Clinical Question: During my internal medicine rotation at NYPQ, I cared for several adult patients admitted with sepsis, many of whom required large-volume fluid resuscitation. I noticed variability in the choice of intravenous fluids. Some patients received normal saline while others received balanced crystalloids, and we wondered whether this difference could impact outcomes such as kidney injury or survival. This observation led me to explore the question: In hospitalized adult patients with sepsis, does the use of balanced crystalloids, compared with normal saline, reduce mortality, the incidence of acute kidney injury, and the need for renal replacement therapy?

PICO Question:  In hospitalized adult patients with sepsis, does the use of balanced crystalloids compared to normal saline improve mortality, incidence of acute kidney injury (AKI), and the need for renal replacement therapy

Question Type: What kind of question is this?

X treatment , X Prognosis , X harm 

Population	Intervention	Comparison	Outcome
Hospitalized adult patients with sepsis	Lactated Ringer’s	0.9% sodium chloride (normal saline)	Mortality
	Plasma-Lyte		Incidence of acute kidney injury
	Crystalloid		Renal replacement therapy

Search strategy 

A structured literature search was conducted to identify high-quality evidence on the use of balanced crystalloids versus normal saline in adult patients with sepsis, with outcomes focused on mortality, acute kidney injury (AKI), and the need for renal replacement therapy (RRT). The search aimed to identify the highest level of evidence available, prioritizing randomized controlled trials, systematic reviews, and meta-analyses. The primary database used was PubMed, chosen for its extensive biomedical coverage. An initial search using the terms “balanced crystalloids,” “normal saline,” and “sepsis outcomes” yielded over 1,000 results. After applying filters for humans, English language, adult populations, randomized controlled trials, and systematic reviews published within the last 10 years, approximately 50–60 relevant studies remained. Additional targeted searches using combinations of “sepsis,” “fluid resuscitation,” “AKI,” and “mortality” were also performed to ensure key landmark trials were identified. The Cochrane Library was searched for high-quality systematic reviews and meta-analyses. Although relevant reviews were identified, many were not specific to sepsis populations or did not directly compare balanced crystalloids with normal saline and were therefore excluded from the final selection. The CINAHL database was also used to capture additional nursing and allied health literature. This search produced several relevant articles; however, most focused on general fluid management in critically ill patients rather than direct comparisons in septic populations, and therefore did not meet the inclusion criteria for the final analysis. Ultimately, four studies were selected: two randomized controlled trials, one secondary analysis of a large multicenter trial, and one systematic review/meta-analysis. These studies were chosen because they represent the highest available level of evidence and directly address clinically meaningful outcomes in sepsis. Together, they provide a strong evidence base for evaluating fluid choice in sepsis management.

Databases searched:

• PubMed (primary database)
• Cochrane Library
• CINAHL (supplementary nursing and allied health literature)

PubMed search strategy:

• “balanced crystalloids AND normal saline AND sepsis” → ~1,200 results
  Filters applied: humans, English, adult, RCTs, systematic reviews → ~60 results
• “sepsis fluid resuscitation AKI mortality crystalloids” → ~450 results
  Filters applied: RCTs and systematic reviews → ~35 results

Cochrane Library:

• ~300 results initially
• After filtering for relevance and full-text availability → ~20 relevant reviews

CINAHL:

• Large initial yield (~18,000 results)
• After filtering (2015–2024, adult, clinical studies) → ~9,000 results
• Most studies were excluded due to a lack of direct comparison in septic populations

Author (Date)	Level of Evidence	Sample/Setting(# of subjects/ studies, cohort definition etc)	Outcome(s) studied	Key Findings	Limitations and Biases
Brown RM, et al. (2022)	Systematic Review and Meta-analysis of Randomized Controlled Trials	Total sample size: >20,000 critically ill adult patients Studies conducted across ICU and emergency department settings internationally Population included: Patients with sepsis and septic shock Other critically ill adults requiring fluid resuscitation Compared: Balanced crystalloids (e.g., lactated Ringer’s, Plasma-Lyte) 0.9% normal saline	All-cause mortality Acute kidney injury (AKI) Need for renal replacement therapy (RRT) Major Adverse Kidney Events (MAKE-30)	Mortality: Balanced crystalloids were associated with reduced mortality in some pooled analyses; however, this finding was not consistently statistically significant across all included trials. The benefit appeared more pronounced in high-risk populations such as patients with sepsis. Renal outcomes (AKI and RRT): Use of balanced crystalloids was consistently associated with lower rates of acute kidney injury and reduced need for renal replacement therapy, supporting a renal-protective effect compared to normal saline. Consistency across studies: Renal outcomes demonstrated the most consistent direction of effect across included trials, strengthening confidence in the renal-protective benefit of balanced crystalloids in critically ill populations. Clinical interpretation: Overall, the evidence suggests that balanced crystalloids are at least as effective as normal saline and appear to be associated with improved renal outcomes, with a possible mortality benefit in sepsis populations.	Heterogeneity of included studies: Variability in patient populations (sepsis vs general ICU), illness severity, and fluid volumes may limit direct comparability and introduce clinical heterogeneity. Variation in study design and protocols: Differences in timing, type, and volume of fluids administered across trials may influence outcomes and reduce uniformity of results. Mortality findings not uniformly significant: While trends favor balanced crystalloids, not all studies demonstrated statistically significant mortality benefit, limiting definitive conclusions. Inclusion of non-sepsis populations: Some included trials involved broader, critically ill populations, which may dilute the applicability of the findings to sepsis patients. Potential publication bias: As with all meta-analyses, there is a risk that studies with positive findings are more likely to be published and included. Short-term outcome focus: Most studies evaluated outcomes such as 30-day mortality and AKI, with limited data on long-term renal function or survival.
Semler MW, et al. (2019)	Randomized Controlled Trial	Cluster-randomized, multiple-crossover trial in 5 ICUs at a single academic center Total 15,802 critically ill adults Assigned to balanced crystalloids or 0.9% saline Median age: 58 years, 57% male Included patients with sepsis (14–15%), mechanical ventilation, or vasopressors	Major Adverse Kidney Events at 30 days (MAKE-30): death, new RRT, persistent renal dysfunction In-hospital mortality Acute kidney injury (AKI)	Major Adverse Kidney Events at 30 days (MAKE-30): Patients receiving balanced crystalloids had a slightly lower MAKE-30 incidence (14.3%) than those receiving saline (15.4%). This composite outcome includes death, new renal replacement therapy (RRT), and persistent renal dysfunction, suggesting that balanced crystalloids may modestly protect kidney function. In-hospital mortality: Mortality was slightly lower in the balanced crystalloids group (10.3%) than in the saline group (11.1%), indicating a trend toward improved survival, though the difference is small. Acute kidney injury (AKI): The incidence of AKI was reduced in the balanced crystalloids group. Patients were less likely to experience progression to severe AKI, particularly those with sepsis or requiring vasopressors, highlighting a potential renal-protective effect. Subgroup consistency: These benefits were observed across key subgroups, including patients with sepsis, trauma, and those requiring intensive care support, suggesting the findings are robust within critically ill populations.	Single-center setting – The study was conducted at one U.S. hospital. Results may not fully generalize to other institutions, especially where ICU protocols, fluid administration practices, or patient demographics differ. Open-label design – Clinicians knew which fluids were given, which could have influenced decisions such as initiating renal replacement therapy or administering additional fluids, introducing potential performance bias. Composite endpoint (MAKE-30): Combining death, initiation of renal replacement therapy, and persistent kidney dysfunction may obscure which specific outcome drives the observed benefit, thereby reducing precision for individual clinical decisions. Short-term follow-up: Outcomes were measured at 30 days, leaving long-term kidney recovery and post-discharge complications unexamined, both of which are important for patient counseling and planning. Residual confounding: Even with randomization, unmeasured factors such as infection severity, nephrotoxic medications, or timing of interventions may have influenced kidney outcomes.
Gelbenegger et al., 2025	Randomized clinical trial / prospective comparative study design	Adult patients with sepsis-induced hypotension were enrolled in the CLOVERS multicenter randomized clinical trial across 60 U.S. hospitals (ICU and ED settings). • Total CLOVERS cohort: 1,563 patients • Included patients with suspected or confirmed infection requiring early vasopressor/fluid resuscitation • Compared fluid strategy effects, then specifically analyzed Lactated Ringer’s (LR) vs Normal Saline (NS) exposure within the early resuscitation phase	90-day all-cause mortality  hospital-free days,ventilator-free days, vasopressor-free days  Mortality differences associated with LR vs NS exposure  Organ support–free days (ICU resource utilization outcomes) Clinical recovery trajectories in septic hypotension	• Lactated Ringer’s (balanced crystalloid) use during early resuscitation was associated with improved survival outcomes compared with normal saline exposure in septic hypotension patients. • Patients receiving LR demonstrated: Lower adjusted mortality risk, Increased hospital-free days (faster recovery trajectory), Reduced need for prolonged organ support in some analyses • Findings reinforce physiologic rationale that balanced crystalloids reduce chloride load and acid–base disturbances, which may improve hemodynamic stability in sepsis. • Overall interpretation: Within a large RCT-derived cohort, LR appears more beneficial than NS during early sepsis resuscitation, supporting a shift toward balanced fluids in initial management strategies.	Secondary analysis: Not the primary randomized comparison, limiting the ability to definitively establish causation between fluid type and outcomes. • Exposure misclassification risk: Fluid type (LR vs NS) was not randomized in this analysis, meaning assignment depended on clinician choice → introduces confounding by indication. • Residual confounding: Severity of illness, timing of antibiotics, and total fluid volume may have influenced outcomes independent of fluid type. • Heterogeneity in care: Multicenter ICU/ED design improves generalizability but introduces variability in resuscitation protocols. • Overlap with CLOVERS intervention: Primary trial compared fluid strategy (liberal vs restrictive), not fluid composition, so LR vs NS comparison is observational within an RCT framework. • Outcome complexity: Mortality and hospital-free days may be influenced by non-physiologic factors (discharge practices, ICU bed availability).
Self WH, et al. (2018)	Randomized Controlled Trial	Single-center study conducted in the emergency department of an academic medical center Total 13,347 noncritically ill adult patients receiving IV fluids Patients were assigned to: Balanced crystalloids (lactated Ringer’s or Plasma-Lyte A) 0.9% normal saline Median fluid volume: approx 1 L Patients were admitted to the hospital outside the ICU Broad population, including general medical patients (not limited to sepsis, but clinically relevant to the early resuscitation phase)	Hospital-free days  Major Adverse Kidney Events at 30 days (MAKE-30): New renal replacement therapy (RRT) Persistent renal dysfunction Acute kidney injury (AKI)	Hospital-free days: There was no significant difference between groups, indicating that the choice of fluid (balanced crystalloids vs normal saline) did not meaningfully impact overall length of hospitalization or recovery time in noncritically ill patients. Major Adverse Kidney Events (MAKE-30): Balanced crystalloids were associated with a lower incidence of MAKE-30 (4.7% vs 5.6%). This suggests a modest but clinically meaningful reduction in the composite outcome of death, need for renal replacement therapy (RRT), or persistent renal dysfunction. The findings support improved renal outcomes with balanced fluids. Acute Kidney Injury (AKI): Patients receiving balanced crystalloids had fewer kidney-related complications, including a lower risk of developing AKI. This reinforces the hypothesis that high chloride content in normal saline may contribute to renal vasoconstriction and kidney injury. Clinical interpretation: Although no difference was seen in hospital length of stay, the reduction in kidney-related adverse events suggests that balanced crystalloids may be the safer option for fluid resuscitation, particularly in patients at risk for renal dysfunction or in early sepsis management.	Single-center design: The study was conducted at a single academic institution, which may limit its generalizability to other hospitals with different patient populations, provider practices, or resource availability. Non-critically ill population: The study focused on patients treated outside the ICU, limiting applicability to critically ill patients, including those with severe sepsis or septic shock who often require larger fluid volumes. Pragmatic multiple-crossover design: Fluid assignment was based on time periods rather than individual randomization, introducing potential temporal confounding (e.g., seasonal variation in illness severity or differences in clinical staffing). Open-label design: Clinicians were aware of the fluid being administered, which could have influenced treatment decisions such as fluid volume, initiation of RRT, or escalation of care, introducing performance bias. Small absolute risk reduction: While statistically significant, the difference in MAKE-30 outcomes was relatively small, which may limit the clinical significance for individual patients despite population-level benefit. Short follow-up duration: Outcomes were assessed at 30 days, so long-term renal function, chronic kidney disease progression, and mortality beyond this period were not evaluated.

1. Semler, M. W., Self, W. H., Wanderer, J. P., Ehrenfeld, J. M., Wang, L., Byrne, D. W., … & Rice, T. W. (2018). Balanced crystalloids versus saline in critically ill adults. New England Journal of Medicine, 378(9), 829–839. https://pubmed.ncbi.nlm.nih.gov/29485925/ 

Abstract

Background: Both balanced crystalloids and saline are used for intravenous fluid administration in critically ill adults, but it is not known which results in better clinical outcomes.

Methods: In a pragmatic, cluster-randomized, multiple-crossover trial conducted in five intensive care units at an academic center, we assigned 15,802 adults to receive saline (0.9% sodium chloride) or balanced crystalloids (lactated Ringer’s solution or Plasma-Lyte A) according to the randomization of the unit to which they were admitted. The primary outcome was a major adverse kidney event within 30 days – a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction (defined as an elevation of the creatinine level to ≥200% of baseline) – all censored at hospital discharge or 30 days, whichever occurred first.

Results: Among the 7942 patients in the balanced-crystalloids group, 1139 (14.3%) had a major adverse kidney event, as compared with 1211 of 7860 patients (15.4%) in the saline group (marginal odds ratio, 0.91; 95% confidence interval [CI], 0.84 to 0.99; conditional odds ratio, 0.90; 95% CI, 0.82 to 0.99; P=0.04). In-hospital mortality at 30 days was 10.3% in the balanced-crystalloids group and 11.1% in the saline group (P=0.06). The incidence of new renal-replacement therapy was 2.5% and 2.9%, respectively (P=0.08), and the incidence of persistent renal dysfunction was 6.4% and 6.6%, respectively (P=0.60).

Conclusions: Among critically ill adults, the use of balanced crystalloids for intravenous fluid administration resulted in a lower rate of the composite outcome of death from any cause, new renal-replacement therapy, or persistent renal dysfunction than the use of saline. (Funded by the Vanderbilt Institute for Clinical and Translational Research and others; SMART-MED and SMART-SURG ClinicalTrials.gov numbers, NCT02444988 and NCT02547779 .)

Why I selected this article 

I chose this article because it directly addresses my PICO question by comparing balanced crystalloids (lactated Ringer’s solution or Plasma-Lyte A) with 0.9% normal saline in a large population of critically ill adults, many of whom had sepsis or sepsis-like physiology requiring intensive care and fluid resuscitation. The study is a pragmatic, cluster-randomized, multiple-crossover trial conducted across five ICUs with 15,802 participants, providing high-quality evidence applicable to real-world clinical practice. It evaluates the same key outcomes in my question about mortality, acute kidney injury, and the need for renal replacement therapy using a clinically meaningful composite endpoint (MAKE-30) that includes death, new RRT, and persistent renal dysfunction. The results demonstrated that balanced crystalloids were associated with a lower rate of major adverse kidney events than normal saline (14.3% vs 15.4%), and with a trend toward lower in-hospital mortality (10.3% vs 11.1%), suggesting potential survival and renal-protection benefits. This directly supports the clinical question by showing that fluid choice can meaningfully impact kidney outcomes in critically ill patients, which is especially relevant in sepsis management, where AKI is a major complication. I selected this study because it provides strong randomized evidence from a large ICU population, uses outcomes that align with my PICO question, and helps guide evidence-based decisions regarding balanced crystalloids versus normal saline in sepsis resuscitation.

1.  Self, W. H., Semler, M. W., Wanderer, J. P., Wang, L., Byrne, D. W., Stollings, J. L., … & Rice, T. W. (2018). Balanced crystalloids versus saline in noncritically ill adults. New England Journal of Medicine, 378(9), 819–828.https://pubmed.ncbi.nlm.nih.gov/29485926/  

Abstract

Background: Comparative clinical effects of balanced crystalloids and saline are uncertain, particularly in noncritically ill patients cared for outside an intensive care unit (ICU).

Methods: We conducted a single-center, pragmatic, multiple-crossover trial comparing balanced crystalloids (lactated Ringer’s solution or Plasma-Lyte A) with saline among adults who were treated with intravenous crystalloids in the emergency department and were subsequently hospitalized outside an ICU. The type of crystalloid that was administered in the emergency department was assigned to each patient on the basis of calendar month, with the entire emergency department crossing over between balanced crystalloids and saline monthly during the 16-month trial. The primary outcome was hospital-free days (days alive after discharge before day 28). Secondary outcomes included major adverse kidney events within 30 days – a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction (defined as an elevation of the creatinine level to ≥200% of baseline) – all censored at hospital discharge or 30 days, whichever occurred first.

Results: A total of 13,347 patients were enrolled, with a median crystalloid volume administered in the emergency department of 1079 ml and 88.3% of the patients exclusively receiving the assigned crystalloid. The number of hospital-free days did not differ between the balanced-crystalloids and saline groups (median, 25 days in each group; adjusted odds ratio with balanced crystalloids, 0.98; 95% confidence interval [CI], 0.92 to 1.04; P=0.41). Balanced crystalloids resulted in a lower incidence of major adverse kidney events within 30 days than saline (4.7% vs. 5.6%; adjusted odds ratio, 0.82; 95% CI, 0.70 to 0.95; P=0.01).

Conclusions: Among noncritically ill adults treated with intravenous fluids in the emergency department, there was no difference in hospital-free days between treatment with balanced crystalloids and treatment with saline. (Funded by the Vanderbilt Institute for Clinical and Translational Research and others; SALT-ED ClinicalTrials.gov number,

Why I selected this article 

I chose this article because it provides strong, practice-changing evidence directly relevant to my PICO question by comparing balanced crystalloids (lactated Ringer’s solution or Plasma-Lyte A) with 0.9% normal saline in a large cohort of hospitalized adults receiving intravenous fluids in the emergency department. While the population includes non–critically ill patients, this setting is highly relevant to sepsis care because it reflects the earliest phase of resuscitation, where fluid choice can significantly influence downstream outcomes such as acute kidney injury and mortality risk. This was a large, pragmatic, single-center, multiple-crossover trial involving 13,347 patients, thereby strengthening its real-world applicability and reducing selection bias by ensuring nearly all patients received the assigned fluid strategy. Importantly, the study directly evaluates clinically meaningful outcomes aligned with my PICO question, including major adverse kidney events (MAKE-30), a composite outcome of death, new renal replacement therapy, or persistent renal dysfunction. The findings demonstrated that balanced crystalloids significantly reduced the incidence of MAKE-30 compared to normal saline (4.7% vs 5.6%), indicating a consistent renal-protective advantage. Although there was no difference in hospital-free days, the reduction in kidney-related adverse outcomes is clinically important because AKI is a major driver of morbidity and mortality in sepsis and critical illness. I selected this study because it provides high-quality, real-world comparative evidence supporting a shift toward balanced crystalloids as the safer default fluid for hospitalized patients, especially those at risk for sepsis-related complications, thereby reinforcing the clinical relevance of fluid choice in improving patient outcomes.

2. Gelbenegger G, Shapiro NI, Zeitlinger M, Jilma B, Douglas IS, Jorda A. Lactated Ringer’s or Normal Saline for Initial Fluid Resuscitation in Sepsis-Induced Hypotension. Crit Care Med.  https://pubmed.ncbi.nlm.nih.gov/39969246/ 

Abstract

Objectives: To assess whether initial fluid resuscitation with lactated Ringer’s solution compared with 0.9% saline is associated with improved clinical outcomes in patients with sepsis-induced hypotension.

Design: Secondary analysis of the randomized controlled Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) trial.

Setting: ICUs and emergency departments in 60 U.S. centers from March 2018 to January 2022.

Patients: Participants from the CLOVERS trial. Adult patients with a suspected or confirmed infection and hypotension caused by sepsis.

Interventions: Participants received 1-3 L of crystalloid fluid for initial fluid resuscitation before randomization. In this analysis, participants were categorized into a lactated Ringer’s group and a 0.9% saline group based on the fluid type predominantly used for the initial fluid resuscitation (i.e., ≥ 95% of pre-randomization fluid).

Measurements and main results: Of 1563 participants with sepsis-induced hypotension included in the CLOVERS trial, 622 (39.8%) received lactated Ringer’s solution and 690 (44.1%) received 0.9% saline as solution for the initial fluid bolus. Death before discharge home by day 90 occurred in 76 of 622 participants (12.2%) in the lactated Ringer’s group and in 110 of 690 participants (15.9%) in the 0.9% saline group, resulting in an adjusted hazard ratio of 0.71 (95% CI, 0.51-0.99; p = 0.043). Patients receiving lactated Ringer’s solution had more hospital-free days at 28 days than those receiving 0.9% saline (16.6 ± 10.8 vs. 15.4 ± 11.4, respectively; adjusted mean difference, 1.6 d [95% CI, 0.4-2.8 d; p = 0.009]). Treatment with 0.9% saline was associated with higher levels of serum chloride and decreased levels of serum bicarbonate.

Conclusions: Initial fluid resuscitation with lactated Ringer’s solution, compared with 0.9% saline, might be associated with improved survival in patients with sepsis-induced hypotension.

Why I selected this article 

I chose this article because it directly evaluates my PICO question by comparing lactated Ringer’s solution (a balanced crystalloid) with 0.9% normal saline in patients with sepsis-induced hypotension, a setting that closely reflects real-world sepsis resuscitation scenarios. This secondary analysis of the large multicenter CLOVERS randomized trial included 1,563 adults with suspected or confirmed infection and hypotension, making it highly relevant to critically ill septic patients requiring early fluid resuscitation. Importantly, the study focuses on clinically meaningful outcomes central to my question, including mortality, hospital-free days, and physiologic effects of kidney injury, such as changes in chloride and bicarbonate. The findings demonstrated a statistically significant reduction in 90-day mortality in the lactated Ringer’s group compared with normal saline (12.2% vs 15.9%), as well as an increase in hospital-free days, suggesting potential benefits for survival and recovery. Additionally, normal saline was associated with higher serum chloride levels and lower serum bicarbonate, consistent with known mechanisms of renal stress and metabolic acidosis. I selected this study because it strengthens the evidence that balanced crystalloids may improve survival and physiologic stability in sepsis, and it provides high-quality, multicenter randomized trial data that directly support shifting clinical practice away from normal saline toward balanced fluids in early sepsis resuscitation. 

3. Dong WH, Yan WQ, Song X, Zhou WQ, Chen Z. Fluid resuscitation with balanced crystalloids versus normal saline in critically ill patients: a systematic review and meta-analysis. Scand J Trauma Resusc Emerg Med. 2022 Apr 18;30(1):28. doi: 10.1186/s13049-022-01015-3. PMID: 35436929; PMCID: PMC9013977.https://pubmed.ncbi.nlm.nih.gov/35436929/ 

Abstract

Background: Intravenous fluids are used commonly for almost all intensive care unit (ICU) patients, especially for patients in need of resuscitation. The selection and use of resuscitation fluids may affect the outcomes of patients; however, the optimal resuscitative fluid remains controversial.

Methods: We systematically searched PubMed, Embase, and CENTRAL. Studies comparing balanced crystalloids and normal saline in ICU patients were selected. We used the Cochrane Collaboration tool to assess the risk of bias in studies. The primary outcome was mortality at the longest follow-up. Secondary outcomes included the incidence of acute kidney injury (AKI) and new renal replacement therapy (RRT).

Results: A total of 35,456 patients from eight studies were included. There was no significant difference between balanced crystalloid solutions and saline in mortality (risk ratio [RR]: 0.96; 95% confidence interval [CI]:0.92-1.01). The subgroup analysis with traumatic brain injury (TBI) showed lower mortality in patients receiving normal saline (RR:1.25; 95% CI 1.02-1.54). However, in patients with non-TBI, balanced crystalloid solutions achieved lower mortality than normal saline (RR: 0.94; 95% CI 0.90-0.99). There was no significant difference in moderate to severe AKI (RR: 0.96; 95% CI 0.90-1.01) or new RRT (RR: 0.94; 95% CI 0.84-1.04).

Conclusions: Compared with normal saline, balanced crystalloids may not improve the outcomes of mortality, the incidence of AKI, and the use of RRT for critically ill patients. However, balanced crystalloids reduce the risk of death in patients with non-TBI but increase the risk of death in those with TBI. Large-scale rigorous randomized trials with better designs are needed, especially for specific patient populations.

Why I selected this article 

I selected this article because it provides a high-level synthesis of the existing evidence comparing balanced crystalloids and normal saline in critically ill adult patients, which directly relates to my PICO question on fluid choice in sepsis. This systematic review and meta-analysis includes 35,456 patients across eight studies, providing a large, comprehensive evidence base for evaluating clinically important outcomes, including mortality, acute kidney injury (AKI), and the need for renal replacement therapy (RRT). Because individual trials often show mixed or modest effects, this pooled analysis is valuable for identifying overall trends across different ICU populations. The study is particularly relevant to sepsis management because it includes subgroup analyses of non–traumatic brain injury patients, in which balanced crystalloids were associated with a modest reduction in mortality (RR 0.94), suggesting potential benefit in general critical illness populations, including septic patients. Although the study found no statistically significant differences in overall mortality, AKI, or RRT among all critically ill patients, it clarifies that the benefits of balanced crystalloids may be population-specific rather than universal. I chose this article because it strengthens my evidence base by providing a broad, high-quality comparison of fluid strategies, helping to contextualize findings from individual randomized controlled trials and supporting a more balanced, evidence-informed conclusion for fluid resuscitation in sepsis.

Conclusion for each article 

1. Semler et al. (2019) – Balanced Crystalloids versus Saline in Critically Ill Adults

Overall, this large cluster-randomized crossover trial provides strong evidence that balanced crystalloids may offer modest clinical advantages over normal saline in critically ill adults, including a lower incidence of major adverse kidney events and a trend toward reduced mortality. Although the absolute differences were small, the consistency of renal benefit across subgroups, including septic patients, supports the biologic plausibility that balanced crystalloids reduce kidney stress compared with high-chloride saline. However, limitations such as a single-center design, an open-label implementation, and a short-term follow-up temper the strength of causal inference. Despite these constraints, this study meaningfully supports the use of balanced crystalloids as a safer default fluid in critically ill and septic populations.

2. Self et al. (2018) – Balanced Crystalloids versus Saline in Noncritically Ill Adults (SALT-ED Trial)

This pragmatic trial demonstrates that in noncritically ill hospitalized adults receiving fluids in the emergency department, balanced crystalloids significantly reduce major adverse kidney events compared with normal saline, despite no difference in hospital-free days. The findings are clinically important because they show that even early, relatively low-volume fluid exposure can influence renal outcomes. While the study population was not limited to sepsis, the early resuscitation setting closely mirrors the initial management of septic patients, making the results highly applicable to your PICO question. Limitations include the single-center design and a calendar-month-based crossover, but overall, the study strongly supports the renal-protective effect of balanced crystalloids in early hospital care.

3. Gelbenegger et al. (2025) – Lactated Ringer’s or Normal Saline for Initial Fluid Resuscitation in Sepsis-Induced Hypotension

This secondary analysis of the CLOVERS trial provides clinically relevant evidence specifically in septic hypotension, demonstrating that lactated Ringer’s is associated with lower 90-day mortality and increased hospital-free days compared with normal saline. These findings directly support your PICO question by focusing on true sepsis resuscitation rather than broader ICU populations. The physiologic data further strengthen the argument, showing that normal saline is associated with hyperchloremia and metabolic acidosis, which may contribute to renal and hemodynamic dysfunction. However, because this is a secondary, non-randomized comparison within an RCT, residual confounding precludes definitive causal inference. Even so, the study adds important sepsis-specific support favoring balanced crystalloids.

4. Dong et al. (2022) – Fluid Resuscitation with Balanced Crystalloids versus Normal Saline in Critically Ill Patients: Systematic Review and Meta-analysis

This large systematic review and meta-analysis synthesizes evidence from over 35,000 critically ill patients and provides a broad overview of outcomes by fluid choice across ICU populations. Overall, it found no statistically significant difference in mortality, AKI, or renal replacement therapy between balanced crystalloids and normal saline, though subgroup analysis suggested potential benefit in non–traumatic brain injury patients. While this tempers conclusions from individual trials, it is valuable in showing that benefits may not be universal across all ICU subgroups and may depend on patient context. The strength of this study lies in its large pooled sample size and rigorous methodology, but heterogeneity among the included trials limits the ability to draw definitive conclusions. Overall, it reinforces that balanced crystalloids are at least non-inferior to saline and may offer selective benefit in non-TBI critically ill and septic populations.

Overall Conclusion

When these four studies are considered together, the overall body of evidence supports balanced crystalloids as the preferred resuscitation fluid over 0.9% normal saline for adults with sepsis and other acute hospitalized populations. The strongest and most consistent advantage across the articles has been improved renal outcomes, including lower rates of major adverse kidney events and reduced acute kidney injury. This benefit was demonstrated in both critically ill and noncritically ill patients, suggesting that fluid choice can influence outcomes across multiple care settings, including the emergency department and ICU.

Although mortality benefits were not uniform across every study, sepsis-specific evidence from Gelbenegger et al. (2025) suggests balanced crystalloids, particularly lactated Ringer’s, may improve survival and hospital-free days in patients with septic hypotension. In contrast, none of the studies had demonstrated greater benefits of the use of normal saline. Rather, a new set of challenges, which included physiologic disadvantages of saline such as hyperchloremia and metabolic acidosis, further support the use of balanced crystalloids in septic patients who are already at risk for renal and hemodynamic compromise.

While some limitations exist, such as single-center designs, subgroup analyses, and heterogeneity across pooled studies, the direction of evidence remains consistent: balanced crystalloids are preferable to normal saline and are frequently associated with better kidney outcomes, with a possible added benefit in septic populations. Collectively, these findings support balanced crystalloids as the safer, more evidence-based option for fluid resuscitation in adults with sepsis.

Clinical Bottom Line

Overall, the current body of evidence supports the use of balanced crystalloids over 0.9% normal saline for fluid resuscitation in adults with sepsis. This conclusion is based on multiple high-quality studies, including large randomized and pragmatic trials (Semler et al., 2019; Self et al., 2018; Gelbenegger et al., 2025) and a systematic review with meta-analysis (Dong et al., 2022). Across these studies, balanced crystalloids consistently performed as well as or better than normal saline, with the strongest benefits observed in renal outcomes and a possible reduction in mortality in septic patients.

The most consistent finding is improved kidney protection. Patients receiving balanced crystalloids had lower rates of acute kidney injury (AKI) and fewer major adverse kidney events (MAKE-30) compared with those receiving normal saline. This is especially important in sepsis, where AKI significantly increases morbidity, mortality, and length of hospitalization. Balanced crystalloids may offer this benefit because their electrolyte composition more closely resembles plasma, while normal saline contains a higher chloride concentration that can contribute to hyperchloremia, metabolic acidosis, renal vasoconstriction, and decreased kidney perfusion.

Additional evidence suggests a possible survival benefit in sepsis populations. Gelbenegger et al. (2025) found improved outcomes with lactated Ringer’s in patients with septic hypotension, supporting the use of balanced crystalloids in higher-risk septic patients. While mortality benefits were not identical across all studies, no major trial demonstrated greater advantages than the use of normal saline. Instead, balanced crystalloids repeatedly showed either modest benefit or no harm.

Strengths of this evidence include large sample sizes, multicenter study designs, and inclusion of ICU and emergency department patients, making the findings applicable to real-world practice. Although some limitations exist, such as differences in patient populations and relatively small absolute differences in outcomes, the overall direction of the evidence remains clear.

For adult patients with sepsis who require intravenous fluid resuscitation, balanced crystalloids such as lactated Ringer’s or Plasma-Lyte should be the preferred first-line fluid over normal saline. Current evidence shows they provide better renal protection, avoid harmful chloride load, and may modestly improve survival, making them the safer and more effective choice for most septic patients.