Oral Triiodothyronine for Children Undergoing Cardiopulmonary Bypass in Indonesia (OTICC)

A condition of decreased serum T3 level in children after cardiac surgery using cardiopulmonary bypass has been commonly recognized as euthyroid sick syndrome (ESS). This syndrome has been closely associated with low cardiac output syndrome after heart surgery. The unique characteristics of pediatric patients with congenital heart disease (CHD) in Indonesia have caused ESS to arise in the population even before surgical managements. Thyroid hormones increase cardiac function, respiration and diuresis. Increased myocardial function occurred through the improvement of mitochondrial effectiveness as the body energy source by utilizing effective energy substrates, lactate and pyruvate. Prevention of decreased serum thyroid hormones level by T3 supplementation could be clinically beneficial. Intravenous T3 unit dose is very expensive and inapplicable for daily use. In adult studies, oral T3 was found to be effective for the prevention of decreased serum T3 levels; similar study on pediatric population, however, has not been elucidated.

Study Overview

• Status: Completed
• Conditions: Postoperative; Dysfunction Following Cardiac Surgery
• Intervention / Treatment: Drug: Oral triiodothyronine; Drug: Placebo

Detailed Description

Methods:

The study was conducted at the cardiac paediatric cardiac intensive care unit of National Cardiovascular Center Harapan Kita. It was performed on paediatric congenital heart disease population who underwent open heart surgery with randomised, double-blind, controlled trial design. All patients with congenital heart disease, 3 years old or less, were included. Types of congenital heart disease suffered required subject to undergo surgery using cardiopulmonary bypass machine with Aristotle score of 6-9. Surgery was aimed for biventricular repair.

The sample size needed almost 200 patients with 50% is in the treatment group. This calculation was based on 90% of patients will be extubated and expected hazard ratio of corresponding treatment group is 1.7 with 5% alpha error and 20% beta error.

Patients were randomised using block randomisation procedure. The stratification factor will be age at the time of recruitment: < 6 weeks old, 6 weeks - 5 months old, > 5 months - 3 years old. Randomization will occur on the day of surgery.

The placebo - saccharum lactis - OR oral T3 (Tetronine, Dalim Biotech Korea) with the dose of 1 mcg per kg body weight were administered via nasogastric tube for every 6 hours starting from the time of anaesthesia induction until 11 doses in total (60 hours after the initial administration). Serial free T3 (FT3) and thyroid stimulating hormone (TSH) measurement were performed starting from the induction of anaesthesia until patient's discharge. Haemodynamics monitoring and echocardiography evaluation was conducted from day 1 to 3 after the surgery.

Statistical analysis:

Primary analysis will be performed using Cox Proportional Hazards for time to extubation result, including terms for stratification factors (age, Aristotle score and nutrition status). Patients will be included in analysis if they were randomised and received at least one dose of study drug according to the principal of Intention-to-Treat (ITT).

• Study Type: Interventional
• Enrollment (Actual): 177
• Phase: Phase 3

Contacts and Locations

Study Locations

• Indonesia
  • DKI Jakarta
    • Jakarta, DKI Jakarta, Indonesia, 11420
      • Pediatric Cardiac ICU National Cardiovascular Center Harapan Kita

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 3 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Children undergoing cardiopulmonary bypass
• Age 36 months old or less
• Aristotle score 6-9
• Total correction or biventricular repair

Exclusion Criteria:

• Single ventricle defects
• Body weight less than 2 kg at the time of recruitment
• Presentation with sepsis
• Tachyarrhythmia or any other arrhythmia before surgery
• Creatinine level of more than 2 mg/dl
• Known thyroid disease
• Known lung abnormalities (including infection) before surgery

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oral triiodothyronine; Oral T3 (triiodothyronine) is given 1 mcg/kg every 6 hourly through naso-gastric tube since induction of anaesthesia for 60 hours	Drug: Oral triiodothyronine; Oral triiodothyronine is given peri-operatively through naso-gastric tube; Other Names: Tetronine; Lyothyronine
Placebo Comparator: Placebo; Placebo (saccharin lactic) is given every 6 hourly through naso-gastric tube since induction of anaesthesia for 60 hours	Drug: Placebo; Placebo consist of saccharin lactis that has the same appearance as Tetronine; Other Names: Saccharin lactis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intubation time	All patients after undergoing congenital heart surgery will be supported by mechanical ventilation. Duration of this support since cross clamp off removal until after surgery will be assessed in the treatment and placebo group. Thyroid supplementation will increase the cardiac function and will make the patients extubated early than the patients without supplementation	Until patients extubated after surgery in ICU OR died OR still intubated within 7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with low cardiac output syndrome	Identified patients with low cardiac output syndrome in which had clinical signs and symptoms of low cardiac output are found with without the increasing of arterial and venous gap and metabolic acidosis and this condition needs 100% of inotropic support or even more than that from the beginning of inotropic used, the use of new inotropic, mechanical support, or other manoeuvres in order to increase cardiac output (e.g pacemaker)	6 hours, 12 hours, 18 hours, 24 hours, 48 hours post aortic cross clamp removal
Drug adverse reaction	Heart rate to evaluate tachycardia, blood pressure for hypertension, heart rate for arrhythmia, body temperature for hyperthermia	Every hourly until 12 hours post cross clamp removal, every 3 hours until 24 hours, every 6 hours until 48 hours, every 12 hours until 72 hours post cross clamp removal, and until the patients discharge from hospital

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inotropic and vasoactive-inotropic score	The amount of inotropic drugs are calculated and reviewed serially since cross clamp removal until all drugs are stopped	1, 6, 12, 18, 24, 36, 48, 60 and 72 hours post cross clamp removal
Diuresis	Amount of urine output per kg body weight per hour	From day 1 until day 3 post surgery
Fluid balance	Difference between input and output of the fluid per kg body weight per day	From day 1until day 3 post surgery
Lactate-pyruvate ratio	Lactate and pyruvate serum was obtained from central venous catheter in internal jugular vein with the distal tip catheter in the right atrium	On induction of anaesthesia, 1 hour, 24 hours post cross clamp removal
Ejection Fraction	Ejection Fraction is measured by Echocardiography	Day 1, 2 and 3 post surgery
Cardiac Index	Cardiac index is measured by Echocardiography	Day 1, 2 and 3 post surgery
Systemic Vascular Resistance Index	Systemic Vascular Resistance Index is measured by Echocardiography	Day 1, 2 and 3 post surgery
Pulse Pressure	Difference between systolic and diastolic pressure	Every hourly until 72 hours post surgery
Number of patients with sepsis	Amount of patients diagnosis with sepsis based on Surviving Sepsis Campaign	since day 1 post surgery until patients discharge

Collaborators and Investigators

• Sponsor: National Cardiovascular Center Harapan Kita Hospital Indonesia
• Collaborators: CRDF Global; Osypka Germany; Dalim BioTech Co., Ltd.
• Investigators: Principal Investigator: Eva M Marwali, MD, PhD, National Cardiovascular Center Harapan Kita Jakarta

Study record dates

Study Major Dates

• Study Start: July 1, 2013
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): January 1, 2015

Study Registration Dates

• First Submitted: August 2, 2015
• First Submitted That Met QC Criteria: August 7, 2015
• First Posted (Estimate): August 13, 2015

Study Record Updates

• Last Update Posted (Estimate): February 17, 2016
• Last Update Submitted That Met QC Criteria: February 16, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: cardiopulmonary bypass; congenital heart disease; euthyroid sick syndrome; time to extubation
• Other Study ID Numbers: 164/H2.F1/ETIK/2013