Author + information
- Received September 8, 2015
- Revision received December 22, 2015
- Accepted January 21, 2016
- Published online August 1, 2016.
- Noboru Ichihara, MD,
- Shinsuke Miyazaki, MD∗ (, )
- Jin Iwasawa, MD,
- Junji Matsuda, MD,
- Hiroshi Taniguchi, MD,
- Hiroaki Nakamura, MD,
- Hitoshi Hachiya, MD,
- Takamitsu Takagi, MD,
- Akio Kuroi, MD and
- Yoshito Iesaka, MD
- ↵∗Reprint requests and correspondence:
Dr. Shinsuke Miyazaki, Cardiology Division, Cardiovascular Center, Tsuchiura Kyodo Hospital, 11-7 Manabeshin-machi, Tsuchiura, Ibaraki 300-0053, Japan.
Objectives This study aimed to evaluate the incidence and pre-procedural predictors of right phrenic nerve injury (PNI) in electromyography-guided, second-generation cryoballoon (CB) ablation.
Background Second-generation CBs perform better pulmonary vein isolation (PVI) than first-generation CBs; however, right PNI remains a concern.
Methods One hundred consecutive patients with paroxysmal atrial fibrillation who underwent cryoablation were prospectively enrolled. Contrast-enhanced cardiac multidetector computed tomography (MDCT) was obtained pre-procedurally. PVI was performed with one 28-mm second-generation balloon using a 3-min freeze technique under electromyography guidance.
Results In all, 377 of 392 (96.2%) PVs were isolated using a CB. In 9 (9.0%) patients, right PNI was observed during the ablation of the right superior PV (RSPV). All events occurred during freezing, except for 1 that occurred during thawing. Right peri-cardiophrenic bundles (RPCBs) were identified at the level of the RSPV on MDCT in 97 patients. In the logistic regression analysis, the distance from the RSPV ostium to the RPCBs (hazard ratio: 0.263; 95% confidence interval [CI]: 0.110 to 0.630; p = 0.003) was the sole predictor of PNI. The optimal cutoff point for the distance for predicting right PNI was 12.4 mm (sensitivity 96.6%, specificity 88.9%) with an area under the curve of 0.968 (95% CI: 0.922 to 1.000). The PNI resolved spontaneously within 1 day and 2 months in 6 and 2 patients, respectively, and at 8 months in the remaining patient, with delayed recognition of an electromyography decrease.
Conclusions Persistent right PNI is a rare complication during electromyography-guided, second-generation CB ablation. Electromyography should be monitored even during the thawing time. Pre-procedural MDCT might be useful for risk stratification of right PNI.
Radiofrequency (RF) catheter ablation is an established therapy for drug-resistant paroxysmal atrial fibrillation (AF) (1–3). However, point-by-point ablation is time consuming, and creating contiguous lesions is challenging. Balloon technologies have been introduced into AF ablation to overcome this issue, and previous studies have demonstrated that first-generation cryoballoon (CB) ablation was similarly effective as RF ablation (4) and more effective than antiarrhythmic drug therapy for paroxysmal AF (5). However, the prevalence of right phrenic nerve injury (PNI) (6) has been 11.2% (5) due to various factors, including anatomical close proximity (7). A recently introduced second-generation CB (8) had a better performance of pulmonary vein isolation (PVI) (9,10), which led to concern for a possible higher incidence of PNI than the first-generation balloon (9) because of the improved cooling of the distal balloon hemisphere. The high performance of the second-generation balloon enabled a single large balloon technique and shortening of the freezing time (e.g., a single 3-min freeze technique) (11). The efficacy of the 3-min ablation was not significantly different from that of the 4-min ablation technique in dogs when using the second-generation CB (12). Although electromyography-guided ablation (13,14) has been emerging as the standard technique to anticipate this complication, right PNI is still a concern of this procedure. The present study aimed to evaluate the incidence and pre-procedural predictors of any right PNI, including any transient PNI, in electromyography-guided, second-generation CB ablation.
This prospective study consisted of 100 consecutive patients with drug-refractory paroxysmal AF who underwent their first PVI using a second-generation CB (Arctic Front Advance, Medtronic, Minneapolis, Minnesota) in our institute. The PVI was performed with a single balloon technique using a 28-mm CB, and touch-up lesions were created with an 8-mm tip conventional cryocatheter (Freezor MAX, Medtronic). AF was classified according to the latest guidelines (3). All patients gave their written informed consent. The study protocol was approved by the hospital’s institutional review board. The study complied with the Declaration of Helsinki.
Mapping and ablation protocol
All antiarrhythmic drugs were discontinued for at least 5 half-lives before the procedure. Transesophageal echocardiography was performed to exclude any atrial thrombi 1 day before the procedure. Contrast-enhanced cardiac multidetector computed tomography (MDCT) was performed to evaluate the cardiac anatomy before the procedure. The surface electrocardiogram and bipolar intracardiac electrograms were continuously monitored and stored on a computer-based digital recording system (LabSystem PRO, Bard Electrophysiology, Lowell, Massachusetts). The bipolar electrograms were filtered from 30 to 500 Hz. A 7-F, 20-pole, 3-site mapping catheter (BeeAT, Japan-Life-Line, Tokyo, Japan) was inserted through the right jugular vein for pacing, recording, and internal cardioversion.
The procedure was performed under moderate sedation using dexmedetomidine. A 100 IU/kg body weight of heparin was administered immediately following the venous access, and heparinized saline was also infused to maintain an activated clotting time of 250 to 350 s. A single transseptal puncture was performed using an RF needle (Baylis Medical, Montreal, Quebec, Canada) and 8-F long sheath (SL0, AF Division, St Jude Medical, Minneapolis, Minnesota). The transseptal sheath was exchanged over a guidewire for a 15-F steerable sheath (Flexcath Advance, Medtronic). A 20-mm circular mapping catheter (Lasso, Biosense Webster, Diamond Bar, California) was used for mapping all the PVs before and after the cryoablation to confirm the electrical isolation. A spiral mapping catheter (Achieve, Medtronic) was used to advance the CB and to map the PV potentials. Complete sealing at the antral aspect of the PV was confirmed by a contrast medium injection. This was followed by a single freeze cycle of 180 s. No additional applications were performed once the isolation was achieved. The procedural endpoint was defined as the electrical PVI without dormant conduction, which was verified by the 20-mm circular mapping catheter. If electrical isolation was not achieved by a total of 3 CB applications per vein, additional touch-up freezes with an 8-mm tip conventional cryocatheter were performed within 2 min of each application.
MDCT scanning and measurement
Gated contrast-enhanced CT of the chest was performed with a 320-row MDCT scanner (Aquilion one, Toshiba, Otawara, Japan). A bolus of 50 to 100 ml of iodinated contrast media was injected intravenously at an injection rate of 3.0 to 4.5 ml/s using an automatic injector to regulate the iodine injection speed at 22.2 mgI/kg/s. Scanning was initiated with a 10-s delay after the signal density level reached a predefined threshold of 200 Hounsfield units in the left atrium. The following parameters were used for scanning: electrocardiographically-gated acquisitions; 120 kVp; 110 to 206 mAs; and 320- × 0.5-mm slice collimation. Scans were performed from the tracheal bifurcation to the diaphragm. Reconstructions were performed with a FC13 to generate 0.5-mm-thick slices, with a reconstruction interval of 0.5 mm with a workstation (SYNAPSE VINCENT, Fujifilm, Tokyo, Japan). All images were acquired in the supine position and reviewed independently by an experienced radiologist and cardiologist.
The ostium of the right superior PV (RSPV) was determined to be the point at which the vein diverged from the extrapolated left atrial contour. Because the right phrenic nerves are contained within the right peri-cardiophrenic bundles (RPCBs), which contain the nerve, peri-cardiophrenic artery, and peri-cardiophrenic vein, the RPCB was defined as a high-attenuation structure (15,16). The diameters of the RSPV ostium (longitudinal and transverse) and the distance between the RSPV ostium and RPCB were measured on the workstation. The measurements were performed offline after the procedure.
Prevention and evaluation of PNI
To avoid right PNI, all CB applications were applied using monitoring of right diaphragmatic compound motor action potentials (CMAPs) during phrenic nerve pacing (13,14). Ablation was terminated at any perceived reduction in the strength of the diaphragmatic contractions or a significant reduction (>30%) in the maximal diaphragmatic CMAP amplitude from baseline using a double-tap technique (17). Then, the diagnosis of any PNI was confirmed by careful differentiation from pacing catheter dislodgement.
The diaphragmatic movement was evaluated throughout the procedure with patients in the supine position. In addition, a chest x-ray (standard posterior anterior view) was taken with all patient in a standing position 1 day before and the next day after the ablation procedure. The level of the right diaphragm was evaluated on the next day after the procedure relative to that before the procedure in all patients.
Continuous data are expressed as the mean ± SD for normally distributed variables or as the median (25th, 75th percentiles) for non-normally distributed variables, and were compared using a Student’s t-test or Mann-Whitney U test, respectively. The results of the t-test were confirmed by a Welch’s test. Categorical variables were compared using the chi-square test, and the results were confirmed by a Fisher’s exact test. The results of the logistic regression analysis were confirmed by a Firth’s penalized likelihood-based logistic regression and exact logistic regression. The distance between the ostium of the RSPV and RPCB in the patients with and without any PNI was compared, and the cutoff point was evaluated. The optimal cutoff point was chosen as the combination with the highest sensitivity and specificity using a receiver-operator characteristic curve. A 95% confidential interval (CI) was presented with the area under the curve (AUC). A p value of <0.05 indicated statistical significance.
The patient characteristics are summarized in the Table 1. No anatomical variants were observed in any of the patients, except for left common PVs. In 100 patients, a total of 392 PVs were identified. Overall, 377 of 392 (96.2%) PVs were isolated successfully using exclusively a 28-mm second-generation CB. The total number of CB applications was 540 (5.4 applications per patient), and the mean number of CB applications resulting in PVI was 1.1 ± 0.4, 1.4 ± 0.7, 1.2 ± 0.6, 1.1 ± 0.6, and 3.5 ± 1.0 for the right superior, right inferior, left superior, left inferior, and left common PVs, respectively. In 87 (87.0%) patients, only a single freeze was applied for the RSPV. Touch-up lesions were created in the remaining 15 (3.8%) PVs, including 0, 3, 1, and 11 in the left superior, left inferior, right superior, and right inferior PVs, respectively. The number of applications for the achievement of the PVI was a median of 3 (range: 2 to 4). In total, all 392 PVs were successfully isolated by cryothermal ablation.
In 1 (1.0%) patient, contrast-enhanced CT was not performed due to chronic kidney disease. Among the remaining 99 patients who underwent MDCT before the procedure, the RPCB could be identified at the level of the RSPV on MDCT in 97 (98.0%) patients (Figure 1). The distance from the RPCB to the ostium of the RSPV, the longitudinal diameter of the RSPV ostium, and the transverse diameter of the RSPV ostium measured on MDCT was a mean of 16.7 ± 4.2 mm (median: 16.6 mm; range: 13.7 to 19.2 mm), 19.5 ± 3.4 mm (median: 19.3 mm; range: 17.1 to 21.4 mm), and 16.8 ± 3.5 mm (median: 16.6 mm; range: 14.5 to 19.0 mm), respectively.
Right PNI and other adverse events
Right PNI was found during the procedure in 9 (9.0%) patients, and all during the ablation of the RSPV. In all 9 patients, the RSPV was isolated without any touch-up ablation. Among these patients, isolation occurred during the freezing time in 8 patients after a median of 97 s (range: 70 to 149 s) of the cryoapplication. In the remaining patient, PNI occurred during the thawing time, after termination of a 180-s freeze. In all cases, a reduction in the CMAP amplitude was preceded by a reduction of palpation. The PNIs resolved spontaneously during the procedure in 6 patients, and persisted on the next day in the remaining 3 patients. During follow-up, the PNI recovered completely at 1, 2, and 8 months after the procedure in 1 patient each. In the patient with PNI that persisted for 8 months, the application at the RSPV was terminated when the CMAP amplitude decreased to 10% of the baseline amplitude due to a delayed recognition. With the exception of right PNI, cardiac tamponade that required pericardiocentesis and a pneumothorax during the puncture of the right subclavian vein occurred in 1 patient each.
Pre-procedural parameters associated with PNI
The clinical characteristic and procedural parameters in patients with and without any PNI are shown in Table 2. There was no significant difference in the number of cryoapplications between the patients with and without PNI (1.1 ± 0.4 vs. 1.2 ± 0.4; p = 0.661). The distance from the RSPV ostium to the RPCB was significantly shorter in the patients with PNI than in those without (p < 0.0001) (Figure 2A), and in the univariate analysis, the distance between the RSPV ostium and the RPCB (hazard ratio [HR]: 0.263; 95% CI: 0.110 to 0.630; p = 0.003 by a logistic analysis; HR: 0.278, 95% CI: 0.100 to 0.548; p < 0.0001 by exact logistic analysis; HR: 0.330; 95% CI: 0.123 to 0.575; p = 0.002 by a Firth’s penalized logistic analysis) was associated with PNI during the procedure. The minimum distance from the RSPV ostium to the RPCB in the group with no PNI was 12.4 mm, and the maximum distance in the group with PNI was 14.0 mm (Figure 2A). The transverse diameter of the RSPV ostium was greater in the patients with PNI than in those without, but this was not significant. Among the 9 patients with PNI, the maximum longitudinal and transverse RSPV ostium diameters were 25.6 and 19.6 mm, respectively. The maximum longitudinal diameter was <20 mm in the remaining 8 patients. For the association between the distance and PNI, the AUC was found to be 0.968 (95% CI: 0.922 to 1.000). The optimal cutoff point for the distance between the RSPV ostium and the RPCB for predicting right PNI was 12.4 mm (sensitivity 96.6%, specificity 88.9%) (Figure 2B).
The present study showed the incidence and pre-procedural predictors of right PNI in electromyography-guided, second-generation CB ablation. We found that: 1) the incidence of right PNI during the procedure and persistent PNI was 9.0% and 3.0%, respectively; however, all patients recovered spontaneously during follow-up; 2) the right phrenic nerve could be localized on cardiac MDCT obtained pre-procedurally in most of the patients; 3) the distance from the RSPV ostium to the RPCB measured on MDCT was the sole pre-procedural predictor of any PNI; and 4) PNI could occur even during the thawing time of the cryoapplication. These data suggest that the incidence of persistent PNI seemed to be relatively rare with second-generation CB ablation when using the currently available techniques to prevent PNI, and that pre-procedural MDCT was useful for the risk stratification.
Cryoballoon ablation and right PNI
The efficacy and safety of CB ablation was confirmed by several studies (4,5); however, the data regarding the second-generation CB are still limited because of its recent introduction. Compared with the first-generation CB, the second-generation CB has a 2-fold greater number of injection spray jets that have been optimally located to more uniformly cool its tip (8). The greater efficacy of the second-generation CB was associated with a significant increase in transient PNI in a previous study (9). As technologies and energy sources evolve toward treatment of larger and deeper lesions, the risk of right PNI is likely to increase. With the introduction of the second-generation CB, with its more distal cooling profile, clinicians should pay attention to this complication. Gentle sealing of the RSPV is technically important to prevent such complications during the procedure, and a pre-procedural risk stratification seems to be helpful for achieving a further reduction of this complication. Although the previously published incidence of PNI has been variable, presumably due to the definition of PNI (4,5,9–11), the incidence of persistent PNI was relatively low in the present study. The reason for the low incidence might be explained by the combined use of the currently available techniques to anticipate PNI. These include CMAP monitoring (13,14), the single big balloon technique (28-mm CB), short freezing times without bonus applications (single 3-min technique) (11), and the double-tap technique when the CMAP amplitude decreases (17), in which a second press of the stop button causes the pump to apply a vacuum to the balloon, which causes an immediate deflation. The use of each technique has been demonstrated in previous studies, and recent animal (12) and clinical studies (11) have supported the feasibility of the single 3-min freeze technique. In addition, the present study showed that PNI could occur even during the thawing time. An in vitro study demonstrated that cooling of the phrenic nerve to subzero temperatures consistently led to a loss of function (18), and an animal study showed that the time to achieve the lowest temperature at the phrenic nerve was 196 ± 11 s with the 3-min ablations (12), which suggests that continuous CMAP monitoring is recommended during the thawing time, especially during the initial 30 s of the thawing time.
Use of pre-procedural MDCT
MDCT has the ability to visualize the cardiac venous anatomy and is being incorporated more routinely into imaging before procedures. In balloon-based ablation, pre-procedural imaging is particularly important because the cardiac anatomy significantly influences the procedural difficulty. Matsumoto et al. (15) initially showed the feasibility of using 64-slice MDCT for the detection and anatomic outline of the phrenic nerves and their relation to the cardiac anatomic structures. Subsequently, Horton et al. (16) proved that imaging the RPCB could reliably locate the right phrenic nerve, and that a phrenic nerve location within 10 mm of the RSPV posed a higher risk of PNI when using balloon ablation devices, by analyzing 7 of 37 patients with PNI after any balloon procedure (4 of 18 patients who underwent high-intensity focused ultrasound, 2 of 13 with a laser balloon, and 1 of 6 patients with a first-generation CB). However, the study included only 6 patients who underwent a first-generation CB ablation.
In the present study, 320-row MDCT was used. High-speed and wide-coverage MDCT scanners have the advantage of decreased cardiac motion and artifact, and improve the image quality. Because the nerve runs in the same vascular bundle as the artery, locating the artery provides highly accurate 3-dimensional positioning of the nerve. Our study investigated the predictors of PNI after second-generation CB ablation, which creates significantly larger lesions than the first-generation CB, in a large number of consecutive patients. The results showed that the distance from the RPCB to the RSPV ostium was the sole significant predictor of right PNI. In general, lower balloon temperatures suggest more distal and tight PV occlusions. In the present study, the patients with PNI tended to have a larger PV ostium; however, the difference was not significant. A recent study demonstrated a strong relationship between the tissue temperatures and distance from the balloon surface using a 28-mm, second-generation CB in vivo model (19). The conductive cooling spread radially from the balloon–tissue contact point to more distant tissue. Thus, the distance between the balloon–tissue contact point and phrenic nerve seems to be critical for the occurrence of PNI. As Okumura et al. (20) showed in an animal model, the balloon inflation at the PV orifice alters the geometry of the native RSPV endocardial surface and reduces the distance from the balloon surface to the phrenic nerve. However, our study showed that the distance was a significant factor for the risk stratification of PNI during the second-generation CB ablation, even in such a situation. This might be explained by the ablation technique in which the gentle sealing of the RSPV, to as great an extent as possible during the procedure, might minimize the anatomical distortion.
The present data revealed a low incidence of persistent right PNI in the second-generation CB ablation procedure under CMAP monitoring, which suggests that usefulness of electromyography-guided ablation to anticipate this complication. PNI could occur not only during the freezing time but also during the thawing time, and thus monitoring the CMAP is recommended during the thawing time. In addition, MDCT could stratify the risk of right PNI pre-procedurally. Offering a noninvasive screening strategy for identifying and excluding patients at high risk for this complication before the invasive procedure may provide added safety for CB ablation.
The study showed the prevalence of PNI using a single big balloon and a single 3-min freeze technique, and therefore, the data with a longer freezing time, bonus applications, and a 23-mm CB are lacking. However, recently published experimental (12) and clinical studies (11) have shown the usefulness of these techniques. The distance from the RPCB to the RSPV ostium overlapped between patients with and without PNI, which might be explained by the change in the distance by pushing the CB into the RSPV ostium during freezing (20). Therefore, although pre-procedural imaging was helpful for the risk stratification of PNI, we believe that CMAP monitoring was important for anticipating PNI during the procedure. In the present study, a palpation reduction was also observed following the CMAP reduction in all cases. The operator should be more vigilant to changes in the CMAP amplitude for an early timing of an emergent termination.
The incidence of any right PNI during the electromyography-guided second-generation CB ablation procedure using a single large balloon and singe 3-min freeze technique was 9.0%; however, all cases of PNI recovered during the follow-up period. Electromyography-guided ablation is useful, and continuous monitoring is recommended even during the thawing time. MDCT might be useful to stratify the risk of right PNI before the procedure.
COMPENTENCY IN MEDICAL KNOWLEDGE: Although right PNI remains a concern during the second-generation CB ablation procedure, all patients with PNIs recovered during the follow-up when electromyography-guided ablation and a single large balloon 3-min freeze technique were used. Because PNI could occur during the thawing time, continuous electromyography monitoring is recommended even during the thawing time. The distance from the RPCB to the RSPV ostium, obtained by pre-procedural cardiac imaging, is the sole significant predictor of right PNI.
TRANSLATIONAL OUTLOOK: The usefulness of the distance from the RPCB to the RSPV ostium, which is obtained by pre-procedural cardiac imaging for the prediction of PNI, should be evaluated in a prospective clinical trial.
The authors would like to thank John Martin for his linguistic help and Toshimitsu Hamasaki for his statistical help in the preparation of this paper.
The authors have reported that they have no relationships relevant to this paper to disclose.
- Abbreviations and Acronyms
- atrial fibrillation
- area under the curve
- confidential interval
- compound motor action potentials
- multidetector computed tomography
- phrenic nerve injury
- pulmonary vein isolation
- right peri-cardiophrenic bundles
- right superior pulmonary vein
- Received September 8, 2015.
- Revision received December 22, 2015.
- Accepted January 21, 2016.
- American College of Cardiology Foundation
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