intérêt de l’étude de l’aptitude aérobie et/ou du

Intérêt de l’étude de l’aptitude aérobie et/ou du

test de marche de 6 min de marche dans

l’évaluation du candidat à une greffe hépatique

Pr Sébastien DHARANCY

Club de la Transplantation Avignon

Adapted from Wasserman K

Aerobic capacity depends on the functional capability

of several organ systems

Lung

O2 uptake

Ventilation

Adapted from Wasserman K

1

Aerobic capacity depends on the functional capability

of several organ systems

Airways Vascular

system

Heart / blood Lung

O2 uptake

Ventilation Gas transport

Adapted from Wasserman K

1 2

Aerobic capacity depends on the functional capability

of several organ systems

Muscle Heart / blood Lung

O2 uptake

Ventilation Gas transport Muscle

activity

Mitochondria

Energy

Adapted from Wasserman K

1 2 3

Aerobic capacity depends on the functional capability

of several organ systems

Muscle Heart / blood Lung

O2 uptake

Ventilation Gas transport Muscle

activity

Mitochondria

Energy

Adapted from Wasserman K

1 2 3

Impaired aerobic capacity in cirrhosis

- Alteration of aerobic capacity is not extensively

investigated in candidates for LT

Aerobic capacity and liver transplantation

- Alteration of aerobic capacity is not extensively

investigated in candidates for LT

- Factors contributing to impairment remain unknown

Aerobic capacity and liver transplantation

- Alteration of aerobic capacity is not extensively

investigated in candidates for LT

- Factors contributing to impairment remain unknown

- Aerobic capacity is usually estimated by the maximal

oxygen uptake at peak exercise (VO2max or VO2peak)

Ex: Mean range of VO2max for male : 35 - 43 mL O2/min/Kg (20-60 years)

Aerobic capacity and liver transplantation

VO2max

• is a standard tool for risk assessment in most

lung and heart transplant centers

• seems to be correlated with Child Pugh score

• is associated with 100-day mortality after LT

Campillo B et al. J Hepatol 1990

Epstein SK et al. Liver Transpl 2004

Aerobic capacity and liver transplantation

VO2max

• is a standard tool for risk assessment in most

lung and heart transplant centers

• seems to be correlated with Child Pugh score

• is associated with 100-day mortality after LT

Campillo B et al. J Hepatol 1990

Epstein SK et al. Liver Transpl 2004

Few data are available concerning the evolution of VO2max

after LT

Aerobic capacity and liver transplantation

Aims of the study

a)To explore aerobic capacity in LT candidates

b)To identify factors independently associated with

aerobic capacity

c)To compare development of aerobic capacity

before and after LT

Dharancy S et al. Transplantation 2008

Patients and methods

1) Between January 2002 and June 2004, all

cirrhotic patients underwent cardiopulmonary

exercise testing on a cycle ergometer

2) During the test, cardiac and respiratory

variables were continuously recorded

Cardiopulmonary exercise testing

Patients and methods

1) Between January 2002 and June 2004, all

cirrhotic patients underwent cardiopulmonary

exercise testing on a cycle ergometer

2) During the test, cardiac and respiratory

variables were continuously recorded

Cardiopulmonary exercise testing

3) Exercise protocol

• Warm up

• Workload increased progressively

• Increments of 1 W every 3’’

• To the limit of tolerance (symptom-limited) Time

Watt Peak exercice VO2max

Warm up

Incremental

work

- Patients were classified according to the Child-Pugh and MELD scores

- Reduction of aerobic capacity was defined according to the

statement on cardiopulmonary exercise testing

- Moderate reduction = VO2max < 85% of age-predicted value

- Severe reduction = VO2max < 60% of age-predicted value

Patients and methods

ATS/ACCP statement on cardiopulmonary exercise testing

Am Rev Respir Dis 2003;167:211-277

Statistical analysis

- Univariate analysis: 2, Kruskal-Wallis, Bonferonni, Kaplan Meier and

log-rank tests

- Multivariate analysis: Multiple regression test

Patients and methods

Predictive variables previously identified to alter aerobic

capacity were recorded

Comparative exercise testing was performed in some

patients after a minimum of 6 months post-transplant

Baseline characteristics at time of exercise testing

* LT candidate with HCC

Ascites was scored as :

- important in 42 pts (31.2%)

- slight in 28 pts (20.7%)

- absent in 65 pts (48.1%)

10

20

30

40

20% 50% 80% 110% 140% VO2max

(% of predicted value)

No o

f candid

ate

s

Distribution of VO2max in population studied

Mean VO2max

17.2 4.4 mL/min/kg

61.1 14 % of predicted value

Determination of VO2max was assessed in 151 candidates of whom 135 were

maximal and interpretable (89%)

Aerobic capacity in LT candidates

10

20

30

40

20% 50 80 110 140

VO2max

(% of predicted value)

No o

f candid

ate

s

Distribution of VO2max in population studied

88% of candidates had

a reduced aerobic capacity

(VO2max < 85% of predicted value)

Determination of VO2max was assessed in 151 candidates of whom 135 were

maximal and interpretable (89%)

Aerobic capacity in LT candidates

10

20

30

40

20 50 80 110 140

VO2max

(% of predicted value)

No o

f candid

ate

s

Distribution of VO2max in population studied

54% had a severe

reduction of aerobic capacity

(<60% of predicted value)

Determination of VO2max was assessed in 151 candidates of whom 135 were

maximal and interpretable (89%)

Aerobic capacity in LT candidates

25

40

60

80

100

Child A

n=38

Child B

n=34

Child C

n=57

VO

2m

ax (

% p

red

icte

d v

alu

e)

p<0.0000001

P = 0.00004

Child-Pugh score

VO

2m

ax (

% p

red

icte

d v

alu

e)

20

50

80

110

140

5 6 7 8 9 10 11 12 13

Correlation: -0.53

p=0.00001

Linear regression showed significant inverse correlation between Child-

Pugh score and VO2max

VO2max is correlated with CP score

73.7% 62.9%

50.4%

p = 0.02

Figure 2

20

50

80

110

140

5 12.5 20 27.5 35

MELD score

VO

2m

ax (

% p

redic

ted v

alu

e)

VO2max is correlated with MELD score

Correlation = -0.35, p<0.0001

Facteurs indépendants associés à la

VO2 (Analyse multivariée)

- Age (0.3 [0.1/0.7], P=0.01)

- Gender (9.9 [16.9/2.9], P=0.005)

- MELD score (0.5 [1/0.01], P=0.04)

- Hemoglobin (9.7 [3.2/16], P=0.003)

- Tobacco use (4.3 [13.7/1.1], P=0.001)

Evaluation cardiaque avant TH

Severe reduction of VO2max and 12-months survival

Prognostic value of VO2max before LT

Facteurs indépendants

associés à la survie

(Analyse multivariée)

- peakVO2 (2 [0/4.1],P=0.05)

- MELD (0.11 [0.2/0.01],P0.03

Sensitivity analysis restricted to patients with MELD >17

Impact of VO2 after LT

• Among patients who underwent LT at the time of

analysis,14 had a MELD >17

• Those with severe impairment of peak VO2 had

– a trend toward a higher mean length of hospitalization after LT

(22.85 days vs. 17.72 days, P= 0.06)

– a significantly longer need for oxygen support to maintain a

PaO2 higher than 60mmHg or a SaO2 higher than 92% (3.31.1

days vs. 7.23.5, P0.035).

• 20 patients cirrhotiques

• EFR repos

• Epreuve d’effort incrémentale sur bicyclette ergométrique

• Avant et après TH

• Délai de réévaluation post-

greffe = 16 mois (5 - 24)

Age (années) 49

Score de Child 7,6

Child C 7 / 20

Ascite 10 / 20

β-bloquants 11 / 20

Tabac 10 / 20

ATCD cardiaque 4 / 20

ATCD respiratoire 4 / 20

Evolution of VO2max after LT

Lemyze M et al. Presse Med 2010

Paramètres Pré Post p

Wattpic 105 121 0,04

VE/VO2 seuil 34 34 NS

Res Vent (%) 47 27 0,00005

FCrepos (bpm) 75 92 0,002

FCpic (bpm) 123 156 0,00001

VO2 /FCpic (%) 96 81 0,02

PASpic (mmHg) 159 191 0,01 Pré-greffe Post-greffe

VO2 pic (% théorique) avant

et après la greffe du foie

p = 0,009

EFR de repos et non modifiées après TH

Resultats

Among the patients who achieved at least 6 months post-LT follow-up, a

15% increase of VO2max was observed (p=0.01)

0

20

40

60

80

100

120

VO

2m

ax (

% o

f p

red

icte

d v

alu

e)

Pre-LT Post-LT

Evolution of VO2max after LT

+15%

63.3%

71.1%

Effet de l’arrêt des -bloquants (11 patients)

Paramètres Pré-greffe Post-greffe p

FCpic (bpm) 106 150 0,003

VO2pic (L/min)

(% théorique)

1,43

67,5

1,48

69

NS

NS

Watt 99 106 NS

Hb (g/dL) 13,1 13,7 NS

EFR de repos et non modifiées après TH

-20

-10

0

10

20

30

40

Δ V

O2 p

ic (

% t

héo

riq

ue)

Répartition des patients en fonction

du VO2 pic

Groupe « non améliorés »

Groupe « améliorés »

6,5%

Distribution identique :

Sexe, ATCD respiratoire et cardiaque, tabac, ascite

Pas de différence pour :

Age, score de Child, Δpoids, ΔHb, délai de réévaluation post-greffe,

EFR de repos

Groupe « non améliorés » vs Groupe « améliorés »

Différence pour :

Lactatémie pic pré-greffe (7,9 versus 5,5 mmol/L ; p = 0,04)

Lactatémie pic pré-greffe / charge (7,4 versus 5,2 µmol/dL/Watt ; p = 0,01)

-20

-5

10

25

40

4 6 8 10

r = - 0,64

p = 0,0034

∆ VO2 pic

(%théorique)

Lactate pic pré-greffe (mmol/L) / Charge maximale (Watt) x 100

Corrélation entre le ΔVO2pic et le rapport Lactatémie

pic charge maximale pré-greffe

DISCUSSION

Amélioration très modeste de l’aptitude aérobie après TH

Corrélation entre le ΔVO2pic et le rapport Lactatémie pic charge

maximale pré-greffe

Limites : Faible nombre de patients

Délai de réévaluation post-greffe variable

Persistance d’une altération de l’AA chez les transplantés

• Poumon n’est pas en cause

• Pas de de VO2pic avec arrêt des -

• Anémie ? Pas de corrélation entre ΔHb et ΔVO2pic

Hb normale après TH

• Cœur ? CMP du cirrhotique réversible après TH /

correction des anomalies échoG structurelles

et fonctionnelles 6 à 12 mois après TH

Comment expliquer l’altération

persistante de l’AA après TH ?

?

Le Muscle et la Mitochondrie

• Wang et al : Altération persistante de l’aptitude aérobie chez

les greffés pulmonaires en rapport avec fibres de type I à

fort potentiel oxydatif + dysfonction mitochondriale

• Toxicité mitochondriale de la Cy

• Myopathie cortico-induite

VO2 max 5,0

1,0

4,0

3,0

2,0

0 1 21 10 60 j

SALTIN Circulation 1968

• Effet délétère du déconditionnement

(Saltin et al : expérience de Dallas 1968)

• Painter et al : 167 patients greffés de rein. A 1 an, 67% des patients

reconditionnés avaient repris une activité physique quotidienne /

36% chez les non-reconditionnés

Expérience de Dallas 1968

A re‐analysis of the 1968 Saltin et al. “Bedrest” paper

“This analysis confirms the conclusion from 1968

that the majority of the loss in VO 2max with bed

rest in the subjects studied can be attributed to

reduced muscle blood flow.

However, it provides a different perspective on how

the increased VO2max after training is supported,

showing that enhanced diffusional conductance of

O2 between red cells and mitochondria, rather than

increased blood flow, is the major contributor”

• Amélioration modeste et inconstante de l’AA chez les cirrhotiques après TH

• Arguments en faveur d’une origine musculaire ou mitochondriale

(Immunosuppresseur + déconditionnement)

REHABILITATION à L’EXERCICE en pré-greffe

et post-greffe ?

En pratique au lit du malade

Le MET (équivalent métabolique)

1 MET = 3,5 mL/min/kg

Neviere R et al. Am J Transplant 2014

Neviere R et al. Am J Transplant 2014

Neviere R et al. Am J Transplant 2014

10% des cas

Croissance et

décroissance oscillatoire

du volume courant

EOV = respiration de Cheyne- Stokes !

Neviere R et al. Am J Transplant 2014

Neviere R et al. Am J Transplant 2014

Critère composite = mortalité précoce, mortalité à M12, hospitalisation >DMS

Neviere R et al. Am J Transplant 2014

Neviere R et al. Am J Transplant 2014

Test de marche de 6 min et mortalité

des candidats à la TH

Carey EJ et al Liv Transpl 2010

Test de marche de 6 min et mortalité

des candidats à la TH

Carey EJ et al Liv Transpl 2010

Synthèse

1 ) Profond déconditionnement du patient cirrhotique

2) Origine multifactrielle

3) Gold standard = VO2 pic

4) Valeur pronostique pré et post-TH

5) En pratique MET et test de marche de 6 min

6) Perspective Score pronostique dédié à la TH

VO2 pic + MELD + âge : avant TH ?

VO2 pic + âge + DRI : après TH ?

Cut-off pronostique = 250m / 2,5 MET / VO2 9 mL/min/kg