Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of acetylcysteine

Harrison, Philip M.; Keays, Rick; Bray, G.; Alexander, Graeme; Williams, Roger

doi:10.1016/0140-6736(90)91388-q

Cited by 360 publications

(149 citation statements)

References 11 publications

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“…1,3,21,27 This includes immediate transfer to a unit experienced in the management of this condition and with facilities of LT because it is the only absolute treatment for many causes of this devastating condition. 28,29 As shown in early studies in adults' with acetaminophen-induced ALF 18,[30][31][32][33][34][35] NAC is a safe drug with minor side effects, most of them self-limited or resolved with either the use of antihistamine drugs or by lowering the infusion rate. In the current study adverse effects were mentioned only in 11% of children and NAC was discontinued in 1.…”

Section: Discussionmentioning

confidence: 99%

“…15 In clinical trials following acetaminophen poisoning, early NAC administration is highly effective in preventing hepatocellular necrosis, by acting as an antidote through glutathione uplifting. 16,17 Harrison et al 18 showed significant improvement of the outcome of acetaminophen-induced ALF even when NAC was administered after 24 hours and they suggested that this was due to the antioxidant effect of NAC rather than its antidote effect. Further prospective studies have shown the valuable effect of NAC on the survival and final outcome of patients with late acetaminophen-induced ALF.…”

Section: See Editorial On Pagementioning

confidence: 99%

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Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure

et al. 2007

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Acute liver failure (ALF) carries a high mortality in children. N-acetylcysteine (NAC), an antioxidant agent that replenishes mitochondrial and cytosolic glutathione stores, has been used in the treatment of late acetaminophen-induced ALF and non-acetaminophen-induced ALF. In our unit, NAC was introduced as additional treatment for non-acetaminophen-induced ALF in 1995. The aim of this study was to evaluate the safety and efficacy of NAC in children with ALF not caused by acetaminophen poisoning. A retrospective review of medical records of 170 children presenting with nonacetaminopheninduced ALF between 1989 and 2004 was undertaken. ALF was defined as either international normalized ratio of prothrombin time (INR) Ͼ 2 and abnormal liver function or INR Ͼ1.5 with encephalopathy and abnormal liver function. Children were divided into the following groups: Group 1 (1989)(1990)(1991)(1992)(1993)(1994), standard care (n ϭ 59; 34 [58%] male; median age 2.03 yr, range 0.003-15.8 yr); and Group 2 (1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004), standard care and NAC administration (n ϭ 111; 57 [51%] male; median age 3.51 yr, range 0.005-17.4 yr). NAC was administered as a continuous infusion (100 mg/kg/24 hours) until INR Ͻ 1.4, death, or liver transplantation (LT). The median duration of NAC administration in Group 2 was 5 (range, 1-77) days. Complications were noted in 8 (10.8%) children: rash in 3, arrhythmia in 3, and dizziness and peripheral edema in 1. One child had an allergic reaction (bronchospasm) and NAC was stopped. A total of 41 (71%) children in Group 1 vs. 85 (77%) in Group 2 required admission to intensive care, P ϭ not significant (ns). The length of intensive care stay was 6 (range, 1-58) days in Group 1 vs. 5 (range, 1-68) days in Group 2, P ϭ ns and length of hospital stay was 25 (range, 1-264) days vs. 19 (range, 1-201) days, P ϭ 0.05. The 10-yr actuarial survival was 50% in Group 1 compared to 75% in Group 2, P ϭ 0.009. Survival with native liver occurred in 13 (22%) in Group 1 vs. 48 (43%) in Group 2, P ϭ 0.005; 15 (25%) in Group 1 died without transplant vs. 21 (19%) in Group 2, P ϭ ns; and LT was performed in 32 (54%) vs. 42 (38%), P ϭ ns. Death after transplantation occurred in 15 (39%) in Group 1 vs. 8 (16%) in Group 2, P ϭ 0.02. In conclusion, NAC is safe in non-acetaminophen-induced ALF. In this retrospective study NAC was associated with a shorter length of hospital stay, higher incidence of native liver recovery without transplantation, and better survival after transplantation. Liver Transpl 14: [25][26][27][28][29][30] 2008 See Editorial on Page 7Acute liver failure (ALF) in children is a rare but often fatal condition without liver transplantation (LT). [1][2][3] Multiorgan dysfunction in ALF is believed to derive from oxidative stress due to reactive oxygen species and reactive nitrogen species 4 and from immunological injury mediated by cytokines. 5-8 N-acetylcysteine (NAC) is a thiol-containing agent that scavenges free oxygen radicals and replenishes cellular mitochon...

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Section: Discussionmentioning

confidence: 99%

Section: See Editorial On Pagementioning

confidence: 99%

Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure

et al. 2007

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“…In acetaminopheninduced ALF, early administration of intravenous NAC can prevent hepatic necrosis by increasing hepatic stores of glutathione. 98 NAC has been shown to increase oxygen delivery to the tissues and increases oxygen consumption, concurrent with increased arterial blood pressure and cerebral perfusion pressure. 99 It has been shown that these effects are mediated through increased nitric oxide/ guanylate cyclase enzyme activity.…”

Section: N-acetylcysteinementioning

confidence: 99%

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

Aldridge

Tranah

Shawcross

2015

Journal of Clinical and Experimental Hepatology

235

190

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The syndrome we refer to as Hepatic Encephalopathy (HE) was first characterized by a team of Nobel Prize winning physiologists led by Pavlov and Nencki at the Imperial Institute of Experimental Medicine in Russia in the 1890's. This focused upon the key observation that performing a portocaval shunt, which bypassed nitrogen-rich blood away from the liver, induced elevated blood and brain ammonia concentrations in association with profound neurobehavioral changes. There exists however a spectrum of metabolic encephalopathies attributable to a variety (or even absence) of liver hepatocellular dysfunctions and it is this spectrum rather than a single disease entity that has come to be defined as HE. Differences in the underlying pathophysiology, treatment responses and outcomes can therefore be highly variable between acute and chronic HE. The term also fails to articulate quite how systemic the syndrome of HE can be and how it can be influenced by the gastrointestinal, renal, nervous, or immune systems without any change in background liver function. The pathogenesis of HE therefore encapsulates a complex network of interdependent organ systems which as yet remain poorly characterized. There is nonetheless a growing recognition that there is a complex but influential synergistic relationship between ammonia, inflammation (sterile and non-sterile) and oxidative stress in the pathogenesis HE which develops in an environment of functional immunoparesis in patients with liver dysfunction. Therapeutic strategies are thus moving further away from the traditional specialty of hepatology and more towards novel immune and inflammatory targets which will be discussed in this review. ( J CLIN EXP HEPATOL 2015;5:S7-S20) H epatic encephalopathy (HE) is the term used to encapsulate the broad spectrum of neuropsychiatric disturbances associated with both acute and chronic liver failure (ALF and CLF, respectively), as well as porto-systemic bypass in the absence of hepatocellular disease. The clinical manifestations of HE can be extremely heterogeneous in nature, with symptoms presenting anywhere on a continuum spanning from seemingly normal cognitive performance, right the way through to states of confusion, stupor and coma. In between these extremes, patients with HE may exhibit signs such as inattentiveness, blunted affect, impairment of memory or reversal of the sleep-wake cycle, as well as physical manifestations such as tremor, myoclonus, asterixis and deep tendon hyperreflexia.ALF is defined by the onset of coagulopathy alongside any degree of encephalopathy in patients with no evidence of pre-existing liver disease. 1 The presence of HE in those with ALF is prognostic, with up to a quarter of cases developing raised intracranial pressure. 2 Patients presenting with ALF are at risk of developing its cardinal, lifethreatening feature, cerebral edema. Left untreated, cerebral edema can rapidly progress to cause herniation of the uncus through the falx cerebri, leading to compression of the brainstem and, ultimately, death. H...

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“…2,3 Second, we have known for two decades that NAC started after acute liver injury has occurred, and well after 24 hours since APAP overdose, actually reduces mortality by half. 4,5 Third, although about 4% of a therapeutic dose undergoes oxidation to form N-acetyl-p-benzoquinoneimine (NAPQI), there is no evidence that this proportion remains fixed in all patients regardless of ingested dose.…”

Section: Re: Remien Et Al: Mathematical Modeling Of Liver Injury Andmentioning

confidence: 99%

Re: Remien etal.: Mathematical modeling of liver injury and dysfunction after acetaminophen overdose

Mullins

Schwarz

2012

Hepatology

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We read with interest the recent analysis by Remien et al. 1 of the prognostic accuracy of the Model for Acetaminopheninduced Liver Damage (MALD). By combining serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, and international normalized ratio INR, the authors demonstrate a negative predictive value (NPV) of 100% for predicting death when applied to a mixed cohort of 53 acetaminophen overdoses. This complex model has several limitations to its use at present, including the difficulty in calculating the formula at the patients' bedside, and in the use of serum AST, which may not always be routinely available in some centers. However, the study does highlight the importance of accurate triage when considering the potential need for liver transplantation following acetaminophen overdose. We similarly demonstrated an extremely high NPV following acetaminophen overdose by utilizing the Sequential Organ Failure Assessment (SOFA) score, where a SOFA score <7 by 96 hours following single timepoint overdose had a NPV of 98.2%. 2 The SOFA score is similarly helpful at ruling out death following multiple timepoint (staggered) acetaminophen overdose, with a SOFA score <6 at tertiary care admission carrying an NPV of 100.0% (Craig DG, unpubl. data). SOFA is a simple scoring system that can be rapidly recalculated at the bedside throughout admission, and, because it is an ordinal rather than a dichotomous variable, a rising SOFA score could function as a gatekeeper to identify deteriorating patients at an early stage and expedite transfer to liver centers.Although the MALD score appears promising as a triage marker, we would urge caution before adopting it as a primary transplant listing criterion. In keeping with several other prognostic studies, the authors compared the prognostic accuracy of their model with the King's College Criteria (KCC) at a single timepoint (hospital admission) rather than dynamically throughout admission, as originally intended, which is likely to invalidate comparisons with the KCC. 3 Furthermore, MALD does not explicitly include hepatic encephalopathy, thereby raising the possibility of undertaking liver transplantation inappropriately in patients with high MALD scores from other (nonacetaminophen) etiologies. As ever, there remains a balance between ensuring patients at risk of death are not missed through the inappropriate use of highly specific listing criteria, such as the KCC, as triage markers, while minimizing unnecessary transplantation of patients who might spontaneously survive. Further evaluation of the MALD and SOFA scores as triage markers in prospective studies between several large centers would be welcome.

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Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of acetylcysteine

Cited by 360 publications

References 11 publications

Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure

Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

Re: Remien etal.: Mathematical modeling of liver injury and dysfunction after acetaminophen overdose

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