IJCA-18719; No of Pages 3 International Journal of Cardiology xxx (2014) xxx–xxx
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Letter to the Editor
Remote ischemic preconditioning for pediatric patients undergoing congenital cardiac surgery: A meta-analysis Hong-Tao Tie a, Ming-Zhu Luo b, Zhen-Han Li c, Qian Wang c, Qing-Chen Wu a,⁎ a b c
Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China The Children's Hospital of Chongqing Medical University, Chongqing 400016, China The First College of Clinical Medicine, Chongqing Medical University, Chongqing 400016, China
a r t i c l e
i n f o
Article history: Received 22 May 2014 Accepted 17 August 2014 Available online xxxx Keywords: Congenital heart disease Remote ischemic preconditioning Pediatrics Congenital heart surgery Meta-analysis
Congenital heart disease (CHD) is the most common congenital anomaly and 95% of neonates with CHD could survive to adulthood owing to the great advances in cardiothoracic surgery [1]. Cardiopulmonary bypass (CPB) is routinely used in the congenital heart surgery, and the injuries induced by ischemia–reperfusion (IR) and CPB contribute to the postoperative morbidity and mortality, particularly prominent in pediatric patients. Remote ischemic preconditioning (RIPC) was a striking strategy to protect target tissues from subsequent lethal ischemia. Given its safe, well-tolerated procedure and potential benefits for human ischemic injury, RIPC has been rapidly transferred and tested in various clinical trials, especially in the setting of cardiac surgery. Moreover, recent meta-analysis demonstrated that RIPC could reduce the release of troponin I in patients after cardiac surgery [2]. However, accumulating evidence of randomized controlled trials (RCTs) found that RIPC failed to show significant benefits on children receiving the congenital heart surgery. Therefore, we performed a meta-analysis of RCTs to evaluate the effect of the RIPC on cardiac protection in pediatric patients undergoing the congenital heart surgery. PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from the inception to Apr 2014 with the following terms: (“Ischemic preconditioning” OR “myocardial ischemic preconditioning” OR “remote ischemic preconditioning” OR “limb
⁎ Corresponding author. Tel.: +86 23 68811360; fax: +86 23 89011138. E-mail address:
[email protected] (Q.-C. Wu).
ischemic preconditioning”) AND (“cardiovascular surgical procedures” OR “cardiac surgical procedures” OR “thoracic surgery” OR “ventricular septal defects” OR “atrial septal defects” OR “cardiopulmonary bypass” OR “cardiac surgery” OR heart surgery) AND (child OR children OR infants OR infant OR newborn OR newborns OR neonate OR neonates). RCTs comparing the effect of RIPC and control on the cardiac protection in pediatric patients undergoing the surgery of CHD were included. Data were extrapolated from figures as needed, and continuous variables expressed as medians with range were converted to means and variances by simple and elementary inequalities and approximations [3]. Additionally, authors would be contacted if necessary. Statistical heterogeneity among studies was tested by the I2 statistic and considered to be low (I2 between 25% and 50%), moderate (I2 between 50% and 75%), and high (I2 more than 75%). Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were used to pool the estimate by random effects model with DerSimonian and Laird weights. A two-tailed P value of less than 0.05 indicates a statistical significance. Stata 12.0 software (StataCorp, College Station, TX, USA) was used for all analysis. Seven eligible [4–10] RCTs involving 359 pediatric patients were included. Table 1 describes the main characteristics of the included RCTs. Compared with control, RIPC was not associated with a reduction in concentrations of postoperative troponin I both at 4–6 h and 20–24 h, with high heterogeneities (for 4–6 h: SMD, −0.25 95% CI (−0.73–0.23), I2 = 75.2%, PH b 0.001, P = 0.311; for 20–24 h: SMD, −0.09 95% CI (−0.51–0.68), I2 = 83.7%, PH b 0.001, P = 0.778, Fig. 1). Omitting one study in each turn with random effects model, sensitivity analysis showed that the non-significant SWD remained stable with ranges from −0.39 95% CI (−0.86–0.07) to −0.05 95% CI (−0.36–0.26) for postoperative troponin I at 4–6 h and from −0.12 95% CI (−0.65–0.40) to 0.31 95% CI (−0.18–0.80) for postoperative troponin I at 20–24 h. RIPC failed to decrease the amount of hemodynamic support (inotropic score) either at postoperative 4–6 h or postoperative 24 h (for 4–6 h: SMD, −0.19 95% CI (−0.51–0.14), I2 = 23.1%, PH = 0.272, P = 0.264; for 24 h: SMD, −0.15 95% CI (−0.49–0.18), I2 = 38.2%, PH = 0.167, P = 0.365, Fig. 2). As for clinical outcomes, the result suggested that RIPC could significantly shorten the length of ICU stay (SMD, −0.38 95% CI (−0.72– −0.04), I2 = 34.2%, PH = 0.193, P = 0.029). No statistically significant difference was found in the ventilation duration (SMD, −0.20 95% CI (− 0.44–0.05), I2 = 0.0%, PH = 0.632, P = 0.118) and HLOS (SMD, −0.43 95% CI (−1.14–0.29), I2 = 67.4%, PH = 0.047, P = 0.243), however, reduced trends could be seen in both of them.
http://dx.doi.org/10.1016/j.ijcard.2014.08.098 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Tie H-T, et al, Remote ischemic preconditioning for pediatric patients undergoing congenital cardiac surgery: A metaanalysis, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.08.098
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H.-T. Tie et al. / International Journal of Cardiology xxx (2014) xxx–xxx
Table 1 The main characteristics of the seven included RCTs. Study
Cheung et al. [4]
No. (RIPC/Con)
Population
17/20
2.2 ± 3.4 years
Surgery type
CHD/CPB
Zhou et al. [10]
30/30
160.83 ± 58.39 days
VSD/CPB
Luo et al. [7]
20/20
2.7 ± 0.9 years
VSD/CPB
Lee et al. [6]
27/28
3.4 (R 0.6–12) months
VSD/CPB
Pavione et al. [8] Jones et al. [5] Pepe et al. [9]
12/10 20/19 20/20
Intervention RIPC
6.1 (R 1.4–13.9) months 5.5 ± 4.2 days 7.6 ± 3.2 months
CHD/CPB TGA, HLHS/CPB TOF/CPB
4×5×5 15 mm Hg N 3×5×5 240 mm Hg 3×5×5 200 mm Hg 4×5×5 30 mm Hg N 4×5×5 15 mm Hg N 4×5×5 15 mm Hg N 4 × 5× 5 30 mm Hg N
RIPC timing
Location of RIPC
Sham operation
5 to 10 min before initiation of bypass
Lower limb
Sham operation
Independently 24 h and 1 h before operation
Sham operation
After anesthetic induction
Left upper arm Lower limb
Sham operation
10 min after induction of anesthesia
Lower limb
Sham operation
24 h before cardiac surgery
Lower limb
Sham operation
After induction of general anesthesia
Lower limb
Sham operation
Immediately after the induction of anesthesia
Lower limb
Con SAP
SAP SAP SAP SAP
RIPC, remote ischemic preconditioning; Con, control; CHD, congenital heart disease; VSD, ventricular septal defect; TOF, tetralogy of Fallot; TGA, transposition of the great arteries; HLHS, hypoplastic left heart syndrome; SAP, systolic arterial pressure. 4 × 5 × 5 15 mm Hg N SAP: Four cycles of 5-min ischemia and 5-min reperfusion using a blood-pressure cuff inflated to a pressure 15 mm Hg greater than the systolic arterial pressure.
The finding was not consistent with the previous meta-analysis [2] which involved a total of 214 pediatric subjects and showed that RIPC could provide cardiac protection in pediatric patients undergoing congenital heart surgery, with high heterogeneity among studies (SMD, −0.75 95% CI (−1.05–−0.46), I2 = 88%). The difference might be attributed to the number of patients, the type of CHD, the children age, and the data report on cardiac protection (time-point measurement vs. area under the curve). Some potential reasons raised recently might explain the controversy and potential negative effects of RIPC on pediatric patients. Firstly, the
immaturity of the children's heart and small skeletal muscle mass affect the effect of RIPC and whether preconditioning shows protection against IR injury for immature heart remains to be established [5,6]. Secondly, chronic myocardial hypoxia could improve the tolerance to IR injury and confer direct protection of immature hearts [5]. Various CHDs manifest different degrees of hypoxia, thus it might mask or confound the effect of RIPC. Thirdly, the long duration of ischemia during cardiac surgery might overwhelm the protective effect of RIPC [8]; consequently, diverse surgery time in various CHDs may be ascribed to the controversy. Moreover, since the sample sizes of included trials were
Fig. 1. Meta-analysis of RCTs evaluating effects of RIPC on postoperative troponin I at 4–6 h and 20–24 h with random effects model.
Please cite this article as: Tie H-T, et al, Remote ischemic preconditioning for pediatric patients undergoing congenital cardiac surgery: A metaanalysis, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.08.098
H.-T. Tie et al. / International Journal of Cardiology xxx (2014) xxx–xxx
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Fig. 2. Meta-analysis of RCTs evaluating effects of RIPC on intropic score 4–6 h and postoperative 24 h with random effects model.
relatively small, the clinically significant protective effect might not be detected, as was supported by reduced length of ICU stay and decreased trends of ventilation duration and HLOS. Further research should focus on the following points. The patients involved should be adequate enough and characterized by specific CHD with specific range of age. Additionally, the timing, the procedure of RIPC, and the location of RIPC should be normalized. Moreover, it is necessary to figure out the relationship among myocardial maturity, hypoxia and RIPC. In summary, RIPC failed to show statistically significant benefit for cardiac protection and hemodynamic support in children undergoing congenital cardiac surgery. However, RIPC could significantly reduce the length of ICU stay; additionally, decreased trends of ventilation duration and HLOS induced by RIPC were identified. Thus, large-scale RCTs are urgently needed before the controversy being a verdict. Ethical statement The authors have certified that they accorded with the Principles of Ethical Publishing in the International Journal of Cardiology. Contributors H.T.T. and Q.C.W. were involved in the conception and design of the study, H.T.T., M.Z.L., Z.H.L., and Q.W. participated in acquisition and interpretation of data, H.T.T. drafted the article, Q.C.W. revised the article, H.T.T., M.Z.L., Z.H.L., Q.W., and Q.C.W. agreed with the final approval of the version to be published.
Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] Zomer AC, Verheugt CL, Vaartjes I, et al. Surgery in adults with congenital heart disease. Circulation 2011;124:2195–201. [2] Haji Mohd Yasin NA, Herbison P, Saxena P, et al. The role of remote ischemic preconditioning in organ protection after cardiac surgery: a meta-analysis. J Surg Res 2014; 186:207–16. [3] Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 2005;5:13. [4] Cheung MM, Kharbanda RK, Konstantinov IE, et al. Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans. J Am Coll Cardiol 2006;47:2277–82. [5] Jones BO, Pepe S, Sheeran FL, et al. Remote ischemic preconditioning in cyanosed neonates undergoing cardiopulmonary bypass: a randomized controlled trial. J Thorac Cardiovasc Surg 2013;146:1334–40. [6] Lee JH, Park YH, Byon HJ, et al. Effect of remote ischaemic preconditioning on ischaemic–reperfusion injury in pulmonary hypertensive infants receiving ventricular septal defect repair. Br J Anaesth 2012;108:223–8. [7] Luo W, Zhu M, Huang R, et al. A comparison of cardiac post-conditioning and remote pre-conditioning in paediatric cardiac surgery. Cardiol Young 2011;21:266–70. [8] Pavione MA, Carmona F, de Castro M, et al. Late remote ischemic preconditioning in children undergoing cardiopulmonary bypass: a randomized controlled trial. J Thorac Cardiovasc Surg 2012;144:178–83. [9] Pepe S, Liaw NY, Hepponstall M, et al. Effect of remote ischemic preconditioning on phosphorylated protein signaling in children undergoing tetralogy of Fallot repair: a randomized controlled trial. J Am Heart Assoc 2013;2:e000095. [10] Zhou W, Zeng D, Chen R, et al. Limb ischemic preconditioning reduces heart and lung injury after an open heart operation in infants. Pediatr Cardiol 2010;31:22–9.
Please cite this article as: Tie H-T, et al, Remote ischemic preconditioning for pediatric patients undergoing congenital cardiac surgery: A metaanalysis, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.08.098