CLASSIC – IVF Restriction in Septic Shock

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Meyhoff TS, Hjortrup PB, Wetterslev J, et al. for the CLASSIC Trial Group.

Restriction of Intravenous Fluid in ICU Patients with Septic Shock.

N Engl J Med. 2022 Jun 17. [Full text]

NEJM Video Summary

The concept of early goal directed therapy (EGDT) changed how patients with septic shock were managed in the ICU and EGDT elements are now part of the standard of care. But these bundled interventions have since fallen out of favor as they do not seem to improve outcome and are associated with more fluid administration [1]. Yet, the Surviving Sepsis guidelines still reflect some of the core elements of EGDT and “suggest” an initial 30 ml per kilogram of body weight crystalloid infusion within the first 3 hours of resuscitation (though the recommendation is noted as a weak one, with low-quality supporting evidence) [2].

In the SOAP study, a large observational cohort of ICU patients, a positive fluid balance was only second to age as a predictor of mortality [3]. Other evidence, for example showed that saline (with is not “normal” [4]) is associated with acute kidney injury [5] and with mortality in critically ill septic patients [6]. Subsequent meta-analysis found a conservative fluid strategy results in an increased number of ventilator-free days and a decreased length of ICU stay with an unclear affect on mortality [7]. The Conservative versus Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care (CLASSIC) trial aimed to evaluate the effects of restriction of intravenous (IV) fluids on mortality and other important outcomes.

Patient population and Design

CLASSIC was a parallel-group, open-label, randomized clinical trial that enrolled patients from 31 ICUs in Europe. Eligible patients were adult ICU patients ≥18 years of age that had onset of septic shock (suspected or confirmed infection, lactate ≥2mmol/L, ongoing vasopressor or inotropic infusion) within 12 hours of screening and had received ≥1L of IV fluids in the 24 hours before screening. Exclusion criteria included life-threatening bleeding, burn with >10% BSA and pregnancy.

Patients were either treated with a restrictive IV fluid therapy strategy or standard IV fluid therapy. In the restrictive group, IV fluids could only be given under four conditions.

  1. Severe hypoperfusion, fluid bolus of 250 to 500 ml, for any of:
  • Plasma lactate ≥4 mmol/L
  • MAP >50 mm Hg despite vasopressor or inotrope
  • Mottling beyond the edge of the kneecap (mottling score >2 ) [8]
  • Urinary output of less <0.1 mL/kg during the first 2 hours after randomization
  1. To replace documented fluid losses (e.g., gastrointestinal or drain losses)
  2. To correct dehydration or electrolyte deficiency if the enteral route was contraindicated
  3. to ensure a total daily fluid intake of 1 liter, including fluids with medication, enteral route was contraindicated.

The authors estimated that 1554 patients would be required for the trial to have 80% power to show an absolute between-group difference of 7% in 90-day mortality.

The primary outcome was death from any cause within 90 days. Secondary outcomes included serious adverse events (cerebral, cardiac, intestinal, or limb ischemic events OR a new episode of severe kidney injury), days alive without life support (circulatory support, invasive mechanical ventilation, or renal replacement therapy) within 90 days and the number of days alive and out of the hospital at 90 days.

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Results

The target total of 1554 patients were enrolled, The median age was 70 years with most enrolled ~3 hrs after ICU admission. The median volume of IV fluids prior to randomization was about 3 L.

The median cumulative volume of IV fluids administered was 1798 mL in the restrictive group and 3811 mL in the standard group. The median cumulative volume of all fluids given, including medications and nutrition, was 10,433 mL in the restrictive group and 12,747 mL in the standard group.

There was no difference in the primary outcome of death within 90 days with 42.3% in the restrictive group and 42.% in the standard group (adjusted absolute difference 0.1%; 95% CI 04.7 to 4.9; p = 0.96). The results of the sensitivity analysis were similar after adjustment for risk factors, when done per-protocol or in subgroup analysis.

There was no difference in serious adverse events within 90 days with 29.4% in the restrictive group and 30.8% in the standard group (adjusted absolute difference -1.7%; 99% CI -7.7 to 4.3; p = 0.46). There was also no difference in number of days alive without life support and days alive and out of the hospital.

Discussion

CLASSIC did not demonstrate a difference in mortality (primary outcome), adverse events, days without life support or days out of the hospital with a restrictive fluid strategy. This is counter to much of the evidence, largely observational, leading up to the trial. So is a restrictive fluid strategy unnecessary?

This is a “negative” trial. But in the ICU, a mortality benefit is notoriously difficult to demonstrate, let alone a 7% difference, as was the design of this study. When one considers that the effective difference between the groups was only about 2L IV (1798 mL vs. 3811 mL) compared to a total volume received of 10-12L (10,433 mL vs. 12,747 mL). It is hard to imagine 2L having a sizable impact.

A McIntyre LA, Marshall JC point out in their accompanying editorial, the 3811 mL received in the standard therapy group is much lower than other studies evaluating goal-directed resuscitation [9]. As a comparison, in the original and subsequent EGDT trials 2-4.5 L of fluid were given just in the first 6 hours [10]! It may be that, just like EGDT, some portions of care become common or standard practice. The idea of judicious IV fluid use has likely permeated practice as well. And regardless of CLASSIC results, more thoughtful administration of fluids based on hemodynamics, clinical targets (cap refill time?), and/or fluid tolerance remains prudent.

F: Follow upYes
R: RandomizationYes
I: Intention to treatYes
S: Similar at baselineYes
B: BlindingYes
E: Equal treatmentYes
S: Source (funding)Novo Nordisk Foundation and others
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  2. Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021 Nov;47(11):1181-1247.
  3. Vincent JL, Sakr Y, Sprung CL, et al.; Sepsis Occurrence in Acutely Ill Patients Investigators. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. 2006 Feb;34(2):344-53.
  4. Awad S, Allison SP, Lobo DN. The history of 0.9% saline. Clin Nutr. 2008 Apr;27(2):179-88. doi: 10.1016/j.clnu.2008.01.008. Epub 2008 Mar 3.
  5. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012 Oct 17;308(15):1566-72.
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  7. Silversides JA, Major E, Ferguson AJ, et al.; Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the resuscitation phase of critical illness: a systematic review and meta-analysis. Intensive Care Med. 2017 Feb;43(2):155-170.
  8. Ait-Oufella H, Lemoinne S, Boelle PY, et al. Mottling score predicts survival in septic shock. Intensive Care Med. 2011 May;37(5):801-7.
  9. McIntyre LA, Marshall JC. Intravenous Fluids in Septic Shock – More or Less? N Engl J Med. 2022 Jun 30;386(26):2518-2519.
  10. Angus DC, Barnato AE, Bell D, Bellomo R, Chong CR, Coats TJ, Davies A, Delaney A, Harrison DA, Holdgate A, Howe B, Huang DT, Iwashyna T, Kellum JA, Peake SL, Pike F, Reade MC, Rowan KM, Singer M, Webb SA, Weissfeld LA, Yealy DM, Young JD. A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. Intensive Care Med. 2015 Sep;41(9):1549-60.