Critical Care Alert: CLOVERS Trial

ARTICLE: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;388(6):499-510.

OBJECTIVE
The Crystalloid Liberal or Vasopressor Early Resuscitation in Sepsis (CLOVERS) trial was designed to compare the effects of an early restrictive fluid strategy (with early use of vasopressors) vs a liberal fluid strategy with regards to 90-day mortality for patients with sepsis-induced hypotension.

BACKGROUND
Intravenous fluids are used in the early resuscitation of patients with sepsis and septic shock. The goal of intravenous fluid administration in sepsis is to increase organ perfusion through improving intravascular volume that is either depleted, or functionally depleted, as a result of vasodilation and capillary leak. IV fluid administration is not without risks. Prior studies have shown that large volumes of intravenous fluid administration can cause a dilutional coagulopathy and edema within vital organs, resulting in organ dysfunction and impairment of oxygen delivery.¹

Vasopressors are also used in the early resuscitation of patients with sepsis and septic shock. They treat hypoperfusion through vasoconstriction of arterioles and venules and through increasing cardiac contractility. Like IV fluids, vasopressors also come with risks such as tissue ischemia, increased cardiac workload, arrhythmias, and traditionally the need for infusion through a central venous catheter.

While physicians have used both intravenous fluids and vasopressors to provide care for patients with sepsis and septic shock, there is limited data about which therapy provides greater benefit early in the resuscitation of sepsis-induced hypotension. The CLOVERS trial was designed to address this question. Prior to this trial, there is a building body of observational data suggesting that a restrictive fluid strategy that initiates vasopressor use earlier for hypotension may be superior to large volume fluid resuscitation, or a liberal fluid strategy.^2-5 In 2022 there was a large randomized control trial published by Meyhoff et al. (the CLASSIC trial) which compared restrictive fluid management to unguided resuscitation which did not show an improvement in 90-day mortality in the restrictive fluid group.⁶

DESIGN
This was a multicenter, randomized, unblinded superiority trial as part of the Prevention and Early Treatment of Acute Lung Injury (PETAL) Network. Patients were enrolled by research assistants usually during daytime and evening hours, with less coverage over the weekends.

Patients were randomly assigned in a 1:1 ratio to either a restrictive fluid strategy (with early vasopressor use) or to a liberal fluid strategy. In each group, the assigned protocol was followed for 24 hours. All recruited patients presented with a systolic blood pressure <100 mm Hg or MAP <65 mm Hg after receipt of 1-3 liters of crystalloids prior to randomization into the two groups.

The restrictive fluid protocol prioritized early vasopressor administration, with permission to use “rescue fluids” at recommended 500 cc bolus doses if there were signs of severe intravascular volume depletion. The group defined this as 1) SBP <70 mm Hg or MAP <50 mm Hg, 2) refractory hypotension SBP <90 mm Hg or MAP <65 mm Hg at a dose of 20 µgram/min norepinephrine or equivalent dose of another vasopressor, 3) lactate >4 mmol/L and increasing after 2h of therapy, 4) sinus tachycardia >130 bpm for 15 min, 5) echocardiographic or hemodynamic evidence of extreme hypovolemia or 6) if the clinical team thought rescue fluids may be in the best interest of the patient.

The liberal fluid protocol consisted of a recommended initial 2000-ml intravenous infusion of isotonic crystalloid, followed by fluid boluses administered on the basis of clinical triggers (e.g. tachycardia) with “rescue vasopressors'' permitted for: 1) SBP <70 mm Hg or MAP <50 mm Hg, 2) lactate >4 mmol/L and increasing after 2h of therapy, 3) clinical manifestations of fluid overload, 4) greater than 5 liters of total IV fluid administered, or 5) if the clinical team thought vasopressors may be in best interest of the patient. An amendment to the trial protocol was added limiting the initial infusion of intravenous fluids to 1000 ml if the patient’s blood pressure had stabilized and the clinical team thought the patient was “volume replete”. A detailed flowsheet of the protocol is provided in figure 1 of the article.

A trial team was present to help implement the protocol with the clinical team during the 24 hour trial period. Protocol adherence was monitored through the first 300 patients and in a 10% random sample of patients through the rest of the trial. Initial administration of vasopressor therapy was allowed through either a central line or a 20G peripheral IV or larger.

Statistical Analysis: The study was powered to detect a difference of 4.5 percentage points in the incidence of death before discharge home by day 90, estimating the need to enroll 2320 patients. Two interim analyses were planned at which point the trial could be terminated early. All analyses used an intention-to-treat approach.

INCLUSION CRITERIA

• Adult patients (>18 years old) with a suspected or confirmed infection (defined as the administration or planned administration of antibiotics) and sepsis-induced hypotension (systolic blood pressure <100 mm Hg after receiving >1000 ml of intravenous fluid)

EXCLUSION CRITERIA

• More than 4 hours since meeting criteria for hypotension refractory to at least 1000 ml of fluid
• More than 24 hours since presentation at hospital
• Previous receipt of more than 3000 ml of IV fluid (including prehospital fluid administration)
• Presence of fluid overload
• Presence of severe volume depletion from non-sepsis causes

PRIMARY OUTCOME

• Death by any cause before discharge home by day 90 (home defined as the same or a similar setting as the one that the patient resided in prior to becoming ill). The primary outcome was also assessed in further subgroups of the total cohort including: age (greater or less than 65), sex, race, Hispanic/Latino ethnicity, SBP < 90 mm Hg, location at time of randomization, history of hypertension, chronic heart failure, end-stage renal disease, SOFA score, and pneumonia as cause of sepsis.

SECONDARY OUTCOMES

• 28-day measures of the number of days free from ventilator use, days free from renal-replacement therapy, days free from vasopressor use, days out of the ICU, and days out of the hospital
• Systematically collected data on safety outcomes included initiation of mechanical ventilation, new-onset atrial and ventricular arrhythmias, and complications related to peripheral and central venous catheter use

KEY RESULTS
A total of 1563 patients at 60 U.S. centers were enrolled between March 2018 and January 2022. Seven hundred and eighty-two patients (50.0%) were assigned to the restrictive fluid group and 781 (50.0%) were assigned to the liberal fluid group. The trial was halted for futility at the second interim analysis due to a lack of differences in the primary and secondary outcomes.

Patients in both groups had similar baseline characteristics (see Table 1) and treatments before randomization:

• Similar volumes of IV fluid were given before randomization with a median of 2050 mL for both groups.
• Vasopressors had been started at the time of randomization in 21% vs. 18% of patients in the restrictive vs. liberal group, respectively.

There were several notable characteristics of each group:

• The mean volume of IV fluid administered over the first 6-hr period was 500 mL vs 2300 mL for the restrictive vs. liberal group, respectively (difference of -1800 mL).
• The mean volume of IV fluid administered over the 24-hr study period was 1267 mL vs 3400 mL for the restrictive vs. liberal group, respectively (difference of -2134).
• Vasopressors were used in 59% vs. 37% of patients in the restrictive vs. liberal group, initiated earlier in the restrictive group with a mean difference of 1.4 hours, and used for longer in the restrictive group with mean difference of 4.2 hours more.
• The total median cumulative volume of fluid administered (including pre-enrollment fluids) through 24 hrs were 3300 ml vs. 5400 mL in the restrictive vs. liberal fluid group, respectively.
• Post hoc analysis showed that 67% vs 59% of patients were admitted to the ICU during the protocol period in the restrictive vs liberal fluids group, respectively.
• Audited protocol adherence was high in both groups at 97% vs 96% for the restrictive vs. liberal group, respectively.

Primary Outcome
Death before discharge home by day 90 occurred in 109 patients (14.0%) in the restrictive fluid group and in 116 patients (14.9%) in the liberal fluid group. (-0.9 absolute percentage difference, 95% CI, -4.4 to 2.6; P=0.61). There were no observed differences in mortality in the prespecified subgroup analyses.

Secondary Outcomes
There were no statistically significant differences in any of the secondary outcomes. Further details can be seen in Table 3. 

Safety Outcomes
The number of serious adverse events were similar in the restrictive fluid group and liberal fluid group at 21 vs 19, respectively (see Tables S14 and S15). There were fewer reports of fluid overload and pulmonary edema at 0 for the restrictive group vs 3 for the liberal group. There were three instances of potential vasopressor extravasation among 500 patients who received peripherally administered vasopressors which all resolved without intervention and did not have residual clinical consequences. This supports the use of vasopressors through peripheral IVs as opposed to traditionally preferred central venous catheters, facilitating the earlier use of vasopressors in general.

LIMITATIONS

• A trial population with a higher initial illness severity may lead to differences in outcomes between the two groups. Overall, there was only a 15% mortality in this study, which is lower than what is typically seen in patients with septic shock⁸ - which may limit the ability to apply these results to a sicker patient population.
• There are possibly further subgroups, such as patients with specific coexisting conditions or a specific sepsis phenotype⁷, that were not assessed which could benefit from one of the two strategies.
• Despite high adherence to study protocol, some patients in the restrictive fluid group received more fluid than intended and received vasopressors later than intended. Some patients in the liberal fluid group received lower fluid volumes and earlier use of vasopressors than intended.
• Mean arterial blood pressure goals and lactate levels were used to guide fluid and vasopressor therapy, which may not be generally applicable to all patients as measures of organ perfusion.
• There was no group in which clinicians received no guidance on therapy (ie, there was no standard of care comparison group).
• The trial was unblinded and group assignments may have influenced the reporting of adverse events.
• The protocol duration was only up to 24 hours. It is possible that a longer treatment period may have shown different results.
• All patients evaluated had early recognized sepsis-induced hypotension after hospital presentation and these findings may not be generalizable to patients recognized as having sepsis in later phases of their care.

EM TAKE-AWAYS

• This trial did not show a significant difference in mortality at 90 days between a restrictive vs liberal fluid resuscitation approach for sepsis-induced hypotension. This adds to a recent study (CLASSIC trial) supporting no difference of outcomes for either approach. It may be equally safe to employ either strategy in a group of patients similar to those in this study.
• This study is particularly relevant to ED-based resuscitation, as the majority of patients presented through the emergency department and the trial protocol focused on the first 24 hours of resuscitation in patients with sepsis-induced hypotension.
• Fluid resuscitation strategies remain a highly debated and complex topic. It is still possible that specific patients may benefit from a restrictive fluid resuscitation strategy. Intravenous fluid or vasopressor treatment should be tailored to the individual patient by using dynamic measures of fluid responsiveness to guide resuscitation.

REFERENCES

1. Self WH, Semler MW, Bellomo R, et al. Liberal versus restrictive intravenous fluid therapy for early septic shock: rationale for a randomized trial. Ann Emerg Med.2018;72:457-466.
2. Kelm DJ, Perrin JT, Cartin-Ceba R, Gajic O, Schenck L, Kennedy CC. Fluid overload in patients with severe sepsis and septic shock treated with early goal directed therapy is associated with increased acute need for fluid-related medical interventions and hospital death. Shock. 2015;43:68-73.
3. Glassford NJ, Eastwood GM, Bellomo R. Physiological changes after fluid bolus therapy in sepsis: a systematic review of contemporary data. Crit Care. 201418:696.
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5. 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;42:1695-705.
6. Meyhoff TS, Hjortrup PB, Wetterslev J, et al. Restriction of intravenous fluid in ICU patients with septic shock. N Engl J Med. 2022;386:2459-70.
7. Gårdlund B, Dmitrieva NO, Pieper CF, Finfer S, Marshall JC, Taylor Thompson B. Six subphenotypes in septic shock: latent class analysis of the PROWESS Shock study. J Crit Care. 2018;47:70-79.
8. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-10.