The absence of robust data led to controversy over the use of crystalloid fluid compared to saline in critically ill patients. This choice is mainly driven by local practices rather than by evidence. There have been concerns that the administration of traditional chloride-liberal intravenous fluids may be associated with toxicity related to metabolic acidosis and may increase the risk of acute kidney injury in the intensive care unit (ICU). In a study published in JAMA, Dr. Yunos et al. assessed the association of a chloride-restrictive intravenous fluid strategy with AKI in critically ill patients compared to a chloride-liberal strategy in a before and after trial. The study suggested that a chloride-restrictive strategy is associated with a significant decrease in the incidence of acute kidney injury (AKI) and the use of renal replacement therapy (RRT) with no effect on hospital mortality, hospital or ICU length of stay, or need for RRT after hospital discharge [1].
The SPLIT Randomized Clinical Trial is a double-blind, cluster randomized, double-crossover trial that included 2,278 patients who were randomized to buffered crystalloid fluid or saline in 4 ICUs in New Zealand. The trial did not show any benefit of buffered crystalloid fluid over saline in relation to the risk of acute kidney injury or the need of RRT [2].
The SMART trial was a pragmatic, cluster-randomized, multiple-crossover trial conducted in five intensive care units at Vanderbilt University Medical Center. The trial randomized 15,802 patients to balanced-crystalloids or saline. The use of balanced-crystalloid resulted in a lower rate of the composite outcome of death from any cause, new renal-replacement therapy, or persistent renal dysfunction compared to the use of saline [3].
The BaSICS trial from Brazil randomized 10,520 patients in intensive care units with a balanced solution vs saline solution for fluid bolus and found no statistically significant difference in 90-day mortality of 26.4% vs 27.2%, respectively [4],
Each of the above studies had its own limitations and could not confirm the benefit of balanced fluid over saline. It is clear that we lacked robust data to base our decision on. This clinical uncertainty was addressed with the Plasma-Lyte 148 versus Saline (PLUS) Study that was done in Australia and New Zealand, published recently in the NEJM. The trial was a double-blind, randomized, controlled trial, that assigned a total of 5037 critically-ill patients to receive Plasma-Lyte 148 (balanced multielectrolyte solution: BMES) or saline as fluid therapy in the intensive care unit. The mortality rate was 21.8% in BMES group compared to 22.0% in the saline group with no statistical significance. New renal-replacement therapy was initiated in 12.7% in the BMES group compared to 12.9% in the saline group without statistical significance. Similarly, the mean maximum increase in serum creatinine level was not different between the two groups [5].
The question is, does the PLUS study provide enough assurance that there is really no benefit of balanced fluid over the saline fluid? I personally think the study was a well designed study and provided a higher level of evidence to answer the question. However, it allowed clinicians to exclude patients when they thought one of the solutions was better. This raises the question of what criteria those clinicians used to exclude patients and whether there is a subgroup of patients who might benefit from one solution versus the other.
A meta-analysis was published in "NEJM Evidence". The journal itself is part of the NEJM family that was launched January 2022 and requires a subscription of $199 per year. This updated meta-analysis included the PLUS study along with 5 other studies that contained low bias. The forest plot graph shows no difference in mortality rate; however, when they did the Bayesian analysis, it suggested a high probability that the use of balanced salt solutions reduces mortality among critically ill adults, with the possibility of important subgroup effects. As I mentioned, this interpretation was based on Bayesian analysis, but when the data was interpreted based on the frequentist approach, there was no difference in mortality. The difference between the Bayesian analysis and the frequentist approach adds more confusion to the practicing clinician [6].
At this time, I am still using more balanced fluid than normal saline for resuscitation of critically-ill patients (except in TBI and acute neurological injuries), especially when using large volume to avoid the complication of dilution metabolic acidosis associated with NS solution. However, there is no convincing evidence that it is associated with better outcome!
REFERENCES
1. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012 Oct 17;308(15):1566-72. doi: 10.1001/jama.2012.13356. PMID: 23073953.
2. Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C, McGuinness S, Mehrtens J, Myburgh J, Psirides A, Reddy S, Bellomo R; SPLIT Investigators; ANZICS CTG. Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial. JAMA. 2015 Oct 27;314(16):1701-10. doi: 10.1001/jama.2015.12334. Erratum in: JAMA. 2015 Dec 15;314(23):2570. PMID: 26444692.
3. Semler MW, Self WH, Wanderer JP, Ehrenfeld JM, Wang L, Byrne DW, Stollings JL, Kumar AB, Hughes CG, Hernandez A, Guillamondegui OD, May AK, Weavind L, Casey JD, Siew ED, Shaw AD, Bernard GR, Rice TW; SMART Investigators and the Pragmatic Critical Care Research Group. Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med. 2018 Mar 1;378(9):829-839. doi: 10.1056/NEJMoa1711584. Epub 2018 Feb 27. PMID: 29485925; PMCID: PMC5846085.
4. Zampieri FG, Machado FR, Biondi RS, et al. Effect of Intravenous Fluid Treatment With a Balanced Solution vs 0.9% Saline Solution on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial. JAMA. 2021;326(9):818–829. doi:10.1001/jama.2021.11684.
5. Finfer S, Micallef S, Hammond N, et al. Balanced Multielectrolyte Solution versus Saline in Critically Ill Adults. N Engl J Med. DOI: 10.1056/NEJMoa2114464
6. Hammond NE, Zampieri FG, Di Tanna GL, et al. Balanced crystalloids versus saline in critically ill adults — a systematic review with meta-analysis. NEJM Evid. DOI: 10.1056/EVIDoa2100010