- Email: [email protected]
Effects of propranolol on renal blood flow and renal function in patients with cirrhosis
LIVER
AND
BILIARY
TRACT
Effects of Propranolol on Renal Blood Flow and Renal Function in Patients With Cirrhosis CHRISTIAN BATAILLE, ERIC BERCOFF, EMILE DOMINIQUE VALLA, and DIDIER LEBREC ITnil& de Kecherchus
de Physiopathologie
A. PARIENTE.
HBllatiqur (II\‘SEKkl]. Hepita
und splunchnic hemodynamics. renal blood flo~ir. und renal function were studied in 13 patients Mrith cirrhosis both before and 1 h after oral udministrulion of 40 mg of proprunolol (acute administration) und I mo after continuous administration of this substunce at doses reducing the heart rote hy ZS(;J, (chronic administration). Curdiac output and the grudient between wedged and free hepatic \.enous pressures significantly decreased nfter acute und chronic mdministration of propranoJoJ; meun urterial pressure did not change significantly and systemic \rnscuJar resistance signj?cantJJ increased. Renal blood flow and renal vasculur resistance did not change signij?cantJJi after acute administration of propranoJoJ und renal function did not chunge significantly after acute or chronic administrution of proprunoloi. We conclude thut proprnnolol does noL ulter renal function in patients rvith cirrhosis lhrho ore in good physical condition. Systemic
In patients with cirrhosis, propranolol seems to be efficient in the prevention of recurrent gastrointestinal bleeding (1).Propranolol, however. decreases cardiac output (2.3) and renin release from the kidneys (4,~) and may thereby decrease renal blood flow and induce subsequent renal function deterioration. 7‘11~ purpose of this paper was to study the effects of propranolol on renal blood flow. the reninaldosteronr: system, and renal function in patients with cirrhosis.
Patients
Hoaujon Clir:tly. k’r,~tlc.c>
and Methods
Thirteen patients with histologicall!; proven cirrhosis, admitted for ruptured esophageal varices, were investigated z wk or more after complete cessation of bleeding. None of the patients had overt ascites. jaundice, or hepatic encephalopathg. Sodium intake was 90-l 20 mmoliday. Patients underwent all studies before receiving propranolol; these studies were repeated I h after oral administration of 40 mg of propranolol and, in 10 patients, 1 mo after the first study, during continuous administration of propranolol at doses that decreased heart rate by -25%. Propranolol mean dose ~vas 18fj i 1OB mg/day [mean k SD). Patients gave verbal informed consent to the investigations now described.
Hemodynamic
Study
After an overnight fast, the patients were brought to a vascular catheterization room in the morning and positioned supinely. With the patient under local anesthesia, a vessel dilatator with a polyprop!.lene sheath (Desilets, Vvgon. Ecouen. France] was introduced into the lumen of the right jugular vein according to the Seldinger technique. In order to estimate portal venous pressure. the gradient between wedged and free hepatic venous pressures (hepatic venous pressure gradient) was measured (6) with a 71: catheter (Cordis SA, Miami, Fla.) introduced under tluoroscopy visualization into a right hepatic: vein: wedging was checked by the absence of reflux into the hepatic vein after injection of 2 ml of contrast medium into the catheter. Cardiac output was then measured by the thermodilution method (7) with a Swan-Ganz thermodilution catheter inserted through the polypropylene sheath and advanced into a pulmonary artery. Before withdrawal of the S\\ranGanz catheter, right atria1 pressure was measured. Arterial pressure was measured by an external monitoring sphygmomanometer (Dinamap. Critikon Inc.. ‘Tampa, Fla.). Mean arterial pressure [MAP] was calculated ac:c.ording to the following formula: MAP = diastolic. arterial pressure I l/i (systolic arterial pressure ~ diastc~lic: arterial pressure). Systemic vascular resistance (SVK) was calculated according to the following formula: SVP .= l(MAF’ ~ right atria1
130 BATAILLE ET AL.
Table
CASTROENTEROLOGY
1. Effects of Propranolol on Hemodynamic in Patients With Cirrhosis
Basal values Hepatic venous pressure gradient (mmHg) Cardiac index (Limin . m’) Mean arterial pressure (mmHg1 Systemic vascular resistance (dyn . s/cm”)
Right renal blood flow (Ljmin) Right renal vascular resistance (mmHg/ ml. mini
One hour after 40 mg
Values
One month after continuous administration
18.1 -+ 4.4”
13.8 + 4.7”
14.8 + 4.4”
4.08
2 0.62
2.71 f 0.50”
2.99 + 0.64”
96.6 2 17.5
96.1 2 18.9’
93.8 + 10.1’
1113
2 256
1563
+ 425”
1414
0.54 2 0.21
0.52
+ 0.21’
+ 413”
t Il.122
0.230
+ 0.114’
Ii Mean t SD. ” Significantly different from the basal values (11 i 0.001). ’ Not significantly different from the basal values. ” Significantly different from the basal values (p < 0.011.
pressure) x 8O]/cardiac output. To estimate renal blood flow, a local thermodilution catheter (Webster Laboratories Inc., Altadena, Calif.) was then inserted and advanced into the right renal vein under fluoroscopic visualization. The local thermodilution catheter was fixed to the polypropylene sheath (so as to be able to repeat right renal blood flow measurement, with the catheter tip being at the same level in the lumen of the right renal vein for the different measurements]. The correct position of the local thermodilution catheter was previously checked by renal venous blood oximetry. Right renal blood flow was determined in triplicate by the local continuous thermodilution method and the mean value was used (8,9). Right renal vascular resistance was calculated according to the following formula: MAP/right renal blood flow.
Renin-Aldosterone
System
Measurement
Plasma renin activity and plasma aldosterone concentration were measured in blood samples drawn from a peripheral vein 1 h before the hemodynamic study (HAM9AM), 1 h after oral administration of 40 mg of propranolol, and 1 mo after continuous administration of propranolol. Blood for estimating plasma renin activity was withethylenediaminetetraacetate drawn into disodium (EDTA), the patient having been supine for at least 1 h. Plasma renin activity was measured with the New England Nuclear kit for radioimmunoassay of angiotensin I (10). Normal plasma renin activity ranges from 0.18 to 0.89 ngiml h; the mean normal value is 0.40 k 0.23 ngiml h. Plasma aldosterone concentration was measured with the radioimmunoassay method (11).Normal plasma aldoster-
86, No.
1
one concentration ranges from 45 to 112 pg/ml; the mean normal value is 73.9 t 23.2 pgiml.
Renal
Function
Study
Glomerular filtration rate, plasma creatinine, and plasma electrolytes were measured 1 day before the hemoadministration dynamic study and 1 mo after continuous of propranolol. Urine was collected over a 24-h period for determination of sodium and creatinine levels. Blood samples for serum creatinine were obtained. Glomerular filtration rate was calculated with the creatinine clearance. Plasma sodium and plasma potassium were estimated by standard procedures. Total body weight was noted during these studies.
Statistical 0.235
Vol.
Analysis
The results are expressed as mean * 1 SD. The Student’s t-test for paired data was used for statistical comparisons.
Results A decrease in the hepatic venous pressure gradient was observed in all our patients with cirrhosis. The mean basal values for the hepatic venous pressure gradient significantly decreased 1 h after oral administration of 40 mg of propranolol as well as
1 mo
after
continuous
administration
of
this
substance (Table 1).Cardiac output also significantly decreased 1 h and 1 mo after oral administration of propranolol (Table 1).Mean right atria1 pressure was 3.8
?
2.3
increased
mmHg;
propranolol after
the
1 h after (7.2
continuous
? 2.8 mmHg,
mean
values
oral administration
? 3.0 mmHg,
of 40 mg of
p < 0.001)
administration p < 0.001).
significantly and
1 mo
of propranolol
Mean
arterial
(6.8
pressure
did
1 mo after oral administration of propranolol (Table 1). The mean basal values for the systemic vascular resistance significantly increased 1 h after oral administration of 40 mg of propranolol and 1 mo after continuous administration of this substance (Table 1). In 10 patients, right renal blood flow ranged from 0.22 to 0.85 mlimin; 1 h after oral administration of 40 mg of not
significantly
propranolol, right >lO”/, in 6 patients
change
1 h and
renal blood flow did (Figure 1). The mean
not
change
basal value for the right renal blood flow did not significantly change 1 h after oral administration of this substance [Table 1, Figure 1). Accordingly, the fraction of cardiac output reaching the right kidney [(right renal blood flow x 100)icardiac output] rose significantly from 7.6 ? 4.1% to 11.0 k 4.8% (p < 0.01). Right renal vascular resistance did ly 1 h after oral administration 101 (Table 1, Figure 1).
not change significantof 40 mg of proprano-
Renal vascular
Renal blood flow’ Vmin ‘[
0.50
NS
1
0
o.5_
resistance
mm Hg/ml/mln
i--_li
o,25_
Y--o L before
NS
z_
/--
1 hr after propranolol
1 hr after propranolol
before
01
Both plasma renin activity and plasma aldosterone concentration significantly decreased 1 h after oral administration of 40 mg of propranolol, as well as 1 mo after continuous administration of this substance (Table 2). A significant correlation was found between the percentage of variations of the fractions of cardiac output reaching the right kidney and the difference between plasma renin activity before and 1 h after oral administration of 40 mg of propranolol (r = 0.746: p < 0.02). Plasma concentrations of sodium, potassium, and creatinint:. urinary sodium, and the glomerular filtration rate before and 1 mo after continuous administration of propranolol are shown in Table 3. None of these renal function tests significantly changed 1
Plasma
renin
activity
Ku
-_.-_
Basal
values”
Discussion In this series of patients with cirrhosis, as in a decreased previously reported series (3), propranolol cardiac output and hepatic venous pressure gradient. In our cirrhotic patients, as in patients without liver disease, propranolol increased systemic vascular resistance (2,121. Because similar catheter manipulations were not associated with significant circulatory changes in a previous study (31, the present hemodynamic observations indicate that /?-adrenergic antagonism is effective in these patients both 1 h after oral administration of 40 mg of propranolol and 1 mo after continuous administration of this substance. In fact, the most interesting finding of the present study was that renal blood flow and renal vascular resistance remained stable 1 h after oral administration of propranolol in spite of a marked fall in cardiac output. This absence of effect of propranolol on renal blood flow had been previously reported in patients with cirrhosis complicated by ascites who received continuous oral administration of propran0101 (5,131. However, these observations are contradicted by results of studies in patients without liver disease (12,14). The redistribution of cardiac output to the kidneys after oral administration of a fiblocker has recently been demonstrated in a group of patients with arterial hypertension in which the /S
h]
(ng/ml
One Patient
mo after continuous administration of propranolol (Table 3). Body weight was 68.5 i 10.4 and 68.4 + 10.3 kg before and 1 mo after continuous administration of propranolol.
Plasma month
aldostrront:
c,onc.i,ntratioil
after
One hour after 40 mg
continuous administration
Basal
\~alurs”
(pgml] One month afttrr mntinuous administration
One 11our att1.r 40 Ins
1
0.10
0.10
0.21
105
2 9
4.02 (I.18
2.82 0.30
2.70 0.27
180 1Ii3
22fl
HO
210
225
‘10
3
0 10
0.15
0.54
2 10
110
205
5
-i.lfl
2.70
1.86
800
240
215
6
0.87
0.10
0.11
1fK5
7
I .fx
0.81
0.90
‘Ifi
8
0 27
0.18
O.,i4
85
‘I
5.34
1.23
0.12
840
74
WI
14
170
1f30
711
I30
22fl
153
10
0 78
0.27
0.22
82
53
50
11
0.3R
0.21
0.30
25
3x
40
12
0.27
0.3 3
0.18
fi.%fl
1.60
0.92
3 10 980
‘30
1:s
3HO
‘40
340 ? 325
162 2 101
144 k 73’
Mean ” Norm;ll:
i SU 0.40
1.9;
ir 2.30
t 0 23 ng,ml
0.83 t 0.97’
. h. I’Normal:
0.68 f 0.78’
73.9 -+ 23.2 pg!ml.
’Significantly
different
from the basal
valuc~s (~1
120
0.05).
132
BATAILLE
Table
ET AL.
GASTROENTEROLOGY
3. Efiects of Propranolol
on Renal
Function
Plasma Sodium
Patient
No.
1 2 3 4 5 6 7 a 9 10 Mean
Basal values 141 143 140 140 139 140 136 138 140 142
f SD
” Not significantly
140 + 2 different
(mmol/L)
One month after continuous administration
With
Basal values 3.8 4.0 3.9 4.5 3.7 4.0 4.2 4.8 3.7 3.8
139 + 2"
4.0 2 0.4
(mmol/L)
One month after continuous administration 3.4 4.9 4.4 4.0 3.5 5.3 4.4 3.9 3.9 4.0
Creatinine
70 90 115 100 100 70 70 90 60 100
4.2 +- 0.6" 87 5 18
Urinary sodium (mol/daJ,)
(PmollL) One month after COIItinuous administration
Basal values
86, No.
1
Cirrhosis
concentration
Potassium
136 141 141 142 139 138 138 139 141 142
from the basal
in Patients
Vol.
Basal values
One month after continuous administration
60 85 120 110 110 70 70 95 60 110
100 106 115 98 20 122 40 105 42 72
112 116 130 94 40 110 82 98 80 68
89 -+ 23"
82 2 36
93 + 26"
Glomerular rate (mlimin
. 1.73 m’)
Basal values
One month after ~011. tinuous administration
96 95 79 92 60 127 99 127 150 100 103 + 26
filtration
79 92 73 79 64 133 110 111 108 102 95 + 21"
values.
adrenergic antagonist was nadolol(15). In that study, the authors suggested that a direct renal vasodilatation effect of nadolol allows independent regulation of renal circulation. In our study, this mechanism cannot be proposed because it is well demonstrated that propranolol decreases renal blood flow in such patients with arterial hypertension (12). The present result of the effect of propranolol on renal blood flow indicates that renal perfusion does not depend directly on the fall in cardiac output and is, therefore, relatively protected from it in these patients with cirrhosis. The mechanism for these hemodynamic renal effects remains unclear. Renal circulation depends on a complex interplay of many factors, but mainly on arterial pressure and renal vascular resistance. The absence of reduction in arterial pressure and the absence of a rise in renal vascular resistance observed in our patients after propranolol administration may explain, at least in part, the persistence of the same degree of renal perfusion. Systemic circulation and arterial pressure, and their regulation in patients with cirrhosis, are different from that of patients without liver disease (16,17). Thus, the effect of propranolol on arterial pressure is not unexpected. In patients without liver disease, renal circulation depends on LYadrenergic tone, which is unopposed and produces a renal vasoconstrictive effect in the presence of propranolol; hence, this effect produces an increase in renal vascular resistance in such patients. In our patients with cirrhosis, this vasoconstrictive effect seems to be absent in the renal vascular network. Suppression of plasma renin activity and, presumably, of angiotensin II concentration, or an activation
of a vasoactive substance, such as prostaglandins or bradykinin, might account for the protection of renal circulation in our patients with cirrhosis. In this series of patients with cirrhosis who were in good condition and who chronically received propranolol for a relatively short time, renal function was not altered. Because the systemic hemodynamic state was similar 1 h after oral administration of propranolol and 1 mo after a continuous administration of this substance, these findings suggest that renal perfusion remained stable. Accordingly, the lack of variation in renal function might be partially attributed to the sustained perfusion of the kidneys during propranolol administration; however, these observations are different from those obtained in patients with arterial hypertension receiving propranolol therapy (18). These findings may explain and confirm the fact that propranolol was well tolerated by the patients in our controlled study on its effectiveness in the prevention of recurrent gastrointestinal bleeding (1).
References Lebrec D, Poynard T, Hillon P, Benhamou j-P. Propranolol for prevention of reccurent gastrointestinal bleeding in patients with cirrhosis. A controlled study. N Engl J Med 1981: 305:1371-4. Frohlich ED, Tarazi RC, Dustan HP, Page IH. The paradox of beta-adrenergic blockade in hypertension. Circulation 1968;67:417-23. Lebrec D, Hillon P, Murioz C. Goldfarb G, Nouel 0. Benhamou J-P. The effect of propranolol on portal hypertension in patients with cirrhosis: a hemodynamic study. Hepatology 1982;2:523-7. Buhler FR. Larage JH, Baer L. Vaughan ED. Brunner HR.
January
1984
Propranolol inhibition of renin secretion. A specific approach to diagnosis and treatment of renin-dependent hypertensive diseases. S Engl J Med 1972;287:1209-14. 5. Wilkinson SP. Bernadi M, Smith IK. Jowett TP. Slater JDH. Williams K. Effect of p adrenergic blocking drugs on the renin-aldosterone system, sodium excretion, and renal hemodynamics in cirrhosis with ascites. Gastroenterology 1977; 73:659-63. 6. Bayer ‘1‘1).‘I‘riger DK. Horisawa M. Redeker AC, Keynolds TB. Direct transhepatic measurement of portal vein pressure using a thin needle. Comparison with wedged hepatic: vein pressure. Gastroenterologq 1977:72:.584-Y. 7. Forester JS. Ganz W. Diamond G. McHugh T, Chonette DW. Swarm HJC. ‘I’hermodilution cardiac output determination \vith a single flow directed catheter. Am Heart 11972;83:306‘1.
8
Hornych A. Brod J, Slechta V. The measurement of the renal venous outflow in man by thr local thermodilution method. Nephron 1971:8:17~:12.
9. Magrini E’. Cue-Quing L. A critical improvement of the local thermodilution method for measuring renal blood flow in man Cardiovasc Kes 1982;16:350-4. 10. Haber E. Koerner T. Page LB. Kliman B. Purnode A. AppliLa1to the physiologtiorr of a ratlioimmurloassa~ for angiotensin
PKOPKANOLOL
AND
KENr\L
FIJNCTION
133
ic measurements of plasma renin dcti\,ilv in normal subjects. J Clin Endocrinol 1969;29:1349-55. 11. Pham-Huu-Trung MT. Corvol P. A direct determination of plasma aldosterone. Steroids 1974:24:587-98. 12. De Leeuw PW, Birkenhiger WH. Renal response to proprano101 treatment in hypertensive humans. Hypertension 1982;4: 125-31. 13. Shohat J, Iaina A, Serban 1. Theodor E, Eliahou HE. The effect of propranolol on renal sodium handling in patients with cirrhosis. Biomedicine 1979;31:128-31. 14. Nayler WG. McInnes J, Swami JB. Carson V, Lowe TE. Effect of propranolol, a beta-adrenergic. antagonist. on blood flow in the coronary and other vascular fields. Am Heart J 1967: 73:207-16. 15. Textor SC, Fouad FM, Bravo EL. Tarazi KC. Vidt DG. Gifford RW. Redistribution of cardiac output to the kidneys during oral nadolol administration. N Engl J Med 1982:307:601-5. 16. Murray JF, Dawson AM, Sherlock S. Circulatory changes in chronic liver disease. Am J Med 1958;24:358--67. 17. Kontos HA, Shapiro W. Mauck HP. Patterson JL. General and regional circulatory alterations in cirrhosis of the liver. Am J Med 1964;37:526-35. 18. Bauer JH, Brooks CS. The long-term effec:t of propranolol therapy on renal function. Am I Meti 1979;66:405-10.
AND
BILIARY
TRACT
Effects of Propranolol on Renal Blood Flow and Renal Function in Patients With Cirrhosis CHRISTIAN BATAILLE, ERIC BERCOFF, EMILE DOMINIQUE VALLA, and DIDIER LEBREC ITnil& de Kecherchus
de Physiopathologie
A. PARIENTE.
HBllatiqur (II\‘SEKkl]. Hepita
und splunchnic hemodynamics. renal blood flo~ir. und renal function were studied in 13 patients Mrith cirrhosis both before and 1 h after oral udministrulion of 40 mg of proprunolol (acute administration) und I mo after continuous administration of this substunce at doses reducing the heart rote hy ZS(;J, (chronic administration). Curdiac output and the grudient between wedged and free hepatic \.enous pressures significantly decreased nfter acute und chronic mdministration of propranoJoJ; meun urterial pressure did not change significantly and systemic \rnscuJar resistance signj?cantJJ increased. Renal blood flow and renal vasculur resistance did not change signij?cantJJi after acute administration of propranoJoJ und renal function did not chunge significantly after acute or chronic administrution of proprunoloi. We conclude thut proprnnolol does noL ulter renal function in patients rvith cirrhosis lhrho ore in good physical condition. Systemic
In patients with cirrhosis, propranolol seems to be efficient in the prevention of recurrent gastrointestinal bleeding (1).Propranolol, however. decreases cardiac output (2.3) and renin release from the kidneys (4,~) and may thereby decrease renal blood flow and induce subsequent renal function deterioration. 7‘11~ purpose of this paper was to study the effects of propranolol on renal blood flow. the reninaldosteronr: system, and renal function in patients with cirrhosis.
Patients
Hoaujon Clir:tly. k’r,~tlc.c>
and Methods
Thirteen patients with histologicall!; proven cirrhosis, admitted for ruptured esophageal varices, were investigated z wk or more after complete cessation of bleeding. None of the patients had overt ascites. jaundice, or hepatic encephalopathg. Sodium intake was 90-l 20 mmoliday. Patients underwent all studies before receiving propranolol; these studies were repeated I h after oral administration of 40 mg of propranolol and, in 10 patients, 1 mo after the first study, during continuous administration of propranolol at doses that decreased heart rate by -25%. Propranolol mean dose ~vas 18fj i 1OB mg/day [mean k SD). Patients gave verbal informed consent to the investigations now described.
Hemodynamic
Study
After an overnight fast, the patients were brought to a vascular catheterization room in the morning and positioned supinely. With the patient under local anesthesia, a vessel dilatator with a polyprop!.lene sheath (Desilets, Vvgon. Ecouen. France] was introduced into the lumen of the right jugular vein according to the Seldinger technique. In order to estimate portal venous pressure. the gradient between wedged and free hepatic venous pressures (hepatic venous pressure gradient) was measured (6) with a 71: catheter (Cordis SA, Miami, Fla.) introduced under tluoroscopy visualization into a right hepatic: vein: wedging was checked by the absence of reflux into the hepatic vein after injection of 2 ml of contrast medium into the catheter. Cardiac output was then measured by the thermodilution method (7) with a Swan-Ganz thermodilution catheter inserted through the polypropylene sheath and advanced into a pulmonary artery. Before withdrawal of the S\\ranGanz catheter, right atria1 pressure was measured. Arterial pressure was measured by an external monitoring sphygmomanometer (Dinamap. Critikon Inc.. ‘Tampa, Fla.). Mean arterial pressure [MAP] was calculated ac:c.ording to the following formula: MAP = diastolic. arterial pressure I l/i (systolic arterial pressure ~ diastc~lic: arterial pressure). Systemic vascular resistance (SVK) was calculated according to the following formula: SVP .= l(MAF’ ~ right atria1
130 BATAILLE ET AL.
Table
CASTROENTEROLOGY
1. Effects of Propranolol on Hemodynamic in Patients With Cirrhosis
Basal values Hepatic venous pressure gradient (mmHg) Cardiac index (Limin . m’) Mean arterial pressure (mmHg1 Systemic vascular resistance (dyn . s/cm”)
Right renal blood flow (Ljmin) Right renal vascular resistance (mmHg/ ml. mini
One hour after 40 mg
Values
One month after continuous administration
18.1 -+ 4.4”
13.8 + 4.7”
14.8 + 4.4”
4.08
2 0.62
2.71 f 0.50”
2.99 + 0.64”
96.6 2 17.5
96.1 2 18.9’
93.8 + 10.1’
1113
2 256
1563
+ 425”
1414
0.54 2 0.21
0.52
+ 0.21’
+ 413”
t Il.122
0.230
+ 0.114’
Ii Mean t SD. ” Significantly different from the basal values (11 i 0.001). ’ Not significantly different from the basal values. ” Significantly different from the basal values (p < 0.011.
pressure) x 8O]/cardiac output. To estimate renal blood flow, a local thermodilution catheter (Webster Laboratories Inc., Altadena, Calif.) was then inserted and advanced into the right renal vein under fluoroscopic visualization. The local thermodilution catheter was fixed to the polypropylene sheath (so as to be able to repeat right renal blood flow measurement, with the catheter tip being at the same level in the lumen of the right renal vein for the different measurements]. The correct position of the local thermodilution catheter was previously checked by renal venous blood oximetry. Right renal blood flow was determined in triplicate by the local continuous thermodilution method and the mean value was used (8,9). Right renal vascular resistance was calculated according to the following formula: MAP/right renal blood flow.
Renin-Aldosterone
System
Measurement
Plasma renin activity and plasma aldosterone concentration were measured in blood samples drawn from a peripheral vein 1 h before the hemodynamic study (HAM9AM), 1 h after oral administration of 40 mg of propranolol, and 1 mo after continuous administration of propranolol. Blood for estimating plasma renin activity was withethylenediaminetetraacetate drawn into disodium (EDTA), the patient having been supine for at least 1 h. Plasma renin activity was measured with the New England Nuclear kit for radioimmunoassay of angiotensin I (10). Normal plasma renin activity ranges from 0.18 to 0.89 ngiml h; the mean normal value is 0.40 k 0.23 ngiml h. Plasma aldosterone concentration was measured with the radioimmunoassay method (11).Normal plasma aldoster-
86, No.
1
one concentration ranges from 45 to 112 pg/ml; the mean normal value is 73.9 t 23.2 pgiml.
Renal
Function
Study
Glomerular filtration rate, plasma creatinine, and plasma electrolytes were measured 1 day before the hemoadministration dynamic study and 1 mo after continuous of propranolol. Urine was collected over a 24-h period for determination of sodium and creatinine levels. Blood samples for serum creatinine were obtained. Glomerular filtration rate was calculated with the creatinine clearance. Plasma sodium and plasma potassium were estimated by standard procedures. Total body weight was noted during these studies.
Statistical 0.235
Vol.
Analysis
The results are expressed as mean * 1 SD. The Student’s t-test for paired data was used for statistical comparisons.
Results A decrease in the hepatic venous pressure gradient was observed in all our patients with cirrhosis. The mean basal values for the hepatic venous pressure gradient significantly decreased 1 h after oral administration of 40 mg of propranolol as well as
1 mo
after
continuous
administration
of
this
substance (Table 1).Cardiac output also significantly decreased 1 h and 1 mo after oral administration of propranolol (Table 1).Mean right atria1 pressure was 3.8
?
2.3
increased
mmHg;
propranolol after
the
1 h after (7.2
continuous
? 2.8 mmHg,
mean
values
oral administration
? 3.0 mmHg,
of 40 mg of
p < 0.001)
administration p < 0.001).
significantly and
1 mo
of propranolol
Mean
arterial
(6.8
pressure
did
1 mo after oral administration of propranolol (Table 1). The mean basal values for the systemic vascular resistance significantly increased 1 h after oral administration of 40 mg of propranolol and 1 mo after continuous administration of this substance (Table 1). In 10 patients, right renal blood flow ranged from 0.22 to 0.85 mlimin; 1 h after oral administration of 40 mg of not
significantly
propranolol, right >lO”/, in 6 patients
change
1 h and
renal blood flow did (Figure 1). The mean
not
change
basal value for the right renal blood flow did not significantly change 1 h after oral administration of this substance [Table 1, Figure 1). Accordingly, the fraction of cardiac output reaching the right kidney [(right renal blood flow x 100)icardiac output] rose significantly from 7.6 ? 4.1% to 11.0 k 4.8% (p < 0.01). Right renal vascular resistance did ly 1 h after oral administration 101 (Table 1, Figure 1).
not change significantof 40 mg of proprano-
Renal vascular
Renal blood flow’ Vmin ‘[
0.50
NS
1
0
o.5_
resistance
mm Hg/ml/mln
i--_li
o,25_
Y--o L before
NS
z_
/--
1 hr after propranolol
1 hr after propranolol
before
01
Both plasma renin activity and plasma aldosterone concentration significantly decreased 1 h after oral administration of 40 mg of propranolol, as well as 1 mo after continuous administration of this substance (Table 2). A significant correlation was found between the percentage of variations of the fractions of cardiac output reaching the right kidney and the difference between plasma renin activity before and 1 h after oral administration of 40 mg of propranolol (r = 0.746: p < 0.02). Plasma concentrations of sodium, potassium, and creatinint:. urinary sodium, and the glomerular filtration rate before and 1 mo after continuous administration of propranolol are shown in Table 3. None of these renal function tests significantly changed 1
Plasma
renin
activity
Ku
-_.-_
Basal
values”
Discussion In this series of patients with cirrhosis, as in a decreased previously reported series (3), propranolol cardiac output and hepatic venous pressure gradient. In our cirrhotic patients, as in patients without liver disease, propranolol increased systemic vascular resistance (2,121. Because similar catheter manipulations were not associated with significant circulatory changes in a previous study (31, the present hemodynamic observations indicate that /?-adrenergic antagonism is effective in these patients both 1 h after oral administration of 40 mg of propranolol and 1 mo after continuous administration of this substance. In fact, the most interesting finding of the present study was that renal blood flow and renal vascular resistance remained stable 1 h after oral administration of propranolol in spite of a marked fall in cardiac output. This absence of effect of propranolol on renal blood flow had been previously reported in patients with cirrhosis complicated by ascites who received continuous oral administration of propran0101 (5,131. However, these observations are contradicted by results of studies in patients without liver disease (12,14). The redistribution of cardiac output to the kidneys after oral administration of a fiblocker has recently been demonstrated in a group of patients with arterial hypertension in which the /S
h]
(ng/ml
One Patient
mo after continuous administration of propranolol (Table 3). Body weight was 68.5 i 10.4 and 68.4 + 10.3 kg before and 1 mo after continuous administration of propranolol.
Plasma month
aldostrront:
c,onc.i,ntratioil
after
One hour after 40 mg
continuous administration
Basal
\~alurs”
(pgml] One month afttrr mntinuous administration
One 11our att1.r 40 Ins
1
0.10
0.10
0.21
105
2 9
4.02 (I.18
2.82 0.30
2.70 0.27
180 1Ii3
22fl
HO
210
225
‘10
3
0 10
0.15
0.54
2 10
110
205
5
-i.lfl
2.70
1.86
800
240
215
6
0.87
0.10
0.11
1fK5
7
I .fx
0.81
0.90
‘Ifi
8
0 27
0.18
O.,i4
85
‘I
5.34
1.23
0.12
840
74
WI
14
170
1f30
711
I30
22fl
153
10
0 78
0.27
0.22
82
53
50
11
0.3R
0.21
0.30
25
3x
40
12
0.27
0.3 3
0.18
fi.%fl
1.60
0.92
3 10 980
‘30
1:s
3HO
‘40
340 ? 325
162 2 101
144 k 73’
Mean ” Norm;ll:
i SU 0.40
1.9;
ir 2.30
t 0 23 ng,ml
0.83 t 0.97’
. h. I’Normal:
0.68 f 0.78’
73.9 -+ 23.2 pg!ml.
’Significantly
different
from the basal
valuc~s (~1
120
0.05).
132
BATAILLE
Table
ET AL.
GASTROENTEROLOGY
3. Efiects of Propranolol
on Renal
Function
Plasma Sodium
Patient
No.
1 2 3 4 5 6 7 a 9 10 Mean
Basal values 141 143 140 140 139 140 136 138 140 142
f SD
” Not significantly
140 + 2 different
(mmol/L)
One month after continuous administration
With
Basal values 3.8 4.0 3.9 4.5 3.7 4.0 4.2 4.8 3.7 3.8
139 + 2"
4.0 2 0.4
(mmol/L)
One month after continuous administration 3.4 4.9 4.4 4.0 3.5 5.3 4.4 3.9 3.9 4.0
Creatinine
70 90 115 100 100 70 70 90 60 100
4.2 +- 0.6" 87 5 18
Urinary sodium (mol/daJ,)
(PmollL) One month after COIItinuous administration
Basal values
86, No.
1
Cirrhosis
concentration
Potassium
136 141 141 142 139 138 138 139 141 142
from the basal
in Patients
Vol.
Basal values
One month after continuous administration
60 85 120 110 110 70 70 95 60 110
100 106 115 98 20 122 40 105 42 72
112 116 130 94 40 110 82 98 80 68
89 -+ 23"
82 2 36
93 + 26"
Glomerular rate (mlimin
. 1.73 m’)
Basal values
One month after ~011. tinuous administration
96 95 79 92 60 127 99 127 150 100 103 + 26
filtration
79 92 73 79 64 133 110 111 108 102 95 + 21"
values.
adrenergic antagonist was nadolol(15). In that study, the authors suggested that a direct renal vasodilatation effect of nadolol allows independent regulation of renal circulation. In our study, this mechanism cannot be proposed because it is well demonstrated that propranolol decreases renal blood flow in such patients with arterial hypertension (12). The present result of the effect of propranolol on renal blood flow indicates that renal perfusion does not depend directly on the fall in cardiac output and is, therefore, relatively protected from it in these patients with cirrhosis. The mechanism for these hemodynamic renal effects remains unclear. Renal circulation depends on a complex interplay of many factors, but mainly on arterial pressure and renal vascular resistance. The absence of reduction in arterial pressure and the absence of a rise in renal vascular resistance observed in our patients after propranolol administration may explain, at least in part, the persistence of the same degree of renal perfusion. Systemic circulation and arterial pressure, and their regulation in patients with cirrhosis, are different from that of patients without liver disease (16,17). Thus, the effect of propranolol on arterial pressure is not unexpected. In patients without liver disease, renal circulation depends on LYadrenergic tone, which is unopposed and produces a renal vasoconstrictive effect in the presence of propranolol; hence, this effect produces an increase in renal vascular resistance in such patients. In our patients with cirrhosis, this vasoconstrictive effect seems to be absent in the renal vascular network. Suppression of plasma renin activity and, presumably, of angiotensin II concentration, or an activation
of a vasoactive substance, such as prostaglandins or bradykinin, might account for the protection of renal circulation in our patients with cirrhosis. In this series of patients with cirrhosis who were in good condition and who chronically received propranolol for a relatively short time, renal function was not altered. Because the systemic hemodynamic state was similar 1 h after oral administration of propranolol and 1 mo after a continuous administration of this substance, these findings suggest that renal perfusion remained stable. Accordingly, the lack of variation in renal function might be partially attributed to the sustained perfusion of the kidneys during propranolol administration; however, these observations are different from those obtained in patients with arterial hypertension receiving propranolol therapy (18). These findings may explain and confirm the fact that propranolol was well tolerated by the patients in our controlled study on its effectiveness in the prevention of recurrent gastrointestinal bleeding (1).
References Lebrec D, Poynard T, Hillon P, Benhamou j-P. Propranolol for prevention of reccurent gastrointestinal bleeding in patients with cirrhosis. A controlled study. N Engl J Med 1981: 305:1371-4. Frohlich ED, Tarazi RC, Dustan HP, Page IH. The paradox of beta-adrenergic blockade in hypertension. Circulation 1968;67:417-23. Lebrec D, Hillon P, Murioz C. Goldfarb G, Nouel 0. Benhamou J-P. The effect of propranolol on portal hypertension in patients with cirrhosis: a hemodynamic study. Hepatology 1982;2:523-7. Buhler FR. Larage JH, Baer L. Vaughan ED. Brunner HR.
January
1984
Propranolol inhibition of renin secretion. A specific approach to diagnosis and treatment of renin-dependent hypertensive diseases. S Engl J Med 1972;287:1209-14. 5. Wilkinson SP. Bernadi M, Smith IK. Jowett TP. Slater JDH. Williams K. Effect of p adrenergic blocking drugs on the renin-aldosterone system, sodium excretion, and renal hemodynamics in cirrhosis with ascites. Gastroenterology 1977; 73:659-63. 6. Bayer ‘1‘1).‘I‘riger DK. Horisawa M. Redeker AC, Keynolds TB. Direct transhepatic measurement of portal vein pressure using a thin needle. Comparison with wedged hepatic: vein pressure. Gastroenterologq 1977:72:.584-Y. 7. Forester JS. Ganz W. Diamond G. McHugh T, Chonette DW. Swarm HJC. ‘I’hermodilution cardiac output determination \vith a single flow directed catheter. Am Heart 11972;83:306‘1.
8
Hornych A. Brod J, Slechta V. The measurement of the renal venous outflow in man by thr local thermodilution method. Nephron 1971:8:17~:12.
9. Magrini E’. Cue-Quing L. A critical improvement of the local thermodilution method for measuring renal blood flow in man Cardiovasc Kes 1982;16:350-4. 10. Haber E. Koerner T. Page LB. Kliman B. Purnode A. AppliLa1to the physiologtiorr of a ratlioimmurloassa~ for angiotensin
PKOPKANOLOL
AND
KENr\L
FIJNCTION
133
ic measurements of plasma renin dcti\,ilv in normal subjects. J Clin Endocrinol 1969;29:1349-55. 11. Pham-Huu-Trung MT. Corvol P. A direct determination of plasma aldosterone. Steroids 1974:24:587-98. 12. De Leeuw PW, Birkenhiger WH. Renal response to proprano101 treatment in hypertensive humans. Hypertension 1982;4: 125-31. 13. Shohat J, Iaina A, Serban 1. Theodor E, Eliahou HE. The effect of propranolol on renal sodium handling in patients with cirrhosis. Biomedicine 1979;31:128-31. 14. Nayler WG. McInnes J, Swami JB. Carson V, Lowe TE. Effect of propranolol, a beta-adrenergic. antagonist. on blood flow in the coronary and other vascular fields. Am Heart J 1967: 73:207-16. 15. Textor SC, Fouad FM, Bravo EL. Tarazi KC. Vidt DG. Gifford RW. Redistribution of cardiac output to the kidneys during oral nadolol administration. N Engl J Med 1982:307:601-5. 16. Murray JF, Dawson AM, Sherlock S. Circulatory changes in chronic liver disease. Am J Med 1958;24:358--67. 17. Kontos HA, Shapiro W. Mauck HP. Patterson JL. General and regional circulatory alterations in cirrhosis of the liver. Am J Med 1964;37:526-35. 18. Bauer JH, Brooks CS. The long-term effec:t of propranolol therapy on renal function. Am I Meti 1979;66:405-10.