cryoballoon pulmonary vein isolation ( pvi ) has emerged as an alternative to radiofrequency pvi in the treatment of drugresistant atrial fibrillation ( af ) .
cryoballoon pvi , compared with radiofrequency pvi , offers potential advantages , including shorter procedure times,1 , 2 , 3 decreased hospital length of stay,1 and decreased fluoroscopy time.3 the data are limited that define the major complication rate of cryoballoon pvi .
additionally , previous literature identifies phrenic nerve injury ( pni ) as the most frequent complication of cryoballoon pvi.4 , 5 , 6 , 7 , 8 , 9 methods including monitoring diaphragmatic electromyographic signals with compound motor action potential ( cmap)10 , 11 , 12 , 13 , 14 and immediate balloon deflation15 have been described to help detect pni and decrease its incidence and longterm persistence .
identifying predictors of major complications and pni will assist in patient selection for this procedure .
the study population included 450 consecutive patients undergoing cryoballoon pvi for af at the university of pittsburgh medical center between august 2011 and august 2015 as part of a prospective registry .
baseline clinical characteristics and detailed medical history , including specific af history , were recorded for all patients .
all patients underwent preprocedural cardiac computed tomography to assess pulmonary venous anatomy and transesophageal echocardiography to rule out intracardiac thrombus .
the cryoballoon pvi procedure has been previously described in detail.16 , 17 , 18 in brief , all ablation procedures were performed with the patient under general anesthesia , avoiding paralytic agents after induction to allow monitoring of phrenic nerve function .
all cases were performed by using the arctic front cryoballoon ( medtronic ) via a transseptal approach . for most cases , after confirming pulmonary vein occlusion via venography , two 180 to 240second lesions were applied in each pulmonary vein and additional lesions were applied if conduction persisted .
isolation was confirmed through elimination or dissociation of pulmonary vein potentials , differential pacing maneuvers , and high output pacing within the pulmonary veins to confirm exit block . for the rightsided pulmonary veins
, pacing was performed from the superior vena cava ( svc ) to monitor phrenic nerve function , and ablation was immediately terminated with any decreased diaphragmatic excursion .
cmap monitoring10 , 11 , 12 , 13 , 14 , 19 and immediate balloon deflation15 were used in a subset of patients once these techniques were described .
anticoagulation during the procedure was with intravenous heparin to maintain an activated clotting time of 300 to 400  seconds .
for patients on warfarin , the procedure was performed with an international normalized ratio 1.5 to 2.5 and for novel oral anticoagulants , the agent was held 1 to 2  days before the procedure and usually restarted 6  hours after the procedure .
patient followup was as per standard protocol with outpatient visits at 6  weeks , 3  months , 6  months , 1  year , and yearly thereafter postprocedure . at the time of the procedure ,
in addition , retrospective chart review of all procedure notes , hospitalizations , office visits , and emergency department visits was performed to assess for additional complications postprocedure .
predefined major complications were persistent pni , symptomatic pericardial effusion , deep vein thrombosis , arteriovenous fistula , atrioesophageal fistula , major bleeding , stroke , or death .
 persistent pni  was defined as pni that persisted or occurred beyond discharge from the electrophysiology laboratory , while episodes of pni that resolved before discharge from the laboratory without recurrence were termed
identification of complications was based on objective evidence of any of the predefined complications or after workup of new symptoms postprocedure .
variables found to be associated with the outcomes in univariable analyses at p<0.2 were selected for multivariable analyses .
the study population included 450 consecutive patients undergoing cryoballoon pvi for af at the university of pittsburgh medical center between august 2011 and august 2015 as part of a prospective registry .
baseline clinical characteristics and detailed medical history , including specific af history , were recorded for all patients .
all patients underwent preprocedural cardiac computed tomography to assess pulmonary venous anatomy and transesophageal echocardiography to rule out intracardiac thrombus .
the cryoballoon pvi procedure has been previously described in detail.16 , 17 , 18 in brief , all ablation procedures were performed with the patient under general anesthesia , avoiding paralytic agents after induction to allow monitoring of phrenic nerve function .
all cases were performed by using the arctic front cryoballoon ( medtronic ) via a transseptal approach . for most cases , after confirming pulmonary vein occlusion via venography , two 180 to 240second lesions were applied in each pulmonary vein and additional lesions were applied if conduction persisted . isolation was confirmed through elimination or dissociation of pulmonary vein potentials , differential pacing maneuvers , and high output pacing within the pulmonary veins to confirm exit block . for the rightsided pulmonary veins ,
pacing was performed from the superior vena cava ( svc ) to monitor phrenic nerve function , and ablation was immediately terminated with any decreased diaphragmatic excursion .
cmap monitoring10 , 11 , 12 , 13 , 14 , 19 and immediate balloon deflation15 were used in a subset of patients once these techniques were described .
anticoagulation during the procedure was with intravenous heparin to maintain an activated clotting time of 300 to 400  seconds .
for patients on warfarin , the procedure was performed with an international normalized ratio 1.5 to 2.5 and for novel oral anticoagulants , the agent was held 1 to 2  days before the procedure and usually restarted 6  hours after the procedure .
patient followup was as per standard protocol with outpatient visits at 6  weeks , 3  months , 6  months , 1  year , and yearly thereafter postprocedure . at the time of the procedure ,
in addition , retrospective chart review of all procedure notes , hospitalizations , office visits , and emergency department visits was performed to assess for additional complications postprocedure .
predefined major complications were persistent pni , symptomatic pericardial effusion , deep vein thrombosis , arteriovenous fistula , atrioesophageal fistula , major bleeding , stroke , or death .
 persistent pni  was defined as pni that persisted or occurred beyond discharge from the electrophysiology laboratory , while episodes of pni that resolved before discharge from the laboratory without recurrence were termed
identification of complications was based on objective evidence of any of the predefined complications or after workup of new symptoms postprocedure .
variables found to be associated with the outcomes in univariable analyses at p<0.2 were selected for multivariable analyses .
all 450 consecutive patients who underwent cryoballoon pvi between august 2011 and august 2015 were included in the final analysis .
there were 9 physicians who performed the procedures described , with a mean of 56.470.2 and median of 27 cryoballoon procedures per operator and a range of 2 to 170 .
the study population was a mean of 599.9  years old , and 26% were women , with a mean cha2ds2vasc score of 1.71.3 and left atrial dimension of 4.32.4  cm .
hypertension was present in 57.6% of the patients , persistent af was present in 30% of the patients , and 75% had af duration > 1  year .
additional baseline characteristics for the total study population , patients stratified by major complications , and patients with phrenic nerve injury are shown in table  1 .
major complications included 5 cases of persistent pni , 3 episodes of symptomatic pericardial effusion , 1 deep vein thrombosis , and 1 arteriovenous fistula .
there were no major bleeds , periprocedural strokes , atrioesophageal fistulas , or periprocedural deaths .
cxr indicates chest radiograph ; ed , emergency department ; pacu , postanesthesia care unit ; pni , phrenic nerve injury ; rspv , right superior pulmonary vein ; sob , shortness of breath .
there were 3 symptomatic echocardiogramconfirmed pericardial effusions that presented during the postprocedural period ; all resolved within 1 week without intervention .
there was 1 case of a right femoral pseudoaneurysm and arteriovenous fistula requiring surgical intervention .
there was 1 right saphenous vein deep vein thrombosis that was discovered 6  days postprocedure .
univariate logistic regression analysis did not reveal any significant potential predictors of major complications . in our study population ,
pni ( transient and persistent ) was the most common complication , occurring in 49 ( 10.8% ) procedures , of which pni was persistent in 5 ( 1.1% ) cases .
two of the persistent pni cases were not detected in the laboratory during svc pacing but rather discovered on chest radiography with right hemidiaphragm elevation during followup after the patients reported symptoms .
persistent pni resolved in all cases at 2 , 20 , 30 , 34 , and 48  days postprocedure ( table  3 ) .
the distribution of veins for the cases of pni was 73% right superior , 23% right inferior , and 4% right middle pulmonary veins .
univariate analysis identified age ( 62.87.7  years versus 58.70.12  years , p=0.006 ) and use of the 23mm balloon ( 16.3% versus 5.3% , p=0.005 ) as associated with pni ( table  4 ) .
there was no significant difference between estimated vein orifice area for veins with pni compared with rightsided veins without pni ( table  4 ) .
variables selected for multivariate analysis by using a cutoff of p<0.2 included redo procedures , age , hypertension , use of 23mm balloon , cha2ds2vasc score , early procedures , and total fluoroscopy time .
multivariate analysis identified 23mm balloon use ( odds ratio 2.94 , p=0.011 ) and age ( odds ratio 1.058 , p=0.014 )  as significant independent predictors for pni . comparison of patients with pni to those without values are presented as meansd or n ( % ) .
af indicates atrial fibrillation ; chf , congestive heart failure ; htn , hypertension ; pni , phrenic nerve injury .
procedural characteristics , including cryoballoon temperature data , number of lesions , and freeze times , were available for 68.0% of patients .
these procedural characteristics were compared for the rightsided veins with pni and the rightsided veins without pni ( table  5 ) .
patients with pni had a significantly shorter total freeze time ( 301148   versus 404117  seconds , p<0.001 ) and number of lesions per vein ( 1.90.7 versus 2.30.6 , p=0.006 ) .
all 450 consecutive patients who underwent cryoballoon pvi between august 2011 and august 2015 were included in the final analysis .
there were 9 physicians who performed the procedures described , with a mean of 56.470.2 and median of 27 cryoballoon procedures per operator and a range of 2 to 170 .
the study population was a mean of 599.9  years old , and 26% were women , with a mean cha2ds2vasc score of 1.71.3 and left atrial dimension of 4.32.4  cm .
hypertension was present in 57.6% of the patients , persistent af was present in 30% of the patients , and 75% had af duration > 1  year .
additional baseline characteristics for the total study population , patients stratified by major complications , and patients with phrenic nerve injury are shown in table  1 .
major complications included 5 cases of persistent pni , 3 episodes of symptomatic pericardial effusion , 1 deep vein thrombosis , and 1 arteriovenous fistula .
there were no major bleeds , periprocedural strokes , atrioesophageal fistulas , or periprocedural deaths .
cxr indicates chest radiograph ; ed , emergency department ; pacu , postanesthesia care unit ; pni , phrenic nerve injury ; rspv , right superior pulmonary vein ; sob , shortness of breath .
there were 3 symptomatic echocardiogramconfirmed pericardial effusions that presented during the postprocedural period ; all resolved within 1 week without intervention .
there was 1 case of a right femoral pseudoaneurysm and arteriovenous fistula requiring surgical intervention .
there was 1 right saphenous vein deep vein thrombosis that was discovered 6  days postprocedure .
in our study population , pni ( transient and persistent ) was the most common complication , occurring in 49 ( 10.8% ) procedures , of which pni was persistent in 5 ( 1.1% ) cases .
two of the persistent pni cases were not detected in the laboratory during svc pacing but rather discovered on chest radiography with right hemidiaphragm elevation during followup after the patients reported symptoms .
persistent pni resolved in all cases at 2 , 20 , 30 , 34 , and 48  days postprocedure ( table  3 ) .
the distribution of veins for the cases of pni was 73% right superior , 23% right inferior , and 4% right middle pulmonary veins .
univariate analysis identified age ( 62.87.7  years versus 58.70.12  years , p=0.006 ) and use of the 23mm balloon ( 16.3% versus 5.3% , p=0.005 ) as associated with pni ( table  4 ) .
there was no significant difference between estimated vein orifice area for veins with pni compared with rightsided veins without pni ( table  4 ) .
variables selected for multivariate analysis by using a cutoff of p<0.2 included redo procedures , age , hypertension , use of 23mm balloon , cha2ds2vasc score , early procedures , and total fluoroscopy time .
multivariate analysis identified 23mm balloon use ( odds ratio 2.94 , p=0.011 ) and age ( odds ratio 1.058 , p=0.014 )  as significant independent predictors for pni .
comparison of patients with pni to those without values are presented as meansd or n ( % ) .
af indicates atrial fibrillation ; chf , congestive heart failure ; htn , hypertension ; pni , phrenic nerve injury .
procedural characteristics , including cryoballoon temperature data , number of lesions , and freeze times , were available for 68.0% of patients .
these procedural characteristics were compared for the rightsided veins with pni and the rightsided veins without pni ( table  5 ) .
patients with pni had a significantly shorter total freeze time ( 301148   versus 404117  seconds , p<0.001 ) and number of lesions per vein ( 1.90.7 versus 2.30.6 , p=0.006 ) .
the main findings of our study were that in our cohort of 450 consecutive cases , the major complication rate of cryoballoon pvi was 2.2% .
overall , the most frequent complication was pni , which was usually transient and eventually resolved in all cases .
our major complication rate is consistent with previously published rates of major complications : 2% to 5.1%.5 , 20 , 21 , 22 the lack of significant predictors for major complications is consistent with most previous studies5 and likely is limited by a lack of statistical power , given the low rate of complications ( table  6).1 , 5 , 6 , 9 , 15 , 20 , 23 , 24 , 25 a previous study has identified predictors that included female sex and procedures performed in july or august.21 further research in larger cohorts may identify additional predictors of major complications . alternatively , cryoballoon pvi may have such a low rate of major complications that no predictors will be identified for most specific complications .
previous literature for complications and pni af indicates atrial fibrillation ; n / a , not available ; pni , phrenic nerve injury ; rspv , right superior pulmonary vein ; svc , superior vena cava .
the most common complication was pni ; the overwhelming majority of cases resolved before discharge from the electrophysiological laboratory , and the persistent cases resolved within 2  months .
other study populations have described longterm resolution of all or nearly all pni cases.5 , 6 , 7 , 16 despite the apparent temporary nature of phrenic nerve injury occurring during cryoballoon pvi , it is important to continue to use methods to reduce the incidence of pni and identify predictors to aid in patient selection and guide estimation of risks and benefits of the procedure in individual patients .
we found that the use of the 23mm balloon and increased age were associated with pni .
we have compared our study with other literature that reviewed complication rates , pni rates , and predictors and found we had identified a similar or an improved pni and major complication rate ( table  6 ) .
we did identify 2 cases of persistent pni that were not detected during the procedure but were discovered after discharge from the electrophysiological laboratory .
both cases were identified when the patients presented as outpatients with symptoms and confirmed with right hemidiaphragm elevation on chest radiography .
these cases highlight the possibility of delayed pni , which is currently not widely described . both cases used svc pacing but not cmap monitoring .
possibilities include missed injury during the procedure ( with svc pacing below balloon position , which is unlikely given operator experience , and in 1 case , stored cine confirms appropriate position ) versus a subtle injury not detected during the procedure with progression over the next several days .
previous studies have established a decrease in cmap of 30% to 35% as highly sensitive for detecting pni , with a decrease in 30% correlating with a cstatistic of 0.965.11 , 14 it is unclear if cmap would have detected subtle injury in these cases .
regardless , our findings emphasize the importance of followup and monitoring for complications after the index cryoballoon procedure . in our cohort ,
there was increased 23mm balloon use for patients with pni which has been reported in previous studies.15 , 16 , 26 an increased risk of pni is likely when the balloon is positioned distal toward the vein , which occurs more frequently with the 23mm balloon compared with the 28mm balloon given its smaller size.16 , 20 , 26 , 27 another hypothesis may be that the 28mm balloon represents later cases in which the operator has gained experience ; however , even when we controlled for early versus late cases , the effect of the 23mm balloon was seen .
we saw that the patients who had pni were older than patients without pni , which is also a novel finding .
this may be a result of deeper tissue penetration in advanced age because of changes in extracellular matrix or possible agerelated shifts in relative position of the phrenic nerve relative to the right pulmonary veins.28 , 29 while pvi has been shown to be effective and safe when evaluating major complications in elderly populations,30 this slight increase in incidence of pni is important to note when offering cryoballoon pvi to elderly patients .
given that there were no differences in maximum negative temperature or average 30second temperature for patients with pni , it is unlikely that more aggressive freezing contributed to pni .
in fact , the patients with pni had lower total freezing duration and number of lesions , which is likely a result of no further ablation performed after pni was detected .
since the adoption of cryoballoon pvi for af , methods to reduce the incidence of pni have emerged .
monitoring using surface electrodes during phrenic nerve pacing to detect a 30% to 35% reduction in diaphragmatic cmap has decreased the incidence of pni by allowing for early detection.14 , 19 additionally , double deflation or rapid balloon deflation , which leads to more rapid tissue rewarming , reduces the risk of persistent pni.15 
  our study has several potential limitations .
it is a retrospective observational study of a prospective registry involving only a single center and , thus , its generalizability may be limited .
it is important to note that this is one of the larger studies to date looking at complications in cryoballoon pvi . given the small percentage of major complications , some potential predictors may not have been identified .
all patients had at least 1 month of followup , and given that the overwhelming majority of pni occurs acutely because of its pathophysiology , it is likely that most of the pnis were detected by using our surveillance methods .
additionally , it is possible that operator experience affected the complication and pni rates ; however , when comparing the first onethird of cryoballoon procedures with the second twothirds of procedures performed at our institution , we did not see a significant difference in pni rates .
finally , we did not include the procedural characteristics in the multivariate analysis because the differences in these characteristics were likely a result of acute pni ( ie , shorter freeze time and number of lesions ) ; however , in doing this , we may have missed some predictors of pni .
it is a retrospective observational study of a prospective registry involving only a single center and , thus , its generalizability may be limited .
it is important to note that this is one of the larger studies to date looking at complications in cryoballoon pvi . given the small percentage of major complications , some potential predictors may not have been identified .
all patients had at least 1 month of followup , and given that the overwhelming majority of pni occurs acutely because of its pathophysiology , it is likely that most of the pnis were detected by using our surveillance methods . however , it is possible that any delayed pni may have gone undetected .
additionally , it is possible that operator experience affected the complication and pni rates ; however , when comparing the first onethird of cryoballoon procedures with the second twothirds of procedures performed at our institution , we did not see a significant difference in pni rates .
finally , we did not include the procedural characteristics in the multivariate analysis because the differences in these characteristics were likely a result of acute pni ( ie , shorter freeze time and number of lesions ) ; however , in doing this , we may have missed some predictors of pni .
in a prospective observational cohort of 450 consecutive cases , the major complication rate of cryoballoon pvi was 2.2% with no identified predictors of major complications .
dr saba reports a research grant from boston scientific ( significant ) , medtronic ( modest ) , and st .
dr jain reports research support from medtronic ( modest ) . the remaining authors have no conflicts of interest to disclose .
 backgroundcryoballoon pulmonary vein isolation ( pvi ) has emerged as an alternative to radiofrequency pvi for atrial fibrillation ( af ) . 
 data are lacking to define the rates and predictors of complications , particularly phrenic nerve injury ( pni).methods and resultswe evaluated a singlecenter prospective registry of 450 consecutive patients undergoing cryoballoon pvi between 2011 and 2015 . 
 patients were 5910  years old , 26% were women , 58% had hypertension , their mean cha 
 2 
 ds 
 2 
 vasc score was 1.71.3 , 30% had persistent atrial fibrillation , and 92% received a secondgeneration 28mm balloon . predefined major complications were persistent pni , pericardial effusion , deep vein thrombosis , arteriovenous fistula , atrioesophageal fistula , bleeding requiring transfusion , stroke , and death . 
 pni was categorized as persistent if it persisted after discharge from the laboratory . 
 logistic regression was performed to identify predictors of complications and specifically pni . 
 we identified a major complication in 10 ( 2.2% ) patients . in 49 ( 10.8% ) 
 patients , at least transient pni was observed ; only 5 persisted beyond the procedure ( 1.1% ) . 
 all cases of pni resolved eventually , with the longest time to resolution being 48  days . 
 we also describe 2 cases of pni manifesting after the index hospitalization . 
 regression analysis identified 23mm balloon use ( 16.3% versus 5.2% , odds ratio 2.94 , p=0.011 ) and increased age ( 62.87.7  versus 58.70.12  years , odds ratio 1.058 , p=0.014 ) as independent significant predictors of pni . 
 there were no significant predictors of major complications.conclusionsin a large contemporary cohort , cryoballoon pvi is associated with low procedural risk , including lower rates of pni than previously reported . older age and 23mm balloon use 
 were associated with pni . 
 our low rate of pni may reflect more sensitive detection methods , including compound motor action potential monitoring and forced doubledeflation . 
Introduction
Methods
Study Population
Cryoballoon Ablation Procedure
FollowUp
Statistical Analysis
Results
Study Population
Major Complications
Phrenic Nerve Injury
Discussion
Limitations
Conclusions
Disclosures