Keywords: acetaminophen overdose, fomepizole, NAC (PubMed Search)
Acetaminophen (APAP) is the leading cause of acute liver failure worldwide. Standard treatment for APAP overdose is with N-acetylcysteine (NAC), which is highly effective if given within 8 hours of ingestion. However, in delayed presenters or massive ingestions patients can still develop hepatotoxicity. Adjunctive therapies can be considered in these cases including augmented NAC dosing, renal replacement, and fomepizole.
A small amount of APAP is metabolized to N-acetyl-p-benzoquinone imine (NAPQI) by cytochrome 2E1. In therapeutic doses, the body is able to detoxify the NAPQI using glutathione. In overdose, glutathione stores get depleted and NAPQI can cause hepatotoxicity. Mitochondrial damage in APAP overdose is mediated by the c-Jun-N-terminal Kinase (JNK) pathway.
NAC works to replenish glutathione stores and detoxify NAPQI. In large overdoses, increased dosing of NAC may be necessary. Fomepizole is typically used for its alcohol dehydrogenase inhibitor property to treat methanol and ethylene glycol poisoning. Fomepizole is also a cytochrome 2E1 and JNK inhibitor and can be used in APAP overdose to block the formation of NAPQI and mitigate mitochondrial damage. Dialysis can be used to eliminate APAP from the body completely in massive overdoses or if significant acidosis or renal failure.
This study is a case series of 14 patients treated for APAP overdose between 2017 – 2021 at a tertiary hospital
Limitations of the study:
Stephanie L. Link, Garrett Rampon, Stephen Osmon, Anthony J. Scalzo & Barry H. Rumack (2022) Fomepizole as an adjunct in acetylcysteine treated acetaminophen overdose patients: a case series, Clinical Toxicology, 60:4, 472-477, DOI: 10.1080/15563650.2021.1996591
Keywords: CO (PubMed Search)
Prolonged exposure (>24hrs)
COHgb level >25%
Weaver LK, Valentine KJ, Hopkins RO. Carbon monoxide poisoning: risk factors for cognitive sequelae and the role of hyperbaric oxygen. American journal of respiratory and critical care medicine. 2007;176(5):491-497. doi:10.1164/rccm.200701-026OC
Keywords: cannabis exposure, pediatric, toxicity, NPDS (PubMed Search)
Medical Cannabis is permitted in 39 states and Washington DC while 18 sates and Washington DC has legalized recreational cannabis use. As cannabis products become more available, pediatric exposure has also increased.
A retrospective study of National Poison Data System involving children < 6 years from 2017 and 2021 showed: Pre-COVID (2017-2019) & COVID (2020-2021)
Common Clinical effects
Tweet MS, Nemanich A, Wahl M. Pediatric Edible Cannabis Exposures and Acute Toxicity: 2017–2021. Pediatrics. 2023;151(2):e2022057761
Keywords: Lithium, Lab error, Toxicity (PubMed Search)
Lithium toxicity can present acutely with gastrointestinal symptoms and chronically with neurologic symptoms such as tremor and ataxia. Diagnosis and treatment with normal saline hydration and/or dialysis depends on lithium levels in conjunction with signs and symptoms.
Lithium levels can be falsely elevated when blood samples are collected in green top tubes which contain lithium heparin, or if the blood collection volume is too small. Not recognizing that a lithium level may be falsely elevated can lead to misdiagnosis as well as unnecessary hospitalizations and treatments. The study by Wills et al found lithium levels as high as 4 mmol/L (therapeutic range 0.6-1.2 mmol/L) in lithium naïve volunteers collected in the wrong tube and with small blood volumes. If a patient has an elevated lithium level in the absence of lithium toxicity symptoms, consider a falsely elevated level and redraw using the appropriate tube and sample size.
Wills BK, Mycyk MB, Mazor S, Zell-Kanter M, Brace L, Erickson T. Factitious lithium toxicity secondary to lithium heparin-containing blood tubes. J Med Toxicol. 2006 Jun;2(2):61-3. doi: 10.1007/BF03161172. PMID: 18072115; PMCID: PMC3550057.
Keywords: amlodipine, non-dihydropyridines, high-dose insulin (PubMed Search)
Calcium channel blocker (CCB) overdose can lead to severe shock/hypotension. A small study was conducted to compare the hemodynamic effects of high-dose insulin (HDI) for two classes of CCB (dihydropyridines vs. non-dihydropyridines) that work differently to manage hypertension.
Median number of maximum concomitant vasopressors (p=0.04)
Median difference in max concomitant vasopressors: 1 (95% CI: 0 – 2)
Median max epinephrine dosing
Use of rescue methylene blue (p=0.009)
Cole JB, Lee SC, Prekker ME, Kunzler NM, Considine KA, Driver BE, Puskarich MA, Olives TD. Vasodilation in patients with calcium channel blocker poisoning treated with high-dose insulin: a comparison of amlodipine versus non-dihydropyridines. Clin Toxicol (Phila). 2022 Nov;60(11):1205-1213. doi: 10.1080/15563650.2022.2131565. Epub 2022 Oct 25. PMID: 36282196.
Keywords: flumazenil, benzodiazepine overdose, adverse events (PubMed Search)
Flumazenil is a reversal agent for benzodiazepine overdose. Adverse events including seizure, agitation and cardiac arrhythmias have been reported but the frequency of adverse events is unknown.
AE and serious AEs were defined as:
Serious AE (SAE):
A systematic review/meta-analyses of 13 randomized controlled trials showed
Most common AEs
Most common SAEs
PENNINGA E ET AL.Adverse Events Associated with Flumazenil Treatment for the Management of Suspected Benzodiazepine Intoxication--A Systematic Review with Meta-Analyses of Randomized Trials. Basic Clin Pharmacol Toxicol. 2016
Keywords: xylazine, adulterate, heroin, fentanyl (PubMed Search)
Xylazine is a central alpha-2 agonist (similar to clonidine) that is used as a veterinary tranquilizer. It also possesses analgesic, and muscle relaxant properties. Heroin/fentanyl is increasingly being adulterated with xylazine and resulting in severe adverse effects (CNS and respiratory depression, bradycardia, and hypotension), including deaths.
According to CDC, 0.1%-5.5% of IMF death in US between 2019 – 2020 involved xylazine.
In Philadelphia, PA:
The detection of xylazine in unintentional overdose death increased from
Approximately 25% of drug seizures in Philadelphia contained xylazine in 2019
There is no effective pharmacologic agent for xylazine toxicity. Similar to clonidine toxicity, high dose naloxone may be tried. But pediatric data show that approximately 50% of pediatric clonidine toxicity response to high-dose naloxone administration. Thus, naloxone administration may not reverse the CNS/respiratory depression, bradycardia and hypotension.
O’Donnell J, Tanz LJ, Gladden RM, Davis NL, Bitting J. Trends in and Characteristics of Drug Overdose Deaths Involving Illicitly Manufactured Fentanyls — United States, 2019–2020. MMWR Morb Mortal Wkly Rep 2021;70:1740-1746. DOI: http://dx.doi.org/10.15585/mmwr.mm7050e3.
Johnson J, et al. Inj Prev 2021;27:395–398. doi:10.1136/injuryprev-2020-043968
Keywords: pediatric fatality, poisoning, US (PubMed Search)
Substance use disorder contributes significantly to pediatric exposure/poisoning. There has been an increase in the opioid overdose deaths in the US, placing pediatric population to possible exposure. A retrospective study of fatal pediatric poisoning in the US was investigated using the National Violent Death Reporting System (NVDRS) from 2012-2017.
17 US states (AK, CO, GA, KT, MD, MA, NJ, NM, NC, OH, OK, OR, RI, SC, UT, VA, WI) reported to NVDRS from 2012-2017.
Age was limited to 0-9 years
1850 violent deaths were identified: n=122 (7%) were poisoning related
Most common exposure/etiology
Hunter AA et a. An examination of fatal child poisonings in the United States using the National Violent Death Reporting System (NVDRS), 2012–2017. Clin Toxicol. 2021
Keywords: ICU requirement score, physiologic score system (PubMed Search)
There are several clinical scoring systems (SAPS II, SAPS III, SOFA, etc.) to assess the severity and/or risk of mortality in critically ill patients. However, the routinely used physiologic scoring systems are not always suitable for poisoned patient.
ICU requirement score (IRS) has been recently developed by investigators from Europe and a validation study (retrospective cohort) has been performed.
ICU requirement score (IRS) components (see inserted table)
Area under the curve for IRS ROC: 0.736 (95% CI: 0.702-0.770)
Keywords: cannabis intoxication, trend, Canada, ICU admission, legalization (PubMed Search)
Canada legalized recreational cannabis use in 2017. A retrospective study of children (0-18 years) who presented to pediatric ED with cannabis intoxication/exposure was performed between Jan 1, 2008 to Dec 21, 2019 to assess the trend/severity of intoxication.
A total of 298 patients were identified
Monthly ED visit
2.1 (IRQ: 1.9-2.5)
1.7 (IQR: 1.0-3.0)
Altered mental status
Age < 12 years
Respiratory symptoms: tachypnea/bradypnea, cyanosis, O2 sat < 92%, bronchospasm, oxygen requirement
Cohen N et al. Pediatric cannabis intoxication trends in the pre and post-legalization era. Clin Toxicol 2021. e-pub Jun 17, 2021.
Keywords: NAC, gluthathione, acetaminophen toxicity (PubMed Search)
What is the mechanism of action of N-acetylcysteine that is used to treat acetaminophen induced liver injury/toxicity?
Excess production of NAPQI via CYP 2E1 from acetaminophen overdose depletes gluthathione, which detoxifies NAPQI. Gluthathione consists of 3 amino acids: glutamate, cysteine and glycine. cysteine availability is the rate limiting step in gluthathione synthesis. hepatotoxicity occurs when gluthathione store is depleted below 30% of the baseline.
Thus NAC works by:
Goldfrank's Toxicologic Emergencies. Ch35 Acetaminophen A3: antidote in depth - N-acetylcysteine
Keywords: household spices, abuse, toxicity (PubMed Search)
There are three commonly household spices that can be abuse/misused or cause toxicity after exposure.
Pure vanilla extract contains at least 35% ethanol by volume per US Food and Drug Administration standards
Nutmeg contains myristicin – serotonergic agonist that possess psychomimetic properties.
Cinnamon contains cinnamaldehyde and eugenol – local irritants.
Johnson-Arbor K et al. Stoned on spices: a mini-review of three commonly abuse housenold spices. Clin Toxicol (Phila) 2020
Keywords: diphenhydramine overdose, seizure, ventricular dysrhythmia, severe toxicity (PubMed Search)
Diphenhydramine is commonly involved in overdose or misused. Although it is primarily used for its anti-histamine property, it also has significant antimuscarinic effect.
A recent retrospective study investigated the clinical characteristics associated with severe outcomes in diphenhydramine overdose using the multi-center Toxicology Investigators Consortium (ToxIC) Registry.
Severe outcomes were defined as any of the following:
863 cases of isolated diphenhydramine ingestion were identified between Jan 1, 2010 to Dec 31, 2016
Most common symptoms:
Factors associated with severe outcome
Hughes AR et al. Clinical and patient characteristics associated with severe outcome in diphenhydramine toxicity. Clin Toxicol (Phila) 2021.
Keywords: occupational poisoning (PubMed Search)
There are different occupational hazards depending on the nature of one’s trade/skill/employment. Although healthcare providers may not always inquire about patient’s occupation, knowledge of a patient’s occupation may provide insightful information when caring for patients with acute poisoning.
From a recent retrospective study of National Poison Data System, the top 10 occupational toxicants were:
Top 10 occupational toxicants associated with fatalities were:
Downs JW et al. Descriptive epidemiology of clincally signifcant occupational poisonings, United States, 2008-2018. Clin Toxicol (Phila). 2021. PMID: 33703981
Keywords: massive acetaminophen overdose, standard NAC, hepatotoxicity (PubMed Search)
Recently, there has been questions if standard n-acetylcysteine (NAC) dose is adequate for massive acetaminophen (APAP) overdose (ingestion of > 32 gm or APAP >300 mcg/mL).
A retrospective study from a single poison center (1/1/2010 to 12/31/2019) investigated the clinical outcome of massive APAP overdose (APAP > 300 mcg/mL at 4 hour post ingestion) treated with standard dosing of NAC.
1425 cases of APAP overdose identified; 104 met the criteria of massive APAP overdose.
Among cases that received NAC within 8 hours post ingestion (n=44)
Among cases that received NAC > 8 hours post ingestion (n=60)
Odds of hepatotoxicity
Keywords: Haloperidol, ondansetron, cannabis hyperemesis syndrome (PubMed Search)
Patients with cannabis hyperemesis syndrome experience recurrent/protracted nausea/vomiting. Cases of cannabis hyperemesis syndrome may increase as cannabis use becomes more common in the United States.
A randomized control trial (triple-blind) was conducted to compare haloperidol (0.05 or 0.1 mg/kg) IV or ondansetron 8 mg IV. Primary outcome was reduction of abdominal pain and nausea from baseline (on a 10 cm visual analog scale) 2 hours after treatment.
Ruberto AJ. et al. Intravenous haloperidol versus ondansetron for cannabis hyperemesis syndrome (HaVOC): a randomized controlled trial. Annals of Emergency Medicine. Nov 2020
Keywords: alcoholic ketoacidosis, toxic alcohol ingestion, anion gap metabolic acidosis (PubMed Search)
Anion gap metabolic acidosis is often found in ED patients. It can be difficult to distinguish between toxic alcohol (TA) ingestion and alcoholic ketoacidosis (AKA). A retrospective study attempted to identify risk factors associated with AKA when TA ingestion was the alternative diagnosis.
New York City poison center data was reviewed from Jan 1, 2000 to April 30, 2019.
Case definition of AKA included
Case definition of TA ingestion
Univariate analysis showed following variables to be associated with AKA diagnosis
Multivariate logistic regression showed elevated ethanol concentration was associated with increased odd of AKA diagnosis
Keywords: Serum insulin level table (Attachment) (PubMed Search)
Keywords: high dose insulin. insulin kinetic (PubMed Search)
High dose insulin (HDI) therapy is commonly used in patients with severe beta-adrenergic antagonist and calcium channel antagonist overdose. Hypoglycemia and hypokalemia are commonly known complication of HDI therapy. However, kinetics of insulin in patients who received HDI therapy is unknown.
A 51 year-old man with amlodipine overdose was infused HDI (10 unit/kg/hr) for 37 hours; Serial serum insulin levels were drawn after discontinuation of HDI.
Serum insulin levels are shown in below table
The serum insulin level remained significantly elevated during the first 24 hours (normal range: 2.6-24.9 microU/mL) and gradually decreased over 6 days.
Corcoran JN et al. Persistent hyperinsulinemia following high-dose insulin therapy: a case report. J Med Toxicol 2020;16:465-469.
Keywords: physostigmine, lorazepam, anticholinergic toxicity, delirium (PubMed Search)
Antimuscarinic agents (e.g. diphenhydramine) are one of the commonly ingested substances in the US. Lorazepam is frequently used to treat delirium and agitation associated with antimuscarinic toxicity. Although physostigmine is also effective, its use is infrequent due to concerns of safety and provider’s limited experience with physostigmine.
A small blinded randomized clinical trial was conducted to compare physostigmine vs lorazepam for the treatment of antimuscarinic toxicity -delirium/agitation.
Plus administration of lorazepam (0.05 mg/kg) IV bolus (max 2 mg) every 2 hours as needed for continued agitation or delirium (at the discretion of treatment team)
Delirium and agitation were assessed by Confusion Assessment Method for the Intensive Care Unit score (CAM-ICU) and Richmond Agitation Sedation Score
Study duration: March 20, 2017 to June 30, 2020
Antimuscarinic agent ingested
Proportion of subject with delirium by CAM-ICU
Prior to first bolus (p >0.99)
After 1st bolus (p=0.01)
End of 4 hr infusion (p <0.001)
No adverse events noted in both group
Wang GS et al. A randomized trial comparing physostigmine vs lorazepam for treatment of antimuscarinic (anticholinergic) toxidrome. Clin Toxicol (Phila.) 2020. Dec 9. Online ahead of print. https://doi.org/10.1080/15563650.2020.1854281