Via Research Recognition Day 2024 VCOM-Carolinas

Clinical Case-Based Reports

Serotonin Syndrome due to Self-Injection of Methylene Blue Maya Aboutanos, OMS-III, Dr. Marc Ciesco, DO. Edward Via College of Osteopathic Medicine, Spartanburg, SC.

Abstract

Report of Case

Discussion

Context: Methylene Blue (MB) is utilized for a variety of medical treatments and procedures such as methemoglobinemia (MetHb), vasoplegic syndrome, and sentinel lymph node biopsies. As a monoamine oxidase inhibitor (MAO-I), MB can precipitate serotonin syndrome in patients concurrently taking a serotonergic agent. Case Report : A 30 year-old African American male presented to the emergency department (ED) with dyspnea, tachycardia, chills, tremors, dizziness, headaches, arthralgias, muscle pain, hypotension, and tachycardia after intentionally injecting himself intravenously with 300 mg of 1% MB. Despite adequate fluid resuscitation, the patient became diaphoretic, agitated, and febrile, with systolic blood pressures dropping to 85 mmHg. He was admitted to the ICU for serotonin syndrome due to MB toxicity and the simultaneous use of fluvoxamine. The patient was treated with a norepinephrine drip, antipyretics analgesics, benzodiazepines, and electrolyte replenishment. His home fluvoxamine was held. As the patient improved clinically, he was weaned off of pressors and slowly restarted on fluvoxamine. Conclusion : In patients taking serotonergic agents, MB can precipitate serotonin syndrome over a dose of 5 mg/kg IV 1% MB solution over 5-30 minutes or more than 100 mg in a single bolus dose. Our patient injected himself with 30 ml of 1% MB solution (300 mg) as a bolus dose. This self administered MB overdose contrasts current literature, which primarily focuses on iatrogenic MB toxicity in hospital settings. MB is considered an antidote for many toxicities, yet this case describes a unique incident exhibiting the toxicity of the antidote. Methylthioninium chloride, commonly called Methylene blue, is a thiazine organic salt primarily utilized within hospital settings as an antidote and procedural visual guide, due to its various mechanisms of actions and blue dye coloring. 1 However, as a MAO-I, MB can precipitate serotonin syndrome in patients who are concurrently taking serotonergic agents such as SSRIs, SNRIs, and TCAs. 2 Serotonin syndrome is a life-threatening condition in which increased levels of serotonergic activity in the body precipitate autonomic hyperactivity, neuromuscular changes, and alterations in mental status. 3,4,5 MB has been shown to precipitate serotonin syndrome over a dose of 5 mg/kg IV 1% MB solution over 5-30 minutes or more than 100 mg in a single bolus dose. 2,6 One literature review identified 23 manuscripts from 2008-2018 with 50 unique cases of MB-induced serotonin syndrome, primarily with perioperative parenteral MB administration for parathyroidectomies (32 cases) or for vasoplegic shock treatment (10 cases). The remaining cases were from ifosfamide toxicity treatment, urological procedures, and a sentinel lymph node biopsy. All patients were simultaneously taking serotonergic antidepressants, with 47 individuals prescribed either a SSRI or SNRI and 3 individuals on TCAs. 7 Current literature supports the treatment of MB-induced serotonin syndrome with discontinuation of serotonergic agents, supportive care, and benzodiazepines. 8,9 Upon initiation of treatment, mild cases will typically resolve in 24-72 hours. 9,10 With more severe cases, there is concern for hypoventilation due to hypothermia and rigidity, 9 and therefore intubation and neuromuscular paralysis should be considered. 10 Cyproheptadine, a serotonin antagonist, has been shown to provide treatment for severe and refractory cases. 9,10,11 This report explores a case of MB-induced serotonin syndrome in which the patient intravenously injected himself with 1% liquid MB solution, contrasting current literature which primarily focuses on iatrogenic MB toxicity in hospital settings. Introduction

References The harmful effects of MB are described in literature as serotonin syndrome in the presence of other serotonergic agents. These MB-induced serotonin syndromes are exclusively reported within hospital settings in which MB is utilized either for treatment or as a visual aid in surgical procedures. This case provides a unique incidence in which the patient intravenously self administered a liquid MB solution. With his simultaneous use of fluvoxamine and associated symptoms, the patient met Hunter Toxicity Criteria for serotonin syndrome 4,5 and was admitted to the ICU. Although the treatment of serotonin syndrome details discontinuation of current serotonergic medications, it can be unclear when to initiate cyproheptadine as there are few case reports detailing such escalation of treatment. This patient’s symptoms began to resolve in parallel with the half-life of MB which is 5.25 hours, 6 providing reassurance that cyproheptadine was not indicated. Serotonin syndrome is often under-recognized and carries a high mortality rate when missed clinically. As the prevalence of mood disorders and use of serotonergic agents increase, 12 the greater the risk of precipitating serotonin syndrome. There are many medications and supplements with serotonergic activity that can contribute to serotonergic syndrome when multiple medications are administered. Despite its MAO-I properties, MB is generally perceived as safe and natural and therefore often recruited to treat and diagnose medical conditions. With MB readily available for purchase online and misinformation on its utilization, there is a greater risk of patient’s self -prescribing and administering MB, leading to toxicity and life-threatening medical conditions. This case report presents a patient who self-administered toxic levels of MB while simultaneously taking fluvoxamine, precipitating serotonin syndrome. Without a current MB toxicity standard of care, treatment focused on serotonin syndrome management including cessation of serotonergic agents and conservative measures such as intravenous fluids, pressors, analgesics, and benzodiazepines. Conclusion 1) Bužga M, Machytka E, Dvořáčková E, et al. Methylene blue: a controversial diagnostic acid and medication?. Toxicol Res (Camb). 2022;11(5):711-717. Published 2022 Aug 30. doi:10.1093/toxres/tfac050 2) Bistas E, Sanghavi DK. Methylene Blue. [Updated 2023 Jun 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557593/ 3) Chiew A, Buckley N The serotonin toxidrome: shortfalls of current diagnostic criteria for related syndromes, Clinical Toxicology, 2022 60:2, 143 158, DOI: 10.1080/15563650.2021.1993242 4) Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003;96(9):635-642. doi:10.1093/qjmed/hcg109 5) Uddin MF, Alweis R, Shah SR, et al. Controversies in Serotonin Syndrome Diagnosis and Management: A Review. J Clin Diagn Res. 2017;11(9):OE05-OE07. doi:10.7860/JCDR/2017/29473.10696 6) Pushparajah Mak, Renita S. MD ∗ ; Liebelt, Erica L. MD ∗ ,†. Methylene Blue: An Antidote for Methemoglobinemia and Beyond. Pediatric Emergency Care 37(9):p 474-477, September 2021. | DOI: 10.1097/PEC.0000000000002526 7) Zuschlag ZD, Warren MW, K Schultz S. Serotonin Toxicity and Urinary Analgesics: A Case Report and Systematic Literature Review of Methylene Blue-Induced Serotonin Syndrome. Psychosomatics. 2018;59(6):539-546. doi:10.1016/j.psym.2018.06.012 8) Haacker L, Maliekel M, Bardsley CEH, Bergren R, Meresh E, Halaris A. Serotonin Syndrome Following Septal Myectomy in Association With Fentanyl and Methylene Blue: A Case Report. Psychosomatics. 2018;59(5):512-516. doi:10.1016/j.psym.2018.02.001 9) Wang RZ, Vashistha V, Kaur S, Houchens NW: Serotonin syndrome: preventing, recognizing, and treating it. Cleve Clin J Med. 2016, 83:810 6.10.3949/ccjm.83a.15129 10) Boyer EW, Shannon M: The serotonin syndrome.N Engl J Med. 2005, 352:1112-20.10.1056/NEJMra041867 11) Simon LV, Keenaghan M. Serotonin Syndrome. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from:https;//www.ncbi.nlm.nih.gov/books/NBK482377/ 12) Brody DJ, Gu Q. Antidepressant Use Among Adults: United States, 2015-2018. NCHS Data Brief. 2020;(377):1-8.

A 30 year-old African American male with a past medical history of bipolar depression and seizures presented to the ED with dyspnea, tachycardia, chills, tremors, dizziness, headache, arthralgias, and back and neck pain. Symptoms began and worsened two hours after intravenously injecting himself in the left arm with 300 mg of 1% MB that he bought online on Amazon (Figure 1) to help with “depression and oxygen levels and to feel better.” Pertinent home medications included fluvoxamine 100 mg daily and brexpiprazole 1 mg daily. He had previously been taking two drops of 1% MB daily in two week intervals. The patient denied changes in weight, chest pain, palpitations, cough, vision changes, syncope, vomiting, and abdominal pain. On arrival to the ED, the patient was in acute distress, ill-appearing, and toxic appearing with diffuse, fine amplitude tremors. He was tachycardic in the 140s and hypotensive with systolic pressures around 95 mmHg. Labs indicated potassium of 3.3, magnesium of 1.2, and lactate of 3.4. The patient exhibited blueish-green tinged urine. There were no concerning electrocardiogram or chest x-ray findings. The patient was negative for G6PD deficiency and elevated methemoglobin levels. The patient was treated with 3 liters of crystalloid, IV lorazepam, broad spectrum antibiotics, morphine, ketorolac, and cyclobenzaprine. Despite this early intervention, the patient became diaphoretic, agitated, spiked a 101.5 ℉ fever, and his systolic blood pressure dropped to 85 mmHg. He was admitted to the ICU with serotonin syndrome due to MB toxicity and fluvoxamine use. The patient was treated overnight with supportive management including norepinephrine drip for hemodynamic support, antipyretics, analgesics, benzodiazepines, and electrolyte replenishment. His home fluvoxamine was held on admission. The next morning the patient was lethargic, but arousable, diaphoretic, and slightly agitated. Around 20 hours after initial presentation to the ED, the patient was weaned off of pressors and had resolution of his agitation, tremors, and diaphoresis. Cyproheptadine was not indicated due to resolution of symptoms. On day three, the patient’s blueish -green tinged urine began to clear. He was restarted on fluvoxamine at a reduced dose of 25 mg at that time and was closely monitored. After four total nights in the hospital, the patient was discharged and instructed to follow up with his primary care physician for further medication management and psychiatric care.

Figure 1: Methylene Blue purchased on Amazon Label: Methylene Blue 1% Compass Laboratory USP-Grade Methylthioninium Chloride Liquid. High Purity Dietary Supplement for Brain Function & Cognitive Health. No Formaldehyde (1) 50ml Glass Dropper Bottle

I would like to thank Dr. Marc Ciesco for his guidance and mentorship throughout the case report. I would also like to thank the patient for allowing us to utilize his case for the report.

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2024 Research Recognition Day