About REDUSE

Overview

The REDUSE trial (NCT06140147) is a multicenter, investigator-initiated, randomized clinical superiority trial comparing a protocolized restrictive strategy for administration of non-resuscitation fluids with usual care in participants with septic shock. Adult patients admitted to participating intensive care units (ICUs) with septic shock are eligible for inclusion. Participants are randomized to the intervention arm or the control arm within 12 hours of admission.

Interventions

In the intervention arm, all intravenous drugs and nutrients are concentrated and administered using a protocol aimed to reduce the total volume of fluid. Participants do not receive maintenance fluids unless the total volume of fluid is not enough to provide hydration. Resuscitation fluids are administered according to local routines. The intervention lasts for the duration of the ICU stay. Participants in the control arm receive usual care.

Outcomes

The primary outcome is mortality at 90 days. Secondary outcomes include complications during ICU stay, cognitive function, health-related quality of life at 6 months, and days alive without mechanical ventilation at 90 days. Healthcare staff involved in the care of the participant are not blinded to the intervention, but participants, outcome assessors, statisticians, data managers, and conclusion-drawers are all blinded to treatment allocation.

Background and rationale

Sepsis is a type of life-threatening organ dysfunction caused by a host response to infection. Recent estimates suggest that 48 million cases of sepsis occur globally every year and that 11 million sepsis-related deaths occur annually, with the majority of cases occurring in developing countries. Septic shock is a type of sepsis with particularly severe circulatory and metabolic abnormalities. Approximately 35-50% of patients with septic shock die.

Administration of fluids is an essential component of the care of patients suffering from septic shock. Fluids are administered for different reasons:

Resuscitation fluids - administered intravenously to ensure adequate tissue perfusion and oxygenation.

Non-resuscitation fluids - administered intravenously and enterally as vehicles for medications, as vehicles for nutrition, as a means to correct electrolyte disturbances, and as maintenance fluids to ensure adequate hydration.

A total of about 1-2 L of fluid per day (about 1 ml/kg/h) is required for adequate hydration in healthy people but may increase in pathophysiological conditions due to higher-than-normal losses. More than 50% of patients with septic shock receive 4 L or more of fluids in the first day in the ICU. This may be adequate in patients with pre-existing deficits, but data suggest that administration of large volumes of fluids is not without risks. Previous non-randomized studies have indicated that excessive fluid administration might have detrimental adverse effects, such as tissue edema, which causes impaired oxygen delivery and organ function, and compartment syndromes. Therefore, it is important to investigate whether reducing excess fluid administration can improve outcomes in patients with septic shock.

In septic shock, resuscitation fluids are the major source of fluids on the first day of ICU admission, but for the rest of the time, non-resuscitation fluids dominate. The majority of fluids administered to septic shock patients during ICU stay are therefore non-resuscitation fluids. Reducing non-resuscitation fluids could thus be the most effective way to reduce excess fluid administration in septic shock patients. In order to ensure that we achieve the greatest possible reduction of excess fluids, we will test the use of a stringent protocol for restriction of non-resuscitation fluids, compared to usual care (no protocol for restriction of non-resuscitation fluids).

Previous evidence and rationale for a new trial

A recent systematic review with meta-analysis identified 13 trials comparing a restrictive approach of fluid administration with usual care in adult patients with sepsis and/or septic shock (Sivapalan 2023). Twelve of these trials assessed interventions with the objective to reduce administration of only resuscitation fluids. One trial assessed interventions to reduce resuscitation and non-resuscitation fluids (Chen 2015). A meta-analysis of the 7 trials including patients with septic shock demonstrated no difference in mortality (RR: 0.97 [97% CI; 0.86-1.09]), but differences in fluid volume between the intervention and control groups were small.

Based on data showing that non-resuscitation fluids are the major source of fluid after the first day in the ICU, we recently performed a feasibility trial comparing a protocolized reduction of non-resuscitation fluids to usual care in septic shock (Lindén-Søndersø 2019, Lindén 2023). Our data show that this approach may reduce the total volume of administered fluids by a median of 3.6 L (95% CI; 1.6 to 5.3) in the first 3 days after inclusion. This reduction is almost twice as large as that with the most effective protocol targeting the restriction of resuscitation fluids (Meyhoff 2022). The effectiveness of this approach warrants a trial assessing the effect of protocolized reduction of non-resuscitation fluid administration on patient-important outcomes in septic shock. The fact that non-resuscitation fluids differ in composition and are administered for different indications than resuscitation fluids means that the balance between benefit and harm for the two groups of fluids may differ, further strengthening the argument for such a trial.