What are the indications and guidelines for using sodium bicarbonate in critically ill patients with severe metabolic acidosis based on the BICAR (Bicarbonate In Critical Care And Resuscitation) ICU 1 and 2 trials?

Overview of BICAR-ICU Trials

BICAR-ICU 1 Trial Design and Key Findings

The BICAR-ICU 1 trial was a multicenter randomized controlled trial that investigated whether sodium bicarbonate infusion (4.2% solution) titrated to maintain pH ≥7.30 could improve outcomes in critically ill patients with severe metabolic acidemia (pH ≤7.20, PaCO2 ≤45 mmHg, bicarbonate ≤20 mmol/L). 1

Primary Population and Intervention

• The trial enrolled critically ill patients presenting with severe metabolic acidemia, defined as pH ≤7.20 with PaCO2 ≤45 mmHg and bicarbonate ≤20 mmol/L 1
• The intervention group received 4.2% sodium bicarbonate infusion (isotonic formulation) titrated to target plasma pH ≥7.30, while the control group received no sodium bicarbonate 1
• The use of 4.2% concentration rather than the standard 8.4% hypertonic solution was designed to reduce risks of hyperosmolar complications and hypernatremia 2

Critical Prespecified Subgroup Finding

• In a prespecified stratum of patients with both severe metabolic acidemia AND moderate-to-severe acute kidney injury, sodium bicarbonate infusion was associated with higher survival rates (secondary endpoint) 1
• This subgroup finding became the foundation for the BICAR-ICU 2 trial design 1
• Patients with acute kidney injury and severe acidemia had baseline mortality rates of approximately 55-60% 1

Limitations of BICAR-ICU 1

• The improved survival in AKI patients was a secondary endpoint, not the primary outcome, limiting the strength of this conclusion 1
• The overall trial did not demonstrate benefit across all patients with severe metabolic acidemia, only in the AKI subgroup 1

BICAR-ICU 2 Trial Design and Rationale

BICAR-ICU 2 is a multicenter randomized clinical trial specifically designed to test whether sodium bicarbonate improves 90-day mortality (primary outcome) in critically ill patients with BOTH severe metabolic acidemia AND moderate-to-severe acute kidney injury. 1

Refined Inclusion Criteria

• The trial specifically targets patients with severe metabolic acidemia (pH ≤7.20, PaCO2 ≤45 mmHg, bicarbonate ≤20 mmol/L) AND moderate-to-severe acute kidney injury 1
• This represents a more focused population based on the positive signal from BICAR-ICU 1 1
• Exclusion criteria include toxicology cases and diabetic ketoacidosis, where bicarbonate has different risk-benefit profiles 2, 3

Intervention Protocol

• The intervention group receives 4.2% sodium bicarbonate infusion titrated to maintain plasma pH ≥7.30 1
• The control group receives no sodium bicarbonate therapy 1
• The 4.2% isotonic formulation continues to be used to minimize hypernatremia and hyperosmolar complications 2

Primary and Secondary Outcomes

• The primary outcome is 90-day mortality, representing a patient-centered, clinically meaningful endpoint 1
• Main secondary outcomes include organ support dependencies, assessing whether bicarbonate reduces the need for mechanical ventilation, vasopressors, or renal replacement therapy 1

Clinical Context and Implications

Current Guideline Recommendations

• The Surviving Sepsis Campaign explicitly recommends AGAINST sodium bicarbonate for hypoperfusion-induced lactic acidemia when pH ≥7.15, as multiple trials show no hemodynamic benefit 2, 4
• However, guidelines acknowledge insufficient evidence for patients with pH <7.15 or those with concurrent acute kidney injury 4
• The European Society of Intensive Care Medicine suggests routine bicarbonate use is not supported for sepsis-related acidosis when pH >7.15 2

The AKI-Acidosis Phenotype

• Observational data suggest that when severe metabolic acidemia (pH <7.20) occurs WITH moderate-to-severe acute kidney injury, mortality approaches 55-60%, substantially higher than acidemia alone 1
• This specific phenotype may represent a population where bicarbonate's benefits (improved hemodynamics, reduced vasopressor requirements) outweigh its risks (sodium overload, increased lactate, decreased ionized calcium) 4, 5
• A 2019 systematic review found that bicarbonate therapy yields improved survival specifically in patients with accompanying acute kidney injury 5

Mechanism of Potential Benefit in AKI

• In acute kidney injury, the kidney's ability to regenerate bicarbonate and excrete acid is impaired, making exogenous bicarbonate potentially more beneficial 3
• Severe acidemia in AKI patients may cause more profound cardiovascular depression and vasopressor resistance, which bicarbonate may help reverse 6
• The combination of metabolic acidosis and AKI creates a vicious cycle that may be interrupted by bicarbonate therapy 5

Practical Application Based on Current Evidence

When to Consider Bicarbonate (Based on BICAR-ICU Trials)

• For patients with pH ≤7.20, PaCO2 ≤45 mmHg, bicarbonate ≤20 mmol/L AND moderate-to-severe AKI, consider 4.2% sodium bicarbonate infusion titrated to pH ≥7.30 1
• Ensure adequate ventilation is established before administration, as bicarbonate produces CO2 that must be eliminated 2
• Do NOT use bicarbonate routinely for pH ≥7.15 in sepsis or lactic acidosis without AKI 2, 4

Dosing Protocol from BICAR-ICU Trials

• Use 4.2% sodium bicarbonate solution (isotonic), prepared by diluting 8.4% solution 1:1 with normal saline or sterile water 2
• Titrate infusion to maintain pH ≥7.30, not to completely normalize pH 1
• Monitor arterial blood gases every 2-4 hours during active therapy 2
• Monitor serum sodium (target <150-155 mEq/L), potassium, and ionized calcium every 2-4 hours 2

Critical Safety Monitoring

• Avoid hypernatremia (serum sodium should not exceed 150-155 mEq/L) 2
• Avoid excessive alkalemia (pH should not exceed 7.50-7.55) 2
• Monitor and replace potassium, as bicarbonate shifts potassium intracellularly 2
• Ensure adequate ventilation to eliminate excess CO2 produced by bicarbonate metabolism 2, 3

Common Pitfalls to Avoid

• Do not use bicarbonate as a substitute for treating the underlying cause of acidosis - restoration of adequate circulation, source control in sepsis, and insulin in DKA remain the primary treatments 2, 3
• Do not mix sodium bicarbonate with calcium-containing solutions or vasoactive amines (causes precipitation or inactivation) 2
• Do not use hypertonic 8.4% solution without dilution in critically ill patients, as this increases risk of hyperosmolar complications 2
• Do not give bicarbonate for respiratory acidosis - these patients need ventilation, not bicarbonate 2

Awaiting Definitive Evidence

• The BICAR-ICU 2 trial results will provide the highest-quality evidence on whether bicarbonate improves 90-day mortality in the specific population of critically ill patients with both severe metabolic acidemia and moderate-to-severe AKI 1
• Until these results are available, clinicians must weigh the suggestive secondary endpoint data from BICAR-ICU 1 against the lack of benefit shown in other acidosis populations 1, 4
• A 2025 target trial emulation from Australian ICUs found a 1.9% absolute mortality reduction with bicarbonate therapy in metabolic acidosis, with benefits seen across multiple subgroups including AKI and vasopressor-dependent patients 7