Restricted Fluid Resuscitation in Sepsis-associated Hypotension (REFRESH) Trial

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Sepsis can occur when a person becomes unwell due to an infection. It is caused by inflammation throughout the body and affects the functions of organs such as the heart, lungs and kidneys. Sepsis can cause low blood pressure and impaired blood flow to the body’s tissues. This is sometimes called ‘septic shock’. First line treatment of septic shock is to give intravenous fluid to help restore the circulation. Standard guidelines recommend at least 30ml/kg initially, or approximately 2 litres in an adult. Often up to 5 litres is given in the first 6 hours. However, the volume required varies between individual patients, and calculating the correct amount can be difficult. There is emerging evidence that giving too much fluid can be harmful by leaking into the tissues (such as lungs), impairing organ function, delaying recovery and increasing the risk of complications. Other research suggests that giving excessive fluid affects the body’s immune responses. In particular this can lead to adverse effects on the normal function of small blood vessels within tissues. This may be one mechanism by which too much fluid leads to harm. An alternative means of restoring adequate blood pressure is to use a drug called noradrenaline. This is a chemical produced naturally by the body, which causes blood vessels to constrict, raising blood pressure. Noradrenaline, given by a continuous infusion through a drip, has been routinely used for decades for this purpose and is known to be safe and effective. Normally noradrenaline is commenced in patients whose blood pressure does not improve after 2-3 litres of intravenous fluid. While our current guidelines recommend initial generous fluid administration for septic shock, it has been suggested that using lower volumes of fluid may result in less inflammation and harmful effects, particularly on the cells which line the walls of blood vessels and control their function. This study aims to test this hypothesis. We propose comparing an approach where patients receive a smaller volume of fluid in their initial resuscitation, against the standard guideline-recommended volume. Participants will be randomised to one or other group. We will measure the blood levels of certain chemical markers of inflammation and blood vessel function. We aim to demonstrate that giving a lower amount of fluid in the initial resuscitation phase is feasible clinically, and results in less alteration of blood vessel function and inflammation in the body.