Keywords: antimuscarinic/anticholinergic toxicity, reversal of delirium (PubMed Search)
From 1960s to 1970s, physostigmine was routinely administered as part of the "coma cocktail." Since the publication of two cases by Pentel (1980) that resulted in asystole after administration of physostigmine in TCA poisoned patient, its use has declined significantly.
However, physostigmine still possess limited but clinically useful role in the management of patients with antimuscarinic/anticholinergic induced delirium.
Recently, a prospective observational study was performed in the use of physostigmine when recommended by a regional poison center.
In 1 year study period, physostigmine was recommended by a regional poison center in 125 of 154 patients with suspected antimuscarinic/anticholinergic toxicity.
common exposures were
57 of 125 patients received physostigmine per treating team.
Of the remaining patients,
Adverse events (physostigmine group vs. non-physo group) - no statistically significant difference.
Physostigmine can safely control antimuscarinic/anticholinergic-induced delirium.
Boley SP et al. Physostimgine is superior to non-antidote therapy in the management of antimuscarinic delirium: a prospective study from a regional poison center. Clin Toxicol 2018 Jun 29:1-6. doi: 10.1080/15563650.2018.1485154. [Epub ahead of print]
Keywords: acute agitation, midazolam, antipsychotics, (PubMed Search)
Acutely agitated patients in the emegency room receive single or combination of benzodiazepine (lorazepam vs. midazolam) and antipsychotic (e.g. haloperidol) agents. Recently, use of ketamine has also been advocated to sedate agitated patients.
A recently published article compared IM administration several medications to treat acutely agitated patients in the ED. According to established protocol, each medication was administered in predetermined 3 week blocks:
N=737 with median age of 40 years, 72% men.
Midazolam resulted in greater proportion of patients with "adequate" sedation (altered mentatl status scale <1) compared to antipsychotics at 15 min post administration. Among antipsychotics, olanzapine resulted in greater proportion of patient with sedation.
Adverse effect were limited
Midazolam 5 mg IM achieve more effective sedation at 15 min in agitated ED patients than antipsychotics.
Klein LR et al. Intramuscular midazolam, olanzapine, ziprasidone or haloperidol for treating acute agitaion in the emergency department. Ann of Emerg Med 2018 June 6. pii: S0196-0644(18)30373-1. doi: 10.1016/j.annemergmed.2018.04.027. [Epub ahead of print]
Keywords: Methylene Blue (PubMed Search)
Methylene Blue Used in the Treatment of Refractory Shock Resulting From Drug Poisoning. Fisher J, et al. Clin Toxicol 2914 Jan;52:63-65.
Calicum channel antagonist and beta blocker overdose: antidotes and adjunct therapies. Graudins A, et al. British Journal of Clin Pharm. 2016;81(3):453-461.
Keywords: Factor Xa inhibitor, reversal agent, adexanet alfa, andexxa (PubMed Search)
On May 3, the FDA approved adexanet alfa, the reversal agent for factor Xa inhibitors - apixaban and rivaroxaban. It received both U.S. Orphan Drug and FDA Breakthrough Therapy designations.
Unlike indarucizumab (a monoclonal antibody fragment) to reverse dabigatran (direct thrombin inhibitor) associated bleeding, adexanet alfa is a recombinant modified human factor Xa decoy protein.
A phase 3 study showed that adexanet alfa decreased the anti-factor Xa activity of rivaroxaban by 92% from baseline and by 94% in apixaban treated participants.
ANNEXA-4 study involving participants with acute major bleeding (GI and intracranial) showed a significant decrease in the anti-factor Xa activity after the bolus dose of adexanet alfa and "effective" hemostasis was noted in 79% of the participants at 12 hours post infusion.
Andexanet alfa is expected to become available in June 2018.
Keywords: Intralipid Emulsion (PubMed Search)
Despite initial excitement for the use of intravenous lipid emulsion (ILE) therapy as an antidote for serious poisonings due to lipohphilic drugs there remains an absence of evidence combined with an incomplete understanding of its efficacy, mechanisms of action, safety, and analytical interferences to recommend its use except in a few clinical scenarios.
The lipid emulsion workgroup performed a comprehensive analysis of four systematic reviews and based recommendations from consensus of expert panelists from the American Academy of Clinical Toxicology, the European Association of Poison Centres and Clinical Toxicologists, the American College of Medical Toxicology, the Asia Pacific Association of Medical Toxicology, the American Association of Poison Control Centers, and the Canadian Association of Poison Control Centers. Toxins evaluated had to have a minimum of three human cases reported in the literature.They concluded that ILE could be indicated for the following clinical situations:
The Bottom Line:
The use of Intravenous Lipid Emulsion in severe poisoning is recommended only for a few poisoning scenarios and was based on very low quality of evidence, and consideration of risks and benefits, adverse effects, laboratory interferences as well as related costs and resources.
Evidence-based recommendations on the use of intravenous lipid emulsion therapy in poisoning. Goseslin S. Hoegeberg L, Hoffman R, et al. Clinical Toxicology, 54:10, 899-923.
Intravenous Lipid Emulsion Therapy and VA-ECMO rescue therapy for Massive Venlafaxine and Clonazepam Overdose. Thomas A, Ovakim D, et al. J Clin Toxicol 2017 7: 368.
Keywords: fentanyl overdose, observation period (PubMed Search)
Non-pharmaceutical fentanyl (NPF) is a major contributor to opioid overdoses and overdose fatality. In certain urban areas such as Vancouver, over 80% of heroin samples contain NPF. For isolated heroin overdose ED patients, they can be safely discharged after brief observation period (~2 hours). However, “safe” observation time for fentanyl is unknown.
Recently, a retrospective study evaluating the safe observation period in 1009 suspected (uncomplicated) fentanyl overdose ED visits (827 unique patients).
In the field:
In the ED:
Scheuermeyer FX et al. Safety of a brief emergency department observation protocol for patients with presumed fentanyl overdose. Ann Emerg Med 2018 (PMID: 29530654)
Bradycardias caused by poisoning are due to the toxin's effects on cardiovascular receptors and cellular channels and transport mechanisms and are often refractory to standard ACLS drugs. The most common drug classes responsible for bradycardias are calcium channel and beta blockers and digoxin (cardiac glycosides). Sodium channel blockers, clonidine, and opiates also can cause bradycardias. Antidotes are as follows:
** ILE is recommended only in life threatening poisonings where other accepted therapies have been use first or in cardiac arrest clinical scenarios.
Toxic Bradycardias in the Critically Ill Poisoned Patient. Givens M. Emergency Medicine International. Vol 2012.
The safety of high-dose insulin euglycaemia therapy in toxin-induced cardiac toxicity.Page CB, Ryan NM, et al. Clin Toxicol. 2017 Oct 26:1-6
Keywords: clonidine toxicity, high-dose naloxone (PubMed Search)
Clonidine, (central alpha-2 receptor agonist) can produce opioid-like toxidrome in addition to its cardiac effects (bradycardia and hypotension). Previous studies have shown that naloxone has variable (~40%) success in reversing CNS/respiratory depression and cardiac effect.
A recent retrospective study (n=51) of pediatric poisoning showed that administration of 5 to 10 mg had improved reversal of clonidine toxicity.
Total of 51 somnolent patients: 5- 10 mg of naloxone reversed 40 patients
There was no adverse effect from naloxone administration.
Repeat administration of naloxone was required in some patients.
Seger DL, Loden JK. Naloxone resersal of clonidine toxicity: dose, dose, dose. Clin Toxicol (Phila) 2018 Mar 16:1-7. doi: 10.1080/15563650.2018.1450986. [Epub ahead of print]
Keywords: adulterated synthetic cannabinoid, elevated INR, brodifacoum (PubMed Search)
In the past couple of weeks, there have been reports from Illinois about patients using adulterated synthetic cannabinoids, resulting in elevated INR and bleeding. To date, there are approximately 70 cases including 3 fatalities. Brodifacoum, a long-acting vitamin K mediated anticoagulant (similar to warfarin) has been identified in 10 cases. Brodifacoum is frequently used as rodenticide.
This week, Maryland Poison Center received our first notification of a patient with bleeding and elevated INR due to suspected adulterated synthetic cannabinoid use.
When evaluating our patient population:
Patient management of suspected cases:
Patient can be discharged when INR < 2 is achieved with oral vitamine K regimen only (without recent FFP infusion).
Review of published cases highlights that most patients are started on a median doses of 100 mg/day (range: 15 - 600 mg) and stabilize on a PO regimen of 50-100 mg/day. Prolonged PO vitamin K course of 2 – 3 months or longer should be anticipated.
Pease call the Maryland Poison Center at 1-800-222-1222 as we are working with the Maryland Department of Health and CDC to track these cases.
Gunja N, Coggins A, Bidny S. Management of intentional superwarfarin poisoning with long-term vitamin K and brodifacoum levels. Clinical Toxicology. 2011;49(5):385-390. doi:10.3109/15563650.2011.587126.
Keywords: nerve agents, organophosphate compounds (PubMed Search)
Recently, an ex-Russian spy and his daughter were poisoned in Salisbury, England using a Soviet nerve agent called Novichok. He joins a list of defectors and ex-spies who's poisoning have been connected to Russia.
Nerve agents are organophosphate compounds, similar to the commercially available pesticides, but significantly more potent. Nerve agents such as VX take seconds to minutes to irreversibly inhibit acetylcholinesterase by “aging” and result in clinical toxicity.
Signs and symptoms
Keywords: cyanide, signs and symptoms (PubMed Search)
Signs and symptoms of acute cyanide poisoning are not well characterized due to its rare occurrence. Commonly mentioned characteristics of bitter almond odor and cherry red skin have poor clinical utility.
Recently published review of 65 articles (102 patients) showed that most patients experienced following signs and symptoms:
There is no clear toxidrome for cyanide poisoning.
In a poisoned patient, health care providers should consider cyanide in their differential diagnosis in the presence of severe metabolic and lactic acidosis (lactic acid > 8 in isolated cyanide poisoning or > 10 in smoke/fire victim).
Parker-Cote JL et al. Challenges in the diagnosis of acute cyanide poisoning. Clin Toxicol 2018 Feb 8:1-9. doi: 10.1080/15563650.2018.1435886. [Epub ahead of print]
Keywords: QTc, Dysrhythmias, drug overdose (PubMed Search)
A leading cause of cardiac arrest in patients 40 years and younger is due to drug poisoning. Adverse cardiovascular events (ACVE) such as myocardial injury (by biomarker or ECG), shock (hypotension or hypoperfusion requiring vasopressors), ventricular dysrhythmias (ventricular tachycardia/fibrillation, torsade de pointes), and cardiac arrest (loss of pulse requiring CPR) are responsible for the largest proportion of morbidity and mortality overdose emergencies. Clinical predictors of adverse cardiovascular events in drug overdose in recent studies include:
Obtain ECG and perform continuous telemetry monitoring in overdose patients with above risk factors. Patients with two or more risk factors have extremely high risk of in-hospital adverse cardiovascular events and intensive care setting should be considered.
Clinical risk factors for in-hospital adverse cardiovascular events after acute drug overdose. Manini AF, Hoffman RS, et al. Acad Emerg Med. 2015:22(5):499-507.
Incidence of adverse cardiovascular events in adults following drug overdose. Manini AF, Nelson LS, et al. Acad Emerg Med. 2012;19:843–9.
Keywords: nystagmus, toxic (PubMed Search)
Abnormal ocular movement (e.g. nystagmus) can often be observed in select CNS pathology.
Certain drugs/toxin overdose can also induce nystagmus.
In an "unknown" intoxication, physical exam findings such as nystagmus may help narrow the identity of the suspected ingestion/overdose.
Keywords: Cardiotoxicity, Bupropion, Ventricular dysrhythmia (PubMed Search)
Bupropion (Wellbutrin, Zyban) is unique monocyclic antidepressant and smoking cessation agent that is structurally similar to amphetamines. Bupropion blocks dopamine and norepinephrine reuptake and antagonizes acetylcholine at nicotinic receptors.
Bupropion is a common cause of drug induced seizures but in severe overdose can also cause prolonged QTc and wide complex ventricular dysrhythmia that may be responsive to sodium bicarbonate. All patients with an overdose of bupropion should have an ECG performed and cardiac monitoring to watch for conduction delays and life-threatening arrhythmias.
Wide complex tachycardia after bupropion overdose. Franco V. Am J Emerg Med. 2015 Oct;33 (10):1540.
Delayed bupropion cardiotoxicity associated with elevated serum concentrations of bupropion but not hydroxybupropion. Al-Abri SA, Orengo JP, et al. Clin Tox. 2013 Dec ;51(10):1230-4.
QRS widening and QT prolongation under bupropion: a unique cardiac electrophysiological profile. Caillier B. Pilote S. et al. Fundam Clin Pharmacol. 2012 Oct;26(5): 599-608.
Comparison of Resuscitative Protocols for Bupropion Overdose Using Lipid Emulsion in a Swine Model. Fulton LV, Fabrich RA, et al, Military Medicine 181, 5:482, 2016.
47 year old woman presents with cough, headache, weakness, and low grade fever. Her symptoms have been present for several days. Vital signs are temperature 99.9 F, HR 96, RR 16, BP 140/88, Pulse Ox 98%. Physical exam is nonfocal. She is Influenza negative. She is treated with Ibuprofen and oral fluids. Upon discharge she mentions she is having difficulty hearing and feels dizzy. Upon further questioning she admits to ringing in her ears. What tests should you order?
ANSWER: Salicylate and Acetaminophen levels.
Patient admits to taking BC Powder, an over the counter medication to self treat over the past few days. The active ingredients of BC powder are 845 mg of aspirin and 65 mg of caffeine. Her salicylate level is 45 mg/dL. Her other labs are unremarkable. Serial salicylate levels should be obtained every 2-4 hours and correlated with blood pH and clinical findings.
Salicylates commonly cause of ototoxicity. Tinnitus and hearing loss are early signs of salicylate toxicity and occur between 20-45 mg/dL. Other CNS effects are vertigo, hyperventilation, delirium, seizure, lethargy, and coma. Salicylate and acetaminophen are contained in numerous over the counter medications and are often mistakenly considered safe by the public resulting in accidental overdose. Early signs of toxicity can be missed or confused with other illness with serious consequences.
American College of Medical Toxicology. Guidance Document: Management Priorities in Salicylate Toxicity. J Med Tox. 2015;11(1):149-152.
Emergency department management of the salicylate-poisoned patient. O'Malley GF. Emerg Med Clin North Am. 2007 May ;25(2):333-46.
Keywords: Liver dialysis, MARS (PubMed Search)
Acute liver failure carries a high morbidity without liver transplantation. Liver support systems can act as “bridge” until an organ becomes available for the transplant procedure or until the liver recovers from injury. Artificial liver support systems temporally provide liver detoxification utilizing albumin as scavenger molecule to clear the toxins without providing synthetic functions of the liver (coagulation factors). One of the most widely used devices is the Molecular Adsorbent Recirculating System (MARS).This system has 3 different fluid compartments: blood circuit, albumin with charcoal and anion exchange column, and a dialysate circuit that removes protein bound and water soluble toxins with albumin.
MARS therapy could be a potentially promising life saving treatment for patients with acute poisoning from drugs that have high protein-binding capacity and are metabolized by the liver, especially when concomitment liver failure. Consider consultation and transfer of patients to liver center.
The Molecular Adsorbent Recirculating System (MARS®) in the Intensive Care Unit: A Rescue Therapy for Patients with Hepatic Failure. F Saliba, Critical Care 10.1 (2006): 118.
Keywords: activated charcoal, large acetaminophen overdose, NAC dose (PubMed Search)
Acetaminophen (APAP) overdose is the leading cause of liver failure in the U.S. and Europe. Large APAP ingestion can result in hepatotoxicity despite the early initiation of n-acetylcysteine (NAC).
A recently published study from Austrialia investigated the effect of activate charcoal and increasing the NAC dose for large APAP overdose patients (3rd bag: 100 to 200 mg/kg over 16 hours) during first 21 hours of NAC therapy
acetaminophen ratio (first APAP level taken between 4 to 16 hour post ingestion / APAP level on the Rumack nomogram line at that time point) was determined to compare APAP levels at different time points among study sample
first APAP level at 4 hour post ingestion = 400
APAP level on the Rumack APAP nomogram at 4 hour post ingestion = 150
APAP ratio = 400/150 = 2.67
Note: Any increase in NAC dosing from the standard 21 hour therapy should be performed after consulting your regional poison center.
Chiew AL et al. Massive paracetamol overdose: an obsevational study of the effect of activated charcoal and increased acetylcysteine dose (ATOM-2). Clin Toxicol 2017;55:1055-1065. PMID: 28644687.
Keywords: Loperamide, cardiotoxicity, QT prolongation (PubMed Search)
Loperamide (Imodium) is a common inexpensive over-the counter antidiarrheal agent. It acts peripherally at the mu opioid receptor to slow gastrointestinal motility and has no CNS effects at therapeutic doses due to it's low bioavailability and limited abillity to cross the blood brain barrier dependent on glycoprotein transport. In the past few years, reports of loperamide abuse causing serious cardio toxicity began to appear in the literature. Abused at daily doses of 25-200 mg to get high or and to treat symptoms of withdrawal. (therapeutic dose: 2-4 mg with a maximun of 8mg for OTC and 16mg for prescription). Loperamide has been called the "poor man's methadone".
At large doses, loperamide effects the cardiac sodium, potassium and calcium channels which prolongs the QRS complex and can lead to ventricular arrhythmias, hypotension, and death. Clinical features includes:
Take Home Point:
Consider loperamide as a possible cause of unexplained cardiac events including QT interval prolongation, QRS widening, Torsades de Pointes, ventricular arrhythmias, syncope, and cardiac arrest. Intravenouse sodium bicarbonate should be utilized to overcome blockade and may temporize cardiotoxic events. Supportive measures necessary may include defibrillation, magnesium, lidocaine, isoproternol, pacing, and extracorporeal life support.
Cardiac Conduction disturbance after loperamide abuse. Marraffa JN, Holland MG, Clin Toxicol. 2014;52(9):952-957.
Poor man's Methadone: A case report of Loperamide toxicity.Dierksen J, Gonsoulin M, et al. Am J Forensic Med Pathol. 2015 Dec:36(4): 268-70.
FDA Drug Safety Communication: FDA warns about serious heart problems with high doses of the antidiarrheal medicine loperamide (Imodium), including from abuse and misuse [06-07-2016]. Available from: http://www.fda.gov/Drugs/DrugSafety/ucm504617.htm
Keywords: green urine (PubMed Search)
Different chemical, food or pharmaceutical agent exposure can change the color of the urine.
What could cause this patient's urine to turn green?
Green or greenish-blue color urine can result from exposure to follow substances:
The picture came from a patient who received methylene blue after being diagnosed with methemoglobinemia (65%).
Keywords: Hemodialysis, lithium (PubMed Search)
Lithium salts have been used therapeutically for over a 150 years to sucessfully treat manic depressive symptoms, schizoaffective disorder, and cluster headaches. Lithium has a narrow therapeutic range (0.6-1.5 meq/L) and is 100% eliminated by the kidneys. Multisystem toxicity occurs however CNS toxicity is significant and consist of confusion, lethargy, ataxia, neuromuscular excitability (tremor, fasciculations, myoclonic jerks, hyperreflexia). Since there is a poor relationship between serum concentration and toxicity in the brain, serum blood levels may not reflect extent of toxicity . The goal of enhanced elimination is to prevent irreversible lithium-effectuated neurotoxcity which causes persistant cerebellar dysfunction with prolonged exposure of the CNS to high lithium levels.
Decision for hemodialysis is determined by clinical judgement after considering factors such as lithium concentration, clinical status of patient, pattern of lithium toxicity (acute vs. chronic), concurrent interacting drugs, comorbid illnesses, and kidney function. Strongly consider hemodialysis for the following:
Extracorpeal treatment for Lithoum Poisoning: Systematic Review and Recommendations from the EXTRIP Workgroup. Decker BS, et al. Clin Am Soc Nephrology 2015 Jan
The Syndrome of irreversible lithium-effectuated neurotoxicity. Adityjee, et al. Clin Neuropharmacol. 2005 Jan-Feb;28(1):38-49.