Prophylactic perioperative sodium bicarbonate to prevent acute kidney injury following open heart surgery: a multicenter double-blinded randomized controlled trial

Abstract

Background: Preliminary evidence suggests a nephroprotective effect of urinary alkalinization in patients at risk of acute kidney injury. In this study, we tested whether prophylactic bicarbonate-based infusion reduces the incidence of acute kidney injury and tubular damage in patients undergoing open heart surgery.

Methods and findings: In a multicenter, double-blinded (patients, clinical and research personnel), randomized controlled trial we enrolled 350 adult patients undergoing open heart surgery with the use of cardiopulmonary bypass. At induction of anesthesia, patients received either 24 hours of intravenous infusion of sodium bicarbonate (5.1 mmol/kg) or sodium chloride (5.1 mmol/kg). The primary endpoint was the proportion of patients developing acute kidney injury. Secondary endpoints included the magnitude of acute tubular damage as measured by urinary neutrophil gelatinase-associated lipocalin (NGAL), initiation of acute renal replacement therapy, and mortality. The study was stopped early under recommendation of the Data Safety and Monitoring Committee because interim analysis suggested likely lack of efficacy and possible harm. Groups were non-significantly different at baseline except that a greater proportion of patients in the sodium bicarbonate group (66/174 [38%]) presented with preoperative chronic kidney disease compared to control (44/176 [25%]; p = 0.009). Sodium bicarbonate increased urinary pH (from 6.0 to 7.5, p<0.001). More patients receiving bicarbonate (83/174 [47.7%]) developed acute kidney injury compared with control patients (64/176 [36.4%], odds ratio [OR] 1.60 [95% CI 1.04-2.45]; unadjusted p = 0.032). After multivariable adjustment, a non-significant unfavorable group difference affecting patients receiving sodium bicarbonate was found for the primary endpoint (OR 1.45 [0.90-2.33], p = 0.120]). A greater postoperative increase in urinary NGAL in patients receiving bicarbonate infusion was observed compared to control patients (p = 0.011). The incidence of postoperative renal replacement therapy was similar but hospital mortality was increased in patients receiving sodium bicarbonate compared with control (11/174 [6.3%] versus 3/176 [1.7%], OR 3.89 [1.07-14.2], p = 0.031).

Conclusions: Urinary alkalinization using sodium bicarbonate infusion was not found to reduce the incidence of acute kidney injury or attenuate tubular damage following open heart surgery; however, it was associated with a possible increase in mortality. On the basis of these findings we do not recommend the prophylactic use of sodium bicarbonate infusion to reduce the risk of acute kidney injury. Discontinuation of growing implementation of this therapy in this setting seems to be justified.

Trial registration: ClinicalTrials.gov NCT00672334 Please see later in the article for the Editors' Summary.

Conflict of interest statement

MH and RB hold a patent on the use of sodium bicarbonate infusions to prevent acute kidney injury. MH, SMB, and PM received lecture fees from companies (incl. Abbott Diagnostics, Alere) involved in the development of neutrophil gelatinase-associated lipocalin as renal biomarker. The authors declare no other competing interests.

Figures

Figure 1. Patient flow through the study reported in a CONSORT diagram.

*Per protocol analysis excluded patients who were not operated on cardiopulmonary bypass or who were not drug-adherent. In both study groups there were two patients meeting both criteria. Six patients were lost to follow-up (all in the sodium chloride group). Major reasons for a patient to be lost to follow-up at 90 d were (i) patient came for open heart surgery from a foreign country and did not respond to contact attempts (n = 3) or (ii) patient was socially disadvantaged and did not provide a contact address or telephone number and did not visit their general practitioner or cardiac outpatient department for postoperative follow up (n = 3). CPB, cardiopulmonary bypass.

Figure 2. Renal endpoints for patients receiving sodium bicarbonate versus sodium chloride.

Number of patients receiving sodium bicarbonate (black bars) developing acute kidney injury after open heart surgery compared to patients receiving sodium chloride (white bars). The OR (with 95% CI) shows the risk of developing a pre-defined renal endpoint of patients treated with sodium bicarbonate compared to those treated with sodium chloride. From left to right: primary endpoint: increase in plasma creatinine >25% or >0.5 mg/dl (>44 µmol/l), secondary endpoints: increase in plasma creatinine >50%, increase in plasma creatinine >100%, RIFLE-classification based acute kidney injury (risk, injury, failure loss, and end stage renal failure criteria, [15]) and acute renal replacement therapy (RRT) within index hospitalization.

Figure 3. Serum creatinine in patients receiving sodium bicarbonate (black squares) or sodium chloride (grey triangles) infusion.

Serum creatinine concentrations are shown over time (median [25th–75th percentiles]).