BICARB-ICU 2 vs BICARB-ICU 1: Mortality Benefit in AKI Stage 2-3
The BICARB-ICU 2 trial is specifically designed to confirm the mortality benefit observed in the AKI subgroup (AKIN stage 2-3) from BICARB-ICU 1, but results are not yet published—only the protocol is available. The original BICARB-ICU 1 trial showed a significant survival benefit in patients with severe metabolic acidosis and moderate-to-severe acute kidney injury, which BICARB-ICU 2 aims to validate as its primary outcome.
BICARB-ICU 1 Trial Findings in AKI Patients
The BICARB-ICU 1 trial demonstrated important differential effects based on kidney injury severity:
Overall population: Sodium bicarbonate infusion (targeting pH ≥7.30) showed no significant effect on the primary composite outcome of day-28 mortality and organ failure at day 7 in the general ICU population with severe metabolic acidemia (pH ≤7.20) 1
AKI subgroup (AKIN 2-3): In the prespecified stratum of patients with AKIN scores of 2 or 3, the Kaplan-Meier estimate of survival by day 28 was significantly higher in the bicarbonate group (54% [95% CI 45-65]) compared to the control group (37% [95% CI 28-48]; p=0.0283) 1
Mortality rates in AKI patients: When both severe metabolic acidemia and moderate-to-severe acute kidney injury are present, day-28 mortality is approximately 55-60% without bicarbonate therapy 2
BICARB-ICU 2 Trial Design
The BICARB-ICU 2 trial was specifically designed to address the AKI subgroup findings:
Primary outcome: Day-90 mortality (rather than the composite outcome used in BICARB-ICU 1) specifically in patients with both severe metabolic acidosis and moderate-to-severe AKI 2
Target population: Critically ill patients with pH ≤7.20, PaCO2 ≤45 mmHg, bicarbonate ≤20 mmol/L, AND moderate-to-severe acute kidney injury 2
Intervention: 4.2% sodium bicarbonate infusion titrated to maintain plasma pH ≥7.30, identical to BICARB-ICU 1 2
Status: Protocol published in 2023, but final results are not yet available 2
Clinical Implications Based on Current Evidence
For ICU patients with severe metabolic acidosis (pH ≤7.20) AND AKIN stage 2-3 AKI, sodium bicarbonate infusion targeting pH ≥7.30 should be strongly considered based on the mortality benefit demonstrated in BICARB-ICU 1's prespecified AKI subgroup analysis. 1
Dosing Protocol from BICARB-ICU 1:
- Administer 4.2% intravenous sodium bicarbonate infusion 1
- Volume per infusion: 125-250 mL over 30 minutes 1
- Maximum: 1000 mL within 24 hours after inclusion 1
- Target: Maintain arterial pH above 7.30 1
Important Caveats:
Monitoring requirements: Bicarbonate therapy increases risk of metabolic alkalosis, hypernatremia, and hypocalcemia, though no life-threatening complications were reported in BICARB-ICU 1 1
Stage-based management limitations: Current guidelines express concern that AKI stage-based management recommendations lack adequate evidence and may not account for the heterogeneity within each stage 3. Management should integrate overall clinical status, trends in kidney function, and specific AKI etiology 3
Conflicting observational data: A 2022 retrospective propensity-matched study found bicarbonate use in rhabdomyolysis patients was associated with higher AKI incidence, dialysis dependency, and mortality 4. However, this conflicts with the randomized controlled trial data from BICARB-ICU 1 1, and observational studies generally show conflicting results on bicarbonate therapy 5
Recent supportive evidence: A 2025 target trial emulation from Australian ICUs (n=6,157) found bicarbonate administration associated with 1.9% absolute mortality reduction (RR 0.86,95% CI 0.80-0.91) in metabolic acidosis patients, with benefits sustained across AKI subgroups 5
The Bottom Line:
The BICARB-ICU 1 trial provides the highest-quality randomized evidence showing mortality benefit specifically in the AKIN 2-3 subgroup 1. BICARB-ICU 2 was designed to definitively answer whether this benefit is real, but until those results are published, the BICARB-ICU 1 subgroup analysis represents the best available evidence supporting bicarbonate use in critically ill patients with both severe metabolic acidosis and moderate-to-severe AKI 2, 1.