Why so many ICU patients can't survive prolonged

How pacing the diaphragm can rescue patients from the .

Andy Hoffer Harvey Mudd College physics 1970 Professor Simon Fraser Univ. since 1991

Hoffer Mudd Talk 27 May 2020 1 1940’s 1950’s 1960’s 1970’s 1980’s 1990’s 2000’s 2010’s 2020’s

Born in K‐10 HMC PhD Staff Montevideo JHU Fellow Professor Professor Uruguay Pre‐engineering NIH U. Calgary Simon Fraser University Alberta Burnaby, British Columbia

Am. Field Service Postdoc Founder/CSO exchange student U. Alberta Neurostream Rochester NY Edmonton

Co‐Founder Bionic Power

Founder/CSO Lungpacer

Hoffer Mudd Talk 27 May 2020 2 Diaphragm Paralysis

Causes of diaphragm paralysis include: • brain or brainstem stroke, ALS • spinal cord injury, syringomyelia, polio • autoimmune (MS, Guillain‐Barré) • phrenic nerve trauma from surgery, radiation, tumor Loss of control of one or both hemidiaphragms: • phrenic neuropathy, viral or bacterial • can be caused by a traumatic injury or disease infections, unknown etiology • affects respiratory drive originating in the brain (idiopathic)

Hoffer Mudd Talk 27 May 2020 3 Temporary vs. Permanent need for Assisted Ventilation

Two kinds of insufficiency

Lifelong

High cervical SCI Brain injury ALS Central apnea

Temporary

Surgeries under general anesthesia Critically ill patients in Intensive Care

Hoffer Mudd Talk 27 May 2020 4 Assisted Breathing Methods: 1. Negative Pressure Mechanical Ventilation

Until 1952, negative pressure ventilation was exclusively applied using Iron Lung and Cuirass .

5 Hoffer Mudd Talk 27 May 2020 5 Assisted Breathing Methods: 2. Positive Pressure Mechanical Ventilation During the 1952 Polio epidemic, iron lung ventilators were in short supply. A Danish anesthetist showed that polio patients could be kept alive by providing positive pressure with bellows.

Thereafter, positive pressure mechanical ventilation (PPMV) became the standard of care for patients requiring assisted breathing in ICUs. 6 BPK 448Hoffer 2020 ‐Mudd1 Lecture Talk 17 27 May 2020 6 Positive Pressure Ventilation ‐ Fundamentals

Air is forced in, either through dialing the applied pressure () or the supplied volume (volume control).

Patients can vary between being deeply comatose to alert and interactive.

The ventilator can

• Provide a mandatory breath, • Assist a patient who can initiate a breath, • or do a combination of the above. BPK 448Hoffer 2020 ‐Mudd1 Lecture Talk 17 27 May 2020 7 The Harms of Positive Pressure Ventilation‐ the Evil “V”s

• Ventilator‐induced lung injury (VILI) • Volutrauma • Atelectotrauma •

• Ventilator‐associated pneumonia (VAP)

• Ventilator‐induced diaphragmatic dysfunction (VIDD)

BPKHoffer 448 2020 Mudd‐1 LectureTalk 27 17 May 2020 8 Ventilator‐Induced Lung Injury (VILI) Volutrauma/

High end-inspiratory volume High airway pressure during PPV causes direct lung damage and causes lung overdistension with inflammation that can result in gross tissue injury and transfer of increased epithelial and air into the interstitial tissues at the microvascular permeability, allowing fluid filtration into the proximal airways. (pneumothorax). alveoli (pulmonary edema)

BPK 448Hoffer 2020 ‐1Mudd Lecture Talk 17 27 May 2020 9 Atelectrauma

• Atelectasis: a complete or partial collapse of a lung or lobe of a lung. Develops when alveoli within the lung become deflated. • Positive pressure ventilation yields inhomogeneous pressure distribution and parts of the lung collapse due to extrinsic weight (chest wall) and intrinsic compression (superior portions of the lung, mediastinal contents). • Cyclical collapse and re-opening of these terminal lung units induces inflammation and damage through recurrent shear stress and alterations in local surfactant.

BPK 448Hoffer 2020 ‐1Mudd Lecture Talk 17 27 May 2020 10 Intraoperative Protective Mechanical Ventilation for Prevention of Postoperative Effects of high and low tidal volumes (VT) at end‐ Pulmonary Complications: A inspiration and end‐expiration with low and high Comprehensive Review of the Role of Tidal Positive End‐Expiratory Pressure (PEEP) during Volume, Positive End‐expiratory Pressure, general anesthesia. and Lung Recruitment Maneuvers. Atelectatic lung regions (red), overinflated regions Güldner et al, Anesthesiology, 2015 (blue), normally aerated regions (pink).

During ventilation with low VT and low PEEP, higher amounts of atelectasis are present at end‐ expiration and end‐inspiration with minimal areas of overinflation. During ventilation with high VT and low PEEP, less atelectasis is present at end‐expiration and end‐ inspiration, with increased areas of overinflation at end‐inspiration. Furthermore, a higher amount of tissue collapsing and decollapsing during breathing is present. During ventilation with low VT and higher PEEP, less atelectasis is present. However, higher overinflation occurs at end‐inspiration and end‐ expiration, with minimal collapse and reopening during the breathing cycle.

Hoffer Mudd Talk 27 May 2020 http://anesthesiology.pubs.asahq.org/article.aspx?articleID=2383205 11 Ventilator‐associated pneumonia (VAP) • VAP is pneumonia that develops 48 hours or longer after mechanical ventilation is given by means of an endotracheal tube or tracheostomy.

• VAP results from invasion by microorganisms into the lower respiratory tract and lung parenchyma. Intubation compromises the integrity of the oropharynx and trachea and allows oral and gastric secretions to enter the lower airways.

• The microbiologic flora responsible for VAP is different from that of the more common community‐ acquired pneumonia (CAP). In particular, viruses and fungi are uncommon causes in people who do not have underlying immune deficiencies. Though any microorganism that causes CAP can cause VAP, several bacteria (referred to as multidrug resistant) are particularly important causes of VAP because of their resistance to commonly used antibiotics.

• Persons with VAP have increased lengths of ICU hospitalization and have up to a 20‐30% death rate.

12 12 Hoffer Mudd Talk 27 May 2020 Ventilator‐Induced Diaphragmatic Dysfunction

VIDD

•“a loss of diaphragmatic force-generating capacity that is specifically related to the use of mechanical ventilation.”

• Work in multiple animal models showed a significant reduction of diaphragmatic force-generating capacity that was proportional to duration of mechanical ventilation.

Vassilakopoulos et al. Am J Respir Crit Care Med 2004 Haistma, Curr Opin Anesth 2011

BPK 448Hoffer 2020 ‐1Mudd Lecture Talk 17 27 May 2020 13 VIDD

Cited by 1103 to-date

Hoffer Mudd Talk 27 May 2020 14 Can VIDD be Prevented?

“daily vacation from sedation”

Hoffer Mudd Talk 27 May 2020 15 Could Phrenic Pacing be used instead of MV?

16 Hoffer Mudd Talk 27 May 2020 Electrophrenic activation: Early visionaries 1780 Galvani Discovered that a dead frog's leg twitched violently when touched with a knife. Volta later showed that electricity flows when moisture (from the frog) comes between two different types of metal. 1783 Hufeland Proposed to treat neonate asphyxia by stimulating the phrenic nerves. 1786 Caldani Probably first to observe diaphragm movement upon electrical stimulation of the phrenic nerve. 1818 Ure Applied electricity to the phrenic nerve in a recently hung criminal and produced “strong and laborious respirations.” 1872 Duchenne Concluded that phrenic nerve stimulation was the “best means of imitating natural respiration.”

1878 Ziemssen Placed moist sponges on neck surface to stimulate phrenic nerves.

1948 Sarnoff Paced a conscious patient with implanted phrenic nerve electrode.

1966 Glenn Treated chronic insufficiency with implanted radiofrequency system. 1971 Glenn Developed the first commercial phrenic pacing system (Avery).

Schechter DC. Application of electrotherapy to noncardiac thoracic disorders. Bull N Y Acad Med. 1970 Nov;46(11):932‐51. Hoffer Mudd Talk 27 May 2020 17 Possible Diaphragm Activation Methods

“Getting Inspiration from Electrophrenic Activation”

1 Transcutaneous

2 Surgically Implanted

3 Laparoscopically Implanted

Hoffer Mudd Talk 27 May 2020 18 1. Transcutaneous Stimulation

1950 Advertising Pamphlet Sanborn Electrophrenic Respirator www.decodog.com/inven/medical1.html

– Electrical

– Magnetic

• Cumbersome. • Can only be applied manually and maintaining long term positioning is difficult in an ICU patient. • not selective enough to stimulate at sufficiently high levels without also recruiting brachial plexus branches. • Suitable for assessment of diaphragm function • But these methods are finicky and not reliable for therapeutic stimulation Hoffer Mudd Talk 27 May 2020 19 Possible Diaphragm Activation Methods

“Getting Inspiration from Electrophrenic Activation”

1 Transcutaneous

2 Surgically Implanted

3 Laparoscopically Implanted

Hoffer Mudd Talk 27 May 2020 20 2. Surgically Implanted Phrenic Pacing Electrodes

Developed by Glenn in Yale since 1960’s Avery Breathing Pacemaker System available since 1970’s for SCI or central apnea.

The implanted receiver is a small electronic device, about the size of a quarter and about 1/4" thick, that receives radiofrequency energy and converts it to electrical impulses that stimulate the diaphragm. The implanted electrode is a highly flexible monopolar stainless steel wire, insulated by silicone rubber, with a platinum nerve contact on one end, and a connector that mates with the receiver. https://youtu.be/hsy1VMnk6yA The I‐110 family of receivers were implemented for phrenic pacing in 1990 and approved by the US FDA in 1991. Obsolete I‐107 receivers are pin‐compatible with the current design and can be upgraded in a simple outpatient surgical procedure. A bipolar configuration is also available for those patients implanted with other medical devices, such as a cardiac pacemaker, to provide an additional margin of electrical isolation. Hoffer Mudd Talk 27 May 2020 www.averybiomedical.com 21 BPK 448 2020‐1 Lecture 17 22 Hoffer Mudd Talk 27 May 2020 22 Clinical Desirability of PNS over MV Hirschfeld et.al, 2008 Prospective clinical study on effects of MV vs. PNS on Respiratory Infection (RI) rates • Treatment‐related data collected over 20 years • 32‐MV / 32‐PNS patients • Results: 0 RI with PNS, vs. 2 RI/100 days with MV

Advantages of PNS over MV Disadvantages of PNS

• Increased freedom • Lengthy/complex invasive surgery • Negative pressure breathing (several hours) • Lower risk of ventilatory‐associated • Possible damage to phrenic nerves pneumonia (VAP) during or after electrode placement • Decreased risk of tracheal • High initial cost (~$60,000 USD) complications • Difficult to retrieve device • Pays for itself within 3‐4 years of • Few patients are eligible operation

Hoffer Mudd Talk 27 May 2020 23 Possible Diaphragm Activation Methods

“Getting Inspiration from Electrophrenic Activation”

1 Transcutaneous

2 Surgically Implanted

3 Laparoscopically Implanted

Hoffer Mudd Talk 27 May 2020 24 3. Laparoscopically Implanted Intramuscular Electrodes

https://www.youtube.com/watch?v=FDBEzup-ciQ Advantages of Diaphragm Intramuscular Electrodes  No thoracotomy, lower risk of nerve damage  Lower risk of complications such as pneumothorax  Faster recovery from laparoscopic surgery than open surgery Disadvantages of Implanted Diaphragm Electrodes o Lengthy, costly surgery, requires full anaesthesia (2‐4 hrs) o Percutaneous wires connect to external control unit o Critically ill patients are not eligible Hoffer Mudd Talk 27 May 2020 25 But what about patients who need Temporary Assisted Ventilation?

Two kinds of breathing insufficiency

Lifelong

High cervical SCI Brain injury ALS Central apnea

Temporary

Surgeries under general anesthesia Critically ill patients in Intensive Care

Hoffer Mudd Talk 27 May 2020 26 Mana and Andy, Baltimore, 1974

Montevideo December 2006

Tema 9 Hoffer 21 Feb 2019 27 Hoffer Mudd Talk 27 May 2020 27 Could VIDD – and VILI ‐ be Prevented by Pacing the Phrenic Nerves in the ICU?

Hoffer Mudd Talk 27 May 2020 28 Possible new Diaphragm Activation Method?

1 Transcutaneous

2 Surgically Implanted

3 Laparoscopically Implanted

4 Transvascular

New Inspiration method –inspiredby having taught BPK 205

Hoffer Mudd Talk 27 May 2020 29 IntraVenous Catheter with Stimulation Electrodes

The SFU Hoffer Lab Minimally Invasive Nerve Stimulation (MINS) approach to diaphragm pacing

Transvascular Nerve Stimulation Apparatus and Methods. Hoffer, Joaquín Andrés. U.S. provisional patent filed January 29, 2007 (priority date); P.C.T. application No. WO2008/092246, published August 7, 2008. 30 Hoffer Mudd Talk 27 May 2020 Ok, we’re inside a Vein… but where are the Phrenic Nerves?

BPKHoffer 448 2020 Mudd‐1 TalkLecture 27 May 18 2020 31 Stimulation Efficacy vs Location in Vein (Chronic Pig 1)

Left Phrenic Nerve Capture - Threshold Current (mA)

16 James Saunders, MD 14 12 10 8 6 4 2 0 567891011 Cathode Electrode Depth into Vein (cm)

BPK Hoffer448 2020 Mudd‐1 LectureTalk 27 May18 2020 32 SFU MINS Team, April 2009

Hoffer Mudd Talk 27 May 2020 33 Lungpacer Medical Inc.

• Company founded in May, 2009

• Spun out from the SFU Neurokinesiology Lab

• Developing a proprietary electrical stimulation technology with the potential to: • Improve clinical outcomes for patients in the Intensive Care Unit (ICU) • Shorten the hospital stay, and • Significantly reduce healthcare costs

• Simple to place

• Easy to use

• Temporary & easily removable

BPKHoffer 448 2020Mudd‐1 TalkLecture 27 18May 2020 34 Diaphragm Pacing Assists Ventilator

Mechanical ventilators use positive pressure;

luft1g.php cause lung injury ‐ ventilator

‐ www.leistungbrasil.com/eng/mechanical http://bodysystems‐rlj00.blogspot.ca/2012/07/respiratory‐system.htmll

POSITIVE

PRESSURE Endotracheal Tube

Chest Wall

HofferBPK 448 Mudd 2020 Talk‐1 Lecture 27 May 18 2020 35 Diaphragm Pacing Assists Ventilator

Mechanical Diaphragm pacing ventilators use provides negative positive pressure; pressure to inflate

luft1g.php cause lung injury lungs more normally ‐ ventilator

‐ www.leistungbrasil.com/eng/mechanical http://bodysystems‐rlj00.blogspot.ca/2012/07/respiratory‐system.htmll

POSITIVE NEGATIVE PRESSURE Endotracheal PRESSURE Tube

Chest Wall

HofferBPK 448 Mudd 2020 Talk‐1 Lecture 27 May 18 2020 36 Immediate Therapeutic Benefit During Pacing

(Acute Pig #11 17 May 2011)

Left phrenic pacing Right Start Pacing phrenic pacing

Airway pressure Peak Ventilator Pressure is reduced

(cm H2O)

Airway flow (L/min)

Required tidal volume (L)

BPKHoffer 448 2020 Mudd‐1 LectureTalk 27 18 May 2020 37 Adjustable pacing onset timing relative to MV

BPKHoffer 448 2020 Mudd‐1 LectureTalk 27 18 May 2020 38 Therapist specifies desired diaphragm output

HofferBPK 448 Mudd 2020 Talk‐1 Lecture 27 May 18 2020 39 Therapist specifies desired diaphragm contribution; Control Unit monitors output and titrates pacing level

BPK 448Hoffer 2020 Mudd‐1 Lecture Talk 1827 May 2020 40 Expected Therapeutic Benefits

1. Protect the diaphragm

2. Protect the lungs

3. Assist the heart (venous return is pumped by the diaphragm)

4. Reduce nosocomial infections, pneumonia

5. Accelerate weaning

6. Liberate patients from MV

7. Reduce mortality rates

8. Improve survivor’s quality of life

BPK 448Hoffer 2020 Mudd‐1 Lecture Talk 1827 May 2020 CONFIDENTIAL41 41 9 Grants and 11 Industry Awards received

Innovation Office 2009 2008, 2010 Emerging Technology Award Prototype Development Funding

2008-9 Phase I 2010-13 Phase II 2010 Idea-to-Innovation Grants Innovation and Achievement Award www.youtube.com/watch?v=_XaE8XM5zpY

2010-2016 Industry Contribution Programs 2012 Most Promising Pre-Commercial Technology Proof‐of‐Principle Phase I and Phase 2012 2013 2012 II grants 2014 2015 Silver Award 2016 2017 2012‐2017 San Diego42 BPK 448Hoffer 2020 Mudd‐1 Lecture Talk 1827 May 2020 42  Lungpacer Medical Inc.

• Company founded in May 2009 • Moved to own premises on 31 October 2014 8602 Commerce Court, Burnaby, BC

HofferBPK 448 Mudd 2020 Talk‐1 Lecture27 May 18 2020 43 https://www.sfu.ca/vpresearch/research-news/2014/lungpacer-expands-into-new-location.html

HofferBPK 448 Mudd 2020 Talk‐1 Lecture 27 May 18 2020 44 Description of Diaphragm Pacing Therapeutic Protection System

3

1. Neurostimulation Catheter • Easy to place in left subclavian vein • Easy to remove 2 • Selectively stimulates both phrenic nerves • Can also be used as a central line catheter 1 2. Airflow Sensor • Single‐use component connects to the

3. Therapy Control Unit • Automatically selects best electrodes • Paces the diaphragm in synchrony with ventilator breaths • Agnostic to ventilator makes and models

45 Hoffer Mudd Talk 27 May 2020 45 First-in-Human Trials

CIHR Proof-of-Principle Grant for First-in-Human Trials at Royal Columbian Hospital

Dr. Steve Reynolds, head of Critical Care and infectious diseases specialist at Royal Columbian Hospital, and Dr. Andy Hoffer, founder of Lungpacer Medical Inc., are collaborating to improve how intensive care units provide respiratory support for their sickest patients.

A $160,000 proof-of principle Phase I grant from the Canadian Institutes for Health Research (CIHR) will fund their trial of a transvenous diaphragm pacing system (DPS).

Phase II grant awarded April 1, 2015 www.sfu.ca/science/news-events/news/2016/new-sfu-professorship- to-boost-research-collaboration-with-rch.html 46 VENTILATOR Preclinical Proof of Concept Study

AIRFLOW SENSOR

LUNGPACER CONTROL Preclinical Objectives UNIT 1. Pace phrenic nerves in synchrony with MV RIGHT LEFT 2. Protect diaphragm from disuse atrophy PHRENIC PHRENIC NERVE 3. Preserve diaphragm endurance NERVE

SUPERIOR VENA LIVE CAVA Am. J. Respir. Crit. Care Med., Feb. 2017 CATHETER DIAPHRAGM LEFT SUBCLAVIAN 195(3):339-348. VEIN

EMG SENSORS ULTRASOUND PROBE ACCELEROMETER

47 BPK 448Hoffer 2020 Mudd‐1 Lecture Talk 2718 May 2020 Preclinical study: Pressure reduction

Test the ability to reduce positive pressure

• Paced every 2nd ventilated breath • Airway pressure was reduced 20-30% • Tidal Volumes were unchanged

Demonstrated the ability to reduce positive pressure while maintaining tidal volumes, which has been documented to reduce the risk of lung injury1,2,3

1. Neto, Lancet Respir Med; March 2016 2. Slutsky et al., N Engl J Med 2013;369:2126-36 3. Fan et al. BMC Medicine 2013, 11:85

BPK 448 2020‐1 Lecture 18 48 BPK 448Hoffer 2019 Mudd‐1 Lecture Talk 2719 May 2020 Pre‐Clinical Study: Ventilated vs. Paced Breaths

Video shows 7 ventilated breaths:

1 Unpaced 2 Paced 3 Unpaced 4 Paced 5 Unpaced 6 Unpaced 7 Paced

• The distal lungs were better ventilated during paced breaths

BPK 448Hoffer 2020 ‐Mudd1 Lecture Talk 18 27 May 2020 49 Preclinical study: Pacing reduces muscle atrophy

Histological comparison

• 60 Hours of IMV caused >25% Atrophy of Diaphragm Muscle Fibers (p <0.05).

 Pacing reduced ventilator‐induced muscle fiber atrophy.

Demonstrated the ability to reduce muscle atrophy, which has been documented to extend MV, ICU, weaning and hospital stay time1,2,3

1. Berger et al., Journal of Cachexia, Sarcopenia and Muscle; 2016 2. Slutsky et al., N Engl J Med 2013;369:2126-36 Hoffer Mudd Talk 27 May 2020 3. Fan et al. BMC Medicine 2013, 11:85 50 Preclinical study: Respiratory muscle endurance

Tolerance of endurance test

Kaplan-Meier representation of the proportions of the 6 Paced and 6 Control group pigs that were able to tolerate endurance testing for 8 minutes and their time characteristics.

MV + PACED

MV Only (not Paced)

All MV + Paced pigs endured the 8-minute test. 50% of the MV Only pigs failed,

due to low O2 saturation, high CO2 levels resulting from diaphragm fatigue.

Hoffer Mudd Talk 27 May 2020 51 First‐in‐Human Clinical Studies Oct 2015 through April 2016

Patient Population: 24 anesthetized, intubated, adult patients on mechanical ventilation.

Study Objectives 1. Place LIVE Catheter, map nerve locations 2. Pace phrenic nerves in synchrony with IMV 3. Demonstrate that Pacing reduces airway pressure 4. Total procedure time < 2 hours

Diaphragm Activation in Ventilated Patients using a Novel Transvenous Phrenic Nerve Pacing Catheter. Reynolds S; Ebner A; Meffen T; Thakkar V; Gani M; Taylor K; Clark L; Meyyappan R; Sadarangani G; Sandoval R; Rohrs E; Hoffer JA. Critical Care Medicine, July 2017 45(7):e691-e694. BPK 448Hoffer 2020 Mudd‐1 Lecture Talk 2718 May 2020 52 Human safety assessment Summary: First‐in‐Human studies, October 2015‐April 2016

Successful N/ Total N Successful LIVE Catheter Insertion and 24/24 Primary Placement Endpoints Absence of device- or procedure-related adverse events 24/24

Bilateral phrenic nerve stimulation 201,3/232

Secondary Diaphragm contraction in synchrony with 22/222,3 Endpoints IMV

Reduction of airway pressure 22/22

1 In two patients, only one phrenic nerve could be stimulated. 2 One patient was excluded from the procedure after LIVE Catheter insertion but prior to nerve stimulation, due to unstable blood pressure that was unrelated to the Lungpacer System. 3 In one patient, neither phrenic nerve could be stimulated. Hoffer Mudd Talk 27 May 2020 53 Fluoroscopy of Diaphragm Pacing

First breath: mechanical ventilation only. Second breath: mechanical ventilation PLUS phrenic pacing.

Hoffer Mudd Talk 27 May 2020 54 Human clinical data Pacing reduces pressure • Pacing reduced Peak Pressure by 25% for same tidal PACED UNPACED volumes

• MV Only = 21 cm H2O

• MV + PACING = 16 cm H2O • Pressure reduction reduces lung injury and pulmonary complications1,2,3 Pressure

Time

1Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med. 2013;269:2126-36. PubMed PMID: 24283226. 2Neto S, Let al., “Association between driving pressure and development of postoperative pulmonary complications in patients undergoing mechanical ventilation for general anesthesia”, Lancet Respir Med (March 2016). 3 Grasso F et al. Negative-Pressure Ventilation: Better Oxygenation and Less Lung Injury. Am J Respir Crit Care Med (2008) 177:412–418. Hoffer Mudd Talk 27 May 2020 55 Anticipated Effects of Phrenic Pacing on Time to Successful Weaning

Protection from VIDD

Rescue from VIDD

56 Hoffer Mudd Talk 27 May 2020 56 Clinical strategy Initial Focus: 1) Rescue Failed‐to‐Wean, and then 2) Protection from likely Failure

Rescue failed-to-wean IMV patients 1)“Rescue” Restore diaphragm strength and endurance by pacing supported exercise in patients who failed to wean in at least two Spontaneous Breathing Trials (SBTs). In May, 2016, the FDA granted Lungpacer the Expedited Access Pathway (EAP) designation for this indication.

Hoffer Mudd Talk 27 May 2020 57 Lungpacer Clinical Trials ‐ Current Status https://clinicaltrials.gov/ct2/results?term=lungpacer&rank=4#rowId3

1 4 Centers in USA Percutaneous Temporary Ventilator Device: U Florida Health Science Ctr COMPLETED Placement of a Phrenic Nerve Induced Lungpacer DPTS New York U Medical Center Feb 2018 Stimulator for Diaphragm Pacing Diaphragm (Diaphragm Pacing Temple U Hosp Philadelphia N = 9 (RESCUE 1) ‐ Pilot Trial Dysfunction Therapy System) U Texas SW Med Ctr Dallas

A Protocol Comparing Temporary 2 Ventilator Transvenous Diaphragm Pacing to Device: 26+ Centers in USA Induced Standard of Care for Weaning Diaphragm Pacing Study Start Date: RECRUITING Diaphragm From Mechanical Ventilation Therapy June 14, 2019 N = 300 (est) Dysfunction (RESCUE 3) ‐ Pivotal Trial 3 Percutaneous Temporary Ventilator COMPLETED Placement of a Phrenic Nerve Device: Italian Hospital Induced Lung Apr 2016 Stimulator for Diaphragm Pacing, LIVE Catheter Injury Asuncion, Paraguay N = 24 a First in Human Trial

4 Percutaneous Temporary Ventilator Device: 21 Centers in Europe RECRUITING Placement of a Phrenic Nerve Induced Diaphragmatic N= 110 (est) Stimulator for Diaphragm Pacing Diaphragm Pacing Therapy 7 Centers in France (RESCUE 2) Dysfunction DPTS 12 Centers in Germany 5 Percutaneous Temporary Placement of a Transvenous Ventilator COMPLETED Device: Italian Hospital Phrenic Nerve Stimulator Induced Lung Apr 2018 LIVE Catheter Asuncion, Paraguay N = 13 for Diaphragm Pacing Injury Using Jugular Access Hoffer Mudd Talk 27 May 2020 58 Lungpacer Medical, Inc. Announces FDA Approval of Emergency Use Authorization of the Lungpacer Diaphragm Pacing Therapy System to Help Address COVID‐19 Pandemic

VANCOUVER, British Columbia, April 14, 2020

Lungpacer Medical, Inc., a medical device company developing an intravenous catheter‐ based phrenic‐nerve‐pacing system, announced today that the FDA has approved the Emergency Use Authorization for the use of the Lungpacer Diaphragm Pacing Therapy System (DPTS) to assist in weaning patients determined by their healthcare provider to be at high risk of weaning failure. According to the FDA letter, “patients at high risk of weaning failure include COVID‐19 patients requiring ventilation and [other] patients being mechanically ventilated for other high‐risk conditions including post‐cardiac and post‐thoracic surgical procedures and medical ICU patients requiring prolonged ventilation.” The approval states that “FDA has concluded that the Lungpacer DPTS may be effective at treating patients during COVID‐19 by helping wean patients off ventilators in healthcare settings, thereby reducing their risks of prolonged mechanical ventilation and increasing the availability of ventilators during the COVID‐19 pandemic.” Lungpacer CEO, Doug Evans, stated that “this amazing honor provides a unique opportunity to help improve outcomes for many patients affected by this global health crisis.” http://lungpacer.com/news/

Hoffer Mudd Talk 27 May 2020 59 lungpacer.com/

Hoffer Mudd Talk 27 May 2020 60