By Kathryn Radigan, MD, MSc
Attending Physician, Division of Pulmonary and Critical Care, Stroger Hospital of Cook County, Chicago
SYNOPSIS: In an international, randomized trial of 1,554 patients with septic shock who had already received > 1 liter of intravenous fluids, patients assigned to the restrictive-fluid group compared to the standard-fluid group did not have reduced mortality at 90 days.
SOURCE: Meyhoff TS, Hjortrup PB, Wettersleve J, et al. Restriction of intravenous fluid in ICU patients with septic shock. N Engl J Med 2022;386:2459-2470.
Intravenous fluids are part of the standard recommendations for septic shock but also have been associated with harm when higher volumes are administered. The Conservative versus Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care (CLASSIC) investigators conducted an international, stratified, parallel-group, open-label, randomized clinical trial that included 1,554 septic shock patients across Europe between 2018 and 2021 to determine whether limiting intravenous fluids for this group could improve 90-day survival. Screening criteria included intensive care unit (ICU) patients ≥ 18 years of age who had septic shock, defined as: suspected or confirmed infection, a plasma lactate level ≥ 2 mmol/liter, and on a vasopressor or inotropic agent who already received ≥ 1 liter of intravenous fluids in the 24 hours before screening.
Septic shock patients who met criteria were identified within 12 hours of shock onset and randomly assigned in a 1:1 ratio, in permuted blocks of six or eight, to receive restrictive or standard intravenous fluid therapy. The data and safety monitoring committee, trial statisticians, and members of the management committee were blinded, but patients, clinicians, and investigators were not. Patients in the restrictive fluid group were given intravenous fluids only if the patient had severe hypoperfusion, defined as a plasma lactate ≥ 4 mmol/liter, a mean arterial pressure < 50 mmHg despite infusion of a vasopressor or an inotropic agent, mottling beyond the edge of the kneecap, or a urinary output < 0.1 mL/kg during the first two hours after randomization. Once these criteria were met, an intravenous fluid bolus of 250 mL to 500 mL of isotonic crystalloid (saline or buffered solutions) could be given. Intravenous fluids also could be administered to replace documented fluid losses and to correct dehydration or electrolyte deficiency, or ensure a total daily fluid intake of 1 liter if the enteral route was contraindicated. For patients in the standard-fluid group, there was no upper limit for the amount of intravenous fluids. Intravenous fluids were given as long as the patient had improvement in hemodynamic factors, to replace expected or observed losses, to correct dehydration or electrolyte derangements, and/or to provide maintenance fluids per ICU protocol. Enteral and oral fluids, nutrition (enteral or parenteral), and fluid used as a medium for medication administration were allowed and administered as indicated. The primary outcome was death from any cause within 90 days after randomization.
Of the 1,554 patients enrolled, 770 were assigned to the restrictive-fluid group and 784 were assigned to the standard-fluid group. Primary outcome data were available for 1,545 patients. The restrictive-fluid group received a median of 1,798 mL of intravenous fluid (interquartile range [IQR] 500 mL to 4,366 mL) and the standard-fluid group received a median of 3,811 mL (IQR 1,861 mL to 6,762 mL). At 90 days, 323 of 764 patients (42.3%) in the restrictive-fluid group had died and 329 of 781 patients (42.1%) in the standard-fluid group had died (adjusted absolute difference 0.1 percentage points; 95% confidence interval [CI], -4.7 to 4.9; P = 0.96). Serious adverse events occurred at least once in 221 of 751 patients (29.4%) in the restrictive-fluid group and in 238 of 772 patients (30.8%) in the standard-fluid group (adjusted absolute difference -1.7 percentage points; 99% CI, -7.7 to 4.3). The number of days alive without life support and days alive out of the hospital was similar in the two groups at 90 days. Compared to standard fluid therapy, intravenous fluid restriction did not result in fewer deaths at 90 days among adult septic shock patients in the ICU.
COMMENTARY
Sepsis remains the leading cause of death in U.S. hospitals, contributing to one in every two to three deaths.1 The Surviving Sepsis Campaign (SSC) recommends rapid administration of 30 mL/kg crystalloid for hypotension or lactate ≥ 4 mmol/L, but also notes there was insufficient evidence to make a recommendation regarding the use of a restrictive vs. liberal fluid strategy after the initial fluid resuscitation.2-6 Early fluid therapy may improve cardiac output, especially in the early stages of sepsis, along with increasing microvascular perfusion, which is associated with improved organ function.7 However, the use of higher volumes of intravenous fluids also has been associated with worsening kidney injury, respiratory failure, and possibly higher risk of death.8 Literature on the optimal amount of fluid to administer to patients after initial resuscitation in septic shock continues to evolve. Although this trial hoped to solve the mystery of a liberal vs. restrictive approach to fluid resuscitation, the authors found no significant difference in mortality at 90 days nor in any of the prespecified secondary outcomes, including days alive without life support, days alive and out of the hospital, severe acute kidney injury, or other serious adverse effects, including cerebral, cardiac, intestinal, or limb ischemic events.
Before 2016, strict early goal-directed therapy (EGDT) targets were stressed, and fluids often were continued without patient reassessment or in situations when no clinical benefit had been shown.9 Subsequent revisions of the SSC guidelines highlighted the importance of dynamic measurements rather than static variables to predict fluid responsiveness.2 Studies supported the transition from a protocolized, quantitative resuscitation strategy to one that was more patient-centered and guided by hemodynamic assessment, especially since data supporting large volume fluid resuscitation in sepsis are scant.9
One of the first studies to support judicious fluids was conducted among children with severe infections and hypotension within Uganda, Kenya, or Tanzania. The Fluid Expansion as Supportive Therapy (FEAST) trial showed higher survival with the use of a more fluid-restrictive approach than with a standard approach to intravenous fluid therapy.10 Years later, a number of randomized trials supported fluid restrictive approaches.4,5,11 A systematic review examined restrictive or active fluid removal approaches with the use of diuretics or renal replacement therapy in critically ill children and adults with acute respiratory distress syndrome (ARDS), sepsis, or systemic inflammatory response syndrome (SIRS).12 Researchers found that a conservative or deresuscitative fluid strategy resulted in an increased number of ventilator-free days and decreased ICU length of stay compared with a liberal strategy or standard care.
More recently, a systematic review with meta-analysis and trial sequential analysis of randomized clinical trials comparing lower vs. higher fluid volumes in adult patients with sepsis found very low quantity and quality of evidence supporting the decision on the volumes of intravenous (IV) fluid therapy in adults with sepsis.13 Since data remained unclear, the CLOVERS trial was planned to determine the effect of a restrictive fluid strategy (vasopressors first followed by rescue fluids) as compared to a liberal fluid strategy (fluids first followed by rescue vasopressors) on 90-day in-hospital mortality in patients with septic shock. An independent data and safety monitoring board found that outcomes were similar in both arms during the scheduled interim analysis on Feb. 2, 2022, and that further enrollment was unlikely to change the result. Formal analyses of study data are in process, and findings are forthcoming, but likely will fail to provide additional answers.
As with other well-designed trials, why was there no difference observed between the restrictive-fluid group and the standard-fluid group? It remains possible that general advances and knowledge of fluid management that may have been leaning toward a more conservative approach for patients with sepsis and septic shock explain the lack of a difference between the restrictive-fluid group and the standard-fluid group. With the exclusion of fluids administered with medication and nutrition, the median cumulative volume of intravenous fluids administered in the ICU was 1,798 mL in the restrictive-fluid group and 3,811 mL in the standard-fluid group. The five-day cumulative fluid balance in the standard group (2,420 mL) was not much greater than in the restrictive group (1,676 mL). With only a difference of 744 mL between the groups, these similarities may result if the standard care delivered in ICUs already was a relatively restricted fluid strategy, highlighting that the judicious use of intravenous fluids already has become the norm.
The large number of protocol violations is notable. It should be noted that the intravenous fluid protocol was violated in the cases of 162 patients (21.5%) in the restrictive-fluid group and 101 patients (13.0%) in the standard-fluid group. In the restrictive group, 64% of violations were for fluid bolus use without criteria being met, which resulted in a median of 97 mL of fluid administered per day. In the standard group, 100% of violations were for no IV fluid being given on any single day in ICU. Although this appears concerning, there was no difference in outcome when violations were removed in per-protocol analysis. It also is important to note that the most common source of infection was gastrointestinal, which is not typical in sepsis studies (36.8% in restrictive group and 38.3% in standard group) and may have necessitated large volumes of replacement fluid, especially if diarrhea or vomiting were the predominant symptoms.
Currently there is insufficient evidence to make a recommendation regarding the use of a restrictive vs. liberal fluid strategy after initial fluid resuscitation in septic shock. For now, until data support an alternative strategy, a restrictive fluid management approach in septic shock patients may be safe, especially when used strategically. If patients have evidence of tissue hypoperfusion, fluids should be administered with a follow-up evaluation to assess whether the fluids administered improved the patient’s clinical status. Additional fluid administration should be based on the patient’s response. Further studies are needed to guide if there are specific groups of septic shock patients who particularly may benefit from a restrictive rather than a liberal fluid strategy and how much fluid is not only appropriate but optimal to improve patient outcomes.
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- Hjortrup PB, Haase N, Bundgaard H, et al. Restricting volumes of resuscitation fluid in adults with septic shock after initial management: The CLASSIC randomised, parallel-group, multicentre feasibility trial. Intensive Care Med 2016;42:1695-1705.
- 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;43:155-170.
- Meyhoff TS, Moller MH, Hjortrup PB, et al. Lower vs higher fluid volumes during initial management of sepsis: A systematic review with meta-analysis and trial sequential analysis. Chest 2020;157:1478-1496.
