doi:10.1111/j.1440-1746.2009.05873.

H E PAT O L O G Y jgh_5873 1791..1797

Effects of terlipressin on systemic, hepatic and renal

hemodynamics in patients with cirrhosis
Yoshiyuki Narahara, Hidenori Kanazawa, Yasuhiko Taki, Yuu Kimura, Masanori Atsukawa,
Tamaki Katakura, Hideko Kidokoro, Hirotomo Harimoto, Takeshi Fukuda, Yoko Matsushita,
Katsuhisa Nakatsuka and Choitsu Sakamoto
Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School, Tokyo, Japan

Key words Abstract

cirrhosis, hepatic arterial resistance, renal
arterial resistance, terlipressin.
Accepted for publication 9 March 2009.
Correspondence
Dr Yoshiyuki Narahara, Department of Internal
Medicine, Division of Gastroenterology,
Nippon Medical School, 1-1-5, Sendagi,
Bunkyo-ku, Tokyo 113-8603, Japan. Email:
y-nara@nms.ac.jp
Background and Aim: Terlipressin has been shown to be effective in the management of
hepatorenal syndrome. However, how terlipressin exerts its effect on the renal artery is
unknown. The aim of the present study was to assess the effects of terlipressin on systemic,
hepatic and renal hemodynamics in cirrhosis.
Methods: Twenty-eight patients with cirrhosis and portal hypertension were studied.
Systemic and hepatic hemodynamics, hepatic and renal arterial resistive indices and neu-
rohumoral factors were measured prior to and 30 min after intravenous administration of
1 mg terlipressin (n = 19) or placebo (n = 9).
Results: After terlipressin, there were significant increases in both mean arterial pressure
(P < 0.001) and systemic vascular resistance (P < 0.001), whereas heart rate (P < 0.001)
and cardiac output (P < 0.001) decreased significantly. There was a significant decrease in
the hepatic venous pressure gradient (P < 0.001). Portal venous blood flow also decreased
significantly (P < 0.001). The mean hepatic arterial velocity increased significantly
(P < 0.001). Although there was a significant decrease in the hepatic arterial resistive index
(0.72 ⫾ 0.08 to 0.69 ⫾ 0.08, P < 0.001) and renal arterial resistive index (0.74 ⫾ 0.07 to
0.68 ⫾ 0.07, P < 0.001), portal vascular resistance was unchanged (P = 0.231). Plasma
renin activity decreased significantly (P < 0.005), and there was a significant correlation
between this decline and the decrease in renal arterial resistive index (r = 0.764, P < 0.005).
The effects of terlipressin on systemic, hepatic and renal hemodynamics were observed
similarly in patients with and without ascites. Placebo caused no significant effects.
Conclusion: Terlipressin decreases hepatic and renal arterial resistance in patients with
cirrhosis.

hepatic arterial resistance evaluated by Doppler ultrasonography

Introduction
Terlipressin (triglycyl-lysine-vasopressin) is a vasopressin ana-
logue that has been shown to be effective in the management of
acute variceal hemorrhage.1 In addition, recent trials indicate that
terlipressin improves renal function in patients with hepatorenal
syndrome.2–7 The effect probably is mediated by an arteriolar
vasoconstriction in the splanchnic area with decreased portal pres-
sure as well as by improving renal blood flow following redistribu-
tion of effective arterial blood volume. Some attempts have been
made to investigate the effects of terlipressin on systemic, portal and
renal hemodynamics in patients with cirrhosis.8–12 However, how
terlipressin exerts its effects on the hepatic and renal arteries is as
yet unknown.
Doppler ultrasonography is useful for non-invasive assessment
of the hepatic and renal arterial resistance indices,13,14 because
these can be calculated from the systolic and diastolic velocities
and are independent of the angle between the vessel and the axis of
the ultrasound beam. In several studies, it has been reported that
was significantly higher for cirrhotic than for healthy subjects13,15
and that infusion of vasopressin decreased hepatic arterial resis-
tance.15 In addition, it has been demonstrated that renal arterial
resistance evaluated by Doppler ultrasonography was already
increased in cirrhotic patients without ascites.14 Doppler hemody-
namic evaluation of hepatic and renal arterial resistance may be
useful for both pathophysiological and clinical studies in cirrhosis.
The aim of the present study was to investigate using Doppler
ultrasonography the effects of terlipressin on the hepatic and renal
arteries in patients with cirrhosis.
Methods
Patients
Between January 2006 and June 2007, 34 patients with cirrhosis
and portal hypertension were considered for inclusion in this
study. Inclusion criteria for this study were: (i) presence of a portal

Journal of Gastroenterology and Hepatology 24 (2009) 1791–1797 © 2009 The Authors 1791
Journal compilation © 2009 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd
Terlipressin in cirrhosis Y Narahara et al.

Table 1 Clinical characteristics of the patients Table 2 Systemic hemodynamics at baseline and 30 min after giving
terlipressin and placebo
Terlipressin Placebo
Baseline After P value
Age (years) 61.4 ⫾ 11.5 63.7 ⫾ 11.1
Sex (male/female) 14/5 4/5 MAP (mmHg)
Etiology Terlipressin 88 ⫾ 11 103 ⫾ 12 <0.001
Alcohol 7 2 Ascites (-) 86 ⫾ 12 100 ⫾ 6 <0.05
Hepatitis C 7 5 Ascites (+) 89 ⫾ 11 105 ⫾ 14 <0.005
Hepatitis B 2 1 Placebo 90 ⫾ 18 90 ⫾ 18 0.672
Others 3 1 HR (b.p.m.)
Ascites (yes/no) 12/7 6/3 Terlipressin 80 ⫾ 15 71 ⫾ 15 <0.001
Child class Ascites (-) 76 ⫾ 15 69 ⫾ 12 <0.05
A 4 2 Ascites (+) 83 ⫾ 16 72 ⫾ 16 <0.005
B 9 5 Placebo 75 ⫾ 14 76 ⫾ 14 0.443
C 6 2 CO (L/min)
Child–Pugh score 8.1 ⫾ 1.9 8.2 ⫾ 1.9 Terlipressin 5.7 ⫾ 1.4 5.0 ⫾ 1.2 <0.001
Serum total bilirubin (mg/dL) 1.5 ⫾ 0.6 1.3 ⫾ 0.9 Ascites (-) 6.5 ⫾ 1.5 5.1 ⫾ 1.5 <0.05
Serum albumin (g/dL) 3.0 ⫾ 0.6 3.0 ⫾ 0.6 Ascites (+) 5.2 ⫾ 1.0 4.9 ⫾ 1.1 <0.05
Creatinine (mg/dL) 0.92 ⫾ 0.40 1.01 ⫾ 0.42 Placebo 6.2 ⫾ 1.9 6.1 ⫾ 1.9 0.859
Urinary sodium excretion (mEq/day) 64.0 ⫾ 48.7 67.8 ⫾ 38.7 SVR (dynes/s per cm5)
Terlipressin 1182 ⫾ 286 1604 ⫾ 458 <0.001
Data are given as mean ⫾ SD.
Ascites (-) 990 ⫾ 139 1520 ⫾ 449 <0.05
Ascites (+) 1295 ⫾ 293 1653 ⫾ 475 <0.005
Placebo 1204 ⫾ 594 1227 ⫾ 673 0.953
vein with a straight section for at least 3 cm; (ii) presence of angles PAP (mmHg)
between the Doppler beam and the longitudinal axis of the portal Terlipressin 15.7 ⫾ 3.7 18.3 ⫾ 3.9 <0.001
vein and the right hepatic artery less than 60°; (iii) presence of Ascites (-) 17.6 ⫾ 3.1 20.3 ⫾ 4.3 <0.05
high-quality Doppler signals of the right hepatic artery and the Ascites (+) 14.6 ⫾ 3.7 17.1 ⫾ 3.3 <0.005
interlobar artery of the kidney; and (iv) cooperation of the patients. Placebo 19.1 ⫾ 9.0 18.2 ⫾ 8.4 0.207
Exclusion criteria were (i) hepatocellular carcinoma; (ii) cardio- PCWP (mmHg)
pulmonary disease; (iii) hypertension; (iv) coronary and/or peri- Terlipressin 10.6 ⫾ 3.5 13.3 ⫾ 3.1 <0.001
Ascites (-) 12.2 ⫾ 3.6 14.9 ⫾ 3.5 <0.05
pheral arterial disease; and (v) renal disease (proteinuria and
Ascites (+) 9.6 ⫾ 3.1 12.3 ⫾ 2.6 <0.005
ultrasonographic evidence of obstructive uropathy or parenchymal
Placebo 11.2 ⫾ 5.5 10.9 ⫾ 5.3 0.500
renal disease). Of the 34 patients, six were excluded because of
RAP (mmHg)
hepatocellular carcinoma (n = 3), coronary disease (n = 1), or
Terlipressin 7.5 ⫾ 2.7 9.3 ⫾ 2.8 <0.001
renal disease (n = 2). Therefore, 28 patients were included in the
Ascites (-) 8.2 ⫾ 3.1 10.0 ⫾ 3.3 <0.05
study. A computer made the randomization code with 30 enve- Ascites (+) 7.0 ⫾ 2.6 8.9 ⫾ 2.5 <0.01
lopes, with one-third for the placebo and two-thirds for the Placebo 7.4 ⫾ 4.0 7.4 ⫾ 3.7 0.666
terlipressin, and 28 were used. Among the 28 patients, 19 were
assigned to receive terlipressin and nine were assigned to receive Data are given as mean ⫾ SD.
placebo. CO, cardiac output; HR, heart rate; MAP, mean arterial pressure; PAP,
The diagnosis of cirrhosis was made on the basis of laboratory pulmonary artery pressure; PCWP, pulmonary capillary wedged pres-
sure; RAP, right atrial pressure; SVR, systemic vascular resistance.
and ultrasonographic findings or transjugular liver biopsy. Clinical
characteristics of the patients in this study are summarized in
Table 1. There were no significant differences between patients
receiving terlipressin and placebo in relation to background
those without ascites (P < 0.01), the other background factors in
factors, baseline hemodynamic parameters and neurohumoral
terlipressin and placebo groups were not significantly different
factors (Tables 1–4). Ten patients (six terlipressin and four
between patients with and without ascites. All patients with ascites
placebo) had undergone treatment of esophageal varices previ-
responded to treatment. There were no patients with hepatorenal
ously. None of the patients received vasoactive drugs, which were
syndrome. None of the patients had undergone a paracentesis
beta-blockers, nitrates, calcium-channel blockers, angiotensin II
within the last week prior to the study.
type 1-receptor blockers, or angiotensin-converting enzyme
This study was approved by the Nippon Medical School Ethics
inhibitors. In the terlipressin group, 12 patients had moderate to
Committee and all patients provided written informed consent.
severe ascites and 13 were receiving diuretics (13 patients furo-
semide, mean 45 mg/day, and 12 patients spironolactone, mean
58 mg/day), whereas in placebo group, six patients had moderate
Study protocol
to severe ascites and seven were receiving diuretics (seven patients
furosemide, mean 51 mg/day, and six patients spironolactone, The baseline data of mean arterial pressure (MAP), heart rate
mean 64 mg/day). Although the Child–Pugh score in the terlipres- (HR), cardiac output (CO), systemic vascular resistance (SVR),
sin group was significantly higher in patients with ascites than in pulmonary artery pressure (PAP), pulmonary capillary wedged

1792 Journal of Gastroenterology and Hepatology 24 (2009) 1791–1797 © 2009 The Authors
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Y Narahara et al. Terlipressin in cirrhosis

Table 3 Hepatic hemodynamics and hepatic and renal arterial resistive Table 4 Changes in neurohumoral factors at baseline and 30 min after
indices at baseline and 30 min after giving terlipressin and placebo giving terlipressin and placebo

Baseline After P value Baseline After P value

HVPG (mmHg) PRA (ng/mL per h)

Terlipressin 19.4 ⫾ 5.3 16.4 ⫾ 5.3 <0.001 Terlipressin 8.0 ⫾ 5.3 4.1 ⫾ 3.3 <0.005
Ascites (-) 16.3 ⫾ 3.1 13.8 ⫾ 3.4 <0.05 Ascites (-) 7.2 ⫾ 0.5 3.0 ⫾ 1.3 <0.05
Ascites (+) 21.2 ⫾ 5.6 17.9 ⫾ 5.8 <0.005 Ascites (+) 8.4 ⫾ 6.3 4.6 ⫾ 3.9 <0.05
Placebo 17.4 ⫾ 6.8 17.4 ⫾ 6.9 0.673 Placebo 7.5 ⫾ 8.3 7.8 ⫾ 7.7 0.588
PVBF (mL/min) PAC (pg/mL)
Terlipressin 691 ⫾ 523 483 ⫾ 398 <0.001 Terlipressin 230 ⫾ 205 181 ⫾ 159 <0.05
Ascites (-) 479 ⫾ 303 337 ⫾ 201 <0.05 Ascites (-) 168 ⫾ 115 137 ⫾ 61 0.472
Ascites (+) 814 ⫾ 594 568 ⫾ 464 <0.005 Ascites (+) 261 ⫾ 239 203 ⫾ 191 <0.05
Placebo 614 ⫾ 245 629 ⫾ 258 0.054 Placebo 162 ⫾ 123 156 ⫾ 118 0.398
PVR (mmHg min/L) NE (pg/mL)
Terlipressin 64.2 ⫾ 110 65.6 ⫾ 98.2 0.231 Terlipressin 653 ⫾ 341 330 ⫾ 196 <0.005
Ascites (-) 99.8 ⫾ 178.9 99.0 ⫾ 159.8 0.463 Ascites (-) 581 ⫾ 372 286 ⫾ 178 0.063
Ascites (+) 43.4 ⫾ 32.4 46.1 ⫾ 27.2 0.308 Ascites (+) 689 ⫾ 345 352 ⫾ 212 <0.05
Placebo 33.2 ⫾ 21.6 33.1 ⫾ 20.9 0.889 Placebo 532 ⫾ 247 611 ⫾ 259 0.441
HAV (cm/s) ANP (pg/mL)
Terlipressin 27.7 ⫾ 8.5 36.2 ⫾ 13.9 <0.001 Terlipressin 26.1 ⫾ 18.9 31.7 ⫾ 19.8 0.285
Ascites (-) 27.9 ⫾ 10.0 40.3 ⫾ 21.3 <0.05 Ascites (-) 43.5 ⫾ 23.4 48.3 ⫾ 18.5 0.784
Ascites (+) 27.6 ⫾ 8.0 33.7 ⫾ 7.2 <0.005 Ascites (+) 17.4 ⫾ 8.0* 23.4 ⫾ 15.3* <0.05
Placebo 24.4 ⫾ 5.5 24.4 ⫾ 5.2 0.953 Placebo 33.2 ⫾ 10.5 35.6 ⫾ 13.8 0.314
HA-RI AVP (pg/mL)
Terlipressin 0.72 ⫾ 0.08 0.69 ⫾ 0.08 <0.001 Terlipressin 1.3 ⫾ 0.4 4.1 ⫾ 0.6 <0.005
Ascites (-) 0.74 ⫾ 0.07 0.69 ⫾ 0.07 <0.05 Ascites (-) 1.3 ⫾ 0.1 4.0 ⫾ 0.5 <0.005
Ascites (+) 0.71 ⫾ 0.09 0.69 ⫾ 0.09 <0.05 Ascites (+) 1.3 ⫾ 0.5 4.1 ⫾ 0.7 <0.05
Placebo 0.78 ⫾ 0.05 0.78 ⫾ 0.06 0.579 Placebo 1.2 ⫾ 0.8 1.0 ⫾ 0.6 0.172
RA-RI
Data are given as mean ⫾ SD.
Terlipressin 0.74 ⫾ 0.07 0.68 ⫾ 0.07 <0.001
*P < 0.05 compared to ascites (-).
Ascites (-) 0.74 ⫾ 0.04 0.68 ⫾ 0.04 <0.05
ANP, atrial natriuretic peptide; AVP, arginine vasopressin; NE, norepi-
Ascites (+) 0.74 ⫾ 0.08 0.68 ⫾ 0.08 <0.005
nephrine; PAC, plasma aldosterone concentration; PRA, plasma renin
Placebo 0.75 ⫾ 0.08 0.74 ⫾ 0.07 0.739
activity.
Data are given as mean ⫾ SD.
HAV, mean hepatic arterial velocity; HA-RI, hepatic arterial resistive
index; HVPG, hepatic venous pressure gradient; PVBF, portal venous
After measurements of baseline data, 1 mg intravenous injec-
blood flow; PVR, portal vascular resistance; RA-RI, renal arterial resistive
tion of terlipressin (Glypressin; Ferring AB, Limhamn, Sweden) or
index.
placebo (5 mL saline) was given and the measurements were
repeated 30 min later.
pressure (PCWP), right atrial pressure (RAP) and hepatic venous
pressure gradient (HVPG) were measured by means of a catheter- Catheterization
ization of the right heart and hepatic vein.
The Doppler hemodynamic studies were carried out at the same After an overnight fast, the right jugular vein was cannulated and
time. Doppler indices included the blood flow of the portal vein, a Swan-Ganz catheter (7 F Thermodilution Catheter; Biosensors
the mean velocity of the hepatic artery and the resistive index of International Co. Ltd, Tokyo, Japan) was placed in the pulmonary
the hepatic and renal arteries. One investigator carried out all artery for measurement of CO, PAP, PCWP and RAP. An auto-
ultrasound measurements. Systemic hemodynamic indices, HVPG matic blood pressure instrument was used to non-invasively
and Doppler indices were estimated from the average of three monitor MAP and HR. SVR was calculated as (MAP - RAP/
consecutive measurements. CO) ¥ 80. Subsequent to this, a 5 F balloon-tipped catheter (Clini-
Measurements of plasma renin activity (PRA), plasma aldoster- cal Supply Co. Ltd, Gifu, Japan) was inserted into the right hepatic
one concentration (PAC), plasma norepinephrine (NE) concentra- vein for measurement of wedged and free hepatic venous pressure.
tion, plasma atrial natriuretic peptide (ANP) concentration, and The HVPG was calculated as wedged hepatic venous pressure—
plasma arginine vasopressin (AVP) concentration were carried out free hepatic venous pressure.
at baseline. Diuretics were discontinued only on the day of the
investigations. Neurohumoral factors were assessed in 12 patients
Doppler hemodynamic measurements
(four had no ascites and eight had ascites), but were not measured
in seven patients in the terlipressin group, whereas all placebo Ultrasonographic examination was carried out at rest in the supine
patients assessed neurohumoral factors. position. A Doppler ultrasonography scanner (Power Vision 6000;

Journal of Gastroenterology and Hepatology 24 (2009) 1791–1797 © 2009 The Authors 1793
Journal compilation © 2009 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd
Terlipressin in cirrhosis Y Narahara et al.

Toshiba, Tokyo, Japan) equipped with a single convex multifre-
quency electronic probe was used in B mode with a pulsed system
(3.75 MHz).
The portal vein was scanned longitudinally and the Doppler
sample volume was then set at the center of the lumen, 1–2 cm
before the bifurcation of the portal vein. Cross-sectional area and
mean velocity measurements were obtained. The blood flow was
calculated as cross-sectional area ¥ mean velocity ¥ 60. Cross-
sectional area was calculated as p ¥ r 2, where r is the radius. Portal
vascular resistance (PVR) was calculated as HVPG/portal venous
blood flow (PVBF).
Under the right intercostal scanning of the liver, the right hepatic
artery, where it crossed the portal vein around the porta hepatis
was identified using color Doppler ultrasonography. After the
Doppler sample volume was located in the right hepatic artery, the
time velocity waveform of the Doppler signal was recorded. Peak
systolic, end diastolic and mean velocity were measured, and the
hepatic arterial resistive index ([peak systolic velocity—end dias-
tolic velocity]/peak systolic velocity) was determined.13 In addi-
tion, the resistive index of the renal artery was determined at the
interlobar artery of the kidney.14
Intraobserver variability for measuring the hepatic and renal
arterial resistive indices was tested in 10 preliminary patients. The
variation was less than 5%.
Assays of neurohumoral factors
Plasma renin activity and PAC were measured by radioimmunoas-
say (TFB, Inc., Tokyo, Japan). Normal values ranged from 0.3 to
2.9 ng/mL per h for PRA and from 29.9 to 159.0 pg/mL for PAC.
Plasma NE concentrations were determined by fluorescent detec-
tion after separation by high performance liquid chromatography
(Tosoh Co., Tokyo, Japan). Normal values of NE concentrations
were from 100 to 450 pg/mL. Plasma ANP concentrations and
plasma AVP concentrations were measured by radioimmunoassay
(Shionogi & Co. Ltd, Osaka, Japan and Mitsubishi Kagaku Iatron,
Inc., Tokyo, Japan). Normal values of ANP concentrations were
less than 40 pg/mL and normal values of AVP concentrations were
from 0.3 to 3.5 pg/mL.
(P < 0.001) and SVR by 36% (P < 0.001). HR and CO decreased
11% (P < 0.001) and 12% (P < 0.001), respectively. PAP, PCWP
and RAP increased after terlipressin infusion (P < 0.001). Sys-
temic hemodynamic indices at baseline were not significantly dif-
ferent between patients with and without ascites. There were no
significant differences between patients with and without ascites in
the changes in MAP, HR, SVR, PAP, PCWP and RAP, but the
changes in CO were significantly lower in patients with ascites
(P < 0.005).
Changes in hepatic hemodynamics
with terlipressin
Table 3 shows the results of hepatic hemodynamic changes. After
terlipressin, HVPG and PVBF decreased 15% (P < 0.001) and
30% (P < 0.001), respectively. PVR was unchanged (P = 0.231).
The mean hepatic arterial velocity (HAV) increased 31%
(P < 0.001). HVPG, PVBF, PVR and HAV at baseline were not
significantly different between patients with and without ascites.
There were no significant differences between patients with and
without ascites in the changes in HVPG, PVBF, PVR and HAV.
Changes in hepatic and renal arterial resistive
indices with terlipressin
The changes in hepatic and renal arterial resistive indices with
terlipressin in the individual patients are shown in Fig. 1. There
were no significant differences between alcoholic cirrhosis and
viral cirrhosis in the changes in hepatic and renal arterial resistive
indices. There was a slight but significant decrease in hepatic
arterial resistive index (HA-RI) (-4%, P < 0.001) after infusion of
terlipressin (Table 3). HA-RI at baseline was not significantly dif-
ferent between patients with and without ascites. The changes in
HA-RI were significantly lower in patients with ascites than in
those without ascites (P < 0.05). Four of the 12 patients with
ascites had no decrease in HA-RI, whereas seven patients without
ascites decreased in HA-RI. Renal arterial resistive index (RA-RI)
decreased significantly (-8%, P < 0.001) after terlipressin

Statistical analysis (a) (b)

All results are expressed as mean ⫾ standard deviation. Compari-
sons between terlipressin and placebo groups were carried out
using the c2-test with Yates’ correction or Fisher’s exact test and
the Mann-Whitney U-test. The Wilcoxon test or paired t-test was
used to compare differences within the patient groups. Compari-
sons between patients with and without ascites were carried out
using the c2-test with Yates’ correction or Fisher’s exact test and
the Mann-Whitney U-test or unpaired t-test. Correlation was ana-
lyzed by the Spearman rank correlation test. A two-tailed P value
of 0.05 was considered statistically significant.

Results

Changes in systemic hemodynamics

with terlipressin
Figure 1 (a) Hepatic arterial resistive index and (b) renal arterial resis-
Table 2 shows the results of systemic hemodynamic changes. tive index at baseline and after terlipressin. Statistical significance:
Following terlipressin administration, MAP increased by 17% *P < 0.001.

1794 Journal of Gastroenterology and Hepatology 24 (2009) 1791–1797 © 2009 The Authors
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Y Narahara et al.
Figure 2 Correlation between the change in plasma renin activity and
the change in renal arterial resistive index after terlipressin.
(Table 3). RA-RI at baseline was not significantly different
between patients with and without ascites. No difference in the
changes in RA-RI was found between patients with and without
ascites.
Changes in neurohumoral factors with
terlipressin
Plasma renin activity, PAC and NE decreased significantly
(P < 0.005, P < 0.05 and P < 0.005, respectively), and AVP
increased significantly (P < 0.005) after terlipressin. ANP was
unchanged (P = 0.285) (Table 4). There was a significant correla-
tion between the change in PRA and the change in RA-RI
(r = 0.764, P < 0.005) (Fig. 2). However, there were no correla-
tions between the change in PAC or NE and the change in RA-RI.
PRA, PAC, NE and AVP at baseline were not significantly differ-
ent between patients with and without ascites. ANP at baseline was
significantly lower in patients with ascites than in those without
ascites (P < 0.05). There were no significant differences between
patients with and without ascites in the changes in neurohumoral
factors.
Effects of giving a placebo
As shown in Tables 2–4, giving a placebo had no significant
effects on systemic and hepatic hemodynamics, hepatic and renal
arterial resistive indices and neurohumoral factors. These param-
eters at baseline and the changes in those were not significantly
different between patients with and without ascites.
Tolerability
Four patients had diarrhea and five patients presented with
abdominal pain after terlipressin administration, both symptoms
resolved without treatments. No adverse effects related to placebo
were seen.
Journal of Gastroenterology and Hepatology 24 (2009) 1791–1797 © 2009 The Authors
Journal compilation © 2009 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd
Terlipressin in cirrhosis
Discussion
Terlipressin, an agonist of the V1 vasopressin receptors, is inactive
in its native form, but is transformed into the biologically active
form, lysine-vasopressin, through enzymatic cleavage of glycyl
residues by tissue peptidases.16 Because of this modification,
terlipressin has a prolonged biological half-life compared with
other vasopressin analogues (such as ornipressin).17 In addition,
Escorsell et al. demonstrated that the peak reduction in HVPG was
achieved at 30 min after giving 1 mg terlipressin.11 Furthermore,
Hansen et al. showed that 1 mg terlipressin produced a significant
reduction in portal venous blood flow at 30 min in healthy pigs.18
Therefore, the hemodynamic measurements in the present study
were carried out at 30 min.
Previous studies demonstrated that the injection of 2 mg terlip-
ressin was effective on systemic and splanchnic hemodynamics in
patients with cirrhosis;8,9,12 however, Escorsell et al. reported that
giving 1 mg terlipressin was effective in such patients.11 Intrave-
nous injection of 1 mg terlipressin is the recommended dose for
the treatment of hepatorenal syndrome and 1 mg terlipressin every
4–6 h improves renal function in patients with hepatorenal syn-
drome.19 Therefore, 1 mg terlipressin was given in this study.
The patient population in the present study had heterogeneity
with respect to the severity of cirrhosis as well as to previous
studies.8–12 Ten patients had no ascites and 18 had ascites.
Although all had portal hypertension, the different clinical stages
reflect a difference in circulatory, hormonal and renal function.
This may significantly affect the results. However, no study has
investigated that the effects of terlipressin on systemic, hepatic
and renal hemodynamics are different between different clinical
stages in cirrhotic patients. Therefore, we also evaluated differ-
ences between cirrhotic patients with and without ascites in all
measurements.
In our study, terlipressin increased MAP and SVR, and
decreased HR and CO, which are consistent with the systemic
hemodynamic effects described previously.8–12 Patients with cir-
rhosis and portal hypertension exhibit a hyperdynamic circulation
with increased HR and CO and decreased MAP and SVR.20 The
changes may be brought about by a peripheral arterial vasodilata-
tion, which appears to be most excessive in the splanchnic area.21
According to the peripheral arterial vasodilation hypothesis,21
splanchnic arterial vasodilatation produced by vasodilators
decreased effective arterial blood volume. Indeed, it has been
demonstrated that patients with cirrhosis and portal hypertension
have increased blood pooling in the splanchnic area and a reduc-
tion of the central blood volume.22,23 V1 receptors are involved in
smooth muscle contraction and are particularly abundant in the
splanchnic area.24 Thus, it was postulated that terlipressin attenu-
ated the hyperdynamic circulation due to increased effective arte-
rial blood volume following arteriolar vasoconstriction in the
splanchnic area.
The present study also showed that terlipressin decreased renal
arterial resistance. The decrease in renal arterial resistance can be
explained largely by the increase in MAP in response to terlipres-
sin. In our study, MAP increased by 17%, which might have a
significant impact on the renal circulation. Thus, it was postulated
that the systemic vasoconstriction produced by terlipressin
increased MAP, which improved renal perfusion pressure and
reduced renin release and sympathetic nervous system activity, as
1795
Terlipressin in cirrhosis
indicated by the decrease in PRA, PAC and NE. This reduction in
vasoconstrictors could decrease renal arterial resistance and
increase renal blood flow (RBF). According to research carried out
on decompensated cirrhotic patients, a constant 4-h infusion of
ornipressin results in an increase in RBF and a decrease in renal
vascular resistance.25 Ornipressin, like terlipressin, appears to
reverse splanchnic vasodilatation without increasing renal vascular
resistance because of the preferential distribution of V1 receptors
in the splanchnic area. Gadano et al. recently reported that terlip-
ressin increased RBF in patients with cirrhosis and refractory
ascites.10 Although we did not measure RBF, we measured RA-RI
using Doppler ultrasonography. The decreases in renal arterial
resistance and PRA in the present study suggest that renal arterial
blood flow is increased.
In comparing cirrhotic patients with and without ascites, RA-RI,
PRA, PAC and NE at baseline were not significantly different and
the changes in these parameters were not different between both
groups. These results indicate that terlipressin decreases renal arte-
rial resistance in cirrhotic patients with and without ascites.
In the present study, PVBF and hepatic arterial resistance
decreased and HAV increased after giving terlipressin. Decreased
hepatic arterial resistance and increased HAV suggest that hepatic
arterial blood flow is increased. Thus, the reduction in PVBF
induced by terlipressin may be compensated by increased hepatic
arterial blood flow. Iwao et al. showed that vasopressin infusion
decreased PVBF and hepatic arterial resistance in cirrhotic
patients.15 Several studies have shown that, when PVBF decreases,
hepatic arterial blood flow increases, and vice versa. This phenom-
enon has been described as the hepatic arterial buffer response
(HABR) and is an intrinsic regulatory mechanism of the liver to
maintain total hepatic blood flow.26–28 Terlipressin infusion had a
marked systemic hemodynamic effect manifested by a significant
increase in MAP and reflex bradycardia in cirrhotic patients. These
effects may alter hepatic artery hemodynamic response because of
the passive effect of the increased arterial blood pressure and
hepatic artery autoregulation in response to increased arterial
blood pressure.27
The changes in HA-RI were significantly lower in cirrhotic
patients with ascites than in those without ascites. The reason
terlipressin infusion dose not decrease HA-RI in some cirrhotic
patients with ascites is not clear. One reason may be individual
differences of HABR. Some studies indicated that the HABR was
blunted in some cirrhotic patients.15,28 It has been suggested that
the HABR is mediated by adenosine, a potent vasodilating sub-
stance.29 Blunted HABR in cirrhotic patients may be explained by
hyposensitivity of adenosine receptors of the hepatic artery.30
Four patients in the present study had diarrhea and five had
abdominal pain after giving terlipressin. Other side-effects
reported in other studies in patients treated with terlipressin, such
as ischemic heart disease, arrhythmia, arterial hypertension,
peripheral ischemia or bronchospasm,2–6 were not observed in the
current investigation.
In conclusion, terlipressin decreases renal arterial resistance and
PRA, PAC and NE. Decreases in renal arterial resistance and PRA
suggest that renal arterial blood flow is increased. Terlipressin also
decreases hepatic arterial resistance. Decreased hepatic arterial
resistance may be a compensatory mechanism to maintain total
hepatic blood flow. The benefit of terlipressin for patients with
hepatorenal syndrome may be achieved by the changes observed.
1796
Journal compilation © 2009 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd
Y Narahara et al.
In addition, further study should be done to clarify the effects of
terlipressin on systemic, hepatic and renal hemodynamics in
patients with hepatorenal syndrome.
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