ENT-based Approach to Cervical Phrenic Nerve Stimulation for the Treatment of Central Sleep Apnea

PROJECT SUMMARY Central sleep apnea (CSA) is a disorder where patients intermittently lose the drive to breath, though they have with no peripheral nerve disorder nor do they have any airway abnormalities, per se. CSA is thought to affect an estimated 1.0% of people over 40 years old in the United States. If left unaddressed, poor sleep leads to daytime drowsiness, thinking problems, and a heightened risk of errors and accidents. Furthermore, CSA is directly related to the worsening of major cardiopulmonary diseases and is prevalent in as many as 50% of heart failure cases. As such, treating CSA can also lead to improved cardiovascular heath, overall quality of life, and improved mortality. Phrenic nerve stimulation is the only approved treatment for CSA; however, the current commercially available device requires over 3-hour thoracic transvascular procedure performed by an electrophysiologist with the patient under general anesthesia. Additionally, the referral pathway is convoluted. Thus, a due to the limited number of trained operators and complicated surgery, many patients are not offered or eligible for this potentially life-saving treatment. This proposal will validate a new, greatly simplified minimally invasive cervical surgical approach to phrenic nerve stimulation. Critical to our approach is that the procedure can be performed in an outpatient setting by sleep-ENTs, who are the logical referral for patients with CSA. Together with sleep physicians, they are already diagnosing, managing, and treating patients with surgically implanted neuromodulation systems for obstructive sleep apnea (OSA); however no option for CSA currently exists for them. Our innovation exploits an anatomical region just above the clavicle where the phrenic nerve that can be accessed comfortably by ENT surgeons by blunt resection along natural muscle boundaries with minimal risk to collateral structures with broadly available training. It has already been demonstrated in humans that cervical phrenic nerve at this level is fully formed and when stimulated generates physiologic tidal volumes without side-effects. We have already completed Phase I equivalency where we developed the novel surgical approach together with two sleep-ENT surgeon collaborators. We then designed a novel multipolar nerve stimulation cuff that minimizes the potential for trauma to the phrenic nerve, but with features that allow it to be secured to nearby structures. Placement of the cuff by ENT surgeons was validated in cadavers and 90-day survival preclinical studies showing ability to stimulate phrenic nerve with the cuff using low power and near-complete healing of the implant site confirmed by histopathology. Finally, we obtained a license to an implantable pulse generator (IPG) with specifications suitable for closed loop phrenic nerve stimulation based on known methods developed previously and validated in clinical trials, importantly is therapy titration based on respiration, which we plan to measure with a validated inertial measurement unit (IMU) already on the IPG. In Phase II of this proposal, we plan to 1) optimize the respiratory sensing capabilities to detect a variety of simulated conditions of sleep apnea and irregular breathing patterns, 2) update the stimulation control algorithm software on the IPG, 3) verify and validate the cuff design for chronic implantation with an FDA manufacturing partner. The safety and durability of our system will then be demonstrated in chronic preclinical studies. The results obtained in this Phase II will be used to support an IDE submission with the FDA.