Editorial 

Sodium Bicarbonate in Severe Acidemia and Acute Kidney Injury—Turning the Tide or Chasing a Myth?

Prit Kusirisin, Fernando G. Zampieri, Sean M. Bagshaw

JAMA Published Online: October 29, 2025

doi: 10.1001/jama.2025.20457

Severe acidemia commonly complicates critical illness.¹ If unresolved or untreated, acidemia may exacerbate multiorgan dysfunction, prompt escalation in life support, and portend greater risk of adverse outcomes. Intravenous (IV) sodium bicarbonate is often used in clinical practice to buffer severe acidemia; however, existing evidence on its effectiveness remains inconclusive.² The most recent iteration of the Surviving Sepsis Guidelines offers only a weak recommendation (low quality of evidence) for use of IV sodium bicarbonate therapy in patients with sepsis and shock, severe acidosis, and acute kidney injury (AKI).³ This recommendation was derived largely from the initial BICARICU trial, a multicenter, open-label, randomized clinical trial suggesting reduced mortality at 28 days and lower use of kidney replacement therapy (KRT) with IV sodium bicarbonate therapy in a prespecified subgroup of patients with severe acidemia (pH ≤7.20) and moderate to severe AKI.⁴

The BICARICU trial was unfortunately inconclusive about whether IV sodium bicarbonate reduced the composite end point of mortality at 28 days and occurrence of greater than or equal to 1 new organ dysfunction in the full randomized population; however, the reduction in KRT use among patients with moderate to severe AKI (47% of the trial population) represented a biologically plausible and potentially important finding.⁴ Severe acidemia, particularly if perceived as refractory to medical therapy, often provokes clinicians to commence KRT.^2,5 This trigger was the second most frequent for KRT initiation after fluid accumulation in the STARRT-AKI trial.⁵

The challenge for clinicians is to extrapolate whether this noteworthy discovery in a subgroup of critically ill patients with moderate to severe AKI at baseline constituted a true beneficial effect or may have been a more spurious finding due to methodological limitations, including a small subpopulation, an open-label design, the risk of clinician bias in thresholds for starting KRT, and the mixed etiology for acidemia among patients, along with significant protocol violations and treatment crossover.⁴ At best, these considerations temper enthusiasm and provide a rationale to examine this subgroup and the hypothesis-generating finding in a further clinical trial focused on IV sodium bicarbonate therapy in critically ill patients with severe acidemia and moderate to severe AKI.

In this issue of JAMA, Jung and colleagues⁶ report the Sodium Bicarbonate for Severe Metabolic Acidemia and Acute Kidney Injury (BICARICU-2) trial, a multicenter, investigator-initiated, open-label, assessor-blinded, randomized clinical trial evaluating whether IV 4.2% sodium bicarbonate therapy targeting a serum pH greater than or equal to 7.30 compared with no IV sodium bicarbonate therapy (control) could improve clinical and health service outcomes in critically ill patients with severe acidemia and moderate to severe AKI, aligned with Kidney Disease Improving Global Outcomes stage 2 to 3 AKI. The BICARICU-2 trial was performed in 43 adult intensive care units in France between October 2019 and December 2023. The primary outcome was 90-day all-cause mortality, and a key secondary end point was any receipt of KRT, in which initiation was recommended by leveraging common conventional indications. The investigators performed both an intention-to-treat and an as-treated analysis of the primary and secondary outcomes, using the χ² test with absolute frequency differences and 95% CIs.

Of 640 patients who were randomized, 627 (98%) were analyzed, with 314 patients allocated to IV sodium bicarbonate and 313 patients to control. Among those enrolled, patients were predominantly medical (nonoperative) with septic shock, exhibited high acuity of illness, and were receiving invasive mechanical ventilation and vasoactive support. The median serum pH at enrollment was 7.15 (IQR, 7.08-7.18) in the bicarbonate group and 7.15 (IQR, 7.09-7.19) in the control group, with serum bicarbonate and lactate levels of 12 to 13 mEq/L and 5.7 to 5.9 mmol/L, respectively. Patients allocated to IV sodium bicarbonate received a median 750 mL (IQR, 500-1000 mL) of 4.2% sodium bicarbonate in the first 48 hours compared with none in the control group, resulting in higher serum pH and bicarbonate levels, along with receipt of greater total fluid therapy. Intravenous sodium bicarbonate therapy compared with control was found to have neutral effects on 90-day mortality (195 of 314 [62.1%] vs 193 of 313 [61.7%]; absolute difference, 0.4; 95% CI, −7.2 to 8.0; P = .91), with no substantial difference in adjusted analysis, in inverse-probability weighted analysis, or in the as-treated analysis. Kidney replacement therapy use, a secondary end point, was markedly less frequent for patients receiving IV sodium bicarbonate compared with control (109 of 314 [35%] vs 157 of 313 [50%]; absolute difference, −15.5; 95% CI, −23.1 to −7.8). This difference was narrowed in the as-treated analysis (134 of 349 [38.0%] vs 118 of 252 [47.0%]; absolute difference, −8.4; 95% CI, −16.4 to −0.4). Additionally, among patients receiving KRT, the time to initiation was longer among those allocated to IV sodium bicarbonate therapy compared with controls (30.9 vs 15.5 hours). Other secondary and exploratory end points were generally inconclusive and were not adjusted for multiplicity of testing. There was suggestion that intensive care unit–acquired bloodstream infections occurred less commonly among patients allocated to IV sodium bicarbonate compared with controls (14 of 314 [4%] vs 28 of 313 [9%]; absolute difference, −4.5; 95% CI, −8.4 to −0.6), which the investigators speculate may have been related to reduced exposure to KRT.

The investigators are to be congratulated for pursuing an unresolved question derived from effects of IV sodium bicarbonate therapy observed in the subgroup with moderate to severe AKI and severe acidemia in BICARICU. The BICARICU-2 trial was a well-performed randomized clinical trial that provides new insight and knowledge into the long-standing practice of IV sodium bicarbonate therapy in critical illness; however, there are important limitations that warrant consideration. The primary outcome in the BICARICU-2 trial implies that IV sodium bicarbonate therapy could contribute to a reduced 90-day mortality by up to 7% or may in fact increase 90-day mortality by up to 8%. This uncertainty in the effect estimate is surely driven by the trial’s having been powered to detect an implausibly large 10% absolute reduction in 90-day mortality on the assumption of a control group 90-day mortality rate of 80%. A recent target trial emulation implied IV bicarbonate therapy may be associated with a more conservative 1.9% absolute reduction in 30-day mortality.⁷ BICARICU-2 was markedly underpowered to detect what may have been smaller and clinically important effects in 90-day mortality.⁸

The secondary outcome of KRT use clearly has both patient-focused and health service implications; however, the open-label design would have predisposed to detection bias. Although BICARICU-2 used recommendations for KRT initiation when patients fulfilled conventional indications, these were not strictly protocolized nor conceivably completely free of the potential cognitive biases of clinicians.⁹ The use of unblinded IV sodium bicarbonate therapy may have influenced decisions about whether and when to initiate KRT.

There was also incomplete information on the criteria primarily used to ascertain the diagnosis of AKI, specifically changes to serum creatinine level, urine output, or both. Similarly, there were limited data provided in the supplement on the etiology of acidemia. Although grossly categorized as high or nonanion gap metabolic acidosis, there was suggestion that most patients had a high anion gap lactic acidosis or mixed acidosis. Observational data have implied the etiology of acidemia may have varying prognostic relevance, speculating there could plausibly be heterogeneity in treatment effect.¹⁰ Patients allocated to IV sodium bicarbonate therapy also had more total fluid intake during the first 48 hours compared with controls. It is unclear whether this fluid represented an important difference to resuscitative volume and could have confounded decision-making for starting KRT in patients with moderate to severe AKI.

In summary, the BICARICU-2 trial does not provide certainty on whether IV sodium bicarbonate therapy affects mortality, although the findings imply it can potentially delay or avoid the use of KRT in critically ill patients with severe acidemia and moderate to severe AKI, with no incremental risk of adverse events. Given the relative paucity of alternative buffering therapies, these findings will likely translate into greater use of IV sodium bicarbonate therapy in this population. Accordingly, clinicians can choose to use short-term IV sodium bicarbonate therapy to manage severe acidemia complications of AKI, knowing that this may avert KRT in select patients and that it does not appear to portend greater risk of adverse events. However, arising from this trial are several important unanswered questions on heterogeneity of treatment effect and optimal IV sodium bicarbonate use, particularly for its effect on mortality. Further research is clearly warranted, including how to best design the next generation of trials to definitively provide evidence to support practice, rather than simply chasing a marginal subgroup finding with underpowered studies.