Acute Ethanol Coingestion Confers a Lower Risk of Hepatotoxicity after Deliberate Acetaminophen Overdose

Waring, W. Stephen; Stephen, A F L; Malkowska, Aleksandra M; Robinson, O D G

doi:10.1111/j.1553-2712.2007.00019.x

Cited by 47 publications

(37 citation statements)

References 25 publications

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“…A third explanation is that staggered overdoses act as a surrogate marker for other risk factors for adverse outcomes following paracetamol overdose, such as older age and chronic alcohol abuse [22,24], both of which were more common in the staggered overdose group. Whilst acute alcohol consumption has an inhibitory effect on the oxidative metabolism of paracetamol and may be hepatoprotective [25], this protective effect is probably lost in the context of chronic alcohol abuse or where there is a delay between alcohol and paracetamol intake [26], perhaps explaining why staggered overdose patients had worse clinical outcomes despite the increased incidence of acute alcohol consumption at the time of overdose (54% vs. 39%) in this subgroup.…”

Section: Figurementioning

confidence: 97%

Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol‐induced hepatotoxicity

Craig¹,

Bates²,

Davidson³

et al. 2012

Brit J Clinical Pharma

141

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WHAT IS ALREADY KNOWN ON THIS SUBJECT• Paracetamol hepatotoxicity is the commonest cause of acute liver failure (ALF) in the UK.• Relatively little is known regarding the impact of staggered overdose pattern or delayed hospital presentation upon subsequent mortality or need for emergency liver transplantation.WHAT THIS STUDY ADDS• Staggered paracetamol overdoses, frequently taken to relieve pain, are strongly associated with reduced survival compared with single time point overdose.• Staggered paracetamol overdoses should be treated as high risk for the development of multiorgan failure, and should be considered for N‐acetyl cysteine treatment irrespective of admission serum paracetamol concentrations.• The King's College poor prognostic criteria may have reduced sensitivity in staggered overdose patients.AIMS Paracetamol (acetaminophen) poisoning remains the major cause of severe acute hepatotoxicity in the UK. In this large single centre cohort study we examined the clinical impact of staggered overdoses and delayed presentation following paracetamol overdose.RESULTS Between 1992 and 2008, 663 patients were admitted with paracetamol‐induced severe liver injury, of whom 161 (24.3%) had taken a staggered overdose. Staggered overdose patients were significantly older and more likely to abuse alcohol than single time point overdose patients. Relief of pain (58.2%) was the commonest rationale for repeated supratherapeutic ingestion. Despite lower total ingested paracetamol doses and lower admission serum alanine aminotransferase concentrations, staggered overdose patients were more likely to be encephalopathic on admission, require renal replacement therapy or mechanical ventilation and had higher mortality rates compared with single time point overdoses (37.3% vs. 27.8%, P= 0.025), although this overdose pattern did not independently predict death. The King's College poor prognostic criteria had reduced sensitivity (77.6, 95% CI 70.8, 81.5) for this pattern of overdose. Of the 396/450 (88.0%) single time point overdoses in whom accurate timings could be obtained, 178 (44.9%) presented to medical services >24 h following overdose. Delayed presentation beyond 24 h post overdose was independently associated with death/liver transplantation (OR 2.25, 95% CI 1.23, 4.12, P= 0.009).CONCLUSIONS Both delayed presentation and staggered overdose pattern are associated with adverse outcomes following paracetamol overdose. These patients are at increased risk of developing multi‐organ failure and should be considered for early transfer to specialist liver centres.

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Section: Figurementioning

confidence: 97%

Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol‐induced hepatotoxicity

Craig¹,

Bates²,

Davidson³

et al. 2012

Brit J Clinical Pharma

141

View full text Add to dashboard Cite

show abstract

“…Gastrointestinal adverse effects do not normally require specific intervention, but in severe cases the infusion may need to be stopped temporarily and an antiemetic administered. It should be remembered that most patients with severe paracetamol poisoning will develop nausea and vomiting, at least in part due to coingestion of ethanol or opioids [Waring et al 2008a;Waring and Benhalim, 2008].…”

Section: Adverse Effects Of Acetylcysteinementioning

confidence: 99%

Novel acetylcysteine regimens for treatment of paracetamol overdose

Waring

2012

Therapeutic Advances in Drug Safety

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Pathophysiology of paracetamol-induced liver injuryAcute paracetamol administration is associated with significant depletion of glutathione (GSH), attributed to covalent binding of an intermediate paracetamol metabolite, N-acetyl-p-benzoquinone imine (NAPQI) to critical proteins and enzymes within hepatocytes. Restoration of intrahepatic glutathione concentrations in animals minimized the extent of NAPQI covalent binding to Novel acetylcysteine regimens for treatment of paracetamol overdose W. Stephen Waring Abstract: Paracetamol (acetaminophen) overdose remains the leading cause of death or transplantation due to acute liver failure in many parts of the world. Acetylcysteine has long been recognized as an effective antidote, via oral or intravenous administration, minimizing the risk and severity of acute liver injury if administered sufficiently early after a paracetamol overdose. Despite this, its mechanisms of action remain obscure, and there is uncertainty regarding the optimal dose and duration of treatment. The intravenous infusion protocol was originally developed as a three-step loading regimen; it causes very high early peak plasma concentrations of acetylcysteine whereas the later maintenance infusion is associated with much lower concentrations. This pharmacokinetic profile is associated with two particular concerns: a high rate of occurrence of adverse effects that occur after the initial loading infusion, and the possibility that the maintenance phase of treatment might deliver too low a dose of acetylcysteine for optimum protection against liver injury. Recently described novel administration regimens offer different rates of intravenous acetylcysteine administration in both the loading and maintenance phases. These alternative regimens appear to be well tolerated in small patient groups, but too few clinical data are available to evaluate their comparative efficacy in preventing paracetamol-induced liver injury.

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“…In contrast, glutathione depletion in the kidney is unrelated to the extent of nephrotoxicity, and acetylcysteine administration affords little or no protection against development of nephrotoxicity [3,[16][17][18]. Specific mechanisms of acetaminophen-induced renal injury have been proposed, including caspase activation, altered regulation of apoptosis [19,20], oxidative stress [21], and activation of cyclooxygenase and microsomal monooxygenase pathways within the kidney [18,22,23]. Liver-derived glutathione conjugates of acetaminophen metabolites may evoke nephrotoxicity by covalently binding to renal macromolecules [24,25], and might contribute to acute renal failure in certain patients exposed to large quantities of acetaminophen [26,27].…”

Section: Discussionmentioning

confidence: 99%

Proteinuria is unrelated to the extent of acute acetaminophen overdose: A prospective clinical study

et al. 2008

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Background: Acute renal failure is a recognized complication of acute acetaminophen overdose. Its detection depends on rising creatinine concentrations, which is an insensitive method. The present study examined whether proteinuria might correspond with the extent of acute acetaminophen exposure as a possible early marker of renal effects.Methods: A prospective case-control study included patients attending the emergency department within 24 hours of acetaminophen ingestion. A urine specimen was collected within 12 hours of hospital attendance for creatinine, albumin, and protein determination. Equivalent 4-hour acetaminophen concentrations were used to indicate drug exposure:. Data are presented as median (interquartile range) and groups compared using Mann Whitney and chi-square tests.Results: Seventy patients were studied (17 men, 53 women), age 37 years (23-45 years). The stated acetaminophen dose was 15 g (8-20 g), and interval between ingestion and presentation was 4.6 hours (4.1-7.9 hours). Urinary albumin concentrations were 8 mg/L (0-12 mg/L) in the mild group, 12 mg/L (5-25 mg/L) in the moderate group, and 11 mg/L (6-22 mg/L) in the severe group. Total protein concentrations were 90 mg/L (50-183 mg/L), 70 mg/L (40 to 130 mg/L), and 110 mg/L (75-205 mg/L), respectively. The proportions of patients who had urine albumin:creatinine ratio Ͼ3 mg/mmol were 20.8%, 23.5%, and 21.2%, respectively. None of the patients developed acute renal failure. Conclusions:No relationship was found between the extent of acute acetaminophen exposure and proteinuria. Further work is required to examine whether urinary protein excretion is altered in patients who subsequently develop acute renal failure following acetaminophen overdose.

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Acute Ethanol Coingestion Confers a Lower Risk of Hepatotoxicity after Deliberate Acetaminophen Overdose

Cited by 47 publications

References 25 publications

Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol‐induced hepatotoxicity

Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol‐induced hepatotoxicity

Novel acetylcysteine regimens for treatment of paracetamol overdose

Proteinuria is unrelated to the extent of acute acetaminophen overdose: A prospective clinical study

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