BICAR-ICU trial: in a subgroup with severe acidemia and severe Acute Kidney Injury a bicarbonate infusion reduces need for renal replacement therapy and potentially mortality at 28 days.

Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial - The Lancet

Appraisal: David Goldenberg DO, Edited: Martin Cearras, MD, FACP.

Summary:

The BICAR-ICU trial was a landmark study designed to evaluate the impact of sodium bicarbonate infusion on clinical outcomes in critically ill patients with severe metabolic acidemia. This multicenter trial (26 intensive care units (ICUs)) in France was a Randomized, open label trial that enrolled 400 adult patients.

The intervention group received bicarbonate IV pushes up to 1 Lt in 24 hrs. The sodium bicarbonate infusion did not improve the primary outcomes, death or at least one organ failure by Day 28. There were significant benefits in a specific high-risk subgroup, patients with severe metabolic acidosis and severe AKI (AKIN 2-3). In this subgroup, survival was higher with the intervention. Treating 6 patients may prevent one additional death and treating 7 patients will prevent 1 additional organ failure. Renal replacement therapy requirement was also lower. For every 6 patients treated with bicarbonate there will be 1 less patient requiring renal replacement therapy.

The trial's patient population reflected the severity and diversity of critical illness:

• Vasopressor dependence: 80% required vasopressors.

• Septic shock: Over 50% of patients had septic shock.

• Cardiac arrest: 9% experienced cardiac arrest.

• Mechanical ventilation: 83% were mechanically ventilated.

• Both medical and surgical ICU patients were represented, ensuring broad applicability of findings.
  

The study design included pre-specified subgroup analyses:

1. Age: Younger or older than 65 years.

2. Sepsis: Presence or absence.

3. Acute Kidney Injury (AKI): Severity classified by the Acute Kidney Injury Network (AKIN) as 0-1 or 2-3.

These findings suggest that targeted use of sodium bicarbonate in critically ill patients with metabolic acidemia may offer survival and renal benefits, warranting further investigation.  It has biological plausibility, the study has good validity and large number of events, adding weight to the observed outcomes.

The BICAR-ICU trial provides critical insights into tailoring therapies for ICU patients, reinforcing the importance of precision medicine in critical care settings.

PICOTT:

Population: 400 critically ill patients admitted to 26 ICUs in France with severe metabolic acidemia, defined as:

• pH ≤ 7.20

• PaCO₂ ≤ 45 mmHg

• Sodium bicarbonate concentration ≤ 20 mmol/L

• SOFA score ≥ 4 or lactate > 2 mmol/L

Intervention: Sodium bicarbonate infusion, administered as a 125–250 mL bolus (maximum of 1,000 mL within 24 hours), to maintain pH ≥ 7.30.

Comparison: No sodium bicarbonate infusion.

Outcomes:

• Primary: Mortality at Day 28 (composite of death from any cause and the presence of at least one organ failure).

Type of Question: Therapy.

Type of Study: Randomized Controlled Trial (RCT).

Interpretation of the Study:

Primary outcomes:

Primary Composite Outcome (Death or at least 1 organ failure) at Day 28: No statistically significant difference was observed.

• Control Group: 71.1%; Bicarbonate Group: 65.6%

• Relative Risk (RR): 0.92 (95% CI: 0.81–1.06, p = 0.244)

• Mortality at Day 28: No statistically significant difference.

• Control Group: 54%; Bicarbonate Group: 45%

• Relative Risk (RR): 0.83 (95% CI: 0.68–1.02, p = 0.08)

• At Least One Organ Failure at Day 7: No statistically significant difference.

• Control Group: 69%; Bicarbonate Group: 62%

• Relative Risk (RR): 0.89 (95% CI: 0.78–1.04, p = 0.15)

Secondary Outcomes:

Patients with severe metabolic acidosis and AKI with AKIN score 2-3 (n=182):

Composite Outcome at Day 28:

• Control Group: 82%; Bicarbonate Group: 70%

• Relative Risk (RR): 0.85 (95% CI: 0.72–1.00, p = 0.046)

• Risk difference (RD) / Absolute Risk Reduction: 12%

• Number Needed to Treat (NNT): 9

Mortality at Day 28:

• Control Group: 63%; Bicarbonate Group: 46%

• Relative Risk (RR): 0.72 (95% CI: 0.55–0.95, p = 0.025)

• Risk difference (RD) / Absolute Risk Reduction: 17%

• Number Needed to Treat (NNT): 6

At Least One Organ Failure at Day 7:

• Control Group: 82%; Bicarbonate Group: 66%

• Relative Risk (RR): 0.81 (95% CI: 0.68–0.96, p = 0.022)

• Risk difference (RD) / Absolute Risk Reduction: 16%

• Number Needed to Treat (NNT): 7

Other patient-important outcomes:

Renal Replacement Therapy During ICU Stay:

• Control Group: 52%; Bicarbonate Group: 35%

• Relative Risk (RR): 0.68 (95% CI: 0.53–0.86, p = 0.0013)

• Risk difference (RD) / Absolute Risk Reduction: 17%

• Number Needed to Treat (NNT): 6

Overall Risk of Bias:

The overall risk of bias is low. Randomization was performed via a computer-generated allocation sequence through a secure, dedicated website, ensuring allocation concealment. The resulting groups were prognostically similar. The authors state that they conducted an intention-to-treat (ITT) analysis of the data; however, 11 patients who withdrew consent were appropriately excluded. This small number is unlikely to have affected the results (as demonstrated by our “worst-case scenario” analysis). Blinding: This was an open-label trial, as blinding physicians and nurses was not feasible due to the need to monitor arterial pH levels. It is unclear whether statisticians and/or data adjudicators were blinded. Even though they used composite outcomes, the primary outcome was negative and not affected by this choice. Secondary outcomes were pre-specified, and the subgroup was almost half of the total sample. It also had biological plausibility. The high number of events seen and the level of the p-value do add some weight to this and make the RRT use outcome more likely to be true.

The multicenter nature adds to the generalizability of the findings.

Context:

The use of bicarbonate solution in critically ill patients remains a subject of debate. However, based on the results of this trial, it appears reasonable to consider bicarbonate solution for patients with severe metabolic acidosis and renal failure, as the potential benefits seem to outweigh concerns related to harm or cost.

Furthermore, as demonstrated by the STARRT-AKI trial, early initiation of renal replacement therapy (RRT) was associated with increased risks, including hypophosphatemia, hypotension, increased percentage of patients remaining on RRT and a higher likelihood of re-hospitalization. Therefore, one could argue that avoiding RRT through the use of bicarbonate solution in patients with acidemia and severe acute kidney injury (AKI) may help mitigate these risks and prevent further harm associated with RRT.

Teaching points:

Composite outcomes

Outcome measures

Relative risk and Risk difference

NNT

Intention-to-treat analysis vs. per-protocol/as-treated analysis

Worst case scenario analysis

Pre-specified (a-priori) analysis

Verdict:

Somewhat settled - Might change with more data