Systemic and hepatic hemodynamics after variceal hemorrhage: Effects of propranolol and placebo

GASTROENTEROLOGY

1987;93:1218-24

Systemic and Hepatic Hemodynamics After Variceal Hemorrhage: Effects of Propranolol and Placebo GILLES BERNARD

POMIER-LAYRARGUES, WILLEMS,

JEAN-PIERRE

P.-MICHEL

Liver Unit, Deaartment of Medicine and Clinical Universitb de MontrBal, Montreal, Canada

Hepatic and systemic hemodynamics were measured in 19 cirrhotic patients with variceal bleeding enrolled in a controlled trial of propranolol for the prevention of rebleeding. The patients were studied on three separate occasions. The first study was performed before randomization within 24 h of the bleeding episode, once hemodynamic stabilization had been achieved. The second study was perand the third after formed after 10 days of treatment, 6 mo without rebleeding. Propranolol dosage was titrated according to blood levels. Wedged and free hepatic venous pressures and the hepatic venous pressure gradient were recorded. Hepatic blood flow and cardiac output were also measured. Before treatment, the groups of patients treated with propranolol (n = 11) or placebo (n = 8) were comparable according to clinical, biochemical, and hemodynamic parameters. After 10 days, hepatic venous pressure gradient decreased similarly in the two groups (-20% in the propranolol group, -25% in the placebo group). Cardiac output fell only in the propranolol group (-40~b). Hepatic blood flow remained unchanged in either group. After 6 mo, hepatic venous pressure gradient remained lower Received November 21, 1986. Accepted June 15, 1987. Address requests for reprints to: Dr. Gilles Pomier-Layrargues. And+Viallet Clinical Research Center, HGpital Saint-Luc, 1058, rue Saint-Denis, Montreal, Quebec, Canada HZX 314. This work was presented in part at the 86th Annual Meeting of the American Gastroenterological Association and appeared in abstract form (Gastroenterology 1985;88:1685). This work was supported by a grant from the Medical Research Council of Canada. Dr. Pomier-Layrargues is a Scholar of the Medical Research Council of Canada; Dr. Villeneuve and Dr. Huet are Chercheur-Boursiers of the Fonds de la Recherche en Sante du Quebec. The authors thank L. Giroux, M. Ulrich, and J. G. BBland for their technical assistance and M. Bourcier for manuscript preparation. 0 1987 by the American Gastroenterological Association 0016-5085/87/$3.50

HUET, Research

VILLENEUVE,

and DENIS MARLEAU Center, HBpital Saint-Luc

and

than the values from the first [within 24 h of bleeding) study in both the propranolol group [n = 5) and the placebo group [n = 6). Our results suggest that portal pressure increases shortly after hemorrhage with a return to baseline values 10 days later, and that propranolol does not further magnify these changes. Spontaneous changes in hepatic hemodynamics after variceal hemorrhage must be taken into account when evaluating the effect of pharmacologic agents on portal pressure.

Pharmacologic therapy has been proposed to stop variceal bleeding or to prevent rebleeding (1). Among various drugs, propranolol has recently been extensively studied. Continuous administration of propranolol was shown to induce a sustained reduction in portal pressure in patients with compensated alcoholic cirrhosis who had bled from esophageal varices or portal hypertensive gastritis (2); these patients were studied 10-15 days after the bleeding episode and 1, 3, and 9 mo later. Variceal hemorrhage is often a dramatic event and may result in marked changes of systemic hemodynnamics. However, there is no consistent information in the literature concerning possible changes of hepatic hemodynamics brought about by variceal hemorrhage. The hemodynamic effects of p-blockers when administered immediately after the bleeding episode are also largely unknown. The aim of the present study was to examine hepatic and systemic hemodynamics when measured 24 h, 10 days, and 6 mo after the bleeding episode in cirrhotic patients receiving propranolol or placebo. Abbreviations used in this paper: HPV, hepatic vein pressure; HVPG, hepatic venous pressure gradient; PVP, portal vein pressure; PVPG, portal venous pressure gradient.

HEMODYNAMICS AFTER VARICEAL HEMORRHAGE

December 1987

and was cryptogenic in 3. Some patients received diuretics but none was treated with vasoactive agents or cimetidine.

Materials and Methods Patients Between July 1982 and July 1985, 79 cirrhotic patients admitted for bleeding esophageal varices were enrolled in a randomized controlled trial comparing the efficacy of propranolol and placebo for the prevention of rebleeding (3). In the last 49 patients included in the study, we tried whenever possible to carry out hepatic and systemic hemodynamic studies immediately before randomization, and at 10 days and 6 mo after inclusion in the trial. Of these 49 patients, 26 could not be studied twice because of early rebleeding (20 cases), refusal (5 cases), or technical problems (1 case), and 4 patients were judged to be too sick to undergo hemodynamic studies. The 19 others were evaluated before and during treatment: 11 patients received propranolol and 8 patients received placebo. Variceal rupture was demonstrated by emergency endoscopy and cirrhosis was proven by liver biopsy. Variceal bleeding stopped spontaneously in 13 patients but required balloon tamponade in 6 (4 from the propran0101 group, 2 from the placebo group); no patients received vasopressin. The clinical characteristics and laboratory data of the two groups on admission are summarized in Table 1. The severity of liver disease was assessed according to Pugh’s modification of the Child-Turcotte classification (4). Four patients were in Pugh’s class A, 10 in class B, and 5 in class C. Cirrhosis was due to chronic alcoholism in 14 patients, chronic hepatitis B virus infection in 2,

Table

1. Clinical Characteristics and Laboratory of the Study Groups on Admission Propranolol group (n = 11)

Age(~4

Sex (M/F) Cause of cirrhosis Alcoholism (alcoholic hepatitis) Chronic hepatitis B Cryptogenic Ascites (No. of patients) No. of transfusions for index bleed Biochemical data Hematocrit (%) Serum bilirubin

(mg/dI) Serum glutamic oxaloacetic transaminase (ILJ/dl) Serum albumin (g/dl] Prothrombin time (s above control] Creatinine (mgidl)

Pugh’s A B

Interval between control (cessation) of index bleed and first hemodynamic study (h) Results between

52 (24-64)a 714

9 (61 1

5 2.8

Values Placebo .8roup (n = 8)

54 (36-76)” 711 5 (4) 1 2 3 3.3

25.7 2 4.2 3.4 * 2.7 63 + 49

24.7 k 6.6 2.6 -c 3.5 39 2 15

2.8 k 0.4 2.3 2 1.0

2.9 ? 0.2 2.4 2 1.5

0.9 + 0.4

1.0 ? 0.2

2 5 4 926

are expressed as mean 2 SD. No significant the two groups. ‘Range.

Hemodynamic

2 5 1 13 2 7

difference

Studies

The first study was performed before randomization within 24 h following control of the bleeding episode and once hemodynamic stabilization had been achieved (defined as a systolic arterial blood pressure higher than 90 mmHg, stable pulse, stable hemoglobin level, and absence of red blood in the gastric aspirate) for at least 3 h. The second study was performed after a IO-day period without rebleeding. Five patients in the propranolol group and 6 in the placebo group had a third study after 6 mo of treatment without rebleeding. Written informed consent was obtained from each patient and the study was approved by our institution’s ethics committee. Pressure

Measurements

Hepatic vein catheterization was performed under local anesthesia without premeditation. The free hepatic vein pressure (free HVP) and wedged hepatic vein pressure (wedged HVP) were measured using a balloon catheter as previously described (5). Portal vein pressure (PVP) was recorded with a Chiba needle by the transhepatic approach (6) in 5 patients in the propranolol group and 6 patients in the placebo group. The hepatic venous pressure gradient (HVPG) was calculated as wedged HVP - free HVP and the portal venous pressure gradient (PVPG) as PVP - free HVP. Right atria1 pressure was also recorded. Arterial blood pressure was recorded with an external sphygmomanometer. Mean arterial pressure was calculated according to the following formula: diastolic pressure + + (systolic - diastolic pressure). Systemic vascular resistance was calculated as [(mean arterial pressure right atria1 pressure) X 80]/cardiac output. Hepatic

Blood

Flow

Determination

Hepatic blood flow was measured with indocyanine green injected as an intravenous bolus (0.5 mg/kg) in a peripheral vein. Serial blood samples were collected simultaneously from the hepatic vein and a peripheral artery up to 15 min after indocyanine green administration. Hepatic blood flow and blood volume were calculated as previously described (7); a hepatic indocyanine green extraction >lO% was required for the calculation of hepatic blood flow. Cardiac

class

L

1219

Output

Measurement

After the injection of a “Tc-labeled albumin bolus in the right atrium, indicator dilution curves were obtained by serial sampling in a peripheral artery. Cardiac output was calculated as QI/AUC X 60 where QI is the amount of “Tc-labeled albumin injected and AUC is the area under the concentration-time curve estimated using the trapezoidal method with extrapolation to infinity.

1220

GASTKOENTEROLOGY Vol. 93, No. 6

POMIER-LAYRARGUES ET AL.

Table

and Placebo

2. Effect of Propranolol

on Hepatic

Propranolol 24 h (n = 11) Cardiac index (L/min . m 3 Heart rate (beats per

4.7 -+ 0.7 102 f 13

minute) Mean arterial pressure

93 + 12

and Systemic

Hemodynamics

group

10 days (n = 11) 3.1 2 0.5d,"

Placebo group 6 mo (n = 5) 3.1 t 0.2","

24 h (n = 8)

10 days (n = 8)

6 mo (n = 6)

5.2 ? 1.7

4.5 2 1.7

3.9 k 0.8

73 Y? 8d,c

68 t gd."

100 t 15

85 '- 13d

77 t ad

85 k 11

81 k 10

107 t 16

94 k 12

88 2 8

918 k 506

901 + 397

903 k 194

(mmHg1

Systemic vascular resistante (dyn/s . cm’) Wedged HVP (mmHg) Free HVP (mmHg) HVPG (mmHg) PVP (mmHg)” PVPG (mmHg)O

Hepatic blood flow (L’ minJb Propranolol daily dose

853 2 308

1251 f 480d,e

29.7 * 7.9 8.6 * 4.7 21.1 I!Z6.5 26.4 * 5

26.9 ? 10.1 * 16.8 * 24.6 2

6.1 4 4.gd 5.6

20.4 2 2.6 1.5 5 0.4

14.6 2 4.0d 1.8 -c 0.5

1245 -c 164d,e 26.4 + 5.6 9.0 " 2.6 17.4 2 2.7

30.8 2 7.3 10.1 2 3.2 21.1 -+ 6.2 31.5 C 7.6

27.4 2 11.6 t 15.8 k 29 2

-

21.4 + 6.3 1.6 -+ 0.4

17.3 + 5.9d 1.5 2 0.8

102 (20-160)

66 (10-160)

-

65 2 45

-

7.9 3.1 5.ld 3.6

-

26.5 2 7.3 10.3 " 2.3 16.4 '- 6.4d

-

-

(w)"

Propranolol blood levels at steady state (@ml)

-

150 * 102

Isoproterenol

-

115 2 14Ze

EDzs

-

4.5 * 2.1

HVP, hepatic vein pressure; HVPG, hepatic venous pressure gradient; PVP, portal venous pressure; PVPG, portal venous pressure gradient. Results are expressed as mean 2 SD. a Measured in 5 subjects in the propranolol group and 6 in the placebo group. b Measured in 6 subjects in the propranolol group and 5 in the placebo group. ’ Range is given in parentheses. d p < 0.05 as compared with 24-h values. e p < 0.05 as compared with the placebo group.

Propranolol

Blood

Level

Determination

Apparent oral blood clearance of propranolol was determined at the time of the second and third hemodynamic studies. Each patient received his daily dose 1 h before hemodynamic measurements, and heparinized blood samples were obtained 5, 15, 30, and 60 min and 2, 3, 4, 5, 6, 8, 12, and 24 h later; blood samples were kept frozen until analyzed. Blood levels were determined by the method of Wood et al. (8). Mean steady state blood concentration of propranolol was calculated as AU&,/t, where AUC, is the area under the oral blood concentration-time curve during the dosage interval (t). Assessment of p-blockade was made by carrying out isoproterenol testing (9). Results are expressed as isoproterenol EDzs (pg), which is the dose of isoproterenol required to increase pulse by 25 beats per minute. Statistical

Calculations

Correlations were studied with Pearson’s r-test. Statistical comparisons were made using Student’s t-test for paired or unpaired values, where appropriate (10). Intergroup comparisons were performed for each hemodynamic study; within each group, the first hemodynamic study was compared with either the second or third study. The differences were considered significant when the p value was cO.05.

Results with

Before treatment, respect to clinical,

the two groups were similar biochemical, and hemody-

namic parameters (Tables 1 and 2; Figure 1). Results of the hemodynamic studies are shown in Tables 2 and 3. After 10 days of treatment, mean steady state blood concentration of propranolol was 150 ng/ml (range 27-321 ng/ml). Cardiac output fell significantly in the propranolol group (-40%; p < O.Ol), whereas its decrease was not significant in the placebo group. Heart rate was significantly reduced in the two groups, but this reduction was more pronounced in the propranolol group (28% vs. 15%; p < 0.01). Mean arterial pressure remained unchanged in both groups and systemic vascular resistance significantly increased in the propranolol group but not in the placebo group. The HVPG decreased similarly in the two groups (-20% in the propranolol group, -25% in the placebo group) (Figure 1); the PVPG also decreased significantly in the two groups (- 28% and -20%, respectively) to the same extent as HVPG. This decrease in portal hypertension was observed in all patients in the placebo group, and all but 1 in the propranolol group. Hepatic blood flow remained unchanged in the two groups and there was no significant change in hematocrit and blood volume (Table 4). After 6 mo, there were no significant changes in systemic hemodynamics in both groups as compared with the values obtained at 10 days; the HVPG remained unchanged in the propranolol group (17.4

3.

HR

Hemodynamic

CI, cardiac index (Limin from the first study.

C SD

Placebo group 1 2 3 4 5 6 Mean 2 SD

HBF.

hepatic

6.9 4.1 5.2 k 1.7

7.2 5.0 2.6 4.3 5.1 * 1.8

6.5

5.3 5.6 3.8 5.0 4.7 c 0.7

4.9 -

4.2 5.3 4.2 4 4.4 + 0.6

-

CI

First study

Measurements

m’);

118 84 100 ? 15

120 112 89 91 87 101 100 k 13

2 SD

7 8 Mean

126 110 100 84 88 100 102 t 13

6 7 8 9 10 11 Mean

Propranolol group 1 100 2 100 3 88 4 121 5 110 Mean f SD 103 k 12

Table

blood flow

18.5 29 21.1 t 6.2

21 19 21 12 17 31 20.2 A 6.3

23 28.5 13 23 24 13 21.1 k 6.5

34 23 18 18 15 21.6 + 7.5

HVPG

(24 h)

HR, heart

1.8 1.5 1.7 2 0.4

2.3 1.7 1.1 -

1.5 -

2.2 1.4 1.6 0.9 1.3 2 0.7

-

1.3 1.6 -

-

HBF

Patients

(Limin);

in 19 Cirrhotic

rate (beats

94 68 85 C 13"

98 104 80 76 72 88 86 * 13"

84 88 76 68 60 72 73 2 9a

68 72 84 62 68 71 +- 8"

HR

per

minute);

4.8 4.9 4.5 + 1.1

4.5 3.6 2.8 4.6 4.3 k 1.3

6.2

2.2 5.4 3.3 2.8 3.4 4.0 3.3 k 0.8"

hepatic

16.5 22 15.8 k 5.1"

13 12 13 11 14 25 14.7 2 5.2"

11 21 10 20 20 10 16.8 t 4.90

24 20 14 17 18 18.6 2 3.7

HVPG

(10 days)

HVPG,

study

3.2 2.7 3.1 3.4 2.9 3.1 ? 0.2"

CI

Second

venous

-

pressure

1.9 1.4 k 0.7

-

1.3 2 0.7

2.5 1.3 0.8 -

0.9

0.9

2.6 1.5 1.1 1.8 1.8 2 0.5

-

-

1.8 1.7 -

HBF

gradient

(mmHg).

85 80 80 70 64 84 77 f 8O

72 68 60 72 68 68 c 50

HR

study

with

data

14 13 15.5 11.5 15.5 29 16.4 2 6.4'

21 17 16 14 19 17.4 2 2.7

HVPG

(6 mo)

a p < 0.05 compared

4.4 3.1 3.8 4.6 2.7 4.2 3.8 2 0.8

2.8 2.8 3 3.3 3.3 3.0 2 0.3"

CI

Third

0.7 1.2 1.7 1.0 0.8

1.3 1.3

1.9 -

HBF

1222

Table

POMIER-LAYRARGUES

4. Blood Volume

GASTROENTEROLOGY

ET AL.

and

Hematocrit

in 19 Cirrhotic

First study

Propranolol group 1 2 3 4 5 Mean r SD

study

-

BV

26 27 33 25 29 28 lr 3

82 62 65 62 73 69 k 9

31 28 23 32 24 28 28 k 4

78 94 66 50 67 59 67 + 16

28 26 30 29 28 30 28 2 3

62 81 87 74 71 56 71 + 10

64 -

t SD

28 28 33 26 23 22 27 -r4

69 60 66 65 65 5 3

32 30 28 27 27 32 29 + 2

71 64 72 78 51 65 67 2 9

-+ SD

25 26 26 2 3

71 67 66 2 4

31 26 29 * 2

2 SD

Third

(10 days)

Ht

58 63 43 88 63 2 19

a

Placebo 1 2 3 4 5 6 Mean

Second

BV

33 26 25 32 24 28 t 4

6 7 9 10 11 Mean

Patients

(24 h)

Ht

Vol. 93, No. 6

study

(6 mo)

Ht

BV

28 30 44 29 35 33 f 7

87 84 68 62 82 77 ? 11

-

-

group

7

a Mean

BV, blood volume (ml/kg); 0.05 when compared with

Ht, hematocrit (%I. No significant the first hemodynamic study.

difference

18.6 mmHg); in the placebo group, the HVPG rose slightly (from 14.7 to 16.4 mmHg) but remained significantly lower than values measured before treatment. During follow-up, 8 patients rebled within 1 yr [3 patients in the placebo group and 5 in the propranolol group); the initial HVPG, cardiac

vs.

PLACE03

Pt=CGRANoux GROUP

I

26 31 37 37 35 30 33 t 40

77 71 69 k 9

was found

between

72 56 71 60 69 75 67 t 8

-

the two groups

for the three

studies.

a p <

index, and the decrease in HVPG were not significantly different between those who rebled and those who did not (Table 5).

Discussion In the first 10 days after variceal hemorrhage, we observed a significant decrease in the HVPG and a small decrease in heart rate in placebo-treated patients in the absence of changes in cardiac output or systemic vascular resistance. The third hemodynamic study performed after a 6-mo treatment period showed that the HVPG remained lower than the

GROUP

Table 5. Relationship Between Hemodynamic Data and Rebleeding Within 1 Year

I

Rebleeders (n = 8) Baseline

Figure

IO days

6 months

Badire

IOdoys

Nonrebleeders (n = 11)

6morlhs

1. Individual values of hepatic venous pressure gradient (HVPG] measured within 24 h and at 10 days and 6 mo after variceal hemorrhage. In the propranolol group, 11 patients were studied twice, and 5 had three measurements. In the placebo group, 8 patients were studied twice, and 6 had three measurements.

HVPG (24 h) (mmHg) CI (24 h) (Wmin m”) Decrease in HVPG CI, cardiac index; ues are expressed between rebleeders

21.2 * 4.8 5.1 + 1.1 3.7 k 1.3

21.0 c 7.3" 4.7 + 1.3" 4.5 -+ 3.7"

HVPG, hepatic venous pressure gradient. Valas mean * SD. ‘No significant difference and nonrebleeders.

December

1987

value measured before treatment. These changes may be interpreted in one of several ways: they could be due to intrinsic variability of the measurements, to a spontaneous improvement, or more likely, to a transient worsening of portal hypertension after hemorrhage. The variability inherent in PVP or wedged HVP determination in our laboratory is <2 mmHg. In the present study, changes in pressure measurements between the 24-h and the lo-day studies were in the same direction in all the patients of the placebo group and were >2 mmHg in 6 of 8 instances (mean decrease 6.5 mmHg). It is therefore unlikely that our results are due to intrinsic variability of the method of measure. Spontaneous improvement in portal hypertension has been previously reported by others (11,12). These changes were observed over a period of several months and were assumed to be related to an improvement in hepatic lesions leading to a decrease in intrahepatic resistance. It is unlikely that the decrease in the HPVG that we observed in subjects from the placebo group can be related to such modifications in view of the short interval (10 days) between the first two studies; moreover, the HVPG decreased in both alcoholic patients (with and without alcoholic hepatitis on liver biopsy) and nonalcoholics. It has been reported that increasing blood volume can induce an acute elevation in portal pressure (13); however, in this study, there was no significant variation in blood volume when comparing the initial and the lo-day studies. Blood viscosity could influence the degree of portal hypertension, but hematocrit also remained unchanged. An alternative explanation may be that portal pressure increases in the initial period after variceal hemorrhage, then returns to the baseline value provided that rebleeding does not occur. A similar rise in portal pressure was recently reported in portal hypertensive rats: after hemorrhage and blood volume restitution, portal pressure increased by 20% when compared with baseline values (14). This effect was assumed to be related to an increase in portal collateral resistance induced by vasoconstrictors released in response to acute hemorrhage. Portal pressure, when measured within 48 h after bleeding, has been shown to be of prognostic value for short-term survival (15); however, its prognostic value for rebleeding has not been assessed. In the present study, there was no relationship between the hemodynamic changes and the recurrence of bleeding. In patients receiving propranolol, there was a marked reduction in cardiac output and heart rate after 10 days of treatment. The HVPG also decreased, but the magnitude of this change was similar to that

HEMODYNAMICS

AFTER VARICEAL

HEMORRHAGE

1223

observed in the control group (20% vs. 25%). This finding is surprising in view of the known portal In pressure lowering effect of propranolol (2,16-18). stable cirrhotic patients, propranolol has been shown to produce a lo%-15% reduction in portal pressure, although up to one-third of patients may be nonresponders after a single dose (1920) or 1 wk of treatment (21). In our patients, the absence of response does not appear to be due to inadequate dosing, as propranolol blood levels were within the therapeutic range (22). Isoproterenol tests also showed an adequate p-blockade, and there were significant effects of propranolol on systemic hemodynamics. It has been suggested that propranolol could be ineffective in patients with severe liver disease (23), but in the present study, there was no evidence that the 4 patients with severe class C liver disease in the propranolol group responded differently. However, it is possible that the spontaneous decrease of the HVPG observed in the placebo group obscured the effect of propranolol; on the other hand, a more significant effect of propranolol on hepatic hemodynamics might have been missed in view of the small size of the treated group. Portal venous pressure gradient changes were similar to HVPG changes in the propranolol group. This finding is in agreement with the observations of Rector (21) and at variance with those of Valla et al. (24),who suggest that in patients with alcoholic cirrhosis, propranolol induces a greater reduction in the HVPG than in the PVPG. In summary, this study shows that the HVPG decreases 10 days after variceal bleeding. This finding might be due to an increase in portal pressure in the immediate period after variceal hemorrhage, with a return to basal levels within 10 days after the bleeding episode. When administered within 24 h after bleeding, propranolol does not appear to further magnify this effect. These findings emphasize the need for a control group when evaluating the effect of pharmacologic agents on hepatic hemodynamics in cirrhotic patients who have bled recently from varices.

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GASTKOENTEROLOGY

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Vol. 93, No. 6

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