Fluid Response Evaluation in Sepsis Hypotension and Shock: A Randomized Clinical Trial

Abstract

Background: Fluid and vasopressor management in septic shock remains controversial. In this randomized controlled trial, we evaluated the efficacy of dynamic measures (stroke volume change during passive leg raise) to guide resuscitation and improve patient outcome.

Research question: Will resuscitation that is guided by dynamic assessments of fluid responsiveness in patients with septic shock improve patient outcomes?

Study design and methods: We conducted a prospective, multicenter, randomized clinical trial at 13 hospitals in the United States and United Kingdom. Patients presented to EDs with sepsis that was associated hypotension and anticipated ICU admission. Intervention arm patients were assessed for fluid responsiveness before clinically driven fluid bolus or increase in vasopressors occurred. The protocol included reassessment and therapy as indicated by the passive leg raise result. The control arm received usual care. The primary clinical outcome was positive fluid balance at 72 hours or ICU discharge, whichever occurred first.

Results: In modified intent-to-treat analysis that included 83 intervention and 41 usual care eligible patients, fluid balance at 72 hours or ICU discharge was significantly lower (-1.37 L favoring the intervention arm; 0.65 ± 2.85 L intervention arm vs 2.02 ± 3.44 L usual care arm; P = .021. Fewer patients required renal replacement therapy (5.1% vs 17.5%; P = .04) or mechanical ventilation (17.7% vs 34.1%; P = .04) in the intervention arm compared with usual care. In the all-randomized intent-to-treat population (102 intervention, 48 usual care), there were no significant differences in safety signals.

Interpretation: Physiologically informed fluid and vasopressor resuscitation with the use of the passive leg raise-induced stroke volume change to guide management of septic shock is safe and demonstrated lower net fluid balance and reductions in the risk of renal and respiratory failure. Dynamic assessments to guide fluid administration may improve outcomes for patients with septic shock compared with usual care.

Clinical trial registration: NCT02837731.

Keywords: dynamic fluid response measure; hemodynamics; resuscitation; sepsis; shock.

Figure 1

Flow chart model of the algorithm used to guide treatment in the Fluid Responsiveness Evaluation in Sepsis-associated Hypotension study. MAP = mean arterial pressure; NE = norepinephrine; PLR = passive leg raise; SBP = systolic BP; SV = stroke volume.

Figure 2

CONSORT patient flow chart diagram that tracks study participation and the number of patients whose condition was assessed for eligibility but could not be included in the study. DNR = do not resuscitate; ITT = intent to treat; mITT = modified intent to treat.

Figure 3

Forest plots of study end points with clarification of 95% CI limits and mean difference. MACE = major adverse cardiac event; TEAE = treatment emergent adverse event.

Figure 4

Boxplots of continuous primary and secondary end points. RRT = renal replacement therapy.

Figure 5

Bar charts compare intervention to usual care for study end points. Bal = fluid balance; MACE = major adverse cardiac event.