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Clinical Trial
. 2024 Mar 5:18:193-208.
doi: 10.1016/j.xjon.2024.02.018. eCollection 2024 Apr.

Bilateral remote ischemic conditioning in children: A two-center, double-blind, randomized controlled trial in young children undergoing cardiac surgery

Nigel E Drury  1   2 , Carin van Doorn  3 , Rebecca L Woolley  4   5 , Rebecca J Amos-Hirst  4   5 , Rehana Bi  2 , Collette M Spencer  3 , Kevin P Morris  6 , James Montgomerie  7 , John Stickley  2 , Adrian Crucean  2 , Alicia Gill  4   5 , Matt Hill  4   5 , Ralf J M Weber  8 , Lukas Najdekr  8 , Andris Jankevics  8 , Andrew D Southam  8 , Gavin R Lloyd  8 , Osama Jaber  3 , Imre Kassai  3 , Giuseppe Pelella  3 , Natasha E Khan  2 , Phil Botha  2 , David J Barron  9   10 , Melanie Madhani  1 , Warwick B Dunn  8   11 , Natalie J Ives  4   5 , Paulus Kirchhof  1   12   13 , Timothy J Jones  1   2 ; Bilateral Remote Ischemic Conditioning in Children Trial Investigators
Collaborators, Affiliations
Clinical Trial

Bilateral remote ischemic conditioning in children: A two-center, double-blind, randomized controlled trial in young children undergoing cardiac surgery

Nigel E Drury et al. JTCVS Open. .

Abstract

Objective: The study objective was to determine whether adequately delivered bilateral remote ischemic preconditioning is cardioprotective in young children undergoing surgery for 2 common congenital heart defects with or without cyanosis.

Methods: We performed a prospective, double-blind, randomized controlled trial at 2 centers in the United Kingdom. Children aged 3 to 36 months undergoing tetralogy of Fallot repair or ventricular septal defect closure were randomized 1:1 to receive bilateral preconditioning or sham intervention. Participants were followed up until hospital discharge or 30 days. The primary outcome was area under the curve for high-sensitivity troponin-T in the first 24 hours after surgery, analyzed by intention-to-treat. Right atrial biopsies were obtained in selected participants.

Results: Between October 2016 and December 2020, 120 eligible children were randomized to receive bilateral preconditioning (n = 60) or sham intervention (n = 60). The primary outcome, area under the curve for high-sensitivity troponin-T, was higher in the preconditioning group (mean: 70.0 ± 50.9 μg/L/h, n = 56) than in controls (mean: 55.6 ± 30.1 μg/L/h, n = 58) (mean difference, 13.2 μg/L/h; 95% CI, 0.5-25.8; P = .04). Subgroup analyses did not show a differential treatment effect by oxygen saturations (pinteraction = .25), but there was evidence of a differential effect by underlying defect (pinteraction = .04). Secondary outcomes and myocardial metabolism, quantified in atrial biopsies, were not different between randomized groups.

Conclusions: Bilateral remote ischemic preconditioning does not attenuate myocardial injury in children undergoing surgical repair for congenital heart defects, and there was evidence of potential harm in unstented tetralogy of Fallot. The routine use of remote ischemic preconditioning cannot be recommended for myocardial protection during pediatric cardiac surgery.

Keywords: clinical trial; cyanosis; myocardial protection; pediatric cardiac surgery; remote ischemic preconditioning; tetralogy of Fallot.

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Conflict of interest statement

The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.

Figures

None
Graphical abstract
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Mean hs-troponin-T release in the first 24 hours after surgery by treatment group.
Figure 1
Figure 1
The Bilateral Remote Ischemic Conditioning in Children trial. A 2-center, double-blind, randomized controlled trial in which 120 young children with the 2 most common congenital heart defects requiring surgery were randomized to bilateral RIPC or sham intervention. AUC for hs-troponin-T in the first 24 hours was higher in the preconditioning group than in controls (P = .04), and subgroup analysis suggested a differential effect by underlying defect (pinteraction = .04). Bilateral RIPC does not attenuate myocardial injury during surgery in young children, with evidence of potential harm in unstented TOF, and its routine use cannot be recommended. AUC, Area under the curve; CI, confidence interval; RVOT, right ventricular outflow tract; RIPC, remote ischemic preconditioning; ToF, tetralogy of Fallot; VSD, ventricular septal defect; hs, high sensitivity.
Figure 2
Figure 2
Mean hs-troponin-T release in the first 24 hours after surgery by treatment group. Mean AUC for hs-troponin-T was higher (ie, worse) in the RIPC group (70.0 ± 50.9 μg/L/h) compared with control (55.6 ± 30.16 μg/L/h), mean difference 13.2 μg/L/h (95% CI, 0.5-25.8; P = .04). RIPC, Remote ischemic preconditioning.
Figure 3
Figure 3
Forest plot of the primary outcome by congenital heart defect group. The overall estimate is the weighted average of the observed treatment effects for each congenital heart defect group, estimated using random effects to allow for variation between groups. CI, Confidence interval; TOF, tetralogy of Fallot; RVOT, right ventricular outflow tract; VSD, ventricular septal defect; RIPC, remote ischemic preconditioning.
Figure E1
Figure E1
CONSORT flow diagram. In this trial, 120 young children undergoing surgery for congenital heart disease were randomized to bilateral RIPC or sham intervention and completed follow-up. aPatients counted in multiple categories due to concomitant reasons for exclusion: 191 reasons in 185 patients. bBefore change to exclusion criteria to allow recruitment. cParticipant randomized in error, later deemed ineligible, did not undergo surgery; therefore, outcome data were not available. Excluded postrandomization, before receipt of any intervention and not included in subsequent analyses. dWith complete primary outcome data available. RIPC, Remote ischemic preconditioning.
Figure E2
Figure E2
Kaplan–Meier plots of time to discharge from (A) pediatric ICU, by treatment group with data censored at 336 hours (14 days), and (B) hospital, by treatment group with data censored at 30 days. Pediatric ICU. 95% CI. HR, Hazard ratio; CI, confidence interval; RIPC, remote ischemic preconditioning; PICU, pediatric intensive care unit; trt, treatment group.
Figure E3
Figure E3
Mean hs-troponin-T release in the first 24 hours by congenital heart defect. TOF, Tetralogy of Fallot; VSD, ventricular septal defect.
See this image and copyright information in PMC

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