BICAR-ICU: Bicarbonate for Severe Acidemia (2018)

“In patients with severe metabolic Acidemia, sodium bicarbonate had no effect on the primary composite outcome. However, sodium bicarbonate decreased the primary composite outcome and 28-day mortality in the prespecified stratum of patients with acute kidney injury.”

  • The BICAR-ICU Study Group

1. Publication Details

  • Trial Title: Effect of Sodium Bicarbonate in Patients with Severe Metabolic Acidemia
  • Citation: Jaber S, Paugam C, Futier E, et al. Effect of Sodium Bicarbonate in Patients with Severe Metabolic Acidemia: The BICAR-ICU Randomised Controlled Trial. Lancet. 2018;392(10141):31-40. DOI: 10.1016/S0140-6736(18)31080-8
  • Published: July 7, 2018, in The Lancet
  • Author: Samir Jaber, M.D., Ph.D.
  • Funding: French Ministry of Health

2. Keywords

  • Metabolic Acidosis, Acidemia, Sodium Bicarbonate, Acute Kidney Injury (AKI), Critical Care, Randomized Controlled Trial

3. The Clinical Question

  • In critically ill adult patients with severe metabolic acidemia (Population), does treatment with intravenous sodium bicarbonate (Intervention) compared to standard care (Comparison) reduce a composite of 28-day all-cause mortality and the presence of at least one organ failure at day 7 (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Severe metabolic acidemia (pH ≤ 7.20) is common in the ICU and is associated with poor outcomes. The administration of sodium bicarbonate to correct acidemia is a long-standing but highly controversial practice. While it can correct pH, it has potential adverse effects, including increased carbon dioxide production, hypernatremia, and fluid overload.
  • Knowledge Gap: Despite its common use, there was no high-quality evidence from a large randomized controlled trial to determine if sodium bicarbonate improved patient-centered outcomes in this population.
  • Proposed Hypothesis: The authors hypothesized that sodium bicarbonate infusion would reduce the risk of the primary composite outcome (death by day 28 or at least one organ failure at day 7) in patients with severe metabolic acidemia.

5. Study Design and Methods

  • Design: A multicenter, prospective, open-label, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 26 intensive care units (ICUs) in France.
  • Trial Period: Enrollment ran from May 2015 to May 2017.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) admitted to the ICU with severe metabolic acidemia, defined as pH ≤ 7.20, PaCO2 ≤ 45 mm Hg, and a SOFA score of ≥ 4 or a lactate level of ≥ 2 mmol/L.
    • Exclusion Criteria: Included patients with ketoacidosis or chronic kidney disease requiring chronic dialysis.
  • Intervention: Patients received a 4.2% sodium bicarbonate infusion to maintain a target arterial pH above 7.30.
  • Control: Patients received standard care with no sodium bicarbonate infusion.
  • Management Common to Both Groups: All other aspects of ICU care, including the management of the underlying cause of the acidemia, were at the discretion of the treating clinicians.
  • Power and Sample Size: The authors calculated that a sample size of 400 patients would provide 80% power to detect a 15% absolute risk reduction in the primary composite outcome. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: A composite of death from any cause by day 28 and the presence of at least one organ failure at day 7.
    • Secondary Outcomes: Included 28-day mortality, the need for renal-replacement therapy (RRT), and organ-failure-free days.

6. Key Results

  • Enrollment and Baseline: 399 patients were randomized (204 to bicarbonate and 195 to control). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the primary composite outcome. The primary outcome occurred in 138 of 199 patients (69%) in the bicarbonate group and in 148 of 194 patients (76%) in the control group (p=0.14).
  • Secondary Outcomes: There was no significant difference in overall 28-day mortality. However, patients in the bicarbonate group required RRT less frequently and had more organ-failure-free days.
  • Adverse Events: The incidence of adverse events was similar between the groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of patients who met the composite endpoint between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute rates of the primary outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.14 for the primary outcome is higher than the 0.05 threshold, indicating that the result was not statistically significant and likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the primary outcome was not met, ARR and NNT are not applicable to the overall population.
  • Subgroup Analyses: In the pre-specified subgroup of patients with severe acute kidney injury (AKIN score 2 or 3), sodium bicarbonate was associated with a significant reduction in the primary composite outcome (63% vs. 82%; p=0.02) and in 28-day mortality (46% vs. 63%; p=0.03).

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design provided the first high-quality evidence on this important clinical question.
  • Generalizability: The pragmatic design across 26 ICUs increases the applicability of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The primary outcome was a composite of mortality and organ failure, which are clinically relevant endpoints.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which is a significant limitation that introduces a risk of performance bias, as clinicians’ knowledge of the intervention could have influenced their decisions about other aspects of care.
  • External Validity (Generalizability): The overall neutral result is the main finding. The positive result in the AKI subgroup, while pre-specified, should be interpreted with some caution as subgroup analyses are often hypothesis-generating.
  • Other: The primary outcome was a composite of two endpoints with different levels of clinical importance (death and organ failure), which can sometimes make interpretation difficult.

10. Conclusion of the Authors

  • In patients with severe metabolic acidemia, sodium bicarbonate had no effect on the primary composite outcome. However, in the pre-specified subgroup of patients with acute kidney injury, sodium bicarbonate was associated with a reduction in the primary outcome and improved 28-day survival.

11. To Summarize

  • Impact on Current Practice: This trial provided important evidence that the routine use of sodium bicarbonate for all patients with severe metabolic acidemia is not beneficial. However, it generated a strong new hypothesis that it may be beneficial in the specific subgroup of patients with concurrent severe AKI.
  • Specific Recommendations:
    • Patient Selection: The results do not support the routine use of bicarbonate for all patients with severe metabolic acidemia.
    • Actionable Intervention: Consider the use of sodium bicarbonate in the specific subgroup of patients who have severe metabolic acidemia (pH ≤ 7.20) and severe acute kidney injury (AKIN stage 2 or 3).
  • What This Trial Does NOT Mean: This trial does NOT mean that bicarbonate is a magic bullet for AKI. The finding in the AKI subgroup requires confirmation in future trials.
  • Implementation Caveats: If bicarbonate is used, it should be administered with careful monitoring of pH, electrolytes, and volume status.

12. Context and Related Studies

  • Building on Previous Evidence: The BICAR-ICU trial (2018) was the first large RCT to provide high-quality evidence on a practice that had been based on physiological reasoning and dogma for decades.
  • Influence on Subsequent Research: The intriguing positive finding in the AKI subgroup has spurred significant interest and debate and is likely to be the focus of future research to confirm or refute this specific indication.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is whether the benefit seen in the AKI subgroup is real or a chance finding.
  • Future Directions: A large randomized controlled trial focused specifically on patients with severe metabolic acidemia and concurrent severe AKI is needed to provide a definitive answer on the role of sodium bicarbonate in this population.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a common and controversial practice in the ICU.
  • Methods: The multicenter RCT design was appropriate. The main methodological weakness is the open-label design, which introduces a risk of performance bias. The use of a composite primary outcome is another point for discussion.
  • Results: The study reported a clear neutral finding for its primary outcome in the overall population. The statistically significant finding in the pre-specified AKI subgroup is the most important and debated result of the trial. While pre-specified, subgroup analyses are generally considered hypothesis-generating and should be interpreted with caution.
  • Conclusions and Applicability: The authors’ conclusion is a fair and accurate reflection of their data. The trial provides strong evidence to discourage the routine use of bicarbonate in all patients with severe acidemia. The applicability of the subgroup finding is a matter of ongoing clinical debate, but it provides a strong rationale for considering bicarbonate in patients with both severe acidemia and severe AKI.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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