**2. Trials for cryoablation**

The first-generation cryoballoon was evaluated in the cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation [First Results of the North American Arctic Front (STOP-AF) Pivotal Trial] [4], which demonstrated an acute isolation rate of 97.6% and a relatively low rate of complications. However, long-term success rates varied from 62% with a single procedure and 77% after multiple procedures. The limitation of the first-generation balloon was a narrow zone of cooling around the equator of the balloon, the second-generation balloon has an extended cooling from the equator of the balloon to the tip, with more uniform lesions independent of balloon positioning.

A meta-analysis of 15 studies showed a success rate of 82% at 1 year in patients with paroxysmal AF and 70% in persistent AF [5]. Another meta-analysis comparing cryoablation versus radiofrequency ablation for paroxysmal AF (PAF) analyzed 16 studies including 7194 patients (2863 with cryo and 4332 with RF). There was no statistical difference between the two strategies (p = 0.159) as well as procedure-related adverse events, but procedure time was shorter with cryoablation [6].

The most impacting trial comparing these two energy sources was the FIRE and ICE Trial, with results presented in 2016. The trial compared RF ablation using a 3D mapping system with cryoablation guided by fluoroscopy in patients with paroxysmal atrial fibrillation and prior antiarrhythmic drug failure. A total of 762 patients were randomized and they found that procedure time was shorter with cryoablation but using more fluoroscopy when compared to radiofrequency. The trial conclusion was that cryoablation is non-inferior to radiofrequency when performing pulmonary vein isolation in paroxysmal atrial fibrillation in terms of efficacy and safety [7].

#### **Figure 1.**

 *Results showing the superiority of cryoablation in atrial fibrillation compared to the antiarrhythmic drug as first-line therapy. (Adapted from Cryoballoon ablation vs. antiarrhythmic drugs: first-line therapy for patients with paroxysmal atrial fibrillation. For the CRYO-First Investigators. Europace (2021) 23, 1033–1041. doi:10.1093/ europace/euab029).* 

#### **Figure 2.**

 *Graphic showing percentual or phrenic nerve injury recovered after 12 months, and full recovery in 2 years. (Adapted from the Phrenic Nerve Injury During Cryoballoon-Based Pulmonary Vein Isolation: Results of the Worldwide YETI Registry. Circ Arrhythm Electrophysiol. 2022;15:e010516).* 

 In 2021, Cryo-FIRST Trial [ 8 ] randomized 218 patients with paroxysmal atrial fibrillation to be treated with cryoablation as first-line therapy compared to antiarrhythmic drugs (AAD). The results were freedom from AAD after 12 months in 82.2% of subjects in the cryoballoon arm against 67.6% in the AAD arm, a 52% benefit with statistical significance (HR = 0.48, P = 0.013) ( **Figure 1** ). The conclusion was that the positive results demonstrate cryoablation being superior to AAD therapy in reducing AF recurrence in the first-line patient population.

Recently, the phrenic nerve injury during cryoballoon-based pulmonary vein isolation: Results of the worldwide YETI registry [9], a retrospective, multicenter, and multinational registry evaluated the incidence, characteristics, prognostic factors for phrenic nerve (PN) recovery and follow-up data during cryoablation. A total of 17356 patients underwent pulmonary vein isolation in 33 centers from 10 countries. Patients experiencing phrenic nerve injury was 4.2% (731), the mean time to occur was 127.7 ± 50.4 seconds, and the mean temperature at the time of injury was −49±8°C [9]. Recovery at 12 months was found in 97.0% (**Figure 2**), with only 0.06% showing symptomatic and permanent injury.

## **3. How to preform tips and tricks**

Patient preparation must be as usual, with a 12-lead electrocardiogram monitoring system, vital parameters, such as heart rate, blood pressure, and oxygen saturation throughout the entire procedure, and external pads prepared, or adhesive pads put on the patient´s chest for electrical cardioversion as needed. If the procedure to be done is for supraventricular tachycardia (focal), the type of sedation can be the physician´s choice, cryoablation with a balloon can be easily performed with deep conscious sedation but, if general anesthesia is chosen, the anesthesiologist must know that curarization/neuromuscular blockade must be reversed when moving to right pulmonary vein ablation, in order not to interfere with phrenic nerve pacing/capture using a decapolar or quadripolar catheter.

For focal procedures, usually, three venous femoral access are done, one for decapolar catheter inside the coronary sinus, another for a quadripolar catheter positioned at the atrioventricular node level, capturing atrial, HIS bundle and ventricular electrograms, and the last one to be used with the cryoablation catheter, which is a 7F catheter 4 mm tipped and deflectable connected to a console and the electrophysiology (EP) system stimulator.

Ablation with a focal catheter can be performed transiently or definitely, the first one is a limited time and temperature to ensure that the chosen area isn´t going to cause any kind of damage, such as atrioventricular block (−30°C for 40–60 seconds), this technique is called cryomapping and can be divided into efficacy cryomapping when the exact site responsible for abolishing the arrhythmia is determined, or safety cryomapping when you search for unintended consequences during ablation. Definitive lesions occur at −50° to −75°C during 2–4 minutes, with the ice ball at the tip of the catheter producing good stability of the catheter. With cryomapping and good catheter adhesion, the risk of atrioventricular block for septal accessory pathways can be eliminated. The acute procedural success rate is around 84%, which is comparable to RF ablation, however, there is a high recurrence rate of approximately 29% [10].

When performing pulmonary vein isolation with cryoballoon only two venous femoral punctions can be done, one to be used with a pacing catheter (either a decapolar or quadripolar), and the other for transeptal access followed by the exchange to cryoballoon sheath. A manifold must be prepared with two connections, one for contrast injection and the other one with 1000 mL of heparinized saline in a compressed bag; another 1000 mL of heparinized saline must be prepared, with or without a second compressed bag, to be connected to the steerable sheath of the cryoballoon.

Transeptal puncture with fixed sheath (FS) must be performed according to physician's practice, either using only fluoroscopy, or complemented by transesophageal echocardiogram (TEE) or intracardiac echocardiogram (ICE); lower transeptal puncture helps a better approach and occlusion of the right inferior pulmonary vein (RIPV), usually the most chalenge vein.

After transeptal access with FS, if one wishes to make left atrial and pulmonary veins angiography, the best way to do it is to maintain the FS at left vein ostium and, during fast ventricular pacing (400 ms), rapidly injecting contrast and recording fluoroscopy, since less amount of contrast will be needed with the first sheath. The next step is exchanging sheaths from FS to the 15F deflectable sheath (DS), which is done by preferably keeping a wire inside the left superior pulmonary vein (LSPV), while removing FS before introducing the DS, deepening the site of puncture with a small blade is needed in order to best pass through it with the sheath, which has a more robust and harder tip. When the sheath is at the transeptal orifice, viewing in left anterior oblique (LAO) projection (30° or 40°), a deflection can be done pointing toward the LSPV so the wire doesn´t come off the left side, while advancing the sheath. With the sheath inside the vein, the wire and dilator can both be retracted, the sheath flushed with heparinized saline solution, and the saline solution connected with continuous slow flushing.

Preparing the cryoballon is crucial to avoid bubbles inside the plastic cap at the tip of the catheter, two fixed sizes are available but the 28 mm is the most used. There are two "dry" connections that must be done before any flushing, one for balloon inflation and deflation with nitric oxide gas (coaxial umbilical), and a second one to capture electrical signals from the cryoConsole, such as temperature, and to energize the catheter (electrical umbilical) this latter catheter has a box in-between that decodify possible catheter or balloon errors to stop ablation and prevent injuries. The manifold and Y-shape device are connected directly to the balloon and flushed; the Y connection is flushed backward then closed and flushed forwards until the solution passes through the balloon tip. In sequence, the tip of the cryoballoon is submerged into a saline solution and its plastic cap is moved in a back-and-forth manner to completely remove air.

The last step before passing the balloon is introducing the circular multipolar diagnostic catheter (called achieve) through the Y connection until the very tip of the system, then the plastic cap is necessarily used to open the DS valve permitting the balloon to get off the sheath.

Common pulmonary vein isolation suggested sequence is LSPV, left inferior pulmonary vein (LIPV), RIPV, and right superior pulmonary vein (RSPV), because the right side is where PN injury can occur, RIPV has a greater distance to PN, pulmonary vein isolation typically precedes PN injury in RSPV, and if RIPV ablation results into PN palsy, at least three veins were already isolated. In pulmonary vein isolation, cryomapping is not usually applied and freezing until, at least, −40°C is the goal.

Ablation time began with a 4-minute freeze using the first-generation balloon in STOP-AF Trial, and in the FIRE and ICE Trial, a 4-minute bonus freeze was applied; for the second-generation balloon, a 3-minute initial ablation time has been suggested. Investigators reported an 80% success rate with 3 minutes of freezing in 143 patients in a single-arm, non-controlled study [11].

During cryoablation some parameters must be observed to ensure good vein isolation—visual fluoroscopy of vein occlusion with the balloon plus contrast injection without leaks to the left atrium (**Figure 3**); once you find this position the operator must maintain it until, at least 30–35 seconds of freezing, enough time to secure the

*Cryoablation: From Techniques to Tips and Tricks DOI: http://dx.doi.org/10.5772/intechopen.105861*

#### **Figure 3.**

*Fluoroscopy showing cryoballoon catheter occluding left inferior pulmonary, and contrast is filling the vein without leaking to the left atrium. (From the authors).*

system in a stable position. A good relationship between freezing time and temperature drop, which best occurs in a one-to-one fashion (e.g., −30°C at 30 seconds of freezing), graphically can be seen as a straight-line drop. Vein isolation in less than 30 seconds or 60 seconds of freezing time helps the physician to decide whether second freeze is to be performed or not, we usually take as practice one full 3 minutes ablation when isolation occurs in less or at 30 seconds, and a 2 or 3 minutes bonus freeze if isolate at or after 60 seconds.

Another parameter indicating good contact and occlusion within the vein is temperature reaching −40°C between 30 to 40 seconds at a maximum of −60°C to halt freezing. A steep and rapid drop in temperature (<−40°C within 30 seconds) and nadir of the temperature of −55°C to −65°C are potential indicators that the balloon is deep inside the vein and not at an antral position, and freezing should be terminated.

There are some techniques described for ablation—the direct approach, the hockey stick approach, and alone or combined with the pull-down maneuver. If the catheter direct occludes the vein ostium, it is called the direct approach (**Figure 4**) and is usually good for LSPV and RSPV.

The so-called hockey stick alone or in combination with a pulldown maneuver is commonly used in LIPV and RIPV. A careful PV angiogram can be used, and the most caudal branch of the inferior PV should be wired with the mapping catheter

#### **Figure 4.**

*Fluoroscopy showing cryoballoon catheter in a direct approach, only pushing at vein antrum, and the vein in the example is a left superior pulmonary vein. (From the authors).*

#### **Figure 5.**

*Fluoroscopy showing the circular mapping catheter (achieve) in an inferior branch of the left inferior vein, and balloon and sheath in a "hockey stick" approach for better occlusion.*

#### **Figure 6.**

*Positioning polygraph electrodes (12-lead electrocardiogram) with the right arm placed 5 cm above the xiphoid, and left-arm surface ECG electrode placed 16 cm from the xiphoid along the costal margin to obtain the CMAP.*

(achieve). After CB inflation, the sheath should be curved down and pushed up with the bending point at the LA roof. The CB should then be advanced to improve contact with the inferior aspect of the inferior PV, resulting in a hockey stick figure on fluoroscopy (**Figure 5**). If an inferior gap remains, we combine the hockey stick with a pulldown maneuver (CB and sheath) after 60 seconds. At this point in time, the CB is frozen to the superior aspect of the inferior PV and a typical response consists of an additional CB temperature drop and isolation in the next 20 seconds.

Before freezing right veins, PN should be paced at twice the capture threshold using a deflectable catheter, a good place for pacing is at the junction of the superior vena cava (SVC) and the right subclavian vein. Monitoring PN function can be done by direct manual palpation of the patient´s thorax or by monitoring de diaphragmatic compound motor action potential (CMAP) since the latter one alters first before PN palsy.

The CMAP is implemented using a modified ECG lead I technique. The right-arm surface ECG electrode is placed 5 cm above the xiphoid, and the left-arm surface ECG electrode is placed 16 cm from the xiphoid along the costal margin (**Figure 6**). Freezing is stopped in the event of a 30% reduction in the maximal diaphragmatic CMAP amplitude or any perceived reduction in the strength of diaphragmatic contraction.
