In the BICAR-ICU study Jaber et al. randomized critically ill patients with metabolic acidosis with pH less than 7.2 and bicarbonate less than 22 mmol/L to receive 4.2% bicarbonate, targeting a pH of 7.3. They compared outcomes with a control group that did not receive bicarbonate.
Three hundred and eighty-nine patients were enrolled, with 195 in the bicarbonate group and 194 in the control group. The primary outcome, a composite of death at 28 days and at least a single organ failure on day 7, was not significantly different. However, the composite outcome was significantly lower in a pre-specified subgroup of patients with an AKIN score of 2 or 3. Besides, the 28-day survival and the presence of at least a single organ dysfunction on day 7 (the individual components of the composite primary outcome) were also significantly lower in this subgroup. The requirement for renal replacement therapy (RRT), based on pre-specified criteria, was also significantly lower in patients who received bicarbonate therapy.
This is indeed an interesting addition to the scarce body of knowledge that addresses the benefit of bicarbonate therapy in metabolic acidosis due to causes other than loss of alkali from the body. Conventional wisdom advocates treatment of the underlying cause in lactic acidosis, in contrast to correction of pH to a pre-set level. The generally held view is that administration of bicarbonate could lead to a release of CO2 and worsening of intracellular acidosis. Does this study challenge tradition-borne practice and suggest a benefit from bicarbonate therapy to correct the pH in metabolic acidosis?
There are several obvious limitations to appropriate interpretation of this study, some of them pointed out by the authors themselves. Composite primary outcomes have often been problematic to interpret; this study is no exception. How does 28-day survival add up with the presence of a single organ failure of day 7? Among the eligible patients, 58% were excluded; a significant proportion (20%) because they had already received bicarbonate therapy. The overall mortality of the cohort was 49%, largely explained by the high baseline severity, with a SAPS of 60. Only 60% of patients who received bicarbonate attained the set pH target of 7.3 by 48 hours. If the intention of correction of acidosis was not achieved in the majority of patients what may be the putative mechanism by which bicarbonate exerts a beneficial effect? The other major limitation of this study is that 47/194 (24%) of patients in the control group were administered bicarbonate therapy, leading to a major problem with the interpretation of intention to treat analysis.
It is interesting to note that overall, the requirement for RRT (based on prespecified criteria) was lower in the bicarbonate-treated group. The requirement for RRT was also lower in the subgroup of patients with an AKIN score of 2-3. Do we conclude that the improved 28-day survival among bicarbonate-treated patients in this subgroup may have been due to adverse outcomes resulting from RRT in the control group? This seems unlikely. The study was unblinded, which could also have led to bias; no placebo was employed because administration of a significant volume of any type of placebo fluid may have led to electrolyte abnormalities. Another point that I would raise is the difference in the composite outcome that was assumed to calculate power. I cannot recall a major study in recent times that assumed such a big difference (15%) in the primary outcome. The larger the assumed outcome difference, the smaller the sample size and the higher the propensity for a type I error.
Overall, I feel it is an interesting study which suggests improved outcomes in critically ill patients with AKI and metabolic acidosis from bicarbonate therapy. I do feel that there may be several critical care physicians in India who follow a similar approach in the hope of delaying RRT or avoiding it altogether. Perhaps we should consider a controlled study that specifically addresses patients with severe AKI and metabolic acidosis to seek a possible outcome benefit. I feel, the primary outcome of such a study should be 90-day mortality, which seems to be a more appropriate benchmark in this stone age.