Balanced Multielectrolyte Solution versus Saline in Critically Ill Adults
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In critically ill adults, intravenous fluid therapy with a balanced multielectrolyte solution did not reduce the risk of 90-day mortality or acute kidney injury compared to 0.9% normal saline.
Key Findings
Study Design
Study Limitations
Clinical Significance
The PLUS trial indicates that for a broad population of critically ill adults requiring fluid therapy, the choice between a balanced multielectrolyte solution (Plasma-Lyte 148) and 0.9% normal saline does not result in a significant difference in survival or renal outcomes. This supports the conclusion that the routine preferential use of balanced crystalloids over saline may not yield the generalized benefits previously hypothesized for unselected ICU populations.
Historical Context
For decades, 0.9% normal saline was the default resuscitation fluid, despite physiologic concerns that its high chloride content could cause hyperchloremic metabolic acidosis and renal vasoconstriction leading to acute kidney injury. The 2018 SMART and SALT-ED trials challenged standard practice by demonstrating a composite mortality and renal benefit with balanced crystalloids over saline. However, the subsequent release of the BaSICS trial in 2021 and the PLUS trial in 2022—both of which were rigorous, double-blind RCTs—revealed neutral results. These contrasting findings have fueled ongoing debate, suggesting that the benefits of balanced solutions might be less pronounced in general ICU populations with modest fluid requirements compared to those with severe sepsis or massive resuscitation needs.
Guided Discussion
High-yield insights from every perspective
Why has 0.9% normal saline traditionally been thought to increase the risk of acute kidney injury in critically ill patients compared to balanced multielectrolyte solutions?
Key Response
0.9% saline contains a supraphysiologic concentration of chloride (154 mEq/L). Large volumes can cause hyperchloremic non-anion gap metabolic acidosis. The excess chloride is filtered by the glomerulus and sensed by the macula densa, triggering tubuloglomerular feedback. This leads to afferent arteriolar vasoconstriction, decreased renal blood flow, and reduced glomerular filtration rate (GFR), potentially causing or exacerbating acute kidney injury.
Given the contrasting results between the SMART trial (favoring balanced crystalloids) and the PLUS and BaSICS trials (showing no difference), how should you choose your initial resuscitation fluid for a newly admitted patient with septic shock?
Key Response
While SMART suggested a benefit of balanced solutions in reducing major adverse kidney events, PLUS and BaSICS showed no mortality or AKI difference. The choice should depend on patient-specific factors. For instance, balanced solutions may be preferred to avoid worsening severe hyperchloremia or acidosis, while saline is indicated in traumatic brain injury to avoid hyponatremia and cerebral edema. Residents must learn to individualize fluid therapy rather than relying on a universal approach, recognizing that the absolute difference in outcomes for the general ICU population is likely very small.
How do the volume and rate of fluid administration, as well as the timing of randomization relative to prior fluid exposure, potentially explain the discrepancy in outcomes between the PLUS trial and the SMART trial?
Key Response
In the PLUS trial, patients may have received significant volumes of fluid (often saline) prior to randomization in the emergency department, potentially diluting the treatment effect. Additionally, the total volume of study fluid administered in PLUS was relatively modest (median of about 4 liters over the ICU stay). If the harm of normal saline is dose-dependent, lower fluid volumes and pre-enrollment saline exposure might mask the benefits of balanced crystalloids that were suggested in earlier, pragmatic trials.
When leading ICU rounds, how do you synthesize the findings of the PLUS trial to teach your team about the concept of fluid stewardship and the marginal gains of fluid composition versus fluid volume?
Key Response
Attendings should emphasize that the debate over fluid type often overshadows the more critical issue of fluid volume and stewardship. The PLUS trial implies that in unselected ICU patients receiving moderate volumes, the exact crystalloid composition does not drive mortality or renal failure. Teaching should pivot toward assessing fluid responsiveness, avoiding volume overload, and active de-resuscitation, rather than obsessing over normal saline versus Plasma-Lyte.
Scholarly Review
Critical appraisal through the lens of expert reviewers and guideline development
The PLUS trial utilized a blinded, multicenter, randomized controlled design, whereas the SMART trial was a pragmatic, unblinded, multiple-crossover cluster-randomized trial. How do these distinct trial designs influence the risk of selection bias and the estimation of the average treatment effect?
Key Response
Pragmatic cluster-crossover designs maximize enrollment and mimic real-world practice but are vulnerable to selection bias and contamination if clinicians alter admission thresholds or use non-study fluids during certain crossover periods. Blinded patient-level RCTs like PLUS minimize selection bias and performance bias but often enroll a narrower, less severely ill patient subset due to strict inclusion criteria and consent processes, potentially reducing generalizability and underpowering the study if the baseline event rate is lower than expected.
If you were reviewing the PLUS trial manuscript, how would you evaluate the impact of pre-randomization fluid therapy and the use of open-label fluids during the trial on the validity of the primary outcome?
Key Response
A rigorous reviewer would flag that significant pre-randomization fluid (often normal saline) and concurrent open-label fluid administration blur the biological separation between the two arms. This cross-contamination biases the results toward the null hypothesis. The editor would require a robust sensitivity analysis excluding patients with massive pre-enrollment saline or quantifying the exact biological separation (such as delta chloride levels) achieved between the groups to ensure the intervention was adequately delivered.
How should the Surviving Sepsis Campaign guidelines synthesize the PLUS trial findings regarding the recommendation of balanced crystalloids over normal saline for the acute resuscitation of adults with sepsis or septic shock?
Key Response
The 2021 Surviving Sepsis Campaign guidelines issued a weak recommendation with low quality of evidence to use balanced crystalloids instead of normal saline for resuscitation. The addition of the PLUS trial, which shows no mortality or renal benefit, weakens the certainty of superiority for balanced fluids. The committee must decide whether to downgrade the recommendation to a conditional recommendation for either fluid, or clarify that balanced fluids might only be preferred when massive volume resuscitation is anticipated, acknowledging the lack of definitive superiority in the latest high-quality RCTs.
Clinical Landscape
Noteworthy Related Trials
SPLIT Trial
Tested
Buffered crystalloid (Plasma-Lyte 148)
Population
ICU patients requiring crystalloid fluid therapy
Comparator
0.9% Sodium Chloride (Saline)
Endpoint
Proportion of patients with acute kidney injury (AKI) within 90 days
SMART Trial
Tested
Balanced crystalloids (Lactated Ringer's or Plasma-Lyte A)
Population
Critically ill adults in the ICU
Comparator
0.9% Sodium Chloride (Saline)
Endpoint
Major adverse kidney events within 30 days (MAKE30)
BaSICS Trial
Tested
Balanced crystalloid solution (Plasma-Lyte 148)
Population
Critically ill adults in the ICU requiring fluid challenges
Comparator
0.9% Sodium Chloride (Saline)
Endpoint
90-day survival
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