Severe Methemoglobinemia Due to Accidental Ingestion of Nitrite-Containing Nail Polish Remover: A Case Report

Introduction

Methemoglobinemia is a hemoglobinopathy caused by oxidation of heme iron from the ferrous (Fe2+) to the ferric (Fe3+) state, which shifts the hemoglobin dissociation curve to the left and impairs oxygen release to tissues [1,2]. Methemoglobin (MetHb) contains ferric heme that does not bind oxygen, resulting in functional anemia that does not improve with supplemental oxygen [1]. The presence of ferric heme also increases the oxygen affinity of the remaining ferrous heme within the same hemoglobin tetramer, further reducing oxygen delivery to tissues [1].

Methemoglobinemia has multiple causes, including hereditary (genetic) and acquired etiologies. Acquired causes include medications (ie, dapsone, antimalarial drugs, topical anesthetics, rasburicase, inhaled nitric oxide) and exposure to nitrites and nitrates from foods, drugs, preservatives, and chemicals [1]. Genetic causes include cytochrome b5 reductase deficiency and hemoglobin M disease [1]. Inhaled amyl nitrites, also known as “poppers,” are recreational drugs that induce vasodilation and produce a sensation of euphoria. They are sometimes used as sexual enhancers by relaxing the anal sphincter. “Poppers” are marketed as nail polish removers or room deodorizers under brand names such as Jungle Juice, Liquid Gold, Purple Haze, Buzz Aroma, RUSH, or HardWare to facilitate legal sale (Figure 1). Additionally, there has been an increasing trend of suicide attempts via sodium nitrite ingestion in recent years; social media platforms and online communities promote self-poisoning methods that involve sodium nitrite, resulting in fatal methemoglobinemia [3–6]. Many of these intentional ingestions are associated with MetHb levels exceeding 30% to 50%, consistent with severe or potentially lethal poisoning [3].

Here, we describe a 67-year-old woman who accidentally ingested Jungle Juice nail polish remover, resulting in severe acute methemoglobinemia with a MetHb level exceeding 30%, which was the upper reporting limit of the hospital laboratory.

Case Report

A 67-year-old White woman with a medical history of hypertension, hyperlipidemia, type 2 diabetes, heart failure with preserved ejection fraction, and hypothyroidism – taking digoxin, carvedilol, spironolactone, simvastatin, losartan, and levothyroxine – presented from triage unresponsive and cyanotic (Figure 2). The patient’s husband brought her to the waiting area and then left to park his car. On initial evaluation, she had a palpable pulse and was breathing spontaneously, with a Glasgow Coma Scale score of 8 [eye opening (E) 2, verbal response (V) 2, motor response (M) 4]. She was placed on telemetry and pulse oximetry monitoring, which showed oxygen saturation of 85% despite supplemental oxygen through a nonrebreather mask at 15 L/min (Figure 3). She was hypotensive, with systolic blood pressure in the range of 50 to 59 mmHg, which warranted treatment with 2 L of intravenous fluids. After fluid resuscitation, her blood pressure normalized, and her level of consciousness improved; she opened her eyes spontaneously and was able to speak, although she remained confused (Glasgow Coma Scale E4V4M5) and unable to provide a reliable history.

Collateral history was obtained when the patient’s husband arrived after initial stabilization had been achieved. He reported that the patient and their family had attended an outdoor event and consumed alcoholic beverages throughout the day. The patient ingested her son’s nail polish remover, labeled “Jungle Juice,” after mistaking it for an alcoholic beverage. The product was contained in a 30-mL bottle, and the patient reportedly consumed most of it. She subsequently became progressively less responsive and experienced multiple falls, prompting her husband to bring her to the emergency department.

Initial arterial blood gas analysis with co-oximetry (Figure 3) demonstrated methemoglobinemia exceeding 30%, which was the upper reporting limit of the hospital laboratory. The partial pressure of oxygen (PaO2) was 394 mmHg, whereas arterial oxygen saturation (SaO2) was 44.8%, demonstrating a pronounced PaO2-saturation gap suggestive of a hemoglobinopathy. Carbon monoxide assessment showed negative results. The patient’s blood samples showed a characteristic brown-to-black color (Figure 4). Laboratory evaluation findings were notable for urine toxicology results (cannabis and amphetamine positivity) and a blood alcohol level of 106 mg/dL. Acetaminophen and salicylate were not detected. All other laboratory results were within normal limits, except for mild hypoglycemia (glucose 71 mg/dL) and an elevated lactate level of 2.6 mmol/L. Serum osmolality was assessed given the history of alcohol use to identify potential toxic alcohol ingestion (ie, ethylene glycol, methanol, propylene glycol, and isopropanol); no osmolar gap was identified, indicating no evidence of toxic alcohol ingestion. Electrocardiography demonstrated sinus rhythm with normal intervals and no ST-segment elevations or ischemic changes.

The patient had no known history of glucose-6-phosphate dehydrogenase (G6PD) deficiency, which may result in hemolytic anemia upon receipt of methylene blue, and she was too critically ill to await confirmatory testing; therefore, the benefits of treatment were presumed to outweigh the risks. She received 88 mg (1 mg/kg) of intravenous methylene blue over 5 minutes. Because there was no immediate clinical improvement, a second dose of 100 mg of intravenous methylene blue was administered over 5 to 10 minutes, corresponding to the hospital’s prepackaged bolus dose. The patient developed nausea and vomiting after methylene blue administration and was treated with 2 doses of intravenous ondansetron (4 mg per dose); her symptoms began to resolve. Approximately 30 minutes later, cyanosis was alleviated, and oxygen saturation improved to the high 90% range (up to 100%) on room air.

Computed tomography of the head and cervical spine was performed due to trauma from falls and altered mental status; the findings were unremarkable. Repeat arterial blood gas analysis demonstrated a methemoglobin level of 4.7%. The patient was admitted for observation, remained clinically stable, and was discharged home neurologically intact and at baseline 2 days later.

Discussion

The diagnosis of methemoglobinemia was rapidly confirmed by arterial blood gas with co-oximetry, which demonstrated a MetHb level exceeding the hospital laboratory cutoff of 30%. Other causes of central cyanosis include cardiac or pulmonary etiologies, as well as carbon monoxide poisoning and sulfhemoglobinemia. Methemoglobin contains ferric heme that does not bind oxygen, resulting in functional anemia that does not improve with supplemental oxygen [1]. Typical methemoglobinemia findings in our patient included cyanosis (Figure 2), apparent hypoxemia unresponsive to supplemental oxygen, and characteristic brown-to-black-colored blood (Figure 4). The patient presented with altered mental status, which may have been attributable to methemoglobinemia, alcohol intoxication, or both. More severe or prolonged methemoglobinemia can lead to coma or death [7].

Clinical manifestations vary according to MetHb levels. Levels below 10% may lead to cyanosis, although patients are often asymptomatic. Levels of 10% to 30% may cause cyanosis, chocolate-colored blood, confusion, and nausea or vomiting. Cyanosis may be less apparent in anemic patients than in individuals with normal hemoglobin levels; however, patients with anemia may exhibit more pronounced symptoms at lower MetHb levels. Levels above 30% may result in dyspnea, dizziness, syncope, confusion, and possibly headache, chest pain, palpitations, or fatigue [7]. Levels of 50% to 70% may produce tachypnea, confusion, and metabolic acidosis on laboratory testing, with increased risk of dysrhythmias, seizures, or coma [7]. Severe cellular hypoxia may lead to death and typically occurs at MetHb levels above 70% [7].

Another hallmark clinical feature of methemoglobinemia is the PaO2-saturation gap, which indicates a hemoglobinopathy, most commonly methemoglobinemia. This gap arises when there is a mismatch between PaO2, which reflects the amount of oxygen dissolved in arterial plasma, and SaO2, which reflects the percentage of hemoglobin bound to oxygen (Figure 3). This phenomenon is often regarded as “refractory hypoxemia” because oxygenation does not improve with supplemental oxygen [8]. Typically, PaO2 is greatly elevated (>100 mmHg) with supplemental oxygen, whereas SaO2 remains disproportionately low, and pulse oximetry oxygen saturation (SpO2) typically ranges from 75% to 90% [8]. This pattern was observed in our patient, who was placed on a nonrebreather mask at 15 L/min, with a PaO2 of 394 mmHg, SaO2 of 44.8%, and SpO2 of 85% (Figure 3).

The Jungle Juice nail polish remover responsible for the toxic exposure contained isobutyl nitrite (as indicated on the label in Figure 1), which oxidized heme iron and induced methemoglobinemia. “Poppers,” such as Jungle Juice (Figure 1), originated from the misuse of amyl nitrite, which was initially developed for the treatment of angina but later became popular for its vasodilatory and euphoric effects. The Anti-Drug Abuse Act of 1988 prohibited butyl nitrite for recreational use in the United States, and the Crime Control Act of 1990 banned the sale of amyl nitrite as a recreational inhalant; however, these compounds remained permitted for commercial applications such as cleaning products [9,10]. Consequently, manufacturers market “poppers” as “room deodorizers,” “leather cleaners,” or “nail polish removers” to circumvent these restrictions; such products are commonly sold in smoke shops and adult stores. Another strategy involves the use of analogs, including isobutyl, isopropyl, and pentyl nitrite. These compounds have been associated with maculopathy, retinal injury, and potential carcinogenicity [11–13]. The widespread availability of “poppers” and related compounds has coincided with an emerging trend of sodium nitrite ingestion to induce methemoglobinemia in suicide attempts. This trend has gained momentum through social media platforms and internet-assisted suicide forums [3–6].

Treatment of methemoglobinemia involves administration of methylene blue, which reduces ferric heme (Fe3+) back to the ferrous state (Fe2+) [14]. This restoration enables hemoglobin to bind oxygen and improves tissue oxygen delivery. The recommended initial dose is 1 to 2 mg/kg of a 1% solution administered intravenously over 5 to 30 minutes; a second dose may be given if there is no response to the initial dose [5]. Methylene blue may precipitate serotonin syndrome and should be used with caution in patients receiving serotonergic medications. Doses of at least 5 mg/kg are associated with an increased risk of serotonin toxicity, characterized by autonomic hyperactivity and neuromuscular abnormalities [14]. It is contraindicated in patients with G6PD deficiency due to the risk of hemolytic anemia; in such cases, ascorbic acid may be utilized as an alternative treatment [14]. Congenital methemoglobinemia, caused by cytochrome b5 reductase deficiency or hemoglobin M disease, may respond to ascorbic acid; however, response to methylene blue is often limited. Management is therefore primarily supportive, with avoidance of oxidant triggers. The pathophysiology, clinical features, causes, diagnostic findings, and treatment of methemoglobinemia are summarized in Table 1.

Conclusions

Methemoglobinemia is an uncommon hemoglobinopathy with hallmark features including cyanosis, chocolate-colored blood, refractory hypoxemia unresponsive to supplemental oxygen, and a PaO2-saturation gap. Prompt diagnosis and treatment with methylene blue are essential to reverse oxidation of heme iron and restore oxygen delivery; however, contraindications such as G6PD deficiency should be excluded, and patients should be monitored for potential serotonin syndrome associated with methylene blue. “Poppers,” such as Jungle Juice nail polish remover, can induce methemoglobinemia. Despite multiple legislative efforts to regulate these products and prevent misuse, manufacturers continue to exploit regulatory loopholes by producing chemical analogs that are exempt from current drug laws [9,10]. These analogs have been associated with ocular toxicity and potential carcinogenic effects, in addition to their ability to induce methemoglobinemia, and should thus be used with caution [11–13]. Although inhalation is the most common route of exposure, ingestion is less common and may result in higher acute toxicity, as demonstrated in the present case. It remains unclear whether ingestion confers a higher risk of long-term sequelae based on current evidence. In addition to accidental exposure, there has been an increasing trend of intentional sodium nitrite ingestion to induce methemoglobinemia in suicide attempts. Accordingly, emergency physicians should be aware of these trends and the associated products to facilitate early diagnosis and prompt treatment of this rare condition [3–6].