May 26, 2006

Supplement may thwart pulmonary hypertension in kids

Featured Image

From left, Geri Rice, R.N., Marshall Summar, M.D., Heidi Smith, M.D., and Rick Barr, M.D., in the Pediatric Critical Care Unit.
Photo by Dana Johnson

Supplement may thwart pulmonary hypertension in kids

Researchers at the Monroe Carell Jr. Children's Hospital at Vanderbilt are finding that a simple dietary supplement may have the ability to save the lives of pediatric heart patients.

The supplement is an amino acid called citrulline, from the Latin word for watermelon, the fruit that contains large amounts of it.

Marshall Summar, M.D., pairing his biophysics and genetic research with clinical investigation led by Rick Barr, M.D., and his team in the Pediatric Critical Care Unit, have found that dangerously high blood pressures in the lungs, or pulmonary hypertension, might be avoided by administering citrulline.

Barr has a $2.3 million NIH grant to pursue the research in children undergoing cardiac surgery for congenital heart defects.

“One of the advantages and, I think, one of the reasons why the NIH and FDA have been so supportive of this research is that this is a naturally occurring amino acid, one our bodies make under normal circumstance, and if you can help the body do what it does best — especially under stress — intuitively, that's a simple way to solve a problem,” Barr said.

Summar and Barr said there is a small population of children citrulline might work very well for, but because it appears — so far — to be safe and effective, it could be given to all patients, avoiding the expensive genetic tests necessary to identify the children at highest risk for developing pulmonary hypertension.

“We have coined a name for this. We call it environmentally determined genetic expression or EDGE.” Summar said. “These are variations in humans that would never turn up or cause any problems, except when the body is under incredible stress.

“What we learned in our research early on is that there is a spectrum of genetic variation related to the development of pulmonary hypertension,” Summar said. “Children with certain genotypes are at very low risk to develop pulmonary hypertension, while other genotypes lead to much higher risk.”

Something about the extraordinary stress of bypass can trigger dangerously high blood pressure in the lungs.

The theory is that a genetic predisposition keeps some children from maintaining the body's natural cycle of vessel relaxation, which is aided by the chemical nitric oxide.

Reversing this 'clampdown' of blood vessels is difficult. Citrulline is a key precurser to making nitric oxide, and is one of two amino acids previously found to be associated with the onset of pulmonary hypertension. It was targeted for study because it's safer and easier for the body to process.

“Some children cannot maintain high enough citrulline levels, so their nitric oxide levels drop dramatically during open heart surgery,” Summar said.

The question was: If lower levels of citrulline are associated with an increased risk of pulmonary hypertension, can keeping blood levels of citrulline artificially high in children undergoing bypass ward off pulmonary hypertension?

Barr pulled together a team of cardiologists, surgeons, nurses and geneticists to test the theory.

Over the course of the last three years, the team has been finding increasingly exciting results.

“We began with a previously proven safe oral dose of citrulline,” Barr said. “Dr. Heidi Smith did a small study with 40 patients, and the lab work kept building on our theory. Her work showed that there is a threshold of citrulline in the blood above which children don't get pulmonary hypertension.”

Smith's results have already won her two young investigator awards, one from the Society of Pediatric Research, another from the Vanderbilt Research Forum, and she recently returned from presenting her results in Japan.

The full details are set to be published in July's Journal of Thoracic and Cardiovascular Surgery, but Smith said the important thing was it showed citrulline could work if used in the right form.

Researchers then began studying intravenous (IV) delivery of the supplement.

“We needed to know what kind of dosing will get them to the threshold Heidi discovered and keep them there,” Barr said. “We did some initial animal tests followed by a larger study in children, and early results show I.V. citrulline is safe and effective in controlling blood levels of the amino acid during open heart surgery.”

Barr's current study is looking at whether fairly large I.V. doses of citrulline, given before, during and after open heart surgeries in children, will effectively reduce, or even eliminate, the risk of pulmonary hypertension.

The study began in May and they plan on enrolling more than 200 patients over two years.

“We fully expect the results of this will be very exciting, as Heidi's results of the oral citrulline were,” Summar said. “It does appear that if you can get a young patient above a certain threshold of citrulline, that you can avoid pulmonary hypertension.”

“It's been surreal,” Smith said. “You're helping the body do under stress what it already does great under normal conditions. I feel blessed to do what I do, thankful to the families who agreed to participate and grateful to be working with so many people who are involved in coordinating and making the project a success.”