Critical illness is frequently punctuated by metabolic acidosis leading to varying degrees of acidemia. Despite a lack of efficacy for its use (Forsythe SM, et al. Chest. 2000;117:260-267; Sabatini S, et al. J Am Soc Nephrol. 2009;20:692-695), sodium bicarbonate therapy is still a mainstay of treatment in the modern intensive care unit (ICU) when attempting to reverse severe acidemic insults. The physiologic argument often cited is based on the loss of protein functionality in a severely acidotic milieu, leading to cardiovascular dysfunction, refractory hypotension, multiorgan failure, and eventual death. But these rationalizations are based on cursory scientific evidence and not on clinical findings. The publication of the BICAR-ICU trial, a large, multicenter randomized, open-label, controlled trail by Jaber et al (Lancet. 2018;392:31-40) represents the first large, high-quality attempt to quantify the benefit of alkalization therapy in a cohort of critically ill ICU patients with metabolic acidosis.
The trial was conducted at 26 ICUs in France. The authors enrolled adults (aged 18 years and older) within 48 hours of admission with severe metabolic acidosis (pH ≤ 7.2, sodium hydroxide ≤ 20 mmol/L), and either a Sequential Organ Failure Assessment score ≥ 4 or a lactate level ≥ 2 mmol/L. Exclusions included respiratory acidosis (Paco2 ≤ 45 mm Hg), proven digestive or urinary tract loss of sodium bicarbonate, stage IV chronic kidney disease, ketoacidosis, and sodium bicarbonate infusion within 24 hours before screening. Patients randomized to receive sodium bicarbonate continued to receive a 4.2% sodium bicarbonate infusion until achieving an arterial pH ≥ 7.30 during the 28-day ICU admission or until ICU discharge (to a maximum dose of 1 L of 4.2% per 24 hours).
Over two years the authors enrolled 400 patients. After randomization, there was no difference in primary outcome, composite all-cause 28-day mortality, or the presence of organ failure at 7 days (71% in the control group vs. 66% in the bicarbonate group, p = 0.24). There was also a lack of statistically significant difference in 28-day mortality (46% in the control group vs. 55% in the bicarbonate group, p = 0.07).
The authors did report notable secondary outcomes in favor of the bicarbonate group. In a priori subgroup analysis of patients with acute kidney injury, the primary outcome occurred significantly more frequently in the control group (82% vs. 70%, p = 0.0462). They also note a statistically significant decrease in Kaplan-Meier method estimated 28-day mortality in the control group versus the bicarbonate group (63% vs. 46%, p = 0.0283). Additionally, the study results show a trend toward improved survival with the use of bicarbonate therapy (absolute risk reduction) and demonstrate a reduction in the need for hemodialysis (52% vs. 35%, p = 0.0009) and less hyperkalemia coupled with a nonclinically significant worsening in hypernatremia and hypocalcemia.
The study has some fundamental flaws. It can be argued that it was vastly underpowered to find a 15% absolute difference in either death at 28 days or the presence of at least one organ system failure at 7 days. There was no mention of the cause of acidemia, which can drastically alter the effect that alkalization would be expected to achieve. It is also difficult to interpret intention-to-treat analysis when 24% of the control group received bicarbonate therapy. Furthermore, eliminating patients who received bicarbonate therapy before randomization eliminated patient subsets that were deemed clinically to meet criteria for benefit of sodium bicarbonate infusion (uremia or normal anion gap metabolic acidosis).
The presence of a negative primary outcome fails to clarify the questionable use of sodium bicarbonate therapy for the correction of acidemia. Further studies will be required to both remedy this study’s limitations and further specify the patient population who would benefit from alkalization therapy. What can be taken from this study is that, in the proper circumstances, such as the presence of kidney injury, sodium bicarbonate can delay or even eliminate the need for renal replacement therapy. This will also require further clarity, but does demonstrate a viable use of bicarbonate replacement in the modern clinical environment.
Authors of this installment of Concise Critical Appraisal:
Rory Spiegel, MD, is a clinical instructor of emergency medicine and a current PGY2 critical care medicine fellow at the University of Maryland Medical Center in Baltimore, Maryland, USA.
James H. Lantry III, MD, is an assistant professor of emergency and critical care medicine and the associate program director of the Critical Care Fellowship at the University of Maryland Medical Center in Baltimore, Maryland, USA. Dr. Lantry is an editor of Concise Critical Appraisal.