The CLASSIC Trial: Restriction of Intravenous Fluid in ICU Patients with Septic Shock

Journal Club Presented by: Dr. Rachel Mirsky

Question:

After the initial resuscitation, does restricting IVF in ICU patients in septic shock within the first 24 hours decrease death at 90 days/improve 90-day mortality?

Background:

The Surviving Sepsis campaign suggests an initial 30 ml/kg of ideal body weight in the first hour of resuscitation in septic shock patients but does not have sufficient evidence to recommend restrictive or liberal use of IVF in the first 24 hours. On the one hand, lower volumes can cause under resuscitation but conversely, higher volumes can cause organ damage (kidney, lung, etc.).

Article Reviewed:

Meyhoff, T. S., Hjortrup, P. B., Wetterslev, J., Sivapalan, P., Laake, J. H., Cronhjort, M., … & Perner, A. (2022). Restriction of Intravenous Fluid in ICU Patients with Septic Shock. New England Journal of Medicine, 386(26), 2459-2470.

Methodology:

• Population:
  • 18 years or older; in the ICU Nov 2018-Nov 2021
  • Septic shock (confirmed or suspected infection, lactate of 2 or greater, need for vasopressor or inotropic agent, and receipt of at least 1L of IVF in the 24 hours before screening)
  • Shock within 12 hours of screening
• Outcomes
  • Primary:
    • Death from any cause within 90 days of randomization
  • Secondary:
    • Serious adverse events (new severe AKI or cerebral, cardiac, intestinal or limb ischemic event)
    • Days alive without life support (renal, circulatory, vent) at 90 days
    • Days alive and out of hospital at 90 days
• Design
  • International, stratified, parallel-group, open-label randomized clinical trial.
  • 31 ICUs.
    • 1554 Patients randomized into restricted (770) vs. Standard (784) IV fluid therapy groups.
  • Restricted: can give 250-500cc bolus crystalloid if:
    • Hypoperfusion:
      • Lactate > 4
      • MAP < 50mmhg despite pressor
      • Mottling beyond kneecap
      • urinary output <0.1ml/kg/hr within first 2 hours of randomization
    • Fluid loss – GI or drains
    • Dehydration or electrolyte deficiency
    • To ensure total daily fluid intake of 1L (including with meds and nutrition)
  • Standard: no upper limit was set but give fluids if:
    • Patient shows improvement in hemodynamics
    • Replace expected or observed losses
    • Correct dehydration or electrolyte derangements
    • Maintenance fluids
  • Both groups got enteral/oral fluids, nutrition, and fluids for meds
    • Albumin only allowed s/p abdominal paracentesis
• Exclusion Criteria
  • Septic shock after 12 hours, no consent, life threatening bleeding, acute burn > 10% of BSA, pregnant

Results:

• Primary Results
  • Death within 90 days
  • Restricted group 42.3% Standard group 42.1%
  • Adjusted absolute difference 0.1% with 95% CI 4.7 to 4.9 p = 0.96 NOT STATISTICALLY SIGNIFICANT
• Secondary Results
  • Serious adverse events
  • Restricted group 29.4% Standard group 30.8%
  • Adjusted absolute difference -1/7% with 99% CI -7/7 to 4.3; p=0.46 NOT STATISTICALLY SIGNIFICANT
  • Number of days alive without life support and alive and out of hospital were similar

Strengths:

• Common question with low evidence published
• Randomized
• Large study across multiple ICUs increases external validity and generalizability
• Groups were well stratified.
• Appropriate antibiotics, norepinephrine and source control
• Minimal loss to follow up

Limitations:

• Treatment groups were not blinded to clinicians, patient, or investigators
• Protocol was violated 21.5% in restrictive and 13% in standard groups
• GI was most common infection source
• No info on hemodynamic parameters
• Some patient received fluids prior to enrollment, protocol violations and most fluids were given outside the volumes specified in the protocol.

Discussion:

• Initial Resuscitation is 30cc/kg of IVF within 3 hours vs Continued Resuscitation
  • CLASSIC trial attempts to address continued resuscitation.
• The fluid difference between groups was small (approximately 1500cc) after 5 days.
  • Was the standard group also being restricted? So, then it would be hard to find 7% difference.
• GI infections was greater than pulmonary infections. Pulmonary infectious are generally predominant in most sepsis trials (could be due to COVID and masks etc.)
• Worth noting- 2 subgroups (respiratory support and IV fluid >30ml/kg body weight at randomization) leaning towards benefit with restrictive fluid resuscitation (see Figure 2 from article, attached below),

Conclusion:

In adult patients with septic shock in the ICU setting, there appears to be no difference in mortality at 90 days when comparing restrictive continued fluid resuscitation with standard continued fluid resuscitation.