Trial explored balanced solution vs. saline solution in critically-ill patients.
One of the most common treatments in critically ill patients is the administration of intravenous fluids. Historically, 0.9% saline has been one of the most common solutions used in resuscitation.
In 2015, we saw the publication of the SPLIT trial, which was a randomized clinical trial of over 2,200 patients in four ICUs in New Zealand comparing 0.9% saline (NS) vs. Plasma-Lyte.
The study found no difference in the proportion of patients with AKI, need for renal replacement therapy or in-hospital mortality. However, this trial had many issues including, >70% of patients coming from the OR, only 15% coming from the ED, and only 4% with sepsis. The biggest issue with this trial was that most patients only received 1 to 2L of fluids, making it unclear if larger volumes of unbalanced crystalloid would have worsened morbidity and mortality.
In 2018, we had the publication of the SALT-ED and SMART trials. These were both, very large, single center RCTs in the ED and ICU, respectively comparing saline against balanced crystalloids (Plasma-Lyte or Lactated Ringers Solution).
Both trials used a composite outcome of MAKE 30 (Major Adverse Kidney Events at 30 Days), which is a combined outcome of unequal events (i.e. Mortality ≠ Renal Replacement Therapy). The biggest benefit of balanced crystalloids in this trial was seen in the subset of patients with sepsis (Mortality 29.4% vs. 25.2%; NNT = 24).
No evidence to date has helped determine a difference between Lactated Ringers Solution vs. Plasma-Lyte, nor provide guidance on patients with traumatic brain injury. We now have two more large trials published to help give us more guidance.
The Balanced Solutions in Intensive Care Study (BaSICS) was a double-blind factorial, randomized trial conducted at 75 ICUs in Brazil. A factorial design allowed for the assessment of fluid type and two different infusion speeds during fluid challenges. In the first part of the BaSICS trial,  patients were randomized to Plasma-Lyte vs saline solution. The primary outcome of the first trial was 90-day mortality.
There were 10,520 patients available for analysis. Planned surgical admission was 48.4% of all patients. About 68% of all patients received a crystalloid fluid bolus before ICU admission (>45% received >1L). Patients in both groups received a median of 1.5L of fluid during the first day of enrollment. The accumulated median fluid administration (including study fluid and non-study fluid) during the first three days after enrollment was 4.1L.
There was no difference in 90-day mortality regardless of fluid type received (Balanced solution 26.4% vs. Saline solution 27.21%). None of the secondary or subgroup analyses demonstrated benefit with the use of balanced solutions. There was even a signal of possible harm for patients in the balanced solution group with a traumatic brain injury and 90-day mortality (Balanced Solution 31.3% vs. Saline Solution 21.1%; HR 1.48; 95% CI 1.03 to 2.12).
In the second part of the BaSICS trial, patients were randomized to slower rate (333mL/hr) compared to control group (999mL/hr). Again, the primary outcome was 90 day mortality. There were 10,520 patients analyzed. Unplanned admissions accounted for just over 50% of patients in both groups. On average the slower infusion group received a mean of 1162mLs on the first day compared to 1252mLs on the first day for the control group (Essentially equal volume of fluid between groups).
The 90-day mortality again showed no difference between groups (Slower rate 26.6% vs. Control group 27.0%; aHR 1.03; 95% CI 0.96 to 1.11). Although there were some differences at day three that favored the slower infusion group, none of these differences were sustained by day seven.
Two Special Cases: DKA and Sepsis?
Recently, the SCOPE-DKA  trial was just published, which was a randomized controlled trial comparing Plama-Lyte to Sodium Chloride in patients admitted to the ICU with severe DKA. This was a small trial of 90 patients and both groups received greater than 5 to 6 liters of fluid.
DKA resolution at 48 hours occurred in 96% of the Plasma-Lyte group compared to 86% in the Sodium Chloride group. Plasma-Lyte compared to Sodium Chloride led to faster resolution of metabolic acidosis without an increase in ketosis as well as a shorter median ICU length of stay (49hrs vs. 55hrs) and median hospital length of stay (81 hours vs. 98 hours).
In the SMART trial, a cluster-randomized trial in five ICUs with almost 16,000 patients, patients were randomized to Sodium Chloride compared to a Balanced Crystalloid (Lactated Ringers or Plasma-Lyte Solution).
In the subset of sepsis patients there was a statistically significant improvement in 30-day mortality (25.2% vs. 29.4%) with a number needed to treat of 24 as well as MAKE 30 (Composite of death from any cause, new renal replacement therapy, or persistent renal dysfunction) with balanced solutions (11.1% vs. 10.3%) with a number needed to treat of 20.
Among critically-ill patients requiring fluid challenges, neither the type of fluid (balanced solution (Plasma-Lyte 148) vs. 0.9% saline solution) nor the rate of fluid administration (333mL/hr vs. 999mL/hr) resulted in improved 90-day mortality.
These findings do not support the use of balanced solutions over 0.9% saline solution or the use of a slower infusion rate. The type and the rate of crystalloid infusion may not be as important as the amount of crystalloid given when given in smaller volumes (<2 – 3L). Although, still unclear, when larger volumes are given (i.e. >3L of fluid), consider sticking with balanced crystalloids
- Zamperi FG 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. [Epub Ahead of Print]
- Zampieri FG et al. Effect of Slower vs Faster Intravenous Fluid Bolus Rates on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial. JAMA 2021. [Epub Ahead of Print]
- Ramanan M et al. Sodium Chloride or Plasmalyte-148 Evaluation in Severe Diabetic Ketoacidosis (SCOPE-DKA): A Cluster Crossover, Randomized Controlled Trial. Intensive Care Med 2021. PMID: 34609547
- Semler MW et al. Balanced Crystalloids Versus Saline in Critically Ill Adults. NEJM 2018. PMID: 29485925