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Myths in Emergency Medicine

Myths in Emergency Medicine

The Real Value of a Sodium Bicarbonate Infusion

Spiegel, Rory MD

doi: 10.1097/01.EEM.0000578588.78228.ce
    sodium bicarbonate, cardiovascular dysfunction, refractory hypotension, multiorgan failure, and death
    sodium bicarbonate, cardiovascular dysfunction, refractory hypotension, multiorgan failure, and death:
    sodium bicarbonate, cardiovascular dysfunction, refractory hypotension, multiorgan failure, and death

    The overwhelming need for euboxia has inspired a multitude of therapeutic endeavors, including the focus on pH and resuscitative efforts to normalize this number. The physiologic plausibility often cited to support these interventions is that protein function suffers in a severely acidotic milieu, leading to cardiovascular dysfunction, refractory hypotension, multiorgan failure, and death.

    But little science supports these dictums, and the body of evidence suggests that the exact level of acidemia matters far less than the physiologic process driving the accumulation of the acid in the first place. The BICAR-ICU trial by Jaber, et al., represents the first large high-quality attempt to quantify the benefit of alkalinization therapy in a cohort of critically ill ICU patients with metabolic acidosis. (Lancet. 2018;392[10141]:31;

    The authors conducted a large multicenter, randomized, open-label, controlled trial in 26 ICUs in France. They enrolled adults 18 or older within 48 hours of admission with severe acidosis (defined as pH ≤7.20, PaCO2 ≤45 mm Hg, and sodium bicarbonate concentration ≤20 mmol/L), and either a SOFA score greater than 4 or a serum lactate greater than 2 mmol/L.

    Burden of Evidence

    Patients were excluded if they had respiratory acidosis, proven digestive or urinary tract loss of sodium bicarbonate, stage IV chronic kidney disease, ketoacidosis, or sodium bicarbonate infusion within 24 hours before screening. Patients randomized to receive sodium bicarbonate received a 4.2% sodium bicarbonate infusion with the aim of achieving an arterial pH of 7.30 or higher during the 28-day ICU admission or until ICU discharge.

    The authors enrolled 400 patients (201 in the control arm, 199 in the bicarbonate arm) over two years. No difference was seen in primary outcome, composite of death from any cause by 28 days after randomization, or the presence of at least one organ failure at seven days after randomization (71% in the control group vs 66% in the bicarbonate group, ARR 5.5%, 95% CI 15.2%-4.2%; p=0.24). Nor did the authors demonstrate a statistically significant difference in 28-day mortality: 46 percent in the control group v. 55 percent in the bicarbonate group (p-value=0.07).

    The authors reported fairly notable secondary outcomes in favor of the bicarbonate group. The primary outcome occurred significantly more frequently in the control group (82% v. 70%) in their a priori subgroup analysis of patients with acute kidney injury. In fact, the patients in the bicarbonate group did noticeably better when compared with the control group in almost every metric examined. While not statistically significant, the authors found a 5.5 percent absolute decrease in their primary outcome, a nine percent decrease in 28-day mortality, a 16.7 percent decrease in the need for renal replacement therapy, and a 12.5 percent decrease in the need for dialysis at ICU discharge.

    Given these results, one could argue that patients randomized to receive the bicarbonate infusion clearly demonstrated improved outcomes, but the trial was underpowered to detect a clinically important difference. We are unable to differentiate a 5.5 percent decrease in the rate of death or severe organ failure from statistical chance. How do we interpret a statistically negative study with strikingly positive results? Where does the burden of evidence fall?

    Random Error

    Adequately assessing the efficacy of bicarbonate therapy requires us to grasp the potential for random sampling error in the current trial and to know the prior evidence of benefit. This includes a plausible biological explanation and previous clinical data demonstrating efficacy. It is thought in this case that acidosis is associated with a significant amount of morbidity and mortality.

    Bicarbonate can potentially correct the serum pH. Correcting the acidosis may limit the unwanted associated outcomes, but the acidosis may just be a symptom of an underlying pathologic process. Fixing the acidosis without correcting the underlying cause may make the laboratory values appear better, but it will not affect patient-oriented outcomes.

    The clinical data examining the use of sodium bicarbonate as a therapeutic buffer was at best sparse before the BICAR-ICU trial was published. A number of small prospective controlled trials found bicarbonate administration had no effect on patient hemodynamics (increased cardiac output or decreased need for vasopressor agents). (Ann Intern Med. 1990;112[7]:492; Crit Care Med. 1991;19[11]:1352.) The BICAR-ICU trial revealed similar results, finding no difference in vasopressor-free days (9 v. 19), vasopressor-free days in survivors (26 in each group), nor a difference in duration of vasopressor therapy (mean of 2 in each group).

    We also have a significant body of evidence suggesting that acidosis in and of itself causes minimal physiologic unrest. (Intern Emerg Med. 2010;5[4]:341; PLoS One. 2013;8[6]:e65283;; Crit Care. 2015;19:175; Frumin demonstrated that patients tolerated acidosis from hypercapnea to extremely low levels (pH as low as 6.8) without any signs of physiologic distress or hemodynamic compromise. (Anesthesiology. 1959;20:789; Olympic rowers have serum pH levels as low as 6.8 without any ill effects shortly after a race. (Acta Physiol Scand. 1999;165[1]:113.)

    We have all seen DKA patients with impressively severe acidosis, often with minimal hemodynamic compromise, yet the septic patient with a lactic acidosis and a pH of 7.1 is often in refractory shock and dying. A recent article by Masevicius, et al., supports this shared anecdotal experience. The authors enrolled 4901 ICU patients in a prospective observational cohort; 1609 met the criteria for a metabolic acidosis. (Crit Care Med. 2017;45[12]:e1233.) The authors reported that an acidosis due to lactate or unmeasured anions had a much higher mortality than a SID acidosis for any given pH, which demonstrated mortality rates similar to those of patients without acidosis.

    Emergency medicine would rejoice if the BICAR-ICU results represented a true therapeutic effect from the use of bicarbonate. No one would argue against a simple low-cost intervention that reduces mortality and the need for dialysis. But a single study, especially one with a negative primary endpoint, is incapable of providing definitive evidence representing the underlying truth. Until these data are replicated, clinicians should focus on treating the underlying cause of the acid-base aberration rather than simply trying to normalize laboratory values.

    Dr. Spiegelis a clinical instructor in emergency medicine and a critical care fellow in the division of pulmonary and critical care medicine at the University of Maryland Medical Center. Visit his blog at, follow him on Twitter@emnerd_, and read his past articles at

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