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Aerobic capacity in patients with chronic liver disease: Very modest effect of liver transplantation
Presse Med. 2010; 39: e174–e181 ß 2010 Elsevier Masson SAS. All rights reserved.
Original article
en ligne sur / on line on www.em-consulte.com/revue/lpm www.sciencedirect.com
Aerobic capacity in patients with chronic liver disease: Very modest effect of liver transplantation Malcolm Lemyze1, Sébastien Dharancy2, Remy Nevière3, François-René Pruvot2, Nicole Declerck2, Benoît Wallaert1
1. Service de pneumologie et immuno-allergologie, Centre de compétence des maladies pulmonaires rares, Clinique des maladies respiratoires, Hôpital Calmette, CHRU de Lille, 59037 Lille cedex, France 2. Service d’hépatologie et des maladies digestives, Hôpital Huriez, CHRU de Lille, 59037 Lille cedex, France 3. Service d’explorations fonctionnelles respiratoires, Hôpital Calmette, CHRU de Lille, 59037 Lille cedex, France Received July 1, 2009 Accepted September 25, 2009 Available online: 4 March 2010
Correspondence: Benoît Wallaert, Clinique des maladies respiratoires, Hôpital Albert-Calmette, Centre hospitalier régional universitaire de Lille, boulevard du Pr-Leclerc, 59037 Lille cedex, France. [email protected]
Résumé La transplantation hépatique a des effets limités sur l’aptitude aérobie des patients avec hépatopathie chronique sévère
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Introduction > L’aptitude aérobie est classiquement altérée au cours de la cirrhose du foie, comme cela a été montré par l’abaissement de la consommation maximale d’oxygène lors d’un effort maximal (VO2 pic). Cette altération est corrélée à la sévérité de la maladie hépatique. Le but de ce travail prospectif était d’analyser les effets de la transplantation hépatique (TH) sur la capacité à l’exercice. Méthode > Vingt patients en attente de TH, âgés de 27 à 61 ans, ont réalisé une exploration fonctionnelle respiratoire de repos et d’exercice (EFX) et une échographie cardiaque avant TH, et exploration fonctionnelle respiratoire de repos et à l’exercice 16,3 1,6 mois après la TH. Résultats > Après TH, le pic de VO2 augmentait en moyenne de seulement 7,7 % (de 63,4 à 71,1 % des valeurs prédites) et diminuait chez un quart des patients. La fonction cardiaque évaluée
Summary Introduction > Aerobic capacity is commonly impaired in patients with liver cirrhosis, as demonstrated by their low oxygen consumption at peak exercise (peak VO2). This impairment is correlated with the severity of the liver disease. We investigated the effect of orthotopic liver transplantation (OLT) alone on exercise capacity in this prospective study of patients with liver cirrhosis. Method > Twenty liver transplant candidates, aged 27 to 61 years, underwent resting pulmonary function tests, echocardiography, and incremental cardiopulmonary exercise testing (CPET) before OLT and 16.3 1.6 months after OLT. Results > Following OLT, peak VO2 increased by a mean of only 7.7% (from 63.4 to 71.1% of predicted value), and decreased in onequarter of the patients. Cardiac function was normal before OLT and no changes in respiratory indicators followed OLT. Change in peak VO2 after OLT (D peak VO2) was related to changes in hemoglobin level (r2 = 0.45, p = 0.04), the stopping of beta-blocker therapy, and muscle impairment, as suggested by the correlation between D peak VO2 and peak lactate concentration before OLT (r2 = 0.64, p < 0.01).
tome 39 > n87/8 > juillet–août 2010 doi: 10.1016/j.lpm.2009.09.027
en échographie était normale avant TH. Il n’existait pas de modification significative des paramètres de repos après TH. Les modifications du pic de VO2 avant et après TH (D pic VO2) étaient associées à l’amélioration du taux d’hémoglobine (r2 = 0,45, p = 0,04), à l’arrêt des bêtabloquants et aux altérations musculaires comme suggéré par la corrélation entre le D pic VO2 et le pic de concentration en lactate avant TH (r2 = 0,64, p < 0,01). Discussion > L’amélioration de l’aptitude aérobie après TH était discrète. La persistance de cette altération était essentiellement d’origine périphérique. L’anémie et le traitement bêtabloquant étaient des facteurs aggravants. La mise en place de programme de réhabilitation doit être envisagée avant et après TH pour améliorer le bénéfice clinique de la TH sur la vie quotidienne.
Discussion > Our study provides evidence of a very modest and inconsistent increase in aerobic capacity in liver transplant candidates after liver transplantation alone. This persistent impairment of exercise tolerance was principally of peripheral origin but anemia and beta-blocker treatment should be considered as major aggravating factors. Rehabilitation programs before and after transplantation may increase its benefits to these deconditioned liver transplant recipients in their daily lives.
I
magnitude of the impairment increases with the progression of liver disease [2,4]. In a multivariate analysis of a population of 135 cirrhotic patients, we reported that the severity of liver disease (as assessed with the Model for End-stage Liver Disease or MELD score) was the independent variable most closely associated with changes in peak VO2. Other factors associated with this decline in exercise performance included anemia, smoking, and age [2]. The close relationship between peak VO2 and severity of hepatic dysfunction suggests that OLT might improve these patients’ performance on exercise tests. Beyer et al. showed [5], in a cohort of 17 transplant recipients, that peak VO2 increased by 43% 6 months after OLT. This improvement seemed to be the result of exercise rehabilitation, which began very early, in the third week after transplantation, and continued for 6 months, with close patient monitoring. The improvement in peak VO2 was correlated with an increase in the strength of the quadriceps muscle in patients who had undergone transplantation and rehabilitation. The effect of OLT alone on peak VO2 of cirrhotic patients has never been evaluated. Moreover, previous studies have always involved highly selected cirrhotic patients. In clinical practice, one of the main problems associated with the interpretation of exercise test indicators in patients with cirrhosis is that many confounding factors associated with liver cirrhosis, especially anemia and beta-blocker treatment, can have a major effect on peak VO2. The aim of this study was thus to compare clinical exercise testing indicators in unselected patients with severe liver cirrhosis before and after OLT to determine the extent to which OLT itself modifies their aerobic capacity and then to study the factors that can affect aerobic capacity and explain these patients’ improved or decreased exercise tolerance after OLT.
n clinical practice, aerobic capacity is evaluated by measuring peak VO2 during symptom-limited cardiopulmonary exercise testing. Peak VO2 is a relevant, precise, and physiologically reproducible measurement that reflects the overall efficiency of the oxygen transport chain from the mouth to the mitochondria [1]. It can be used to assess the capacity of the body to respond to an increase in oxygen demand, due to surgical stress, for example. For this reason, it is useful to determine peak VO2 in patients awaiting organ transplantation. It has been used as a prognostic factor and is strongly associated with mortality after orthotopic liver transplantation (OLT) [2,3]. Impaired peak VO2 is found in almost all patients with liver cirrhosis, and the
What was known?
Aerobic capacity is commonly impaired in patients with liver cirrhosis. The mechanisms responsible for this aerobic impairment are unclear but are related to liver disease.
The effect of liver transplantation alone on aerobic capacity is not known.
What this study adds
Impaired aerobic capacity in patients with liver cirrhosis is primarily of peripheral origin but anemia and beta-blocker treatment should be considered as major aggravating factors.
Liver transplantation alone is associated with a very modest and inconsistent improvement of aerobic capacity.
The modesty of the effect of surgery alone shows the need for
Methods
surpervised rehabilitation programs to improve the functional
Patients
capacities on exercise of liver transplant recipients.
Twenty consecutive patients who had undergone orthotopic whole-liver transplantation at Lille University Hospital were
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Original article
Aerobic capacity in patients with chronic liver disease: Very modest effect of liver transplantation
M Lemyze, S Dharancy, R Nevière, F-R Pruvot, N Declerck, B Wallaert
prospectively re-evaluated at rest and during exercise tests. The exclusion criteria were combined transplantation, reduced-liver transplantation, or an inability to cooperate. Patients with alcoholic cirrhosis were eligible for OLT after an average period of 6 months of sobriety. The local ethics committee approved the protocol, and all subjects provided informed consent. Anthropometric data, duration of post-transplantation hospitalization, time until re-evaluation after OLT, and other factors (smoking habits, past medical history of respiratory or cardiac disease, treatments, and hemoglobin level) that might affect aerobic capacity, were recorded. The clinical severity of hepatic dysfunction was graded with the MELD prognostic classification system [6], in which a score below 17 corresponded to mild hepatic dysfunction whereas patients with moderate to severe dysfunction had MELD score of 17 or higher.
Resting pulmonary function tests Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1/FVC ratio and total lung capacity (TLC) were measured by plethysmography in a Jaeger-MasterlabW cabin. Single-breath diffusing capacity for carbon monoxide (DLCO)
was determined in mL/min/mmHg in apnea and was then adjusted for hemoglobin level (Hb). The values obtained were compared with reference values [7].
Cardiac function assessment To detect alcoholic cardiomyopathy [8] and cirrhotic cardiomyopathy [9] during the pretransplantation screening period, all candidates underwent two-dimensional echocardiography performed by experienced ultrasonographers using an HP Sonos 5500 ultrasound system with a 2–4 MHz transducer. Chamber quantification, left ventricle (LV) function, and valvular pathology were evaluated according to guidelines established by the American Society of Echocardiography [10].
Cardiopulmonary exercise testing Incremental CPET was conducted according to the same protocol and by the same physician before and after transplantation on an Ergoline-Ergometrics 800W bicycle, with 10 watts per minute increments after a warm-up period of three minutes at 20 watts [2]. Predicted values for peak VO2 were calculated from reference equations [11,12].
Table I Principal characteristics of the 20 patients Patient
Sex
Age (years)
BMIa (kg/m2)
Cause of liver disease a
MELD score a
Smoker a
Ascites a
Betablocker a
DHb (g/dl) a
Duration of hospitalization (days)
DpeakVO2 (% predicted)
1
M
48
24
Alcohol
12.5
Yes
Refractory
Yes
S0.4
26
S12.8
2
M
52
29
Hepatitis C
20.1
No
No
Yes
2.5
16
S8.7
3
M
55
24
Alcohol
10.1
Yes
Refractory
Yes
1
23
S8
4
M
54
25
Hepatitis C
10
No
No
Yes
1.3
22
S7.6
5
M
61
32
HCC
11.3
Yes
No
Yes
S0.3
16
S5.6
6
M
51
29
PBC
15
No
Slight
No
3
18
3
7
F
58
20
Alcohol
19.5
No
Refractory
Yes
0.6
20
4.2
8
F
37
28
HCC
14.7
Yes
No
Yes
S0.2
38
4.5
9
M
56
30
HCC
9.7
Yes
No
No
1
22
5.2
10
M
48
22
Alcohol
6.8
Yes
Refractory
Yes
1.1
16
6.5
11
M
59
26
HCC
8.1
Yes
No
No
1.6
26
6.6
12
M
49
27
Hemochromatosis
12.9
Yes
Refractory
No
5
19
9.8
13
M
59
29
HCC
7.6
No
No
Yes
S0.6
25
10.4
14
M
53
26
Alcohol
25.4
Yes
Refractory
Yes
1.9
21
10.5
15
M
29
23
HCC
7.1
No
No
No
1.3
37
12.2
16
M
53
27
Alcohol
10
Yes
Refractory
No
S0.2
28
13.5
17
M
50
27
Alcohol
23.4
No
Slight
No
2.8
21
22
18
F
55
25
Hepatitis C
10.2
No
Refractory
Yes
0.3
20
24.3
19
M
27
25
BuddSChiari
13.8
No
No
No
2.6
20
27.7
20
M
30
19
HCC
28.6
No
No
No
5.5
20
36.7
BMI: body mass index; HCC: hepatocellular carcinoma; MELD: score assessing the severity of liver disease; PBC: primary biliary cirrhosis; DHb: hemoglobin change after liver transplantation; DpeakVO2: change in maximal oxygen uptake after liver transplantation.
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a
Before orthotopic liver transplantation.
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Statistical analysis
Table II
Statistical analysis was performed with NCSS 2001 software. The results are reported as means standard errors. Paired ttests were used to compare variables before and after transplantation when the difference was normally distributed, and the nonparametric Wilcoxon test when it was skewed. Variables of ‘‘improvers’’ and ‘‘non-improvers’’ were compared with the Mann-Whitney rank sum test. Possible correlations between change in peak VO2 after OLT and severity of liver disease, change in Hb concentration, duration of hospitalization, and time until re-evaluation after OLT were investigated with Spearman’s rank correlation test. For all tested variables, p values lower than 0.05 were considered statistically significant.
Respiratory function indicators at rest before and after transplantation (20 patients)
Results
Before OLT FVC (% of predicted)
89 W 2.6
FEV1 (% of predicted) TLC (% of predicted)
After OLT
p
95 W 3.1
NS
88 W 3
91.8 W 3.9
NS
96 W 4
95.1 W 2.6
NS
DLCO (% of predicted)
74.6 W 2.5
73.5 W 3
NS
pH
7.43 W 0.01
7.41 W 0.01
NS
PCO2 (mmHg)
34.5 W 0.8
36.3 W 0.9
NS
PaO2 (mmHg)
90.7 W 2.3
95.4 W 2.6
NS
P(A-a)O2 (mmHg)
21.2 W 2
15.5 W 2.1
NS
Original article
Aerobic capacity in patients with chronic liver disease: Very modest effect of liver transplantation
DLCO: single-breath diffusing capacity for carbon monoxide; FEV1: forced expired volume in 1 s; FVC: forced vital capacity; NS: not significant; OLT: orthotopic liver transplantation; TLC: total lung capacity. Data are mean W SE.
Principal characteristics of the study population
Comparison of clinical and functional indicators at rest and during exercise, before and after transplantation Weight (77.4 13.2 kg vs 81.5 17.7 kg) and body mass index (25.9 3.3 vs 27.2 4.1) did not change significantly after OLT. In contrast, Hb levels increased significantly (from 12.5 1.9 g/dL to 14.0 1.6 g/dL) after transplantation (p = 0.0009). Respiratory function indicators at rest were within normal range (table II). The only marked abnormality was a qualitative alteration in DLCO. OLT did not modify any of these features. Aerobic capacity was impaired in all but one patient before transplantation, that is, peak VO2 was 84% or less of the predicted value, in accordance with the American Thoracic tome 39 > n87/8 > juillet–août 2010
Society guidelines [11]. Peak VO2 increased significantly, by 7.7%, after OLT. As figure 1 shows, maximal aerobic capacity was normalized in only four patients after OLT. The mean gain in maximal workload was 17 watts (table III). Peak VO2 decreased after OLT in 5 patients (‘‘non-improvers’’), from 72.8 3.1% to 64.2 3% predicted value. Inversely, 15 patients (improvers) increased their peak VO2 from 60.2 4.1% to 73.4 4.2% predicted value after OLT. Ventilatory adaptation was characterized, both before and after transplantation, by hyperventilation, assessed by a high VE/ VO2 at peak exercise. As expected from the increased VO2, VE increased and consequently ventilatory reserve decreased after OLT (table III). No hypoxemia was observed on exercise and the alveolar-arterial O2 gradient was unaffected by OLT. The cardiovascular measurements changed after transplantation, both at rest and during exercise. Resting HR increased from 75 3.6 to 92 3.7 bpm (p = 0.002) and systolic blood pressure (SBP) from 127 5.6 to 147 6.2 mmHg (p = 0.019) after OLT. Table III summarizes the changes in maximal exercise cardiovascular indicators after OLT.
Comparison of non-improvers (n = 5) and improvers (n = 15) As illustrated in table I, the ‘‘non-improvers’’ include patients 1 to 5 whereas ‘‘improvers’’ correspond to patients 6 to 20. All but one of the potential confounding factors were equally distributed between the non-improvers and the improvers: sex (5 vs 12 men), smoking (3 vs 7 smokers), presence of ascites (2 vs 8), and history of respiratory (3 vs 5) or cardiac disease (1 vs 3). Only beta-blocker treatment was not evenly distributed between the two groups (5 vs 6, p = 0.03). Similarly, the two groups did not differ for age (54 4.5 vs 48 2.6 years old), BMI (26.0 1.1 vs 25.9 1.0 kg/m2),
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The study population consisted of 3 women and 17 men (table I). Half the patients had ascites. Eleven had been treated with betablockers, which were always discontinued after OLT. Immunosuppressive treatment included systemic corticosteroids in 16 patients, cyclosporin in 11, mycophenolate mofetil in 12, and tacrolimus in 12. Ten patients were smokers. History of respiratory disorders was minimal: three cases of stage 0 or 1 chronic obstructive pulmonary disease, according to GOLD guidelines [13], and one case of intermittent asthma. One patient had a right hydrothorax associated with refractory ascites. Four patients had controlled hypertension. Left ventricle ejection fraction (LVEF) (71.9 2.1, min: 55, max: 86%), septal or posterior wall thickness (8.9 0.4, min: 6, max: 11 mm), and left ventricle end-diastolic dimension (LVEDD) (47.7 1.2, min: 37, max: 59 mm) were all normal in 19 patients. Mild mitral regurgitation was found in two patients and moderate aortic regurgitation in one. Two patients were anemic before transplantation. The mean time to re-evaluation after OLT was 16.3 1.6 months, and the mean duration of postsurgical hospitalization was 22.7 1.3 days.
M Lemyze, S Dharancy, R Nevière, F-R Pruvot, N Declerck, B Wallaert
Figure 1 Maximal aerobic capacity in 20 liver transplant candidates before and after liver transplantation
Table III Maximal indicators during exercise before and after transplantation (20 patients)
Workload (watt)
Before OLT
After OLT
p
104.6 W 5.5
121.5 W 7.1
0.004
VO2 (L/min)
1.47 W 0.08
1.68 W 0.09
< 0.01
VO2 (% of predicted)
63.4 W 3.4
71.1 W 3.3
0.01
6.2 W 0.6
6.3 W 0.3
Lactate (mmol/L)
NS
VE (L/min)
62.4 W 3.6
75.4 W 4
< 0.001
VT (L)
1.97 W 0.6
1.95 W 0.55
NS
VE/VO2
42.7 W 1.3
45.8 W 1.8
NS
Ventilatory reserve (%)
46.8 W 3.5
27.3 W 3.9
0.004
pH
7.36 W 0.01
7.36 W 0.01
NS
PCO2 (mmHg)
34.4 W 1
33.4 W 0.9
NS
PaO2 (mmHg)
95.5 W 2.9
98.2 W 2.9
NS
P(A-a)O2 (mmHg)
24.2 W 2.1
23.5 W 2.7
NS
HR (bpm)
123.5 W 5.9
156 W 3.7
< 0.00001
HR (% of predicted)
69.3 W 3.2
88 W 1.9
< 0.00001
VO2 /HR (% of predicted)
96.3 W 7.4
81.2 W 3.8
0.02
SBP (mmHg)
159 W 5.8
191 W 9.4
0.01
HR: heart rate; OLT: orthotopic liver transplantation; SBP: systolic blood pressure; VE: minute ventilation; VO2: oxygen uptake; VT: tidal volume. Data are mean W SE.
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severity of liver disease assessed by the MELD score (12.8 2.9 vs 14.2 1.7), duration of post-transplantation hospitalization (20.6 2.7 vs 23.4 1.6 days), time to re-evaluation (15.5 3.2 vs 16.5 1.9 months), defined as the time from hospital discharge to exercise challenge after OLT, resting pulmonary function tests (FEV1, 84.8 6.1 vs 89.1 3.5% predicted value; DLCO, 79.7 4.9 vs 72 2.8% predicted value), echocardiographic parameters (LVEDD, 46.6 2.4 vs 47.5 1.4 mm; septal or posterior wall thickness, 9.4 0.7 vs 8.9 0.5 mm), except for LVEF, which was normal in both
groups but higher in non-improvers (77.4 3.1 vs 68.9 2%, p = 0.03). As table IV indicates, heart rate in both groups increased after OLT, both at rest and at peak exercise, whereas only in improvers did Hb level increase as VE increased and ventilatory reserve decreased.
Comparison of patients treated and not treated with beta-blockers before OLT Table V compares CPET measurements for the patients initially treated with beta-blockers and those who were not.
Variables associated with change in peak VO2 after OLT Changes in Hb levels after OLT were slightly correlated with peak VO2 variation (% of predicted value) (r2 = 0.45, p = 0.045). Peak blood lactate levels on exercise before transplantation was significantly higher in patients whose peak VO2 did not improve after transplantation than in those showing improvement (7.9 mmol/L vs 5.5 2.1 mmol/L; p = 0.04). In addition, improvement in aerobic capacity after OLT (D peak VO2 as a percentage of the predicted value) was inversely correlated with peak lactate concentration (mmol/L) before transplantation (figure 2).
Discussion We observed a very modest increase in maximal aerobic capacity following liver transplantation in patients with chronic liver disease. Transplantation did not modify ventilatory or respiratory indicators. Paradoxically, cirrhotic patients whose aerobic capacity did not improve after OLT were those whose beta-blocker treatment was discontinued. Changes in peak VO2 after transplantation were correlated with changes in Hb level. Moreover, the change in peak VO2 after transplantation was also related to peak blood lactate levels before transplantation. tome 39 > n87/8 > juillet–août 2010
Table IV Functional exercise indicators parameters before and after liver transplantation in‘‘improvers’’ and ‘‘non-improvers’’ Improvers (n = 15) Before OLT
Non-improvers After OLT
Before OLT
After OLT
Hb (g/dL)
12.4 W 0.6
14.1 W 0.5 b
13.1 W 0.5
HR rest (bpm)
78.3 W 4.1
91.5 W 3.6 b
65.2 W 6.4
95.2 W 11.2 a
HR max (bpm)
127.1 W 6.9
157.3 W 3.4 b
112.8 W 11
151.2 W 11.5 a
VO2/HRmax (mL/b)
11.3 W 0.8
10.9 W 0.7
% of predicted
89.5 W 8.5
82.9 W 4.3 b
VE (L/min)
58.6 W 4
76.8 W 5.1
Ventilatory reserve (%)
43.3 W 3.4
28.2 W 4.9 b
13.9 W 0.4
15.4 W 1.7
10.4 W 0.7 a
116.9 W 11.7
96 W 8 a
70.3 W 8
71.2 W 4.4
27.4 W 7.9
24.5 W 6.4
Original article
Aerobic capacity in patients with chronic liver disease: Very modest effect of liver transplantation
HR: heart rate; OLT: orthotopic liver transplantation; VE: minute ventilation; VO2: oxygen uptake; VT: tidal volume. Data are mean W SE. a
Significant difference in indicators for non-improvers before and after OLT.
b
Significant difference in indicators for improvers before and after OLT.
Table V Comparison of exercise indicators before and after OLT according to beta-blocker treatment before OLT No beta-blocker (n = 9) Before OLT Age Body mass index Hb (g/dl)
11.8 W 0.6 58.3 W 4.3
HR rest (bpm)
86.4 W 5
VO2/HRmax (ml/b) (% of predicted) VE/VO2 max
145.3 W 5.2
After OLT
52.7 W 2.9 25.9 W 1 13.5 W 1.6
111.1 W 6.6
Peak VO2 (% of predicted)
VO2/HRmax (ml/b)
Before OLT
26 W 1.1 14.3 W 6.7
HR max (bpm)
After OLT
44.9 W 3.2
MELD score Maximum workload (watts)
Beta-blocker (n = 11)
14.3 W 0.5 a
13.1 W 0.5
13.8 W 0.5
140 W 10.3 a
99.4 W 7.4
106.4 W 8.4
73.5 W 5.1 a
67.5 W 4.5
69.1 W 4.6
91 W 5
65.7 W 3.9 a
162.8 W 3.1
10.5 W 0.8
a
11.8 W 0.9
105.7 W 5.3 13.7 W 1
a
a
93.6 W 18.5 b 150 W 5.8 b 9.9 W 0.6 b
a
81.5 W 19.4 b
73.7 W 5.9
80.8 W 4.8
114.8 W 7.9
43 W 1.6
45.1 W 3.2
42.4 W 1.8
46.4 W 2.2
35.1 W 4.6
23.9 W 4.9 b
Ventilatory reserve (%)
44.4 W 4.4
31.4 W 6.4 a
Peak lactate (mmol/l)
5.1 W 0.7
6.9 W 1.2
7 W 0.7
5.6 W 0.9
HR: heart rate; OLT: orthotopic liver transplantation; VE: minute ventilation; VO2: oxygen uptake; VT: tidal volume. Data are mean W SE. a
Significant difference in indicators for patients who did not take beta-blockers before and after OLT.
b
Significant difference in indicators for patients who took beta-blockers before and after OLT.
tome 39 > n87/8 > juillet–août 2010
plantation with a mean time to re-evaluation of 16.3 months. The principal postsurgical complications occurred during the first four months after transplantation, and the survival curve was linear after the sixth month following transplantation. Reevaluation thus took place after this critical period. Nor did the duration of postsurgical hospitalization differ between patients whose aerobic capacity did and did not improve after OLT.
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The main limitation of this study is the small number of patients. No study comparing all of these functional indicators at rest or during exercise before and after liver transplantation has included more transplant recipients. The short postsurgical hospitalization indicates that it is unlikely that surgical complications influenced post-OLT VO2. In addition, patients were reevaluated between the fifth and the 26th month after trans-
M Lemyze, S Dharancy, R Nevière, F-R Pruvot, N Declerck, B Wallaert
Figure 2 Correlation between change in maximal oxygen consumption after and peak blood lactate levels before liver transplantation
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Finally, there was no correlation between time to re-evaluation and improvement in peak VO2. We note that Iscar et al. have reported no increase in VO2max at 3 months after OLT and a slight increase at 12 months after OLT [14]. The only previous study to compare the aerobic capacity of cirrhotic patients before and after liver transplantation reported an increase of more than 43% in maximal O2 uptake [5]. These patients, however, were included in an exercise rehabilitation program very shortly after transplantation. In contrast to these very encouraging results, our study demonstrated a very modest and inconsistent improvement in aerobic capacity (peak VO2 increased only 7.7%). Furthermore, four-fifths of these transplant recipients had a persistent, significant alteration in aerobic capacity with a mean peak VO2 that reached only 71% of predicted value. These results are in accordance with those previously reported by Stephenson et al. showing a peak VO2 of 66% of the predicted value in 8 patients, more than 30 months after liver transplantation [15]. The normality of almost all ventilatory and gas exchange indicators at rest and during exercise provides no suggestion of pulmonary disorders. The only detectable abnormality was a decrease in DLCO, which is common in cirrhotic patients, but cannot explain this decrease in peak VO2. Both minute ventilation, which increased after transplantation, and ventilatory reserve, which decreased after transplantation, were clearly associated with the increase in aerobic capacity after transplantation. The principal changes in exercise test results after transplantation concerned cardiovascular indicators, with the appearance of a hyperkinetic state characterized by an increase in HR at rest
and during exercise, a decrease in oxygen pulse, and an increase in SBP. As more than half the patients were treated with beta-blockers and this treatment was stopped after transplantation in all patients, we investigated the extent to which discontinuation of this treatment before transplantation might have affected our patients’ maximal aerobic capacity. Interestingly, despite their powerful negative chronotropic and inotropic effect, the discontinuation of beta-blockers was not associated with an improvement of aerobic capacity after OLT. Peak VO2 was unaffected by liver transplantation in patients initially treated with these agents. This observation is consistent with several studies showing the lack of any change in exercise tolerance and peak VO2 in cirrhotic patients after the initiation of beta-blocker treatment [16,17]. As Hb and SaO2 were unchanged after OLT in patients initially treated by bblocker, the persistent alteration in aerobic capacity in this group after OLT may be related to impaired peripheral oxygen diffusion and utilization processes. Hb is one of the principal determinants of sustained oxygen delivery to tissue. Because maximal exercise capacity and peak VO2 decrease in proportion to the reduction in Hb [18], anemia is a common complication of liver cirrhosis. In our study, the mean Hb concentration was significantly higher after transplantation. The patients who had the best improvement in peak VO2 also had the greatest increases in Hb concentration after OLT. Moreover, D peak VO2 was correlated with DHb after OLT. These changes in Hb level after OLT must be considered a relevant factor that can strongly affect peak VO2. But although anemia may be involved in the impairment of aerobic capacity in cirrhotic patients before transplantation [2], its correction was not in itself sufficient to account for the entire variation in peak VO2 in these liver transplant recipients. This was particularly evident given that significant peak VO2 impairment persisted in patients with normal Hb levels after transplantation. Poor exercise performance in cirrhotic patients with cardiac dysfunction at exercise may be difficult to distinguish from the effects of inactivity. Both patterns include low peak VO2, hyperkinetic cardiovascular response to exercise with decreased VO2/HR, hyperventilation, and high lactate concentration relative to workload. Our patients had no history of moderate or severe cardiac disease. In any case, Torregrosa et al. showed that the hyperdynamic circulatory state and structural and functional cardiac modifications, aggravated by exercise and defining cirrhotic cardiomyopathy, resolve within 6 to 12 months after OLT [19]. In our patients, the excessive lactate production seen at low workloads cannot result simply from reduced oxygen delivery due to low maximum cardiac output. An increase in blood lactate levels during exercise occurs as a consequence of a failure in the oxidative ATP synthesis process in skeletal muscle. Arterial lactate concentrations are higher in patients developing contractile fatigue after exercise and are correlated with the fall in quadriceps tome 39 > n87/8 > juillet–août 2010
twitch force [20]. In our study, the correlation found between changes in peak VO2 after OLT and peak lactate concentration before OLT suggests that the persistent alteration of aerobic capacity in our liver transplant recipients may be related to muscular impairment due to deconditioning. The deleterious effects of deconditioning are not negligible in chronic diseases such as liver cirrhosis. Saltin et al. showed that healthy sedentary subjects spending 3 weeks in bed develop a severe reduction of their exercise performance with reduced stroke volume leading to a decline in peak VO2, which decreased by 40% from its initial value [21]. Recovery takes several weeks
with a special rehabilitation program. Quality of life and peak VO2 increase significantly between months 2 and 24 after liver transplantation, but only half of liver transplant recipients have restarted daily physical activity 2 years after OLT [22]. Treatment of hepatic dysfunction alone may not improve the exercise capacity of patients whose muscles are weak and produce excess lactate unless muscle strength and aerobic capacity are concurrently improved by exercise rehabilitation programs.
Original article
Aerobic capacity in patients with chronic liver disease: Very modest effect of liver transplantation
Conflicts of Interest: none.
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[1]
Original article
en ligne sur / on line on www.em-consulte.com/revue/lpm www.sciencedirect.com
Aerobic capacity in patients with chronic liver disease: Very modest effect of liver transplantation Malcolm Lemyze1, Sébastien Dharancy2, Remy Nevière3, François-René Pruvot2, Nicole Declerck2, Benoît Wallaert1
1. Service de pneumologie et immuno-allergologie, Centre de compétence des maladies pulmonaires rares, Clinique des maladies respiratoires, Hôpital Calmette, CHRU de Lille, 59037 Lille cedex, France 2. Service d’hépatologie et des maladies digestives, Hôpital Huriez, CHRU de Lille, 59037 Lille cedex, France 3. Service d’explorations fonctionnelles respiratoires, Hôpital Calmette, CHRU de Lille, 59037 Lille cedex, France Received July 1, 2009 Accepted September 25, 2009 Available online: 4 March 2010
Correspondence: Benoît Wallaert, Clinique des maladies respiratoires, Hôpital Albert-Calmette, Centre hospitalier régional universitaire de Lille, boulevard du Pr-Leclerc, 59037 Lille cedex, France. [email protected]
Résumé La transplantation hépatique a des effets limités sur l’aptitude aérobie des patients avec hépatopathie chronique sévère
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Introduction > L’aptitude aérobie est classiquement altérée au cours de la cirrhose du foie, comme cela a été montré par l’abaissement de la consommation maximale d’oxygène lors d’un effort maximal (VO2 pic). Cette altération est corrélée à la sévérité de la maladie hépatique. Le but de ce travail prospectif était d’analyser les effets de la transplantation hépatique (TH) sur la capacité à l’exercice. Méthode > Vingt patients en attente de TH, âgés de 27 à 61 ans, ont réalisé une exploration fonctionnelle respiratoire de repos et d’exercice (EFX) et une échographie cardiaque avant TH, et exploration fonctionnelle respiratoire de repos et à l’exercice 16,3 1,6 mois après la TH. Résultats > Après TH, le pic de VO2 augmentait en moyenne de seulement 7,7 % (de 63,4 à 71,1 % des valeurs prédites) et diminuait chez un quart des patients. La fonction cardiaque évaluée
Summary Introduction > Aerobic capacity is commonly impaired in patients with liver cirrhosis, as demonstrated by their low oxygen consumption at peak exercise (peak VO2). This impairment is correlated with the severity of the liver disease. We investigated the effect of orthotopic liver transplantation (OLT) alone on exercise capacity in this prospective study of patients with liver cirrhosis. Method > Twenty liver transplant candidates, aged 27 to 61 years, underwent resting pulmonary function tests, echocardiography, and incremental cardiopulmonary exercise testing (CPET) before OLT and 16.3 1.6 months after OLT. Results > Following OLT, peak VO2 increased by a mean of only 7.7% (from 63.4 to 71.1% of predicted value), and decreased in onequarter of the patients. Cardiac function was normal before OLT and no changes in respiratory indicators followed OLT. Change in peak VO2 after OLT (D peak VO2) was related to changes in hemoglobin level (r2 = 0.45, p = 0.04), the stopping of beta-blocker therapy, and muscle impairment, as suggested by the correlation between D peak VO2 and peak lactate concentration before OLT (r2 = 0.64, p < 0.01).
tome 39 > n87/8 > juillet–août 2010 doi: 10.1016/j.lpm.2009.09.027
en échographie était normale avant TH. Il n’existait pas de modification significative des paramètres de repos après TH. Les modifications du pic de VO2 avant et après TH (D pic VO2) étaient associées à l’amélioration du taux d’hémoglobine (r2 = 0,45, p = 0,04), à l’arrêt des bêtabloquants et aux altérations musculaires comme suggéré par la corrélation entre le D pic VO2 et le pic de concentration en lactate avant TH (r2 = 0,64, p < 0,01). Discussion > L’amélioration de l’aptitude aérobie après TH était discrète. La persistance de cette altération était essentiellement d’origine périphérique. L’anémie et le traitement bêtabloquant étaient des facteurs aggravants. La mise en place de programme de réhabilitation doit être envisagée avant et après TH pour améliorer le bénéfice clinique de la TH sur la vie quotidienne.
Discussion > Our study provides evidence of a very modest and inconsistent increase in aerobic capacity in liver transplant candidates after liver transplantation alone. This persistent impairment of exercise tolerance was principally of peripheral origin but anemia and beta-blocker treatment should be considered as major aggravating factors. Rehabilitation programs before and after transplantation may increase its benefits to these deconditioned liver transplant recipients in their daily lives.
I
magnitude of the impairment increases with the progression of liver disease [2,4]. In a multivariate analysis of a population of 135 cirrhotic patients, we reported that the severity of liver disease (as assessed with the Model for End-stage Liver Disease or MELD score) was the independent variable most closely associated with changes in peak VO2. Other factors associated with this decline in exercise performance included anemia, smoking, and age [2]. The close relationship between peak VO2 and severity of hepatic dysfunction suggests that OLT might improve these patients’ performance on exercise tests. Beyer et al. showed [5], in a cohort of 17 transplant recipients, that peak VO2 increased by 43% 6 months after OLT. This improvement seemed to be the result of exercise rehabilitation, which began very early, in the third week after transplantation, and continued for 6 months, with close patient monitoring. The improvement in peak VO2 was correlated with an increase in the strength of the quadriceps muscle in patients who had undergone transplantation and rehabilitation. The effect of OLT alone on peak VO2 of cirrhotic patients has never been evaluated. Moreover, previous studies have always involved highly selected cirrhotic patients. In clinical practice, one of the main problems associated with the interpretation of exercise test indicators in patients with cirrhosis is that many confounding factors associated with liver cirrhosis, especially anemia and beta-blocker treatment, can have a major effect on peak VO2. The aim of this study was thus to compare clinical exercise testing indicators in unselected patients with severe liver cirrhosis before and after OLT to determine the extent to which OLT itself modifies their aerobic capacity and then to study the factors that can affect aerobic capacity and explain these patients’ improved or decreased exercise tolerance after OLT.
n clinical practice, aerobic capacity is evaluated by measuring peak VO2 during symptom-limited cardiopulmonary exercise testing. Peak VO2 is a relevant, precise, and physiologically reproducible measurement that reflects the overall efficiency of the oxygen transport chain from the mouth to the mitochondria [1]. It can be used to assess the capacity of the body to respond to an increase in oxygen demand, due to surgical stress, for example. For this reason, it is useful to determine peak VO2 in patients awaiting organ transplantation. It has been used as a prognostic factor and is strongly associated with mortality after orthotopic liver transplantation (OLT) [2,3]. Impaired peak VO2 is found in almost all patients with liver cirrhosis, and the
What was known?
Aerobic capacity is commonly impaired in patients with liver cirrhosis. The mechanisms responsible for this aerobic impairment are unclear but are related to liver disease.
The effect of liver transplantation alone on aerobic capacity is not known.
What this study adds
Impaired aerobic capacity in patients with liver cirrhosis is primarily of peripheral origin but anemia and beta-blocker treatment should be considered as major aggravating factors.
Liver transplantation alone is associated with a very modest and inconsistent improvement of aerobic capacity.
The modesty of the effect of surgery alone shows the need for
Methods
surpervised rehabilitation programs to improve the functional
Patients
capacities on exercise of liver transplant recipients.
Twenty consecutive patients who had undergone orthotopic whole-liver transplantation at Lille University Hospital were
tome 39 > n87/8 > juillet–août 2010
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Original article
Aerobic capacity in patients with chronic liver disease: Very modest effect of liver transplantation
M Lemyze, S Dharancy, R Nevière, F-R Pruvot, N Declerck, B Wallaert
prospectively re-evaluated at rest and during exercise tests. The exclusion criteria were combined transplantation, reduced-liver transplantation, or an inability to cooperate. Patients with alcoholic cirrhosis were eligible for OLT after an average period of 6 months of sobriety. The local ethics committee approved the protocol, and all subjects provided informed consent. Anthropometric data, duration of post-transplantation hospitalization, time until re-evaluation after OLT, and other factors (smoking habits, past medical history of respiratory or cardiac disease, treatments, and hemoglobin level) that might affect aerobic capacity, were recorded. The clinical severity of hepatic dysfunction was graded with the MELD prognostic classification system [6], in which a score below 17 corresponded to mild hepatic dysfunction whereas patients with moderate to severe dysfunction had MELD score of 17 or higher.
Resting pulmonary function tests Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1/FVC ratio and total lung capacity (TLC) were measured by plethysmography in a Jaeger-MasterlabW cabin. Single-breath diffusing capacity for carbon monoxide (DLCO)
was determined in mL/min/mmHg in apnea and was then adjusted for hemoglobin level (Hb). The values obtained were compared with reference values [7].
Cardiac function assessment To detect alcoholic cardiomyopathy [8] and cirrhotic cardiomyopathy [9] during the pretransplantation screening period, all candidates underwent two-dimensional echocardiography performed by experienced ultrasonographers using an HP Sonos 5500 ultrasound system with a 2–4 MHz transducer. Chamber quantification, left ventricle (LV) function, and valvular pathology were evaluated according to guidelines established by the American Society of Echocardiography [10].
Cardiopulmonary exercise testing Incremental CPET was conducted according to the same protocol and by the same physician before and after transplantation on an Ergoline-Ergometrics 800W bicycle, with 10 watts per minute increments after a warm-up period of three minutes at 20 watts [2]. Predicted values for peak VO2 were calculated from reference equations [11,12].
Table I Principal characteristics of the 20 patients Patient
Sex
Age (years)
BMIa (kg/m2)
Cause of liver disease a
MELD score a
Smoker a
Ascites a
Betablocker a
DHb (g/dl) a
Duration of hospitalization (days)
DpeakVO2 (% predicted)
1
M
48
24
Alcohol
12.5
Yes
Refractory
Yes
S0.4
26
S12.8
2
M
52
29
Hepatitis C
20.1
No
No
Yes
2.5
16
S8.7
3
M
55
24
Alcohol
10.1
Yes
Refractory
Yes
1
23
S8
4
M
54
25
Hepatitis C
10
No
No
Yes
1.3
22
S7.6
5
M
61
32
HCC
11.3
Yes
No
Yes
S0.3
16
S5.6
6
M
51
29
PBC
15
No
Slight
No
3
18
3
7
F
58
20
Alcohol
19.5
No
Refractory
Yes
0.6
20
4.2
8
F
37
28
HCC
14.7
Yes
No
Yes
S0.2
38
4.5
9
M
56
30
HCC
9.7
Yes
No
No
1
22
5.2
10
M
48
22
Alcohol
6.8
Yes
Refractory
Yes
1.1
16
6.5
11
M
59
26
HCC
8.1
Yes
No
No
1.6
26
6.6
12
M
49
27
Hemochromatosis
12.9
Yes
Refractory
No
5
19
9.8
13
M
59
29
HCC
7.6
No
No
Yes
S0.6
25
10.4
14
M
53
26
Alcohol
25.4
Yes
Refractory
Yes
1.9
21
10.5
15
M
29
23
HCC
7.1
No
No
No
1.3
37
12.2
16
M
53
27
Alcohol
10
Yes
Refractory
No
S0.2
28
13.5
17
M
50
27
Alcohol
23.4
No
Slight
No
2.8
21
22
18
F
55
25
Hepatitis C
10.2
No
Refractory
Yes
0.3
20
24.3
19
M
27
25
BuddSChiari
13.8
No
No
No
2.6
20
27.7
20
M
30
19
HCC
28.6
No
No
No
5.5
20
36.7
BMI: body mass index; HCC: hepatocellular carcinoma; MELD: score assessing the severity of liver disease; PBC: primary biliary cirrhosis; DHb: hemoglobin change after liver transplantation; DpeakVO2: change in maximal oxygen uptake after liver transplantation.
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a
Before orthotopic liver transplantation.
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Statistical analysis
Table II
Statistical analysis was performed with NCSS 2001 software. The results are reported as means standard errors. Paired ttests were used to compare variables before and after transplantation when the difference was normally distributed, and the nonparametric Wilcoxon test when it was skewed. Variables of ‘‘improvers’’ and ‘‘non-improvers’’ were compared with the Mann-Whitney rank sum test. Possible correlations between change in peak VO2 after OLT and severity of liver disease, change in Hb concentration, duration of hospitalization, and time until re-evaluation after OLT were investigated with Spearman’s rank correlation test. For all tested variables, p values lower than 0.05 were considered statistically significant.
Respiratory function indicators at rest before and after transplantation (20 patients)
Results
Before OLT FVC (% of predicted)
89 W 2.6
FEV1 (% of predicted) TLC (% of predicted)
After OLT
p
95 W 3.1
NS
88 W 3
91.8 W 3.9
NS
96 W 4
95.1 W 2.6
NS
DLCO (% of predicted)
74.6 W 2.5
73.5 W 3
NS
pH
7.43 W 0.01
7.41 W 0.01
NS
PCO2 (mmHg)
34.5 W 0.8
36.3 W 0.9
NS
PaO2 (mmHg)
90.7 W 2.3
95.4 W 2.6
NS
P(A-a)O2 (mmHg)
21.2 W 2
15.5 W 2.1
NS
Original article
Aerobic capacity in patients with chronic liver disease: Very modest effect of liver transplantation
DLCO: single-breath diffusing capacity for carbon monoxide; FEV1: forced expired volume in 1 s; FVC: forced vital capacity; NS: not significant; OLT: orthotopic liver transplantation; TLC: total lung capacity. Data are mean W SE.
Principal characteristics of the study population
Comparison of clinical and functional indicators at rest and during exercise, before and after transplantation Weight (77.4 13.2 kg vs 81.5 17.7 kg) and body mass index (25.9 3.3 vs 27.2 4.1) did not change significantly after OLT. In contrast, Hb levels increased significantly (from 12.5 1.9 g/dL to 14.0 1.6 g/dL) after transplantation (p = 0.0009). Respiratory function indicators at rest were within normal range (table II). The only marked abnormality was a qualitative alteration in DLCO. OLT did not modify any of these features. Aerobic capacity was impaired in all but one patient before transplantation, that is, peak VO2 was 84% or less of the predicted value, in accordance with the American Thoracic tome 39 > n87/8 > juillet–août 2010
Society guidelines [11]. Peak VO2 increased significantly, by 7.7%, after OLT. As figure 1 shows, maximal aerobic capacity was normalized in only four patients after OLT. The mean gain in maximal workload was 17 watts (table III). Peak VO2 decreased after OLT in 5 patients (‘‘non-improvers’’), from 72.8 3.1% to 64.2 3% predicted value. Inversely, 15 patients (improvers) increased their peak VO2 from 60.2 4.1% to 73.4 4.2% predicted value after OLT. Ventilatory adaptation was characterized, both before and after transplantation, by hyperventilation, assessed by a high VE/ VO2 at peak exercise. As expected from the increased VO2, VE increased and consequently ventilatory reserve decreased after OLT (table III). No hypoxemia was observed on exercise and the alveolar-arterial O2 gradient was unaffected by OLT. The cardiovascular measurements changed after transplantation, both at rest and during exercise. Resting HR increased from 75 3.6 to 92 3.7 bpm (p = 0.002) and systolic blood pressure (SBP) from 127 5.6 to 147 6.2 mmHg (p = 0.019) after OLT. Table III summarizes the changes in maximal exercise cardiovascular indicators after OLT.
Comparison of non-improvers (n = 5) and improvers (n = 15) As illustrated in table I, the ‘‘non-improvers’’ include patients 1 to 5 whereas ‘‘improvers’’ correspond to patients 6 to 20. All but one of the potential confounding factors were equally distributed between the non-improvers and the improvers: sex (5 vs 12 men), smoking (3 vs 7 smokers), presence of ascites (2 vs 8), and history of respiratory (3 vs 5) or cardiac disease (1 vs 3). Only beta-blocker treatment was not evenly distributed between the two groups (5 vs 6, p = 0.03). Similarly, the two groups did not differ for age (54 4.5 vs 48 2.6 years old), BMI (26.0 1.1 vs 25.9 1.0 kg/m2),
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The study population consisted of 3 women and 17 men (table I). Half the patients had ascites. Eleven had been treated with betablockers, which were always discontinued after OLT. Immunosuppressive treatment included systemic corticosteroids in 16 patients, cyclosporin in 11, mycophenolate mofetil in 12, and tacrolimus in 12. Ten patients were smokers. History of respiratory disorders was minimal: three cases of stage 0 or 1 chronic obstructive pulmonary disease, according to GOLD guidelines [13], and one case of intermittent asthma. One patient had a right hydrothorax associated with refractory ascites. Four patients had controlled hypertension. Left ventricle ejection fraction (LVEF) (71.9 2.1, min: 55, max: 86%), septal or posterior wall thickness (8.9 0.4, min: 6, max: 11 mm), and left ventricle end-diastolic dimension (LVEDD) (47.7 1.2, min: 37, max: 59 mm) were all normal in 19 patients. Mild mitral regurgitation was found in two patients and moderate aortic regurgitation in one. Two patients were anemic before transplantation. The mean time to re-evaluation after OLT was 16.3 1.6 months, and the mean duration of postsurgical hospitalization was 22.7 1.3 days.
M Lemyze, S Dharancy, R Nevière, F-R Pruvot, N Declerck, B Wallaert
Figure 1 Maximal aerobic capacity in 20 liver transplant candidates before and after liver transplantation
Table III Maximal indicators during exercise before and after transplantation (20 patients)
Workload (watt)
Before OLT
After OLT
p
104.6 W 5.5
121.5 W 7.1
0.004
VO2 (L/min)
1.47 W 0.08
1.68 W 0.09
< 0.01
VO2 (% of predicted)
63.4 W 3.4
71.1 W 3.3
0.01
6.2 W 0.6
6.3 W 0.3
Lactate (mmol/L)
NS
VE (L/min)
62.4 W 3.6
75.4 W 4
< 0.001
VT (L)
1.97 W 0.6
1.95 W 0.55
NS
VE/VO2
42.7 W 1.3
45.8 W 1.8
NS
Ventilatory reserve (%)
46.8 W 3.5
27.3 W 3.9
0.004
pH
7.36 W 0.01
7.36 W 0.01
NS
PCO2 (mmHg)
34.4 W 1
33.4 W 0.9
NS
PaO2 (mmHg)
95.5 W 2.9
98.2 W 2.9
NS
P(A-a)O2 (mmHg)
24.2 W 2.1
23.5 W 2.7
NS
HR (bpm)
123.5 W 5.9
156 W 3.7
< 0.00001
HR (% of predicted)
69.3 W 3.2
88 W 1.9
< 0.00001
VO2 /HR (% of predicted)
96.3 W 7.4
81.2 W 3.8
0.02
SBP (mmHg)
159 W 5.8
191 W 9.4
0.01
HR: heart rate; OLT: orthotopic liver transplantation; SBP: systolic blood pressure; VE: minute ventilation; VO2: oxygen uptake; VT: tidal volume. Data are mean W SE.
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severity of liver disease assessed by the MELD score (12.8 2.9 vs 14.2 1.7), duration of post-transplantation hospitalization (20.6 2.7 vs 23.4 1.6 days), time to re-evaluation (15.5 3.2 vs 16.5 1.9 months), defined as the time from hospital discharge to exercise challenge after OLT, resting pulmonary function tests (FEV1, 84.8 6.1 vs 89.1 3.5% predicted value; DLCO, 79.7 4.9 vs 72 2.8% predicted value), echocardiographic parameters (LVEDD, 46.6 2.4 vs 47.5 1.4 mm; septal or posterior wall thickness, 9.4 0.7 vs 8.9 0.5 mm), except for LVEF, which was normal in both
groups but higher in non-improvers (77.4 3.1 vs 68.9 2%, p = 0.03). As table IV indicates, heart rate in both groups increased after OLT, both at rest and at peak exercise, whereas only in improvers did Hb level increase as VE increased and ventilatory reserve decreased.
Comparison of patients treated and not treated with beta-blockers before OLT Table V compares CPET measurements for the patients initially treated with beta-blockers and those who were not.
Variables associated with change in peak VO2 after OLT Changes in Hb levels after OLT were slightly correlated with peak VO2 variation (% of predicted value) (r2 = 0.45, p = 0.045). Peak blood lactate levels on exercise before transplantation was significantly higher in patients whose peak VO2 did not improve after transplantation than in those showing improvement (7.9 mmol/L vs 5.5 2.1 mmol/L; p = 0.04). In addition, improvement in aerobic capacity after OLT (D peak VO2 as a percentage of the predicted value) was inversely correlated with peak lactate concentration (mmol/L) before transplantation (figure 2).
Discussion We observed a very modest increase in maximal aerobic capacity following liver transplantation in patients with chronic liver disease. Transplantation did not modify ventilatory or respiratory indicators. Paradoxically, cirrhotic patients whose aerobic capacity did not improve after OLT were those whose beta-blocker treatment was discontinued. Changes in peak VO2 after transplantation were correlated with changes in Hb level. Moreover, the change in peak VO2 after transplantation was also related to peak blood lactate levels before transplantation. tome 39 > n87/8 > juillet–août 2010
Table IV Functional exercise indicators parameters before and after liver transplantation in‘‘improvers’’ and ‘‘non-improvers’’ Improvers (n = 15) Before OLT
Non-improvers After OLT
Before OLT
After OLT
Hb (g/dL)
12.4 W 0.6
14.1 W 0.5 b
13.1 W 0.5
HR rest (bpm)
78.3 W 4.1
91.5 W 3.6 b
65.2 W 6.4
95.2 W 11.2 a
HR max (bpm)
127.1 W 6.9
157.3 W 3.4 b
112.8 W 11
151.2 W 11.5 a
VO2/HRmax (mL/b)
11.3 W 0.8
10.9 W 0.7
% of predicted
89.5 W 8.5
82.9 W 4.3 b
VE (L/min)
58.6 W 4
76.8 W 5.1
Ventilatory reserve (%)
43.3 W 3.4
28.2 W 4.9 b
13.9 W 0.4
15.4 W 1.7
10.4 W 0.7 a
116.9 W 11.7
96 W 8 a
70.3 W 8
71.2 W 4.4
27.4 W 7.9
24.5 W 6.4
Original article
Aerobic capacity in patients with chronic liver disease: Very modest effect of liver transplantation
HR: heart rate; OLT: orthotopic liver transplantation; VE: minute ventilation; VO2: oxygen uptake; VT: tidal volume. Data are mean W SE. a
Significant difference in indicators for non-improvers before and after OLT.
b
Significant difference in indicators for improvers before and after OLT.
Table V Comparison of exercise indicators before and after OLT according to beta-blocker treatment before OLT No beta-blocker (n = 9) Before OLT Age Body mass index Hb (g/dl)
11.8 W 0.6 58.3 W 4.3
HR rest (bpm)
86.4 W 5
VO2/HRmax (ml/b) (% of predicted) VE/VO2 max
145.3 W 5.2
After OLT
52.7 W 2.9 25.9 W 1 13.5 W 1.6
111.1 W 6.6
Peak VO2 (% of predicted)
VO2/HRmax (ml/b)
Before OLT
26 W 1.1 14.3 W 6.7
HR max (bpm)
After OLT
44.9 W 3.2
MELD score Maximum workload (watts)
Beta-blocker (n = 11)
14.3 W 0.5 a
13.1 W 0.5
13.8 W 0.5
140 W 10.3 a
99.4 W 7.4
106.4 W 8.4
73.5 W 5.1 a
67.5 W 4.5
69.1 W 4.6
91 W 5
65.7 W 3.9 a
162.8 W 3.1
10.5 W 0.8
a
11.8 W 0.9
105.7 W 5.3 13.7 W 1
a
a
93.6 W 18.5 b 150 W 5.8 b 9.9 W 0.6 b
a
81.5 W 19.4 b
73.7 W 5.9
80.8 W 4.8
114.8 W 7.9
43 W 1.6
45.1 W 3.2
42.4 W 1.8
46.4 W 2.2
35.1 W 4.6
23.9 W 4.9 b
Ventilatory reserve (%)
44.4 W 4.4
31.4 W 6.4 a
Peak lactate (mmol/l)
5.1 W 0.7
6.9 W 1.2
7 W 0.7
5.6 W 0.9
HR: heart rate; OLT: orthotopic liver transplantation; VE: minute ventilation; VO2: oxygen uptake; VT: tidal volume. Data are mean W SE. a
Significant difference in indicators for patients who did not take beta-blockers before and after OLT.
b
Significant difference in indicators for patients who took beta-blockers before and after OLT.
tome 39 > n87/8 > juillet–août 2010
plantation with a mean time to re-evaluation of 16.3 months. The principal postsurgical complications occurred during the first four months after transplantation, and the survival curve was linear after the sixth month following transplantation. Reevaluation thus took place after this critical period. Nor did the duration of postsurgical hospitalization differ between patients whose aerobic capacity did and did not improve after OLT.
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The main limitation of this study is the small number of patients. No study comparing all of these functional indicators at rest or during exercise before and after liver transplantation has included more transplant recipients. The short postsurgical hospitalization indicates that it is unlikely that surgical complications influenced post-OLT VO2. In addition, patients were reevaluated between the fifth and the 26th month after trans-
M Lemyze, S Dharancy, R Nevière, F-R Pruvot, N Declerck, B Wallaert
Figure 2 Correlation between change in maximal oxygen consumption after and peak blood lactate levels before liver transplantation
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Finally, there was no correlation between time to re-evaluation and improvement in peak VO2. We note that Iscar et al. have reported no increase in VO2max at 3 months after OLT and a slight increase at 12 months after OLT [14]. The only previous study to compare the aerobic capacity of cirrhotic patients before and after liver transplantation reported an increase of more than 43% in maximal O2 uptake [5]. These patients, however, were included in an exercise rehabilitation program very shortly after transplantation. In contrast to these very encouraging results, our study demonstrated a very modest and inconsistent improvement in aerobic capacity (peak VO2 increased only 7.7%). Furthermore, four-fifths of these transplant recipients had a persistent, significant alteration in aerobic capacity with a mean peak VO2 that reached only 71% of predicted value. These results are in accordance with those previously reported by Stephenson et al. showing a peak VO2 of 66% of the predicted value in 8 patients, more than 30 months after liver transplantation [15]. The normality of almost all ventilatory and gas exchange indicators at rest and during exercise provides no suggestion of pulmonary disorders. The only detectable abnormality was a decrease in DLCO, which is common in cirrhotic patients, but cannot explain this decrease in peak VO2. Both minute ventilation, which increased after transplantation, and ventilatory reserve, which decreased after transplantation, were clearly associated with the increase in aerobic capacity after transplantation. The principal changes in exercise test results after transplantation concerned cardiovascular indicators, with the appearance of a hyperkinetic state characterized by an increase in HR at rest
and during exercise, a decrease in oxygen pulse, and an increase in SBP. As more than half the patients were treated with beta-blockers and this treatment was stopped after transplantation in all patients, we investigated the extent to which discontinuation of this treatment before transplantation might have affected our patients’ maximal aerobic capacity. Interestingly, despite their powerful negative chronotropic and inotropic effect, the discontinuation of beta-blockers was not associated with an improvement of aerobic capacity after OLT. Peak VO2 was unaffected by liver transplantation in patients initially treated with these agents. This observation is consistent with several studies showing the lack of any change in exercise tolerance and peak VO2 in cirrhotic patients after the initiation of beta-blocker treatment [16,17]. As Hb and SaO2 were unchanged after OLT in patients initially treated by bblocker, the persistent alteration in aerobic capacity in this group after OLT may be related to impaired peripheral oxygen diffusion and utilization processes. Hb is one of the principal determinants of sustained oxygen delivery to tissue. Because maximal exercise capacity and peak VO2 decrease in proportion to the reduction in Hb [18], anemia is a common complication of liver cirrhosis. In our study, the mean Hb concentration was significantly higher after transplantation. The patients who had the best improvement in peak VO2 also had the greatest increases in Hb concentration after OLT. Moreover, D peak VO2 was correlated with DHb after OLT. These changes in Hb level after OLT must be considered a relevant factor that can strongly affect peak VO2. But although anemia may be involved in the impairment of aerobic capacity in cirrhotic patients before transplantation [2], its correction was not in itself sufficient to account for the entire variation in peak VO2 in these liver transplant recipients. This was particularly evident given that significant peak VO2 impairment persisted in patients with normal Hb levels after transplantation. Poor exercise performance in cirrhotic patients with cardiac dysfunction at exercise may be difficult to distinguish from the effects of inactivity. Both patterns include low peak VO2, hyperkinetic cardiovascular response to exercise with decreased VO2/HR, hyperventilation, and high lactate concentration relative to workload. Our patients had no history of moderate or severe cardiac disease. In any case, Torregrosa et al. showed that the hyperdynamic circulatory state and structural and functional cardiac modifications, aggravated by exercise and defining cirrhotic cardiomyopathy, resolve within 6 to 12 months after OLT [19]. In our patients, the excessive lactate production seen at low workloads cannot result simply from reduced oxygen delivery due to low maximum cardiac output. An increase in blood lactate levels during exercise occurs as a consequence of a failure in the oxidative ATP synthesis process in skeletal muscle. Arterial lactate concentrations are higher in patients developing contractile fatigue after exercise and are correlated with the fall in quadriceps tome 39 > n87/8 > juillet–août 2010
twitch force [20]. In our study, the correlation found between changes in peak VO2 after OLT and peak lactate concentration before OLT suggests that the persistent alteration of aerobic capacity in our liver transplant recipients may be related to muscular impairment due to deconditioning. The deleterious effects of deconditioning are not negligible in chronic diseases such as liver cirrhosis. Saltin et al. showed that healthy sedentary subjects spending 3 weeks in bed develop a severe reduction of their exercise performance with reduced stroke volume leading to a decline in peak VO2, which decreased by 40% from its initial value [21]. Recovery takes several weeks
with a special rehabilitation program. Quality of life and peak VO2 increase significantly between months 2 and 24 after liver transplantation, but only half of liver transplant recipients have restarted daily physical activity 2 years after OLT [22]. Treatment of hepatic dysfunction alone may not improve the exercise capacity of patients whose muscles are weak and produce excess lactate unless muscle strength and aerobic capacity are concurrently improved by exercise rehabilitation programs.
Original article
Aerobic capacity in patients with chronic liver disease: Very modest effect of liver transplantation
Conflicts of Interest: none.
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