# Lidocaine for Sodium Channel Toxicity in Diphenhydramine Overdose: A Case Report

Kassem Michael Makki, David Mandil, Roger Hopson, Maxim Kashin, Roger

Rothenberg, Noah Reisman, Brenna Farmer

► To cite this version:

Kassem Michael Makki, David Mandil, Roger Hopson, Maxim Kashin, Roger Rothenberg, et al. Lidocaine for Sodium Channel Toxicity in Diphenhydramine Overdose: A Case Report. Clinical Practice and Cases in Emergency Medicine, 2025, 9 (2), pp.223-227. 10.5811/cpcem.41491. inserm-05345004

HAL Id: inserm-05345004

https://inserm.hal.science/inserm-05345004v1

Submitted on 3 Nov 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
**Title**

Lidocaine for Sodium Channel Toxicity in Diphenhydramine Overdose: A Case Report

**Permalink**

https://escholarship.org/uc/item/2b49595b

**Journal**

Clinical Practice and Cases in Emergency Medicine, 9(2)

**Authors**

Makki, Kassem Michael
Mandil, David
Hopson, Roger
et al.

**Publication Date**

2025-04-30

**DOI**

10.5811/cpcem.41491

**Copyright Information**

This work is made available under the terms of a Creative Commons Attribution License,
available at https://creativecommons.org/licenses/by/4.0/

Peer reviewed
# Lidocaine for Sodium Channel Toxicity in Diphenhydramine Overdose: Case Report

Kassem Makki DO*

*New York Presbyterian-Brooklyn Methodist Hospital, Division of Emergency Medicine

David Mandil MD*

†New York Presbyterian-Brooklyn Methodist Hospital, Division of Internal Medicine, Pulmonary and Critical Care

Roger Hopson MD†

Maxim Kashin MD†

‡New York University Langone Health, Division of Toxicology

Roger Rothenberg MD‡

Noah Reisman MD†

Brenna Farmer MD*

Section Editor: Steven Walsh, MD

Submission history: Submitted December 17, 2024; Revision received February 4, 2025; Accepted February 28, 2025

Electronically published April 30, 2025

Full text available through open access at http://escholarship.org/uc/uciem_cpcem

DOI: 10.5811/cpcem.41491

**Introduction:** Diphenhydramine overdose is a growing concern, particularly among adolescents influenced by online challenges. Traditionally managed with supportive care and sodium bicarbonate, severe cases may exhibit refractory symptoms due to sodium channel toxicity, necessitating alternative treatments.

**Case Report:** A 28-year-old male with a history of anxiety and depression presented to the emergency department unresponsive, next to an empty bottle of diphenhydramine and wine bottles. Vital signs indicated hypotension and hypoxia. The patient was intubated and administered vasopressors. Initial electrocardiogram (ECG) showed a widened QRS complex and terminal R wave in lead aVR, suggesting sodium channel blockade. Treatment with multiple boluses of sodium bicarbonate was ineffective. Lidocaine (95 milligrams intravenously) was administered, resulting in improved ECG findings and patient stabilization. Subsequent care focused on supportive measures and treatment for aspiration pneumonia. The patient was extubated on day two and discharged on day seven to a behavioral health facility.

**Conclusion:** This case underscores the effectiveness of lidocaine as a secondary treatment for diphenhydramine-induced sodium channel toxicity when standard sodium bicarbonate therapy fails. Lidocaine's ability to restore myocardial conduction illustrates its potential as a critical intervention in toxicological emergencies. [Clin Pract Cases Emerg Med. 2025;19(2):223-227.]

**Keywords:** diphenhydramine overdose; sodium channel toxicity; lidocaine; case report; sodium bicarbonate resistance.

## INTRODUCTION

Diphenhydramine is a commonly misused over-the-counter drug intended for allergies or as a sleep aid, with overdose rates particularly high among children and adolescents due to rising social media challenges like the TikTok "Benadryl Challenge" became popular.¹ Among overdose deaths, diphenhydramine is the most common antihistamine found.² Although perceived as

an H1 receptor antagonist, it functions as an inverse agonist, affecting histamine and acetylcholine receptor activity.³ In overdose, effects can range from mild sedation and tachycardia to coma, seizures, and cardiac dysrhythmias.⁴ First-generation antihistamines like diphenhydramine cross the blood-brain barrier, leading to central nervous system effects, unlike second-generation antihistamines, which are more selective for
peripheral receptors. Most drugs from both generations are
metabolized hepatically via the cytochrome P450 system, but
their duration of action differs significantly.⁵

After oral intake at therapeutic doses, diphenhydramine
concentration peaks in the bloodstream within two to three
hours. After first-pass metabolism, 40-60% of an oral dose
enters systemic circulation, with excretion predominantly via
urine. The drug's half-life ranges from 4-17 hours, increasing in
duration with patient age.⁴,⁶ Toxicity may manifest as
antimuscarinic effects such as tachycardia, blurred vision, dry
mucous membranes, and urinary retention. Sodium channel
blockade from tricyclic antidepressant (TCA) effects can lead to
QRS widening and subsequent cardiovascular collapse from
dysrhythmias. Pediatric fatalities have been reported at doses
below 500 milligrams (mg), with seizures noted at 150 mg. For
adults, the fatal dose is estimated at 20-40 mg per kilogram
(kg). Overdose treatment is largely supportive. However,
antidotal therapy with physostigmine to treat the antimuscarinic
effects and treatment of sodium channel blockade with sodium
bicarbonate to treat dysrhythmia may be necessary.⁷

## CASE REPORT

A 28-year-old man with a past medical history of anxiety,
depression, stiff person syndrome, and Hashimoto thyroiditis
was brought to the emergency department (ED) unresponsive
after being found next to an empty bottle of diphenhydramine
and multiple wine bottles. Upon presentation to the ED, vital
signs were noted as follows: blood pressure, 104/27
millimeters mercury (mm Hg); heart rate, 90 beats per minute;
respiratory rate, 18 breaths per minute; and oxygen saturation
was low at 87% on room air. Due to the patient's altered
mental status, critical illness, and concern for airway
protection, he was orotracheally intubated with etomidate and
rocuronium and placed on mechanical ventilation. Post rapid
sequence intubation sedation was done with propofol and

<figure><img src="image_2.png" /><figcaption>**Image 1.** Initial electrocardiogram (8:52 AM) notable for widened QRS to 162 milliseconds (blue bracket) with terminal R wave noted in AVR (blue arrow).</figcaption></figure>

## CPC-EM Capsule

What do we already know about this clinical
entity?

*Diphenhydramine overdose can cause severe sodium channel blockade, leading to widened QRS, ventricular arrhythmias, and hemodynamic instability.*

What makes this presentation of disease
reportable?

*Despite multiple sodium bicarbonate boluses, the patient had persistent QRS widening and ventricular tachycardia, which was successfully reversed with lidocaine.*

What is the major learning point?

*Lidocaine may serve as an effective alternative treatment for refractory sodium channel toxicity when sodium bicarbonate fails in diphenhydramine overdose.*

How might this improve emergency medicine
practice?

*This case highlights the importance of recognizing lidocaine as a secondary therapy in diphenhydramine toxicity and optimizing treatment protocols for sodium channel blockade.*

dexmedetomidine. Due to the patient's hypotension,
norepinephrine was initiated. Initial electrocardiogram (ECG)
demonstrated sinus rhythm at a rate of 54 beats per minute, a
terminal R wave in lead aVR of 9 mm, and a QRS interval of
162 milliseconds (msec) (reference range: 80-100 msec),
findings suggestive of sodium channel blockade like those
seen in TCA overdoses⁸,⁹ (Image 1).

Poison control was called at this time; their
recommendations were to give sodium bicarbonate and repeat
vitals and ECGs on the patient. They did not specify dosing.
They suggested that we look for co-ingestions as well, and if
there was no improvement to possibly try extracorporeal
membrane oxygenation. Venous blood gas (VBG) revealed
severe metabolic acidosis with pH less than 7.00 (7.32-7.43), a
markedly elevated partial pressure of carbon dioxide over 115
mmHg (40-60 mm Hg), and a lactic acid level exceeding 20
millimoles per liter (mmol/L) (0.5-2.0 mmol/L). To treat
sodium channel blockade, the patient received 11 boluses of
8.4% sodium bicarbonate totaling 550 milliequivalents. A
repeat ECG showed no improvement, with sinus tachycardia
<figure><img src="image_3.png" /><figcaption>**Image 2.** Electrocardiogram after sodium bicarbonate and amiodarone administration 10:12 AM (notable for persistently widened QRS to 144 milliseconds with terminal R wave in AVR still present (blue arrow).</figcaption></figure>

at a rate of 156, widened QRS complex of 174 msec, and a terminal R wave in lead aVR of 7 mm (Image 2). The patient's blood pressure did improve to 122/24 after administration of norepinephrine post-intubation.

Initially, this rhythm was interpreted as ventricular tachycardia ventricular tachycardia by the bedside team, who administered a bolus of 150 mg amiodarone and attempted synchronized cardioversion twice, with no appreciable response. Repeat VBG at this time demonstrated a pH of 7.31. Given the lack of appreciable ECG changes despite alkalinization, further sodium bicarbonate was not administered. The attending physician made the decision to administer 95 mg intravenous lidocaine based on the patient's weight (1-1.5 mg/kg) at 10:16 AM due to minimal improvement of V-tach and refractory V-tach. At 10:38 AM the patient's ECG improved, demonstrating sinus tachycardia with a rate of 140 beats per minute, QRS 104 msec, and a decreased terminal R wave amplitude in aVR to 2.5 mm (Image 3).

<figure><img src="image_4.png" /><figcaption>**Image 3.** Electrocardiogram after lidocaine administration QRS duration decreased to 102 milliseconds 10:38 AM – lidocaine administered at 10:30 AM (per electronic health record).</figcaption></figure>

Activated charcoal, 100 grams, was then administered via nasogastric tube. The urine toxicology screen was negative for any commonly detected drugs of abuse. Serum acetaminophen and salicylate concentrations were undetectable. The patient was admitted to the intensive care unit (ICU), where he continued to receive supportive care and treatment for aspiration pneumonia. Given that sodium bicarbonate has considerable effects on their serum potassium concentration, the initial potassium once the patient was stabilized and then admitted to the ICU was 2.7 mmol/L. An initial potassium was not determined before the boluses of sodium bicarbonate were given. A serum diphenhydramine concentration obtained approximately eight hours after arrival was found to be elevated at 2,500 nanograms/mL. To note, the recommendations for diphenhydramine dosing are 25–50 mg orally every 4–6 hours, with a maximum dose of 300 mg/day.

The patient was extubated on hospital day two and transferred to the general medical floor on hospital day three, during which time he admitted to psychiatry and hospital staff that the overdose was intentional. He was discharged to a behavioral health facility on hospital day seven where an additional ECG showed normal sinus rhythm (Image 4).

## DISCUSSION

This patient exhibited severe cardiovascular toxicity from diphenhydramine overdose as evidenced by his ECG changes. He presented with severe sodium channel toxicity secondary to diphenhydramine overdose, exhibiting hypotension, widened QRS, and acidosis. Despite initial treatment with sodium bicarbonate and amiodarone, the QRS complex remained persistently wide with a terminal R wave in aVR. After a bolus of lidocaine, the QRS narrowed significantly, and the patient stabilized. He was admitted to the ICU on a bicarbonate drip and did not require additional doses of lidocaine. A detailed timeline of this case can be seen in Figure below.

Diphenhydramine, an H1 histamine receptor inverse agonist commonly used for its antiallergic and sedative

<figure><img src="image_5.png" /><figcaption>**Image 4.** Electrocardiogram with normal sinus rhythm on day seven.</figcaption></figure>
<figure><img src="image_6.png" /><figcaption>**Figure.** Case timeline.

bicarb, bicarbonate; i-STAT, portable blood analysis system (Abbott Laboratories, Chicago, IL).</figcaption></figure>

properties, works on many different pathways including the histamine and muscarinic receptors as well as sodium channels in the neurologic and cardiovascular systems. The ECG findings in this case demonstrated sodium channel blockade with a prolonged QRS interval (>100 msec) and terminal R wave in lead aVR, similar to ECG findings seen in TCA toxicity. The presence of a terminal R wave in lead aVR (terminal rightward axis deviation) and a widened QRS interval suggested severe toxicity, consistent with the patient's clinical condition.¹⁰ These ECG changes were effectively managed with hypertonic sodium bicarbonate therapy in this scenario.

The literature provides multiple instances where these specific ECG alterations have been observed, such as the case of a 13-year-old female who overdosed on diphenhydramine. Treatment with sodium bicarbonate usually reverses these changes and improves symptoms.¹¹ Unfortunately, although sodium bicarbonate improved our patient's acidemia, it did not improve the cardiovascular toxicity as reflected by ECG.

The cardiotoxic effects attributed to diphenhydramine, including wide-complex tachycardia, arise from its blockade of fast sodium channels on cardiac membranes. This prolongs phase 0 of the cardiac action potential and delays electrical conduction through the heart, akin to the action of class Ia antiarrhythmics.¹² Sodium bicarbonate counteracts the cardiotoxic effects by increasing the transcellular sodium concentration gradient, decreasing xenobiotic affinity for the sodium channel by increasing pH, and restoring normal myocardial conduction.¹² In this case, a large amount of sodium bicarbonate was given with little, if any, improvement in the cardiac conduction abnormalities, despite effective alkalinization as demonstrated by VBG.

Lidocaine is a class Ib anti-dysrhythmic with affinity for

inactivated sodium channels, resulting in decreased action potential duration and decreased effective refractory period.¹³ Lidocaine exhibits “fast on, fast off” sodium channel binding kinetics, meaning it rapidly binds to and inhibits the channel before quickly dissociating, restoring normal function. This property allows lidocaine to effectively compete with diphenhydramine, displacing it from the sodium channel. Despite its rapid dissociation, a single dose of lidocaine may lead to sustained improvement by transiently restoring normal sodium channel function, allowing endogenous recovery mechanisms—such as drug redistribution or metabolism—to reduce diphenhydramine’s inhibitory effects over time.¹³ This property allows lidocaine to “compete” with diphenhydramine and effectively displace it from the sodium channel. This case demonstrates the effective use of lidocaine in refractory sodium channel blockade unresponsive to sodium bicarbonate therapy and its utility for toxicologic Advanced Cardiovascular Life Support (ACLS). Lidocaine has become a second- or third-line antidysrhythmic in ACLS algorithms due to the evolution of the medical literature over the years.¹³

## CONCLUSION

This report highlights the successful use of lidocaine for refractory sodium channel toxicity following a diphenhydramine overdose in a 28-year-old male. Despite initial management with sodium bicarbonate, only lidocaine effectively reversed the severe cardiotoxic effects. This case emphasizes lidocaine's potential utility in ACLS for toxicological emergencies. It also underscores the variability in treatment responses, urging further investigation into alternative therapeutic strategies for managing drug-induced cardiac disturbances.
The authors attest that their institution requires neither Institutional Review Board approval, nor patient consent for publication of this case report. Documentation on file.

**Address for Correspondence:** Kasem Makki, DO, New York - Presbyterian Brooklyn Methodist Hospital, Emergency Department, 506 6th Street, Brooklyn, NY 11215. Email: ake9002@nyp.org.

**Conflicts of Interest:** By the CPC-EM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.

**Copyright:** © 2025 Makki et al. This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) License. See: http://creativecommons.org/licenses/by/4.0/

## REFERENCES

1. FDA. Benadryl (Diphenhydramine): Drug Safety Communication— Serious Problems with High Doses of the Allergy Medicine. Available from: https://www.fda.gov/safety/medical-product-safety-information/ benadryl-diphenhydramine-drug-safety-communication-serious- problems-high-doses-allergy-medicine. Accessed August 21, 2024.

2. Dinwiddie AT, Tanz LJ, Bitting J, et al. Notes from the field: antihistamine positivity and involvement in drug overdose deaths - 44 jurisdictions, United States, 2019-2020. *Morb Mortal Wkly Rep.* 2022;71(41):1308-1310.

3. Abdi A, Rose E, Levine M. Diphenhydramine overdose with intraventricular conduction delay treated with hypertonic sodium bicarbonate and IV lipid emulsion. *West J Emerg Med.* 2014;15(7):855-858.

4. Gosselin S. (2019). Antihistamines and decongestants. In: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS, eds. *Goldfrank's Toxicologic Emergencies*. 11th ed. New York, NY: McGraw-Hill Education.

5. Farzam K, Sabir S, O'Rourke MC. Antihistamines. *StatPearls* [Internet]. Treasure Island, FL: StatPearls Publishing; 2024 Jan. Updated July 10, 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538188/. Accessed May 2, 2024.

6. Simons KJ, Watson WT, Martin TJ, et al. Diphenhydramine: pharmacokinetics and pharmacodynamics in elderly adults, young adults, and children. J Clin Pharmacol. 1990;30(7):665-671.

7. Patel J and Edwards J. Treating diphenhydramine overdose: a literature review of currently available treatment methods. *Toxics*. 2024;12(6):376.

8. Boehnert MT and Lovejoy FH Jr. Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. *N Engl J Med*. 1985;313(8):474-479.

9. Liebelt EL, Francis PD, Woolf AD. ECG lead aVR versus QRS interval in predicting seizures and arrhythmias in acute tricyclic antidepressant toxicity. *Ann Emerg Med*. 1995;26(2):195-201

10. Jang DH, Manini AF, Trueger NS, et al. Status epilepticus and wide-complex tachycardia secondary to diphenhydramine overdose. *Clin Toxicol (Phila)*. 2010;48(9):945-948.

11. Bruss P, Bowman C, Carroll T. Electrocardiogram abnormalities following diphenhydramine ingestion: a case report. *J Educ Teach Emerg Med*. 2023;8(1):V11-V13.

12. Clark RF and Vance MV. Massive diphenhydramine poisoning resulting in a wide-complex tachycardia: successful treatment with sodium bicarbonate. *Ann Emerg Med*. 1992;21(3):318-321.

13. Güler S, Könemann H, Wolfes J, et al. Lidocaine as an antiarrhythmic drug: Are there any indications left? *Clin Transl Sci*. 2023;16(12):2429-2437.