Development of Lungpacer-PROTECT, a Neurostimulation Device to Improve Respiratory Health and Outcomes for Mechanically Ventilated Patients

FY20 PRMRP Topic: Respiratory Health. Focus Area Alignment: "Ventilation and Extracorporeal Life Support approaches and technologies to support lung function or airway management in response to COVID-19 that increase survivability and/or minimize care provider burden or exposure." Problem: Positive-pressure mechanical ventilation (MV) is a life-saving intervention for many patients with severe lung infections in ICU. Over one-third of the COVID-19 patients admitted to New York City hospitals required invasive MV. Traditional MV utilizes positive pressure to cyclically "inflate" a patient's lungs to support adequate gas exchange, while the patient's natural diaphragmatic breathing is suppressed. As a result, MV patients, particularly those with respiratory diseases, are at risk for diaphragm muscle atrophy, ARDS-like complications and lung injury. With remarkably rapid progression, ventilator-induced diaphragm dysfunction (VIDD) occurs within the first 18 to 24 hours of MV; VIDD is associated with longer durations of MV and difficult or failed MV liberation. The risk of death increases with every hour on MV. COVID-19 MV patients often experience Ventilator-Induced Lung Injury (VILI); both lower-lung dysfunction/injury (i.e., atelectasis), requiring proning, and upper-lung high-pressure injury (i.e., barotrauma), each associated with low weaning success and increased mortality. Solution: Lungpacer is developing a novel neurostimulation technology, the Lungpacer Diaphragm Pacing Therapy System (DPTS), to provide temporary minimally invasive transvenous diaphragm pacing to improve respiratory function, increase inspiratory muscle strength, and improve weaning success and survival rates in difficult-to-wean MV patients. DPTS activates the diaphragm muscle, supporting a more physiological respiration (e.g., via negative pressure). The first-generation device, in Phase 3 clinical trials for patients who have failed to wean from traditional positive pressure MV "rescues" patients from MV by rebuilding weakened respiratory muscles via daily diaphragm pacing therapy sessions. The FDA designated Lungpacer DPTS a "Breakthrough Device," and recently also granted Emergency Use Authorization to treat COVID-19 and non-COVID patients during the pandemic. Lungpacer's proposed preclinical program will adapt the existing first-generation device, combining it with MV, to enable continuous diaphragm pacing therapy from the onset of MV, using both positive and negative pressure cycles to provide safer respiratory support to patients. Rationale: The second-generation device, the Lungpacer-PROTECT-Plus, synchronizes the diaphragm muscle contractions with positive pressure ventilation, thus drawing air into the patient in a manner similar to natural breathing. This innovation will improve current MV outcomes by 1) allowing ventilation at lower pressures, believed to reduce upper lung barotrauma, 2) increasing airflow into the lower lung regions, which is expected to reduce atelectasis, and 3) reducing risk of VIDD by maintaining diaphragm activity. An early prototype of the Lungpacer-PROTECT-Plus, tested in preclinical models, produced statistically significant reductions in lung injury and demonstrated its ability to maintain and/or build diaphragm muscle strength. Objective: The proposed project aims to develop an integrated design for the Lungpacer-PROTECT-Plus System and to submit the compiled documentation as required for regulatory approval by the FDA for clinical trials. The Specific Aims address the design innovations necessary to integrate phrenic nerve neurostimulation modules with mechanical ventilation, creating a unified system for more effective and safer MV. Specific Aim 1: Design, develop and verify the Lungpacer-PROTECT-Beta LCU, by revising existing software to provide multiple stimulation profiles and frequencies, with an updated graphical user interface. Specific Aim 2: Design, develop, and verify the Lungpacer-PROTECT-Beta Trigger Unit component, which is responsible for synchronizing the Lungpacer control unit (LCU) (stimulation device, Aim 1) with the MV breathing cycle. Manufacture five units for feasibility studies. Specific Aim 3: Design, develop and verify a Mechanical Ventilation module that provides positive-pressure mechanical ventilation, and that can be incorporated into the Lungpacer-PROTECT-Plus System. Finalize the design and documentation for manufacturing and for an IDE submission to the FDA. Impact: Lungpacer-PROTECT-Plus is expected to improve outcomes and survivability of patients with severe cases of COVID-19 who are receiving mechanical ventilation. It will help to decrease both morbidity and mortality and can substantially reduce the burden placed upon care providers and medical treatment facilities. The technology can be utilized by any personnel trained to place a standard central venous catheter. In addition, by reducing the amount of time a patient spends on MV, this device can free up both ICU beds and critical care personnel. Lungpacer-DPTS is broadly applicable and has the potential to improve outcomes for patients on MV for causes other than COVID-19. Less