Updates in Antidotal Therapy

Educational Objectives

The goal of this program is to improve management of common toxicities. After hearing and assimilating this program, the clinician will be better able to:

1. Recognize patients with sodium nitrite poisoning who require treatment with methylene blue.

Summary

Acetaminophen toxicity: ingested acetaminophen is typically metabolized to nontoxic conjugates; small amounts may be oxidized to N-acetyl-p-benzoquinone imine (NAPQI), which causes organ toxicity; however, glutathione binds to NAPQI in normal therapeutic dosing to make it nontoxic; conjugation is saturated and the oxidation process is increased in acetaminophen overdose, which produces high NAPQI levels; glutathione is depleted and the patient experiences toxicity; acetyl cysteine is a common antidote for acetaminophen that acts on the glutathione pathway; fomepizole may be an ideal antidote of acetaminophen overdose because it inhibits the oxidative pathway (it is a potent inhibitor of cytochrome 2E1) and the pathway that causes hepatocyte destruction

N-acetyl cysteine (NAC): limits the production of NAPQI, increases capacity to detoxify NAPQI, acts as a glutathione precursor and substitute, and preserves multiorgan function; NAC has near complete efficacy when given <8 hr after acetaminophen overdose (<6 hr of very severe overdoses)

Presentations of acetaminophen toxicity: early presenter — presents <8 hr after ingestion; a significant amount of acetaminophen has not metabolized; later presenter — presents 8 to 24 hr after ingestion; patients have normal or high transaminase and may have high oxidative stress; late presenter — present >24 hr after ingestion; hepatotoxicity and potentially liver failure is seen; NAC is usually administered; large overdose early presenters may have an acetaminophen level of 300 to 600 mcg/mL, which increases incidence of hepatic injury despite NAC initiation; liver function tests are elevated despite timely initiation of NAC

Fomepizole: intraperitoneal acetaminophen followed by fomepizole prevented hepatotoxicity in mouse models; 80 mg/kg of acetaminophen followed by fomepizole decreased oxidative metabolites in human volunteers; data for fomepizole are confounded by concurrent administration of NAC

Antimuscarinic delirium (AD): AD results from the blocking of antimuscarinic receptors in the brain; benzodiazepines (BDZ) are often used for AD, but BDZ do not treat the underlying pathophysiology and have adverse effects; cholinesterase inhibitors are preferred; physostigmine is effective but not currently available; not all cholinesterase inhibitors are centrally acting because some are unable to cross the blood brain barrier; rivastigmine crosses the blood brain barrier and reverses delirium; time to peak concentration is 1 to 2 hr and half-life is ≈2 hr for oral rivastigmine; transdermal patches take an extended period to achieve peak concentration but have a sustainable effect; the oral dose of rivastigmine is 3 to 6 mg; patches are dosed at 13 mg/day; no significant adverse effects have been reported

Contraindications: patients with bradycardia should not receive cholinesterase inhibitors because of the risk for bronchoconstriction and QRS prolongation; cholinesterase inhibitors lower the seizure threshold; oral tolerability is an issue; the adult dose is 3 to 6 mg repeated in 2 hr, if needed

Sodium nitrite poisoning: done with suicidal intent; reagent grade sodium nitrite is readily available; acquired methemoglobinemia is typically mild, but patients with intentional poisoning ingest higher doses and present with severe symptoms; central and peripheral cyanosis occurs but may be hard to detect in some patients; methemoglobinemia is a functional deficiency of hemoglobin which can be exacerbated by pulmonary dysfunction and anemia; chocolate-colored blood may be seen; methemoglobin interferes with pulse oximetry because of higher absorbance of methemoglobin than oxy- and de-oxyhemoglobin; methemoglobin levels of 30% produce pulse oximetry readings of 80% to 85% despite supplemental oxygen; another etiology should be considered if patients respond to supplemental oxygen; hemoglobinopathy should be considered if patients have no response to oxygen

Management: monitor levels in patients with methemoglobin levels <30% who are asymptomatic with no other signs of end-organ toxicity; initiate antidote therapy (methylene blue) in patients with symptoms of end-organ damage and respiratory distress; methylene blue is recommended in patients with levels >30% regardless of symptoms; the dose of methylene blue 1% solution is 1 to 2 mg/kg over 5 min followed by fluids; an initial reduction in pulse oximetry should recover 5 to 10 min after administration; repeat the dose if no response is seen in 30 to 60 min; ascorbic acid is not recommended; exchange transfusion may be considered in severe poisoning; hyperbaric oxygen is reported to have been used; death is reported in 30% of patients and serious outcomes in 84%; good communication with pre-hospital providers is important; cardiopulmonary resuscitation in patients with cardiac arrest is generally ineffective because the inability of blood to carry oxygen; administer methylene blue as soon as possible; severe cases may require 3 mg/kg initial dose with rapid repeat; doses >6 mg/kg increases risk for hemoglobinemia

Readings

Benlamkaddem S, Iken I, Houari N, et al. Paracetamol self-poisoning: When oral N-acetylcysteine saves life? a case report. Pan Afr Med J. 2018;29:83. Published 2018 Jan 29. doi:10.11604/pamj.2018.29.83.10595; Fratta KA, Ginder M, Haggerty DA. Oral and transdermal rivastigmine for the treatment of anticholinergic delirium: A case report. J Emerg Med. 2023;65(4):e366-e368. doi:10.1016/j.jemermed.2023.06.008; Katabami K, Hayakawa M, Gando S. Severe methemoglobinemia due to sodium nitrite poisoning. Case Rep Emerg Med. 2016;2016:9013816. doi:10.1155/2016/9013816; Pohanka M. Inhibitors of acetylcholinesterase and butyrylcholinesterase meet immunity. Int J Mol Sci. 2014;15(6):9809-9825. Published 2014 Jun 2. doi:10.3390/ijms15069809; Wang GS, Baker K, Ng P, et al. A randomized trial comparing physostigmine vs lorazepam for treatment of antimuscarinic (anticholinergic) toxidrome. Clin Toxicol (Phila). 2021;59(8):698-704. doi:10.1080/15563650.2020.1854281.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose. Dr. Yakey's lecture includes information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Yakey was recorded at Michigan Emergency Medicine Assembly, held July 30 to August 2, 2023, on Mackinac Island, MI, and presented by the Michigan College of Emergency Physicians. For information on future CME activities from this presenter, please visit https://www.mcep.org/. Audio Digest thanks speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0.75 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0.75 CE contact hours.

Lecture ID:

EM411502

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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