By: Paige Machado, M.D.

Faculty Editors: Emily Cleveland, M.D. and Laura Welsh, M.D.

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IV fluids are one of the most commonly administered interventions in the emergency department, but many of us don’t really think of fluids as a therapeutic intervention like we would other medications. We give fluids for a myriad of indications, but several questions arise when we do. What type of fluids should I give? What is the evidence behind giving fluids to my patient? Our most recent Journal Club further investigated these questions.

Paper I: SALT-ED Trial: Balanced Crystalloids versus Saline in Noncritically Ill Adults by Self et al in the New England Journal of Medicine (2018)

Background: It’s an age-old debate in medicine: should we give patients who need fluid resuscitation normal saline or lactated ringers? Although theoretical physiologic concerns and animal studies abound, there have been few large-scale human trials aiming to answer this question.

Methods: This was a single-center, unblinded, multiple crossover trial with an intention-to-treat analysis comparing normal saline to balanced crystalloids (Lactated Ringers or Plasmalyte) in noncritically ill emergency department patients. Patients were excluded if they received less than 500cc of fluid or were subsequently hospitalized in the ICU (a different trial studied this patient population concurrently). The primary outcome was hospital free days to day 28, and the secondary outcome was “major adverse kidney events” at 30 days, a composite outcome including persistent kidney injury, new renal replacement therapy, and death.

Results: 13,347 patients were randomized in this study. The median amount of fluid given to each group was one liter. There was no difference in hospital-free days between the groups (OR 0.98, CI 0.92-1.04, p 0.41). However, there was a difference in the composite secondary outcome, with a lower incidence of major adverse kidney events in the balanced crystalloids group (4.7% vs 5.6%, OR 0.82, CI 0.7-0.95, p 0.01).

Our Journal Club Discussion:  This was a large trial powered to detect small differences in outcomes. Even though there was no difference in the primary outcome, there was a difference between the groups in “major adverse kidney events” (MAKE), a composite of death, new renal replacement therapy, or persistent kidney injury. Patients given balanced crystalloids had lower rates of MAKE than patients given normal saline. The difference was small, only 0.9% between the two groups, with a number needed to treat of 111. You could argue that this difference is too small to be meaningful, but given the millions of non-critically ill patients who get fluids in the ED every year across the country, this finding might still be clinically significant. Furthermore, secondary outcomes are not typically powered to detect major differences and are rather meant to be hypothesis-generating, so findings should be interpreted with caution. Some pitfalls of this study include that it was a single center study and was unblinded. The type of fluid given beyond the ED was not controlled for, which could impact outcomes. The major finding in this study comes from a composite outcome, which increases the risk of confounding. Additionally, the difference in the composite outcome for MAKE was largely driven by an increase in persistent kidney injury in the NS group, defined as a final serum creatinine greater than 200% of baseline, which is not a patient centered outcome. Finally, some questions were raised about the ethics of using waived consent in this study, and what that may have meant if a difference in mortality had in fact been discovered.

The upshot: It could be debated whether this study is practice changing given the small difference in outcomes, but many argued that since LR administration makes more sense physiologically, it has already become their fluid of choice when the option arises.

Paper II: RIFTS Trial: The Restricted IV Fluid Trial in Severe Sepsis and Septic Shock: A Randomized Pilot Study by Corl et al in Critical Care Medicine (2019)

Background: Since the widespread adoption of the Surviving Sepsis guidelines, the current accepted practice in sepsis management is “aggressive fluid resuscitation” with expectations of a 30ml/kg bolus of fluid within the first three hours and often much more than that over the first 1-2 hospital days.  However, there is increasing evidence – albeit mostly from animal models and retrospective studies – that this strategy of large-volume fluid resuscitation may be causing more harm to patients than first thought. The RIFTS trial explored the idea of a restrictive IV fluid strategy compared to usual standard of care.

Methods: This was a multi-center, prospective, unblinded randomized control trial using an intention-to-treat analysis. Patients were randomized to receive restrictive fluids (less than or equal to 60ml/kg) or usual standard of care within the first 72 hours of treatment. The primary outcome was 30 day all-cause mortality, and the secondary outcomes included hospital length of stay, vasopressor free days, ventilator free days, mechanical ventilation hours, and AKI among others.

Results: 109 patients were randomized in this study. The intervention group received less fluid than the control group (47.1 mL/kg vs 61.1 mL/kg in the first 72h). There was no difference in 30 day all-cause mortality between the groups (OR 1.02, CI 0.41-2.53). Among the secondary outcomes, the only statistically significant finding was a reduced number of mechanically ventilated hours in the intervention group (16.8, CI 7.0–26.5 vs 37.8, CI 22.0–126.5, p 0.01).

Our Journal Club Discussion:  Unlike the SALT-ED trial, this was a very small trial, billed as a ‘pilot study’ by its authors. Unfortunately, the trial was not powered to study its primary outcome, which makes it very difficult to generalize results. It should not be used to change practice. Some concerns were raised about the study’s methods including the fact that the patients in the restrictive fluids group had higher rates of CKD, that few patients in either group had elevated lactate – suggesting that despite targeting septic patients the study may not have enrolled many sicker individuals – and also that patients with altered mental status (likely a sizeable portion of those with septic shock) were excluded. Ultimately the difference in fluid administered between the groups was only 800ml, and both groups received two- to three-fold less fluid than was given in the other surviving sepsis studies: Rivers (168ml/kg), ProCESS (108-130ml/kg), ProMISe (98ml/kg) and ARISE (108-109ml/kg), so both groups in this trial might really be considered fluid restrictive. The authors argue that despite this, the trial still suggests no increase in mortality compared to other studies of septic patients, and may show that restrictive fluids are non-inferior to the usual standard of care in sepsis.

The upshot: We are hesitant to make any big conclusions from the study given that it was underpowered for its primary outcome, but it does raise an interesting and important question about sepsis management. We look forward to the results of the CLOVERS trial, a much larger undertaking meant to further investigate essentially the same clinical question.

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References:

1. Self, W. H., Semler, M. W., Wanderer, J. P., Wang, L., Byrne, D. W., Collins, S. P., Slovis, C. M., Lindsell, C. J., Ehrenfeld, J. M., Siew, E. D., Shaw, A. D., Bernard, G. R., & Rice, T. W. (2018). Balanced crystalloids versus saline in noncritically ill adults. New England Journal of Medicine, 378(9), 819-828. https://doi.org/10.1056/nejmoa1711586

2. Corl KA, Prodromou M, Merchant RC, et al. The Restrictive IV Fluid Trial in Severe Sepsis and Septic Shock (RIFTS): A Randomized Pilot Study. Crit Care Med. 2019;47(7):951-959. doi:10.1097/CCM.0000000000003779

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