Primary prophylaxis with nadolol in cirrhotic patients: Doppler patterns of splanchnic hemodynamics in good and poor responders☆
Introduction
Non-selective beta-blockers, such as propranolol and nadolol, are the first-line prophylactic treatment for cirrhotic patients with esophageal varices at medium–high risk of bleeding [1], since they decrease portal pressure by reducing cardiac index via β-1 adrenoceptors blockade and increasing splanchnic vasoconstriction via β-2 adrenoceptors blockade [2]. In conditions of increased sinusoidal resistance, portal pressure can be reliably estimated by its equivalent hepatic venous pressure gradient (HVPG), which is measured during hepatic veins' catheterization [3]. Variceal bleeding can occur when HVPG increases over 12 mmHg [4], [5]. It has been previously demonstrated that cirrhotic patients who had never bled from varices and who show a decrease of HVPG under 12 mmHg or ≥20% vs. baseline during chronic treatment with beta-blockers, are protected from the risk of first bleeding from varices [6], [7]; when beta-blockers are given for the prevention of rebleeding, a reduction of HVPG ≥20% reduces both the risk of bleeding [8] and that of developing of other complications of portal hypertension [9]. Patients showing this reduction in HVPG during pharmacological treatment are therefore considered hemodynamic responders. Patients who do not respond to beta-blockers are still at risk of variceal rupture, and it has been recently suggested that these patients may be shifted to endoscopic banding ligation [10], making noteworthy to know whether a patient is or not a responder to pharmacological treatment.
At the moment, the only method to define the hemodynamic response to beta-blockers is the repeat measurement of HVPG, since clinical and laboratory data do not predict beta-blockers' effect on portal pressure [3]. Nonetheless, the need for researching non-invasive methods to obtain such information has been stated during the last consensus conference on portal hypertension [1], since this would simplify the clinical management of portal hypertensive cirrhotic patients.
Echo-color-Doppler is a non-invasive technique, which allows the study of splanchnic circulation. To date, only one study examined the usefulness of repeat measurements of Doppler variables in patients undergoing as well HVPG measurements during chronic administration of beta-blockers [11]. In that study, Merkel and colleagues could not demonstrate any predictive value of Doppler changes on hemodynamic response to therapy; however the study was carried out both in patients who where receiving nadolol or nadolol+nitrates, and only portal blood flow and portal vein congestion index changes were evaluated.
The aim of this prospective study was to characterize the splanchnic hemodynamics by echo-color-Doppler in a consecutive series of cirrhotic patients undergoing a primary prophylaxis with nadolol and repeated HVPG measurement.
Section snippets
Patients
From January 2003 to January 2005, 42 patients with clinically and laboratory proven cirrhosis, with medium/large size esophageal varices at a recent endoscopy (performed within 1–3 months) and without history of previous variceal bleeding were consecutively observed at our Unit. Exclusion criteria were portal vein thrombosis, age >75 yrs, multifocal hepatocellular carcinoma, previous treatments for portal hypertension, absolute contraindications to non-selective beta-blockers' therapy and
Baseline HVPG and Doppler hemodynamics (Tables 1 and 2)
At baseline all patients showed clinically significant sinusoidal portal hypertension (HVPG 19.4±4.6 mmHg; range 13–33.5 mmHg). On Doppler examination they showed a low portal vein velocity and a high portal vein congestion index, as well as an hyperemic flow in the splanchnic area, and high intrahepatic and intrasplenic arterial vascular impedance as compared to accepted normal values [15], [16], [17], [18].
Effect of nadolol on HVPG, clinical data and Doppler hemodynamics
In the whole studied population nadolol induced a significant reduction of HVPG (after
Discussion
This is the first study simultaneously evaluating a large number of splanchnic Doppler variables and HVPG in patients with cirrhosis and portal hypertension before and after chronic primary prophylaxis with nadolol. The effects of beta-blockers on splanchnic vessels have been studied by non-invasive means in several papers. Some reported effects are reduction of portal blood flow [21], decrease in the diameter of splenic vein and superior mesenteric vein [22] and increase in impedance indexes
Acknowledgements
We thank the nursing and technologist staff of the Sala Angiografica-Radiologia Canini-Policlinico S.Orsola-Malpighi for their cooperation in the study.
This work has been supported by a grant from Ministero dell'Università e della Ricerca Scientifica e Tecnologica (MURST)-Progetti di Ricerca di Interesse Nazionale.
References (35)
Evolving consensus in portal hypertension report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension
J Hepatol
(2005)- et al.
Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage
Gastroenterology
(1990) - et al.
The hemodynamic response to medical treatment of portal hypertension as a predictor of clinical effectiveness in the primary prophylaxis of variceal bleeding in cirrhosis
Hepatology
(2000) - et al.
Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis
Lancet
(1995) - et al.
Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis
Hepatology
(2003) - et al.
‘A La Carte’ treatment of portal hypertension: adapting medical therapy to hemodynamic response for the prevention of bleeding
Hepatology
(2002) - et al.
Doppler sonography and hepatic vein catheterization in portal hypertension: assessment of agreement in evaluating severity and response to treatment
J Hepatol
(1998) - et al.
A model to predict survival in patients with end-stage liver disease
Hepatology
(2001) - et al.
Interobserver and interequipment variability of echo-Doppler examination of the portal vein: effect of a cooperative training program
Hepatology
(1995) - et al.
Interobserver and interequipment variability of hepatic, splenic, and renal arterial Doppler resistance indices in normal subjects and patients with cirrhosis
J Hepatol
(1997)
Effects of chronic therapy with nadolol on portal hemodynamics and on splanchnic impedance indices using Doppler sonography: comparison between acute and chronic effects
J Hepatol
Comparison of portal vein velocity and the hepatic venous pressure gradient in assessing the acute portal hemodynamic response to propranolol in patients with cirrhosis
Am J Gastroenterol
Noninvasive hemodynamic measurements of superior mesenteric artery in the prediction of portal pressure response to propranolol
J Hepatol
Propranolol and haemodynamic response in cirrhosis
J Hepatol
Noninvasive measurement of femoral blood flow and portal pressure response to propranolol in patients with cirrhosis
Hepatology
The portal pressure response to beta-blockade is greater in cirrhotic patients without varices than in those with varices
Gastroenterology
Effect of propranolol on portosystemic collateral circulation estimated by per-rectal portal scintigraphy with technetium-99m pertechnetate
J Hepatol
Cited by (18)
Mexican consensus on portal hypertension
2013, Revista de Gastroenterologia de MexicoEffect of chronic β-blockade on QT interval in patients with liver cirrhosis
2008, Journal of HepatologyCitation Excerpt :All patients gave written informed consent before the study. Wedged and free hepatic vein pressure was measured as described in detail elsewhere [25]. HVPG was calculated as the difference between WHVP and FHVP.
New abdominal collaterals at ultrasound: A clue of progression of portal hypertension
2008, Digestive and Liver DiseaseCitation Excerpt :Probably depending from a different anatomy, in some cases portal hypertension seems to lead first to the opening of APC and later to that of oesophageal varices, while in other cases, oesophageal varices may open before the opening of APC; along time, as portal hypertension progresses, both US and endoscopic signs of portal hypertension simultaneously progress as demonstrated by the present study. Due to the inclusion criteria of this study, we could not test the hypothesis that US collaterals are more frequently found in patients with larger oesophageal varices; yet, in a prospective study recently performed by our group on cirrhotic patients with medium–large oesophageal varices [18], we found that one or more collateral vessels were visible at US in 66.7% of patients, a prevalence about two-fold that we report in the present study in patients with milder endoscopic signs of portal hypertension. As for the rate of appearance and growth of oesophageal varices, our data confirm previous observations by our group [19] and by other authors [20–22], but more importantly, the presence of abdominal collaterals at the first US examination was not correlated to a higher rate of development or worsening of endoscopic signs of portal hypertension.
Duplex Doppler ultrasonography in portal hypertension
2007, Journal of Medical Ultrasound
- ☆
The authors who have taken part in this study declared that they have not a relationship with the manufacturers of the drugs involved either in the past or present and did not receive funding from the manufacturers to carry out their research.