Approximately 40,000 infants are born each year in the United States with congenital heart defects (CHD), and heart defects are the leading cause of birth defect-related deaths in the United States. While advances in surgical treatment and cardiopulmonary bypass have improved survival for children born with CHD, these infants continue to suffer morbidity from post-operative multiple organ dysfunction (MODS)2,26. Infants with left sided obstructive CHD are at particular risk of MODS. Putative mechanisms for post-operative MODS are via loss of intestinal epithelial barrier function (EBF) and low intestinal microbiome diversity9,15,27. In a single center pilot study of 20 infants and children after surgical repair of CHD, we found that delayed enteral nutrition (EN) initiation was associated with worse intestinal epithelial integrity. We also identified that longer duration of post- operatve antibiotics was associated with loss of tight junction integrity and worse intestinal permeability, perhaps through reduced intestinal microbiome diversity 22,23,28. These lines of evidence suggest that delayed EN initiation and longer duration of post-operative antibiotic prophylaxis may increase risk for MODS in infants after surgical correction of left sided obstructive CHD through negative effects on the host intestinal EBF and microbiome diversity. The goal of this proposal is to prepare Dr. Typpo for an independent career in clinical- translational research investigating the role intestinal EBF and microbiome diversity on MODS incidence and severity through an educational program and completion of the following 2 specific aims:
Specific Aim 1 : Determine the effect of timing and composition of EN on the recovery of intestinal EBF over the first 7 post- operative days for infants undergoing surgical correction of left sided obstructive cardiac defects.
Specific Aim 2 : Determine the effect of duration and type of perioperative antibiotic exposure on change from baseline microbiome diversity, intestinal EBF, and site-specific intestinal permeability over the first 7 post-operative days in infants undergoing surgica correction of left sided obstructive cardiac defects. We will leverage existing practice variation for timing of EN initiation and antimicrobial prophylaxis across three cardiac centers. This proposal is significant, because we will address gaps in knowledge regarding the optimal timing of EN initiation after surgical correction of infant CHD to maintain intestinal barrier functions. This proposal is innovative, because we will apply knowledge gained from animal models to investigate how duration of perioperative antibiotics and EN timing and composition might negatively alter the intestinal microbiome for human children. Care strategies with the intent to limit negative effects on the intestinal microbiome during a critical window of microbiome development may have long lasting effects on the development of several chronic illnesses, in addition to immediate effects on risk of MODS25,30-32,80,81. This career development award will prepare Dr. Typpo to apply the emerging science of minimally invasive intestinal EBF assessment and microbiome analysis to identify strategies to reduce post-operative MODS in her patients.

Public Health Relevance

Malnutrition affects 1 in 2 children hospitalized in the pediatric cardiac intensive care unit, may develop or worsen over the course of critical illness, and is associated with increased mortality and organ dysfunction. By addressing fundamental knowledge gaps regarding the extent to which nutritional support and routine care practices alter intestinal barrier dysfunction and the intestinal microbiome for critically ill infants and children after repair of congenital heart disease, this proposed research address two major NIH content and methods focus areas; childhood nutrition and biomarker development. The proposed studies have the potential to change policy regarding optimal nutritional support in the pediatric cardiac intensive care unit, and promote more focused diagnostic testing to identify early intestinal epithelial barrier dysfunction

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23DK106462-03
Application #
9416121
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Saslowsky, David E
Project Start
2016-04-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Arizona
Department
Pediatrics
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Hartman, Mary E; Saeed, Mohammed J; Bennett, Tellen et al. (2017) Readmission and Late Mortality After Critical Illness in Childhood. Pediatr Crit Care Med 18:e112-e121
Typpo, Katri V; Wong, Hector R; Finley, Stacey D et al. (2017) Monitoring Severity of Multiple Organ Dysfunction Syndrome: New Technologies. Pediatr Crit Care Med 18:S24-S31
Doctor, Allan; Zimmerman, Jerry; Agus, Michael et al. (2017) Pediatric Multiple Organ Dysfunction Syndrome: Promising Therapies. Pediatr Crit Care Med 18:S67-S82
Wilson, Bryan; Typpo, Katri (2016) Nutrition: A Primary Therapy in Pediatric Acute Respiratory Distress Syndrome. Front Pediatr 4:108