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CLOVERS Trial – Early restrictive vs liberal fluid resuscitation for Septic shock

Dr Swapnil Pawar January 29, 2023 608

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    CLOVERS Trial – Early restrictive vs liberal fluid resuscitation for Septic shock
    Dr Swapnil Pawar


Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension

(The CLOVERS trial)

National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network; Shapiro NI, Douglas IS, Brower RG, et al. Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension. N Engl J Med. 2023 Jan 21. doi: 10.1056/NEJMoa2212663. Epub ahead of print. PMID: 36688507.

Blog written by Dr Jose Chacko


Fluid resuscitation is one of the key early interventions in patients with septic shock. However, excessive fluid administration may result in fluid overload and organ dysfunction. An alternative strategy is a fluid-restrictive approach combined with the early use of vasopressors to maintain perfusion pressures. A restrictive strategy may reduce adverse effects associated with fluid overload an improve clinical outcomes. The CLASSIC pilot randomized clinical trial (2022) revealed no difference in 90-day mortality with a restrictive approach compared with unguided resuscitation.

Population and design

The study was conducted between March 7, 2018, to January 31, 2022, and enrolled 1563 patients at 60 centers in the US.


  • Adult patients with suspected for confirmed infection and hypotension with a systolic blood pressure <100 mm Hg after ≥1000 ml of IV fluids.


  • More than 4 h after meeting the eligibility criteria above
  • More than 24 h after presentation to hospital
  • Received >3000 ml fluid
  • Fluid overload
  • Severe hypovolemia not due to sepsis

Patients were randomized in a 1:1 ratio to a restrictive or a liberal strategy. A sample size of 2320 patients was to demonstrate a 4.5% difference in death before discharge (the primary outcome) in favor of the restrictive group (15% vs. 10.5%) for 90% power and two-sided alpha level of 0.05

Restrictive group

Boluses up to 2 L, including pre-randomization  norepinephrine, second vasopressor for MAP <65 or sys BP <90

Rescue fluid of 500 ml bolus if   –

  • Severe hypotension (SBP < 70, MAP < 50 mmHg)
  • Refractory hypotension (SBP <90 or MAP <65 on Norepinephrine > 20 mcg min or equivalent)
  • Lactate > 4 mmol/L and increasing after 2 hours of therapy
  • Sinus HR > 130 for 15 mins
  • Echocardiographic evidence or haemodynamic evidence of extreme hypovolaemia
  • Felt to be in the best interests by treating the team

Liberal group

2 L at randomization (may restrict to 1 L)   additional 500 ml boluses if

  • MAP < 65 or SBP < 90 mmHg
  • Lactate > 4 mmol/L and increasing
  • UOP < 30mls/hr
  • HR > 110 bpm (sinus)
  • Requirement for vasopressors
  • Measured or clinical assessment

Rescue vasopressors if:

  • severe hypotension (defined as per restrictive group),
  • lactate > 4 mmol/L and increasing after 2 hours,
  • > 5L total IV fluid given,
  • clinical manifestations of fluid overload or
  • treating the team felt to be in the best interests


The study was stopped for futility after the enrolment of 1563 patients. Patients were well-matched at baseline.

Fluids received, restrictive vs. liberal groups.


Timeline Restrictive (ml) Liberal (ml)
6 h post-randomization 500 (130–1097) 2300 (2000–3000)
24 h post-randomization 1267 (555–2279) 3400 (2500–4495)
24 h including pre-enrolment 3300 (2550–4350) 5400 ml (4400–6575)


  • Vasopressors: 59% vs. 37%; initiated earlier, continued for longer in the restrictive group in the first 24 hours
  • Ringer’s Lactate the most common fluid
  • Peripheral administration of vasopressors was safe. Five hundred patients received peripherally administered vasopressors; there were three possible instances of extravasation, with no clinical consequences


Outcome Restrictive (782) Liberal (781)
Death before discharge at 90 d 14% 14.9%
Organ support-free at 28 d 24 d 23.6 d
Ventilator-free at 28 d 23.4 d 22.8 d
RRT-free at 28 d 24.1 d 23.9 d
Vasopressor-free at 28 d 22 d 21.6 d
ICU-free at 28 d 22.8 d 22.7 d
Hospital-free at 28 d 16.2 d 15.4 d
All-cause mortality 90 d (any location) 22.4% 21.9%


*None of the outcomes were significantly different between groups

Limitations – 

  • Fluid administration of 1–3 liters was allowed before enrolment
  • Vasopressors were already in use prior to randomization in both groups (restrictive vs. liberal: 21% vs. 18%)
  • Protocol amendment: the initial bolus fluid could be restricted to 1 L if the patient was considered fluid replete
  • The study was terminated early before attaining sample size
  • Enrolment was left to physician judgment
  • No specific strategy was employed for the assessment of volume responsiveness
  • Some patients in the restrictive group received more fluids than according to protocol; those in the liberal group received early vasopressors
  • The results may not apply to subgroups of patients with different co-morbidities
  • The trial was unblinded trial with the potential for bias
  • Both groups were protocol driven; there was no “usual” care group (this created a major controversy with citizens groups contending that the trial was purely experimental)
  • Hemodynamic targets were the same for both groups
  • The study was limited to 24 hours
  • Patients were in the early phase of sepsis, who presented to the emergency department. The results may not apply to more severely ill patients and later in the course of illness

Summary –

It’s essential to have a vigilant approach to fluid resuscitation and use vasopressors cautiously if and when needed.

We recommend against a fixed dogmatic approach towards resuscitation in patients with septic shock.




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