Safety and feasibility of 3D‐electroanatomical mapping‐guided zero or near‐zero fluoroscopy catheter ablation for pediatric arrhythmias: Meta‐analysis

Abstract Background Catheter ablation in the pediatric population using fluoroscopy has been known to cause adverse events. This study aims to assess the effectiveness and safety of zero fluoroscopy (ZF) and near‐ZF‐guided catheter ablation for the treatment of arrhythmias in the pediatric population. Methods The PubMed, Embase, and Cochrane library databases were searched and reviewed for relevant studies. Outcomes of interest include safety, short‐term, and long‐term effectiveness. We classified patients ≤21 years old who underwent ZF or near‐ZF ablation with fluoroscopy time ≤1.5 min as our study group and patients within the same age range who underwent conventional fluoroscopy and/or near‐ZF ablation with a mean fluoroscopy time >1.5 min as our control group. Both ZF and near‐ZF ablation utilized 3D‐electroanatomical mapping (3D‐EAM). Results Ten studies composed of 2279 patients were included in this study. Total fluoroscopy time (MD –15.93 min, 95% CI (−22.57 – (−9.29), p < .001; I 2 = 84%)) and total procedural time (MD –22.06 min, 95% CI (−44.39 – (−0.28), p < .001; I 2 = 88%)) were significantly lower in the near‐ZF group. Both ZF and near‐ZF demonstrated a trend towards improved success rates compared to conventional fluoroscopy but did not achieve statistical significance for all subgroup analyses. Ablation in the study group also decreased incidence of complication compared to the control (RR 0.35; 95% CI (0.14–0.90); p = .03; I 2 = 0%). Conclusion ZF and near‐ZF ablation reduced the overall duration, compares in effectiveness, and shows a superior safety profile compared to control group.


| INTRODUC TI ON
Catheter ablation, established as the primary treatment modality for a majority of tachyarrhythmias, is associated with inherent risks, prominently manifest through the use of fluoroscopy. 1 This effect is pronounced in the pediatric population, who are up to 10 times more likely to develop complications, leading to increased long-term morbidity and reduced quality of life. 2 The American College of Cardiology Task Force recommends the acronym ALARA, which stands for "as low as reasonably achievable", as a guiding principle for cardiovascular imaging, thus limiting the dose of exposure to ionizing radiation. 35][6] Unique pediatric arrhythmias and faster conduction further demand procedural modifications. 7,8[11][12] According to a recent trial, zero fluoroscopy (ZF) in supraventricular ablation shows a 96% risk reduction in cancer-related events and deaths. 13Nevertheless, further research is required to determine the safety, effectiveness, and recurrence rate of arrhythmias caused by 3D-EAM-guided zero or near-zero fluoroscopy catheter ablation in the pediatric population.More research is required to optimize the procedure in this group, including understanding the differences in outcomes for distinct types of arrhythmias using ZF and near-ZF ablation compared to conventional procedures.This systematic review and meta-analysis aim to prove the effectiveness and safety of ZF and near-ZF-guided catheter ablation in the pediatric population.

| ME THODS
This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. 14The protocol is registered in the international prospective register of systematic reviews (CRD42023406584).

MEDLINE (Medical Literature Analysis and Retrieval System
Online) via PubMed, EMBASE (Excerpta Medical Database), and the Cochrane Library were searched using the following search string: 'Zero Fluoroscopy' or 'ZF' or 'Near Zero Fluoroscopy' or 'Fluoroless' and 'Ablation'; and 'Pediatric' or 'Young' or 'Children'.
All identified studies were screened by title and abstract.Three investigators independently identified studies that met the inclusion criteria.The study population included patients ≤21 years old who underwent ablation with ZF or near-ZF with mean fluoroscopy time of ≤1.5 min guided by 3D-EAM.This cutoff aligns with ALARA recommendations 3 and is adopted from the adjusted mean fluoroscopy time from near-ZF reports encountered in literature.Meanwhile, the control group included pediatric patients who underwent conventional fluoroscopy-guided ablation and/or a mean fluoroscopy time of >1.5 min.Studies were excluded if the subjects were >21 years old and included patient groups with a mean fluoroscopy time of >1.5 min, ZF or near-ZF guided by echocardiography, or a control group in studies with a fluoroscopy duration of ≤1.5 min.Subsequently, the systematic quality assessment of included studies was evaluated with the preferred Newcastle-Ottawa Scale (NOS) for observational studies. 15Investigations were classified as having low (<5 points), moderate (5-7 points), or high quality (>7 points).

| Outcome measurement
We focused on the effectiveness and safety of ZF or near-ZF as the main clinical outcomes of this study.Short-term effectiveness or acute success is generally defined as suppression or modulation of the slow pathway in the case of Atrioventricular Nodal Re-entry Tachycardia (AVNRT), as the absence of inducibility in the case of Atrial Tachycardia (AT), absence of bidirectional conduction after adenosine triphosphate infusion in the case of Accessory Pathway (AP)/Atrioventricular Re-entry Tachycardia (AVRT), 16,17 and absence of ventricular arrhythmias under ventricular extra-stimulation (maximum of three), with or without isoproterenol infusion in the case of Ventricular Tachycardia (VT). 18Long-term effectiveness is determined by arrhythmia recurrence, defined by the recurrence of arrhythmias similar to that identified at the time of catheter ablation.
We gauged procedural safety by assessing complications associated with catheter ablation that occurred within 30 days of ablation.
Other specific criteria are reported in the results table labelled as study characteristics.The secondary outcomes in this study are the total procedural time and fluoroscopy time.

| Data synthesis and analysis quality assessment
We synthesized data that were presented in at least two included studies.Each outcome was analyzed as a subgroup based on the type of zero fluoroscopy.True zero fluoroscopy (true ZF) did not use fluoroscopy at all, and near-ZF used fluoroscopy with a mean fluoroscopy time of ≤1.5 min.We classified arrhythmias into three subgroups: AVNRT, AVRT, and nonspecified/other arrhythmias, as AVRT and AVNRT were the most frequently studied arrhythmias and several studies did not distinguish between type.These subgroups were compared using the Z statistic.Mean and standard deviation (SD) were used to present continuous variables.Sample size, median, range, and quartiles were used to approximate the mean and SD if they were not reported. 19,20Subgroup analysis was also performed based on the application of 3D-EAM and comparison between ZF/ NZF with 3D-EAM and conventional fluoroscopy.
Heterogeneity between study populations was calculated using the I 2 statistic, 12 where values of less than 25%, 50%, and 75% were considered evidence of low, medium, and high levels of heterogeneity, respectively.Data were summarized across groups using the Mantel-Haenszel (M-H) risk ratio (RR) fixed-effect model if I 2 < 25%.
The random-effect model is used if I 2 > 25%. 21Publication bias was then evaluated using funnel plots and our analysis was carried out using Review Manager 5.4.

| Selection and description of studies
The PRISMA flow diagram in Figure 1 summarizes the study selection process.The primary search identified 1528 citations, and after removing duplicates, the remaining 853 abstracts were independently screened by three researchers.Considering the inclusion criteria, a total of 67 potentially relevant studies were selected for full-text review and 57 studies were excluded.At the end of this process, 10 cohort studies were included in our data synthesis (Figure 1 and Table 1). 9,18,22-29

| Characteristics of included studies
Characteristics of the included studies are presented in Tables 1   and 2. Five studies used a single radio-frequency catheter ablation (RFCA) strategy for the procedure, 22,23,[25][26][27] while others used either RFCA or cryoablation alone, or a combination of both. 9,23,24,28,29In the study group, four studies used true ZF. 18,23,26,28 One study using near-ZF in the study group included subgroup analysis data based on true ZF and near-ZF. 23The control group as a whole used conventional fluoroscopy guidance only except for four studies that also used 3D-EAM guidance. 22,25,26,28asons for ablation were varied, with the majority being AP/ AVRT and AVNRT.
The definitions, specific measurements, and outcome complications for each endpoint are further presented in Table 2.The average follow-up period in studies that included follow-up time was 18.6 months and the mean of all population body weight was 49.41 kg.All but one study 25 reported details of the population with existing CHD.One study completely excluded patients with CHD. 27Five studies excluded subjects with significant CHD but did not specify the type of CHD that was included. 18,23,24,26The remaining four studies included patients with CHD, including subjects with bicuspid aortic valve, mitral valve prolapse, Ebstein's anomaly, cardiomyopathy, tetralogy of Fallot, repaired CHDs, and CHDs that were not specifically described.One study considered the presence of CHD as an indication for conducting 3D-EAMguided ZF. 22

| Data synthesis
The 10 studies comprised of 2279 patients were included in this study with a mean age of 12.7 years and predominately of the male gender (55.7%) (Table 2).The results of the analysis showed

| Risk of bias
The overall quality of included studies ranged from good to moderate, with NOS values ranging from 6 to 9 (Supplementary Information S1).Two studies categorized as having moderate quality omitted specifying the follow-up duration. 22,24All observational studies obtained their data directly from medical records; however, two studies had the disadvantage of employing suboptimal control groups.Their subjects came from different communities or CHD status was taken into account to consider control variables, which has the potential to introduce confounding variables. 22,28As previously explained, four studies performed ablation with 3D-EAM guidance in the control group.We did not exclude these studies as our aim focused more on the outcome comparison between ZF/near-ZF and conventional fluoroscopy ablation.As additional data, we conducted a sub-analysis of primary outcomes, specifically in studies using 3D-EAM in both study and control groups (Supplementary

TA B L E 2 (Continued)
We found that 3D-EAM ZF or near-ZF-guided ablation in the pediatric population was as effective in both the short and long term compared to conventional fluoroscopy-guided ablation.Additionally, this technique was associated with a lower risk of complications and a shorter duration of fluoroscopy.However, the true ZF group was not linked with a shorter overall procedural time.Given the many benefits provided by 3D-EAM-guided ZF or near-ZF ablation, this study challenges the need for routine fluoroscopy in the pediatric population, even for short durations and suggests that the 3D-EAMguided ZF ablation strategy should be the technique of choice for ablation of the two most common substrates (AVNRT and AVRT) in the pediatric population, at least in the absence of existing structural heart disease.
In its early days, RFCA in the pediatric population reported significant x-ray exposure. 30,31Today, nonfluoroscopic imaging modalities are widely available, and the reduction of radiation exposure during ablation, especially in children, is considered a critical issue, as underlined by the principle of ALARA. 32The pediatric population naturally has a greater life expectancy compared to the general population, and when paired with their rapid physiological somatic growth, augments their vulnerability to the stochastic effects of radiation. 18In 2002, Drago et al. first described how radiation exposure could be substantially reduced by using electro-anatomical mapping systems to carry out ablation in the pediatric population, as well as to help limit the number of catheters utilized. 17Besides the side effect of radiation, fluoroscopy can cause skin reddening especially when repeated procedures with the same skin area and hair loss.Further uses will also increase cancer risk and contract-induced nephropathy (CIN). 33[24][25][26][27][28][29] Unfortunately, ablation in the pediatric population has not been established as a routine treatment modality.5][36][37] Based on 2016 PACES-HRS Catheter ablation guideline, catheter ablation is recommended for documented SVT, even it is recurrent or persistent and preferred by the family to avoid long-term antiarrhythmic medication consumption. 38Another reason for not routine treatment is because of the high cost needed in electrophysiology lab because of the high manufacturing cost and we have assumption that the prices will not drop.However, the costs are not standardized between institutions and agencies, so positive effect of CA can be given if the children and teenagers have the higher statistical life values correction factors.A positive effect of value statistical life especially in child's life will give a rise correction factors in children and cause high cost-effectiveness. 39evious meta-analyses in 2016 and 2022 included 2261 and 9074 patients, respectively and compared ZF or near-ZF to fluoroscopic approaches during cardiac arrhythmia ablation. 40,41nsistent with the findings of this study, the meta-analyses also demonstrated significant reductions in fluoroscopy and ablation time, whereas acute and long-term success rates were similar between the two groups.Our study involved a more homogeneous population, namely the pediatric population, with outcomes that turned out to be slightly different from those of these studies.
In interpreting the study results, we have emphasized the influence of utilizing 3D-EAM, which appears to play a dominant role in the outcomes of ablation compared to the use of ZF or NZF alone without 3D-EAM support.Despite the short fluoroscopy time, it is essential to acknowledge the potential contribution of 3D-EAM to the results.To address this concern, we conducted subgroup analysis comparing cases using 3D-EAM (all baseline cases included 3D-EAM) with nonsignificant results, indicating that the focus indeed lies on the utilization of 3D-EAM, which is shown in Supplementary Information S6.

| Procedural parameters
Although the dose threshold for safe radiation is not clearly defined, the subset of subjects we included in this study was exposed to zero or nearzero fluoroscopy, meaning they were unlikely to result in unwanted longterm stochastic effects of radiation. 25Theoretically, three-dimensional visualization with the 3D-EAM system reduces the procedural duration and allows for easier catheter manipulation.However, the 3D-EAM system requires several minutes to create, which takes longer than conventional methods of fluoroscopy. 41Previous meta-analyses reveal no differences in the procedural time between groups.However, our study found that the overall procedural time in both the combined ZF and near-ZF group, and the near-ZF subgroup alone were significantly shorter compared to conventional fluoroscopy.However, I 2 analysis revealed substantial heterogeneity in our findings.One reason is that subgroup analysis was not carried out for the type of arrhythmia but was performed for other outcomes.Additionally, procedural outcome is greatly influenced by the skills of the operator and standard operating procedures, which differs from center to center. 27,42It is uncommon to find arterial or valvular diseases in the pediatric population, such as peripheral arterial occlusive disease or aortic stenosis, that could potentially interfere with procedures.For this reason, establishing arterial access through the aortic valve is much easier in children compared to adults.Additionally, operators may experience lag time from catheter manipulation to visualization on the 3D-EAM screen.Upon crossing the aortic valve, curvature of the ablation catheter demands additional dexterity to advance to the ideal ablation site.This is of minimal concern with respect to right-sided substrates, which bypasses the aortic conundrum and explains why Tseng's study showed unique results, as his study was the only one to solely focus on left-sided substrate ablation. 18anseptal puncture from right atrium to left atrium may also contribute to time consuming.This technique combined with 3D-EAM and contributes towards a zero fluoroscopy will help in visualizing the electrode tip of round needle, which may not affect the procedural time or outcomes. 43In the true ZF subgroup, limited evidence may be the reason there was no significant difference in procedural time.Two of the four studies specified reasons for a shorter procedural time in the control

| Effectiveness
The overall acute success rate in the study group was 98%, while that in the control group was 96%.Although both had relatively good success rates, the difference was statistically significant.
Despite promising outcomes for acute success, we were unable to The acute success rate of AP ablation of the left ventricular free wall is reported to be the highest among all Aps, and has similar outcomes when compared to conventional fluoroscopy, whereas AP ablation of the right ventricular free wall has the lowest success rate and a high rate of recurrence. 44,45The use of 3D-EAM guidance in areas close to the insertion pathway precisely locates and marks atrial and ventricular AP insertion sites, and proves a superior technique when compared to conventional methods.We believe that this explains the positive findings in the study group for acute success rate as majority of interventions involve substrates that would benefit from the use of 3D-EAM.7][48][49][50] Regardless of the cause, our findings confirm that ZF or near-ZF guiding during ablation in the pediatric population is at least as effective as traditional fluoroscopically guided procedures.None of the trials demonstrated inferior effectiveness outcomes in the study group.

| Complications
Although the overall complication rates were low, they were significantly lower in the study group (0.5% and 1.9%, respectively), with no heterogeneity in these outcomes.We considered this finding somewhat interesting as previous meta-analyses conducted in the adult population found no significant difference in complication rates between the two groups because of the small sample size that was included in this study.Although the complications reported in this study varied, the most common was AV block.This may have resulted from the unique cardiac anatomy of pediatric patients, where the coronary sinus and sub-eustachian isthmuses are smaller.The compact AV node is more likely to be injured in children because it is situated close to the posterior septal region. 51,523D-EAM-guided ZF or near-ZF ablation may provide additional benefits in preventing development of AV block by providing continuous visualization of the catheter during the procedure as well as providing tools to mark crucial conduction system landmarks that remain on the image even after the catheter has been removed. 24

| Limitations
This study has the typical limitations of a systematic review and meta-analysis.All included studies were observational and, although generally of good quality, they are not a substitute for large-scale RCTs.However, our results were generally consistent across all cohorts, which adds to the robustness of our findings.Learning curve effects cannot be ruled out for nonrandomized studies as several included studies observed findings during 3D-EAM's early days.
However, this appears to have little effect on the main endpoint as it shows consistent effectiveness and safety outcomes across studies with very low heterogeneity.Important differences in patient demographics and procedures that may influence the outcome and were not accounted for in this analysis include infancy (0-12 months of age), body mass index, type of energy in ablation, type and mode of 3D-EAM, as well as specific types of arrhythmias.Additionally, data limitation on radiation exposure would impact the use of fluoroscopy time which affect the safety and complication in this study.

| CON CLUS ION
The first meta-analysis to evaluate the outcomes of 3D-EAM-guided ZF or near-ZF ablation strategy in the pediatric population showed similar, if not better outcomes compared to conventional fluoroscopy, along with the added benefits of a reduction in radiation exposure and possibly more time-effective procedures.This strategy should be considered first line with regards to ablation procedures in the pediatric population.

ACK N OWLED G EM ENTS
We would like to thank all the staff from Cardiology and Vascular Medicine, Prof. dr.I.G.N.G Ngoerah General Hospital, Denpasar, Bali, Indonesia who were involved and reviewed in this meta-analysis.

CO N FLI C T O F I NTER E S T S TATEM ENT
Authors declare no conflict of interests for this article.

DATA AVA I L A B I L I T Y S TAT E M E N T
All data will be provided in this manuscript and supplementary material.

E TH I C S S TATEM ENT
No human participant was involved in this study.The protocol is registered in the international prospective register of systematic reviews (CRD42023406584).
Standard forms were used to extract the following information from each study: (i) study design and methodology; (ii) type of 3D-EAM used; (iii) specific characteristics of the intervention and control groups (patient inclusion criteria); (iv) type of ablation (radiofrequency catheter ablation (RFCA) or cryoablation); (v) presence or absence of congenital heart disease (CHD) in the population; (vi) mean fluoroscopy time; (vii) type of arrhythmias ablated; and (viii) effectiveness and safety outcome as stated in the protocol of the current meta-analysis.

F I G U R E 2
Forest plots of procedural outcomes.(A) A mean difference of fluoroscopy time in near-ZF compared with the control group.Test for overall effect: Z = 76.68 (p < .001).Heterogeneity: I 2 = 98%.(B) The mean difference in procedural time.Test for subgroup differences: Z = 1.65 (p < .10).Test for overall effect: Z = 1.65 (p < .10).Overall heterogeneity: I 2 = 29.9%.CI, 95% confidence interval; RCT, randomized clinical trial; ZF, zero fluoroscopy.F I G U R E 3 Forest plots of acute success.(A) Risk ratio of acute success based on the type of arrhythmia.Test for subgroup differences: Chi 2 = 0.83 (p = .66).Test for overall effect: Z = 1.27 p = .20.Overall heterogeneity: I 2 = 0%.(B) Risk ratio of acute success based on the type of fluoroscopy in the study group.Test for subgroup differences: Chi 2 = 0.49 (p = .49).Test for overall effect: Z = 2.15 p = .03.Overall heterogeneity: I 2 = 0%.CI, confidence interval; MH, Mantel-Haenzel; ZF, zero fluoroscopy.The locations of the forest plot graphs between the controls and the ZF/near-ZF favors were switched.F I G U R E 4 Forest plots of arrhythmia recurrence outcome.(A) Risk ratio of arrhythmia recurrence based on the type of arrhythmia.Test for subgroup differences: Chi 2 = 1.67 (p = .43).Test for overall effect: Z = 0.90 (p = .43).Overall heterogeneity: I 2 = 0%.(B) Risk ratio of arrhythmia recurrence based on the type of fluoroscopy in the study group.Test for subgroup differences: Chi 2 = 1.09 (p = .28).Overall heterogeneity: I 2 = 12.0%.CI, confidence interval; MH, Mantel-Haenzel; ZF, zero fluoroscopy.the failure of one antiarrhythmic drug.Catheter ablation is only indicated once two or more antiarrhythmic drugs fail or tachycardiomyopathy is suspected, 31 even though various studies have shown that early intervention for arrhythmia has proven to provide good long-term outcomes in the pediatric population,

F I G U R E 5
Forest plots of complication outcome.Test for overall effect: Z = 2.19 (p = .03).Heterogeneity: I 2 = 0%.CI, confidence interval; MH, Mantel-Haenzel; ZF, zero fluoroscopy.group.One study involved procedures focused on left-sided substrates and another combined 3D-EAM with conventional fluoroscopy in the control group.These two reasons, along with limited available evidence, resulted in statistically insignificant results.18,26 prove long-term success because of the lack of statistical significance.More subgroup analyses involving large data sets are needed to identify factors that may demonstrate statistically significant improvement in long-term outcomes, such as the type of ablation, type and mode of 3D-EAM, presence of absence of CHD, and more specific classification of arrhythmia, among other factors.

No First author, year Study design Sample size Description of procedures Study group (n) Control group (n) Study group Control group Type of ablation and guidance Type of arrhythmias (n)
No First

TABLE 1 (
Continued) TA B L E 2 Primary endpoint and baseline characteristics of population in included studies.No First author,