Case Report

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American Journal of Emergency Medicine

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Troponin leak associated with drug-induced methemoglobinemia?,??,?

Abstract

Drug-induced methemoglobinemia is a well-described entity but has not been previously associated with elevated troponins in the absence of cardiac symptoms. We report a case of a patient presenting to the emergency department (ED) with complaints related to an exacerbation of her long-standing cystitis. A low pulse oximetry reading prompted an evaluation, revealing a troponin leak, which peaked at 10 hours. Her methemoglobin level was found to be elevated at 11.4%, but a preexisting anemia apparently prevented the clinical recognition of cyanosis. The methemoglobinemia was determined to be secondary to her ingestion of phenazopyridine and trimethoprim-sulfamethoxizole. Although phenazopyridine and sulfa agents have long been known to cause methemoglobinemia, our patient exhibited an asymptomatic troponin leak that has not been previously reported as a complication of drug-induced methemoglobinemia. Clinicians should be aware of this potential association.

A 59-year-old white woman presented to the emergency department (ED) with a chief complaint of abdominal pain for 36 hours. Medical history was positive for chronic cystitis for several years of duration, hypertension, hyperlipidemia, bipolar disorder, and low back pain. She was a nonsmoker with a remote 10-pack-year history. She had been taking phenazopyridine 100 mg 4 times a day for approximately 2 months and had taken one dose of trimetho- prim-sulfamethoxizole the evening before her ED visit for presumed urinary tract infection. Other medicines included lamotrigine, amitriptyline, venlafaxine XR, olanzapine, aspirin, diltiazem, simva- statin, hydrochlorothiazide, zolpidem, fentanyl patch, hydrocodone/ acetaminophen as needed (prn), and acetaminophen/codeine (prn). Her abdominal pain was mostly suprapubic; she had no complaints of chest pain, shortness of breath, or cyanosis.

Vital signs included oxygen saturation, 91% on room air; pulse, 97 mm Hg; blood pressure, 167/99 mm Hg; and respiratory rate, 18 breaths/min. She was afebrile. Three liters of oxygen by nasal cannula only increased her oxygen saturation to 92%. Physical examination was notable only for suprapubic and unilateral flank tenderness. There were no cardiac or Pulmonary findings; there was no cyanosis. Electrocardiogram demonstrated a left bundle

? The authors have no outside support information, conflicts, or financial interest to disclose, and this work has not been presented elsewhere.

?? RC, JJ, and MW researched the case; RC and JJ supervised data collection; RC and JJ

drafted the manuscript; and all authors contributed substantially to its revision. JJ takes

responsibility for the manuscript as a whole.

? We thank Bernadette Porter BS, CIM; Scholarly Activity Coordinator.

branch block, which was unchanged from prior testing. Computed tomography of the abdomen and chest were normal. Notable laboratory abnormalities were hemoglobin level of 9.3 g/dL (similar to prior values).

An arterial blood gas on 3 L by nasal cannula revealed pH, 7.36; carbon dioxide, 41 mm Hg; oxygen, 114 mm Hg; serum bicarbonate, 22.2 meq/L; oxygen saturation, 97%; and oxygen content, 10.6 mL/dL (normal 15-33 mL/dL). Cooximetry revealed a methemoglobin level of 11.4%, (normal b 3), oxyhemoglobin of 82.5%, and carboxyhemoglobin of 3.7%. The patient’s serial Troponin I levels were as follows: (1) b 0.04 ng/mL at 14:56, (2) 0.20 ng/mL at 18:41, (3) 0.41 ng/mL at 01:20, and

(4) 0.33 ng/mL at 04:15. A cardiology consult was obtained, and the patient was admitted to a monitored bed. Methylene blue was not given as the patient was asymptomatic, and there were no new Ischemic changes on her ECG. On discharge 2 days later, she had no evidence of cardiac ischemia; phenazopyridine and trimethoprim- sulfamethoxizole were discontinued.

Acquired methemoglobinemia occurs when the oxygen carrying ferrous iron (Fe²⁺) in the hemoglobin molecule is oxidized to the ferric state (Fe³⁺) as a result of exposure to oxidizing drugs or their metabolites. Methemoglobin causes tissue hypoxia by 2 mecha- nisms: increased affinity for oxygen, which shifts the oxygen dissociation curve to the left and decreasing the amount of free hemoglobin available to transport oxygen [1]. Phenazopyridine has long been known to cause methemoglobinemia as a result of its major metabolite, aniline.

Methemoglobinemia after phenazopyridine ingestion has been reported after both overdose and usual dosing and in the absence of renal dysfunction [2-5]. Trimethoprim-sulfamethox- asole has also been reported to cause methemoglobinemia [1]. Saha et al [6] report acute methemoglobinemia causing cardiorespiratory failure after topical benzocaine that responded to Methylene blue therapy. To our knowledge, elevated troponin I secondary to methemoglobinemia has not been previously reported [7].

Methemoglobin commonly results in cyanosis because of its pigmentation; only 1.5 g/dL of methemoglobin is necessary to cause visible cyanosis. In contrast, approximately 5 g/dL of deoxyhemoglobin is necessary before cyanosis results. Our patient was anemic at baseline (hemoglobin level 9.3 g/dL). With 11.4% methemoglobin, our patient’s absolute concentration of methemoglobin was roughly 1.0 g/dL and insufficient to cause the clinical finding of cyanosis. Having 1.0 g/dL of methemoglobin left only 8.3 g/dL of normal hemoglobin level to carry and deliver oxygen to the tissues. Although the methemo- globin percentage was relatively low, anemia caused increased susceptibility to even small derangements in oxygen carrying capacity and delivery.

0735-6757/(C) 2014

Pulse oximeters measure absorbance at the peak wavelengths of oxyhemoglobin and deoxyhemoglobin (940 nm and 660 nm, respectively). They compare the ratio of oxyhemoglobin to deoxyhemoglobin to determine the percentage of total oxygen- saturated hemoglobin level. Because methemoglobin’s absorption at these wavelengths is greater than that of either oxyhemoglobin or deoxyhemoglobin, pulse oximeter readings become inaccurate. These readings tend to decrease as metHemoglobin levels increase but not necessarily in a proportional manner [8]. If an abnormal species of hemoglobin is present, like methe- moglobin, the calculated oxygen saturation on ABG will be falsely elevated. This difference between the oxygen saturation from the pulse oximeter and the blood level is known as the “saturation gap.” It can be a clue to the presence of an abnormal hemoglobin species, prompting further evaluation. Our patient exhibited this phenomenon-her oxygen saturation persistently read 88% to 91%, yet on ABG it was resulted at 97%. Cooximetry must be used when a suspected abnormal hemoglobin species is present. A cooximeter can identify accurate proportions of multiple hemoglobin species at different wavelengths.

We hypothesize that, in this patient with baseline anemia (9.3 mg/dL), induction of methemoglobinemia (11%) caused sufficient tissue hypoxia to cause stress ischemia, even in the absence of coronary artery disease. It is likely that the addition of sulfa drug hours before presentation exacerbated the methemoglobinemia.

Robert D. Cannon, DO Michael Wagner, DO Jeanne L. Jacoby, MD?

Department of Emergency Medicine, Lehigh Valley Hospital and Health Network, 1240 South Cedar Crest Boulevard, Allentown, PA 18103

?Corresponding author at: Emergency Medicine Research Lehigh Valley Hospital and Health Network

1240 South Cedar Crest Boulevard, Suite No. 212, Allentown, PA 18103.

Tel.: +1 610 402 7262/7666; fax: +1 610 402 7160.

E-mail address: [email protected] http://dx.doi.org/10.1016/j.ajem.2014.03.015

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