The CLASSIC Trial: IV Fluid Restriction in Septic Shock

Background: The Surviving Sepsis Campaign guidelines recommend an initial fixed volume of 30mL/kg of IDEAL body weight within the first 3 hours of resuscitation (weak recommendation, low-quality evidence). [2].  Additionally, the Surviving Sepsis Campaign Guidelines state there is insufficient evidence to make a recommendation on the use of restrictive versus liberal fluid strategies in the first 24 hours of resuscitation in patients with sepsis and septic shock who still have signs of hypoperfusion and volume depletion after initial resuscitation [2]. On one hand the use of higher volumes of intravenous fluids can be associated with harm (i.e. kidney injury, respiratory failure, and higher risk of death) .  On the other hand, lower volumes of intravenous fluids could lead to under resuscitation of patients with sepsis and septic shock. There is no real substantial evidence for the benefit of fluids after the initial resuscitation of patients with septic shock, and although weak, there is evidence for being more restrictive with IV fluids.

Paper: Meyhoff TS et al. Restriction of Intravenous Fluid in ICU Patients with Septic Shock. NEJM 2022. PMID: 35709019 [Access on Read by QxMD]

Clinical Question: After the initial resuscitation of patients with septic shock, does a restrictive fluid strategy improve 90 day mortality in the ICU compared to a standard care fluid strategy?

What They Did:

• Conservative versus Liberal Approach to Fluid Therapy of Septic Shock in the Intensive Care (CLASSIC)
• International, stratified, parallel-group, open-label randomized clinical trial
• 31 ICUs in Denmark, Norway, Sweden, Switzerland, Italy, the Czech Republic, the United Kingdom and Belgium
• Patients with septic shock in the ICU randomized to:
  • Restricted IV Fluids: At least 1L (Given in 250 to 500mL boluses)
    • Could only give fluids under certain circumstances:
      • Severe hypoperfusion
        • Defined as a plasma lactate ≥4mmol/L
        • MAP <50mmHg despite infusion of vasopressor or inotrope
        • Mottling beyond the edge of the kneecap (Mottling score >2 on a scale of 0 to 5, with higher scores indicating a greater area of mottling)
        • Urinary output <0.1mL/kg/hr during 1^st 2 hours after randomization
      • Fluid losses (GI or drains)
      • Dehydration or electrolyte deficiency if enteral route contraindicated
      • Ensure a total daily fluid intake of 1L including fluids with medication and nutrition if enteral route contraindicated
    • Standard IV Fluids: Standard IV fluid therapy
      • No upper limit was set for the amount of IV fluids
      • Could only give fluids under any of the following 3 conditions:
        • As long as patient had improved hemodynamic factors
        • Replace expected or observed losses or to correct dehydration or electrolyte derangements
        • Maintenance fluids
      • Enteral/oral fluids, nutrition (enteral or parenteral), and fluid used as a medium for administration of meds were allowed in both groups
      • Albumin only used following abdominal paracentesis

Outcomes:

• Primary: Death from any cause within 90d after randomization
• Secondary:
  • Serious Adverse Events (Cerebral, cardiac, intestinal, or limb ischemic events OR a new episode of severe kidney injury)
  • Number of days alive without life support (circulatory support, invasive mechanical ventilation, or renal replacement therapy) at 90d
  • Number of days alive and out of the hospital at 90d

Inclusion:

• Adults (≥18 years of age)
• In the ICU
• Had septic shock (Defined as a suspected or confirmed infection, a plasma lactate level of ≥2mmol/L, receipt of ongoing infusion of a vasopressor or inotropic agent, and receipt of at least 1L of IV fluids in 24 hours before screening)
• Onset of shock within 12hrs before screening

Exclusion:

• Septic shock >12hrs
• No consent
• Life-threatening bleeding
• Acute burn injury involving >10% of body surface area
• Pregnant

Results:

• 1554 patients enrolled
  • 1545 (99.4%) of patients enrolled had data available for primary outcome
  • Median age: 70 years
  • Median time from ICU admission to randomization: 3hrs
  • Median predicted 90d mortality: 40%
  • Admission from ED/Prehospital: 39%
  • Primary focus of infection: GI (37%), Pulmonary (27%), and Urine (16%)
  • Median volume of IV fluids 24hrs prior to randomization: ≈3100mL
  • Use of systemic glucocorticoid: 28%
  • Use of respiratory support: ≈50%
  • Median Fluids Received (Excluding fluids administered with meds and nutrition):
    • Restricted IV Fluids: 1798mL (Range: 500 to 4366mL)
    • Standard IV Fluids: 3811mL (Range: 1861 to 6762mL)
  • Median Cumulative Volume of All Fluids Given in ICU:
    • Restricted IV Fluids: 10,433mL
    • Standard IV Fluids: 12,747mL
  • Death within 90d of Randomization (Primary Outcome):
    • Restricted IV Fluids: 42.3%
    • Standard IV Fluids: 42.1%
    • Adjusted Absolute Difference: 0.1%; 95% CI 04.7 to 4.9; p = 0.96
    • Findings consistent after risk factors at baseline adjustment, per-protocol analysis (This is important due to the imbalance in protocol violations), and predefined subgroup analyses
  • Serious Adverse Events:
    • Restricted IV Fluids: 29.4%
    • Standard IV Fluids: 30.8%
    • Adjusted Absolute Difference: -1.7%; 99% CI -7.7 to 4.3; p = 0.46
  • At 90d after randomization number of days alive without life support and days alive and out of the hospital were similar in the two groups

Strengths:

• Asks a clinically important question about a common clinical presentation with low quality evidence previously
• Multinational and multicenter increasing external validity
• 31 ICUs across multiple European countries increases external validity and generalizability
• Novo Nordisk Foundation (funder of the study) had no role in the design, conduct, analyses, or reporting of results
• Groups were well balanced in terms of age, sex, comorbidities, time to randomization, source of ICU admission, focus of infection, body weight, blood values and interventions
• Appropriate antibiotics, norepinephrine, and source control in both groups
• Minimal loss to follow up (0.6%)

 Limitations:

• Treatment groups were not blinded to patients, clinicians, or investigators however this is mitigated by an objective endpoint
• IV fluid protocol was violated in 21.5% of patients in the restrictive-fluid group and 13.0% of patients in the standard fluid group (i.e. a restrictive strategy, could be more labor intensive)
• Most common infection source was gastrointestinal as opposed to pulmonary or urinary (i.e. may have increased need for larger volumes of fluid replacement)
• Patients received fluids before enrollment, there were protocol violations, and most fluid was given outside the volumes specified by the protocol. All of these issues could have significant impacts on the results
• Limited power to detect differences in some outcomes in the subgroup analyses
• There is no information on hemodynamic parameters in this study (i.e. MAP). It would be nice to know if there was a difference or no difference between groups

Discussion:

• It is important to understand the two phases of resuscitation:
  • Initial 30cc/kg of IV crystalloid within 3hrs (NOT ANSWERED BY THIS TRIAL)
  • Ongoing resuscitation after the initial resuscitation
  • This trial is attempting to answer the second part of this construct

• Despite the between group difference of volume of intravenous fluids of ≈2L, there were no significant differences in 90-day mortality or serious adverse events among ICU patients with septic shock
• The difference between groups in terms of fluids given was actually quite small after 5 days (1500cc) raises an important question…was the standard care group already being treated restrictively which made finding a 7% difference not truly possible?
  • Additionally, the difference in cumulative fluid balance (≈750mL) was also quite small after 5 days
• Focus of infection was predominantly GI in this study, which is interesting, because in most sepsis trials, pulmonary infections tend to predominate
  • One thought on this from the trial authors is that during COVID-19 with interventions to prevent airborne/aerosol spread (i.e. masks, ventilation improvements, distancing, avoiding indoors, etc) could have caused the lower number of pulmonary infections seen in this trial compared to historical sepsis trials
• Looking at the subgroup analyses, there was no statistically significant difference between groups but there are two groups worth noting as there were numeric trends toward benefit with a restrictive fluid strategy
  • Requiring respiratory support (My thought – Developing ARDS)
  • Initial fluid resuscitation >30mL/kg (My thought – No longer fluid responsive)

Author Conclusion: “Among adult patients with septic shock in the ICU, intravenous fluid restriction did not result in fewer deaths at 90 days than standard intravenous fluid therapy.”

Clinical Take Home Point: In critically ill adult patients with septic shock who received their initial 30cc/kg fluid resuscitation there are two ways to look at ongoing resuscitation based on this trial:

1. Restrictive fluid strategy ≠ fewer deaths at 90 days than standard fluid therapy
2. Restrictive fluid strategy is not worse than standard fluid therapy in terms of fewer deaths at 90 days (i.e. Safe but not superior to a standard fluid strategy)

A major caveat however is the between group differences of overall fluids given at 5 days (≈1500cc) and the rather small difference in fluid balance between groups (≈750cc) has to make one wonder how much standard care has changed to more of a conservative strategy overall in terms of fluid balance.

References:

1. Meyhoff TS et al. Restriction of Intravenous Fluid in ICU Patients with Septic Shock. NEJM 2022. PMID: 35709019 [Access on Read by QxMD]
2. Evans L et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Intensive Care Med 2021. PMID: 34599691
3. McIntyre LA et al. Intravenous Fluids in Septic Shock – More or Less? NEJM 2022. PMID: 35709013
4. Angus DC et al. A systematic Review and Meta-Analysis of Early Goal-Directed Therapy for Septic Shock: The ARISE, ProCESS and ProMISe Investigators. Intensive Care Med 2015. PMID: 25952825
5. Maitland K et al. Mortality After Fluid Bolus in African Children with Severe Infection. NEJM 2011. PMID: 21615299

For More Thoughts on This Topic Checkout:

• The Bottom Line: CLASSIC

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)