Case Presentation: A 67 year old African American man with extensive stage small cell neuroendocrine lung cancer presented to the ED with one month of shortness of breath. On exam, he was in mild distress requiring 2L nasal cannula (NC). RR 23-37. CXR revealed a large right pleural effusion. A thoracentesis confirmed the effusion to be exudative (pleural LDH 4150) with cytology fluid negative for malignancy. Carboplatin/Etoposide chemotherapy was started inpatient for small cell lung cancer. In preparation, he was given rasburicase, allopurinol, and IV fluids for tumor lysis syndrome prophylaxis. The next morning, the patient was found hypoxic with spo2 of 60% on 5LNC, but he denied major dyspnea. An arterial blood gas showed 96% po2 but an elevated methemoglobin to 9%. Labs were significant for hgb decrease from 7 to 6, LDH 10,000, haptoglobin 8 and direct coombs negative. Blood smear was negative for schistocytes or spherocytes and hemoglobin electrophoresis was negative for thalassemia or sickle cell disease. G6PD levels were adequate.

The patient was suspected to have rasburicase induced methemoglobinemia and hemolysis.  He was transfused 2U red blood cells and started on ascorbic acid, with improvement in oxygen requirements. Follow up blood gas showed methemoglobin level of 2%. Unfortunately, the patient’s course was complicated by multi-organ failure requiring mechanical ventilation. He expired shortly after.

Discussion: Rasburicase has been associated with hemolytic anemia and methemoglobinemia as a result of increased oxidative stress inside the erythrocyte. Methemoglobin is formed when iron in heme is oxidized. The remaining ferrous atoms in the heme tetramer have increased oxygen affinity and thus are less likely to release oxygen molecules in the periphery. This produces a functional anemia without profound dyspnea and also leads to erythrocyte destruction, producing a hemolytic anemia. Treatment is supportive with blood transfusion, supplemental oxygen and ascorbic acid as an antioxidant. There have been at least 15 reported cases of methemoglobinemia with rasburicase use. It was first reported in patients with G6PD deficiency but can occur in G6PD adequate individuals. Methemoglobinemia can also be treated with methylene blue, which catalyzes methemoglobin’s reduction back to hemoglobin. However, in individuals with G6PD deficiency, methylene blue becomes oxidized itself, further increasing the oxidative stress on the cell.

Conclusions: Our case highlights one very distinct point: hemolysis and methemoglobinemia can occur secondary to rasburicase, a less common though relatively well documented etiology. This can occur despite adequate G6PD levels. Treatment with oxygen, ascorbic acid, and transfusions is simple, but one must rule out G6PD deficiency prior to initiating standard treatment of methylene blue.