Noradrenaline vs terlipressin in the treatment of type 2 hepatorenal syndrome: a randomized pilot study

C IRRHOS IS AND L IVER FAILURE

Noradrenaline vs terlipressin in the treatment of type 2 hepatorenalsyndrome: a randomized pilot studySaubhik Ghosh1, Narendra S. Choudhary1, Arun K. Sharma1, Baljinder Singh2, Pradeep Kumar2, Ritesh Agarwal3,Navneet Sharma4, Ashish Bhalla4, Yogesh K. Chawla1 and Virendra Singh1

1 Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

2 Department of Nuclear Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India

3 Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India

4 Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Keywords

Ascites – renal dysfunction – splanchnic

vasodilatation – vasopressor

Correspondence

Dr Virendra Singh, MD, DM, FASGE,

Department of Hepatology, PGIMER,

Chandigarh 160012, India

Tel: +911722756338

Fax: +911722744401

e-mail: [email protected]

Received 31 August 2012

Accepted 23 March 2013

DOI:10.1111/liv.12179

Liver Int. 2013: 33: 1187–1193

AbstractBackground: Various vasoconstrictors have shown promising results in themanagement of type 1 hepatorenal syndrome (HRS). However, there are veryfew studies on vasopressors in the management of type 2 HRS. Terlipressinhas been used commonly; however, it is costly and not available in somecountries. In this study, we evaluated the safety and efficacy of terlipressinand noradrenaline in the treatment of type 2 HRS. Methods: Forty-sixpatients with type 2 HRS were managed with terlipressin (group A, N = 23)or noradrenaline (Group B, N = 23) with albumin in a randomizedcontrolled trial at a tertiary centre. Results: HRS reversal could be achievedin 17(73.9%) patients in group A as well as in group B (P = 1.0). Univariateanalysis showed that the baseline model of end-stage liver disease score, urineoutput, urinary sodium, serum creatinine and mean arterial pressure wereassociated with response. However, in multivariate analysis only baselineserum creatinine, urine output and urinary sodium were associated with theresponse. Eight patients in group A and 9 in group B died within 90 days offollow-up (P > 0.05). Noradrenaline was less expensive than terlipressin(P < 0.05). No major adverse effects were seen. Conclusions: The results ofthis randomized study suggest that terlipressin and noradrenaline are safeand effective in the treatment of type 2 HRS and baseline serum creatinine,urine output and urinary sodium are predictive of response. Noradrenalineis less expensive than terlipressin in the treatment of type 2 HRS (ClinicalTrials.gov, Number NCT01637454).

Hepatorenal syndrome (HRS) is a frequent occurrencein decompensated cirrhosis and carries a high mortality(1–3). Marked circulatory dysfunction with splanchnicarterial vasodilatation and renal vasoconstriction plays amajor role in the pathogenesis of HRS (4). Several stud-ies have evaluated the efficacy of various vasopressors inpatients with post-paracentesis circulatory dysfunction(5–8), refractory ascites (9, 10) and HRS (11–15). Terli-pressin is a drug of choice particularly in type 1 HRS(16–19). However, terlipressin is not readily availablein several countries and the therapy is expensive.Noradrenaline, a catecholamine with predominantlyalpha-adrenergic activity is widely available and is rela-tively inexpensive. Noradrenaline has shown encourag-ing results in post-paracentesis circulatory dysfunction(6) and type 1 HRS (14, 15, 20). There are very fewstudies on the role of vasopressors (12, 16, 20–23) and

more so on noradrenaline in type 2 HRS (20). Variousstudies have also predicted factors of response inpatients with HRS (15, 16, 18, 19, 24, 25). We plan tostudy the safety and efficacy of terlipressin and nor-adrenaline and predictive factors of response in type 2HRS.

Methods

This study included 58 consecutive patients with cirrho-sis and type 2 HRS attending Hepatology department ofa tertiary centre between January 2009 and December2011, prospectively. Twelve patients were excluded dur-ing this study because of various reasons (severe coro-nary artery disease in 1, sepsis in 7, hepatocellularcarcinoma in 1, diabetic nephropathy in 1 and refusal toparticipate in 2 patients). This study was approved by

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Ethics committee of Postgraduate Institute of MedicalEducation and Research, Chandigarh. Written informedconsent was taken. Diagnosis of type 2 HRS was basedon the criteria of International Ascites Club (26).

Inclusion criteria were cirrhosis with ascites withserum creatinine more than 1.5 mg/dl and less than2.5 mg/dl; absence of shock, fluid losses and treatmentwith nephrotoxic drug; no improvement in renal func-tion following diuretic withdrawal and plasma volumeexpansion; no ultrasound evidence of renal parenchymaldisease or obstructive uropathy and absence of protein-uria more than 500 mg/24 h. Patients with the historyof coronary artery disease, cardiomyopathy, ventriculararrhythmia or obstructive arterial disease of limbs wereexcluded.

Patients were randomized to either terlipressin ornoradrenaline group. A computer made the randomi-zation code with 46 envelops with half for terlipressin(group A) and half for noradrenaline (group B).Patients and investigators were not blinded to the treat-ment assignments because of the nature of interven-tion. Patients in either group received treatment withterlipressin or noradrenaline with 20 gm albumin/day.Patients in group A received terlipressin as an intrave-nous bolus of 0.5 mg every 6 h. If a significant reduc-tion in serum creatinine level (� 1 mg/dL) was notobserved during 3-day period, the dose of terlipressinwas increased in a stepwise fashion every 3 days to amaximum of 2 mg every 6 h. Patients in group Breceived a continuous infusion of noradrenaline at aninitial dose of 0.5 mg/h, designed to achieve anincrease in mean arterial pressure (MAP) of at least10 mmHg or an increase in 4-h urine output to morethan 200 ml. When one of these goals was notachieved, the noradrenaline dose increased every 4 h insteps of 0.5 mg/h, up to the maximum dose of 3 mg/h.Albumin was withheld if central venous pressure wasmore than 18 cm of saline. All patients were admittedfor 15 days in hospital for treatment. Clinical andbiochemical parameters were assessed at baseline andat day 15. Arterial blood sample was collected afterovernight fast and bed rest at least for 8 h in supineposition for plasma renin activity and aldosterone con-centration. Blood samples were taken from the radialartery, put into chilled ethylenediamine tetraacetic acidtubes, centrifuged at 1013 rcf for 10 min at �3°C andstored at �80°C. Plasma renin activity was measuredby radioimmunoassay using Gamma Coat- 125I RIAplasma renin activity kit (Immunotech SA, Marseille,France). Plasma aldosterone concentration was mea-sured by radioimmunoassay using RIA aldosterone kit(Immunotech SA, France).

Outcome measures

The primary end point of this study was serum creati-nine less than 1.5 mg. Secondary end points includedeath of patients or maximum 15 days of therapy.

Follow-up

Patients were followed-up until death or 3 monthsat regular intervals. During follow-up, patients weretreated with diuretics and large volume paracentesis asneeded. Recurrence of HRS was treated with terlipressinor noradrenaline as earlier.

Statistical analysis

The results were expressed as mean ± standard devia-tion (SD) or median with range. Comparisons betweengroups were performed using Student’s t-test or theMann–Whitney U-test, in case the distribution of datawas normal or skewed respectively. For categorical datachi-squared test (or Fisher’s exact test if the value in anycell was � 5) was applied. The values for repeatedmeasures were analysed using the two-way repeatedmeasures analysis of variance with Bonferroni adjust-ment for multiple comparisons. A value of P < 0.05 wastaken as significant value. The results were analysed atbaseline and at day 15 of this study. The mortality wasshown by Kaplan–Meier survival curve. Factors affectingresponse to vasopressor therapy were evaluated usingmultivariable logistic regression analysis. Initially, thevariables were analysed using univariate analysis toderive crude odds ratio and if found significant(P < 0.05) these variables were then entered in a multi-variate logistic regression model to derive adjusted oddsratio and 95% confidence limits. As we conducted apilot study, no power calculation was performed.

Results

The baseline clinical, biochemical and haemodynamicparameters were similar in group A and B (Table 1).Table 2 shows the effect of noradrenaline in comparisonwith terlipressin on different parameters at baseline andat day 15 of this study period. There was a significantdecrease in serum creatinine from baseline in bothgroups (P < 0.05, Table 2). Mean arterial pressures,urine output and urinary sodium increased significantlyin both the groups at day 15 (P < 0.05, Table 2). Plasmarenin activity and aldosterone concentrations decreasedsignificantly in both the groups at day 15 (P < 0.05,Table 2). Seventeen (73.9%) patients in group A as wellas in group B responded to the therapy (P = 1.0,Table 2). Twelve (Gr A-6, Gr B-6) patients did notrespond to the treatment. At the end of 90 days offollow-up, 8 (34.7%) patients in group A (2 responderand 6 non- responder) and 9 (39.1%) in group B (3responder and 6 non-responder) died (P > 0.05). Therewas recurrence in 6 (35.3%) and 7 (41.2%) respondersin terlipressin and noradrenaline groups, respectively,during the follow-up till 90 days. Recurrence of HRSwas treated with terlipressin or noradrenaline andshowed a response in 66.7% (4/6) and 57.1% (4/7)patients respectively. The main causes of death were

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Vasopressors in type 2 hepatorenal syndrome Ghosh et al.

sepsis (N = 8), liver failure (N = 2), gastrointestinalhaemorrhage (N = 3) and multiorgan failure (N = 4).The survival curves shown by the Kaplan–Meier method(Fig. 1) and compared with the log-rank test were notdifferent in both the groups (P = 0.789) at 90 days. Themean duration of therapy in group A and B were8.6 ± 3.2 days (range 4–15 days) and 8.7 ± 3.8 days(range 4–15 days) respectively. The cost of the treat-ment with terlipressin with a median dose of 1.9mg/day for 15 days was 804 USD and that of noradren-aline with a median dose of 11.3 mg/day for 15 dayswas 311 USD (P < 0.05) excluding the cost of albuminand that of hospital admission in either group.

Urine output, urinary sodium and MAP increasedsignificantly and there was a marked suppression ofrenin-angiotensin-aldosterone system in responders atday 15 (Table 3). There was no significant increase inurine output and MAP and no suppression of renin-angiotensin-aldosterone system in non-responders atday 15 (Table 3). However, there was a significantincrease in urinary sodium in non-responders at day 15.

Several variables obtained at baseline were analysedfor predictive value of response to the treatment. Uni-variate analysis (Table 4) showed baseline model ofend-stage liver disease score, urine output, urinarysodium, serum creatinine and MAP to be associatedwith response; however, on multivariate analysis onlybaseline serum creatinine, urine output and urinarysodium were associated with the response (Table 5).

In terlipressin group, 2 patients developed abdomi-nal cramps and increased frequency of stools, 1developed cyanosis of toe and another developed

transient ventricular extrasystole. These adverse eventswere self-limiting. In the noradrenaline group, onepatient experienced atypical chest pain with normalcardiac investigations. No adverse effects related to theintravenous albumin infusion were seen.

Discussion

Vasoconstrictors have demonstrated encouraging resultsin patients with HRS by increasing effective arterialblood volume in various studies specially terlipressin intype 1 HRS (11–15). Vasopressors have been used inpatients with type 2 HRS (12, 16, 20–23), however, thereis insufficient evidence to recommend their use in type2 HRS (27). There is only one study on the use ofnoradrenaline in patients with type 2 HRS (20). How-ever, vasopressors have also been used in patients withrefractory ascites with normal renal function (9, 10). Inthis study, we evaluated the role of terlipressin and nor-adrenaline with albumin for the management of type 2HRS in patients with cirrhosis. This study showed rever-sal of HRS in 73.9% patients in each group. There arevery few studies evaluating the effect of vasoconstrictortherapy in type 2 HRS in a small number of patients(12, 16, 20–23). Marta Martin et al. (16) showedreversal of type 2 HRS in 67% (4/6) of patients withterlipressin therapy. Alessandria et al. (21) reportedimprovement of renal function in 73% (8/11) of type 2HRS patients with terlipressin. Alessandria et al. (20)also reported in a prospective, randomized, unblinded,pilot study of type 2 HRS patients a reversal of HRSin 67% (4/6) and 86% (6/7) in noradrenaline and

Table 1. Baseline clinical, biochemical and hormonal variables of patients in the study groups

Variables Terlipressin (n = 23) Noradrenaline (n = 23) P value

Age (years) 45.8 ± 9.2 48.2 ± 10.5 0.363Male sex 20 (87%) 16 (69.6%) 0.284AetiologyAlcohol 15 (65.2%) 16 (69.5%) 0.753Others 8 (34.7%) 7 (30.4%)NASH/Cryptogenic 3 (13%) 2 (8.6%)HBV 0 4 (17.3%)HCV 4 (17.3%) 0Autoimmune 1 (4.3%) 1 (4.3%)

Spontaneous bacterial peritonitis 4 (17.4%) 3 (13%) 0.685Child Pugh score 10.0 ± 1.77 10.5 ± 2.35 0.561MELD score 21.3 ± 2.79 21.0 ± 3.28 0.536Serum albumin (g/dl) 2.85 ± 0.22 2.92 ± 0.34 0.319Serum bilirubin (mg/dl) 2.38 ± 0.76 2.67 ± 0.86 0.261Serum sodium (meq/L) 128.2 ± 5.6 128.4 ± 5.1 0.991Blood urea (mg/dl) 82.7 ± 27.1 80.3 ± 24.3 0.754Serum creatinine (mg/dl) 2.15 ± 0.21 2.05 ± 0.22 0.106Urinary sodium (meq/ml) 24.8 ± 10.5 23.7 ± 9.8 0.725Urine output/24 h (ml) 717.1 ± 290 670.4 ± 260 0.598Mean arterial pressure (mmHg) 65.3 ± 7.2 66.2 ± 9.5 0.652Plasma renin activity (ng/ml/h) 35.2 ± 13.3 33.0 ± 12.3 0.482Plasma aldosterone concentration (pg/ml) 1615.6 ± 618.5 1619.3 ± 668.3 0.985

Data are mean ± SD or number (%) of patients; MELD, model for end-stage liver disease.


Ghosh et al. Vasopressors in type 2 hepatorenal syndrome

terlipressin groups respectively. Ortega et al. (12)reported complete response in 80% (4/5) of type 2 HRSpatients with terlipressin. In another study including 11

patients with type 2 HRS, octreotide with albumin wasnot effective for the treatment of type 2 HRS (22). In arecent retrospective study, 26 patients with type 2 HRS

Table 2. Change in parameters with therapy in two study groups

Parameter

Terlipressin group (A) Noradrenaline group (B)

Day 1 Day 15 P value Day 1 Day 15 P value

Serum creatinine (mg/dl) 2.12 ± 0.21 1.41 ± 0.58 0.000 1.98 ± 0.19 1.27 ± 0.23 0.000Urine output (ml/d) 833.3 ± 200.2 1287.2 ± 303.7 0.000 716.1 ± 266.2 1213.3 ± 312.7 0.000Urinary sodium (mEq/L) 28.1 ± 9.4 60.9 ± 10.2 0.000 25.8 ± 9.4 62.4 ± 7.2 0.000Mean arterial pressure (mmHg) 67.3 ± 7.2 77.3 ± 5.3 0.000 66.6 ± 8.8 76.3 ± 4.9 0.000Plasma renin activity (ng/ml/h) 36.4 ± 14.4 12.3 ± 6.9 0.000 34.6 ± 13.1 10.6 ± 3.92 0.000Plasma aldosterone concentration (pg/ml) 1659.4 ± 657.9 647.7 ± 269.0 0.000 1697.5 ± 716.4 597.7 ± 289.1 0.000Number of responders (%) 0 17 (73.9) 0 17 (73.9)*Cost of treatment for 15 days ($) 804 311†

Data are mean ± SD; values between group A and group B at baseline and day 15 were not significantly different.

*P = 1.0 (group A vs B).

†P < 0.05 (group A vs B).

Fig. 1. Kaplan–Meier curve showing the cumulative probability of survival of patients treated with terlipressin and noradrenaline.

Table 3. Change in parameters according to the response in study group

Parameter

Responders Non-responders

Day 1 Day 15

P value(day 1 vsday 15) Day 1 Day 15

P value(day 1 vsday 15)

Serum creatinine (mg/dl) 2.04 ± 0.21 1.22 ± 0.14 0.000 2.22 ± 0.15 2.35 ± 0.80 0.752Urine output (ml/d) 792.4 ± 242.1 1302.7 ± 261.0 0.000 580 ± 72.1 673.3 ± 75 0.115Urinary sodium (mEq/L) 28.2 ± 8.6 63.1 ± 7.2 0.000 14.6 ± 8.9 46.0 ± 10.5 0.003Mean arterial pressure (mmHg) 66.5 ± 8.1 77.0 ± 5.1 0.000 69.6 ± 6.4 74.3 ± 4.6 0.250Plasma reninactivity (ng/ml/h)

34.3 ± 12.5 11.7 ± 5.8 0.000 48.4 ± 21.0 9.1 ± .9 0.083

Plasma aldosteroneconcentration (pg/ml)

1608.6 ± 601.7 643.0 ± 278.5 0.000 2446.6 ± 1136.0 400.0 ± 121.6 0.098

Data are mean ± SD.



treated with octreotide, midodrine and albumin showedsignificantly improved short-term survival and renalfunction (23). In this study, HRS recurrence was seen in6 (35.3%) and 7 (41.2%) patients after treatment with-drawal in terlipressin and noradrenaline groups, respec-tively, upto 90 days of follow-up. Alessandria et al. (20)reported recurrence of 25% in noradrenaline and 67%in terlipressin groups, in patients with Type 2 HRS. Alower relapse rate of 0% (15) and 5.3% (19) has beenreported after vasoconstrictor therapy in HRS type 1.HRS type 1 is an acute disease often induced by precipi-tating factors (21). In contrast, HRS type 2 is not precip-itated by acute events, but is characterized by aprogressive deterioration of renal function in direct rela-tion to the degree of portal hypertension (21). In theacute disease, vasoconstrictor induces the inhibition ofthe activated neurohormonal systems, which then stabi-lize when the precipitating factors come under control(21). On the contrary, in HRS type 2, the vasoactive

mechanisms are continuously activated in response toportal hypertension, so their inhibition by vasoconstric-tors is only temporary and vasopressor activity resumesafter the drug is discontinued (21) thereby indicatinglimited role of the drug.

In our study, mean dose of terlipressin received was2.06 ± 0.62 mg/day and mean duration of treatmentwas 8.6 ± 3.06 days. Earlier workers have reported vari-able response with wide range of terlipressin doses perday for different durations of treatment (16, 20, 21). Inthis study in group B, patients received 0.5-3 mg/h ofnoradrenaline (mean dose 0.51 ± 0.13 mg/h) for amean duration of 8.7 ± 3.8 days. In this study, HRSreversal was seen in 73.9% (17 out of 23) patients innoradrenaline group which is similar to terlipressingroup.

The results of this study confirm the previous obser-vations of studies (15, 16, 19), indicating the responseto treatment is associated with an improvement of cir-culatory function as evidenced by significant increase inurine output, urinary sodium, MAP (P < 0.05) andmarked suppression of renin-angiotensin-aldosteronesystem in responders on day 15 in patients with HRS.On the contrary, there was no significant increase inurine output, MAP and suppression of renin-angioten-sin-aldosterone system in non-responders. However,urinary sodium in non-responders was higher on day 15which may be as a result of possible transition to acutetubular necrosis (28) and the presence of adrenal insuf-ficiency in some patients with cirrhosis (29). Trawaleet al. (30), also demonstrated acute tubular necrosis incirrhotic patients with HRS (high serum creatinine lev-els, proteinuria <0.5 g/day and no haematuria). Non-response in some patients may be because of theincreased levels of vasodilator cytokines (31), increasedbacterial products or latent infections (32) and the pres-ence of concomitant adrenal insufficiency (29) or acutetubular necrosis (30).

At the end of 90 days of follow-up, 8(34.7%) patientsin group A and 9 (39.1%) in group B died (P > 0.05).In a study comparing the noradrenaline and terlipressintherapies in type 2 HRS in noradrenaline group, 5underwent liver transplant and one died while all 7 inthe terlipressin group were alive without transplant at1 month (20). Skagen et al. (23) reported survival ratesof 82% and 75% with octreotide, midodrine and albu-

Table 4. Comparison of baseline characteristics and hormonalprofile in those with and without response to vasopressor therapy

VariablesResponders(n = 34)

Non responders(n = 12)

Pvalue

Demographic characteristicsAge(years) 47.6 ± 8.6 45.8 ± 13.3 0.592SexMale 27 (79.4%) 9 (75%) 0.706Female 7 (20.6%) 3 (25%)

AetiologyAlcohol 23 (67.6%) 7 (58.3%) 0.726Others 11 (32.4%) 5 (41.7%)

SBP 3 (8.8%) 4 (33.3%) 0.064Biochemical investigationsSerum bilirubin(mg/dl)

2.47 ± 0.81 2.70 ± 0.83 0.401

Serum albumin(g/dl)

2.93 ± 0.28 2.75 ± 0.26 0.051

Child Pugh score 9.97 ± 2.02 11.25 ± 2.0 0.058MELD 20.5 ± 2.98 22.9 ± 2.46 0.013PTI (%) 69.9 ± 9 65.6 ± 7 0.059Serum sodium(mEq/L)

128.6 ± 5.8 127.5 ± 3.8 0.572

Blood urea (mg/dl) 79.9 ± 25.7 86.1 ± 25.4 0.471Serum creatinine(mg/dl)

2.03 ± 0.21 2.28 ± 0.14 0.001

Urine output/24 h (ml)

780.8 ± 247.7 447 ± 179.9 0.000

Urinary sodium(mEq/L)

27.1 ± 9.4 16.2 ± 7.1 0.001

Mean arterialpressure (mmHg)

67.4 ± 8.1 61.1 ± 7.7 0.019

Hormonal profilePlasma reninactivity (ng/ml/h)

34.3 ± 12.4 33.7 ± 14.3 0.726

Plasma aldosteroneconcentration(pg/ml)

1607.5 ± 592.5 1645.8 ± 777.1 0.860

Data are expressed as mean ± SD; MELD,

model for end-stage liver disease.

Table 5. Multivariate logistic regression analysis of factors affect-ing response to vasopressor therapy (Among those P value <0.05 inunivariate analysis)

Adjusted odds ratio (95% CI) P value

MELD 2.772 (0.854–8.993) 0.090Urine output 1.011 (1.001–1.020) 0.030Serum creatinine 0.000 (0.000–0.296) 0.037MAP 1.172 (0.977–1.407) 0.088Urinary sodium 1.266 (1.029–1.56) 0.025

MELD, model for end-stage liver disease; MAP, mean arterial pressure.



min therapy and 49% and 40% in controls in type 2HRS at 1 and 3 months respectively.

In this study, baseline predictive factors of responseto terlipressin/noradrenaline and albumin in patientswith type 2 HRS were also assessed. Multivariate analy-sis showed that serum creatinine, urine output and uri-nary sodium were associated with response. However,little information exists on predictors of outcome intype 2 HRS. In this study, serum creatinine, urine out-put and urinary sodium as predictor of response indi-cate degree of renal dysfunction and is explained bysplanchnic vasodilatation and renal vasoconstriction.

Several studies reported frequent occurrence ofcardiovascular adverse effects with terlipressin (16, 19).On the other hand, others reported terlipressin to besafe (11, 12, 15, 20). Other ischaemic adverse events asfinger/toe ischaemia were reported in 5% of patientswith terlipressin (11, 12) as seen in this study. In thisstudy, the adverse effect profile in both the groups wassimilar with no major side effect requiring drug with-drawal or modification in doses. Noradrenaline in HRSproved safe in previous studies too (14, 15, 18, 20).

We also did the cost calculation showing a majoradvantage of noradrenaline over terlipressin in the costeffective analysis. The cost of treatment in terlipressingroup was 804 USD and 311 USD in noradrenalinegroup (P < 0.05). However, the total cost of treatmentdid not include cost of albumin and hospital expenses inthe cost calculation and analysis. Alessandria et al. (20)also reported noradrenaline therapy to be less expensivein comparison to terlipressin in treating type 2 HRS.

In conclusion, the results of this randomized studysuggest that noradrenaline may be as effective and safeas terlipressin in reversal of type 2 HRS in cirrhotics,but at a fraction of the cost. Baseline serum creatinine,urine output and urinary sodium were found to be thepredictors of response. There was a high rate of recur-rence of HRS after treatment discontinuation. There-fore, more studies are needed to establish this drug as analternate therapy.

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Noradrenaline vs terlipressin in the treatment of type 2 hepatorenal syndrome: a randomized pilot study