Methemoglobinemia secondary to automobile exhaust fumes

Brief Reports

Methemoglobinemia Secondary to Automobile ExhaustFumes ROBERT F. LANEY, MD,* ROBERTS.

HOFFMAN,

Methemogloblnemia is an uncommon cause of cyanosis. A 28-year-old male presented to the emergency department cyanotic and short of breath after exposure to noxious automobile fumes. He did not improve with the administration of 100% oxygen therapy. The initial arlerial blood gas with cooximetty was: pH of 7.38, Pace, of 43 mm Hg, Paoz of 118 mm Hg, measured oxygen saturation of 70%, and a methemoglobin level of 24.8%. Methylene blue was given (2 mg/kg intravenously) and the patient’s symptoms resolved. On the following day he was discharged home without complication. A comprehensive review of the llteraturo revealed no reported cases of methemoglobinomia secondary to accidental exposure to exhaust fumes. (Am J Emerg Mad 1992;10:426-428. Copyright 0 1992 by W.B. Saunders Company)

Cyanosis is clinically evident in the presence of 5 g/dL of reduced hemoglobin, 1.5 g/dL of methemoglobin, or 0.5 g/dL

of sulfhemoglobin.’ Central cyanosis results from arterial hypoxemia, and is usually associated with an arterial oxygen saturation of less than 85%. Central cyanosis indicates impaired pulmonary function, anatomic shunts, decreased inspired oxygen, or dyshemoglobinemias. Compared with other causes of cyanosis, methemoglobinemia is rare. A review of the data for 1990 of 72 regional poison control centers (1,713,462 human exposures) indicates that methemoglobinemia requiring methylene blue therapy was reported only 141 times.* We present a case of methemoglobinemia induced by automobile exhaust fumes, and review the pathophysiology, diagnosis, and treatment of this disorder. CASE REPORT A 28-year-old white male presented to the emergency department via the mobile intensive care unit with a chief compliant of “difliculty breathing.” The patient was the driver of a sports car (1991 Toyota MR-2) and was driving behind a truck that was emitting noxious exhaust fumes. While stopped behind this truck at a traffic light, the patient rolled up his windows, and turned off the ventilation system of the car. Approximately 15 minutes later, the patient reported shortness of breath, headache, nauseousness, and blurred

From the *Department of Emergency Medicine, Morristown Memorial Hospital, Morristown, NJ; and the tNew York City Poison Control Center and the tDepartment of Surgery/Emergency Medicine, New York University School of Medicine, New York, NY. Manuscript received July 8, 1991; revision accepted February 13, 1992. Address reprint requests to Dr Laney, Department of Emeraencv Medicine, Malcolm Grow US Air Force Medical Center, indr&ws Air Force Base, MD 20331-5300. Key Words: Methemoglobinemia, methylene blue, cyanosis. Copyright 0 1992 by W.B. Saunders Company 0735-6757/92/l 005-0006$5.00/O 426

MDt

vision. Upon looking in the rear view mirror, he also noted that his skin was pale and his lips were blue. He gave no prior history of similar episodes, and denied the use of tobacco, recreational drugs, or occupational exposures. Specifically, he denied the use of inhaled nitrites or exposure to aniline derivatives finks, polishes, paints, and varnishes). He also denied the ingestion of preserved meats or well water. His medications included a steroid inhaler and a theophylline preparation which he used for asthma. Physical examination revealed a well-developed male with perioral cyanosis, in mild respiratory distress. He had a blood pressure of 130/82 mm Hg, a pulse of % beats/minute, unlabored respirations of 18 breaths/minute, and a tympanic membrane temperature of 37.3”C. Aside from perioral cyanosis, the examination of the head, eyes, ears, nose, and throat was unremarkable. His neck had no venous distention or carotid bruit. His chest was clear with good air exchange and his heart was regular in rate and rhythm with no murmurs or gallops. His abdomen was soft without masses. There was no clubbing of his extremities, and his pulses were full and symmetrical. His neurologic exam was normal. The patient was given oxygen (3 L/minute via nasal canula), was placed on a monitor, and an intravenous line of five percent dextrose in water was started. As laboratory work (complete blood count, electrolytes. blood urea nitrogen, creatinine, glucose, arterial blood gas with cooximetry) was being drawn, the blood was noted to be dark brown in color. The oxygen was changed to 100% via nonrebreather face mask. Portable chest x-ray and electrocardiogram were normal. An arterial blood gas obtained on 3 L/minute oxygen revealed a pH of 7.38, a Pace, of 43 mm Hg, and a Pao, of 118 mm Hg. The measured oxygen saturation was 70%, with a methemoglobin level of 24.8%. and a carboxyhemoglobin level of 0%. His white blood cell count was 8,0QO/mm3 with 73% segmented forms, 2% bands, 18% lymphs; hemoglobin was 14.3 g/dL; mean corpuscular volume 94 fL; and platelets 281,000/mm3. His theophylline level was 6.6 p&mL. The electrolytes, blood urea nitrogen, creatinine, and glucose measurements were normal. Despite 100% oxygen therapy, the patient remained pale, cyanotic, and short of breath. In consultation with the New York City Regional Poison Control Center, the patient was given definitive therapy with methylene blue 160 mg (2 mg/kg) given intravenously over several minutes. The patient’s symptoms resolved. The results of a repeat arterial blood gas (drawn on 2 L/minute oxygen via nasal canula) were: pH 7.40, Pace, 35 mm/Hg, and Pao, 94 mmlHg. The measured oxygen saturation was 95% with a methemoglobin level of 0.6%. The patient was admitted to the intensive care unit where he remained asymptomatic. He was discharged home on the following day.

DISCUSSION Methemoglobin is the oxidative product of hemoglobin in which the ferrous (Fe”) form has been converted to the

LANEY AND HOFFMAN

n METHEMOGLOBINEMIA

SECONDARY

ferric (Fe3+) form, which is then bound to either a water molecule or a hydroxyl group.’ This additional positive charge renders the ferric molecule unable to bind oxygen. Not only does methemoglobin reduce the oxygen-carrying capacity of the blood, but it also shifts the oxygenhemoglobin dissociation curve to the left, further impairing oxygen delivery to the tissue.3 Normally the body maintains a methemoglobin level of less than l%.’ Methemoglobinemia occurs when the concentration of methemoglobin raises above this baseline level. Physiology The body has four mechanisms for maintaining methemoglobin levels at or below 1%; two are enzymatic, and the other two act directly. One mechanism is nicotine adenine dinucleotide-dependent methemoglobin reductase (NADHMetHb reductase), which accounts for about 95% of “in viva” methemoglobin reduction.’ An auxiliary reduction system, nicotine adenine dinucleotide phosphate-dependent methemoglobin reductase (NADPH-MetHb reductase), is responsible for approximately 5% of methemoglobin reduction. The NADPH is provided by the hexose monophosphate shunt (a glucosed-phosphate dehydrogenase dependent system).’ This pathway becomes clinically significant when, in the presence of an exogenous cofactor (methylene blue), the reaction is greatly acceIerated.4 The two nonenzymatic mechanisms of methemoglobin reduction include ascorbic acid and glutathione, which act directly with and reduce methemoglobin. These two agents play only a very minor role in maintaining physiologic methemoglobin levelss Pathophysiology Methemoglobinemia can be divided in three basic categories: the hereditary presence of an abnormal hemoglobin in which the substitution of one amino acid creates a molecule that is easily oxidized and not amenable to reduction,’ hereditary deficiency of the various methemoglobin reductases, or exposure to drugs or chemicals that increase the rate of oxidation beyond the protective capacity of the erythrocyte (acquired methemoglobinemia).6 Acquired methemoglobinemia is the most common form of methemoglobinemia. Nearly 90 compounds have been implicated in the production of methemoglobinemia.4 Nitrates and aniline derivatives are among the most common agents. Nitrites are present in food preservatives, pharmaceuticals, and recreational drugs.’ Although aniline compounds are used in manufacturing, they are also found in many household products (ink, shoe polish, paints, vamishes).4 It is of special note that infants are much more susceptible to the effects of oxidizing agents because of low physiologic levels of NADH-dependent methemoglobin reductase and higher concentrations of bacterial species capable of reducing nitrates to nitrites in their gastrointestinal tract.5.8 There have been reports of methemoglobinemia resulting from smoke inhalation following fires,’ and from urban pollution. ‘O Katsumata described 10 suicide victims in Japan with elevated postmortem blood Levels of both carboxyhemoglobin (50.3% to 81.6%) and methemoglobin (1.8% to 26.9%). I1 These investigators conclude that the methemoglobinemia in their victims was secondary to inhalation of

TO EXHAUST

FUMES

427

oxides of nitrogen found as combustion products. Methemoglobinemia secondary to incidental exposure to automobile exhaust fumes was previously unrecognized. Diagnosis The fundamental clue to the presence of methemoglobinemia is cyanosis unresponsive to oxygen therapy.’ This, in conjunction with a history of drug or chemical exposure, should lead to the consideration of methemoglobinemia. Blood with more than 15% methemoglobin appears dark red or brown, and does not become bright red (representing the conversion of deoxyhemoglobin to oxyhemoglobin) on exposure to oxygen. Methemoglobin levels of up to 20% are usually well tolerated in previously healthy adults. As levels approach 40%, patients complain of headache, dizziness, fatigue, and shortness of breath. Levels of 60% produce lethargy, stupor, and coma.” Patients with cardiovascular compromise or anemia will manifest symptoms at lower methemoglobin levels4 The definitive diagnosis is made by arterial blood gas analysis with cooximetry. Usually methemoglobinemia is seen with a normal PO, and a low measured oxygen saturation. The PO, is unaffected because it is a measure of dissolved oxygen in the plasma.’ Similarly, the calculated oxygen saturation is expected to be normal since it is derived from the PO,. Because pulse oximetry is widely used in emergency departments, their lack of usefulness in diagnosing methemoglobinemia is noteworthy. Pulse oximeters overestimate the oxygen saturation in the presence of methemoglobin. They also demonstrate a diminished response to changes in oxygen saturation when methemoglobin is present.‘3.‘4 Treatment As with all poisonings, the initial treatment is supportive. This includes removing the inciting agent from the clothes, skin, and gastrointestinal tract (which may include emesis, lavage, charcoal, cathartics). In many cases, patients require no further therapy.’ If the patient is still symptomatic, or has a methemoglobin level greater than 30%, the patient should receive methylene blue 1 to 2 m&g intravenously over 5 minutes.6 Methylene blue is not without risks, as it may cause electrocardiographic changes (diminished or inverted T waves, diminished R wave amplitude), shortness of breath, chest pain, paresthesias, restlessness, apprehension, tremors, nausea and vomiting, hemolytic anemia, and, in high concentrations, methemoglobinemia.‘5 For these reasons methylene blue is reserved for the more seriously ill patients. The patients who do not respond to appropriate decontamination and methylene biue therapy require further evaluation for hereditary causes of methemoglobinemia (glucose-6-phosphate dehydrogenase deficiency, NADPHMetHb reductase deficiency, hemoglobin M). Chlorate poisoning is another rare cause of methemoglobinemia refractory to methylene blue therapy.16 Also, some drugs which can cause methemoglobinemia can produce sulfhemoglobinemia, which is not affected by methylene blue therapy.’ If these patients remain severely symptomatic, alternative forms of therapy can include exchange transfusion or hyperbaric oxygen therapy.12*”

428

AMERICAN

JOURNAL

OF EMERGENCY

SUMMARY We report the case of a patient who presented to the emergency department with a methemoglobin level of 24.8% after exposure to automobile exhaust fumes. While methemoglobinemia is an uncommon disorder, it should always be considered in the differential diagnosis of cyanosis. This is especially true in the presence of toxin exposure or ingestion. Why methemoglobinemia secondary to incidental automobile exhaust exposure is not more widely recognized remains to be determined. Perhaps further research is forthcoming. The authors thank John Kealy, MD, Director, Emergency Medicine Residency Program, Morristown Memorial Hospital (Morristown, NJ) for assistance with the preparation of this case.

REFERENCES 1. Jaffe ER: Methemoglobinemia in the differential diagnosis of cyanosis. Hosp Prac 198$20:92-l 10 2. Litovitz TL, Bailey KM, Schmitz BF, et al: 1990 Annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med 1991;9(5): 461-509 3. Charache S: Methemoglobinemia-Sleuthing for a new cause. N Engl J Med 1986;314(12):776-778 (editorial) 4. Curry S: Methemoglobinemia. Ann Emerg Med 1982;ll: 214-221 5. Mansouri A: Review: Methemoglobinemia. Am J Med Sci 1985;289:200-209 6. Goldfrank LR, Price D, Kirsten RH: Nitroglycerin (methemoglobinemia). In Goldfrank LR, Flomenbaum NE, Lewin NA, et

MEDICINE

n Volume

10, Number

5 n September

1992

al (eds): Goldfrank’s Toxicologic Emergencies. Norwalk, CT, Appleton & Lange, 1990, pp 391-396 7. Phillips DM, Gradisek R, Heiselman DE: Methemoglobinemia secondary to aniline exposure. Ann Emerg Med 1990;19: 425-429 8. Geffer ME, Powars DR, Choctaw WT: Acquired methemoglobinemia. West J Med 1981;134:7-10 9. Hoffman RS, Sauter D: Methemoglobinemia resulting from smoke inhalation. Vet Hum Toxicol 1989;31:168-170 10. Medeiros MHG, Bechara EJH: Oxygen toxicity and hemoglobinemia in subjects from a highly polluted town. Arch Eviron Health 1983;38:11-15 11. Katsumata Y, Aoki M, Oya M, et al: Simultaneous determination of carboxyhemoglobin and methemoglobin in victims of carbon monoxide poisoning. J Forensic Sci 1980;25:546-549 12. Caudill L, Walbridge J, Kuhn G: Methemoglobinemias cause of coma. Ann Emerg Med 1990;19(6):95-97 13. Barker SJ, Tremper KK, Hyatt J: Effects binemia on pulse oximetry and mixed venous thesiology 1989;70:112-117

as a

of methemoglooximetry. Anes-

14. Tremper KK, Barker SJ: Using pulse oximetry when hemoglobin levels are high. J Crit III 1988;3(11):103-107

dys-

15. Howland MA: Antidotes in depth: Methylene blue. In Goldfrank LR. Flomenbaum NE. Lewin NA. et al feds): Goldfrank’s Toxicolo&c Emergencies. Norwalk, CT; Appleion i Lange, 1990, pp 397-399 16. Lee DBN, Brown DL, Baker LRI, et at: Haemotologic plications of chlorate poisoning. Br Med J 1970;2:31

com-

17. Goldstein GM, Doull J: Treatment of nitrite-induced methemoglobinemia with hyperbaric oxygen. Proc Sot Exp Biol Med 1971;138:137-139