Author + information
- Received December 30, 2016
- Revision received March 11, 2017
- Accepted March 16, 2017
- Published online October 16, 2017.
- Duy T. Nguyen, MDa,∗ (, )
- Edward P. Gerstenfeld, MDb,
- Wendy S. Tzou, MDa,
- Paul T. Jurgens, MDa,
- Lijun Zheng, MSa,
- Joseph Schuller, MDa,
- Matthew Zipse, MDa and
- William H. Sauer, MDa
- aSection of Cardiac Electrophysiology, Division of Cardiology, University of Colorado, Aurora, Colorado
- bSection of Cardiac Electrophysiology, Division of Cardiology, University of California-San Francisco, San Francisco, California
- ↵∗Address for correspondence:
Dr. Duy T. Nguyen, Section of Cardiac Electrophysiology, Division of Cardiology, University of Colorado, B-132, Leprino Building, 12401 East 17th Avenue, Aurora, Colorado 80045.
Objectives This study evaluated the use of half-normal saline (HNS) as the radiofrequency ablation (RFA) cooling irrigant.
Background Some instances of ventricular arrhythmia may originate deep within myocardium and can be refractory to standard ablation using open irrigated RFA. Recent data suggest that deeper ablation lesions can be created by decreasing the irrigant ionic concentration delivered through open irrigated RFA than by using normal saline (NS).
Methods Bovine myocardium was placed in a circulating saline bath. Two RFA catheters were oriented across from each other, with myocardium in between. Sequential unipolar HNS-irrigated RFA was performed and compared to bipolar ablation by using NS or HNS. Unipolar HNS ablation of the ventricles in a porcine model was performed and compared to ablation using NS.
Results Sequential ex vivo unipolar RFA with HNS produced larger lesions than sequential unipolar RFA with NS and produced lesions of similar size to those created with bipolar RFA using NS. Ex vivo bipolar RFA using HNS created the largest lesions. In vivo unipolar HNS ablation in porcine endocardium created larger lesion volumes, 152.9 ± 29.2 μl, compared to 94.7 ± 33.4 μl for unipolar ablation using NS.
Conclusions By decreasing ionic concentration and charge density in RFA using HNS instead of NS irrigant, larger ablation lesions can be created and are similar in size to lesions created using bipolar ablation. This may be a useful ablation strategy for deep myocardial circuits refractory to standard ablation. Further studies are needed to evaluate this novel RFA strategy.
With the advent of irrigated ablation and contact force, radiofrequency ablation (RFA) of cardiac arrhythmia has become an effective and standard therapy (1–6). Nevertheless, several obstacles remain that prevent curative success and durable ablation lesions, particularly for ventricular arrhythmias originating from intramyocardial sources, such as interventricular septum, non-septal mid-myocardial sites, or papillary muscle tissues, which are not amenable to current RFA technologies. Bipolar RFA, which uses 2 ablation catheters as the active and ground RF sources, has recently been explored as a strategy to produce deeper and larger ablation lesions than those created by sequential unipolar ablations (7–9).
Standard externally irrigated RFA is performed using normal saline (NS) with a concentration of 0.9% (9 grams per liter) sodium chloride. We previously demonstrated that externally irrigated ablation using a lower ionic concentration and charge density can create larger and deeper lesions (10). Specifically, in an ex vivo model, we found that decreased ionic concentration and charge density increased RF delivery to targeted tissue and resulted in larger lesions for both open and closed irrigated RFA systems. Half-normal saline (HNS) ablation created larger lesions than NS ablation, and lesions created using 5% dextrose in water (D5W) were significantly larger than either HNS or NS lesions. We hypothesized that the lower charge density of HNS and D5W decreased loss of RFA through dispersion to a lower impedance environment surrounding the catheter, thereby allowing for more effective RF current delivered to myocardial tissue (Figure 1A).
In this study, we sought to confirm the previous ex vivo findings with in vivo endocardial RFA, using HNS irrigant in a porcine model. In addition, we compared biophysical parameters and ablation lesion characteristics after unipolar RFA by using HNS to open irrigated bipolar ablation, using NS or HNS.
Ex vivo model
Experimental protocols were approved by the Institutional Animal Care and Use Committees of the University of Colorado. An ex vivo model consisting of recently excised bovine myocardium, a submersible load cell, a circulating bath, and catheters was assembled. A load cell was submerged in the bath and contained a section of bovine ventricular myocardium excised within 1 h of experimentation. This load cell measured force applied to the overlying myocardial tissue by both ablation catheters. The same amount of force (10 grams-force) was applied by both ablation catheters. This ex vivo model has been validated and described in further detail elsewhere (11–13).
For bipolar ablation, 2 ablation catheters were oriented across from each other, with myocardium in between, as previously described (14). Both catheters were 3.5 mm open irrigated-tip catheters (Biosense Webster, Diamond Bar, California). Bipolar ablations were performed at 50 W for 60 s using either NS or HNS as the irrigant. In addition, sequential unipolar ablations using HNS irrigation were performed and compared to bipolar ablations using NS or HNS (Figure 1B). Ablation lesions were sectioned and analyzed. Due to distortion of myocardial geometry, ablations resulting in “steam pops” (an audible sound associated with pressure/steam build up and then gas release during an ablation) were excluded from lesion analysis.
Ablation lesion volume measurements
Lesion volumes were acquired by analyzing tissue sections with a digital micrometer. Single lesion volumes were calculated using the equation for an oblate spheroid. For each lesion, maximum depth, maximum diameter, depth at maximum diameter, and lesion surface diameter were measured, using the volume of an oblate spheroid equation [4/3πr2R] (where r is the transverse radius and R is the axial radius in millimeters).
In vivo endocardial ablation
Yorkshire pigs (n = 4) were anesthetized, and intravenous amiodarone (200 to 400 mg) was used intraoperatively for ventricular arrhythmia prophylaxis. The right ventricle (RV) was accessed using the femoral veins. The left ventricle (LV) was accessed using a retrograde aortic approach through femoral arterial access. An electroanatomic map of RV and LV endocardium was created using the CARTO3 mapping system (Biosense Webster).
Endocardial ablations were delivered at 30 W for 30 s with the same amount of force as measured by force sensing technology on the externally irrigated tip RF catheters (SmartTouch, Biosense Webster); ablation lesions were tagged by the electroanatomic mapping system. The irrigation flow rate was 30 cc/min for a power of 30 W. Ablations with either HNS or NS were performed in the LV or RV septum. Operators were blinded to the irrigant used during external irrigation. Following ablation, animals were sacrificed, and hearts were immediately explanted and fixed in formalin. Gross pathology was performed, and ablation lesions were analyzed in a blinded fashion.
SPSS software was used to perform all calculations. The analysis of variance (ANOVA) test was used to compare continuous variables, and the chi-square test was used for dichotomous comparisons in lesion characteristics between various testing conditions (sequential unipolar NS ablation, bipolar NS ablation, and bipolar HNS ablations). The p values in Tables 1, 2, and 3⇓⇓⇓ and Figure 2 are from paired comparisons within each condition. For comparisons using pooled results from the same animal or slab, hierarchical analysis with adjustment for possible bias due to clustering was performed. A p value of <0.05 was considered statistically significant.
Effect of sequential unipolar externally irrigated ablation using HNS compared with bipolar ablation using NS
Table 1 shows ablation lesion characteristics after unipolar irrigated ablation of ex vivo bovine endocardium and epicardium, using HNS versus NS. For both epicardial and endocardial ablations, irrigated HNS ablation at 50 W, compared to NS irrigation, led to larger volumes, deeper lesions, and greater impedance drops. There were no significant differences in steam pop rates.
Table 2 shows ablation lesion characteristics of bipolar ablation, using active and ground catheters irrigated with NS. Sequential unipolar ablation with HNS created lesion volumes similar to those of bipolar NS ablation, 913 ± 91.1 μl versus 901.3 ± 194.5 μl, respectively (p = 0.700) (Figure 1C). Bipolar ablation with NS created a statistically significant deeper lesion, 13.0 ± 1.4 mm vs. 12.5 ± 0.5 mm, respectively (p = 0.021), although the absolute numerical difference was small.
Ablation lesion characteristics of bipolar ablation using HNS
Table 2 also contains ablation lesion characteristics of bipolar ablation, using active and ground catheters irrigated with HNS. Bipolar HNS created deeper lesions, 14.5 ± 1.2 mm, and larger ablation lesion volumes, 977.2 ± 152.9 μl, than either sequential HNS ablation or bipolar NS. Bipolar HNS did cause a statistically higher rate of steam pops than either sequential HNS or bipolar NS.
In vivo endocardial ablation with HNS compared with NS irrigant in a porcine model
Figure 2 compares representative porcine ablation lesions formed by using HNS versus NS irrigation. In vivo porcine externally irrigated ablation using HNS created larger lesion volumes in the RV and LV, 152.9 ± 29.2 μl versus 94.7 ± 33.4, respectively, compared to NS (Figure 3A). Larger impedance changes were observed with HNS ablation (33 ± 15 Ω for HNS vs. 22 ± 9 Ω for NS) (Figure 3B). There were no differences in contact force used for either HNS or NS irrigation (Table 3). No steam pops occurred in either group.
For ex vivo and in vivo ablations, ablation lesions had a dense necrotic core with destruction of cellular and vascular architecture. In the periphery of the lesions, there was a rim of contraction necrosis with partially intact myocardial structure and at times intralesional hematomas. For lesion volume analyses, the area of the necrotic core and the total area of HNS lesions were larger than those for NS lesions.
In this study, we performed ex vivo and in vivo experiments designed to evaluate the effect of RFA using external irrigation with HNS. We found that using HNS as an irrigant resulted in deeper and larger lesions in all experimental models used compared to those using NS. Specifically, on average, ex vivo lesions were 12% deeper and 18% larger than unipolar ablation lesions created with NS irrigation. Sequential unipolar ablation with HNS created ablation lesions that were of similar size but not as deep compared to bipolar ablation using NS. In vivo porcine ablation irrigated with HNS were almost 60% larger than those irrigated with NS, despite similar contact force.
Biophysical mechanisms for improved efficacy of RF energy delivery using HNS
The delivery of RFA can be limited by higher temperatures at the catheter tip-tissue interface, resulting in coagulum and char formation, thereby impeding efficient application of RA to targeted tissues (2,15,16). One method for reducing RF electrode temperatures is to actively cool the electrode by circulating saline through the catheter tip during RFA (1,17–20). Saline has an ionic charge and will conduct electrical current with low impedance. Because the electrical impedance of saline is lower than that of blood or tissue, RF will preferentially disperse to the saline cloud in contact with the ablation electrode created with irrigation. However, if this irrigant has higher electrical impedance, then RF will preferentially focus to the targeted cardiac tissue that has a relatively lower electrical impedance. This is the basis for our hypothesis in using lower ionic irrigation to improve RF delivery without compromising electrode cooling.
Using ex vivo models with bovine cardiac tissue, we previously demonstrated increased ablation lesion sizes associated with HNS without an increase in steam pop rates (10). The use of D5W (an irrigant with no ionic components and thus with a very high electrical impedance) resulted in even larger lesions but higher steam pop rates. Thus, HNS was selected for further study because of its potential clinical applicability. Furthermore, it is a common infusion that is administered intravenously to patients, and thus its effects on electrolytes, volume status, and glucose can be predicted, minimizing fluid-related adverse events.
Comparison with bipolar radiofrequency ablation
Bipolar ablation is sometimes required to affect ventricular arrhythmia originating from deep intramyocardial sources. The irrigant used for all studies evaluating bipolar ablation as a potential method for improving RF energy delivery has been normal saline. Koruth et al. (8) in 2012 used 2 externally irrigated catheters (Thermocool, Diamond Bar, California) in their clinical series, demonstrating clinical success for the treatment of ablation-resistant cardiac tissue.
In the present study, sequential ablation with HNS on either side of the targeted tissues achieved lesion volumes similar to those induced by bipolar NS ablation, with a small difference in lesion depth. Taking this information into account, when the physician encounters arrhythmogenic cardiac tissue that is refractory to standard unipolar irrigated ablation, it may be worthwhile to consider unipolar irrigated ablation with HNS before bipolar ablation, as it does not require a more complex setup or the use of a second ablation catheter. In addition, there are limitations to bipolar ablation if pericardial access is required, sometimes preventing adequate treatment due to adhesions from prior surgery and proximity to coronary arteries or the phrenic nerve (21).
If the use of unipolar RF ablation using HNS as an irrigant cannot adequately ablate a ventricular arrhythmia, we provide evidence for increased lesion depth with bipolar ablation. Our evaluation of bipolar ablation using 2 externally irrigated catheters is unique because we attempt to augment the improved efficiency of this strategy by altering the ionic concentration of the irrigant. For all the reasons that a lower ionic concentration irrigant could improve standard unipolar ablation, one would expect a similar improvement in RF delivery when this principle is applied to a bipolar configuration using open irrigated catheters. We thus demonstrated that ex vivo bipolar ablation with HNS created larger lesions than bipolar ablation with NS, although there was a higher rate of steam pops observed.
Potential use of HNS as an irrigant for the creation of deeper or more durable lesions
Ablation failure is often due to the inability to reach an arrhythmic substrate or create deep and durable lesions. Evidence for this has been described in autopsy studies including ablation in patients with hypertrophic cardiomyopathy (22–24). Recent observational data describing a high rate of ablation failure for papillary muscle premature ventricular complexes and epicardial targets support the need for improved ablation technology capable of safely delivering deeper lesions (25,26).
The need to create deeper lesions for uncommon cases, such as those described in preceding text, has led to the use of several different ablation strategies in a limited number of patients. These strategies include ethanol injection into coronary arteries or veins overlying targeted tissue, use of 2 catheters to deliver bipolar ablation as described previously, and the use of an irrigated needle ablation catheter to deliver RF deeper into tissue (8,27–29). In addition, the use of metallic nanoparticles to improve RF energy delivery has been proposed with promising results in experimental models (13,30,31). The main advantage of using HNS over these strategies is its ease in incorporating the fluid in the catheter already being used.
The limitations of ex vivo studies have been detailed previously and include variability in circulating bath currents, catheter contact or angulation, passive catheter cooling, and presence of ischemic myocardium due to nonperfusion (10–13,31). These variables were nondifferential among controls and test groups, and repeated measurements within groups were performed to reduce the impact of these variables. Our ex vivo and in vivo experimental models were performed using normal cardiac tissue and did not necessarily replicate pathophysiologic substrates during clinical ablation.
Finally, although our results are intriguing and have implications for clinically relevant ablation strategies, particularly those involving deep or mid-myocardial substrates, further studies involving HNS as an external irrigant are necessary, including prospective and, ideally, multicenter randomized studies comparing it to standard unipolar ablation.
The use of half-normal saline to cool an electrode delivering RF resulted in deeper lesions in ex vivo and in vivo experimental models, building upon prior limited research. The alteration of the local electrical environment surrounding an ablation electrode will affect RF lesion creation and may be an important variable for the delivery of RF into cardiac tissue. Further study of techniques designed to alter the impedance environment surrounding an ablation catheter and their potential clinical use for enhancing radiofrequency ablation is warranted.
COMPETENCY IN MEDICAL KNOWLEDGE: Open irrigated RF ablation, particularly for ventricular arrhythmia, can sometimes be limited by inadequate lesion durability and inability to reach mid-myocardial circuits, despite the use of high power. We sought to demonstrate that the lower charge density of HNS as the RF irrigant would lead to decreased loss of RF through dispersion to a lower impedance environment surrounding the catheter, thereby allowing for more effective RF current delivered to myocardial tissue. We found that in vivo ablation using HNS irrigant produced larger ablation lesions than NS irrigant. Ex vivo sequential unipolar HNS ablation created similar ablation volumes to those created by bipolar ablation.
TRANSLATIONAL OUTLOOK: There are potential clinical applications of our findings for deep myocardial circuits refractory to standard ablation. However, further studies are needed to evaluate the safety and long-term efficacy of this novel RFA strategy.
Drs. Sauer and Nguyen have received research support from Biosense Webster and CardioNXT; educational grants from St Jude Medical, Boston Scientific, and Medtronic; hold a provisional patent (the University of Colorado is the assignee); and hold nonpublic equity in CardioNXT. Dr. Gerstenfeld has received research support and honoraria from Biosense Webster and St Jude Medical; and honoraria from Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- Abbreviations and Acronyms
- 5% dextrose in water
- half-normal saline
- left ventricle
- normal saline
- premature ventricular contraction
- radiofrequency ablation
- right ventricle
- Received December 30, 2016.
- Revision received March 11, 2017.
- Accepted March 16, 2017.
- 2017 American College of Cardiology Foundation
- Aryana A.,
- d'Avila A.
- Jesel L.,
- Sacher F.,
- Komatsu Y.,
- et al.
- Nakagawa H.,
- Yamanashi W.S.,
- Pitha J.V.,
- et al.
- Nguyen D.T.,
- Tzou W.S.,
- Brunnquell M.,
- et al.
- Haines D.E.,
- Verow A.F.
- Baldinger S.H.,
- Kumar S.,
- Barbhaiya C.R.,
- et al.
- Nakajima K.,
- Miyamoto K.,
- Matsuyama T-a,
- Noda T.,
- Ishibashi-Ueda H.,
- Kusano K.
- van Huls van Taxis C.F.,
- Wijnmaalen A.P.,
- Piers S.R.,
- van der Geest R.J.,
- Schalij M.J.,
- Zeppenfeld K.
- Rivera S.,
- Ricapito MeL.,
- Tomas L.,
- et al.
- Latchamsetty R.,
- Yokokawa M.,
- Morady F.,
- et al.
- Schurmann P.,
- Peñalver J.,
- Valderrábano M.
- Nguyen D.T.,
- Tzou W.S.,
- Zheng L.,
- et al.
- Nguyen D.T.,
- Barham W.,
- Moss J.,
- et al.