Remote ischemic preconditioning in children undergoing cardiac surgery with cardiopulmonary bypass: a single-center double-blinded randomized trial

Brian W McCrindle, Nadia A Clarizia, Svetlana Khaikin, Helen M Holtby, Cedric Manlhiot, Steven M Schwartz, Christopher A Caldarone, John G Coles, Glen S Van Arsdell, Stephen W Scherer, Andrew N Redington, Brian W McCrindle, Nadia A Clarizia, Svetlana Khaikin, Helen M Holtby, Cedric Manlhiot, Steven M Schwartz, Christopher A Caldarone, John G Coles, Glen S Van Arsdell, Stephen W Scherer, Andrew N Redington

Abstract

Background: Remote ischemic preconditioning (RIPC) harnesses an innate defensive mechanism that protects against inflammatory activation and ischemia-reperfusion injury, known sequelae of cardiac surgery with cardiopulmonary bypass. We sought to determine the impact of RIPC on clinical outcomes and physiological markers related to ischemia-reperfusion injury and inflammatory activation after cardiac surgery in children.

Methods and results: Overall, 299 children (aged neonate to 17 years) were randomized to receive an RIPC stimulus (inflation of a blood pressure cuff on the left thigh to 15 mm Hg above systolic for four 5-minute intervals) versus a blinded sham stimulus during induction with a standardized anesthesia protocol. Primary outcome was duration of postoperative hospital stay, with serial clinical and laboratory measurements for the first 48 postoperative hours and clinical follow-up to discharge. There were no significant baseline differences between RIPC (n=148) and sham (n=151). There were no in-hospital deaths. No significant difference in length of postoperative hospital stay was noted (sham 5.4 versus RIPC 5.6 days; difference +0.2; adjusted P=0.91), with the 95% confidence interval (-0.7 to +0.9) excluding a prespecified minimal clinically significant differences of 1 or 1.5 days. There were few significant differences in other clinical outcomes or values at time points or trends in physiological markers. Benefit was not observed in specific subgroups when explored through interactions with categories of age, sex, surgery type, Aristotle score, or first versus second half of recruitment. Adverse events were similar (sham 5%, RIPC 6%; P=0.68).

Conclusions: RIPC is not associated with important improvements in clinical outcomes and physiological markers after cardiac surgery in children.

Clinical trial registration url: clinicaltrials.gov. Unique identifier: NCT00650507.

Keywords: congenital; heart defects; pediatrics; remote ischemic preconditioning; surgery.

© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1.
Figure 1.
Consolidated Standards of Reporting Trials diagram: flow of patients through the study. RIPC indicates remote ischemic preconditioning; SHAM, sham stimulus.
Figure 2.
Figure 2.
Duration of care (hours) for RIPC and SHAM patients. Unadjusted P values and P values adjusted for propensity score, duration of aortic cross‐clamping, and surgery Aristotle score are reported. ICU indicates intensive care unit; RIPC, remote ischemic preconditioning; SHAM, sham stimulus.
Figure 3.
Figure 3.
Serial ventilation parameters. P values are reported for the mean difference and the difference in slope between RIPC and SHAM. All P values are adjusted for propensity score, duration of aortic cross‐clamping, surgery Aristotle score, and proportion of patients extubated at each time point. Average indicates mean difference; CPB, cardiopulmonary bypass; FiO2, fraction of inspired oxygen; MVe, minute ventilation; PEEP, positive end‐expiratory pressure; Ppeak, peak inspiratory pressure; RIPC, remote ischemic preconditioning; SHAM, sham stimulus; slope, difference in slope; VTE, exhaled tidal volume.
Figure 4.
Figure 4.
Serial measures of myocardial injury and hemodynamic stability. P values are reported for the mean difference and the difference in slope between RIPC and SHAM. All P values are adjusted for propensity score, duration of aortic cross‐clamping, and surgery Aristotle score. Average indicates mean difference; CPB, cardiopulmonary bypass; MVO2, mixed venous oxygen saturation; RIPC, remote ischemic preconditioning; SHAM, sham stimulus; slope, difference in slope.
Figure 5.
Figure 5.
Serial measures of metabolic markers. P values are reported for the mean difference and the difference in slope between RIPC and SHAM. All P values are adjusted for propensity score, duration of aortic cross‐clamping, and surgery Aristotle score. Average indicates mean difference; CPB, cardiopulmonary bypass; RIPC, remote ischemic preconditioning; SHAM, sham stimulus; slope, difference in slope.
Figure 6.
Figure 6.
Serial measures of inflammatory markers. P values are reported for the mean difference and the difference in slope between RIPC and SHAM. All P values are adjusted for propensity score, duration of aortic cross‐clamping, and surgery Aristotle score. Average indicates mean difference; CPB, cardiopulmonary bypass; IL, interleukin; RIPC, remote ischemic preconditioning; SHAM, sham stimulus; slope, difference in slope; TNF, tumor necrosis factor.
Figure 7.
Figure 7.
Unadjusted effect of RIPC (vs SHAM) on postoperative hospital length of stay (log transformed) among patient subgroups. The effect of RIPC (vs SHAM) on hospital length of stay is reported with 95% confidence interval for relevant patient subgroups. RIPC was not found to have any statistically significant effect in any of these subgroup analyses. *Steroids given 24 hours before surgery and/or in the pump prime. **Propofol given at induction of anesthesia, during surgery, or during transfer to the intensive care unit. CPB indicates cardiopulmonary bypass; RIPC, remote ischemic preconditioning; SHAM, sham stimulus; TGA, transposition of the great arteries.

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