Persistent phrenic nerve palsy after atrial fibrillation ablation: Follow‐up data from The Netherlands Heart Registration

Abstract Background Persistent phrenic nerve palsy (PNP) is an established complication of atrial fibrillation (AF) ablation, especially during cryoballoon and thoracoscopic ablation. Data on persistent PNP reversibility is limited because most patients recover <24 h. This study aims to investigate persistent PNP recovery, freedom of PNP‐related symptoms after AF ablation and identify baseline variables associated with the occurrence and early PNP recovery in a large nationwide registry study. Methods In this study, we used data from the Netherlands Heart Registration, comprising data from 9549 catheter and thoracoscopic AF ablations performed in 2016 and 2017. PNP data was available of 7433 procedures, and additional follow‐up data were collected for patients who developed persistent PNP. Results Overall, the mean age was 62 ± 10 years, and 67.7% were male. Fifty‐four (0.7%) patients developed persistent PNP and follow‐up was available in 44 (81.5%) patients. PNP incidence was 0.07%, 0.29%, 1.41%, and 1.25%, respectively for patients treated with conventional‐RF, phased‐RF, cryoballoon, and thoracoscopic ablation respectively. Seventy‐one percent of the patients fully recovered, and 86% were free of PNP‐related symptoms after a median follow‐up of 203 (113–351) and 184 (82–359) days, respectively. Female sex, cryoballoon, and thoracoscopic ablation were associated with a higher risk to develop PNP. Patients with PNP recovering ≤180 days had a larger left atrium volume index than those with late or no recovery. Conclusion After AF ablation, persistent PNP recovers in the majority of patients, and most are free of symptoms. Female patients and patients treated with cryoballoon or thoracoscopic ablation are more prone to develop PNP.

PNP-related symptoms after AF ablation and identify baseline variables associated with the occurrence and early PNP recovery in a large nationwide registry study.
Methods: In this study, we used data from the Netherlands Heart Registration, comprising data from 9549 catheter and thoracoscopic AF ablations performed in 2016 and 2017. PNP data was available of 7433 procedures, and additional followup data were collected for patients who developed persistent PNP.
Seventy-one percent of the patients fully recovered, and 86% were free of PNP-related symptoms after a median follow-up of 203 (113-351) and 184 (82-359) days, respectively. Female sex, cryoballoon, and thoracoscopic ablation were associated with a higher risk to develop PNP. Patients with PNP recovering ≤180 days had a larger left atrium volume index than those with late or no recovery.
Conclusion: After AF ablation, persistent PNP recovers in the majority of patients, and most are free of symptoms. Female patients and patients treated with cryoballoon or thoracoscopic ablation are more prone to develop PNP.

| INTRODUCTION
Phrenic nerve palsy (PNP) is a common complication of atrial fibrillation (AF) ablation. Persistent PNP (lasting > 24 h) occurred in 1.5% of the patients who underwent cryoballoon (CB) ablation in the Netherlands. 1 PNP frequently complicates CB ablation, but has also been described after radiofrequency (RF), phased RF, or thoracoscopic ablation. [1][2][3][4][5][6][7] Most PN injuries recover during the initial hospital admission. However, longerlasting PNP resulting in unilateral diaphragm paralysis can result in exercise intolerance, shortness of breath, or orthopnea. 8 Persistent PNP after AF ablation is a well-known complication, but data on its reversibility is sparse or limited to CB ablation. [3][4][5][6]9 We investigated rates of PNP-related symptoms and PNP recovery, and identified baseline variables associated with persistent PNP after AF ablation.

| METHODS
We included all patients who underwent AF ablation in 2016 or 2017 from the Netherlands Heart Registration (NHR), a nationwide quality registry in which 14 out of 16 Dutch ablation centers report outcomes of AF ablation. 1 We performed additional follow-up in patients with persistent PNP. During CB ablation, phrenic nerve pacing from the superior vena cava was performed to monitor the phrenic nerve function and all patients received a chest X-ray after surgical ablation.
Follow-up data were collected in a cross-sectional manner according to standard clinical care and based on physicians' discretion. Besides the patients' history, follow-up of patients with PNP consisted of a chest X-ray, sniff test, and/or physical examination. Patients were considered to have proven PNP if diaphragm elevation was present on a chest X-ray following AF ablation. Persistent PNP was defined as PNP lasting >24 h. 1 At follow-up, PNP recovery was defined as normalization of abnormalities at sniff test, chest X-ray, and/or as specified in the medical chart. A waiver for informed consent for participation in the NHR was previously obtained from the Ethics Committee MEC-U, Nieuwegein, The Netherlands.
The primary outcome was recovery of a proven PNP after AF ablation. Secondary outcomes included: the presence of PNP-related symptoms and early (≤180 days) or late/no (>180 days) PNP recovery. We further sought to identify baseline clinical variables associated with PNP occurrence.
Normally distributed clinical variables are presented with a mean ± standard deviation, non-normally distributed with a median and interquartile range (IQR), and categorical variables with numbers and percentages. Parametric t-test, nonparametric Mann-Whitney U test, χ 2 test, and Fishers' exact test were used to compare groups. The endpoints proven PNP recovery and freedom of PNP-related symptoms are presented in survival curves. Multivariate logistic regression analysis was performed for adjustment for co-variables with a univariate p-value < .1. Data are presented as adjusted odds ratio (OR) and 95%-confidence intervals (CI). R-studio (version 1.1.383) was used for statistical analysis.
The mean age was 62 ± 10 years, and 68% of patients were male (Table 1)      PNP fully recovered in 71% of the patients and 86% were free of PNP-related symptoms. These findings are in line with other studies reporting phrenic nerve recovery in 78%-100% of the patients. [3][4][5]9 After thoracoscopic ablation, PNP has been described in up to 11% of the patients, of whom 80% recovers within 12 months of follow-up. 6 In contrast to catheter ablation, PNP during thoracoscopic ablation can also occur after a blunt trauma from manipulation of ablation and endoscopic tools or traction on the pericardial cradles. 7,10 An essential factor for PNP occurrence during catheter ablation is the distance between the ablation site and the phrenic nerve. Smaller and more distally positioned CB has been associated with more PNP. 11,12 Also, an early study reporting PNP after radiofrequency ablation demonstrated that most patients who developed PNP received the more distal segmental or focal pulmonary vein isolation. 13 In contrast, the FIRE and ICE trials did not observe any PNP in patients who underwent PV atrium radiofrequency ablation. 14 This suggests a lower risk for PNP because most energy during conventional RF ablation is delivered at the antrum of the pulmonary vein.
Aside from the distance between the phrenic nerve and the ablation site, the second-generation CB with improved cooling abilities has increased the number of patients developing PNP. 15 Also, PNP in patients treated with the second generation CB appears to recover slower than in patients treated with the first generation CB.
Similarly, PNP after LB ablation was associated with a longer recovery time compared to CB. 4,5 Here, we did not observe any significant difference in recovery time among the ablation modalities.
We show that female patients have a 2.3 times higher risk for persistent PNP. Compared with males, females tend to have a smaller left atrium, and thinner atrial wall thickness. [16][17][18] Also, the right phrenic nerve is located more anteriorly in the thoracic cavity in females than in males. 19 A small study investigating 28 human cadavers demonstrated that the distance between right superior pulmonary veinphrenic nerve was smaller than 10 mm in 67% of the females compared to 53% of males. 20 Additionally, the authors also observed a trend towards an increased pulmonary veinphrenic nerve distance with an increasing left atrial size. 20

| CONCLUSION
In this large real-world study, PNP recovered in most patients after AF ablation and 86% of the patients were free of PNP-related symptoms. Female patients and patients treated with CB or thoracoscopic ablation were at higher risk to develop PNP.

ACKNOWLEDGMENT
This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

AUTHOR CONTRIBUTIONS
All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

DATA AVAILABILITY STATEMENT
The data underlying this article were provided by The Netherlands Heart Registration by the permission of the participating hospitals.
Data are available upon reasonable request to the corresponding author and with permission of the Netherlands Heart Registration.