Robert S. Hoffman

The Clinical Toxicology Recommendations Collaborative was established by three international clinical toxicology societies and tasked to produce recommendations on the management of poisonings. The Activated Charcoal in Clinical Toxicology Workgroup (the Workgroup) was formed to provide recommendations on the administration of activated charcoal for gastrointestinal decontamination and enhanced elimination in poisoning. Based on a systematic review of the literature, 43 poisons or poison categories were selected for appraisal. Voting statements were drafted using a predetermined format. Strength of consensus was measured using the Disagreement Index as defined by the RAND/University of California at Los Angeles Appropriateness Method. A two-round modified Delphi method was used to reach expert consensus. The Workgroup concluded that there is no role for activated charcoal in poisoning from arsenic, caesium, copper, ethanol, methanol, ethylene glycol, iron, lead, lithium, and metformin. Activated charcoal is appropriate after ingestion of antidysrhythmics (types I and III not discussed specifically), beta-adrenergic antagonists, bupropion, calcium-channel blockers, carbamazepine, cardiac glycosides, chloroquine, cocaine, colchicine, cyanide, dapsone, diphenhydramine, disopyramide, factor Xa inhibitors, ibuprofen, isoniazid, lamotrigine, methotrexate, moclobemide, opioids, organophosphorus insecticides, paracetamol (acetaminophen), paraquat, phenobarbital, phenytoin, quinidine and quinine, salicylates, selective serotonin reuptake inhibitors, sulfonylureas, thallium, theophylline, tricyclic antidepressants, valproic acid, venlafaxine, and warfarin. An additional dose of activated charcoal to complete gastrointestinal decontamination is appropriate after ingestion of carbamazepine, paracetamol, paraquat, phenobarbital, salicylates, thallium, theophylline, valproic acid and verapamil. The maximum time post-ingestion for which activated charcoal administration is recommended differs for each poison and different formulations. According to an individualized risk assessment, activated charcoal is appropriate up to 6 h post-ingestion for many poisons. If ongoing absorption is suspected, which may occur, for example, with pharmacobezoar formation, certain modified-release preparations, or when drug burden exceeds the limits of solubility, then activated charcoal can be administered beyond 6 h post-ingestion for gastrointestinal decontamination. Multiple-dose activated charcoal for enhanced elimination is appropriate in poisoning with carbamazepine, cardiac glycosides, colchicine, dapsone, phenobarbital, phenytoin, thallium and theophylline. Before deciding to perform endotracheal intubation to assist with the administration of activated charcoal, every clinician needs to weigh the potential complications and adverse effects of this procedure against the toxicity expected to be prevented by the administration of activated charcoal. This is a challenging decision, and a local poison centre and/or a bedside toxicology consultation can assist with this decision. Endotracheal intubation is not a benign procedure and is associated with a high rate of various adverse events, such as new haemodynamic instability, severe hypoxaemia, and cardiac arrest, which seem more common in children. In three studies that evaluated the risks of endotracheal intubation in over 2,200 poisoned patients, the rates of hypotension were between 1.5% and 11.8%, desaturation between 3.4% and 7.1%, and cardiac arrest in 0.4%. The risk of aspiration following administration of activated charcoal after endotracheal intubation is reported to be low (1-4%). Therefore, the decision to endotracheally intubate a patient to administer activated charcoal needs to carefully assess the patient's other comorbidities and the expected toxicity of the ingestion, which needs to be clinically significant to outweigh the risk of endotracheal intubation. Endotracheal intubation may also be considered if another treatment, such as haemodialysis or extracorporeal circulation, might be required or for transportation to another institution for ongoing clinical care. In these situations, for which endotracheal intubation has been performed for another indication, the risk-benefit will change in favour of activated charcoal administration. The following good practice statements were adopted to address the use of endotracheal intubation to facilitate the administration of activated charcoal.Endotracheal intubation should not be performed solely for the purpose of administration of activated charcoal in patients not anticipated to develop clinically significant complications of poisoning.In patients in whom endotracheal intubation is clinically indicated (e.g., compromised or unprotected airway, respiratory failure, significantly diminished level of consciousness, refractory seizures, hemodynamic instability), insertion of a nasogastric or orogastric tube is reasonable to facilitate gastrointestinal decontamination with activated charcoal.In patients with a clinically significant risk of developing life-threatening toxicity, endotracheal intubation is reasonable to safely facilitate gastrointestinal decontamination, especially if other treatment options are nonexistent or unavailable.Use of nasogastric or orogastric tube insertion without endotracheal intubation to facilitate the administration of activated charcoal: The following good practice statement was adopted: Nasogastric or orogastric tube insertion without endotracheal intubation should not be performed solely for the purpose of administration of AC. The decision to use activated charcoal is complex and depends primarily on the nature of the poison(s), the time since ingestion, the severity of the symptoms present at the time of decision or expected based on the dose ingested or patient comorbidities, and the availability of antidotes or other treatments. Although the existing level of evidence is primarily of low or very low quality, clinical decisions are still necessary. The Workgroup recommends the administration of a single-dose of activated charcoal beyond the traditional 1 h post-ingestion time point in selected poisons and introduces the concept of an additional dose of activated charcoal to prevent further absorption of poisons that may remain in the gastrointestinal tract for prolonged periods of time. Multiple-dose activated charcoal is also recommended to enhance elimination in selected clinical scenarios.

Patients with severe acute behavioural disturbance commonly present to the emergency department. Differing expert opinion dominates treatment strategies. We describe an evidence-based approach to parenteral sedation for the management of emergency department patients with severe acute behavioural disturbance. The most common cause of severe acute behavioural disturbance in the emergency department setting is alcohol and drug intoxication, both being relatively short-lived. The goal of parenteral sedation is to provide safe observation until the effect of any intoxication wears off and allow time for further clinical investigation and treatment as required. A validated scoring tool, such as the sedation assessment tool score, is useful to guide objective assessment of behavioural disturbance. We recommend the intramuscular route initially, unless intravenous access is already available (i.e., placed by first responders), as it allows rapid administration and requires less physical restraint. We recommend droperidol, or olanzapine where droperidol is unavailable, as the preferred first-line parenteral agent, due to strong evidence of effectiveness and safety. When rescue therapy is required or in extremely dangerous circumstances, we recommend using ketamine. We do not routinely recommend benzodiazepines, such as midazolam, except for treating specific causes of agitation which respond well to benzodiazepines, such as alcohol withdrawal or stimulant intoxication. We recommend avoiding combination therapy (antipsychotic and benzodiazepine) due to an increased adverse effect profile, without clear evidence for increased effectiveness. Following sedation, we recommend close observation in all patients, including at a minimum regular monitoring of vital signs, level of sedation, and continuous pulse oximetry without supplemental oxygen. End-tidal carbon dioxide monitoring should be used when available. There is a good evidence base to recommend a standardized approach to the management of severe acute behavioural disturbance in the emergency department. We recommend using intramuscular droperidol (or olanzapine if droperidol is not available) as a first-line therapy, which can be repeated at 15 min if effective sedation is not achieved. If rescue sedation is required or in extremely dangerous scenarios when immediate control is required, we recommend ketamine. We do not routinely recommend benzodiazepines as first-line therapy, unless specifically treating a condition likely to benefit from benzodiazepines, such as alcohol (or sedative hypnotic) withdrawal or stimulant intoxication. We do not recommend combination therapy (antipsychotic and benzodiazepines).

Antipsychotic medications are often associated with QT interval prolongation, which can lead to ventricular dysrhythmias, including torsade de pointes. However, unstable or significant dysrhythmic events are rare. Evidence-based recommendations on the assessment and management of poisoned patients at risk for QT interval prolongation are lacking. Current practice often involves costly and lengthy cardiac monitoring, leading to delayed disposition of the patient from emergency departments or prolonged monitoring times in other hospital units. To address this issue, the QT Interval Prolongation in Clinical Toxicology Workgroup was formed by the Clinical Toxicology Recommendations Collaborative to develop evidence-based recommendations for the management and treatment of QT interval prolongation in acute overdose patients. This article reports our findings on patients with antipsychotic poisoning. A systematic review of the literature regarding QT interval prolongation in all acute overdoses was undertaken, and the evidence was summarized for antipsychotic medication overdose. Voting statements were drafted using a predetermined format for monitoring the QT interval and use of continuous cardiac monitoring. A two-round modified Delphi method was used to reach a consensus. The strength of consensus was measured using the disagreement index as defined by the RAND/UCLA Appropriateness Method. From the 327 articles that were included in the systematic review of QT interval prolongation in all acute overdoses, a total of 55 articles were relevant to antipsychotic medication-induced QT prolongation in acute overdose. Medications with more than three articles were reviewed individually for recommendations, whilst medications with less than three were grouped together for discussion as miscellaneous. Individual medication recommendations were made for amisulpride (15 articles), thioridazine (11 articles), ziprasidone (eight articles) and quetiapine (13 articles), whilst consensus statements based on limited data were made for acute ingestions of clozapine, haloperidol, iloperidone, pimozide, pipamperone, olanzapine and risperidone (14 articles in total). The electrocardiogram is suggested as a risk assessment tool for ingestion of all antipsychotic medication. We recommend continuous cardiac monitoring for patients ingesting more than amisulpride 2 g, thioridazine 1 g, and ziprasidone 3 g. We suggest continuous cardiac monitoring for the above-mentioned medications for lower dose ingestions as well as for ingestions of haloperidol, iloperidone, pimozide and pipamperone. We do not suggest continuous cardiac monitoring for acute clozapine and risperidone poisoning, and do not recommend continuous cardiac monitoring for the QT interval in acute olanzapine or quetiapine poisoning. The need for ongoing cardiac monitoring should be guided by an individual risk assessment considering the medication and dose ingested, the time since ingestion, as well as other factors such as heart rate or co-ingestions. The quality of evidence for the risk of QT interval prolongation and torsade de pointes is heterogeneous among different antipsychotics and inherently constrains the recommendations. Available data suggest that amisulpride, thioridazine and ziprasidone are associated with QT interval prolongation and torsade de pointes, while the risk is likely overstated for quetiapine, olanzapine and risperidone. Ongoing research is needed to improve management strategies for acute antipsychotic overdose-induced QT interval prolongation and dysrhythmias. The QT Interval Prolongation in Clinical Toxicology Workgroup recommends the use of screening electrocardiograms in all patients with acute antipsychotic medication overdose and cardiac monitoring in patients with at-risk overdoses from thioridazine, amisulpride, and ziprasidone. The QT Interval Prolongation in Clinical Toxicology Workgroup suggests the same approach for patients with overdoses of haloperidol, iloperidone, pipamperone and pimozide. The risk of torsade de pointes is likely overstated for acute antipsychotic medication overdose as a general class group, and concern should rather focus on a few specific medications.

Unadjusted doses of valacyclovir can cause neurotoxicity in patients with chronic kidney disease. There are no well documented reports of valacyclovir or acyclovir toxicity providing pre‐ and postdialysis concentrations of acyclovir in the blood, dialysate and urine of acutely neurotoxic patients. We report an elderly woman with stage 5 chronic kidney disease who developed neurotoxicity after being prescribed unadjusted doses of valacyclovir and provide measurements of the amount of the drug eliminated through haemodialysis vs. native renal clearance. The patient's estimated body‐burden of drug before the first session of dialysis was estimated at 580.3 mg. During the first haemodialysis session acyclovir plasma concentrations decreased from 8.8 to 3.2 mg/L (63.6%). Her body‐burden of drug before the second session of haemodialysis was estimated as 131.9 mg. During the 2.5 h of the second dialysis session a total of 66.6 mg was eliminated based on measured dialysate concentrations. Urinary elimination was 17.7 mg over 30 h. Despite minimal urinary elimination her blood concentration fell from 8.8 to 0.88 mg/L with a total of 4.5 h of haemodialysis. Haemodialysis appears to be an effective method of eliminating acyclovir, especially in patients with advanced kidney disease.

A 72 year-old female with past medical history that included anxiety, depression, hypertension, and hyperlipidemia was found unconscious in her bed at home by family members, surrounded by pill bottles and numerous loose baclofen tablets. Emergency medical service (EMS) was activated and responded quickly, finding an unresponsive patient with snoring respirations, clenched jaw, and foamy, bilious emesis with vital signs including tachycardia and hypoxia. Initial attempts at basic airway management were followed by movement to a waiting ambulance, and the arrival of an EMS physician and advanced paramedic. Despite use of sodium bicarbonate and multiple doses of a vasopressor, the patient developed widening QRS complex on electrocardiogram and refractory hypotension. After rapid sequence intubation, aspiration and low-volume gastric lavage was performed with a 34F Edlich tube, resulting in removal of visible pill fragments. Subsequently, the patient's hypotension resolved, and she was transferred to the care of the emergency department in stable condition. Gastric lavage remains clinically indicated for rare cases of recent, potentially lethal ingestions of poisons without effective antidotes, and is a standard component of emergency medicine residency training. The proliferation of EMS fellowship trained physicians suggests that this procedure should be considered an option in highly select cases, and EMS physician vehicles may consider carrying Edlich lavage tubes or similar prepackaged kits.

Despite the widely accepted use of methylthioninium chloride (methylene blue) to treat methemoglobinemia, data regarding clinical outcomes are sparse. We sought to better elucidate the efficacy and tolerability of methylthioninium chloride. We identified all cases reported to the New York City Poison Center from 2000 to 2024 in which methylthioninium chloride was administered for methemoglobinemia. We extracted clinical data from these cases, which we assessed using primarily descriptive statistics. A total of 185 cases were included. The median methemoglobin level was 29% (IQR: 19-42%). Implicated xenobiotics were most frequently volatile nitrites (41%), local anesthetics (15%), and dapsone (11%). The median methylthioninium chloride dose was 1 mg/kg (IQR: 1-2 mg/kg; range: 0.5-4 mg/kg). Multiple doses of methylthioninium chloride were administered in 11% of cases, with a median total dose of 2 mg/kg (IQR: 2-3 mg/kg), the majority of which were associated with volatile nitrites (n = 7) or dapsone (n = 6). Improvement after administration of methylthioninium chloride was reported in 98% of cases (95% CI: 96-100%). Adverse effects attributable to methylthioninium chloride were reported in nine cases (4.9%; 95% CI: 4.6-5.1%), including one instance of hemolysis. Glucose-6-phosphate dehydrogenase activity was found to be deficient in two of seven patients tested, only one of whom did not improve after methylthioninium chloride. Two deaths occurred in this series, both associated with sodium nitrite exposure. Most patients with methemoglobinemia improved after 1-2 mg/kg of methylthioninium chloride, supporting current treatment recommendations. Despite few instances of glucose-6-phosphate dehydrogenase activity testing, major adverse effects attributable to methylthioninium chloride were extremely rare. A relatively large proportion of cases receiving multiple doses were associated with dapsone exposure. In this series, methylthioninium chloride was both efficacious and well tolerated in patients with methemoglobinemia, with a single dose of 1-2 mg/kg being sufficient to treat most patients.

Hemodialysis has an essential role in the treatment of certain poisoned patients, both by enhancing the elimination of select poisons and correcting underlying fluid, electrolyte, and acid-base disturbances. We sought to identify barriers to the performance of hemodialysis when it was recommended by our poison center. Data from a single United States poison center were retrospectively queried for adult patients for whom the poison center recommended intermittent hemodialysis for poison removal. The primary outcome was the performance of intermittent hemodialysis within 12 h of the poison center recommendation, which we defined as timely hemodialysis. Univariable and multivariable logistic regressions were performed to assess the effect of the following variables on this outcome: age group, patient sex, time of day of the recommendation, day of week of the recommendation, year of the recommendation, hospital location, and poison category. A total of 535 patient encounters were analyzed. The majority (72%) of patients had intermittent hemodialysis performed within 12 h of when it was recommended. The multivariable analyses showed that the odds of receiving recommended intermittent hemodialysis within 12 h were significantly lower when the recommendation was made during the nighttime (OR: 0.660; 95% CI: 0.442-0.987) compared to daytime and during the weekend (OR: 0.605; 95% CI: 0.398-0.918) compared to weekdays. Intermittent hemodialysis is resource-intensive and requires specialized equipment and personnel, which is likely less available outside of regular business hours. This study is limited by its retrospective nature and may not be generalizable to other poison centers. Patients for whom our poison center recommended intermittent hemodialysis during non-weekday times had lower odds of receiving timely hemodialysis. Hospital administrators and healthcare providers should be aware of this potential treatment obstacle for poisoned patients and identify the specific barriers involved in order to facilitate timely hemodialysis.

Poisoning management includes gastrointestinal decontamination strategies to decrease the burden of poison entering the body and change the expected severe toxicity expected to a less toxic, more favourable outcome. Common modalities are orogastric lavage, oral‐activated charcoal and whole‐bowel irrigation. Endoscopic retrieval and laparotomy are rare options reserved for severe ingestions and body packers. Although supporting data are generally of low quality, gastrointestinal decontamination is likely to improve patient outcome in many situations. Unfortunately, technical limitations and contraindications can explain their infrequent use. Orogastric lavage can be useful for early lethal ingestions, albeit with significant complications such as aspiration and perforation. Activated charcoal cannot adsorb every substance. Usual dosing is 1 g/kg per dose. Whole‐bowel irrigation is reserved for charged molecules or substances not adsorbed to activated charcoal but requires intact gut motility. Indications depend on several factors inherent to the ingestion (dose, time, poison) and patient's characteristics. During recent decades, studies of newer pharmaceuticals or modified‐release formulations showed that significant amounts of poison, especially pharmacobezoars, persist in the gut hours postingestion, thus are amenable to gastrointestinal decontamination. Improved understanding of gut motility in volunteer studies and overdose showed clinically significant reduction in drug exposure with activated charcoal. The 1‐h dogma for gastrointestinal decontamination, especially activated charcoal, is now obsolete. Clinicians must perform a risk assessment for each ingestion to determine the expected benefit at the time of decision‐making, choosing the modality to achieve reduction in the toxicity burden while planning for complications or contraindications.