HPB, 2007; 9: 183Á189

ORIGINAL ARTICLE

Prospective randomized study of the benefits of preoperative corticosteroid administration on hepatic ischemia-reperfusion injury and cytokine response in patients undergoing hepatic resection

CARLO PULITANO` , LUCA ALDRIGHETTI, MARCELLA ARRU, RENATO FINAZZI, LAURA SOLDINI, MARCO CATENA & GIANFRANCO FERLA

Department of Surgery Á Liver Unit, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy

Abstract Background. Hepatic injury secondary to warm ischemia and reperfusion (I/R) remains an important clinical issue following liver surgery. The aim of this prospective, randomized study was to determine whether steroid administration may reduce liver injury and improve short-term outcome. Patients and methods. Forty-three patients undergoing liver resection were randomized to a steroid group or a control group. Patients in the steroid group received 500 mg of methylpredniso- lone preoperatively. Serum levels of alanine aminotransferase (ALT), aspartate amminotransferase (AST), total bilirubin, anti-thrombin III (AT-III), prothrombin time (PT), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-a) were compared between the two groups. Length of stay and type and number of complications were recorded. Results. Postoperative serum levels of ALT, AST, total bilirubin, and inflammatory cytokines were significantly lower in the steroid group than in controls. The postoperative level of AT-IIIin the control group was significantly lower than in the steroid group (ANOVA pB0.01). The incidence of postoperative complications in the control group tended to be significantly higher than that in the steroid group. Conclusion. These results suggest that steroid pretreatment represents a potentially important biologic modifier of I/R injury and may contribute to maintenance of coagulant/anticoagulant homeostasis.

Key Words: hepatic ischemia-reperfusion, surgical stress, liver surgery, corticosteroid administration

Introduction has been used to reduce I/R-dependent liver injury and surgical stress following hepatic resection [8,9]. Blood loss and transfusions during liver resection are Although several studies in rodent models have demon- associated with unfavorable short- and long-term strated the biological efficacy of steroids in attenuating outcomes [1Á4]. Inflow occlusion through clamping hepatic I/R injury [10 14], data about the clinical of the portal triad (Pringle maneuver) is routinely Á effectiveness of perioperative steroid administration in used in many centers to prevent blood loss during liver surgery are still limited [15 17]. The aim of this transection of the liver parenchyma. However, the Á Pringle maneuver causes ischemia and reperfusion prospective randomized study was to investigate the (I/R) injury to the remaining liver, with a risk of poor effects of preoperative steroid administration on hepa- postoperative outcome [2,5]. Diseased liver with tic ischemic injury and short-term outcome in patients chronic liver disease poorly tolerates reperfusion undergoing hepatic resection. injury and can develop liver failure even after short periods of ischemia [6]. Patients and methods Different strategies have been reported to confer a Patients state of protection against hepatic I/R injury [7]. In this context, pharmacologic protection, such as the admin- From April to September 2004, 43 consecutive istration of steroid before or during portal clamping, patients undergoing elective hepatic resection in the

Presented to the Annual Meeting of the American Hepato-Pancreato-Biliary Association (AHPBA), Fort Lauderdale, FL, USA, April 14 Á17, 2005 (Session: Young Investigator Award). Correspondence: Carlo Pulitano`, Department of Surgery Á Liver Unit, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy. Tel: 39 02 2643 7808. Fax: 39 02 2643 7807. E-mail: [email protected]

(Accepted 14 January 2007) ISSN 1365-182X print/ISSN 1477-2574 online # 2007 Taylor & Francis DOI: 10.1080/13651820701216984 184 C. Pulitano` et al. Department of Surgery Á Liver Unit at San Raffaele Serum levels of TNF-a and IL-6 Scientific Institute, were enrolled into the trial. Serum levels of TNF-a and IL-6 were measured at Patients were assigned randomly to a steroid group the induction of anesthesia, and on POD 1, 2, and 5. (n21) or a control group (n22). Patients in the Serum levels were quantified by using an ELISA kit steroid group received 500 mg of methylprednisolone according to the manufacturer’s specifications (Bouty, (Pharmacia Corp., Peapack, NJ, USA) just before the Milan, Italy). Data were then presented as picograms surgery. Patients requiring concomitant thoracic or per milliliter of serum TNF-a. The detection limit colorectal surgery, additional ablation therapies of the assay was 1 pg/ml for TNF-a and 0.1 pg/ml (radiofrequency), as well as liver resections performed for IL-6. under total vascular exclusion were excluded from the study. Patients undergoing a total ischemia time of B20 min were also excluded. All patients gave Statistical analysis informed consent before enrolment in the trial. Post- A minimal sample size of 17 patients per group was operative complications were evaluated for 30 days calculated to detect a 100 U/L difference in the peak after surgery. ALT levels with a SD of 100 U/L with a level of statistical significance of 0.05 and a power of 0.80, using a post hoc two-sample t test. Continuous Surgical procedure variables were expressed using the MannÁWhitney Laparatomy was performed through a right subcostal test and categorical variables were compared using the incision and a midline incision. The intermittent x2 test or Fisher’s exact test, as appropriate. Multiple Pringle maneuver was applied at the time of liver comparisons were made using repeated-measure ana- transection and consisted of cross-clamping of the lysis of variance (ANOVA) as needed. Results are hepatoduodenal ligament for 20 min and releasing reported as mean9SD. Significance was defined as the clamp for 10 min until the transection was pB0.05. All analyses were performed using the completed. The procedure was repeated as necessary. statistical package SPSS 12.0 (SPSS, Chicago, IL, Transection of the hepatic parenchyma was carried USA). out by a combination of the clamp fracture techni- que, ultrasonic dissector (Soring, Quickborn, Ger- Results many), and harmonic scalpel (Ultracision, Ethicon, Cincinnati, OH, USA) along with hemostasis of the Clinical variables of patients vessels by clips or ligation, and coagulation by Twenty-nine males and 14 females were included in electrocautery or argon beam. A closed suction drain the study. There was no significant difference regard- was placed in the peritoneal cavity in all patients. ing the patients’ age, gender, ischemia time, or Each patient was operated under the supervision of underlying liver disease between patients randomized the same hepatobiliary surgeon (L.A.), who was in the steroid group versus control group (Table I). unaware of the patient’s group allocation. Unless Even though ischemia time was longer in the steroid clinically contraindicated, a systemic antibiotic, first- group (48918 min) than in the control group (299 generation cephalosporin (Cefazolin, Mead Johnson, 17 min), possibly because of a higher number of Princeton, NJ, USA) was routinely applied just extended right hepatectomies in the steroid group, before the surgery, ending on the fourth postopera- no significant difference was recorded. Thirteen tive day. patients were operated for liver metastases from colorectal cancer, 16 for hepatocellular carcinoma, 5 for various kinds of metastatic diseases, 3 for cholan- Clinical variables giocellular carcinoma, 2 for hemangioendothelioma, and 1 patient for gallbladder cancer. In three patients Postoperative markers of hepatocyte damage and liver resection was performed for benign diseases, recovery, including alanine aminotransferase (ALT), such as focal nodular hyperplasia, hemangioma or aspartate aminotransferase (AST), bilirubin, and hepatolithiasis. The different diagnoses were distrib- coagulative parameters [prothrombin time (PT-INR) uted homogeneously between the steroid and control and antithrombin III (AT-III)] were measured on groups. An extended right hepatectomy was per- postoperative day (POD) 1, 2, and 5. Data regarding formed in five patients and a formal left or right preoperative variables, duration of surgery, intrao- hepatectomy was performed in nine and eight pa- perative blood loss and transfusion, intraoperative and tients, respectively. Nine patients received a segmental postoperative complications, and hospital stay were resection involving at least two segments, a segmen- collected prospectively. Underlying liver disorders tectomy was performed in seven patients and a wedge such as steatosis, fibrosis, and other types of injury resection in five patients. The type and number of were also evaluated. procedures were comparable between both groups. Steroids administration in liver surgery 185 Table I. Comparison of preoperative and intraoperative variables between the control and steroid group.

Preoperative and intraoperative variables Control group (n22) Steroid group (n21) p value

Age (years) 6598.9 60.7913.4 0.149 Gender (male/female) 16/6 13/8 0.449 Diagnosis (HCC/CCC/CMET/NCM/GBL/HEM/BEN) 10/1/6/3/1/2/1 6/2/7/2/0/0/2 0.358 Underlying liver disease (normal/hepatitis/steatosis) 11/8/3 12/7/2 0.386 Concomitant diseases Diabetes 8 5 Hypertension 3 3 Previous systemic chemotherapy 3 3 Previous intrahepatic chemotherapy 1 1 Arrhythmia 0 2 TACE 1 2 COPD 0 2 Total [no. (%)] 16 (72%) 18 (85%) 0.295 Albumin (g/L) 4898.1 4497.2 0.132 Total bilirubin (mg/dl) 0.9290.4 0.9790.6 0.756 ALT (U/L) 37921 38921 0.896 AST (U/L) 48932 37922 0.270 Prothrombin time (INR) 1.0290.04 1.0290.05 0.926 AT-III (%) 84.5915.3 83.6916 0.894 Operative procedures (Rhr/Lhr/ExRhr/Biseg/Seg/Wedge) 6/3/1/6/3/3 2/6/4/3/4/2 0.146 Operation time (min) 4219112 378997 0.191 Ischemia time (min) 29917 48918 0.134 Blood loss (ml) 5859436 4879245 0.125 Transfusion (units) Red blood cells 1.190.8 0.890.9 0.321 Fresh frozen plasma 1.193.2 0.792.4 0.112

HCC, hepatocellular carcinoma; CCC, cholangiocellular carcinoma; CMET, colorectal metastasis; NCM, non-colorectal metastasis; GBL, gallbladder cancer; BEN, benign diseases; HEM, hemangioendothelioma; TACE, transarterial chemoembolization; COPD, chronic obstructive pulmonary disease; Rhr, right hepatectomy; Lhr, left hepatectomy; ExRhr, extended right hepatectomy; Biseg, bisegmentect- omy; Seg, segmentectomy; Wedge, wedge resection. Data are given as mean9SD.

Postoperative liver injury meters. Prothrombin time was significantly prolonged in the control group compared with the steroid The degree of I/R injury of the liver was assessed by postoperative peak serum ALT and AST levels. The group on POD1 (1.2890.19 vs 1.1490.85 INR, transaminase peak occurred within the first post- p0.06), POD2 (1.290.14 vs 1.1190.07 INR, operative day in all patients. Patients treated with p0.023). preoperative steroid pulse had a significantly lower AT-III levels in both groups significantly decreased peak ALT value when compared with the control compared with the preoperative levels and reached group on POD1 (3539221 vs 7529345 U/L, their minimal levels on POD1. The AT-III levels in p0.002) and POD2 (2959120 vs 4769280 U/L, the control group were significantly lower than in p0.045). Similarly, peak AST values were signifi- the steroid group on POD1 (55910 vs 68913%, cantly reduced in the steroid group when compared p0.012), POD2 (58910.6 vs 76914%, p0.01), with patients receiving portal clamping alone on and POD5 (59911 vs 83919%, p0.02) (Figure 3). POD1 (3519269 vs 7939369 U/L, p0.001) ANOVA with repeated measures revealed that the and POD2 (2319180 vs 4369210 U/L, p0.040) AT-III levels in the steroid group were significan- (Figure 1). tly maintained compared with the control group The postoperative bilirubin values were also sig- (p B0.01). nificantly lower in the steroid group than in the control group on POD1 (1.1690.54 vs 2.391.4 mg/dl, p0.0001), POD2 (1.1290.6 vs 1.891.1 Serum cytokines levels mg/dl, p0.004), and POD5 (0.890.3 vs 1.391.0 Il-6 serum levels in both groups reached a peak on mg/dl, p0.037) (Figure 2). POD1 and declined thereafter, TNF-a levels peaked later on POD2 and declined thereafter. IL-6 and Coagulation parameters TNF-a levels in the steroid group were significantly Significant differences between the steroid and con- lower than in the control group at each time point trol groups were also observed for coagulant para- measured after the surgery (Table II, Figure 4). 186 C. Pulitano` et al.

Figure 1. Comparison of mean ALT and AST levels between the control and steroid groups.

Postoperative complications and hospital stay outflow occlusion (total vascular exclusion) are in- duced to minimize blood loss while dividing the liver Two patients (9.5%) in the steroid group and eight parenchyma [20]. Therefore, there is a considerable patients (37%) in the control group had one or more interest in the prevention of hepatic I/R injury. complications within 30 days after surgery. The post- The first reports on the protective effects of steroids operative complications are summarized in Table III. on liver ischemia were published in 1975 [12]. Significantly fewer patients in the steroid group had Santiago-Delpin and Figueroa found that methyl- infectious complications, defined as positive culture of prednisolone treatment before hepatic occlusion re- blood, sputum, or other fluids in the presence of sulted in increased animal survival and reduced liver clinical evidence of infection (p0.027) [18]. There damage, as demonstrated by histology, when com- was no death within 30 days of surgery in either pared with ischemic controls. Even though the exact group. Patients in the steroid group experienced a molecular-biologic mechanisms of steroid action on reduced hospital stay compared with the control hepatic I/R injury remain partially unknown, it is group (p0.040). supposed that steroid therapy suppresses liver injury by a variety of mechanisms, including increased tissue Discussion blood flow and suppression of oxygen free radicals, Hepatic injury and failure secondary to warm I/R lysosomal proteases, suppression of calpain m activa- injury remains an important clinical issue [19]. It tion, reduced cytokine production and apoptotic occurs in a variety of situations including transplanta- activity [10Á14]. tion, trauma, shock, and liver surgery, when hepatic inflow occlusion (Pringle maneuver) or inflow and

Figure 2. Comparison of mean postoperative total bilirubin levels Figure 3. Comparison of mean AT-III levels between the control between the control and steroid groups. and steroid groups. Steroids administration in liver surgery 187 Table II. Serum cytokine levels. a meta-analysis with data from more than 1900 patients concluded that perioperative methylpredni- Control group Steroid group solone administration in major surgery, trauma, and Cytokines (n22) (n21) p value spinal cord injury was not associated with any adverse IL-6 preoperative 190.5 190.4 0.810 effects [22]. IL-6 POD1 61916.4 23918.9 0.001 The liver plays an important role in maintaining IL-6 POD2 42.3913 17911 0.025 the balance between thrombosis and bleeding. Major IL-6 POD5 30.296.8 11.398.6 0.012 liver surgery is often characterized by modifications in TNF-a preoperative 0.890.4 0.790.3 0.840 hemostatic balance [23,24]. Postoperative liver dys- TNF-a POD1 11.498.8 5.497.2 0.040 TNF-a POD2 24.7912 7.798.2 0.005 function following removal of significant hepatic TNF-a POD5 12.996 5.394.1 0.006 volume, vascular clamping, and heavy hemorrhage may result in a hypocoagulable state. On the other Data are given as mean SD. POD, postoperative day. 9 hand, a hypercoagulable status can result from impaired synthesis of anticoagulants, hemodilution, Based on their biological effects, routine periopera- and excessive activation of inflammatory response tive administration of steroids has been advocated [24]. AT-III is known to play a fundamental role to reduce hepatic ischemic injury. Although, some in the anticoagulant system by preventing thrombin series recommended the preoperative administration formation and inhibiting coagulation by down- of steroids [8,9], the use of corticosteroids in hepatic regulating procoagulant activities [25]. Decrease of surgery remains controversial and clinical benefits AT-III after major surgery is associated with an are still uncertain [15Á17]. This disagreement prob- increased risk of complications and mortality ably stems from the limited number of patients, their [26,27]. In addition to the anticoagulant effects, AT- dosage, administration schedule, and endpoints of III has important anti-inflammatory activity [28]. clinical outcome in different studies. This prospective Harada et al. have recently demonstrated that AT-III randomized study in an unselected group of patients reduces I/R induced liver injury in rats by increasing establishes preoperative methylprednisolone adminis- the COX-1-mediated production of PGI1 and PGE2 tration as a protective strategy against I/R injury in [29]. Shimada et al. reported that preoperative humans. Postoperative indicators of hepatocyte da- administration of AT-III concentrates significantly mage and recovery (aminotransferase, bilirubin) were decreases postoperative complications such as liver significantly modified by steroid administration. failure and hyperbilirubinemia after hepatic resection Several clinical trials in patients undergoing elective for hepatocellular carcinoma [30]. Methylpredniso- cardiothoracic or gastrointestinal surgery, as well as in lone administration resulted in a better preservation of cases of septic shock [21], have evaluated the efficacy coagulative function as shown by the preserved of steroid administration. Results suggest that several prothrombin time and attenuated the reduction of aspects of the surgical stress responses, organ dys- AT-III. As described previously [31], methylpredni- function, and postoperative recovery are improved by solone pretreatment attenuates the decrease in AT-III administering preoperative steroids. by reducing the postoperative production of the The potential side effects of perioperative steroid inflammatory cytokine IL-6 which occurred after administration have been of much concern. However, hepatic resection. Similar results were previously

Figure 4. Comparison of mean IL-6 and TNF-a levels between the control and steroid groups. 188 C. Pulitano` et al. Table III. Postoperative complications in the control and steroid groups.

Postoperative complications Control group (n22) Steroid group (n21) P value

Hemorrhage [no. (%)] 1 (4.5%) 0 0.512 Bile leakage [no. (%)] 2 (9%) 0 0.256 Transitory hepatic decompensation [no. (%)] 1 (4.5%) 1 (4.7%) 0.744 Cardiac [no. (%)] 2 (9%) 0 0.256 Pleural effusion [no. (%)] 1 (4.5%) 0 0.512 Infective complications [patients no. (%)]* 7 (31%) 1 (4.7%) 0.027 Hospital stay [median (range)] 8 (5Á39) 6 (5Á21) 0.040

*Only a single infective event from each patient was counted as an infective complication. described for esophagectomy [32]. IL-6 certainly half-life in the blood is 2.8 h [42]. As a result, both has a significant role in the activation of the coagula- early and late phase of hepatic I/R injury should be tion cascade: in fact this cytokine is thought to act covered [43]. Intravenous administration of 500 mg over hemostasis activating the extrinsic pathway of methylprednisolone has been confirmed to result through tissue factor expression [33]. It is of clinical in a methylprednisolone level of1 mg/ml in blood interest that preoperative steroid administration or10 mg/ml in liver tissue [16], and10 mg/ml of before hepatic resection may maintain coagulant/ methylprednisolone can significantly suppress lym- anticoagulant homeostasis, attenuating postoperative phocyte blastoid transformation, immunoglobulin cytokine levels. production, and NK cell activity [42]. This prospec- Elevated plasma levels of IL-6 have been reported tive randomized study suggests that preoperative to correlate with postoperative morbidity and mortal- methylprednisolone administration may represent a ity [34], and the cytokine TNF-a Á one of the main valid protective strategy against hepatic ischemia mediators of hepatic I/R injury Á is known to have reperfusion and confirmed the efficacy and safety of both local deleterious effects on the hepatocytes and steroids in reducing surgical stress in patients under- to mediate remote organ damage [35]. Inflammatory going hepatic resection. cytokines such as IL-6 and TNF-a are also known to play a critical role in liver generation [36,37], and on the other hand, hyperstimulation of IL-6 has been suggested to inhibit liver regeneration [38]. Serum References levels of inflammatory cytokines IL-6 and TNF-a [1] Wobbes T, Bemelmans BL, Kuypers JH, Beerthuizen GI, were significantly reduced in the steroid group. This Theeuwes AG. Risk of postoperative septic complications after trial confirmed the effect of suppression of surgical abdominal surgery treatment in relation to perioperative blood stress by preoperative steroid administration in pa- transfusion. Surg Gynecol Obstet 1990;171:/ 1990./ tients undergoing hepatic resection. [2] Makuuchi M, Mori T, Gunven P, Yamazaki S, Hasegawa H. Infectious complications were less frequent in the Safety of hemihepatic vascular occlusion during resection of

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