The Relationship Between Serum Chloride Concentration and Intravenous Fluid Therapy Outcomes

Background Introduction

In the intensive care unit (ICU), intravenous fluid therapy is a common treatment, with “balanced solutions” and 0.9% sodium chloride solution (saline) being the most commonly used fluids. In recent years, multiple randomized controlled trials and patient-level meta-analyses have shown that balanced solutions may reduce mortality and the need for renal replacement therapy compared to saline. However, in patients with traumatic brain injury, the use of balanced solutions has been associated with increased mortality. This discrepancy has prompted an exploration into the mechanisms of action of balanced solutions.

The chloride concentration in saline (154 mmol/L) is much higher than in balanced solutions (approximately 98-111 mmol/L). Thus, clinicians are concerned that administering saline to patients with high serum chloride levels could lead to hyperchloremic metabolic acidosis, resulting in adverse outcomes. Although experimental and non-randomized studies have indicated that rapid infusion of large amounts of saline can cause hyperchloremic metabolic acidosis and acute kidney injury, there is no randomized trial data supporting the choice of fluid based on baseline serum chloride concentrations or changes in serum chloride.

To address this gap, the authors conducted a secondary analysis of the PLUS trial (Plasma-Lyte 148® vs. Saline) to investigate the impact of baseline serum chloride concentration on clinical outcomes in ICU patients treated with balanced solutions or saline.

Source of the Paper

This study was conducted by scholars from various research institutions in Australia and New Zealand, including Mahesh Ramanan, Naomi Hammond, Laurent Billot, and others. The research team is affiliated with institutions such as The George Institute for Global Health, University of New South Wales, and Royal Brisbane and Women’s Hospital. The paper was published in the journal Intensive Care Medicine on December 14, 2024.

Research Process

Study Design

This study is a secondary analysis of the PLUS trial. The PLUS trial was a multicenter, prospective, double-blind, randomized controlled trial involving 5,037 patients. Participants were aged 18 years or older, expected to stay in the ICU for at least three consecutive days, and judged by clinicians to require intravenous fluid resuscitation. Patients were randomly assigned to receive either Plasma-Lyte 148® or saline as their primary fluid therapy.

Data Collection

Baseline data collected included demographic information, Acute Physiology and Chronic Health Evaluation II (APACHE-II) scores, serum chloride concentration, pH values, and other biochemical markers. During the first seven days of treatment, daily measurements of serum chloride, pH, serum creatinine, hemodynamic variables, and organ support status were recorded. From day 8 to day 90, mechanical ventilation status, receipt of renal replacement therapy, and fluid volumes were documented.

Data Analysis

Patients were divided into four quartiles based on baseline serum chloride concentration and pH. The primary endpoint was all-cause mortality within 90 days after randomization. A generalized linear mixed model was used to analyze treatment effects across different serum chloride and pH subgroups, with ICU sites included as random effects.

Main Results

Impact of Serum Chloride Concentration

A total of 4,823 patients were included in the analysis, divided into four subgroups based on baseline serum chloride concentration: <102 mmol/L, 102–106 mmol/L, 107–109 mmol/L, and >109 mmol/L. The results showed no significant difference in 90-day mortality between patients receiving balanced solutions versus saline. The adjusted odds ratios (ORs) for the four serum chloride subgroups were 1.23, 0.95, 0.88, and 0.76, respectively, with an interaction P-value of 0.10, indicating no significant effect of baseline serum chloride concentration on treatment outcomes.

Impact of pH

Patients were also divided into four subgroups based on baseline pH: ≤7.27, 7.27–7.34, 7.34–7.39, and >7.39. The analysis showed no significant difference in 90-day mortality between patients receiving balanced solutions versus saline. The ORs for the four pH subgroups were 0.89, 0.94, 0.96, and 1.15, respectively, with an interaction P-value of 0.63, indicating no significant effect of baseline pH on treatment outcomes.

Changes in Biochemical Markers

During the first seven days of treatment, patients receiving balanced solutions had significantly lower serum chloride concentrations compared to those receiving saline (mean difference -1.99 mmol/L, 95% CI -2.21 to -1.76) and significantly higher pH values (mean difference 0.01, 95% CI 0.01 to 0.01). There was no significant difference in serum creatinine levels between the two groups.

Conclusion

This study demonstrated that baseline serum chloride concentration or pH does not significantly affect the treatment outcomes of balanced solutions versus saline in ICU patients receiving intravenous fluid therapy. Although the balanced solution group had lower serum chloride concentrations and higher pH during treatment, these differences did not translate into significant clinical outcome benefits. The findings provide important guidance for clinicians in selecting fluid therapy, particularly in patients with abnormal serum chloride concentrations or pH values.

Key Highlights

1. Secondary Analysis of a Large-Scale Randomized Controlled Trial: Based on the extensive data from the PLUS trial, this study provides high-quality evidence on the impact of serum chloride concentration and pH on fluid therapy outcomes.
2. Comprehensive Assessment of Biochemical Markers: The study not only focused on clinical outcomes but also analyzed changes in serum chloride, pH, and creatinine during treatment, offering insights into the mechanisms of balanced solutions.
3. Clinical Implications: The results suggest that when choosing fluid therapy, clinicians do not need to overly consider baseline serum chloride concentration or pH, simplifying decision-making in clinical practice.

Other Valuable Information

The study noted that although no significant differences were found in the overall analysis, there was a trend in treatment effects between balanced solutions and saline in the highest and lowest serum chloride subgroups. This suggests that serum chloride concentration may still be a factor worth considering in certain specific scenarios. Additionally, the research team emphasized that future studies should further explore the impact of different types of acid-base disorders on fluid therapy outcomes.

This study provides crucial scientific evidence for selecting intravenous fluid therapy in ICU patients and points the way for further research.