Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease

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).

Inclusion Criteria:

1. < 12 months of age (including premature newborns),

2. diagnosed with congenital heart disease (including anatomic, myopathic and arrhythmic
conditions),

3. received ≤ 1 dose of SUP (including histamine-2 receptor antagonists, proton pump
inhibitors, and sucralfate) during current admission, AND

4. anticipated to require respiratory support for > 24 hours during their CICU stay.
Respiratory support includes mechanical ventilation, non-invasive positive-pressure
ventilation and high-flow oxygen therapy.

Exclusion Criteria:

1. prior use of antacids (including histamine-2 receptor antagonists, proton pump
inhibitors, or sucralfate) in the past month for > 7 days,

2. active gastrointestinal bleeding,

3. active Helicobacter pylori infection,

4. administration of high-dose steroids (equivalent dosing to 15 mg/kg/day of
methylprednisolone),

5. will receive ketorolac (intravenous nonsteroidal anti-inflammatory drug) during
admission,

6. exposed to specific anticoagulants (high-dose aspirin, direct thrombin inhibitors and
GPIIbIIIa inhibitors),

7. planned to undergo or recently has undergone gastrointestinal surgery (i.e. repair of
duodenal atresia)

8. supported by extracorporeal membrane oxygenator (ECMO) or ventricular assist device
(VAD),

9. currently enrolled in another intervention trial,

10. known to be allergic to H2RAs,

11. admitted for palliative care,

12. prior enrollment in the study, OR

13. primary provider declines enrollment.