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