ARCH GASTROENTEROHEPATOL 2001; 20 ( No 3 – 4 ):
haemodynamics in patients with chronic liver
disease
Efekat *lozartana i somatostatina na hepaticnu hemodinamiku u pacijenata sa hronicnim bolestima jetre
( accepted November 11th, 2001 )
1Aysun ERDEM, 2Turan Taner GÜNDOĞDU, 3Mualla ŞEYHOĞULLARI, 1Suna ÖZGÜR, 4İlknur ERDEM, 1Saadettin Hülagü
1Department of Internal Medicine, School of
Medicine, Kocaeli University Kocaeli,
2Department of Cardiology ( Internal
Medicine ), School of Medicine, Kocaeli University, Kocaeli,
3Department of Radiology, School of
Medicine, Kocaeli University, Kocaeli,
Turkey,
4Haydarpaşa Numune Hospital, Istanbul,
Turkey.
Address correspondence to: Dr Aysun
Erdem
Nemlizade sokak, Güleryüz apartmanı.
9/5 Kadıköy-İstanbul-Turkey
E-mail: [email protected]
* Losartan ( Cozaar, MSD; Diovan, Novartis )`is specific
angiotensin-II receptor antagonist
Abbrevations used in this article: PBF, Portal blood flow
volume; PBV: Portal blood velocity.
…………………….. …………………………
Angiotensin-2 antagonist, Gastroenteroloska sekcija SLD-
portal haemodynamics, 01712, 2001.
portal hypertension.
ABSTRACt
ObjectIve: No study has demonstrated the combined short term effects of losartan and somatostatin on liver haemodynamics, which may be important in control of variceal bleeding. The present study was aimed to examine whether combined thearapy with losartan and somatostatin achieves better haemodynamic effects than treatment with both drugs alone.
Methods: Seventeen patiens with chronic liver disease received 25 mg oral losartan on the first day. On the second day, patients received both somatastatin as a continous intravenous infusion of 250mg/hr for two hours after an initial bolus of 250mg and 25 mg oral losartan. Portal vein blood flow and velocity were determined at baseline and 30th, 60th, 120th, 240 th minutes during the study.
Results: Portal blood flow volume and velocity were
increased by administration of 25 mg losartan. Combined
administration of losartan and somatostatin resulted further
increase in these parameters.
ConclusIons: We suggest that short-term combined effect of losartan and somatostatin on liver haemodynamics may be important in control of portal hypertension with variceal bleeding.
Key words: losartan, somatostatin, chronic liver disease
CILJEVI: Do sada nije ispitan udruzen, kratkorocni efekat losartana i somatostatina na hemodinamiku jetre sto moze da ima veliki znacaj za kontrolu variksnog krvarenja. Ova studija je uradjena sa ciljem d se ispita da li se kombinovanom primenom lozartana i somatostatina postize bolji efekat na hemodinamiku nego sa ovim lekovima pojedinacno.
METODE: Sedamnaest bolesnika sa razlicitim hronicnim
bolestima jetre je leceno oralnom primenom 25mg lozartana prvog
dana terapije. Drugoga dana, posle pocetne intravenske “
bolus” doze somatostatina od 250ug i 25mg lozartana davan je
kontinuirano intavenski somatostatin 250 ug/h tokom dva sata. Tok
portne krvi i dinamika protoka krvi kroz venu porte su odredjivani
pre davanja lekovam i posle 30,60,120,240
minuta,
REZULTATI: Volumni tok krvi i brzina protoka su se povisili posle davanja 25mg lozartana. Kombinovano davanje lozartana i somatostatina je dovelo da daljeg povisavanja pomenutih pokazatelja.
ZAKLJUCAK: Mi upucujemo da krtokorocni efekat lozartana i
somatostatina na hemodinamiku jetre moze da bude znacajan za
kontrolu portne hipertenzije i variksonog
krvarenja.
Kljucne reci: lozartan, somatosttatin, hronicne bolesti
jetre.
INTRODUCTION
Cirrhosis is a chronic liver disease characterised by marked changes in hepatic haemodynamics. Variceal haemorrhage is a leading cause of death in patients with cirrhosis. Despite the advances introduced in the treatment and prevention of this complication, the mortality rate remains high ( 1 ). The introduction of continous pharmacologic treatment has been a major innovation in therapy of portal hypertension.
Several studies suggest that to achieve effective protection from the risk of variceal bleeding, the hepatic venous pressure gradient has to decrease <12 mm Hg or at least by 20 % of baseline values (2,3). The use of beta blockers that reduce portal pressure by lowering splanchnic blood inflow has proved effective in this indication (3,4). Unfortunately, achieving such a decrease in portal pressure was possible in few patients; the portal pressure is decreased by less than 10 % in 30-50 % of patients (3,5,6). On the other hand, propranolol may cause adverse effects by decreasing liver blood flow in patients with advanced liver failure. Because of these limitations other pharmacological agents have been studied, especially the long acting nitrates, calcium-channel blockers, and serotonin antagonists, but none has been shown to be superior to propranolol or suitable for prolonged therapy (7,8,9).
Recently one study has suggested that angiotensin II – which is considered a potential mediator of intrahepatic portal hypertension – blockade with orally administared losartan is safe and highly effective in the treatment of portal hypertension ( 10 ). It is well known that because of their vasoactive effects , somatostatin and its analogs are increasingly used in the management of complications of liver disease.
To our knowledge no study has demonstrated the combined short term effects of losartan and somatostatin on liver haemodynamics, which may be important in control of variceal bleeding. The present study was aimed to clarify the effects of losartan on portal pressure and examine whether combined therapy with losartan and somatostatin achieves better haemodynamic effects than treatment with losartan alone.
PATIENTS AND METHODS
The study
was performed in seventeen patients with chronic liver disease
admitted to the Liver Unit of Kocaeli University Hospital.
Seven patients were men and 10 were women; the mean age was 48
±7 years ( mean ±standard
deviation, SD; range 25-60 years ). Each patient gave informed
consent to participate in the study. The protocol was in accordance
with the guidelines of the Decleration of Helsinki.
Six of 17 patients with chronic liver disease had chronic hepatitis, 3 compensated liver failure diagnosed by biopsy. The remaining 8 patients had decompensated liver failure diagnosed by their clinical and biochemical characteristics compatible with liver failure.
Patients with an alcoholic etiology of cirrhosis who had not stopped drinking 3 months ago, patients already receiving antihypertensive treatment, and patients who had been bleeding from esophageal varices with in the last 4 weeks were excluded from the study. Routine medications was continued during the study without modification.
In patients with chronic liver disease portal hypertension was evaluated by Doppler ultrasound parameters of portal vein. Sonographic examination was made in the supine position after an overnight fast. The computerized instrument ( Toshiba-Ecco-Cee ) was equipped with a real time B-mode sector scanner ( 3.5 mHz ) and integrated pulse Doppler flowmeter. Flow direction was determined by color coded imaging and velocity was calculated from the spectral shift of the Doppler signal. A software feature of the sonographic unit was used to determine the time averaged velocity from each Doppler tracing. The diameter of the vessel wall was measured from the inner to the outer wall at the site of Doppler examinations. Portal vein cross-sectional area ( D2 in mm2 ) was calculated from the mean diameter ( 2r ) of the vessel postulating a round lumen (D2 = pxr2 ) ( 11 ). Portal blood flow (PBF, ml/min ) was derived from the portal vein cross-sectional area and the mean portal blood velocity ( PBV, cm/s ) according to the formula: PBF = p/4xD2xPBVx60 ( 12 ). Portal blood velocity was measured in suspended light inspiration and averaged during a 3-s interval. The portal vein was insonated in perpendicular fashion, using an angle between the Doppler beam and the longitudinal axis of the vessel < 45°. To minimaze the variability of ultrasound measurements, all investigations were performed by a single investigator.
Study was
undertaken in 2 days for each patient. On the first day of the
study, after the patients received 25 mg oral losartan, PBF
and PBV were determined at baseline, 60, 120, 240 minutes. On the
second day, patients received 25 mg oral losartan and somatastatin
was administered as a continous intravenous infusion of
250mg/hr for two hours after an initial bolus of
250mg. Portal vein blood flow and velocity were
determined at baseline, 30, 60, 120, 240 minutes during
somatostatin infusion.
Results are expressed as means ±SD. The student t test and Wilcoxon test were used for paired data. Results were considered significant at p < 0.05
RESULTS
While flow volume were increased significantly in patients
received losartan at 60, 120, 240 minutes comparing with the values
at baseline, we observed significant increase in velocity only at
120th and 240th minutes ( flow volume values were 0.40
±0.19 liter/min. at baseline, 0.73
±0.29 liter/min. at 60th minutes, 0.88
±0.05 liter/min. at 240th minutes; portal blood
velocity values were 0.11±0.33 m/s at
baseline, 0.15 ±0.07 m/s at 60th minutes,
0.19 ±0.10 m/s at 120th minutes, 0.18
±0.15 m/s at 240th minutes).
In patients received both somatostatin and losartan at the same time, we observed significant increase in flow volume and velocity at 30, 60, 120, 240 minutes. The increase at 120 minutes was significant comparing with that at 30th and 60th minutes ( portal blood flow volume values were 0.47 ±0.24 liter/min. at baseline, 0.76 ±0.39 liter/min. at 30th minutes, 0.83 ±0.32 at 60th minutes, 0.86 ±0.36liter/min. at 120th minutes, 1.12 ±0.71 liter/min. at 240th minutes; portal blood velocity values were 0.11 ±0.17 m/s at baseline, 0.16 ±0.03 at 30th minutes, 0.17 ±0.03 m/s at 60th minutes, 0.19 ±0.06 m/s at 120th minutes, 0.22 ±0.09 m/s at 240 minutes ). Table 1 and 2.
DISCUSSION
In this study we have demonstrated that in patients with
chronic liver disease short term administration of losartan
increases hepatic blood flow. Combined thearapy with losartan and
somatostatin further increases hepatic blood
flow.
Losartan is an active pro-drug which binds competitively to ATI receptors, while its metabolite, E-3174, a product of hepatic oxidation provides the more potent non-competetive ATI receptor blockade. As a result of this hepatic involvement a lower starting dose of 25 mg is recommended (13). In our study, we used a dose of 25 mg of losartan to minimaze the occurance of symptomatic hypotension.
In one patient in our study, a symptomatic hypotensive reaction occurred 3 hours after losartan administration. After short-term bed rest, blood pressure recovered, and symptoms abated. This symptomatic decrease in blood pressure may be due to metabolite of losartan, E-3174, Which is 40 times more potent than losartan and has been found to produce consistent reduction in blood pressure over a 24 hour period ( 14 ). No other serious side effects occured. Our findings are in accordance with previous reports that demonstrated relative tolerability of losartan ( 14, 15, 16 ).
In previous studies it was shown that losartan, a selective AT1 receptor antagonist, effectively dilates portal vein and arterioles by inhibiting angiotensin-2 induced calcium and catecholamine release. ( 17, 18, 19 ), Recently, in their study Schneider et al. found that angiotensin-II blockade with orally administered losartan may higly effective in the treatment of portal hypertension. In their investigation, losartan, in an oral dose of 25 mg once daily, caused a significant decrease of hepatic venous pressure gradient.
In patients with liver cirrhosis duplex sonography is a good non-invasive method for measuring portal blood flow and quantifiying portal hemodynamics (20). It was previously reported that portal flow velocity and portal blood flow rate decrease with worsening grades of cirrhosis (21, 22, 23). In the present study, portal hypertension was evaluated by the determination of portal blood flow volume and velocity. After 25 mg oral losartan administration at 120 and 240 minutes, portal blood flow volume and velocity increased significantly. This finding is in accordance with the pharmacokinetics of losartan as previously explained.
Somatostatin, an agent that causes selective splanchnic arteriolar vasoconstriction and decreases portal and collateral blood flow and portal pressure, is widely used in cirrhotic patients for the treatment of acute variceal bleeding ( 24 ). It is measured as increased velocity by dupplex ultrasonography due to increase flow from right atrium to portal vein as a result of decrease in intrahepatic vascular resistance.
To our knowledge, effect of losartan was studied in only one study (10). As yet its combined effect on portal hemodynamics has not been studied. In our study, we demonstrated that with combined use of somatostatin and losartan, portal blood flow and velocity increased more than administration of losartan alone. This finding may be important in treatment of portal hypertension with variceal bleeding. Further investigations in larger patients groups are required to clarify the short-term combined effect of somatostatin and losartan in portal hypertension.
In summary, portal blood flow volume and velocity detected by duplex ultrasonography has decreased by administration of 25 mg oral losartan. Combined administration of somatostatin and losartan demonstrated significant increase in these parameters. We suggest that this short-term shown combined effect of losartan and somatostatin may be important in control of portal hypertension with variceal bleeding.
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Table 1. Portal blood flow values of patients with chronic liver disease at baseline, 30 th.,
60 th., 120 th. and 240 th. minutes after losartan and somatostatin + losartan administration .
|
Portal blood flow ( liter/min.) |
Baseline |
30 th. min. |
60th. min. |
120 th. min. |
240 th. min. |
Losartan |
0.40 ± 0.19 |
_ |
0.73 ± 0.29* |
0.88 ± 0.35*b |
0.88 ± 0..35*b |
|
Somatastatin Losartan |
0.47 ± 0.24* |
0.76 ± 0.39* |
0.83 ± 0.32* |
0.86 ± 0.36* |
1.12 ± 0.71*d b |
*p < 0.05 vs. baseline
d p < 0.05 vs. 30 th. min.
bp < 0.05 vs. 60 th. min.
Table 2. Portal blood velocity values of patients with chronic liver disease at baseline, 30 th.,
60 th., 120 th. and 240 th. minutes after losartan and somatostatin + losartan administration .
|
Portal blood velocity ( meter/second ) |
Baseline |
30 th. min. |
60th. min. |
120 th. min. |
240 th. min. |
Losartan |
0.11 ± 0.03 |
_ |
0.15 ± 0.07 |
0.19 ± 0.10* |
0.18 ± 0.05* |
|
Somatastatin + Losartan |
0.11 ± 0.07* |
0.16 ± 0.03* |
0.17 ± 0.03* |
0.19 ± 0.06* |
0.22 ± 0.09*d |
*p < 0.05 vs. baseline
d p < 0.05 vs. 30 th. min.