Lisa Wickerson BSc PT, MSc(c)Lung Transplant ProgramToronto General Hospital

Canadian Respiratory ConferenceApril 28-30,2011

Exercise training after lung transplant

Disclosure of potential conflicts of interest

None to declare

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

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

Functional capacity before lung transplant

Lung functionObstructive lung disease (FEV1 < 25%pred)Restrictive lung disease ( VC and TLC < 65%pred)Septic lung disease (FEV1 < 30%pred)

Maximal exercise capacitySevere limitation (VO2 peak 20-32%pred)Ventilatory limitation present

Functional exercise capacity6-minute walk test < 400mVascular lung disease (NYHA functional classes III-IV) OtherResting hypoxemia/ oxygen dependencyVery low physical functioning subscales on HRQOL questionnaires (i.e. SF 36)

Lung function after lung transplant

Single Lung transplant(SLTx)

Double Lung transplant(DLTx)

COPD•Obstructive defect (FEV1 50-60%)

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

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

What is the nature of exercise limitation in lung transplant

recipients?

Physiological limitations to maximal exercise

Exercise limitation

Ventilatory Peripheral Cardiac/ vascular

-Adequate HR, SV-Mild anemia-Decreased RVF in SLTx with PHTN

- Adequate ventilation- Adequate gas exchange- Mild defects in SLTx

Abnormal oxidative capacity of skeletal muscles•Impaired oxygen uptake•Impaired oxygen utilization•Intrinsic abnormalities

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

When does peripheral muscle function deteriorate in lung

transplant recipients?

Post-transplant peripheral muscle dysfunction

Peripheral muscle dysfunction

Pre-operative factors

Post-operative factors

Peri-operative factors

Pre-transplant peripheral muscle dysfunction

Muscle changes observed in chronic lung diseaseDecreased muscle mass (cross-sectional area)Decreased muscle strength and enduranceIncreased 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

Pre-transplant peripheral muscle dysfunction

Contributing factorsChronic 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)

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

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

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

Post-transplant peripheral muscle dysfunction

Pre-LTXPre-LTX Post-LTXPost-LTX Post Post

RehabilitationRehabilitation

BMI kg/m2 22.7 ± 4.2 21.7 ± 4.2 23.1 ± 3.7FEV1 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

A cohort study of 36 lung transplant recipients (15 SLTx, 21 DLTx)

Post-transplant peripheral muscle dysfunction

Maury et al. Am J Transplant 2008

•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

Exercise limitation post organ transplantation

Similar exercise profiles seen in heart, kidney and liver transplant recipientsDecreased VO2peak

Early anaerobic thresholdAbsence of circulatory or ventilatory limitation

Common to all organ transplantsPre-transplant

Deconditioning Central limitations to exercise Months to years of chronic disease

Post-transplant Prolonged hospital stay Immunosuppression medications ( calcineurin inhibitors, corticosteroids)

To what extent can exercise training improve exercise capacity and peripheral muscle function in

lung transplant recipients?

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)  

RCT 16 Lumbar resistance exercises

Lumbar BMD -BMD 19.5% below baseline (controls)-BMD 5 % below baseline (intervention)

Munro (2009)

Prospective cohort   

36 Aerobic & resistance exercise

6MWDFEV1, FVCSF 36

Increase in 6MWD, FEV1 and FVC, HRQOL

Maury (2008)   

Prospective cohort

36 Aerobic & resistance exercise

6MWDQF, HGFFEV1

Increase in 6MWD, QF, HGF 

Stiebellehner(1998) 

 

Prospective cohort 

9 Aerobic exercise VO2 peak

Peak power outputIncrease in VO2 peak and peak workload

Ross (1993)  

Prospective cohort

8 Aerobic exercise VO2max

Hemo-dynamic responses

Increased VO2max and work rate

Guerrero (2005) 

Controlled trial (healthy controls)

12 Aerobic exercise Mitochondrial respiration

Significant increase in bioenergetics at cellular level, Wmax , endurance time

Wickerson et al. J Heart Lung Transplant 2010

Exercise prescriptions

Study Mode Duration

Frequency

Intensity Progression

Braith(2007)

Lumbar extension training

6 months 1/week 1 set 10-12 reps to fatigue

Increase load 5% once 12 reps achieved

Mitchell(2003)

Lumbar extension training

6 months 1/week 1 set 15-20 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 10-15 reps to tolerance)

NS

Maury(2008)

Treadmill, cycle, multigym, stairs

3 months 3/week Endurance (Borg 4-6, SpO2 >90%), resistance (60% 1RM, 3 sets 8 reps)

NS

Stiebellehner(1998)

Cycle 6 weeks 3-5/week 60% max HRRLactate levels <4.5.M/L

Increase 12 min/week to 120 mins/week

Ross(1993)

Treadmill, arm ergometry

6-8 weeks 3/week 60-70% max pred HR NS

Guerrero(2005)

Cycle 3 months 3/week 50% Wmax (10 min)30% Wmax (5 min)

Increase to 80% WmaxWickerson et al. J Heart Lung Transplant

2010

Aerobic training vs. normal daily activity

Stiebellehner et al. Chest 1998

Physical activity in lung transplant recipients

Langer et al. J Heart Lung Transplant 2009

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

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 +/- 21.2peak Vo2

Painter et al. Transplantation 1997

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)

What is the current clinical practice of exercise training in

Canadian lung transplant programs?

Lung transplant rehabilitation programs in Canada

Survey sent to 6 different Canadian sites performing lung transplants4/6 sites respondedAll recommended rehabilitation pre-transplantAll had mandatory rehabilitation post-transplant

Lung transplant exercise programs

Exercise Prescription Outcome measuresFrequenc

yIntensity Duration Mode Progressio

n2-3/week for6-12 weeks or individual need

• Post-op restrictions

• individualized assessment

• RM• Borg (leg

fatigue)• RPE• target HR• medical

stability• patient

tolerance

60-120 minutes

• Treadmill• Cycle• Resistanc

e training (upper and lower extremities)

• flexibility

• Individual assessment

• RPE• target HR• Borg• weekly

progression of time

• patient tolerance

• RM

• Borg• 6MWT• TUG• Manual

muscle testing

• Dynamometry

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)

ACKNOWLEDGEMENTS

Dina Brooks PhD, University of TorontoSunita Mathur PhD, University of TorontoLianne Singer MD, Toronto General HospitalDenise Helm BScPT, Toronto General HospitalPhysical Therapy MScPT Program, University of Toronto

Funding sources:Ontario Respiratory Care SocietyCanadian Respiratory Health Professionals