Comparison of bolus vs continuous infusion of terlipressin for treatment of hepato renal syndrome in cirrhosis of liver

INTRODUCTION

 Hepatorenal syndrome (HRS) is a serious complication of cirrhosis with high morbidityand mortality rates. Prognosis for Type 1 HRS is poor, with an average survival of just less than 2 weeks[1] . Itsdevelopment is associated with functional circulatory changes inthe kidneys which are a maladaptive response of physiologicalcompensatory mechanisms leading to a significant decrease inthe estimated glomerular filtration rate (eGFR) [2].Thiscirculatory condition is reversible if renal blood flow is reestablished,either by liver transplantation or by the use of vasoconstrictortherapy [3] .

 Treatment of HRS is based on the use of vasoconstrictive agents in combinationwith albumin and terlipressin is the most widely used vasoconstrictor drug, witha high response rate. Recent times recommendation is Terlipressin be administered intravenously at 0.5-1 mg every 4-6 hours, then gradually increased to a maximum dose of 2 mg every 4 hours.Treatment should be maintained until a complete response is obtained or for a maximum of 14 days[4] . When the effect of terlipressinon the splanchnic hemodynamics, namely the reductionof portal pressure, was tested in patients with cirrhosis,it was shown that it lasted no more than 3 to 4 hoursafter the intravenous bolus of the drug.(7) However, thecurrent regimen for terlipressin given by intravenous boluses reveals that the interval between one bolus andthe next can range from 4 to 6 hours [5] . Therefore, thiscannot ensure that the drug is able to exert its positiveeffect on arterial splanchnic hemodynamics and continueto maintain its effect for 24 hours.Again previous studies shown that bolusterlipressin administration may cause serious ischemic complications such as skin ischemia, peripheral gangrene, and ischemic bowel necrosis also with a risk of myocardial infarction [6].Thus we want to conduct this study of  comparing the efficacy ,survival and adverse events in bolus vscontinuous infusionof  terlipressin in the treatment oftype 1 HRS in patients with cirrhosis.

REVIEW OF LITERATURE

There are very limited number of studies published on the continuous infusion of terlipressin in patients with cirrhosis and hepatorenal syndrome. A study by Cavallin et al in their randomized controlled trail of 132 patients had found that administration of terlipressin by continuous infusion has a better safety profile than its administration by intravenous boluses. Moreover,the administration of terlipressin by continuous intravenous infusion was associated with a lower rate not only of all the

  adverse events [7] .Another study by Bajaj et al on patients with refractory ascites revealed that  continuous IV infusion of terlipressin provides a consistent and predictable pharmacokinetics profile  in patients with cirrhosis and refractory ascites [5]. This could improve safety and tolerability of the drug in these patients. Based on thisresults, we plan to undertake this study comparing efficacy between Continuous vs bolus terlipressin in patients with cirrhosis with HRS AKI

 AIMS AND OBJECTIVES

To compare the efficacy,adverse events and survival between continuous versus bolus administration of terlipressin in cirrhotic patients presented with hepato

renalsyndrome-Acute kidney injury (HRS-AKI ) .

Primary objective

To assess the efficacy of terlipressin infusion in comparison  toterlipressin bolus injection for achieving complete response in patients of cirrhosis with HRS -AKI

·         Complete response is defined as decline in serum creatinine < 1.5 mg/dl.

Secondary objective

1.To assess the development of terlipressin induced adverse event between the two groups

2. To compare the 90-day transplant-free survival between two groups.

MATERIALS AND METHODS

STUDY DESIGN- single-center, prospective,and open level randomized controlled studyin a tertiary care center of Odisha.

**STUDY AREA-**Department of Hepatology, SCB Medical College, Cuttack.

STUDY DURATION- 1.5 years

 STUDY POPULATION-

Patients who are confirmedcirrhotic, presenting atSCB Medical College, Cuttack fulfilling the inclusion criteria will be enrolled in the study.

INCLUSION CRITERIA:

(1) Cirrhosis as diagnosed by clinical, biochemical,ultrasound, endoscopy finding and/or liver biopsy if needed.

(2) Age  18years upto 75 yr

(3) Diagnosis of type 1 HRS(HRS-AKI) as defined bythe criteria of the International Club of Ascites(ICA)

The following criteria will be followed for the diagnosisof HRS AKI

a) Cirrhosis with ascites,

b) Increase in serum creatinine0.3 mg/dL within 48 hours or 50% frombaseline  value, known or presumed, to have occurred within the prior 7 days and/orurine output <0.5 mL/kg for 6 hr.

c) Absence of improvement in serum creatinine and/orurine output within 24 hours following adequate volume resuscitation (when clinicallyindicated) and

d)  Absence of strong evidence for an alternative explanation as theprimary cause of AKI.

EXCLUSION CRITERIA:

Following cirrhoticpatients were excluded:

(1) Hepatocellularcarcinoma .

(2) Septic shock;

(3) Cardiac or respiratory failure or other severe extrahepatic

disease; or

(4) Contraindications to the use ofterlipressin.

 SAMPLE SIZE:Primary end point of a complete response was taken into consideration for the estimation of the sample size of the study. A previous study found that the complete response to terlipressin continuous infusion was 55% and the complete response to terlipressin bolus doses was 46% [1]. Assuming a 95% confidence interval, α error of 5% and β error of 10%, a sample size of 48 in each group was calculated.

  STUDY DESIGN

**CONSENT:**Written informed consent will be taken from each prospective participant.All those patients consenting for the study will be enrolled.

 RANDOMIZATION:

Patients of HRS-AKI will be randomized in a 1:1 ratio  into two groups. One group will   receive terlipressinby continuous intravenous infusion (TERLI-INF group) and second group will receive terlipressin bolus (TERLI-BOL group). In both the groups albumin   will be given at a dose of 1 g/kg at day 1 and then at a maintenance dose of 20-40 g/day. Other treatment and supportive measures will be given as per prevailing guidelines for management of HRS-AKI.

 BASELINE DATA: All baseline data of patient will be documented in a prescribed   format The variables – age, gender, presentation at the time of diagnosis.

·         Laboratory parameters:

Ø  Complete haemogram: haemoglobin (Hb), Mean Corpuscular Volume (MCV), platelet count and peripheral blood smear.

Ø  Liver function test: ALT,AST,Serum bilirubin(total/direct),total protein/ albumin, ALP) and GGT,PT-INR,Serum Protein ,Albumin

Ø  Renal function test: Serum Urea, Creatinine, Na,K, urine RE/ME, urinary Alb-Cr ratio

Ø  Chest X ray, ECG, USG Abdomen &Pelvis,Upper GI endoscopy

Liver indices- MELD Na, CTP, scores were calculated at baseline

    TERLI-INF group: Terlipressin will be given in infusion form. Starting dose will be of   2 mg/day.For the continuous intravenousinfusion, the dose of terlipressin will be dissolved in 50 mL of 5% dextrose solution and infused with a infusion pump.Serum Creatinine will be  monitored every 48 hourly. If sCr decreases by<25% of the pretreatment value, the dose of terlipressin will be progressively increased by 2 mg per day upto a maximum dose of 12 mg/day.

  TERLI-BOL group: ,Terlipressin will be  given  by intravenous boluses. Starting dose will be 0.5 mg every 4 hours.  Serum Creatinine will be monitoredevery 48 hourly. If sCr decreases by <25% of the pretreatmentvalue, the dose of terlipressin will be progressively increasedby 0.5 mg   every 4 hourly upto a maximum dose of 2mg every 4 hourly(or 12 mg per day).

  **MONITORING:**All patients will be monitored daily for physical examination,every alternate day for WBC ,LFT ,RFT and Liver indices MELD Na, CTP  scores.

 RESPONSE TO TREATMENT

·         Complete response,will be defined as decline in serum creatinine < 1.5 mg/dl within 14 days of starting treatment.

·          Partial response,will be defined as decline in Serum creatinine bymore than 25% from baseline value, but not reaching below 1.5 mg/dl even after using maximum dose till the end of 14 days of treatment.

·         No response, will be defined as decline in serum creatinine by less than 25% from   baseline value even after using maximumdose, till the end of 14 days of treatment.

  TREATMENT END POINT.Inboth  thearms of the study, terlipressin will be  continued until sCr decreases to less than 1.5 mg/dL or patient completes  14 days of treatment.If patient attains complete response before 14 days treatment will be continued for next  24 hours.

 MONITORING OF ADVERSE DRUG REACTION- Allpatients will be monitored for adverse drug reactions. Any ADR attributed to terlipressin will be documented in prescribed format and will be presented to the appropriate authority as per govt guidelines.

 **FOLLOW UP :**During the 3-mo follow-up period, patients will be  monitored for the following parameters: the levels of serum bilirubin and albumin, prothrombin time and concentration, INR, the levels of ALT and aspartate aminotransferase, the levels of blood urea and serum creatinine, complete blood analysis, estimation of the degree of ascites, CTP score, MELD score, and hepatic encephalopathy. The survival rates will be evaluated over a period of 3-month.

Assessed for eligibility

As per  ICA –HRS AKI CRITERA

Randomized-in a 1:1 ratio  to either terlipressin infusion or bolus group

Allocated to Terli-infusion group

Allocated to terlipressin bolus group

Analyzed

Analyzed

Once Eligible ,patients will undergo ,detailed physical  and clinical examination, Routine investigations (CBC,RFT,LFT,Sr Na/K,FBS,PT-INR,CXR,ECG) at baseline.liver indices  like CTP,MELD-Na calculated

Monitoring: All patients will be  monitored daily for any new complains, physical examination and every  day  serum creatinine monitoring .

Dose escalation will be done as follows

25% decrease –continue same dose till complete response

<25% decrease-dose escalation by 2mg/every 48 hr max-12mg/day till complete response achievedor  maximum 14 day.

Patient Categories into complete /partial/nonresponder

**Follow Up :**Patients will be prospectively followed up for mortality assessment upto 90 days

                 Statistical methods: Statistical analysis will be performed using Statistical Package for Social Sciences (SPSS; version-20.0). Normality will be tested using the Kolmogorov-Smirnovtest. Categorical variables will be compared using the Chisquare test and Fisher’s exact test as appropriate. Continuous, normally distributed variables will be expressed as mean ± standard deviation (SD), will be compared using the independent Student t test and variance will be tested using Levene’s test. Continuous, non-normally distributed variables will be expressed as median with inter quartile range (IQR), will be compared using Mann-WhitneyU test. Correlation of two normally distributed variables will be done using Pearson correlation coefficient and of non-normally distributed variables by Spearman correlation coefficient.

 PROFORMA FOR STUDY

 1.      REGD. NO.-

2.      NAME OF THE HOSPITAL-

3.      PATIENT PARTICULARS:Name/Age/Sex/Caste/Religion/ Address-

4.      PRESENTING COMPLAINTS:

   5.      PAST HISTORY: Past h/o any hospitalization/ BT/ Painful Episodes/ acute pain abdomen/umbilical venous catheterization/umbilical sepsis/dehydration in children.

6.      FAMILY HISTORY:  Relevant family history

7.      IMMUNISATION HISTORY.

8.      DIETARY HISTORY.

9.      BIRTH HISTORY & DEVELOPMENTAL HISTORY (CHILDREN):

10.  GENERAL EXAMINATION.

General Findings-Pallor / Icterus / Cyanosis / Clubbing / Lymphoadenopathy / Edema.

 11.  SYSTEMIC EXAMINATION.

 Ã˜  Gastrointestinal System.

·         Abdomen- Soft/ Tense/ Normal/ Distended.

·         Skin- Normal/Venous Prominence.

·         Umbllicus- Normal/ Everted.

·         Liver-  __________ cm.

·         Spleen- _________ cm.

·         Fluid- Present/Absent.

Ø  Respiratory System.

Ø  Cardiovascular System.

Ø  Nervous System.

Ø  Skeletal System.

Ø

 12.  INVESTIGATIONS.

Ø  Haematology.(Auto analyser method)

Date

Hb

TLC

N

L

E

B

M

Platelet

Retic

MCV

MCH

MCHC

ESR

PBS

|                |                |

  Â·         Biochemical

Date

TB

DB

AST

ALT

ALP

GGT

TP

Alb

INR

Urea

Creat

TSH

HbsAg

HCV

HIV

|                 |                 |

 Â·         Microbiological

o   Blood culture

o   Bronchoalveolar lavage

o   Endotracheal aspirates

o   Urine samples and a colony count

 IMAGING :Ultrasonography of abdomen

CECT abdomen

**ESOPHAGOGASTRODUODENOSCOPY (EGD):**Grading of varices, red color signs (RCS - red wale markings, cherry red spot, hematocystic spots, and diffuse redness).

     Informed Consent form

 PATIENT’S NAME:                                                   AGE:

1.         I confirm that I have read and understood the information sheet for the above study and had the opportunity to ask questions.

2.         I understand that my participation is voluntary and that I am free to withdraw at any time, without having to give a reason, and without any my medical care or legal rights being affected.

3.         I understand my data will be kept confidential but individuals authorized by the Principal Investigator, the ethics committee of the institute where the study will be conducted and government drug regulatory authority will have access to my health records both in respect of current study and further research that may be conducted in relation to it. Even if I withdraw, I agree to this access. However, I understand that my identity will not be revealed and confidentiality of information will be maintained.

4.         I agree not to restrict the authorized use of any data or results that arise from this study.

5.         I agree to voluntarily take part in the study.

Signature/ thumb impression of the subject:

Date:                                                        place:

Study doctors name:

Study doctors signature:

Date:                                                        place:

Where subject has provided thumb impression:

Signature of witness:

Date:                                                        place:

Name and address of the witness:

Relation to the subject if any:

        Informed Consent form (Odia)

Participant’s name:                                                                          Address:

 REFERENCES

.

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**2.**European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol 2010;53:397-417.

 **3.**Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rodes J. Peripheral arterial vasodilatation hypotesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. HEPATOLOGY 1988;8:1151-1157.

**4.**Angeli P, Merkel C. Pathogenesis and management of hepatorenal syndrome in patients with cirrhosis. J Hepatol 2008;48(Suppl. 1):S93-S103.

5. Sanyal AJ, Boyer T, Garcia-Tsao G, Regenstein F, Rossaro L, Appenrodt B, et al. A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome. Gastroenterology 2008;134:1360-1368.

**6.**Martin-Llahi M, Pepin MN, Guevara M, Dıaz F, Torre A, Monescillo A, et al. Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. Gastroenterology 2008;134:1352-1359.

7.  Angeli P, Guarda S, Fasolato S, Miola E, Craighero R, Piccolo F, et al. Switch therapy with ciprofloxacin vs. intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis in patients with cirrhosis: similar efficacy at lower cost. Aliment PharmacolTher2006;23:75-84.

**8.**Escorsell A, Bandi JC, Moitinho E, Feu F, Garcıa-Pagan JC, Bosch J, et al. Time profile of the haemodynamic effects of terlipressin in portal hypertension. J Hepatol 1997;26:621- 627

9. Angeli P. Review article: prognosis of hepatorenal syndrome--has it changed with current practice? Aliment PharmacolTher. 2004 Sep;20 Suppl 3:44-6; discussion 47-8.

10. Simonetto DA, Gines P, Kamath PS. State of the art reVIeWHepatorenal syndrome: pathophysiology, diagnosis, and management.BMJ. 2020;370:2687.

11. Francoz C, Durand F, Kahn JA, Genyk YS, Nadim MK. Hepatorenalsyndrome. Clin J Am Soc Nephrol. 2019;14(5):774-781.