Treating ethylene glycol poisoning with alcohol dehydrogenase inhibition, but without extracorporeal treatments: a systematic review.

CONTEXT: Ethylene glycol is metabolized to toxic metabolites that cause acute kidney injury, metabolic acidemia, and death. The treatment of patients with ethylene glycol poisoning includes competitively inhibiting alcohol dehydrogenase with ethanol or fomepizole to prevent the formation of toxic metabolites, and extracorporeal treatments such as hemodialysis to remove ethylene glycol and its metabolites. In the absence of significant metabolic acidemia or kidney injury, it is hypothesized that extracorporeal treatments may be obviated without adverse outcomes to the patient if alcohol dehydrogenase inhibitors are used. OBJECTIVES: The objectives of this study are to: (1) identify indicators predicting ADH inhibitor failure in patients with ethylene glycol poisoning treated with either ethanol or fomepizole for whom extracorporeal treatment was not performed (aside from rescue therapy, see below) (prognostic study), and (2) validate if the anion gap, shown in a previous study to be the best surrogate for the glycolate concentration, is associated with acute kidney injury and mortality (anion gap study). METHODS: We conducted a systematic review to identify all reported patients with ethylene glycol poisoning treated without extracorporeal treatments but with either fomepizole (fomepizole monotherapy) or ethanol (ethanol monotherapy). Analyses were performed using both one case per patient and all cases (if multiple events were reported for a single patient). Data were compiled regarding poisoning, biochemistry, and outcomes. Treatment failure was defined as mortality, worsening of acid-base status, extracorporeal treatments used as rescue, or a worsening of kidney or neurological function after alcohol dehydrogenase inhibition was initiated. Also, we performed an analysis of previously described anion gap thresholds to determine if they were associated with outcomes such as acute kidney injury and mortality. RESULTS: Of 115 publications identified, 96 contained case-level data. A total of 180 cases were identified with ethanol monotherapy, and 231 with fomepizole monotherapy. Therapy failure was noted mostly when marked acidemia and/or acute kidney injury were present prior to therapy, although there were cases of failed ethanol monotherapy with minimal acidemia (suggesting that ethanol dosing and/or monitoring may not have been optimal). Ethylene glycol dose and ethylene glycol concentration were predictive of monotherapy failure for ethanol, but not for fomepizole. In the anion gap study (207 cases), death and progression of acute kidney injury were almost nonexistent when the anion gap was less than 24 mmol/L and mostly observed when the anion gap was greater than 28 mmol/L. CONCLUSION: This review suggests that in patients with minimal metabolic acidemia (anion gap <28 mmol/L), fomepizole monotherapy without extracorporeal treatments is safe and effective regardless of the ethylene glycol concentration. Treatment failures were observed with ethanol monotherapy which may relate to transient subtherapeutic ethanol concentrations or very high ethylene glycol concentrations. The results are limited by the retrospective nature of the case reports and series reviewed in this study and require prospective validation.

Consensus Development of a Core Content for a Standardized Medical Toxicology Curriculum for Medical Students.

BACKGROUND: Currently, no standardized core content in medical toxicology exists for medical students. The goals of this study were to (1) assess the current state and needs of medical toxicology clerkships and (2) develop a consensus-derived list of core topics that should be covered during a medical toxicology clerkship. METHODS: We assembled a task force established by the American College of Medical Toxicology (ACMT) of nine experts in medical toxicology or emergency medicine. We developed a needs assessment survey that was sent to all medical student clerkship directors in medical toxicology. Based on their responses, we used a modified Delphi process to develop a consensus of core topics that should be covered during a medical student clerkship. RESULTS: Nineteen out of 42 (45%) clerkship directors completed the survey; 18 met inclusion criteria. The majority of clerkships were 4 weeks in duration with an average of 15 students/year. The three most common teaching methods used were bedside teaching (n = 17/18), classroom teaching (n = 17/18), and journal club (n = 14/18). All the clerkship directors (n = 18/18) reported they would use a standardized curriculum as well as educational content developed by ACMT. There was overwhelming consensus on the core topics which included, but were not limited to, pharmacology/toxicology; drugs; drugs of abuse; natural products; pharmacological basis of antidote use; toxicologic syndromes; vital sign abnormalities; initial management; supportive and other care; withdrawal syndrome management; industrial, household, and environmental toxins; differential diagnosis by clinical findings; and ABCs-resuscitation. CONCLUSION: The ACMT task force developed a medical toxicology clerkship core content. The task force also identified a need for shared resources among clerkships.

A Liquid-Chromatography High-Resolution Mass Spectrometry Method for Non-FDA Approved Benzodiazepines.

Benzodiazepines (BZDs) are widely used for treatment of anxiety and insomnia, however, this class of drugs is also commonly abused. Many different BZDs and analogs have been produced that are not FDA-approved. We tested 15 of these with the ThermoFisher CEDIA® BZD-immunoassay. With the exception of ketazolam, all compounds showed significant reactivity, highlighting the need for mass spectrometry confirmation assays. We developed a liquid-chromatography high-resolution mass spectrometry method for the detection of these 15 non-FDA approved BZDs. The limit of detection for most compounds ranged from 1 to 50 ng/mL, with mostly positive matrix effects observed in urine and negative matrix effects in serum. In a clinical research case, clonazolam and etizolam were detected in serum at 10.2 and 281 ng/mL, with an apparent elimination half-life of 3.6 and 4.8 hours, respectively. Although we did not detect non-FDA approved BZDs in 211 urine samples that were previously determined to be BZD-positive by immunoassay, abuse of these drugs is on the rise and clinical and forensic toxicology laboratories should consider developing methods to detect them.

Snakebites and climate change in California, 1997-2017.

BACKGROUND: Climate change effect on flora and fauna has been scientifically documented, but the effect on North American venomous snakebites is unknown. The objectives were to examine Californian snakebite incidence and correlate with weather patterns and climate changes. METHODS: A retrospective analysis of snakebites reported to the Californian Poison Control System from 1 September 1997 to 30 September 2017. Venomous snakebite reports were aggregated by caller zip code, and correlated per county with weather data, air temperature, precipitation, population data, eco-regions, and land characteristics. Time series decomposition by seasonality and trend, regression, and autocorrelation were used to assess association between climate variables and incidence. RESULTS: There were 5365 reported venomous snakebites during the study period, with a median age of 37 years (22-51) with 76% male (p < .001, 95% CI 75.6-77.9%). Most snakebite outcomes were coded as minor (1363, 25%) or moderate (2607, 49%), with three deaths. Adjusted for population, the annualized incidence of snakebites statewide slightly decreased (rho = -0.11, p = .65). The snakebite incidence per million people rose after a period of no drought and declined during drought (r = -0.41, p ≪ .01). Snakebite incidence decreased by 6-month prior drought (-3.8% for each 10% increase in drought), and increased by 18-month prior precipitation (+3.9% for each 10% increase in precipitation). CONCLUSIONS: Patterns of precipitation and drought had a significant and predictive effect on snakebites in California over a 20-year period. Snakebite incidence decreased following drought, and increased after precipitation.

Non-targeted screening for novel psychoactive substances among agitated emergency department patients.

CONTEXT: Novel psychoactive substances (NPS) are being created and introduced at an unprecedented rate, causing frequent, large-scale epidemics. Current identification of NPS in clinical settings in the USA is limited to the retrospective case or small cluster analysis. OBJECTIVE: The purpose of this study was to assess the utility of non-targeted comprehensive drug screening in the agitated patients in an emergency department (ED) setting. MATERIALS AND METHODS: This is a prospective, observational case series that was conducted in the ED of an urban Level I Trauma Center with an annual census of approximately 65,000 patients per year. Since it is common clinical practice at this facility for haloperidol to be used as a second-line chemical restraint when initial dose(s) of benzodiazepines are deemed insufficient, we surmised that the subset of ED patients with psychomotor agitation severe enough to receive both these pharmaceuticals would be likely users of NPS. For 1 month, biweekly pharmacy medication audits identified 49 of these patients. There were sufficient, remaining blood samples from 23 of these patients for analysis. Serum from stored blood samples was analyzed using liquid chromatography-time-of-flight mass spectrometry (LC-TOF/MS; LC 1260, TOF/MS 6230, Agilent). Retrospective chart review was done to identify patient clinical information. RESULTS: Six patient samples yielded seven different NPS: JWH-073, JWH-081, JWH-200, methylenedioxybenzylpiperazine, mephedrone, methoxetamine, and herkinorin. CONCLUSION: This study demonstrates that prospective, non-targeted NPS screening in a selected ED patient population is feasible and effective in identifying NPS.

Predictors of Death and Prolonged Renal Insufficiency in Ethylene Glycol Poisoning.

BACKGROUND: We assessed the predictive value of selected factors on the outcomes of death and prolonged renal insufficiency (RI) from ethylene glycol poisoning. METHODS: Retrospective, observational California Poison Control System study, over a 10-year period (1999-2008). We compared 2 groups. The first group (D/RI) included 59 patients who died (9 patients) or had prolonged RI (50 patients). Prolonged RI was defined as kidney injury in which dialysis was required for greater than 3 days after presentation. The second group (RECOV) of 62 patients had an uncomplicated recovery. Secondarily, we evaluated the association of time to antidote (ethanol and/or fomepizole) and time to dialysis with these outcomes. RESULTS: The D/RI group was more likely than the RECOV group to present comatose, have seizures, and require intubation. The D/RI group had a lower mean initial arterial pH of 7.03 (standard deviation [SD] 0.20), compared to 7.27 (SD 0.14) for the RECOV group. The D/RI group had a higher initial creatinine (1.7 mg/dL, SD 0.71) than that of the RECOV group (1.0 mg/dL, SD 0.33). Patients with a time to antidote greater than 6 hours had a higher odds of dying or having prolonged RI (OR 3.34, 95% CI : 1.21-9.26) Patients with a time to dialysis greater than 6 hours had a lower odds of dying or having prolonged RI (OR 0.36, 95% CI : 0.15-0.87). CONCLUSION: Compared to survivors with an uncomplicated recovery, patients poisoned with ethylene glycol who died or had prolonged RI were more likely to exhibit clinical signs such as coma, seizures, and acidosis. Antidote administration within 6 hours is associated with better outcomes, unlike earlier time to dialysis.

Cardiotoxicity in a citalopram and olanzapine overdose.

BACKGROUND: This is a case of a citalopram and olanzapine overdose causing seizures and severe cardiotoxicity. CASE REPORT: A 21-year-old man presented unresponsive, with seizures, to an Emergency Department. The patient's initial electrocardiogram demonstrated a widened QRS of 160 ms and a normal QT/QTc interval of 400/487 ms consistent with cardiac sodium channel blockade. Within 30 min of arrival, peak citalopram and olanzapine levels were measured to be 522 ng/mL and 505 ng/mL, respectively. Measured levels remained supratherapeutic until 13.6 h and 42.6 h after arrival for citalopram and olanzapine, respectively. The patient developed bradycardia and hypotension that required multimodal therapies including sodium bicarbonate boluses, vasopressors, and transvenous pacing. Seizures and cardiotoxicity continued while citalopram, but not olanzapine, was supratherapeutic. CONCLUSIONS: This case describes cardiotoxicity directly correlated with supratherapeutic citalopram levels in overdose.

Prolonged ventilatory failure and flaccid quadriparesis after ingestion of poison hemlock.

INTRODUCTION: A 28-year-old man presented with acute flaccid paralysis and respiratory failure that persisted for 2 weeks after suicidal ingestion of unknown substances. METHODS: Extensive clinical, nerve, laboratory, and neuroimaging testing excluded alternative causes of this neuromuscular syndrome. Prompted by clues provided by family members, liquid chromatography time-of-flight mass spectrometry was used to investigate for the presence of poison hemlock. RESULTS: Testing of the residue in a jar used for the ingestion of a poisonous concoction confirmed the presence of the nicotinic alkaloid coniine. Analysis of patient serum suggested the presence of conhydrine. Concentrations of amitriptyline and diazepam were also found to be supratherapeutic, but only through the first few days of hospitalization. CONCLUSIONS: Herein we describe a case of reversible coma, flaccid quadriparesis, and neuromuscular respiratory failure caused by intentional ingestion of poison hemlock.

Evaluation of the use and safety of octreotide as antidotal therapy for sulfonylurea overdose in children.

OBJECTIVES: The objectives of this study were to evaluate the effect of octreotide on number of hypoglycemic episodes and blood glucose concentrations (BGCs) in a case series of young children who received octreotide for treatment of sulfonylurea-induced hypoglycemia and to identify the frequency of adverse effects associated with octreotide's use for this indication. METHODS: A retrospective review of 9 years of National Poison Data System pediatric sulfonylurea overdoses treated with octreotide was conducted. Inclusion criteria were age younger than 6 years with acute sulfonylurea overdose managed in a health care facility. Redacted poison center charts were obtained, and data on pretreatment and posttreatment number of hypoglycemic episodes and BGCs as well as medical outcomes and adverse reactions were extracted and analyzed. RESULTS: There were 121 octreotide cases. Patients experienced a median of 2.0 and 0.0 hypoglycemic episodes before and after treatment, respectively (P < 0.0001). The median lowest BGC was significantly higher after octreotide administration (P < 0.001). In 73% of children, only 1 dose of octreotide was given. Hyperglycemia was noted in 3 children who also received dextrose in whom adverse effects to therapy were coded. CONCLUSIONS: Octreotide administration decreases number of hypoglycemic events and increases BGCs. The majority of children who receive octreotide require only 1 dose. There were no adverse effects documented in these children who received octreotide as an antidote for sulfonylurea-induced hypoglycemia.

Significant toxicity in a young female after low-dose tricyclic antidepressant ingestion.

BACKGROUND: Tricyclic antidepressant (TCA) ingestions are a relatively common pediatric ingestion, with significant potential for both cardiac and neurological toxicity. Previous studies on pediatric TCA ingestions have found the threshold of toxicity to be 5 mg/kg. CASE: We report a case of an 8-year-old girl who presented to the emergency department with depressed mental status and seizure-like movements. An extensive workup was pursued to evaluate the cause of her mental status, which only revealed a positive urine toxicology screen for TCA. Quantified serum levels of amitriptyline were 121 ng/mL (therapeutic range, 50-300 ng/mL) and nortriptyline were 79 ng/mL (therapeutic range 70-170 ng/mL), 18 hours after onset of symptoms. Subsequent history obtained after her mental status returned to normal revealed that she had ingested amitriptyline at a dose of 0.8 mg/kg. CONCLUSIONS: Tricyclic antidepressant ingestion has a high potential for toxicity in pediatric patients. This case suggests, contrary to previous literature, that toxicity may occur even with small doses.

An intervention to improve compliance with transmission precautions for influenza in the emergency department: successes and challenges.

BACKGROUND: Concern with the potential for hospital-based transmission of influenza has come to the forefront due to emergency department (ED) crowding and the novel H1N1 pandemic. Compliance with infection control guidelines for influenza in the ED is generally unknown, and effective yet low-resource training is needed to educate staff on the importance of decreasing the potential for ED transmission of the virus. OBJECTIVES: This study evaluates compliance with patient assignment and transport precautions for influenza in an urban ED before and after implementation of electronic reminders. METHODS: We included patients with a diagnosis of influenza for two consecutive influenza seasons, and retrospectively collected limited patient encounter data on patient location, transport, and compliance with assignment and transport precautions for both years. For the second influenza season we sent monthly reminders to all ED providers via the electronic medical record (EMR), explaining the importance and proper use of infection control precautions in patients with suspected influenza. Compliance between the two seasons was compared using descriptive statistics and chi-squared analysis. RESULTS: Overall compliance with infection control precautions was poor, but increased with the use of electronic reminders from 29% to 45% (p = 0.015). Compliance with precautions for patients moved to the hallway or Radiology increased from 7% to 24% (p = 0.001). CONCLUSIONS: The EMR may be a useful tool for improving compliance with transmission-based precautions by implementing reminders on order sets and informational mailings, and by tracking compliance. Future study should be undertaken to determine the most effective interventions to prevent ED transmission of influenza.

Confirmed glyburide poisoning from ingestion of "street Valium".

BACKGROUND: Pharmaceuticals with little to no abuse potential are often sold surreptitiously as drugs of abuse on the street. Anecdotally, sulfonylureas are suspected to be commonly sold as "street Valium." CASE REPORTS: Two patients presented with altered mental status and persistent hypoglycemia requiring continuous intravenous dextrose, in the context of suspected attempted benzodiazepine abuse. Supratherapeutic glyburide levels of 1198 and 647 ng/mL were measured in these patients. CONCLUSIONS: These are two cases of glyburide poisonings from ingestion of "street Valium" that have been confirmed by laboratory testing.

Hypoglycemia in pediatric sulfonylurea poisoning: an 8-year poison center retrospective study.

OBJECTIVE: The goal of this study was to describe the clinical effects and time of onset of hypoglycemia in pediatric sulfonylurea poisoning. METHODS: This was a retrospective, descriptive study of pediatric (<6 years old) sulfonylurea exposures with hypoglycemia (glucose concentration <60 mg/dL) that were consulted on by the California Poison Control System for the 8-year period between January 1, 2002, and December 31, 2009. RESULTS: Of the 1943 consultations for pediatric sulfonylurea exposure in the study period, 300 children developed hypoglycemia. Ten percent had hypoglycemia occurring or persisting ≥ 12 hours after ingestion despite receiving treatment. All 5 children with seizures experienced these before hospital presentation. The mean (SD) time to onset of hypoglycemia in children not given any prophylactic treatment was 2.0 (1.2) hours. The mean (SD) times in children receiving prophylactic food only, intravenous glucose only, and both food and intravenous glucose were 5.9 (3.9), 5.7 (2.5), and 8.9 (3.6) hours, respectively. Ranges were 1 to 18, 1.5 to 9, and 2.5 to 15 hours. Seven of 40 patients (18%) receiving prophylactic food only had an onset of hypoglycemia >8 hours after sulfonylurea ingestion. CONCLUSIONS: Pediatric sulfonylurea exposure can result in significant poisoning. Severe effects such as seizures occurred only in cases of unrecognized sulfonylurea ingestion. The onset of hypoglycemia after pediatric sulfonylurea ingestion can be delayed by as much as 18 hours by either free access to food or administration of intravenous glucose.

Diphenhydramine dose-response: a novel approach to determine triage thresholds.

CONTEXT: It is unclear how much diphenhydramine (DPH) is toxic in humans. Previous dose-response studies have had conflicting results. Objective. We sought to evaluate DPH dose-response using a unique method that utilizes acetaminophen (APAP) serum concentrations to estimate DPH doses in patients ingesting APAP/DPH in a fixed-combination product. METHODS: We retrospectively analyzed APAP/DPH-only exposures in patients 2-80 years of age using case data from 15 U.S. poison centers. DPH dose was extrapolated from measured serum APAP concentrations. A clinically significant response (CSR) was predefined in terms of eight specific manifestations (e.g., coma) that would warrant emergency department intervention. Nominal logistic regression was used to model the probability of each recorded manifestation across DPH dose ranges examining fits for mg, mg/kg, log10 mg, and log10 mg/kg DPH doses. The threshold value where patients reliably became symptomatic was determined by further examining receiver operating characteristic curves. RESULTS: There were 509 cases that met inclusion criteria. Forty-five patients (9%) developed CSRs. A higher percentage of patients developed CSR at ≥ 7.5 mg/kg DPH and ≥1 g total DPH cutoff points (p < 0.05, Fisher's exact test). The best model for predicting the probability of CSR was a logistic fit of log(10) mg/kg dose (p < 0.05). By this model, for every 1 log(10) unit increase of mg/kg DPH dose, the odds of developing a CSR increased 47-fold (95% CI 17, 154). Receiver operating characteristic analyses showed a dose-related progression of symptoms. The cut-point with greatest sensitivity (98%) versus 1-specificity (57%) corresponded to an extrapolated mg/kg DPH dose of 8.2 mg/kg (95% CI 5.6, 10.5). CONCLUSION: Our findings support the current American Association of Poison Control Centers' guideline recommendation to refer patients to the hospital for evaluation if they have ingested greater than or equal to 7.5 mg/kg of DPH.