Evaluation of methotrexate clearance with an enteral urine alkalinization protocol for patients receiving high-dose methotrexate

Purpose Methotrexate is an antifolate agent used in treatment of several malignancies. Many toxicities accompany methotrexate that are minimized with urine alkalinization. Parenteral sodium bicarbonate is the historical standard alkalinizing agent, but use has been limited by intermittent shortages. However, intravenous sodium acetate may be considered as a chemically equivalent alternative. The primary objective of this study is to determine the efficacy of sodium acetate versus sodium bicarbonate for urine alkalinization for high-dose methotrexate (HDMTX). Methods This is a retrospective cohort study including adults admitted to Barnes-Jewish Hospital to receive HDMTX for lymphoma, breast cancer with leptomeningial spread, or osteosarcoma. Patients must have received intravenous sodium acetate or sodium bicarbonate alkalinization. Results Of 192 HDMTX encounters, 154 (sodium bicarbonate, n = 86; sodium acetate, n = 68) were evaluated for efficacy and safety. Safety outcomes were not significantly different between groups except for higher peak methotrexate level in the bicarbonate group (2.9 mcmol/L vs. 1.7 mcmol/L, p = 0.023), and increased incidence of grade 3–4 ALT in the sodium bicarbonate group (23.5% vs. 9%, p = 0.02). Time from alkalinizer initiation to pH ≥7 was significantly shorter with sodium bicarbonate (4 vs. 5.15 h, p = 0.021). Nonetheless, outcomes such as length of stay (4.4 vs. 4 days respectively, p = 0.037) and time to methotrexate clearance (3.6 vs. 3.2 days respectively, p = 0.023) reveal that inpatient time was shorter with sodium acetate overall. Conclusion This retrospective analysis suggests that sodium acetate has similar efficacy and safety to sodium bicarbonate for alkalinization and may be considered as an alternative in future shortage situations.

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Evaluation of an Oral Sodium Bicarbonate Protocol for High-Dose Methotrexate Urine Alkalinization

10.21203/rs.3.rs-328004/v1 ◽

2021 ◽

Author(s):

Rachel Heisler ◽

Jordan Kelly ◽

Sara Abedinzadegan Abdi ◽

Jennifer Hawker ◽

Leanne Fong ◽

...

Keyword(s):

Serum Creatinine ◽

Sodium Bicarbonate ◽

Retrospective Chart Review ◽

High Dose ◽

High Dose Methotrexate ◽

Dose Methotrexate ◽

Urine Alkalinization ◽

Nausea And Emesis ◽

Alberta Health ◽

Oral Sodium

Abstract Purpose: Intravenous (IV) sodium bicarbonate is considered standard therapy for high-dose methotrexate (HDMTX) urine alkalinization. Due to a national IV sodium bicarbonate shortage, an oral (PO) sodium bicarbonate protocol was implemented by Alberta Health Services (AHS) for HDMTX urine alkalinization. This study aims to evaluate the efficacy and safety of the PO sodium bicarbonate protocol compared to IV sodium bicarbonate for HDMTX urine alkalinization. Methods: A retrospective chart review of adult patients who received HDMTX (>500 mg/m2) with sodium bicarbonate for urine alkalinization at 4 hospitals in Alberta was conducted. Patients who received IV sodium bicarbonate between January-June 2017 and PO sodium bicarbonate between July-December 2017 were compared for the primary outcome of time to methotrexate clearance. Results: A total of 84 and 78 HDMTX cycles were included in the IV and PO cohorts, respectively. No difference in time to methotrexate clearance was seen between the IV and PO cohorts, 91.6 (± 35.4) hours and 95.2 (± 44) hours respectively; p=0.5. The proportion of HDMTX cycles that experienced a >25% increase in serum creatinine was not statistically significant, IV protocol 12% and PO protocol 5%; p=0.13. Nausea and emesis occurred more frequently in the PO cohort than the IV cohort, though rarely resulted in refused doses or change to alternate sodium bicarbonate formulations.Conclusions: The results of this study indicate that the AHS PO sodium bicarbonate protocol was no different in time to methotrexate clearance or rates of increased serum creatinine when compared to IV sodium bicarbonate.

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Use of the extracorporeal detoxification methods for methotrexate elimination

EMERGENCY MEDICINE ◽

10.22141/2224-0586.17.8.2021.245585 ◽

2021 ◽

Vol 17 (8) ◽

pp. 90-94

Author(s):

R.Yu. Sobko ◽

T.T. Borachok ◽

T.B. Oranskyi ◽

M.O. Kovalov ◽

Kh.M. Zapotochna ◽

...

Keyword(s):

Liver Failure ◽

Acute Liver Failure ◽

Clinical Case ◽

Methylenetetrahydrofolate Reductase ◽

Mthfr C677t ◽

High Dose ◽

High Dose Methotrexate ◽

Dose Methotrexate ◽

Urine Alkalinization ◽

Intravenous Hydration

The article considers a clinical case of a 12-year-old child with osteosarcoma of the left tibia, T1N0M0G3, treated with high-dose methotrexate 12 g/m2. As a result of delayed elimination of methotrexate, the patient developed acute liver failure. The ALT level increased to 4790 U/L, AST — to 4320 U/L, which indicates life-threatening acute liver damage. There was no coagulopathy, significant increase in bilirubin, and hepatic encephalopathy. The timely use of efferent therapy allowed avoiding the complete course of acute liver failure. The patient received intravenous hydration therapy and urine alkalinization with 3000 ml/m2/day of 5% glucose in combination with 20 μmol NaHCO3/L and 20 μmol KCl/L. The urine output was more than 600 ml/m2/6 hours. Additionally, antidote therapy with calcium folinate was administered. In this case, we used continuous venous-venous hemodiafiltration using Prismaflex. After the first session, which lasted for 78 hours, there was a re-increase in serum methotrexate concentration and ALT, AST levels, which indicates a large volume of distribution of methotrexate and the need for long-term extracorporeal therapy. Therefore, the second session of continuous venous-venous hemodiafiltration was provided. After the second session, there was no re-increase in methotrexate level in the blood and the transaminases and total bilirubin returned to normal levels. Additionally, the patient was tested for homocysteine levels for hyperhomocysteinemia, as well as 4 genes that also determine the predisposition to hyperhomocysteinemia — methylenetetrahydrofolate reductase gene MTHFR C677T, A1298C, methionine synthase MTRR, and MTR. The presence of elevated levels of homocysteine, as well as heterozygosity of these genes, indicate a slow excretion of methotrexate or a complete delay in its excretion. Our patient presented the negative results of these tests. Conclusions. This clinical case indicates the effectiveness of continuous venous-venous hemodiafiltration in combination with intravenous hydration, urine alkalinization, and antidote therapy in the treatment of hepatotoxicity of high-dose methotrexate on the background of delayed excretion.

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