Photos by Apnex Medical Inc

By Bill Pruitt, MBA, RRT, CPFT, AE-C

More than 10 years ago, hypoglossal nerve stimulation (HNS) as a treatment for obstructive sleep apnea (OSA) captured the attention of the sleep research community. Studies employing HNS were conducted with great hope in the outcomes, but after researchers hit technical snags with the therapy, it primarily fell out of the sights of the sleep medicine community. Now, after more than a 10-year hiatus, the therapy is being researched again, undergoing close scrutiny and evaluation as a plausible treatment option for OSA.1

EARLY RESEARCH IN HYPOGLOSSAL NERVE STIMULATION

From 1995 to 2005, animal studies uncovered many facets of using stimulation of the pharyngeal muscles and nerves to bring about dilation of the upper airway. In particular, these studies found that contraction of the genioglossus muscle (brought about either by direct stimulation or indirectly by stimulation of the hypoglossal nerve) resulted in the enlargement of the pharynx to a greater degree than targeting other muscles. In addition, long-term use of an implanted nerve stimulator’s action on the hypoglossal nerve did not bring about any damage to the nerve.2

For OSA patients, there was a major break in stimulation of the hypoglossus nerve with the research done at Johns Hopkins University and published in 2001. This study involved implanting a pulse generator in the infraclavicular pocket in the region of the pectoralis muscle (similar to the placement of a cardiac pacemaker), which was connected by wires traveling subcutaneously up the neck to a half-cuff nerve stimulator electrode placed on the hypoglossus nerve. The last piece of this system was a pressure transducer placed into a hole drilled through the manubrium of the sternum, which allowed the system to monitor and respond to inspiratory effort to trigger the pulse generator and stimulate the nerve. This was a phase 1 feasibility study involving eight patients. The system was programmable to allow for selection of the stimulation amplitude, the pulse width, and the stimulation frequency. This setup was called Inspire I (Medtronic). The patients had a remote programmer for the system to turn the device on prior to sleeping (including a preset delay to begin the stimulation after sleep onset) and turn it off after awakening. In seven of the eight patients, the AHI dropped from a mean of 53.4 events/hr (±2.2) to 21.4 events/hr (±9.8). The stimulator activity on the nerve/muscle did not bring about any arousals from sleep. Technical problems ended the long-term assessment of the systems, although some 6 months of data were recorded prior to the beginning of these problems and three patients used the system until the internal power supply died.2,3

HYPOGLOSSAL NERVE STIMULATION TODAY

In recent years, there has been a resurgence of interest in HNS as three companies have started new research. All three have released preliminary findings about various nerve stimulation devices at the May 2011 American Thoracic Society (ATS) International Conference in Denver. In no particular order, the research involves the Hypoglossal Nerve Stimulation (HGNS) System (Apnex Medical Inc), the Inspire II system (Inspire Medical Systems), and the aura6000 system (ImThera Medical). All three systems are installed surgically under general anesthesia, and the three have many features in common.

The HGNS system from Apnex Medical stimulates the hypoglossus nerve during inspiration based on the signals it receives through thoracic impedance. In a study employing the HGNS system, 21 subjects received the implanted device and had data collected at the start of the study (after implantation and stabilization), then at 3 and 6 months. The participants had moderate to severe OSA and could not tolerate CPAP. After HNS therapy, the AHI index dropped from a baseline measurement mean of 43.1 events/hr (SD 17.5) to 19.0 events/hr (SD 10.7) at 3 months and dropped again at 6 months to a mean of 16.3 events/hr (SD 9.1). The baseline Epworth Sleepiness Scale (ESS) dropped from a mean of 12.0 (SD 4.7) to 7.8 (SD 4.1) but rose slightly on the 6-month reading to a mean of 8.2 (SD 4.6). The Functional Outcomes of Sleep Questionnaire (FOSQ) had an increase from a mean of 14.4 (SD 2.0) at baseline to 17.1 (SD 2.0) and a slight drop at 6 months to a mean of 16.9 (SD 2.2). The researchers noted that the therapy was used a median of 98% of the nights during the study and a mean of 6.5 ± 1.1 hrs/night. At the 6-month check, 75% of the subjects had a 50% or greater reduction in their AHI.4,5

Apnex Medical Inc has received CE Mark approval for its HGNS system for use by people who suffer from OSA. The system was approved for sale in Europe based on the positive results of clinical studies conducted in the United States and Australia. The company also has received investigational device exemption (IDE) approval from the US Food and Drug Administration (FDA) to study the safety and effectiveness of its Hypoglossal Nerve Stimulation System to treat OSA. Data from this clinical study are intended to support the Premarket Approval application for the HGNS System to the FDA.

The Inspire II system by Inspire Medical Systems is a modified version of the Inspire I from the 2001 research. This system uses a single lead pressure sensor to trigger HNS on inspiration. The study presented at ATS involved placing the implanted system in 22 patients who had moderate to severe OSA and were intolerant of CPAP. The study had two phases to examine the effectiveness of the system and to identify predictors of therapy success. Phase 1 collected preimplant baseline data including body mass index (BMI), AHI, ESS, and FOSQ score. These same indices were examined at 2, 4, and 6 months post-implant. Eight of the 22 patients were found to be responders to the HNS. These patients showed a significant change in AHI—baseline 34 events/hr (±13) dropped to 8 events/hr (±6); significant change in ESS; and significant change in the FOSQ. From data derived in phase 1, patient selection criteria were established and nine patients were enrolled using these criteria. Eight of the nine patients in phase 2 showed significant changes in the AHI, moving from a baseline of 39 events/hr (±9) to 12 events/hr (±13), which was a 72% reduction in the AHI. The researchers concluded that the baseline AHI, BMI, and site of airway obstruction were important predictors of therapy success. This device has gone on for further evaluation covering 2 years and has been found to be safe, stable, and reliable.6,7

Inspire Medical Systems has received approval from the FDA to begin its multicenter study, dubbed the STAR (Stimulation Therapy for Apnea Reduction) trial, designed to evaluate both the safety and effectiveness of Inspire Upper Airway Stimulation therapy in patients with moderate to severe OSA. The STAR trial is under way at nine medical centers in the United States and four sites in Europe. Results from the study are intended to provide a basis for a Premarket Approval application to the FDA.

The aura6000 system from ImThera Medical has a silicone cuff electrode that contains six independent programmable contacts placed around the hypoglossal nerve and connected to the nerve stimulator. Implantation takes around 60 to 90 minutes, and after a period of healing and recovery (2 to 4 weeks), the unit is programmed while the patient is awake and while asleep to find the right settings for therapy. Unlike the other devices that are triggered by the inspiratory cycle, this system generates a constant stimulation to the hypoglossus nerve during the full respiratory breathing cycle to provide a muscle tone (similar to the daytime level) to the muscles. The study presented at the ATS meeting involved 11 patients who had moderate to severe OSA and were noncompliant with CPAP therapy. After titration and settings were established, baseline measurements were made. These findings were compared to new measurements taken after 3 months of therapy. The mean AHI decreased by 59%, dropping from 47.4 events/hr (±16.9) to 19.4 events/hr (±12.6). The mean desaturation index decreased by 60%, dropping from 33.0 per hour slept (±24.1) to 13.3 per hour slept (±14.7). The micro-arousal index decreased by 35%, dropping from 35.5 (±13.8) to 25.1 (±15.0).8,9

ImThera is currently preparing for next phase research as it looks forward to the CE mark in Europe and beginning an FDA clinical trial, according to comments from the company’s president and CEO, Marcelo Lima.

FUTURE RESEARCH AND CONSIDERATIONS

As seen in the preliminary results from these studies, HNS is not a complete fix for OSA and is not appropriate for all patients. Selection criteria are needed to find the most appropriate patients for this therapy. Although the approach has been improved as technology has advanced, there are still some hazards and complications that may be correctable as experience is gained. It is interesting to note that chronic stimulation of the muscles may cause positive changes by decreasing tongue volume and fat content—thus reducing the potential for airway obstruction to occur. Clearly, for those patients who cannot tolerate CPAP and have no clear alternative that is as effective in treating OSA, HNS offers some significant changes that could help these patients get better quality sleep, have fewer comorbidities due to OSA, and improve their overall quality of life. Future research is needed to examine the long-term safety and effectiveness of HNS as well as assess the issue of activating other muscles of the upper airway. Optimal settings need to be examined so that the best signal frequency, amplitude, and duration are determined for the patients.3 More research also needs to be conducted comparing signals triggered by inspiration versus constant signal. There is also a potential that HNS combined with CPAP could allow for a much lower pressure setting needed on the CPAP—thus improving adherence to CPAP therapy for those who have required high levels of support and have been intolerant of the pressure/flow needed to overcome OSA. Finally, this is an expensive and invasive approach to treating OSA, but if it continues to prove its worth, we may see more patients using HNS.

Bill Pruitt, MBA, RRT, CPFT, AE-C, is a senior instructor and director of clinical education in the Department of Cardiorespiratory Sciences, College of Allied Health Sciences, at the University of South Alabama in Mobile, and a PRN therapist at Springhill Medical Center and Mobile Infirmary Medical Center in Mobile, Ala. The author has over 30 years’ experience as a respiratory therapist and is involved in state and national issues related to pulmonary health. He can be reached at [email protected].

REFERENCES
  1. Kuna ST. Back to the future or forward to the past? Sleep. 2011;34:1455-1456.
  2. Oliven A. Treating obstructive sleep apnea with hypoglossal nerve stimulation. Curr Opin Pulm Med. 2011;17:419-424.
  3. Kezirian EJ, Boudewyns A, Eisele DW, et al. Electrical stimulation of the hypoglossal nerve in the treatment of obstructive sleep apnea. Sleep Med Rev. 2010;14:299-305.
  4. Eastwood PR, McEvoy RD, Wheatley J, et al. Hypoglossal nerve stimulation therapy to treat obstructive sleep apnea: interim feasibility trial results. Am J Respir Crit Care Med. 2011;183:A2726.
  5. Apnex Medical Inc. www.apnexmedical.com. Accessed November 26, 2011.
  6. Badr MS, Oliven A, Maurer J, et al. Predictor of response for upper airway stimulation in obstructive sleep apnea. Am J Respir Crit Care Med. 2011;183:A2727.
  7. Inspire Medical Systems. www.inspiresleep.com/inspire-system.php. Accessed November 26, 2011.
  8. Rodenstein D, Rombaux P, Dury B, et al. Unilateral targeted hypoglossal neurostimulation (THN) for the treatment of obstructive sleep apnea (OSA). Am J Respir Crit Care Med. 2011;183:A6383.
  9. ImThera Medical. www.imtheramedical.com. Accessed November 25, 2011.