Skip to main content

Advertisement

SpringerLink
Log in

Evaluation of an oral sodium bicarbonate protocol for high-dose methotrexate urine alkalinization

  • Original Article
  • Published:
Supportive Care in Cancer Aims and scope Submit manuscript

A Letter to the Editor to this article was published on 19 October 2022

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 and June 2017 and PO sodium bicarbonate between July and 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Howard SC, McCormick J, Pui C et al (2016) Preventing and managing toxicities of high-dose methotrexate. Oncologist 21:1471–1482

    Article  CAS  Google Scholar 

  2. Widemann BC, Adamson PC (2006) Understanding and managing methotrexate nephrotoxicity. Oncologist 11:694–703

    Article  CAS  Google Scholar 

  3. Drost SA, Wentzell JR, Giguere P et al (2017) Outcomes associated with reducing the urine alkalinization threshold in patients receiving high-dose methotrexate. Pharmacotherapy 37(6):684–691

    Article  CAS  Google Scholar 

  4. Alrabiah Z, Luter D, Proctor A, Bates JS (2015) Substitution of sodium acetate for sodium bicarbonate for urine alkalinization in high-dose methotrexate therapy. Am J Health-Syst Pharm 72(15):1932–1934

  5. Sterrett SP, Penniston KL, Wolf JS et al (2008) Acetazolamide is an effective adjunct for urinary alkalinization in patients with uric acid and cystine stone formation recalcitrant to potassium citrate. Urology 72:278–281

    Article  Google Scholar 

  6. Shamash J, Earl H, Souhami R (1991) Acetazolamide for alkalinization of urine in patients receiving high-dose methotrexate. Cancer Chemother Pharmacol 25(2):150–151

    Article  Google Scholar 

  7. Whiteside H, Gandhi A, Ajebo G, Bryan LJ (2018) When baking soda goes on shortage: urine alkalinization with acetazolamide and oral sodium bicarbonate. Ann Pharmacother 52(3):297–298

    Article  Google Scholar 

  8. Cohen B, Laish I, Brosh-Nissimov T, Hoffman A, Katz LH, Braunstein R, Sagi R, Michael G (2013) Efficacy of urine alkalinization by oral administration of sodium bicarbonate: a prospective open-label trial. Am J Emerg Med 31:1703–1706

    Article  Google Scholar 

  9. Roy AM, Lei M, Lou U (2019) Safety and efficacy of a urine alkalinization protocol developed for high-dose methotrexate patients during intravenous bicarbonate shortage. J Oncol Pharm Practice 25(8):1860–1866

    Article  CAS  Google Scholar 

  10. Kramer E, Filtz M, Pace M (2020) Evaluation of methotrexate clearance with an enteral urine alkalinization protocol for patients receiving high-dose methotrexate. J Oncol Pharm Practice. 27:26–32. https://doi.org/10.1177/1078155220908946

    Article  CAS  Google Scholar 

  11. Rouch JA, Burton B, Dabb A, Brown V, Seung AH, Kinsman K, Holdhoff M (2017) Comparison of enteral and parenteral methods of urine alkalinization in patients receiving high-dose methotrexate. J Oncol Pharm Practice 23(1):3–9

    Article  CAS  Google Scholar 

  12. Diachinsky M, Tran T, Jupp J, McKinnon K (2020) Oral sodium bicarbonate protocol for high-dose methotrexate urine alkalinization: a pediatric experience. J Oncol Pharm Practice 27:119–127. https://doi.org/10.1177/1078155220915769

    Article  CAS  Google Scholar 

  13. Visage R, Kaiser N, Williams M, Kim A (2019) Oral method of urinary alkalinization for high-dose methotrexate administration: alternatives to intravenous sodium bicarbonate during a critical drug shortage. J Pediatr Hematol Oncol 41(5):371–375

    Article  CAS  Google Scholar 

  14. Reed DR, Pierce EJ, Sen JM, Keng MK (2019) A prospective study on urine alkalinization with an oral regimen consisting of sodium bicarbonate and acetazolamide in patients receiving high-dose methotrexate. Cancer Manag Res 11:8065–8072

    Article  CAS  Google Scholar 

  15. Schmickl CN, Owen RL et al (2020) Side effects of acetazolamide: a systematic review and meta-analysis assessing overall risk and dose dependence. BMJ Open Resp Res 7:e000557. https://doi.org/10.1136/bmjresp-2020-000557

    Article  PubMed  PubMed Central  Google Scholar 

  16. Swenson ER (2014) Safety of carbonic anhydrase inhibitors. Expert Opin Drug Saf 13(4):459–472

    Article  CAS  Google Scholar 

  17. Maisey DN, Brown RD (1981) Acetazolamide and symptomatic metaboic acidosis in mild renal failure. Br Med J (Clin Res Ed) 283(6305):1527–1528

    Article  CAS  Google Scholar 

  18. Pampin R, Lebeaga Y, Rodriguez B et al (2019) Experience with ambulatory high-dose methotrexate administration as CNS prophylaxis in patients with non-Hodgkin lymphoma. J Oncol Pharm Practice 26(3):549–555

    Article  Google Scholar 

  19. Bernard S, Hachon L, Diasonama J et al (2021) Ambulatory high-dose methotrexate administration as central nervous system prophylaxis in patients with aggressive lymphoma. Ann Hematol 100:979–986. https://doi.org/10.1007/s00277-020-04341-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Matthew Newman, PharmD, BCOP, and The Johns Hopkins Hospital Department of Pharmacy, Weinberg Oncology Division, for their assistance with the study. We would also like to thank Melanie Varghese, BSc Pharm; Tyler Moore, BSc Pharm; Deonne Dersch-Mills, BSc Pharm, ACPR, PharmD; Ashley Yim; Eric Duong; Alexandra Yuriyivna Spirkina; and Jessica Kim for their contributions.

Availability of data and material

The authors maintain control of all the data used for the completion of this study. Anonymized data can be made available upon request.

Code availability

N/A

Funding

No funding was received for the completion of this study.

Author information

Authors and Affiliations

  1. Pharmacy Services, University of Alberta Hospital/Stollery Children’s Hospital/Mazankowski Alberta Heart Institute, Edmonton, AB, Canada

    Rachel D. Heisler

  2. Pharmacy Services, Alberta Health Services, Calgary, AB, Canada

    Jordan J. Kelly & Jennifer C. Jupp

  3. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada

    Sara Abedinzadegan Abdi

  4. Pharmacy Services, Foothills Medical Centre, Alberta Health Services, Calgary, AB, Canada

    Jennifer L. Hawker & Leanne G. Fong

  5. Pharmacy Services, Peter Lougheed Centre, Alberta Health Services, Calgary, AB, Canada

    Janet L. Quon & Josee Z. Rioux

Authors
  1. Rachel D. Heisler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jordan J. Kelly
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sara Abedinzadegan Abdi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jennifer L. Hawker
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Leanne G. Fong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Janet L. Quon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Josee Z. Rioux
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jennifer C. Jupp
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: Jennifer C. Jupp. Methodology: Jennifer C. Jupp, Jennifer L. Hawker, Leanne G. Fong, Josee Z. Rioux, Janet L. Quon, and Jordan J. Kelly. Project administration and supervision: Jennifer C. Jupp. Data collection: Jordan J. Kelly. Data analysis: Rachel D. Heisler. Writing—original draft: Rachel D. Heisler and Sara Abedinzadegan Abdi. Writing—review and editing: Rachel D. Heisler, Sara Abedinzadegan Abdi, Jennifer C. Jupp, Jennifer L. Hawker, Leanne G. Fong, Josee Z. Rioux, and Janet L. Quon.

Corresponding author

Correspondence to Rachel D. Heisler.

Ethics declarations

Ethics approval

Ethics approval was obtained from The Health Research Ethics Board of Alberta Cancer Committee (HREBA-CC).

Consent to participate

A waiver of consent to participate was obtained.

Consent to publish

A waiver of consent to publish was obtained.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Appendix

Appendix

Johns Hopkins Hospital Oral Sodium Bicarbonate Protocol

Sodium Bicarbonate Shortage – Changes in Urine Alkalinization for IV High-Dose Methotrexate (≥ 5 g/m2)

 

Recommendations (assuming an 80 kg patient)

Total daily sodium bicarbonate

Patients who are able to tolerate PO or have alternate enteral access (i.e., PEG tube)

Pre-admission: Sodium bicarbonate 1300 mg PO q6 hours OR Bicitra 20 ml PO q8 hours starting one day prior to planned methotrexate administration.

Upon admission:

If urine pH ≥ 7.5: D5½NS IV at 3 ml/kg/h, and continue pre-methotrexate urine alkalinization regimen.

If urine pH < 7.5:

• Start D5½NS IV at 3 ml/kg/h, and bolus with Bicitra 120 mL orally/enterally × 1 dose.

• Continue D5½NS IV at 3 ml/kg/h, and give sodium bicarbonate 9750 mg (15 tablets) orally/enterally q6 hours OR Bicitra 120 mL orally/enterally q6 hours. Bolus with an additional oral/enteral dose of Bicitra 120 mL if urine pH < 7.5

Pre-admission: 64 mEq (tablets); 60 mEq (Bicitra)

During admission: 480 mEq

Patients unable to tolerate PO, but have enteral access (i.e., PEG tube)

Pre-admission: Bicitra 20 ml enterally q8 hours starting one day prior to planned methotrexate administration.

Upon admission:

If urine pH ≥ 7.5: D5½ NS IV at 3 ml/kg/h, and continue pre-methotrexate urine alkalinization regimen.

If urine pH < 7.5:

•Start D5½ NS IV at 3 ml/kg/h and bolus with Bicitra 120 mL enterally × 1 dose.

• Continue D5½NS IV at 3 ml/kg/h, and give Bicitra 120 mL enterally q6 hours. Bolus with additional enteral dose of Bicitra 120 mL if urine pH < 7.5.

Pre-admission: 60 mEq (Bicitra)

During admission: 480 mEq

Patients with no enteral access

• Sodium bicarbonate 100 mEq/L IV at 3 mL/kg/h

OR

• Start D5½NS IV at 3 ml/kg/h, and place NG tube, and administer Bicitra 120 ml via NG tube q6 hours. Bolus with an additional NG dose of Bicitra 120 mL if urine pH < 7.5.

576 mEq/day

480 mEq/day

Sodium Bicarbonate Shortage-Changes in Urine Alkalinization for IV Intermidiate/Moderate-Dose Methotraxate (> 1 g/m2 and < 5 g/m2)

 

Recommendations (assuming an 80 kg patient)

Total daily sodium bicarbonate

Patients who are able to tolerate PO or have alternate enteral access (i.e., PEG tube)

Pre-admission: Sodium bicarbonate 1300 mg PO q6 hours OR Bicitra 20 ml PO q8 hours starting one day prior to planned methotrexate administration.

Upon admission:

If urine pH ≥ 7: Lactated Ringer’s IV at ml/kg/h, and continue pre-methotrexate urine alkalinization regimen.

If urine pH < 7:

• Start Lactated Ringer’s IV at 2 ml/kg/h and bolus with Bicitra 120 ml orally/enterally × 1 dose.

• Continue Lactated Ringer’s IV at 2 ml/kg/h and give sodium bicarbonate 9750 mg (15 tablets) orally/enterally q6 hours OR Bicitra 120 mL orally/enterally q6 hours. Bolus with an additional oral/enteral dose of Bicitra 120 mL if urine pH < 7.

Pre-admission: 64 mEq (tablets); 60 mEq (Bicitra)

During admission: 588 mEq

Patients unable to tolerate PO, but have enteral access (i.e., PEG tube)

Pre-admission: Bicitra 20 ml enterally q8 hours starting one day prior to planned methotrexate administration.

Upon admission:

If urine pH ≥ 7: Lactated Ringer’s IV at 2 ml/kg/h, and continue pre-methotrexate urine alkalinization regimen.

If urine pH < 7:

•Start Lactated Ringer’s IV at 2 ml/kg/h and bolus with Bicitra 120 mL enterally × 1 dose.

•Continue Lactated Ringer’s IV at 2 ml/kg/h, and give Bicitra 120 mL enterally q6 hours. Bolus with additional enteral dose of Bicitra 120 mL if urine pH < 7.

Pre-admission: 60 mEq (Bicitra)

During admission: 588 mEq

Patients unable to tolerate PO, but have enteral access (i,e., PEG tube)

Pre-admission: Bicitra 20 ml enterally q8 hours starting one day prior to planned methotrexate admission.

Upon admission:

If urine pH ≥ 7: Lactated Ringer’s IV at 2 ml/kg/h and continue pre-methotrexate urine alkalinization regimen.

If urine pH < 7:

• Start Lactated Ringer’s IV at 2 ml/kg/h and bolus with Bicitra 120 mL enterally × 1 dose.

• Continue Lactated Ringer’s IV at 2 ml/kg/h and give Bicitra 120 mL enterally q6 hours. Bolus with additional enteral dose of Bicitra 120 mL if urine pH < 7.

Pre-admission: 60 mEq (Bicitra

During admission: 588 mEq

Patients with no enteral access

• Sodium bicarbonate 100 mEq/L IV at 2 mL/kg/h

OR

• Start Lactated Ringer’s IV at 2 mL/kg/h, place NG tube, and administer Bicitra 120 ml via NG tube q6 hours. Bolus with additional NG dose of Bicitra 120 mL if urine pH < 7.

576 mEq

588 mEq

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Heisler, R.D., Kelly, J.J., Abedinzadegan Abdi, S. et al. Evaluation of an oral sodium bicarbonate protocol for high-dose methotrexate urine alkalinization. Support Care Cancer 30, 1273–1281 (2022). https://doi.org/10.1007/s00520-021-06503-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00520-021-06503-3

Keywords

Search

Navigation