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Comparison of portal vein velocity and the hepatic venous pressure gradient in assessing the acute portal hemodynamic response to propranolol in patients with cirrhosis
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2000 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 95, No. 10, 2000 ISSN 0002-9270/00/$20.00 PII S0002-9270(00)01995-X
Comparison of Portal Vein Velocity and the Hepatic Venous Pressure Gradient in Assessing the Acute Portal Hemodynamic Response to Propranolol in Patients With Cirrhosis Michael Schepke, M.D., Peter Raab, M.D., Alexander Hoppe, M.D., Peter Schiedermaier, M.D., Karl-August Brensing, M.D., and Tilman Sauerbruch, M.D. Department of Internal Medicine I, University of Bonn, Bonn, Germany
OBJECTIVE: The aim of this prospective study was to compare noninvasive Doppler sonography and invasive measurement of the hepatic venous pressure gradient (HVPG) to determine the acute portal hemodynamic response to propranolol in patients with liver cirrhosis. METHODS: In a blinded study design, portal vein velocity (PVV) and HVPG were simultaneously assessed in 11 cirrhotic patients for 4 h after oral ingestion of 40 mg propranolol. RESULTS: Both HVPG (17.2% ⫾ 4.3%, p ⬍ 0.0001) and PVV (15.6% ⫾ 2.1%, p ⬍ 0.0002) showed a highly significant reduction during the study period versus baseline. Based on HVPG measurements, four patients (36%) were classified as nonresponders. These patients had a significantly lower PVV reduction compared to the responders (responders: 18.8% ⫾ 2.0% vs nonresponders: 10.0% ⫾ 2.1%, p ⬍ 0.05). Nonresponders were identified by Doppler sonography with a sensitivity of 1.0, specificity of 0.86, and positive predictive value of 0.9 when a threshold of 20% PVV reduction 120 min after drug intake was applied. CONCLUSIONS: Doppler sonography is a useful tool for assessment of the acute portal hemodynamic effect of propranolol. To distinguish portal hemodynamic nonresponders from responders to propranolol, PVV measurements should be carried out 2 h after drug administration, and PVV reduction should be not ⬍20% in propranolol responders. (Am J Gastroenterol 2000;95:2905–2909. © 2000 by Am. Coll. of Gastroenterology)
INTRODUCTION For the medical treatment of portal hypertension, propranolol is a highly effective drug to reduce portal pressure and related risk of first or recurrent intestinal hemorrhage (1–3). However, in a considerable proportion of patients (30 – 40%), an adequate response cannot be achieved (4 – 6). Unfortunately, easily accessible systemic hemodynamic parameters such as heart rate reduction, or clinical characteristics such as etiology or severity of liver disease, do not predict the hemodynamic effect of propranolol on the portal
venous system (4, 5, 7, 8). Therefore, portal hemodynamics have to be assessed directly. The best established method is the determination of the wedged hepatic venous pressure gradient. A reduction of the hepatic venous pressure gradient below 12 mm Hg or by ⱖ20% of baseline values is associated with a very low bleeding risk (8 –10). Because catheterization of a hepatic vein is an invasive and timeconsuming procedure, quantitative Doppler sonography has been evaluated as a noninvasive alternative (11–24). However, very few studies have validated Doppler sonography for assessing the acute response to drug treatment by simultaneously determining the hepatic venous pressure gradient and the portal vein velocity or the portal blood flow (12, 13). So far, no study exists that investigates the temporal relationship between invasive and noninvasive portal hemodynamic parameters after acute medical treatment using parallel measurements. Thus, the aim of this study was to determine whether changes in the portal vein velocity, easily assessed by pulsed Doppler sonography, reliably reflect the effect of propranolol on the hepatic venous pressure gradient, and whether the portal vein velocity can be used in clinical practice to distiguish propranolol responders from nonresponders.
MATERIALS AND METHODS Patients Eleven patients with liver cirrhosis participated in this study after giving written informed consent (Table 1). All had endoscopic signs of portal hypertension (esophageal and/or gastric varices and/or severe hypertensive gastropathy) and clinical indication for treatment with propranolol to prevent intestinal hemorrhage. Patients who were already under treatment with -blockers, patients with contraindications against propranolol treatment (e.g., systolic blood pressure ⬍100 mm Hg, bradycardia ⬍50/min, obstructive airway disease), and patients with an established portosystemic shunt were excluded from the study. The patients were part of a larger group in which the stereoselective metabolism of propranolol and its role for the portal hemodynamic response was investigated (14).
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Table 1. Clinical and Biochemical Characteristics of the Patients Enrolled in the Study (mean ⫾ SE) Characteristic All patients (n ⫽ 11) Responders (n ⫽ 7) Age (yr) 58.8 ⫾ 1.65 56.1 ⫾ 1.45 Sex (male/female) 9/2 5/2 Weight (kg) 76.5 ⫾ 3.93 73.0 ⫾ 5.44 Height (cm) 172.9 ⫾ 2.42 171.0 ⫾ 3.22 Etiology of liver cirrhosis 5/3/3 3/2/2 (alcoholic/viral/other) Child-Pugh’s group (A/B/C) 6/3/2 3/2/2 Ascites (yes/no) 4/7 3/4 Serum bilirubin (mol/L) 25.7 ⫾ 4.79 25.0 ⫾ 6.84 Prothrombin activity (%) 83.4 ⫾ 3.70 83.3 ⫾ 5.42 Serum albumin (g/dl) 3.68 ⫾ 0.15 3.44 ⫾ 0.16
Hemodynamic Evaluation The hepatic venous pressure gradient was calculated as wedged hepatic venous pressure minus free hepatic venous pressure. The main right hepatic vein was catheterized percutanously with a balloon catheter through the right internal jugular vein under local anesthesia with angiographical guidance using the Seldinger technique. In serial measurements the wedged hepatic venous pressure was determined after inflating the balloon with 0.5 ml of saline; the free hepatic venous pressure was determined after completely deflating the balloon. Pressures were measured using a Exadyn transducer set (Braun, Melsungen, Germany) and registered by the Sirecust 1280 monitor (Siemens, Erlangen, Germany). The values were accepted when, after complete deflation (free hepatic venous pressure) or inflation (wedged hepatic venous pressure) of the balloon, a typical curve and constant pressure values were registered. The portal vein velocity was chosen as the most important Doppler sonographic parameter for portal hemodynamics because the diameter of the portal vein has been shown to remain unchanged after propranolol treatment (13). Doppler measurements were performed as previously described in detail (14). Briefly, portal vein velocity and cross-sectional area of the portal vein were assessed from a subcostal approach at its crossing point with the hepatic artery as average of triplicate measurements at a ⬍60° Doppler angle (SSH-140 A, Toshiba, Tokyo, Japan). The coefficient of variation for the portal vein velocity measurements with this method in our laboratory is 3% (15). The portal venous flow was calculated as portal vein velocity * portal vein’s crosssectional area. The invasive and the noninvasive measurements were carried out by two different investigators, each blinded to the results of the other technique. The patients were examined after an overnight fast in a supine position starting at 9:00 AM. Stable baseline values of heart rate, blood pressure, wedged hepatic venous pressure, free hepatic venous pressure, portal vein velocity, and portal blood flow were obtained after a 60-min period at rest. Each patient then received one 40-mg tablet of propranolol (Dociton, Zeneca, Plankstadt, Germany). One initial dosage of 40 mg propranolol was chosen because, in our
Nonresponders (n ⫽ 4) 63.5 ⫾ 2.36 4/0 82.5 ⫾ 3.4 176.3 ⫾ 2.88 2/1/1 3/1/0 1/3 27.0 ⫾ 3.59 83.5 ⫾ 2.78 4.1 ⫾ 0.12
experience, this starting dosage is tolerated without systemic side effects in the majority of patients and leads to an initial reduction of the hepatic venous pressure gradient of ⱖ20% in at least two thirds of patients. Within the study period, HR was monitored continuously; systolic and diastolic blood pressure were registered at 5-min intervals. Wedged hepatic venous pressure, free hepatic venous pressure, portal vein velocity, central venous pressure, and the portal vein’s cross-sectional area were measured every 30 min for 4 h after drug administration. All hemodynamic effects during this 4-h study period were calculated as mean changes and compared to baseline levels. The study was performed according to the 1975 Declaration of Helsinki. The study protocol was approved by the ethical committee of the University of Bonn, Germany. Definition of Response For the definition of portal hemodynamic propranolol responders and nonresponders, the seven hepatic venous pressure gradient values determined in 30-min intervals 60 –240 min after drug administration were averaged. Patients showing an average hepatic venous pressure gradient reduction of ⱖ20% during this period were defined as responders. The hemodynamic changes within the first 60 min were not taken into account for the responder definition because differences in absorption and distribution of the drug may obscure the pharmacodynamic effects during this time. Data Analysis Results are expressed in mean ⫾ SEM. Differences between groups were analyzed by Fisher’s exact test and the unpaired Student’s t test; hemodynamic effects were compared by analysis of variance for repeated measurements and paired or unpaired Student’s t test, as appropriate. A two-tailed p value ⬍0.05 was considered to demonstrate statistical significance. The best cut-off point for the prediction of hepatic venous pressure gradient response by Doppler sonography was selected using the receiver operating characteristic curve (ROC curve, 25). At each time point after drug administration sensitivity and specificity (1 ⫺ false-positive rate) for the nonresponder definition were calculated for each threshold for portal vein velocity reduction between 5% and 45% at 2.5% intervals.
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Figure 1. Percentage changes (mean ⫾ SE) of the hepatic venous pressure gradient (HVPG) and portal vein velocity (PVV) after 40 mg propranolol p.o. HVPG and PVV were assessed simultaneously and independently by two different observers each blinded for the results of the other method.
RESULTS The effect versus time profiles of the hepatic venous pressure gradient reduction and the portal vein velocity reduction after 40 mg of propranolol per os are given in Figure 1. Remarkably, the hepatic venous pressure gradient and the portal vein velocity showed an almost parallel, highly significant decrease after drug administration. The maximal effects for both parameters were observed after 2.5 h (HVPG: 24.8 ⫾ 5.4% reduction vs baseline values, p ⬍ 0.002; PVV: 23.3 ⫾ 3.1% reduction vs baseline values, p ⬍ 0.001). For the definition of portal hemodynamic responders and nonresponders on the basis of the hepatic venous pressure gradient, the HVPG measurements after the first 1 h after propranolol intake (which was allowed for absorption and initial distribution of the drug) until the end of the study period after 4 h were averaged. These results allowed a clear-cut distinction between propranolol responders (n ⫽ 7, 65%) and nonresponders (n ⫽ 4, 35%) (range HVPG reduction1– 4 h in responders: 22.8 –37.9%; range HVPG reduction1– 4 h in nonresponders: ⫺5.7% to 4.6%). When only the 2-h HVPG values with the accepted threshold of 20% reduction were used (5), the patients were identically classified as propranolol responders or nonresponders (Fig. 2). Only one responder did not reach a hepatic venous pressure gradient of ⱕ12 mm Hg but showed a sustained 27% reduction. In all other responders this goal was reached, whereas none of the nonresponders achieved a reduction of the hepatic venous pressure gradient to ⱕ12 mm Hg. When Doppler criteria were applied, ROC analysis revealed that a threshold of 20% portal vein velocity reduction 2 h after drug administration generated the best agreement between invasive and noninvasive classification of respond-
ers and nonresponders (Fig. 3). No other time interval after drug administration showed a better distinction than the 2-h portal vein velocity values: Only one patient (9.1%) belonging to Child’s class C with massive ascites was incorrectly classified as a nonresponder, whereas each responder was
Figure 2. Reduction of hepatic venous pressure gradient (HVPG) and portal vein velocity (PVV) 2 h after 40 mg of propranolol p.o. Classification of patients according to their mean HVPG response 1– 4 h after drug intake. The one patient who showed a HVPG reduction of 17.9% after 2 h could clearly be classified as a nonresponder because the mean HVPG reduction 1– 4 h after propranolol intake in this patient was only 4.0%. Note that the PVV values 2 h after drug intake corresponded well with the HVPG values, although a minor reduction of PVV was observed in the nonresponders as well, whereas HVPG on average was unchanged.
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Figure 3. Receiver operating characteristic curve (sensitivity vs specificity) for the identification of portal hemodynamic nonresponders to 40 mg propranolol p.o. by assessment of portal vein velocity (PVV) 2 h after propranolol intake. The percent values printed in italics depict the threshold of maximum PVV reduction versus baseline to fulfill the nonresponder definition. The threshold of 20% PVV reduction (arrow) proved to allow the best distinction of nonresponders, with a sensitivitiy of 100% and a specificity of 86%.
correctly classified. Thus, these Doppler criteria allowed the detection of portal hemodynamic nonresponders to propranolol with a sensitivity of 1.0, specificity of 0.86, and positive predictive value of 0.9. When the five patients initially classified as nonresponders were re-evaluated 4 h after drug administration, only the one patient incorrectly classified as nonresponder after 2 h showed a portal vein velocity reduction of ⱖ17.5%. The cross-sectional area of the portal vein did not change significantly after propranolol administration. The portal blood flow (portal vein velocity * portal vein’s cross-sectional area) did not discriminated portal hemodynamic nonresponders from responders as accurately as the portal vein velocity (Table 2).
DISCUSSION In the present study we investigated the temporal relationship between the hepatic venous pressure gradient and the portal vein velocity assessed by Doppler ultrasound after acute administration of propranolol in patients with liver
cirrhosis. We are not aware of other studies that have investigated this issue so far. We were able to demonstrate that the hepatic venous pressure gradient and the portal vein velocity show a remarkably similar reduction after propranolol administration with a maximal effect 2–2.5 h after drug administration. The hepatic venous pressure gradient is the gold standard for assessing the effects of drugs on portal hemodynamics and may predict variceal bleeding (8 –10). However, the measurement of the portal vein velocity also allowed a reliable appraisal of the portal hemodynamic response to propranolol. Our data suggest a simple, clinically applicable algorithm for the detection of propranolol nonresponders by Doppler ultrasound. All of the responders in our series of patients showed a portal vein velocity reduction of ⱖ20% 2 h after propranolol administration, whereas all of the nonresponders either showed a ⬍20% portal vein velocity reduction after 2 h or a ⬍17.5% portal vein velocity reduction 4 h after drug intake. The portal vein velocity allowed a more accurate distinction between propranolol responders and nonresponders than did the portal blood flow. This is probably due to the fact that the portal vein’s cross-sectional area did not change significantly. Thus, the measurement of this second parameter for the calculation of the portal bood flow does not give further relevant information but, rather, may flaw the determination of the response to propranolol. Although numerous studies have shown that Doppler ultrasound parameters can reliably detect pharmacological effects on portal hemodynamics (12–21, 23), only very few studies have validated this method for the determination of the acute response to drug treatment by simultaneously assessing the hepatic venous pressure gradient and Doppler parameters (12, 13). In a recent study, Albillos et al. reported that changes of the portal vein velocity are closely correlated with the effect of propranolol on the hepatic venous pressure gradient (13). These investigators, however, only determined single values of the hemodynamic parameters and did not perform serial measurements as in the present study. Most studies that evaluated the relationship between baseline parameters of HVPG and Doppler sonographic parameters in patients with liver cirrhosis found a significant
Table 2. Hemodynamic Effects of 40 mg Propranolol p.o. Responders (n ⫽ 7)
Nonresponders (n ⫽ 4)
Parameter
Baseline
Propranolol
p
Baseline
Propranolol
p
WHVP (mm Hg) FHVP (mm Hg) HVPG (mm Hg) HR (L/min) MAP (mm Hg) PVV (m/s) PBF (L/min)
23.3 ⫾ 1.53 5.4 ⫾ 1.34 18.0 ⫾ 1.36 74.6 ⫾ 4.43 82.6 ⫾ 3.40 0.181 ⫾ 0.0146 1.25 ⫾ 0.14
19.6 ⫾ 1.52 6.8 ⫾ 1.45 12.8 ⫾ 0.83 6.28 ⫾ 2.43 77.3 ⫾ 3.62 0.147 ⫾ 0.0113 1.03 ⫾ 0.11
⬍0.001 NS ⬍0.001 ⬍0.01 NS ⬍0.001 ⬍0.02
23.9 ⫾ 3.65 4.5 ⫾ 0.92 20.0 ⫾ 3.48 76.1 ⫾ 4.29 98.5 ⫾ 2.8 0.156 ⫾ 0.0207 1.22 ⫾ 0.17
24.3 ⫾ 3.29 4.6 ⫾ 0.65 19.8 ⫾ 3.04 64.8 ⫾ 3.2 98.4 ⫾ 2.8 0.1366 ⫾ 0.0177 1.06 ⫾ 0.15
NS NS NS ⬍0.01 NS NS ⬍0.05
All parameters are experssed as mean ⫾ SE. Propranolol effects are shown as mean values during the 4 h after drug administration. FHVP ⫽ free hepatic venous pressure; HR ⫽ heart rate; HVPG ⫽ hepatic venous pressure gradient; MAP ⫽ mean arterial pressure; PBF ⫽ portal blood flow; PVV ⫽ portal vein velocity; WHVP ⫽ wedged hepatic venous pressure.
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correlation (11, 24), whereas some studies did not (16). These studies indicate that— because of the physiological fluctuations in portal hemodynamics and intraobserver variance—a standardized design (single skilled observer, short time frame, measurement at identical time periods) is necessary to identify pharmacological effects by Doppler sonography. All requirements were fulfilled in our study. The observer was blind to the simultaneous hepatic venous pressure gradient measurements. Most of the patients in our study belonged to Child’s class A and B. Thus, we cannot exclude that the correlation between the portal vein velocity and the hepatic venous pressure gradient reduction may be worse when effects of drug treatment in patients with less well preserved liver function are determined. In conclusion, the present study demonstrated that the noninvasive assessment of portal vein velocity by Doppler sonography allows an accurate distinction of portal hemodynamic responders and nonresponders to propranolol. These data warrant prospective studies correlating Doppler parameters with clinical endpoints (e.g., variceal bleeding) to assess the response to pharmacological treatment.
ACKNOWLEDGMENT The authors thank the colleagues from the Department of Radiology, University of Bonn (Prof. Dr. H. H. Schild), for inserting the balloon catheters under angiographical guidance. Reprint requests and correspondence: Michael Schepke, M.D., Department of Internal Medicine I, University of Bonn, SigmundFreud-Strasse 25, D-53127 Bonn, Germany. Received Nov. 4, 1999; accepted Apr. 28, 2000.
Hemodynamic Response to Propranolol in Cirrhotics
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events in a prospective randomized clinical trial of propranolol versus placebo in the prevention of first variceal hemorrhage. Gastroenterology 1990;99:1401–7. Feu F, Garcia-Pagan JC, Bosch J, et al. Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis. Lancet 1995;346:1056 –9. Villanueva C, Balanzo J, Novella MT, et al. Nadolol plus isosorbide mononitrate compared with sclerotherapy for the prevention of variceal rebleeding. N Engl J Med 1996;334: 1624 –9. Taourel P, Blanc P, Dauzat M, et al. Doppler study of mesenteric, hepatic and portal circulation in alcoholic cirrhosis: Relationship between quantitative Doppler measurements and the severity of portal hypertension and hepatic failure. Hepatology 1998;28:932– 6. Iwao T, Oho K, Sakai T, et al. Noninvasive hemodynamic measurements of superior mesenteric artery in the prediction of portal pressure response to propranolol. J Hepatol 1998;28: 847–55. Albillos A, Perez-Paramo M, Cacho G, et al. Accuracy of portal and forearm blood flow measurements in the assessment of the portal pressure response to propranolol. J Hepatol 1997; 27:496 –504. Schepke M, Raab P, Hoppe A, et al. Propranolol stereoisomer plasma concentrations and portal haemodynamic response in patients with liver cirrhosis. Aliment Pharmacol Ther 1999; 13:1451–9. Schiedermaier P, Hansen S, Asdonk D, et al. Effects of ursodeoxycholic acid on portal and systemic hemodynamics. A double-blind, cross-over, placebo-controlled study in healthy volunteers. Digestion 2000;61:107–12. Merkel C, Sacerdoti D, Bolognesi M, et al. Doppler sonography and hepatic vein catheterization in portal hypertension: Assessment of agreement in evaluating severity and response to treatment. J Hepatol 1998;28:622–30. Sabba C, Ferraioli G, Buonamico P, et al. Echo-Doppler evaluation of acute flow changes in portal hypertensive patients: Flow-velocity as a reliable parameter. J Hepatol 1992;15:356 – 60. Zoli M, Marchesini G, Brunori A, et al. Portal venous flow in response to acute beta-blocker and vasodilatory treatment in patients with liver cirrhosis. Hepatology 1986;6:1248 –51. Gaiani S, Bolondi L, Fenyves D, et al. Effect of propranolol on portosystemic collateral circulation in patients with cirrhosis. Hepatology 1991;14:824 –9. Merkel C, Sacerdoti D, Bolognesi M, et al. Hemodynamic evaluation of the addition of isosorbide-5-mononitrate to nadolol in cirrhotic patients with insufficient response to the betablocker alone. Hepatology 1997;26:34 –9. Piscaglia F, Gaiani S, Siringo S, et al. Duplex-doppler evaluation of the effects of propranolol, and isosorbide-5-mononitrate on portal fow, and splanchnic arterial circulation in cirrhosis. Aliment Pharmacol Ther 1998;12:475– 81. Iwao T, Toyonaga A, Oho K, et al. Value of Doppler ultrasound parameters of portal vein and hepatic artery in the diagnosis of cirrhosis and portal hypertension. Am J Gastroenterol 1997;92:1012–7. Bolognesi M, Sacerdoti D, Merkel C, et al. Effects of chronic therapy with nadolol on portal hemodynamics and on splanchnic impedance indices using Doppler sonography: Comparicon between acute and chronic effects. J Hepatol 1997;26: 305–11. Moriyasu F, Nishida O, Ban N, et al. Congestion index of the portal vein. Am J Roentgenol 1986;146:735–9. McNeil BJ, Keeler E, Adelstein SJ. Primer on certain elements of medical decision making. N Engl J Med 1975;293:211–5.
Vol. 95, No. 10, 2000 ISSN 0002-9270/00/$20.00 PII S0002-9270(00)01995-X
Comparison of Portal Vein Velocity and the Hepatic Venous Pressure Gradient in Assessing the Acute Portal Hemodynamic Response to Propranolol in Patients With Cirrhosis Michael Schepke, M.D., Peter Raab, M.D., Alexander Hoppe, M.D., Peter Schiedermaier, M.D., Karl-August Brensing, M.D., and Tilman Sauerbruch, M.D. Department of Internal Medicine I, University of Bonn, Bonn, Germany
OBJECTIVE: The aim of this prospective study was to compare noninvasive Doppler sonography and invasive measurement of the hepatic venous pressure gradient (HVPG) to determine the acute portal hemodynamic response to propranolol in patients with liver cirrhosis. METHODS: In a blinded study design, portal vein velocity (PVV) and HVPG were simultaneously assessed in 11 cirrhotic patients for 4 h after oral ingestion of 40 mg propranolol. RESULTS: Both HVPG (17.2% ⫾ 4.3%, p ⬍ 0.0001) and PVV (15.6% ⫾ 2.1%, p ⬍ 0.0002) showed a highly significant reduction during the study period versus baseline. Based on HVPG measurements, four patients (36%) were classified as nonresponders. These patients had a significantly lower PVV reduction compared to the responders (responders: 18.8% ⫾ 2.0% vs nonresponders: 10.0% ⫾ 2.1%, p ⬍ 0.05). Nonresponders were identified by Doppler sonography with a sensitivity of 1.0, specificity of 0.86, and positive predictive value of 0.9 when a threshold of 20% PVV reduction 120 min after drug intake was applied. CONCLUSIONS: Doppler sonography is a useful tool for assessment of the acute portal hemodynamic effect of propranolol. To distinguish portal hemodynamic nonresponders from responders to propranolol, PVV measurements should be carried out 2 h after drug administration, and PVV reduction should be not ⬍20% in propranolol responders. (Am J Gastroenterol 2000;95:2905–2909. © 2000 by Am. Coll. of Gastroenterology)
INTRODUCTION For the medical treatment of portal hypertension, propranolol is a highly effective drug to reduce portal pressure and related risk of first or recurrent intestinal hemorrhage (1–3). However, in a considerable proportion of patients (30 – 40%), an adequate response cannot be achieved (4 – 6). Unfortunately, easily accessible systemic hemodynamic parameters such as heart rate reduction, or clinical characteristics such as etiology or severity of liver disease, do not predict the hemodynamic effect of propranolol on the portal
venous system (4, 5, 7, 8). Therefore, portal hemodynamics have to be assessed directly. The best established method is the determination of the wedged hepatic venous pressure gradient. A reduction of the hepatic venous pressure gradient below 12 mm Hg or by ⱖ20% of baseline values is associated with a very low bleeding risk (8 –10). Because catheterization of a hepatic vein is an invasive and timeconsuming procedure, quantitative Doppler sonography has been evaluated as a noninvasive alternative (11–24). However, very few studies have validated Doppler sonography for assessing the acute response to drug treatment by simultaneously determining the hepatic venous pressure gradient and the portal vein velocity or the portal blood flow (12, 13). So far, no study exists that investigates the temporal relationship between invasive and noninvasive portal hemodynamic parameters after acute medical treatment using parallel measurements. Thus, the aim of this study was to determine whether changes in the portal vein velocity, easily assessed by pulsed Doppler sonography, reliably reflect the effect of propranolol on the hepatic venous pressure gradient, and whether the portal vein velocity can be used in clinical practice to distiguish propranolol responders from nonresponders.
MATERIALS AND METHODS Patients Eleven patients with liver cirrhosis participated in this study after giving written informed consent (Table 1). All had endoscopic signs of portal hypertension (esophageal and/or gastric varices and/or severe hypertensive gastropathy) and clinical indication for treatment with propranolol to prevent intestinal hemorrhage. Patients who were already under treatment with -blockers, patients with contraindications against propranolol treatment (e.g., systolic blood pressure ⬍100 mm Hg, bradycardia ⬍50/min, obstructive airway disease), and patients with an established portosystemic shunt were excluded from the study. The patients were part of a larger group in which the stereoselective metabolism of propranolol and its role for the portal hemodynamic response was investigated (14).
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Table 1. Clinical and Biochemical Characteristics of the Patients Enrolled in the Study (mean ⫾ SE) Characteristic All patients (n ⫽ 11) Responders (n ⫽ 7) Age (yr) 58.8 ⫾ 1.65 56.1 ⫾ 1.45 Sex (male/female) 9/2 5/2 Weight (kg) 76.5 ⫾ 3.93 73.0 ⫾ 5.44 Height (cm) 172.9 ⫾ 2.42 171.0 ⫾ 3.22 Etiology of liver cirrhosis 5/3/3 3/2/2 (alcoholic/viral/other) Child-Pugh’s group (A/B/C) 6/3/2 3/2/2 Ascites (yes/no) 4/7 3/4 Serum bilirubin (mol/L) 25.7 ⫾ 4.79 25.0 ⫾ 6.84 Prothrombin activity (%) 83.4 ⫾ 3.70 83.3 ⫾ 5.42 Serum albumin (g/dl) 3.68 ⫾ 0.15 3.44 ⫾ 0.16
Hemodynamic Evaluation The hepatic venous pressure gradient was calculated as wedged hepatic venous pressure minus free hepatic venous pressure. The main right hepatic vein was catheterized percutanously with a balloon catheter through the right internal jugular vein under local anesthesia with angiographical guidance using the Seldinger technique. In serial measurements the wedged hepatic venous pressure was determined after inflating the balloon with 0.5 ml of saline; the free hepatic venous pressure was determined after completely deflating the balloon. Pressures were measured using a Exadyn transducer set (Braun, Melsungen, Germany) and registered by the Sirecust 1280 monitor (Siemens, Erlangen, Germany). The values were accepted when, after complete deflation (free hepatic venous pressure) or inflation (wedged hepatic venous pressure) of the balloon, a typical curve and constant pressure values were registered. The portal vein velocity was chosen as the most important Doppler sonographic parameter for portal hemodynamics because the diameter of the portal vein has been shown to remain unchanged after propranolol treatment (13). Doppler measurements were performed as previously described in detail (14). Briefly, portal vein velocity and cross-sectional area of the portal vein were assessed from a subcostal approach at its crossing point with the hepatic artery as average of triplicate measurements at a ⬍60° Doppler angle (SSH-140 A, Toshiba, Tokyo, Japan). The coefficient of variation for the portal vein velocity measurements with this method in our laboratory is 3% (15). The portal venous flow was calculated as portal vein velocity * portal vein’s crosssectional area. The invasive and the noninvasive measurements were carried out by two different investigators, each blinded to the results of the other technique. The patients were examined after an overnight fast in a supine position starting at 9:00 AM. Stable baseline values of heart rate, blood pressure, wedged hepatic venous pressure, free hepatic venous pressure, portal vein velocity, and portal blood flow were obtained after a 60-min period at rest. Each patient then received one 40-mg tablet of propranolol (Dociton, Zeneca, Plankstadt, Germany). One initial dosage of 40 mg propranolol was chosen because, in our
Nonresponders (n ⫽ 4) 63.5 ⫾ 2.36 4/0 82.5 ⫾ 3.4 176.3 ⫾ 2.88 2/1/1 3/1/0 1/3 27.0 ⫾ 3.59 83.5 ⫾ 2.78 4.1 ⫾ 0.12
experience, this starting dosage is tolerated without systemic side effects in the majority of patients and leads to an initial reduction of the hepatic venous pressure gradient of ⱖ20% in at least two thirds of patients. Within the study period, HR was monitored continuously; systolic and diastolic blood pressure were registered at 5-min intervals. Wedged hepatic venous pressure, free hepatic venous pressure, portal vein velocity, central venous pressure, and the portal vein’s cross-sectional area were measured every 30 min for 4 h after drug administration. All hemodynamic effects during this 4-h study period were calculated as mean changes and compared to baseline levels. The study was performed according to the 1975 Declaration of Helsinki. The study protocol was approved by the ethical committee of the University of Bonn, Germany. Definition of Response For the definition of portal hemodynamic propranolol responders and nonresponders, the seven hepatic venous pressure gradient values determined in 30-min intervals 60 –240 min after drug administration were averaged. Patients showing an average hepatic venous pressure gradient reduction of ⱖ20% during this period were defined as responders. The hemodynamic changes within the first 60 min were not taken into account for the responder definition because differences in absorption and distribution of the drug may obscure the pharmacodynamic effects during this time. Data Analysis Results are expressed in mean ⫾ SEM. Differences between groups were analyzed by Fisher’s exact test and the unpaired Student’s t test; hemodynamic effects were compared by analysis of variance for repeated measurements and paired or unpaired Student’s t test, as appropriate. A two-tailed p value ⬍0.05 was considered to demonstrate statistical significance. The best cut-off point for the prediction of hepatic venous pressure gradient response by Doppler sonography was selected using the receiver operating characteristic curve (ROC curve, 25). At each time point after drug administration sensitivity and specificity (1 ⫺ false-positive rate) for the nonresponder definition were calculated for each threshold for portal vein velocity reduction between 5% and 45% at 2.5% intervals.
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Figure 1. Percentage changes (mean ⫾ SE) of the hepatic venous pressure gradient (HVPG) and portal vein velocity (PVV) after 40 mg propranolol p.o. HVPG and PVV were assessed simultaneously and independently by two different observers each blinded for the results of the other method.
RESULTS The effect versus time profiles of the hepatic venous pressure gradient reduction and the portal vein velocity reduction after 40 mg of propranolol per os are given in Figure 1. Remarkably, the hepatic venous pressure gradient and the portal vein velocity showed an almost parallel, highly significant decrease after drug administration. The maximal effects for both parameters were observed after 2.5 h (HVPG: 24.8 ⫾ 5.4% reduction vs baseline values, p ⬍ 0.002; PVV: 23.3 ⫾ 3.1% reduction vs baseline values, p ⬍ 0.001). For the definition of portal hemodynamic responders and nonresponders on the basis of the hepatic venous pressure gradient, the HVPG measurements after the first 1 h after propranolol intake (which was allowed for absorption and initial distribution of the drug) until the end of the study period after 4 h were averaged. These results allowed a clear-cut distinction between propranolol responders (n ⫽ 7, 65%) and nonresponders (n ⫽ 4, 35%) (range HVPG reduction1– 4 h in responders: 22.8 –37.9%; range HVPG reduction1– 4 h in nonresponders: ⫺5.7% to 4.6%). When only the 2-h HVPG values with the accepted threshold of 20% reduction were used (5), the patients were identically classified as propranolol responders or nonresponders (Fig. 2). Only one responder did not reach a hepatic venous pressure gradient of ⱕ12 mm Hg but showed a sustained 27% reduction. In all other responders this goal was reached, whereas none of the nonresponders achieved a reduction of the hepatic venous pressure gradient to ⱕ12 mm Hg. When Doppler criteria were applied, ROC analysis revealed that a threshold of 20% portal vein velocity reduction 2 h after drug administration generated the best agreement between invasive and noninvasive classification of respond-
ers and nonresponders (Fig. 3). No other time interval after drug administration showed a better distinction than the 2-h portal vein velocity values: Only one patient (9.1%) belonging to Child’s class C with massive ascites was incorrectly classified as a nonresponder, whereas each responder was
Figure 2. Reduction of hepatic venous pressure gradient (HVPG) and portal vein velocity (PVV) 2 h after 40 mg of propranolol p.o. Classification of patients according to their mean HVPG response 1– 4 h after drug intake. The one patient who showed a HVPG reduction of 17.9% after 2 h could clearly be classified as a nonresponder because the mean HVPG reduction 1– 4 h after propranolol intake in this patient was only 4.0%. Note that the PVV values 2 h after drug intake corresponded well with the HVPG values, although a minor reduction of PVV was observed in the nonresponders as well, whereas HVPG on average was unchanged.
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Figure 3. Receiver operating characteristic curve (sensitivity vs specificity) for the identification of portal hemodynamic nonresponders to 40 mg propranolol p.o. by assessment of portal vein velocity (PVV) 2 h after propranolol intake. The percent values printed in italics depict the threshold of maximum PVV reduction versus baseline to fulfill the nonresponder definition. The threshold of 20% PVV reduction (arrow) proved to allow the best distinction of nonresponders, with a sensitivitiy of 100% and a specificity of 86%.
correctly classified. Thus, these Doppler criteria allowed the detection of portal hemodynamic nonresponders to propranolol with a sensitivity of 1.0, specificity of 0.86, and positive predictive value of 0.9. When the five patients initially classified as nonresponders were re-evaluated 4 h after drug administration, only the one patient incorrectly classified as nonresponder after 2 h showed a portal vein velocity reduction of ⱖ17.5%. The cross-sectional area of the portal vein did not change significantly after propranolol administration. The portal blood flow (portal vein velocity * portal vein’s cross-sectional area) did not discriminated portal hemodynamic nonresponders from responders as accurately as the portal vein velocity (Table 2).
DISCUSSION In the present study we investigated the temporal relationship between the hepatic venous pressure gradient and the portal vein velocity assessed by Doppler ultrasound after acute administration of propranolol in patients with liver
cirrhosis. We are not aware of other studies that have investigated this issue so far. We were able to demonstrate that the hepatic venous pressure gradient and the portal vein velocity show a remarkably similar reduction after propranolol administration with a maximal effect 2–2.5 h after drug administration. The hepatic venous pressure gradient is the gold standard for assessing the effects of drugs on portal hemodynamics and may predict variceal bleeding (8 –10). However, the measurement of the portal vein velocity also allowed a reliable appraisal of the portal hemodynamic response to propranolol. Our data suggest a simple, clinically applicable algorithm for the detection of propranolol nonresponders by Doppler ultrasound. All of the responders in our series of patients showed a portal vein velocity reduction of ⱖ20% 2 h after propranolol administration, whereas all of the nonresponders either showed a ⬍20% portal vein velocity reduction after 2 h or a ⬍17.5% portal vein velocity reduction 4 h after drug intake. The portal vein velocity allowed a more accurate distinction between propranolol responders and nonresponders than did the portal blood flow. This is probably due to the fact that the portal vein’s cross-sectional area did not change significantly. Thus, the measurement of this second parameter for the calculation of the portal bood flow does not give further relevant information but, rather, may flaw the determination of the response to propranolol. Although numerous studies have shown that Doppler ultrasound parameters can reliably detect pharmacological effects on portal hemodynamics (12–21, 23), only very few studies have validated this method for the determination of the acute response to drug treatment by simultaneously assessing the hepatic venous pressure gradient and Doppler parameters (12, 13). In a recent study, Albillos et al. reported that changes of the portal vein velocity are closely correlated with the effect of propranolol on the hepatic venous pressure gradient (13). These investigators, however, only determined single values of the hemodynamic parameters and did not perform serial measurements as in the present study. Most studies that evaluated the relationship between baseline parameters of HVPG and Doppler sonographic parameters in patients with liver cirrhosis found a significant
Table 2. Hemodynamic Effects of 40 mg Propranolol p.o. Responders (n ⫽ 7)
Nonresponders (n ⫽ 4)
Parameter
Baseline
Propranolol
p
Baseline
Propranolol
p
WHVP (mm Hg) FHVP (mm Hg) HVPG (mm Hg) HR (L/min) MAP (mm Hg) PVV (m/s) PBF (L/min)
23.3 ⫾ 1.53 5.4 ⫾ 1.34 18.0 ⫾ 1.36 74.6 ⫾ 4.43 82.6 ⫾ 3.40 0.181 ⫾ 0.0146 1.25 ⫾ 0.14
19.6 ⫾ 1.52 6.8 ⫾ 1.45 12.8 ⫾ 0.83 6.28 ⫾ 2.43 77.3 ⫾ 3.62 0.147 ⫾ 0.0113 1.03 ⫾ 0.11
⬍0.001 NS ⬍0.001 ⬍0.01 NS ⬍0.001 ⬍0.02
23.9 ⫾ 3.65 4.5 ⫾ 0.92 20.0 ⫾ 3.48 76.1 ⫾ 4.29 98.5 ⫾ 2.8 0.156 ⫾ 0.0207 1.22 ⫾ 0.17
24.3 ⫾ 3.29 4.6 ⫾ 0.65 19.8 ⫾ 3.04 64.8 ⫾ 3.2 98.4 ⫾ 2.8 0.1366 ⫾ 0.0177 1.06 ⫾ 0.15
NS NS NS ⬍0.01 NS NS ⬍0.05
All parameters are experssed as mean ⫾ SE. Propranolol effects are shown as mean values during the 4 h after drug administration. FHVP ⫽ free hepatic venous pressure; HR ⫽ heart rate; HVPG ⫽ hepatic venous pressure gradient; MAP ⫽ mean arterial pressure; PBF ⫽ portal blood flow; PVV ⫽ portal vein velocity; WHVP ⫽ wedged hepatic venous pressure.
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correlation (11, 24), whereas some studies did not (16). These studies indicate that— because of the physiological fluctuations in portal hemodynamics and intraobserver variance—a standardized design (single skilled observer, short time frame, measurement at identical time periods) is necessary to identify pharmacological effects by Doppler sonography. All requirements were fulfilled in our study. The observer was blind to the simultaneous hepatic venous pressure gradient measurements. Most of the patients in our study belonged to Child’s class A and B. Thus, we cannot exclude that the correlation between the portal vein velocity and the hepatic venous pressure gradient reduction may be worse when effects of drug treatment in patients with less well preserved liver function are determined. In conclusion, the present study demonstrated that the noninvasive assessment of portal vein velocity by Doppler sonography allows an accurate distinction of portal hemodynamic responders and nonresponders to propranolol. These data warrant prospective studies correlating Doppler parameters with clinical endpoints (e.g., variceal bleeding) to assess the response to pharmacological treatment.
ACKNOWLEDGMENT The authors thank the colleagues from the Department of Radiology, University of Bonn (Prof. Dr. H. H. Schild), for inserting the balloon catheters under angiographical guidance. Reprint requests and correspondence: Michael Schepke, M.D., Department of Internal Medicine I, University of Bonn, SigmundFreud-Strasse 25, D-53127 Bonn, Germany. Received Nov. 4, 1999; accepted Apr. 28, 2000.
Hemodynamic Response to Propranolol in Cirrhotics
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18.
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