Comparison of enteral and parenteral methods of urine alkalinization in patients receiving high-dose methotrexate

Abstract

Purpose Hyperhydration and urinary alkalinization is implemented with all high-dose (HD)-methotrexate infusions to promote excretion and prevent precipitation of methotrexate in the renal tubules. Our institution utilized enteral alkalinizing agents (sodium bicarbonate tablets and sodium citrate/citric acid solution) to alkalinize the urine of patients receiving HD-methotrexate during a parenteral sodium bicarbonate and sodium acetate shortage. The purpose of this study is to establish the safety and efficacy of the enteral route for urine alkalinization. Methods A single-center, retrospective, cohort study was conducted comparing cycles of HD-methotrexate using enteral alkalinizing agents to parenteral sodium bicarbonate. The primary objective was to compare the time, in hours, from administration of first inpatient administered dose of alkalinizing agent to time of achieving goal urine pH. Secondary objectives evaluated total dose of sodium bicarbonate required to achieve goal urine pH, time from start of urine alkalinizing agent until time of achieving methotrexate level safe for discharge, and toxicities associated with methotrexate and the alkalinizing agents. Results A total of 118 patients were included in this study, equally divided into two cohorts based on parenteral versus enteral routes of administration. No statistical difference was determined between the two cohorts regarding time to goal urine pH (6.5 h versus 7.9 h, P = 0.051) or regarding time to methotrexate level deemed safe for discharge (63.5 h versus 62.5 h, p = 0.835). There were no significant differences in methotrexate-induced toxicities. Conclusion Our study found enteral routes of urine alkalinization to be a viable alternative to the traditional parenteral sodium bicarbonate, especially during parenteral sodium bicarbonate and acetate shortages.

<p>A prospective study on urine alkalization with an oral regimen consisting of sodium bicarbonate and acetazolamide in patients receiving high-dose methotrexate</p>

“…We demonstrated in our study no significant difference in MTX clearance rate, which is similar to previous studies using PO sodium bicarbonate 7. There are several limitations to this study.…”

“…Roy et al investigated an PO alkalization regimen similar to ours with sodium bicarbonate and PO acetazolamide; however, they used higher doses and more frequent PO sodium bicarbonate and reserved acetazolamide for use as needed when urine pH was <7.5 15Table 6Overview of previously published alternative regimens to intravenous sodium bicarbonate for urine alkalizationAuthorRegimenComparator armOutcomesAdverse eventsShamash et al8Acetazolamide 500 mg IV every 6 hrs for 48 hNo comparatorNo delayed clearanceNo significant AEsRouch et al7Sodium bicarbonate: 650 mg tablet orsodium citrate 500 mg/ citric acid 334 mg/ 5 mL every 6 hrsParenteral sodium bicarbonate (50–150 mEq) physician preferenceNo difference in AKI or hepatic injuryDiarrhea P =0.002Visage et al17Sodium bicarbonate: 1950 mg/m 2 or Sodium citrate-citric acid oral solution: 22.5 mEq/m 2 /dose every 6 hrsNo comparatorDelayed clearance seen in 2% of casesGI side effects reported in 43%Roy et al15Sodium bicarbonate: 3250 mg PO every 12 hrsAcetazolamide 250 mg-500 mg PO or IV every 6 hrs PRN urine pH <7.5+ possible outpatient alkalinizationIntravenous sodium bicarbonate (150 mEq per 1000 mL) AND oral sodium bicarbonate at 3250 PO every 4 hrs PRN for urine pH <7.5No difference in MTX clearanceIncrease in LOS P =0.23No difference in toxicity (AKI, hepatoxicity, myelosuppression)No difference in change in creatinine clearanceAlrabiah et al18Sodium acetate IVParenteral sodium bicarbonateNo difference in LOS, time to pH >8, MTX clearance, or AKINo adverse events identified Abbreviations: MTX, methotrexate; PO, oral; IV, intravenous; LOS, length of stay; PRN, as needed; GI, gastrointestinal. …”

“…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.…”

A Rapidly Fatal Case of Low-Dose Methotrexate Toxicity

“…Methotrexate excretion can be enhanced by hydration with >3 L/m 2 per day to maximize urine output [ 3 ]. Methotrexate can precipitate in the acidic urine causing crystalluria, hence alkalinizing the urine with oral or parenteral sodium bicarbonate can help prevent this and improve methotrexate excretion [ 18 ]. Another way to enhance elimination is via extracorporeal methods such as hemodialysis, high-flux hemodialysis, plasma exchange, and continuous renal replacement therapy [ 19 ].…”

Prevention of toxicity in chemotherapy with high doses of methotrexate in children

“…Одним из маркеров предшествующей нефротоксичности служит снижение клиренса креатинина до начала введения ВДMTX [14]. Ранее считалось, что нормальный уровень креатинина сыворотки и расчетный клиренс креатинина больше 60 мл/мин позволяет обеспечить адекватную элиминацию МТХ, однако на сегодня известно, что токсические эффекты могут развиться даже при адекватной функции почек [25].…”