Acute Hemodynamic Response to Carvedilol in Children With Clinically Significant Portal Hypertension.

Institute of Liver and Biliary Sciences, India

Status

Completed

Conditions

Portal Hypertension

Treatments

Drug: Carvedilol

Study type

Interventional

Funder types

Other

Identifiers

NCT05767229

ILBS-Cirrhosis-56

Details and patient eligibility

About

Clinically significant portal hypertension (CSPH) is defined as Hepatic Venous Pressure gradient (HVPG) >10 mmHg. Patients with CSPH are at risk of developing esophageal varices and clinical decompensation (variceal bleeding, ascites, jaundice, encephalopathy), which mark the transition from compensated stage to a stage of the disease (decompensated) associated with higher mortality. HVPG is calculated by subtracting the free hepatic venous pressure (FHVP), a measure of systemic pressure, from the wedged hepatic venous pressure (WHVP), a measure of hepatic sinusoidal pressure. HVPG is surrogate marker in many clinical applications such as gold standard test to evaluate presence and severity of portal hypertension (PHT) diagnosis, risk stratification, monitoring of the patients on beta blockers. Non-selective beta-blockers like propranolol and carvedilol are indicated in adults for primary and secondary prophylaxis of variceal hemorrhage. Acute hemodynamic response to intravenous propranolol with HVPG values coming down to < 12 mm Hg or reduction to >20% from baseline have been shown to be associated with reduced long-term risk of variceal bleed. Portal Hypertension in biliary atresia (BA) occurs early and is due to recurrent cholangitis and portal sclerosis. HVPG in children is feasible and safe in children according to previous studies, however, there are no recommendations to suggest beta-blockers based on HVPG reduction in children. Hence, we are planning the current work to study the acute hemodynamic response to carvedilol in children with CSPH, and to compare the HVPG values in children with chronic liver disease.

Full description

Aim: To study acute hemodynamic response Hepatic Venous Pressure Gradient (HVPG) reduction to <12 mm Hg or by ≥ 20% from initial value) to carvedilol in from 2 to 18 year of age children with Chronic liver disease.

Methodology Study population: All children (2-18) years of age with CLD as per inclusion and exclusion criteria

Study design: Prospective cohort

Baseline parameters that will be recorded:

Baseline characteristics:
History and etiology of liver disease
Symptomatology, Evidence of decompensation (jaundice,organomegaly, encephalopathy, ascites, infections, variceal bleed etc)
Clinical and demographic profile
Variceal bleed, ascites, infections, hepatic encephalopathy, AKI
Endoscopic findings:
Esophageal varices
Red colour signs
Gastric varices
Clinically significant varices
Portal hypertensive gastropathy
Liver and splenic stiffness
Splenic Z-score - based on ultrasound measure of spleen (in cm) and calculation of Z-scores based on centiles from Indian children
Anthropometric parameters:
Weight for age
Height for age
Weight for length
BMI
Triceps skin fold thickness

Study period: 2 years

Sample size with justification: Since it is a pilot study we will take 40 patients

Methodology for HVPG measurement:

6-hour fasting
procedure will be done either without sedation or minimal Sedation using propofol and ketamine
Continuous ECG and Pulse-OX monitoring.
4 or 5 Fr venous introducer sheath will be places in right IJV using Seldinger technique under Doppler USG guidance
Right or middle hepatic vein will be catheterized under fluoroscopic guidance with a 3 or 4 Fr Cobra angiographic catheter and a hydrophilic wire.
The angiographic catheter will be exchanged with a 4 or 5 Fr occlusion balloon catheter
All measurements will be recorded using a pressure transducer set linked to a multichannel recorder with a 50mmHg scale
Zeroing: Before recording, the transducer will be placed at the level of right atrium (mid-axillary line) and kept it open to zero.
FHVP will be measured by maintaining the tip of the catheter ''free'' in the hepatic vein, 1 to 3 cm from its opening into the IVC.
WHVP will be measured while the catheter in hepatic vein and a balloon will be inflated at the tip of catheter. Adequate occlusion of the hepatic vein will be checked by slow injection of 2-5 mL of iodinated contrast (iodixanol iso-osmolar contrast medium, Visipaque 320 mgI/ml) with the catheter tip positioned in the mid/distal portion of the vein; typical ''wedged'' pattern, without reflux of the contrast or washout through communications with other hepatic veins will be considered confirmatory.
Repeat testing will be done in children with HVPG >/= 10 mm Hg 90 minutes after giving carvedilol through nasogastric route.

Acute Hemodynamic response to oral carvedilol:

Baseline heart rate and non-invasive BP monitoring (appropriate cuff).
Following HVPG measurement, a single dose of carvedilol will be administered (0.2 mg/kg) via nasogastric route/oral and 90 minutes later, we will recheck heart rate, BP and HVPG. Percent change in HVPG will be calculated.
Acute hemodynamic response is characterized as HVPG <12 mm Hg or reduction by >/=20%

Monitoring and Assessment:

All patients with esophageal varices or HVPG >10 mm Hg or both, will be started on oral Carvedilol 0.2 mg/kg/day, which will be increased every 3rd day upto 0.8 mg/kg/day to titre decrease in heart rate upto 25% from baseline.
Repeat UGIE after 6 months to see change in variceal status.

Statistical Analysis All the categorical variables will be expressed as frequencies, whereas continuous ones will be expressed as mean+ SD or median (IQR). Chi-square , Fisher's exact test and student's t-test will be applied for assessment of causality. Kaplan-Meier statistics will be done for survival and liver related morbidity besides this an appropriate analysis will be carried out at the time of data analysis like diagnostic test, logistic regression etc. Significance will be mentioned in the form of p-value <0.05.

Adverse effects:

There are few side effects of beta blockers (carvedilol) like suppression of chronotropic effect, bronchospasm, hypoglycemia, exercise intolerance and hypotension and the patient will be carefully monitored for these for a duration of 6 hours post-procedure.
Reversal of effect of carvedilol: In case of excessive bradycardia, hypotension or bronchospasm following measures will be taken:
Bradycardia & hypotension: Intravenous atropine 1-2 mg +/- Intravenous glucagon 2.5-5 mg over 3-5 minutes, followed by continuous infusion at the rate of 1-5 mg/hour +/- Adrenaline / Dobutamine infusion as per weight adjusted dose.
Bronchospasm: Nebulization with salbutamol/levosalbutamol/Adrenaline +/- intravenous aminophylline.

Stopping rule of study:

Progression to exclusion criteria
Adverse effects
Potential liver transplant within 15 days

Enrollment

40 patients

Sex

All

Ages

2 to 18 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

All children 2-18 years of age with CLD defined as presence of either of the following histological evidence of advanced fibrosis more than F2 on METAVIR staging or radiological imaging suggestive (heterogeneous hepatic echotexture, irregular nodular liver and/or caudate hypertrophy). .
Splenomegaly and/or platelets </= 100 (X10^3/mm3)
Coming for upper gastrointestinal endoscopy for variceal screening
Informed consent for HVPG and UGIE

Exclusion criteria