Gary R. Cutter, PhD
Professor of Biostat/Biomath
Department of Biostatistics

Waldemar A. Carlo, MD
Professor of Pediatrics
Department of Pediatrics, Division of Neonatology

Namasivayam Ambalavanan, MD
Assistant Professor of Pediatrics
Department of Pediatrics, Division of Neonatology

The University of Alabama at Birmingham
Birmingham, Alabama

In accordance with the Accreditation Council for Continuing Medical Education Standards for Commercial Support, the faculty report the following affiliations:

Gary R. Cutter, PhD, grant support NHLBI, INO Therapeutics

Waldemar A. Carlo, MD, grant support NIH

Namasivayam Ambalavanan, MD, grant support NIH, Children's Center Research Innovations

The University of Alabama School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

The University of Alabama School of Medicine designates this educational activity for a maximum of 0.25 AMA PRA Category 1 credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The boards of nursing in many states, including Alabama, recognize Category 1 continuing medical education courses as acceptable activities for the renewal of license to practice nursing.

In 2006 two large, multicenter clinical trials published in The New England Journal of Medicine found early treatment with low-dose iNO improved neurologic or respiratory outcomes in some premature infants.

UAB biostatistician Gary R. Cutter, PhD, directed the coordinating center in the National Institutes of Health-funded trial by Kinsella et al designed to reduce BPD and death without increasing brain injury in premature infants with respiratory failure requiring endotracheal intubation and ventilation (N Engl J Med. 2006;355:354-364).

Investigators randomized 793 babies, gestational age ≤34 weeks, to 5 ppm iNO or placebo within the first 48 hours of life. Treatment continued for 21 days or until extubation. The primary outcome measure was the combined end point of death or BPD (defined as the need for supplemental oxygen or ventilation at 36 weeks postconceptual age [gestational age plus chronological age] and abnormal chest radiography). To enable assessment of brain injury, cranial ultrasonography was performed before enrollment, at 7 to 14 days of age, and at >30 days of age.

Investigators stratified infants into 3 weight categories: 500 to 749 g, 750 to 999 g, and 1000 to 1250 g. Overall combined end points did not differ between groups, but there was a significant interaction between birth weight and treatment. Nitric oxide reduced the incidence of BPD by 50% among babies weighing 1000 to 1250 g. This same prespecified subgroup’s combined endpoint of intracranial hemorrhage and periventricular leukomalacia improved significantly (P=.04). The risk of brain injury in the overall population was reduced. We found a protective quality of nitric oxide in a variety of ways, Cutter says. Researchers are following participants for up to 4.5 years to determine long-term effects and confirm the protective effects of iNO on brain development.

The second National Institute of Health-funded large-scale trial, led by Ballard et al, randomized 582 premature newborns weighing less than 1250 g to iNO or placebo (N Engl J Med. 2006; 355:343-353). This trial differed from Kinsella et al in its timing and dose. Previous studies administered NO in the first few days of life. Investigators theorized that a later initiation would reduce brain injury and, thus, administered iNO at 7 to 21 days of age. They also designed a longer treatment period to prevent increased airway resistance. Another difference was concentration: Infants first received 20 ppm, which was decreased weekly to 10, 5, and 2 ppm.

Investigators found that iNO improved survival without chronic lung disease at 36 weeks and reduced duration of oxygen therapy and hospitalization. A post hoc analysis revealed this improvement occurred only in the babies weighing ≥1250 g. Moreover, benefit was seen mainly in infants who entered the study between 7 and 14 days of age and who had less severe lung disease at entry. Investigators, who did not address brain injury, will follow participants for 2 years to assess whether low-dose iNO reduces late pulmonary complications and affects neurocognitive outcomes.

These 2 recent studies contradict some previous trials that have shown no significant benefit with iNO treatment and indicated increased risk of brain injury or mortality.

A 2006 review of 7 randomized controlled trials found no significant effect of iNO on mortality or BPD and no evidence of effect on the risk of intracranial hemorrhage risk. (Cochrane Database of Systematic Reviews. 2006;1:Art No: CD000509.)

One large multicenter study by Van Meurs et al, in which UAB participated, reported no survival benefit and no overall reduction in BPD. Post hoc analysis showed increased rates of mortality and severe intracranial hemorrhage in participants weighing <750 g with an average gestational age of just 26 weeks. However, babies >1000 g had a significantly reduced rate of combined outcome of death and BPD, which is consistent with Cutter's results. Cutter and researchers hypothesize that iNO may act within a narrow therapeutic range in these infants who are in severe respiratory failure and are the least stable.

Cutter says potential protection of the brain is the most intriguing finding from his study. Many of these children develop cerebral palsy or cognitive problems, and preventing such injuries provides a lifetime of benefit, he says, noting that their results are consistent with the 2005 single-center study by Mestan et al, which found infants treated with iNO had less brain injury on ultrasonography and, at 2 years, demonstrated better neurodevelopmental outcomes than untreated patients (N Engl J Med. 2005;353[1]:23-32). Although Van Meurs results indicated increased intracranial hemorrhage, the infants may have had brain injury previous to iNO treatment.

Seeing a protective effect with iNO treatment is a surprising result, but it was not our primary endpoint, Cutter says. Neonatologists will determine whether this finding is real or serendipitous.
UAB neonatologist Waldemar A. Carlo, MD, who discontinued his nitric oxide study because of increased risk of intracranial hemorrhage (later ultrasound examination showed brain injury was insignificant overall), believes Cutter and colleagues may have found less risk of brain injury, but not a protective effect.

A New England Journal of Medicine editorialist notes initiation or exacerbation of hemorrhagic or ischemic brain injury by iNO remains a concern in such a vulnerable population. Evidence of reduced brain injury may be reassuring, she says, but long-term follow-up is important. She concludes that iNO treatment has not been tested thoroughly and cannot be deemed safe for general hospital practice (N Engl J Med. 2006;355:404-405).

The editorialist also notes NO therapy costs $3000 a day, capped at $12,000 a month, and writes such high costs are “hard to justify until benefit is proven. ”Cutter acknowledges the treatments expense, but believes while economic considerations are necessary, “the lifelong costs to these children may outweigh the initial expense.”

Future research of lung development and other factors may pinpoint the threshold at which the gas is not beneficial, Cutter says. “From term babies down the spectrum, iNO works to a point, then stops. We would like to study frozen blood samples for inflammatory markers, which may help identify a biomarker that indicates the lung is sufficiently developed to reap advantages from this treatment.”

“Future studies are necessary to evaluate the potential benefit of routine use of iNO and determine risks of brain injury and long-term neurodevelopmental outcomes, Carlo says.

One of the most important research initiatives, says Carlo, is that of UAB's neonatologist Namasivayam Ambalavanan, MD. Because intubation and prolonged ventilation are invasive and associated with lung inflammation and worse outcomes, Ambalavanan designed a system that allows iNO delivery via oxygen hood without mechanical ventilation. A pilot study by Ambalavanan and Carlo demonstrated that hood NO administration is feasible and improved oxygenation for infants ≥35 weeks gestation. Carlo believes using this hood to deliver iNO could benefit premature infants and may decrease severe respiratory failure.

For more information:

Dr. Gary Cutter
Dr. Waldemar Carlo
Dr. Namasivayam Ambalavanan
1-800-UAB-MIST
mist@uabmc.edu

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