BICAR-ICU

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Jaber S, et al. "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. 2018. 392(10141):31-40.
PubMedFull text

Clinical Question

In acutely ill patients in the intensive care unit with severe metabolic acidosis, does treatment with sodium bicarbonate reduce all-cause mortality at day 28 or the presence of ≥1 organ failure at day 7?

Bottom Line

In this study, ICU patients with severe metabolic acidosis treated with sodium bicarbonate did not have improvement in all-cause mortality at day 28 or the presence of ≥1 organ failure at day 7. However, patients with AKI (a pre-specified subgroup) did experience a reduction in this endpoint.

Major Points

Severe metabolic acidosis carries a poor prognosis among ICU patients. Sodium bicarbonate may correct this derangement but the use of this medication has not been evaluated in a large prospective study. While bicarbonate may increase the pH, its administration may contribute to volume overload, decrease serum calcium, increase lactate levels, and increase PaCO2.[1] This may in turn worsen intracellular pH as CO2 is able to diffuse across cell membranes.

Published in 2019, the BICAR-ICU trial randomized 394 French ICU patients with metabolic acidosis to bicarbonate or no bicarbonate. Metabolic acidisis was defined by a pH ≤7.20 PaCO2 ≤45 mm Hg and sodium bicarbonate concentration ≤20 mmol/L. Patients also needed to have an elevated SOFA score or lactate level. There was no difference in the primary outcome of all-cause mortality at day 28 or the presence of ≥1 organ failure at day 7 between the groups (cumulative incidence 66% in bicarbonate group vs. 71% in control group; P=0.24). Among participants with AKI (defined by an AKIN score 2-3),[2] there was a 12% reduction in this composite outcome with bicarbonate (70% vs. 82%; P=0.046), as well as an 18% reduction in 28-day mortality (46% vs. 63%; P=0.017). From these results, it seems that ICU patients with AKI and severe metabolic acidosis may benefit from bicarbonate infusion. Its utility among other ICU patients remains unclear.

Guidelines

As of February 2019, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, open-label, randomized, controlled, phase 3 trial
  • N=389 ICU patients with severe acidemia
    • Bicarbonate (n=195)
    • Control (n=194)
  • Setting: 26 ICUs in France
  • Enrollment: 2015-2017
  • Analysis: Intention-to-treat
  • Primary outcome: All-cause mortality at day 28 or the presence of ≥1 organ failure at day 7

Population

Inclusion Criteria

  • Adult patients age ≥18 years
  • 48 hours within admission to ICU with severe acidemia, defined as pH ≤7.20, PaCO2 ≤ 45 mm Hg, and sodium bicarbonate concentration ≤ 20 mmol/L
  • Sequential Organ Failure Assessment (SOFA) score of 4 or more, or arterial lactate concentration of 2 mmol/L or more

Exclusion Criteria

  • Respiratory acidosis
  • Proven digestive or urinary tract loss of sodium bicarbonate (volume loss ≥ 1500 mL/day)
  • Stage IV chronic kidney disease
  • Ketoacidosis
  • Sodium bicarbonate infusion within 24 hours before screening

Baseline Characteristics

Comparisons are control group vs. bicarbonate group

  • Median age: 65 vs. 66 years
  • Female sex: 37% vs. 41%
  • BMI: 27 vs. 26
  • Simplified Acute Physiology Score II: 60 vs. 59
  • Sepsis: 59% vs. 63%
  • AKIN 2-3: 46% vs. 47%
  • Condition associated with acidemia at enrollment:
    • Cardiac arrest: 9% vs. 9%
    • Septic shock: 51% vs. 55%
    • Hemorrhagic shock 21% vs. 23%
    • Others 20% vs. 13%
  • Laboratory results
    • Arterial pH: 7.15 vs. 7.15
    • Serum bicarbonate: 13 vs. 13 mmol/L
    • PaCO2: 37 vs. 38 mm Hg
    • Serum lactate 5.3 vs. 6.3 mmol/L
    • Serum creatinine: 1.76 vs. 1.67 mg/dL
  • Physiologic support:
    • Invasive mechanical ventilation: 82% vs. 84%
    • Vasopressor support: 80% vs. 79%

Interventions

  • Randomized to a group in an open label fashion:
    • Control - No bicarbonate
    • Bicarbonate 4.2% sodium bicarbonate intravenously with aim of goal arterial pH of ≥7.30 during 28-day ICU admission or ICU discharge; recommended infusion at 125-250 mL in 30 min, with max 1L in 24 hours after inclusion
  • Randomization was stratified by study site, age with cutoff of 65 years, presence of suspected sepsis, and presence of AKIN score of 2 or 3

Outcomes

Comparisons are control vs. bicarbonate.

Primary Outcomes

All-cause mortality at day 28 or the presence of ≥1 organ failure at day 7
71% vs. 66% (absolute difference estimate -5.5, 95% CI -15.2 to 4.2; P=0.24)
Note that the following outcomes were not defined as primary outcomes.
All-cause mortality at day 28: 54% vs. 45% (absolute difference estimate -9.0, 95% CI -19.4 to 1.4; P=0.07)
≥1 organ failing at day 7: 69% vs. 62% (absolute difference estimate -2.8, 95% CI -15.4 to 9.8; P=0.15)
In patients with AKIN scores of 2-3 (n=182), composite of death from any cause by day 28 or the presence of at least one organ failure at day 7
A pre-specified subgroup analysis.
82% vs. 70% (absolute difference estimate -12.3, 95% CI -26.0 to -0.1; P=0.046)
All-cause mortality at day 28: 63% vs. 46% (absolute difference estimate -17.7, 95% CI -33.0 to -2.3; P=0.017)
≥1 organ failing at day 7: 82% vs. 66% (absolute difference estimate -15.9, 95% CI -28.4 to -3.4; P=0.014)

Secondary Outcomes

Renal replacement during ICU stay
52% vs. 35% (absolute difference estimate -16.7, 95% CI -26.4 to -7.0; P<0.001)
Time from enrollment to initiation of renal replacement therapy (hours)
7 vs. 19 (absolute difference estimate 8.8, 95% CI 3.9 to 15.6; P<0.0001)
Renal replacement therapy-free days during ICU stay in survivors
28 vs. 28 (absolute difference estimate 0, 95% CI 0 to 0; P=0.47)
Renal replacement therapy-free days during ICU stay
8 vs. 19 (absolute difference estimate 0, 95% CI 0 to 1.0; P=0.015)

Adverse Events

In the supplementary appendix.[3]

≥1 lab with serum Na >145 mmol/L
29% vs. 49% (absolute difference 19.9, 95% CI 10.4 to 29.4; P<0.001)
≥1 lab with serum Ca <0.9 mmol/L
15% vs. 24% (absolute difference 9.7, 95% CI 1.8 to 17.5; P=0.017)
≥1 lab with blood pH >7.45
9% vs. 16% (absolute difference 7.1, 95% CI 0.6 to 13.6; P=0.032)
Patients with ≥1 lab with serum K >5 mmol/L
49% vs. 32% (absolute difference -17.2, 95% CI -26.8 to -7.6; P<0.001)

Criticisms

  • Unable to blind treating physicians and nursing since arterial blood gases are affected by bicarbonate administration
  • 24% of control group received sodium bicarbonate, potentially underestimating treatment effect.

Funding

  • French Ministry of Health and the Society Francaise d'Anesthesie Reanimation

Further Reading

  1. Rhodes A et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit. Care Med. 2017. 45:486-552.
  2. Mehta RL et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007. 11:R31.
  3. Supplementary Appendix (PDF).