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

Jaber. Lancet 2018; published on line 14th June. doi:

Clinical Question

  • In critically ill patients with severe metabolic acidaemia (pH ≤7⋅20), does the infusion of sodium bicarbonate, compared with no infusion, to reach and maintain a targeted pH of 7⋅30 decrease the primary composite out­come of mortality by day 28 or the presence of at least one organ failure at day 7?


  • Acute acidaemia is frequently observed during critical illness
  • Persistent acidaemia has been associated with poor prognosis
  • Sodium bicarbonate infusion for the treatment of severe metabolic acidaemia is a possible treatment option but remains controversial as no studies to date have examined its effect on clinical outcomes


  • Multicentre, open labelled, randomised controlled, phase 3 trial
  • Stratified randomisation according to study site and three pre-specified factors: age with a cutoff of 65 years, presence or absence of suspected sepsis and presence or absence of Acute Kidney Injury Network (AKIN) score of 2 or 3
  • Computer­ generated allocation sequence
  • No physician or nurse blinding. Rationale was sodium bicarbonate infusion influences arterial pH levels and because routine arterial blood gases must be done in critically ill patients
  • Deferred consent process for emergency situations
  • Planned interim analysis
  • Intention to treat analysis
  • On the basis of a previous study, a total of 376 patients were needed for an 80% statistical power to show an absolute difference of 15% between groups in the primary outcome at a two­-sided α level of 0⋅03 (0⋅02 for the interim analysis and 0⋅03 for the analysis), assuming that the administration of sodium bicarbonate would be associated with a decrease from 45% to 30% in the primary endpoint


  • 26 French ICUs
  • May 2015 to May 2017


  • Inclusion: adult patients (aged ≥18 years) who were admitted within 48 h to the ICU with severe acidaemia
    • pH ≤7⋅20, PaCO2 ≤45 mm Hg, and sodium bicarbonate concentration ≤20 mmol/L
  • AND with a total Sequential Organ Failure Assessment (SOFA) score of 4 or more or an arterial lactate concentration of 2 mmol/L or more
  • Exclusion: respiratory acidosis, proven digestive or urinary tract loss of sodium bicarbonate (volume loss ≥1500 mL per day), stage IV chronic kidney disease, ketoacidosis, and sodium bicarbonate infusion (including renal­ replacement therapy) within 24 h before screening
  • 389 patients were included
    • 942 patients with severe metabolic acidaemia were assessed for trial eligibility. 542 were excluded and 400 were randomly assigned to the study groups. After secondary exclusion of 11 patients who withdrew consent, a total of 389 patients were included in the intention­ to­ treat analysis (n=194 in the control group and n=195 in the bicarbonate group).
  • Baseline characteristics of the patients were well balanced between the two groups. At randomisation:
    • sepsis was present in 238 (61%) patients
    • acute kidney injury with AKIN scores of 2 or 3 in 182 (47%) patients
    • invasive mechanical ventilation was used in 324 (83%) of 389 patients
    • vasopressors in 310 (80%) patients
    • median SOFA score of 10 in both groups


  • 4.2% sodium bicarbonate intravenously infused
    • aim of achieving an arterial pH of 7⋅30 or more during the 28­ day ICU admission or ICU discharge
    • protocol recommended that the volume of each sodium bicarbonate infusion should be within the range of 125–250 mL in 30 min, with a maximum of 1000 mL within 24 h after inclusion
    • measurement of arterial blood gas should be done 1–4 h after the end of each infusion


  • No infusion of intravenous 4.2% sodium bicarbonate or placebo

Management common to both groups

  • Indications for renal-replacement therapy (RRT) were standardised
  • RRT was strongly recommended in the event of hyperkalaemia (>6⋅5 mmol/L) with electrocardiogram signs or cardiogenic pulmonary oedema with no urine output, or both
  • At 24 h after inclusion, RRT was recommended when two of three criteria were present:
    • urine output less than 0⋅3 mL/kg per h for at least 24 h
    • arterial pH less than 7⋅20 despite resuscitation
    • hyperkalaemia (>6⋅5 mmol/L)
  • Each study site chose the method of RRT according to the local guidelines
  • Initiation of invasive mechanical ventilation was indicated if patients had one major or two minor predefined clinical events


  • Primary outcome: No statistical difference in composite of death from any cause by 28 days after randomisation and the presence of at least one organ failure at 7 days after randomisation
    • Composite outcome: 138 (71%) of 194 patients in the control group and 128 (66%) of 195 in the bicarbonate group
      • absolute difference estimate –5⋅5%, 95% CI –15⋅2 to 4⋅2; p=0⋅24
    • Day 28 mortality: 54% in the control group vs 45% in the bicarbonate group; p=0.07
    • One or more organ failure at day 7: 69% in the control group vs 62% in the bicarbonate group; p=0.15
    • In patients with Acute Kidney Injury (AKIN) score of 2-3 (n=182), there was a statistically significant difference in:
      • primary composite outcome: 74/90 (82%) in the control group vs 64/92 (70%) in the bicarbonate group; p=0·0462
      • day 28 mortality: 57/90 (63%) in the control group vs 42/92 (46%) in the bicarbonate group; p=0·0166
      • one or more organ failure at day 7: 74/90 (82%)in the control group vs 61/92 (66%) in the bicarbonate group; p=0·0142
  • Secondary outcome:
    • Worse outcomes in the control group, reaching statistical difference, in the following:
      • Use of RRT during ICU stay: 100 (52%) vs 68 (35%); p=0·0009
      • Median RRT-free days during ICU stay: 8 vs 19; p=0·01
      • Time (hours) from enrolment to initiation of renal replacement therapy: 7 vs 19; p=<0.0001
        • Hyperkalaemia and acidaemia main reasons for initiation of RRT in the control group whilst serum creatinine and serum blood urea nitrogen were the main reasons to start RRT in the bicarbonate group
    • No statistical difference in outcomes for control group vs sodium bicarbonate group in the following:
      • Renal replacement therapy-free days during ICU stay in survivors
      • Median vasopressor free days: 9 vs 19; p=0.1
      • Dependence on dialysis at ICU discharge
      • Length of ICU stay
    • Adverse events
      • Metabolic alkalosis, hypernatraemia, and hypocal­caemia were observed more frequently in the bicarbonate group than in the control group, with no life ­threatening complications reported

Authors’ Conclusions

  • In patients with severe metabolic acidaemia, sodium bicarbonate had no effect on the primary composite outcome. However, sodium bicarbonate decreased the primary composite outcome and day 28 mortality in the a-priori defined stratum of patients with acute kidney injury


  • An important clinical question is evaluated with patient focussed outcome measures
  • Multicentre
  • Baseline characteristics were well balanced
  • Data for the primary outcome were available for all patients


  • Composite primary outcome
  • 24% of the control group received bicarbonate
  • 109 patients were excluded because they had already received sodium bicarbonate
  • The proportion of patients in whom the targeted pH of 7⋅30 was reached and maintained for at least 36 h from enrolment to day 2 was only 60%. The control group achieved this same target in 26% of patients
  • Physicians were not blinded and there was no control infusion. The authors provide adequate explanation for this
  • The protocol suggested a range of 4⋅2% sodium bicarbonate volume (125–250 mL per infusion) in the bicarbonate group rather than using a formula to calculate the base deficit and provide a tailored sodium bicarbonate infusion; therefore, we cannot extrapolate whether different ways of administration would have resulted in different outcomes
  • No data was collected for mechanical ventilation settings which may have influenced the patients acid-base status

The Bottom Line

  • In patients with severe metabolic acidaemia, sodium bicarbonate treatment had no effect on the primary composite outcome (ie, mortality by day 28 or the presence of at least one organ failure at day 7)
  • In a subgroup of patients with acute kidney injury, sodium bicarbonate treatment did decrease the composite outcome and 28 day mortality although this may represent a type I error based on the outlined limitations of the study
  • This study will reassure clinicians that already use sodium bicarbonate for correcting metabolic acidaemia, that this may delay and/or reduce the requirement for RRT. Equally, for those that opt to avoid sodium bicarbonate, there is no compelling evidence to change practice

External Links


Summary author: Steve Mathieu
Summary date: 20th June 2018
Peer-review editor: Dave Slessor


  • Adnane Lahlou

    In patients with severe acidosis i.e pH <7.10 or bicar < 10 mmol/l, one can only feel compelled to give bicar and as this study shows there is a benefit even though not regarding mortality….. The question here is how much bicar to give and what kind of solution….. In my workplace I only have the 14‰ solution and I usually give 250 ml which is hardly enough if we calculate the base deficit. I believe the bicar administration should be standardized and early recourse to RRT and vasopressin should be favoured.

    • I’ve seen people who use standard infusion of bicarbonate 1 mEq/kg/hr until achieving normal pH, what do you thing about it?

    • Phil

      As much as you may feel compelled to give NaHCO3, since there is quite a bit of human data out there on using NaHCO3 in a wide variety of conditions, and the vast majority of it has shown NaHCO3 to either be not superior to other crystalloids or to cause harm, I think not giving it is probably the more justifiable stance.

      As far as I am aware, there isn’t any clinical human evidence to support the idea that acidosis itself is harmful, or that if the bodies response to a pathophysiological state has induced it that intervening to increase the pH and/or plasma bicarbonate level will improve outcomes.

      I think the over-enthusiastic desire to normalize the results of all of our blood tests combined with the anchored belief handed to us by our teachers and those before them that catecholamines don’t work at low pH’s/acidosis is bad, and the anecdotal accounts that after pusing an ampule of concentrated sodium bicarbonate on an unstable/hypotensive/arrested patient they showed improvement, keeps pushing this idea forward.

      The more these controversies in fluid go on the more I feel like we are working towards equipoise on whether many of these patients need any supplementary IV fluids prescribed at all.

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