reversing muscle dysfunction in copd › toraksfd23njkl4nj4h3bg3jh › mse... · 2016-05-20 ·...

Reversing Muscle Reversing Muscle Dysfunction in COPDDysfunction in COPDRichard Casaburi, Ph.D., M.D.Richard Casaburi, Ph.D., M.D.

Los Angeles Biomedical Los Angeles Biomedical Research Institute atResearch Institute at

HarborHarbor--UCLA Medical CenterUCLA Medical CenterTorrance, CaliforniaTorrance, California

Systemic Manifestations of Systemic Manifestations of COPDCOPD

Sleep DisordersSleep DisordersSystemic InflammationSystemic InflammationWasting SyndromeWasting SyndromeDysfunction of the Muscles of Dysfunction of the Muscles of AmbulationAmbulation

Muscle Dysfunction and Muscle Dysfunction and Physical Limitation in COPDPhysical Limitation in COPD

Mechanisms of Muscle Dysfunction in Mechanisms of Muscle Dysfunction in COPDCOPDRelation of Muscle Dysfunction to Relation of Muscle Dysfunction to Physical LimitationPhysical LimitationMuscle Dysfunction as a Determinant Muscle Dysfunction as a Determinant of Prognosisof PrognosisTherapies for Muscle DysfunctionTherapies for Muscle Dysfunction

Skeletal Muscle Dysfunction in Skeletal Muscle Dysfunction in COPDCOPD

--MechanismsMechanisms--Low Muscle MassLow Muscle MassPoor CapillarityPoor CapillarityLow Aerobic Enzyme ConcentrationLow Aerobic Enzyme ConcentrationLow Fraction of Type I FibersLow Fraction of Type I FibersMuscle InflammationMuscle InflammationCorticosteroid Corticosteroid MyopathyMyopathyLow Levels of Anabolic HormonesLow Levels of Anabolic HormonesVasoregulatoryVasoregulatory AbnormalitiesAbnormalities

Testosterone Levels in Men with Testosterone Levels in Men with COPDCOPD

Testosterone (ng/dl)

0-99100-199

200-299300-399

400-499500-599

600-699700-799

800-899900-999

% o

f Pat

ient

s

0

5

10

15

20

25

30

Casaburi, et al., AJRCCM, 2004



To What Extent is Dysfunction Due to Deconditioning?

Evidence that Improving Muscle Evidence that Improving Muscle Function Increases Exercise Function Increases Exercise

ToleranceTolerance

Demonstration that improving Demonstration that improving muscle function relieves muscle function relieves ventilatoryventilatory limitationlimitationDemonstration that exercise Demonstration that exercise tolerance is not only limited by tolerance is not only limited by pulmonary factorspulmonary factors

Changes in Responses to Identical Constant Work Changes in Responses to Identical Constant Work RateExerciseRateExercise Tasks Resulting from Exercise Tasks Resulting from Exercise

Training in COPD PatientsTraining in COPD Patients

Casaburi, et al., ARRD, 1991

Effect of Exercise Training on Oxygen Uptake Effect of Exercise Training on Oxygen Uptake and Ventilation During Constantand Ventilation During Constant--Work Rate Work Rate

Exercise in a Patient with Severe COPDExercise in a Patient with Severe COPDVE Post

VE Pre

VO2 Post

VO2 Pre

Work rate Pre

Work rate Post

120

Porszasz et al. Chest, 2005

Time (min)

100

80

60

40

20

0

Time (min)

50

10

0 5 10 15 20 25 30

40

30

20

0

1.0

0.5

00 5 10 15 20 25 30

Lung Volume Response to ExerciseLung Volume Response to Exercise--Dynamic HyperinflationDynamic Hyperinflation--

TLCIC IC

EELVRV

IC

HealthIRV

EELV

TLC

RV

COPD

IC IC IC

Effect of Exercise Training on Hyperinflation Effect of Exercise Training on Hyperinflation during Constantduring Constant--Work Rate Exercise in a Work Rate Exercise in a

Patient with Severe COPDPatient with Severe COPD

1.0

1.5

2.0

2.5

-5 0 5 10 15 20

Post-trainingPre-training

Insp

irato

ry C

apac

ity (L

)

Time (min)

Porszasz et al. Chest, 2005

Effect of Exercise Training on Breathing Effect of Exercise Training on Breathing Pattern and Hyperinflation in COPDPattern and Hyperinflation in COPD

∆VE (L/min)

-4

-3

-2

-1

0

*

f (br/min)

-5

-4

-3

-2

-1

0

*

∆IC (L)

0.0

0.1

0.2

0.3

0.4

0.5

*

Isotime

Porszasz et al., Chest, 2005

Evidence that Improving Muscle Evidence that Improving Muscle Function Increases Exercise Function Increases Exercise

ToleranceTolerance

Demonstration that improving Demonstration that improving muscle function relieves muscle function relieves ventilatoryventilatory limitationlimitationDemonstration that exercise Demonstration that exercise tolerance is not only limited by tolerance is not only limited by pulmonary factorspulmonary factors

Exercise Symptom Limitation Exercise Symptom Limitation in COPDin COPD

Subjectively, Subjectively, a substantial fraction a substantial fraction of COPD patients report that leg of COPD patients report that leg fatigue, rather than fatigue, rather than dyspneadyspnea is is their limiting symptomtheir limiting symptom

Killian et al., 1991

AJRCCM 168:425,2003

Limitation to Exercise in COPD:Limitation to Exercise in COPD:Role of the Exercising MusclesRole of the Exercising Muscles


Half of COPD patients exercising Half of COPD patients exercising maximally were found to have maximally were found to have evidence of muscle fatigueevidence of muscle fatigueImproving lung function in these Improving lung function in these patients did not improve exercise patients did not improve exercise tolerancetolerance


Half of COPD patients exercising Half of COPD patients exercising maximally were found to have maximally were found to have evidence of muscle fatigueevidence of muscle fatigueImproving lung function in these Improving lung function in these patients did not improve exercise patients did not improve exercise tolerancetolerance

In these patients, the exercising muscles, not the lungs limits exercise


Mechanisms of Muscle Dysfunction in Mechanisms of Muscle Dysfunction in COPDCOPDRelation of Muscle Dysfunction to Relation of Muscle Dysfunction to Physical LimitationPhysical LimitationMuscle Dysfunction as a Determinant Muscle Dysfunction as a Determinant of Prognosisof PrognosisTherapies for Muscle DysfunctionTherapies for Muscle DysfunctionOutcomes Relevant to Muscle Outcomes Relevant to Muscle Dysfunction in COPDDysfunction in COPD

Muscle Weakness or Atrophy is a Muscle Weakness or Atrophy is a Negative Prognostic Factor in COPDNegative Prognostic Factor in COPD

DecramerDecramer, M., R., M., R. GosselinkGosselink, T., T. TroostersTroosters, M., M. VerschuerenVerschueren, , and G. Evers. and G. Evers. Muscle weakness is related to utilization of Muscle weakness is related to utilization of health care resources in COPD patientshealth care resources in COPD patients.. EurEur..RespirRespir.J..J.10:41710:417--423, 1997.423, 1997.DecramerDecramer, M.,, M., GosselinkGosselink, R.,, R., TroostersTroosters, T., and, T., and SchepersSchepers, ,

R. R. Peripheral muscle force is a determinant of survival in Peripheral muscle force is a determinant of survival in COPD.COPD. EurEur..RespirRespir.J..J. 12, 261S. 12, 261S. 1998. 1998. Marquis, K., R. Debigare, Y. Lacasse, P. LeBlanc, J. Jobin, Marquis, K., R. Debigare, Y. Lacasse, P. LeBlanc, J. Jobin,

G. Carrier, and F. Maltais. G. Carrier, and F. Maltais. MidthighMidthigh muscle crossmuscle cross--sectional sectional area is a better predictor of mortality than body mass index in area is a better predictor of mortality than body mass index in patients with chronic obstructive pulmonary diseasepatients with chronic obstructive pulmonary disease. . Am.J.Am.J.RespirRespir..CritCrit Care Med.Care Med. 166:809166:809--813, 2002.813, 2002.

Influence of muscle crossInfluence of muscle cross--sectional area on sectional area on survival in 142 patients with COPDsurvival in 142 patients with COPD

Therapies for Muscle Therapies for Muscle Dysfunction in COPDDysfunction in COPD

Exercise TrainingExercise Training

Pharmacologic TherapiesPharmacologic Therapies

Exercise Training Strategies for Exercise Training Strategies for COPD PatientsCOPD Patients

Adequate frequency and duration of Adequate frequency and duration of exercise sessions and duration of exercise sessions and duration of programprogramHigh intensity targetsHigh intensity targetsEmploy strategies to make higher Employ strategies to make higher intensity training possibleintensity training possible

Strategies to Maximize Exercise Strategies to Maximize Exercise Intensity in COPDIntensity in COPDBronchodilatorsBronchodilatorsOxygen breathingOxygen breathingHelium breathing Helium breathing Pressure support ventilationPressure support ventilationInterval trainingInterval trainingElectrical muscle stimulationElectrical muscle stimulation

Improvement in Exercise Improvement in Exercise Tolerance with the Combination Tolerance with the Combination

of of TiotropiumTiotropium and Pulmonary and Pulmonary Rehabilitation in Patients with Rehabilitation in Patients with

COPDCOPD

R Casaburi, D R Casaburi, D KukafkaKukafka, CB Cooper, , CB Cooper,

TJ TJ WitekWitek, S , S KestenKesten

Chest, 127:809Chest, 127:809--817, 2005817, 2005

Study drug

Effect of Effect of TiotropiumTiotropium on the Improvement in on the Improvement in Treadmill Endurance Time Resulting from Treadmill Endurance Time Resulting from

RehabilitationRehabilitation

8

12

16

20

24

0 2 4 6 8 10 12 14 16 18 20 22 24

Weeks on Treatment

Endu

ranc

e tim

e (m

in)

Tiotropium Placebo*P<0.05

* *RehabilitationRehabilitation

16%16%

32%32% 42%42%

Does Supplemental Oxygen Does Supplemental Oxygen Improve the Benefits of a High Improve the Benefits of a High Intensity Exercise Program in Intensity Exercise Program in

NonNon--HypoxemicHypoxemic COPD Patients?COPD Patients?

M M EmtnerEmtner, J , J PorszaszPorszasz, M Burns, A , M Burns, A SomfaySomfay, R , R CasaburiCasaburi

Am J Am J Respir Crit Respir Crit Care Med 168:1034Care Med 168:1034--1042,2003 1042,2003

Rehabilitation Clinical Trials Rehabilitation Clinical Trials CenterCenter

HarborHarbor--UCLA Research and Education Institute UCLA Research and Education Institute

Increase in Constant Work Rate Test Increase in Constant Work Rate Test Endurance after Exercise TrainingEndurance after Exercise Training

02468

10121416

Tim

e (m

in)

Oxygentraining group

Air traininggroup

air and oxygenbreathing tests

*

Increase in Constant Work Rate Test Increase in Constant Work Rate Test Endurance after Exercise TrainingEndurance after Exercise Training

02468

10121416

Tim

e (m

in)

Oxygentraining group

Air traininggroup

air and oxygenbreathing tests

* 38% greater gain in endurance

Impact of Pulmonary Rehabilitation Impact of Pulmonary Rehabilitation on Exercise Capacity*on Exercise Capacity*

Endurance exercise time improved an Endurance exercise time improved an average of average of 87%87%Peak work rate improved an average Peak work rate improved an average of of 18%18% from baselinefrom baselinePeak oxygen uptake improved by Peak oxygen uptake improved by 11%11% compared with controlscompared with controls

*Based on pooled data from several trials*Based on pooled data from several trialsTroosters T et al. Am J Respir Crit Care Med. 2005;172:19-38

Impact of Pulmonary Rehabilitation Impact of Pulmonary Rehabilitation on Healthon Health--Related Quality of LifeRelated Quality of Life

3C

hang

e in

HR

QoL

(MC

ID)

2

MCID

0

-10 12 24 36 48 60 >18 months

Time of treatment or follow-up (weeks)

MCID: minimal clinically important differenceTroosters T et al. Am J Respir Crit Care Med. 2005;172:19-38

Therapies for Muscle Therapies for Muscle Dysfunction in COPDDysfunction in COPD

Exercise TrainingExercise Training

Pharmacologic TherapiesPharmacologic Therapies

Pharmacologic Interventions that Pharmacologic Interventions that Improve Leg Muscle EnduranceImprove Leg Muscle Endurance

1. 1.

2. 2.

3. 3.

4. 4.

Pharmacologic Interventions that Pharmacologic Interventions that Improve Leg Muscle EnduranceImprove Leg Muscle Endurance

1. 1. ErythropoetinErythropoetin (maybe) (maybe)

2. 2.

3. 3.

4. 4.

Pharmacologic Interventions that Pharmacologic Interventions that Improve Leg MuscleImprove Leg Muscle StrengthStrength

1. Anabolic Steroids 1. Anabolic Steroids

2. Growth Hormone 2. Growth Hormone

3. 3.

4. 4.

I. Placebo + No TrainingI. Placebo + No TrainingII. Testosterone + No TrainingII. Testosterone + No TrainingIII. Placebo + Strength TrainingIII. Placebo + Strength TrainingIV. Testosterone + Strength trainingIV. Testosterone + Strength training

Am. J. Respir. Crit. Care Med., 2004

InterventionsInterventions-- 10 Week Duration 10 Week Duration --

Testosterone Testosterone enanthateenanthate, 100 mg , 100 mg IM weeklyIM weekly

Strength training of the leg Strength training of the leg muscles, 3 sessions/week, 45 muscles, 3 sessions/week, 45 minutes/sessionminutes/session

Characteristics of ParticipantsCharacteristics of Participants

FEVFEV1 1 = 40= 40±±12 % 12 % predpred..TLC = 125TLC = 125±±23% 23% predpred..DDLLCO = 54CO = 54±±20% 20% predpred..PaOPaO2 2 = 70= 70±±14 14 torrtorrPaCOPaCO22 = 45= 45±±7 7 torr

47 men47 menAge =67Age =67±±8 y8 yHeight = 176Height = 176±±7 7 cmcmWeight = 85Weight = 85±±19 19 kgkgTestosterone= Testosterone= 357357±± 163 163 ngng/dl/dl torr

Nadir Testosterone LevelsNadir Testosterone Levels

P+NE T+NE P+E T+E

Tes

tost

eron

e (n

g/dl

)

0

200

400

600

800mean ± SE

Time Course of Body Weight Time Course of Body Weight Change from PreChange from Pre--intervention intervention

ValuesValues

pre 1 2 3 4 5 6 7 8 9 10 post

Wei

ght C

hang

e (k

g)

-2.0

-1.0

0.0

1.0

2.0

3.0

P + NET + NEP + ET + E

Time (weeks)

Change in Lean Body Mass Change in Lean Body Mass DEXADEXA

P+NE T+NE P+E T+E-1

0

1

2

3

4

5mean ± SE

*

*

∆ L

ean

Bod

y M

ass

(kg)

Changes in Leg StrengthChanges in Leg StrengthBilateral Leg Press 1RMBilateral Leg Press 1RM

P+NE T+NE P+E T+E0

20

40

60

80

100

120

140

160

180mean ± SE

*

*

∆ L

eg P

ress

(lb)

*

-3

-2

-1

0

1

2

3

4

Response to Testosterone and Strength Training in Response to Testosterone and Strength Training in COPDCOPD

-- Constant Work Rate Test DurationConstant Work Rate Test Duration--C

hang

e in

exer

cise

dur

atio

n(m

in)

P+NE T+NE P+E T+E

Mean ± SE

Results of Quadriceps Muscle Results of Quadriceps Muscle BiopsyBiopsy

Both testosterone and resistance Both testosterone and resistance training increased muscle fiber crosstraining increased muscle fiber cross--sectional areasectional areaTestosterone increased IGFTestosterone increased IGF--1 1 mRNA mRNA Testosterone and resistance training Testosterone and resistance training decreased decreased myostatin mRNA myostatin mRNA Resistance training increased Resistance training increased eNOS eNOS mRNA mRNA

ConclusionsConclusionsIn men with COPD:In men with COPD:

Strength training increased leg muscle Strength training increased leg muscle mass and strengthmass and strengthPhysiologic testosterone Physiologic testosterone supplementation increased muscle mass supplementation increased muscle mass and strengthand strengthThe combined intervention yielded The combined intervention yielded additive effectsadditive effectsBoth interventions were safe and wellBoth interventions were safe and well--toleratedtolerated


Mechanisms of Muscle Dysfunction in Mechanisms of Muscle Dysfunction in COPDCOPDRelation of Muscle Dysfunction to Relation of Muscle Dysfunction to Physical LimitationPhysical LimitationMuscle Dysfunction as a Determinant Muscle Dysfunction as a Determinant of Prognosisof PrognosisTherapies for Muscle DysfunctionTherapies for Muscle DysfunctionOutcomes Relevant to Muscle Outcomes Relevant to Muscle Dysfunction in COPDDysfunction in COPD

Outcomes Relevant to Therapies Outcomes Relevant to Therapies for Muscle Dysfunctionfor Muscle Dysfunction

Structural, biochemical and gene Structural, biochemical and gene expression changes in muscleexpression changes in muscleExercise performanceExercise performanceActivities of daily livingActivities of daily livingQuality of lifeQuality of lifeUse of health care resourcesUse of health care resourcesDisease modificationDisease modificationSurvivalSurvival

Activity MonitorsActivity Monitors

Outcomes Relevant to Therapies Outcomes Relevant to Therapies for Muscle Dysfunctionfor Muscle Dysfunction

Structural, biochemical and gene Structural, biochemical and gene expression changes in muscleexpression changes in muscleExercise performanceExercise performanceActivities of daily livingActivities of daily livingQuality of lifeQuality of lifeUse of health care resourcesUse of health care resourcesDisease modificationDisease modificationSurvivalSurvival

reversing muscle dysfunction in copd › toraksfd23njkl4nj4h3bg3jh › mse... · 2016-05-20 ·...

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