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
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