Article Identification

Article Title: 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

Authors (Top 5): Samir Jaber, Catherine Paugam, Emmanuel Futier, Jean-Yves Lefrant, Sigismond Lasocki

Journal Name, Year, Volume, Issue: The Lancet, 2018, Volume 392, Issue July 7

Type of Study: Multicentre, open-label, randomised controlled, phase 3 trial

DOI/PMID: DOI, PMID not provided

Quick Reference Summary

Primary Outcome: Sodium bicarbonate infusion did not significantly reduce the composite outcome of death by day 28 or at least one organ failure by day 7 in the overall population (p=0.24).

Subgroup Finding: In patients with acute kidney injury (AKIN scores 2 or 3), sodium bicarbonate significantly decreased the primary composite outcome and day 28 mortality (p=0.0283).

Core Clinical Question

Does intravenous sodium bicarbonate infusion improve clinical outcomes in critically ill adults with severe metabolic acidaemia compared to no bicarbonate infusion?

Background

Disease Overview: Severe metabolic acidaemia (pH ≤7.20) is common in critical illness, associated with high mortality rates (up to 57%).

Prior Data: Sodium bicarbonate use in ICU is common but controversial due to unclear effects on clinical outcomes. Previous studies (animal, physiological, retrospective) have not provided conclusive evidence on its benefits.

Current Standard of Care: Supportive measures including improvement of tissue perfusion, mechanical ventilation, and renal-replacement therapy.

Knowledge Gaps: Lack of high-level evidence on the efficacy and safety of sodium bicarbonate infusion in improving survival and reducing organ failure in severe metabolic acidaemia.

Study Rationale: To provide robust evidence from a randomized controlled trial on whether sodium bicarbonate infusion benefits critically ill patients with severe metabolic acidaemia.

Methods Summary

Study Design: Multicentre, open-label, randomised controlled, phase 3 trial.

Setting and Time Period: 26 Intensive Care Units (ICUs) in France, May 2015 – May 2017.

Population Characteristics: Adults (≥18 years) admitted to ICU within 48 hours with severe metabolic acidaemia (pH ≤7.20, PaCO2 ≤45 mm Hg, bicarbonate ≤20 mmol/L) and SOFA score ≥4 or lactate ≥2 mmol/L.

Inclusion/Exclusion Criteria:

• Included: Adults with severe metabolic acidaemia as defined above.
• Excluded: Respiratory acidosis, significant digestive/urinary bicarbonate loss, stage IV chronic kidney disease, ketoacidosis, prior bicarbonate infusion within 24 hours.

Intervention Details:
Bicarbonate Group: 4.2% IV sodium bicarbonate to maintain pH >7.30, dosed 125–250 mL in 30 minutes, max 1000 mL/day.

Control Group Details: No sodium bicarbonate infusion.

Primary and Secondary Outcomes:

• Primary: Composite of death by day 28 or at least one organ failure by day 7.
• Secondary: Renal-replacement therapy usage, vasopressor-free days, mechanical ventilation-free days, electrolyte disturbances, ICU-acquired infections, ICU length of stay.

Statistical Analysis Approach: Intention-to-treat, χ² tests, multiple logistic and Cox regression models, Kaplan-Meier survival analysis.

Sample Size Calculations: 400 patients for 80% power to detect a 15% absolute difference in primary outcome.

Ethics and Funding: Approved by central ethics committee, funded by French Ministry of Health and Société Française d’Anesthésie Réanimation.

Detailed Results

Participant Flow and Demographics:

Total Enrolled: 389 patients (194 control, 195 bicarbonate).

Baseline Characteristics: Well-balanced between groups (age, sex, severity scores, comorbidities).

Primary Outcome Results:

• Overall Population: 71% (138/194) control vs. 66% (128/195) bicarbonate group (Absolute Difference: -5.5%, 95% CI -15.2 to 4.2; p=0.24).
• AKIN 2-3 Stratum: 82% (74/90) control vs. 70% (64/92) bicarbonate group (Absolute Difference: -12.3%, 95% CI -26.0 to -0.1; p=0.0462).

Survival Analysis:

• Overall: 46% survival control vs. 55% survival bicarbonate (p=0.09).
• AKIN 2-3 Stratum: 37% vs. 54% (p=0.0283).

Secondary Outcome Results:

Renal Replacement Therapy:

• Overall: 52% control vs. 35% bicarbonate (Absolute Difference: -16.7%, 95% CI -26.4 to -7.0; p=0.0009).
• AKIN 2-3 Stratum: 73% vs. 51% (Absolute Difference: -22.2%, 95% CI -36.0 to -8.5; p=0.0020).

Vasopressor-Free Days in AKIN 2-3: Higher in bicarbonate group (p=0.022).

Adverse Events: Metabolic alkalosis, hypernatraemia, hypocalcaemia more frequent in bicarbonate group; no life-threatening complications.

Results Tables

Outcome	Intervention Group	Control Group	Difference (95% CI)	P-value
Primary Outcome (Death or Organ Failure)	66% (128/195)	71% (138/194)	-5.5% (-15.2 to 4.2)	0.24
AKIN 2-3 Stratum Composite	70% (64/92)	82% (74/90)	-12.3% (-26.0 to -0.1)	0.0462
Renal Replacement Therapy Overall	35% (68/195)	52% (100/194)	-16.7% (-26.4 to -7.0)	0.0009
Renal Replacement Therapy AKIN 2-3	51% (47/92)	73% (66/90)	-22.2% (-36.0 to -8.5)	0.0020
Vasopressor-Free Days (AKIN 2-3)	Higher	Lower		0.022
Adverse Events	More frequent	Less frequent		Various

Authors' Conclusions

Primary Conclusion: Sodium bicarbonate infusion did not significantly improve the composite outcome of mortality by day 28 or organ failure by day 7 in the overall population of critically ill patients with severe metabolic acidaemia.

Subgroup Findings: In patients with acute kidney injury (AKIN scores 2 or 3), sodium bicarbonate reduced the primary composite outcome and day 28 mortality.

Clinical Implications: Sodium bicarbonate may benefit a specific subgroup of critically ill patients with both severe metabolic acidaemia and acute kidney injury.

Future Research: Further studies are needed to confirm these findings in larger populations and to explore different administration protocols.

Literature Review

Comparisons to Other Studies:

• BICAR-ICU vs. AKIKI Trial: While BICAR-ICU suggested benefits in AKIN 2-3 patients, the AKIKI trial indicated no mortality difference with delayed renal-replacement therapy.
• Guidelines: The 2016 Surviving Sepsis Campaign guidelines acknowledged the unknown effects of sodium bicarbonate on clinical outcomes, highlighting the need for trials like BICAR-ICU.
• Meta-Analyses: Previous meta-analyses indicated insufficient randomized trials to assess sodium bicarbonate's efficacy in acute kidney injury.

Detailed Literature Context

Previous Studies and Meta-Analyses:

• Cooper DJ et al. (Ann Intern Med. 1990;112:492–98): Found bicarbonate does not improve hemodynamics in lactic acidosis.
• Mathieu D et al. (Crit Care Med. 1991;19:1352–56): Showed no clear benefits of bicarbonate therapy on hemodynamics and tissue oxygenation.

Contrasting Methodological Quality:

• BICAR-ICU: Large, multicentre RCT with defined subgroups.
• Previous Studies: Mostly small, single-centre, physiological or retrospective designs with limited applicability.

Comparisons with Guidelines:

• Surviving Sepsis Campaign (Intensive Care Med. 2017;43:304–77): Recommended against routine use of bicarbonate due to lack of evidence.

This Trial’s Contribution:

BICAR-ICU provides high-level evidence suggesting potential benefits in a specific subgroup with acute kidney injury, addressing the previous evidence gap.

Critical Analysis

A. Strengths:

• Methodological Strengths:
  • Randomized controlled design with intention-to-treat analysis.
  • Large sample size for a phase 3 trial.
  • Multicentre approach enhancing generalizability.
• Internal Validity:
  • Well-balanced baseline characteristics.
  • Predefined stratification factors.
  • Masked assessment of outcomes despite open-label design.
• External Validity:
  • Diverse ICU settings in France increase applicability to similar healthcare environments.

B. Limitations:

• Study Design Limitations: Open-label design could introduce performance bias.
• Potential Biases: Lack of blinding for intervention may affect management decisions.
• Generalizability Issues: Study conducted solely in France; results may differ in other healthcare systems.
• Statistical Limitations: Primary outcome not met; subgroup analyses may be underpowered.
• Missing Data Handling: No imputation for missing values, but primary outcome had complete data.

C. Literature Context:

• Direct Comparisons to Previous Studies: BICAR-ICU findings contrast with earlier small-scale studies showing no benefit.
• Position within Existing Evidence: Confirms the controversial role of bicarbonate, providing evidence for specific patient subsets.
• Reference to Guidelines: Aligns with and extends the Surviving Sepsis Campaign's stance on the uncertain benefits of bicarbonate.
• Identified Knowledge Gaps: Need for further research on administration protocols and broader patient populations.
• Ongoing Research: Future trials should explore different dosing strategies and long-term outcomes.

Clinical Application

Practice Change: Sodium bicarbonate infusion should not be universally adopted for all patients with severe metabolic acidaemia in the ICU. However, it may be beneficial for those with concurrent acute kidney injury.

Specific Populations: Particularly applicable to critically ill patients with severe metabolic acidaemia (pH ≤7.20) and acute kidney injury (AKIN scores 2 or 3).

Implementation Considerations: Monitor for metabolic alkalosis, hypernatraemia, and hypocalcaemia; adjust bicarbonate dosing to achieve target pH without exceeding recommended infusion volumes.

How To Use This Info In Practice: Recommendation to consider sodium bicarbonate infusion for ICU patients with severe metabolic acidaemia and acute kidney injury, while monitoring for potential electrolyte disturbances.

Additional Notes for Clarity

• Statistical Significance: Bolded in relevant sections (e.g., p=0.24, p=0.0283).
• Confidence Intervals: Included where available.
• Conflicts of Interest: Authors reported various grants and personal fees from pharmaceutical and medical device companies.
• Areas of Uncertainty: Efficacy in broader populations, optimal dosing protocols.
• Funding Sources: French Ministry of Health and Société Française d’Anesthésie Réanimation; no role in study design or analysis.

This structured summary aims to provide a comprehensive and accessible overview of the BICAR-ICU trial, facilitating informed clinical decision-making and highlighting areas for future research.