Custodiol versus blood cardioplegia in pediatric cardiac surgery: a randomized controlled trial

We conducted a randomized clinical trial to compare the outcomes of Custodiol cardioplegia (CC) vs. blood cardioplegia (BC) in pediatric cardiac surgery. The study was conducted between January 2018 and January 2021 in King Faisal Specialist Hospital and Research Centre-Jeddah, Saudi Arabia. The data were collected using approved CRFs, and all the data were transferred to REDCap software for management. However, the trial stopped due to COVID-19 and the difficulty of enrollment at the time, and only 487 patients were assessed for eligibility. We included pediatric patients who had a repair on cardiopulmonary bypass and cardioplegia, and neonates were eligible. We excluded adult patients with congenital heart disease, patients who refused to consent (or their guardians), emergency cases, and patients who were lost to follow-up. The study flowchart is presented in Fig. 1. The patients were divided into the Custodiol cardioplegia group (n = 107) and the blood cardioplegia group (n = 119).

The study was approved prior to patient recruitment by the Institutional Review Board of King Faisal Specialist Hospital and Research Center, Jeddah (Approval# 2016–8). All study activities and methods were in accordance with ICH-GCP and local regulatory guidelines. Informed consent for retention and use of patient data for research purposes was obtained from their guardians at the time of the procedure consent before randomization. The patients or their guardians retained the right to withdraw from the study at any time.

Since both cardioplegia solutions are already in use and FDA-approved, there are no safety concerns at the time being. However, an interim analysis will be carried out every 6 months, and the principal investigator will decide whether to stop or carry on if any major discrepancies in outcomes are observed.

The day before the surgery, the study team approached eligible patients for enrollment. They were randomly assigned to one of two study arms using computer-generated simple random samples.

Triple blinding (participants, investigators, outcome assessors) was used. Surgeons knew the type of cardioplegia in the operating room, while other assessors were blinded. The research coordinator generated the random allocation sequence, and the investigators enrolled the patients while study surgeons assigned the interventions to the patients.

The primary outcome was a composite of 30-day mortality, ICU stay of more than 5 days, and postoperative arrhythmia occurring within 48 h of surgery and requiring intervention.

Secondary endpoints were the length of stay (days), length of mechanical ventilation (days), myocardial biomarkers (troponin) measured (preoperatively, 6 h, 24 h, 48 h postoperatively), ventricular function assessed by fractional shortening and ejection fraction, extracorporeal membrane oxygenation support (ECMO) and vasoactive inotropic score [dopamine dose (μg/kg/min) + dobutamine dose (μg/kg/min) + 100X epinephrine dose (μg/kg/min) + 10X milrinone dose (μg/kg/min) + 100X norepinephrine dose (μg/kg/min) + 10,000X vasopressin dose (U/kg/min)].

The sample size was determined a priori for a noninferiority design with an expected primary outcome of 40% and a clinical significance difference of 20%.

Categorical data are presented as numbers and percentages and were compared with the chi-squared test or Fisher’s exact test if the expected frequency was less than five. Continuous data were expressed as the median and (Q1–Q3) and compared with the Mann‒Whitney test. The random effect model was used to compare the changes in troponin levels between groups. A Kaplan‒Meier curve was used for survival distribution, which was compared with the log-rank test. Stata 16.1 was used for analysis (Stata Corp- College Station- TX- USA).

There were no differences in age, gender, body surface area, preoperative left and right ventricular function, ventricular repair, cyanotic heart disease, or preoperative troponin levels between the groups (Table 1).

The ischemic and cardiopulmonary bypass times, lowest core temperature, and cardioplegia temperature did not differ significantly between groups (Table 2).

There was no difference in the composite endpoint between the CC and BC groups, 65 (60.75%) vs. 71 (59.66%), respectively, P = 0.87. The total length of stay in the hospital was 14 (25–75th percentiles: 10–19) days in the CC group vs. 13 [10] days in the BC group, P = 0.85. The vasoactive inotropic score was not significantly different between the CC and BC groups; VIS was 5 (2.6–7.45) vs. 5 (2.6–7.5) in the CC vs. BC groups, respectively (P = 0.82). There was no difference in postoperative arrhythmia between groups (P = 0.87). The most common types of arrhythmia were junctional ectopic tachycardia (n = 23, 41.07%) and complete heart block (n = 22, 39.29%) (Table 3).

The cardiac troponin level and ventricular function did not differ significantly between the two groups, P = 0.34 and P = 0.85, respectively (Fig. 2). The median duration of follow-up was 32.75 (Q2–Q3: 18.73–41.53) months. Mortality occurred in 3 patients in the CC group and five patients in the BC group, and there was no difference in survival between the two groups (log-rank P = 0.55) (Fig. 3).

We included different age groups and patients who had one-ventricle and two-ventricle repair. This wide variability of the preoperative characteristics could have affected the outcomes. We used simple randomization that could have created an imbalance in the number of patients between groups. Last, our center is a tertiary referral center; not all patients were available for follow-up. Some patients were foreigners and were unavailable in the country after surgical repair.

On the other hand, this study evaluated the effect of cardioplegia on different clinical, laboratory, and echocardiographic outcomes, which is not frequently reported in the literature. Additionally, the study reported long-term mortality in those patients with a median follow-up of 33 months.