Sodium Bicarbonate for Severe Metabolic Acidemia and Acute Kidney Injury

Jung et al. JAMA 2025. doi: 10.1001/jama.2025.20231

Clinical Question

• In patients with severe metabolic acidosis (pH ≤7.20) and moderate to severe AKI  does the administration of sodium bicarbonate (NaHCO3) compared to placebo reduce 90-day mortality?

Background

• Multiple cardiac, respiratory, renal and neurological pathophysiological consequences of severe academia have been reported
• The administration of NaHCO3 to manage this cohort of patients is controversial
  • BICARICU-1 compared the administration of 4.2% NaHCO3 (with no NaHCO3) in those with severe acidosis; no difference in the composite of mortality at day 28 or presence of organ failure at day 7 was shown
  • However in those with severe AKI mortality was lower (46 vs 63%) with lower rates of KRT (Kidney Replacement Therapy) (51 vs 73%)
• A recently published large Australian target trial emulation suggested an association between bicarbonate administration and reduced mortality

Design

• Open-label, investigator-initiated
• Multi-centre RCT
• Informed consent prior where possible, otherwise if too unwell then emergency enrolment allowed
• Centrally performed randomisation
• Stratification by age (<65/≥65 years) and pH (<7.10/7.11-7.20)
• Sample size based on a 10% absolute decrease in 90 day all cause mortality from 80 to 70% based on BICARICU-1 and allowing for ~8% loss to follow up / unevaluable data 640 patients required
• Intention to treat (primary) and per-protocol (including cross over and exclusion of deviations) analyses planned
• Pre-specified subgroups (pH, age, sepsis, SOFA score)
• Registered with clinical trials.gov (NCT04010630)

Setting

• 43 ICUs in France
• October 2019 – December 2023

Population

• Inclusion:
  • 18 years or older
  • SOFA > 4 or arterial lactate ≥ 2 mmol/L
  • Within 48 hours of ICU admission
  • pH ≤ 7.20 AND serum HCO3- ≤ 20 mEq/L AND PaCO2 ≤ 45 mmHg AND moderate/severe AKI (KDIGO stage 2/3)
• Exclusion:
  • Respiratory acidosis (PaCO2 > 45 mmHg)
  • Bicarbonate wasting via GI or urinary tract
  • Baseline eGFR ≤ 10 ml/min
  • Ketoacidosis
  • NaHCO3 infusion
  • KRT 24 hours before screening or planned within following 6 hours
  • Exogenous acid poisoning (e.g. methanol)
  • Pregnant or breastfeeding
  • Life expectancy < 48 hrs
• 3202 screened > 640 randomised > 320 in each group
  • 13 subsequent exclusions from intention to treat group (withdrawal of consent, under guardianship, lack of insurance and double enrolment)
• Comparing baseline characteristics of bicarbonate vs. control group
  • Largely balanced except some differences in underlying co-morbidities
    • Age: 67 vs 67
    • Male: 62 vs 59%
    • SAPSII: 61 vs 61
    • SOFA Score: 10 vs 11
    • Median Elixhauser comorbidity score: 0 vs 3
      • Increased rates of COPD and immunodeficiency in control group
    • Medical Admission: 68 vs 69%
    • Cause of academia:
      • Septic Shock: 55 vs 53%
      • Haemorrhagic Shock: 14 vs 14%
      • AKI: 8 vs 8%
      • Cardiac Arrest: 6 vs 6%
    • MAP: 72 vs 72 mmHg
    • Invasive Ventilation: 77 vs 74%
    • Vasopressors: 81 vs 79%
    • pH: 7.15 vs 7.15
    • PaCO2: 37 vs 37 mmHg
    • HCO3: 13 vs 12
    • Lactate: 5.9 vs 5.7
    • Creatinine: 2.2 vs 2.3 mg/dL

Intervention

• 4.2% bicarbonate infusion
  • Targeting a pH of 7.30 or higher through next 28 days or until ICU discharge
  • Each infusion 125-250ml over 30 minutes
  • Maximum of 1L within 24 hours (500 mEq)
  • ABG 1 to 4 hours following cessation
  • Median 750mls received in first 48 hours

Control

• No bicarbonate infusion

Management common to both groups

• Standardised indications for KRT

Outcome

• Primary outcome:
  • Day 90 mortality (comparing bicarbonate vs control)
    • 62.1% (195/314) vs 61.7% (193/313)
    • Absolute Difference 0.4 (95% CI -7.2 to 8.0)
  • No evidence of group effect in any subgroup
• Secondary outcomes:
  • Comparing bicarbonate vs. control group
  • No significant difference in
    • Mortality at 28 (54 vs 54%) and 180 days (65 vs 63%)
    • KRT free days by day 28 (0 vs 0)
    • Invasive ventilation by day 28 (91 vs 88%)
    • ICU LOS (5 vs 5 days) and ICU free days by day 28 in survivors
    • Hospital LOS by day 90 (10 vs 8 days) and hospital free days by day 90 in survivors
    • SOFA score at Day 1,2 and 7
  • Significantly greater in intervention group
    • Enrolment to KRT initiation (31 vs 16 hours)
    • Vasopressor therapy (97 vs 94%)
    • Day 2 fluid balance (2.8 vs 2.2L)
  • Significantly less in intervention group
    • Use of KRT by day 28 (35 vs 50%)

Authors’ Conclusions

• For critically ill patients with both severe metabolic acidosis and moderate to severe AKI, sodium bicarbonate therapy did not significantly decrease mortality

Strengths

• Multi-site RCT with high internal validity
• Designed to test an important and clinically relevant hypothesis generated from prior randomised research
• Standardised criteria for KRT initiation
• Low numbers of protocol violations
• Separation in arterial pH (eFigure 2) and bicarbonate (eFigure3)

Weaknesses

• Single country
  • Some countries use different concentrations (e.g. 1.26%)
• Open-label but objective primary outcome
• Some cross-over but rates relatively low (15%) and per-protocol analysis showed no difference
• There may be some heterogeneity of treatment effect by type of metabolic acidosis (HAGMA, HAGMA with predominant lactic acidosis and combined HAGMA/NAGMA)
  • eTable 3 shows varying point estimates in 90-day all cause mortality
• Rates of observed mortality lower than anticipated, and power calculation based on a 10% reduction in mortality
  • Much smaller reductions in mortality are clinically relevant

The Bottom Line

• The administration of 4.2% NaHCO3 does not appear to impact mortality, however does seem to reduce the incidence of KRT
  • This still may be clinically important due to the potential KRT induced dialy-trauma
• Further studies assessing the use of NaHCO3 in metabolic acidosis are SODa-BIC and MOSAICC

External Links

• article Sodium Bicarbonate for Severe Metabolic Acidemia and Acute Kidney Injury
• editorial Sodium Bicarbonate in Severe Acidemia and Acute Kidney Injury—Turning the Tide or Chasing a Myth?

Metadata

Summary author: George Walker @hgmwalker89
Summary date: 30 October 2025
Peer-review editor: David Slessor

Picture by: Karola G / Pexels