Fluid Management: Buffered Crystalloid No Benefit vs Saline

Diana Phillips

October 12, 2015

Fluid therapy with a buffered crystalloid solution does not reduce the risk for acute kidney injury (AKI) or kidney failure relative to saline among intensive care unit (ICU) patients who need intravenous fluids, according to a new study.

These findings contradict previously reported observational data that suggested buffered crystalloids may decrease the risk for AKI and death compared with saline in critically ill patients, Paul Young, MB ChB, from the Medical Research Institute of New Zealand in Wellington, and colleagues write in an article published online October 7 in JAMA.

It has been suggested that the high chloride content of saline might have adverse renal effects in critically ill patients, and that buffered, or balanced, crystalloid solutions may be a better option because they more closely mimic the properties of plasma.

To date, however, "the effects of buffered crystalloids have not been evaluated in randomized trials in the broad range of patients in the ICU to whom they might be administered if used in preference to saline," the authors explain.

Therefore, the team designed a cluster randomized, double-crossover study to determine the relative effectiveness of both intravenous fluid options in a heterogeneous population of patients treated in the ICU. "The aim of our study was primarily to determine the effect of specific fluid type on the development of AKI in this patient population," the authors write.

The study population included 2278 patients receiving treatment in four ICUs in New Zealand, who required crystalloid fluid therapy between April 2014 and October 2014. The predominantly postoperative population was moderate risk or lower, according to Acute Physiology and Chronic Health Evaluation (APACHE) II score. Participating ICUs were assigned to use either 9% saline or buffered crystalloid (Plasma-Lyte 148) for alternating 7-week treatment blocks, with two crossovers occurring during the course of the study.

The overall exposure to study fluids was small (a median of 2 L per patient) during the ICU stay, and most of the fluid administration occurred during the first 24 hours, the authors note.

Of the enrolled patients who were available for analysis, 1152 received a buffered crystalloid solution, and 1110 received conventional saline. Within 90 days of enrollment, 9.6% of the patients in the buffered crystalloid group and 9.2% in the saline group developed AKI (relative risk [RR], 1.04; 95% confidence interval [CI], 0.80 - 1.36; P = .77). In addition, 3.3% of the patients in the buffered crystalloid group required renal replacement therapy compared with 3.4% in the saline group (RR, 0.96; 95% CI, 0.62 - 1.50; P = .91); the indications for initiation of renal replacement therapy were similar between the groups.

Overall, 7.6% of patients in the buffered crystalloid group and 8.6% of patients in the saline group died in the hospital (RR, 0.88; 95% CI, 0.67 - 1.17; P =.40). One serious adverse event, the development of lactic acidosis and progressive multiorgan failure culminating in circulatory collapse and death in a patient who was admitted to the ICU after a renal transplant and was assigned to the buffered crystalloid group, was judged by a site principal investigator to be potentially related to study treatment.

No significant between-group differences were observed for median days in the ICU (1.5), median days in the hospital, and median hours of ventilation, the authors note.

The findings are inconsistent with those observed in previous observational cohort study, in which removing chloride-rich fluids from a single ICU reduced the incidence of AKI and requirements for dialysis, the authors say. However, "[o]ur results are consistent with a retrospective study of nonsurgical patients with sepsis in which there was no significant association between use of balanced vs unbalanced crystalloids and acute renal failure," the authors write.

"Further large randomized clinical trials are needed to assess efficacy in higher-risk populations and to measure clinical outcomes such as mortality," they stress.

"Unphysiologic" Composition of Normal Saline an Issue

In an accompanying editorial, John A. Kellum, MD, from the Center for Critical Care Nephrology and the Clinical Research, Investigation, and Systems Modeling of Acute Illness Center, Department of Critical Care Medicine, University of Pittsburgh, Pennsylvania, and Andrew D. Shaw, MBBS, from the Division of Cardiothoracic Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee, acknowledge that the current study was "well conducted with excellent adherence to study protocol and near-complete follow-up," giving the findings high "face validity." However, they identify points they believe merit discussion.

Specifically, the authors did not report serum chloride data, "which may have allowed an estimate of whether there was sufficient difference between the groups to permit a plausible effect on clinical outcomes," the editorialists write.

Also, Dr Kellum and Dr Shaw suggest there was insufficient total exposure to both fluids to demonstrate a plausible hazard in a study population at low risk for AKI or other adverse effects.

They also call attention to the higher-than-physiologic chloride composition of isotonic saline, and its potential for toxicity, and they question whether the study's use of adverse event measurement, rather than an assessment of the effectiveness of fluid management by patient indication, qualifies it as an effectiveness trial.

"This fundamental premise that large pragmatic studies can be used to assess the effectiveness of fluids on outcomes such as AKI, requirement for dialysis, and mortality should be carefully considered when the intervention is not being used specifically for these purposes," they write. "Drugs such as 0.9% saline or other electrolyte solutions might result in differences in these outcomes, but it will be as a result of differences in toxicity, not efficacy, and studies should be designed accordingly."

By providing reassurance that neither 0.9% saline nor a low-chloride electrolyte solution "appears to be particularly hazardous when the total dose used in patients at low to moderate risk is about 2 L," the study findings are an important contribution to the care of patients in the ICU, the editorialists write. "However, the large body of 'circumstantial' evidence that points to a harm signal for saline — with scant, if any, evidence of comparative benefit — should behoove intensivists and other clinicians to proceed with caution when ordering intravenous fluids."

The editorialists' argument that the study should be reproduced in patients at risk for AKI "may be valid, and will perhaps increase the sensitivity of a future study, but to critique this study for that reason is not right," said Jorge Cerdá, MD, clinical professor of medicine in the Division of Nephrology, Department of Medicine, Albany Medical College, New York.

The investigation is a well-designed, well-powered crossover trial offering important insight for fluid management in critically ill patients, Dr Cerdá said in an interview. "It addresses the claim is that [normal saline] causes AKI, and shows it does not in a representative sample of standard ICU patients. And importantly, [normal saline] does not cause AKI throughout the spectrum of AKI severity: there was no difference even at the levels of minimal injury [both by Risk, Injury, Failure, Loss of Kidney Function, and End-stage Kidney Disease and Kidney Disease: Improving Global Outcomes criteria]."

In addition, said Dr Cerdá, "the suggestion by editorialists that imaging studies demonstrating minimal changes in intrarenal blood flow would be necessary to demonstrate an effect is not practical, and probably not clinically relevant."

What is useful, Dr Cerdá stated, is the drawing attention to the "unphysiologic" composition of normal saline, "which is anything but normal." All of the fluids being used deserve scrutiny, he said. "They should be considered drugs and treated accordingly. The problem with normal saline is not so much the chloride, but the inexperienced intern who infuses saline with abandon."

The study was funded by the Health Research Council of New Zealand through a Research Partnership for Health Delivery grant and by Baxter Healthcare Corporation. Dr Young reports receiving nonfinancial support from Baxter Healthcare Corporation in the form of supply and distribution of study fluids. Coinvestigators report various financial relationships with Edwards Lifesciences, Fisher, Paykel Healthcare, CSL Bioplasma, Fresenius Kabi, and B. Braun Medical. Dr Kellum reports receiving grant funding from Baxter and Grifols and personal fees from Baxter, Grifols, and Fresenius. Dr Shaw reports receiving grant funding from Baxter and personal fees from Baxter and Grifols. Dr Cerdá has disclosed no relevant financial relationships.

JAMA. Published online October 7, 2015. Article full text, Editorial full text

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