NIH Panel Drafts Consensus Statement on Nitric Oxide for Premature Infants

Jacquelyn K. Beals, PhD

November 03, 2010

November 3, 2010 (Bethesda, Maryland) — An independent panel of experts convened by the National Institutes of Health (NIH) has drafted a consensus statement on the use of inhaled nitric oxide (iNO) therapy in premature infants with respiratory problems. Panelists are discouraging the routine use of iNO in premature infants less than 34 weeks of gestation.

iNO therapy, approved by the US Food and Drug Administration for treating infants born after 33 weeks of pregnancy, increases blood circulation to the lungs and reduces the development of bronchopulmonary dysplasia (BPD) in these near-term babies. However, since its approval in 2000, iNO has been used off-label in babies much younger than 34 weeks (some as small as 401 g), despite the fact that data on such uses are inconsistent.

The 3-day Consensus Development Conference, held here October 27 to 29, included presentations by leading researchers in the field. F. Sessions Cole, MD, chaired the conference and the panel. He is professor and vice chair, Department of Pediatrics; director of the Division of Newborn Medicine, Washington University School of Medicine; and chief medical officer, St. Louis Children's Hospital, in Missouri.

In a telebriefing after the close of the conference, Dr. Cole referred to iNO as "an important potential therapy for critically ill newborn infants who are born far too soon, far too vulnerable.

"Preterm birth is a major public health problem in the United States," said Dr. Cole. "Therapies that attempt to improve outcomes, both short-term and long-term, for prematurely born infants must focus on improving outcomes of lungs and brains in these patients."

Praising the investigators for their commitment, their intellect, and their passion, Dr. Cole continued: "At present, we do not find sufficient evidence to warrant the routine use of this inhaled gas to improve outcomes for prematurely born newborn infants." However, the panelists hope that investigators continue to pursue strategies, including the use of iNO, for this important patient population.

A planning committee developed a set of questions for the panel to address in its deliberations:

  • Does iNO therapy increase survival and/or reduce the occurrence or severity of BPD among premature infants who receive respiratory support?

     

  • Are there short-term risks for iNO therapy among premature infants who receive respiratory support?

     

  • Are there effects of iNO therapy on long-term pulmonary and/or neurodevelopmental outcomes among premature infants who receive respiratory support?

     

  • Does the effect of iNO therapy on BPD and/or death or neurodevelopmental impairment vary across subpopulations of premature infants?

     

  • Does the effect of iNO therapy on BPD and/or death or neurodevelopmental impairment vary by timing of initiation, mode of delivery, dose and duration, or concurrent therapies?

     

  • What are the future research directions needed to better understand the risks, benefits, and alternatives to nitric oxide therapy for premature infants who receive respiratory support?

     

Recommendations by the Panel

In a phone interview with Medscape Medical News after the telebriefing, Dr. Cole summarized the panel's recommendations: "We examined the totality of data available about iNO in premature infants. Our first conclusion was that the current data do not support routine use of iNO in infants less than 34 weeks of gestation to try to prevent BPD or adverse neurodevelopmental outcomes."

However, Dr. Cole and other panelists acknowledged that rare, but sometimes desperate, clinical situations require physicians to consider and use iNO in these highest-risk prematurely born infants.

"We're going to distinguish between [that use and] the recommendation not to use it routinely, but also to get across the idea that, in rare situations with very ill infants, there may be reason to use iNO as a sort of saving therapy in these children," said Dr. Cole. "When iNO is going to be used in these rare situations, communication between the physicians and the families of the babies is critical, so that the families understand the potential benefits, but also the lack of confirming data about the benefits of this therapy."

The issue in this case is the fact that "families want to hope." Communication about both the benefits and risks is critical. Otherwise, families might get the impression in these dire situations that using iNO is the only life-saving therapy available.

The panel encouraged future research "to help continue to build upon the significant biologic plausibility of the use of iNO to improve outcomes of premature infants because of the substantial body of basic and animal research. We want to make sure that that continues," Dr. Cole said. "Future trials should build upon the successes of treatments of specific groups of premature infants who seem to have responded more favorably to iNO. There may, for example, be a window of development in the lung during which iNO is more effective."

Preliminary analyses from the trials already available suggest which subgroups these might be. Rather than continuing to give iNO to every premature baby, the panel felt that focusing on certain groups of premature babies and babies in certain gestational-age windows might help optimize the impact of iNO.

iNO and the Economics of Medicine

Finally, the panel advocated strongly that the "marketing of iNO by any institution, individual, or organization should not promote its potential benefits in babies born more than 6 weeks early."

"If you put 'inhaled nitric oxide' into Google," continued Dr. Cole, "you come up with some very interesting Web sites [from hospitals and physicians] that seem to make provision or availability of iNO for premature infants a marker of clinical care excellence, when in fact we have recommended that it continue to be studied and not be employed for routine use."

The final consensus statement will not be completed for about 6 weeks. Medscape Medical News asked Dr. Cole how the completed statement might affect medical practice, expectations about "routine" clinical care, and insurance coverage of iNO therapy.

"In terms of what clinicians should or shouldn't be doing, these consensus statements are certainly meant to be benchmarks that are used by a variety of organizations — for example, hospital medical staffs — to try to help them with expert opinion concerning the administration of this kind of a drug," explained Dr. Cole. However, physicians are responsible personally for individual decisions about care for individual patients. "That's why we try to include provision for clinical discretion in certain rare, desperate situations."

Regarding insurance companies, Dr. Cole said: "I may be somewhat jaded in my response, but I think that insurance companies tend to look at consensus statements as a way of restricting access, especially to expensive therapies. And iNO is an expensive therapy. So my guess is that insurance companies will likely attempt to use this consensus statement to restrict further access to iNO, and that that will impact the ability of physicians across the country to use nitric oxide routinely in prematurely born infants."

The conference was presented by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Office of Medical Applications of Research, with additional support from the National Heart, Lung, and Blood Institute. Although travel expenses were covered by NIH, panelists were not compensated for their time. The panelists issue their statement as an independent group; it does not represent a policy or position statement of NIH or the federal government.

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