Automatic Phrenic Nerve Stimulation to Rescue Opioid Induced Respiratory Depression - Project Summary
The United States is in the midst of an opioid overdose crisis. According to the CDC, there were more than
33,000 opioid overdose deaths in 2015 alone. The number of opioid overdose deaths has more than quadrupled
since 1999, with much of this increase attributable to the rise in prescription opioid use. The mechanism of death
in opioid overdose is primarily through opioid-induced respiratory arrest, defined as the centrally mediated
reduction in ventilatory drive after opioid use. Naloxone, an opioid receptor antagonist that temporarily reverses
this process, is the first line medication for treatment of opioid overdose, and there have been substantial efforts
to reduce overdose deaths in the community by distributing naloxone rescue kits to individuals who are likely to
witness opioid overdoses. These efforts have shown significant promise.
However, many opioid overdose deaths that occur are either unwitnessed or naloxone is not immediately
available. Additional lives could be saved by technologies that can both recognize and treat opioid overdose
safely and automatically, in the absence of a bystander. The ideal technology would be safe, reliable and self-
contained. Moreover, such a device would require no day-to-day maintenance (e.g. replacing of expired drug,
placing of sensors), which is particularly important in a target population known to have poor compliance with
treatments.
Our proposal will validate a new implantable device-based approach for rescuing opioid overdose by
automatically sensing and reversing the opioid-induced respiratory arrest in order to keep the patient stable until
definitive treatment with naloxone can be provided. This system would be targeted towards those individuals at
the highest risk for opioid overdose - those with a history of overdose, poor response to treatment, using high
opioid doses, concomitant sedative-hypnotic and alcohol use, and mental disorders
Coridea has previously developed an approach that uses the body's natural ability to control respiration by
stimulation of the phrenic nerve. The system is a fully implantable pacemaker-like device that is currently used
for the treatment of central sleep apnea in heart failure, and has been shown to be safe and effective for this
purpose. It consists of a transvenous pacing lead and an implantable pacemaker-like pulse generator. It can
sense specific phases/patterns of respiration and then stimulate the phrenic nerve to break the intermittent
pattern of sleep disordered breathing that is characteristic of central sleep apnea in heart failure. However, this
device has never been tested in the context of prolonged respiratory depression/arrest, which is characteristic
of opioid overdose. The ability to fully support respiration has been previously shown using a surgically implanted
phrenic nerve cuff, but not with a less invasive, transvenous design. Another novel aspect proposed in this grant
is the design and development of a software algorithm to automatically detect and respond to critical respiratory
depression and arrest. Our eventual clinical device will be placed via a simple 30-60-minute procedure, very
similar to the currently clinically-used cardiac pacemakers or neurostimulators for pain, in the catheterization
laboratory under conscious sedation and local anesthesia with patients able to go home the same day.
This project will be completed in sequential stages. As deliverables for the Phase I SBIR, we will demonstrate
the proof of concept by determining and optimizing the parameters of unilateral transvenous phrenic nerve
stimulation required to generate a physiological pattern of respiration sufficient to stabilize gas exchange while
maintaining airway patency and maintain blood oxygenation levels in an animal model of opioid-induced
respiratory arrest. In parallel, we will also validate a method an index for detecting inadequate respiration using
transthoracic impedance. Using the results obtained in the Phase I proof of concept studies, the future Phase II
SBIR deliverables will include design and development of a software algorithm to combine automatic detection
and treatment of respiratory depression/arrest. The detection algorithm will be optimized for energy efficiency to
enable incorporation into a small implantable pulse generator. Following the completion of Phase II, we will seek
to fund feasibility clinical trial using a combination of venture and/or industry funding, potentially also as matching
funds for a Phase IIb SBIR submission. Ultimately, a fully implantable, clinically usable system will be developed
that incorporates the ability to automatically call 911 and provide GPS coordinates to responders to locate the
overdosed patient.
