Liberal Versus Restrictive Intravenous Fluid Therapy for Early Septic Shock: Rationale for a Randomized Trial

Abstract

Prompt intravenous fluid therapy is a fundamental treatment for patients with septic shock. However, the optimal approach for administering intravenous fluid in septic shock resuscitation is unknown. Two competing strategies are emerging: a liberal fluids approach, consisting of a larger volume of initial fluid (50 to 75 mL/kg [4 to 6 L in an 80-kg adult] during the first 6 hours) and later use of vasopressors, versus a restrictive fluids approach, consisting of a smaller volume of initial fluid (≤30 mL/kg [≤2 to 3 L]), with earlier reliance on vasopressor infusions to maintain blood pressure and perfusion. Early fluid therapy may enhance or maintain tissue perfusion by increasing venous return and cardiac output. However, fluid administration may also have deleterious effects by causing edema within vital organs, leading to organ dysfunction and impairment of oxygen delivery. Conversely, a restrictive fluids approach primarily relies on vasopressors to reverse hypotension and maintain perfusion while limiting the administration of fluid. Both strategies have some evidence to support their use but lack robust data to confirm the benefit of one strategy over the other, creating clinical and scientific equipoise. As part of the National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Network, we designed a randomized clinical trial to compare the liberal and restrictive fluids strategies, the Crystalloid Liberal or Vasopressor Early Resuscitation in Sepsis trial. The purpose of this article is to review the current literature on approaches to early fluid resuscitation in adults with septic shock and outline the rationale for the upcoming trial.

Trial registration: ClinicalTrials.gov NCT03434028.

Figure 1.

Volume^a of early intravenous fluid administration (bars; left axis) and mortality^b (diamonds; right axis) in severe sepsis and septic shock studies comparing usual care to Early Goal Directed Therapy. Bars show the volume of fluid administered in liters for the usual care and Early Goal Directed Therapy groups in each study. The connected dots demonstrate the percentage of patients who died in usual care and Early Goal Directed Therapy groups in each study. Patients in the usual care group of later studies tended to receive more fluid than those in the usual care group of earlier studies, and similar to patients in the Early Goal Directed Therapy groups. Mortality was higher in the usual care group of studies in which usual care patients received less fluid than Early Goal Directed Therapy patients, but similar in the later studies in which the usual care and Early Goal Directed Therapy groups received similar volumes of fluid. UC: usual care; EGDT: Early Goal Directed Therapy; L: liter Footnotes: a. Time window for reported mean fluid volumes: first 6 hours after ED presentation: Rivers, Shapiro, Puskarich; total volume during ED stay: Trzeciak, Micek; pre-randomization period plus 6 hours post-randomization: ProCESS, ARISE, ProMISe. b. Time window for reported mortality: in-hospital: Rivers, Trzeciak, Puskarich, ProMISe; 28-day in-hospital: Shapiro; 28-day: Micek; 60-day in-hospital: ProCESS, ARISE.

Figure 2.

Scatterplot demonstrating the relationship between the difference in mean volume of fluid resuscitation^a in the Early Goal Directed Therapy group and usual care group (x-axis) verses difference in survival^b in the Early Goal Directed Therapy group and usual care group (y-axis) among 8 studies comparing Early Goal Directed Therapy and usual care for early sepsis treatment. Studies with a larger difference in fluid volumes between groups tended to have a larger difference in survival. The reference for each study is listed in brackets. UC: usual care; EGDT: Early Goal Directed Therapy; L: liter Footnotes: a. Time window for reported mean fluid volumes: first 6 hours after ED presentation: Rivers, Shapiro, Puskarich; total volume during ED stay: Trzeciak, Micek; pre-randomization period plus 6 hours post-randomization: ProCESS, ARISE, ProMISe. b. Time window for reported survival: in-hospital: Rivers, Trzeciak, Puskarich, ProMISe; 28-day in-hospital: Shapiro; 28-day: Micek; 60-day in-hospital: ProCESS, ARISE.

Figure 3.

Trial design summary for the Crystalloid Liberal Or Vasopressor Early Resuscitation in Sepsis (CLOVERS) trial.