By Trushil Shah, MD, MSc
Assistant Professor of Medicine, University of Texas Southwestern Medical Center, Dallas
Dr. Shah reports he receives grant/research support from Actelion Pharmaceuticals, Liquidia Technologies, and Bayer Pharmaceuticals.
SYNOPSIS: Sodium bicarbonate therapy for severe metabolic acidemia did not affect a primary composite outcome of all-cause mortality at 28 days and at least one organ failure at day 7. However, in an a priori-defined stratum of patients with acute kidney injury, sodium bicarbonate therapy decreased 28-day mortality and the primary outcome.
SOURCE: Jaber S, Paugam C, Futier E, et al. Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): A multicentre, open-label, randomized controlled, phase 3 trial. Lancet 2018;392:31-40.
Sodium bicarbonate therapy for metabolic acidosis in the ICU setting remains controversial and understudied.1 As such, Jaber et al hoped to address this controversy. BICAR-ICU was a multicenter, open-label, randomized, controlled, Phase III trial that included an intention-to-treat analysis of sodium bicarbonate therapy for severe metabolic acidosis in patients across 26 ICUs in France. Adult patients admitted < 48 hours to the ICU with severe acidemia (pH ≤ 7.2, PaCO2 ≤ 45, and sodium bicarbonate ≤ 20 mmol/L) and with a Sequential Organ Failure Assessment (SOFA) score ≥ 4 or serum lactate ≥ 2 mmol/L were included. Notable exclusion criteria were: stage four chronic kidney disease, ketoacidosis, respiratory acidosis (PaCO2 ≥ 45), proven digestive or urinary tract loss of sodium bicarbonate, and sodium bicarbonate infusion (including renal replacement therapy [RRT]) within 24 hours of screening. Eligible patients were randomized to sodium bicarbonate infusion vs. usual care, stratified according to study site and three pre-specified factors: presence or absence of suspected sepsis, age with cutoff of 65 years, and presence or absence of Acute Kidney Injury Network (AKIN) score of 2 or 3.
In the intervention group, 4.2% sodium bicarbonate was infused, with an aim of achieving an arterial pH ≥ 7.30 during 28-day ICU admission or until ICU discharge. The volume of each sodium bicarbonate infusion was restricted to 125-250 mL in 30 minutes, with a maximum of 1,000 mL within 24 hours. Arterial blood gas was performed one to four hours after the end of the infusion. Indications for RRT were standardized in both groups and at 24 hours after inclusion. RRT was recommended when two of three criteria were met: hyperkalemia > 6.5 mmol/L, urine output < 0.3 mL/kg/hour for at least 24 hours, and arterial pH < 7.2 despite resuscitation. The primary outcome was a composite of death from any cause by day 28 and the presence of at least one organ failure by day 7. Most patients received invasive mechanical ventilation (84% of bicarbonate group vs. 82% of controls), vasopressor support (79% of bicarbonate group vs. 80% of controls), had severe acidosis (mean pH of 7.15 in both groups), and lactic acidosis (86% of bicarbonate group and 78% of controls had a serum lactate ≥ 2 mmol/L). In the overall population, there was no difference in the primary outcome between the bicarbonate intervention group vs. control (66% vs. 71%; P = 0.24). However, the need for renal replacement therapy was lower in the bicarbonate group vs. controls (35% vs. 52%; P = 0.0009). In patients with acute kidney injury (AKIN score, 2-3), both mortality and the composite endpoint were significantly lower in the bicarbonate group (46% vs. 63%; P = 0.0166; 70% vs. 82%; P = 0.0462, respectively). However, patients who received bicarbonate therapy experienced more hypocalcemia, hypernatremia, and metabolic alkalosis.
Metabolic acidosis is detrimental to the survival of ICU patients.2 While this is common knowledge, current data evaluating sodium bicarbonate therapy for metabolic acidosis in the ICU setting largely have been negative for any beneficial effect.3,4 Bicarbonate therapy is associated with hypocalcemia and intracellular accumulation of carbon dioxide, both of which cause decreased cardiac contractility and increased arrhythmogenicity.1,5 Currently, sodium bicarbonate therapy has been used as a last resort in severe metabolic acidosis without much data to support its use.
Despite efforts by Jaber et al to clarify this issue, the use of sodium bicarbonate in mixed and anion gap metabolic acidosis remains controversial. In BICAR-ICU, most patients had lactic acidosis; hence, it is not surprising that bicarbonate therapy did not affect mortality or the primary composite outcome between groups. However, bicarbonate therapy decreased the need for renal replacement therapy compared to controls. In patients with acute kidney injury, bicarbonate therapy decreased mortality and the composite outcome in patients with severe metabolic acidosis, possibly by decreasing need for vasopressor and renal replacement therapies. Based on this trial, sodium bicarbonate therapy could be considered in patients with acute kidney injury and severe metabolic acidosis. Overall, the utility of sodium bicarbonate therapy for lactic acidosis in the absence of acute kidney injury remains unanswered. Efforts should focus on reversing the primary cause of lactic acidosis in these patients.
- Kraut JA, Madias NE. Lactic acidosis. N Engl J Med 2014;371:2309-2319.
- Jung B, Rimmele T, Le Goff C, et al. Severe metabolic or mixed acidemia on intensive care unit admission: Incidence, prognosis and administration of buffer therapy. A prospective, multiple-center study. Crit Care 2011;15:R238.
- Kim HJ, Son YK, An WS. Effect of sodium bicarbonate administration on mortality in patients with lactic acidosis: A retrospective analysis. PLoS One 2013;8:e65283.
- El-Solh AA, Abou Jaoude P, Porhomayon J. Bicarbonate therapy in the treatment of septic shock: A second look. Intern Emerg Med 2010;5:341-347.
- Cooper DJ, Walley KR, Wiggs BR, Russell JA. Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis. A prospective, controlled clinical study. Ann Intern Med 1990;112:492-498.