Acetaminophen and acetylcysteine dose and duration: past, present and future

Acetylcysteine has been utilized successfully in the treatment of acetaminophen overdose since the 1970s. Although prospective trials as to efficacy and safety of acetylcysteine were conducted, there were no randomized controlled trials. This commentary addresses the reasons for this, and the background to choice of dose of acetylcysteine utilized in the oral and IV dosing regimens. Nomograms to predict possible hepatotoxicity based upon time of ingestion of acetaminophen were developed from a relatively arbitrary definition of toxicity as an aspartate aminotransferase/alanine aminotransferase (ALT/AST) greater than 1000 IU/L. While these have proved generally useful, patients still continue to develop hepatic damage after acetaminophen overdose, particularly if they present late after ingestion. The optimum management of these patients remains unclear, and one area of uncertainty is the dose and duration of acetylcysteine in various circumstances. This article discusses the issues that need to be elucidated to better target changes in acetylcysteine dose. The potential for measurements of other markers to improve treatment selection is the subject of further research.     

Risk prediction of hepatotoxicity in paracetamol poisoning

Context: Paracetamol (acetaminophen) poisoning is the most common cause of acute liver failure in the developed world. A paracetamol treatment nomogram has been used for over four decades to help determine whether patients will develop hepatotoxicity without acetylcysteine treatment, and thus indicates those needing treatment. Despite this, a small proportion of patients still develop hepatotoxicity. More accurate risk predictors would be useful to increase the early detection of patients with the potential to develop hepatotoxicity despite acetylcysteine treatment. Similarly, there would be benefit in early identification of those with a low likelihood of developing hepatotoxicity, as this group may be safely treated with an abbreviated acetylcysteine regimen.

Aim: To review the current literature related to risk prediction tools that can be used to identify patients at increased risk of hepatotoxicity.

Methods: A systematic literature review was conducted using the search terms: “paracetamol” OR “acetaminophen” AND “overdose” OR “toxicity” OR “risk prediction rules” OR “hepatotoxicity” OR “psi parameter” OR “multiplication product” OR “half-life” OR “prothrombin time” OR “AST/ALT (aspartate transaminase/alanine transaminase)” OR “dose” OR “biomarkers” OR “nomogram”. The search was limited to human studies without language restrictions, of Medline (1946 to May 2016), PubMed and EMBASE. Original articles pertaining to the theme were identified from January 1974 to May 2016. Of the 13,975 articles identified, 60 were relevant to the review.

Paracetamol treatment nomograms: Paracetamol treatment nomograms have been used for decades to help decide the need for acetylcysteine, but rarely used to determine the risk of hepatotoxicity with treatment.

Reported paracetamol dose and concentration: A dose ingestion >12?g or serum paracetamol concentration above the treatment thresholds on the paracetamol nomogram are associated with a greater risk of hepatotoxicity.

Paracetamol elimination half-life: Patients with more severe hepatotoxicity are more likely to have a longer paracetamol elimination half-life. While median elimination half-life increases in those developing hepatotoxicity, there is wide variation in half-life, making this an insensitive parameter to use as a negative risk prediction tool.

Prothrombin time (PT): An initially normal PT is associated with a lower risk of developing hepatotoxicity, but cannot be used alone to identify patients not requiring acetylcysteine treatment.

Hepatic aminotransferase activity: A normal ALT activity on presentation is associated with a high negative predictive value of hepatotoxicity following paracetamol-poisoning.

Psi parameter: The psi parameter takes into account the time from ingestion, the serum paracetamol concentration and the time to initiation of acetylcysteine. A hepatotoxicity risk nomogram based on this parameter may be easier to use, but is limited to acute ingestions.

Paracetamol–aminotransferase multiplication product: If a hepatotoxicity risk nomogram is not available, an alternate strategy may be to use the paracetamol–aminotransferase product (<1500 low risk, 1500–10,000 low to moderate risk, >10,000?mg/L?×?IU/L high risk) to define liver injury risk. Serial blood tests can be performed if patients present prior to 8?h post-overdose for ultimate specificity, or a single blood test can be taken if presenting more than 8?h post-overdose. Patients receiving acetylcysteine within 8?h of their overdose, with a product less than 10,000?mg/L?×?IU/L have a low likelihood of developing hepatotoxicity. Any clinical trials of intensified treatment (e.g., higher dose) to prevent fulminant hepatic failure might potentially use a product of >10,000?mg/L?×?IU/L as a criterion for inclusion. The paracetamol–aminotransferase product <1500?mg/L?×?IU/L may also identify those suitable for an abbreviated acetylcysteine regimen.

Newer biomarkers: These show promise in the early identification of patients with a higher risk of developing hepatic injury. Point of care devices measuring paracetamol adducts need further trials.

Conclusions: Risk prediction tools can stratify those that are more likely to develop hepatotoxicity. Currently, the paracetamol–aminotransferase multiplication product may be such a tool. Novel biomarkers show promise but need further validation and greater clinical availability. These tools may help inform clinical trials on modified acetylcysteine regimens.     

Antidote removal during haemodialysis for massive acetaminophen overdose

Abstract

Context. Haemodialysis is sometimes used for patients with massive acetaminophen overdose when signs of “mitochondrial paralysis” (lactic acidosis, altered mental status, hypothermia and hyperglycaemia) are present. The role of haemodialysis is debated, in part because the evidence base is weak and the endogenous clearance of acetaminophen is high. There is also concern because the antidote acetylcysteine is also dialyzable. We prospectively measured serum acetylcysteine concentrations during haemodialysis in three such cases. Case details. Three adults each presented comatose and acidemic 10 to ? 18 h after ingesting > 1000mg/kg of acetaminophen. Two were hypothermic and hyperglycaemic. Serum lactate concentrations ranged from 7 mM to 12.5 mM. All three were intubated, and initial acetaminophen concentrations were as high as 5980 μM (900 μg/mL). An intravenous loading dose of 150 mg/kg acetylcysteine was initiated between 10.8 and ? 18 h post ingestion, and additional doses were empirically administered during haemodialysis to compensate for possible antidote removal. A single run of 3–4 h of haemodialysis removed 10–20 g of acetaminophen (48–80% of remaining body burden), reduced serum acetaminophen concentrations by 56–84% (total clearance 3.4–7.8 mL/kg/min), accelerated native acetaminophen clearance (mean elimination half-life 580 min pre-dialysis, 120 min during and 340 min post-dialysis) and corrected acidemia. Extraction ratios of acetylcysteine across the dialysis circuit ranged from 73% to 87% (dialysance 3.0 to 5.3 mL/kg/min). All three patients recovered fully, and none developed coagulopathy or other signs of liver failure. Discussion. When massive acetaminophen ingestion is accompanied by coma and lactic acidosis, emergency haemodialysis can result in rapid biochemical improvement. As expected, haemodialysis more than doubles the clearance of both acetaminophen and acetylcysteine. Because acetylcysteine dosing is largely empirical, we recommend doubling the dose during haemodialysis, with an additional half-load when dialysis exceeds 6 h.     

Accuracy of the paracetamol-aminotransferase product to predict hepatotoxicity in paracetamol overdose treated with a 2-bag acetylcysteine regimen

Introduction: Paracetamol concentration is a highly accurate risk predictor for hepatotoxicity following overdose with known time of ingestion. However, the paracetamol–aminotransferase multiplication product can be used as a risk predictor independent of timing or ingestion type. Validated in patients treated with the traditional, "three-bag" intravenous acetylcysteine regimen, we evaluated the accuracy of the multiplication product in paracetamol overdose treated with a two-bag acetylcysteine regimen.

Methods: We examined consecutive patients treated with the two-bag regimen from five emergency departments over a two-year period. We assessed the predictive accuracy of initial multiplication product for the primary outcome of hepatotoxicity (peak alanine aminotransferase ≥1000IU/L), as well as for acute liver injury (ALI), defined peak alanine aminotransferase ≥2× baseline and above 50IU/L).

Results: Of 447 paracetamol overdoses treated with the two-bag acetylcysteine regimen, 32 (7%) developed hepatotoxicity and 73 (16%) ALI. The pre-specified cut-off points of 1500?mg/L?×?IU/L (sensitivity 100% [95% CI 82%, 100%], specificity 62% [56%, 67%]) and 10,000?mg/L?×?IU/L (sensitivity 70% [47%, 87%], specificity of 97% [95%, 99%]) were highly accurate for predicting hepatotoxicity. There were few cases of hepatotoxicity irrespective of the product when acetylcysteine was administered within eight hours of overdose, when the product was largely determined by a high paracetamol concentration but normal aminotransferase.

Conclusions: The multiplication product accurately predicts hepatotoxicity when using a two-bag acetylcysteine regimen, especially in patients treated more than eight hours post-overdose. Further studies are needed to assess the product as a method to adjust for exposure severity when testing efficacy of modified acetylcysteine regimens.     

Analysis of an 8-hour acetylcysteine infusion protocol for repeated supratherapeutic ingestion (RSTI) of paracetamol

Objectives: In Australia, the treatment guideline for patients with repeated supratherapeutic ingestion (RSTI) of paracetamol recommends an abbreviated acetylcysteine regimen if the paracetamol concentration is low (<10?mg/L) and alanine aminotransferase (ALT) is normal or static after 8 hours of infusion. There are currently no studies of this recommendation.

Method: A retrospective review of paracetamol overdose presentations from October 2009 to August 2016 in two hospital toxicology networks was performed. All cases of RSTI treated with acetylcysteine were extracted.

Results: Of the 2249 paracetamol overdose presentations, 91 cases of RSTI were treated with acetylcysteine. Median time to initial blood tests was 6 hours post-last paracetamol dose (IQR 4–6). Sixty-three (69%) presentations had an initial detectable paracetamol concentration, median 30?mg/L (IQR 18–60). Median ALT on presentation was 48?IU/L (IQR 18–109). After 8 hours of acetylcysteine infusion, median ALT was 34?IU/L (IQR 16–71) in those receiving abbreviated treatment and 74?IU/L (IQR 40–231) in those continuing acetylcysteine. Thirty-nine presentations (43%) had an abbreviated regimen. Nine (10%) patients had an initial ALT ≥50?IU/L and subsequently developed hepatotoxicity (ALT >1000?IU/L). No patients with an initial ALT <50?IU/L developed hepatotoxicity. Median duration of acetylcysteine infusion for those receiving a non-abbreviated regimen was 20 hours (IQR 20–25) vs. 10.4 hours (IQR 4.8–12.0) who received an abbreviated regimen. There were no re-presentations with hepatotoxicity.

Conclusions: An 8-hour acetylcysteine infusion regimen for treatment of paracetamol RSTI may be safe and is likely to reduce length of stay for patients at low risk of hepatotoxicity. Larger prospective studies are needed to examine the efficacy of this abbreviated acetylcysteine protocol.     

Acetaminophen concentrations prior to 4 hours of ingestion: Impact on diagnostic decision-making and treatment

Abstract

Background. Consensus recommendations for acute acetaminophen exposure include plotting an acetaminophen concentration at ≥ 4 h post ingestion on the Rumack–Matthew nomogram to determine the need for acetylcysteine treatment. We studied the frequency of acetaminophen concentrations drawn within 4 h post ingestion and whether the Rumack–Matthew nomogram was properly used in making acetylcysteine treatment decisions. Methods. This was a retrospective, observational case series at three regional poison centers of acute acetaminophen exposures between 1/1/13 and 12/31/13. Cases were analyzed for demographics, timing of acetaminophen concentrations, and application of the Rumack–Matthew nomogram in acetylcysteine initiation or termination. Results. 1,123 cases of acute acetaminophen exposure were reviewed. Of 520 acute acetaminophen exposure cases presenting < 4 h post ingestion, 323 (62%) had a pre-4-hour acetaminophen concentration measured and 197 (38%) did not. Those with a known pre-4-hour acetaminophen concentration were less likely to have a 4-hour acetaminophen concentration (59% vs. 93%) or an acetaminophen concentration within 8 h (87% vs. 99%) and were more likely to be treated with acetylcysteine (29% vs. 17%) and less likely to be treated based on the Rumack–Matthew nomogram (72% vs. 97%). Conclusions. Patients with a known exposure time and presenting within 4 h of acetaminophen ingestion had a pre-4-hour acetaminophen concentration obtained 62% of the time. Pre-4-hour acetaminophen concentrations cannot be used to determine the need for acetylcysteine therapy and are associated with an increased likelihood of not obtaining optimally timed acetaminophen concentrations and acetylcysteine management not based on the proper application of the Rumack–Matthew nomogram. Current practice results in additional cost, unnecessary treatment, potential adverse medication effects, and the possibility of non-treatment of patients at risk of hepatotoxicity.     

Massive acetaminophen overdose: effect of hemodialysis on acetaminophen and acetylcysteine kinetics

Context: Early onset acidosis from mitochondrial toxicity can be observed in massive acetaminophen poisoning prior to the development of hepatotoxicity. In this context, the efficacy of acetylcysteine to reverse mitochondrial toxicity remains unclear and hemodialysis may offer prompt correction of acidosis. Unfortunately, toxicokinetics of acetaminophen and acetylcysteine during extracorporeal treatments hemodialysis have seldom been described.

Case details: An 18-year-old woman presented to the emergency department 60?minutes after ingestion of 100?g of acetaminophen, and unknown amounts of ibuprofen and ethanol. Initial assessment revealed an agitated patient. Her mental status worsened and she required intubation for airway protection. Investigations showed metabolic acidosis with lactate peaking at 8.6?mmol/L. Liver and coagulation profiles remained normal. Acetaminophen concentration peaked at 981?μg/ml (6496?μmol/L). Pending hemodialysis, the patient received 100?g of activated charcoal and an acetylcysteine infusion at 150?mg/kg over 1?hour, followed by 12.5?mg/kg/h for 4?hours. During hemodialysis, the infusion was maintained at 12.5?mg/kg/h to compensate for expected removal before it was decreased to 6.25?mg/kg for 20?hours after hemodialysis. The patient rapidly improved during hemodialysis and was discharged 48?hours post-admission.

Toxicokinetics: The acetaminophen elimination half-life was 5.2?hours prior to hemodialysis, 1.9-hours during hemodialysis and 3.6?hours post hemodialysis. The acetaminophen and acetylcysteine clearances by A-V gradient during hemodialysis were 160.4?ml/min and 190.3?ml/min, respectively. Hemodialysis removed a total of 20.6?g of acetaminophen and 17.9?g of acetylcysteine.

Conclusion: This study confirms the high dialyzability of both acetaminophen and acetylcysteine. Hemodialysis appears to be a beneficial therapeutic option in cases of massive acetaminophen ingestion with coma and lactic acidosis. Additionally, these results suggest that the infusion rate of acetylcysteine must be more than double during hemodialysis to compensate for its ongoing removal and provide similar plasma concentrations to the usual acetylcysteine regimen.     

N‐acetylcysteine‐induced headache in hospitalized patients with acute acetaminophen overdose

Intravenous N‐acetylcysteine (IV‐NAC) is usually regarded as a safe antidote to acetaminophen overdose. However, during infusion of the loading dose, adverse drug reactions such as a headache may occur. The objectives of this study were to investigate the prevalence of headache in patients presenting to hospital after acetaminophen overdose and to determine which clinical findings are most predictive of headache among these patients. This is a retrospective cohort study of hospital admissions for acute acetaminophen overdose that was conducted over a period of 4 years from January 1, 2005 to December 31, 2008. Demographic data, clinical characteristics, and predictors of headache were analyzed. spss 15 was used for data analysis. Two‐hundred and fifty‐five patients were studied; their mean age was 23.1 ± 1.6; 83.9% of them were women and 14.9% had a headache during hospitalization. Headache among patients was significantly associated with IV‐NAC administration (P = 0.001), intentional ingestion of drug (P = 0.04), acetaminophen concentration above ‘possible toxicity’ treatment line (P = 0.04), a high acetaminophen concentration (P = 0.04), and a long hospital stay (P = 0.03). Multiple logistic regression showed a significant risk factor for headache in patients administered IV‐NAC (P = 0.04). We recorded a high frequency of headache in patients with acute acetaminophen overdose in our geographical area. This study suggests that among those patients, the use of IV‐NAC is associated with an increased risk of headache.     

Hemolysis and Hemolytic Uremic Syndrome following Five-fold N-Acetylcysteine Overdose

Context. Intravenous acetylcysteine (Acetadote? in the US) is the treatment of choice for acute acetaminophen poisoning in most of the world. However, the complicated dosing regimen is prone to errors in preparation and administration. Case report. A 21 year-old woman (70 kg) took an overdose of acetaminophen and ethanol. Her serum acetaminophen concentration was > 200 mg/L. Acetylcysteine infusion was ordered. Due to misreading of the columns in the table in the Acetadote? package insert, she received a five-fold overdose of 52.5 g of acetylcysteine in 500 mL over 1 h and then 17.5 g of acetylcysteine in 500 mL to run over 4 h. The dose error was detected 20 min into the second infusion. Her acetaminophen concentration fell quickly, and her highest transaminase concentrations occurred day 2. Her hemoglobin and hematocrit quickly dropped from 14.8 g/dL and 44.0% on admission to 6.2 g/dL and 17.3% on day 7. Subsequently she developed hematuria and a rapidly rising serum creatinine. She was transferred to a tertiary care hospital, where she underwent hemodialysis every two days for two weeks, transfusions of packed red blood cells, and plasmapheresis until hematologic testing ruled out thrombotic thrombocytopenia purpura. Discussion. A five-fold overdose of acetylcysteine was followed by unexpected hemolysis and acute renal failure. The mechanism of hemolysis after acetylcysteine overdose is unclear. A simpler infusion regimen with standard concentrations would prevent a similar error.     

Accuracy of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity in modified-release paracetamol overdose

Context: The paracetamol-aminotransferase multiplication product (APAP?×?ALT) is a risk predictor of hepatotoxicity that is somewhat independent of time and type of ingestion. However, its accuracy following ingestion of modified-release formulations is not known, as the product has been derived and validated after immediate-release paracetamol overdoses.

Objective: The aim of this retrospective cohort study was to evaluate the accuracy of the multiplication product to predict hepatotoxicity in a cohort of patients with modified-release paracetamol overdose.

Methods: We assessed all patients with modified-release paracetamol overdose presenting to our hospital network from October 2009 to July 2016. Ingestion of a modified-release formulation was identified by patient self-report or retrieval of the original container. Hepatotoxicity was defined as peak alanine aminotransferase ≥1000?IU/L, and acute liver injury (ALI) as a doubling of baseline ALT to more than 50?IU/L.

Results: Of 1989 paracetamol overdose presentations, we identified 73 modified-release paracetamol exposures treated with acetylcysteine. Five patients developed hepatotoxicity, including one who received acetylcysteine within eight hours of an acute ingestion. No patient with an initial multiplication product <10,000?mg/L?×?IU/L developed hepatotoxicity (sensitivity 100% [95%CI 48%, 100%], specificity 97% [90%, 100%]). Specificity fell to 54% (95%CI: 34, 59%) at a product cut-off point <1500?mg/L?×?IU/L. When calculated within eight hours of ingestion, mild elevations of the multiplication product fell quickly on repeat testing in patients without ALI or hepatotoxicity.

Conclusions: In modified-release paracetamol overdose treated with acetylcysteine, the paracetamol-aminotransferase multiplication product demonstrated similar accuracy and temporal profile to previous reports involving mostly immediate-release formulations. Above a cut-point of 10,000?mg/L?×?IU/L, it was very strongly associated with the development of acute liver injury and hepatotoxicity, especially when calculated more than eight hours post-ingestion. When below 1500?mg/L?×?IU/L the likelihood of developing hepatotoxicity was very low. Persistently high serial multiplication product calculations were associated with the greatest risk of hepatotoxicity.     

Impact of reducing the threshold for acetylcysteine treatment in acute paracetamol poisoning: The recent United Kingdom experience

Background. On 3 September 2012, the licensed indication for acetylcysteine was changed in the United Kingdom (UK) so that all patients with a plasma paracetamol concentration above a “100 mg/L” (4 h post ingestion) nomogram treatment line after an acute paracetamol (acetaminophen) overdose should be treated. This is a lower threshold than that used in the United States, Canada, Australia, and New Zealand. Here we report the impact of this change in the UK on the management of patients with acute overdose in different paracetamol concentration ranges. Methods. This is a cohort study, consisting of a retrospective analysis conducted on prospectively collected audit data in three UK hospitals. Following appropriate ethical and data protection authority approval, data for patients presenting within 24 h of an acute timed single paracetamol overdose were extracted. Numbers of admissions and use of antidote in relation to different paracetamol concentration bands (< 100 mg/L; 100–149 mg/L; 150–199 mg/L; and ≥ 200 mg/L at 4 h) were analyzed for one-year periods before and after the change. Results. Comparing the year before with the year after the change, there was no change in the numbers of patients presenting to hospital within 24 h of acute timed paracetamol overdose (1246 before and 1251 after), but more patients were admitted (759 before and 849 after) and treated with acetylcysteine (389 before and 539 after). Of the 150 additional patients treated with acetylcysteine in the year following the change, 114 (76%, 95% CI: 68.4–82.6) were in the 100–149 group and 9 (6.0%, 95% CI: 2.8–11.1) in the 150–199 group. Conclusions. Changes to national guidelines for managing paracetamol poisoning in the UK have increased the numbers of patients with acute overdose treated with acetylcysteine, with most additional treatments occurring in patients in the 100–149 mg/L dose range, a group at low risk of hepatotoxicity and higher risk of adverse reactions.     

Modified release paracetamol overdose: a prospective observational study (ATOM-3)

Background: Modified-release (MR) paracetamol is available in many countries as 665?mg tablets of which 69% is MR and 31% is immediate release. There are concerns that MR paracetamol overdose has higher rates of liver injury despite standard treatment algorithms. The objective of this study was to describe the clinical characteristics and outcomes of acute MR paracetamol overdose.

Methods: Prospective observational study, recruiting patients from January 2013 to June 2017, from five clinical toxicology units and calls to two Poisons Information Centres in Australia. Included were patients >14 years who ingested ≥10?g or 200?mg/kg (whichever is less) of MR paracetamol. Data collected included demographics, ingestion history, pathology results, treatments, and outcomes including hepatotoxicity (ALT >1000?U/L).

Results: In total, 116 patients were recruited, 85(73%) were female. The median dose ingested was 32?g (IQR: 20–49?g) and median time to presentation was 3?h (IQR: 2–9?h). 78(67%) had an initial paracetamol concentration above the nomogram line (150?mg/L at 4?h). A further 12(10%) crossed the nomogram after repeat paracetamol measurements, of which five crossed after two non-toxic levels 4?h apart. Six had a double paracetamol peak, in three occurring >24?h post-ingestion. 113(97%) received acetylcysteine of which 67 received prolonged treatment beyond the standard 21?h. This was because of an elevated paracetamol concentration at the completion of acetylcysteine in 39 (median paracetamol concentration 25?mg/L, IQR: 16–62?mg/L). 21 (18%) developed hepatotoxicity, including six treated within 8?h of ingestion. Activated charcoal and double doses of acetylcysteine did not significantly decrease the risk of hepatotoxicity.

Conclusions: Drug regulatory authorities are considering restrictions on MR paracetamol preparations. Following an acute MR paracetamol overdose, this study found that many patients had a persistently elevated paracetamol concentrations, many required prolonged treatment and some developed liver injury despite early acetylcysteine treatment. Furthermore, activated charcoal and increased acetylcysteine did not appear to significantly alter the risk of liver injury. Hence, research into better treatment strategies is required.

Trial registration: Australian Toxicology Monitoring (ATOM) Study – Australian Paracetamol Project: ACTRN12612001240831 (ANZCTR) Date of registration: 23/11/2012.     

Nephrotoxicity After Acute Severe Acetaminophen Poisoning in Adolescents

Objective: To determine the rate of acetaminophen related nephrotoxicity in adolescents who present after acute severe acetaminophen intoxication and to identify potential predictors of this outcome. Study Design: Retrospective analysis of consecutive patients between the ages of 12 and 18 years who were admitted at a tertiary care children's hospital for treatment of acute severe acetaminophen intoxication with N-acetylcysteine. The main outcome measure was the frequency of acetaminophen-related nephrotoxicity, defined as abnormal blood urea nitrogen (> 6.4 mmol/L or >18 mg/dL) and/or elevated creatinine (97.2 μmol/L or >1.1 mg/dL) in association with one or both of the following: elevated blood pressure (systolic blood pressure >140 mm Hg/diastolic blood pressure >85) or abnormal urinalysis (urinalysis with hematuria or proteinuria). Statistical analyses used were measures of central tendency, Student's t-test, Mann-Whitney, and multivariate logistic regression. Results: Fourty-five patients were included. Acetaminophen-related nephrotoxicity occurred in 4 (8.9%) cases. One victim developed severe renal injury in association with elevated hepatic transaminases. Intergroup analyses revealed no statistically significant association between acetaminophen-related nephrotoxicity and amount/kg of acute severe acetaminophen ingested, delay in treatment with N-acetylcysteine, or measures of hepatic function. Conclusions: Acetaminophen-related nephrotoxicity occurred in 8.9% [95% CI: 4.52, 20.48] of children with severe overdose. There are no obvious predictors of this complication of acetaminophen overdose. Because the occurrence of renal injury can not be predicted, serial blood pressure, blood urea nitrogen/creatinine, and urinalysis should be considered an integral part of the management of children with acute, severe acetaminophen intoxication.     

Paracetamol metabolite concentrations following low risk overdose treated with an abbreviated 12-h versus 20-h acetylcysteine infusion

Context: To compare degree of liver injury and paracetamol metabolite concentrations after treatment with standard of care (20-h) vs. abbreviated (12-h) acetylcysteine regimens used in paracetamol overdose (NACSTOP trial).

Methods: Timed blood samples from a cohort of subjects enrolled in the cluster-controlled NACSTOP trial evaluating a 12-h acetylcysteine regimen (200?mg/kg over 4?h, 50?mg/kg over 8?h) were assayed for paracetamol metabolites as a pilot study, using liquid chromatography/mass spectrometry. Control group subjects received a 20-h course of acetylcysteine (200?mg/kg over 4?h, 100?mg/kg over 16?h). The intervention group received a 12-h acetylcysteine regimen (stopped after at least 12?h of treatment). Positive control groups not in the trial with acute liver injury (ALI) or hepatotoxicity were also studied.

Results: One hundred and forty-one blood samples were collected from 40 patients receiving acetylcysteine after paracetamol overdose. Median ALT after 20?h of acetylcysteine was 12?U/L (IQR 8.14) in the abbreviated regimen group, compared to the control group 16?U/L (IQR 11.21) (p?=?.46). There was no significant difference in median metabolite concentrations on presentation and after 20?h of acetylcysteine between these two groups (p?>?.05). Presentation median sum CYP-metabolite/total metabolite percentages were 2.5 and 3.0 in the abbreviated and control NACSTOP groups, respectively.

Conclusions: An abbreviated 12-h acetylcysteine regimen for paracetamol overdose used in the NACSTOP trial had similar circulating metabolite concentrations compared to a 20-h regimen in selected subjects with low risk of hepatotoxicity. This suggests that further acetylcysteine may not be needed in the abbreviated group at time of cessation.     

Nomogram line crossing after acetaminophen combination product overdose

Background: The Rumack–Matthew nomogram predicts the risk of hepatotoxicity following acute acetaminophen overdose based on a serum concentration obtained?≥4-hour post-ingestion. Some patients with low-risk concentrations at 4 hours may have subsequent values indicating increased risk (above the nomogram treatment line), especially if coingestants that slow gastrointestinal motility are involved. The treatment line currently used to identify low risk patients in the United States, Canada, and Australia begins at 150?mcg/mL (993?μmol/L) and intersects at 18.75?mcg/mL (124.1?μmol/L) 16 hours post-ingestion. Objective: To determine the incidence of nomogram line crossing after acute overdose of acetaminophen combination products containing an opioid or antihistamine. Methods: This was a prospective cohort study of hospitalized patients reported to a regional poison center (RPC) after acute overdose of a combination product containing an opioid or antihistamine. If a 4-hour acetaminophen concentration was detectable but below the nomogram treatment line, the RPC recommended repeat concentrations. Patients were entered into the study if at least one subsequent concentration was available. During follow-up calls hospital providers were queried regarding clinical features, treatment, and indicators of liver injury. Results: Over a 4-year period 76 patients met entry criteria. 5/76 (6.6%) had measureable acetaminophen concentrations below the treatment line at or close to 4-hour post-ingestion followed by values above the line obtained at 6.5–12.5 hours. Four of the five were treated with acetylcysteine and none developed hepatotoxicity. Four of the five had clinical features reported to the RPC suggesting toxicity from the opioid or antihistamine component. Conclusion: After acute overdose of acetaminophen combination products, patients with detectable but non-toxic 4-hour acetaminophen concentrations should have repeat concentrations obtained in a time frame that would allow providers to initiate acetylcysteine treatment, if needed, without undue delay.     

Management of acute acetaminophen overdose

Acetaminophen is a popular analgesic and antipyretic medication that has few side effects and little toxicity when used in recommended doses. With ingestion of overdose quantities, accumulation of toxic metabolites may cause hepatotoxicity. Acetylcysteine is an effective antidote when used early in the course of an acute overdose. An accurate history of the time of ingestion and an acetaminophen plasma level will determine which patients require treatment with acetylcysteine.     

Massive paracetamol overdose: an observational study of the effect of activated charcoal and increased acetylcysteine dose (ATOM-2)

Context: Paracetamol is commonly taken in overdose, with increasing concerns that those taking “massive” overdoses have higher rates of hepatotoxicity and may require higher doses of acetylcysteine. The objective was to describe the clinical characteristics and outcomes of “massive” (≥?40?g) paracetamol overdoses.

Methods: Patients were identified through the Australian Paracetamol Project, a prospective observational study through Poisons Information Centres in NSW and Queensland, over 3 and 1.5 years, respectively, and retrospectively from three clinical toxicology unit databases (over 2.5 to 20 years). Included were immediate-release paracetamol overdoses ≥?40?g ingested over ≤?8?h. Outcomes measured included paracetamol ratio[defined as the ratio of the first paracetamol concentration taken 4–16?h post-ingestion to the standard (150?mg/L at 4?h) nomogram line at that time] and hepatotoxicity (ALT >1000?U/L).

Results: Two hundred paracetamol overdoses were analysed, reported median dose ingested was 50?g (interquartile range (IQR): 45–60?g) and median paracetamol ratio 1.9 (IQR: 1.4–2.9, n?=?173). One hundred and ninety-three received acetylcysteine at median time of 6.3?h (IQR: 4–9.3?h) post-ingestion. Twenty-eight (14%) developed hepatotoxicity, including six treated within 8?h of ingestion. Activated charcoal was administered to 49(25%), at median of 2?h post-ingestion (IQR:1.5-5?h). Those receiving activated charcoal (within 4?h of ingestion), had significantly lower paracetamol ratio versus those who did not: 1.4 (n?=?33, IQR: 1.1–1.6) versus 2.2 (n?=?140, IQR: 1.5–3.0) (p?Seventy-nine had a paracetamol ratio ≥2, 43 received an increased dose of acetylcysteine in the first 21?h; most commonly a double dose in the last bag (100 to 200?mg/kg/16?h). Those receiving increased acetylcysteine had a significant decrease risk of hepatotoxicity [OR:0.27 (95% CI: 0.08–0.94)]. The OR remained similar after adjustment for time to acetylcysteine and paracetamol ratio.

Conclusion: Massive paracetamol overdose can result in hepatotoxicity despite early treatment. Paracetamol concentrations were markedly reduced in those receiving activated charcoal within 4?h. In those with high paracetamol concentrations, treatment with increased acetylcysteine dose within 21?h was associated with a significant reduction in hepatotoxicity.