Pragmatic Pediatric Trial of Balanced Versus Normal Saline Fluid in Sepsis: A Pilot Feasibility Study
Condition: Shock, Septic
MeSH terms: Sepsis; Shock, Septic
Study type: Interventional
Phase: Phase 1

Summary: 
      The objective of this pilot study is to assess overall feasibility prior to embarking on a
      larger randomized pragmatic trial comparing the clinical effectiveness of fluid resuscitation
      with NS versus LR for pediatric patients with suspected septic shock. Necessary feasibility
      assessments include ensuring appropriate compliance with study fluid in each of the two arms,
      effectiveness of study enrollment using a pragmatic study design embedded within routine
      clinical practice, and acceptability of using Exception from Informed Consent (EFIC).
    

Detailed description: 
      Approximately 5,000 children die from septic shock each year in the US and thousands more die
      worldwide. Despite widespread implementation of resuscitation protocols, contemporary studies
      still report 2-6% mortality for children with septic shock treated in the pediatric emergency
      department (ED). In the investigators' recent survey of the Pediatric Emergency Care Applied
      Research Network (PECARN), 45% of physicians had treated a child for septic shock in the ED
      who subsequently died in the hospital in the past two years.

      Fluid resuscitation is the cornerstone of resuscitation for hypovolemia and shock, and
      intravenous fluids are among the most commonly used therapies worldwide. Yet, there remains
      uncertainty as to the most appropriate fluid type to restore effective blood volume and
      optimize organ perfusion. In the absence of a clear role for the early use colloids,
      administration of crystalloid fluids is generally preferred (except in cases of hemorrhage).
      For septic shock, in particular, crystalloid fluids have long been the standard resuscitative
      fluid. Crystalloid fluids can be categorized as non-buffered (most commonly 0.9% normal
      saline [NS]) or buffered/balanced (in the US, this is most commonly lactated Ringer's [LR])
      solutions. NS and LR are inexpensive, stable at room temperature, and nearly universally
      available with identical storage volumes and dosing strategies. Notably, both are also of
      proven clinical benefit in septic shock and have extensive clinical experience for use in
      fluid resuscitation of critically ill patients. However, while NS is currently used in 80-95%
      of cases of septic shock, an increasing body of data now suggest that LR resuscitation may
      have superior efficacy and safety. Buffered crystalloids, including LR, have demonstrated a
      1-4% absolute mortality reduction and up to a 50% lower odds of dialysis compared to NS in
      observational and non-randomized interventional studies in adult sepsis. Nevertheless,
      because definitive conclusions have not been able to be drawn from existing observational and
      non-randomized studies, NS overwhelmingly remains the most commonly used fluid based on
      historical precedent while controversy remains.

      To definitively test the comparative effectiveness of NS and LR, a well-powered randomized
      controlled trial (RCT) is necessary. A large pragmatic randomized trial embedded within
      everyday clinical practice provides a cost-efficient and generalizable approach to inform
      clinicians about best comparative effectiveness of common therapies. Unlike explanatory RCTs,
      pragmatic trials need heterogeneity in patients, non-study therapies, and settings. To
      accomplish this, these trials must be large enough to detect small effects and simple enough
      to incorporate into routine clinical practice. The characteristics of LR and NS provide the
      ideal scenario for a large pragmatic trial.18 An ED-based trial is necessary to enroll
      patients at initiation of resuscitation. While any benefit is expected to be small, even a
      1-2% absolute reduction in mortality that is in line with prior adult studies would be a
      clinically important difference by saving the lives of 50-100 children in the US (and many
      more worldwide) each year. This overall public health impact is commensurate with changing
      from NS to LR because such a practice change is a simple, cost-neutral shift from largely
      using NS to largely using LR.

      However, before embarking on a large, pragmatic randomized trial that will determine the
      comparative effectiveness and safety of NS and LR, several concerns regarding feasibility of
      such a trial need to be addressed including a) ensuring adequate compliance with study fluid
      administration within each randomized arm using the proposed pragmatic study design, b)
      determining that a sufficient proportion of patients can be enrolled using the proposed
      pragmatic study design that will be embedded within routine clinical practice rather than use
      of a dedicated study team, and c) demonstrating that the study can feasibly be performed
      using EFIC when enrolling critically ill infants, children, and adolescents into this
      clinical trial. Demonstrating these feasibility criteria at a single site will strongly
      support success in a larger, multicenter study that will enroll several thousand patients
      across the 18 sites comprising Pediatric Emergency Care Applied Research Network (PECARN) to
      test morbidity and mortality outcomes.
    

Intervention name(s): Lactated Ringer; Normal saline
Intervention type(s): Drug; Drug
Intervention description(s): LR is a sterile, nonpyrogenic "balanced" solution used for fluid and electrolyte replenishment via intravenous or intraosseous administration. Each 100 mL of LR contains 600 mg sodium chloride (NaCl), 310 mg of sodium lactate (C3H5NaO3), 30 mg of potassium chloride (KCl), and 20 mg of calcium chloride (CaCl2 · 2H20) with an approximate potential of hydrogen (pH) of 6.5 (6.0 to 7.5).; Normal saline solution is an "unbalanced" crystalloid solution containing 154 mEq/L of sodium and 154 milliequivalent (mEq/L) of chloride.
Other intervention name(s): LR; 0.9% Saline; NS
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Single-center, open-label, randomized pragmatic clinical trial
Masking: None (Open Label)
Primary purpose: Other
Keywords: Sepsis; Septic shock; Pediatric; Fluid resuscitation; Saline; Lactated Ringer's; Crystalloid; Mortality; Pragmatic trial; Feasibility