Journal of Interventional Cardiac Electrophysiology (2020) 59:347–355 https://doi.org/10.1007/s10840-019-00661-5 Esophageal cooling for protection during left atrial ablation: a systematic review and meta-analysis Lisa WM Leung 1 & Mark M Gallagher 1 & Pasquale Santangeli 2 & Cory Tschabrunn 2 & Jose M Guerra 3 & Bieito Campos 3 & Jamal Hayat 4 & Folefac Atem 5 & Steven Mickelsen 6 & Erik Kulstad 7 Received: 13 September 2019 / Accepted: 31 October 2019 / Published online: 22 November 2019 # The Author(s) 2019 Abstract Purpose Thermal damage to the esophagus is a risk from radiofrequency (RF) ablation of the left atrium for the treatment of atrial fibrillation (AF). The most extreme type of thermal injury results in atrio-esophageal fistula (AEF) and a correspondingly high mortality rate. Various strategies for reducing esophageal injury have been developed, including power reduction, esophageal deviation, and esophageal cooling. One method of esophageal cooling involves the direct instillation of cold water or saline into the esophagus during RF ablation. Although this method provides limited heat-extraction capacity, studies of it have suggested potential benefit. We sought to perform a meta-analysis of published studies evaluating the use of esophageal cooling via direct liquid instillation for the reduction of thermal injury during RF ablation. Methods We searched PubMed for studies that used esophageal cooling to protect the esophagus from thermal injury during RF ablation. We then performed a meta-analysis using a random effects model to calculate estimated effect size with 95% confidence intervals, with an outcome of esophageal lesions stratified by severity, as determined by post-procedure endoscopy. Results A total of 9 studies were identified and reviewed. After excluding preclinical and mathematical model studies, 3 were included in the meta-analysis, totaling 494 patients. Esophageal cooling showed a tendency to shift lesion severity downward, such that total lesions did not show a statistically significant change (OR 0.6, 95% CI 0.15 to 2.38). For high-grade lesions, a significant OR of 0.39 (95% CI 0.17 to 0.89) in favor of esophageal cooling was found, suggesting that esophageal cooling, even with a low-capacity thermal extraction technique, reduces the severity of lesions resulting from RF ablation. * Erik Kulstad Steven Mickelsen Erik.Kulstad@UTSouthwestern.edu mickelsenone@gmail.com Lisa WM Leung 1 Lisa.Leung@stgeorges.nhs.uk Department of Cardiology, St George’s University Hospitals NHS Foundation Trust, St. George’s, University of London, Cranmer Mark M Gallagher Terrace, Tooting, London SW17 0RE, UK Mark.Gallagher@stgeorges.nhs.uk 2 Perelman School of Medicine, University of Pennsylvania, 3400 Pasquale Santangeli Civic Center Blvd, PA 19104 Philadelphia, United States pasquale.santangeli@uphs.upenn.edu 3 Hospital de la Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, CIBERCV, Carrer de Sant Quintí, 89, Cory Tschabrunn 08041 Barcelona, Spain cory.tschabrunn@uphs.upenn.edu 4 Department of Gastroenterology, St George’s University Hospitals Jose M Guerra NHS Foundation Trust, St. George’s, University of London, Cranmer jguerra@secardiologia.es Terrace, Tooting, London SW17 0RE, UK 5 Bieito Campos Department of Neurology and Neurotherapeutics, UT Southwestern bcamposg@santpau.cat Medical Center, 5323 Harry Hines Blvd, 75390 Dallas, TX, United States Jamal Hayat 6 Department of Internal Medicine, University of Iowa Carver College jamal.Hayat@stgeorges.nhs.uk of Medicine, 200 Hawkins Drive, 52242 Iowa City, United States 7 Folefac Atem Department of Emergency Medicine, UT Southwestern Medical Folefac.Atem@UTSouthwestern.edu Center, 5323 Harry Hines Blvd, 75390 Dallas, TX, United States 348 J Interv Card Electrophysiol (2020) 59:347–355 Conclusions Esophageal cooling reduces the severity of the lesions that may result from RF ablation, even when relatively low heat extraction methods are used, such as the direct instillation of small volumes of cold liquid. Further investigation of this approach is warranted, particularly with higher heat extraction capacity techniques. Keywords Atrial fibrillation . Radiofrequency ablation . Esophageal injury . Esophageal cooling . Atrio-esophageal fistula 1 Introduction 2.2 Eligibility criteria Thermal damage to the esophagus is a risk from radiofre- We excluded preclinical studies, bench-top, agar phantom, quency (RF) ablation or cryoablation of the left atrium and mathematical model studies, and studies that did not in- for the treatment of atrial fibrillation (AF) [1–3]. The clude formal endoscopy as an outcome measure. most extreme type of thermal injury is an atrio- esophageal fistula (AEF), with a mortality rate of 80% 2.3 Data collection or more [4–8]. Various strategies for protecting the esophagus during RF ablation or reducing the severity The primary data of interest were esophageal lesions identi- of injury have been developed, including power reduc- fied endoscopically after RF ablation. Because we anticipated tion, avoidance of greater contact force, temperature inconsistency in the categorization of lesion severity, we monitoring, esophageal deviation, and esophageal aimed to simplify all lesion severity measurement into severe cooling, with varying degrees of success [9–11]. lesions characterized by the presence of ulceration and mild to Esophageal cooling for the purpose of protecting the moderate lesions encompassing all other abnormalities. esophagus during RF ablation has been investigated in Studies identified were then assessed for quality using the multiple studies [12–20]. The techniques used have in- Newcastle Ottawa Scale, which evaluates three quality param- cluded the insertion of expandable balloon devices or eters (selection, comparability, and outcome) divided across cooling sacs that circulate water, and the direct instilla- eight specific items. Each item on the scale is scored with up tion of ice-cold water or saline into the esophagus. The to one point, except for comparability, which can be adapted study designs have included animal models and mathe- to the specific topic of interest to score up to two points, such matical models as well as human clinical studies. Most of that the maximum for each study is 9, with studies having less the human clinical studies have used direct instillation of than 5 points being identified as representing a high risk of ice cold water or saline as the cooling method, and for bias [21]. this reason, we performed a meta-analysis of the data obtained in these studies to examine their range of effect sizes and estimate the potential efficacy of esophageal 2.4 Statistical analysis cooling for protection during RF ablation. For this meta-analysis, we input the study data into Review Manager 5.3, and we present the results graphically. SAS ver- sion 9.4 (SAS Institute Inc., Cary, NC, USA) was used for 2 Methods additional analyses. The Cochran–Mantel–Haenszel (CMH) method was employed to test the null hypothesis that the re- 2.1 Data sources and search strategy sponse rate is the same for the two arms (control versus treat- ment), after adjusting for possible differences in study re- Using PubMed, we searched the literature dated from sponse rates. Furthermore, we fitted a random effect model 1985 (prior to the earliest reports of endocardial ablation using SAS procedures GLIMMIX and NLMIXED by treating to treat atrial fibrillation) to June 2019 for studies pub- the studies as a random effect. Because lesion grades are often lished on esophageal cooling during cardiac ablation. We considered to be dichotomized into those that are likely to conducted a broad search with the following Boolean progress to AEF and those that are not, we initially analyzed structure: (esophag* OR oesophag*) AND cooling AND the data as a binary outcome (high-grade lesions concerning (ablation OR fibrillation). We did not restrict the search for progression versus low grade lesions likely to heal spon- to studies published in English only. Details of the sys- taneously). Then, to further estimate effect size, we used an tematic review were submitted for registration in ordinal logistic random intercept model, taking into account PROSPERO on June 21, 2019, with further details de- the ordered nature of lesion grading (low to high, scribing the statistical plan added on September 11, 2019. numerically). J Interv Card Electrophysiol (2020) 59:347–355 349 55.5 +/− 9.1% 66.8 +/− 6.8% 3 Results 64 +/− 6.6% Ejection fraction We identified 9 studies using the above criteria. Five of these studies were excluded for being non-clinical. Berjano et al. utilized a finite element model in three dimensions to investi- gate the effects of a cooled intraesophageal balloon [12]. 26.3% CHF N/A N/A Lequerica et al. performed studies using an agar phantom- based model that was built to provide temperature readings at points between the esophageal lumen and the myocardium Diabetes 18.7% [13, 14]. Arruda et al. studied a custom developed system 4.1% N/A utilizing temperature-controlled saline or water in an in vitro lamb heart and esophagus preparation, followed by an in vivo model with six dogs [15]. Scanavacca et al. presented a study 68.4% 14.8% HTN N/A of the use of a saline filled esophageal balloon to attempt esophageal protection in a dog model [17]. A clinical study of 8 patients by Tsuchiya et al. was excluded for not using 30.5 +/− 5.1 endoscopy to determine the presence of lesions after RF abla- 24 +/− 2.0 tion [16]. BMI N/A The remaining 3 studies included a total of 494 patients. Details of these studies and the characteristics of the patients are shown in Tables 1, 2, 3.Because the manner of grading (% paroxysmal) lesions varied among the studies, we incorporated the scales AF subtype used in the three studies into a common stratification (Grades I, II, III, and IV). 40.8% 57.2% 32.0% John et al. studied 76 patients, half of which were actively cooled by injecting a 20 mL bolus of ice-cold saline via orogastric tube into the upper esophagus if/when the luminal (% male) esophageal temperature (LET) increased by 0.5 °C above Gender 63.2% 40.0% 72.6% baseline [20]. The authors found that this method of esopha- Characteristics of included studies, population demographics, and comorbidities geal cooling did not decrease the overall incidence of thermal lesions, but noted a trend toward fewer severe lesions with 63.3 +/− 7.9 63.5 +/− 10 Patient age cooling (Fig 1). The authors graded lesions as follows: grade 63 +/− 8.7 0, no esophageal lesion; grade 1, mucosal damage <1 cm width; grade 2, mucosal damage 1–3 cm width; grade 3, mu- cosal damage >3 cm width or visualization of deeper layer; and grade 4, bleeding ulcer or with overlying clot. Assessment Number of of the study quality resulted in a score of 8 using the patients Newcastle Ottawa Scale. 100 318 76 Kuwahara et al. studied 100 patients using very small vol- umes (5 mL) of ice water as the coolant for half of them. This Prospective observational Prospective observational volume was injected prior to RF energy delivery as well as subsequently if/when the LET reached 42 °C [18]. The au- Randomized control thors found that this approach reduced the severity of esoph- ageal lesions, but did not reduce the incidence: lesions oc- curred in 20% of the treatment group and 22% of the controls, Design with 3 moderate and 7 mild in the cooled group and 3 severe, 1 moderate, and 7 mild in the control group (Fig 2). The authors graded the severity of the lesions as mild, moderate, or severe, according to their extent and color. Assessment of the study Kuwahara et al. quality resulted in a score of 8 using the Newcastle Ottawa Sohara et al. John et al. Scale. Table 1 Sohara et al. studied 318 consecutive patients divided into Study three groups, one receiving only temperature monitoring 350 Table 2 Ablation techniques and characteristics for each included study Study Ablation technology Power Mapping technology Ablation type Average Mean RF time Anesthesia Endoscopy timing Contact per lesion Force (seconds) John et al. RF open-irrigation, 3.5-mm-tip, 24–28 W CARTO mapping system Bilateral antral PVI, creation of 10 g 12.3 +/− 5.3 General Within 24 h of the 8-Fr, force-sensing catheter and Pentaray NAV a left atrial roof and floor line, procedure (SmartTouch) multipolar mapping and ablation across the mitral catheter isthmus Kuwahara et al. 3.5 mm irrigated-tip ablation 25–30 W CARTO system Circumferential PVI with focal ablation, N/A N/A Conscious sedation Within 24 h of the catheter (Thermocool, Biosense and creation of left atrial roof or procedure Webster, Inc.) mitral isthmus lines with posterior wall isolation in non-paroxysmal AF Sohara et al. 12F radiofrequency hot balloon N/A CARTO system Balloon-based box isolation N/A N/A General Within 3 days of the catheter (Hayama Arrhythmia procedure Institute, Kanagawa, Japan) Table 3 Characteristics of temperature monitoring and esophageal cooling utilized in each included study Study Temperature sensor type Temperature sensor characteristics Gastric tube type Coolant Cooling threshold Follow-up duration John et al. 18-Fr esophageal temperature Tube diameter 6 mm, cuff 18-Fr orogastric tube 20 mL ice-cold 0.5 °C increase in N/A probe (400 series M1024215, diameter 8.8 mm, single (nasogastric sump saline temperature from GE Healthcare, Chicago, IL) thermistor inside of the tube 0046180, Bard, baseline cuff at the distal tip Inc., Covington, GA) Kuwahara et al. A multi-thermocouple temperature Three thermocouples; one Unspecified gastric tube 5 mL ice-water 42 °C temperature Up to probe (Sensitherm, St Jude of which was placed at the (0 °C) peak 8 weeks Medical) same level of the esophagus as the site of RF energy delivery on the LA posterior wall Sohara et al. Thermocouple thermometer Thermal sensor of a deflectable, Unspecified gastric tube 10–20 mL ionized contrast 43 °C temperature >10 months minimum, (Delta Ohm, Caselle 4-mm tip ablation catheter coated with xylocaine medium (Gastrografin) or peak (group B) or mean 3.6 years di Selvazzano, PD, Italy) jelly nonionized low osmotic 39 °C temperature contrast medium (iopamidol) peak (group C) diluted 1:2 with physiologic saline refrigerated to about 10 °C J Interv Card Electrophysiol (2020) 59:347–355 J Interv Card Electrophysiol (2020) 59:347–355 351 Fig. 1 Results from John et al. Patients in the treatment group were actively cooled by injecting a 20 mL bolus of ice-cold saline via orogastric tube into the upper esophagus if/when the LET in- creased by 0.5 °C above baseline. Grade III and grade IV lesions are shown separately without cooling, the second receiving temperature monitoring The studies by Kuwahara et al. and John et al. show a clear with cooling when the LET exceeded 43 °C, and the third shift from high-grade to lower-grade lesions between the con- receiving temperature monitoring with cooling when the LET trol and treatment arms [18, 20]. In contrast, the data from exceeded 39 °C. These authors used cooled saline mixed with Sohara et al. show a general reduction in lesions of all grades Gastrografin or iopamidol as the coolant. The total volumes [19]. injected were slightly higher than those used by John et al. and The forest plot comparing the outcome of all lesions Kuwahara et al. but were still limited (10–20 mL in repeated (grades I, II, III, and IV) as events between control and injected aliquots with a temperature of approximately 10 treatment arms is shown in Fig 4. Although fewer le- °C).[19] The percentage of patients free from any ulceration sions occurred in the treatment arms of the Sohara et al. or erosion in each group was found to be 63.6%, 87.5%, and and Kuwahara et al. studies, in meta-analysis this de- 95.2%, respectively (Fig 3). The authors classified the lesions crease did not reach statistical significance (OR 0.6, as normal (score 1), erosion (patchy mucosal ulceration: score 95% CI 0.15 to 2.38). 2), mild ulcer (necrosis less than 3 mm in diameter with red The slight increase in low-grade lesions seen in the John spot: score 3), severe ulcer (necrosis more than 3 mm in diam- et al. and Kuwahara et al. studies is shown in the forest plot in eter with red spot and/or with a hemorrhagic appearance, often Fig 5, with an OR of 1.0 (95% CI 0.26 to 3.93). The number of with fibrinoid material: score 4). Assessment of the study qual- low-grade lesions is not significantly impacted with this ity resulted in a score of 9 using the Newcastle Ottawa Scale. treatment. Fig. 2 Results from Kuwahara et al. Patients in the treatment group were actively cooled by injecting 5 mL of ice water prior to RF energy delivery and subsequently when the LET reached 42 °C. The Grade III/IV lesion category represents all le- sions qualitatively graded as “se- vere,” with mild lesions in Grade I and moderate lesions in Grade II 352 J Interv Card Electrophysiol (2020) 59:347–355 Fig. 3 Results from Sohara et al. Patients in group A received only LET monitoring without cooling of the esophagus. Patients in groups B and C received LET monitoring with esophageal cooling when the LET exceeded 43 °C and 39 °C, respectively. Cooling was by infusion of cooled saline mixed with Gastrografin. The Grade III/IV lesion category represents all le- sions graded as ulcers (scored as 3 or 4 by Sohara et al.) Evaluating the occurrence of high-grade lesions (grade III point estimate of a −23% reduction in lesion grade, with 95% and IV) results in the forest plot shown in Fig 6, demonstrating CI ranging from −85% to +38%. a significant OR of 0.39 (95% CI 0.17 to 0.89) in favor of the treatment arm. Separately, using the CMH method, we obtain- ed a significant p value of 0.016 indicating that the association 4 Discussion between treatment and lesion grade remains strong. Furthermore, in a binary logistic regression model, an OR of Esophageal injury from RF ablation remains a feared compli- 0.46 (95% CI 0.28 to 0.75) was found. cation in the treatment of atrial fibrillation, and a variety of The I2 statistic, which describes the percentage of total techniques have been developed to reduce this risk. variation across studies that is due to heterogeneity rather than Esophageal cooling has shown promise in a number of stud- chance, is shown in each of Figs. 4, 5, and 6. For the analysis ies, with such cooling being brought about by the instillation using an outcome of severe lesions (Fig. 6), the I2 = 0%, which of cold water or saline directly into the esophagus via indicates no observed heterogeneity. Increasing heterogeneity orogastric tube. Even with the relatively high heat capacity of effect is seen (shown in the forest plots) when looking at the of water, the amount of thermal energy that can actually be outcome of all lesions, and low-grade lesions, in Figs. 4 and 5, absorbed by this method is limited by the low total volumes of respectively. liquid instilled. Nevertheless, our meta-analysis of three stud- Finally, using an ordinal logistic random intercept model ies that used this approach suggests that cooling in this manner rather than dichotomized outcome, we used GLIMMIX and offers a clinically significant protective effect from severe le- NLMIXED in SAS to obtain an additional estimate of effect sions, and provides a 61% reduction in high-grade lesion for- size for each category of lesion independently. This method mation (with a 95% CI of 11% to 83% reduction). showed that esophageal cooling by the method of direct instil- Prototypes of various balloon devices have been evaluated lation of cold water or saline used in these studies results in a for possible use in preventing thermal injury during RF Fig. 4. Forest plot comparing the outcome of all lesions in the three clinical studies. Events are the occurrence of grade I, II, III, and IV lesions J Interv Card Electrophysiol (2020) 59:347–355 353 Fig. 5. Forest plot comparing the outcome of low-grade lesions in the three clinical studies. Events are the occurrence of grade I and II lesions ablation [13–16]. These devices provided flow rates of 25 mL the mechanism of AEF formation is not well under- to 300 mL per minute, and although preclinical as well as stood, there is general agreement that thermal injury is mathematical models of the devices suggested benefits in le- a precursor and that higher-grade thermal injury has a sion reduction, none of the early prototypes evolved into com- higher risk of progression to AEF [26]. mercially available products. A more recently developed Analyzing each lesion grade independently in a statistical intraesophageal cooling device has a flow rate of up to 1900 model allows an alternative approach to estimate effect size mL per minute. This device was designed for whole-body that may provide further refinement of the estimate, at the cost temperature manipulation, for which it is commercially avail- of decreased precision of the estimate. The point estimate that able, and has been shown to have protective effects in animal we found using this approach suggests a reduction in high- and mathematical models of RF ablation. It is currently under grade lesions of −23%, although a higher number of patients clinical investigation for use during RF ablation, and preclin- with a greater number of high-grade lesions would be neces- ical data suggest a close correlation between water tempera- sary to narrow the confidence intervals around this estimate, ture and protective effect, such that increased heat ex- which, with the population included here, ranges from −85% traction results in greater reduction in lesion thickness to +38%. It seems likely that cooling methods that have a [22, 23]. Recent data in the burn literature also suggests higher heat extraction capacity will lead to increased effect that there are improved outcomes from thermal burns size point estimates when the data are analyzed by either bi- (reduced full thickness depth, skin grafting requirement, nary logistic or ordinal regression. hospitalization, and other operative interventions) with cooling, with a dose-response relationship noted be- tween the odds of grafting and duration of cool running 5 Limitations water, which may offer further support for the idea of a threshold effect to preventing progression of thermal The three studies that we analyzed differed in patient charac- injury after the initial thermal insult [24]. teristics and other details as well as in the specific radiofre- A recent meta-analysis of two studies that used the direct quency techniques and equipment used (see Tables 1, 2, 3). instillation of ice-cold water to cool the esophagus fo- Nevertheless, all studies used radiofrequency ablation, and the cused on the outcome of overall lesion frequency, but variation in technology reflects current real-world practice. did not distinguish between lesion severity and lesion One of the studies randomized the patients. There was no frequency, and produced inconclusive results [25]. In description of any attempt at blinding the patients to the pro- contrast, in our meta-analysis of 3 studies that used this tection strategy used. Lesion grading varied between studies, cooling method, we stratified the lesions according to but the scales used in each study fitted easily into a common their severity and found that cooling by this method stratification. The differences between the studies may serve reduced the number of high-grade lesions. Although to broaden the generalizability of this meta-analysis. Fig. 6 Forest plot comparing the outcome of severe lesions. Events are the occurrence of grade III/IV lesions 354 J Interv Card Electrophysiol (2020) 59:347–355 6 Conclusions 8. Zakaria A, Hipp K, Battista N, Tommolino E, Machado C: Fatal esophageal-pericardial fistula as a complication of radiofrequency catheter ablation. SAGE open medical case reports 2019, 7: Esophageal cooling reduces the severity of the lesions that 2050313x19841150. may result from RF ablation, even when relatively low heat 9. Deviating the esophagus in atrial fibrillation ablation - clinicaltrials. extraction methods are used, such as the direct instillation of gov listing [https://clinicalt rials.gov/ct2/show/NCT01546168]. Accessed 13 Sep 2019 small amounts of cold liquid. Further investigation of esoph- 10. Kadado AJ, Akar JG, Hummel JP. Luminal esophageal temperature ageal cooling is warranted, particularly with higher heat ex- monitoring to reduce esophageal thermal injury during catheter ab- traction capacity techniques. lation for atrial fibrillation: a review. Trends in Cardiovascular Medicine. 2019;29(5):264–71. Author contributions LL: design, data acquisition, data analysis/interpreta- 11. Deneke T, Bunz K, Bastian A, Pasler M, Anders H, Lehmann R, tion, manuscript drafting; MG: concept, data analysis/interpretation, manu- et al. Utility of esophageal temperature monitoring during pulmo- script drafting; PS: data analysis/interpretation, manuscript drafting; CT: data nary vein isolation for atrial fibrillation using duty-cycled phased analysis/interpretation, manuscript drafting; JG: data analysis/interpretation, radiofrequency ablation. J Cardiovasc Electrophysiol. 2011;22(3): manuscript drafting; BC: data analysis/interpretation, manuscript drafting and 255–61. revisions; JH: data analysis/interpretation, endoscopy expertise, manuscript 12. Berjano EJ, Hornero F. A cooled intraesophageal balloon to prevent review; FA: statistical analysis, data analysis/interpretation; SM: data analysis/ thermal injury during endocardial surgical radiofrequency ablation interpretation, manuscript revisions; EK: concept, design, data analysis/inter- of the left atrium: a finite element study. Phys Med Biol. pretation, manuscript drafting. All authors provided critical review, revision, 2005;50(20):N269–79. and approval of the manuscript. 13. Lequerica JL, Berjano EJ, Herrero M, Hornero F. Reliability assess- ment of a cooled intraesophageal balloon to prevent thermal injury during RF cardiac ablation: an agar phantom study. J Cardiovasc Compliance with ethical standards Electrophysiol. 2008;19(11):1188–93. 14. Lequerica JL, Berjano EJ, Herrero M, Melecio L, Hornero F. A Conflict of interest EK declares equity interest in Attune Medical, man- cooled water-irrigated intraesophageal balloon to prevent thermal ufacturer of an esophageal cooling device; MG, PS, CT, JG, and BC serve injury during cardiac ablation: experimental study based on an agar as Principal Investigators for studies of esophageal cooling sponsored by phantom. Phys Med Biol. 2008;53(4):N25–34. Attune Medical, which includes institutional support and travel reim- 15. Arruda MS, Armaganijan L, Di Biase L, Rashidi R, Natale A. bursements. SM has provided consulting services for Attune Medical. Feasibility and safety of using an esophageal protective system to All other authors declare no relevant conflicts of interest. eliminate esophageal thermal injury: implications on atrial- esophageal fistula following AF ablation. J Cardiovasc Open Access This article is distributed under the terms of the Creative Electrophysiol. 2009;20(11):1272–8. 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