Acute Procedural Complications of Cryoballoon Ablation: A Comprehensive Review

Abstract

Catheter ablation is increasingly performed for treatment of atrial fibrillation (AF). Balloon based procedures have been developed aiming at safer, easier and more effective treatment as compared to point to point ablation. In the present review article, we aimed to discuss acute procedural complications of cryoballoon ablation.

INTRODUCTION

Atrial fibrillation (AF) is the most common sustained arrhythmia in Europe and U.S [1,2]. Despite promising improvements in the management of patients with AF, this arrhythmia remains one of the leading causes of stroke, heart failure, sudden death, and cardiovascular morbidity [3]. Once the demonstration of that the pulmonary veins (PVs) and also non-PV triggers initiates AF, catheter ablation has developed as gold standard method in selected population of patients for AF treatment [4]. CABANA trial tested whether primary catheter ablation for the elimination of AF was superior to state-of-the-art drug therapy and demonstrated that ablation is a safe and effective therapy for AF and, in some cases, is superior to drug therapy [5]. Pulmonary vein isolation (PVI) is now widely accepted as the cornerstone of AF ablation procedures. Radiofrequency based ablation techniques try to achieve this goal by "point by point" ablation; however, in the last years, the use of novel alternative ablation strategies such as cryoballoon (CB) or laserballoon is growing rapidly [6-8]. As expected, CB ablation is related to a significantly had a shorter procedure time and a non-significantly shorter fluoroscopy time compared with radiofrequency catheter ablation because the single or just a couple bonus applications are adequate for durable and complete lesions [6,7,9]. Cryoballoon ablation technique as a single shot deviece also provides acceptable success rates in complex AF substrates such as; persistent AF, elderly patients, patients with PV abnormalities and even in patients with heart failure [10-14]. With its relatively short learning curve, use of CB has been increased. And the possible concern about the efficacy and safety of the procedure in relatively low-volume centers may be raising. Good news is that, experience does not influence long-term outcome and peri-procedural complications after cryoballoon ablation of paroxysmal AF patients [15]. In the present article, we try to comprehensively review acute procedural complications associated with CB ablation.

DEFINITION AND CLASSIFICATION

By definition, peri-procedural complications and complications occurring within the first 24 hours denote as acute complications. Ablation-related complications can be classified into following 4 groups according to their severity: (1) life-threatening complications; (2) severe complications; (3) moderate or minor complications; and (4) complications with unknown significance [3]. Simply, potentially fatal complications such as esophageal injury, cardiac tamponade, and periprocedural stroke are classified as life-threatening complications. Although the definition of serious complication is unclear, when life-threatening complications are removed, it seems to state the same as the definition of major complication used in previous studies. According to this classification, PV stenosis, persistent phrenic nerve palsy (PNP), vascular complications requiring transfusion or surgical intervention, and other rare complications such as mitral valve damage, cardiac conduction system damage requiring pacemaker implantation, and myocardial infarction are called as severe complications. However, there are some limitations related to this classification method. A moderate or minor complication such as femoral hematoma may convert a major complication during the course of the illnes, when it requires transfusion or surgical intervention. Contrary, most patients with significant PV stenosis and persistent PNP remain asymptomatic or have few symptoms [16,17].

In the rest of the article, acute procedural complications of CB ablation will discuss according to place of occurrence.

COMPLICATIONS RELATED TO VASCULAR ACCESS SITE

Peripheral vascular complications are the most common complications of AF ablation regardles of used energy type [18]. The complications consist of bleeding, groin or retroperitoneal hematomas, pseudoaneurysms, arteriovenous fistulas, arterial thromboembolism, and arterial air embolism which are cumulatively reported in about 1-2% of cases [19,20]. Theoratically, the risk of access site bleeding should be more during ablation of AF than other cardiac arrhythmias due to peri-procedural anticoagulation requirement. Fortunately, the study results did not confirm this assumption and periprocedural uninterrupted oral anticoagulation therapy was found to be associated with more effective for preventing thromboembolism without any increase in incidence of bleeding complications [20,21]. Furthermore, under uninterrupted warfarine regimen with a therapeutic INR was associated with lower minor bleeding complications than bridging with heparin or LMWH [22]. During CB application, use of a special calibre delivery sheath (FlexCath Advance® Steerable Sheath, Medtronic Inc. ) is needed. The sheath has a wide 12F inner and 15F outer diameters, respectively. This may be accepted as a potentially enhancing factor for the risk of vascular complications. However, larger size of the sheath does not seem to cause a serious problem in that case because the sheath is advanced via venous system. In the relevant literature, the similar vascular complication rates between CB and radiofrequency ablation confirms this reasoning [18,19].

The studies for radiofrequency ablation demonstrated that risk of vascular complications may be increased with female gender, older age, and less experienced operators [24,25]. Although similar factors were studied for CB, only female gender was found related to higher vascular complications [25,27]. Theoretically, a higher proportion of vascular access site complication in women might be associated with more, increased body mass index, more sensitive connective tissue and vascular wall or variable femoral veincourse in this population. In a Russian pilot survey, Mikhaylov et al [25] compared AF ablation results between high- and low-volume AF ablation centres. Surprisingly, a higher proportion of vascular access-site complications occured in high-volume AF ablation centres. As a potential explanation, they speculated that, in the lower-volume AF ablation centres, venous access was performed by well experienced vascular puncture operators whereas the higher-volume centres were mainly academic teaching centres, where preparations for ablation procedures were carried out by younger fellow physicians. Therefore, it should be kept in mind that operator experience is more important than volume of center to predict periferic vascular complications.

Arterial pseudoaneurysms are related to inadvertent punctures of the neighboring femoral artery during puncture of femoral vein. Mugnai et al [28] reported incidence of complications in those patients who underwent CBA for AF and the impact of novel oral anticoagulants on adverse events compared with vitamin K antagonists. The incidence of femoral pseudoaneurysms was 1.3%; 1 patient required surgical repair; 1 patient underwent percutaneous thrombin injection due to a false aneurysm; and the other 3 patients were successfully treated conservatively by compression only. Although there is no data related to CBA, ultrasound guidance during femoral puncture may be suggested to reduce this complications [29].

The great majority of bleeding and hematomas resolve spontaneously and are classified as minor complication. Any bleeding severe enough to require a blood transfusion or hematomas requiring surgical intervention is called as major bleeding and encountered in up to 1.5% of cases [30]. Arteriovenous fistula is a rare complication and should be treated surgically.

Despite various precautions to achieve complete hemostasis in a safe and effective manner, no standard approach or technique is available yet. Device-based invasive vascular closure techniques have significant cost with a risk of device failure and specific vascular complications [31]. Despite, modified figure-of-eight suture for femoral venous hemostasis has been found to be safe and time saving hemostasis method for CB procedures [32], manual compression is the most commonly used technique to achieve access site hemostasis after CB procedure. Protamine reversal of anticoagulation may be an option for veinous hemostasis during manual compression. Gurses et al.[33] studied safety and efficacy of protamine administration for reversal of heparin with manuel compression following CBA. Hospital stay was significantly shorter in patients who were administered protamine. Furthermore, all hematoma, pseudoaneurysm and arteriovenous fistula requiring surgical or interventional repair in the femoral access site were lower in patients who received protamine (1.1 %) than patients who did not (6.3%) (p = 0.011). In our clinic we routinely use manual compression without heparine reversal and major hematoma requiring intervention was detected in one case (2.1%) [34].

COMPLICATIONS RELATED TO TRANSSEPTAL PUNCTURE

AF ablation procedure requires transseptal puncture (TSP). In routine approach, Brockenbrough needles are used with a wide variety of sheaths to access the left atrium (LA). To understand complications related to TSP, it should be kept in mind that interatrial septum (IAS) is bordered by the ostia of the inferior vena cava, superior vena cava, coronary sinus, tricuspid septal leaflet, right atrial appendage and posterior wall folds. Therefore, only 20% of total septal area is suitable to be crossed without exiting the heart [35].

Cardiac perforation with or without tamponade is the most common acute procedural life threatening complication of TSP. The main cause is inadvertent penetration of the posterior segments. Less commonly, left atrial lateral wall, left atrial roof or left atrial appendage (LAA) may be damaged due to sudden jumping of needle across the IAS [36]. TSP guided only by fluoroscopy is complicated by tamponade in 0.1–3.2% of cases [37]. ICE or TEE provided direct visualization of the septum may offer a safer TSP, especially in atypical anatomy, a resistant/elastic septum and inexperienced operators [38-40]. As demonstrated in our recently published article, a simple deep inspiration maneuver during TSP may be a reliable and safe method after failed conventional attempts in some of these cases [41]. However, it should be kept in mind that the need for multiple punctures and intraprocedural systemic/ongoing oral anticoagulation may increase the risk or aggravate the consequences of complications. In the presence of hypotension, diaphoresis, sinus tachycardia or asystole, cardiac tamponade should be taken into account, immediately. Although the diagnosis is easily confirmed by transthoracic echocardiography, fluoroscopic reduction in the excursion of cardiac silhouette on fluoroscopy is an early diagnostic sign of cardiac tamponade during the procedure and may be used to detect impending pericardial tamponade before hemodynamic collapse [42]. Once perforation or tamponade is detected, the effect of anticoagulants (heparin or oral anticoagulant) should be reversed by using proper reversal agent such as protamine, four-factor prothrombin complex concentrate rather than fresh frozen plasma, idarucizumab, andexanet alpha or recombinant factor VIIa in addition to fluid administration [43,44]. If tamponade does not resolve with these precautions, the patient should prepare for immediate pericardiocenthesis with autologous transfusion without wasting time. Urgent cardiac surgery should be attempted in case of continuos bleeding [45].

Due to large outer diameter of the FlexCath catheter the rate of iatrogenic atrial septal defect (ASD) may be high up to 38% at 6 months, with a mean size of 5.5 mm [46]. The incidence of iatrogenic ASD has been found significantly higher in CBA compared to double transseptal conventional radiofrequency ablation.[47]. Despite hemodinamically significant iatrogenic ASD has been reported previously [48], in the majority of the cases this complication is not clinically relevant and mostly does not cause any adverse events not only in acute period but also during the follow-up. Transient inferior ST-segment elevation accompanied by profound hypotension and bradycardia has been reported in 0.3% of cases [49]. The most plausible mechanism of this phenomenon is Bezold-Jarisch–like vasovagal responsedue to the mechanical effects of puncture on the vagal network located close to the puncture site. This vagal network usually innervates the right coronary artery and leaves it vulnerable to cholinergic vasospasm [50]. However coronary embolism should be kept in mind as an alternative diagnosis in all cases. If the cause is vagal hyperactivity, it usually resolves spontaneously. In rare situations, dopamine or fast saline drip can resolve the problem without sequelae or other complications [49].

Peripheral or central embolism including silent microemboli, transient ischemic attack and stroke is usually caused by thrombus formation in the space between the needle and the dilator, if proper anticoagulation is not administered prior to or immediately following TSP. Once the TSP system reaches the LA, ACT of at least 300-350 seconds with intravenous heparin should be achieved and maintained until all the catheters are removed from the LA. According to the latest expert consensus statement on catheter and surgical ablation of AF, uninterrupted oral anticoagulation regimen is recommended with VKAs or NOACs in addition to intraprocedural heparin infusion [4].

Air embolism to the systemic circulation is another important complication during TSP. Recurrent catheter exchanges and rapid removal of catheters or dilators, deep sedation and prolonged apnea periods with deep breaths during general anesthesia, and incomplete hemostasis valves are the most commonly reported causes of air embolism [51]. All these causes inadvertent negative pressure in catheter lumen or in the LA and air passage into the left hear chamber. To avoid this devastating complication, usage of a continuous flush through a closed system is mandatory. Also, the wire and dilators should be withdrawn from the catheter gradually. Also, the syringe should be held upright during hand injections. Once the complication is happening, the target should be to prevent further air entry, reduce the volume of the air embolus, and provide haemodynamic support. Administration of high-flow oxygen therapy is usually suggested to accelerate reabsorption of the air and minimize the size of the air bubble [52]. In a recently published article, Cay et al [53] presented a case of massive coronary air embolism and discussed its acute management. Excange of large diameter FlexCath with thinner transseptal sheath, aspiration of the air through coronary artery by an aspiration catheter solved the problem in their case. Then, full patency of the vessel and complete resolution of ST segment elevations was achieved after multiple rapid suctions through the catheter. Aortic root injury is a rare complication of TSP due to penetration of the anterior segments. Proper usage of fluoroscopy, transesophageal or intracardiac echocardiography is mandatory to avoid inadvertent aortic root needle puncture. Also, contrast injection and pressure recording after the needle has been passed septum may facilitate to recognize aortic puncture before advancing the sheath. In case of aortic puncture with needle, withdrawing of the needle slowly is reported to be safe and effective strategy [54]. If the sheath entered the aorta, the sheath should be pulled back with a wire left in the aorta in the presence of surgical standby. Once ensuring hemodynamic stabilization, the wire may also be pulled back. Careful haemodynamic and echocardiographic observation is mandatory during all these steps. Gerbode defect is a rare congenital anomaly that permits shunting from the left ventricle to the right atrium [55]. Preprocedural evaluation of IAS with echocardiography is important in terms of uncovering existence of this defect because it may cause inadvertent aortic root puncture.

COMPLICATIONS DURING ABLATION

Pericardial effusion is a relatively common complication of CB ablation. In a recently published study, mild and moderate pericardial effusion was detected in 78% of patients undergoing CB ablation [56]. Although the incidence of cardiac tamponade has been reported to be higher with radiofrequency energy, the incidence of pericardial effusion were similar in both energy types [57,58]. Acute pericarditis is another pericardial complication of CB ablation and may occurr in up to 4% of patients [56]. The total number of cryoapplications and the total freeze duration were significantly higher in patients with pericarditis compared with those without. In patients demonstrating altering findings such as low blood pressure, tachycardia, and narrowed pulse pressure, a transthoracic echocardiography should be performed without wasting time. Becasue the approach in cardiac tamponade is described in detail in the above section; it is not mentioned again, here.

Although published complication rates of CB2 based-PVI are relatively low and several safety algorithms have been implemented in the protocols the most frequent complication is right-sided phrenic nerve injury (PNI). PNI develops due to the close proximity to the PNs with the PVs. Although the incidence of PNI has decreased over the years due to advanced balloon and improved techniques for early detection, PNI was noted in 3.2%-7% of patients [59,60]. High incidence of PNI after CB ablation is related to close anatomical relationship between the PNs and PV anatomy. The right PN descends posteriorly in between the right PVs and the superior vena cava–right atrial junction. Sánchez-Quintana et al [61] studied by gross dissection the courses of the right and left PNs in 6 cadavers and demonstrated that the distance between the right PN and the anterior wall of the right superior PV may be as few as 2.1±0.4 mm whereas the distance with the right inferior PV is higher (7.8 mm±1.2). As an expected result of this close proximity, the risk of PNI is highest during ablation of the right superior PV [62] however, it is not clear why PNI appears to be more common with CB compared with radiofrequency ablation [63]. One suggested mechanism implicates anatomic distortion of the PV orifice/PN relationship, through increasing contact or shortening the relative distance between the ablation site and the PN, even without displacement of the balloon into the PV [64].

Although the left PN courses anteriorly across the LAA and is far from the left PVs, there are published cases of left PNI during CB ablation of the left superior PV [65,66]. The risk may be higher during isolation of the LAA by using CB [67]. Despite this general acceptance, the incidence and prognosis of left-sided PNI during CB ablation was recently evaluated by recording the amplitude of the compound motor action potentials during the CB ablation. Premature termination of the freezing was required to avoid PNP in 1.8% of patients [68].

Following pre-operative computed tomography findings have been associated with the development of PNI: (1) shorter distance between the right superior PV and right PN; (2) larger PV dimensions; (3) Larger external angle between the right superior PV and right anterolateral wall of the LA; and (4) smaller eccentricity index (ratio of maximum over minimum ostial diameter). In a recently published study, the prevalence of right common ostium and temperature drop velocity from basal to - 20 °C were found as predictors of PNI in the multivariate analysis [69].

Additionally, type of CB has also an impact on possibility of PNI. Comparison of first and second generation of CB ablation showed significantly larger number of reversible and persistent PNI with the second-generation CB [70,71].

The CB ablation protocol may influence the incidence of PNI. Rottner and coworkers studied to to assess the impact of different ablation protocols on the incidence and characteristics of procedural complications. Time-to effect protocol was found to be safe and effective. The observed difference in the occurrence of procedural complications between the ablation protocols is mainly driven by the higher incidence of PNI in bonus freeze and no-Bonus freeze arm. However, distinctive risk factors for the occurrence of procedural complications could not identified, lower number and shorter length of the applied freeze-cycles in the 'time-to-effect' protocol could possibly explain the low incidence of PNI [72].

The diagnosis of PNI is usually made with evidence of diaphragmatic elevation at the chest X-ray or a paradox diaphragmatic movement in the fluoroscopy in a patient demonstrating complaints such as dyspnea, cough, or hiccups. To diagnose during CB ablation, anciently, the PN function was evaluated by direct visulation of diaphragmatic motion on fluoroscopy; however, it is the least optimal method as it exposes the patient and operator to additional radiation and may delay the diagnosis ([Figure 1], movie 1-2). As a second method, the PN function may be evaluated by manual palpation of the patient's abdomen to monitor the excursion of the right hemidiaphragm during high amplitude pacing from the superior vena cava (Movie 3). Weakening of the diaphragmatic motion can indicate PNI. This method is easily applicable but the subjectivity associated with the measurement and respiratory variations in the diaphragmatic contraction strength can be mistaken as PNI. To provide earlier warning of PNI, novel techniques utilizing diaphragmatic compound motor action potential (CMAP) has been recently developped [73,74]. During ablation of the right-sided PVs, CMAP recordings were obtained using two leads: a standard surface right arm ECG electrode positioned 5 cm above the xiphoid and a left arm ECG electrode positioned 16 cm along the right costal margin. The PN is paced continuously with high-output during CB application. A decrease in CMAP amplitude by 35% from baseline may predict and prevent PNI [73].

Figure 1. Deep settlement of cryoballoon catheter is seen on fluroscopy. To facilitate demonstration of catheter position and shape borders of cryoballoon, the right superior pulmonary vein, and the left atrium was drawn with White, blue, and red lines, respectively (B).

Once the suspicion of PNI is determined by one of the methods described above, immediate termination of cryoenergy is the cornerstone of the prevention. If the PN function returns immediately, another CB application may attempt with condition more antral position of the balloon to be confirmed. Otherwise, ablation should be continued with radiofrequency energy. Prognosis of PNI after CBA has been investigated in a large YETI registry [74]. a total of 13693 patients received CB2 or CB3 based-PVI in 23 EP centers. A total of 596 (4.4%) of patients experienced PNI during treatment of the right superior (84%) right inferior (15%) right middle (0.3%) (and left superior (0.3%) pulmonary veins. After 1-3 months 18% of patients showed persistent PNI including 13% of patients complaining of dyspnea. After 6-12 months of follow-up including fluoroscopic evaluation PNI was persistent in 1.8% of patients while dyspnea was reported by 1.7% patients. Only 0.08% of the overall population of 13693 patients showed permanent and symptomatic PNI.

Bronchial injury is a less defined but potentially serious complication of CB ablation. While the most obvious finding is haemoptysis, cough or dyspnea may be the only complaint [75-77]. Persistent cough was reported as high as 17% in the STOP-AF Trial, and hemoptysis has been reported in 1% of cases in the cryoballoon STOP-AF Post Approval Study [75,76]. Unfortunately, the exact cause of this complication is uncertain. Although collateral thermal injury of the bronchial tree is the most widely accepted mechanism of haemoptysis, it might be related to pulmonary infarct, pulmonary haemorrhage or PV stenosis [77-79]. Also, direct damage to the tissue surrounding the PN or deeper inside the lung could be caused by catheterizing it with the guide wire or by distal inflation of the balloon. High-resolution computed tomography of the chest should be used to diagnose [Figure 2]. There is no well accepted treatment option for these cases. Although some groups suggest reversal of anticoagulation and urgent bronchoscopy, haemoptysis usually resolves spontaneously and does not reoccur after restarting anticoagulation theraphy [78-81].

Figure 2. A The computed tomography scan of the chest demonstrates the consolidation in the left lower lobe at the superior boundary suggestive of a pulmonary haemorrhage. B Complete resolution of pulmonary haemorrhage is seen in control computed tomography 1 month later.

Table 1. Complications of CBA.

Complication	Mechanism	Incidence	Management	How to avoid
Vascular Access site: Inguinal bleeding, hematoma, pseudoaneurism, atriovenous fistula, arterial thromboembolism, arterial air embolism	Vascular damage, inadequate hemostasis, inadvertent puncture, inadequate anticoagulation	1-2% More common in women, elderly pts, less experienced operators, high volume centers	Conservative compression, thrombin injection, surgery for pseudoaneurism, Most hematomas resolve spontaneously Surgery for AV fistula	USG guidance during puncture, Protamine reversal, figure of eight suture for hemostasis
Cardiac perforation	During TSP inadvertent posterior segment penetration, LAA, LA lateral wall injury, Aortic root injury	0.1%-3.2%	Heparine reversal, fluids, pericardiocentesis, surgery, if the sheath advanced to aorta surgery is generally needed.	ICE/TEE guidance, Deep inspiration maneuver
Iatrogenic ASD	Thick transseptal sheath	38% at 6 months	Mostly clinical nonrelevant	-
Transient ST elevation	Mostly Besold Jarich like reflex, Coronary embolism	0.3%	Coronary angiogram, Dopamine, fast saline drip	Proper anticoagulation, 300-500 ACT, uninterrupted anticoagulation
Air embolism	Recurrent catheter change, rapid catheter removal, deep sedation, deep breathing, incomplete hemostatic valves	Recurrent catheter change, rapid catheter removal, deep sedation, deep breathing, incomplete hemostatic valves	Positioning, high pressure O2, hemodynamic support, air aspiration	Proper anticoagulation, 300-500 ACT, uninterrupted anticoagulation, removal of air bubbles from catheter
TIA, Stroke	Mostly due to air embolism	Silent cerebral lesions common, clinical TIA/Stroke less than %1	Anticoagulation, consider neurology consultation	Proper anticoagulation, 300-500 ACT, uninterrupted anticoagulation, removal of air bubbles from catheter
PNI	Anatomical relationship between right sided veins and right PN Anatomical relationship between LAA and left PN	3.2-7%	Diagnosed by fluoroscopic evaluation 1-3 days 35% recovery 1-3 months 18% recovery 0.018% persistent and symptomatic	Operator hand control CMAP
Bronchial injury hemoptisis	Thermal trauma, Catheter injury	rare	Reverse anticoagulation, mostly recurs	Avoid lower freezing temperature
Gastroparesis, esophageal injury	Periesophageal plexus or esophageal thermal injury		Gastroparesis mostly during inferior sided vein application with large balloon in small LA	Use temperature probe
PV stenosis	Large PV ostia, low freezing temperature	rare	PV angioplasty, surgery	Avoid low freezing temperature
AV block		Very rare	Careful rhythm control	-
Cx arterial vasosplasm	During LAA isolation	Very rare	ECG ST elevation	-
Achieve catheter breakage	Mechanical	Very rare

Atrioesophageal fistula due to direct esophageal injury has been reported as anecdotal case reports after CB ablation [82,83]. Thus, knowledge about the clinical findings and the clinical course of the disease is derived from ablation studies using radiofrequency energy. It usually occurs within 1-4 weeks following ablation procedure with non-specific signs and symptoms such as fever, fatigue, malaise, chest discomfort, nausea, vomiting, dysphagia, odynophagia, hematemesis, melena, and dyspnea. Because the current article is dedicated to inform about acute complications of CB ablation, atrioesophageal fistula will not discuss in detail. But, in patients presenting with infection findings without a clear focus, retrosternal pain, and cerebrovascular findings, the diagnosis should be considered. The esophageal effects of CB have been studied by different groups by using endoscopy. Lower freezing temparature and lower average minimal luminal esophageal temperature was found related to higher esophageal effects and gastrointestinal complaints [84-89].

Although efficacy real-time luminal esophageal temperature monitoring by placing a temperature probe into the esophagus has not been investigated for CB ablation, the data from radiofrequency ablation suggests that it may be successful to detect a decrease in luminal esophageal temperature. There is no other well defined prevention strategy for this complication.

Gastroparesis is a relatively common but little known complications of CB ablation. The most possible mechanism of gastroparesis related with AF ablation is collateral periesophageal vagal nevre injury. Gastroparesis has been reported mostly occurring during CBA in inferior PVs with relatively larger balloon in small LA [90].

The diagnosis should be considered in the present of following symptoms: epigastric discomfort, abdominal pain, heartburn, bloating, nausea, or vomiting during the procedure. As it demonstrated in our report, all symptomatic patients may be evaluated by fluoroscopy for an air-filled stomach or air fluid level in the fundus of an enlarged fluid-filled stomach [Figure 3] [90]. The patients showing these scopical findings should evaluated by gastric emptying scintigraphy (GES) to confirm the diagnosis. Although the FIRE AND ICE trial reported no instance of gastroparesis, the ratio of patients reporting symptoms that are shared with gastroparesis (abdominal pain, diabetic gastroparesis, epigastric discomfort, gastritis, impaired gastric emptying, nausea, and vomiting) was 3.2% for CB ablation and 2.1% radiofrequency ablation, respectively [91]. However, in our study gastroparesis was higher with CB ablation. Fortunately, gastroparesis had a good prognosis and resolving in all patients who received CB ablation [90].

Figure 3. Fluoroscopy demonstrates the stomach which is completely full of air.

Pulmonary vein stenosis (PVS) is a well defined and serious complication of point by point radiofrequency ablation. Evolving of ablation from osteal and segmental to wide area circumferential caused a decrease in the incidence of PVS from 20%-%30 to approximately 1% [92-95]. The incidence of PVS by CB ablation is approximately 3.1% after cryoablation with the first generation balloon [96]. The diagnosis should be considered in the patients demonstrating symptoms such as cough, dyspnea, chest pain, and hemoptysis. The severity of PV stenosis is generally defined as mild (<50%), moderate (50–70%) or severe (>70%), according to the percentage reduction of the luminal diameter and it determines the severity of the clinical presentation [97].

In recently published studies, a larger PV ostium, lower minimum freezing temperature, and an increased number of applications per vein during CB ablation were found as independent predictors of PVS [98,99]. Although cardiac computed tomography and magnetic resonance imaging are well defined imaging modalities to diagnose, acute edema and dissection-like changes on intravascular ultrasonography might be used for early diagnosis during the procedure [100]. Although there is no an effective treatment strategy, percutaneous balloon angioplasty alone or in conjuction with stent implantation might be a potential alternative in the acute setting. However, high restenosis rish should be kept in mind in long-term follow-up [101].

Peripheral or central embolism is one of the most devastating complications of CB ablation. Theoratically, cryoenergy should be related to lower incidence of thrombus formation because it causes lower platelet and fibrin activation by preserving the endothelial layer during ablation [102,103] whereas recent studies reported similar levels of platelet activity and coagulation activation by cryoenergy and radiofrequency energy [102]. Besides symptomatic cerebral events such as transient ischemic attack or stroke, AF ablation also carries a risk of silent cerebral embolic lesions. By using pre and post-procedural cerebral magnetic resonance imaging, different groups demonstrated that new embolic lesions might be detected in up to 10% of cases after radiofrequency ablation [104,105]. A similar finding was recently demonstrated for CB ablation by using real-time transcranial doppler monitoring [106]. To reduce the incidence of asymptomatic cerebral embolism during cryoablation, the removal of air bubbles from CB in heparinized saline water with extracorporeal balloon inflation before utilization was suggested by Tokuda et al [107].

Despite high rate of silent cerebral embolic lesions, the incidence of TIA or stroke has been reported lower than 1% [108]. To decrease thromboembolic complications of ablation, uninterrupted anticoagulation strategy should be preferred compared with bridging strategies using heparin or enoxaparin regardles of used anticoagulant agent [109,110]. To reveal the presence of thrombus formation in the LAA, routine usage of transesophageal echocardiography is recommended by some authors. Although the incidence of LAA thrombus before AF ablation is low (0.6% to 2%) in patients using uniterrupted anticoagulation or bridging with low-molecular-weight heparin, it should be kept in mind that it is not 0% [111,112]. In a recently published study, dual-source cardiac-computed tomography was succesfully used to exclude thrombus formation. As a main advantage of this new modality, it may deliver additional anatomic details of PVs and LA anatomy with an acceptable radiation exposure [113]. The diagnosis of acute brain lesion can be detected by high-resolution diffusion-weighted magnetic resonance imaging [Figure 4]. Once the diagnosis is confirmed, treatment of the disease should be maintained under the supervision of a neurologist.

Figure 4. Acute cortical infarcts within the left parietal lobe is seen on diffusion weighted cranial magnetic resonance imaging.

Transient ST-segment elevation during cryoballoon application due to coronary slow flow during CB application was firstly reported by our group [114]. During the first freezing attempt in the left superior PV, at 188 seconds and -48°C, an ST-segment elevation was observed in the V1 and V6 leads, without any complaint. Coronary artery angiography was performed less than 5 minutes after balloon deflation and revealed coronary slow flow without any significant flow-limiting lesion, coronary vasospasm, thromboembolus, or air embolus. The ST-segment elevation started to decrease within 3 minutes and returned to baseline in 14 minutes, without any intervention.

Breakage of the achieve circular mapping catheter in a the right PV was recently reported by Makimoto et al [115]. As a main cause of this unique complication, authors accused the wedged position of the catheter in PV, although they had felt no grating or resistance during catheter advencement. The circular part of catheter was remained and followed-up in the right PV without any complaint.

Canpolat et al [116] recently published a case with vasospasm at the proximal segment of the circumflex artery after CB application in the LAA due to close relationship between the LAA and the the circumflex artery. After administration of intracoronary nitrate, vasospasm was rapidly relieved.

Atrioventricular block is a rare complication of CB ablation [117,118]. Atrioventricular node ischemia is hypothesized as the most probable mechanism because coronary angiography performed 30 min after atrioventricular block demonstrated a patent atrioventricular node artery originating from the right coronary artery. In the case of Fedida et al, a short distance between the RIPV ostium and aortic annulus at proximity of the AV node region showed by CT-scan reconstruction could explain mechanical AV bock during manipulation of the 28 mm cryoballoon catheter. This could be due to mechanical bump of the IAS and crux cordis, but also to left sided pathway of the AV-node. Data for comparison with CT-scan reconstruction are needed to confirm this hypothesis.

Conclusion

Cryoablation has become a commonly used tool for the management of AF due to require less experience than radiofrequency ablation without affecting effectivity. However, it can lead to some significant and even fatal acute complications. Although the ratio of these complications are rare, operators should know how to detect and manage the complications, quickly.