Archives of Academic Emergency Medicine. 2022; 10(1): e75 CA S E RE P O RT Cocaine and Volatile Nitrite–Induced Methemoglobine- mia; a Case Report and Treatment Approach Review Milena Ribeiro Paixão1∗, Tarso Augusto Duenhas Accorsi1, Luis Felipe Lopes Prada1, Lucas Zoboli Pocebon1, Karine De Amicis Lima1, Karen Francine Köhler1, Leandro Santini Echenique2, José Leão de Souza Júnior1 1. Emergency Department, Israelita Albert Einstein Hospital, Sao Paulo, Brazil. 2. Cardiology Department, Israelita Albert Einstein Hospital, Sao Paulo, Brazil. Received: July 2022; Accepted: August 2022; Published online: 21 September 2022 Abstract: Cyanosis is typically a sign of a potentially life-threatening condition in the emergency department and re- quires immediate workup and treatment. This case report highlights the diagnostic reasoning and clinical ap- proach to cocaine- and volatile nitrite–induced methemoglobinemia (MHG). MHG is a rare, life-threatening cause of cyanosis. The diagnosis must be suspected in the emergency department in the presence of hypoxia and cyanosis disproportionate to cardiopulmonary repercussions and refractory to oxygen supplementation. Acquired causes are more prevalent than genetics, and recreational drugs should be highly suspected. Despite the rarity of this situation, cyanosis precipitants and the specificities of each hemoglobinopathy are reviewed in this article. Keywords: Methemoglobinemia; Cocaine; Nitrites; Emergency Medicine; Case Reports Cite this article as: Ribeiro Paixão M, Duenhas Accorsi TA, Lopes Prada LF, Zoboli Pocebon L, Amicis Lima KD, et al. Cocaine and Volatile Nitrite–Induced Methemoglobinemia; a Case Report and Treatment Approach Review. Arch Acad Emerg Med. 2022; 10(1): e75. https://doi.org/10.22037/aaem.v10i1.1753. 1. Introduction Acute cyanosis is a singular, potentially life-threatening sign and requires a fast emergency department (ED) approach. The most common disorders that accompany cyanosis are pulmonary and cardiovascular diseases due to systemic de- saturation or increased oxygen extraction. Methemoglobine- mia (MHG) is a rare, potentially fatal cause of cyanosis and should be considered in patients with cyanosis and hypoxia (1-3). This report presents an uncommon case of cocaine- and volatile nitrite–induced MHG in a patient admitted to the ED of Israelita Albert Einstein Hospital, São Paulo, Brazil. Further, this report aims to clarify the diagnostic approach to acute cyanosis. 2. Case Presentation A previously healthy 31-year-old male patient presented to the emergency department with dizziness, sweating, anxiety, ∗Corresponding Author: Milena Ribeiro Paixão; Av. Albert Einstein, 627. Bloco B, 2º andar, Secretaria da Unidade de Pronto Atendimento, Sao Paulo – SP. Zip code 05652-900 - Brazil. Phone: +55 11 2151-1233. Email: milena.paixao@einstein.br, ORCID: https://orcid.org/0000-0002-1565-3915. muscle spasms, shortness of breath, and bluish hands and lips. The symptoms had started two hours before admission, about 90 minutes after using inhaled cocaine and "poppers" (volatile nitrites). The patient reported that it was the second time he had used cocaine in his lifetime, had used volatile ni- trites, and had used cocaine and poppers simultaneously for the first time. On admission, the vital signs were as follows: blood pres- sure of 138/75 mmHg, heart rate of 89 beats per minute, res- piratory rate of 20 breaths per minute, and oxygen satura- tion of 88–90% while breathing in ambient air. He had cyan- otic lips, hands, and feet but no remarkable findings on car- diopulmonary examination. The electrocardiogram (ECG) performed on admission showed an apiculate T wave in V3- V4 derivation, normalized in subsequent minutes (Figure 1, left). The chest radiograph showed normal lung tissue and cardiac area (Figure 1, right). On arrival and after two hours, the troponin levels were < 40 pg/mL (within the normal range). Admission laboratory tests showed hemoglobin 17.1g/dL, leukocytes 13,760 µL, neu- trophils 12,246, platelets 298,000 µL, and creatinine, sodium, potassium, calcium, d-dimer, and NT-proBNP within normal range. There was no improvement in oxygen saturation de- spite a progressive offer of supplementary oxygen. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Ribeiro Paixão et al. 2 Table 1: Blood gas analysis during emergency department care Variables On admission After treatment∗ A Normal range Arterial Venous 1mg/kg& 2mg/kg# pH 7.407 7.395 7.457 7.417 7.35–7.45 PCO2 (mmHg) 35.0 36.6 31.7 36.8 35–45 PO2 (mmHg) 62.4 25.5 297 74.1 80–90 A / 41–50V Base excess (mmol/L) -1.8 -1.8 -0.2 -0.3 -2.0–2.0 Bicarbonate (mmol/L) 21.6 22.0 22.1 24.4 24–28 Oxygen saturation (%) 91.3 59.4 98.8 93.9 96-97 A /40-70V Methemoglobin (%) 41.3 43.8 13.2 1.3 <1.5 *: Treatment was done with methylene blue injection. #Samples was collected while patient was breathing ambient air. & Sample was collected while patient was receiving 15L/min of supplemental oxygen with non-rebreathing mask. PCO2 = partial pressure of carbon dioxide, PO2 = partial pressure of oxygen, A: arterial blood sample, V: venous blood sample. Figure 1: A) Admission electrocardiogram showing apiculate T wave in V3-V4 derivation, B) Spontaneously normalized electrocardiogram in subsequent minutes (left). Chest radiograph with normal lung tissue and cardiac area (right). Cardiovascular causes of cyanosis were unlikely as the pa- tient had no chest pain, heart sounds were normal, shock signs were absent, ECG abnormalities (V3-V4 apiculate T wave) did not progress to ST-elevation myocardial infarc- tion, and troponin, NT-proBNP, and d-dimer levels were nor- mal. Pulmonary diseases were also implausible since there were no history or pulmonary findings suggestive of bron- chospasm, pulmonary embolism, pneumothorax, upper ob- struction, aspiration, and infectious or chronic pulmonary diseases. MHG was suspected, especially after no improve- ment in saturation with progressive high oxygen offer. His venous and arterial blood samples were dark red. The arte- rial blood gas (table 1) was readily available and confirmed methemoglobin levels > 40% (normal range < 1.5%). He was treated with methylene blue at 1 mg/kg for 20 min- utes with clinical improvement, and the methemoglobin level decreased to 13%. Another dose of 1 mg/kg was admin- istered after one hour, with symptom resolution and methe- moglobin level of 1.3%. The patient was discharged asymp- tomatic on the third day of hospitalization after performing echocardiogram and holter monitoring, the results of which were normal. 3. Discussion MHG is potentially fatal because it impairs the oxygen- carrying capacity of blood by converting iron species from This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2022; 10(1): e75 Figure 2: Diagnosis and management of central cyanosis in the emergency department. Table 2: Hemoglobinopathies’ characteristics Character Methemoglobin Carboxyhemoglobin Sulfhemoglobin Precipitants Hereditary, Medicine, Recreational, drugs Food poisoning Inhalation of carbon monoxide during fires and the burning of gasoline, wood, coal, kerosene, and other fuels in poorly ventilated areas. Induction by drugs (i.e., dapsone, sulphonamides, phenazopyridine) Blood color Dark red Cherry red Green Diagnosis Measurements through co-oximetry or blood gas Measurements through co-oximetry or blood gas Measurement through co-oximetry, spectrophotometry, or gas chromatography Treatment Methylene blue, Ascorbic acid, Oxygen, supplementation High flow or hyperbaric oxygen Support (no antidote) Resolution after erythrocyte turnover (definitively linked to hemoglobin), exchange transfusion in severe cases the reduced ferrous (Fe 2+) to the oxidized ferric (Fe 3+) form in the circulation of hemoglobin. The latter is unable to ad- here to and transport oxygen. Thus, the O2 offered to the tissues is decreased, and the ferric heme shifts the oxyhe- moglobin curve to the left (2). In addition to cyanosis, other symptoms of MHG range from headaches, blurred vision, irritability, lack of short-term memory, agitation, combativeness, confusion, lethargy, un- consciousness, and respiratory distress (4, 5). Recreational drugs that cause MHG include e-cigarettes, volatile nitrites (known as "poppers” because of the sound the small glass containing the liquid makes on being crushed between the fingers), cocaine, heroin, and other substances used as diluting adulterants (6, 7). Less commonly, exoge- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Ribeiro Paixão et al. 4 nous intoxication with antifreeze, naphthalene balls, sol- vents, and pesticides were also reported as possible causes of MHG (8, 9). Cocaine is widely consumed worldwide, with an estimated 20 million current users (10). In the emergency depart- ment, cocaine is responsible for 30% of all drug-related eval- uations (11). Though cocaine itself is not a usual precipi- tant for MHG, its most frequent diluents are. These include phenacetin, lidocaine, benzocaine, and procaine (12-14). The recreational use of volatile nitrites ("poppers") became popular since the 1970s, especially in the gay community, because of its property of relaxing smooth muscles, such as the throat and anal sphincter, in addition to inducing eu- phoria and warmth. Meanwhile, undesirable effects include headaches, dizziness, anxiety, ataxia, loss of vision (macu- lopathy), and MHG (15, 16). An estimated 3.3% of the adults in the United States have used poppers. In the gay man pop- ulation, the prevalence is estimated at 35% (17). MHG can also be acquired through medicine and food. Medicines that can precipitate MHG are local and inhaled anesthetics like lidocaine, benzocaine, prilocaine, and ni- tric oxide; antimalarial agents such as chloroquine and pri- maquine; dapsone, used in Hansen’s disease, as prophylaxis in Pneumocystis pneumonia in HIV, and present in some anti-acne agents; and acetaminophen (18-20). Food items include choy sum, fennel, root vegetables such as carrots and beetroots, meat and cheese contaminated with high nitrate content to preserve it longer, and possibly well water. Hereditary MHG is a rare autosomal recessive disorder re- lated to cytochrome B5 reductase deficiency. Because of the decrease in the enzyme that reduces ferric heme to ferrous heme, the conversion of methemoglobin to hemoglobin be- comes difficult. In hemoglobin M disease, a dominant disor- der leads iron to connect to phenolate, a complex that makes the reduction of ferric heme difficult. The final form of inher- ited MHG is cytochrome B5 deficiency, an unlikely disorder that disables the electron donation for methemoglobin con- version to hemoglobin (21, 22). A structured reasoning flow from diagnosis to treatment for patients with central cyanosis in the ED is proposed in Figure 2. The starting point is the immediate work to differentiate cardiovascular and pulmonary diseases, and hemoglobinopathies. The symptoms are similar among the hemoglobinopathies (Table 2) (1-5, 23, 24). In these cases, typically, there is no improvement in oxygen saturation even with a progressive increase in oxygen supply; however, this is insufficient to exclude cardiovascular and pulmonary condi- tions. Recently some colleagues have reported a case of MHG pre- sumably induced by cocaine adulterants. They reinforced the importance of the laboratory routinely reporting methe- moglobin and carboxyhemoglobin levels or at least report- ing them when values are above the normal range even when not requested (25). Our hospital implemented the routine of alerting the team responsible for the patient about all the non-requested altered findings in the blood gas analysis (hemoglobin, glucose, creatinine, electrolytes, and lactate) to prevent adverse events due to lack of diagnosis. 4. Limitations Because of the lack of tests to define the precipitant of MHG, we acknowledge that the precipitant could have been only volatile nitrite or cocaine diluents. However, knowing that the patient used these recreational drugs alone in the past without complications and that both can be related to MHG, we presumed the precipitant was their combination. 5. Conclusion MHG is a rare, life-threatening cause of cyanosis. The diag- nosis must be suspected in the emergency department in the presence of hypoxia and cyanosis disproportionate to car- diopulmonary repercussions and refractory to oxygen sup- plementation. Acquired causes are more prevalent than ge- netics, and recreational drugs should be highly suspected. 6. Declarations 6.1. Acknowledgments INTEGRATE Investigators (EINsTein EmerGency ReseArch TEam). 6.2. Authors’ contributions All authors met the criteria for authorship contribution based on recommendations of international committee of medical journal editors. Conception, planning, analysis, and inter- pretation of data: MRP, TADA. Data collection: LFLP, LZP, LSE, MRP. Writing of the article or its critical intellectual re- view: MRP, TADA, KAL, KFK. Responsibility for final review and approval for publication: all author. 6.3. Funding and Support None. 6.4. Conflict of Interest Authors have no conflict of interest. 6.5. Ethical consideration and consent The study and consent waiver were approved by the Hospital Israelita Albert Einstein Review Board (CAAE Protocol Num- ber: 52261321.0.0000.0071). This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 5 Archives of Academic Emergency Medicine. 2022; 10(1): e75 References 1. Skold A, Cosco DL, Klein R. Methemoglobinemia: patho- genesis, diagnosis, and management. South Med J. 2011;104(11):757-61. 2. Mansouri A, Lurie AA. Concise review: methemoglobine- mia. Am J Hematol. 1993;42(1):7-12. 3. do Nascimento TS, Pereira RO, de Mello HL, Costa J. Methemoglobinemia: from diagnosis to treatment. Rev Bras Anestesiol. 2008;58(6):651-64. 4. Wright RO, Lewander WJ, Woolf AD. Methemoglobine- mia: etiology, pharmacology, and clinical management. Ann Emerg Med. 1999;34(5):646-56. 5. Rehman HU. Methemoglobinemia. 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