Paracetamol overdose in Danish children and adolescents during the Covid-19 restrictions.

INTRODUCTION: To assess the effect of long-term isolation on the mental state of Danish youth. This study aimed to investigate trends in paracetamol overdoses among people under 18 years of age in Denmark during Covid-19 restrictions as an indicator of mental health. METHODS: All patients under the age of 18 years presenting with paracetamol overdose at one of the 18 paediatric departments in Denmark from 2016 to 2021 were included. They were identified in all Danish hospital databases using specific diagnostic codes. RESULTS: From 2016 to 2021, a total of 3,217 people under 18 years of age were admitted for paracetamol overdose. Among these, 86% (n = 2,755) were girls and 14% (n = 462) were boys. During 2020, a slight (7%) decrease in admissions was observed among both boys and girls compared with the preceding four-year mean value. In 2021, the number of overdoses among girls exceeded by 35% the former all-time high from 2016. Furthermore, the number of overdoses among girls exceeded the pre-four-year period mean value by 43%. Among boys, an 8% increase was seen from the highest ever previous value recorded in 2019 and a 23% increase compared with the previous four-year mean value. CONCLUSIONS: During the first year of restrictions, a slight decrease in paracetamol overdoses was observed, possibly associated with limited accessibility. The second year showed a considerable increase in paracetamol overdoses, which may imply an affected mental state among youth during the prolonged lockdown restrictions as seen in previous epidemics. Therefore, further studies are warranted to develop a pandemic preparedness plan to protect general mental health. FUNDING: None. TRIAL REGISTRATION: Not relevant.

Assessing the impact of a new medical toxicology service on the treatment of paracetamol overdose at a large tertiary care hospital.

BACKGROUND: Paracetamol overdose is the most common cause of acute liver failure in the United States. Administration of acetylcysteine is the standard of care for this intoxication. Laboratory values and clinical criteria are used to guide treatment duration, but decision-making is nuanced and often complex and difficult. The purpose of this study was to evaluate the effect of the introduction of a medical toxicology service on the rate of errors in the management of paracetamol overdose. METHODS: This was a single center, retrospective, cohort evaluation. Patients with suspected paracetamol overdose were divided into two groups: those attending in the 1 year period before and those in the 1 year after the introduction of the medical toxicology service. The primary outcome was the frequency of deviations from the established management of paracetamol intoxication, using international guidelines as a reference. RESULTS: Fifty-four patients were eligible for the study (20 pre-toxicology-service, 34 post-toxicology-service). The frequency of incorrect therapeutic decisions was significantly lower in the post-toxicology service implementation versus the pre-implementation group (P = 0.005). DISCUSSION: Our study suggests that a medical toxicology service reduces the incidence of management errors, including the number of missed acetylcysteine doses in patients with paracetamol overdose. The limitations include the retrospective study design and that the study was conducted at a single center, which may limit generalizability. CONCLUSIONS: The implementation of a medical toxicology service was associated with a decrease in the number of errors in the management of paracetamol overdose.

Intestinal injury in paracetamol overdose (ATOM-8).

BACKGROUND AND AIM: Paracetamol, a widely used medication, is known for its delayed hepatotoxicity in cases of overdose. However, the potential for intestinal toxicity resulting from very high paracetamol concentrations during absorption is not well explored. This study aims to investigate the presence of intestinal toxicity and its correlation with observations in early and late paracetamol toxicity. METHODS: Serial samples of 30 patients with acute paracetamol overdose (> 10 g or 200 mg/kg) were prospectively tested. Markers of enterocyte damage, including plasma intestinal fatty acid binding protein (IFABP) and selected gut-related microRNAs (miR-21, miR-122, miR-194, and miR-215), were analyzed. Sub-analysis was performed on patients presenting with hyperlactatemia defined as a lactate greater than 2 mmol/L within 12 h post ingestion. RESULTS: In paracetamol overdose patients, median plasma IFABP was significantly elevated compared with healthy controls (720 µg/L [interquartile range, IQR, 533-1644] vs 270 µg/L [IQR 153-558], P < 0.001). Four patients had early hyperlactatemia and had significantly higher median plasma IFABP compared with those without early hyperlactatemia (3028 µg/L [IQR 1399-3556] vs 574 µg/L [IQR 526-943], P = 0.007). Furthermore, two microRNAs (miR-122 and miR-215) were downregulated in early hyperlactatemia (P = 0.019 and P = 0.006, respectively). Plasma IFABP concentrations correlated with paracetamol concentration (Spearman's r = 0.55) and lactate (r = 0.60). CONCLUSIONS: Paracetamol overdose causes concentration-related intestinal toxicity, and this is a possible explanation for the early hyperlactatemia syndrome. Intestinal toxicity has potential impacts on pharmacokinetics of other agents ingested and on the evolution of hepatotoxicity. Further studies are required to explore the mechanisms and prognostic implications of intestinal toxicity.

Comparing N-acetylcysteine and 4-methylpyrazole as antidotes for acetaminophen overdose.

Acetaminophen (APAP) overdose can cause hepatotoxicity and even liver failure. N-acetylcysteine (NAC) is still the only FDA-approved antidote against APAP overdose 40 years after its introduction. The standard oral or intravenous dosing regimen of NAC is highly effective for patients with moderate overdoses who present within 8 h of APAP ingestion. However, for late-presenting patients or after ingestion of very large overdoses, the efficacy of NAC is diminished. Thus, additional antidotes with an extended therapeutic window may be needed for these patients. Fomepizole (4-methylpyrazole), a clinically approved antidote against methanol and ethylene glycol poisoning, recently emerged as a promising candidate. In animal studies, fomepizole effectively prevented APAP-induced liver injury by inhibiting Cyp2E1 when treated early, and by inhibiting c-jun N-terminal kinase (JNK) and oxidant stress when treated after the metabolism phase. In addition, fomepizole treatment, unlike NAC, prevented APAP-induced kidney damage and promoted hepatic regeneration in mice. These mechanisms of protection (inhibition of Cyp2E1 and JNK) and an extended efficacy compared to NAC could be verified in primary human hepatocytes. Furthermore, the formation of oxidative metabolites was eliminated in healthy volunteers using the established treatment protocol for fomepizole in toxic alcohol and ethylene glycol poisoning. These mechanistic findings, together with the excellent safety profile after methanol and ethylene glycol poisoning and after an APAP overdose, suggest that fomepizole may be a promising antidote against APAP overdose that could be useful as adjunct treatment to NAC. Clinical trials to support this hypothesis are warranted.

Decision tree outcome prediction of acute acetaminophen exposure in the United States: A study of 30,000 cases from the National Poison Data System.

Acetaminophen is one of the most commonly used analgesic drugs in the United States. However, the outcomes of acute acetaminophen overdose might be very serious in some cases. Therefore, prediction of the outcomes of acute acetaminophen exposure is crucial. This study is a 6-year retrospective cohort study using National Poison Data System (NPDS) data. A decision tree algorithm was used to determine the risk predictors of acetaminophen exposure. The decision tree model had an accuracy of 0.839, an accuracy of 0.836, a recall of 0.72, a specificity of 0.86 and an F1_score of 0.76 for the test group and an accuracy of 0.848, a recall of 0.85, a recall of 0.74, a specificity of 0.87 and an F1_score of 0.78 for the training group. Our results showed that elevated serum levels of liver enzymes, other liver function test abnormality, anorexia, acidosis, electrolyte abnormality, increased bilirubin, coagulopathy, abdominal pain, coma, increased anion gap, tachycardia and hypotension were the most important factors in determining the outcome of acute acetaminophen exposure. Therefore, the decision tree model is a reliable approach in determining the prognosis of acetaminophen exposure cases and can be used in an emergency room or during hospitalization.

A review of alternative intravenous acetylcysteine regimens for acetaminophen overdose.

INTRODUCTION: Acetylcysteine is the standard treatment for preventing hepatotoxicity caused by acetaminophen overdose. Several novel approaches to the management of acetaminophen overdose have been suggested to improve patient safety by reducing adverse drug reactions and dosing errors. This article reviews these alternative treatment regimens and intends to offer a detailed assessment of the available options to assist providers in managing cases of acetaminophen overdose. AREAS COVERED: This review article covers observational and experimental studies that assessed the efficacy and safety of alternative intravenous acetylcysteine regimens for acetaminophen overdose. A literature search was conducted using PubMed, ProQuest, and Scopus to identify the studies, which included results through April 2021. The assessment of alternative regimens consists of a discussion on the limitations and benefits, barriers to implementation, and important considerations for each regimen. EXPERT OPINION: Several alternative regimens have been studied and implemented in various institutions. Many of these dosing regimens have supporting safety data but most lack robust data. A reduction in infusion-related side effects is an important outcome, but established efficacy, local poison center familiarity with the regimen, institutional resources, and patient-specific factors should be equally considered when deciding on implementing and using an alternative dosing strategy.

Plasma procalcitonin may be an early predictor of liver injury in acetaminophen poisoning: A prospective cohort study.

BACKGROUND AND AIMS: Acetaminophen is a common cause of poisoning and liver injury worldwide; however, patient stratification is suboptimal. We aimed to assess the contribution of admission plasma procalcitonin concentration (PCT) to better identify acetaminophen-poisoned patients likely to develop liver injury. METHODS: We conducted a prospective observational cohort study including all acetaminophen-poisoned patients requiring N-acetylcysteine admitted in a toxicological intensive care unit between 2012 and 2017. Multivariate analysis was performed using a Cox regression model to investigate factors associated with liver injury, defined as an increase in alanine aminotransferase (ALT) >100 IU/L. RESULTS: One hundred seventeen patients (age, 32 years (21-53), median [25th-75th percentiles]) were included after self-ingesting 16 g (9-30) acetaminophen and received N-acetylcysteine infusion administered within a median 6 h-delay (4-12) from exposure. Co-ingestions were reported in 77% of patients. Rumack-Matthew nomogram was non-interpretable in 47% cases. Liver injury occurred in 38 patients (32%) with a median peak ALT of 2020 IU/L (577-4248). In liver injury patients, admission PCT was significantly increased in comparison to patients without liver injury (21.5 ng/ml (3.2-44.9) versus 0.1 ng/ml (0-0.4), respectively, p < 0.01). The increase in PCT preceded the increase in ALT by 33 h (10-74). In a multivariate analysis, PCT > 1 ng/ml was significantly associated with liver injury (hazard ratio, 7.2 [95% confidence interval, 2.3-22.6; p < 0.001]). PCT (area under the receiver-operating characteristics curve, 0.91 [95%CI: 0.84-0.97]) predicted liver injury with sensitivity, specificity, negative, and positive predictive values of 0.92, 0.84, 0.96, and 0.73, respectively. CONCLUSION: PCT on admission is associated with liver injury in acetaminophen poisoning. PCT might be used as a predictive tool of liver injury to improve clinical decision-making.

Clinical outcome of massive acetaminophen overdose treated with standard-dose N-acetylcysteine.

BACKGROUND: Recent recognition of "massive" acetaminophen (APAP) overdoses has led to the question of whether standard dosing of N-acetylcysteine (NAC) is adequate to prevent hepatoxicity in these patients. The primary aim of this study was to evaluate the clinical outcome for patients with massive APAP overdose who received standard intravenous NAC dosing of 300 mg/kg over 21 h. METHODS: This was a single-center retrospective cohort study conducted by chart review of APAP overdoses reported to a regional poison center from 1 January 2010 to 31 December 2019. Massive APAP overdose was defined by single, acute overdose resulting in an APAP concentration exceeding 300 mcg/mL at 4 h post-ingestion. Standard univariate statistical analysis was conducted to describe the cohort, and a multivariate logistic model was utilized to calculate adjusted odds ratios for risk of hepatoxicity. RESULTS: 1425 cases of APAP overdose were reviewed. 104 cases met the inclusion criteria of massive APAP overdose. Overall, 79 cases (76%) had no acute liver injury or hepatotoxicity, and 25 (24%) developed hepatoxicity. Nine percent (n = 4) of cases receiving NAC within 8 h developed hepatotoxicity. Crude odds for hepatoxicity was 5.5-fold higher for cases who received NAC after 8 h. CONCLUSIONS: Standard NAC dosing received within 8 h prevented hepatoxicity in 91% (n = 40) of cases in our series of massive APAP overdoses. Additional data is needed to determine the clinical outcomes of massive APAP overdose using current intravenous NAC dosing.

Protective role of Chlorella vulgaris with Thiamine against Paracetamol induced toxic effects on haematological, biochemical, oxidative stress parameters and histopathological changes in Wistar rats.

Paracetamol is extensively consumed as an analgesic and antipyretic drug, but at a high dose level, it leads to deleterious side effects, such as hepatic and nephrotoxicity. This research aimed to estimate the prophylactic efficacy of Chlorella vulgaris and/or thiamine against paracetamol (P) induced hepatorenal and cardiac toxicity. Forty-eight female Wistar rats were randomly divided into eight equal groups (n = 6 rats). Group 1, normal control group. Group 2, Paracetamol group. Groups 3, 4 and 5 were treated with Silymarin drug, Chlorella vulgaris alga, Chlorella vulgaris alga supplemented with thiamine, respectively daily for 7 successive days, then all were administered Paracetamol (2gm/kg. bwt.). While, Groups 6, 7 and 8 were treated by Silymarin, Chlorella vulgaris alga, Chlorella vulgaris supplemented with thiamine, respectively daily for 7 successive days without paracetamol administration. Our results clarified that Paracetamol toxicity caused significant adverse effects on hematological, serum biochemical parameters, and oxidant -antioxidant status as well as histopathological picture of heart, liver, and kidney. However, in the Paracetamol intoxicated groups pretreatment either with Chlorella vulgaris alone or plus thiamine successfully improved the undesirable deleterious effects of paracetamol, and restored almost all variables to near their control levels. This study has finished to that oxidative stress participates in the pathogenesis of paracetamol-induced toxicity in rats and using Chlorella vulgaris alga either alone or plus thiamine alongside their health benefits can protect against oxidative harmful effects induced by paracetamol through their free radical scavenging and powerful antioxidant effects, and they can be used as propylactic agents against paracetamol-induced toxicity.

A Case Report of a Severe, Unusually Delayed Anaphylactoid Reaction to Intravenous N-Acetylcysteine During Treatment of Acute Acetaminophen Toxicity in an Adolescent.

INTRODUCTION: Anaphylactoid reactions are well-documented adverse events associated with the intravenous administration of N-acetylcysteine (NAC) in patients with acetaminophen overdose. Most reactions are mild, occurring within the first 1-5 hours of initiation. This report presents the case of an adolescent with a delayed, life-threatening anaphylactoid reaction 24.5 hours after starting NAC, where discontinuing NAC could have resulted in fulminant hepatic failure (FHF) and death. CASE REPORT: A 17-year-old previously healthy female presented with nausea, vomiting, and abdominal pain 10 hours after an acute acetaminophen ingestion. Her 11-hour serum acetaminophen concentration was above the treatment line (149 µg/mL), and she had elevated transaminases (AST = 202 U/L, ALT = 284 U/L). She was treated with intravenous NAC, which was suspended for 3 hours after she developed an apparent life-threatening anaphylactoid reaction with angioedema and respiratory distress 24.5 hours after treatment initiation. Given her high risk of progression to FHF, NAC was resumed at double the previous rate along with scheduled corticosteroids and antihistamines after resolution of her symptoms. Her AST increased to 10,927 U/L, and INR peaked at 3.6, but she had no further anaphylactoid symptoms. She was discharged in her normal state of health after 6 days. DISCUSSION: Discontinuing NAC in this case of severe, delayed anaphylactoid reaction could have resulted in FHF requiring liver transplant. The reason for her reaction is unclear but could be related to patient risk factors or medication error. Guidelines for reinitiation of NAC after development of delayed anaphylactoid reactions are not well-established.  Close observation beyond the first 1-5 hours of NAC administration is warranted.

Delayed peaks of acetaminophen in overdose patients with concomitant abdominal trauma.

OBJECTIVE: To present two cases of delayed acetaminophen absorption in abdominal trauma patients with concomitant acetaminophen overdose. CASES: Case 1. A 25-year-old female arrived to the emergency department with multiple stab wounds. She had ingested an unknown amount of acetaminophen and was then stabbed by her boyfriend in a suicide pact. Initial acetaminophen concentration was 211.7 mcg/mL and the patient was started on N-Acetylcysteine (NAC) therapy. She was found to have injuries and was taken for operative repair. Acetaminophen concentrations were down trending and nearly undetectable until 58 h post-presentation when concentrations began to rise again. CASE 2: A 41-year-old female ingested approximately 500 tablets of acetaminophen prior to jumping from a four-story building in a suicide attempt. She was found to have multiple traumatic injuries as well as an initial acetaminophen concentration of 225 mcg/mL and was started on NAC therapy. The patient underwent multiple interventions to treat her traumatic injuries. Despite receiving no acetaminophen while inpatient, the patient's acetaminophen concentrations peaked a second time on her third hospital day. CONCLUSIONS: In this case series, two patients with abdominal trauma and coexistent massive acetaminophen ingestions were described. Both cases demonstrated a delayed rise in serum acetaminophen concentrations and required extended NAC therapy.

Increased risk of acute liver failure by pain killer drugs in NAFLD: Focus on nuclear receptors and their coactivators.

Non-alcoholic fatty liver disease (NAFLD) is a global condition characterized by an accumulation of lipids in the hepatocytes. NAFLD ranges from simple steatosis, a reversible and relatively benign condition, to fibrosis with non-alcoholic steatohepatitis (NASH), potentially leading to cirrhosis and hepatocarcinoma. NAFLD can increase the susceptibility to severe liver injury with eventual acute liver failure induced by specific hepatotoxic drugs, including acetaminophen (APAP), which is commonly used as analgesic and antipyretic. Although several animal models have been used to clarify the predisposing role of hepatic steatosis to APAP intoxication, the exact mechanism is still not clear. Here, we shed a light into the association between NAFLD and APAP toxicity by examining the peculiar role of nuclear receptor peroxisome proliferator-activated receptor α (PPARα) and coactivator peroxisome proliferator-activated receptor gamma coactivator 1-ß (PGC-1ß) in driving fatty acid metabolism, inflammation and mitochondria redox balance. The knowledge of the mechanism that exposes patients with NAFLD to higher risk of acute liver failure by pain killer drug is the first step to eventually claim for a reduction of the maximal diurnal dose of APAP for subjects with liver steatosis.

Successful orthotopic liver transplantation in a patient with a positive SARS-CoV2 test and acute liver failure secondary to acetaminophen overdose.

SARS-CoV2, first described in December 2019, was declared a pandemic by the World Health Organization in March 2020. Various surgical and medical societies promptly published guidelines, based on expert opinion, on managing patients with COVID-19, with a consensus to postpone elective surgeries and procedures. We describe the case of an orthotopic liver transplantation (OLT) in a young female who presented with acute liver failure secondary to acetaminophen toxicity to manage abdominal pain and in the setting of a positive SARS-CoV2 test. Despite a positive test, she had no respiratory symptoms at time of presentation. The positive test was thought to be residual viral load. The patient had a very favorable outcome, likely related to multiple factors including her young age, lack of respiratory COVID-19 manifestations and plasma exchange peri-operatively. We recommend a full work-up for OLT in COVID-19 patients with uncomplicated disease according to standard of care, with careful interpretation of COVID-19 testing in patients presenting with conditions requiring urgent or emergent surgery as well as repeat testing even a few days after initial testing, as this could alter management.