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CLASSIC vs CLOVERS Trial for Fluid Strategy

Updated: Apr 9, 2023


The results of the CLOVERS trial are now released at NEJM and revealed that 90-day mortality is not different between conservative fluid strategy with early vasopressor use and liberal fluid strategy with fluid-predominant approach. All patients who were eligible to be included in the study were:

  • Adult (≥18 years of age) with a suspected or confirmed infection defined as the administration or planned administration of antibiotic agents) and

  • Had sepsis-induced hypotension defined as systolic blood pressure, <100 mm Hg after the administration of ≥1000 ml of intravenous fluid (up to 3 liters).

The study protocol excluded patients with the following criteria

  • An elapse of more than 4 hours since the meeting of the criteria.

  • An elapse of more than 24 hours since presentation at the hospital.

  • Previous receipt of more than 3000 ml of intravenous fluid during this episode (including prehospital administration of fluid by emergency medical services).

  • The presence of fluid overload, and severe volume depletion from nonsepsis causes.


On the other hand, the CLASSIC trial included patients with:

  • Septic shock defined as per sepsis-3 criteria AND

  • Receipt of at least 1 liter of intravenous fluids in the 24 hours before screening.

The trial excluded patients who have had septic shock for more than >12 hours at the time of screening, who have life-threatening bleeding, or acute burn injury of >10% of the body surface area, and who are pregnant.




The following table summarizes comparisons of the two trials in relation to different parameters:

CLASSIC Trial

CLOVERS Trial

Blinded Trial

No

No

Countries

Europe and UK

USA

Number of patients

755

782

Median age (years)

72

59

Patient's Diagnosis

Septic Shock

Sepsis-induced hypotension

Patient source

>90% from ER

ER, hospital wards, OR, or ICU

SOFA score

?

3.4±2.8

Pre-randomization fluid

At least 1 liter

1-3 liters

Rescue boluses

Yes

Yes

Duration

ICU course

24 hours

Median fluid in 24 hours (IQR)

500 mL (0-1400)

1267 (555 to 2279)

90-day mortality

42.3%

14%

Evidently, the table reflects that patients in the CLASSIC trial are generally older and have the diagnosis of septic shock along with elevated lactic acid levels. Therefore, they must be sicker than the patients in the CLOVERS trial even though no report of SOFA score in the CLASSIC trial. The CLOVERS trial is distinctive in its patient population, since it mostly included those who initially visited an emergency room with sepsis. In contrast, the CLASSIC trial included a substantial portion of patients (34%) who previously received care on hospital wards and another 23% from operating rooms prior to ICU admission. Restriction of fluid extended for the duration of the ICU admission in the CLASSIC trial compared to 24 hours after randomization in the CLOVERS trial. In both trials, patients received rescue fluid based on specific criteria. The amount of fluid (median) received in the first 24 hours was higher in the CLOVERS trial compared to the CLASSIC trial reflecting the more stringent criteria for fluid rescue in the CLASSIC trial. Nevertheless, there were no difference noted in 90-day all-cause mortality between the two group in either study. Mortality rate in the CLASSIC trial was much higher compared to the mortality in the CLOVERS trial reflecting a higher severity of illness in the population of the CLASSIC trial.


Some benefits of the CLOVERS and CLASSIC trials:

  • Initial fluid resuscitation volume does not necessarily have to be 30 mL/kg.

  • Vasopressors can be used through a peripheral IV line in the first 24 hours at a low dose safely and reliably.

  • Restrictive strategy is not harmful, nor is the liberal strategy!

  • Please list any other conclusions of your own in the comment section of this blog!


So, let's conclude with the following poll:

Based on the results of CLASSIC and CLOVERS trials, which fluid strategy would you use in septic patient?

  • Restrictive fluid strategy

  • Liberal fluid strategy

  • Other strategy




Reference

  1. Meyhoff TS, Hjortrup PB, Wetterslev J, Sivapalan P, Laake JH, Cronhjort M, Jakob SM, Cecconi M, Nalos M, Ostermann M, Malbrain M, Pettilä V, Møller MH, Kjær MN, Lange T, Overgaard-Steensen C, Brand BA, Winther-Olesen M, White JO, Quist L, Westergaard B, Jonsson AB, Hjortsø CJS, Meier N, Jensen TS, Engstrøm J, Nebrich L, Andersen-Ranberg NC, Jensen JV, Joseph NA, Poulsen LM, Herløv LS, Sølling CG, Pedersen SK, Knudsen KK, Straarup TS, Vang ML, Bundgaard H, Rasmussen BS, Aagaard SR, Hildebrandt T, Russell L, Bestle MH, Schønemann-Lund M, Brøchner AC, Elvander CF, Hoffmann SKL, Rasmussen ML, Martin YK, Friberg FF, Seter H, Aslam TN, Ådnøy S, Seidel P, Strand K, Johnstad B, Joelsson-Alm E, Christensen J, Ahlstedt C, Pfortmueller CA, Siegemund M, Greco M, Raděj J, Kříž M, Gould DW, Rowan KM, Mouncey PR, Perner A; CLASSIC Trial Group. Restriction of Intravenous Fluid in ICU Patients with Septic Shock. N Engl J Med. 2022 Jun 30;386(26):2459-2470. doi: 10.1056/NEJMoa2202707. Epub 2022 Jun 17. PMID: 35709019.

  2. Self WH, Semler MW, Bellomo R, Brown SM, deBoisblanc BP, Exline MC, Ginde AA, Grissom CK, Janz DR, Jones AE, Liu KD, Macdonald SPJ, Miller CD, Park PK, Reineck LA, Rice TW, Steingrub JS, Talmor D, Yealy DM, Douglas IS, Shapiro NI; CLOVERS Protocol Committee and NHLBI Prevention and Early Treatment of Acute Lung Injury (PETAL) Network Investigators. Liberal Versus Restrictive Intravenous Fluid Therapy for Early Septic Shock: Rationale for a Randomized Trial. Ann Emerg Med. 2018 Oct;72(4):457-466. doi: 10.1016/j.annemergmed.2018.03.039. Epub 2018 May 10. PMID: 29753517; PMCID: PMC6380679.

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