Coral Byrns, OMS-IV


This case is to serve as a refresher on methemoglobinemia and the different pathologies, ‎both well understood and newly discovered, that surround it. Patient X, a 66-year-old African ‎American female, was seen in the emergency department with complaints of dyspnea and cough ‎with known COVID-19. She was admitted to the hospital due to hypoxia with COVID-19 ‎pneumonitis. The patient also was noted to have hemolytic anemia at the time of admission. ‎Known comorbid conditions include obesity, erythema dyschromium perstans, ocular ‎sarcoidosis, hyperlipidemia, and hypertension. Of note, she has dapsone, an oxidative drug, on ‎her home medication list. On the first and second day of her hospital stay her oxygen saturation ‎remained low while on BiPAP and, on day three, she was transferred to the intensive care unit. ‎The patient did not receive dapsone inpatient until being transferred to the intensive care unit ‎‎(day three). The patient’s methemoglobin was 2.7% on day two of admission and went up to ‎‎6.4% one day three of admission after receiving dapsone. Dapsone was then discontinued and ‎G6PD levels were ordered. G6PD level testing returned within normal limits. After consulting ‎with the patient’s rheumatologist, it was found she was lost to follow up and had not been on ‎dapsone for several months. While this is likely the reason for her critical methemoglobin ‎levels, it is important to note the elevated methemoglobin on day two of the patient’s ‎hospitalization as well. It has been documented that COVID-19 has shown G6PD levels within ‎normal limits during hospitalization and low levels suggesting deficiency when retested at ‎follow-up. The patient’s methemoglobin trended downwards and was <1% the entirety of her ‎stay. Follow up G6PD levels would have been recommended, but unfortunately the patient ‎passed in the intensive care unit due to many complications regarding her pulmonary status. ‎

Patient X is a 66-year-old African American female who presented to the emergency ‎department with chief complaints of dyspnea and cough. She was brought in by emergency ‎medical services with an Sp02 of 60% on room air. The patient stated that she was seen in a ‎different emergency department five days prior and was diagnosed with COVID-19. She was ‎then discharged home on steroids. This patient had many comorbidities including: morbid ‎obesity (BMI of 53.73), ocular sarcoidosis without known lung involvement, hyperlipidemia, ‎hypertension, and erythema dyschromium perstans. The patient’s home medication list includes ‎albuterol, amlodipine, aspirin, atorvastatin, dapsone, hydrochlorothiazide, and prednisone. In ‎the emergency department the patient was diagnosed with acute hypoxic respiratory failure and ‎COVID-19 pneumonitis (Figure 1.). The patient was weaned from ten liters of oxygen with ‎nasal cannula to six liters and remained in the 90% oxygen saturation range. ‎


Figure 1. CT showing bilateral diffuse ground glass airspace disease suggesting COVID-19 ‎pneumonitis

The patient was initially admitted to medicine, where her respiratory function continued to ‎decline. She had a trial of BiPAP in the progressive care unit and failed this. During this time, ‎she was treated with remdesivir and dexamethasone for her COVID-19 pneumonitis. She was ‎taking hydroxychloroquine at home for ocular sarcoidosis was discontinued temporarily as it ‎decreases the efficacy of remdesivir. Because she continued to decline, she was intubated, ‎ventilated, and transferred to the intensive care unit on day three. ‎

The initial plan in the ICU included maintenance of mechanical ventilation and ‎finishing her course of remdesivir and dexamethasone. After her course of remdesivir, the plan ‎was to resume her home hydroxychloroquine and dapsone 100 mg, the latter of which had not ‎been administered during her hospitalization yet. Her initial labs in the ICU were significant for ‎respiratory acidosis, hemolytic anemia, methemoglobin of 2.7%, and an elevated white blood ‎cell count of 25,000 meeting SIRS (tachypneic, tachycardic, hypotensive) and sepsis criteria. ‎

The infectious disease (ID) team was consulted at this point in the setting of COVID-19 ‎and sepsis. ID decided to continue dexamethasone/ remdesivir, order blood cultures for sepsis ‎work up, and empirically started the patient on vancomycin and cefepime with plans to de-‎escalate as needed. ID also mentioned they were unsure why the patient was on dapsone at ‎home and decided to consult the patient’s outpatient rheumatologist. The patient’s ‎rheumatologist noted that the patient takes dapsone for a skin condition called erythema ‎dyschromium perstans. This skin condition is an acquired hyperpigmentation of the dermis and ‎is a variant of lichen planus. The gold standard of treatment is dapsone as it acts as an anti-‎inflammatory and anti-microbial agent [2.]. ‎

On day two in the ICU, the patient continues to have respiratory acidosis. She also had a ‎normocytic hemolytic anemia and her hemoglobin decreased to 7.3, down from 8.5 the day ‎prior. Her white blood cell count improved to 14,000 from 25,000 the day prior. Most critically, ‎the patient had a methemoglobinemia with a methemoglobin of 6.4%, up from 2.7% the day ‎prior. Of note, a normal methemoglobin is <1% unless under oxidative stress [1.] and critical ‎level is anything over 3%. Physiologically speaking, each hemoglobin has a heme group with ‎iron. Usually ferrous (Fe2+) and can bind oxygen and transport it. When an extra electron is ‎lost, Ferrous Fe2+ becomes Ferric Fe3+ which yields methemoglobin. This occurs frequently ‎during oxidative stress. Methemoglobin cannot transport O2 without the lost electron, which ‎yields hypoxemia. Normal methemoglobin is controlled by two mechanisms, major and minor. ‎The minor pathway is a Hexose-monophosphate shunt in RBC (reduced (gain e- back, lose ‎proton) by glutathione). The major shunt is Diaphorase I/II and requires NADH/Cytochrome B5 ‎Reductase/NADPH (reduced by Glucose-6-phosphate dehydrogenase-G6PD and glutathione) ‎‎[3.,6.]. ‎

Oxidative stress is a key factor in methemoglobinemia as the reduction pathways are ‎overwhelmed. In addition to methemoglobinemia, the system is overwhelmed by cellular ‎oxidants caused by infection, a lack of antioxidants, or environmental agents like ozone, drug ‎induced oxidation, or lifestyle choices (smoking, drinking). The reactive oxygen species 02, ‎HOCL, H202, OH) build up during these instances and cannot be reduced fast enough, which ‎yields oxidative stress [1.]. This is known to cause irreversible damage and inflammation to ‎cells/DNA/protein and can be attributed to diseases such as CVD, cancer, Alzheimer’s, COPD, ‎RA, and many others [8.]. ‎

Clinically, methemoglobinemia presents as a refractory hypoxemia, which gets worse as the ‎percent of methemoglobin goes up. It is normal to have 100% Sp02 with pulse oximetry with ‎lower PO2 on ABG as pulse oximeters cannot differentiate hemoglobin types. Hemolytic ‎anemia may follow drug induced methemoglobinemia (Heinz bodies/fragmented RBCs) as ‎well. Both of these were seen in our patient. Physical examination differs based on percent of ‎methemoglobin in the blood. With 3-15% (our patient’s category), blue-gray skin can be ‎observed. Higher levels can cause darkening of the blood and can progress to end organ damage ‎and death [6.]. ‎

A differential diagnosis for methemoglobinemia includes congenital diseases, such as G6PD ‎deficiency in combination with infection or oxidants (dapsone, fava beans, nitrous oxide, sulfa ‎drugs), Cytochrome B5 Reductase Deficiency, or Hemoglobin M and E variants. Acquired ‎variants (most common) include sepsis (release of NO), exposure to oxidant drugs, chemicals, ‎or toxins (dapsone, benzocaine, nitroglycerin, hydroxychloroquine), and possibly hemolytic ‎crisis. In our patient, we considered G6PD deficiency due to her risk factor of being African ‎American [3.]. We also considered her use of dapsone, though it was our understanding that the ‎patient has been on dapsone for months and her methemoglobin was <1% on initial ‎presentation. Additionally, her methemoglobin level was 2.7% before receiving any dapsone. ‎

With this newfound critical methemoglobinemia in patient X, ID was consulted again. ‎They decided to order G6PD levels and discontinue dapsone as it is a well-known cause of ‎oxidative stress [7.]. The patient’s rheumatologist was consulted once again to determine if the ‎patient had been tested for G6PD in the past with her being on dapsone. At this time, it was ‎discovered that she was lost to follow up after her first prescription of dapsone (where they ‎would test for G6PD deficiency) over three months ago and had not been on the medication ‎since. ‎

On day three in the ICU, one day after critical methemoglobin level and discontinuation ‎of dapsone, the patient’s methemoglobin was down to 1.7. Dapsone has a half-life of 24 hours, ‎so the level was expected to continue to decline to <1%. It was <1% on day four. On this day ‎her G6PD levels came back within normal limits at 5.4 U/g. With her levels down, there was no ‎need for medical treatment. Methylene blue is the gold standard treatment for ‎methemoglobinemia. This cannot be given to patients with G6PD deficiency as G6PD is ‎required for methylene blue to aid in the reduction of ferric iron to ferrous iron. In these ‎patients, hyperbaric oxygen can be considered to oxygenate the tissues peripherally [4.]. ‎

Following resolution of methemoglobinemia on ICU Day 3, Patient X’s methemoglobin ‎level continued to remain low. Unfortunately, this patient expired on day 56 of her ‎hospitalization due to multiple comorbidities (both new and old) experienced inpatient. These ‎include acute renal failure, left pneumothorax, COVID-19 pneumonitis, sepsis, sarcoidosis, ‎acute hypoxemic and hypercapnic respiratory failure, hyperglycemia, fluid overload, morbid ‎obesity, thrombocytopenia, atelectasis, and hemolytic anemia. ‎

Interestingly, research has been done on methemoglobinemia and hemolytic anemia after ‎COVID-19. Once specific case study did not involve an eliciting drug. This study found ‎methemoglobinemia (10.5%) in a patient whose G6PD levels were within normal limits while ‎hospitalized (7.7 U/g) (normal 4.5-13.5). This patient was not on oxidizing drugs and had no ‎history of taking any. This patient had COVID-19 along with hemolytic anemia (Hb 7.9 g/dL) ‎with elevated LDH (2882 u/L) and bilirubin (2.23 mg/dL). At a five month follow up retest of ‎G6PD levels, they were low (3.7 U/g) and the patient was diagnosed with G6PD deficiency [5.]. ‎This study serves two important points: be aware of possible false negative G6PD testing during ‎hemolytic crisis and the importance of follow up, as well as the role COVID-19 contributes to ‎oxidative stress.‎

In conclusion, this case of methemoglobinemia was likely due to the patient’s one-time ‎‎100 mg dose of dapsone given in the hospital. Consideration for follow up is always ‎recommended in these patients post-hospitalization and primary care physicians should consider ‎serial monitoring G6PD levels in this type of patient. Our patient had a slight bump in ‎methemoglobin before dapsone was given. This could have been related to her possible ‎COVID-19 related hemolysis, so rechecking her G6PD outpatient would have been ‎recommended to confirm the levels were not falsely elevated in the hospital. Overall, ‎methemoglobinemia can be covered up by several comorbidities, especially when oxidative ‎stress could be coming from more than one predisposing factor. This should be kept in mind ‎when obtaining family histories, medication lists, past medical history/ family history, and ‎physical examination/physical exam. ‎


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