World J Surg (2016) 40:2202–2212 DOI 10.1007/s00268-016-3506-1

ORIGINAL SCIENTIFIC REPORT

Pharmacological Modulation of Ischemic-Reperfusion Injury during Pringle Maneuver in Hepatic Surgery. A Prospective Randomized Pilot Study

1 2 2 Matteo Donadon • Andrea Forastieri Molinari • Francesco Corazzi • 2 2 1 1 2 Laura Rocchi • Paola Zito • Matteo Cimino • Guido Costa • Ferdinando Raimondi • Guido Torzilli1

Published online: 19 April 2016 Ó Socie´te´ Internationale de Chirurgie 2016

Abstract Background The Pringle maneuver, which is performed during liver surgery to reduce blood loss, may result in liver ischemia/reperfusion injury resulting in metabolic, immunological, and microvascular changes, which may lead to hepatocellular damage. The aim of this study was the investigation of the effects of N-acetylcysteine (NAC) and methylprednisolone (MET) in the modulation of liver warm ischemia during hepatic resection. Methods Forty-eight patients were enrolled in a pilot double-blind, randomized clinical trial. The patients received either NAC, MET, or placebo. The primary endpoint was the reduction in postoperative alanine aminotransferase and bilirubin. The secondary endpoint was the difference in morbidity and mortality. Results All the 48 patients had liver resection with no mortality. Morbidity was observed in 8 (16 %) patients equally distributed among the groups. There was a significant favorable recovery of liver function tests in patients treated with NAC or MET compared with the placebo when the Pringle maneuver exceeded 70 min. Conclusions The administration of NAC or MET prior to the Pringle maneuver during hepatic resection is asso- ciated with lower postoperative aberration in liver function tests compared with placebo when the Pringle maneuver exceeded 70 min. Larger studies are required to validate our findings and to investigate the specific role of NAC and MET in liver surgery.

Introduction hepatic hilum, referred as Pringle maneuver, may be per- formed [6]. This maneuver has been proven safe and One of the major determinants of complications after effective in many studies, including healthy liver donors hepatic resection is intraoperative bleeding [1–5]. To avoid [7], and recently even cumulative prolonged Pringle massive blood loss, intermittent vascular clamping of the maneuvers were reported to be safe [8]. However, hepatic ischemia and subsequent reperfusion result in activation of complex process leading to metabolic, immunological, & Guido Torzilli microvascular, and inflammatory alterations leading to [email protected] cellular injury [9–12]. Such processes involve the genera- Matteo Donadon tion of reactive oxygen species (ROS) and proteolytic [email protected] enzymes that finally lead to cellular damage [13]. Several 1 Department of Hepatobiliary and General Surgery, authors have already studied the issue of the ischemia– Humanitas University, Humanitas Research Hospital, reperfusion (IR) injury in liver surgery due to pedicle Via Manzoni, 56, 20089 Rozzano, Milan, Italy clamping. Mainly two drugs were tested with such purpose, 2 Department of Anesthesiology and Intensive Care, the methylprednisolone (MET) and N-acetylcysteine Humanitas University, Humanitas Research Hospital, (NAC), with controversial results [14–19]. In general, NAC Via Manzoni, 56, 20089 Rozzano, Milan, Italy 123 World J Surg (2016) 40:2202–2212 2203 is thought to be more active in the early phase of the IR Patient selection criteria injury when the damage mechanisms are characterized by production and release of ROS. Conversely, MET has a The inclusion criteria were age C18, primary and sec- well-known anti-inflammatory and immunosuppressive ondary liver neoplasms, and normal renal function. Of effect, and may have a therapeutic role in reducing the note, we included both minor and major hepatic resections, subsequent inflammatory processes [20]. Various protocols which types were equally distributed among the groups. have been attempted to decrease the IR injury associated The exclusion criteria were refusal of consent, renal failure with Pringle maneuver during liver surgery, but no of any grade, cirrhosis, American Society of Anesthesiol- definitive protocol exists. Therefore, we conducted this ogy (ASA) score 4, associated major surgery, and intra- pilot study in which we hypothesized that the IR injury operative bleeding more than 1500 ml, or allergy to NAC related to the Pringle maneuver may be pharmacologically or MET. Of note, major bleeding was considered as modulated. exclusion criterion because in such a case, the aberration of postoperative liver function tests might be related to the intraoperative hemodynamic changes rather than to the Methods Pringle maneuver only.

Study design Randomization

This was a prospective, double-blind, randomized pilot The study followed the recommendations of the study, with three arms: (1) methylprednisolone (MET) arm; CONSORT statement [23]. Randomization was performed (2) N-acetylcysteine (NAC) arm; and (3) placebo arm. All the day before the operation by a single investigator not patients gave their written informed consent before involved in the operations using the software Excel (ran- enrollment. The research protocol was approved by the dom number generation). ethical committee of the Humanitas Research Hospital and was also submitted to the international clinical trials reg- Medications istry (clinicaltrials.gov; ID NCT01726465). The hospital pharmacy provided the medications in a Definitions blinded fashion. Each patient had the first medication as a bolus infusion for 1 h before the beginning of the hepate- Hepatic resections were considered major when at least ctomy. The second medication was a continuous infusion three adjacent segments were removed [21]. Postoperative for approximately 6 h. In the placebo arm, the patients morbidity was defined using the Clavien–Dindo classifi- received 250 ml of glucose—5 % administered as a bolus cation [22]. Postoperative mortality was calculated at day and then as a continuous infusion. In the MET arm, the 90 after surgery. patients received 500 mg of Methylprednisolone in 250 ml of glucose—5 % administered as a bolus and then as a Study endpoints continuous infusion. Finally, in the NAC arm, the patients received 150 mg/kg of NAC administered as a bolus and The primary endpoint was the modulation of IR injury for then as a continuous infusion of 50 mg/kg/h. patients receiving NAC or MET compared with placebo as assessed by postoperative serum alanine aminotransferases Anesthesiology protocol (ALT) and bilirubin. Serum liver function tests were sampled the day before the operation and on postoperative All patients received general anesthesia and tracheal intu- days (POD) 1, 3, 5, and 7. Such values of serum ALT and bation. Anesthesia was induced by intravenous injections bilirubin were analyzed against the duration of the Pringle of propofol (2 mg/kg), fentanyl (1–2 mg/kg), and cis- maneuver. To confirm that our findings were not related to atracurium (0.2 mg/kg). The lungs were mechanically intraoperative hemodynamic changes, we analyzed the ventilated at a frequency of 10–12 per min with a tidal values of the main hemodynamic parameters registered by volume of 7–8 ml/kg. The zero-end expiratory pressure intraoperative monitoring system. This was done to avoid was maintained during hepatic resection to reduce the either the selection or the performance bias. Indeed, sig- intrathoracic pressure. Anesthesia was maintained with nificant differences in hemodynamic parameters might be 1.5–2 % end-tidal sevoflurane accompanied by a remifen- responsible for differences in the postoperative outcome. tanil infusion and bolus doses of cis-atracurium for neu- The secondary endpoint was the difference in morbidity romuscular block. A central venous catheter for monitoring and mortality among the groups. the central venous pressure (CVP) and two large-bore 123 2204 World J Surg (2016) 40:2202–2212

Fig. 1 The CONSORT flow diagram of the study venous access catheters to permit rapid fluid or blood furosemide or nitroglycerine if necessary. Postoperative infusion were placed once the patient was in the operating analgesia was ensured with intravenous opioids. room. A radial arterial line was placed and was connected to the VigileoTM system (Edwards LifeSciences, Irvine, Surgical technique and Pringle maneuver USA) for hemodynamic monitoring (CO, SVV, SV SVR). The infusions consisted of crystalloids (5 ml/kg/h) and A J-shaped laparotomy was performed. In cases with albumin, which were infused to maintain diuresis tumors in segments 1, 4-superior, 7, and 8 and in cases of (C0.5 ml/kg/h). The target was a CVP B5 mmHg during redo-hepatectomy, narrow thoracic cage or obese patients, hepatic resection, which was obtained with an injection of a J-shaped thoracoabdominal approach was considered

123 World J Surg (2016) 40:2202–2212 2205

Table 1 Baseline characteristics Placebo NAC MET p value

No. 16 16 16 – Sex Men 9 (56 %) 11 (69 %) 10 (62.5 %) Women 7 (44 %) 5 (31 %) 6 (37.5 %) 0.766 Age Median, range 63; 22–77 63; 46–77 65; 27–80 0.974 Pathology CLM 12 (75 %) 11 (69 %) 6 (37.5 %) HCC 2 (12.5 %) 2 (12.5 %) 6 (37.5 %) MFCCC – 2 (12.5 %) 4 (25 %) Other 2 (12.5 %) 1 (6 %) 0 0.023 ASA score 1 1 (6 %) – 1 (6 %) 2 14 14 (87.5 %) 13 (81.5 %) 3 1 (6 %) 2 (12.5 %) 2 (12.5 %) 4 – – – 0.470 BMI \30 13 (81.5 %) 15 (94 %) 14 (87.5 %) C30 3 (18.5 %) 1 (6 %) 2 (12.5 %) 0.565 Hb Median, range 13.5; 10.6–16.8 13.2; 11.7–15.5 14.2; 9.2–16.3 0.750 Ht Median, range 40.3; 32.3–49.9 39.2; 35.7–45.7 42; 28.5–48 0.575 Total bilirubin Median, range 0.55; 0.29–1.49 0.69;0.4–2.67 0.74;0.31–1.35 0.300 AST Median, range 22; 15–135 25.5; 17–92 31.5; 15–70 0.0546 ALT Median, range 28.5; 10–20 28.5; 17–80 31; 12–147 0.844 CHE Median, range 9650; 6500–16,800 10,000; 6300–11,700 11,350; 4900–14,300 0.261 CLM colorectal liver metastases, HCC hepatocellular carcinoma, MFCCC mass-forming cholangiocarcinoma, ASA American Society of Anesthesiologists, BMI Body Mass Index, Hb Hemoglobin, Hct hematocrit, AST aspartate aminotransferases, ALT alanine aminotransferases, CHE cholinesterases

[24, 25]. The surgical strategy was planned based on pre- liver with the rule of one drain per area of resection. The operative imaging and on the intraoperative ultrasound drains were left in place for a minimum of 7 days based on findings, and a parenchymal sparing approach was applied the reported protocol [31]. based on our previously reported techniques [26]. Parenchymal transection was performed using the crush- Sample size calculation clamping technique and thin ligatures. No surgical clips or coagulation instruments were used [27–29]. The Pringle A randomization ratio (MET:NAC:placebo = 1:1:1) was maneuver was performed with a standard Rummel tourni- planned. Based on our previous experience [8] and on quet with 15 min of clamping and 5 min of declamping as previous publications [15, 32], it was assumed that with the previously reported [8, 30]. Each patient was systemati- placebo the mean value of postoperative alanine in POD1 cally drained after surgery with standard closed suction (ALT) was 800 UI/l with a standard deviation of 100 UI/l. systems. The drains were placed on the cut surface of the Similarly, the mean value of postoperative bilirubin in

123 2206 World J Surg (2016) 40:2202–2212

Table 2 Surgical data Placebo NAC MET p value

No. 16 16 16 – Number of Pringle Median, range 3.5; 1–7 4; 1–7 4; 2–7 0.519 Length of Pringle (min) Median, range 80.5; 35–168 89; 35–183 83; 46–162 1.000 Blood loss (ml) Median, range 200; 0–700 500; 50–900 275; 100–1000 0.266 Red blood cell transf. N (%) 1 (6 %) 2 (12.5 %) 2 (12.5 %) 0.800 Frozen plasma transf. N (%) 4 (25 %) 7 (44 %) 5 (31 %) 0.519 Hepatic resection Minor, N (%) 11 (69 %) 10 (62.5 %) 9 (56 %) Major, N (%) 5 (31 %) 6 (37.5 %) 7 (44 %) 0.766 Thoracotomy N (%) 5 (31 %) 8 (50 %) 12 (75 %) 0.046 Length of operation (min) Median, range 351; 226–640 426.5; 221–697 383.5; 235–546 0.472 Length of stay (days) Median, range 8; 8–12 8; 8–9 8; 8–13 0.718 Morbidity Dindo’s I–II 2 (12.5 %) 1 (6 %) 2 (12.5 %) 0.447 Dindo’s III–IV – 2 (12.5 %) 1 (6 %) 0.344 Mortality 90-day – – – –

POD1 was 2.4 mg/dl with a standard deviation of 0.7 mg/ Results dl. These differences in ALT and bilirubin were combined and used as co-primary endpoints [33]. The sample size of Patients 48 patients (16 in each group) was then required to detect these differences among the groups in POD1 and POD3, Figure 1 shows the CONSORT flow diagram of the study. considering a value of 0.025 (one-sided) and 90 % power From November 2012 to June 2013, 48 patients were [15, 32]. Of note, the differences in ALT, and bilirubin enrolled in this study. Table 1 lists the baseline charac- were considered as a surrogate of better outcome in terms teristics. Apart from a greater proportion of patients of liver function recovery. affected by colorectal liver metastases in the placebo group, there were no differences in any other recorded Statistical analysis variable. Thus, the patients were well matched for age, sex, ASA score, obesity, and preoperative blood tests. The three The categorical data were summarized as frequencies and treatment arms were homogeneous with the types of sur- proportions with 95 % confidence intervals (CIs), while gical procedures, as listed in Table 2, except for a greater continuous data were summarized as medians or means use of the thoracoabdominal approach in the MET arm due with ranges or the 95 % CIs. The comparisons among to different tumor presentations. In particular, the numbers groups were conducted using the Chi-square test, the Fisher and lengths of the Pringle maneuvers, the rates of blood exact test, and the Wilcoxon–Mann–Whitney test when loss and red blood cell transfusions, and the rates of minor appropriated. The correlations coefficients between vari- and major resections were not significantly different among ables were calculated using the Spearman’s correlation the three groups. Table 3 lists the changes of the main coefficient. A p value \0.05 was considered as limit of hemodynamic parameters registered by intraoperative statistical significance. All calculations were performed monitoring system among the three groups, which as using the IBMÒ SPSSÒ Statistics 20 Software. shown were well matched. As mentioned, this was

123 World J Surg (2016) 40:2202–2212 2207

Table 3 Hemodynamic changes Placebo NAC MET p value

No. 16 16 16 – Basal SP Median, range 120; 96–160 120; 80–140 105.5; 81–144 0.426 Final SP Median, range 115; 85–140 124.5; 90–140 121.5; 100–160 0.459 Basal HR Median, range 61.5; 40–82 62.5; 44–80 65.5; 57–94 0.379 Final HR Median, range 79; 58–93 87; 68–110 83; 61–102 0.338 Basal CO Median, range 4.5; 3.9–6 5.6; 3.9–8.9 5; 3.4–7.1 0.116 Final CO Median, range 5.7; 3.7–8.8 6.4; 3.2–9.3 6.1; 3.36–9.3 0.735 Basal CI Median, range 2.5; 1.2–3.4 3; 1.5–4.2 2.8; 2–4.1 0.242 Final CI Median, range 3.25; 2–4.1 3.1; 2–4.7 3.35; 2.4–5.1 0.670 Basal SVV % Median, range 7.3; 2–20 8; 3–17 8; 6–14 0.633 Final SVV % Median, range 7.5; 4–13 10; 4–18 7; 2–18 0.245 Basal CVP Median, range 9; 1–21 6.5; 1–14 6; 3–15 0.368 Final CVP Median, range 5.5; 0–14 5; 4–10 5.5; 2–20 0.459 Basal pH Median, range 7.44; 7.34–7.50 7.43; 7.35–7.54 7.44; 7.38–7.52 0.543 Final pH Median, range 7.41; 7.34–7.48 7.41; 7.32–7.5 7.4; 7.23–7.47 0.869 Basal lactate Median, range 0.65; 0.4–1.1 0.75; 0.5–1 0.7; 0.4–1 0.543 Final lactate Median, range 4.45; 1.6–6 3.75; 2–7.3 3.8; 2.2–11.7 0.583 SP systolic pressure, HR heart rate, CO cardiac output, CI Cardiac Index, SVV stroke-volume variation, CVP central vein pressure important to confirm that the postoperative course was not further tested the relationship between serum ALT and influenced by the general intraoperative management and total bilirubin obtained in POD1 and POD3 based on a outcome. 70-min Pringle maneuver duration as a cutoff value. Fig- ure 3 shows the error bar plots of the values of ALT and Recovery of hepatic function tests total bilirubin in POD1 and POD3 for the patients with Pringle maneuver durations exceeding 70 min. As shown, Figure 2 shows the linear regression model of ALT and there were statistically significant differences between the total bilirubin plotted against the Pringle maneuver dura- placebo and the NAC or MET groups meaning an advan- tions in POD1 and POD3. As shown by the interpolation tage of these last two groups over the placebo group. To lines, the liver function tests were lower in the patients confirm that our findings were not related to intraoperative treated with NAC or MET. In particular, the placebo arm hemodynamic changes, we studied also the trends of the had a trend of less favorable recovery in patients with a cardiac index, central vein pressure, stroke-volume varia- Pringle maneuver duration exceeding 70 min (Fig. 2). We tions, and lactate plotted against the operation lengths

123 2208 World J Surg (2016) 40:2202–2212

Fig. 2 Linear regression model of serum ALT and total bilirubin patients with cumulative Pringle maneuver greater than 70 min as plotted against the duration of the Pringle maneuver on postoperative shown by the dotted lines (a ALT in POD1; b ALT in POD3; days 1 (POD1) and 3 (POD3). Interpolation lines show favorable c Bilirubin in POD1; d Bilirubin in POD3) recovery of liver function for treatment groups in particular for

showing that there were no statistically significant differ- Discussion ence (Fig. 4). The Pringle maneuver is often performed during hepatic Morbidity and mortality resection to minimize blood loss. Indeed, the liver tolerates prolonged ischemic injury better than the effects of mas- No adverse events attributable to NAC or MET were sive bleeding and blood transfusions that may happen when recorded. Minor morbidity was observed in 5 (10 %) performing hepatectomy without the Pringle maneuver [3, patients, while major morbidity was observed in 3 (7 %) 5, 34]. Moreover, several authors report that intermittent patients. No statistically significant differences among the rather than continuous clamping allows the liver to better three arms were recorded. There was no postoperative tolerate ischemia for prolonged duration, reducing both the mortality at 90-day in any group. The length of hospital- risks of massive bleeding and postoperative liver failure ization was similar in the three arms (Table 2). [35–37]. Kosuge et al. [38] and Wu et al. [39] applied

123 World J Surg (2016) 40:2202–2212 2209

Fig. 3 Error bar plots of ALT and total bilirubin in POD1 and POD3 statistical significant advantage for the treatment groups over the for the groups of patients with Pringle maneuver durations exceeding placebo group. (a ALT in POD1; b ALT in POD3; c Bilirubin in 70 min (No = 33; 12 MET; 10 NAC; 11 Placebo). There is a POD1; d Bilirubin in POD3) intermittent clamping in cirrhotic patients reaching total [7, 29, 45]. However, as a consequence of Pringle maneu- ischemic times of 195 and 204 min, respectively. Saka- ver, IR injury develops. The clinical effects of IR injury moto et al. [40] reported a case in which the cumulative remain to be clarified, but the main finding is an increase in hepatic ischemia time reached a total of 322 min. Ishizaki postoperative liver function tests (ALT and bilirubin), peaks et al. [41] recently showed how the limit can be extended to of which are correlated with the Pringle maneuver duration 325 min in a normal liver without major complications. [35, 46]. Even if these peaks usually decrease within a few Furthermore, our group reported a case of the 49 colorectal days after surgery, they remain a sign of liver function liver metastases being removed in one-stage hepatectomy deterioration. For some authors, this liver function deteri- with cumulative Pringle time lasting 348 min without oration is a reason to avoid Pringle maneuver [47]. Thus, the complications [42]. Until now, no reports have demon- possibility of reducing IR injury after Pringle maneuver strated any clinically relevant disadvantage of intermittent remains of utmost interest for the liver surgeon. warm ischemia, and recently, intermittent clamping was Several authors have already studied the issue of IR shown to have no impact on patients’ long-term prognosis. injury in liver surgery. These studies were prospective and Thus, even from the oncological standpoint, the Pringle randomized trials with controversial results both for ster- maneuver should not be considered contraindicated [43, oids and NAC, which are the two most tested drugs [14– 44]. Indeed, the intermittent Pringle maneuver was, in fact, 19]. In general, NAC is thought to be more active in the used in the best-published series ever reported in terms early phase of the IR injury when the damage mechanisms of surgical safety also including the donor hepatectomy are characterized by production of ROS. Indeed, during

123 2210 World J Surg (2016) 40:2202–2212

Fig. 4 Trends of the main hemodynamic parameters plotted against (a Cardiac Index; b CVP Central Vein Pressure; c SVV% Stroke the operation lengths. Interpolation lines and simple scatter do not Volume Variation %; d lactate) show statistically significant differences among the three groups ischemia, adenosine triphosphate is depleted, and some proinflammatory cytokines following ischemic insults ROS are generated, which are usually counteracted by the [20]. To our knowledge, there are only three published glutathione (GSH) reserves [48, 49]. GSH, a tri-peptide studies that have evaluated the role of MET in liver composed of glutamic acid, glycine, and cysteine, is an resection with disparate results [18, 19, 32]. The basic endogenous thiol buffer involved in the removal of ROS. hypothesis is that the MET effect is directly proportional NAC’s main mechanism of action is through the metabo- to the extent of the liver resection and the duration of lism to cysteine in vivo and the synthesis of GSH [50, 51]. Pringle maneuver. Thus, for patients submitted to minor NAC also, unlike GSH, may enter freely into cells due to liver resection and/or short pedicle clamping times, MET its smaller size. NAC also has an indirect anti-inflamma- may be ineffective. Of note, in the herein presented study, tory action by reducing chemotaxis and the generation of we included both minor and major hepatic resections. ROS by the inflammatory cells [52, 53]. MET has a well- This point deserves a brief explanation. As a consequence known anti-inflammatory and immunosuppressive effect, of our surgical attitude, we perform ultrasound-guided and may have a therapeutic role in reducing the inflam- parenchymal-sparing hepatectomy, which by definition is matory processes associated with IR injury. Effects of classified as minor resection. Some authors could argue corticosteroids, such as MET, are maybe mediated by their that the Pringle maneuver is useless when perform- action on the intracellular glucocorticoid receptors that ing minor hepatectomy. However, most of these resec- initiates alterations in nuclear factor (NF)-kB activation, tions were complex as documented by the median which is critical for the expression of numerous Pringle number (approximately four time) and length

123 World J Surg (2016) 40:2202–2212 2211

(approximately 80 min), use of thoracotomy (up to 75 %), References and the median length of operations (approximately 400 min) (Table 2). These numbers indicate that most of 1. Jamieson GG, Corbel L, Campion JP et al (1992) Major liver our patients had a complex tumoral presentation, and they resection without a blood transfusion: is it a realistic objective? Surgery 112:32–36 were operated with minor but complex hepatic resections. 2. Kooby DA, Stockman J, Ben-Porat L et al (2003) Influence of Moreover, these resections may be associated with transfusions on perioperative and long-term outcome in patients increased blood loss compared with the standard major following hepatic resection for colorectal metastases. Ann Surg hepatic resections that are conducted on avascular planes 237:860–870 3. Makuuchi M, Takayama T, Gunve´n P et al (1989) Restrictive after the extrahepatic ligation of the pedicle (right or left versus liberal blood transfusion policy for hepatectomies in cir- elements). Thus, for these complex but minor resections, rhotic patients. World J Surg 13:644–648. doi:10.1007/bf0165 the inflow control with the Pringle maneuver is essential. 8893 Finally, the present study was not thought to investigate 4. Torzilli G, Makuuchi M, Inoue K et al (1999) No-mortality liver resection for hepatocellular carcinoma in cirrhotic and noncir- the utility of the Pringle maneuver but the utility of its rhotic patients: is there a way? A prospective analysis of our pharmacological modulation. approach. Arch Surg 134:984–992 For the first time in this study, the IR injury related to 5. Yamamoto J, Kosuge T, Takayama T et al (1994) Perioperative the Pringle maneuver and its pharmacological modulation blood transfusion promotes recurrence of hepatocellular carci- noma after hepatectomy. Surgery 115:303–309 has been studied with regard to the duration of the Pringle 6. Pringle JH (1908) Notes on the arrest of hepatic hemorrhage due maneuver. And, we found a significant trend of favorable to trauma. Ann Surg 48:541–549 recovery of liver function tests in patients treated with 7. Imamura H, Kokudo N, Sugawara Y et al (2004) Pringle’s NAC or MET compared with patients treated with pla- maneuver and selective inflow occlusion in living donor liver hepatectomy. Liver Transpl 10:771–778 cebo. Specifically, the placebo group had worse trends for 8. Torzilli G, Procopio F, Donadon M et al (2012) Safety of inter- ALT and total bilirubin when Pringle maneuvers excee- mittent Pringle maneuver cumulative time exceeding 120 minutes ded 70 min (Figs. 2, 3). For shorter durations, MET and in liver resection: a further step in favor of the ‘‘radical but NAC showed no benefit. The knowledge of this effect conservative’’ policy. Ann Surg 255:270–280 9. Glanemann M, Vollmar B, Nussler AK et al (2003) Ischemic produced by NAC and MET is of utmost importance for preconditioning protects from hepatic ischemia/reperfusion-in- several reasons. First, such drugs should be avoided in jury by preservation of microcirculation and mitochondrial redox- patients resected with a short Pringle maneuver because state. J Hepatol 38:59–66 they are unlikely to produce any relevant effect. Any 10. Jaeschke H (2003) Molecular mechanisms of hepatic ischemia- reperfusion injury and preconditioning. Am J Physiol Gastrointest potential allergy, side effect, idiosyncrasy, or immuno- Liver Physiol 284:G15–G26 suppressant effect can thus be avoided in these patients. 11. Serracino-Inglott F, Habib NA, Mathie RT (2001) Hepatic Second, the enhanced recovery of the liver function tests ischemia-reperfusion injury. Am J Surg 181:160–166 produced by NAC and MET in those patients with a 12. Kupiec-Weglinski JW, Busuttil RW (2005) Ischemia and reper- fusion injury in liver transplantation. Transpl Proc 37:1653–1656 prolonged Pringle maneuver suggests their use in the 13. Ilmakunnas M, Tukiainen EM, Rouhiainen A et al (2008) High postoperative course in case of liver dysfunction after mobility group box 1 protein as a marker of hepatocellular injury resection, even if such role was not tested in the present in human liver transplantation. Liver Transpl 14:1517–1525 study. 14. Abu-Amara M, Gurusamy K, Hori S et al (2010) Systematic review of randomized controlled trials of pharmacological This study has some limitations, including the small interventions to reduce ischaemia-reperfusion injury in elective sample size. However, the study was a double-blind, ran- liver resection with vascular occlusion. HPB (Oxford) 12:4–14 domized clinical trial, and the sample size was statistically 15. Hayashi Y, Takayama T, Yamazaki S et al (2011) Validation of calculated a priori as mentioned above. It is a pilot study, perioperative steroids administration in liver resection: a ran- domized controlled trial. Ann Surg 253:50–55 which might be followed by further larger studies. Fur- 16. Jegatheeswaran S, Siriwardena AK (2011) Experimental and thermore, this being a pilot study on a relative small sample clinical evidence for modification of hepatic ischaemia-reperfu- size, no subgroup analyses were planned. sion injury by N-acetylcysteine during major liver surgery. HPB In conclusion, this study demonstrates that NAC and (Oxford) 13:71–78 17. McKay A, Cassidy D, Sutherland F et al (2008) Clinical results of MET may be helpful in the modulation of IR injury after N-acetylcysteine after major hepatic surgery: a review. J Hepa- prolonged Pringle maneuvers by reducing the peaks of tobiliary Pancreat Surg 15:473–478 ALT and bilirubin in the early postoperative course. Our 18. Muratore A, Ribero D, Ferrero A et al (2003) Prospective ran- results suggest that the administration of NAC and MET domized study of steroids in the prevention of ischaemic injury during hepatic resection with pedicle clamping. Br J Surg increases the margin of safety after liver surgery, and then 90:17–22 we recommend their use when Pringle maneuver exceed 19. Yamashita Y, Shimada M, Hamatsu T et al (2001) Effects of 70 min. Further external validations are needed to confirm preoperative steroid administration on surgical stress in hepatic our results. resection: prospective randomized trial. Arch Surg 136:328–333

123 2212 World J Surg (2016) 40:2202–2212

20. Saidi RF, Chang J, Verb S et al (2007) The effect of methyl- 36. Elias D, Desruennes E, Lasser P (1991) Prolonged intermittent prednisolone on warm ischemia-reperfusion injury in the liver. clamping of the portal triad during hepatectomy. Br J Surg 78:42–44 Am J Surg 193:345–347 37. Makuuchi M, Mori T, Gunven P et al (1987) Safety of hemi- 21. Belghiti J, Clavien P, Gadzijev E et al (2000) The Brisbane 2000 hepatic vascular occlusion during resection of the liver. Surg terminology of liver anatomy and resections. HPB (Oxford) Gynecol Obstet 164:155–158 2:333–339 38. Kosuge T, Yamamoto J, Takayama T et al (1994) An isolated, 22. Dindo D, Demartines N, Clavien PA (2004) Classification of complete resection of the caudate lobe, including the paracaval surgical complications: a new proposal with evaluation in a portion, for hepatocellular carcinoma. Arch Surg 129:280–284 cohort of 6336 patients and results of a survey. Ann Surg 39. Wu CC, Hwang CR, Liu TL et al (1996) Effects and limitations 240:205–213 of prolonged ischaemia for hepatic resection of the cirrhotic liver. 23. Schulz KF, Altman DG, Moher D (2010) CONSORT 2010 Br J Surg 83:121–124 statement: updated guidelines for reporting parallel group ran- 40. Sakamoto Y, Makuuchi M, Takayama T et al (1999) Pringle’s domised trials. BMJ 340:c332 maneuver lasting 322 min. Hepatogastroenterology 46:457–458 24. Torzilli G, Procopio F, Costa G (2014) Resection guidance. In: 41. Ishizaki Y, Yoshimoto J, Miwa K et al (2006) Safety of pro- Ultrasound-guided liver surgery: an atlas. Springer, New York, longed intermittent Pringle maneuver during hepatic resec- NY, pp 117–168 tion. Arch Surg 141:649–653 25. Donadon M, Costa G, Gatti A et al (2014) Thoracoabdominal 42. Procopio F, Torzilli G (2012) Forty-nine colorectal cancer liver approach in liver surgery: how, when, and why. Updates Surg metastases in one-stage hepatectomy with cumulative Pringle 66:121–125 time lasting 348 min. Updates Surg 64:241–243 26. Torzilli G, Procopio F, Costa G (2014) Planning of the surgical 43. Ferrero A, Russolillo N, Vigano L et al (2010) Does Pringle strategy. In: Ultrasound-guided liver surgery: an atlas. Springer, maneuver affect survival in patients with colorectal liver metas- New York, NY, pp 75–116 tases? World J Surg 34:2418–2425. doi:10.1007/s00268-010- 27. Gurusamy KS, Pamecha V, Sharma D et al (2009) Techniques for 0682-2 liver parenchymal transection in liver resection. Cochrane Data- 44. Giuliante F, Ardito F, Pulitano C et al (2010) Does hepatic base Syst Rev 1:Cd006880 pedicle clamping affect disease-free survival following liver 28. Lesurtel M, Selzner M, Petrowsky H et al (2005) How should resection for colorectal metastases? Ann Surg 252:1020–1026 transection of the liver be performed?: a prospective randomized 45. Imamura H, Seyama Y, Kokudo N et al (2003) One thousand study in 100 consecutive patients: comparing four different fifty-six hepatectomies without mortality in 8 years. Arch Surg transection strategies. Ann Surg 242:814–823 138:1198–1206 29. Takayama T, Makuuchi M, Kubota K et al (2001) Randomized 46. Sugiyama Y, Ishizaki Y, Imamura H et al (2010) Effects of comparison of ultrasonic vs clamp transection of the liver. Arch intermittent Pringle’s manoeuvre on cirrhotic compared with Surg 136:922–928 normal liver. Br J Surg 97:1062–1069 30. Torzilli G, Makuuchi M, Inoue K (2002) The vascular control in 47. Capussotti L, Muratore A, Ferrero A et al (2006) Randomized liver resection: revisitation of a controversial issue. Hepatogas- clinical trial of liver resection with and without hepatic pedicle troenterology 49:28–31 clamping. Br J Surg 93:685–689 31. Donadon M, Costa G, Cimino M et al (2015) Diagnosis and 48. Hammond CL, Lee TK, Ballatori N (2001) Novel roles for glu- management of bile leaks after hepatectomy: results of a tathione in gene expression, cell death, and membrane transport prospective analysis of 475 hepatectomies. World J Surg of organic solutes. J Hepatol 34:946–954 39:237–243. doi:10.1007/s00268-015-3143-0 49. McCord JM (1985) Oxygen-derived free radicals in postischemic 32. Pulitano` C, Aldrighetti L, Arru M et al (2007) Prospective ran- tissue injury. N Engl J Med 312:159–163 domized study of the benefits of preoperative corticosteroid 50. Aruoma OI, Halliwell B, Hoey BM et al (1989) The antioxidant administration on hepatic ischemia-reperfusion injury and cyto- action of N-acetylcysteine: its reaction with hydrogen peroxide, kine response in patients undergoing hepatic resection. HPB hydroxyl radical, superoxide, and hypochlorous acid. Free Radic 9:183–189 Biol Med 6:593–597 33. Sugimoto T, Sozu T, Hamasaki T (2012) A convenient formula 51. Zafarullah M, Li WQ, Sylvester J et al (2003) Molecular mech- for sample size calculations in clinical trials with multiple co- anisms of N-acetylcysteine actions. Cell Mol Life Sci 60:6–20 primary continuous endpoints. Pharm Stat 11:118–128 52. Kharazmi A, Nielsen H, Schiotz PO (1988) N-acetylcysteine 34. Man K, Fan ST, Ng IO et al (1997) Prospective evaluation of inhibits human neutrophil and monocyte chemotaxis and oxida- Pringle maneuver in hepatectomy for liver tumors by a ran- tive metabolism. Int J Immunopharmacol 10:39–46 domized study. Ann Surg 226:704–713 53. Majano PL, Medina J, Zubia I et al (2004) N-Acetyl-cysteine 35. Belghiti J, Noun R, Malafosse R et al (1999) Continuous versus modulates inducible nitric oxide synthase gene expression in intermittent portal triad clamping for liver resection: a controlled human hepatocytes. J Hepatol 40:632–637 study. Ann Surg 229:369–375

123