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Stanford Report, August 9, 2000

Pediatric surgery clinical trial is unorthodox approach to addressing disorder  

BY RUTHANN RICHTER

For some 15 years, controversy has lingered over what treatment is most likely to save premature newborns suffering from an intestinal disorder known as necrotizing enterocolitis (NEC). At least 10 studies and some case reports on the potentially fatal condition exist, yet it remains "a difficult, unsolved problem" with no clear treatment option, said Larry Moss, MD, an assistant professor of surgery and pediatrics.

Moss now hopes to settle the issue through an approach considered unorthodox in pediatric surgery circles: a clinical trial that will compare two surgical treatments for the condition. In June, Moss received a $1.1 million NIH grant to lead a national, multicenter study that he believes is the first of its kind.

The trial will compare two procedures now commonly used to treat NEC -- a conventional surgery that requires opening up the baby's abdomen and repairing the damaged intestine, and a much less invasive alternative that involves inserting a drain through a tiny hole in the abdomen. Moss' colleagues in the study are pediatric surgeons Baird Smith, MD, and Erik Skarsgard, MD; neonatologist Louis Halamek, MD; and statisticians Richard Olshen and Brad Efron.

"The key [to success of the trial] is a complete commitment and belief on the part of the investigators that this is an unanswered question that can only be addressed by means of a trial," Moss said. "There is no precedent for this -- to go to a family with a baby who's dying and say, 'We have no idea which operation is better and that's why we need to do a trial.' "

Moss is a strong believer in the value of rigorous science and says he regrets that his specialty relies so heavily on techniques that have evolved over time on the basis of case studies alone."When you scratch the surface, it's astounding how much of what we do is based on anecdote," he said.

NEC is a prime example. The disease occurs as a result of poor blood flow and overgrowth of bacteria in the fragile, underdeveloped intestine of the premature newborn. The organ then becomes inflamed and can begin to fail or perforate, he said. Some 5,000 to 9,000 babies each year die as a result of the condition, he said.

The disease is easy to recognize, as babies show multiple signs of infection, including vomiting, bloody stools and distended bellies. But treating NEC is not nearly as easy as identifying it.

Traditionally, pediatric surgeons have followed the adult model, opening up the abdomen, removing the damaged portion of the intestine and bringing the ends of the intestine out through the abdominal wall into a stoma, or small bag. Once the intestine has healed several months later, the stoma can be closed and the organ returned to its rightful home.

But, Moss notes, "That's a big operation for a baby who may weigh a pound or two."

In the 1970s, Canadian physicians stumbled across an alternative to this major surgery. They made a 1/4-inch incision in the lower abdomen, flushed out the bacteria-ridden cavity and then inserted a tube to drain the area. To their astonishment, many babies treated in this fashion lived, Moss said.

Some doctors in the United States then began to adopt this alternative method, which Moss and his colleagues now use sometimes in patients at Lucile Packard Children's Hospital. But it's never been shown which surgical procedure is really most effective, Moss said.

Recently, Moss and his colleagues conducted a statistical analysis of all the medical literature on both procedures and found that the survival rate for babies undergoing the drainage procedure was 55 percent, compared to 67 percent for those subjected to major surgery. However, the data were skewed by the fact that the drainage procedure was done more often on low-birth-weight babies and on those infants with the most severe disease.

When that was taken into account, "We found there was absolutely no way to conclude which [procedure] is better," said Moss, who will present the results of that analysis in October at a meeting of the American Academy of Pediatrics.

He decided the question was ripe for a clinical trial. Historically, surgeons have shied away from trials that compare two different operations for a number of reasons, he said.

For one, it's expensive and time-consuming to enroll patients. For another, the design typically used for drug studies must be modified for surgical studies; you can't "blind" patients or surgeons in trials, and standardizing surgical care is more difficult than standardizing a drug regimen. Moreover, conventional wisdom says that patients will be unwilling to consent to be randomly assigned to one of two study groups when surgery is involved.

But, Moss said, "Work from our group and others has shown that [a surgical clinical trial] can be done. The barriers . . . . are self-imposed and not insurmountable."

He also notes that among surgeons, there is a "deeply ingrained belief that data from individual case reports is acceptable" as the basis for widely practiced procedures -- a notion he finds objectionable.

"My goal is to totally change the culture in pediatric surgery -- to get people to reject this reliance on case series," he said.

The NEC study is expected to involve 118 babies over a three-year period. SR