Achy Breaky Heart: A case of methemoglobinemia induced cardiac dysfunction
“Methemoglobinemia is a life-threatening condition characterized by a global decrease in tissue oxygen supply due to the oxidation of heme to the ferric state, which can no longer bind or transport oxygen [1]”
Case
A 16-year-old male with autism was brought to the emergency department after his mom found him confused and cyanotic. Patient arrived with a GCS of 14, was difficult to arouse, and had central cyanosis. Pulse oximetry read 85% despite adequate respiratory effort and clear lung sounds. The patient’s oxygen saturation did not improve despite appropriate supplemental oxygen therapy. A venous blood sample was brown in color (see table one) and revealed a pH of 7.1 and lactate of 17.0 mEq/L. Laboratory evidence of end-organ damage included a newly elevated creatinine of 1.37 mg/dL and high sensitivity troponin of 2,000 ng/L. EKG showed sinus tachycardia with mild ST depressions in inferolateral leads. The providers had clinical suspicion of methemoglobinemia based on refractory hypoxemia and brown color of the patient’s venous blood. The patient’s initial methemoglobin level was 29.9%. Intravenous methylene blue 2mg/kg was administered. The patient improved clinically, with a resolution of his cyanosis and return to baseline mental status within 1 hour. Interestingly, there was a transient decrease in his recorded pulse oximetry reading to 75% despite improved clinical picture. This resolved within 20 minutes. Lactic acidosis improved to 10.2mEq/L within the hour and fully resolved within 20 hours. Renal function also returned to normal during this time. However, high-sensitivity troponin climbed over a 24-hour period to 34,000 ng/L. Initial echocardiogram showed mild-to-moderate global biventricular dysfunction with an estimated left ventricular ejection fraction of 39% and left ventricular shortening fraction of 22%. Same-day cardiac MRI showed mild global hypokinesis with an ejection fraction of 47%. Repeat EKG three days later showed resolution of previously observed ST depressions. After extensive evaluation, no identifiable cause of the patient’s methemoglobinemia was discovered. However, evaluation for G6PD deficiency and HbM mutation was still pending at time of discharge. The patient was discharged after a four day stay in the PICU, with plans for close cardiology and genetics outpatient follow-up.
Discussion
Methemoglobinemia is a life-threatening condition characterized by a global decrease in tissue oxygen supply due to the oxidation of heme to the ferric state, which can no longer bind or transport oxygen [1]. This conformational molecular change results in a functional acute anemia. Congenital methemoglobinemia occur through a variety of autosomal dominant and recessive mutations to the underlying structure of the hemoglobin molecule. Acquired methemoglobinemia results from exposure to oxidizing agents. This can include direct oxidizing agents (e.g. benzocaine), and indirect oxidizing agent (e.g. nitrates). This accelerated creation of methemoglobinemia exceeds the body’s capacity to convert the iron within the hemoglobin back to its ferrous state, which leads to functional anemia. Characteristic clinical manifestations of methemoglobinemia include central cyanosis, dyspnea, refractory hypoxemia by pulse co-oximetry, metabolic acidosis, seizures, central nervous system depression, and brown discoloration of venous blood [1,2]. The severity of symptoms hinges on duration and amount of exposure, the quantifiable amount of methemoglobin present, the rate at which it accumulated, the patient's baseline ability to clear it, and underlying patient comorbidities. It is well recognized that, as methemoglobin levels rise, progressive global tissue hypoxia results in significant morbidity and mortality.
Diagnosis is based on clinical suspicion and the ratio of methemoglobin to hemoglobin in the patients system. Most labs report this as a percentage.
Treatment depends largely on the causative nature of the presentation. For suspected environmental exposures, methylene blue is the mainstay of therapy. Dosing is 1-2mg/kg over a five minute period. Repeated doses can be given every 30 to 60 minutes, with a maximum dose not being fully established in the literature. However, most experts agree if multiple doses are given, alternative therapies should also be pursued. In any suspected acquired methemoglobinemia, a local toxicologist should be consulted. If congenital methemoglobinemia is suspected, vitamin C is the alternative therapy.
The literature on cardiac effects of methemoglobinemia is limited to a handful of case reports describing acute coronary syndrome-like events in adult patients. Most patients with methemoglobinemia respond well to treatment, have minor tissue hypoxic complications, and can be discharged readily from the hospital with a few hours of observation [3,4,5]. Even with severe cases, end-organ damage from global tissue hypoxia resolved at varying time points, as evidenced in this case by a return to baseline mental status within an hour of treatment, resolution of kidney injury within the day, and improvement of myocardial dysfunction within four days. Previously unrecognized, myocardial dysfunction due to methemoglobinemia is an important entity to acknowledge, as patients should be closely monitored to ensure resolution. In this case, prompt recognition and treatment resulted in a full return to normal cardiac function.
Conclusion
Methemoglobinemia is a rare congenital or acquired functional anemia caused by fundamental changes in the body's hemoglobin structure [1]. Although rare, there are identifiable physical exam findings, objective vital signs, laboratory indicators, and known causative agents that can aid the clinician in making a timely diagnosis. Severity is based on a multitude of factors, with resulting varying degrees of end-organ dysfunction. Treatment given in an expeditious manner should lead to prompt resolution and recovery of these insults. In particular, myocardial ischemia is an important complication of methemoglobinemia that, if recognized and treated promptly, may result in transient myocardial stunning rather than persistent cardiomyopathy.
Author: Brian Drury, MD, MEd, is a third-year resident and an Education Chief at Brown Emergency Medicine
Faculty Reviewer: Kristina McAteer, MD, is an attending physician and Rhode Island Hospital and Newport Hospital.
References
1. Ludlow JT, Wilkerson RG, Nappe TM. Methemoglobinemia. 2022 Aug 29. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 30726002.
2. Prchal, Josef. (2023). Methemoglobinemia. In Burns, M., Takemoto, C, Ed. Uptodate. Waltham, Mass.: UpToDate, 2023. www.uptodate.com/contents/methemoglobinemia. Accessed April 15, 2023.
3. Rehmani, Arsalan, et al. (2021). Severe Methemoglobinemia Clinically Presenting as Acute Coronary Syndrome. Journal of the American College of Cardiology 77.18_Supplement_1: 1890-1890.
4. Saha, S. A. , Kordouni, M. R. , Siddiqui, M. & Arora, R. R. (2006). Methemoglobinemia-induced Cardio-respiratory Failure Secondary to Topical Anesthesia. American Journal of Therapeutics, 13 (6), 545-549. doi: 10.1097/01.mjt.0000208876.69103.c7.
5. Sammarrai, F. A., D. Patel, and N. Arnous. (2016). Dark Coronary Toxidrome- A Case of Methemoglobinemia Presenting as Acute Coronary Syndrome in a Patient with Polysubstance Abuse. J Clin Toxicol 6.277: 2161-0495.