Classic Trial

Standard vs Restrictive Fluid Administration

Restriction of Intravenous Fluid in ICU Patients with Septic Shock | New England Journal of Medicine (nejm.org)

The Classic Trial randomized 1554 patients in septic shock to either standard vs restrictive fluid strategies. Patients were much more critical than the CLOVERS trial, with an overall mortality of 42% (Published mortality for septic shock is in general around 30-35%)

Population: 1554 patients in septic shock. Multicenter trial with 31 ICUs in Denmark, Norway, Sweden, Switzerland, Italy, the Czech Republic, the United Kingdom, and Belgium.

Intervention: Restrictive fluid resuscitation strategy (1Ltr difference in the first day, 2 Liters difference by day 5 with large differences in the interquartile ranges)

Comparison: Standard Fluid Resuscitation.

Outcomes: No difference in mortality, serious adverse events or acute kidney injury. No difference in days alive without life support or days alive and out of the hospital.

Type of question: Therapy

Type of Study: RCT

Risk of bias: small. As with CLOVERS, the investigators couldn't be blinded. They could have blinded other trial participants such as assessors of outcomes or statisticians, but they didn't. Other cointerventions were unclear, as there are many possibilities and many different ICUs, however this is probably not adding much bias due to the size of the study and the trial site stratification.

Clinical Significance:

There is no difference in mortality or any of the above secondary outcomes when less fluid is used to resuscitate patients in septic shock. As a limitation, the difference in fluid given on average was not much, but it was much larger in a significant group of patients (should have potentially shown a difference, due to the high number of events for mortality).

Context: Previous data has shown fluid given in distributive shock is short lived, blood pressure and cardiac output improvements last approximately 30 minutes and are gone by the 1-hour mark. Most fluid goes to the extracellular compartment and only a small fraction remains intravascular. Observational data in the past has shown a dose-response increased mortality with larger amounts of fluid given (quantities beyond what these studies looked at)

Mostly Settled Science - Unlikely to change.

Refer to CLOVERS trial for additional context and information.