Nov. 28, 2003 Low doses of inhaled nitric oxide can decrease the risk of chronic lung disease and death by nearly one-fourth in premature infants who have respiratory distress syndrome (RDS), report researchers from the University of Chicago in the Nov. 27, 2003, issue of the New England Journal of Medicine.
Nitric oxide also can cut the risk of severe bleeding into the brain and loss of brain tissue – devastating complications of prematurity – by almost half.
The combination of prematurity and RDS may be lethal despite aggressive treatment, including mechanical ventilation. Approximately 60,000 children are born each year in the United States weighing less than 1,500 grams (about 3.3 pounds). Many of those who survive suffer permanent lung damage, which can slow growth, increase susceptibility to infection and is associated with abnormal brain development.
In the study, 64 percent of infants who received standard therapy died or developed chronic lung disease, compared to only 49 percent of those who received standard therapy plus inhaled nitric oxide.
"Inhaled nitric oxide gives neonatologists a simple and effective tool to help protect premature infants," says Michael Schreiber, M.D., associate professor of pediatrics at the University of Chicago and director of the study. "Our data demonstrate that starting nitric oxide soon after birth in at-risk babies has few downsides and makes a major difference in their long-term health."
Adding small amounts of nitric oxide to oxygen for neonates requiring ventilation may soon become standard practice, Schreiber predicts, stressing the need to start treatment early. "Chronic lung disease often begins in utero," he says, "so if you're going to intervene, you need to start therapy as soon as possible."
Nitric oxide, a gas produced by the body and used to transmit chemical signals, was approved in 1999 by the Food and Drug Administration for use in full-term babies. Because it can relax constricted blood vessels, it has been used in infants with pulmonary hypertension, a life-threatening disease in full-term infants.
This study, however, was designed to test its ability to protect premature infants' undeveloped lungs from the stresses caused by their disease and by mechanical ventilation – a much larger and more vulnerable group of patients.
Between October 1998 and October 2001, 207 infants in the neonatal intensive care unit at the University of Chicago Children's Hospital were enrolled in this study. The premature infants in this study averaged 27 weeks gestation (full term is 38-40 weeks) and weighed an average of 1,000 grams (2.2 pounds). Participants required a ventilator and surfactant treatment to help breathing.
Beginning within a few hours of birth and continuing for one week, the infants received – through the ventilator – either oxygen plus inhaled nitric oxide, or oxygen alone. The nitric oxide doses were very small, 10 parts per million for the first day and 5 PPM for the rest of the week.
Eighty-five percent of the 105 infants in the nitric oxide group survived, compared to 78 percent of the 102 infants who received oxygen alone. Furthermore, 61 percent of the 89 surviving nitric oxide patients were free of chronic lung disease, compared to 47 percent of the 79 who survived without nitric oxide.
"Nitric oxide did not rescue the sickest infants," Schreiber says, "but it was able to limit the extent of lung disease in many newborns at risk, preventing the lung damage that can cause lifelong illness."
Because nitric oxide may interfere with platelets and increase bleeding time in adults and full-term babies, the researchers were concerned that their treatment might increase the risk of two common problems associated with prematurity. These complications – known as intraventricular hemorrhage (bleeding into the ventricles, the fluid spaces within the brain) and periventricular leukomalacia (damage to the brain tissue near the ventricles) – are the primary cause of serious long-term brain damage in premature infants and are associated with the subsequent development of cerebral palsy and mental retardation.
They were reassured to find that nitric oxide did not cause either problem. Instead, it seemed to prevent the most severe brain injuries. Although nitric oxide did not reduce the risk of all neurologic complications, only 12 percent of the infants who received it suffered a severe brain hemorrhage or tissue damage, compared to 24 percent of those who did not.
Infants who received nitric oxide also tended to spend less time on the ventilator (a median of 16 days vs. 28.5 days) and required less time in the hospital (65 days vs. 76 days).
Although the study stopped enrolling new patients in 2001, the researchers intend to follow these children for five years. So far, no late complications have emerged. The research team also is planning a follow-up study providing inhaled nitric oxide to ventilator-dependent newborns for one month. They will compare those results to treatment of one week to help determine the optimal duration and dose.
INOTherapeutics Inc. of Clinton, N.J., which supplies nitric oxide for medical use, funded this study in response to a proposal by the investigators. The company was not involved in the study design, safety monitoring, data analysis and interpretation, or manuscript preparation.
Additional authors of the paper include Karen Gin-Masten, M.D., Jeremy Marks, M.D., Ph.D., Grace Lee, B.A., and Pimol Srisuparp, M.D., of the department of pediatrics, and Dezheng Huo, M.S., of the department of health studies, all at the University of Chicago.
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