Diaphragm Pacing:What we Learned since the First Implant

Raymond P Onders MD FACS

Cindy Kaplan MSN

Mary Jo Elmo CNP

University Hospitals Case Medical CenterDepartment of Surgery11100 Euclid AvenueCleveland, Ohio 44106Phone: 216-844-8594Fax: 216-983-3069

Objectives

• Review how we breath and the history of diaphragm pacing

• Outline the optimal role of diaphragm pacing in ALS and how to screening patients

• Identify other surgical procedures that can improve quality of life of patients with ALS

• Review Case Examples

BackgroundOver 17 years of work

ALS for 10 years• Animal Models

– Canine, swine, and rats• Human - over 1400 patients worldwide

– 25 normal– >200 SCI patients– >300 ALS patients– Multiple various other patients including acute

Summarizing multiple IDE trials and over ten IRB protocols at UHCMC

How Do We Breathe?Consists of UMN & LMN Components

• UMN– Cerebral Cortex- volitional– Carotid Body

• O2 saturation – Brainstem- Special somatic nuclei

• CO2 levels

• LMN – C3-5– Small, medium and large neurons

with different resistance levels• Diaphragm Motor Units

– Slow twitch Type I– Fast Twitch Type IIb

The Diaphragm is the Key for Breathing

• 24 hour use (24/7/365)• Different day/night control• Night REM - diaphragm• Atrophy occurs faster

than extremity muscles from disuse

• Disuse causes change of slow twitch oxidative (Type I) to fast twitch glycolytic (Type IIb)

Methods: Implantation

Mapping to Identify Optimal Location for Wire Implantations

Clinical Station to Program Unit To condition diaphragm with no pain

Conditioning the Diaphragm with external system

Laparoscopic Surgery

Implanting 2 electrodes In each Diaphragm

DP Started for UMN Loss Spinal Cord Injury

• 100% success in meeting tidal volumes for successfully implanted patients

• Over 300 cumulative years- longest 13 years• 100% had improved speech and more normal breathing• 100% increased sense of independence• 100% of patients prefer DP over ventilators

Christopher Reeve “Superman”Second patient implanted

Pediatric DP Implantations- Now WorldwideSpain, US, Canada, Norway, Germany, Italy, Saudi

Arabia, Jordan

• Age 5-17, weight as low as 15 Kg

• Time on MV 11 days to 7 years

• 12 additional children since article- youngest 2 years old

Other Pediatric Implantations:SMA

Pompe

Early Implantation and Neuroplasticity in SCI patients

• Patients have gone from Mechanical Ventilators to DP to volitional breathing

• DP electrodes functions as EMG to assess recovery

• Functional Electrical Stimulation can lead to recovery- improves spinal cord environment

Prior to DP: No EMG Activity

After DP Conditioning: Recovery of Natural Function

Large burst activity

SCI Conclusions: Nobody Chooses to go Back to Ventilators

Replacing the Ventilator- Changes the life of a SCI patient

Can delaying a ventilator do the same in ALS?

The First Child: The boy who came back from heaven

Cannot skydive with a ventilator

Delaying Ventilators in ALSInitial concept after 2nd SCI patient

• ALS is UMN and LMN• DP overcomes UMN loss of control• DP conditions the diaphragm before failure

DP Augments Respiration

Diaphragm Pacing in MND (ALS)Mechanism of Action

• Demonstrated in various studies– Conditioning will convert muscle fiber type from fast

twitch (Type II) to slow twitch (Type I) fatigue resistant fibers

– Conditioning will strengthen remaining fibers– Pacing will replace signal from lost upper motor

neuron pathways– Improved respiratory system compliance

• Possible actions not specifically studied– Potential for trophic effects– Promotion of collateral sprouting

Indication for DPS Across UMN/LMN Distribution in ALS

Pure LMN Pure UMN

Sp

ina

l Mu

scu

lar

Atr

oph

yP

ost

-po

lio S

ynd

rom

e

Pri

ma

ry L

ate

ral S

cle

rosi

sH

igh

Le

vel S

pin

al C

ord

Inju

ry

Indication for DPS

Percentage of presenting patients (Ravits – 2007)

21% 17% 4%44%14%

Ravits – 2007• Predominant UMN in 4% of population• Predominant LMN in 21% of population

Device Clinical Trials

• Different from Drug Trials– Device itself is classified, Class I, II, or III

depending on risk of the device– The Class of the device dictates the type of

trial– From Pilot to Pivotal

• HDE –Humanitarian Device Exemption– Must contain sufficient information for FDA to

determine that the probable benefit to health outweighs the risk of injury or illness.

PMA-track IDE G040142 Pivotal Study of Diaphragm Pacing in ALS

• PMA-track IDE– Study design powered (N=70) to demonstrate a primary endpoint of

reduction in decline of FVC between lead-in control period and treatment period for patients not using NIV

• 144 Patients Enrolled:– 106 patients implanted (2005 – 2009)– 88 Patients w/ chronic hypoventilation– 22 Patients w/o NIV

• Clinical Trial Centers:– UH of Cleveland( Katirji, Onders)– Johns Hopkins(Rothstein, Maragakis)– Stanford(So, Cho)– The Methodist Hospital(Appel, Simpson)– Groupe Hospitalier Pitie-Salpetriere (Meininger, Similowski, Gonzalez)– Henry Ford Health System(Newman)– Forbes Norris (CPMC)(Katz, Miller)– Mayo Clinic Jacksonville (Boylan)

FDA Conclusions for Efficacy

• Significant improvement in survival from diagnosis (by 16 months) and from the start of NIV (by 9 months) compared to standard-of-care NIV

• Remarkable 100% 30-day and improved long term survival with simultaneous PEG and DP compared to 30-day mortality expectations of 2% - 25%

• 16 month survival after DP for patients with no other respiratory options who are intolerant of NIV

• Significant sleep improvement after 4 months of DP conditioning

Results of DP in ALS HUD SubgroupMatch Comparison to Lechtzin et al

Lechtzin, 2007

NeuRx DPSCH Patients

Standard NIV

Early NIV

• Comparison to Lechtzin 2007– Matched baseline demographics

between DP and Lechtzin subpopulations

• DP Patient’s Survival

– 100% 30 day survival– 86% 6 month survival– 74% 12 month survival

• 37.5 months median survival from diagnosis for DP patients as compared to Lechtzin’s 21.4 month

Lechtzin, N., et al., Early use of non-invasive ventilation prolongs survival in subjects with ALS. Amyotroph Lateral Scler, 2007. 8(3): p. 185-8.

UHCMC Experience

• First Implant in ALS – March 2005• 5 separate IRB Protocols • 210 ALS patients implanted • FDA approved since 2011

Diaphragm Pacing is Safe in ALSOver 2,450 months of use in study

25% still alive- 40 months post study

Anesthesia Protocol

• No paralytics• Short acting anesthetic agents:

remifentanil, sevoflorane, propofal

DP utilized for subsequent operations

• 452 implant months– 2260 months of wire exposure- one infection

• Median survival 19.7 months– Respiratory cause of death only 31%– LONGEST PATIENT 6 YEARS THEN

TERMINAL WEAN OF DP• Improvement in rate of decline of FVC• Decrease in rate of Hypercarbia• 50% used with sleep

Augmenting Respiration: Pilot StudyDP Increases Muscle Thickness/Mass:

DPS converts Type IIb (fast twitch) to Type 1(slow twitch) muscle fibers

Augmenting Respiration: DP Improved Movement of Diaphragm

Under Fluoroscopy• Increase in diaphragm

contraction with stimulation compared to volitional movement

• Allows visualization of upper motor neuron involvement

• Confirms surgical findings

Healthy Chest X-Ray• Diaphragms equal• Left HD –bottom heart border

Significantly Elevated Right Hemi-diaphragm

Significantly ElevatedLeft Hemi-diaphragm

Why ALS patients should getChest X-Ray : 70% had significant unilateral abnormalities

Onders et al ALS 2013

Pt. with FVC 85%

Why does the diaphragm become elevated and elongated?

• Instability of control of the diaphragm

• LMN may be intact• With disuse rapid atrophy• No diaphragm burst activity

on left but excellent stimulation at surgery

• Elongated diaphragm muscle can lead to permanent sarcomere damage- non-recoverable

Arterial Blood Gas is Underutilized

• 20 patients with FVC > 50% had CO2 ≥ 45• 15 of the 20 used NIV • 1 pt CO2 62, FVC 58, no NIV

Augmenting Respiration: Treating Hypercarbia

• Multi-center Trial Paired Sample

• Post DP pCO2- Total (n=74)– Decreased 2.0 mmHg– P<0.001

• Elevated pCO2 greater than 45 pre-implant(n=18)– Decreased 2.6mm Hg– P< 0.03

Pt 01-11- DPS decreased pCO2 from 54 to 40Patient became more alert

Only 2 breaths a minute

Augmenting Respiration: Overcome Central Sleep Apnea & NIV Impact on Diaphragm Activity

Sleep studies show diaphragm EMG suppression when on NIV

Diaphragm EMG w/o NIV

Diaphragm EMG with NIV

1. Aboussouan, L.S et al Objective measures of the efficacy of NIPPV in ALS. Muscle Nerve, 2001 24(3): p403-9

2. Hermans, G et al Increased duration of MV is associated with decreased diaphragmatic force, Crit Care, 2010. 14(4): p R127

Augmenting Respiration: Improvements in Sleep with DP

When is the right time for DP Evaluation?

• “My Doctor says I am not ready”– You need to have correct diaphragm evaluation before

reaching this conclusion• Typically if you meet criteria for NIV you will likely meet

criteria for DP • “My doctor says I need a trach vent or a pacer”

– This is patient who is usually too late in disease course• Pacing maintains diaphragm muscle and slows down the rate

of respiratory decline. It should be thought of as therapy/treatment not a last ditch effort

• You can be too late in disease to benefit from pacing

Evaluation for Implantation

• Clinical Assessment for Diaphragm LMN involvement• Assess for Chronic Hypoventilation• Assess for stimulatable Diaphragm

– Fluoroscopy and/or phrenic nerve studies

• Assess for Feeding Tube Needs– Increased patient acceptance for low profile tubes– 88% simultaneous PEG

• End of Life Discussion– 30% of our patients had to turn off DP during terminal care

Problem with FVC Indication• MIP and Supine FVC have consistently shown to be more

sensitive in identifying respiratory problems compared to sitting FVC

• 130 patients since approval– 80 had FVC > 50%

• 45 of those had MIP <60– 43 had FVC > 65% (Average FVC 79%)

• 25 of those had MIP <60

• 102 (78%) of the 130 had MIP < 60 • 50 (38%) had FVC below 50%

• Using FVC to screen for Diaphragm Pacing usually identifies patients very late in their disease – often too late for pacing to help

Reasons for Not Implanting• No Evidence of Stimulatable Diaphragm• Excessive Secretions

– Aspiration risk would lead to risk of death greater than possible benefit of pacing

• Benefit does not outweigh risk• End of Life Discussions

– Treatment withdrawal issues– Incongruent treatment decisions

Post Operative CarePostPost--OpOp

• Admitted for overnight

• Resume regular activity

• Resume regular diet

–No routine post-op blood work or CXR

Steri Strips:These cover and protect your newly placed wiresOk for wires to get wet/ shower post-op day 1 –

~Be careful not to touch/pull wires~Steri-Strips will fall off by themselves in 10-14

days (do not pick at them)

Exit wires:Cleaning with rubbing alcohol needs to be done routinely – ~Three (3) times a week and/or after a shower

• ~If site becomes reddened: clean and change dressing three (3) times daily

Dressings –• ~Cover wire site with gauze and tape/clear dressing

(do not let the adhesive stick to the actual wires.)• ~Best to keep dressing over wires at all times – it

will prevent snagging and pulling - this is true even after granulation tissue forms

• For PULLED OUT WIRES, PAIN, BRUISING, DRAINAGE, and/or BLEEDING at wire site – please call!!!!

*Unless otherwise ordered, you may resume regular activity and diet, as you are able. *

Programming Settings• Setting optimized for each

patient– Comfortable tidal volume with

frequency less than 20• Each diaphragm and electrode

different settings• Control options

– Amplitude– Frequency– Rate– Pulse Width– Pulse Modulation

• Day time – 5 times – 30 min each

• Night time

• NIV

• Full time

→ Little respiratory compromise→ No NIV use

→ Any sleep disordered breathing→ Patient preference

→ Always use DP when utilizing NIVDP BPM rate > than NIV rate

→ DP breathing is better than volitional breathing

→ Respiratory instability→ Moderate respiratory decline

Pacer Utilization

Long Term Pacer Usage

• Increase pacing time as disease progresses

• Follow diaphragm EMG’s, Sleep Studies• Monitor CO2

• Breathing Patterns– OK to use Cough Assist, Vest, NIV, etc.

Why Improved Survival with DP and PEG? DP Augments Respiration by Increasing

Respiratory Compliance• Compliance related to atelectasis and work of breathing• Patients report an easier sense of breathing• Peri-operative measurement of respiratory system

compliance in group of patients gave 23% increase with stimulation

Patient Without DPS With DPS Change

01-12p 50 68 36%

01-14p 59 68 15%

01-15p 63 75 19%

01-01 59 72 22%

Respiratory System Compliance (ml / cm H2O)

*Onders, Elmo et al , Chest 2007

Simultaneous ProceduresFeeding Tubes

• Both regular PEG and low profile gastrostomy successfully placed

• Cosmesis of standard PEG is a major reason patients refuse PEG

• 117 HDE patients simultaneous DP/PEG

• 114 chose low profile tube

Pros Cons of Low Profile Tube

• More post operative pain with either tube• Slightly more discomfort than standard

PEG• Need to attach an extension for each use• Limited by abdominal girth• Significantly more aesthetically pleasing• Does not get tangled with clothing• Preferred by most patients

What is a Suprapubic Catheter• Common surgical procedure where a catheter is inserted

through the abdomen and into the bladder under cystoscopic guidance

• Performed under light sedation in <30 min• Drains urine from the bladder• Held in place by a balloon• Connected to a closed drainage system

Urinary Function in ALS• Not extensively studied• Commonly reported “urination not usually

affected”• Two studies in ALS

– 41% (22 of 54) - symptoms of nocturia, feeling of incomplete empting, frequency and post-micturition dribble

– urinary incontinence stated a high impact on their quality of life

• Disease progression/physical limitations– Ability to stand/walk/move to commode– Caregiver availability– Time

• Non-invasive methods to assist urination are preferred

MDA/ALS Newsmagazine 2013 pgs1-4

SPC and DP• 18 Total ALS patients since October 2012

– 3 patients had pre DP placement– 1 patient had post DP placement

• 1 month to 6 years with average of 1 year• 8 women - 10 men• Wheelchair bound

– Reasons for choosing catheter • Difficulty getting to commode• Problems with condom catheters (skin breakdown, erosions,

smells)• Smells from accidents• Problems with night time urination• Affecting social life

Patient FeedbackComplications

• Urinary Tract Infection• 3 patient reports of spasticty• 1 patient –catheter pulled out bladder,

chose to under go repeat placement• 1 patient – site slow to heal

Patient FeedbackBenefits

• No skin breakdown• No odor• Improved uninterrupted sleep• Easier to leave the house• Easier to care for than transferring to commode• Increased fluid intake• More self respect

Benefits Continued

• Every patient wished they had it sooner• Every patient would recommend to others• Every patient would do it again• Every patient said benefits outweigh the

negatives

Case Example- 1FVC 65%, MIP of 33, elevated Right diaphragm,

Paradoxical movement under fluoroscopy, pCO2 of 46, Good phrenic EMG on right

Excellent diaphragm movementNo longer paradoxical movement

Case Example-2• 61 -year old male- former marine• Onset – June 2006• Results 04/20/2010

– FVC 19% (was 41% Feb 2010)– MIP/MEP 12.8/13%– ABG: 7.43-38-77– CXR – Elevated left

hemidiaphragm– PNCT – No Response bilaterally– Minimal bulbar – no weight loss– NIV at night– Tracheostomy mechanical

ventilation – unacceptable

Not a Surgical CandidatePoor Movement

Case- 3

• 44 yo male• Ex-football player• Diagnosed ALS June 2011• NIV at night, SOB during day• Increasing dysphagia, lost 12 pounds• FVC 84%, MIP 48, pCO2 45

Case 3: Diaphragm Analysis

Post-op Diaphragm EMGOn NIV

Off of NIV

Two weeks post implant

• Can lie flat• Significant improvement in Diaphragm

EMG

Conclusions• DP can be implanted safely in ALS patients with

chronic hypoventilation and stimulatable diaphragms

• DP is a tool to help Augment Respiration • Understanding and augmenting respiration

improves safety of other procedures to improve quality of life– Low profile gastrostomy tubes– Supra-pubic catheters

AcknowledgementsWithout Funding No Research

•University Hospitals Case Medical Center•Rehabilitation Research Service of the Department of VA•FDA- Orphan Drugs•Prentiss Foundation•The Winters Family for ALS•Feintech Family•The Bailey Foundation •Kali’s Cure

Thanks

Contact Information

Diaphragm PacingMary Jo Elmo CNPCindy Kaplan MSNRaymond Onders MD11100 Euclid AvenueCleveland, Ohio 44106-5047Phone: 216-844-8594FAX: 216-983-3069E-mail:MaryJo.Elmo@uhhospitals.orgCynthia.Kaplan@uhhospitals.orgRaymond.onders@uhhospitals.org