Intravenous Acetylcysteine Research Articles

Intravenous Acetylcysteine: What Should Replace the Prescott "Three-Bag" Protocol?

Intravenous Acetylcysteine: What Should Replace the Prescott "Three-Bag" Protocol?

Medication Safety Practice Corner Key learnings: Preventing errors with intravenous acetylcysteine

ISMP Canada received three reports of death or severe harm involving intravenous acetylcysteine (also known as N-acetylcysteine) overdose related to one type of error—continuation of the loading dose IV infusion rate instead of reduction to a lower rate for the maintenance dose. All resulted in a 10-fold dosing error. An alert was published in 2022, and a follow-up safety bulletin in 2023 shared findings from a multi-incident analysis with recommendations (ISMP Canada, 2022 & 2023). There are many protocols/regimens in use across Canada for the preparation and administration of acetylcysteine, each with potential benefits and risks. This column shares key findings and several strategies to support the safe administration of acetylcysteine. Critical care nurses’ specialized expertise in patient monitoring and fluid management is vital for optimal care outcomes.

Contrast induced nephropathy in interventional cardiology; identification of high-risk patients and its prevention

Abstract Funding Acknowledgements Type of funding sources: None. Background CIN is a serious and potentially preventable complication of coronary angiography and/or percutaneous coronary interventions (PCI). The definition of CIN, its incidence and risk factors and therapeutic interventions are not well established . Purpose To study incidence and risk factors of CIN in patients undergoing coronary angiography and/or PCI, to investigate high-risk patients with CIN and to evaluate its preventive therapies (Hydration an Acetylcysteine). Method This was a prospective trial, in one center with patients undergoing coronary angiography and/or PCI, during 2010-2014. The renal function was evaluated through serum Creatinine (Cr) and GFR (Cockcroft –Gault formula ). CIN was defined as an increase in Creatinine by 25% and/or by 0.5 mg/dL at 48/72 h after the index procedures. Patients with CIN were considered high-risk when Creatinine increased more than 50% and/or by 2 mg/dL, or needing dialysis. We evaluated the major risk factors for CIN such as: Preexisting Renal Lesion (PRL), Age≥65 years, Heart Failure (HF), Diabetes Mellitus (DM), Anemia (Hb < 12 g/dL) and the Quantity of Contrast used. We evaluated the role of hydration with intravenous saline and acetylcysteine (ACC) in the prevention of CIN. Results Out of the 1231 patients enrolled, 804 patients fulfilled the inclusion criteria. The incidence of CIN resulted 14.4%, higher in the group of patients with risk factors for CIN (15.3%) versus without risk factors (9.1%); p=0.05. Risk factors HF (OD: 4.63; CI95%: 2.10-10.05, p<0.001), PRL (OD: 1.57; CI95%: 1.02-2.41, p=0.039) and Age ≥ 65 years (OD: 1.82; CI95%: 1.37-3.73, p=0.038 ) resulted independent risk factors, for CIN whereas Anemia (p=0.171), DM (p=0.502) and the Quantity of contrast used (p=0.479) did not result independent risk factors. Creatinine at 24 hours after the procedure resulted a predictive factor for the development of CIN. (sensitivity 64.7%, specificity 91.7%, positive predictive value 63.5%, negative predictive value 92.1% ). Creatinine > 1.5 mg/dL before the procedure resulted an independent risk factor for CIN, with a higher specificity than eGFR < 60 ml/min. The incidence of patients with CIN at high risk was 3.9% and HF resulted the only independent risk factor in this subgroup of patients (OD:4.49, CI 95%: 2.03-9.95). Intravenous hydration with saline resulted efficient in the prevention of the development of CIN (p=0.029), whereas ACC did not (p=0.485). Conclusions The frequency of CIN is higher in the group with risk factors. The HF, PRL, Age≥ 65 years resulted as independent risk factors for, and intravenous hydration with saline was a simple and efficient method for the prevention of CIN. Although our definition of CIN is widely used, the need for a universal definition for CIN is a contemporary need.

Large paracetamol overdose - Higher dose NAC is NOT required.

Paracetamol overdose is common in developed countries but less than 10% involve large ingestions exceeding 30 g or 500 mg/kg. High dose acetylcysteine (NAC) has been proposed in patients taking large paracetamol overdoses based on reports of hepatotoxicity despite early initiation of NAC treatment with the commonly used 300 mg/kg intravenous acetylcysteine regimen. The evidence from cohorts of patients treated with the standard NAC regimen after large paracetamol overdoses shows that it is effective in most patients. A small study in patients with paracetamol overdoses of 40 g or more and paracetamol concentrations above the 300 mg/L nomogram line showed that modification of the standard NAC regimen to provide a total of 400-500 mg/kg NAC over 21-22 h may reduce the risk of hepatotoxicity (peak ALT > 1000 IU/L) but the impact on development of hepatic failure, liver transplantation and mortality with this approach is presently unknown. Better risk stratification of patients taking paracetamol overdose may allow higher dose NAC and adjunctive treatments such as CYP2E1 inhibition and extracorporeal removal of paracetamol to be targeted to those patients at the highest risk of hepatotoxicity after a large paracetamol overdose.

A two-bag acetylcysteine regimen is associated with shorter delays and interruptions in the treatment of paracetamol overdose

Background The three-bag intravenous (IV) acetylcysteine regimen for paracetamol overdose is associated with frequent and long delays during treatment. This has not been previously studied in regard to the two-bag regimen. Aims Our primary aim was to compare the cumulative duration of delays during IV acetylcysteine infusion between the three-bag and two-bag regimens. Secondary aims were to compare the frequency of delays and to identify causes for delay. Methods This was a retrospective cohort study of patients receiving IV acetylcysteine for the treatment of paracetamol overdose, conducted at three Australian emergency departments. A cohort of patients treated with the three-bag regimen from October 2009 to October 2013 was compared to patients treated with the two-bag regimen from February 2014 to May 2020. Start times of each infusion were sourced from medical records and delays were calculated by comparing actual infusion time against prescribed time. Evidence of adverse drug reactions – gastrointestinal reactions and cutaneous and systemic non-allergic anaphylactoid reactions (NAARs) – were also recorded. Results The three-bag cohort included 271 cases and the two-bag cohort included 598 cases. Delays were significantly shorter in the two-bag cohort, compared to the three-bag cohort: median delay 35 min (IQR: 15, 70) vs 65 min (IQR: 40, 105), p < 0.01. Delays longer than 1 h were less frequent in the two-bag cohort: 31% vs 51%, p < 0.01. NAARs were associated with significantly longer delays in both cohorts and were more frequent in the three-bag cohort. Conclusions The two-bag regimen was associated with significantly fewer and shorter delays. NAARs, which were more frequent in the three-bag cohort, were associated with significantly longer delays.

Acute Renal Failure and Hemolytic Uremic Syndrome in Overdose With N-acetyl Cysteine After Acetaminophen Poisoning

Context: Acetylcysteine is an effective treatment for acetaminophen poisoning. The preparation and dose calculation of acetylcysteine is associated with medical errors. The prevalence of this error is 34% globally. Case report: A 15-year-old girl took an overdose of acetaminophen in a suicide attempt. Acetylcysteine intravenous was ordered. Due to the medication error by the nurse, she received a 10-fold overdose of intravenous acetylcysteine in both initial loading dose and maintenance dose, at first day. On the second day, the patient showed abdominal pain, nausea, vomiting, and elevated liver enzymes. Her hemoglobin, hematocrit, and platelet quickly decreased. Subsequently, she developed oliguria, anuria, and rising serum creatinine levels. The patient was diagnosed with uremic hemolytic syndrome. She underwent hemodialysis and was treated with plasmapheresis, blood transfusions, and platelets. Discussion: The effects of acetaminophen poisoning and acetylcysteine overdose may be much more severe and have a greater impact on patient survival than each poisoning alone. Timely and accurate treatment measures can help prevent long-term side effects.

Efficacy of a two bag acetylcysteine regimen to treat paracetamol overdose (2NAC study)

BackgroundPrevious studies of paracetamol overdose treatment show that a 2-bag, 20-h intravenous (IV) acetylcysteine regimen decreased the incidence of non-allergic anaphylactic reactions compared to the 3-bag, 21 h IV regimen, but have not examined efficacy of the 20-h 2 bag regimen. MethodsThis was a multi-centre observational study of paracetamol overdose presentations treated with a 2-bag IV acetylcysteine regimen (200 mg/kg over 4 h, 100 mg/kg over 16 h) compared to a 3-bag regimen, performed from 2009 to 2019. Patients were referred from the emergency department to the inpatient toxicology units for continued management. For the primary non-inferiority analysis: subjects had single, acute ingestions, a serum paracetamol-concentration performed 4 to 8-h post-ingestion. The primary outcome was development of acute liver injury (ALI), defined as peak ALT>150 U/L; and > double admission baseline ALT (for presentations within 24 h post-overdose). Secondary outcomes included adverse reactions to acetylcysteine (cutaneous and systemic). FindingOut of 6419 paracetamol overdoses, 2763 received acetylcysteine. For the primary analysis, 1003 received the 2-bag and 783 the 3-bag acetylcysteine regimen. When presentation bloods were performed 4 to 8-h post-overdose, 21 (3.1%) developed ALI with the 2-bag regimen vs 16 (2.9%) with the 3-bag regimen (Difference: 0.2%, 95%CI:-1.6 to 2.2). The incidence of hepatotoxicity was: 1.2% (n = 8) with the two-bag regimen and 1.6% (n = 9) with the three-bag regimen (Difference -0.4%, 95%CI -1.75, 0.91). When presentation bloods were performed 8 to 24-h post-overdose, 70 (21%) developed ALI with the 2-bag regimen vs 46 (23%) with the 3-bag regimen (Difference: -2%, 95%CI -9.12 to 5.36). There were significantly less cutaneous and systemic non-allergic anaphylactic reactions recorded after treatment with the two-bag than the three-bag regimen (1.3% [n = 17] and 7.1% [n = 65], Difference: -5.8%, 95%CI -7.6 to -4.0, p < 0.0001), respectively. InterpretationA two-bag intravenous acetylcysteine regimen was found to be non-inferior to the three-bag regimen with regards to efficacy in preventing acute liver injury for early presentations of paracetamol overdose. No important differences were seen for any other presentations. The two-bag regimen also decreased the incidence of both non-allergic anaphylactic reactions and gastrointestinal adverse events from acetylcysteine treatment. FundingAW is funded by a National Health and Medical Research Council (NHMRC) Early Career Fellowship ID 1159907. GI is funded by a NHMRC Senior Research Fellowship ID 1061041. The NHMRC had no role in the design, writing of this manuscript. The corresponding author (AW) had full access to all the data in the study and final responsibility for the decision to submit the manuscript for publication.

Hepatotoxicity in a child following an accidental overdose of liquid paracetamol

Introduction: Accidental pediatric liquid paracetamol exposure is common. Most children do not require treatment with acetylcysteine and acute liver injury is rare.Case report: An otherwise well 3-year-old (15.4 kg) girl with recent vomiting and low-grade fever presented 1 h post-accidental ingestion of up to 150 mL of 24 mg/mL (240 mg/kg) of liquid paracetamol. Paracetamol concentrations 2 and 4 h post-ingestion were 105 and 97 mg/L, respectively, both below the nomogram treatment threshold so acetylcysteine was not administered. The ALT was elevated to 52 U/L 4 h post-ingestion, and then 219 U/L at 17 h, so intravenous acetylcysteine was commenced at 25 h. ALT peaked at 1393 U/L 5d post-ingestion, and INR peaked at 1.5 at 44 h post-ingestion. Acetylcysteine continued for 64 h and she made an uneventful recovery. Paracetamol metabolites were measured including, nontoxic glucuronide and sulphate conjugates and toxic cytochrome P450 (CYP) metabolites (cysteine and mercapturate). The apparent paracetamol half-life was 6.3 h. Her CYP metabolites were higher than usual, 11% of total metabolites. Glucuronide and sulphate conjugates accounted for 71 and 18% of total metabolites, respectively.Conclusion: This uncommon case of hepatotoxicity in a child following accidental liquid paracetamol ingestion may have been due to increased susceptibility from a recent viral illness with decreased oral intake, as evidenced by the higher proportion of CYP metabolites.

Adverse reactions in patients treated with the one-bag method of N-acetylcysteine for acetaminophen ingestion

Acetaminophen (paracetamol) remains the leading pharmaceutical agent in overdoses in North America. The three-bag Prescott protocol for intravenous (IV) acetylcysteine is complex and prone to errors. It has frequent adverse reactions, particularly non-allergic anaphylactoid reactions (NAARs). Over 15 years ago, we adopted a simplified, one-bag protocol using a standard concentration to reduce errors. We report the adverse reactions with this protocol. We used hospital pharmacy records to retrospectively identify patients who received IV acetylcysteine between 12 January 2005 and 20 June 2016. We excluded patients without acetaminophen overdose or with any part of their IV acetylcysteine at an outside hospital. We searched pharmacy records for diphenhydramine or any antiemetic after commencing IV acetylcysteine. We reviewed progress notes for descriptions of nausea, dyspnea, itching/pruritus, or rash. Out of 252 patients receiving IV acetylcysteine, 202 met our inclusion criteria. Thirty-three patients had at least one adverse reaction including nausea in 28 patients and any symptom of NAAR in 8 patients. Twenty-eight patients received an antiemetic. Eleven patients received diphenhydramine (nine for NAAR and two with prochlorperazine). Nausea was the most common adverse reaction. The rate of non-allergic anaphylactoid reactions with the one-bag protocol was 4%.

Updated guidelines for the management of paracetamol poisoning in Australia and New Zealand.

Paracetamol is a common agent taken in deliberate self-poisoning and in accidental overdose in adults and children. Paracetamol poisoning is the commonest cause of severe acute liver injury. Since the publication of the previous guidelines in 2015, several studies have changed practice. A working group of experts in the area, with representation from all Poisons Information Centres of Australia and New Zealand, were brought together to produce an updated evidence-based guidance. The optimal management of most patients with paracetamol overdose is usually straightforward. Patients who present early should be given activated charcoal. Patients at risk of hepatotoxicity should receive intravenous acetylcysteine. The paracetamol nomogram is used to assess the need for treatment in acute immediate release paracetamol ingestions with a known time of ingestion. Cases that require different management include modified release paracetamol overdoses, large or massive overdoses, accidental liquid ingestion in children, and repeated supratherapeutic ingestions. The new guidelines recommend a two-bag acetylcysteine infusion regimen (200mg/kg over 4h, then 100mg/kg over 16h). This has similar efficacy but significantly reduced adverse reactions compared with the previous three-bag regimen. Massive paracetamol overdoses that result in high paracetamol concentrations more than double the nomogram line should be managed with an increased dose of acetylcysteine. All potentially toxic modified release paracetamol ingestions (≥10g or ≥200mg/kg, whichever is less) should receive a full course of acetylcysteine. Patients ingesting ≥30g or ≥500mg/kg should receive increased doses of acetylcysteine.

Early acetaminophen-protein adducts predict hepatotoxicity following overdose (ATOM-5)

Acetaminophen-protein adducts are specific biomarkers of toxic acetaminophen (paracetamol) metabolite exposure. In patients with hepatotoxicity (alanine aminotransferase [ALT] >1,000 U/L), an adduct concentration ≥1.0 nmol/ml is sensitive and specific for identifying cases secondary to acetaminophen. Our aim was to characterise acetaminophen-protein adduct concentrations in patients following acetaminophen overdose and determine if they predict toxicity. We performed a multicentre prospective observational study, recruiting patients 14 years of age or older with acetaminophen overdose regardless of intent or formulation. Three serum samples were obtained within the first 24 h of presentation and analysed for acetaminophen-protein adducts. Acetaminophen-protein adduct concentrations were compared to ALT and other indicators of toxicity. Of the 240 patients who participated, 204 (85%) presented following acute ingestions, with a median ingested dose of 20 g (IQR 10-40), and 228 (95%) were treated with intravenous acetylcysteine at a median time of 6 h (IQR 3.5-10.5) post-ingestion. Thirty-six (15%) patients developed hepatotoxicity, of whom 22 had an ALT ≤1,000 U/L at the time of initial acetaminophen-protein adduct measurement. Those who developed hepatotoxicity had a higher initial acetaminophen-protein adduct concentration compared to those who did not, 1.63 nmol/ml (IQR 0.76-2.02, n= 22) vs. 0.26 nmol/ml (IQR 0.15-0.41; n= 204; p <0.0001), respectively. The AUROC for hepatotoxicity was 0.98 (95% CI 0.96-1.00; n= 226; p <0.0001) with acetaminophen-protein adduct concentration and 0.89 (95% CI 0.82-0.96; n= 219; p <0.0001) with ALT. An acetaminophen-protein adduct concentration of 0.58 nmol/ml was 100% sensitive and 91% specific for identifying patients with an initial ALT ≤1,000 U/L who would develop hepatotoxicity. Adding acetaminophen-protein adduct concentrations to risk prediction models improved prediction of hepatotoxicity to a level similar to that obtained by more complex models. Acetaminophen-protein adduct concentration on presentation predicted which patients with acetaminophen overdose subsequently developed hepatotoxicity, regardless of time of ingestion. An adduct threshold of 0.58 nmol/L was required for optimal prediction. Acetaminophen poisoning is one of the most common causes of liver injury. This study examined a new biomarker of acetaminophen toxicity, which measures the amount of toxic metabolite exposure called acetaminophen-protein adduct. We found that those who developed liver injury had a higher initial level of acetaminophen-protein adducts than those who did not. Australian Toxicology Monitoring (ATOM) Study-Australian Paracetamol Project: ACTRN12612001240831 (ANZCTR) Date of registration: 23/11/2012.

Diagnostics and treatment of selected clinically relevant, acute drug intoxications

Acute drug poisoning due to accidental or self-damaging overdoses is responsible for 5-10% of emergency medical interventions in Germany. The treatment of asymptomatic to life-threatening courses requires extensive expertise. On the basis of aselective literature search, this article gives an overview of selected clinically relevant, acute drug poisonings with regard to epidemiology, symptomatology, diagnostics, and therapy.Intoxications with psychotropic drugs are the most common drug intoxications. Poisoning with tricyclic antidepressants causes anticholinergic, central nervous, and cardiovascular symptoms. Less toxic are selective serotonin reuptake inhibitors (SSRIs); the intoxication may be characterized by serotonin syndrome. Malignant neuroleptic syndrome is asevere complication of neuroleptic poisoning.Poisoning with analgesics is clinically relevant due to its high availability. For paracetamol poisoning, intravenous acetylcysteine is available as an antidote. Hemodialysis may be indicated for severe salicylate intoxication. Poisoning with nonsteroidal anti-inflammatory drugs is usually only associated with mild signs of intoxication.Poisoning with cardiac drugs (β-blockers and calcium antagonists) can cause life-threatening cardiovascular events. In addition to symptomatic therapy, insulin glucose therapy also plays an important role.The majority of acute drug poisonings can be treated adequately by symptomatic and partly intensive care therapy - if necessary with the application of primary and secondary toxin elimination. Depending on the severity of the intoxication, pharmacology-specific therapy must be initiated.

Delayed onset of liver injury after intentional chloroform overdose: a case report and literature review

Chloroform is a recognised cause of acute liver injury, although now rarely encountered in clinical practice. We present a case of inhalational chloroform self-poisoning in a 47-year-old man that presented to hospital initially with reduced conscious level and later developed acute liver injury that was treated with intravenous acetylcysteine. This paper reviews the existing literature and presents a summary of the mechanisms of chloroform hepatotoxicity. Published cases show that there is a characteristic delay of 24 to 48 hours between chloroform exposure and elevation of liver transaminase activity. Therefore, clinicians need to provide an appropriate duration of monitoring in order to detect the occurrence of this important toxic effect.

An evaluation of the role of mixing techniques in the observed variation in acetylcysteine infusion concentrations.

Intravenous acetylcysteine is commonly prescribed as a course of three infusions for the management of paracetamol poisoning. Previous studies have demonstrated large variation in administered doses of intravenous acetylcysteine, which has been attributed to numerous factors, including inadequate mixing of infusion bags. The aim of this study was to determine whether the amount of mixing of infusion bags contributes significantly to this variation. Using acetylcysteine doses for a 60-69kg patient, we added the appropriate volume of acetylcysteine to 5% glucose and subsequently inverted the infusion bags 0-5 times to mix the solutions. Infusion bags were then run through using an infusion pump and acetylcysteine concentrations measured at the beginning and end of the infusions. We found no significant difference between the beginning and end concentrations of acetylcysteine regardless of whether bags were mixed or not; infusion 1 (150mgkg-1 ) showed beginning and end concentrations of 44.61 and 42.48mgml-1 respectively after 0 mixes, whilst beginning and end concentrations were 44.45 and 44.58mgml-1 respectively after five mixes. The same trend was observed for infusions 2 and 3. This confirmed that mixing does not play a substantial role in variation of drug concentrations; these are likely to be caused by an accumulation of small errors in infusion preparation.

Fewer adverse effects associated with a modified two-bag intravenous acetylcysteine protocol compared to traditional three-bag regimen in paracetamol overdose

Context: The intravenous (IV) N-acetylcysteine (NAC) regimen used worldwide in paracetamol overdose is complex with three separate weight-based doses and is associated with a high incidence of adverse events including non-allergic anaphylactoid reactions (NAARs). In 2012, Denmark adopted the two-bag IV NAC regimen which combined the first two infusions of the three-bag regimen and kept the third infusion unchanged. We compared the safety and efficacy of the two-bag IV NAC regimen with the traditional Danish three-bag regimen.Methods: A medical chart review was conducted in three Danish medical centers from January 2012 through December 2014. Safety and efficacy data were compared for patients who received the traditional infusion protocol in Denmark or the 20-h two-bag IV regimen.Results: Four hundred and ninety-three cases received the two-bag regimen and 274 received the three-bag regimen. The overall incidence of NAARs was 9% with all being mild to moderate in intensity. Fewer subjects in the two-bag group (4%) developed NAARs compared to 17% in the three-bag group (p < .001). Overall, 31 patients (4%) developed hepatotoxicity. There was no apparent difference in hepatotoxicity rates between the groups and no deaths or liver transplants. Patients receiving the two-bag regimen had fewer interruptions or delays (5%) compared to the three-bag regimen cohort (12%). Overall, there were very few medication errors reported (1%).Conclusions: The incidence of NAARs was lower in patients receiving acetylcysteine in a two-bag regimen compared to the traditional Danish three-bag regimen without an apparent reduction in efficacy.

Interventions for paracetamol (acetaminophen) overdose.

Interventions for paracetamol (acetaminophen) overdose.

Risk stratification after paracetamol overdose using mechanistic biomarkers: results from two prospective cohort studies

SummaryBackgroundParacetamol overdose is common but patient stratification is suboptimal. We investigated the usefulness of new biomarkers that have either enhanced liver specificity (microRNA-122 [miR-122]) or provide mechanistic insights (keratin-18 [K18], high mobility group box-1 [HMGB1], and glutamate dehydrogenase [GLDH]). The use of these biomarkers could help stratify patients for their risk of liver injury at hospital presentation.MethodsUsing data from two prospective cohort studies, we assessed the potential for biomarkers to stratify patients who overdose with paracetamol. We completed two independent prospective studies: a derivation study (MAPP) in eight UK hospitals and a validation study (BIOPAR) in ten UK hospitals. Patients in both cohorts were adults (≥18 years in England, ≥16 years in Scotland), were diagnosed with paracetamol overdose, and gave written informed consent. Patients who needed intravenous acetylcysteine treatment for paracetamol overdose had circulating biomarkers measured at hospital presentation. The primary endpoint was acute liver injury indicating need for continued acetylcysteine treatment beyond the standard course (alanine aminotransferase [ALT] activity >100 U/L). Receiver operating characteristic (ROC) curves, category-free net reclassification index (cfNRI), and integrated discrimination index (IDI) were applied to assess endpoint prediction.FindingsBetween June 2, 2010, and May 29, 2014, 1187 patients who required acetylcysteine treatment for paracetamol overdose were recruited (985 in the MAPP cohort; 202 in the BIOPAR cohort). In the derivation and validation cohorts, acute liver injury was predicted at hospital presentation by miR-122 (derivation cohort ROC–area under the curve [AUC] 0·97 [95% CI 0·95–0·98]), HMGB1 (0·95 [0·93–0·98]), and full-length K18 (0·95 [0·92–0·97]). Results were similar in the validation cohort (miR-122 AUC 0·97 [95% CI 0·95–0·99], HMGB1 0·98 [0·96–0·99], and full-length K18 0·93 [0·86–0·99]). A combined model of miR-122, HMGB1, and K18 predicted acute liver injury better than ALT alone (cfNRI 1·95 [95% CI 1·87–2·03], p<0·0001 in the MAPP cohort; 1·54 [1·08–2·00], p<0·0001 in the BIOPAR cohort).InterpretationPersonalised treatment pathways could be developed by use of miR-122, HMGB1, and full-length K18 at hospital presentation for patient stratification. This prospective study supports their use for hepatic safety assessment of new medicines.FundingEdinburgh and Lothians Health Foundation, UK Medical Research Council.

The use of sustained low efficiency dialysis (SLED) in massive paracetamol overdose

Context: Massive paracetamol ingestion causing mitochondrial dysfunction is uncommon. Use of sustained low-efficiency dialysis (SLED) to improve acidaemia and enhance paracetamol elimination has not been previously described.Case details: A 44-year-old male presented to the emergency department 2.5 hours post overdose of 200 g (2.5 g/kg) of paracetamol. Examination revealed a BP 85/60 mmHg, pulse 112 bpm, temperature 33.9 °C and blood glucose of 13.9 mmol/l. Venous blood gas 5.5-hours post-ingestion showed a pH 6.9, pCO2 58 mmHg, HCO3 13 mmol/l and lactate 14 mmol/l. Fifty-grams of nasogastric activated charcoal and double-strength intravenous acetylcysteine were administered. Paracetamol concentration peaked at 4207 µmol/l six hours post-ingestion. SLED was commenced nine-hours post ingestion and acetylcysteine dose was doubled again during dialysis. Paracetamol extraction ratio was 47–52%. Plasma paracetamol clearance was steady throughout SLED (53–58 ml/min). Hepatotoxicity did not develop and the patient recovered.Discussions: Intermittent hemodialysis (IHD) is more efficient than SLED or continuous renal replacement therapy for enhancing paracetamol elimination and clearance. IHD plasma clearance is reported to range from 36 to 215 ml/min compared with endogenous clearance of 224 ml/70 kg/min.Conclusions: SLED improved acidaemia with only moderate overall increase in paracetamol plasma clearance. Lack of development of hepatotoxicity was likely the result of early administration of acetylcysteine rather than any effect of SLED on paracetamol elimination.

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.

Chloroform ingestion causing severe gastrointestinal injury, hepatotoxicity and dermatitis confirmed with plasma chloroform concentrations

Context: Poisoning due to chloroform ingestion is rare. The classic features of acute chloroform toxicity include central nervous system (CNS) and respiratory depression, and delayed hepatotoxicity.Case details: A 30-year-old female ingested 20–30 mL of 99% chloroform solution, which caused rapid loss of consciousness, transient hypotension and severe respiratory depression requiring endotracheal intubation and ventilation. She was alert by 12 h and extubated 16 h post-overdose. At 38-h post-ingestion, her liver function tests started to rise and she was commenced on intravenous acetylcysteine. Her alanine transaminase (1283 U/L), aspartate transaminase (734 U/L) and international normalized ratio (2.3) peaked 67- to 72-h post-ingestion. She also developed severe abdominal pain, vomiting and diarrhoea. An abdominal CT scan was consistent with severe enterocolitis, and an upper gastrointestinal endoscopy showed erosive oesophagitis, severe erosive gastritis and ulceration. She was treated with opioid analgesia, proton pump inhibitors, sucralfate and total parenteral nutrition. Secretions caused a contact dermatitis of her face and back. Nine days post-ingestion she was able to tolerate food. Her liver function tests normalized and the dermatitis resolved. Chloroform was measured using headspace gas chromatograph mass spectrometry, with a peak concentration of 2.00 μg/mL, 4 h 20 min post-ingestion. The concentration-time data fitted a 1-compartment model with elimination half-life 6.5 h.Discussion: In addition to early CNS depression and delayed hepatotoxicity, we report severe gastrointestinal injury and dermatitis with chloroform ingestion. Recovery occurred with good supportive care, acetylcysteine and management of gastrointestinal complications.