Experimental and clinical evidence for modification of hepatic ischaemia–reperfusion injury by N-acetylcysteine during major liver surgery

Abstract

Background

Hepatic ischaemia–reperfusion (I/R) injury occurs in both liver resectional surgery and in transplantation. The biochemistry of I/R injury involves short-lived oxygen free radicals. N-acetylcysteine (NAC) is a thiol-containing synthetic compound used in the treatment of acetaminophen toxicity. The present study is a detailed overview of the experimental and clinical evidence for the use of NAC as a pharmaco-protection agent in patients undergoing major liver surgery or transplantation.

Methods

A computerized search of the Medline, Embase and SCI databases for the period from 1st January 1988 to 31st December 2008 produced 40 reports. For clinical studies, the quality of reports was assessed according to the criteria reported by the Cochrane communication review group.

Results

Nineteen studies evaluated NAC in experimental liver I/R injury. NAC was administered before induction of ischaemia in 13. The most widely used concentration was 150 mg/kg by intravenous bolus. Fifteen studies report an improvement in outcome, predominantly a reduction in transaminase. Seven studies used an isolated perfused liver model with all showing improvement (predominantly an improvement in bile production after N-acetylcysteine). Two out of four transplantation models showed an improvement in hepatic function. Clinical studies in transplantation show a modest improvement in transaminase levels with no beneficial effect on either patient or graft survival.

Conclusion

N-acetylcysteine, given before induction of a liver I/R injury in an experimental model can ameliorate liver injury. Clinical outcome data are limited and there is currently little evidence to justify use either in liver transplantation or in liver resectional surgery.

Introduction

Hepatic ischaemia followed by reperfusion occurs both during liver resectional surgery and during liver transplantation. Liver transplantation is further characterized by periods of cold and warm ischaemia. Both contribute to hepatic ischaemic injury. This ischaemia–reperfusion (I/R) injury has effects on post-operative liver function and remote organ injury and is thought to be influential in post-operative recovery and eventual clinical outcome.^1,2

Restoration of blood flow results in a series of events that exacerbate the ischaemic injury.³ Interactions between hepatic sinusoidal endothelium, hepatic Kupffer cells and the cellular and soluble messenger components of blood inflow results in the production of local injury and a systemic inflammatory response. At the hepatocellular level, short-lived intracellular oxygen-free radicals are produced primarily by the mitochondria as a by-product of normal metabolism. In addition to central mechanisms in cellular homeostasis, they are known to have roles in intracellular signalling and gene expression.⁴ Oxygen-free radicals are by convention described as mediators of oxidative stress. Over-activity of these oxygen-free radicals (either because of excess production or inadequate quenching) leads to cellular injury – a process termed oxidative injury.

The intra-cellular defence mechanisms involved in the regulation of oxidative stress are well recognized and involve enzymatic pathways catalyzed by superoxide dismutase and glutathione peroxidise.⁵ Glutathione (GSH), a tri-peptide composed of glycine, glutamic acid and cysteine, is the most abundant non-protein sulfhydryl-containing compound and constitutes the largest component of the endogenous thiol buffer involved in removal of oxygen-free radicals.⁶ For tissue GSH synthesis, the availability of cysteine is generally the limiting factor. A potentially important cysteine precursor is N-acetylcysteine.⁷ N-acetylcysteine (NAC) is a thiol-containing synthetic compound. Unlike GSH, NAC readily diffuses into cells and hydrolyzes into L-cysteine and this in turn replenishes depleted stores of GSH. Currently the most established clinical use for NAC is in the treatment of acetaminophen (Paracetamol) poisoning to prevent fulminant hepatic failure.^8,9 There is a large body of clinical data for using NAC in patients with acetaminophen toxicity.^8–11

Given this role in the treatment of drug-induced liver injury, there is a case for evaluation of NAC in surgically-induced liver I/R injury, both in terms of hepatic resection and liver transplantation. To this end, there is a substantial body of experimental work evaluating the role of NAC in liver I/R injury. Individually, these studies are small and utilize a widely disparate range of protocols.

The aim of the present study was to provide a concise overview of the experimental and clinical evidence for the use of NAC as a pharmaco-protection agent to reduce liver injury in patients undergoing major liver surgery.

Methods

Literature search

A computerized search was performed of the Medline and Embase databases for the period from 1st January 1988 to 31st December 2008 using the OVID search engine (Ovid Technologies, Inc., New York, NY, USA; Version: rel10.5.1, Source ID 1.13281.2.21). The Science Citation Index (SCI) was also searched using the ISI Web of Knowledge (v.4.9). The keywords liver or hepat#, surgery, resection, hepatectomy, transplant, segmentectomy, ischae$, ische$, reperfusion were used and the results were combined with N-acetylcysteine, acetylcysteine, parvolex, flumucil and acetadole. This search yielded 484 citations. Exclusion of repeat articles produced a list of 270 citations. The abstracts of these 270 articles were examined to exclude reviews, case reports, articles un-related to the use of NAC in liver surgery, duplicate publications, articles providing no original data and non-English language publications. This produced a population of 36 reports. Manual cross-referencing of the bibliography of these articles yielded a further four reports. These 40 reports constitute the final study population. The article selection process is summarised in figure 1. The Cochrane Database of Systematic Reviews was then cross-checked to confirm that no similar reviews have already been undertaken.

Figure 1.

QUORUM flowchart

Data quality and extraction

Experimental studies are reported with reference to species, experimental model, NAC intervention protocol and principal outcomes.

For clinical studies, the quality of reports included was assessed according to the criteria reported in the study quality guide reported by the Cochrane consumers and communication review group (http://www.latrobe.edu.au/cochrane/resources.html).¹² In brief, studies were assessed on seven criteria: validity of randomization, concealment of allocation, blinding, baseline comparability, follow-up, intention-to-treat analysis and validation of tools.

Results

Experimental studies evaluating NAC in liver I/R injury (n= 19)

Nineteen studies evaluating the role of NAC in experimental liver I/R injury are summarized in Table 1.^13–31 No studies reported the use of sample power calculations. A wide range of experimental animals and protocols are reported. NAC was administered before induction of ischaemia in 13 studies^{14–16,19,21–23,25,27–31} and in 3 studies^17,20,24 after the ischaemic event but before or during re-perfusion. In three studies^13,18,26 NAC was administered before and after ischaemia and re-perfusion.

Table 1.

Design and key summary findings of experimental studies evaluating N-acetylcysteine in liver ischaemia-reperfusion (I/R) injury (n= 19)

First author/year	Species	Experimental model	NAC intervention	Principal outcome
Fukuzawa et al. 199513	Pig	2 h warm ischaemia by hilar clamp above portacaval shunt followed by re-perfusion	150 mg/kg NAC (20% solution) in 0.09% saline, as continuous infusion. Pre- and post- ischaemia groups	Lower AST, LDH & higher ATP content and bile output in intervention groups.
Koeppel et al. 199614	Rat	70 min warm ischaemia (left lobe) followed by reperfusion	400 mg/kg NAC intravenous infusion 20 min before ischaemia.	Improvement in hepatic microcirculation.
Demir et al. 199815	Rat	30 min warm ischaemia (left & median lobe) followed by reperfusion	500 mg/kg NAC 20 min before ischaemia (also a joint pentoxifylline group)	NAC reduced markers of oxidative injury. No synergistic effect with pentoxifylline.
Chavez-Cartaya et al. 199916	Rat	45 min warm ischaemia (medial and left lobe) followed by reperfusion	300 mg/kg NAC as intramuscular injection 30 min before ischaemia.	No beneficial effect of NAC.
Hur et al. 199917	Rat	45 min median and left lateral lobe warm ischaemia. Measurement of iNOS gene expression.	20 mg/kg NAC bolus. 10 min before reperfusion.	NAC inhibited expression of iNOS mRNA & upregulated NF-kB.
Sener et al. 199918	Rat	45 min warm ischaemia (total hepatic ischaemia)	150 mg/kg NAC (also a joint melatonin group) 15 before ischemia and immediately before reperfusion.	NAC reduced liver I/R injury. Synergistic effect with melatonin.
Rudiger et al. 200319	Mouse	75 min warm ischaemia. Partial and total ischaemia models.	100 mg/kg NAC pre-treatment.	NAC reversed the protective effects of preconditioning.
Glantzounis et al. 200420	Rabbit	60 min warm ischaemia followed by 7 h reperfusion.	150 mg/kg NAC as intravenous infusion prior to reperfusion.	Hepatic microcirculation improved.
Montero et al. 200521	Rat	Warm ischaemia ± ischaemic preconditioning ± selective biliary exclusion	150 mg/kg NAC intravenous bolus 15 min before ischaemia.	No beneficial effect of NAC on liver IR injury.
Okay et al. 200522	Rat	Partial hepatectomy	400 mg/kg NAC intravenous bolus before resection.	NAC attenuated bacterial translocation and lung injury.
Smyrniotis et al. 200523	Rat	60 min warm ischaemia (medial and left lobe)	300 mg/kg NAC intravenous bolus prior to ischaemia.	Attenuates liver I/R, less platelet aggregation, increases cAMP.
Fusai et al. 2005.24	Rabbit	60 min warm ischaemia of rabbit median and left lobe.	150 mg/kg NAC intravenous infusion prior to reperfusion.	NAC decreased I/R injury during late reperfusion. Microcirculation improved.
Chen et al. 200525	Rat	40 min warm ischaemia (total hepatic ischaemia).	20 mg/kg NAC 20 min prior to ischaemia.	Reduction in reperfusion induced MMP9
Glantzounis et al. 200726	Rabbit.	60 min lobar ischaemia and 7 h re-perfusion.	150 mg/kg NAC prior to and during reperfusion.	NAC prevented increase in RNS during reperfusion.
Jin et al. 200727	Mouse	60 min partial hepatic ischaemia. Measurement of TLR 2 and 4.	Pre-treatment with 150 mg/kg NAC	NAC inhibited the activation of TLR2/4 and the induction of TNFα.
Oz et al. 200728	Rat	Partial hepatectomy (left anterior and median lobe resection)	250 mg/kg NAC given prior to resection.	Reduction in bacterial growth in spleen and mesenteric lymph nodes.
Galhardo et al. 200729	Rat	10 min ischaemic pre-condition + 40 min warm ischaemia	150 mg/kg NAC intravenous bolus prior to ischaemia period.	NAC reduced hepatic necrosis and pulmonary oedema.
Bauman et al. 200830	Dog	60 min warm ischaemia.	150 mg/kg NAC intravenous bolus 2 min prior to ischaemia.	No beneficial effect of NAC on liver IR injury.
Keles et al. 200831	Rat	90 min left lobe ischaemia. 90 min reperfusion.	250 mg/kg NAC bolus pre-ischaemia.	NAC reduced 8-OHdG formation and lipid peroxidation.

AST, aspartate aminotransferase; LDH, lactate dehydrogenase; ATP, adenosine triphosphate; iNOS, inducible nitric oxide synthase; NAC, N-acetylcysteine; Nf-kB, nuclear factor kappa B; mRNA, messenger ribonucleic acid; cAMP, cyclic adenosine monophosphate; RNS, reactive nitrogen species; MMP 9, matrix metalloproteinase 9; TLR 2, TLR 4, toll-like receptor 2 and toll-like receptor 4; TNF-α, tumour necrosis factor-alpha; 8-OHdG, 8-hydroxydeoxyguanosine.

The most widely used concentration of NAC in these studies was 150 mg/kg (range 20 to 500 mg/kg) given by intravenous (i.v.) bolus.

In terms of effect of NAC on endpoints, 15 (79%) of the 19 studies reported a beneficial effect of intervention on outcome. A wide range of endpoints were utilized. Seven of the studies that reported a beneficial effect used plasma levels of transaminases and/or acute phase proteins such as tumour necrosis factor-alpha (TNF-α) as surrogate endpoints for reduction in I/R injury.^{13,15,18,23,25,27,31} Three of the studies that reported a beneficial effect of NAC reported an improvement in hepatic microcirculation.^14,20,24 A reduction of free radicals was reported in two studies.^17,26 A reduction in bacterial growth in lymphatic tissue and bacterial translocation in the intestine was reported in two studies.^22,28 The study by Galhardo et al.²⁹ showed that NAC reduced hepatic necrosis and pulmonary oedema.

Four studies showed no benefit of NAC on markers of liver I/R injury.^16,19,21,30 These negative studies included protocols which involved administration of NAC before induction of ischaemia.

The study by Rudiger et al. ¹⁹ is of particular interest in that they demonstrated that NAC inhibited the oxidative burst of ischaemic pre-conditioning and reversed the protective effects associated with pre-conditioning.

Experimental studies evaluating NAC in the isolated perfused liver (n= 7)

Seven studies evaluating the role of NAC in an isolated perfused liver model are summarized in Table 2.^32–38 All isolated perfused studies followed a protocol of prolonged cold storage before isolated perfusion of the liver. This was either 24 (4 studies) or 48 h (3 studies). The period of isolated perfusion ranged from 60 to 180 min. All the studies administered NAC before hepatectomy, but the route of administration varied. In five studies^34–38 NAC was administered intraportally or via the superior mesenteric vein. The remaining two studies used the intraperitoneal and subcutaneous routes, respectively.

Table 2.

Design and key summary findings of experimental studies evaluating N-acetylcysteine in isolated perfused liver models (n= 7)

First author/year	Species	Experimental model	NAC intervention	Principal outcome
Vivot et al. 199332	Rat	Isolated perfused rat liver with pre, post and pre&post NAC treatment groups.	100 mg/kg NAC pre-treatment. 20 mg/dL NAC added to perfusate in post-treatment.	NAC associated with lower transaminase in perfusate & improved bile production.
Dunne et al. 199433	Rat	Isolated perfused liver. Sequential cold and warm ischaemia	100 mg/kg NAC Subcutaneously prior to hepatectomy 100 mmol/l in the UW solution and perfusate	NAC induced transient improvement in blood and bile flow.
Nakano et al. 199534	Rat	Isolated perfused rat liver. 48 h cold & 2 h reperfusion.	intraportal injection of 150 mg/kg NAC pre-hepatectomy.	NAC enhances hepatocyte cysteine & has a protective effect on Kupffer cells.
Nakano et al. 199635	Rat	Isolated perfused rat liver after 24 h of cold storage	Intraportal injection of 150 mg/kg of NAC with or without intraperitoneal injection of BSO before isolation and perfusion	Pre ischemia administration of NAC attenuated hepatic injury. Protective effect lost when NAC at reperfusion.
Nakano et al. 199736	Rat	Isolated perfused liver studies (24 h cold storage 120 min re-perfusion) and left lobar I/R series (60 min clamp)	150 mg/kg NAC via mesenteric vein 15 min before liver harvest.	NAC before cold storage improved transaminases and bile production in steatotic livers.
Nakano et al. 199837	Rat	isolated perfused rat liver (24-hour cold storage in UW followed by 120 min reperfusion.	150 mg/kg NAC via superior mesenteric vein 15 min before harvesting	NAC before liver harvesting might prevent cold I/R injury in steatotic liver. (ALT Bile production and liver tissue GSH)
Nagasaki et al. 199838	Rat	isolated perfused liver (cold-storage 48 h and reperfusion for 120 min).	150 mg/kg NAC via superior mesenteric vein 15 min before harvesting.	Bile production improved significantly in the NAC group.

BSO, L-buthionine-[S,R]-sulfoxamine; ALT, alanine transaminase; GSH, glutathione; NAC, N-acetylcysteine.

The most frequently used concentration was 150 mg/kg (range-100–150 mg initial dose). In terms of the effect of NAC on endpoints all seven studies showed some beneficial effects of NAC in amelioration of liver injury. Bile production by the isolated perfused liver was a principle outcome in five out of the seven studies^{32,33,36–38} with all reporting improved bile production. Nakano et al. showed that NAC enhanced hepatocyte cysteine and had a protective effect on hepatic Kupffer cells.³⁴ Another study by Nakano et al. is of interest as it showed that pre-ischaemia administration of NAC attenuated hepatic injury but that the protective effect was lost when NAC was given at reperfusion.³⁵

Experimental studies evaluating NAC in liver transplantation (n= 4)

Four studies evaluating the role of NAC in experimental liver transplantation are summarized in Table 3.^39–42 Two studies used a rat^39,40 model and two utilized a porcine^41,42 model. Both rat models utilized periods of storage of the explanted liver in cold university of Wisconsin solution before transplantation (20 and 24 h, respectively). The timing of administration and the dose of NAC varied between the four studies. The dose given to the donor varied from 150 mg/kg to 3 g/kg. In three studies NAC was given to the both donor and recipient.^39,40,42 Two studies showed no beneficial effects of NAC on outcome after liver transplantation.^39,42 Two studies showed some beneficial effects.^40,41 The beneficial effects included a reduction in non-perfused sinusoids⁴⁰ and a reduction in transaminase associated with improved production of coagulation factors and better survival.⁴¹

Table 3.

Design and key summary findings of experimental studies evaluating N-acetylcysteine (NAC) in liver transplantation (n= 4)

First author/year	Species	Experimental model	NAC intervention	Principal outcome
Walcher et al. 199539	Rat	Livers stored for 20 h in University of Wisconsin (UW) solution and transplanted orthotopically	Donors 150 mg/kg NAC PLUS 83 mg/kg NAC at start of recipient operation.	No change in early microvascular failure after liver transplantation.
Koeppel et al. 199640	Rat	Orthotopic liver transplant following cold storage in University of Wisconsin (UW) solution for 24h	400 mg/kg NAC before hepatectomy and after re-perfusion in recipients.	NAC reduced non-perfused sinusoids and improved bile flow.
Regueira et al. 199741	Pig	Controlled trial of NAC in OLTX	3 g NAC to donor 1 h before warm ischemia	Reduced SGOT rise, Improved coagulation, better survival rate and reduce graft nonfunction.
Manika et al. 199942	Pig	RCT of porcine liver OLTX	150 mg/kg NAC infusion to donor and recipient.	No effect of NAC on liver histology or graft survival.

OLTX, orthotropic liver transplant; SGOT, serum glutamic oxaloacetic transaminase; RCT, randomized controlled trial.

Clinical studies evaluating NAC in liver transplantation (n= 9)

Nine clinical trials evaluating the role of NAC in liver transplantation are summarized in Table 4.^43–51 The total of all patients allocated to treatment arms is 175 [mean number of patients per study = 19 (range 9–30)]. Six studies are randomized controlled trials and the majority reported biochemical endpoints. Applying contemporary assessment criteria, these studies failed to adequately report their methods of randomization, concealment and blinding. Baseline comparability is acceptable and the results are reported on an intention-to-treat basis (except in one). Follow-up is complete but is short term.

Table 4.

Design and key summary findings of clinical studies evaluating N-acetylcysteine in liver transplantation (n = 9)

First author/year	Experimental design	NAC intervention	Number treated with NAC	Number without NAC	Endpoint: Liver function	Endpoint: Graft/patient survival
Bromley et al. 199543	Double-blind, Placebo-controlled RCT	Recipient: 150 mg/kg NAC over 15 min followed by 12.5 mg/kg for 4 h & 6.25 mg/kg for remainder.	25	25	Higher AST in NAC group at day 6.	Not reported.
Regueira et al. 199744	Cohort series: group receiving NAC and group without NAC.	To donor 6 g NAC iv 1h before retrieval.	25	37	SGOT: 825.97 control Vs 353.56 NAC	No primary failure. Poor graft function – 5 in control 0 in NAC.
Thies et al. 199845	RCT	150 mg/kg before re-perfusion. Then 50 mg/kg over 4 h.	30	30	AST -NAC 773 ± 133 vs control 1102 ± 225 U/L	Not reported
Steib et al. 199846	RCT	150 mg/kg NAC over 30 minutes at SVC anastomosis Followed by 50 mg/kg for 4 h and 100 mg/kg for 16 h.	30	30	No difference in ALT or AST.	No difference
Bucuvalas et al. 200147	Open-label, non-randomised, comparative study	70 mg/kg at reperfusion and 12 hrly for 6 days (in conjunction with PGE1).	12	13	Peak ALT 499 IU/L NAC vs 867 IU/L control.	100% at 3 months in both groups.
Taut et al. 200148	Non randomized case-control	150 mg/kg NAC at reperfusion. 50 mg/kg over 4 hours. 100 mg/kg over 16 hours.	9	10	Not reported	Not reported
Weigand et al. 200149	RCT	liver flushed with 1l Ringer's + 1000 mg/L NAC. Plus 150 mg/kg NAC before reperfusion + continuous infusion of 50 mg/kg NAC for 4 hr. Then 100 mg/kg NAC 16 hr	10	10	No significant difference in serum AST, ALT and total bilirubin.	Not reported
Khan et al. 200550	RCT	Donors: 150 mg/kg NAC before cardiac arrest And 75 mg/kg during cold phase. Recipients did not receive NAC.	9	9	No difference in trans-aminase.	Not reported.
Santiago et al. 200851	Double-blind, Placebo-controlled RCT	Recipients 100 mg/kg after 15 minutes into anhepatic phase followed by 50 mg/kg infusion over 24 h.	25	25	Not reported	Not reported

AST = Aspartate transaminase, SGOT = Serum glutamic oxaloacetic transaminase (AST), ALT = Alanine transaminase, ICAM1 = Intercellular adhesion molecule 1, VCAM1= vascular cell adhesion molecule 1, IL4 = interleukin 4.

There was variation in the approach to administration of NAC with some studies administering the agent to the donor and others to the recipient. Three studies^44,45,47 reported a reduction in post-operative liver enzymes. Three studies^46,49,50 reported no difference in post-operative liver enzymes. No studies showed a difference in graft survival although the study by Bucuvalas et al.⁴⁷ suggests that rejection episodes were more severe in the patient group who did not receive N-acetylcysteine. No studies showed any other difference in a clinically important endpoint in treatment groups.

Clinical studies evaluating NAC in liver resection (n= 1)

To date, there is one small study, reported only in abstract form, describing the outcome of a randomized controlled trial in patients undergoing liver resection.⁵² Patients in the treatment arm received NAC as an i.v. infusion (150 mg/kg loading dose followed by 50 mg/kg over 4 h and 50 mg/kg over the subsequent 8 h). After excluding patients with operative findings of unresectable disease, 31 patients were randomized: 15 to NAC and 16 to placebo. Endpoints showed a significant reduction in transaminase and a reduction in the number of patients having increased expression of soluble intercellular adhesion molecule-1 (ICAM-1). As the report is available in abstract form only, it is not possible to comment further on the study. However, at the least, this is an underpowered study with no mention of an a priori sample power calculation.

In an indirectly related work, Szakmany et al.⁵³ undertook a randomized trial of the effect of prophylactic NAC on post-operative organ dysfunction after major abdominal surgery. Their study of 93 patients included 6 patients undergoing liver resection. This manuscript is not in the 40 manuscript study population as it does not principally address liver surgery or report discrete outcomes of NAC in liver resection. It is retained as it does add to the published experience on NAC in liver resection and is one of only two studies in this area. Overall, Szakmany and colleagues reported no difference in organ dysfunction, length of critical care occupancy or mortality in patients receiving N-acetylcysteine.

Discussion

The present review reports the outcome of a comprehensive review of studies examining the role of NAC in modulation of I/R injury associated with major liver surgery and/or transplantation. Although the authors accept that it is possible that not all reported work in the field will have been reviewed or cited, the thorough and reproducible search history makes the present study the most comprehensive to date on this topic.

There is a wealth of experimental evidence in relation to both I/R and liver transplantation.

An overview of the experimental studies on liver I/R would be critical of sample size and the lack of power calculations in allocation of group numbers and also of the lack of pre-defined primary endpoints. Accepting these limitations, it is accepted that 15 out of the 19 studies examining the role of NAC in liver I/R injury show a beneficial effect from intervention with positive outcomes in terms of lower transaminases, reduction in oxidative injury and lower bacterial translocation. It appears that in order to be effective, NAC should be administered before induction of I/R injury. In order to retain a balanced perspective, it should be acknowledged that 4 of 19 experimental studies in this area show no positive findings^16,19,21,30 and that one of these showed that NAC reversed the beneficial effects of ischaemic pre-conditioning.¹⁹

Similar findings are seen in relation to the role of NAC in the isolated perfused liver model and in experimental liver transplantation. If administered before induction of ischaemia, NAC can have a beneficial effect in terms of reduction in hepatic injury.

Clinical studies of the use of NAC are almost uniformly of poor quality. All randomized trials are small in number, with little evidence of high-quality study markers. In their defence it could be argued that most of these studies date from over a decade ago and are from an era when the role of NAC could legitimately be assessed in small pilot trials. In the context of liver transplantation, of the nine clinical studies, only three examined graft survival, and only six reported accepted biochemical indices of injury and therefore it is possible that more comprehensive studies may show different outcomes. However, on the available evidence NAC is unlikely to be of benefit in liver transplantation.

Further evidence for this comes from the study by Hilmi et al., although out with the primary search period, this randomized controlled trial showed that NAC had no effect on hepato-renal ischaemia or survival in patients undergoing orthotopic liver transplantation.⁵⁴

In liver resectional surgery, there is even less evidence to support the use of N-acetylcysteine. Although the Pringle manoeuvre is widely used to reduce blood loss during parenchymal transection and this temporary inflow occlusion is a form of ischaemia reperfusion, there is little evidence to support the use of NAC in the clinical setting. Those units that do currently use this drug in the post-operative setting do so on the basis of extrapolation from the experimental evidence. However, it can be seen that the experimental evidence is not uniform, that studies are contradictory and that none are powered for direct extrapolation to the clinical setting.

The present report is the most comprehensive review of the role of NAC in liver surgery to date. There is a wealth of experimental evidence of the use of NAC in I/R injury and in transplantation. There appears to be some beneficial effect of NACin terms of a reduction in experimental liver I/R injury, in particular if the drug is administered before the onset of the IR injury. Similar benefits can be seen in the experimental isolated perfused liver scenario.

In conclusion, it would appear that N-acetylcysteine, given before induction of liver I/R injury in an experimental model, may have a positive effect on markers of liver injury. Currently, there remains little evidence that this effect translates in a positive fashion to any clinically relevant end point either in liver transplantation or in liver resectional surgery.

Conflict of interest

None declared.