A 64-year-old man developed severe methotrexate-induced cardiotoxicity and transudative pleural effusions requiring bilateral chest tubes to facilitate drug clearance from third-spaced compartments.
Case Report (n=1)
Pleural effusions can act as a third-space reservoir for methotrexate, delaying clearance and exacerbating rare but severe cardiotoxicity, which may necessitate chest tube placement for mitigation.
Abstract Introduction Methotrexate is an important antineoplastic therapeutic option, but it carries a significant risk of renal toxicity. Acute kidney injury (AKI) is the most recognized adverse effect of methotrexate, yet complications involving other organs are less well described. We present a rare case of severe methotrexate-induced cardiotoxicity. Case A 64-year-old man with diffuse large B-cell lymphoma with CNS relapse and doxorubicin-associated cardiomyopathy was admitted for chemotherapy with methotrexate, temozolomide, and rituximab. Following chemotherapy, his methotrexate level exceeded 600 µmol/L and he developed an anuric AKI requiring continuous renal replacement therapy. Later that day, he developed cardiogenic shock with an ejection fraction of 20% and a mixed venous oxygen saturation of 33%, requiring dobutamine infusion, as well as acute hypoxic respiratory failure secondary to bilateral pleural effusions. He received leucovorin rescue therapy, bicarbonate infusion, and glucarpidase for methotrexate toxicity, which initially lowered his serum methotrexate levels to 29.37 µmol/L. However, levels rapidly increased again to 148.80 µmol/L due to redistribution from third-spaced compartments. Thoracentesis showed pleural fluid studies with methotrexate level 89 µmol/L, protein 1.6 g/dL, albumin 1.0 g/dL, LDH 120 U/L, and cholesterol 25 mg/dL, and serum protein 4.9 g/dL, albumin 3.3 g/dL, and LDH 664 U/L, consistent with a transudative effusion. The effusions rapidly reaccumulated and their methotrexate levels persisted to be elevated on subsequent thoracenteses (22 and 11.38 µmol/L), worsening his respiratory status and delaying drug clearance. After multidisciplinary discussions with the patient, he consented to bilateral chest tube placement. Daily serum and pleural methotrexate levels were monitored until they decreased to 0.1 µmol/L. The chest tubes were eventually removed; unfortunately, his cardiac function did not recover leading to the initiation of palliative milrinone. Discussion Methotrexate toxicity remains a life-threatening complication, particularly in patients with renal dysfunction. Methotrexate-induced cardiotoxicity is exceedingly rare, with few case reports published. Animal studies have demonstrated that methotrexate-induced cardiotoxicity is characterized by distortion of cardiac histology and increased oxidative and nitrosative stress. Methotrexate sequesters within third-space compartments, such as pleural or peritoneal fluid, leading to delayed clearance and prolonged toxicity. Glucarpidase and leucovorin are key therapies, however, glucarpidase only reduces intravascular methotrexate, leaving extravascular stores unaffected. We report a rare case of methotrexate-induced cardiotoxicity complicated by transudative pleural effusions requiring bilateral chest tubes to facilitate drug clearance. Clinicians should recognize that pleural effusions can serve as a significant barrier to methotrexate clearance and, in rare cases, require chest tube placement to mitigate toxicity. This abstract is funded by: None
Erp et al. (2026) conducted a case report in Methotrexate-induced cardiotoxicity (n=1). Methotrexate was evaluated. A 64-year-old man developed severe methotrexate-induced cardiotoxicity and transudative pleural effusions requiring bilateral chest tubes to facilitate drug clearance from third-spaced compartments.