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What Is Known and Objective: Treating an opioid overdose using an opioid receptor antagonist (such as naloxone) makes mechanistic sense and can be effective. Unfortunately, the majority of current drug overdose deaths involve polysubstance use (i.e., an opioid plus a non-opioid)., Comment: Respiratory depression induced by opioids results from excessive opioid molecules binding to opioid receptors. This effect can be reversed by an opioid receptor antagonist. However, the respiratory depression induced by non-opioid drugs is not due to action at opioid receptors; thus, an opioid receptor antagonist is ineffective in many of these cases. For respiratory depression induced by non-opioids, receptor antagonists are either not available (e.g., for propofol overdose) or there may be attendant risks with their use (e.g., seizures with flumazenil). This gives rise to a need for more effective ways to treat polysubstance overdose., What Is New and Conclusion: A new approach to treating opioid-induced respiratory depression due to drug overdose focuses on agents that stimulate respiratory drive rather than competing for opioid receptors. Such an approach is "agnostic" to the cause of the respiratory depression, so might be a potential way to treat polysubstance overdose., (© 2021 John Wiley & Sons Ltd.)

This article will review the epidemiology and pharmacology of gabapentinoids (gabapentin and pregabalin) relevant to their emerging misuse potential and provide guidance for clinical and regulatory management. Gabapentinoids are γ-aminobutyric acid analogues that produce their therapeutic effects by inhibiting voltage-gated calcium channels and decreasing neurotransmitter release. Recently gabapentinoid prescribing and use have increased tremendously. Although traditionally thought to possess a favorable safety profile, gabapentinoid misuse has also risen significantly. Gabapentinoid misuse generally occurs in combination with other substances, most notably opioids, and may be for purposes of eliciting euphoric effects, enhancing the effects of other substances, or self-treating conditions such as withdrawal, pain, anxiety, or insomnia. Given its faster onset, increased bioavailability and potency, and nonsaturable absorption, pregabalin's pharmacokinetics theoretically enhance its misuse liability versus gabapentin. However, gabapentin can produce similar euphoric effects, and epidemiologic studies have identified higher rates of gabapentin misuse in the United States, likely because of greater availability and less regulated prescribing. Although adverse events of gabapentinoid-only ingestion are relatively benign, a growing body of evidence indicates that gabapentinoids significantly increase opioid-related morbidity and mortality when used concomitantly. In addition, significant withdrawal effects may occur on abrupt discontinuation. As a result of these trends, several US states have begun to further regulate gabapentinoid prescribing, reclassifying it as a controlled substance or mandating reporting to local prescription drug-monitoring programs. Although increased regulation of gabapentin prescribing may be warranted, harm reduction efforts and increased patient and provider education are necessary to mitigate this concerning gabapentinoid misuse trend., (© 2021, The American College of Clinical Pharmacology.)

There are many nonopioid central nervous system depressant substances that share a gamma-aminobutyric acid (GABA) receptor-related mechanism of action. These sedatives-hypnotics can be indicated to treat anxiety, seizures, depression, and insomnia but are also used as substances of abuse and used to facilitate sexual assault. Barbiturates, methaqualone, and glutethimide were among the first type A GABA receptor-mediated sedative-hypnotics. Their clinical use was limited for most indications by serious adverse events and strong abuse potential but continue to be used illicitly around the world. The benzodiazepines supplanted barbiturates for most indications because they were less likely to cause severe adverse events in monotherapy. Flunitrazepam is a newer benzodiazepine that is preferentially used recreationally and to facilitate sexual assault. Flunitrazepam has greater potency and higher affinity for the type A GABA receptor than most benzodiazepines. Gamma-hydroxybutyric acid is sought illicitly for its hypnotic, euphoric and anabolic effects as well as to facilitate sexual assault. When any of these GABAergic drugs are used in high doses or with other sedative hypnotic agents, respiratory depression, coma, and death have occurred. Chronic use of these GABAergic drugs can lead to significant withdrawal syndromes. Phenibut and selank are poorly studied Russian drugs with GABAergic mechanisms that are inexplicably sold to US consumers as dietary supplements. Poison control center calls regarding phenibut have increased substantially over the past 5 years. Desired euphoriant effects account for the recreational and illicit use of many GABA-modulating agents. However, illicit use can lead to significant toxicities related to abuse, dependence, and subsequent withdrawal syndromes. Significant evaluation of developing agents with GABA properties should be conducted to determine abuse potential before public access ensues., (© 2021, The American College of Clinical Pharmacology.)

Purpose: Paracetamol is the only drug recommended to treat fever in neonates. At recommended doses, paracetamol has not been associated with liver injury in neonates, while hepatotoxicity may occur after intake of a single high dose or multiple excessive doses. The aim of this narrative review is to critically analyze and summarize the available literature on newborns and infants exposed to supratherapeutic doses of paracetamol, with special focus on their clinical features, outcome, and management., Methods: The PubMed, SCOPUS, and Google Scholar search engines were used to collect data, without time limitation. The following keywords were used: paracetamol/acetaminophen, overdose, hepatotoxicity, N-acetylcysteine, newborn, infant., Results: The literature search identified a total of 27 case reports, a number of review articles, and few other relevant publications. Neonatal poisoning from paracetamol resulted from transplacental drug transfer after maternal overdose in some published cases, while it was the consequence of medication errors in other cases. Newborns and infants who have received a single overdose and have paracetamol concentrations below the Rumack-Matthew nomogram limits are at low risk of serious hepatic damage, while those who have recently ingested more than one supratherapeutic dose of paracetamol should be managed with caution. The treatment of choice for paracetamol poisoning is N-acetylcysteine, a specific antidote which reduces paracetamol hepatotoxic effects. N-Acetylcysteine should be given according to specific regimens through weight-based dosing tables., Conclusions: Caution should be used when paracetamol is administered to the newborn. In the event of an overdose, careful patient monitoring and personalization of post-overdose procedures are recommended.

Encorafenib (Braftovi) is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation, in combination with binimetinib (Mektovi). According to the product label of encorafenib, there are no specific treatment recommendations in case of an overdose. We report on a 63-year-old man who ingested a double dose (900 mg) of encorafenib for 16 days. He developed overall minor chronic overdose symptoms such as nausea and vomiting grade 1 and muscle pain. Based on the most occurring adverse events of encorafenib, liver values, kidney function parameters and QTc interval were measured. Kidney function parameters were normal, whereas liver values were slightly increased (grade 1) and QTc slightly prolonged. The plasma concentration 3 h after the last dose was 2110 ng/mL. We describe the course of a case with a chronic overdose during 16 days of the double dose of encorafenib as well as the followed approach, which could be taken into account when observing an encorafenib overdose. Providing information in times of Covid-19 is challenging, but remains necessary for good clinical care., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Opioid poisoning is a frequent cause of death in drug addicts and occurs with opioid treatment. Quetiapine is often found in forensic autopsies and may increase the risk of fatal opioid poisoning by enhancing sedation, respiratory depression, hypotension and QT prolongation. We systematically searched for studies of acute toxicity of quetiapine or other antipsychotics combined with morphine or methadone. Case reports describing toxicity of quetiapine combined with morphine or methadone were also included. We retrieved one human study that observed pharmacokinetic interaction between quetiapine and methadone, and 16 other human studies. Fourteen investigated the combination of droperidol and morphine in treatment doses, and some indicated an additive sedative effect. Five animal studies with acepromazine in combination with morphine or methadone were located and indicated an additive effect on sedation and hypotension. Six forensic case reports in which death could have been caused solely by quetiapine, the opioid, or other drugs were found. Thus, acute toxicity of quetiapine combined with morphine or methadone has not been studied. Because of quetiapine's effects on alpha-adrenoceptors, muscarinic and histamine receptors, human ether-a-go-go-channels and methadone kinetics, we suggest further research to clarify if the indicated additive effects of opioids and droperidol or acepromazine are also true for quetiapine., (© 2020 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Introduction: Endotracheal intubation (ETI) is an essential component of the supportive care provided to the critically ill patient with pharmaceutical poisoning; however, specific nuances surrounding intubation including techniques and complications in the context of pharmaceutical poisoning have not been well elucidated., Discussion: A search of the available literature on ETI in pharmaceutical-poisoned patients was undertaken using Medline, ERIC, Cochrane database, and PsycINFO using the following MeSH and keyword terms: ("toxicology" OR "poisons" OR "drug overdose" OR "poisoning") AND ("intubation, intratracheal" OR "intubation, endotracheal" OR "airway management" OR "respiration, artificial"). A hand-search was also performed when the literature in the above search required additional conceptual clarification, including using the "Similar Articles" feature of PubMed, along with reviewing articles' reference lists that discussed intubation in the context of a poisoning scenario. Articles with any discussion around the ETI process in the context of a pharmaceutical poisoning were then included. Intubation may be performed in patients poisoned with pharmaceuticals in the context of both single and multiple organ dysfunction including central and peripheral nervous system, pulmonary, or cardiovascular toxicity with hemodynamic instability, or localized effects resulting in mechanical airway obstruction. Certain classes of poisonings may require modifications to the standard rapid sequence induction airway management algorithm., Conclusions: ETI is a key component of the supportive care provided to the patient poisoned by a pharmaceutical agent. Clinicians should be aware of the spectrum of toxicities that can necessitate intubation, as well as airway management nuances that are specific to various poisoning presentations.

Introduction: While emergency department (ED) visits for acute drug overdose are at an all-time high, the importance of vasopressors to treat circulatory shock in this patient population remains unclear. This study investigated the association between first-line vasopressor and mortality, for both push-dose and infusion, in this patient population., Methods: From a prospective cohort of consecutive ED patients with drug overdose at two urban teaching centers over 5 years, we performed a secondary data analysis of patients with circulatory shock, defined as hypotension requiring either vasopressors, high-dose insulin euglycemia therapy, or both. The first-line vasopressor (push-dose and infusion) was analyzed for associations with the primary outcome (in-hospital mortality) and secondary outcomes (24-hour mortality, ICU LOS). Subgroup analysis of beta-/calcium-channel blocker overdose was performed to evaluate impact of antidotal therapies. Data analysis included multivariable regression., Results: Fifty-five patients with circulatory shock were analyzed, in whom there was 20% 24-hour mortality, 42% in-hospital mortality, 730-minute mean vasopressor duration, and 53.4-hour median ICU LOS. On multivariable analysis, there was significantly decreased adjusted odds of in-hospital mortality with first-line push-dose phenylephrine (aOR 0.06, CI 0.01-0.55), and significantly increased adjusted odds of in-hospital mortality with first-line push-dose epinephrine (aOR 60.8, CI 6.1-608). Of the first-line infusions, norepinephrine had the lowest odds of in-hospital mortality (aOR 0.80, CI 0.2-3.1)., Conclusions: In ED patients with undifferentiated drug overdose and circulatory shock, the first-line vasopressor is associated with in-hospital mortality. First-line push-dose phenylephrine was associated with the lowest odds of in-hospital mortality. Future randomized studies are warranted for validation.

Vasoactive agents should be administered through a controlled well-marked infusor pump, ideally via a central venous catheter if given over longer periods of time. During transfer of haemodynamically unstable patients with limited staffing and resources on site, a peripheral vasopressor infusion is sometimes resorted to as a temporary measure of optimising haemodynamic parameters. We report a case of accidental norepinephrine overdose after such practice, resulting in cardiac arrest. It illustrates the importance of careful use and labelling of vasoactive agents during the transport and handover of critically ill patients. Finally, we explore human factor issues associated with transfer from the pre-hospital to the in-hospital environment when such preparations are used., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Severe QT prolongation (SQTP) has been identified as a strong predictor of adverse cardiovascular events in acute drug overdose, but drug-specific causes of SQTP in the setting of acute drug overdose remain unclear. We aimed to perform the most definitive study to date describing drug-specific risk of SQTP following acute drug overdose. Methods: This was a prospective multicenter cohort study at >50 hospital sites across the US using the ToxIC Registry between 2015 and 2018. Inclusion criteria were adults (≥18 years) receiving medical toxicology consultation for acute drug overdose. The primary outcome was SQTP, which was defined using the computer automated Bazett QT correction (QTc) on the ECG with the previously validated cut point of 500 milliseconds. Mean difference in QTc was also calculated for specific drugs. Drugs associated with SQTP were analyzed using multivariable logistic regression to control for known confounders of QT risk (age, sex, race, cardiac disease). Results: From 25,303 patients screened, 6473 met inclusion criteria with SQTP occurring in 825 (13%). Drugs associated with increased adjusted odds of SQTP included Class III antidysrhythmics (sotalol), sodium channel blockers (amitriptyline, diphenhydramine, doxepin, imipramine, nortriptyline), antidepressants (bupropion, citalopram, escitalopram, trazodone), antipsychotics (haloperidol, quetiapine), and the antiemetic serotonin antagonist ondansetron. Conclusions: This large US cohort describes drug-specific risk of SQTP following acute drug overdose. Healthcare providers caring for acute drug overdoses from any of these implicated drugs should pay close attention to cardiac monitoring for occurrence of SQTP.

Breathing resumes within one to two minutes following fentanyl overdose induced apnea in spontaneously breathing rats. As this regular rhythm is produced at a time wherein fentanyl concentrations and receptor occupancy are likely to be extremely high, the mechanisms initiating and sustaining such a respiratory activity remain unclear. Forty-four un-anesthetized adult rats were studied in an open-flow plethysmograph. Regardless of the dose of fentanyl that was used, i.e. 50 μg.kg -1 (n = 8), 100 μg.kg -1 (n = 8) or 300 μg.kg -1 (n = 7), all rats developed an immediate central apnea followed by a depressed regular rhythm that was produced 118, 97 and 81 s (median) later, respectively. Only one rat did not recover. This inspiratory and regular activity consisted of a low frequency and tidal volume pattern with a significant reduction in V̇E/V̇CO2 ratio, which persisted for at least 30 min and that was not different between 100 or 300 μg.kg -1 . The time at which this respiratory rhythm emerged, following the highest dose of fentanyl, was not affected by 100 % O 2 or 8% CO 2 /15 % O 2 . The absolute level of ventilation was however higher in hypercapnic and moderately hypoxic conditions than in hyperoxia. When a second injection of the highest dose of fentanyl (300 μg.kg -1 ) was performed at 10 min, ventilation was not significantly affected and no apnea was produced in major contrast to the first injection. When a similar injection was performed 30 min after the first injection, in a separate group of rats, an apnea and breathing depression was produced in 30 % of the animals, while in the other rats, ventilation was unaffected. We conclude that the depressed regular respiratory activity emerging during and following fentanyl overdose is uniquely resistant to fentanyl., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Verbal orders in the operating room between the surgeon and circulating nurse are prevalent at many institutions. We present a case in which a communication breakdown involving a verbal order resulted in the patient receiving an excessively high dose of epinephrine via subcuticular infiltration. The overdose was quickly identified by an increase in T-wave amplitude on electrocardiogram (ECG). The hemodynamic changes were treated, and the patient suffered no long-term sequelae. This report emphasizes the need to have strategies in place to prevent medication errors.

This case presentation describes the clinical management of a pediatric patient during transport after a single-drug overdose of clonidine. Clonidine overdose closely resembles opiate intoxication, and treatment is largely supportive; however, the patient in this case presentation had a declining altered mental status with evidence of airway compromise within 1 to 2 hours after ingestion, which warranted protective airway management. The patient was extubated the following day with a successful outcome., (Copyright © 2019 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.)

Background: Opioid users regularly consume other drugs such as alcohol (ethanol). Acute administration of ethanol can rapidly reverse tolerance to morphine-induced respiratory depression. However, alcohol consumption by opioid users is likely to occur over prolonged time periods. We have therefore sought to determine the effect of prolonged alcohol consumption on the development of tolerance to opioid respiratory depression., Methods: Mice were fed control or ethanol (5%) liquid diet for 16 days. On days 9-16 morphine tolerance was induced by administration of 3 priming injections of morphine followed by subcutaneous implantation of a morphine-filled osmotic mini-pump. Control mice received saline. Respiration was measured by plethysmography and the effect of an acute morphine challenge dose was measured on day 16 to assess the development of morphine tolerance., Results: Prolonged ethanol consumption for 14 days did not alter the respiratory depressant effect of an acute dose of morphine. Control mice treated with prolonged morphine developed tolerance to acute morphine respiratory depression whereas ethanol diet fed mice treated with prolonged morphine showed significant respiratory depression during morphine-pump treatment and remained sensitive to the respiratory depressant effect of the acute challenge dose of morphine. The ethanol consumption did not alter blood or brain levels of morphine, whilst conversely prolonged morphine treatment did not alter blood levels of ethanol., Conclusions: Prolonged ethanol consumption prevents the development and maintenance of tolerance to the respiratory depressant effect of morphine. These data suggest that ethanol inhibition of tolerance will greatly increase the risk of fatal heroin overdose in humans., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Loperamide, an antidiarrheal agent, is a µ-opioid receptor agonist increasingly abused to prevent opioid withdrawal or to produce euphoric effects. At supra-therapeutic doses, loperamide can cause cardiac toxicity due to blockade of Na and I Kr channels, resulting in wide QRS rhythms, severe bradycardia, prolonged QTc, polymorphic ventricular tachycardia, cardiac arrest, and death. There are limited data on the cardiotoxic effects of high dose loperamide., Methods and Results: A case report of loperamide toxicity is presented and then added to a contemporary review of the literature. In total, the presentation and management of 36 cases of loperamide cardiotoxicity are summarized. The overall median daily dose (interquartile range) of loperamide was 200 (134-400) mg. The median QRS duration was 160 (125-170) ms. The median QTc duration was 620 (565-701) ms. Ventricular tachycardia was experienced by 24/36 (67%) of patients, 20 of which were specified to be polymorphic. Treatment was supportive, providing advanced cardiopulmonary life support and aggressive electrolyte repletion. Isoproterenol infusion or overdrive pacing was employed in 19/36 (53%) of cases. The median time to electrocardiogram normalization or hospital discharge, whichever came first, was 5 (3.5-10) days., Conclusion: Loperamide overdose is a toxidrome that remains underrecognized, and in patients with unexplained cardiac arrhythmias, loperamide toxicity should be suspected. Prompt recognition is critical due to the delayed recovery and high risk for life-threatening arrhythmias., (© 2019 Wiley Periodicals, Inc.)

Background: Serotonin toxicity is a common cause of drug-induced altered mental status. However, data on the causes of serotonin toxicity, symptomatology, complications, and rate of antidotal treatment are limited., Methods: This study evaluated cases of serotonin toxicity in the ToxIC registry, an international database of prospectively collected cases seen by medical toxicologists. Serotonin toxicity was diagnosed by bedside evaluation of medical toxicology specialists and explicit criteria were not used. The database was searched for "serotonin syndrome" between January 1, 2010, and December 31, 2016., Results: There were 1010 cases included. Females made up 608 (60%) cases. Ages are as follows: younger than 2 years (3, 0.3%), 2 to 6 years (8, 0.8%), 7 to 12 years (9, 0.9%), 13 to 18 years (276, 27.3%), 19 to 65 years (675, 67%), older than 66 years (33, 3.4%), unknown (6, 0.6%). Reasons for encounter: intentional (768, 76%), adverse drug event/reaction (127, 12.6%), unintentional (66, 6%), and unknown (55, 5.4%). Signs/symptoms: hyperreflexia/clonus/myoclonus (601, 59.5%), agitation (337, 33.4%), tachycardia (256, 25.3%), rigidity (140, 13.9%), seizures (139, 13.7%), and hyperthermia (29, 2.9%)., Complications: rhabdomyolysis (97, 9.7%), dysrhythmias (8, 0.8%), and death (1, 0.1%)., Treatments: benzodiazepines 67% (677/1010), cyproheptadine 15.1% (153/1010). There were 192 different xenobiotics reported with 2046 total exposures. Antidepressants were most common (915, 44.7%) with bupropion the most frequent overall (147, 7.2%). Common non-antidepressants were dextromethorphan (95, 6.9%), lamotrigine (64, 3.1%), and tramadol (60, 2.9%)., Discussion: Serotonin toxicity most often occurred in adult patients with intentional overdose. Antidepressants were the most common agents of toxicity. Interestingly, bupropion, a norepinephrine/dopamine reuptake inhibitor, was the most frequently mentioned xenobiotic. Though often cited as a potential antidote, only 15% of patients received cyproheptadine. Severe toxicity was rare. A single death was reported.

Rationale: Colchicine can inhibit cell division and intracellular transport in affected organs by fixing intracellular tubulin and preventing its polymerization into microtubules. A lethal dose of colchicine is considered to be 0.8 mg/kg. The wide distribution of colchicine through 70% of the body following an overdose makes it difficult to eliminate., Patient Concerns: A 56-year-old man with a clear history of colchicine overdose was admitted to our hospital nearly 40 hours after taking 12 mg (0.17 mg/kg) of colchicine. He had a history of gout and chronic kidney disease. As the disease progressed, he showed most of the clinical manifestations and pathological features of colchicine overdose., Diagnoses and Interventions: Colchicine overdose was clear, with symptoms of multiple organ failure including primary gastrointestinal failure, bone marrow hematopoietic inhibition, rhabdomyolysis, cardiac damage, hepatocyte damage. The patient developed secondary septic shock, renal failure, circulatory failure, and respiratory failure. We performed continuous renal replacement therapy and gastric lavage, and administered norepinephrine, frozen plasma, proton-pump inhibitors, adenosylmethionine, antibiotics, granulocyte colony stimulating factor, and total parenteral nutrition., Outcomes: The patient rapidly developed complete hematopoietic function inhibition, gastrointestinal failure, and cardiac damage 32 hours after admission. Sustained severe infection and circulatory instability caused a progressive deterioration of respiratory function. Tracheal intubation was performed but the patient continued to deteriorate, and death occurred approximately 132 hours after admission., Lessons: Excessive colchicine levels cause continuous organ damage due to extensive tissue distribution, eventually leading to multiple organ failure. Colchicine metabolism is delayed in patients with liver or kidney dysfunction, and even a low dose of colchicine may result in poisoning in these individuals. Early diagnosis and reduction of colchicine levels is critical to improve prognosis, and colchicine poisoning should be considered in patients with poor liver or kidney function even when the ingested dose is low.

Flecainide intoxication is a severe intoxication that can lead to cardiogenic shock. We report on a 68-year-old female patient, who presented with a flecainide intoxication in the setting of renal failure. She was managed with invasive supportive therapy at the ICU and infusion of sodium bicarbonate and intravenous lipid emulsion (ILE, intralipid 20%), after which she made a complete recovery.

We describe a 27-year-old female with repeated episodes of pulseless electrical activity due to intoxication with a substance that was unidentified at presentation. Severe QRS widening was observed and empiric treatment with sodium bicarbonate and intravenous lipid emulsion was administered. In this case, intraosseous administration of lipid emulsion failed to improve haemodynamic parameters, suggesting that this dose remained in the bone marrow compartment. We recommend that physicians become aware of this possibility and to avoid intraosseous administration of lipid emulsion.

Background: Lacosamide is a third-generation antiepileptic drug. Its likely mechanism of action is via neuronal sodium channel blockade, via a unique manner compared with other antiepileptic drugs that block sodium channels. A paucity of information exists regarding lacosamide overdosage. Lacosamide overdosage is thought to cause QRS prolongation and seizures, due to its effect of sodium channel blockade. The potential efficacy of sodium bicarbonate to reverse the effects of lacosamide has not been well studied. Furthermore, prior reports of lacosamide toxicity have occurred in the setting of concomitant polypharmacy. Thus, the isolated toxic effects of the drug have not been well elucidated., Case Report: We report a case of a suspected, single-ingestion overdose on lacosamide. The patient developed signs of cardiotoxicity and seizure. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: After lacosamide overdosage, the emergency physician must be capable of acute management of subsequent lacosamide toxicity. Understanding the mechanisms of action causing toxicity due to this drug can help the clinician to anticipate the interventions that may be needed or useful to treat this potentially toxic ingestion., (Published by Elsevier Inc.)

Objectives: To estimate the number of US emergency department visits for prescription opioid harms by patient characteristics, intent, clinical manifestations, and active ingredient., Methods: We used data from medical record-based surveillance from a nationally representative 60-hospital sample., Results: Based on 7769 cases, there were 267 020 estimated emergency department visits annually (95% confidence interval [CI] = 209 833, 324 206) for prescription opioid harms from 2016 to 2017. Nearly half of visits (47.6%; 95% CI = 40.8%, 54.4%) were attributable to nonmedical opioid use, 38.9% (95% CI = 32.9%, 44.8%) to therapeutic use, and 13.5% (95% CI = 11.0%, 16.0%) to self-harm. Co-implication with other pharmaceuticals and concurrent illicit drug and alcohol use were common; prescription opioids alone were implicated in 31.5% (95% CI = 27.2%, 35.8%) of nonmedical use visits and 19.7% (95% CI = 15.7%, 23.7%) of self-harm visits. Unresponsiveness or cardiorespiratory failure (30.0%) and altered mental status (35.7%) were common in nonmedical use visits. Gastrointestinal effects (30.4%) were common in therapeutic use visits. Oxycodone was implicated in more than one third of visits across intents., Conclusions: Morbidity data can help target interventions, such as dispensing naloxone to family and friends of those with serious overdose, and screening and treatment of substance use disorder when opioids are prescribed long-term.

An 84-year-old woman presented to hospital with severe clinical and metabolic sequelaesequelae of a massive paracetamol overdose (concentration=822 mg/L). In spite of N-acetylcysteine therapy, she deteriorated with evidence of mitochondrial dysfunction. Although the EXtracorporeal TReatments In Poisoning group recommend adjunct haemodialysis (HD) in such a context, this was difficult to start due to haemodynamic instability. Instead, a trial of continuous venovenous haemodiafiltration (CVVHDF) was initiated in an attempt to restore normal mitochondrial function, normal pH and to actively remove the offending drug. Fortunately, plasma paracetamol levels fell exponentially over the subsequent 24-48 hours without the need to commence HD. The patient made a full recovery and was later discharged from the hospital. This case highlights that CVVHDF can be a reasonable alternative to HD for managing massive paracetamol overdoses in the context of mitochondrial dysfunction., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Tramadol overdose is disproportionately more common in Iran, and in recent years, it has become one of the most common causes of poisoning admissions to emergency departments in this country. Tramadol is a synthetic analogue of codeine and a weak opioid receptor (μ) agonist that can cause seizures even in commonly used doses., Aims: This study aimed to examine the relationship between seizure and plasma tramadol concentration in patients with tramadol poisoning who referred to one of the hospitals in Ghaemshahr, Iran., Study Design: This research is an analytical cross-sectional study., Methods: A total of 121 tramadol users (non-seizure group=61 and seizure group=60) were admitted to hospital. Demographic characteristics and clinical findings were collected by a questionnaire. Plasma was harvested after separation from blood cells and quantified using the HPLC method. Biochemical parameters, including urea, creatinine, troponin I, and creatine phosphokinase (CPK-MB) were determined by spectrophotometry. This study was a single blind design study., Results: The mean age of participants was 25 years. Ninety-five participants were classified as smokers. The mean serum concentrations of tramadol in subjects with seizures and those without seizures were 491.90 μg/ml and 374.42 μg/ml (p=0.211), respectively. Average concentrations of biochemical parameters in the seizure group were 53.33 (9.38) µg/ml urea, 1.71 (0.29) µg/ml Cr, 6.53 (2.89) µg/ml TPI, and 58.23 (22.20) µg/ml CPK- MB. Average concentrations of biochemical parameters were significantly higher in the seizure group than in the non-seizure group (p<0.001)., Conclusion: Tramadol-induced seizures were not found to be related to age, gender, or dosage. This complication can lead to cardiac and renal complications in individuals on tramadol experiencing seizures. This result indicates that stricter restrictions should be imposed on the distribution and administration of the drug tramadol., Competing Interests: The authors report no conflicts of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Case Presentation: A 33-year-old woman was brought to the ED with altered mental status. She was combative on presentation but spontaneously progressed into a comatose state and was intubated for airway protection. Naloxone failed to improve her mental status. When family was reached, they reported a history of seizures that were controlled on treatment., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Acute liver failure patients who meet poor prognostic criteria have high early mortality without emergency liver transplantation. A recent study however, reported that patients that survive spontaneously have a poorer outcome compared with patients undergoing transplantation. In this single centre study, we aimed to confirm or refute this observation., Methods: Early survivors (acute liver failure patients who survived 90 days after the ICU admission) were assessed for long-term outcomes in four distinctive cohorts, incorporating aetiology (Acetaminophen overdose or non-Acetaminophen overdose), and management strategy (conservative or liver transplantation). Chi Squared or Fisher test were used to compare outcomes among the four cohorts (P < 0.05) and Kaplan-Meier curve (Log Rank test) to represent cumulative survival., Results: Two hundred consecutive acute liver failure patients between 1990 and 2014 were included; mean age 38.3, ±12.8, male 70, 35%. 124/200 (62%) early survivors were identified; 13/124 (10.5%) acetaminophen patients underwent transplantation and 48/124 (38.7%) survived spontaneously; 36/124 (29.0%) non-acetaminophen underwent transplantation and 27/124 (21.8%) survived spontaneously. A total of 11/124 (8.9%) died subsequently (median survival 5.3± IQR 9.1), three spontaneous survivors and eight transplanted patients (P = 0.025); of the eight transplanted patients, six died of transplant related complications and two of suicide., Conclusion: The results of this study suggest that although liver transplantation is a life-saving procedure for acute liver failure patients, they have a worse long-term outcome compared with spontaneous survivors. Novel therapies to increase the percentage of spontaneous survivors are urgently needed., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We describe the hospital course of a 42-year-old patient who presented to the Emergency Department following an ingestion of an unknown quantity of chlorfenapyr, an organochlorine pesticide that acts as a mitochondrial uncoupler (MU). There is limited data on chlorfenapyr toxicity in humans, but reports indicate a 100% mortality rate after a 7-10 day quiescent period.3-6 Our patient was admitted for a 5-day asymptomatic observation period before becoming critically ill. Supportive care, antioxidant therapy, and late hemodialysis (HD) proved futile. The patient expired from complications due to uncontrollable hyperthermia on hospital day 6. This case represents the first reported fatality due to chlorfenapyr in North America, and illustrates: 1) its potency as a human toxin, 2) the futility of extracorporeal decontamination once late toxicity has set in; 3) the potential need for early and aggressive decontamination in the ED; and 4) the need for a better understanding of this unique poison., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Rationale: Venlafaxine is an antidepressant and anxiolytic agent that functions by inhibiting central serotonin and norepinephrine reuptake, and it is a relatively recently introduced drug. In particular, overdose of venlafaxine has been reported to cause severe cardiac toxicity including ventricular tachycardia, prolongation of QT interval, and seizure or severe muscular injury. However, reports describing venlafaxine-induced rhabdomyolysis with neuropathy remain scarce. Accordingly, we report such a case involving a 49-year-old woman with bilateral sciatic neuropathy combined with rhabdomyolysis following venlafaxine overdose., Patient Concerns: The patient complained of severe pain and tenderness in both thighs, weakness in both ankle flexor and extensor muscles, and a tingling sensation in the toes of both feet., Diagnoses: Bilateral sciatic neuropathy combined with rhabdomyolysis following venlafaxine overdose., Intervention: Needle electromyography revealed fibrillation potentials and positive sharp waves, with absent recruitment in all the major muscles innervating the sciatic nerve bilaterally. Pelvic magnetic resonance imaging was performed after electromyography and revealed multifocal enhancement of signal intensity, suggesting muscle necrosis in the gluteus and thigh muscles, and swelling of both sciatic nerves on short tau inversion recovery (STIR) imaging sequences., Outcomes: Two months later, the patient's ankle dorsiflexion strength, measured with manual muscle test, was grade 0/0, and ankle plantar flexion was grade 0/0. The patient reported little sensation at the lateral and posterior aspects of her lower leg, and dorsum and sole of the foot. A follow-up electromyography study revealed improvement in the long head of the right biceps femoris; polyphasic motor unit action potentials with diminished recruitment were observed, but otherwise unchanged., Lessons: When encountering patients who have overdosed on venlafaxine, it is very important to detect and treat severe complications such as cardiac toxicity, seizure, and rhabdomyolysis, among others. However, if rhabdomyolysis has already materialized, it should not be forgotten that the secondary damage caused by it. Physicians should rapidly detect and be minimized to mitigate future complications.

Background: Medication overdose is a prevalent issue and despite mixed reports of efficacy, the use of intravenous lipid emulsions, notably Intralipid®, for the management of toxicity from lipid-soluble drugs is becoming increasingly prevalent. Whether alternative lipid emulsion formulations have similar efficacy for resuscitation compared to Intralipid is not known. Here, we compared the efficacy of Intralipid and ClinOleic® for resuscitation following overdose with the lipid-soluble beta-adrenergic antagonist propranolol., Methods: Male Sprague-Dawley rats (age 3-4 months) were anesthetized with isoflurane and instrumented for direct hemodynamic assessments. In Study One, rats (n = 22) were pre-treated with Intralipid 20% (n = 12) or ClinOleic 20% (n = 10) to determine whether the hemodynamic effects of propranolol could be prevented. In Study Two, rats were randomly assigned to Intralipid 20% (1, 2, or 3 mL/kg IV, n = 21) or ClinOleic 20% (1, 2, or 3 mL/kg IV, n = 20) resuscitation groups following propranolol overdose (15 mg/kg IV). In Study Three the effect of Intralipid 20% (1 mL/kg IV, n = 3) and ClinOleic 20% (1 mL/kg IV, n = 3) in the absence of propranolol was investigated. The primary endpoint in all studies was survival time (up to a maximum of 120 minutes), and secondary endpoints were time to achieve 50%, 75%, and 90% of baseline hemodynamic parameters., Results: In Study One, pre-treatment with Intralipid prior to propranolol administration resulted in prolonged survival compared to pre-treatment with ClinOleic at low doses (1 mL/kg; P = 0.002), but provided no benefit at higher doses (3 mL/kg; P = 0.95). In Study Two, Intralipid conferred a survival advantage over ClinOleic, with 18/21 rats surviving 120 minutes in the Intralipid group and only 4/20 survivors in the ClinOleic group (P<0.0001). Median survival times (with interquartile ranges) for rats treated with Intralipid, and ClinOleic, and saline were 120 (80.5-120) min, 21.5 (3.25-74.5) min, and 1 (0.25-2.5) min respectively (P<0.001). Only 3/21 rats in the Intralipid group survived less than 30 minutes, whereas 12/20 ClinOleic treated rats had survival times of less than 30 minutes. The number of rats achieving 75%, and 90% of baseline mean arterial pressure was also greater in the Intralipid group (P<0.05 for both values). Treatment in Study Three did not alter survival times., Conclusions: Low-dose Intralipid (1, 2, or 3 mL/kg IV) confers a survival advantage up to 120 minutes post-propranolol overdose (the end-point of the experiment) and better hemodynamic recovery compared to ClinOleic (1, 2, or 3 mL/kg IV) in rats with propranolol overdose. As health care centres choose alternate intravenous lipid emulsions, limited availability of Intralipid could impact efficacy and success of overdose treatment for lipid-soluble drugs., Competing Interests: The authors have declared that no competing interests exist.

Baclofen, a γ-amino-butyric acid type-B receptor agonist with exponentially increased use at high-dose to facilitate abstinence in chronic alcoholics, is responsible for increasing poisonings. Baclofen overdose may induce severe encephalopathy and electroencephalographic (EEG) abnormalities. Whether prior prolonged baclofen treatment may influence the severity of baclofen-induced encephalopathy in overdose has not been established. We designed a rat study to characterize baclofen-induced encephalopathy, correlate its severity with plasma concentrations and investigate the contribution of tolerance. Baclofen-induced encephalopathy was assessed using continuous EEG and scored based on a ten-grade scale. Following the administration by gavage of 116 mg/kg baclofen, EEG rapidly and steadily impaired resulting in the successive onset of deepening sleep followed by generalized periodic epileptiform discharges and burst-suppressions. Thereafter, encephalopathy progressively recovered following similar phases in reverse. Periodic triphasic sharp waves, non-convulsive status epilepticus and even isoelectric signals were observed at the most critical stages. Prior repeated baclofen administration resulted in reduced severity (peak: grade 7 versus 9; peak effect length: 382 ± 40 versus 123 ± 14 min, P = 0.008) and duration of encephalopathy (18 versus > 24 h, P = 0.0007), supporting the acquisition of tolerance. The relationship between encephalopathy severity and plasma baclofen concentrations fitted a sigmoidal E max model with an anticlockwise hysteresis loop suggesting a hypothetical biophase site of action. The baclofen concentration producing a response equivalent to 50% of E max was significantly reduced (8947 μg/L, ±11.3% versus 12,728 μg/L, ±24.0% [mean, coefficient of variation], P = 0.03) with prior prolonged baclofen administration. In conclusion, baclofen overdose induces early-onset and prolonged marked encephalopathy that is significantly attenuated by prior repeated baclofen treatment. Our findings suggest a possible role for the blood-brain barrier in the development of tolerance; however, its definitive involvement remains to be demonstrated., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Chronic salicylate toxicity is an uncommon, potentially life-threatening poisoning that requires high clinical suspicion in order to make the diagnosis. We created a simulation case that challenges learners to analyze case information, construct a differential diagnosis of an elevated anion gap metabolic acidosis with respiratory alkalosis, and initiate treatment for this toxicity., Methods: The simulation case was designed for emergency medicine residents and pediatric emergency medicine fellows. The activity began with a brief overview of the monitors, equipment, and simulation experience. For interns, a team of two learners comanaged the case; for senior learners, the case was managed solo. The learners had 15 minutes to complete a focused history and physical exam, request and interpret labs and studies, and initiate specific treatments. The simulation was followed by a 15-minute facilitated debrief session that included an overview of key learning points and learner performance based on an evaluation checklist., Results: Residents completed a postparticipation questionnaire consisting of six questions rated on a 5-point Likert scale. Overall, residents reported a high degree of satisfaction with the simulation experience. The case and debrief were effective in meeting the educational objectives and proved to be an effective modality to fill this educational gap., Discussion: This simulation exercise was effective in showing residents the uncommon presentation of chronic salicylate toxicity. Learners reported increased confidence in recognizing and managing this ingestion. The simulation experience closed an identified education gap and provided an experiential learning opportunity that accomplished the targeted learning objectives., Competing Interests: None to report.

Introduction: Brain tissue hypoxia may contribute to preventable secondary brain injury after cardiac arrest. We developed a porcine model of opioid overdose cardiac arrest and post-arrest care including invasive, multimodal neurological monitoring of regional brain physiology. We hypothesized brain tissue hypoxia is common with usual post-arrest care and can be prevented by modifying mean arterial pressure (MAP) and arterial oxygen concentration (PaO 2 )., Methods: We induced opioid overdose and cardiac arrest in sixteen swine, attempted resuscitation after 9 min of apnea, and randomized resuscitated animals to three alternating 6-h blocks of standard or titrated care. We invasively monitored physiological parameters including brain tissue oxygen (PbtO 2 ). During standard care blocks, we maintained MAP > 65 mmHg and oxygen saturation 94-98%. During titrated care, we targeted PbtO2 > 20 mmHg., Results: Overall, 10 animals (63%) achieved ROSC after a median of 12.4 min (range 10.8-21.5 min). PbtO 2 was higher during titrated care than standard care blocks (unadjusted β = 0.60, 95% confidence interval (CI) 0.42-0.78, P < 0.001). In an adjusted model controlling for MAP, vasopressors, sedation, and block sequence, PbtO 2 remained higher during titrated care (adjusted β = 0.75, 95%CI 0.43-1.06, P < 0.001). At three predetermined thresholds, brain tissue hypoxia was significantly less common during titrated care blocks (44 vs 2% of the block duration spent below 20 mmHg, P < 0.001; 21 vs 0% below 15 mmHg, P < 0.001; and, 7 vs 0% below 10 mmHg, P = .01)., Conclusions: In this model of opioid overdose cardiac arrest, brain tissue hypoxia is common and treatable. Further work will elucidate best strategies and impact of titrated care on functional outcomes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Intentional insulin overdose may lead to severe and refractory hypoglycemia. Exogenous dextrose administration is the mainstay of therapy for these patients and is effective in most cases. However, in patients with a functional pancreas, exogenous dextrose administration may precipitate endogenous insulin release leading to rebound hypoglycemia. We describe a case report of a 41-year-old woman who injected 300 units of insulin aspart with suicidal intent. Her initial blood glucose was 2.3 mmol/L (41 mg/dL). Over the next 12 hours, she experienced recurrent hypoglycemic episodes despite 10% dextrose infusions and 14 ampoules of 50% dextrose. Our patient experienced complications, including peripheral edema, related to the large volumes of intravenous dextrose required to attempt to maintain euglycemia. Octreotide, a somatostatin analogue, may help prevent dextrose-induced hypoglycemia and improve the management in select insulin overdose patients; large infusion volumes resulted in significant peripheral edema. Treatment with octreotide was initiated 12.5 hours post-injection and was followed by a stabilization of blood glucose concentration in this non-diabetic patient.

Rationale: Vortioxetine is a new multimodal antidepressant approved by the Food and Drug Administration for the treatment of Major Depressive Disorder and recently introduced in Europe. While antidepressant properties of vortioxetine and its tolerability have been demonstrated by preclinical and clinical studies data on the safety of vortioxetine after overdose are still lacking., Patient Concerns: A 50-year-old Caucasian man presenting a severe depressive episode that in a suicide attempt he took vortioxetine at 250 mg., Diagnoses: Suicide attempt by vortioxetine in a patient affected by Major Depressive Disorder., Interventions: General evaluations and gastric lavage with 2 L of water plus 50 g of activated charcoal was performed. After 12 hours of clinical stability, the patient was discharged from the emergency department and considering the suicidal ideation he was admitted to the inpatients psychiatric department., Outcomes: After vortioxetine overdose the patient displayed no clinical signs or symptoms resulting from the exposure suggesting a good safety in overdose., Lesson: Overdose safety of different antidepressant drugs is a matter of great considering that overdose in individuals affected by Major Depressive Disorder frequently involves prescribed antidepressants. Previous studies showed wide variation in the relative toxicity of different antidepressant drugs with higher toxicity for tricyclic antidepressants, followed by venlafaxine bupropion and mirtazapine and lower for selective serotonin reuptake inhibitors. By now there is limited clinical trial experience regarding human overdose with vortioxetine and the maximum single dose tested was 75 mg in men associated with increased rates of nausea, dizziness, diarrhea, abdominal discomfort, generalized pruritus, somnolence, and flushing. Even if there is still limited available evidence and further investigation is needed to better understand the potential risk of vortioxetine overdose; from our case, it seems that vortioxetine overdose at 250 mg (12 times the common daily dose) showed no signs or symptoms resulting from the exposure suggesting a good safety in overdose.

A 54-year-old female presented after taking an overdose of an unknown amount of hydrochlorothiazide, doxazocin, atenolol and amlodipine. She was initially refractory to treatment with conventional therapy (intravenous fluids, activated charcoal, glucagon 5 mg followed with glucagon drip, calcium gluconate 10%, and atropine). Furthermore, insulin at 4 U/kg was not effective in improving her hemodynamics. Shortly after high dose insulin was achieved with 10 U/kg, there was dramatic improvement in hemodynamics resulting in three of five vasopressors being weaned off in 8 h. She was subsequently off all vasopressors after six additional hours. The role of high dose insulin has been documented in prior cases, however it is generally recommended after other conventional therapies have failed. However, there are other reports that suggest it as initial therapy. Our patient failed conventional therapies and responded well only with maximum dose of insulin. Physicians should consider high dose insulin early in severe beta blocker or calcium channel blocker overdose for improvement in hemodynamics. This leads to early discontinuation of vasopressors. It is important that emergency physicians be aware of the beneficial effects of high dose insulin when initiated early as opposed to waiting for conventional therapy to fail; as these patients often present first to the emergency department. Early initiation in the emergency department can be beneficial in these patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The aim of this study was to characterize the clinical signs and symptoms of exposures to aripiprazole overdoses. We retrospectively identified all aripiprazole exposures reported to the Danish Poison Information Centre (DPIC) from June 2007 to May 2015. Information concerning demographics, ingested dose and symptoms was extracted from the DPIC database and medical records. Information on death and admission to hospital was obtained from Danish national registers. We analysed 239 cases, 86 concerning single-drug exposures to aripiprazole, and 153 cases where aripiprazole had been taken with at least one other substance (mixed-drug). The median ingested aripiprazole dose was 105 mg (IQR: 50-1680 mg) in the single-drug exposure group and 120 mg (IQR: 60-225 mg) in the mixed-drug exposure group. The most commonly reported symptom was light sedation, reported in 63% of the single-drug group and 50% of the mixed-drug exposure group. There were no malignant arrhythmias or ECG abnormalities after single-drug exposures. No deaths were recorded in relation to the intake. We found a long-term mortality rate of 13 deaths per 1000 person-years (95% CI: 7; 23 per 1000 person-years), which is significantly higher than in an age- and gender-matched background population. In conclusion, we found that aripiprazole overdoses had few and mild symptoms predominantly related to the sedative properties. We detected a benign cardiovascular safety profile and no new safety concerns. Our findings may support an increased threshold of 300 mg for hospital admission after a single-drug exposure with aripiprazole and symptoms not worse than light sedation., (© 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background: Relapse to opioid use is common after rapid opioid withdrawal. As a result, short-term tapers of opioid agonist/partial agonist medications, such as methadone and buprenorphine/naloxone, are no longer recommended by recent clinical care guidelines for the management of opioid use disorder. Nonetheless, rapid tapers are still commonplace in medically supervised withdrawal settings., Case Summary: We report a case of an individual with opioid use disorder who was prescribed a rapid buprenorphine/naloxone taper in a medically supervised withdrawal facility and who had a subsequent opioid overdose and death after discharge., Discussion: The fatal outcome in this case study underscores the potential severe harms associated with use of rapid tapers. Given the increased overdose risk, tapers should be avoided and continuing care strategies, such as maintenance pharmacotherapy, should be initiated in medically supervised withdrawal settings.

Background: Inquiries relating to ibuprofen overdose have more than tripled in the last ten years in our poison control center. Although the vast majority of cases have a benign clinical course, there are few severe or even fatal cases present with refractory circulatory failure., Case Presentation: We describe a case of a 48 year-old male with suicidal mono-ingestion of approximately 72 g ibuprofen. Despite an initial rapid spontaneous drop in the total ibuprofen plasma concentration (IPC) from 550 to 275 mcg/mL within the first 5 h after admission, the patient developed a circulatory failure, refractory to aggressive fluid resuscitation and high doses of vasopressors. Due to ibuprofen's favorable pharmacokinetics (>95% bound to albumin, low volume of distribution) and in the absence of specific therapeutic alternatives thereby avoiding escalating vasopressor doses, therapeutic plasma exchange (TPE) for extracorporeal elimination of ibuprofen was considered as a therapeutic rescue option. An improvement of hemodynamics with a significant reduction of vasopressors was observed with TPE-initiation. However, neither the observed IPC-profile nor a pharmacokinetic (PK) simulation provided evidence for a quantitative effective elimination of ibuprofen by TPE. Based on PK-modeling we calculated an overall ibuprofen half-life of 17.2 h for the entire observation period over 5 days., Conclusions: To our knowledge this is the first report of a severe ibuprofen-mono intoxication treated with TPE and providing serial IPCs over a period of five days, indicating an estimated fivefold overall-elimination half-life of 17.2 h. Despite TPE clinically improved persistent hemodynamic instability, this procedure was neither consistent with the observed IPC-profile nor correlated with a meaningful quantitative elimination of ibuprofen.