Custodiol Versus Blood Cardioplegaia in Paediatric Cardiac Surgery

Study Overview
=================
Brief Summary
-----------------
Cardioplegic arrest is an essential part of cardiac surgery which aims to allow myocardial preservation and minimise myocardial swelling ,while providing a motionless and bloodless field ,.Blood cardioplegia has proven its efficacy for several decades and surgeons are still preferring to use it for myocardial protection of paediatric cardiac surgery ,although it is thought to be more time consuming since it is given with interrupted doses, . Even when advancement has came along the field of myocardial protection and cardioplegia solutions with the introduction of Bretschneider Histidine-Tryptophan-Ketoglutarate solution ,custodiol ,in 1970 ,which is given as a single dose and believed to be convenient, simple to deliver , and less time consuming . Many Surgeons haven't change their practice possibly due to paucity of studies comparing cardioplegia solutions in paediatric cardiac surgery and conflicting reports regarding the superiority of different cardioplegia solution.The investigators aim to provide evidence that will help paediatric cardiac surgeons to choose the optimal solution for their practice .

Detailed Description
-----------------
Hypothesis : Custodial is not inferior to blood cardioplegia in myocardial protection in paediatric cardiac surgery .. Methodology : Study design : Randomized controlled trial Data collection: All demographic data ,diagnosis ,procedure(type.CPB time ,crossclamp time) , surgeon and hospital course details . Computer generated randomisation into two groups based on cardioplegia solution . if randomised to blood patient will receive blood cardioplegia, delivered by microplegia delivery system by adding potassium to the blood (K= 35 ml eq/L) . The initial dose will be 35ml/ kg, and subsequent doses 20-15 ml/kg given every 20 minutes at a Temperature of 10 - 15 °C, while maintaining a perfusion pressure of 100-125 mmHg. if randomised to custodial patient will receive single dose of HTK custodiol cardioplegia. at temperature of 4-8°C and will be perfused for 6-8 minutes. Dose will start from 400 up to 1000 ml according to the child's body weight. Perfusion pressure will be kept at 70 - 80 mmHg until the heart is arrested.. Blinding : Surgeons will know the type of cardioplegia in the OR while other assessor will be blinded . Sample size calculated with an online calculator based on α error of 0.05 and β error of 0.2 to detect an absolute risk difference of 15% in composite end point between the two groups yielded 137 in each arm ,The results will be presented as mean (SD), median (interquartile range), or proportion . Using relative risk and log rank for statistical analysis .A P value of less than 0.05 will be considered statistically significant. Statistical analyses will be carried out using the SPSS . Safety monitoring and interim results : Both cardioplegia solutions are already in use and FDA approved there is no safety concerns at the time being . However , an interim analysis will be carried on every 6 months and the principal investigator will decide weather to stop or carry on if any major discrepancies in outcomes literature review : After an extensive literature review the investigators found only one randomised trial by elmorsy et al , which concluded that A single dose of an HTK cardioplegic solution provides better myocardial and cerebral protection than repeated doses of oxygenated blood cardioplegia during pediatric congenital cardiac surgery. On the other hand there was another retrospective report by bojan et al, found that The use of Custodiol cardioplegia in neonates undergoing ASO was associated with a larger troponin release when compared with warm blood cardioplegia,p <0.001 suggesting poor myocardial protection. koruon et al, done a tissue level comparison between htk and conventional crystalloid cardioplegia and their statistical analysis revealed no significant difference between the two groups regarding the clinical variables, apoptotic indices and proliferation indices. Liu j et al ,did a retrospective study comparing custodiol to St. Thomas crystalloid cardioplegia which concluded That HTK group had shorter cross-clamping time and more frequent spontaneous defibrillation than St. Thomas group. Also an animal study by Chen Y et al, on piglets that were randomised to either a single dose of HTK or multidose cold blood cardioplegia .. No significant differences were noted in the myocardial lactate content, ATP content, and histopathological score between both groups . Finally a retrospective report by E Qulisy et al concluded that Custodiol cardioplegia is associated with less myocardial protection and higher adverse outcomes compared to blood cardioplegia in pediatric age group undergoing cardiac surgery.

Official Title
-----------------
Custodiol Versus Blood Cardioplegaia in Paediatric Cardiac Surgery

Conditions
-----------------
Congenital Heart Disease

Intervention / Treatment
-----------------
* Drug: Custodiol Solution
* Drug: Blood cardioplegia


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: All paediatric patients referred to our hospital which will undergo open cardiac repair with cardiopulmonary bypass and cardioplegic arrest . Exclusion Criteria: All emergency procedure( require immediate surgery) Cases that don't require use of cardioplegia .

Ages Eligible for Study
-----------------
Minimum Age: 1 Day
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomisation : Computer generated randomisation into two groups based on cardioplegia solution . if randomised to blood patient will receive blood cardioplegia, delivered by microplegia delivery system by adding potassium to the blood (K= 35 ml eq/L) . The initial dose will be 35ml/ kg, and subsequent doses 20-15 ml/kg given every 20 minutes at a Temperature of 10 - 15 °C, while maintaining a perfusion pressure of 100-125 mmHg. if randomised to custodial patient will receive single dose of HTK custodiol cardioplegia. at temperature of 4-8°C and will be perfused for 6-8 minutes. Dose will start from 400 up to 1000 ml according to the child's body weight. Perfusion pressure will be kept at 70 - 80 mmHg until the heart is arrested.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: blood cardioplegia group<br>patient will receive blood cardioplegia, delivered by microplegia delivery system by adding potassium to the blood (K= 35 ml eq/L) . The initial dose will be 35ml/ kg, and subsequent doses 20-15 ml/kg given every 20 minutes at a Temperature of 10 - 15 °C, while maintaining a perfusion pressure of 100-125 mmHg. | Drug: Blood cardioplegia<br>* After cross clamping patient will receive blood cardioplegia, delivered by microplegia delivery system by adding potassium to the blood (K= 35 ml eq/L) . The initial dose will be 35ml/ kg, and subsequent doses 20-15 ml/kg given every 20 minutes at a Temperature of 10 - 15 °C, while maintaining a perfusion pressure of 100-125 mmHg.<br>|
| Experimental: custodiol group<br>patient will receive single dose of HTK custodiol cardioplegia. at temperature of 4-8°C and will be perfused for 6-8 minutes. Dose will start from 400 up to 1000 ml according to the child's body weight. Perfusion pressure will be kept at 70 - 80 mmHg until the heart is arrested. | Drug: Custodiol Solution<br>* After cross clamping patient will receive single dose of HTK custodiol cardioplegia. at temperature of 4-8°C and will be perfused for 6-8 minutes. Dose will start from 400 up to 1000 ml according to the child's body weight. Perfusion pressure will be kept at 70 - 80 mmHg until the heart is arrested.<br>* Other names: htk;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality (yes/no) | Death of all causes | up to 30 days | 
| ICU stay (days) | length of ICU stay | up to 90 days (length of ICU stay required after the operative procedure recorded by days until discharge or death) | 
| Arrhythmia (yes/no) | post operative arrythmia that required intervention | up to 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| length of stay (days) |  | up to 90 days (length of the hospital stay required since admission recorded by days until discharge or death ) | 
| length of mechanical ventilation (hours) |  | up to 5 days | 
| myocardial biomarkers | (troponin and CKMB) measured (preoperatively,postoperatively 6h,24h,48h,) | up to 5 days | 
| Subjective ventricular function (normal,mildly depressed ,moderately depressed ,moderately-severe depressed ,severly depressed ) | assessed by a cardiologist subjective assessment of the echocardiographically (preoperative ,immediate post repair ,24h post operative ) | up to 24 hours | 
| Ejection fraction (percentage) | assessed by echocardiography (preoperative ,immediate post repair ,24h post operative ) | up to 24 hours | 
| ECMO support (yes/no) |  | intraoperative | 
| vasoactive inotropic score ( low or high) | Vasoactive Inotropic score : (all doses of inotropes recorded hourly during 48 h) Dopamine dose (μg/kg/min) + Dobutamine dose (μg/kg/min) +100 × epinephrine dose (μg/kg/min)+ 10 X Milrinone dose (μg/kg/min) +10,000 × Vasopressin dose (U/kg/min) + 100 × Norepinephrine dose (μg/kg/min) calculated hourly for 48 hours and added than divided by 48 to give the score . if maximum score < 20 its low VIS and if maximum score ≥ 20 its a high VIS | up to 48 hour | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
htk, cardioplegia, myocardial protection, custodiol