Submaximal oxygen consumption in liver cirrhosis

163

Submaximal

oxygen consumption

in liver cirrhosis

Evidence of severe functional aerobic impairment

We studied maximal aerobic work capacity in 24 cirrhotic patients whose clinical condition was well compensated. Nineteen of our patients had no heart 01 tong disease, and five bad mild mechanical ventilatay impabment. The patients performed incremental exercisa on a treadmill until subjective exhaustion. Tbe maximal exercise tevek reached by atl were relatively low and led to a lower observed maximal oxygen uptake (VOp max), than predicted uptake (19.6 f 0.5 vs. 37.9 f 0.6 ml&g: p < 0.001). Observed VOz mu; values correlated strongly with the Pugh score, wbicb reflects the degree of liver failure (r = -0.571; p < 0.01). Since there were IK) clear cardiac or pulmonary causes to explain the decrease in work capacity, these observations suggest that liver cirrhosis might induce or be accompanied by muscular impairment. VO, max, which teems to decline with the functional severity of the disease, may be a u&d index fen evaluatingtbe capacity cd patients for physical rehabilitation.

Many diseases

are known to impair aerobic work ca-

pacity by interfering with normal metabolic cadiovascular ventiiatory coupling, which is orgtied so as to fulfit exercise requirements (1). Aerobic work capacity is estimated

by the maximal

oxygen

uptake

index used in clinical practice (for instatw, plaints) to express the functional severity

(VO, ma).

an

in heart cornof the disease

over, alcohol abuse, which is usually the origin of &hosis, may induce myopathy which is not necessarily reverbible when the abuse ceases (9). Consequently, the aim of this study was to evaluate VO, max in well-compensated cirrhotic patients, to determine whether or not aerobic work capacity is related to the severity of the disease.

(2). Although weakness and exercise intolerance are common in patients with chronic liver diseases, aerobic work capacity has never been extensively studied under these conditions. Lung disorders have been observed in liver cirrhosis, but they are relatively mild, both at rest and

Twenty four male patients were enrolled in this study; all were informed of the possible risks involved in the exercise testing and gave their consent before participat-

during exercise (3-6). Furthermore. liver failure involves many metabolic and hormonal abnomalities, concerning, in particular, the regulation of lipid and carbohydrate metabolism, and one may wonder whetba such abnommlit& help to induce muscular impairment (7.8). More-

ing. The aim of the study was approved by the Ethics Committee of the Henri Mondor Hospital. Liver cirrhosis was diagnosed from the usual clinical, bic4ogical and endosmpic signs of portal hypertension and liver failure. It was histologically proven in 18 cases,

Patiemtsand Me(hada

164

B. CAMpILL

and lesions of mild alcoholic hepatitis were observed in seeven cases. The aetiology of cirrhosis was alcoholism in 23 cases

and post-viral

the patients

hepatitis

had exhibited

h ox. at least

Before

the study,

all

in one. All the patients

were hospitalized for several weeks in a Readaptation Unit for Metabolic and Digestive Disease and had recovered a good clinical seizure

condition by the time the exercise teal was performed, a few days before their discharge from hospital. Nine patients had mild ascites at the time of the study. The severity of their disease was assessedby the Pugh Score (10). Nutritional calculated

status from

was assessed

the

arm

by the muscular

muscle

area

maas,

according

to

et al. (11). Triceps skinfold thickness and arm muscle circumferencewere measured with a Harpenden call@. Anthmpometric measurements (Table 1) included weight, height, body mass index (weightmeighti) and muscular mass. The biological parameters measured (Table 2) were the levels of haemoglobin, albumin and Heymsfield

prealbutnin,

None of

time, bilitubi

prorhromhin

the patients

had severe

and Pugh Score.

pulmonary

illness

but

had had pleuropulmonary tuberculosis many years ago, Each patient underwent pulmonary function tests before exercise (results given inTable 3). In the five patients who had a bronfour had a history of mild bronchitis

chial or pulmonary cant mechanical

disease,

veutilatory

and one

we observed

mild but signifi-

impairment,

compared

tore-

of the other patients. (FEV, lis: 1.92 f 0.1 vs. 3.09 f 0.1, respectively,p < 0.001). However, all these five patients had ncmnal arterial blood gases at the time of the study. None of the 24 patients displayed any signs of cardiovascular disease or of any other chronic diseases such as diabetes mellitus, dysthryroidism,canceror renal impairment, and nune was taking any drug known to impair pulmottatyor cardiacfunction at rime of the study. suits

Exercise TABLE

Observed Ref.values HaemopJobia(gldl) Atbumin (@I Prcalbumin (gil)

Prothrombin time(sProlonged) Btlimbin (urn&l) PwbQo=

11.7 * 0.3 29.8zt 1.1 0.10 k 0.01 3.8iO.6 2.51 + 3.1 7.2zkO.3

14-M 40-45 0.28-0.32 s20 -

hours after the patients had finished their usual breakfast. Before exercise,they all had at least l/z hour of rest in the position. The exercise was performed on a treadmill. Maximal oxygen uptake was determined by serial 3min bouts of work at incremental speeds and grades, until subjective exhaustion. The protocol used was similar to

sitting

that described by Bruce (12). The speed and grades were the same for all patients. Ventilatory parameters were measuredduring the third minute of each stage. EKG was continuously monitored throughout the test. While it was in progress, the subjectsbreathed through a Hans-Rudolf valve (dead space of 120ml) equipped with a mouth-piece and nose-clip. Ventilatmy and gas exchangedata were obtained by an open circuit ia which a

pttetunotachograph(Fleisch No. 3) was positioned on the inspiratory tubing with a differential pressure transducer (Validyne PM45). The expiratory hibiig was attached to a mixing box (8 I) and the mixed expired air was analysed by a mBp spectrometer (Centronics MGA ZOD).The pne.umatachographand mass spectrometer were calibmted before each exercise. All the attalogue signals were converted at 20 Hz, and conventional calculations (11) and one-line prinrittg were performed with a PDP 11/23 Computer (Digital Equipment Corporation). Data were recorded during the third minute of every increment of exercise, aad values were averaged over 1 min. Pulmonary

function

tests were measured

using a

closed-circuit spirometer (Mijnhatdt, The Netherlands); blood gases were measured with an ABUT Radiometer (Denmark).

testing was performed in the morning, about 3 TABLE

1

Age and aathmpomelric data for 24 cirrhotic patients who prfomred I graded exercise test Weight (kg)

Height (m)

Bhw

(Yr) 44.8 f 1.4

64.5 * 1.8

1.69 & 0.01

22.6 f 0.6

Age

2

one severe complica-

tion of their disease: ascites in twelve cases, oesophageal vaticeal bleeding in ten, severe sepsis (i.e., spontaneous bacterial peritonitis or septicaemia) in three. gastroduodenal bleeding in one, subdural haematoma in one attd epileptic

TABLE

et al.

XI.5 + 0.9

yadedexercise

Observed

Percen1age Of

3.68 + 0.13 2.82 * 0.13

82.4 f 1.h 82.2 f 3.ff

Predicted

Muscular mass Z$ty

’ Body mass index (!q(m height)-‘&).

3

Pulmonary function for 24 cirrhotic patients during

VC (I) FEV, (Vs)

VC = vital capacity (kBTFS): FEV,: tamed expirarory v&me, second (I.BTPSI. ’ % of the ptiicred values.

1st

165 To awss the effect of bed rest and inactivity on the reduction of VO, max. four ptttients were included in a physical training programme. For 4-5 weeks, 5 days a week. they exercised for 45-60 min on a bicycle or treadmill, as they preferred, at SO-60% of their VO, max. After completing the programma, the four patients performed a maximal exercise test with the same protocol as that dexribed above. Predicted VOz max were calculated according to Bruce et al. (13) and predicted heart rate max was from the formula 210-0.66 x age (14); fUnctional aemhic impaimtent was obtained from the formula 1CO+‘02 max predictedV&man obse~ed)lVO~ max predicted.

Results are given as means & SE. Statistical analysis was performed with the unpaired Student’s t-test and least-square regression analysis. Pvalues of less than 0.05 were considered signiiicant.

For both oxygen uptake and heart rate (Vo, max and HR max), the pwiieted values were signiiicantly higher than the observed values @ < 0.001) (Table 4). Furthermore, there was a signiftcant correbnion between these two parameters (I = 0.487; p
between functional aerobic impairment and the Pugh Score (r = 0.693,~ 4 0.001) (Fig. I). As regards the four patients who completed the physical training programtne, VO, max remained unchanged in two, but increased in the two others by 21.2 and 27.5%, respectively; as in the rest of tbe group, the VO, max values observed in these four patients remained distinctly lower than those predicted. lo the two patients in whom VOz max increased, muscular mass increased by 20 and 18%. respectively, but other biologifal parameters remained unchanged. Fbwlly, clinical condilion, assessed by the Pugh Score, remained unchanged in two of these patiena but improved in the two others. 7he nine subjats who bad ascites exbibited the same V& max and HR max as the other patients (ER max beatsimin: 132 * 6.7 vs. 143 + 6.2; VO, max ml&: lg.6 f 1.0”s. 19.9 f 0.6).

pairment, VO, max did not differ from that of the 19 other patients (ml&: 20.3 f 1.2 vs. 19.2 f 0.6, respectively, not si@icant). Observed

VO, max values correlated

stnmgly with the

Pugh Score ittdexof disease severity (r = 0.571,~ c 0.01). but did not correlate with either muscular mass or the haemoglobin kvel.

Especially

significant was the correlation

This study showsthat

even when cirrhotic patientspres-

ent with a weU.eompensared

clioical condition.

they are

unable to reach high kvels of graded exercise, and tbht maximal oxygen uptake during sueb exercise is low. One of the difficulties encountered in exercise testing such as that carried oat in this study is that there is no objective index to indicate when the patient has really reached maximal work capacity. The symptoms which limit this capacity are obviously subjective; our patients essentially complained of leg fatigue at the end of exezcise and were unable to perform one stage more, although we strongly urged them to do LD. A rise in heart rate during this kind of exercise testing may give an objective indicttion of the level reached at the end of exe&e. In most of our patients,

the observed HR max values were low com-

166 pared to those predicted, which is surprising, because they usually exhibited an increased sympathetic activity, et least at rest (15). However, certain ObserVatiOnS prompted us ro consider that the patients were in fact probably close ro their maximal work capacity when they stopped exercising. As in normal subjects, HR miu and

who showed that VO, max rises as normal nutri ion is restored (20). In the present work, anthropometic measurements indicatcd a decrease in muscular mass, but it wes relatively limited, and at the time of the study, our patients had recovered a relatively good nutritional condition. Moreover, no correlation was found between VO,

V02 max correlated linearly and signiticantly in all 24 patients, which seems to indicate that they had not reached their cerdiovascular limit when they stopped exercise. Six patients behaved differently because they had e higher BR mex than the others, i.e., close to their predicted values, although their peak oxygen uptake was in the same low range as that of the others. It is therefore proba-

max and muscular mess. The Pugh Score index, which reflects impairment of liver function was the only parameter which was strongly correlated with the VO, max. The reason for this observation is not obvious. Besides the effects of bed rest mmtioned above, there are three possible explanations,

ble that our patients reached, or were close to their actual maximal work capacity, but we have no clear evidence lo explain why in most ceses their HR levels did not reach those usually observed under such conditions of eXerCiM. Perhaps the explanation is related to 8-adrenoceptor responsiveness which, when assessed by isoprenaline semitivity, alters in cirrhotics, as shorm by Ramon et al. (16). Our results for oxygen uptake agree with thw of Ritland et al. (17) who also observed low peak VO, mex values in response to graded exercise. However, in their work, VO, mex was deduced from HR and was not measured directly. Several factors might help to reduce aerobic work capacity, including bed rest, inactivity and acute illness (18). In the present study, all the patients had been hospitalized for severrd weeks when the test was performed. At enrolment, they were alert, and presented with a well-mmpensated clinical condition. Even though rest might have affected VO, max, it cannot have been responsible for all the results reported in this study. Moreover, the four patients who underwent physical training displayed peak oxygen consumption which either did not change or only

which especiallyrelate to muneular!imtion: (i) The lactic acid produced during exercise might not have been cleared by the liver and might therefore have caused weakness end exhaustion. In fact, however, lactate eccumulation in the blood during graded exercise was probably small in our patients, es their exercise levels were relatively low end they were never observed to reach the enaerobic threshold; (ii) we recently showed (21) that hyperinsulinemia, which is present in liver cirrhosis, induces the blocked= of lipid mobiliiation. Therefore, to sustain the workload imposed by exercise, the patients mainly used c&dating glucose, and hypoglycemia was frequmtly observed et the end of exercise. We may also assume that they used most of the glycogen stored in the muscles and may have experienced glycogen breakdown: (iii) lastly, the abnormalities of muscular functioning involved in’ liver failure have not yet been extensively investigared, but Moller et al., who examined muscle biopsies from ten cirrhotic patients, reported a reduction in rbe level of energy-rich phosphagen metabolites, a rise in the water Ievel end a decline in the concentration of magnesium (22). Moreover, it is well documented that alcoholic myopathy may cause certain defects which are not ehva~s reversible

rose moderately. Here again, our results agree with those of Ritland et

with the cessation of alcohol abuse (9). To sum up, it was striking in the present

al. (19), who subjected

that the index reflecting liver failure (i.e., the Pugh Score) exhibited a correlation with the patients’ ability to per.

nine patients to a physical training

progranune of 4-5 weeks or lo-12 weeks. This resulted in average rises of 19 and 29% in the V02 max of the respective groups. Although these increases arenot negligible, they are, like our values, still far from the normal range. Anacmia is one of the diseases known to reduce maxintum 01 uptake (1). Here, the mild anaemia exhibited

investigation

fan.. sustained exercise. This link would imply that the maximum oxygen consumption observed during graded exercise might reflect both the degree of liver failure and the presence of a type of myopathy to which we propose to give the term %irrhotic myopathy’.

by

our patients probably had some effect in this respect, but no correlation was found between haemoglobin levels and observed VO, ma% so that we may justifiably assume that anaemia had little or no effet:t. Protein-caloric undemoudshment clearly also affects aerobic work capacity, as established by Barac-Nieto,

The authors gratefully acknowledge rhc secretarial assistance of Mrs M. Roulet and thank Mrs M. Dreyfus for revising the English of the manuscript.

?.“BMAxIMAL

EXEBCBE

AND

LIVER

CIRBHOSIS

167