How the Gut Microbiome May be Key in Post-Surgery Organ Failure after Heart Surgery in Children

05/02/16

University of Arizona pediatric critical care physician-scientist Katri Typpo, MD, wants to improve the health of infants and children with congenital heart disease (CHD). These patients often suffer organ failure after heart repair surgery.

Toward that end, Dr. Typpo, assistant professor, UA Department of Pediatrics and the UA Steele Children’s Research Center at the UA College of Medicine - Tucson, within the University of Arizona Health Sciences, was awarded a four-year, $740,000, K23 “Mentored Patient-Oriented Research Career Development” grant by the National Institute of Diabetes and Digestive and Kidney Diseases.

Her mentor is Fayez K. Ghishan, MD, professor and head, UA Department of Pediatrics, and director of the UA Steele Center.

The project—“The KIND (Kids Intestinal Dysfunction in Congenital Heart Disease) Heart Study”—is a multi-center study that includes the UA Steele Center (clinical center: Banner Children’s at Diamond Children’s Medical Center), Baylor College of Medicine (clinical center: Texas Children's Hospital), the University of California San Francisco (clinical center: Benioff Children's Hospital) and the University of Nebraska (clinical center: Children's Hospital and Medical Center).

The goal of the study is to develop feeding and antibiotic guidelines for infants and young children with CHD that will stabilize the gut, preserve organ function, and minimize the impact the therapies have on the gut microbiome after surgery. The long-term consequences of alterations to the gut microbiome during infancy are unknown, but may affect the development of several chronic illnesses of adulthood.  

“Although heart surgery techniques have improved over the years, children with CHD often have high incidences of organ failure after surgery—such as kidney failure, heart problems and gut dysfunction,” said Dr. Typpo.  “We are going to explore the role of the gut in determining post-operative outcomes after repair of heart defects in infants.”

Post-surgery multi-organ failure in children with CHD has been linked to a disrupted gut barrier in several studies. A disrupted gut barrier can cause a “leaky gut,” releasing dangerous bacteria or their toxins into the bloodstream, which can lead to multi-organ failure.

“Findings from research we completed at the UA Steele Center in 2014 showed that earlier delivery of nutrition results in better gut barrier function in children with CHD,” said Dr. Typpo. Dr. Typpo received a Sarver Heart Center William “Billy” Gieszl Award to obtain the preliminary data on her project.

The researchers also identified that longer duration of antibiotics after surgery was associated with delayed recovery of post-operative gut function. Those findings led them to evaluate the gut microbiome. Since antibiotics may affect the microbes that reside in the gastrointestinal tract, it may be that the gut microbiome is somehow regulating gut barrier function. As part of the KIND Heart Study, the researchers will look at changes in the gut microbiome both before and after surgery.

Antibiotics and Nutrition

The study will focus is on two areas: antibiotics used for patients before and after surgery, and determining what the best nutrition is to maintain the patients’ gut barrier after surgery.  

“Our study will examine the different standards of care that exist across the four study centers—all of whom have excellent surgical outcomes—to see what the best practice is regarding antibiotics and nutrition, with regard to preserving the gut barrier,” explained Dr. Typpo.

It is routine standard of care that patients receive antibiotics prior to heart surgery, to prevent post-operative wound infections.  Withholding antibiotics is not possible. With regard to nutrition, children with CHD are often malnourished before surgery because of feeding intolerance and heart failure. After surgery, patients receive enteral nutrition (EN) to provide calorie, fat and protein requirements. EN is nutrition delivered to the GI tract, but there are often delays in delivering full nutrition needs after surgery.

“We currently lack objective data to inform decisions regarding EN —an area where subjective decision-making is currently the rule,” said Dr. Typpo. “Providers may hold off on EN because they are concerned the child won’t tolerate the nutrition.”

Complications from early feeding in a gut that has inadequate blood flow may be quite serious. “Physicians are appropriately concerned and may slowly advance nutrition because of this,” Dr. Typpo said.  “And yet, it is well known that acute malnutrition worsens surgical outcomes for infants with CHD, and almost two-thirds of patients do not receive recommended calorie or protein requirements in the first seven post-operative days. It’s very important that we figure out how to safely feed kids after heart surgery.  With this research program, we hope to develop objective tools in the form of gut biomarkers to help physicians decide if it is safe to begin EN in their patients.”

The researchers also want to see how antibiotic use before surgery impacts the bacteria in the gut. “Perhaps we could choose a different type of antibiotic, or discover that there is an antibiotic regimen that is superior and might maintain the healthy populations of bacteria that should be in the gut,” said Dr. Typpo. The researchers believe there is an interaction between the bacteria that are living inside the gut and the health of the gut barrier. “If we can stabilize the gut barrier, then patients may experience less organ dysfunction after surgery,” she said.

The researchers will examine the plasma biomarkers of the intestinal epithelial barrier function (EBF) and microbiome from the GI tracts of approximately 80 children from the four clinical centers. This will enable the researchers to determine the differences in how physicians provide antibiotics before surgery and EN after surgery. Once the data has been collected and analyzed, the researchers hope to identify an antibiotic and post-operative nutritional strategy that results in the best outcomes for the gut barrier and microbiome, which they believe will lead to less organ failure after surgery.

“We know that enteral nutrition is important to maintaining gut integrity,” said Dr. Typpo. “We will leverage the practice variation that already exists at these centers, to determine if there are subtle differences in the instance of various organ failures across these institutions.”

“Dr. Typpo is one of the best clinician-scientists I know who conducts translational research to improve the lives of critically-ill children,” said Dr. Ghishan.  “As her mentor, the only thing I need to do is give her an idea and she designs a successful research project that will make a positive impact on children’s health. It is a pleasure to serve as Dr. Typpo’s mentor, and I predict she will be a leader in her field of pediatric critical care.”

About the UA Steele Children’s Research Center

The UA Steele Children’s Research Center is one of the prestigious Centers of Excellence at the UA College of Medicine – Tucson at the University of Arizona Health Sciences. It is the state’s only academic pediatric research center designated by the Arizona Board of Regents, and the only facility in Southern Arizona where researchers and physician-scientists are dedicated to advancing medical knowledge through basic and translational research to improve children’s health. As researchers, they seek to discover answers to children’s medical mysteries. As physician-scientists, they provide compassionate care to hospitalized patients at Banner Children’s at Diamond Children’s Medical Center and pediatric outpatient clinics throughout Tucson and the state. And, as faculty members with the UA Department of Pediatrics, they teach and train the next generation of pediatricians and researchers.

About the University of Arizona Health Sciences

The University of Arizona Health Sciences is the statewide leader in biomedical research and health professions training. The UA Health Sciences includes the UA Colleges of Medicine (Phoenix and Tucson), Nursing, Pharmacy and Mel and Enid Zuckerman College of Public Health, with main campus locations in Tucson and the growing Phoenix Biomedical Campus in downtown Phoenix. From these vantage points, the UA Health Sciences reaches across the state of Arizona and the greater Southwest to provide cutting-edge health education, research, patient care and community outreach services. A major economic engine, the UA Health Sciences employs almost 5,000 people, has nearly 1,000 faculty members and garners more than $126 million in research grants and contracts annually. For more information: http://uahs.arizona.edu