The ALS Association 2014 Clinical Conference Phoenix, AZ

1. 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 Center
Department of Surgery
11100 Euclid Avenue
Cleveland, Ohio 44106
Phone: 216-844-8594
Fax: 216-983-3069

2. 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

3. Background
Over 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

4. 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

5. 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)

6. Methods: Implantation
Mapping to Identify
Optimal Location for
Wire Implantations
Conditioning the Diaphragm
with external system
Clinical Station to Program Unit
To condition diaphragm with no pain
Laparoscopic Surgery
Implanting 2 electrodes
In each Diaphragm

7. 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

8. Pediatric DP Implantations- Now Worldwide
Spain, 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

9. 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

10. SCI Conclusions: Nobody Chooses to
go Back to Ventilators

11. 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

12. Delaying Ventilators in ALS
Initial 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

13. 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

14. Indication for DPS Across
UMN/LMN Distribution in ALS
Spinal Muscular Atrophy
Post-polio Syndrome
Primary Lateral Sclerosis
High Level Spinal Cord Injury
Percentage of presenting patients (Ravits – 2007)
21% 14% 17% 44% 4%
Pure LMN Pure UMN
Indication for DPS
Ravits – 2007
•Predominant UMN in 4% of population
•Predominant LMN in 21% of population

15. 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.

16. 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)

17. 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

18. Results of DP in ALS HUD Subgroup
Match Comparison to Lechtzin et al
NeuRx DPS
CH Patients
Early NIV
Lechtzin, 2007
Standard 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.

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

20. Diaphragm Pacing is Safe in ALS
Over 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

21. • 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

22. Augmenting Respiration: Pilot Study
DP Increases Muscle Thickness/Mass:
DPS converts Type IIb (fast twitch) to Type 1(slow twitch) muscle fibers

23. 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

24. Healthy Chest X-Ray
•Diaphragms equal
•Left HD –bottom heart border
Significantly
Elevated
Right Hemi-diaphragm
Pt. with FVC 85%
Significantly Elevated
Left Hemi-diaphragm
Why ALS patients
should get
Chest X-Ray :
70% had significant
unilateral
abnormalities
Onders et al ALS 2013

25. 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

26. 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

27. 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 40
Patient became more
alert
Only 2 breaths a minute

28. 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

29. Augmenting Respiration: Improvements in
Sleep with DP

30. 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

31. 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

32. 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

33. 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

34. Post Operative Care
Post-Op
• 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 wires
Ok 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. *

35. 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

36. • Day time
Pacer Utilization
– 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 NIV
DP BPM rate > than NIV rate
→ DP breathing is better than
volitional breathing
→ Respiratory instability
→ Moderate respiratory decline

37. 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.

38. 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
Respiratory System Compliance (ml / cm H2O)
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%
*Onders, Elmo et al , Chest 2007

39. Simultaneous Procedures
Feeding 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

40. 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

41. 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

42. 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

43. 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

44. Patient Feedback
Complications
• 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

45. Patient Feedback
Benefits
• 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

46. 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

47. Case Example- 1
FVC 65%, MIP of 33, elevated Right diaphragm,
Paradoxical movement under fluoroscopy, pCO2 of
46, Good phrenic EMG on right
Excellent diaphragm movement
No longer paradoxical movement

48. 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 Candidate Poor Movement

49. 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

50. Case 3: Diaphragm Analysis

51. Post-op Diaphragm EMG
On NIV
Off of NIV

52. Two weeks post implant
• Can lie flat
• Significant improvement in Diaphragm
EMG

53. 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

54. Acknowledgements
Without 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 Pacing
Mary Jo Elmo CNP
Cindy Kaplan MSN
Raymond Onders MD
11100 Euclid Avenue
Cleveland, Ohio 44106-5047
Phone: 216-844-8594
FAX: 216-983-3069
E-mail:
MaryJo.Elmo@uhhospitals.org
Cynthia.Kaplan@uhhospitals.org
Raymond.onders@uhhospitals.org