Interest in the consequences of hyperchloremia and metabolic acidosis from supra-physiologic chloride concentrations in normal saline first stemmed from data in preclinical models, which demonstrated that chloride-induced renal inflammation adversely impacted renal function and mortality [1,2]. While in theory “balanced” solutions carry dual benefits of both an electrolyte composition that closely mirrors plasma and the presence of buffers which improve acid-base milieu, the exact repercussions on patient-centered outcomes with use of one over the other remain unknown.
An exploratory randomized control trial (RCT) evaluating biochemistry up to day 4 in normal saline vs Plasma-Lyte groups in 70 critically ill adults showed significantly higher hyperchloremia with normal saline but no difference in AKI rates between the two groups [3]. A pilot study evaluating “chloride-restrictive vs chloride liberal” strategies in 760 ICU patients involved use of Hartmann’s solution and Plasma-Lyte in place of saline for a 6-month period except in case of specific contraindications such as traumatic brain injury. Results indicated that incidence of AKI and use of RRT significantly reduced by limiting chloride. No changes in mortality, ICU length of stay or RRT on discharge were noted [4].A large retrospective study in over 53,000 ICU patients admitted with sepsis and on vasopressors across 360 US hospitals showed that balanced fluids were associated with lower in-hospital mortality especially when higher volume of IVFs were infused. While no differences were seen in terms of AKI rates, lower risk of CKD was noted in balanced fluid groups [5].
In post-surgical populations, an observational study analyzing saline vs balanced fluids over 30,000 patients showed significantly lower mortality, renal failure, acidosis investigation/intervention rates with balanced fluids [6].Additionally, a meta-analysis assessing outcomes in peri-operative and ICU patients based on whether they received high or low chloride containing fluids was performed on over 6000 patients across 21 studies. No association with mortality was found. However, statistically significant correlations were noted between high chloride fluids and hyperchloremia, metabolic acidosis, AKI, mechanical ventilation times and blood transfusion volumes [7].
In 2015, a large RCT involving ICUs in New Zealand evaluated balanced crystalloids vs normal saline and rates of AKI in a double-blind, cluster-randomized, double-crossover trial (the SPLIT study). 2278 patients from medical and surgical ICUs were enrolled. Patients already receiving RRT were excluded. No significant difference in incidence of AKI (defined as a two-fold rise or a 0.5mg/dL increase in creatinine), new RRT or mortality was detected between the two groups [8].
Given the ambiguity and lack of consensus on outcomes, the current SMART study addresses an important gap in knowledge. Its large sample size makes it well powered, geared to detect small signals in outcomes. Inclusion of medical, surgical, and neurologic ICUs helps diversify applicability. Being a pragmatic, intention-to-treat RCT, the study design mirrors real-world clinical practice.
In terms of patient acuity, less than a third of the patients were intubated or on vasopressors. Predicted mortality rates were 9%. In addition, median volume infused was around 1 L. Given the investigators’ conclusions that the MAKE30 outcome signals were more pronounced with larger volumes of infusions, this brings into question whether more dramatic signals could have been appreciated in each of the 3 components of the primary outcome had the study population been a higher acuity group requiring larger infusion volumes.
While the composite MAKE30 outcome reflects a sense of an overarching benefit with balanced crystalloids, there was no statistically significant improvement noted in each primary component. This questions the rationale for combining the components of the MAKE30 outcome as well as how generalizable the results are. Overall, as is the case with many studies that evaluate a composite outcome, this raises concern about overestimation of the intervention’s true impact.
The study was un-blinded, raising concern for bias, and it was a single-center trial, which raises questions regarding generalizability. Un-blinding may have played a role in influencing decisions to initiate RRT earlier in the saline group. The extent to which this impacted RRT rates (one of the MAKE30 outcomes), remains unclear. Furthermore, approximately 5% of the participants received unassigned fluids, and while this is in line with the pragmatic/intention-to-treat design, the clinical repercussions remain unclear. Hyperkalemia is an exclusion criterion for balanced fluids and it is unclear whether a proportion of patients presenting with AKI-associated hyperkalemia were restricted from receiving balanced fluids. In addition, very few patients received Plasma-Lyte, confining the study’s conclusions to lactated Ringer’s alone.
Despite these pitfalls, the study addresses an extremely relevant clinical question. It urges clinicians to tailor fluid choices on a case-by-case basis and pay attention to the long-term implications of daily biochemical changes on renal outcomes, particularly in large volume resuscitation scenarios. There is a negligible cost difference between lactated Ringer’s and saline, making use of a balanced fluid economically feasible. The number needed to treat for MAKE30 based on this study is 94 patients, and changes in clinical practice extrapolated to ICUs nationwide could have an impact on renal outcomes from an epidemiologic point of view without risking financial burden at an institution level.