Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
Condition: Congenital Heart Disease; Upper Gastrointestinal Bleeding; Stress Ulcer; Infection
MeSH terms: Gastrointestinal Hemorrhage; Heart Diseases; Heart Defects, Congenital; Ulcer
Study type: Interventional
Phase: Phase 4

Summary: 
      Infants with congenital heart disease often require an intervention during their first year
      of life. Infants are generally admitted to a cardiac intensive care unit and are routinely
      prescribed stress ulcer prophylaxis to decrease acid release from the stomach to prevent
      stress ulcer formation. However, these medicines may not be safe and could put infants at
      increased risk for hospital-acquired infections, necrotizing enterocolitis and alteration to
      the infant's microbiome. The investigators plan to assess the feasibility of conducting a
      prospective, blinded randomized control trial to determine the safety of withholding stress
      ulcer prophylaxis in critically ill infants with congenital heart disease. In addition, the
      investigators plan to examine the changes to the infant's microbiome through oral, gastric
      and stool samples and compare hospital-acquired infections.
    

Detailed description: 
      Background & Significance. Approximately 36,000 infants are born with congenital heart
      disease (CHD) in the United States each year, often requiring surgical intervention in the
      first year of life. They are vulnerable to postoperative morbidities including infection,
      growth failure and neurodevelopmental delay. Upon admission to the cardiac intensive care
      unit (CICU), infants are routinely prescribed stress ulcer prophylaxis (SUP) to decrease acid
      release from the stomach thus preventing ulcer-induced upper gastrointestinal (UGI) bleeding.
      Although adopted from the adult literature, this practice is expensive and has not been shown
      to be effective in infants. More importantly, recent literature suggests that this may not be
      safe. Studies show an increased risk of hospital-acquired infections, necrotizing
      enterocolitis and alterations in the evolving healthy gut flora in infants. The study
      investigators have recently demonstrated an increased risk of infection in children receiving
      SUP and also reported differences in microbial diversity among children in the CICU. It is
      necessary to proceed with a prospective trial to determine the safety of withholding SUP in
      critically ill children with CHD.

      Specific Aims & Hypothesis. The overarching hypothesis of the proposal is withholding SUP
      from critically ill infants with CHD is safe and results in favorable microbial diversity,
      thus decreasing hospital-acquired infections. Primary Aim 1 of the study is to assess the
      feasibility of this pilot randomized, controlled clinical trial of SUP versus placebo in
      infants admitted to the CICU. The study investigators hypothesize that a priori feasibility
      measures will be achieved during the study period. Primary Aim 2 of the study is to examine
      the differences of UGI bleeding in critically ill infants with CHD receiving SUP versus those
      receiving placebo. The study investigators hypothesize that the rate of UGI bleeding will be
      no different between infants exposed to SUP and to placebo. Secondary Aim 1 of the study is
      to compare the differences in the abundance of microbial taxa and functional profiles of the
      aerodigestive tract microbiome between infants receiving SUP and those receiving placebo and
      before/after the start of SUP. The study investigators hypothesize that there will be
      significant differences in the abundance of microbial taxa and the functional profiles
      between the 2 groups - with a more favorable microbial profile present in infants in the
      placebo group. Secondary Aim 2 is to examine the difference in the incidence of
      hospital-acquired infections in critically ill infants with CHD receiving SUP versus placebo.
      The study investigators hypothesize the rate of hospital-acquired infections will be higher
      in patients exposed to SUP when compared to placebo.

      Study Design & Methods. A single-center, prospective, double-blinded, randomized, controlled
      trial will be conducted as a feasibility study for a larger multicenter trial. Consecutive
      infants < 12 months of age with CHD admitted to the CICU and anticipated to require
      respiratory support for > 24 hours will be enrolled and randomized to receive a histamine-2
      receptor antagonist (H2RA) medication or study placebo. Patients will remain in the study
      until discontinuation of respiratory support, discharge from the CICU or study day 14. Oral,
      gastric and stool samples will be obtained prior to receiving the first dose of study drug
      and subsequently at the end of the study. The samples will be analyzed for 16S RNA and
      metagenomic shotgun sequencing for microbiome composition. Gastric pH will be recorded on all
      gastric samples. Demographics, nutrition variables, medications, and respiratory data will be
      collected for all patients while enrolled in the study. An independent Drug Safety and
      Monitoring Board (DSMB) will monitor patient safety every 6 months and after any significant
      adverse event.

      Outcomes. The primary outcomes will be study feasibility and incidence of clinically
      significant UGI bleeding. Feasibility will be defined as: 1) > 80% screening of eligible
      patients, 2) > 20% consent rate, 3) > 80% receive timely first dose of study drug, and 4) >
      80% protocol adherence. Clinically significant UGI bleeding will be defined as new-onset
      bleeding with subsequent pre-defined physiologic or hemodynamic changes. The secondary
      outcomes of the study will be observed differences in the aerodigestive microbial diversity
      between study groups, mortality, length of stay, duration of respiratory support, bleeding
      events, incidence of necrotizing enterocolitis and incidence of hospital-acquired infections
      (ventilator-associated pneumonia, central line-associated bloodstream infections,
      catheter-associated urinary tract infections, superficial sternal infection or
      mediastinitis).
    

Intervention name(s): Famotidine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Patients will be randomized to either receive a placebo or famotidine (study drug).; Patients will be randomized to either receive a placebo or famotidine (study drug).
Other intervention name(s): Pepcid; Normal saline or stevoside-free syrup
Intervention MeSH terms: Famotidine
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Prospective, double-blinded randomized placebo-controlled pilot feasibility trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Other