STEPCARE

The REDUSE trial is a multi-centre, investigator-initiated, randomised clinical superiority trial comparing protocolised restrictive strategy for the administration of non-resuscitation fluids with usual care in participants with septic shock. Adult patients with septic shock will be eligible for inclusion. Participants will be randomised within six hours of admission to the intensive care unit.

In the intervention arm participants will not receive maintenance fluids unless total volume of fluid is not enough to provide hydration. All intravenous drugs and nutrition will be concentrated and administered with the objective to reduce volume of fluid. Resuscitation fluids will be administered according to local routines. The intervention will last for the duration of the intensive care unit stay. Participants in the control arm will receive usual care.

The primary outcome will be all-cause mortality at 90 days. Secondary outcomes will be complications during ICU stay, neuro-cognitive function and 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 will not be blinded to the intervention but participants, outcome assessors, statisticians, data managers, and conclusion drawers will be blinded to treatment allocation.

Sepsis is defined as life-threatening organ dysfunction caused by a host response to infection (Singer 2016). 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 (Rudd 2020). Septic shock is a subgroup of sepsis with particularly severe circulatory and metabolic abnormalities and 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 theoretical reasons. Resuscitation fluids are administered intravenously to ensure adequate tissue perfusion and oxygenation (Rhodes 2016) whereas non-resuscitation fluids are administered intravenously and enter rally as vehicles for medications, as vehicles for nutrition, to correct electrolyte disturbances, and to ensure adequate hydration (maintenance fluids). The latter purpose is considered to require a total of about 1-2 litres of fluids per day (1 ml/kg/h) in the healthy humans and 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 (Marik 2017).

This may be adequate in patients with pre-existing deficits, but data suggest that large volumes of fluids are not without risks. Non-randomised studies have indicated that excessive fluid administration might have detrimental adverse effects such as tissue oedema, with impaired oxygen delivery and organ function, and compartment syndromes (Boyd 2011, Payen 2008, Silversides 2018, Sakr 2017). These observations have inspired trials investigating if restrictive fluid administration improve outcomes in septic shock participants.