Balanced Multielectrolyte Solution versus Saline in Critically Ill Adults (The PLUS Trial)
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In a large, multicenter, randomized trial of critically ill adults, the use of a balanced multielectrolyte solution (Plasma-Lyte 148) compared to 0.9% saline did not result in a significant difference in 90-day all-cause mortality.
Key Findings
Study Design
Study Limitations
Clinical Significance
The study suggests that for critically ill adults in the ICU, the choice between balanced multielectrolyte solutions like Plasma-Lyte 148 and 0.9% saline does not significantly impact 90-day mortality. Clinicians may choose between these fluids based on other factors, such as cost, availability, and specific patient electrolyte or acid-base requirements, rather than an expectation of mortality benefit from balanced solutions.
Historical Context
The choice of intravenous crystalloid for fluid resuscitation has been a subject of intense debate in critical care for decades. Historically, 0.9% saline was the standard, but concerns regarding its high chloride content and potential for hyperchloremic metabolic acidosis led to the investigation of 'balanced' crystalloids. Previous observational and cluster-randomized studies (such as SMART and SALT-ED) had suggested potential benefits for balanced solutions, prompting this large-scale, definitive randomized controlled trial to clarify the mortality impact.
Guided Discussion
High-yield insights from every perspective
What is the physiological basis for the hypothesis that balanced multielectrolyte solutions, like Plasma-Lyte 148, might be superior to 0.9% saline in critically ill patients?
Key Response
0.9% saline is 'unbalanced' because its chloride concentration (154 mmol/L) is significantly higher than human plasma (approx. 100 mmol/L). Infusing large volumes of saline can induce hyperchloremic metabolic acidosis. Theoretically, this acidosis leads to renal afferent arteriole vasoconstriction and decreased glomerular filtration rate (GFR). Balanced solutions use organic anions like acetate or gluconate to replace some chloride, maintaining a more physiological pH and electrolyte balance.
The PLUS trial showed no difference in 90-day mortality between saline and balanced crystalloids. In light of this, how should a clinician approach fluid selection for a patient with severe traumatic brain injury (TBI) compared to a patient with septic shock?
Key Response
For most ICU patients (like those in septic shock), the choice between saline and balanced solutions appears to have negligible impact on mortality. However, in TBI, saline is often preferred because balanced solutions like Plasma-Lyte 148 are slightly hypotonic (effective osmolarity ~270 mOsm/L). Hypotonic fluids can promote cerebral edema and increase intracranial pressure. Clinical guidelines and subgroup analyses from fluid trials generally favor the use of isotonic 0.9% saline in neuro-critical care.
How does the achieved 'separation' in chloride levels and pH between the intervention and control groups in the PLUS trial influence your interpretation of its neutral findings compared to the earlier SMART trial?
Key Response
In the PLUS trial, the mean difference in plasma chloride between groups was only about 2 mmol/L. This limited separation suggests that either the 'toxic' threshold of chloride was not reached in the saline group or that the volume of fluid administered (median 3.9L) was insufficient to manifest the harm seen in observational studies or the SMART trial. If the dose of the 'intervention' (chloride avoidance) is low, detecting a mortality difference becomes statistically challenging, emphasizing that fluid type may only matter at very high volumes.
Given the neutral results of PLUS and the earlier BASICS trial, what are the primary teaching points regarding 'fluid stewardship' beyond simply the composition of the crystalloid?
Key Response
The focus of teaching should shift from the saline vs. balanced debate toward the 'Four Ds' of fluid therapy: Drug, Dose, Duration, and De-escalation. The PLUS trial suggests that for the average ICU patient, the *type* of crystalloid is less important than the *volume* administered. Clinicians should be taught to avoid fluid overload, utilize dynamic predictors of fluid responsiveness, and promptly transition to a conservative fluid strategy once hemodynamic stability is achieved.
Scholarly Review
Critical appraisal through the lens of expert reviewers and guideline development
Critique the use of a 90-day mortality endpoint in the PLUS trial versus the 'Major Adverse Kidney Events within 30 days' (MAKE30) composite endpoint used in the SMART trial.
Key Response
Mortality is a 'hard' endpoint but is influenced by many factors beyond fluid choice, potentially requiring enormous sample sizes to show a difference. MAKE30 is a composite including mortality, new RRT, and persistent renal dysfunction. While composites increase statistical power and capture organ-specific harm (like chloride-induced AKI), they can be driven by their less clinically significant components (e.g., small creatinine rises). The choice between them reflects a trade-off between the clinical relevance of the outcome and the statistical feasibility of the study.
The PLUS trial utilized a pragmatic, double-blind design. What are the potential threats to internal validity introduced by 'pre-randomization' fluid exposure in this study population?
Key Response
Most patients in the PLUS trial received significant volumes of fluid (often saline) in the Emergency Department or during initial resuscitation before being randomized in the ICU. This 'contamination' means both groups had a baseline exposure to the control. If the harm of saline occurs early (the 'first hit'), the trial might fail to show a benefit of balanced solutions because the damage was already done, potentially leading to a type II error.
Based on the results of the PLUS trial and the 2021 Surviving Sepsis Campaign recommendations, should the preference for balanced crystalloids be upgraded from a 'weak' to a 'strong' recommendation?
Key Response
No. The Surviving Sepsis Campaign currently provides a 'weak recommendation, low quality of evidence' for balanced crystalloids. Because PLUS (and BASICS) were large, high-quality RCTs that failed to demonstrate a mortality benefit, they actually reinforce the idea that the benefit is marginal at best. The recommendation is likely to remain 'weak' or be downgraded to a statement of equivalence, acknowledging that while balanced fluids are more physiological, they have not proven to be life-saving compared to saline.
Clinical Landscape
Noteworthy Related Trials
SALT Trial
Tested
Balanced crystalloids
Population
Hospitalized adults receiving IV fluids
Comparator
Saline
Endpoint
Major adverse kidney events within 30 days (MAKE30)
SMART Trial
Tested
Balanced crystalloids
Population
Critically ill adults in the ICU
Comparator
Saline
Endpoint
Major adverse kidney events within 30 days (MAKE30)
BaSICS Trial
Tested
Balanced crystalloids
Population
Critically ill adults
Comparator
Saline
Endpoint
90-day mortality
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