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NEWS: Not so normal but still ok: Normal Saline vs balanced crystalloid fluid in critically ill patients

By Currents Editor posted 12-20-2021 09:24


Zampieri FG, Machado FR, 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 Aug 10. doi: 10.1001/jama.2021.11684 

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Background: Intravenous fluids are a mainstay of therapy for critically ill patients and much debate has existed over the optimum fluid. 0.9% NaCl was identified by a Dutch chemist in the 1890s who found that it did not cause red cell lysis in vitro and had the same freezing point as human serum; he thus referred to it as an “indifferent fluid”1. Over time it became known as “normal saline” despite having 10% higher sodium and 50% higher chloride concentrations than normal physiological levels.  The disparity between physiological states and saline osmolality has raised concerns about its use in resuscitation.  Two large single-center trials in the US found that utilizing balanced crystalloids in critically ill patients led to better outcomes2,3, however review of the literature is inconclusive4. This trial aims to better understand if a balanced solution vs. saline (0.9% NaCl) could improve mortality by utilizing a double-blind, factorial randomized clinical trial design. 

Methods: This study included patients from over 75 ICUs in Brazil.  Patients admitted to the ICU were included if they needed at least 1 fluid expansion, were not expected to be discharged within a day and had at least 1 of the following criteria for acute kidney injury: (1) >65 years old, (2) hypotension (MAP<65mmHg or SBP <90mm Hg or vasopressor use), (3) sepsis, (4) invasive or non-invasive mechanical ventilation, (5) AKI defined as oliguria or elevated creatinine or (6) acute liver failure or cirrhosis.  Patients were randomized to receive saline or balanced IV solution (Plasma-Lyte-148) in a 2x2 design with two different rates of bolus including 333ml/h and 999ml/h in each group.  Patients, physicians and individuals assessing outcomes were blinded to assigned treatment.  Primary outcome was 90-day survival and secondary outcomes included need for renal replacement, occurrence of AKI using KDIGO stage 2 or 3, SOFA score and number of days free from ventilator 28 days after enrollment. Tertiary outcomes were hospital length of stay, ICU and hospital mortality. Power analysis was done prior to enrollment. 

Results: 11,052 patients were randomized and 10,520 included: 5230 in the balanced solution group and 5290 in the saline group. The mean age was 61.1 years [SD 17] and 44.2% of participants were female. Study groups were similar in admission diagnoses, APACHE II scores, KDIGO stages, and comorbidities. About half of patients were admitted to the ICU (48.4%). Hypotension or vasopressor use existed in 60.6% of patients and 44.3% were intubated at enrollment. Sixty-eight percent received a crystalloid fluid bolus prior to enrollment with 45% receiving >1 L of fluid. Patients in both groups received a median of 1.5L of fluid during the first 24 hours post-enrollment and a median of 4 L during the first 3 study days [SD 2.9L]. Volumes administered were similar between groups. 90-day mortality rate was 26.4% in the balanced solution group vs 27.2% in the saline group (p=0.47). Nineteen secondary outcomes were evaluated and 2 were found to be statistically significant favoring balanced solution (cardiovascular SOFA score >2 at day 3 and neurological SOFA score>2 at day 7) but authors did not adjust for multiple comparisons. Prespecified subgroup analyses were done and there was a statistically significant interaction between presence of TBI, fluid type and 90-day mortality with a higher mortality in the balanced solution group (31.3% vs. 21.1%, p=0.02).  Serum chloride levels were higher in the saline group compared to the balanced group (p<0.001). 

Commentary: In this well-designed, randomized-control trial of saline vs balanced solution resuscitation, there was no significant difference in 90-day mortality between critically ill patients given saline and those given balanced fluids. This study was well designed and notable as patients received around 4 liters of fluid over 3 days, which suggests if a true deleterious effect existed, ample volume was administered to unmask this effect. It is worth noting that one prior positive trial referenced above had lower volumes administered. Additionally, most patients received fluid boluses pre-enrollment, which could confound the relationship between fluid type and outcome. To address this, the study authors did a subgroup analysis looking at patients who were given <1.0 or ³1.0 liters of saline prior to randomization and found no difference (p=0.12). 

This study does have some limitations.  The study included 10,520 patients in their final analysis, but their power analysis determined a target of 11,000.  Trial design utilized Plasma-lyte-148 not lactated ringers; the acetate in Plasma-lyte-148 might have differential effects but there is not a strong reason to think lactated ringers would be better.  Prespecified subgroup analyses were done by KDIGO stage, APACHE II score, and amount of saline administered before enrollment as well as for surgical and TBI patients. There are numerous other patient subgroups that one could hypothesize might benefit from a more balanced solution, but the study authors only analyzed data based on their pre-specified analyses.  TBI patients likely do better with a higher osmolality solution, although this subgroup analysis is limited by small sample size (78 in balanced solution group and 50 in saline group). 

Overall, I think this study lends strong evidence that saline and balanced fluid resuscitation are relatively equivocal for mortality, however it does not have the granularity to determine optimum fluid type for every patient subgroup.


Sara Stern-Nezer, MD, MPH
Assistant HS Professor,
Department of Neurology and Neurological Surgery,
University of California, Irvine



  1. Li H, Sun SR, Yap JQ, Chen JH, Qian Q. 0.9% saline is neither normal nor physiological. J Zhejiang Univ Sci B 2016;17(3):181-7. DOI: 10.1631/jzus.B1500201.
  2. Self WH, Semler MW, Wanderer JP, et al. Balanced Crystalloids versus Saline in Noncritically Ill Adults. N Engl J Med 2018;378(9):819-828. DOI: 10.1056/NEJMoa1711586.
  3. Semler MW, Self WH, Wanderer JP, et al. Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med 2018;378(9):829-839. DOI: 10.1056/NEJMoa1711584.
  4. Antequera Martin AM, Barea Mendoza JA, Muriel A, et al. Buffered solutions versus 0.9% saline for resuscitation in critically ill adults and children. Cochrane Database Syst Rev 2019;7:CD012247. DOI: 10.1002/14651858.CD012247.pub2.

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