Exercise training after lung transplant

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 2000-2009 • 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

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 VentilatoryPeripheral 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 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 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 • Infection • 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-LTXPost-LTXPost Rehabilitation BMI kg/m2 22.7 ± 4.2 21.7 ± 4.2 23.1 ± 3.7 FEV1 L 0.85 ± 0.47 1.96 ± 0.85* 2.20 ± 0.99* % pred 31 ± 15 70 ± 21* 78 ± 25* 6MWD m 311 ± 124 320 ± 138 449 ± 128*,† % pred 45 ± 19 46 ± 19 65 ± 17*,† QF % pred 72 ± 30 51 ± 28* 59 ± 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 Wickerson et al. J Heart Lung Transplant 2010

23. Exercise prescriptions 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. 8645 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 VO2 22.7 +/- 5.6 (ml kg min-1) % age pred 85.6 +/- 21.2 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

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