Highlight
1. This large, pragmatic randomized trial compared the effects of two commonly used balanced crystalloid solutions, Normosol-R and lactated Ringers, on critically ill adults in the ICU.
2. There was no significant difference in plasma bicarbonate levels over 7 days, indicating similar effects on acid-base status.
3. Secondary outcomes including new kidney replacement therapy and 30-day mortality were also comparable between groups.
4. These findings suggest both fluids offer equivalent safety and efficacy for intravenous fluid therapy in this population.
Study Background and Disease Burden
Intravenous fluid therapy is a cornerstone intervention in the management of critically ill patients, often involving large-volume resuscitation. Historically, saline (0.9% sodium chloride) was the fluid of choice, but balanced crystalloids have emerged as preferred alternatives due to better physiologic composition that may reduce complications such as hyperchloremic metabolic acidosis and acute kidney injury (AKI).
Balanced crystalloid solutions like lactated Ringers and Normosol-R provide electrolyte profiles closer to plasma and include buffers designed to mitigate acid-base disturbances. However, subtle differences in their electrolyte and buffer composition have raised the question of whether one solution might confer superior clinical outcomes over the other. Given the high morbidity and mortality risks associated with fluid choice in the critically ill, elucidating such differences is of significant clinical importance.
Study Design
This pragmatic, cluster-randomized, multiple-crossover trial was conducted at an academic medical center in the United States. The study enrolled 2,084 critically ill adults between June 1, 2018, and January 31, 2019. Patients received either Normosol-R or lactated Ringers for intravenous fluid therapy based on the cluster assignment of their intensive care unit (ICU) at each time period.
Key inclusion criteria included adult patients requiring fluid resuscitation in the ICU setting. The primary outcome was the change in plasma bicarbonate (HCO3-) concentration from enrollment to 7 days, chosen as a marker of acid-base status. Secondary outcomes included the initiation of kidney replacement therapy (KRT) during hospitalization and all-cause mortality by day 30.
Key Findings
The study cohort had a median age of 59 years, with 48.3% females, and median Sequential Organ Failure Assessment (SOFA) score of 5, reflecting notable illness severity.
Regarding the primary outcome, there was no significant difference in plasma bicarbonate levels over 7 days between Normosol-R and lactated Ringers groups (mean difference -0.12 mmol/dL; 95% CI -0.61 to 0.36; P = .61). This suggests that both fluids maintain acid-base balance similarly in critically ill patients.
Secondary outcomes also showed equivalence. Kidney replacement therapy was required in 6.0% of patients receiving Normosol-R compared with 5.0% in the lactated Ringers group (absolute risk difference 1.0%; 95% CI -1.2% to 3.1%), indicating no statistically significant difference. Thirty-day mortality was nearly identical between groups: 16.3% vs 16.0% (absolute risk difference 0.3%; 95% CI -2.9% to 3.6%).
The safety profiles were consistent, with no fluid-specific adverse events or complications reported in excess in either arm.
Expert Commentary
This well-powered trial adds rigorous evidence that the choice between Normosol-R and lactated Ringers does not affect key clinical outcomes in critically ill adults. Previous concerns regarding differences in electrolyte composition, such as the presence of calcium in lactated Ringers or acetate in Normosol-R, do not translate into meaningful clinical effects on acid-base homeostasis, renal function, or survival.
The cluster crossover design strengthened internal validity and minimized confounding from patient-level variables. Despite the study being conducted at a single academic center, the pragmatic nature and real-world ICU setting support its generalizability.
Limitations include the possibility that rarer or longer-term effects were not captured and that some subpopulations might still benefit from tailored fluid selection. Further research could explore outcomes in specific conditions like traumatic brain injury or severe metabolic derangements.
Conclusion
In critically ill adults requiring intravenous fluid therapy, Normosol-R and lactated Ringers are clinically equivalent regarding acid-base effects, kidney replacement therapy need, and short-term mortality. Clinicians may choose either balanced crystalloid without concern for compromising these important outcomes. This trial supports current guidelines favoring balanced crystalloids but suggests no compelling evidence to prefer one balanced solution over another based solely on these outcomes.
References
Qian ET, Brown RM, Jackson KE, Wang L, Stollings JL, Freundlich RE, Wanderer JP, Siew ED, Bernard GR, Self WH, Casey JD, Rice TW, Semler MW; Pragmatic Critical Care Research Group. Normosol-R vs Lactated Ringers in the Critically Ill: A Randomized Trial. Chest. 2025 Aug;168(2):336-345. doi: 10.1016/j.chest.2025.02.008. Epub 2025 Feb 17. PMID: 39971001.