Purpose: Intravenous (IV) sodium bicarbonate is typically used in alkalization regimens for the safe use of the chemotherapeutic agent high-dose methotrexate (HDMTX). Urine parameters including urine output and pH are important in order to minimize the risk of kidney injury, which increases adverse effects and hospital length of stay following HDMTX. IV sodium bicarbonate has been on shortage, and there are limited literature describing the safety of alternative regimens.
Patients and methods: A single institution, prospective analysis of non-Hodgkin’s lymphoma and acute lymphoblastic leukemia patients receiving HDMTX for central nervous system (CNS) prophylaxis or disease. Patients received an oral (PO) regimen of sodium bicarbonate and acetazolamide to achieve a urine pH >7. This cohort was compared to a subsequent IV sodium bicarbonate control cohort. Multiple co-primary safety outcomes assessed the incidences of acute kidney injury and delayed methotrexate clearance as well as change in liver function tests. Secondary outcomes included time to urine pH, time to urine output, and length of stay.
Results: A total of 126 encounters were studied for the primary safety outcome. There was no difference between AKI incidence in patients receiving the PO alkalization regimen compared to patients receiving IV sodium bicarbonate (14.5% vs 9.3%, respectively, P=0.41). There was no difference in methotrexate clearance between the PO and IV groups (26.5% vs 37.2%, respectively, P=0.21). The use of PO alkalization regimen is estimated to have saved 2002 vials of IV sodium bicarbonate and was approximately US$226 less expensive per encounter.
Conclusion: This analysis supports the use of PO regimens to achieve urine alkalization necessary for safe administration of HDMTX during periods of IV sodium bicarbonate shortage. Further studies may determine optimal dosing strategies that decrease length of stay and ensure noninferiority of efficacy outcomes with PO regimens for urine alkalization with HDMTX.

Keywords: non-Hodgkin’s lymphoma, acute lymphoblastic leukemia, oral alkalization, alkalization, high-dose methotrexate, chemotherapy administration


High-dose methotrexate (HDMTX) is a chemotherapeutic agent used in the treatment and prevention of central nervous system (CNS) disease for lymphoma, leukemia, and other malignancies like sarcoma. Methotrexate (MTX) is a competitive inhibitor of the enzyme dihydrofolate reductase that interrupts DNA biosynthesis. Because of poor penetration of the blood–brain barrier, HDMTX is administered to adequately penetrate cerebrospinal fluid (CSF) and parenchyma. HDMTX is typically given at doses 1–12 grams per square meter of body-surface area (g/m2).1

Following intravenous MTX administration, 90–95% is excreted unchanged by the kidneys.2 Therefore, acute kidney injury (AKI) after administration of HDMTX, is a medical emergency since prolonged MTX exposure leads to severe cytopenias, mucositis, febrile neutropenia, and liver toxicity. Previous studies have shown the rate of AKI to be 2–12%.3 MTX is poorly soluble at pH less than 7, and an acidic environment within the renal tubules may result in increased risk of MTX precipitation and AKI.2,4 Urine alkalization and hyperhydration with adjustment based upon serial monitoring of urine pH and output are cornerstones in the prevention of nephrotoxicity following HDMTX. In addition, avoidance of medications that interact with MTX clearance or plasma protein-binding, monitoring of serum creatinine (SCr) and MTX concentrations, and utilizing pharmacokinetic-guided leucovorin rescue per treatment protocols are necessary for safe administration.3 Implementation of supportive measures and monitoring, the incidence of life-threatening toxicity has decreased from approximately 10% to less than 1%.5

Hospitalization is warranted prior to and following administration of HDMTX due to the intensity of monitoring required. At the University of Virginia Medical Center, intravenous (IV) sodium bicarbonate has historically been utilized to achieve a goal urine pH of at least 7 and hyperhydration with a goal urine output of at least 125 mL/hr (over a 4-hr period) is required before and after administration of HDMTX.

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In May 2017, IV sodium bicarbonate was on national shortage, which led our institution’s Pharmacy and Therapeutics Committee to implement restrictions based upon indication.6 At the time of the shortage, there were limited published data on the use of PO regimens to achieve urine alkalization in patients receiving HDMTX. Rouch et al detailed the safety and feasibility of utilizing PO sodium bicarbonate tablets and sodium citrate/citric acid suspension but did not define a standard dose.7 Shamash et al utilized an acetazolamide monotherapy regimen; however, there were concerns at our institution that prolonged carbonic anhydrase inhibition may lead to metabolic acidosis, the eventual inability to concentrate bicarbonate ions in the urine, and potentially, AKI. Therefore, an approach combining PO sodium bicarbonate and acetazolamide was conceived to prevent development of metabolic acidosis and to ensure consistent achievement of goal urine alkalization.8 This study aims to determine the safety and tolerability of this PO regimen for urine alkalization in patients receiving HDMTX.