ToxCard: Nitrite Abuse

Authors: Anthony James, MD, (Emergency Medicine Resident, Atrium Health’s Carolinas Medical Center); Kathryn T Kopec, DO (@KopecToxEM, EM Attending Physician, Medical Toxicologist, Carolinas Medical Center, Charlotte, NC) // Reviewed by: James Dazhe Cao, MD (@JamesCaoMD, Associate Professor of EM, Medical Toxicology, UT Southwestern Medical Center, Dallas, TX); Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Case:

A 71-year-old man with a history of hypertension presents to the emergency department (ED) via EMS after a syncopal episode. His syncopal episode occurred at an adult novelty store.  On arrival to the ED his vital signs are T 98.4 F, BP 110/86 mmHg, HR 65 beats per minute, O₂ sat 86% despite non-rebreather, and RR 20 breaths/minute. The patient is noted to be cyanotic but does not appear to be in respiratory distress. The patient is complaining of dizziness and weakness.

Questions:

1. What was the agent of abuse that caused the patient’s presentation?
2. Which accessible products contain alkyl nitrites?
3. What potentially serious or life-threatening conditions can occur from nitrite use?
4. What is the management of both minor and severe complications that occur secondary to nitrite use?

Background:

This patient purchased “poppers” from the adult novelty store. “Poppers” are nitrite-containing products that are used recreationally.¹ Alkyl nitrites are compounds that act as nitric oxide donors.² While initially used in the medical field for anti-anginal purposes due to their ability to cause coronary vasodilation, they have overall fallen out of favor for this purpose and have largely been replaced by nitroglycerin.² However, they are still found in older cyanide antidote kits in the form of amyl nitrite and sodium nitrite.^2,3

Outside the realm of medicine, nitrites are commonly used as a recreational drug in the form of “poppers.” This is due to their ability to relax the involuntary muscles of the throat, anus, and vagina. They also have mild psychoactive effects such as euphoria and sexual arousal.⁴ While generally well tolerated in recreational inhalation, they can have complications associated with their use, particularly in cases of ingestion and/or aspiration.^5,6

Clinical Presentation:

Patients most commonly present with mild adverse effects related to hypotension but can have more severe complications depending on the route of exposure⁷:

• CNS
  • Headache
  • Presyncope or syncope*
  • Stroke*
  • Transient maculopathy^#
• Cardiovascular
  • Flushing
  • Hypotension*
  • Reflex tachycardia
• Pulmonary
  • Dyspnea
  • Hypoxia
  • Lipoid pneumonia (secondary to aspiration)
• Dermatologic
  • Caustic irritation
  • Contact dermatitis^8,9
• Hematologic
  • Methemoglobinemia (potential complication if ingested but can also rarely occur with inhalation)

*Risk increases with concurrent use of phosphodiesterase (PDE) inhibitors such as sildenafil or tadalafil or with use of alcohol.¹⁰ Additionally, PDE inhibitors have been found unregulated in both weight loss and sexual enhancement supplements, increasing the risk of unintentional co-ingestion.¹¹ Nitrogen donors catalyze the formation of cGMP which has effects of smooth muscle relaxation, decreased vascular tone, and decreased blood pressure. PDE inhibitors decrease the degradation of cGMP to GMP causing an upstream accumulation of cGMP which can lead to profound hypotension if co-administered with nitrogen donors such as nitrates and nitrites.¹²

^#Rare complication. Potentially increased risk in individuals living with HIV along with increased risk associated with concurrent use of alcohol and PDE inhibitors.^13,14

Diagnosis:

The diagnosis of nitrite abuse is mainly clinical, based on a thorough history and physical examination. Being aware of the complications of nitrite use can help providers following a thorough history and physical to identify nitrite exposures. Providers should make every effort to ask patients about recreational exposure in a non-judgmental way to decrease risk of diagnostic and treatment delay.

There are no accessible blood laboratory tests to look for the presence of nitrites and its clinical utility would be negligible. However, often these patients will initially get baseline laboratory testing such as a CBC, BMP, and troponin, along with an EKG and CXR depending on their initial presenting symptoms.

Methemoglobinemia (MetHb) is a complication of nitrite use/abuse that can be diagnosed by laboratory testing. Normal physiologic levels of MetHb range from 0% to 2%. Patients can, however, tolerate levels up to 10% to 20% well without significant symptoms. Clinical symptoms of MetHb start at 20% to 30% and can include symptoms of anxiety and lightheadedness and can progress to seizures, coma, and death in the 50% to 70% range.^15,16

Other clues to this pathology include PaO₂-O₂ saturation gap in which patients will have a normal PaO₂ in response to oxygen therapy but will have oxygen saturations around 85% on pulse oximetry. There may also be a “chocolate” appearance to the blood samples drawn. Physical exam can show skin discoloration in line with cyanosis.^15,16 (See ToxCard: Methemoglobinemia)

Management:

Most complications or adverse events associated with nitrite use are minor and transient. Due to the short acting nature of inhaled nitrites, it should not be surprising that patients will often present to the emergency department with minimal or no symptoms. Management should be targeted to any persistent symptoms and providers should ensure that they are not overlooking any potential severe complications such as methemoglobinemia. Management of a select few complications are listed below:

Hypotension

1. Fluid resuscitation as needed as this may help in the case of vasoplegia
2. Nitrite-induced hypotension is transient in nature, while persistent hypotension is a red flag for a more severe complication such as methemoglobinemia or may be indicative of concurrent PDE inhibitor use
3. Vasopressors should be initiated for management of hypotension refractory to fluid resuscitation

Syncope

1. Ensure no significant trauma was sustained
2. Check for any neurological deficits which might indicate more severe pathology
3. ECG recommended to evaluate for other causes including dysrhythmias

Methemoglobinemia

1. Initiate supplemental oxygen therapy although be aware that pulse oximetry will be lower than the true PaO₂
2. Antidote treatment is methylene blue 1-2 mg/kg IV given over 5 to 30 minutes
   1. If an hour after the first dose the methemoglobin level remains >30% or clinical symptoms persist, a repeat dose of up to 1 mg/kg IV can be considered¹⁶
   2. (See ToxCard: Methylene Blue)

Case Follow-up:

Our patient states that he bought “poppers” from the adult novelty store. The bottle listed the contents as butyl nitrite. He states that he misunderstood how to use them and ingested the entire bottle before returning to the store for another. His labs were remarkable for a methemoglobin level of 25%. He was treated with methylene blue, and his oxygen saturation improved along with his methemoglobin level normalizing over the course of the day. He was discharged home the following morning.

Clinical Pearls:

1. Nitrites are commonly used for recreational purposes and are easily accessible in “commercial products”
2. Asking patients about their use of nitrites in a non-judgmental manner can aid in diagnosing associated adverse effects and complications
3. Complications of nitrites tend to be more severe with routes of exposure other than inhalation such as ingestion or aspiration
4. Methemoglobinemia is a less common but potentially life-threatening complication of nitrite exposure
5. Treatment is supportive care and methylene blue administration
6. Harm reduction conversations should include avoiding concurrent use of alcohol and PDE inhibitors if a patient plans to continue using alkyl nitrites recreationally

References:

1. Nitrite “poppers”. U.S. Food and Drug Administration. Retrieved May 2, 2022, from https://www.fda.gov/consumers/consumer-updates/nitrite-poppers
2. Brazil, R. (2021, September 16). Explainer: The Science of Alkyl Nitrites aka Poppers. Chemistry World. Retrieved May 2, 2022, from https://www.chemistryworld.com/news/explainer-the-science-of-alkyl-nitrites-aka-poppers/4014395.article
3. Jillings, L., Kupust, P. J. (2020, March 31). Cyanide Antidotes. Occupational Safety and Health Administration. Retrieved May 2, 2022, from https://www.osha.gov/laws-regs/standardinterpretations/2020-03-31
4. Gosselin, R. E., Smith, R. P., & Hodge, H. C. (1984). Nitrite. Clinical Toxicology of Commercial Products, 5th ed. Williams & Wilkins, Baltimore, 1984, II, 314-319.
5. Dixon, D. S., Reisch, R. F., Santinga, P. H. (1981). Fatal methemoglobinemia resulting from ingestion of isobutyl nitrite, a “room odorizer” widely used for recreational purposes. Journal of Forensic Sciences, 26(3). https://doi.org/10.1520/jfs11404j
6. Hagan, I. G., Burney, K. (2007). Radiology of Recreational Drug Abuse. RadioGraphics, 27(4), 919–940. https://doi.org/10.1148/rg.274065103
7. Publication of interim decisions proposing to amend, or not amend, the current Poisons Standard. Therapeutic Goods Administration (TGA). (2018). Retrieved 15 May 2022. https://www.tga.gov.au/book-page/13-alkyl-nitrites
8. Latini, A., Lora, V., Zaccarelli, M., Cristaudo, A., Cota, C. (2017). Unusual presentation of poppers dermatitis. JAMA Dermatology, 153(2), 233. https://doi.org/10.1001/jamadermatol.2016.4262
9. Bos, J. D., Jansen, F. C., Timmer, J. G. (1985). Allergic contact dermatitis to amyl nitrite (‘poppers’). Contact Dermatitis, 12(2), 109–109. https://doi.org/10.1111/j.1600-0536.1985.tb01064.x
10. Mayo Foundation for Medical Education and Research. (2022, February 1). Amyl nitrite (inhalation route) side effects. Mayo Clinic. Retrieved May 3, 2022, from https://www.mayoclinic.org/drugs-supplements/amyl-nitrite-inhalation-route/side-effects/drg-20061803?p=1
11. Tucker J, Fischer T, Upjohn L, Mazzera D, Kumar M. Unapproved Pharmaceutical Ingredients Included in Dietary Supplements Associated With US Food and Drug Administration Warnings [published correction appears in JAMA Netw Open. 2018 Nov 2;1(7):e185765]. JAMA Netw Open. 2018;1(6):e183337. Published 2018 Oct 5. doi:10.1001/jamanetworkopen.2018.3337
12. Jackson, G. (2004). Sildenafil and cardiovascular events—drug interactions. Sildenafil, 143-149.
13. Fledelius, H. C. (1999). Irreversible blindness after amyl nitrite inhalation. Acta Ophthalmologica Scandinavica, 77(6), 719–721. https://doi.org/10.1034/j.1600-0420.1999.770625.x
14. Pece, A., Patelli, F., Milani, P., Pierro, L. (2004). Transient visual loss after amyl isobutyl nitrite abuse. Seminars in Ophthalmology, 19(3-4), 105–106. https://doi.org/10.1080/08820530490882292
15. Wright, R. O., Lewander, W. J., Woolf, A. D. (1999). Methemoglobinemia: Etiology, pharmacology, and Clinical Management. Annals of Emergency Medicine, 34(5), 646–656. https://doi.org/10.1016/s0196-0644(99)70167-8
16. Abouelezz, K. (2021, November 5). Methemoglobinemia. Medscape. Retrieved May 3, 2022. https://emedicine.medscape.com/article/204178-overview