Less Fluid Not Better for Septic Shock

A more restrictive protocol for IV fluids didn’t reduce mortality for adults in the ICU receiving treatment for septic shock, the CLASSIC trial showed.

Restricting IV crystalloid fluids to small boluses only for severe hypoperfusion, to replace documented fluid losses, or for dehydration and electrolyte deficiency for patients who couldn’t take fluids enterally yielded a 42.3% survival rate at ICU discharge or up to 90 days, compared with 42.1% without a restriction on fluids.

Serious adverse events were similar between groups as well (29.4% vs 30.8% at 90 days), Anders Perner, MD, PhD, of Rigshospitalet Blegdamsvej in Copenhagen, Denmark, and colleagues reported in the New England Journal of Medicine.

The study findings were also presented at the 2022 Critical Care Reviews meeting.

Number of days alive, days alive without life support, and days out of the hospital also came out similar between groups.

However, the difference in volume of fluids actually administered came out to only about 2 liters between groups (median 1,798 vs 3,811 mL).

This suggested “that the patients in the standard-care group were also treated according to a conservative fluid strategy, making the detection of a 7-percentage-point difference in 90-day mortality (the difference for which the trial was powered) appear infeasible,” wrote editorialists Lauralyn McIntyre, MD, of the University of Ottawa, and John Marshall, MD, of the University of Toronto.

Usual care can be a tricky comparator.

The standard-care group got an IV volume “substantially less than that observed in previous national and international trials of early, goal-directed resuscitation involving patients with septic shock and in cohort studies,” McIntyre and Marshall noted.

The usual care group in the CLASSIC trial was supposed to have followed the 2016 Surviving Sepsis Campaign guidelines for an initial IV fluid dose of 30 mL/kg body weight to improve circulation, then further fluids as long as the patient’s hemodynamics were improving, to replace expected or observed losses, to correct dehydration or electrolyte problems, or if the ICU’s protocol recommended maintenance fluids. No upper limit was set.

However, the editorialists pointed out, “The results of work completed previously by the authors that suggested benefit from a more restrictive fluid-management strategy might have changed clinical practice in northern Europe sufficiently that this trial was unable to answer the question it set out to address.”

The CLASSIC trial included 1,554 patients in 31 ICUs across Belgium, the U.K., Czech Republic, Italy, Switzerland, Sweden, Norway, and Denmark.

Participants had to be adults with confirmed or suspected infections, plasma lactate levels of 18 mg/dL or higher, and be receiving an ongoing vasopressor or inotropic agent. Those with septic shock for 12 or more hours, life-threatening bleeding, acute burns on ≥10% of their bodies, or pregnancy were excluded.

Those in the fluid-restricted group were able to receive a bolus of 250 to 500 mL of isotonic crystalloid IV fluids under the following conditions:

• Severe hypoperfusion
• Mean arterial pressure below 50 mm Hg
• Mottling beyond edge of the kneecap
• Urinary output of less than 0.1 mL/kg body weight during the first 2 hours

Both groups were able to receive fluids to meet daily fluid intake requirements of 1 liter, and as a medium to receive medication.

The researchers acknowledge that patients and personnel knowing which groups they belonged to could be a potential limitation, along with lack of data on co-interventions, hemodynamic factors, and receipt of fluids not limited to the investigational protocol before being enrolled in the trial.

Despite the limitations, the editorialists concluded that “the CLASSIC trial generated rigorous, high-quality evidence related to a complex research question with regard to fluids in patients with septic shock. These findings show that a highly restrictive fluid-management strategy is safe and raise important new questions that challenge conventional wisdom regarding the management of shock.”