[Cyanide, in And Then There Were None, Sparkling Cyanide].

And Then There Were None and Sparkling Cyanide, two of Agatha Christie's famous novels describe potassium cyanide-induced deaths. Cyanide, a tasteless, odorless, strongly alkaline poison is a powerful gastrointestinal irritant, following oral ingestion. It reacts with hydrochloric acid in the gastric juice to produce hydrogen cyanide gas, which is absorbed and inhibits the mitochondrial electron transfer system and consequently suppresses adenosine triphosphate (ATP) production. Therefore, the central nervous system, which consumes a large amount of ATP, is first affected and symptoms of poisoning manifest as dizziness, disorientation, coma, and convulsions. The orally lethal dose is approximately 300 mg.

A Case of an Intraoperative Iatrogenic Methanol Exposure.

BACKGROUND ThinPrep Cytolyt is a methanol-based cell preservation solution frequently used to fix tissue samples immediately following endobronchial ultrasound-guided fine-needle aspiration. Currently, no published reports describe an iatrogenic exposure to Cytolyt. We report the only known case of an accidental intraoperative administration of a methanol solution, with corresponding plasma concentrations, and successful treatment with fomepizole. CASE REPORT A 70-year-old woman with a history of stage IIIA rectal adenocarcinoma was referred for evaluation of a newly identified lung mass. During the procedure, a bronchoalveolar lavage (BAL) of the right upper lobe was performed. After BAL, the proceduralist was informed that the syringe used to instill fluid for the BAL contained Cytolyt rather than saline. The Department of Medical Toxicology was contacted immediately, and the patient received a 15 mg/kg dose of fomepizole. The first plasma methanol level, before fomepizole administration, was elevated to 21 mg/dL. The methanol level was 13 mg/dL 3 h after fomepizole treatment and even lower thereafter; therefore, no additional fomepizole was required. The patient did not develop signs of systemic toxicity and was discharged on hospital day 3. CONCLUSIONS Following methanol exposures, patients can exhibit metabolic acidosis, with potential for blindness, hemodynamic instability, and possibly death if untreated. Fomepizole (4-methylpyrazole) inhibits alcohol dehydrogenase and is a mainstay of treatment. Preventing medical errors is key in ensuring optimal patient care and decreasing adverse events. Providers using CytoLyt and any similar products should be aware of this potential error and approach the possibility of methanol toxicity as they would other routes of methanol exposure.

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.

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.

Novel strategies for the treatment of acetaminophen hepatotoxicity.

INTRODUCTION: Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the western world. Despite extensive investigations into the mechanisms of cell death, only a single antidote, N-acetylcysteine, is in clinical use. However, there have recently been more efforts made to translate mechanistic insight into identification of therapeutic targets and potential new drugs for this indication. AREAS COVERED: After a short review of the key events in the pathophysiology of APAP-induced liver injury and recovery, the pros and cons of targeting individual steps in the pathophysiology as therapeutic targets are discussed. While the re-purposed drug fomepizole (4-methylpyrazole) and the new entity calmangafodipir are most advanced based on the understanding of their mechanism of action, several herbal medicine extracts and their individual components are also considered. EXPERT OPINION: Fomepizole (4-methylpyrazole) is safe and has shown efficacy in preclinical models, human hepatocytes and in volunteers against APAP overdose. The safety of calmangafodipir in APAP overdose patients was shown but it lacks solid preclinical efficacy studies. Both drugs require a controlled phase III trial to achieve regulatory approval. All studies of herbal medicine extracts and components suffer from poor experimental design, which questions their clinical utility at this point.

The incidence of thrombotic events with idarucizumab and andexanet alfa: A systematic review and meta-analysis.

INTRODUCTION: Direct thrombin inhibitor, dabigatran and factor Xa inhibitors, apixaban, edoxaban, and rivaroxaban (DOACs/NOACs), are currently the first-choice drugs in some indications. Life-threatening bleeding occurring during DOACs treatment may benefit from the use of reversal agents, however there are some concerns regarding potential rebound thrombotic events. In this systematic review we aimed to estimate the incidence of thrombotic events in patients treated with idarucizumab or andexanet alfa. METHODS: This systematic review included all prospective and retrospective studies, enrolling patients that received specific antidotes (idarucizumab, andexanet alfa and cirapantag) for anticoagulation reversal, published until October 2019 in CENTRAL, MEDLINE and PsycINFO. Studies in healthy individuals and those with less than 10 patients were excluded. The primary outcome was the incidence of thrombotic events and the secondary outcome was all-cause mortality. Studies screening and data extraction was performed in duplicate by reviewers. A random-effects meta-analysis was performed using the Freeman-Tukey transformation of the data. The results are expressed in percentages, with 95%-confidence intervals (CI), limited between 0 and 100% due to the data transformation. RESULTS: Overall 16 studies with 1774 patients were included (13 studies enrolling 1384 patients that received idarucizumab; 3 studies enrolling 390 patients that received andexanet alfa; cirapantag studies were not found). The pooled incidence rate of thrombotic events in the patients treated with specific antidote was 5.5% (95% CI 2.0-10.1%) until 30-90 days. The incidence of all-cause mortality was 13.3% (95% CI 9.6-17.5%). CONCLUSIONS: In patients requiring idarucizumab or andexanet alfa to reach haemostasis, our data shows that there were 5.5% thrombotic events. The causality of harm associated to antidotes remains to be established due to the design of studies without a control group.

Possible role for acetylcysteine as a treatment for acute liver failure secondary to antitubercular medication use.

PURPOSE: Drug-induced liver injury (DILI) that progresses to acute liver failure (ALF) has a high mortality rate, and therapeutic options are limited. Acetylcysteine has a labeled indication for use as an antidote for acetaminophen toxicity and has also been used with limited success in treatment of non-acetaminophen-induced liver injury, with small clinical trials indicating an increase in transplant-free survival. Recommendations for management of non-acetaminophen-induced DILI include withdrawal of the offending agent and supportive care. Treatment guidelines generally discourage a rechallenge with an offending medication, except in cases where there are no other therapeutic options for management of a serious disease, such as active tuberculosis (TB). SUMMARY: This case report describes the reversal of ALF due to DILI in a patient receiving antitubercular agents for active TB. After withdrawal of initially prescribed antitubercular agents, the patient was switched to a less hepatotoxic anti-TB regimen and intravenous acetylcysteine pending results of antimicrobial susceptibility testing. After stabilization of the patient's liver enzyme levels, intravenous acetylcysteine was discontinued and oral acetylcysteine was continued for 5 days without an increase in hepatic enzyme levels or clinical deterioration. After 5 days, oral acetylcysteine was discontinued due to patient-reported nausea and vomiting. CONCLUSION: Given the limited number of therapeutic interventions shown to be beneficial in ALF and data suggesting a protective effect against DILI with initiation of acetylcysteine at the start of treatment with anti-TB medications, acetylcysteine can be considered for patients with anti-TB - associated DILI.

Antidotal use of lipid emulsion - the pendulum swings.

Intravenous lipid emulsion (ILE) is a widely accepted treatment for local anesthetic systemic toxicity (LAST), particularly resulting from bupivacaine. The past decade has seen interest in antidotal use of ILE for other poisonings wax and wane. Numerous anecdotes have raised enthusiasm while more rigorous reviews have cast skepticism. The truth may lie between these two poles.We illustrate the recent trends in published reports on ILE. We highlight the gaps in our knowledge and suggest sources of data that may clarify how useful ILE may be for poisonings other than LAST. We offer the example of bupropion, which is hazardous in overdose and which has a Log P (octanol-water partition coefficient) similar to that of bupivacaine.Current data sources including the AAPCC National Poison Data System (NPDS), the ACMT Toxic Investigators Consortium (ToxIC), and a voluntary online registry (www.lipidrescue.org) each give an incomplete view of the problem. We propose analysis of newer NPDS data, which will include ILE as a treatment field code beginning with the 2019 data, and a structured, prospective registry of antidotal use of ILE for poisonings other than LAST.

A review of oral anticoagulants, old and new, in major bleeding and the need for urgent surgery.

Oral anticoagulants, old and new, are effective therapies for prevention and treatment of venous thromboembolism and reduction of stroke risk in patients with atrial fibrillation. However, blocking elements of the clotting cascade carries an inherent risk of bleeding. Also, anticoagulated patients sometimes require urgent surgery or invasive procedures. This has led to the emergence of a body of scientific literature on the reversal of anticoagulation in these two settings. Traditionally, vitamin K antagonists (VKAs), which indirectly inactivate clotting factors II, VII, IX and X (and natural anticoagulant proteins C and S), had been the mainstay of oral anticoagulation for half a century. Only a few years ago, the US Food and Drug Administration (FDA) approved a specific VKA reversal agent, 4-Factor Prothrombin Complex Concentrate (4F-PCC). The last decade has seen the rise of non-Vitamin K oral anticoagulants (NOACs), which target specific factors, i.e. Factors IIa and Xa. Investigators have rapidly developed reversal agents for these agents as well, idarucizumab for the Factor IIa inhibitor dabigatran (Pradaxa) and andexanet alfa for the entire class of Factor Xa inhibitors (FXaIs), currently four drugs: rivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Savaysa) and betrixaban (Bevyxxa). Clinicians still use off-label PCC for reversing FXaIs in some settings, and a universal reversal agent, ciraparantag, remains in development. This review summarizes the safety and efficacy of these reversal agents in the setting of anticoagulant-associated major bleeding and the need for urgent surgery.

Two-bag intravenous N-acetylcysteine, antihistamine pretreatment and high plasma paracetamol levels are associated with a lower incidence of anaphylactoid reactions to N-acetylcysteine.

Context:N-acetylcysteine (NAC) is used worldwide to prevent liver injury after paracetamol overdoses. Anaphylactoid reactions to NAC occur frequently and often lead to treatment interruptions or discontinuations. In Denmark in 2013, the NAC treatment regimen was simplified from a three-bag to a two-bag NAC regimen. Factors of importance for the development of anaphylactoid reaction to this new regimen are poorly explored. Previous studies have suggested a protective effect of high plasma levels of paracetamol on the development of anaphylactoid reactions. Likewise, exposure to antihistamines prior to NAC treatment may protect against these reactions.Methods: This is a retrospective cohort study of patients treated with NAC and with at least one plasma paracetamol sample performed in the Capital Region of Denmark from 2010 to 2017. The primary outcome was the incidence of anaphylactoid reactions to NAC requiring intravenous treatment with antihistamines and/or glucocorticoids. Logistic regression analyses were carried out to identify the risk of developing an anaphylactoid reaction to NAC affected by influencing factors.Results: Of 4315 admissions included in the study, 259 (6.0%) developed an anaphylactoid reaction to NAC. The two-bag regimen (adjusted OR 0.44 [95%CI: 0.32-0.60]), increasing age (adjusted OR 0.84 [95%CI: 0.78-0.90] per 10-year increase) or children <10 years (adjusted OR 0.14 [95%CI: 0.04-0.36]) and antihistamine co-ingestion in overdose (adjusted OR 0.17 [95%CI: 0.02-0.64]) were associated with significantly fewer anaphylactoid reactions. High plasma paracetamol concentrations protected against development of anaphylactoid reactions during the two-bag regimen (adjusted OR 0.59 [95%CI: 0.47-0.71] and three-bag regimen 0.82 [95%CI: 0.72-0.94] per doubling of paracetamol concentration). The effect differed between the two regimens (p = .004 for interaction).Conclusion: In this retrospective cohort, a high peak plasma paracetamol concentration, age, antihistamine co-ingestion and use of the two-bag NAC regimen were associated with fewer anaphylactoid reactions to NAC.

[Simplified N-acetylcystein treatment after paracetamol overdose - new recommendations from Swedish Poisons Information Centre]. / Ny förenklad motgiftsbehandling vid förgiftning med paracetamol - Giftinformationscentralen ändrar sin doseringsanvisning för N-acetylcystein.

Since the late 1970s N-acetylcystein has been used as an antidote after paracetamol intoxication. The treatment is traditionally given as three consecutive infusions for 20 hours and 15 minutes. The total dose given is 300 mg/kg. Half of this amount is given as a bolus during the first 15 minutes of treatment.  This regime has proven very efficient in avoiding liver injury. However, side effects, caused by histamine release, are common (10-15%). Symptoms as flush, urticaria and, in rare cases, bronchospasm, angioedema and circulatory shock typically appear during the bolus dose and may lead to interrupted and inadequate treatment. In addition, the regime is complicated leading to a risk of administration errors. During the last years several publications have described the use of a model with two infusions instead of three. The first and the second infusions are merged and given over four hours. The third infusion and the total dose are left unchanged. This modified regime has been shown to reduce side effects and seems not to increase the risk of liver injury. As of November 1, 2019, the Swedish Poisons Information Centre will change its recommendations to the new two-infusion protocol.

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.

Mechanisms of action and clinical use of specific reversal agents for non-vitamin K antagonist oral anticoagulants.

OBJECTIVES: With a steadily growing number of patients with non-valvular atrial fibrillation, anticoagulation use increases. Anticoagulation therapy is associated with increased risk of serious bleeding and an increased complexity in management of patients in need for urgent surgery. We wanted to assess the magnitude of this challenge as well as review current and potential future clinical management strategies. DESIGN: A review of the literature on the magnitude of patients using antigoaculants in potential need for acute restoration of hemostasis was conducted, as well as current status of reversal agents for non-vitamin K antagonist oral anticoagulants (NOACs). Additionally, a case illustration of its use is presented. RESULTS: Two main groups of patients may need acute restoration of hemostasis, those in need of acute surgery or acute invasive procedures, ∼ 2% of patients annually, and those with serious and critical hemorrhage, ∼1.5% annually. One specific reversal agent is available on the market (idarucizumab) and two (andexanet alfa, ciraparantag) are in clinical development. Idarucizumab is a specific antidote for the thrombin inhibitor dabigatran while andexanet alfa is factor Xa inhibitor class-specific currently in late-stage development. Ciraparantag is a universal reversal agent in early-phase development. These agents can facilitate effective management of bleeding or bleeding risk, as illustrated in a patient on dabigatran in urgent need for a pacemaker. CONCLUSIONS: Amongst patients using anticoagulants, around 3.5%, could be in need of immediate restoration of hemostasis annually. The availability and use of specific reversal agents for NOACs could be crucial for the clinical outcomes.

Anaphylactoid Reactions to Intravenous N-Acetylcysteine during Treatment for Acetaminophen Poisoning.

BACKGROUND: Anaphylactoid reactions to intravenous (IV) N-acetylcysteine (NAC) are well-recognized adverse events during treatment for acetaminophen (APAP) poisoning. Uncertainty exists regarding their incidence, severity, risk factors, and management. We sought to determine the incidence, risk factors, and treatment of anaphylactoid reactions to IV NAC in a large, national cohort of patients admitted to hospital for acetaminophen overdose. METHODS: This retrospective medical record review included all patients initiated on the 21-h IV NAC protocol for acetaminophen poisoning in 34 Canadian hospitals between February 1980 and November 2005. The primary outcome was any anaphylactoid reaction, defined as cutaneous (urticaria, pruritus, angioedema) or systemic (hypotension, respiratory symptoms). We examined the incidence, severity and timing of these reactions, and their association with patient and overdose characteristics using multivariable analysis. RESULTS: An anaphylactoid reaction was documented in 528 (8.2%) of 6455 treatment courses, of which 398 (75.4%) were cutaneous. Five hundred four (95.4%) reactions occurred during the first 5 h. Of 403 patients administered any medication for these reactions, 371 (92%) received an antihistamine. Being female (adjusted OR 1.24 [95%CI 1.08, 1.42]) and having taken a single, acute overdose (1.24 [95%CI 1.10, 1.39]) were each associated with more severe reactions, whereas higher serum APAP concentrations were associated with fewer reactions (0.79 [95%CI 0.68, 0.92]). CONCLUSION: Anaphylactoid reactions to the 21-h IV NAC protocol were uncommon and involved primarily cutaneous symptoms. While the protective effects of higher APAP concentrations are of interest in understanding the pathophysiology, none of the associations identified are strong enough to substantially alter the threshold for NAC initiation.

Reversal agents for non-vitamin K antagonist oral anticoagulants.

The non-vitamin K antagonist oral anticoagulants (NOACs) include dabigatran, which inhibits thrombin, and apixaban, betrixaban, edoxaban, and rivaroxaban, which inhibit coagulation factor Xa. Although clinical studies of NOACs were conducted without antidotes, patient outcomes with major bleeding when receiving NOACs were no worse than those in patients treated with a vitamin K antagonist. Nonetheless, in patients with life-threatening bleeding or requiring urgent surgery, the capacity for rapid NOAC reversal is likely to increase patient safety. Three NOAC reversal agents are in various stages of development: idarucizumab, a specific reversal agent for dabigatran; andexanet alfa, which reverses factor Xa inhibitors; and ciraparantag, which is purported to reverse all NOACs. Idarucizumab is licensed in many countries, andexanet is under consideration by regulatory agencies, and ciraparantag is undergoing phase III evaluation. In the absence of licensed reversal agents for the oral factor Xa inhibitors, prothrombin complex concentrates are often used in patients taking these agents who present with life-threatening bleeding. In this Review, we summarize the approved indications for the NOACs, outline how to measure their anticoagulant effects, describe the mechanism of action of the reversal strategies, assess the preclinical and clinical data supporting their use, provide guidance on potential indications for reversal, and offer a management approach for patients treated with NOACs who present with serious bleeding or require urgent surgery.

Therapeutic effects of oral liothyronine on aluminum phosphide poisoning as an adjuvant therapy: A clinical trial.

BACKGROUND: In aluminum phosphide (AlP) poisoning, death is mainly due to cardiovascular failure and refractory acute heart failure. There is a lot of evidence showing thyroid hormones have cardioprotective effects. OBJECTIVE: The purpose of this study was to evaluate the effect of oral liothyronine in the treatment of AlP poisoning. METHODS: Twenty-four patients from intensive care unit of Baharloo Hospital, Tehran, Iran, were included based on the inclusion and exclusion criteria. They were randomly divided into two parallel groups of 12 cases and 12 controls. Intervention in the case group was administration of 50 µg liothyronine via nasogastric tube after gastric lavage, in the first 6 h of poisoning. In both groups, the routine treatment of AlP poisoning was performed. Blood samples were prepared at the beginning of the study and after 12 h. Patients were followed up till discharge from the hospital or death. RESULTS: The findings demonstrated that oral liothyronine was able to significantly improve systolic blood pressure, arterial blood pH, and total thiol molecules and also could decrease lipid peroxidation, increase catalase activity, and prevent further decline in total antioxidant capacity. CONCLUSION: Liothyronine administration is effective in controlling AlP poisoning and can improve patients' outcome.