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

Summary

Background

Acute acidaemia is frequently observed during critical illness. 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. Therefore, we aimed to evaluate whether sodium bicarbonate infusion would improve these outcomes in critically ill patients.

Methods

We did a multicentre, open-label, randomised controlled, phase 3 trial. Local investigators screened eligible patients from 26 intensive care units (ICUs) in France. We included 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 score of 4 or more or an arterial lactate concentration of 2 mmol/L or more. We randomly assigned patients (1:1), by stratified randomisation with minimisation via a restricted web platform, to receive either no sodium bicarbonate (control group) or 4·2% of intravenous sodium bicarbonate infusion (bicarbonate group) to maintain the arterial pH above 7·30. Our protocol recommended that the volume of each infusion should be within the range of 125–250 mL in 30 min, with a maximum of 1000 mL within 24 h after inclusion. Randomisation criteria were stratified among three prespecified strata: age, sepsis status, and the Acute Kidney Injury Network (AKIN) score. The primary outcome was a composite of death from any cause by day 28 and the presence of at least one organ failure at day 7. All analyses were done on data from the intention-to-treat population, which included all patients who underwent randomisation. This study is registered with ClinicalTrials.gov, number NCT02476253.

Findings

Between May 5, 2015, and May 7, 2017, we enrolled 389 patients into the intention-to-treat analysis in the overall population (194 in the control group and 195 in the bicarbonate group). The primary outcome occurred in 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). The Kaplan-Meier method estimate of the probability of survival at day 28 between the control group and bicarbonate group was not significant (46% [95% CI 40–54] vs 55% [49–63]; p=0·09. In the prespecified AKIN stratum of patients with a score of 2 or 3, the Kaplan-Meier method estimate of survival by day 28 between the control group and bicarbonate group was significant (37% [95% CI 28–48] vs 54% [45–65]; p=0·0283). Metabolic alkalosis, hypernatraemia, and hypocalcaemia were observed more frequently in the bicarbonate group than in the control group, with no life-threatening complications reported.

Interpretation

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.

Funding

French Ministry of Health and the Société Française d'Anesthésie Réanimation.

Introduction

Acute acidaemia is frequently observed during critical illness, with a reported incidence varying from 14% to 42%.1, 2, 3, 4, 5 Persistent acidaemia has been associated with poor prognosis,1, 2, 3, 6 with a mortality rate as high as 57% when the pH stays below 7·20.⁵ Along with case-specific treatment, improvement of tissue perfusion and supportive measures such as mechanical ventilation and renal-replacement therapy are the cornerstones of severe metabolic acidaemia management in critically ill patients.2, 3, 7 Because an acidotic cellular environment can cause cellular dysfunction, intravenous sodium bicarbonate administration to increase the pH might also be beneficial. In a survey done in North America, more than two-thirds of the programme directors in nephrology or intensive care units (ICUs) declared that they used sodium bicarbonate for the treatment of acidaemia with hyperlactataemia.⁸

Research in context

Evidence before this study

We searched PubMed from Jan 1, 1990, to Feb 1, 2018, using the search terms “sodium bicarbonate” or “metabolic acidemia”. Studies were included if they evaluated sodium bicarbonate infusion as an intervention to treat severe metabolic acidaemia. Our review indicates that sodium bicarbonate infusion to increase the arterial pH in this condition has been sparsely evaluated. Animal studies, single centre crossover studies with physiological parameters as a main outcome, and reviews from experts have recommended against its use. Surveys and observational studies have, however, reported that more than half of the critical care physicians or nephrologists would consider sodium bicarbonate infusion for a patient with severe metabolic acidaemia whatever its cause. Finally, the 2017 Surviving Sepsis Campaign stated that “the effect of sodium bicarbonate administration on hemodynamics and vasopressor requirements at lower pH (than 7–15 as well as the effect on clinical outcomes at any pH level, is unknown” and that “no studies have examined the effect of bicarbonate administration on outcomes”.

Added value of this study

This is the first large randomised clinical trial comparing two groups of no sodium bicarbonate infusion (control group) with sodium bicarbonate infusion (bicarbonate group) in 400 critically ill patients with severe metabolic acidaemia (pH ≤7·20) from 26 Intensive Care Units. In this trial, we report that in the overall population sodium bicarbonate infusion was not associated with an improvement in the primary outcome (ie, composite criteria of organ failure at day 7 and any cause of death at day 28). In the a-priori defined clinical stratum of patients with acute kidney injury (with Acute Kidney Injury Network scores of 2 or 3 at enrolment), the primary outcome occurred less frequently in the bicarbonate group than in the control group. Additionally, the number of days alive and free from renal-replacement therapy was higher in the bicarbonate group than in the control group both in the overall study population and in the a-priori defined stratum of patients with acute kidney injury. No other organ support parameters were different among treatment groups.

Implications of all the available evidence

The findings of the BICAR-ICU trial suggest that sodium bicarbonate infusion is associated with an improved outcome and a reduced rate of mortality from enrolment to day 28 in critically ill patients with severe metabolic acidaemia (pH ≤7·20) and acute kidney injury. Sodium bicarbonate infusion was also associated with more days alive and free from renal-replacement therapy. However, in the overall non-selected patients, sodium bicarbonate infusion was not associated with a clinical outcome. Further studies should be done to investigate whether sodium bicarbonate infusion might improve survival in a larger dataset and in selected patients with severe metabolic acidaemia and acute kidney injury.

Despite the frequency of its use in ICUs across the world, the effect of sodium bicarbonate infusion for the treatment of metabolic acidaemia remains controversial.⁹ Small physiological studies,10, 11 along with retrospective or observational studies,12, 13 have not shown clear conclusions. The reluctance to use sodium bicarbonate for the treatment of severe metabolic acidaemia might be related to the absence of cardiovascular effects in two physiological studies10, 11 and potential side-effects, principally intracellular acidification due to the accumulation of carbon dioxide and the risk of hypocalcaemia.3, 10, 14 However, sodium bicarbonate could compensate for the deleterious effects of acidotic cells on cardiovascular and oxygen delivery, and might delay or avoid unnecessary early renal-replacement therapy.

The 2016 update of the Surviving Sepsis Campaign International Guidelines for Management of Sepsis and Septic Shock¹⁵ suggested that the effect of sodium bicarbonate administration on haemodynamics and vasopressor requirements at lower pH as well as its effect on clinical outcomes at any pH level is unknown, and no studies have examined the effect of sodium bicarbonate administration on clinical outcomes. The absence of high-level evidence leaves ICU clinicians uncertain whether sodium bicarbonate infusion is beneficial, ineffective, or indeed harmful to patients with severe metabolic acidaemia. Given such uncertainties, we aimed to evaluate whether sodium bicarbonate infusion would improve clinical outcome in critically ill patients with severe metabolic acidaemia. Specifically, we hypothesised that early sodium bicarbonate infusion compared with no infusion would result in fewer deaths from any cause by 28 days and lower incidence of at least one organ failure at 7 days in adult ICU patients with severe metabolic acidaemia.