Does Crystalloid Composition or Rate of Fluid Administration Make a Difference When Resuscitating Patients in the ICU?

Michael J. Connor Jr, Craig M. Coopersmith

JAMA. Published online August 10, 2021. doi:10.1001/jama.2021.11119

Administration of intravenous fluids is among the most common interventions performed in intensive care units (ICUs). The first description of fluids for resuscitation of a critically ill patient occurred during the 1830s cholera outbreak in England.¹ In the 200 years since, debates continue surrounding the volume, composition, and rate of fluid administration, with few definitive answers to guide clinicians.

Previous studies have demonstrated that mortality is decreased when critically ill patients receive early fluid resuscitation during septic shock²^,3 and hemorrhagic shock,⁴ although studies exploring the rate of fluid resuscitation have largely been absent. Although there is some intuitive appeal to rapid resuscitation in an underresuscitated patient, the potential benefits may be counterbalanced by concerns that overly rapid fluid administration may impair right ventricular function, worsen tissue edema, and decrease organ function.

The ideal type of fluid for use in resuscitation is equally unclear. Hemorrhagic shock is ideally treated with a balanced approach of packed red blood cells, fresh frozen plasma, and platelets.⁵ However, among patients who do not have hypotension from blood loss, considerable controversy remains.

A robust literature comparing colloids with isotonic crystalloid fluids demonstrates no difference in a heterogeneous ICU patient population,⁶ with a small potential benefit with colloids as adjunctive therapy in patients with sepsis.⁷ Even though many clinicians historically paid little attention to the composition of isotonic crystalloids administered for fluid resuscitation, this topic has come under more scrutiny after studies in both animals and healthy human volunteers suggested that rapid administration of chloride-rich solutions (ie, 0.9% sodium chloride) can be detrimental to kidney function,⁸ vascular smooth muscle function, and vasomotor tone, as well as promoting inflammation compared with balanced solutions with compositions that more closely mimic the electrolyte composition of human plasma.

Multiple prospective observational studies and cluster-randomized, crossover trials as well as retrospective investigations have suggested small, but potentially important, increases in acute kidney injury, need for kidney replacement therapy, and mortality when chloride-rich solutions are compared with balanced solutions in critically ill patients.⁹^-11 In addition, 2 large clinical trials that compared balanced solutions with chloride-rich solutions have reached divergent results. The 0.9% Saline vs Plasma-Lyte 148 for ICU fluid Therapy (SPLIT) trial randomized 2278 patients to examine whether fluid type affected outcomes.¹² No between-group differences were detected for the primary outcome of acute kidney injury or for the secondary outcomes of kidney replacement therapy or mortality.¹²

In contrast, the Isotonic Solutions and Major Adverse Renal Events Trial (SMART) examined 15 802 patients who received balanced crystalloids (either lactated ringer solution or Plasma-Lyte A) or saline (0.9% sodium chloride) in a single-center, multiple ICU, pragmatic, cluster-randomized, multiple-crossover trial.¹³ The trial demonstrated a small but statistically significant decrease in the primary composite outcome of death from any cause, new kidney replacement therapy, or persistent kidney dysfunction.¹³

This issue of JAMA presents 2 simultaneous reports from a single trial that examined both rate of fluid resuscitation and optimal fluid composition for resuscitation in the ICU.¹⁴^,15 The Balanced Solutions in Intensive Care Study (BaSICS) was a randomized, factorial trial that enrolled 10 520 patients and evaluated 2 interventions. The first intervention compared a slower rate (333 mL/h) vs a conventional rate (999 mL/h) of fluid infusion.¹⁵ The second intervention compared the use of a balanced solution (Plasma-Lyte 148) vs saline solution (0.9% sodium chloride), in which patients received a single solution for all fluids during their ICU care including boluses, maintenance fluids, and carriers of medications.¹⁴ Patients were eligible if they required at least 1 episode of fluid expansion, were not expected to be discharged within 24 hours, and had at least 1 risk factor for acute kidney injury.

There was no difference in the primary outcome of 90-day mortality between the slower and conventional infusion rates (26.6% vs 27.0%, respectively; adjusted hazard ratio, 1.03 [95% CI, 0.96-1.11]; P = .46).¹⁵ Secondary end points showed no difference in the rates of acute kidney injury or kidney replacement therapy. There was a small decrease in Sequential Organ Failure Assessment scores at day 3 in the slower infusion group, but this difference is of unclear clinical significance because the scores were similar by day 7.¹⁵

There was also no difference between the administration of a balanced solution and saline solution for the primary outcome of 90-day mortality (26.4% vs 27.2%, respectively; adjusted hazard ratio, 0.97 [95% CI, 0.90-1.05]; P = .47).¹⁴ Notably, in the prespecified subgroup analysis of 486 patients with traumatic brain injury, mortality was significantly higher in the balanced solution group (31.3% vs 21.1% in the saline solution group; hazard ratio, 1.48 [95% CI, 1.03-2.12]), suggesting possible harm from using the balanced solution in patients with traumatic brain injury.¹⁴ Other secondary end points and subgroup analyses demonstrated no difference between the 2 solution types.¹⁴

When determining how to incorporate these findings into clinical practice, it is important to note the strengths of the trial. The authors performed one of the largest randomized clinical trials ever conducted in the critical care setting. The trial included more than 10 000 patients, the majority of whom were randomized on their first day in the ICU at 75 ICUs in Brazil. Furthermore, there was little crossover between groups after enrollment, excellent adherence to the trial protocols, and near-complete follow-up.

Of the 2 fluid interventions in the trial, the rate of fluid administration is more straightforward to interpret. No difference was noted between the slower and conventional infusion rates; however, the mean fluid volume administered was only 1.2 L on the first day in the ICU, which is a surprisingly low volume especially considering that nearly half of patients required surgical intervention. This suggests that while there are physiological rationales to support either slower or faster fluid administration, both strategies represent viable approaches for critically ill patients who require at least 1 episode of volume expansion but generally have low need for additional fluids. However, it is difficult to draw conclusions about patients who need high-volume resuscitation due to profound volume depletion at admission or significant ongoing fluid losses because the potential benefits (rapid volume expansion) and risks (increased edema leading to organ dysfunction) would both be theoretically exacerbated in patients who need 5 L to 10 L of fluid during the first ICU day.

The question of whether there are advantages to balanced crystalloids or 0.9% sodium chloride is more controversial. There are numerous factors to consider when interpreting the results of the BaSICS trial. Patients received a median of only 2.9 L of study fluid during the first 3 days following randomization. This small volume of study fluid (mean volume, <1 L/d) may have obscured an effect that would be seen with more vigorous volume administration.

Furthermore, 68% of all patients received nonstudy fluid prior to enrollment with 45% receiving more than 1 L prior to randomization, which is a confounder in interpreting the results because some patients could have received a significant volume of a different fluid than they were subsequently randomized to receive. The finding that there was minimal separation in mean serum chloride levels between the groups despite significant differences in chloride levels in the saline solution and the balanced solution is consistent with the relatively small amount of fluid given as well as potentially reflecting signal dilution by receiving other fluids prior to randomization. Together, this may help explain the absence of a between-group difference. In addition, the observed mortality in the control groups was less than the trial was powered for, meaning that the trial may have been underpowered to demonstrate small differences in the primary outcome.

The BaSICS trial needs to be understood in the context of the SPLIT and SMART trials,¹²^,13 which previously examined the same question. In each trial, patients had relatively low severity of illness based on Acute Physiology and Chronic Health Evaluation II scores, low to moderate median volumes of fluid administered, and relatively low risk of acute kidney injury. However, some key differences may help explain the divergent outcomes. The 3 trials did not use the same balanced solutions. Both the BaSICS¹⁴^,15 and SPLIT¹² trials examined Plasma-Lyte 148, whereas the SMART trial¹³ used both lactated ringer and Plasma-Lyte A. Notably, the pH of Plasma-Lyte 148 is 5.5, the pH of lactated ringer is 6.5, and the pH of Plasma-Lyte A is 7.4 (for comparison, the effective pH of 0.9% sodium chloride is 5.4).¹⁶ It is possible that the differences in pH between the different fluids account for the divergent outcomes observed in the 3 trials.

In addition, the trials did not enroll the same patient population. Nearly half of the patients in the BaSICS trial¹⁴^,15 and the SPLIT trial¹² were admitted to the ICU after elective surgery, whereas most patients in the SMART trial¹³ were unplanned admissions from the emergency department or hospital ward and only 21% were patients who had undergone surgery (elective or emergency).

After 20 years of trials comparing balanced solutions with chloride-rich solutions, how should a clinician respond when confronted with the daily task of providing volume resuscitation to critically ill patients? The results of the BaSICS trial, combined with the results from previous trials, demonstrate no measurable risk for administration of 0.9% sodium chloride when used in small to moderate quantities in critically ill patients who are at relatively low risk for acute kidney injury. Clinicians should feel confident in using any type of isotonic crystalloid in this setting. Even though the finding among patients with traumatic brain injury was a secondary outcome and requires validation, the significantly increased mortality among the subgroup of patients with traumatic brain injury who received the balanced solution is concerning enough to suggest preferentially using saline solution in this patient population until a well-done clinical trial can be performed.

Despite multiple studies that have compared fluid type, there continues to be insufficient data to guide management in critically ill patients who require significant volume resuscitation. Although there are theoretical reasons to suggest that balanced solutions may offer a benefit in a more severely ill patient population, the paucity of controlled data from rigorous clinical trials in this population precludes a recommendation. This offers an opportunity for further research in higher-risk populations to determine if there are clinical situations in which balanced solutions truly offer improved outcomes or if the type of isotonic crystalloid is simply unimportant for most patients in the ICU.