Critical Care, Critical Care Alert

Critical Care Alert: The Restrictive IV Fluid Trial in Severe Sepsis and Septic Shock (RIFTS)

Critical Care Alert

Article
Corl KA, Prodromou M, et al. The Restrictive IV Fluid Trial in Severe Sepsis and Septic Shock (RIFTS): A Randomized Pilot Study. Crit Care Med. 2019;47(7):951-959.

OBJECTIVE
To assess the feasibility and initial efficacy of a restrictive resuscitation strategy that significantly limits the amount of IV fluid administered to septic patients (less than or equal to 60 mL/kg) over the first 72 hours of ED and intensive care unit ICU care.

BACKGROUND
Fluid resuscitation guidelines for severe sepsis and septic shock presently address only the initial phase of resuscitation. Significant volume resuscitation with aggressive IV fluid boluses became a widely adopted practice following the 2001 study of Early Goal Directed Therapy (EGDT) by Rivers and was included as a mainstay of the Surviving Sepsis Campaign 1 hour bundle, which includes initiation of 30mL/kg of crystalloid when severe sepsis or septic shock is clinically suspected. Since that time, further studies have contradicted the external validity of EGDT, calling into question the mortality benefit of high-volume fluid resuscitation in the setting of severe sepsis and septic shock. Furthermore, research has suggested a paradox wherein aggressive fluid loads with end targets such as stroke volume and tissue perfusion may worsen sepsis physiology by insulting the microvasculature with resultant organ edema and dysfunction. The RIFTS trial examines the efficacy of a restrictive IV fluid resuscitation strategy following early guideline directed fluid interventions in the setting of sepsis and septic shock.

DESIGN

  • Multicenter, prospective, parallel group, open label, blinded, randomized controlled trial
  • Intention to treat (ITT) analysis 

Inclusion Criterion

  • Patients admitted from emergency department suspected by attending physician of having severe sepsis or septic shock per Sepsis 2 International Consensus definitions or with less than 2 systemic inflammatory response syndrome criteria if attending physician believed the primary cause of critical illness was due to sepsis that also met the following criteria:

    • Refractory hypotension (mean arterial pressure [MAP] < 65 mm Hg following administration of 1,000 mL IV fluid OR
    • Lactic acid greater than or equal to 4 mmol/L

Exclusion Criterion

  • Age < 18 years old
  • Pregnancy
  • Primary admitting diagnosis not severe sepsis or septic shock
  • Presence of an active fluid wasting condition
  • Presence of a diagnosis indicating high-volume IV fluid resuscitation
  • Requirement for immediate surgery or extracorporeal membrane oxygenation
  • Receipt of > 60 mL/kg of IV fluid prior to randomization
  • Incarceration

Randomization

  • Between November 2016 and February 2018, 109 patients in 2 sites in the United States underwent randomization

  • 513 patients screened for trial eligibility

    • 113 patients were enrolled at 2 participating sites
    • 4 patients were withdrawn because of ineligibility identified following randomization
      • 2 from study group
      • 2 from control group
  • Eligible patients randomly assigned in 1:1 ratio to receive a restrictive (less than or equal to 60 mL/kg) IV fluid resuscitation strategy (study group) or usual care with no specified limits on IV fluid volume (control group) for the first 72 hours of treatment 

  • Resuscitative fluid volume given to either group included all IV crystalloid boluses (NS, LR) and maintenance IV infusions (NS, LR, sodium bicarbonate), with 65 mm Hg or greater target MAP achieved via fluid infusion and vasopressor administration; resuscitative fluid boluses administered prior to randomization was included in subjects' IV fluid total

  • The final analysis includes 55 patients randomized to the intervention group and 54 patients randomized to the control group

Population Characteristics

  • Baseline population characteristics were reviewed; with the exception of chronic kidney disease, the authors report balanced patient baseline characteristics between the restrictive-fluid and usual care groups

Outcomes Measured

  • Primary

    • 30-day all-cause mortality 

  • Secondary

    • 60-day all-cause mortality

    • ICU length of stay
    • Hospital length of stay
    • Development of new organ failure (cardiovascular, pulmonary, and renal)
    • Vasopressor free days
    • Ventilator free days
    • Mechanical ventilation hours
    • Electrolyte abnormalities
    • Myocardial infarction
    • Acute kidney injury (AKI), defined as a doubling in baseline (ED triage) creatinine
    • Repeat intubations
    • Disseminated intravascular coagulation (DIC)
    • Limb eschemia

KEY RESULTS

  • Primary

    • All-cause mortality at 30 days for the fluid-restrictive vs. usual care group was, respectively, 12 (21.8%) vs. 12 (22.2%), Odds ration, 1.02; 95% confidence interval [C1] 0.41-2.53.

  • Secondary

    • Amongst the secondary end-points included in the study's design, only a statistically significant difference in mechanical ventilation hours was observed for the fluid-restrictive vs. usual care group: 16.8 (7.0-26.5) vs. 37.8 (22.0-126.5), respectively, p = 0.02

Study Strengths

  • All outcomes studied are patient-centered
  • Study is randomized
  • Zero patient attrition to follow-up 

Study Limitations

  • Small cohort of subjects included in study
  • 30-day mortality is a modest primary end-point
  • By design, the study is not blinded
  • Difference in total fluid administration between groups may not be clinically significant

Authors' Conclusions
The use of a fluid resuscitation strategy that significantly limits IV fluid administration in the setting of severe sepsis and septic shock did not appear to increase mortality, organ dysfunction, or adverse events.

Discussion
Aggressive fluid resuscitation has been a mainstay of therapy in the management of sepsis and septic shock following the 2001 Trial of Early Goal Directed Therapy, and current treatment guidelines for the initial resuscitation in the setting of these syndromes calls for a standard initial bolus of 30 cc/kg of crystalloid to be completed within 3 hours with reassessment of volume status and tissue perfusion by 6 hours. However, at present there are no established guidelines to direct further IV fluid therapy beyond the 6-hour time point. A further challenge is that there is conflicting evidence regarding the mortality benefit of high-volume IV fluid resuscitation. The EGDT study from 2001 has been criticized for its use of a multimodal treatment strategy without stratification by impact on survival of individual protocol components, raising questions as to which therapeutic interventions of the protocol were most impactful on mortality. As a single center study with a total enrollment of 263 subjects, questions regarding the external validity of EGDT have also been raised. Several multi-site, randomized controlled trials - ProCESS, ARISE, and ProMISe - adopted the EGDT protocol from the Rivers study and determined that EGDT failed to reduce 90-day mortality. Further, the 2011 Fluid Expansion as Supportive Therapy (FEAST) trial and a 2017 randomized controlled trial of an early sepsis resuscitation protocol vs. usual care by Andrews et al both demonstrated an increased in-hospital mortality with high volume fluid resuscitation in the setting of sepsis and septic shock. Together, these studies prompt a consideration that high- volume IV fluid therapy may be deleterious for patient outcomes in severe sepsis and septic shock. This, in conjunction with an absent consensus on fluid resuscitative strategies in severe sepsis and septic shock beyond the initial treatment window directed by the 1-hour and 6-hour sepsis bundle, introduces an impetus for the RIFTS trial. The RIFTS trial demonstrates that the use of a restrictive IV fluid strategy (≤60 mL/kg) for the first 72 hours of care in severe sepsis and septic shock does not increase mortality at 30 days compared to IV fluid therapy with no pre-specified volume limitations. Though the results of this study serve to challenge an existing regulatory dogma that favors high volume IV fluid therapy, as a single center study of a small patient cohort, these results must be demonstrated further in larger studies prior to an adoption of this practice as standard of care. These studies are of significant relevance to the emergency medicine physician, given that the management of patients with severe sepsis or septic shock may continue in the emergency department beyond the Surviving Sepsis Campaign guidelines window of 6 hours before care is transferred to an inpatient service.


References
1. Corl KA, Prodromou M, Merchant RC, et al. The Restrictive IV Fluid Trial in Severe Sepsis and Septic Shock (RIFTS): A Randomized Pilot Study. Crit Care Med. 2019; 47(7):951-959.
2. Rivers E, Nguyen B, Havstad S, et al. Early Goal Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. N Engl J Med. 2001;345(19):1368-1377. 
3. ProCESS Investigators, et al. A Randomized Trial of Protocol-Based Care for Early Septic Shock. N Engl J Med. 2014;370:1683-1693.
4. Mouncey PR, Osborn TM, Power S, et al. Trial of Early, Goal-Directed Resuscitation for Septic Shock. N Engl J Med. 2015;372:1301-1311.
5. ARISE Investigators, et al. Goal-directed resuscitation for patients with early septic shockN Engl J Med. 2014;371(16):1496-1506.
6. Andrews B, Semler MW, Muchemwa L, et al. Effect of an Early Resuscitation Protocol on In-hospital Mortality Among Adults With Sepsis and Hypotension: A Randomized Clinical TrialJAMA. 2017;318(13):1233–1240.
7. Maitland K, Kiguli S, Opoka RO, et al. Mortality after Fluid Bolus in African Children with Severe Infection. N Engl J Med. 2011;364:2483-2495.

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