Congenital Heart Disease

DOI: 10.32604/CHD.2021.016396

REVIEW

Effect of Cardioplegia for Myocardial Protection in Pediatric Cardiac Surgery: A Network Meta-Analysis

Ke Zhou1, Dongyu Li1, Xintong Zhang2, Wensheng Wang1, Shusen Li1 and Guang Song2,*

1Department of Cardiac Surgery, Shengjing Hospital of China Medical University, Shenyang, China
2Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China
*Corresponding Author: Guang Song. Email: songg84@163.com
Received: 03 March 2021; Accepted: 26 April 2021

1  Introduction

Approximately 100 congenital heart surgeries are performed by each pediatric cardiac surgeon in North America every year [1], and 40,000 children undergo congenital heart surgical procedures in the United States each year [2]. It is important to protect the myocardium during open heart surgery because cardiopulmonary bypass can cause myocardial ischemia and reperfusion injury, leading to impaired cardiac function. During cardiopulmonary bypass surgery, there are several methods of myocardial protection, including cardioplegia solution, hypothermia, and local cooling [3]. The most studied method, however, is the application of cardioplegia.

Cardioplegia is a chemical cardiac arrest solution that is administered to intentionally and temporarily arrest the heart. Cardioplegia decreases the myocardial metabolic demand. Cardioplegia is divided into two main categories (crystalloid- or blood-based solutions). Cold crystalloid cardioplegia (cCCP) has been the cornerstone of cardiac surgical practice since the 1950s. Cold blood cardioplegia (cBCP) was introduced in the 1970s due to the increased oxygen-carrying capacity, maintenance of oncotic pressure, and scavenging of free radicals [4]. Since the introduction of cBCP, several modified types of cardioplegia have been used in clinical applications, including del Nido (DN) and histidine-tryptophan-ketoglutarate (HTK) solutions. Although there are numerous studies comparing the effects of two or three cardioplegia solutions, there is no consensus on a cardioplegia solution that affords optimal myocardial protection. Therefore, we conducted this network meta-analysis (NMA) to systematically evaluate the myocardial protective effects of various cardioplegia solutions currently used in pediatric cardiac surgery.

2  Material and Methods

We followed a reporting guideline (Preferred Reporting Items for Systematic Reviews and Meta-Analyses for NMA) to conduct this study [5]. The review protocol (number: CRD42020215431) was registered in the PROSPERO database. Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, we assessed the certainty of evidence derived from the network meta-analysis results. GRADE provides a system for rating the quality of NMAs, and evaluates the quality of evidence at 4 levels (high, moderate, low, and very low).

2.1 Search Strategy

Two examiners (KZ and XZ) independently searched for the significant studies in databases, including PubMed, MEDLINE, Web of Science, EMBASE, Scopus, ClinicalTrials.gov, and the Cochrane library on 20 January 2021. The search words were ‘cardioplegia,’ ‘pediatric,’ and ‘randomized controlled trials (RCTs).’ The details of the search strategy are shown in Tab. S1. At the same time, we read the references cited in the studies to further locate the literature which met the criteria.

2.2 Data Extraction

Reviewers (KZ and XZ) were assigned to screen the titles and abstracts for eligibility. The third reviewer (DL) resolved any disagreement between the reviewers. Original studies were eligible if the following criteria were met: (I) RCTs of cardiac surgery; (II) full text with language restrictions; and (III) literature on assessment of the effect of myocardial protection using different cardioplegia solutions in pediatric cardiac surgery. Original studies were ineligible for the following reasons: (I) reviews, observational studies, case-control studies, abstracts, letters, or case reports; (II) patients other than children; (III) cardioplegia with adjuncts, such as nicardipine or esmolol, or leukocyte-depleted cardioplegia studies; and (IV) laboratory animal studies. If there were several publications from the same study, the study with the most cases and relevant information was included.

For eligible studies, the first author (year of publication), region, median age of participants, gender, cardioplegia type and number of participants in each group, temperature, delivery method, aortic cross-clamp time, cardiopulmonary bypass time, and outcomes were extracted by two independent authors (WW and SL). Numeric data were gathered directly from tables, or when presented in graphs only, were inferred by digitizing the figure with GetData Graph Digitizer 2.26 [6].

2.3 Study Outcomes

Researchers generally used biochemical and/or clinical outcomes to evaluate the myocardial protective effects. In this NMA, the outcomes included biochemical and clinical outcomes. Biochemical outcomes were the serum concentrations of the creatine kinase-myocardial band (CK-MB) 6 h postoperatively (IU/L) and cardiac troponin I (cTnI) 4, 12, and 24 h postoperatively (ng/ml). The clinical outcomes included spontaneous beating after declamping, postoperative arrhythmias, inotropic support (%), inotropic duration hours, mechanical ventilation hours, intensive care unit (ICU) stay in days, hospital stay in days, and risk of postoperative mortality.

2.4 Statistical Analysis

Before analyzing the data, the risk of trial bias of the included studies was assessed using the Cochrane Collaboration’s Tool. Mean differences (MDs) and 95% confidence intervals (CIs) were used to report the 6-h CK-MB, 4-h cTnI, 12-h cTnI, 24-h cTnI, inotropic duration hours, mechanical ventilation hours, ICU stay in days, and hospital stay in days. Odds ratios (ORs) were used to report the risk of spontaneous beating after declamping, postoperative arrhythmias, inotropic support percentage, and mortality.

We evaluated the myocardial protection of various cardioplegia solutions using NMA. In the Bayesian NMA, random effects and consistency models were used for analyzing data and carrying out the network meta-analysis (4 chains, 50,000 iterations, and 20,000 per chain). We assessed inconsistency using the node-splitting method, and the inconsistency was reported by the Bayesian P value. The publication bias was evaluated using a comparison-adjusted funnel plot [7]. All analyses were conducted using the “gemtc” package of R (version 4.0.2; R Foundation) and Stata (version 16.0; StataCorp, College Station, TX, USA).

3  Results

Our exhaustive search strategy retrieved 536 potentially relevant publications from 7 databases. After screening, 22 RCTs s were included in our final analysis (Fig. 1 shows the PRISMA flow-chart) [8–29].

Figure 1: Flow-chart of study selection

The 22 RCTs conducted in Europe, Asia, and the USA between 1994 and 2020 involved 1529 patients (Tab. 1). Six types of cardioplegia solutions were described in these studies, including cBCP, cCCP, DN, HTK, terminal warm blood cardioplegia, and warm blood cardioplegia (wBCP). Most cardioplegia solutions were delivered in an antegrade fashion. The temperature of cold cardioplegia solutions was 2°C–10°C. The temperature of warm cardioplegia solutions was 33°C–37°C. Additional details of the selected studies are shown in Tabs. S2–S4.

Evaluation of the bias risk for all RCTs is presented in the supplemental file (Figs. S1 and S2). Only two studies were high risk. Five studies were considered low risk and 14 studies were considered to have an unclear risk, which indicated that the selected RCTs were of good quality.

The geometry of the network is shown in Fig. S3 in the supplemental file. Ten studies with 5 types of cardioplegia solution involving the 24-h cTnI were included (Tab. 2). The serum concentration of the 24-h cTnI with wBCP (MD = −2.52, 95% CI: −4.74 to −0.27) was significantly lower than cCCP (Fig. 2). The serum concentration of the 24-h cTnI with HTK (MD = 4.91, 95% CI:2.84–7.24) was significantly higher than cCCP (Fig. 2). There was no significant difference in other biochemical outcomes among seven cardioplegia solutions (Fig. 3).

Figure 2: Forest plots of network meta-analysis of all trials for biochemical outcomes. cBCP: cold blood cardioplegia; cCCP: cold crystalloid cardioplegia; CK-MB: creatine kinase-myocardial band; cTnI: cardiac troponin I; DN: del Nido; HTK: Histidine-tryptophan-ketoglutarate; twBCP: terminal warm blood cardioplegia; wBCP: warm blood cardioplegia

Figure 3: Forest plots of network meta-analysis of all trials for clinical outcomes. cBCP: cold blood cardioplegia; cCCP: cold crystalloid cardioplegia; DN: del Nido; HTK: Histidine-tryptophan-ketoglutarate; ICU: intensive care unit; twBCP: terminal warm blood cardioplegia; wBCP: warm blood cardioplegia

There was no significant difference in spontaneous beating after declamping, postoperative arrhythmias, inotropic support percentage, inotropic duration hours, mechanical ventilation hours, ICU stay in days, hospital stay in days, or mortality of the five cardioplegia solutions when compared with cCCP. The head-to-head comparisons of each outcome are shown in Tabs. S5–S16.

The results of evaluating inconsistencies for all outcomes are presented in Figs. S4–S12 in the supplemental file. We noted a significance level of P > 0.05 for most of cases, which indicated that inconsistency was not present for most comparisons. After comparison results were obtained, we used the GRADE system to evaluate the certainty of evidence (Tab. 2). No significant asymmetry was detected in the funnel plots of primary and secondary outcomes (Fig. S13).

4  Discussion

Based on this Bayesian NMA, cTnI measurements indicated that wBCP may afford better myocardial protection with lower cTnI levels 24 h postoperatively after cardiac surgery in children. The clinical outcomes were similar for various cardioplegia solutions. Indeed, this NMA is the first to compare the myocardial protective effects of various cardioplegia solutions during pediatric cardiac surgery.

There are several systematic reviews and meta-analyses that have compared cardioplegia during cardiac surgery over the years [30–33]. Fang et al. [30] compared cCCP and cBCP/wBCP in 5 RCTs and found that the 4-, 12-, and 24-h cTnI levels postoperatively, duration of mechanical ventilation, and ICU stays were not significantly different between groups. Mylonas et al. [31] concluded that the 4-h cTnI level was lower in the cBCP/wBCP group compared to cCCP based on 6 RCTs and 2 retrospective studies. Moreover, the duration of mechanical ventilation, length of hospital stay, and early mortality were similar in the analysis. Drury et al. [32] reported that the most common end points of cardioplegia in pediatric cardiac surgery were biomarkers of myocardial injury (cTnI [42.3%] and CK-MB [30.8%]), inotropic support (57.7%), and ICU stay (42.3%) in a systematic review involving 26 RCTs. Ler et al. [33] determined that the ICU stay and early mortality rate were similar when comparing DN and cCCP in three RCTs and one retrospective study.

The cTnI, cardiac troponin T, and CK-MB levels are specific and sensitive biomarkers of myocardial (ischemic–reperfusion) injury. Cardiac troponins are more specific markers of myocardial injury in pediatric cardiac surgery than CK-MB [34]. The diagnostic value of cTnI is similar to cardiac troponin T, but compared with cardiac troponin T, cTnI has the advantage of not being influenced by renal failure [35]. Several studies have shown the same trend; specifically, cTnI peaks at 4 h postoperatively and gradually decreases at 12 and 24 h [36–38]. Therefore, we chose 4, 12, and 24 h as the time points for cTnI in this NMA. cTnI values immediately postoperatively reflect the extent of myocardial damage from both incisional injury and intraoperative factors [39]. The 24-h cTnI level is also a good predictor for clinical outcomes following pediatric cardiac surgery, and correlated with ICU and hospital stays [39–41].

The advantages of wBCP during adult cardiac surgery were demonstrated as early as 1989 [42]. Since that time, wBCP has been shown to be safe and effective based on several RCTs involving adult cardiac surgery and widely used in clinical practice [43–45]; however, wBCP needs to be proven to become the standard method in pediatric patients. Two retrospective studies [46,47] and two RCTs [8,16] focused on wBCP during pediatric cardiac surgery. Chen et al. [8] published the first Chinese report which found that wBCP has a better myocardial protective effect with higher ATP and creatine phosphate, and lower inotropic support. Durandy et al. [46] published the first English report which showed that myocardial protection with wBCP during pediatric cardiac surgery was safe and effective in 1400 patients, with advantageous results in terms of fluid balance, sinus rhythm recovery, and time-to-extubation when compared to cBCP. Pouard et al. [47] reported that wBCP has a lower 24-h cTnI level, shorter duration of mechanical ventilation, and a trend to reduce the ICU length of stay. Poncelet et al. [16] confirmed that wBCP is as safe as cCCP through clinical outcomes, cardiac metabolic, and late neurologic and neuropsychologic assessments. The advantages of wBCP are as follows: (1) improved oxygen supply and reduced myocardial edema; and (2) easier to apply and cost-effective because cooling equipment is no longer required [48]. In addition, there is a RCT involving wBCP that is ongoing which may provide evidence to support the benefits of wBCP to clinical and biochemical outcomes during and after pediatric congenital heart surgery [48].

There were several limitations in this study. First, some of the selected studies were limited sample-sized, single-centered trials that could reduce the credibility of the results and conclusions. Second, the approach of administering cardioplegia, whether antegrade, retrograde, or a combination of both, was not analyzed in this NMA because most cardioplegia solutions were delivered in an antegrade fashion. Third, despite the use of NMA, some underlying confounders, such as the surgical complexity of the selected patients, surgical competence, and surgical proficiency may not be adjustable.

5  Conclusion

We are of the opinion that wBCP may have a superior myocardial protective effect with a lower 24-h cTnI level postoperatively and similar clinical outcomes after pediatric cardiac surgery.

Authors’ Contributions: The authors’ contributions were as follows: KZ participated in data collection, data analysis, and manuscript writing. DL participated in data collection and data analysis. XZ participated in data analysis. WW participated in data analysis. SL participated in project development. GS participated in project development, data analysis, and manuscript writing. All authors have read and approved the final manuscript.

Funding Statement: The authors received no specific funding for this study.

Conflicts of Interest: The authors declare that they have no conflicts of interest to report regarding the present study.

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Appendix

Figure S1: Risk of bias summary. +: low risk of bias; –: high risk of bias; ?: unclear risk of bias

Figure S2: Risk of bias graph

Figure S3: Geometry of the network. cBCP: cold blood cardioplegia; cCCP: cold crystalloid cardioplegia; CK-MB: creatine kinase-myocardial band; cTnI: cardiac troponin I; DN: del Nido; HTK: Histidine-tryptophan-ketoglutarate; ICU: intensive care unit; twBCP: terminal warm blood cardioplegia; wBCP: warm blood cardioplegia. Notes: circles represent the intervention as a node in the network, lines represent direct comparisons using randomized controlled trials (RCTs) and the thickness of lines corresponds to the number of RCTs included in each comparison

Figure S4: Inconsistency test of cTnI 4-h. cTnI: cardiac troponin I

Figure S5: Inconsistency test of cTnI 24-h. cTnI: cardiac troponin I

Figure S6: Inconsistency test of spontaneous beating after declamping

Figure S7: Inconsistency test of inotropic support (%)

Figure S8: Inconsistency test of inotropic duration hours

Figure S9: Inconsistency test of mechanical ventilation hours

Figure S10: Inconsistency test of ICU stays. ICU: intensive care unit

Figure S11: Inconsistency test of hospital stays

Figure S12: Inconsistency test of mortality

Figure S13: Funnel plot of outcomes. CK-MB: creatine kinase-myocardial band; cTnI: cardiac troponin I; ICU: intensive care unit.

e-References

1.    Chen, R. W., Wang, Z. W., Xu, F. X. (1994). Myocardium protection using warm blood cardioplegia in corrective operation of tetralogy Fallot. Chinese Journal of Surgery, 32(8), 499–501.

2.    Young, J. N., Choy, I. O., Silva, N. K., Obayashi, D. Y., Barkan, H. E. (1997). Antegrade cold blood cardioplegia is not demonstrably advantageous over cold crystalloid cardioplegia in surgery for congenital heart disease. Journal of Thoracic and Cardiovascular Surgery, 114(6), 1002–1009.

3.    Caputo, M., Modi, P., Imura, H., Pawade, A., Parry, A. J. et al. (2002). Cold blood versus cold crystalloid cardioplegia for repair of ventricular septal defects in pediatric heart surgery: A randomized controlled trial. Annals of Thoracic Surgery, 74(2), 530–535.

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PRISMA NMA Checklist of Items to Include When Reporting a Systematic Review: Involving a Network Meta-Analysis

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