterioration of energy metabolism. There is growing evidence that the activation of Kupffer cells and the release of cytokines initiate and maintain the inflammatory response, resulting in IRI.7 Kupffer cell activation is also an important component in the early initiation of liver regeneration. It has been shown that Kupffer cells can trigger a local inflammatory response, leading to the release of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which then act on hepatocytes, leading to proliferation. Therefore, TNF-α and IL-6 are required for the initiation of liver regeneration.8,9 Tiberio et al10 demonstrated in animal models that exogenous administration of IL-6 improves postoperative survival and hepatic regeneration.
 
Despite extensive research, the best strategy for volume therapy after liver resection is still the focus of debate. The “ideal” volume replacement regimens should go beyond simply stabilizing hemodynamics and have additional positive effects such as modulating inflammation. The liver has a key role in producing inflammatory cytokines during sepsis or following other adverse circulatory conditions. Due to this and to the complex relationship among inflammation, IRI, and liver regeneration, we are interested in the effects of different intravascular volume replacement regimens on liver function in patients with hepatocellular carcinoma undergoing hepatic resection. Although human albumin (HA) has been frequently used for volume therapy in patients with poor liver function, most of whom have a low plasma albumin concentration, the cost of albumin limits its usage. Artificial colloids, such as HES, have been extensively investigated as alternatives to albumin. However, few studies have been undertaken to investigate the impact of volume therapy, in terms of the alteration of the inflammatory response, on liver function. To address this issue, the following study focused on the impact of intravascular volume replacement strategy on inflammatory response and liver function in patients with hepatocellular carcinoma undergoing hepatic resection.
 
METHODS
 
Patients
After obtaining approval from the local ethics committee and patients’ informed consent, 90 consecutive patients between the ages of 18 and 75 with hepatocellular carcinoma and cirrhosis undergoing partial hepatectomy were included. Patients with renal insufficiency requiring dialysis, severe liver insufficiency (Child C), cardiac insufficiency (New York Heart Association class III–IV), steroid therapy, and pre-existing signs of bacteremia (white cell count > 10 × 109/L and body temperature >38.0°C) were excluded. Patients with known allergic reactions to starch preparations were also excluded from the study. The severity of cirrhosis was evaluated and graded based on the size of the largest nodule visualized on the liver surface intraoperatively: mild (<0.4 cm), moderate (0.4–0.8 cm), severe (>0.8 cm) and significant size-reduction and deformity.
 
Study design and treatment protocol
Using a computerized random number generator, eligible patients were prospectively randomized to receive 20% HA (group 1, HA group; n=30), artificial colloids (Voluven, a third generation, small molecular weight colloid; 6% HES 130/0.4; group 2, HES group; n=30), or crystalloids (lactated Ringer’s (LR); group 3, LR group; n=30). For group 1, 20% HA was administered at 200 ml/d during the first three days after operation and 100 ml/d during postoperative days four and five. For group 2, 1000 ml/day HES was administered in the first three days post-operatively and 500 ml/d during days four and five. In group 3, LR solution was used exclusively for volume replacement. Additional crystalloid solutions were administered to maintain a central venous pressure (CVP) between 5 and 9 mmHg throughout the period in the intensive care unit (ICU) and a mean arterial pressure (MAP) of 60–80 mmHg throughout the remainder of the study period. When MAP was <60 mmHg despite sufficient intravascular volume, dopamine (3–9 μg∙kg–1∙min–1) was given. Epinephrine (0.01–0.04 μg∙kg–1∙min–1) was added when volume therapy and dopamine were not successful in keeping MAP > 60 mmHg. If the hemoglobin (Hb) concentration was <7 g/dl, a red blood cell suspension was administered. HA was administered to patients when their serum albumin concentration was <25 g/L, and fresh frozen plasma was administered when bleeding occurred. Non-steroidal anti-inflammatory drugs were not administered throughout the investigation period. Monitoring, anesthetic, and surgical techniques were standardized.
 
Data collection
Hemodynamic
CVP was monitored in the ICU. MAP, urine output, and fluid balances were collected in the study period outside the ICU. Hemodynamic data were recorded throughout the entire study period.
 
Laboratory tests
Aspartate aminotransferase (AST), alanine amino- transferase (ALT), total bilirubin (TB), serum albumin level, and Child-Turcotte-Pugh (CTP) grading, as well as the model for end-stage liver disease (MELD), were measured to assess liver function. Data from renal function tests (BUN and creatinine), inflammatory response factors (C-reactive protein (CRP) and IL-6), coagulation parameters (international normalized ratio or INR), and plasma osmolality were collected before the surgery and on postoperative days 1, 3, and 5. Serum levels of IL-6 were measured with commercially available enzyme-linked chemiluminescence assays, and serum levels of CRP were measured with rate nephelometry assays.
 
Other variables
All other aspects of routine patient care were performed. All complications, including pulmonary complications, nosocomial infections, bleeding, and in-hospital mortality, were recorded.
 
Statistical analysis
All statistical analyses were conducted using a PC-based statistical program SPSS 16.0 (SPSS Inc., IL, USA). Data are presented as the mean ± standard deviation (SD) or median ± interquartile range. The mean ± SD and median ± interquartile range were calculated for relevant variables at every data point. The Kolmogorov-Smirnov test was used to examine the assumption of normality; continuous, normally distributed data were compared using analysis of variance (ANOVA). Continuous, non-normally distributed or nonhomogeneity of variance data were compared using the Kruskal-Wallis test. Categorical data were compared using the Kruskal-Wallis test and the Fisher’s exact test. Repeated measures with sphericity were analyzed using Mauchly’s test. The Greenhouse-Geisser test or the Huynh-Feldt test was used when appropriate; multivariate ANOVA was also used. If the two results were inconsistent, results were based on a multivariate ANOVA analysis. For multiple comparisons between two means, the Bonferroni correction was applied. P-values <0.05 were considered statistically significant.
 
RESULTS
 
Four patients in the HES group and five in the LR group requiring HA to correct postoperative hypoproteinemia were excluded from the study. At inclusion, the groups were not significantly different in terms of demographic data, preoperative data relating to comorbidities, characteristics of primary lesions, baseline laboratory parameters or intraoperative findings (Table 1).
 

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Table 1. Demographic and perioperative data
 
Morbidity and mortality during the study period were not significantly different in the HA group and the HES group but were significantly better than in the LR group. The length of ICU stay was similar in all groups, but the duration of postoperative hospitalization was significantly shorter in the HA and HES groups (HA: (7.6±0.9) days, HES: (7.6±0.6) days, and LR: (8.6±1.3) days, P <0.001).
 
A total of (3163.3±999.5) ml, (3484.6±1072.5) ml and (3372.0±965.9) ml fluid were administered intraopera- tively in the HA group, HES group, and LR group, respectively. There were no significant differences among groups concerning intraoperative fluid administration. A total of (10210.0±255.1) ml, (10235.0±393.9) ml, and (10724.0±770.4) ml fluid were administered during the postoperative period in each group. The HA and HES groups required less fluid volume (P=0.005). There were no differences between the groups throughout the study period in regard to the use of blood or blood products, urine output or hemodynamics. During the postoperative period, no patient required vasopressors, blood or fresh frozen plasma (Tables 2, 3).
 

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Table 2. Fluid input and output (cumulative)
 
During the study period, TB, ALT, and AST increased from baseline in all groups. ALT and AST showed higher levels in the LR group, but without significant differences (Table 4, Figure 1). Serum concentrations of albumin decreased in all groups on the first post-operative day (POD), but they were significantly higher in the HA group (P=0.028, Table 4, Figure 2). Plasma osmolality was significantly higher in the HA groups postoperatively (P <0.001), but in the POD 5 there was no significant difference between HA and HES groups (P=0.116, Table 4, Figure 3). The INR increased from baseline in all groups without significant differences (P=0.699). In POD 1 the CTP score of LR group was significantly higher than HA group (P=0.003), and was significantly higher in the HES and LR groups in POD 3 and 5 (POD 3: HA group vs. HES group: P=0.012, HA group vs. LR group: P=0.004; POD 5: HA group vs. HES group: P=0.01, HA group vs. LR group: P=0.004). However MELD scores increased in all groups with no significant differences (P=0.101). We speculate that the observation of significantly higher CTP scores in the HES and LR groups may be explained by the lower albumin levels.
 

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Table 3. Hemodynamic data
Table 4. Laboratory variables
 

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Figure 1. Change in total bilirubin (TB), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) during the study period. Values are mean ± standard deviation. POD1: first postoperative day; POD3: third postoperative day; POD5: fifth postoperative day.
 
CRP plasma levels increased in all groups postoperatively. They were significantly lower in the HES group (P <0.001, Table 4, Figure 4). IL-6 plasma levels also increased postoperatively. Although there was a trend toward lower levels in the HA and HES groups, this was not significant (P=0.08, Table 4, Figure 5).
 

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Figure 2. Changes in the serum albumin concentration.
Figure 3. Changes in osmolality.
Figure 4. Changes in the plasma levels of C-reactive protein (CRP).
Figure 5. Changes in the plasma levels of interleukin-6 (IL-6).
 
Hb concentrations and platelet levels decreased and the white blood cell count tended to increase from baseline in all groups after operation, but there were no significant differences among the groups. The levels of creatinine and BUN were within the normal range, without significant differences between groups.
 
DISCUSSION
 
Hemodynamic stability is paramount to the treatment of patients following major surgery, and the controversy surrounding the type of volume therapy best suited for postoperative fluid resuscitation persists. In recent years, besides natural colloid albumin, several synthetic colloids have become available as plasma substitutes. The primary goal of using colloids for volume therapy is to maintain plasma osmolality and to promote retention of intravascular volume. In addition to aiding in volume replacement by improving organ perfusion and microcirculation, some colloids have considerable additional properties, including antioxidant, and anti-inflammatory effects. The pathogenesis of systemic inflammatory processes following major surgery has become of increasing interest.11 An increasing number of studies confirm that major surgery may alter the physiologic immune balance and initiate systemic inflammatory processes; the level of systemic inflammation is thought to be responsible for the development of severe postoperative complications such as multiple organ dysfunction syndromes. While many investigators have begun to pay attention to the effects of colloids on the inflammatory response in patients undergoing major surgery, information about the interaction between the local or systemic inflammatory response and liver function after liver resection for hepatocellular carcinoma is lacking. The major result from our study was that use of HES for volume therapy demonstrated a significant anti-inflammatory effect compared to HA and LR; this finding is consistent with previous research. In contrast to other studies, HES did not show a significantly negative effect on the recovery of liver function and coagulation in patients with hepatocellular carcinoma undergoing hepatic resection. A retrospective study by Christidis et al12 showed that HES deposition in hepatic Kupffer cells and the minimization of a local inflammatory response after HES infusion was associated with a worsening of hepatic dysfunction. In our study, ALT and AST tended to be lower in the HES and HA groups, although this difference did not reach statistical significance.
 
Treatment options for the maintenance of hemodynamic stability in surgical patients include crystalloids and colloids. Based on Starling’s equation, plasma osmolality should theoretically be important for maintaining the fluid balance between the intravascular and extravascular compartments. Compared to crystalloids, colloids are often preferred due to a prolonged intravascular half-life and an improved intravascular volume effect. In recent years, HA has been frequently used for volume therapy, but high prices restrict its use. The controversy concerning the most appropriate volume replacement strategy includes the colloid/colloid debate. HES appears to be one of the most often studied plasma substitutes. In our study, HA and HES are clearly more efficient in volume replacement therapy than crystalloids, as judged by the decreased amount of fluid volume required in the HA and HES groups. The levels of plasma osmolality were significantly higher in the HA group compared to the HES group; in this regard, HA may exert more effects.

Major surgery may induce an early hyperinflammatory response accompanied by a large number of systemic changes including the specific and non-specific immune response, collectively called the acute phase response. The acute phase response can modulate the systemic immunologic state, repair tissue damage, and maintain homeostasis. On the other hand, an excessive acute phase response may lead to a counterproductive outcome such as postoperative complications including multiple organ dysfunction.13 CRP has been widely used as a marker for monitoring the magnitude of the acute phase response. Cytokines, which are intercellular signaling polypeptides produced by activated cells, have a key role in the acute phase response. In particular, IL-6 is considered the main cytokine for mediating the local inflammatory response and initiating systemic changes. It was recognized that concentration of IL-6 may reflect the degree of tissue trauma. 14 Both HA and HES 130/0.4 have been reported to be able to regulate inflammatory processes; however, several divergent actions were noted.15 The inflammation- modulating properties of HA include its function of scavenging free radical and reactive inflammatory mediators in the intravascular compartment.16 However, the mechanism of inflammation modulation by HES 130/0.4 is controversial. It was speculated that HES 130/0.4 can influence the inflammatory response due to its direct, substance-specific beneficial effects on reticuloendothelial cells, resulting in less release of mediator molecules. Indeed, recent studies show that HES 130/0.4 may exert its anti-inflammatory effect by influencing a specific signaling pathway.17 The liver plays a vital role in the inflammatory response after major surgery; most of the acute phase proteins are produced in the liver. In addition, hepatic IRI may be accompanied by the acute phase response characterized by the activation of Kupffer cells and the subsequent release of cytokines.18 A study by Kim et al19 indicated that overproduction of acute reactant cytokines (IL-6 from the portal system and IL-8 from the systemic circulation) in hepatic ischemia/reperfusion has a positive correlation with postoperative hepatocyte injury in humans. However, a large number of studies also suggested that hepatocytes need to be primed by cytokines TNF and IL-6, in addition to other agents, before they can fully respond to the growth factors.20 Webber et al8 showed that regenerative cytokines are produced during the first few hours following IRI. The regulatory roles of cytokines and other mediators in regeneration after IRI have been reported in many other organs.21 This relationship between IRI and regeneration after liver resection remains to be clarified.

The value of HA in liver disease has been consistently and unambiguously documented in many studies.22 However, cost concerns have made the appropriate indication of albumin usage an intense and sustained debate. A large amount of research has been designed to find alternatives to albumin. Unfortunately, no formal guidelines accounting for both cost and effect were identified. HES 130/0.4 has been extensively investigated as an alternative to albumin; however, concerns about its side effects limit its use, even though several studies have demonstrated that HES 130/0.4 has less adverse effects compared with prior HES preparations. Although recent data in liver disease patients suggest that albumin may improve outcomes with respect to morbidity and mortality, available evidence supporting the superiority of albumin compared to other colloids to improve such clinical outcomes and the indication of HA use in hepatocellular carcinoma patients following hepatic resection are inadequate and inconclusive. Although hypoproteinemia is frequently encountered in hepatocellular carcinoma patients, it is unknown whether correction of hypoalbuminemia after hepatic resection bestows benefit. In our study, morbidity and mortality during the whole study period were without significant differences between the HA and the HES groups and were significantly better than the LR group.
 
In conclusion, in patients with hepatocellular carcinoma undergoing hepatic resection who had serum albumin concentrations >25 g/L, we did not routinely use 20% albumin to correct serum albumin levels in the HES and LR groups. Patients in the HES and LR groups experienced more severe hypoalbuminemia compared with those in the HA group. However, compared to HA, infusion of HES had equivalent outcomes in terms of hemodynamic stability, liver function and postoperative clinical outcomes. In addition, HES may exert more favorable effects on the acute phase response. Therefore, we conclude that in patients with hepatocellular carcinoma undergoing hepatic resection, when the serum albumin concentration is >25 g/L, HA cannot be routinely used, can be replaced by HES or LR.
 
Acknowledgments: We thank Dr. SHAO Zheng-yong for his technical assistance and CHEN Pei-xian for her assistance in manuscript preparation.
 
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