High-impact PCCM Article Summaries: Restriction of Intravenous Fluid in Patients with Septic Shock

Meyhoff et al. Restriction of Intravenous Fluid in Patients with Septic Shock: The CLASSIC Trial. NEJM 2022

Question: Does a restrictive fluid strategy improve 90-day mortality in ICU patients with septic shock?

Why ask it: When to administer intravenous fluids (IVF) to patients with sepsis and septic shock remains a source of debate. Restrictive resuscitation may improve outcomes by avoiding the harms associated with unnecessary fluid loading. However, the safety and efficacy of this approach has not been studied in a large, randomized trial.

Intervention: 1,554 ICU patients in 8 European countries who developed septic shock within 12 hours of screening randomized to a restrictive or standard fluid strategy (see comment for details) for the duration of their ICU stay. Septic shock was defined as suspected or confirmed infection + lactate  ≥ 2 + ongoing vasopressor or inotrope use + ≥ 1L IVF administered in the 24 hours prior to screening.

Results:

• Death within 90 days (primary outcome)
  • 42.3% in the restrictive fluid group vs 42.1% in the standard-fluid group (adjusted absolute difference, 0.1 percentage points [95% CI, -4.7 to 4.9], p=0.96)
• No difference in serious adverse events, serious adverse reactions, number of days alive without life support, or number of days alive and out of the hospital
• Results were robust to a sensitivity analysis
• There was no heterogeneity in the effect of the intervention across a range of pre-specified subgroups

Conclusion: In ICU patients with septic shock, a restrictive fluid strategy did not improve 90-day mortality compared to a standard fluid strategy

Comment:

• Worth being aware of some the arguments in favor of restrictive resuscitation (an incomplete list):
  • 2021 Surviving Sepsis Campaign Guidelines recommendation for 30 cc/kg of IVF for all patients with sepsis-induced hypoperfusion or septic shock supported by low quality of evidence 
  • Analysis of mandated sepsis care in New York which found that prompt administration of antibiotics but not IVF was associated with improved mortality 
  • Across a range of studies and assessment techniques, many ICU patients with sepsis are not fluid-responsive 
  • Observational data suggesting a positive fluid balance is associated with increased mortality in patients with sepsis 
  • Re-analysis of RCTs suggesting restrictive resuscitation associated with improved outcomes 
• CLASSIC was an international, stratified, parallel-group, open-label RCT conducted in both university and community ICUs
• Notable patient characteristics
  • Median age: ~ 70 years
  • Male: 59%
  • Comorbidities
    • Ischemic heart disease or heart failure: 17%
    • Long-term dialysis: 1%
  • Median time from ICU admission to randomization: ~3 hours
  • Source of admission
    • ED or prehospital: 39%
    • Hospital ward: 37%
  • Source of infection
    • GI: 38%
    • Pulmonary: 27%
  • Median volume of IVF in the 24 hours prior to randomization: ~3L
  • Use of respiratory support: 51%

• Details of interventions
  • Restrictive-fluid group: Indications for 250-500 mL crystalloid bolus:
    • Severe hypoperfusion
      • Lactate  ≥ 4
      • MAP < 50 mmHg despite vasopressors
      • Mottling of skin beyond the edge of the kneecap
      • Urine output < 0.1 mL/kg/hr during the first 2 hours after randomization
    • Replace documented fluid loss
    • Correct dehydration or electrolyte deficiencies because of limited enteral access
    • Ensure a total daily fluid intake of 1L
  • Standard-fluid group: No upper limit on the amount of IVF that could be given for any of the following:
    • Improvement in hemodynamic factors in response to IVF
    • Replace fluid losses or correct electrolyte deficiencies
    • Need for maintenance fluids

• Results of intervention (all written as restrictive-fluid vs standard-fluid group)
  • Median IVF volume (Ls)
    • Day 1: 0.5 vs 1.3
    • Day 5: 1.5 vs 3.1
    • Day 90: 1.8 vs 3.8
  • Median total fluid volume (Ls)
    • Day 1: 1.8 vs 2.7
    • Day 5: 8.9 vs 10.8
    • Day 90: 10.4 vs 12.8
  • Median cumulative fluid balance (Ls)
    • Day 1: 0.7 vs 1.3
    • Day 5: 1.7 vs 2.4
    • Day 90: 1.7 vs 2.4
• My take
  • CLASSIC is a rigorous, large RCT with very few patients lost to follow-up, a robust primary outcome, and a diverse range of study sites that increase its external validity. The intervention produced a durable difference in management in that patients in the standard-fluid group received more fluid at every time point. Yes, the trial was open label, there were some protocol violations, and the trial was powered for an eyebrow-raising 7% difference in mortality, but I do not think these limitations detract from the study’s major findings.
  • Some, including the editorial, have raised concerns about the standard-fluid arm of this trial – noting that this approach was too “restrictive” to be viewed as usual practice and thus biased the trial towards a negative result. As just one comparison, in the PROCESS trial of early goal-directed therapy for sepsis, the protocol-based standard therapy arm received a mean of 8L of IVF between 0 and 72 hours and the usual care arm received 7L over that time frame. These differences are worth noting and comparing to your practice, but I think most would agree that the CLASSIC investigators should not have mandated extra IVF beyond what they felt was reflective of standard care.
  • Depending on one’s enthusiasm for restrictive resuscitation, you will hear the results of this trial framed as “look, restrictive resuscitation is safe” or “look, restrictive resuscitation isn’t helpful.”
  • Coupled with the preliminary results of the CLOVERS trial, CLASSIC pours cold water on the idea that restrictive resuscitation is the next innovation in sepsis care and a necessary response to the fluid-happy practice that followed the Rivers trial. We should give IVF when we think it will benefit our patients, with that decision informed by all of the (imperfect) clinical markers at our disposal. Early antibiotics, prompt source control, and frequent bedside reassessment remain the critical components of early sepsis care.