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Abnormal tissue oxygenation in patients with cirrhosis and liver failure
98
Journal of Hepatology, 1988: 7:98-105
Elscvier HEP 00421
Abnormal tissue oxygenation in patients with cirrhosis and liver failure
R i c h a r d M o r e a u I , S a m u e l S. L e e 2, T h i e r r y S o u p i s o n 1, Jacqueline Roche-Sicot 3 and Christian Sicot ~ IService de REanimation et de Mddecine d'Urgence, HOpital Emile Roux, Eaubonne, 'Unite de Recherches de Physiopathologie HEpatique (INSERM U-24), HOpital Beau]on, Clichy and ~Servicede M~decine lnterne, HOpital Emile Roux, Eaubonne (France)
(Received 12 January 1988) (Accepted 17 February 1988)
Summary Systemic haemodynamic and hepatic venous pressures, arterial and mixed venous gases and arterial lactate concentration were measured in 35 patients with histologically proven alcoholic cirrhosis who had been classified into three groups (A, B and C). Eight alcoholic patients without cirrhosis on liver biopsy were also studied. Compared with group A patients, group C patients had significantly higher hepatic venous pressure gradient, cardiac index, O2 transport and arterial lactate concentration and significantly lower systemic vascular resistance, arteriovenous O, content difference and 02 uptake. In group B patients, corresponding values fell between those of groups A and C. Group A patients, unlike group C patients, were not significantly different from patients without cirrhosis with respect to cardiac index, systemic vascular resistance, O 2 uptake and arterial lactate concentration. Our results suggest that in patients with cirrhosis, liver failure-associated hyperdynamic circulation may be accompanied by an abnormal tissue oxygenation.
Introduction Hyperdynamic systemic circulation is a well-documented alteration associated with cirrhosis [1-5] and with liver failure [6,7]. Recently, features compatible with the presence of a tissue hypoxia have been observed in association with hyperdynamic circulation in patients with fulminant hepatic failure [8,9]. These features were more marked in patients who subse-
quently died [9]. The aim of the present study was to determine whether, in patients with cirrhosis, liver failure-associated hyperkineticism may be accompanied by abnormal tissue oxygenation.
Patients and Methods Thirty-five patients with histologically proven al-
Correspondence: Dr R. Moreau, Service de Rfanimation et de Mfdecine d'Urgence, H6pital Emile Roux, 95602 Eaubonne Cedex,
France. 0168-8278/88/$03.50 (~ 1988 Elsevier Science Publishers B.V. (Biomedical Division)
TISSUE OXYGENATION IN CIRRHOSIS
99
coholic cirrhosis were investigated. They were admitted to the hospital for variceal bleeding (20 patients), ascites (9 patients) and hepatic encephalopathy (6 patients). The severity of liver failure was assessed on the day of the h a e m o d y n a m i c study by means of Pugh's score [10]. Patients whose score totailed five. six or seven were considered to be in good condition (group A ) , those with scores of eight and nine were considered m o d e r a t e (group B) and patients with a score of ten to fifteen were considered to be in p o o r condition (group C). In this study, there were 13 group A (3 had five points, 3 had six points and 7 had seven points), 8 group B (6 had eight points and 2 had nine points) and 14 group C (3 had ten points, 5 had eleven points, 5 had twelve points and 1 had fourteen points). Characteristics and l a b o r a t o r y values are shown in Table I. All patients had oesophageal varices, normal renal function and euglycaemia. They were, when ascites was present, on a sodium-restricted diet, but diuretics and vasoactive drugs were stopped at least 1 week before the study. Patients admitted for bleeding were investigated at least 10 days after cessation of the h a e m o r r h a g e and in a stable h a e m o d y n a m i c condition. No patients had
a septic complication or h e p a t o c a r c i n o m a . Eight alcoholic patients without histologically proven alcoholic cirrhosis were also investigated. These patients were admitted to the hospital for t r e a t m e n t of chronic alcoholism. Characteristics and l a b o r a t o r y values are shown in Table 1. No patient received fl-adrenergic antagonists or sympatholytic drugs. Patients were investigated at least 14 days after admission. All patients with or without cirrhosis gave oral informed consent to the investigation described below which was done at the same time as transvenous liver biopsy [11]. None had signs of recent alcohol intake or withdrawal syndrome. A r t e r i a l hypertension, severe chronic obstructive lung disease and ischaemic card i o m y o p a t h y were absent. The h a e m o d y n a m i c studies were p e r f o r m e d in patients in the supine position after an overnight fast. U n d e r local anaesthesia, a vessel dilator with a polypropylene sheath (Desilets; Vygon, E c o u e n , France) was introduced into the lumen of the right internal jugular vein in o r d e r to introduce different catheters successively. The gradient between wedged and free hepatic venous pressures (hepatic venous pressure gradient) was measured with a 7F catheter (Cordis
TABLE 1 CHARACTERISTICS AND LABORATORY VALUES OF ALCOHOLIC PATIENTS WITHOUT CIRRHOSIS AND OF PATIENTS WITH ALCOHOLIC CIRRHOSIS CLASSIFIED ACCORDING TO THE DEGREE OF LIVER FAILURE BY MEANS OF PUGH'S CLASSIFICATION Patients without cirrhosis No. of patients No. of patients who previously bled Age (yr)`~ Sex (male/female) Body weight (kg)`''b Body height (cm) ~' Body surface area (m2)'' Serum bilirubin ( u m o l / l ) ~ (normal wdue < 20,umol/l) Serum albumin (g/l)¢ (normal range: 36-48 g/l) Prothrombin time ( %)~ (normal range: 70-100%)
Patients with cirrhosis group A
group B
group C
8 0 46 - 8 8/0 66.7 + 9.3 170 _+6 1.76 -+ 0.12 6 (3-22)
13 7 52 + 10 11/2 68.0 + 11.5 171 + 7 1.76 + 0.16 23 (12-52)
8 5 59 + 6 7/1 76.0 + 19.4 167+8 1.84 + 0.27 27 (21-73)
14 8 53 + 10 9/5 64.3 + 10.1 167+ 10 1.72 + 0.16 87 (39-490)
43 (34-52)
39 (25-51)
29 (22-33)
26 (20-38)
100 (80-100)
62 (51-88)
47 (40-80)
37 (24-53)
Mean + S.D. b Body weight is corrected for patients with ascites (see Patients and Methods section). Median (range).
100 SA, Miami, FL, U.S.A.) introduced into a right hepatic vein under fluoroscopy; the wedged position of the catheter was checked as previously described with contrast medium [12]. Cardiac output was measured in triplicate by thermodilution method with a Swan-Ganz catheter; this catheter was used for measurement of mean right atrial pressure, and for control of pulmonary artery wedged pressure. During the procedure, arterial pressure was measured by an external monitoring sphygmomanometer (Dinamap; Critikon Inc, Tampa, FL, U.S.A.) and heart rate was determined by continuous ECG monitoring. Arterial (radial artery) and mixed venous (pulmonary artery) samples were simultaneously withdrawn after cardiac output determination for immediate measurements of O, tension (Po2) (mmHg), pH (units), CO, tension (Pco2) (mmHg) by specific electrodes (IL 1302, Lexington, MA, U.S.A.) and for measurement of haemoglobin concentration ([Hb]) (g/dl) and of oxyhaemoglobin saturation (So2) (%) by a hemoxymeter (OSM 3; Radiometer Tacussel, Copenhagen). In addition, haemoglobin concentration was checked by means of another method (Coulter counter S+, Chicago, IL, U.S.A.). An arterial sample for the measurement of lactate concentration was kept in ice and immediately analyzed. LLactate concentration was measured in arterial plasma by means of an automated spectrophotometer (model ACA; Du Pont Instruments, Newtown, CT, U.S.A.) using a method derived from that of Marbach and Weft [13]. Cardiac index (CI) (I.min-t.m -2) was calculated by dividing the cardiac output by the body surface area. In patients with ascites we used the corrected weight, i.e., the measured weight at the time of the haemodynamic study minus the estimated weight of ascites. Mean arterial pressure (MAP) (mmHg) was electronically integrated. Systemic vascular resistance index (SVRI) (dynes.s.cm-S.m-2; normal value: 2160 + 240 [14]) was calculated according to the formula: SVRI = ( M A P - mean right atrial pressure) x 80/CI
Arterial O, content (Cao2) (ml/dl; normal range: 15-20 [14]) was calculated by means of the formula:
R. MOREAU et al. Cao2 = ([Hb] x 1.34 x Sao2 ) + (0.003pao2)
Mixed v e n o u s 0 2 content (C~'o2) (ml/dl; normal range: 10-15 [14]) was calculated by means of the same formula: C9o2 = ([Hb] x 1.34 x S~,o2) + (0.003p902)
Oxygen transport ( O 2 T ) (ml.min-l.m-2; normal range: 520-720 [15]) was calculated according to the formula: O2T = Cao2 x CI x 10
Oxygen uptake (Vo2) (ml.min-l.m-2; normal range: 120-160 [15]) was obtained by means of the formula:
Vo2=
(Cao2- C'1,o2) x CI x 10
Arteriovenous O 2 content difference (AVD) (ml/dl; normal range: 3.5-5.0 [14]) was obtained by calculating the difference: AVD = Cao2-
C9o2
Oxygen extraction ratio (O2ext) (%; normal range: 22-30 [14]) was obtained according to the formula: O2ex t -
AVD Cao 2
The results are expressed as means _+ S.D. Data were analyzed by one-way analysis of variance with a Bonferroni correction for multiple comparisons [16]. Correlations were assessed by means of the Pearson coefficient.
Results
Systemic and hepatic haemodynamic values in patients without cirrhosis and in patients with cirrhosis who were classified according to the degree of liver failure are shown in Table 2. There was no significant difference between the four groups of patients with
TISSUE OXYGENATION IN CIRRHOSIS
101
TABLE 2 SYSTEMIC AND HEPATIC HAEMODYNAMICS IN ALCOHOLIC PATIENTS WITHOUT CIRRHOSIS AND IN PATIENTS WITH ALCOHOLIC CIRRHOSIS CLASSIFIED ACCORDING TO THE DEGREE OF LIVER FAILURE BY MEANS OF PUGH'S CLASSIFICATION Values are means + S.D. Patients without cirrhosis Heart rate (bpm) Mean arterial pressure (mmHg) Cardiac index (I.min-Lm-2) Systemic vascular resistance index (dyne.s.cm-5.m -2) Wedged hepatic venous pressure (mmHg) Free hepatic venous pressure (mmHg) Hepatic venous pressure gradient (mmHg)
Patients with cirrhosis group A
group B
group C
76 + 10 99+ 16 3.89 + 1.20 2023 _+682
76 + 11 89+11 3.82 + 0.60 1881 + 365
86 + 13 93 + 8 4.12 + 0.50 1790 + 285
95 + 86+ 5.57 + 1202 +
8.2 + 4.1 4.2 + 4.0 4.0 + 2.1
20.7 + 5.0** 3.3 + 2.9 17.4 + 4.7**
28.1 + 7.0**'* 5.8 + 3.6 22.3 + 4.3 **'~
31.0 + 5.8*** 6.3 + 5.0 24.7 + 3.1"**
10"** 13 0.70*'*** 212"**'*
* Significantly different from group A (P < 0.01). ** Significantly different from patients without cirrhosis (P < 0.01). ' Significantly different from group B (P < 0.01). Significantly different from group A (P < 0.05).
respect to mean arterial pressure and free hepatic venous pressure. H e a r t rate, cardiac index, systemic vascular resistance index, w e d g e d hepatic venous pressure and hepatic venous pressure gradient were significantly different between group C and group A patients and between group C patients and patients without cirrhosis. Cardiac index and systemic vascular resistance index were significantly different between group C and group B patients. W e d g e d hepatic venous pressure and hepatic venous pressure gradient were significantly different between group B and group A patients, between group B patients and patients without cirrhosis and between group A patients and patients without cirrhosis. H e p a t i c venous pressure gradient was significantly c o r r e l a t e d with cardiac index in all patients with cirrhosis (r = 0.582; P < 0.001). Oxygen contents and acid-base balance values in patients without cirrhosis and in those with cirrhosis who were classified according to the degree of liver failure are shown in Table 3. T h e r e was no significant difference between the four groups with respect to arterial and mixed venous 02 tensions, arterial oxyhaemoglobin saturation, mixed venous 02 content, arterial p H , arterial carbon dioxide tension and arterial bicarbonate concentration. A r t e r i a l 02 content
and haemoglobin concentration were significantly different between group A patients and patients without cirrhosis and between group C patients and patients without cirrhosis. Mixed venous oxyhaemoglobin saturation was significantly different between group C and group A patients and between group C patients and patients without cirrhosis. Values of O 2 transport and utilization in patients without cirrhosis and in those with cirrhosis who were classified according to the degree of liver failure are shown in Table 4. Oxygen transport was significantly different between g r o u p C and group A patients. Oxygen uptake, arteriovenous 02 content difference, 02 extraction ratio and arterial lactate concentration were significantly different between group C and group A patients and between group C patients and patients without cirrhosis. A r t e r i o v e n o u s 02 content difference and arterial concentration of lactate were significantly different between group C and group B patients. A r t e r i o v e n o u s 02 content difference was significantly different between group B patients and patients without cirrhosis. In all patients with cirrhosis there was a significant correlation between systemic vascular resistance index and 02 extraction ratio (r = 0.602; P < 0.001) and arterial lactate concentration (r = -0.517; P < 0.01).
102
R. MOREAU et al.
TABLE 3 O, CONTENT AND ACID-BASE BALANCE IN ALCOHOLIC PATIENTS WITHOUT CIRRHOSIS AND IN PATIENTS WITH ALCOHOLIC CIRRHOSIS CLASSIFIED ACCORDING TO THE DEGREE OF LIVER FAILURE BY MEANS OF PUGH'S CLASSIFICATION Values are means _+ S.D. Patients without cirrhosis Arterial O, tension (mmHg) Arterial oxyhaemoglobin saturation (%) Arterial O_, content (ml/dl) Mixed venous O_, tension (mmHg) Mixed venous oxyhacmoglobin saturation (c4) Mixed venous O, content (ml/dl) Haemoglobin concentration (g/dl) Arterial pH (units) Arterial carbon dioxide tension (mmHg) Arterial bicarbonate concentration (mmol/I)
84.0 + 13.(I 95.7 + 7.0 17.1 _+ 2.0 39.7 _+ 6.0 72.2 _+ 8.2 12.9 _+ 2.3 13.2 _+ 1.4 7.41 + (I.(13 39.3 _+ 0.3 25.6 + 1.5
Patients with cirrhosis group A
group B
group C
88.8 _+ 12.0 97.0 _+ 1.0 14.5 -+ 2.0* 39.0 _+ 3.0 73.2 + 4.5 10.8 _+_ 1.9 11.(1 _+ 1.4" 7.39 _+ [).[)2 36.4 _+ 2.8 22.6 _+ 2.0
82.0 + 9.(1 96.3 + 1.4 14.9 _+ 2.[1 40.0 +_ 2.3 76.2 _+_3.1 11.7 _+ 2.[I 11.3 + 1.5 7.44 _+ 0.01 34.1 + 1.9 23.0 _+ 1.2
75.0 + 16.0 93.7 + 6.7 13.1 -+ 1.8"* 42.[I + 4.3 78.7 + 6.0 *~ 11.(I _+ 1.7 10.3 -+ 1.7"* 7,42 + 0.03 35.1 + 5.6 22.7 + 4.4
* Significantly different from patients without cirrhosis (P < 0.05). ** Significantly different from patients without cirrhosis (P < 0.01). : Significantly different from group A (P < 0.05).
Discussion
s h o w s t h a t p o r t a l p r e s s u r e ( e s t i m a t e d by w e d g e d h e p a t i c v e n o u s p r e s s u r e ) is h i g h e r in p a t i e n t s with se-
T h e results o f the p r e s e n t s t u d y are in a g r e e m e n t with the view t h a t , in p a t i e n t s with c i r r h o s i s , liver
vere liver failure t h a n in t h o s e with g o o d h e p a t i c f u n c t i o n [7].
failure is a s s o c i a t e d with a h y p e r d y n a m i c s y s t e m i c
O u r s t u d y d e m o n s t r a t e s t h a t , w h e n liver failure
c i r c u l a t i o n , i.e., with an e l e v a t e d c a r d i a c o u t p u t a n d
progresses, systemic 0 2 uptake, i.e., whole body O ,
a low s y s t e m i c v a s c u l a r r e s i s t a n c e [6,7]. T h e p r e s e n t
c o n s u m p t i o n , d e c r e a s e s w h e r e a s t h e r e is an i n c r e a s e
findings are also in k e e p i n g with a r e c e n t s t u d y w h i c h
in 0 2 t r a n s p o r t ( d u e to the a u g m e n t a t i o n in c a r d i a c
TABLE 4 O, TRANSPORT AND UTILIZATION IN ALCOHOLIC PATIENTS WITHOUT CIRRHOSIS AND IN PATIENTS WITH ALCOHOLIC CIRRHOSIS CLASSIFIED ACCORDING TO THE DEGREE OF LIVER FAILURE BY MEANS OF PUGH'S CLASSIFICATION Values are means + S.D. Patients without cirrhosis 0 2 transport (ml.min-l.m --') 0 2 uptake (ml-min-l-m-2) Arleriovenous O, content difference (ml/dl) O, extraction ratio (%) Arterial lactate concentration (mmol/l)
674 + 154 154 + 28 4.2 + 1.2 24.0+8.1 0.87 _+ 0.42
* Significantly different from group A (P < 0.05). ** Significantly different from patients without cirrhosis (P < 0.(11 ). Significantly different from patients without cirrhosis (P < 0.05). Significantly different from group A (P < 0.01). L Significantly different from group B (P < 0.01).
Patients with cirrhosis group A
group B
group C
553 + 100 138 _+ 14 3.7 + (I.5 25.0+4.5 [I.79 + 0.27
614 + 100 128 _+ 19 3.2 + (I.3~ 21.0+3.4 0.87 + 0.29
732 _+ 120" 117 _+_ 18"** 2.1 + 0 . 3 * * " : ' 16.1 __+2.6**'" 2.17 + 0.55 **'=''''
TISSUE OXYGENATION IN CIRRHOSIS output). This link between the degree of liver failure and the decrease in 02 consumption had not previously been demonstrated. In this study 02 uptake was calculated (Fick method) and not measured directly by measuring the inspired and expired gas concentrations. However, it has been demonstrated that calculated 02 uptake correlated significantly with measured 02 uptake in clinically stable patients [17]. Our results are in keeping with those of a previous study [1] which demonstrated, in patients with cirrhosis, a discrepancy between a high cardiac output state and a low measured 02 uptake. Two explanations can be proposed. On one hand, the decrease in 02 consumption could be the result of a reduction in 02 needs. Many chronic alcoholic patients are malnourished and malnutrition may reduce metabolic requirements [181. On the other hand, it is possible that 02 consumption decreases, despite a high level of 02 transport, owing to an abnormal limitation of tissue 02 'extraction so that 02 demand remains unsatisfied. Thus, tissue hypoxia may occur. More evidence supports the last hypothesis. First, preliminary results have shown that during pharmacological manipulation of cardiac output in patients with cirrhosis, 02 consumption was abnormally dependent on O_~ transport, even though the latter was as high as or above the level usually considered as normal [19]. This result suggests that tissue 02 extraction might be limited in patients with cirrhosis so that the satisfaction of O, demand becomes dependent on blood flow. A similar relationship has already been described between 02 uptake and O, transport in patients with fulminant hepatic failure
[91. Second, the high mortality in patients with cirrhosis, due to complications, such as variceal bleeding, sepsis or hypoxaemia [20,21], may be due, at least in part, to the aggravation of a preexisting subtle tissue hypoxia. Third, there is a sympathetic hyperactivity in patients with deteriorated liver function [22,23] and elevated catecholamine levels are known to increase whole body O2 demand [24,25]. Thus, in our patients with liver failure, an increase in sympathetic nervous
103 activity could contribute to further increase the imbalance between O~ needs and 02 supply. Fourth, in the present study, an elevated arterial lactate concentration was observed in patients with high-degree liver failure and low values of 02 consumption. This suggests the development of some tissue hypoxia with deterioration of liver function. Blood lactate accumulation has also been noted in the above-mentioned studies in patients with fulminant hepatic failure [8,9]. The augmented level of arterial lactate can be viewed, on the other hand, as the consequence of the hepatic underutilization of lactate due to a reduction in gluconeogenesis by the diseased liver. The association between hypoglycaemia and hyperlactataemia has been demonstrated in patients with liver failure [26]. However, defective hepatic lactate metabolism may be, at least in part, compensated by an increase in lactate utilization by kidney, skeletal muscle and myocardium [27,28]. Furthermore, the disturbance in lactate uptake by the failing liver might be related to hepatic hypoxia [29,30]. Evidence for this was seen in non-cirrhotic animals in which graded tissue hypoxia was followed by a progressive reduction in hepatic uptake of lactate and eventually by a conversion of the liver from a lactate-consuming to a lactate-producing organ [31-34]. Similar findings were observed in normal humans subjected to hypoxaemia [35]. A decrease in hepatic 02 consumption, assessed by organ reflectance spectrophotometry, has been observed in patients with cirrhosis [36]. In the latter study, there was also a correlation between hepatic 02 consumption and certain liver function tests such as serum albumin and prothrombin. Gluconeogenesis, unlike gtycogenolysis, is an O2-consuming process and thus contributes to hepatic 02 demand in patients with cirrhosis [18]. Hepatic gluconeogenesis critically depends on intact mitochondrial function and lactate contributes to gluconeogenesis after its transformation into cytosolic pyruvate and mitochondrial oxaloacetate. Thus, it may be speculated that liver failure is associated with defective lactate processing and hypoglycaemia, both related to a hypoxia-induced decrease in gluconeogenesis.
104 Mechanisms responsible for the limitation of tissue
R. MOREAU et al. rhosis [40].
O2 extraction in patients with cirrhosis and liver fail-
In conclusion, our results suggest that the decrease
ure are unclear. It may be linked to a r t e r i o v e n o u s
in O 2 uptake which, in patients with cirrhosis, accom-
shunting [37]. This is suggested in our patients with
panies liver failure-associated hyperkineticism may
hepatic insufficiency by the low O 2 extraction ratio
reflect an abnormal tissue oxygenation.
and the high mixed venous o x y h a e m o g l o b i n saturation [38] and by the significant correlations of systemic vascular resistance with arterial lactate concentration and O 2 extraction ratio. A leftward shift
Acknowledgements
of the oxyhaemoglobin dissociation curve, by increasing the affinity of h a e m o g l o b in for 02, might
The authors thank D r D. L e b r e c and D r A. Ha-
contribute to the decrease in 02 uptake. H o w e v e r ,
dengue for their critical reading of the manuscript,
evidence for this mechanism remains questionable
D r A. Soulier for examining the liver biopsy speci-
[39] and it is a rightward shift of the dissociation
mens and A. D e f o o r for her expert technical assistance.
curve which is usually observed in patients with cir-
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Journal of Hepatology, 1988: 7:98-105
Elscvier HEP 00421
Abnormal tissue oxygenation in patients with cirrhosis and liver failure
R i c h a r d M o r e a u I , S a m u e l S. L e e 2, T h i e r r y S o u p i s o n 1, Jacqueline Roche-Sicot 3 and Christian Sicot ~ IService de REanimation et de Mddecine d'Urgence, HOpital Emile Roux, Eaubonne, 'Unite de Recherches de Physiopathologie HEpatique (INSERM U-24), HOpital Beau]on, Clichy and ~Servicede M~decine lnterne, HOpital Emile Roux, Eaubonne (France)
(Received 12 January 1988) (Accepted 17 February 1988)
Summary Systemic haemodynamic and hepatic venous pressures, arterial and mixed venous gases and arterial lactate concentration were measured in 35 patients with histologically proven alcoholic cirrhosis who had been classified into three groups (A, B and C). Eight alcoholic patients without cirrhosis on liver biopsy were also studied. Compared with group A patients, group C patients had significantly higher hepatic venous pressure gradient, cardiac index, O2 transport and arterial lactate concentration and significantly lower systemic vascular resistance, arteriovenous O, content difference and 02 uptake. In group B patients, corresponding values fell between those of groups A and C. Group A patients, unlike group C patients, were not significantly different from patients without cirrhosis with respect to cardiac index, systemic vascular resistance, O 2 uptake and arterial lactate concentration. Our results suggest that in patients with cirrhosis, liver failure-associated hyperdynamic circulation may be accompanied by an abnormal tissue oxygenation.
Introduction Hyperdynamic systemic circulation is a well-documented alteration associated with cirrhosis [1-5] and with liver failure [6,7]. Recently, features compatible with the presence of a tissue hypoxia have been observed in association with hyperdynamic circulation in patients with fulminant hepatic failure [8,9]. These features were more marked in patients who subse-
quently died [9]. The aim of the present study was to determine whether, in patients with cirrhosis, liver failure-associated hyperkineticism may be accompanied by abnormal tissue oxygenation.
Patients and Methods Thirty-five patients with histologically proven al-
Correspondence: Dr R. Moreau, Service de Rfanimation et de Mfdecine d'Urgence, H6pital Emile Roux, 95602 Eaubonne Cedex,
France. 0168-8278/88/$03.50 (~ 1988 Elsevier Science Publishers B.V. (Biomedical Division)
TISSUE OXYGENATION IN CIRRHOSIS
99
coholic cirrhosis were investigated. They were admitted to the hospital for variceal bleeding (20 patients), ascites (9 patients) and hepatic encephalopathy (6 patients). The severity of liver failure was assessed on the day of the h a e m o d y n a m i c study by means of Pugh's score [10]. Patients whose score totailed five. six or seven were considered to be in good condition (group A ) , those with scores of eight and nine were considered m o d e r a t e (group B) and patients with a score of ten to fifteen were considered to be in p o o r condition (group C). In this study, there were 13 group A (3 had five points, 3 had six points and 7 had seven points), 8 group B (6 had eight points and 2 had nine points) and 14 group C (3 had ten points, 5 had eleven points, 5 had twelve points and 1 had fourteen points). Characteristics and l a b o r a t o r y values are shown in Table I. All patients had oesophageal varices, normal renal function and euglycaemia. They were, when ascites was present, on a sodium-restricted diet, but diuretics and vasoactive drugs were stopped at least 1 week before the study. Patients admitted for bleeding were investigated at least 10 days after cessation of the h a e m o r r h a g e and in a stable h a e m o d y n a m i c condition. No patients had
a septic complication or h e p a t o c a r c i n o m a . Eight alcoholic patients without histologically proven alcoholic cirrhosis were also investigated. These patients were admitted to the hospital for t r e a t m e n t of chronic alcoholism. Characteristics and l a b o r a t o r y values are shown in Table 1. No patient received fl-adrenergic antagonists or sympatholytic drugs. Patients were investigated at least 14 days after admission. All patients with or without cirrhosis gave oral informed consent to the investigation described below which was done at the same time as transvenous liver biopsy [11]. None had signs of recent alcohol intake or withdrawal syndrome. A r t e r i a l hypertension, severe chronic obstructive lung disease and ischaemic card i o m y o p a t h y were absent. The h a e m o d y n a m i c studies were p e r f o r m e d in patients in the supine position after an overnight fast. U n d e r local anaesthesia, a vessel dilator with a polypropylene sheath (Desilets; Vygon, E c o u e n , France) was introduced into the lumen of the right internal jugular vein in o r d e r to introduce different catheters successively. The gradient between wedged and free hepatic venous pressures (hepatic venous pressure gradient) was measured with a 7F catheter (Cordis
TABLE 1 CHARACTERISTICS AND LABORATORY VALUES OF ALCOHOLIC PATIENTS WITHOUT CIRRHOSIS AND OF PATIENTS WITH ALCOHOLIC CIRRHOSIS CLASSIFIED ACCORDING TO THE DEGREE OF LIVER FAILURE BY MEANS OF PUGH'S CLASSIFICATION Patients without cirrhosis No. of patients No. of patients who previously bled Age (yr)`~ Sex (male/female) Body weight (kg)`''b Body height (cm) ~' Body surface area (m2)'' Serum bilirubin ( u m o l / l ) ~ (normal wdue < 20,umol/l) Serum albumin (g/l)¢ (normal range: 36-48 g/l) Prothrombin time ( %)~ (normal range: 70-100%)
Patients with cirrhosis group A
group B
group C
8 0 46 - 8 8/0 66.7 + 9.3 170 _+6 1.76 -+ 0.12 6 (3-22)
13 7 52 + 10 11/2 68.0 + 11.5 171 + 7 1.76 + 0.16 23 (12-52)
8 5 59 + 6 7/1 76.0 + 19.4 167+8 1.84 + 0.27 27 (21-73)
14 8 53 + 10 9/5 64.3 + 10.1 167+ 10 1.72 + 0.16 87 (39-490)
43 (34-52)
39 (25-51)
29 (22-33)
26 (20-38)
100 (80-100)
62 (51-88)
47 (40-80)
37 (24-53)
Mean + S.D. b Body weight is corrected for patients with ascites (see Patients and Methods section). Median (range).
100 SA, Miami, FL, U.S.A.) introduced into a right hepatic vein under fluoroscopy; the wedged position of the catheter was checked as previously described with contrast medium [12]. Cardiac output was measured in triplicate by thermodilution method with a Swan-Ganz catheter; this catheter was used for measurement of mean right atrial pressure, and for control of pulmonary artery wedged pressure. During the procedure, arterial pressure was measured by an external monitoring sphygmomanometer (Dinamap; Critikon Inc, Tampa, FL, U.S.A.) and heart rate was determined by continuous ECG monitoring. Arterial (radial artery) and mixed venous (pulmonary artery) samples were simultaneously withdrawn after cardiac output determination for immediate measurements of O, tension (Po2) (mmHg), pH (units), CO, tension (Pco2) (mmHg) by specific electrodes (IL 1302, Lexington, MA, U.S.A.) and for measurement of haemoglobin concentration ([Hb]) (g/dl) and of oxyhaemoglobin saturation (So2) (%) by a hemoxymeter (OSM 3; Radiometer Tacussel, Copenhagen). In addition, haemoglobin concentration was checked by means of another method (Coulter counter S+, Chicago, IL, U.S.A.). An arterial sample for the measurement of lactate concentration was kept in ice and immediately analyzed. LLactate concentration was measured in arterial plasma by means of an automated spectrophotometer (model ACA; Du Pont Instruments, Newtown, CT, U.S.A.) using a method derived from that of Marbach and Weft [13]. Cardiac index (CI) (I.min-t.m -2) was calculated by dividing the cardiac output by the body surface area. In patients with ascites we used the corrected weight, i.e., the measured weight at the time of the haemodynamic study minus the estimated weight of ascites. Mean arterial pressure (MAP) (mmHg) was electronically integrated. Systemic vascular resistance index (SVRI) (dynes.s.cm-S.m-2; normal value: 2160 + 240 [14]) was calculated according to the formula: SVRI = ( M A P - mean right atrial pressure) x 80/CI
Arterial O, content (Cao2) (ml/dl; normal range: 15-20 [14]) was calculated by means of the formula:
R. MOREAU et al. Cao2 = ([Hb] x 1.34 x Sao2 ) + (0.003pao2)
Mixed v e n o u s 0 2 content (C~'o2) (ml/dl; normal range: 10-15 [14]) was calculated by means of the same formula: C9o2 = ([Hb] x 1.34 x S~,o2) + (0.003p902)
Oxygen transport ( O 2 T ) (ml.min-l.m-2; normal range: 520-720 [15]) was calculated according to the formula: O2T = Cao2 x CI x 10
Oxygen uptake (Vo2) (ml.min-l.m-2; normal range: 120-160 [15]) was obtained by means of the formula:
Vo2=
(Cao2- C'1,o2) x CI x 10
Arteriovenous O 2 content difference (AVD) (ml/dl; normal range: 3.5-5.0 [14]) was obtained by calculating the difference: AVD = Cao2-
C9o2
Oxygen extraction ratio (O2ext) (%; normal range: 22-30 [14]) was obtained according to the formula: O2ex t -
AVD Cao 2
The results are expressed as means _+ S.D. Data were analyzed by one-way analysis of variance with a Bonferroni correction for multiple comparisons [16]. Correlations were assessed by means of the Pearson coefficient.
Results
Systemic and hepatic haemodynamic values in patients without cirrhosis and in patients with cirrhosis who were classified according to the degree of liver failure are shown in Table 2. There was no significant difference between the four groups of patients with
TISSUE OXYGENATION IN CIRRHOSIS
101
TABLE 2 SYSTEMIC AND HEPATIC HAEMODYNAMICS IN ALCOHOLIC PATIENTS WITHOUT CIRRHOSIS AND IN PATIENTS WITH ALCOHOLIC CIRRHOSIS CLASSIFIED ACCORDING TO THE DEGREE OF LIVER FAILURE BY MEANS OF PUGH'S CLASSIFICATION Values are means + S.D. Patients without cirrhosis Heart rate (bpm) Mean arterial pressure (mmHg) Cardiac index (I.min-Lm-2) Systemic vascular resistance index (dyne.s.cm-5.m -2) Wedged hepatic venous pressure (mmHg) Free hepatic venous pressure (mmHg) Hepatic venous pressure gradient (mmHg)
Patients with cirrhosis group A
group B
group C
76 + 10 99+ 16 3.89 + 1.20 2023 _+682
76 + 11 89+11 3.82 + 0.60 1881 + 365
86 + 13 93 + 8 4.12 + 0.50 1790 + 285
95 + 86+ 5.57 + 1202 +
8.2 + 4.1 4.2 + 4.0 4.0 + 2.1
20.7 + 5.0** 3.3 + 2.9 17.4 + 4.7**
28.1 + 7.0**'* 5.8 + 3.6 22.3 + 4.3 **'~
31.0 + 5.8*** 6.3 + 5.0 24.7 + 3.1"**
10"** 13 0.70*'*** 212"**'*
* Significantly different from group A (P < 0.01). ** Significantly different from patients without cirrhosis (P < 0.01). ' Significantly different from group B (P < 0.01). Significantly different from group A (P < 0.05).
respect to mean arterial pressure and free hepatic venous pressure. H e a r t rate, cardiac index, systemic vascular resistance index, w e d g e d hepatic venous pressure and hepatic venous pressure gradient were significantly different between group C and group A patients and between group C patients and patients without cirrhosis. Cardiac index and systemic vascular resistance index were significantly different between group C and group B patients. W e d g e d hepatic venous pressure and hepatic venous pressure gradient were significantly different between group B and group A patients, between group B patients and patients without cirrhosis and between group A patients and patients without cirrhosis. H e p a t i c venous pressure gradient was significantly c o r r e l a t e d with cardiac index in all patients with cirrhosis (r = 0.582; P < 0.001). Oxygen contents and acid-base balance values in patients without cirrhosis and in those with cirrhosis who were classified according to the degree of liver failure are shown in Table 3. T h e r e was no significant difference between the four groups with respect to arterial and mixed venous 02 tensions, arterial oxyhaemoglobin saturation, mixed venous 02 content, arterial p H , arterial carbon dioxide tension and arterial bicarbonate concentration. A r t e r i a l 02 content
and haemoglobin concentration were significantly different between group A patients and patients without cirrhosis and between group C patients and patients without cirrhosis. Mixed venous oxyhaemoglobin saturation was significantly different between group C and group A patients and between group C patients and patients without cirrhosis. Values of O 2 transport and utilization in patients without cirrhosis and in those with cirrhosis who were classified according to the degree of liver failure are shown in Table 4. Oxygen transport was significantly different between g r o u p C and group A patients. Oxygen uptake, arteriovenous 02 content difference, 02 extraction ratio and arterial lactate concentration were significantly different between group C and group A patients and between group C patients and patients without cirrhosis. A r t e r i o v e n o u s 02 content difference and arterial concentration of lactate were significantly different between group C and group B patients. A r t e r i o v e n o u s 02 content difference was significantly different between group B patients and patients without cirrhosis. In all patients with cirrhosis there was a significant correlation between systemic vascular resistance index and 02 extraction ratio (r = 0.602; P < 0.001) and arterial lactate concentration (r = -0.517; P < 0.01).
102
R. MOREAU et al.
TABLE 3 O, CONTENT AND ACID-BASE BALANCE IN ALCOHOLIC PATIENTS WITHOUT CIRRHOSIS AND IN PATIENTS WITH ALCOHOLIC CIRRHOSIS CLASSIFIED ACCORDING TO THE DEGREE OF LIVER FAILURE BY MEANS OF PUGH'S CLASSIFICATION Values are means _+ S.D. Patients without cirrhosis Arterial O, tension (mmHg) Arterial oxyhaemoglobin saturation (%) Arterial O_, content (ml/dl) Mixed venous O_, tension (mmHg) Mixed venous oxyhacmoglobin saturation (c4) Mixed venous O, content (ml/dl) Haemoglobin concentration (g/dl) Arterial pH (units) Arterial carbon dioxide tension (mmHg) Arterial bicarbonate concentration (mmol/I)
84.0 + 13.(I 95.7 + 7.0 17.1 _+ 2.0 39.7 _+ 6.0 72.2 _+ 8.2 12.9 _+ 2.3 13.2 _+ 1.4 7.41 + (I.(13 39.3 _+ 0.3 25.6 + 1.5
Patients with cirrhosis group A
group B
group C
88.8 _+ 12.0 97.0 _+ 1.0 14.5 -+ 2.0* 39.0 _+ 3.0 73.2 + 4.5 10.8 _+_ 1.9 11.(1 _+ 1.4" 7.39 _+ [).[)2 36.4 _+ 2.8 22.6 _+ 2.0
82.0 + 9.(1 96.3 + 1.4 14.9 _+ 2.[1 40.0 +_ 2.3 76.2 _+_3.1 11.7 _+ 2.[I 11.3 + 1.5 7.44 _+ 0.01 34.1 + 1.9 23.0 _+ 1.2
75.0 + 16.0 93.7 + 6.7 13.1 -+ 1.8"* 42.[I + 4.3 78.7 + 6.0 *~ 11.(I _+ 1.7 10.3 -+ 1.7"* 7,42 + 0.03 35.1 + 5.6 22.7 + 4.4
* Significantly different from patients without cirrhosis (P < 0.05). ** Significantly different from patients without cirrhosis (P < 0.01). : Significantly different from group A (P < 0.05).
Discussion
s h o w s t h a t p o r t a l p r e s s u r e ( e s t i m a t e d by w e d g e d h e p a t i c v e n o u s p r e s s u r e ) is h i g h e r in p a t i e n t s with se-
T h e results o f the p r e s e n t s t u d y are in a g r e e m e n t with the view t h a t , in p a t i e n t s with c i r r h o s i s , liver
vere liver failure t h a n in t h o s e with g o o d h e p a t i c f u n c t i o n [7].
failure is a s s o c i a t e d with a h y p e r d y n a m i c s y s t e m i c
O u r s t u d y d e m o n s t r a t e s t h a t , w h e n liver failure
c i r c u l a t i o n , i.e., with an e l e v a t e d c a r d i a c o u t p u t a n d
progresses, systemic 0 2 uptake, i.e., whole body O ,
a low s y s t e m i c v a s c u l a r r e s i s t a n c e [6,7]. T h e p r e s e n t
c o n s u m p t i o n , d e c r e a s e s w h e r e a s t h e r e is an i n c r e a s e
findings are also in k e e p i n g with a r e c e n t s t u d y w h i c h
in 0 2 t r a n s p o r t ( d u e to the a u g m e n t a t i o n in c a r d i a c
TABLE 4 O, TRANSPORT AND UTILIZATION IN ALCOHOLIC PATIENTS WITHOUT CIRRHOSIS AND IN PATIENTS WITH ALCOHOLIC CIRRHOSIS CLASSIFIED ACCORDING TO THE DEGREE OF LIVER FAILURE BY MEANS OF PUGH'S CLASSIFICATION Values are means + S.D. Patients without cirrhosis 0 2 transport (ml.min-l.m --') 0 2 uptake (ml-min-l-m-2) Arleriovenous O, content difference (ml/dl) O, extraction ratio (%) Arterial lactate concentration (mmol/l)
674 + 154 154 + 28 4.2 + 1.2 24.0+8.1 0.87 _+ 0.42
* Significantly different from group A (P < 0.05). ** Significantly different from patients without cirrhosis (P < 0.(11 ). Significantly different from patients without cirrhosis (P < 0.05). Significantly different from group A (P < 0.01). L Significantly different from group B (P < 0.01).
Patients with cirrhosis group A
group B
group C
553 + 100 138 _+ 14 3.7 + (I.5 25.0+4.5 [I.79 + 0.27
614 + 100 128 _+ 19 3.2 + (I.3~ 21.0+3.4 0.87 + 0.29
732 _+ 120" 117 _+_ 18"** 2.1 + 0 . 3 * * " : ' 16.1 __+2.6**'" 2.17 + 0.55 **'=''''
TISSUE OXYGENATION IN CIRRHOSIS output). This link between the degree of liver failure and the decrease in 02 consumption had not previously been demonstrated. In this study 02 uptake was calculated (Fick method) and not measured directly by measuring the inspired and expired gas concentrations. However, it has been demonstrated that calculated 02 uptake correlated significantly with measured 02 uptake in clinically stable patients [17]. Our results are in keeping with those of a previous study [1] which demonstrated, in patients with cirrhosis, a discrepancy between a high cardiac output state and a low measured 02 uptake. Two explanations can be proposed. On one hand, the decrease in 02 consumption could be the result of a reduction in 02 needs. Many chronic alcoholic patients are malnourished and malnutrition may reduce metabolic requirements [181. On the other hand, it is possible that 02 consumption decreases, despite a high level of 02 transport, owing to an abnormal limitation of tissue 02 'extraction so that 02 demand remains unsatisfied. Thus, tissue hypoxia may occur. More evidence supports the last hypothesis. First, preliminary results have shown that during pharmacological manipulation of cardiac output in patients with cirrhosis, 02 consumption was abnormally dependent on O_~ transport, even though the latter was as high as or above the level usually considered as normal [19]. This result suggests that tissue 02 extraction might be limited in patients with cirrhosis so that the satisfaction of O, demand becomes dependent on blood flow. A similar relationship has already been described between 02 uptake and O, transport in patients with fulminant hepatic failure
[91. Second, the high mortality in patients with cirrhosis, due to complications, such as variceal bleeding, sepsis or hypoxaemia [20,21], may be due, at least in part, to the aggravation of a preexisting subtle tissue hypoxia. Third, there is a sympathetic hyperactivity in patients with deteriorated liver function [22,23] and elevated catecholamine levels are known to increase whole body O2 demand [24,25]. Thus, in our patients with liver failure, an increase in sympathetic nervous
103 activity could contribute to further increase the imbalance between O~ needs and 02 supply. Fourth, in the present study, an elevated arterial lactate concentration was observed in patients with high-degree liver failure and low values of 02 consumption. This suggests the development of some tissue hypoxia with deterioration of liver function. Blood lactate accumulation has also been noted in the above-mentioned studies in patients with fulminant hepatic failure [8,9]. The augmented level of arterial lactate can be viewed, on the other hand, as the consequence of the hepatic underutilization of lactate due to a reduction in gluconeogenesis by the diseased liver. The association between hypoglycaemia and hyperlactataemia has been demonstrated in patients with liver failure [26]. However, defective hepatic lactate metabolism may be, at least in part, compensated by an increase in lactate utilization by kidney, skeletal muscle and myocardium [27,28]. Furthermore, the disturbance in lactate uptake by the failing liver might be related to hepatic hypoxia [29,30]. Evidence for this was seen in non-cirrhotic animals in which graded tissue hypoxia was followed by a progressive reduction in hepatic uptake of lactate and eventually by a conversion of the liver from a lactate-consuming to a lactate-producing organ [31-34]. Similar findings were observed in normal humans subjected to hypoxaemia [35]. A decrease in hepatic 02 consumption, assessed by organ reflectance spectrophotometry, has been observed in patients with cirrhosis [36]. In the latter study, there was also a correlation between hepatic 02 consumption and certain liver function tests such as serum albumin and prothrombin. Gluconeogenesis, unlike gtycogenolysis, is an O2-consuming process and thus contributes to hepatic 02 demand in patients with cirrhosis [18]. Hepatic gluconeogenesis critically depends on intact mitochondrial function and lactate contributes to gluconeogenesis after its transformation into cytosolic pyruvate and mitochondrial oxaloacetate. Thus, it may be speculated that liver failure is associated with defective lactate processing and hypoglycaemia, both related to a hypoxia-induced decrease in gluconeogenesis.
104 Mechanisms responsible for the limitation of tissue
R. MOREAU et al. rhosis [40].
O2 extraction in patients with cirrhosis and liver fail-
In conclusion, our results suggest that the decrease
ure are unclear. It may be linked to a r t e r i o v e n o u s
in O 2 uptake which, in patients with cirrhosis, accom-
shunting [37]. This is suggested in our patients with
panies liver failure-associated hyperkineticism may
hepatic insufficiency by the low O 2 extraction ratio
reflect an abnormal tissue oxygenation.
and the high mixed venous o x y h a e m o g l o b i n saturation [38] and by the significant correlations of systemic vascular resistance with arterial lactate concentration and O 2 extraction ratio. A leftward shift
Acknowledgements
of the oxyhaemoglobin dissociation curve, by increasing the affinity of h a e m o g l o b in for 02, might
The authors thank D r D. L e b r e c and D r A. Ha-
contribute to the decrease in 02 uptake. H o w e v e r ,
dengue for their critical reading of the manuscript,
evidence for this mechanism remains questionable
D r A. Soulier for examining the liver biopsy speci-
[39] and it is a rightward shift of the dissociation
mens and A. D e f o o r for her expert technical assistance.
curve which is usually observed in patients with cir-
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