1. Exercise training after lung transplant
Lisa Wickerson BSc PT, MSc(c)
Lung Transplant Program
Toronto General Hospital
Canadian Respiratory Conference
April 28-30,2011

2. Disclosure of potential conflicts of interest
None to declare

3. Learning objectives
Describe the physiological limitations to exercise in lung transplant recipients
Identify the evidence for exercise training in improving functional outcomes following lung transplantation
Recognize the specific components and structure of exercise training programs in lung transplant centres across Canada

4. Lung transplantation
Established treatment option for a wide range of end-stage lung diseases (COPD, restrictive lung disease, cystic fibrosis, pulmonary hypertension)
1499 lung transplants performed in Canada between
180 lung transplants performed in 6 Canadian transplant programs in 2010
Goals of transplant:
Decrease disabling symptoms
Improve functional capacity
Improve health-related quality of life
Increase life expectancy
CIHI Canadian Organ Replacement Register 2011

5. Functional capacity before lung transplant
Lung function
Obstructive lung disease (FEV1 < 25%pred)
Restrictive lung disease ( VC and TLC < 65%pred)
Septic lung disease (FEV1 < 30%pred)
Maximal exercise capacity
Severe limitation (VO2 peak 20-32%pred)
Ventilatory limitation present
Functional exercise capacity
6-minute walk test < 400m
Vascular lung disease (NYHA functional classes III-IV)
Other
Resting hypoxemia/ oxygen dependency
Very low physical functioning subscales on HRQOL
questionnaires (i.e. SF 36)

6. Lung function after lung transplant
Single Lung transplant
(SLTx)
Double Lung transplant
(DLTx)
COPD
Obstructive defect (FEV %)
Restrictive lung disease
Restrictive defect (FEV1 80%)
Moderately decreased DLCO (62%)
Mild desaturation on exertion
Pulmonary Hypertension
Decreased DLCO
Very mild restriction
Usually no further improvement after 6 months
Mild restriction
Mild decrease DLCO
No desaturation on exertion
* Ventilatory limitation would be indicative of a pathology (infection, rejection, BOS, airway stricture)
Spirometry can continue to improve for up to 2 years

7. Maximal exercise capacity after lung transplant
Results of maximal symptom-limited cardiopulmonary exercise testing:
Low peak oxygen consumption
(VO2peak 40-60% predicted)
Low peak work rate
(Wpeak < 40% predicted)
Early anaerobic threshold
(30% of VO2 peak)
Exercise terminated at similar intensity and symptoms regardless of pre-transplant lung disease or transplant procedure (single or double lung)
Persistent limitations seen in recipients up to 2 years post lung transplant
Williams et al., 1992, Orens et al., 1995, Schwaiblmair et al., 1999, Evans et al., 1997

8. What is the nature of exercise limitation in lung transplant recipients?

9. Physiological limitations to maximal exercise
Exercise limitation
Ventilatory Peripheral
Cardiac/ vascular
- Adequate ventilation
- Adequate gas exchange
- Mild defects in SLTx
Abnormal oxidative capacity of skeletal muscles
Impaired oxygen uptake
Impaired oxygen utilization
Intrinsic abnormalities
-Adequate HR, SV
-Mild anemia
-Decreased RVF in SLTx with PHTN

10. Peripheral muscle function
Measures
Findings
Muscle biopsies
Lower proportion of Type 1 muscle fibres
Low mitochondrial oxidative enzyme activity
Higher glycolytic enzyme activity
Low ATP production rate
Arterial blood sampling
Abnormal potassium regulation
Non-invasive
31P-MRS
NIRS
MRI
Low resting muscle pH
Earlier drop in intracellular pH with exercise
Smaller drop in hemoglobin and myoglobin oxygen saturation during exercise
Decreased muscle volume
Increased intramuscular fat infiltration
Computerized dynamometry
Decreased peak torque
Decreased isometric endurance
Evans et al, 1997, Mathur et al, 2008, Tirdel et al, 1998, Wang et al, 1999, McKenna et al, 2003

11. When does peripheral muscle function deteriorate in lung transplant recipients?

12. Post-transplant peripheral muscle dysfunction
Pre-operative factors
Post-operative factors
Peri-operative factors

13. Pre-transplant peripheral muscle dysfunction
Muscle changes observed in chronic lung disease
Decreased muscle mass (cross-sectional area)
Decreased muscle strength and endurance
Increased fatigability (decreased twitch force and mandatory voluntary contraction)
Increased reliance anaerobic metabolism
Decreased proportion of type 1 fibres
Decreased muscle capillarity
Early onset lactic acidosis
Decreased concentration of oxidative enzymes
ATS/ERS Am J Respir Crit Care Med 1999

14. Pre-transplant peripheral muscle dysfunction
Contributing factors
Chronic lung disease
Nutritional status/ catabolic conditions
Corticosteroid use
Oxidative stress
Systemic inflammation
Exacerbations of disease
Deconditioning / decreased physical activity
General
Comorbidities
Aging
End-stage lung failure
Mechanical ventilation, ICU admission
Bridge to transplant (Novalung)

15. Pre-transplant peripheral muscle dysfunction
Healthy subjects (open bars), control patients with COPD (hatched bars), patients with steroid- induced myopathy (closed bars).
Decramer et al. Am J Respir Crit Care Med 1996

16. Post-transplant peripheral muscle dysfunction
Thigh muscle volume and composition, strength and endurance assessed in 6 stable SLTx recipients compared with 6 COPD controls
Similar muscle mass, composition and strength between groups
Quadriceps endurance tended to be lower in lung transplant recipients
Mathur et al. Cardiopulm Phys Ther J 2008

17. Post-transplant peripheral muscle dysfunction
Peri-operative issues
Ischemic injury
Allograft quality
Protein catabolism (response to sepsis)
Critical illness myopathy / use of neuromuscular blocking agents
Systemic organ dysfunction
Immobilization / prolonged hospitalization
Nutritional status
Infection
Rejection
Post-operative/ long term issues
Rejection (acute, chronic)
Medications (calcineurin inhibitors, corticosteroids)
Decreased physical activity

18. Post-transplant peripheral muscle dysfunction
A cohort study of 36 lung transplant recipients (15 SLTx, 21 DLTx)
Pre-LTX Post-LTX Post
Rehabilitation
BMI kg/m ± ± ± 3.7
FEV1 L 0.85 ± ± 0.85* 2.20 ± 0.99*
% pred ± ± 21* ± 25*
6MWD m 311 ± ± ± 128*,†
% pred ± ± ± 17*,†
QF % pred ± ± 28* ± 26*,†
*p < 0.05 vs. pre-LTX. †p < 0.05 vs. post-LTX.
Maury et al. Am J Transplant 2008

19. Post-transplant peripheral muscle dysfunction
Significant negative relationship between time spent in ICU/medium care unit (MC) and reduction in skeletal muscle force
Linear regression analysis suggest a decline of 0.8Nm of quadriceps force/day
Maury et al. Am J Transplant 2008

20. Exercise limitation post organ transplantation
Similar exercise profiles seen in heart, kidney and liver transplant recipients
Decreased VO2peak
Early anaerobic threshold
Absence of circulatory or ventilatory limitation
Common to all organ transplants
Pre-transplant
Deconditioning
Central limitations to exercise
Months to years of chronic disease
Post-transplant
Prolonged hospital stay
Immunosuppression medications ( calcineurin inhibitors, corticosteroids)

21. To what extent can exercise training improve exercise capacity and peripheral muscle function in lung transplant recipients?

22. Systematic review of exercise training after lung transplant
Wickerson et al. J Heart Lung Transplant 2010
Author
Study Design
Sample Size
Interventions
Outcome Measures
Significant Findings
Braith
(2007)
RCT 30
Alendronate and lumbar resistance exercises
Lumbar BMD
-BMD 14.1± 3.9% below baseline (controls)
-BMD 10.8±2.3% above baseline (alendronate + resistance)
Mitchell
(2003) 16
Lumbar resistance
exercises
-BMD 19.5% below baseline (controls)
-BMD 5 % below baseline (intervention)
Munro
(2009)
Prospective cohort 36
Aerobic & resistance exercise
6MWD
FEV1, FVC
SF 36
Increase in 6MWD, FEV1 and FVC, HRQOL
Maury
(2008)
Aerobic & resistance
exercise
QF, HGF
FEV1
Increase in 6MWD, QF, HGF
Stiebellehner
(1998) 9
Aerobic exercise
VO2 peak
Peak power output
Increase in VO2 peak and peak workload
Ross
(1993) 8
VO2max
Hemo-dynamic responses
Increased VO2max and work rate
Guerrero
(2005)
Controlled trial (healthy controls) 12
Mitochondrial respiration
Significant increase in bioenergetics at cellular level, Wmax , endurance time
Wickerson et al. J Heart Lung Transplant 2010

23. Exercise prescriptions
Study
Mode
Duration
Frequency
Intensity
Progression
Braith
(2007)
Lumbar extension training
6 months
1/week
1 set reps to fatigue
Increase load 5% once 12 reps achieved
Mitchell
(2003)
1 set reps to fatigue
Increase load 5% once 20 reps achieved
Munro
(2009)
Treadmill, cycle, resistance training
2 months
3/week
Endurance (30 mins, RPE 13-14), resistance (3 sets reps to tolerance) NS
Maury
(2008)
Treadmill, cycle, multigym, stairs
3 months
Endurance (Borg 4-6, SpO2 >90%), resistance (60% 1RM, 3 sets 8 reps)
Stiebellehner
(1998)
Cycle
6 weeks
3-5/week
60% max HRR
Lactate levels <4.5.M/L
Increase 12 min/week to 120 mins/week
Ross
(1993)
Treadmill, arm ergometry
6-8 weeks
60-70% max pred HR
Guerrero
(2005)
50% Wmax (10 min)
30% Wmax (5 min)
Increase to 80% Wmax
Wickerson et al. J Heart Lung Transplant 2010

24. Aerobic training vs. normal daily activity
Stiebellehner et al. Chest 1998

25. Physical activity in lung transplant recipients
22 stable lung recipients > 1 year post-transplant compared to healthy controls
Daily steps
4977 vs steps/day
Daily walking time
55 vs. 81 minutes/ day
Other physical activity outcomes
Reduced daily standing time
Increased daily sedentary time
Reduced time spent in moderate intensity activity
Langer et al. J Heart Lung Transplant 2009

26. Physical potential after transplant
1996 U.S Transplant Games (6 lung transplant recipients) Peak VO /- 5.6 (ml kg min-1) % age pred / peak Vo2
Painter et al. Transplantation 1997

27. Challenges for rehabilitation research and clinical practice
The optimal exercise prescription for lung transplant recipients is not known
? How reversible are the changes to skeletal muscle
? Is there a slower recovery process following lung transplant
? Is the training stimulus adequate to induce improvements in skeletal muscle
and exercise capacity
? What are the cumulative effects on age and length of disuse on recovery
? What is the role for exercise in recipients with a complicated post-operative
course, multiple and serious comorbidities and marginal organ function
? What is the role for exercise in long-term outcomes
(survival, chronic rejection, CV risk factors)

28. What is the current clinical practice of exercise training in Canadian lung transplant programs?

29. Lung transplant rehabilitation programs in Canada
Survey sent to 6 different Canadian sites performing lung transplants
4/6 sites responded
All recommended rehabilitation pre-transplant
All had mandatory rehabilitation post-transplant

30. Lung transplant exercise programs
Exercise Prescription
Outcome measures
Frequency
Intensity
Duration
Mode
Progression
2-3/week for
6-12 weeks or individual need
Post-op restrictions
individualized assessment RM
Borg (leg fatigue)
RPE
target HR
medical stability
patient tolerance
minutes
Treadmill
Cycle
Resistance training (upper and lower extremities)
flexibility
Individual assessment
Borg
weekly progression of time
6MWT
TUG
Manual muscle testing
Dynamometry

31. Future directions
More studies needed to assess effect of exercise training
Different intensities, durations, modes, progression
Specific training strategies (endurance, resistance training)
Different groups of recipients
Complicated course
Multiple comorbidities
Older
Role of prehabilitation in lung transplant candidates
Role of early mobility during peri-operative period
Physical activity counselling (long-term)

32. ACKNOWLEDGEMENTS
Dina Brooks PhD, University of Toronto Sunita Mathur PhD, University of Toronto Lianne Singer MD, Toronto General Hospital Denise Helm BScPT, Toronto General Hospital Physical Therapy MScPT Program, University of Toronto Funding sources: Ontario Respiratory Care Society Canadian Respiratory Health Professionals