International Journal of Cardiology xxx (2014) xxx–xxx

IJCA-18719; No of Pages 3

Contents lists available at ScienceDirect

International Journal of Cardiology

j ourna l homepage: www.e lsev ie r .com/ locate / i j ca rd

Letter to the Editor

Remote ischemic preconditioning for pediatric patients undergoingcongenital 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 Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, Chinab The Children's Hospital of Chongqing Medical University, Chongqing 400016, Chinac The First College of Clinical Medicine, Chongqing Medical University, Chongqing 400016, China

⁎ Corresponding author. Tel.: +86 23 68811360; fax: +E-mail address: qcwucq@163.com (Q.-C. Wu).

http://dx.doi.org/10.1016/j.ijcard.2014.08.0980167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved

Please cite this article as: Tie H-T, et al, Remanalysis, Int J Cardiol (2014), http://dx.doi.o

a r t i c l e i n f o

Article history:

Received 22 May 2014Accepted 17 August 2014Available online xxxx

Keywords:Congenital heart diseaseRemote ischemic preconditioningPediatricsCongenital heart surgeryMeta-analysis

OR “cardiac surgical procedures” OR “thoracic surgery” OR “ventricularseptal defects” OR “atrial septal defects” OR “cardiopulmonary bypass”OR “cardiac surgery” OR heart surgery) AND (child OR children OR in-fants OR infant OR newborn OR newborns OR neonate OR neonates).RCTs comparing the effect of RIPC and control on the cardiac protectionin pediatric patients undergoing the surgery of CHDwere included. Datawere extrapolated from figures as needed, and continuous variablesexpressed as medians with range were converted to means and vari-ances by simple and elementary inequalities and approximations [3].Additionally, authorswould be contacted if necessary. Statistical hetero-geneity among studieswas tested by the I2 statistic and considered to be

Congenital heart disease (CHD) is the most common congenitalanomaly and 95% of neonates with CHD could survive to adulthoodowing to the great advances in cardiothoracic surgery [1]. Cardiopulmo-nary bypass (CPB) is routinely used in the congenital heart surgery, andthe injuries induced by ischemia–reperfusion (IR) and CPB contribute tothe postoperative morbidity and mortality, particularly prominent inpediatric patients. Remote ischemic preconditioning (RIPC) was a strik-ing strategy to protect target tissues from subsequent lethal ischemia.Given its safe, well-tolerated procedure and potential benefits forhuman ischemic injury, RIPC has been rapidly transferred and testedin various clinical trials, especially in the setting of cardiac surgery.Moreover, recent meta-analysis demonstrated that RIPC could reducethe release of troponin I in patients after cardiac surgery [2]. However,accumulating evidence of randomized controlled trials (RCTs) foundthat RIPC failed to show significant benefits on children receiving thecongenital heart surgery. Therefore, we performed a meta-analysis ofRCTs to evaluate the effect of the RIPC on cardiac protection in pediatricpatients 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 fol-lowing terms: (“Ischemic preconditioning” OR “myocardial ischemicpreconditioning” OR “remote ischemic preconditioning” OR “limb

86 23 89011138.

.

ote ischemic preconditioningrg/10.1016/j.ijcard.2014.08.09

ischemic preconditioning”) AND (“cardiovascular surgical procedures”

low (I2 between 25% and 50%),moderate (I2 between 50% and 75%), andhigh (I2 more than 75%). Standardized mean differences (SMDs) with95% confidence intervals (CIs) were used to pool the estimate by ran-dom effects model with DerSimonian and Laird weights. A two-tailedP value of less than 0.05 indicates a statistical significance. Stata 12.0software (StataCorp, College Station, TX, USA) was used for all analysis.

Seven eligible [4–10] RCTs involving 359 pediatric patients were in-cluded. Table 1 describes the main characteristics of the included RCTs.Compared with control, RIPC was not associated with a reduction in con-centrations of postoperative troponin I both at 4–6 h and 20–24 h, withhigh 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 onestudy in each turnwith randomeffectsmodel, sensitivity analysis showedthat the non-significant SWD remained stable with ranges from −0.3995% CI (−0.86–0.07) to −0.05 95% CI (−0.36–0.26) for postoperativetroponin 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 de-crease the amount of hemodynamic support (inotropic score) either atpostoperative 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 sig-nificantly 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 significantdifference 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.

for pediatric patients undergoing congenital cardiac surgery: A meta-8

Table 1The main characteristics of the seven included RCTs.

Study No.(RIPC/Con)

Population Surgery type Intervention RIPC timing Location ofRIPC

RIPC Con

Cheung et al. [4] 17/20 2.2 ± 3.4 years CHD/CPB 4 × 5 × 515 mm Hg N SAP

Sham operation 5 to 10 min before initiation of bypass Lower limb

Zhou et al. [10] 30/30 160.83 ± 58.39 days VSD/CPB 3 × 5 × 5240 mm Hg

Sham operation Independently 24 h and 1 h before operation Left upperarm

Luo et al. [7] 20/20 2.7 ± 0.9 years VSD/CPB 3 × 5 × 5200 mm Hg

Sham operation After anesthetic induction Lower limb

Lee et al. [6] 27/28 3.4 (R 0.6–12) months VSD/CPB 4 × 5 × 530 mm Hg N SAP

Sham operation 10 min after induction of anesthesia Lower limb

Pavione et al. [8] 12/10 6.1 (R 1.4–13.9) months CHD/CPB 4 × 5 × 515 mm Hg N SAP

Sham operation 24 h before cardiac surgery Lower limb

Jones et al. [5] 20/19 5.5 ± 4.2 days TGA, HLHS/CPB 4 × 5 × 515 mm Hg N SAP

Sham operation After induction of general anesthesia Lower limb

Pepe et al. [9] 20/20 7.6 ± 3.2 months TOF/CPB 4 × 5× 530 mm Hg N SAP

Sham operation Immediately after the induction of anesthesia Lower limb

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.

2 H.-T. Tie et al. / International Journal of Cardiology xxx (2014) xxx–xxx

The finding was not consistent with the previous meta-analysis [2]which involved a total of 214 pediatric subjects and showed that RIPCcould provide cardiac protection in pediatric patients undergoingcongenital heart surgery, with high heterogeneity among studies(SMD, −0.75 95% CI (−1.05–−0.46), I2 = 88%). The difference mightbe attributed to the number of patients, the type of CHD, the childrenage, and the data report on cardiac protection (time-point measure-ment vs. area under the curve).

Some potential reasons raised recently might explain the controver-sy and potential negative effects of RIPC on pediatric patients. Firstly, the

Fig. 1.Meta-analysis of RCTs evaluating effects of RIPC on postoperat

Please cite this article as: Tie H-T, et al, Remote ischemic preconditioninganalysis, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.08.09

immaturity of the children's heart and small skeletal muscle mass affectthe effect of RIPC and whether preconditioning shows protectionagainst IR injury for immature heart remains to be established [5,6].Secondly, chronic myocardial hypoxia could improve the tolerance toIR injury and confer direct protection of immature hearts [5]. VariousCHDs manifest different degrees of hypoxia, thus it might mask or con-found the effect of RIPC. Thirdly, the long duration of ischemia duringcardiac surgery might overwhelm the protective effect of RIPC [8]; con-sequently, diverse surgery time in various CHDs may be ascribed to thecontroversy. Moreover, since the sample sizes of included trials were

ive troponin I at 4–6 h and 20–24 h with random effects model.

for pediatric patients undergoing congenital cardiac surgery: A meta-8

Fig. 2.Meta-analysis of RCTs evaluating effects of RIPC on intropic score 4–6 h and postoperative 24 h with random effects model.

3H.-T. Tie et al. / International Journal of Cardiology xxx (2014) xxx–xxx

relatively small, the clinically significant protective effect might not bedetected, aswas supported by reduced length of ICU stay and decreasedtrends of ventilation duration and HLOS.

Further research should focus on the following points. The patientsinvolved should be adequate enough and characterized by specificCHD with specific range of age. Additionally, the timing, the procedureof RIPC, and the location of RIPC should be normalized. Moreover, it isnecessary to figure out the relationship among myocardial maturity,hypoxia and RIPC.

In summary, RIPC failed to show statistically significant benefit forcardiac protection and hemodynamic support in children undergoingcongenital cardiac surgery. However, RIPC could significantly reducethe length of ICU stay; additionally, decreased trends of ventilation du-ration andHLOS induced by RIPCwere identified. Thus, large-scale RCTsare urgently needed before the controversy being a verdict.

Ethical statement

The authors have certified that they accorded with the Principles ofEthical Publishing in the International Journal of Cardiology.

Contributors

H.T.T. and Q.C.W. were involved in the conception and design of thestudy, H.T.T., M.Z.L., Z.H.L., and Q.W. participated in acquisition and in-terpretation 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 ofthe version to be published.

Please cite this article as: Tie H-T, et al, Remote ischemic preconditioninganalysis, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.08.09

Conflict of interest

The authors report no relationships that could be construed as aconflict of interest.

References

[1] Zomer AC, Verheugt CL, Vaartjes I, et al. Surgery in adults with congenital heartdisease. Circulation 2011;124:2195–201.

[2] Haji Mohd Yasin NA, Herbison P, Saxena P, et al. The role of remote ischemic precon-ditioning 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 ofthe effects of remote ischemic preconditioning on children undergoing cardiac sur-gery: 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 cyanosedneonates 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 onischaemic–reperfusion injury in pulmonary hypertensive infants receiving ventricularseptal defect repair. Br J Anaesth 2012;108:223–8.

[7] LuoW, ZhuM, Huang R, et al. A comparison of cardiac post-conditioning and remotepre-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 inchildren undergoing cardiopulmonary bypass: a randomized controlled trial. JThorac Cardiovasc Surg 2012;144:178–83.

[9] Pepe S, Liaw NY, Hepponstall M, et al. Effect of remote ischemic preconditioning onphosphorylated protein signaling in children undergoing tetralogy of Fallot repair: arandomized controlled trial. J Am Heart Assoc 2013;2:e000095.

[10] Zhou W, Zeng D, Chen R, et al. Limb ischemic preconditioning reduces heart andlung injury after an open heart operation in infants. Pediatr Cardiol 2010;31:22–9.

for pediatric patients undergoing congenital cardiac surgery: A meta-8