Esophageal Damage Protection During Pulmonary Vein Ablation. Pilot Study.
Esophageal Damage Protection During Pulmonary Vein Ablation. Pilot Study.
Catheter ablation of atrial fibrillation with electrical isolation of the pulmonary veins in
 the left atrium carries risk of esophagus thermal lesion. EnsoETM is a device . This study
 evaluates the benefit of using the EnsoETM, a device device for esophageal temperature
 adjustments, during catheter ablation of atrial fibrillation. Half of participants will
 undergo esophageal temperature adjustment during pulmonary vein catheter ablation, while the
 other half will undergo catheter ablation with no esophageal temperature adjustment.
1. THEORETICAL FRAMEWORK. APPROACH TO THE PROBLEM

 Background and justification

 Atrial fibrillation is the most common type of heart arrhythmia. Electrical isolation of the
 pulmonary veins in the left atrium with ablation is standard therapy in the invasive
 treatment of atrial fibrillation. One of the risks of this intervention is thermal lesion of
 the esophagus, since it is in contact with the posterior wall of the left atrium. The energy
 applied for electrical isolation via either radiofrequency or cryotherapy can cause thermal
 lesions due to proximity with the esophagus and the vagus nerve/parasympathetic nervous
 system of the upper digestive tract. The incidence is not well established and data in the
 existing scarce publications show a very wide range, from 3 to 60%, according to the
 definition and means of the study used. The most recent systematic studies show values around
 40-50%. The lesions observed vary in degree, from erythema or minor erosion to ulcers of the
 esophageal mucosa, including local hematomas, spasms, and esophageal/gastric motility
 disorders and even atrial-esophageal fistula, the extreme consequence of thermal esophageal
 lesion; the incidence of the latter is low (0.25%), but it has an elevated mortality. The
 best examination to diagnose and evaluate these lesions in all phases is upper digestive
 endoscopy or fibro esophagogastroscopy. Although it is routine in digestive services
 throughout the world, enabling the direct visualization and characterization of lesions, this
 technique is not performed systematically after ablation procedures, which explains the
 contradictory data in the literature.

 Likewise, the possible long-term consequences of minor lesions are unknown, which, in a large
 number of patients are totally asymptomatic. For this reason, it cannot be ignored that acute
 tissue damage, however minimal, could lead to future changes in the form of late onset
 chronic esophageal pathology. The incidence and magnitude of esophageal involvement has been
 directly related to the ablation technique and protocol. Most available studies have been
 carried out in centers with ablation protocols that are significantly more aggressive than
 those used in our care facility. For this reason, the investigators do not have reliable data
 regarding the size of the problem in our center, which could present some differential
 characteristics.

 To date, the prevention of these esophageal lesions has entailed: limits in the energy
 applied on the posterior wall of the left atrium (less power or shorter application time);
 monitoring of the luminal esophageal temperature during radio frequency or cryotherapy
 applications; stopping application early if certain temperatures considered risky were
 reached. However, the success of luminal esophageal temperature monitoring in preventing
 lesions varies widely, given that the temperature probes are very thin with respect to the
 total diameter of the esophagus, their position varies with respect to the cardiac tissue
 treated, and contact with the esophageal mucosa is inconstant. In fact, it has been reported
 that the temperature probes used for monitoring can contribute to increasing thermal lesions,
 given that their metal elements can boost direct heating/cooling of the tissue and make the
 lesion larger and last longer. In fact, the incidence of esophageal lesions is very similar,
 independent of the use of the temperature probe, or if it is a single or multi-sensor.
 Another controversial aspect of these temperature probes is that their use can lead to - at
 least potentially and in pursuit of safety - shorter, limited applications, which could cause
 incomplete non-transmural lesions and hamper the correct treatment of patients, thereby
 becoming a factor that increases the recurrence of atrial fibrillation. In addition, these
 probes should be deployed during the procedure so they are as close as possible to the
 application site (right or left veins depending on the time), which increases the procedure
 and fluoroscopy time, with consequent risks for both the patient and the medical team. All
 these limitations, together with significant economic cost overruns have meant that the use
 of this approach in our care facilities has been minimal and only for research purposes.

 Even if the possible long-term consequences of esophageal lesions are minimal, studying new
 strategies for esophageal protection that are easy to implement and do not affect the
 efficacy of ablation procedures is of great clinical and scientific interest. In this
 context, there is a plan to use the probes to regulate and maintain patient temperature in
 prolonged surgeries or critical units as a method of esophageal protection during ablation.
 Multiple clinical studies have demonstrated the efficacy and safety of these probes in
 different medical/surgical areas. In particular, they are indicated to minimize the
 neurological damage associated with heart attacks through the induction of therapeutic
 hypothermia. They are also indicated to reduce the temperature of patients with malignant
 hyperthermia, to prevent unexpected peri-operative hypothermia, and to reduce elevated
 intracranial pressure.

 The prevention of esophageal lesions via temperature control (local cooling of the esophagus
 when radiofrequency is used or heating when cryotherapy is used, thanks to various probe
 configurations) has been investigated with mathematical models, preclinical models, and in
 the clinical field in a preliminary way. Data are available that demonstrate its efficacy in
 this approach, although with limitations in the number of cases and the systems used. In most
 of these studies, prototypes of anterior probes were used, which are difficult to place and
 require changes in the work routine, which has made the expansion of devices using this
 approach more difficult up to now.

 The appearance of a new, easier-to-use device for esophageal temperature adjustments
 (EnsoETM, Attune Medical, Chicago, Illinois, USA) when managing patient temperature for a
 large variety of needs has facilitated the reintroduction of this therapeutic option.

 The EnsoETM, made by Attune Medical, received its CE mark in Europe in 2014, with an expanded
 indicated use of up to 120 hours in 2016 and a CE mark for its use with the Altrix system by
 Stryker® in 2017. (CE certificate attached.) The EnsoETM is used as part of treatment to
 obtain therapeutic hypothermia during the management of a heart attack. It is also used in
 the treatment of hyperthermia, the prevention of unexpected peri-operative hypothermia, and
 the reduction of elevated intracranial pressure.

 The device is situated in the esophagus like a standard orogastric sensor. A multi-channel
 cylindrical silicone tube connected to a closed water circuit allows the surrounding tissue
 to be warmed or cooled according to the need or desired temperature. This effect is achieved
 through the transfer of heat via conduction through the esophagus and by convection through
 the device. One must keep in mind that the posterior wall of the left atrium is in close
 contact with the esophagus and the modular effect of the temperature therefore also acts on
 the wall of the atrium.

 The EnsoETM is designed to use the high-blood-flow surroundings of the esophagus and achieve
 high heat-exchange performance. In addition, the EnsoETM has a distal end that reaches the
 stomach and allows it to be decompressed, avoiding distension of the esophagus, which ensures
 good contact between the device and the esophageal mucosa, thereby maximizing the transfer of
 heat between the device and the patient. The EnsoETM is composed of standard medical-grade
 silicone, and is generally similar in shape and size to gastric probes and other devices that
 are routinely situated in the esophagus (esophagogastroduodenoscopes, transesophageal
 echocardiogram probes, Ewald tubes, etc.). It is also smaller than other more aggressive
 devices (the EnsoETM measures approximately 1/3 the size of the Sengstaken-Blakemore tube
 used to treat esophageal varices).

 The preliminary data available show that the use of probes that regulate the esophageal
 temperature would allow the mucosa of thermal lesions to be protected, thereby reducing and
 preventing lesions on this level during the fibrillation ablation treatment. However, it is
 not known whether the modulation of esophageal temperature or contact with the atrial wall
 affect the efficacy of the actual lesions induced on the atrium and therefore on the success
 of the ablation procedure.

 Hypothesis

 General hypothesis:

 Esophageal protection probes allow the deleterious effects of pulmonary vein ablation to be
 counteracted on the wall of the esophagus.

 Secondary hypotheses:

 1. The incidence of esophageal lesions in our setting, in which a conservative approach is
 applied to the ablation of pulmonary veins, is low but not insignificant.

 2 The use of esophageal protection probes allows the incidence of esophageal lesions to be
 decreased.

 3 The use of esophageal protection probes does not alter the clinical result of the pulmonary
 vein ablation procedure.

 2. GENERAL AND SPECIFIC OBJECTIVES:

 Main objective:

 Assess the role of esophageal protection probes during pulmonary vein ablation procedures.

 Secondary objectives

 1. Assess the incidence of esophageal lesions in our setting.

 2. Assess if the use of a probe for esophageal protection reduces the incidence of
 esophageal lesions.

 3. Assess if the use of esophageal protection probes alters the clinical result of the
 pulmonary vein ablation procedure.

 3. METHODS:

 Study design

 The investigators propose a prospective pilot study to assess the incidence of esophageal
 lesions following a pulmonary vein ablation procedure in our care center in which a
 conservative approach is used to apply the energy. In addition, in a limited number of
 patients, the study aims to assess the effect of an esophageal protection probe on the
 occurrence of thermal lesions and the results of the ablation.

 The study protocol will be carried out under the directives of the Institutional Ethics
 Committee in the Hospital de la Santa Creu i Sant Pau.

 Patients referred for catheter ablation of atrial fibrillation (either cryoablation or
 radiofrequency ablation (1/1)) will be randomized to either receive or not (1/1) an
 esophageal temperature adjustment EnsoETM device, to evaluate its role for esophageal
 protection.

 Ablation procedure:

 All patients included in the study will be subject to an ablation procedure following the
 standard guidelines in our center with no modification, where the investigators carry out the
 procedures under general anesthesia. Instead of using a conventional orogastric probe, the
 patients in the probe-evaluation group will systematically use the probe protecting against
 thermal lesions with no other variation.

 Use of the EnsoETM esophageal probe:

 Placement of the EnsoETM will follow standard recommendations according to the instructions,
 which are similar to recommendations for inserting a transesophageal echocardiogram probe
 (routine procedure in some centers to guide the transseptal puncture) or the orogastric
 aspiration probe during surgical procedures. The EnsoETM will be connected to the appropriate
 console (Meditherm, Blanketrol, or Altrix). The configuration will be adjusted according to
 the ablation technique (cryoablation or radiofrequency ablation). If radio frequency is used,
 before beginning the ablation of the left posterior wall, the heat exchanger connected to the
 EnsoETM will be adjusted to a cooling mode (5°C), with ablation beginning at least 1 min
 after the circulating water reaches a temperature of 5°C. If cryoablation is used, before
 beginning the application, the heat exchanger connected to the EnsoETM will be adjusted to a
 heating mode (45°C), with cryoablation beginning at least 1 min after the circulating water
 reaches a temperature of 45°C.

 Esophagogastroscopy:

 An esophagogastroscopy will be done on all patients, a day later after the catheter ablation,
 following the usual guidelines of the Gastroenterology Service. Local anesthesia will be used
 with superficial sedation following a 12-hour fast. Basal anticoagulant treatment will be
 maintained without any precise antibiotic prophylaxis. The gastroenterologist will provide a
 report on the procedure, classifying the findings in agreement with Zargar's criteria,
 assessing them qualitatively as light, moderate, or serious. Special focus will be placed on
 the anterior zone of the esophagus at the level of the left atrium, which is where the energy
 (radio frequency or cryoablation) is applied during the procedure.

 Monitoring:

 The usual treatment and controls will both be followed unless the gastroenterologist changes
 the recommendations due to the endoscopy findings. Follow-up visits will be made at 1, 3, 6,
 and 12 after the procedure to assess the presence of cardiological and gastrointestinal
 symptoms.

 Study population. The population will consist of patients subjected to their first pulmonary
 vein ablation procedure in the left atrium to treat atrial fibrillation.

 Definition of variables

 1. Demographic variables: age, gender, weight, and height

 2. Clinical variables: cardiovascular risk factors, atrial fibrillation factors (alcohol,
 sleep apnea, obesity, …), previous atrial fibrillation arrhythmia, history of
 gastrointestinal pathology (reflux, esophagitis, gastritis, H Pylori infection, …),
 history of cardiological pathology (basic structural cardiomyopathy: ischemic, valvular,
 hypertensive, diameter and volume of the left atrium, ejection fraction, …).

 3. Family history of early atrial fibrillation (<40 years).

 4. Previous pharmacological treatment: especially anti-arrhythmia, anticoagulant and
 anti-secretion or gastric protector (indication, dosage, time, and administration
 route).

 5. Effectiveness of pulmonary vein isolation.

 6. Radio-physical variables of the ablation (number of applications, duration of
 application, maximum or minimum temperature, power (W), ablation index per region
 (anterior, posterior).

 7. Duration of procedure: fluoroscopy, catheterization in the left atrium.

 8. Clinical or electrical efficacy. Recurrence of arrhythmia (palpitations, ECG, or Holter
 monitor)

 9. Esophageal lesions per Zargar endoscopy classification

 10. Adverse clinical events

 -  Dysphagia: the patient relates difficulty swallowing for more than 24 hours after
 the use of the device; diagnosed via modified barium swallow study,
 videofluoroscopic swallow study, or related directly by the patient.

 -  Odynophagia: the patient relates pain when swallowing for more than 24 hours after
 the use of the device; diagnosed via the patient's subjective feelings.

 -  Esophageal lesion not due to ablation: evidence of traumatic lesions or other
 esophageal lesions diagnosed by a gastroenterologist.

 Sample size and strength Given that the incidence of esophageal lesions in recent studies was
 estimated to be 40-50%, and a reduction of 20% was calculated in the appearance of lesions
 with the use of the probe compared to control conditions (without modification of the
 esophageal temperature), with a power of 80% and an alpha error of 0.05. A necessary sample
 size of 28 patients was specified for each of the techniques used (radio frequency and
 cryoablation).

 Method. Sources of information The information gathered throughout the study will be
 collected in an encrypted database designed and built specifically for the study. Atrial
 fibrillation ablation is a common technique in our center, with more than 100 procedures
 performed annually.

 Data management and analysis Statistical analysis will be carried out with the statistics
 program SPSS, version 25.0 (IBM Corporation). The continuous variables will be expressed as
 an average and standard variation or medians and interquartile range, depending on whether
 the distribution is statistically different from a normal distribution. Qualitative variables
 will be presented as numbers and percentages. To study the relationship between qualitative
 variables, the chi-squared test (X2) will be used; Fisher's exact test will be used for
 variables that do not follow a normal distribution. The quantitative variables will be
 compared using Student's t-test if two groups are compared; analysis of variance (ANOVA) will
 be used for more than two groups. If the quantitative variables do not follow a normal
 distribution, non-parametric tests will be used: the Mann-Whitney U-test for two groups or
 the Kruskal-Wallis test for more than two groups. The correlation between the variables will
 be studied using the Pearson or Spearman tests, depending on whether the distribution is
 normal or not. Differences with a p-value of 0.05 or higher will be considered significant.

 The only significant change with respect to usual practice is that an upper digestive
 endoscopy will be performed on all patients included. However, this activity is not expected
 to lead to a change in the length of admission or in the treatment administered. Although it
 is a new element, the introduction of the probe is not expected to lead to significant
 changes, since all patients are intubated in the usual way and, based on need, a nasogastric
 probe of reduced size will simultaneously be introduced in the same way as the study probe to
 avoid gastric distension.

 5. WORK PLAN (tasks, benchmarks and timeline of the study): Month 1 Development of the
 protocol. Editing of study materials. Design of the database. Researcher meeting to resolve
 doubts. Preparation of logistical aspects to begin the study.

 Month 2 Presentation to the Research Ethics Committee. Months 3-12 Beginning of the study.
 Dissemination of the services involved (cardiology, anesthesiology, gastroenterology). Data
 collection and entry.

 Months 12-18 Data cleaning and analysis. Researcher meeting to resolve doubts and close the
 study. Drafting of the final report. Drafting of a manuscript to publish the results.

 Duration: 18 months
Inclusion Criteria:

 -  Adult patients (older than 18 years of age) subjected to their first pulmonary vein
 isolation procedure with a catheter or balloon.

 Exclusion Criteria:

 -  Patients with known esophageal deformity or evidence of esophageal trauma (for
 example, history of esophagectomy, previous swallowing disorders, achalasia, etc.)

 -  Patients with known ingestion of acidic or caustic poison in the previous 24 hours.

 -  Patients weighing less than 40 kg.

 -  Patients who know they are pregnant.

 -  Patients under chronic daily treatment with an proton pump inhibitor or any
 gastrointestinal acid suppressant.

 -  Patients under 18 years of age.

 -  Patients who have not signed the informed consent form.