Clinical Context
In the November 3, 1979, issue of the BMJ, Prescott and colleagues reported the use of intravenous N-acetylcystine (NAC) for the treatment of early, nonstaggered acetaminophen (paracetamol) overdose. However, the clinical course and outcomes for acetaminophen overdose resulting from repeated supratherapeutic doses (staggered overdoses) and delayed presentation beyond 15 hours are not clear.
This retrospective review of prospectively collected data by Simpson and colleagues assesses the incidence, clinical course, and outcome of staggered and delayed acetaminophen overdoses vs a single-time overdose.
Study Synopsis and Perspective
Repeated doses of slightly too much acetaminophen (known as paracetamol in the United Kingdom and elsewhere in Europe) can be fatal, according to the results of a large, single-center cohort study published online November 22 in the British Journal of Clinical Pharmacology.
"On admission, these staggered overdose patients were more likely to have liver and brain problems, require kidney dialysis or help with breathing and were at a greater risk of dying than people who had taken single overdoses," senior author Kenneth J. Simpson, MBChB (Hons), MD, FRCP (Edin), from the University of Edinburgh and Scottish Liver Transplant Unit in the United Kingdom, said in a news release.
"They haven't taken the sort of single-moment, one-off massive overdoses taken by people who try to commit suicide, but over time the damage builds up, and the effect can be fatal," he adds.
In the United Kingdom, acetaminophen hepatotoxicity is the leading cause of acute liver failure (ALF). However, the effect of a staggered overdose pattern or delayed hospital presentation on mortality or need for emergency liver transplantation was previously unknown.
Of 663 patients admitted with acetaminophen-induced severe liver injury between 1992 and 2008, 161 (24.3%) had taken a staggered overdose. Compared with patients who took an overdose at a single time, patients with staggered overdose were significantly older and more likely to abuse alcohol.
When asked why they repeatedly ingested more than the recommended dose of acetaminophen, patients with staggered overdose most often cited pain relief as their rationale (58.2%).
Compared with patients who took an overdose at a single time, those who took staggered overdoses had lower total ingested doses and lower serum alanine aminotransferase (ALT) levels on admission. Nonetheless, they were more likely to be encephalopathic and to require renal replacement therapy or mechanical ventilation.
Although mortality was higher in staggered overdoses than in single-time overdoses (37.3% vs 27.8%; P = .025), the staggered overdose pattern was not an independent predictor of mortality. For staggered overdoses, sensitivity of the King's College poor prognostic criteria was reduced (77.6%; 95% confidence interval [CI], 70.8% - 81.5%).
Delayed presentation to medical services more than 24 hours after single-time overdose occurred in 44.9% of those in whom accurate timings could be determined, and was independently associated with death or liver transplantation (odds ratio [OR], 2.25; 95% CI, 1.23 - 4.12; P = .009).
In their logistic regression analysis, the investigators controlled for signs and symptoms, such as hepatic encephalopathy and prothrombin time, as well as various demographic factors.
"Staggered overdoses or patients presenting late after an overdose need to be closely monitored and considered for the paracetamol antidote, N-acetylcysteine [NAC], irrespective of the concentration of paracetamol in their blood," Dr. Simpson said.
Because both these groups are at increased risk of developing multiorgan failure, they should be considered for early transfer to specialist liver centers.
Limitations of this study include reliance on patient recall regarding the time of last ingestion, total paracetamol dose, and suicidal intent; limited data regarding the use of concomitant P450 enzyme inducers or recent fasting; and selection bias for the more severe cases of acetaminophen toxicity in Scotland.
"[T]his large cohort study demonstrates the deleterious effects of delayed presentation and staggered overdose pattern upon outcome following paracetamol-induced acute liver injury," the study authors conclude. "Both delayed presentation > 24 hours and staggered overdoses are strongly associated with multiorgan injury and the need for [liver transplantation]. Patients presenting with these overdose patterns should be treated as high risk for progression to ALF, and should receive NAC in their presenting hospital whilst awaiting serial ALT and PT levels."
This study received no external funding. The authors have disclosed no relevant financial relationships.
Br J Clin Pharmacol. Published online November 22, 2011.
Study Highlights
During a 16-year period, 938 patients were admitted to the Scottish Liver Transplantation Unit for severe acute liver injury.
663 patients (70.7%) had acetaminophen-induced severe acute liver injury.
Severe acute liver injury was defined as a sudden deterioration in liver function with coagulopathy in the absence of chronic liver disease.
Acetaminophen overdose was defined as more than 4 g/day of acetaminophen ingestion within 7 days of presentation, a serum acetaminophen level of more than 10 mg/L, a serum ALT level of more than 1000 IU/L within 7 days of a history of acetaminophen ingestion, and exclusion of other causes of acute severe liver injury.
All patients were treated with continuous NAC at 6.25 mg/kg/hour until the international normalized ratio was less than 2.
King's College Hospital poor prognostic criteria were used to identify patients most likely to die without liver transplantation.
Mean age of the patients was 34 years, and 52.5% were women.
450 patients (73.6%) took a single-time overdose of more than 4 g of acetaminophen.
161 (24.3%) took a staggered overdose of acetaminophen, defined as 2 or more supratherapeutic doses at more than an 8-hour interval resulting in a cumulative dose of more than 4 g/day.
Patients taking a staggered overdose vs those with a single-time overdose were more likely to be older, more likely to abuse alcohol, more likely to have taken alcohol concomitantly with the overdose, less likely to receive NAC in the referring hospital, had lower serum acetaminophen levels at admission (37.8 vs 75.6 mg/L), and had lower total acetaminophen ingestion (24 vs 27 g).
Compared with patients taking a single-time overdose, those taking a staggered overdose had the following findings:
Lower admission ALT (4622 vs 8415 IU/L)
Lower sodium level (134 vs 136 mmol/L)
Higher creatinine level (172 vs 114 µmol/L)
Lower albumin (33 vs 37 g/L)
Lower platelet count (113 vs 130 x 109/L)
Increased likelihood of encephalopathy on admission (43.5% vs 34.5%) or at any stage (55.9% vs 46.9%)
Increased need for renal replacement therapy
Increased need for mechanical ventilation (47.8% vs 38.2%)
Decreased spontaneous survival duration (62.7% vs 72.4%)
Similar prothrombin time, King's College Hospital poor prognostic criteria, transplantation, and development of encephalopathy during admission
In patients with staggered acetaminophen overdose, independent predictors of death were hepatic encephalopathy on admission, increased prothrombin time, leukocytosis, renal impairment, and hypoalbuminemia.
396 (88.0%) of 450 patients with single-time overdose had data on the accurate timing of dose: 19.7% presented to emergency services within 12 hours of the last acetaminophen dose, 35.4% presented after 12 to 24 hours, and 44.9% presented after 24 hours (delayed presentation).
Patients who presented to the hospital after 24 hours, at 12 to 24 hours, and within 12 hours had the following respective findings:
Lower serum acetaminophen levels (37 vs 89 vs 139 mg/L)
Higher creatinine levels (162 vs 94 vs 94 µmol/L)
Increased likelihood for development of hepatic encephalopathy during illness (57.3% vs 41.4% vs 28.2%)
Increased need for mechanical ventilation (47.2% vs 32.9% vs 20.5%)
Increased need for renal replacement therapy (39.9% vs 22.9% vs 12.8%)
Increased King's College Hospital poor prognostic criteria (33.7% vs 19.3% vs 10.3%)
Decreased spontaneous survival duration (64.0% vs 76.4% vs 88.5%)
Similar ALT, bilirubin, albumin, sodium, prothrombin time, and platelet count
In patients with single-time overdose, independent predictors of death were delayed presentation (> 24 hours; OR, 2.25; P = .009), older age, hepatic encephalopathy on admission, leukocytosis, and prothrombin time.
King's College Hospital poor prognostic criteria had a decreased sensitivity for staggered overdose vs single-time overdose (77.6% vs 89.9%), but the specificity was similar.
Study limitations were reliance on patient recall for the time and dose of acetaminophen use and lack of data on other medications or recent fasting.
Clinical Implications
Patients with staggered overdose vs those with a single-time overdose of acetaminophen are more likely to have encephalopathy on admission, need renal replacement therapy or mechanical ventilation, and have higher mortality rates.
In patients with a single-time overdose of acetaminophen, delayed presentation (> 24 hours) to the hospital vs presentation at 12 to 24 hours or within 12 hours is linked with a higher risk for death or the need for liver transplantation.
