WASHINGTON—New research into a reflex of the pharynx that occurs when pressure drops during breathing while people sleep could yield new medications that better target patients’ root problems with obstructive sleep apnea (OSA), according to a researcher who spoke here during a session at the 2012 Annual Meeting of the American Academy of Otolaryngology-Head and Neck Surgery, held Sept. 9–12.
Measuring the so-called “negative pressure reflex,” which activates to keep the pharynx patent as a sleeping person breathes, might also help improve the success rate of surgery. This is because it may be that the person with OSA has a reflex problem rather than an anatomical problem, and might not be helped by surgery, said Atul Malhotra, MD, an associate professor of medicine at Boston’s Brigham and Women’s Hospital and Harvard Medical School.
The sleep apnea session also covered new therapies and combinations of therapies for children with sleep apnea and the presentation of new computer modeling that has allowed researchers to see how air travels through the upper airway, offering a new depth of understanding that could have clinical implications.
Dr. Malhotra said that taking aim at the negative pressure reflex is important, because surgery does not work for many patients. “Pharyngeal anatomy explains only a minimal proportion of the variance in the apnea hypopnea index,” Dr. Malhotra said. “You can have severe sleep apnea and have fairly normal anatomy. You can have severe sleep apnea and have horrendous anatomy. It’s not surprising, perhaps, that surgery doesn’t work in everybody, because some of these people don’t primarily have an anatomical problem.”
The reflex can be measured by simultaneously looking at genioglossus electromyography and pressure in the epiglottis, he said. Studies have found that carbon dioxide, along with negative pressure, yields “more than a doubling of genioglossus activity,” Dr. Malhotra said. “If you more than double genioglossus activity during stable sleep, you predict a sturdy airway with good mechanics that wouldn’t be prone to collapse,” he said. “There are pathways which can activate these muscles during stable sleep.”
For someone with a poor negative pressure reflex, “if you had a drug that could activate these reflexes, you predict it might work in somebody like this.” Such a drug is not currently available, but “we have some ideas that we’re now testing,” he said.
He said he’s made it the aim of his research to develop ways of treating OSA with something other than a CPAP machine. “I don’t think CPAP is the be-all-end-all,” he said. “I spend most of my time in clinic helping patients who are intolerant to CPAP.”
The Role of Genetics
Leila Kheirandish-Gozal, MD, director of clinical sleep research in the department of pediatrics at the University of Chicago Pritzker School of Medicine, said the emergence of two new therapies for children with OSA is encouraging.
A different approach is required for OSA in children, because it is associated with increased inflammation in the upper airway as well as systemic inflammation and has its peak incidence between ages 2 and 8. It can also have long-lasting neurobehavioral, cardiovascular, metabolic and somatic growth consequences, Dr. Kheirandish-Gozal said.
Nasal budesonide, a glucocorticoid steroid, and oral montelukast, an anti-inflammatory drug, have been shown to be effective individually in treating OSA. Together, they’ve been shown to be effective as well, especially after adenotonsillar surgery when residual sleep apnea is identified, with improvements in apnea hypopnea index, oxygen levels, and the number of arousals from sleep, compared with controls (Pediatrics. 2006;117(1):e61-e66).
Work is now turning to genetics. Dr. Kheirandish-Gozal said her lab screened about 30,000 genes that are involved in the enlargement of tonsils and, from those, found 49 candidate genes that they think might play a role in pediatric OSA. “In the past few years we have been, one by one, testing every one of them,” she said. “Maybe in the near future—it may sound like science fiction—but maybe we can come up with a novel treatment or drug component that can be topically applied on the adenoids or tonsils,”—not in the severe cases, she added, but in the cases in which surgery isn’t necessarily an option.
Surgery is truly successful, meaning complete resolution of OSA, in only about 27 percent of cases, she said, even though improvements will occur in the vast majority. “In some cases surgery is not needed,” she said.
Computer Modeling for Airflow
In another presentation, Nelson Powell, MD, DDS, adjunct clinical professor of sleep disorders medicine and research at Stanford Medical Center in Palo Alto, Calif., showed how researchers have developed a way to “see” the flow of air through the pharynx using three-dimensional CT imaging and computational fluid dynamics, in which a computer is applied to math models created to track phenomena with fluid qualities.
The technology, which could come into clinical use as research continues and fleshes out the way that abnormal airflow has real effects on the tissues of the upper airway, might be able to help direct treatment. Using colors and numerical values within a real-time and real-life image of the airway, the technology allows users to see the speed of the air, the pressure on the airway wall and the shear, as well as the amount of shear stress on the wall. “We’re able to really look at what the airflow is doing to the airway, from the nose all the way to the epiglottis,” Dr. Powell said.
The project has joined doctors and aerospace engineers at Stanford, the Royal Institute of Technology in Sweden, the University of Washington and the University of Cincinnati. More work needs to be done to test the technology’s ability to predict success with surgery, CPAP and other treatments of sleep-disordered breathing, Dr. Powell said.
The studies so far haven’t been designed to determine whether the flow through the airway results in tissue damage, but that is a suspicion, he said. “Inferentially,” he said, “this work suggests a possible relationship.”Multi-Page