Crucial Studies, Fragile Subjects

April 15, 2013

15 Apr (NY TIMES) – How much oxygen should a premature baby be given in the first days and weeks of life? Neonatologists have been trying to answer that question since the 1940s, sometimes with disastrous results. 

                                                                                                                                                                        By Sabrina Tavernise N.Y Times

Premature infants need oxygen because their lungs are not fully formed, but early attempts to save lives by turning up oxygen inadvertently caused blindness in many babies.

“They did a lot of damage before they realized what was going on,” said Arthur L. Caplan, head of the division of medical ethics at NYU Langone Medical Center.

That experience has cast a long shadow over subsequent efforts to pioneer medical interventions for newborns. And the issue arose again last week when it came to light that a federal watchdog agency, the Office for Human Research Protections, had formally notified a network of 23 major research institutions that they had failed to warn parents about the risks of their infants’ participation in a large oxygen study.  The underlying ethical question remains: How do researchers balance protecting these most vulnerable patients from the risks of medical studies with the potential benefits of such research for all premature babies?

The purpose of the study, known as SUPPORT, was to find the sweet spot for oxygen concentration in an infant. The American Academy of Pediatrics had set the standard treatment at a band between 85 and 95 percent, and researchers were trying to determine what part of that was optimal.

The goal was laudable, the federal watchdog said, but the method was not. Researchers randomly assigned infants to two groups, with half the children to get an oxygen concentration on the low end, 85 percent to 89 percent, and the other half to get 91 percent to 95 percent, on the high end. But the researchers did not explain to parents in consent forms that the risk of an eye disease, retinopathy of prematurity, was greater in the higher oxygen group. Based on past studies, there was reason to expect that infants in the upper band would be at higher risk. Indeed, the results found that infants in the upper band developed eye disease at more than twice the rate of those in the lower band — 18 percent compared with 9 percent.

“Based on their very hypothesis, they were thinking that there might well be a difference,” said Dr. Jerry A. Menikoff, the director of the Office for Human Research Protections. “Being in the higher end should have put you at greater risk of developing eye disease.”

The study’s designers agreed that the risk of blindness should have been more clearly explained, but said that the infants were within the standard band of care, and therefore facing the same steep odds as any premature infant not in the study.

Dr. Menikoff disagreed.

“To be told that this was all standard care — it wasn’t,” he said. “It was taking a child and flipping a coin and giving them 50 percent chance of being at the higher end and 50 percent chance of being at the lower end. They were changing what happened to all of the children.”

Some experts contend that there is a lot of guesswork in oxygen care because there still is no established evidence for a particular level of concentration and that the risks were effectively the same for infants in the study as those outside it.

“A really honest clinician just flips a coin in his head,” said David C. Magnus, a professor of pediatrics and the director of the Stanford Center for Biomedical Ethics. “Physicians could have their own views, but there was no evidence supporting any given spot on the band.”

In the late 1990s, neonatologists began calling for systematic studies to establish that evidence. Dr. Ola Didrik Saugstad, a professor of pediatrics at the University of Oslo, who is an expert in neonatology and oxygen, said there had been about 12 studies since. Among them were three large clinical trials involving thousands of babies, including the SUPPORT study.

The SUPPORT study’s results, published in 2010, surprised researchers. Infants in the lower oxygen band had a higher mortality rate — 20 percent — than those in the higher one — 16 percent. The finding has had a profound effect on medical practice.

“We changed our practices immediately, almost overnight,” said Dr. Saugstad, who did not participate in the study. “We increased saturation targets again.”

 Also see  OMSJ Neonates and Study of Babies Did Not Disclose Risks, U.S. Finds (April 11, 2013)

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