Introduction

Isobutyl nitrite, commonly known as “poppers,” is inhaled recreationally to elicit euphoria and sexual arousal. It is readily available in adult novelty shops, in video stores, and online. It is commonly advertised as “liquid air freshener” or “incense.”¹ It is sold under the brand names of Rush, Super Rush, Iron Horse, Locker Room, among others.2 When inhaled, this substance results in smooth muscle relaxation, vasodilation, and tachycardia. Ingestion, however, can be deadly.

Case Description

A 56-year-old male with past medical history of hypertension, gastroesophageal reflux disease, and alcohol use disorder presented to the emergency department with altered mental status, cyanosis, respiratory failure and hypotension. He had mistakenly ingested (rather than inhaled) 10 mL of isobutyl nitrite (Photo 1) at a nightclub and immediately collapsed. On presentation to the emergency department, his vitals were:

Photo 1: Isobutyl nitrite in a 10 mL bottle.

• Heart rate 119 bpm
• Blood pressure 86/47 mmHg
• Pulse oximetry 77 percent on nonrebreather
• Respiratory rate 20
• Temperature  34.2 degrees C

He required endotracheal intubation and dual pressor support with norepinephrine and vasopressin.

Arterial blood draw revealed a classic chocolate-brown appearance (Photo 2).  An arterial blood gas revealed pH 7.08, partial pressure of carbon dioxide 41, partial pressure of oxygen 73, bicarbonate 12 and oxygen saturation of 89 percent. Additionally, his labs were significant for creatinine kinase level of 1,077 units/L, anion gap of 21 mmol/L and lactate level of 12.1 mmol/L. He had an ethanol level of 63 mg/dL, with a negative quantitative volatile screen for methanol, isopropanol, and ethylene glycol. Urine drug screen was positive for amphetamine and cocaine. His methemoglobin level on arrival was more than 31 percent (greater than the laboratory’s maximum detectible level).

Three doses of methylene blue were given intravenously at a total of 2 mg/kg, and post-treatment methemoglobin level decreased to 0.7 percent. The patient developed green urine as is common after administration of methylene blue (Photo 3). Complete blood count with differential did not reveal evidence of hemolysis. The patient was extubated on hospital day three and made a full recovery.

Photo 2: Chocolate-brown blood color.

Discussion

In 1859, amyl nitrite was reported to cause flushing of the skin on the neck and face after inhalation.³ It was then prescribed therapeutically for managing angina in 1867.³ Nitrites originally were available in crushable mesh-enclosed glass capsules called pearls, and when they were crushed with the fingers, a popping sound was made and they were subsequently inhaled by the patient.³ This sound is thought to be the reason nitrites are referred to as poppers.³

Nitrite use enhances sexual arousal and pleasure. Inhaled nitrites are absorbed rapidly in the bloodstream, with onset of effects in seconds.3 Metabolism is primarily hepatic via glutathione-organic nitrate reductase.³ Given their vasodilatory effect, they relax the involuntary muscles of the vasculature, causing facial flushing, warm sensations, hypotension, tachycardia, lightheadedness and headache. Nitrite abuse is more common among homosexual men, as it is believed to dilate the anal sphincter and facilitate anal intercourse.⁴ A potential life-threatening effect of large nitrite exposure is methemoglobinemia, which occurs when iron is oxidized from the ferrous (Fe2+) to ferric (Fe3+) state. This ferric state does not bind to oxygen and is unable to transport oxygen to the tissue, thereby leading to tissue hypoxia manifested by cyanosis, headache, weakness, central nervous system depression, seizures, coma, and death.

Photo 3: Post methylene green urine.

The mainstay therapy for treating methemoglobinemia is methylene blue, which is converted to leucomethylene blue in the presence of NADPH and NADPH methemoglobinemia reductase.⁵ The leucomethylene facilitates the reduction of ferric to ferrous iron state through the NADPH reductase pathway.⁵ Methylene blue is administered at one to two mg/kg of body weight intravenously over five minutes. It is important to note that methylene blue will display a spurious pulse oximeter reading owing to its blue color absorbance at 660 nm.⁶ Cautious use of methylene blue in patients with G6PD deficiency should be noted as the treatment can lead to hemolysis. Alternative or adjunctive treatments include ascorbic acid and exchange transfusion.

Conclusion

Oral ingestion of isobutyl nitrite leads to life-threatening hemodynamic instability and methemoglobinemia due to its vasodilatory and oxidizing effects, respectively. Methylene blue is the mainstay treatment of symptomatic methemoglobinemia. 

References

1. Nitrite “poppers.” FDA. https://www.fda.gov/consumers/consumer-updates/nitrite-poppers.
2. Elgendy F, Del Rio-Pertuz G, Nguyen D, et al. “Popper” induced methemoglobinemia [published online Feb. 2, 2022]. Proc (Bayl Univ Med Cent).
3. Romanelli F, Smith KM, Thornton AC, et al. Poppers: epidemiology and clinical management of inhaled nitrite abuse. Pharmacotherapy. 2004;24(1):69-78.
4. Vaccher SJ, Hammoud MA, Bourne A, et al. Prevalence, frequency, and motivations for alkyl nitrite use among gay, bisexual and other men who have sex with men in Australia. Int J Drug Policy.2020;76:102659.
5. 5. Taylor GM, Avera RS, Strachan CC, et al. Severe methemoglobinemia secondary to isobutyl nitrite toxicity: the case of the ‘Gold Rush.’ Oxf Med Case Reports. 2021;2021(2):omaa136.
6. Kirlangitis JJ, Middaugh RE, Zablocki A, et al. False indication of arterial oxygen desaturation and methemoglobinemia following injection of methylene blue in urological surgery. Mil Med. 1990;155(6):260-262.

Dr. Shaker is medical toxicology fellow at the University of Texas Southwestern Medical Center in Dallas. Dr. Onisko and Dr. Sharma are both medical toxicologists and assistant professors also in the department