Effect of propranolol and depot lanreotide SR on postprandial and circadian portal haemodynamics in cirrhosis.

BACKGROUND: Long-acting somatostatin analogues have been suggested as an alternative to propranolol for the prevention of variceal rebleeding. AIM: To compare the effectiveness of lanreotide SR, a new depot formulation injected once-weekly, and propranolol in reducing circadian portal blood flow (PVF) and meal-stimulated hepatic venous pressure gradient (HVPG) in patients with liver cirrhosis. METHODS: Patients were randomized to receive either lanreotide SR intramuscularly (30 mg once weekly, n=12) or propranolol (n=12) orally. Hemodynamic measurements were performed on day 0 and on day 21 after a 3-week period of drug administration, while patients received three standard oral liquid test meals. On each study day 27 PVF measurements were performed over 24 h and eight measurements of HVPG during the first postprandial period. RESULTS: Propranolol was more effective than lanreotide SR in reducing baseline HVPG (-21.9 vs. -13.6%, P=0.04) and meal-stimulated HVPG (-16.6 vs. -3.8%, P=0.04). Propranolol reduced circadian PVF significantly by 9.3% (P=0.03) but not lanreotide SR. CONCLUSIONS: Long-term treatment with propranolol reduced baseline and postprandial HVPG and circadian PVF, while lanreotide SR did not. The results of our study do not encourage clinical testing of lanreotide SR 30 mg for the prevention of variceal haemorrhage.

Relationship between cytochrome P-450 induction by rifampicin, hepatic volume and portal blood flow in man.

OBJECTIVE: Induction of hepatic cytochrome P-450-dependent oxidative metabolism is related to an almost identical increase (30%) in both the liver weight and portal blood flow in animals. In humans by contrast, an increased liver blood flow (44%) but no significant increase in liver volume has been reported. DESIGN: Therefore, we studied prospectively the relationship between P-450 induction by rifampicin, hepatic volume and portal blood flow in 10 healthy volunteers. METHODS: After a pre-treatment phase (day 1 to 7) the 10 volunteers received 600 mg/day of rifampicin from day 7 to 12. The urinary 6-beta-hydroxycortisol output as a measure of oxidative metabolism (CYP3A4) and portal blood flow (pulsed Doppler ultrasound) were determined on days 1, 7, 11 and 13. Hepatic magnetic resonance volumetry was performed on days 1 and 13. RESULTS: Urinary 6-beta-hydroxycortisol output increased in all volunteers (P = 0.0051) from a median of 2.15 micrograms/day/kg (1.8-3.3 micrograms/day/kg) on day 1 to 9.9 micrograms/day/kg (5.7-14 micrograms/day/kg) on day 13. In 9 of 10 volunteers induction by rifampicin was related to an increase (P = 0.0218) in liver volume from a median of 1570 cm3 (1390-1830 cm3) to a median of 1690 cm3 (1420-1860 cm3). The portal flow as assessed by colour Doppler ultrasound did not change significantly between day 1 (median 22 cm/s (15-35 cm/s)) and day 13 (median 19 cm/s (16-39 cm/s)). CONCLUSION: A fourfold increase of urinary 6-beta-hydroxycortisol output after induction of cytochrome P-450 by rifampicin is associated with a significant but less than 10% increase in human liver volume. No increase of portal perfusion as assessed by Doppler ultrasound could be detected in this study.

Effects of different octreotide dosages on splanchnic hemodynamics and glucagon in patients with TIPS.

OBJECTIVE: The aim of this study was to evaluate the hemodynamic effects of octreotide in patients treated with transjugular intrahepatic portosystemic stent shunt in relation to plasma levels of octreotide and glucagon and the correlation between portal pressure and noninvasive Doppler parameters. METHODS: In 15 fasting patients, we i.v. administered isotonic sodium chloride followed by octreotide 25 microg/h and 100 microg/h, each over 1 h. We measured portal pressure (PP) directly and portal vein blood flow velocity by Doppler ultrasound simultaneously and calculated portal vascular resistance (PVR) and portal venous flow (PVF). Blood samples were taken for glucagon and octreotide (mean +/- SE). RESULTS: Octreotide reduced PP (120': -7.7+/-2.2%, p < 0.01 vs baseline; 180': - 11.4+/-2.1%, p < 0.01 vs baseline) and PVF (120': -21.7+/-31.7%, p < 0.01 vs baseline; 180': -11.6+/-18.1%, p < 0.05 vs baseline). Glucagon decreased with the increase in octreotide levels and showed a correlation with the decrease in PP and with PVF. In patients with a high PVR, we found a close inverse correlation between PP and portal vein blood flow velocity (r = -0.83, p = 0.03) as well as Cl (r = 0.81, p = 0.05), whereas poor correlation was found in patients with low PVR. CONCLUSIONS: Octreotide caused a dose-related, moderate but sustained reduction in PP in patients with transjugular intrahepatic portosystemic stent shunt. PVR seems to be an important parameter that influences the efficacy of octreotide and the relation between PP and noninvasive Doppler parameters.

Variability of gallbladder emptying after oral stimulation.

BACKGROUND: To date, the intraindividual reproducibility of fasting and postprandial gallbladder (GB) volumes has not been established satisfactorily. Hence we examined the variability of postprandial GB motility, using the biplane Simpson method as a new sonographic tool for GB volume determination. METHODS: The biplane Simpson method was validated in vitro and in vivo and compared with the sum-of-cylinders method. Thereafter, postprandial GB emptying after a defined test meal was examined in 10 healthy volunteers over 108 min on days 1, 31, and 61. RESULTS: The results of the biplane Simpson method correlated with real volumes (r = 0.99) and provided a intra- and inter-observer variation of less than 5%. Intraindividually, differences in fasting GB volume ranged from 1.9 to 24.0 ml within the observation period. The patterns of GB emptying also showed fluctuations characterized by a rather large interindividual and intraindividual variability. CONCLUSIONS: The biplane Simpson method is a reliable tool for measuring GB volumes. The fasting and the postprandial GB volumes vary considerably within individuals when measured over a period of 2 months.

Comparison of portal vein velocity and the hepatic venous pressure gradient in assessing the acute portal hemodynamic response to propranolol in patients with cirrhosis.

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.

[Increased demand for psychosomatic consultation service (C-service) in a department of cardiology/pneumology due to psychometric screening]. / Vermehrte Inanspruchnahme psychosomatischer Konsiliarleistungen einer kardiologisch/pulmologischen Klinik durch psychometrisches Screening.

The aim of the study was to test whether the routine use of the Hospital Anxiety and Depression Scale HADS changes the frequency and the duration of calling the psychosomatic C-service. 70% of all patients of the department of cardiology/pneumology were registered by the HADS. Psychometric screening raised the number of patients checked by the C-service (15.3 vs. 2.7% of all patients of the department; p < 0.01) and reduced the duration of the call for the C-service (2.7 vs. 6.4 days; p < 0.01) compared to conventional C-service. Elevated scores in HADS were found in 26% of the patients (21% depression, 12% anxiety).

Effects of ursodeoxycholic acid on splanchnic and systemic hemodynamics. A double-blind, cross-over, placebo-controlled study in healthy volunteers.

BACKGROUND: Recently, the beneficial effects of ursodeoxycholic acid (UDCA) on the portal hypertensive state have been demonstrated in patients with primary biliary cirrhosis. However, it is not known whether UDCA has direct or indirect effects on the vascular smooth muscles in humans, thereby leading to a change in splanchnic or systemic hemodynamics. AIMS: We therefore evaluated the hemodynamic effects of UDCA as to its established effect on gallbladder motility under fasting and postprandial conditions in healthy volunteers. METHODS: In a double-blind, cross-over study of 20 healthy volunteers, placebo or UDCA (750 mg/d) were randomly administered over 4 weeks with an interim 4-week washout period. Portal blood flow, cardiac output and gallbladder motility were measured using echo-Doppler and b-mode sonography before and after placebo and verum, respectively. ECG, blood pressure, heart rate and blood chemistry were also measured. RESULTS: UDCA did not significantly change fasting portal flow or meal-induced portal hyperemia. Both fasting and postprandial gallbladder volumes increased (26.5 +/- 6.0 vs. 40.7 +/- 13.8 ml, p < 0.05, and 11.2 +/- 6.2 vs. 14.8 +/- 6.7 ml, p < 0.05). Diastolic blood pressure decreased under UDCA (71.2 +/- 8.7 vs. 66.5 +/- 6.5 mm Hg, p < 0.05). Serum levels of chloride and gamma-glutamyltransferase decreased slightly, while alkaline phosphatase increased. CONCLUSIONS: UDCA affected systemic but not portal hemodynamics. The increase in gallbladder volume is obviously mediated by factors that do not influence the splanchnic vascular bed.

Effects of different octreotide dosages on splanchnic hemodynamics and glucagon in healthy volunteers.

AIMS: This study evaluated the dependence of portal and mesenteric blood flow and plasma glucagon levels on octreotide dosage and its mode of application. METHODS: Two groups of 10 individuals each received octreotide either subcutaneously (placebo, 100 and 200 microgram) or intravenously (100- microgram bolus i.v., 25 and 100 microgram/h) in a double-blind, random order. Using Doppler ultrasound, we examined portal and mesenteric blood flow and measured plasma glucagon levels at regular intervals within a 4-hour period under fasting conditions. RESULTS: Contrary to placebo, octreotide caused a decrease in portal blood flow (PVF) and in superior mesenteric artery blood flow (SMAF) together with an increase in the mesenteric pulsatility index (PI). The same total dose of 100 microgram octreotide caused a similar PVF response, averaged over 4 h, given either subcutaneously (-28.0 +/- 4.8%), intravenously (-29.4 +/- 4.3%) or as a continuous infusion (-29.3 +/- 4.6%). As concerns intravenous infusions, 100 microgram/h was more effective than 25 microgram/h (-37.8 +/- 6.2 vs. -29.3 +/- 4.6%). The PVF reduction remained constant during intravenous infusion, whereas glucagon levels decreased progressively over the entire observation time. CONCLUSIONS: The decrease in PVF is dependent on the octreotide dose. However, this is not constantly paralleled by a decrease in plasma glucagon concentration.

Renal functional reserve is well maintained in patients with advanced liver cirrhosis and ascites.

BACKGROUND: Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) in healthy humans can be induced by amino acid stimulation. The rise in GFR from baseline to maximum is referred to as the renal functional reserve (RFR). Recently, we showed that the RFR is preserved in patients with compensated cirrhosis despite impaired renal function. In the present study, we evaluated RFR in decompensated cirrhotics with ascites. METHODS: Steady-state inulin- and para-aminohippurate (PAH) clearances were performed at rest and during amino acid infusion in 22 patients with decompensated liver cirrhosis and ascites. RESULTS: Baseline GFR and ERPF (means +95% confidence intervals) were: GFR 25.2 (21.1-29.2) ml min(-1), ERPF 266.6 (229.7-303.5). Amino acid infusion significantly increased GFR by 67% (38.3-95.8) to 34.6 (29.2-40.0) ml min(-1) (means + (95% confidence intervals), P < 0.001) and ERPF by 29% (11.9-46.3) to 326.3 (274.1-378.5) ml min(-1) (P = 0.002). Renal vascular resistance dropped by 13.4% (3.3-23.5) from 29.4 (24.8-33.9) mmHg ml(-1) min(-1) to 26.4 (22.0-30.7) mmHg ml(-1) min(-1) (P = 0.036). The improved kidney function was accompanied by a decrease in systemic aldosterone levels (P < 0.05). CONCLUSION: In patients with liver cirrhosis and ascites, amino acid infusion improves kidney function. Trials are warranted to test the long-term effects of amino acid infusions in patients with hepatorenal syndrome.

Hemodynamic effects of propranolol and nitrates in cirrhotics with transjugular intrahepatic portosystemic stent-shunt.

BACKGROUND: The combination of tailored TIPS with vasoactive drugs might allow reduction of the rate of subsequent shunt-related sequelae. METHODS: We studied cirrhotic patients 8 weeks (median) after TIPS insertion (8-10 mm) for variceal bleeding. Nitrate (0.1 mg/kg) and propranolol (0.15 mg/kg) alone or combined (same dosages) were infused (I h) sequentially at 1-h intervals (n = 17). Similarly, propranolol was randomly compared to placebo (NaCl, n = 14). We measured mean arterial pressure (MAP, mmHg), heart rate (HR) and portal pressure gradient (PPG: portal minus central venous pressure) prior to and after drugs. RESULTS: Propranolol reduced PPG (mean +/- s, mmHg) significantly (14.8 +/- 3.7 versus 12.1 +/- 3.7; -21% +/- 10%; P < 0.001), while nitrates alone (14.3 +/- 3.4 versus 13.7 +/- 3.4; -11% +/- 3%; P=0.06) or nitrates plus propranolol (12.9 +/- 4 versus 12.4 +/- 4; -7% +/- 8%; P=0.2) induced only minor additive effects on portal pressure. However, nitrate reduced MAP (P < 0.001) and increased HR (P < 0.01), whereas propranolol reduced only HR (P < 0.001) with unchanged MAP, and the combination decreased MAP (P < 0.001). Compared to placebo (no effect), propranolol decreased PPG (14.4 +/- 5.6 versus 11.1 +/- 5.5; -23% +/- 11%; P < 0.001) and HR (P < 0.001). Overall, most patients (92%) responded to propranolol and 54% showed a marked PPG decrease (>20%). CONCLUSIONS: Propranolol significantly reduced portal pressure in cirrhotic patients after TIPS, whereas nitrates induced only minor benefit. TIPS-treated patients might therefore profit from additive propranolol therapy allowing limited shunts to be applied initially and/or to reduce the need for TIPS revisions in the case of shunt-dysfunction during follow-up.

Long term outcome after transjugular intrahepatic portosystemic stent-shunt in non-transplant cirrhotics with hepatorenal syndrome: a phase II study.

BACKGROUND: Recent small studies on hepatorenal syndrome (HRS) indicate some clinical benefit after transjugular intrahepatic portosystemic stent-shunt (TIPS) but sufficient long term data are lacking. AIM: We studied prospectively feasibility, safety, and long term survival after TIPS in 41 non-transplantable cirrhotics with HRS (phase II study). PATIENTS AND METHODS: HRS was diagnosed using current criteria (severe (type I) HRS, n=21; moderate (type II) HRS, n=20). Thirty one patients (14 type I, 17 type II) received TIPS (8-10 mm) while advanced liver failure excluded shunting in 10. During follow up (median 24 months) we analysed renal function and survival (Kaplan-Meier). RESULTS: TIPS markedly reduced the portal pressure gradient (21 (5) to 13 (4) mm Hg (mean (SD)); p<0.001) with one procedure related death (3.2%). Renal function deteriorated without TIPS but improved (p<0.001) within two weeks after TIPS (creatinine clearance 18 (15) to 48 (42) ml/min; sodium excretion 9 (16) to 77 (78) mmol/24 hours) and stabilised thereafter. Following TIPS, three, six, 12, and 18 month survival rates were 81%, 71%, 48%, and 35%, respectively. As only 10% of non-shunted patients survived three months, total survival rates were 63%, 56%, 39%, and 29%, respectively. Multivariate Cox regression analysis revealed bilirubin (p<0.001) and HRS type (p<0.05) as independent survival predictors after TIPS. CONCLUSIONS: TIPS provides long term renal function and probably survival benefits in the majority of non-transplantable cirrhotics with HRS. These data warrant controlled trials evaluating TIPS in the management of HRS.

Hemodynamic effects of the angiotensin II receptor antagonist irbesartan in patients with cirrhosis and portal hypertension.

BACKGROUND & AIMS: Angiotensin II receptor antagonists have been proposed as new drugs for portal hypertension. This randomized, placebo-controlled, double-blind study aimed to assess the effect of the angiotensin II receptor antagonist irbesartan on portal and systemic hemodynamics and renal function in patients with cirrhosis. METHODS: Thirty-six patients with cirrhosis and portal hypertension received 150 mg/d irbesartan or placebo for 1 week. Systemic hemodynamics, kidney and liver function parameters were recorded regularly; hepatic venous pressure gradient and plasma renin were assessed on days 0 and 7. RESULTS: Irbesartan reduced the hepatic venous pressure gradient by 12.2% +/- 6.6% (P < 0.05) and mean arterial pressure by 5.3% +/- 4.0% in 13 of 18 verum patients. In 4 (22%) verum patients, arterial hypotension, accompanied by significant renal impairment, required withdrawal of irbesartan. In these patients, baseline plasma renin (P < 0.002) and cystatin C (P < 0.001) levels were higher, and creatinine clearance (P < 0.02), serum sodium (P < 0.01), and albumin (P < 0.05) were lower than in patients who tolerated irbesartan. Four of five patients with baseline renin >900 microU/mL developed treatment-limiting hypotension. CONCLUSIONS: The angiotensin II receptor antagonist irbesartan is not advisable in patients with advanced cirrhosis and high plasma renin because it may induce arterial hypotension and only moderately reduces portal pressure.