Assessing the impact of adding acetazolamide to oral or intravenous sodium bicarbonate as compared with intravenous bicarbonate monotherapy as urinary alkalinization in adults receiving high-dose methotrexate



High-dose methotrexate (HD-MTX) requires urine alkalinization to pH ≥ 7 for adequate excretion to prevent toxicity. Due to shortages of IV sodium bicarbonate (IV-NaHCO3), few reports have demonstrated utility of oral bicarbonate (PO-NaHCO3); however, the addition of acetazolamide (Acet) has not been well described. Our study compares outcomes between alkalinization methods of IV-NaHCO3 monotherapy versus IV-NaHCO2 + Acet and PO-NaHCO3 + Acet.


A single-center, IRB exempt, retrospective review was conducted from Jan 2016 to Sept 2019 of adults receiving HD-MTX ≥ 500 mg/m2. The primary outcome was time from start of alkalinization to pH ≥ 7. Secondary outcomes included time from start of alkalinization to initiation of HD-MTX, time to MTX clearance, length of stay (LOS), percentage of urine pH assessments < 7, and incidence of MTX toxicity. Statistical analysis was performed using SAS9.4 with alpha 0.05.


Overall demographics (n = 196 HD-MTX cycles for 55 patients) include a mean age 55 years, HD-MTX dose ~ 5400 mg/m2, and 69% with a diagnosis of lymphoma. Adjusting for baseline demographic differences among groups, median time from first dose alkalinization to pH ≥ 7 and to start of HD-MTX was longer for those receiving IV-NaHCO3 (n = 41) vs either IV-NaHCO3 + Acet (n = 70) or PO-NaHCO3 + Acet (n = 76) (p = 0.0001). HD-MTX clearance to a level < 0.1 μmol/L was not improved with the addition of Acet. No difference existed among groups for pH results < 7, LOS, or incidence of MTX toxicity (p > 0.05).


Addition of Acet to NaHCO3 reduces time to pH ≥ 7 and initiation of HD-MTX but does not appear to improve LOS, MTX toxicities, or time to MTX clearance.

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The use of REDCap was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR002378. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Correspondence to Amber B. Clemmons.

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Clemmons, A.B., Chase, A., Duong, P. et al. Assessing the impact of adding acetazolamide to oral or intravenous sodium bicarbonate as compared with intravenous bicarbonate monotherapy as urinary alkalinization in adults receiving high-dose methotrexate. Support Care Cancer 29, 1527–1534 (2021).

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  • Alkalinization
  • Acetazolamide
  • Bicarbonate
  • Clearance
  • Methotrexate
  • Supportive care