In the article “The potential role of efficacy and safety evaluation of N-acetylcysteine administration during liver procurement,” authors Gomez-Gavara et al present a single-center randomized controlled trial evaluating the effect of pre- and peri-liver procurement N-acetylcysteine (NAC) infusion on postoperative graft function and development of early allograft dysfunction (EAD). The protective effects of NAC administration in the setting of liver injury are well established. Classically administered during acetaminophen-induced liver injury, NAC reduces hepatotoxicity, especially when administered early after ingestion.1 Outside of acute acetaminophen toxicity, effects of NAC have been extensively studied in the setting of non–acetaminophen-induced acute liver failure with variable results.2,3 Although preclinical work with NAC has been promising in the mitigation of liver ischemia/reperfusion injury,4 results in clinical studies of liver transplantation have been variable, with meta-analyses demonstrating no overall survival benefit.3 With the success of liver transplantation for the treatment of end-stage liver disease, demand continues to exceed the supply of available donor livers. As centers increasingly rely on extended criteria grafts to meet demands and cold ischemia times are potentially lengthened by the recent transition of liver allocation to Acuity Circles, strategies to mitigate injury and improve graft function are paramount. With its previously shown efficacy in acute liver injury, as well as wide clinical availability, low cost, and good safety profile, NAC is certainly a good candidate for the expansion of therapeutic indications in the mitigation of ischemia-reperfusion injury in liver transplantation.
In this article, the authors compare NAC infusion during liver procurement with standard portal and aortic flush. A clear allocation paradigm and NAC infusion scheme are described, using dosing and administration rationale and protocols based on previously published work,5 with the added modification of 300 mg NAC to initial Celsior flush (Genzyme Corporation, Cambridge, MA). The authors select EAD as their primary endpoint based on the 2013 study by D’Amico et al,5 which notes statistically significant differences in liver allograft survival after NAC administration, as well as lower rates of primary dysfunction. In this work, however, no statistically significant difference was detected in EAD between groups, even when accounting for different EAD scoring paradigms. Interestingly, supplemental subgroup analysis of livers with prolonged cold ischemia >6 h, which has known association with increased organ injury and postoperative complications,6 demonstrates blunting of postoperative transaminase rise, favoring NAC. This suggests a protective effect when a greater degree of ischemic injury is present and mimics prior findings by D’Amico et al, who reported graft primary dysfunction was lower after NAC treatment in organs with higher baseline donor risk indices.5 Gomez-Gavara et al also report a trend toward a significant decrease in EAD among subjectively steatotic livers treated with NAC. Although intriguing, the results are limited by the small number of patients in these subgroups. Of note is that significantly fewer patients in the present study experienced early graft loss requiring retransplantation in the NAC group, and no cases of graft loss due to EAD occurred in the NAC treatment group. Although the authors discount the significance of this finding due to hepatic artery thrombosis accounting for graft loss in 4 of 7 cases (n = 1 NAC and n = 3 control), risk of hepatic artery thrombosis is increased in patients with severe ischemia-reperfusion injury due to an increase in intrahepatic resistance to vascular flow.7 Further study, especially in extended criteria donors, including a more granular analysis of tissue injury, biomarkers, and clinical outcomes, is necessary to flush out the effect of NAC in grafts at high risk for preservation and reperfusion injury.
Evaluating postoperative complications, the authors report NAC infusion results in a lower rate of overall complications, especially major morbidities (Clavien-Dindo grades 3–4); however, the lower rate of serious complications did not improve overall patient or graft survival. Lacking from the analysis is statistical comparison or multivariate analysis of the effect of specific donor or recipient characteristics, including the administration of NAC, on development of EAD and early graft loss. Such analyses might serve to greatly enhance the evidence for periprocurement administration of NAC in abrogation of reperfusion injury. The limited analysis of biochemical indices of injury and oxidative stress failed to demonstrate any discernable difference between groups; however, although serial liver biopsies were obtained, the rate of discarded samples was high. An analysis of additional measures of cellular bioenergetics and inflammatory markers might offer more mechanistic insight and validate the use of NAC during organ procurement.8,9 It would also be interesting to see the tissue pathological evaluation for a more granular understanding of the effects of NAC on liver injury, especially in those organs with longer preservation times. Overall, although the present study offers an interesting addition to the literature, the utility of NAC in the setting of liver transplantation remains ambiguous.
NAC can certainly become an important tool, and its use in liver transplantation is expanding. With wide availability and a good safety profile, it can be easily applied in the clinical setting. Here, the authors incorporate NAC into their preservation protocol, which eases intraoperative administration and may facilitate adoption. Relying on its antioxidant properties and longer bioavailability, NAC has already been incorporated as an additive in Vasosol (Organ Recovery Systems, Itasca, IL), a novel machine perfusion solution, in efforts to improve liver organ preservation and function.10 As intense clinical research into optimal organ preservation strategies continues, NAC infusion protocols during procurement or preservation may be an important addition to our treatment paradigms, especially in grafts at high risk for ischemic injury.
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