Present Understanding of Shock Polarity for Internal Defibrillation: The Obvious and Non-Obvious Clinical Implications

Transcription

1 REVIEWS Present Understanding of Shock Polarity for Internal Defibrillation: The Obvious and Non-Obvious Clinical Implications MARK W. KROLL,* IGOR R. EFIMOV, and PATRICK J. TCHOU From the *California Polytechnic University, St. Louis, Missouri, Washington University in St. Louis, and Cleveland Clinic Foundation, Cleveland, Ohio Background: Uncertainty about the best electrode configuration has combined with the programming flexibility in modern implantable cardioverter-defibrillators (ICDs) to result in routine polarity reversal during an implant to deal with a high defibrillation threshold (DFT). We feel that this practice is not always supported by the clinical data and the present scientific understanding of defibrillation. Method: A meta-analysis of the clinical studies on ICD shock polarity was performed. Subgroup analyses were also performed to test the impact of high DFTs, various tilts, and the use of the hot can electrode. A review of the basic research surrounding the effects of polarity in defibrillation is also presented. Results: A total of 224 patients were studied. The use of an anodal right ventricular (RV) coil lowers the mean DFT by 14.8% (P = ). It provides thresholds equal to or lower than cathodal defibrillation in 83% of patients. The fraction of patients with lower anodal DFTs was 94/224 versus 38/224 for cathodal polarity. This phenomenon may be explained by virtual electrode effects. In particular, anodal electrodes tend to produce collapsing wavefronts while cathodal electrodes tend to produce expanding proarrhythmic wavefronts. Conclusion: In an ICD implant, the RV coil should be the anode. Furthermore, DFT testing beginning with cathodal defibrillation is most likely unnecessary and needlessly extends the procedure s duration and increases the risks for the patient. (PACE 2006; 29: ) biphasic waveform, defibrillation threshold, defibrillator electrode, ICD programming, implantable cardioverter defibrillator, polarity, burping theory, ventricular fibrillation Introduction The fundamental mechanisms underlying ventricular fibrillation (VF) and defibrillation have not been conclusively described. The reviews by Dillon and Kwaku 1 and Ideker et al. 2 provide an excellent discussion of our current understanding of the general concepts of fibrillation and defibrillation. Fortunately, the absence of a conclusive understanding of these phenomena has not impeded the adoption and widespread use of implantable cardioverter-defibrillator (ICD) therapy for the prevention of death in patients prone to ventricular tachyarrhythmias. The growing body of clinical research is facilitating progress in basic understanding, and synthesizing the implications Mark Kroll is a consultant to St. Jude Medical, Inc., Adjunct Professor of Biomedical Engineering, California Polytechnic University, and Adjunct Professor of Biomedical Engineering, University of Minnesota. Igor Efimov is a consultant to Medtronic, Inc. Address for reprints: Mark W. Kroll, Ph.D., FACC, Mark Kroll and Associates, LLC, Box 23, Crystal Bay, MN Fax: ; Mark@krolls.org Received January 9, 2006; revised February 17, 2006; accepted February 26, of these results with those of more basic research efforts holds the potential to improve both the theoretical understanding and clinical control of VF. We believe there exists compelling data from a number of clinical studies that anodal defibrillation (i.e., the first phase has the right ventricular shocking electrode positive, with the ICD can and/or proximal electrode negative) requires less energy to defibrillate the heart than cathodal defibrillation. At the same time, basic research has progressed to the point where reasonable inferences can be made about why this is so. In this paper, we will briefly review clinical evidence for the superiority of anodal stimulation, taking into account the history of research in defibrillating waveforms, and suggest the reasons for this superiority. This remains a significant clinical issue, as the combination of programming flexibility offered by modern ICDs and uncertainty about the superior electrode configuration is often resulting in the anodal polarity selection late in an implant. These repetitive arrhythmia inductions increase the attendant time and patient risk. Theoretical Framework Because of their superior performance over monophasic waveforms, biphasic waveforms are C 2006, The Authors. Journal compilation C 2006, Blackwell Publishing, Inc. PACE, Vol. 29 August

2 KROLL, ET AL. universally used in today s ICDs. While the description of biphasic waveforms is hampered by the uncertainty surrounding basic defibrillation mechanisms, the burping theory 3 currently offers the most accepted explanation. This theory has been supported by a number of subsequent animal 4 7 and human 8,9 studies. Briefly, the burping theory holds that the function of the first phase of a biphasic shock is to depolarize or extend the refractory periods of virtually all ventricular myocytes, and that of the second phase is to remove excess charge from any cells where it remains. This may be important in three areas: first, marginally stimulated cells, which may give a delayed (and hence desynchronizing) potential; second, cells whose membranes were temporarily damaged (electroporated) 10 by the extreme current near the electrodes tend to be healed by the cancellation of the second phase 11,12 ; finally, in the areas bordering the virtual electrodes, the second phase acts to remove residual charges, which could otherwise have the potential to launch new wavefronts and interfere with defibrillation. 13,14 The Role of the Virtual Electrode in Monophasic Shocks The intrinsic benefits of anodal defibrillation are being explained by recent basic research, where advances in experimental techniques have enabled a better determination of electrical potentials during and immediately following a high voltage shock. Traditional measurement techniques aimed at describing localized changes in electrical potential have been susceptible to enormous artifacts from the shock (similar to the surface ECG recording of a fibrillation-shock sequence), effectively obscuring the changes in transmembrane potentials during and immediately following the shock. Recently, the use of potentiometric transmembrane dyes has enabled optical signal measurements of transmembrane potentials with the needed resolution and without the shock artifact. 15,16 This research has substantiated and refined the concept of the virtual electrode. The existence of virtual electrode behavior, in the heart, was predicted on the basis of bidomain modeling of unipolar pacing by Sepulveda et al., 17 and has been confirmed in subsequent studies of ventricular unipolar epicardial pacing. 18,19 The virtual electrode effect makes the defibrillation electrode effectively much larger than the physical electrode. 20 More importantly, the region of depolarization or hyperpolarization near the physical electrode is surrounded by regions with opposite polarity. In addition, the shapes of these regions are influenced by anisotropy of con- Figure 1. Optical map of transmembrane potentials in a Langendorff-perfused rabbit heart at the end of the first phase of a biphasic shock delivered during the ST segment (reproduced by permission from Efimov et al. 20 ) This figure illustrates two key concepts: (1) the sizes of the negatively and positively charged areas following a shock are significantly larger than the physical electrodes (the virtual electrode effect), and (2) the distribution of charges is not graded, exhibiting two large, oppositely charged areas. Arrow points to the cathodal coil. ductance due to fiber orientation. These effects can be seen in Figure 1, taken from Efimov et al. 20 This image is an optical map of transmembrane potentials in a Langendorff-perfused rabbit heart at the end of a monophasic shock delivered during the ST segment. The cathode was a coil in the right ventricle (RV), and the anode was a remote plate in the bath. At shock termination, the cardiac tissue adjacent to the ventricular electrode assumes a transmembrane shift in voltage opposite to the electrode polarity. Note that the sizes of the negatively and positively polarized areas are significantly larger than the physical electrodes (hence, the term virtual electrode ). Also, the distribution of charges is not graded and this leaves two large, oppositely charged areas. The borders between these oppositely charged areas are likely to be highly proarrhythmic. 13 Cells in the virtual anode in Figure 1 are brought close to their resting potential, making them amenable to stimulation; cells in the virtual cathode have sufficient potential to produce this stimulation, resulting in the launch of new wavefronts at the boundaries toward the anode (see Fig. 2, taken from Efimov et al. 20 ). 886 August 2006 PACE, Vol. 29

3 INTERNAL SHOCK POLARITY Figure 2. Changes in transmembrane potential following an unsuccessful monophasic defibrillation shock in a Langendorff-perfused rabbit heart (reproduced by permission from Efimov et al. 20 ). This figure illustrates the virtual cathode attacking the virtual anode, highlighting the ability of cathodal shocks to support the launch of new wavefronts capable of sustaining or re-initiating fibrillation after a shock. Maps of transmembrane potential reproduced every 10 ms. Thus anodal shocking produces a wavefront that originates at the boundary of positively charged regions and spreads toward the physical anode and its negatively charged areas. 21 This produces collapsing wavefronts that frequently collide and neutralize one another near the RV coil. Conversely, a cathodal electrode produces expanding wavefronts that propagate away from the physical RV coil and frequently turn and produce sustained reentrant circuits likely to re-initiate the arrhythmia, as shown in Figure 2. Consider an ICD implant with a cathodal RV coil (which formerly was typically referred to as the normal polarity). The hot can and possible superior vena cava (SVC) coil are then anodal. With the delivery of a monophasic shock, the region around the RV coil becomes the virtual cathode and the cardiac cells take a positive charge as shown in the left-hand frame of Figure 3. The remaining cells form the virtual anode and briefly take a negative potential as shown in the righthand frame of Figure 3. Being amenable to stimulation, they allow wavefront propagation from the virtual cathode as shown in the top frame of Figure 4. The propagation of new wavefronts into the main cardiac mass is proarrhythmic and will tend to reduce the probability of successful defibrillation. Consider the converse situation shown in the bottom frame of Figure 4. There, the wavefronts propagate inward to the virtual anode around the RV coil and most likely annihilate each other. This will not interfere with successful defibrillation. (This model also helps explain why polarity is irrelevant with external shocks. 22 Since no electrode is close to the heart, there is no asymmetry in the launching of new wavefronts with the external shock.) Figure 3. Stylized responses of cardiac myocytes to the two shock polarities. The left-hand frame shows the transmembrane potential for an already depolarized cell receiving a cathodal shock. Note that the response is the opposite of the electrode polarity. The right-hand frame gives the potential for a cell near the anode. Its response is to briefly return to a near-resting potential. PACE, Vol. 29 August

4 KROLL, ET AL. Figure 4. Cathodal shocks (top) produce expanding wavefronts that propagate away from the physical RV coil, while anodal shocks (bottom) produce collapsing wavefronts that propagate toward the RV coil. Thus, there is a clear theoretical basis for the benefit of the monophasic anodal shock. The few monophasic endocardial lead studies have shown significant benefit across the board for the positive shock. For example, Strickberger et al. found a 30% defibrillation threshold (DFT) reduction with anodal monophasic shocks. 23 Shorofsky and Gold found a 27% DFT reduction with anodal monophasic shocks but, in the exact same patients, found only a 9% reduction in the mean DFT for the biphasic shock with the anodal polarity. 31 It is quite possible that electroporation (acute collapse of membrane insulation from high electrical fields) plays a role in the sensitivity of defibrillation to the polarity. However, it is unclear exactly what that role is, since some researchers report that the cathode 24 generates the most electroporation while others find that the anode generates the most. 25 Polarity and the Biphasic Shock The role of polarity in biphasic defibrillation is much harder to explain, from a theoretical basis, than its role in monophasic defibrillation. One can certainly hypothesize that the same type of proarrhythmic cathodal wavefront launching occurs with the biphasic shock as with a monophasic shock. But, one of the functions of an appropriately matched second phase is to burp the cell membranes and hence discharge the virtual electrodes. 3,13 This is probably why biphasic waveforms launch fewer new wavefronts than do monophasic shocks. 26 Thus, there would appear to be some redundancy between the use of an anodal shock and the addition of the second phase. Many interesting studies have found results consistent with this hypothesized redundancy. For example, Strickberger et al. found that a non-optimized biphasic waveform had essentially equivalent defibrillation efficacy as an anodal monophasic shock in humans. 27 Schauerte et al. 6 and Huang et al. 28, 29 have demonstrated, in three separate animal studies, that the more optimal biphasic waveforms benefited the least from a positive polarity. Another factor which may be important with biphasic waveforms is the greater homogeneity of the membrane time constant (τ m ) with anodal shocks. In a Langendorff preparation optical mapping study, the first phase mean τ m varied from 2 5 ms for anodal shocks of various voltages while the mean τ m varied from 2 8 ms for cathodal shocks. 42 Similarly, the dispersion of τ m in the second phase was far greater for cathodal than for anodal shocks. This larger dispersion decreases the efficiency of biphasic defibrillation according to the burping theory. Meta-Analysis We performed a meta-analysis of the existing published clinical data. Medline was searched for human studies with the words defibrillation, polarity, and biphasic, anywhere in the abstract or title. A total of 24 citations were produced. These abstracts were then reviewed to find those covering randomized trials comparing both polarities with conventional endocardial lead systems. This left 8 papers for analysis Studies were weighted by sample size for the DFT reduction calculations. Means were weighted averages and the standard deviations were calculated from the weighted variance. Unless stated otherwise, comparisons were made by Student s t-test. Table I shows the results of this meta-analysis. With the exception of the report by Strickberger et al., 33 each study found that the DFT was lower when the RV electrode formed the anode. Overall, anodal shocking provided the same or lower DFT in 83% of patients, with an average reduction of 14.8% (P = ). The papers were then sub-analyzed for the use of the hot can. With the hot can (80 patients), an anodal RV reduced the mean DFT by 18.0% from August 2006 PACE, Vol. 29

5 INTERNAL SHOCK POLARITY Table I. Meta-Analysis of Studies Comparing Anodal vs Cathodal RV Coils in ICD Therapy Anodal Cathodal Anodal Anodal Polarity Cathodal Study Can N DFT DFT Reduction Better Neutral Better Schauerte et al. 30 None % Shorofsky and Gold 31 Hot % Natale et al. 32 None % Strickberger et al. 33 None % Keelan et al. 34 Mixed % Olsovsky et al. 35 None % Neuzner et al. 36 None % Narasimhan et al. 37 Mixed % Grouped % to 7.7 J which was nearly identical to the reduction with the 144 non-hot can patients of 13.6% from 13.0 down to 11.3 J. The benefit difference for the positive polarity between the hot can (18.0%) and the purely transvenous leads (13.6%) was not statistically significant. The fraction of hot-can patients that did better with a cathodal shock was 9/45 compared to 29/178 of the purely transvenous patients (NS by Yates χ 2 ). Thus the hot can usage is irrelevant for the issue of polarity. The High-DFT Patient A noteworthy finding in many of these studies, as with those using monophasic waveforms, is that the DFT-lowering benefit of anodal stimulation was more pronounced in patients who exhibited a high DFT. The study of Narasimhan gave the DFTs for each polarity for each of their patients. An analysis of these individual patient data found a strong correlation between the cathodal DFT and the percentage DFT reduction seen with the anodal shock (P = by Spearman s ρ). This effect was even seen with other electrode systems not included in the meta-analysis such as the Rashba et al. study of patients with patch-coil systems. 38 We were concerned that some of the reported stronger benefit with high DFT patients was actually a regression-to-the-mean effect (i.e., a pa- tient was classified as high-dft because of a single unlucky reading which then regressed to normal with later readings giving the false impression that the change in polarity was the cause). We thus defined a high DFT bilaterally, i.e., a patient was classified as high DFT if either their cathodal or anodal DTF was 15 J. Table II presents the results of this subgroup analysis for the patients with a high DFT with either polarity. A total of 37 patients are included. The DFT was reduced 12.0% from 15.2 to 13.4 J by the use of the positive polarity (P = 0.028). Only 9 of these 37 patients had a lower DFT with the cathodal configuration while 19 of the 37 had lower anodal DFTs (P = by Yates χ 2 ). (Note: due to the multiple comparisons, this would not necessarily be considered statistically significant.) Contrary to some individual reports, our metaanalysis does not support the contention that high DFT patients do better with the anodal polarity than do the overall population. Nor do they do better than the subgroup of the low DFT patients. The fraction of high DFT patients with a lower anodal DFT (19/37) was not statistically significantly different from the fraction (75/187) of low DFT patients helped by an anodal polarity (P = 0.28 by Yates χ 2 ). Similarly, the fraction of high DFT patients benefiting from a cathodal polarity (9/37) Table II. Effect of Polarity with High-DFT Patients Anodal Cathodal Anodal Anodal Polarity Cathodal Study N DFT DFT Reduction Better Neutral Better Shorofsky and Gold % Olsovsky et al % Narasimhan et al % Grouped % PACE, Vol. 29 August

6 KROLL, ET AL. was not different from the fraction (29/187) of the low DFT patients benefiting by a cathodal polarity (P = 0.29 by Yates χ 2 ). Why Would Cathodal Shocks Ever Be Better? All of the above studies were done with the classical tilt-based waveforms. No human studies have been done on the effects of polarity with optimized millisecond durations. However, animal studies have shown minimal to no benefit from polarity changes with optimized durations. 6,28,29 Thus, one should not expect a benefit from a cathodal polarity certainly not at the 17% frequency seen with tilt-based waveforms. The burping theory would predict that an excessively long second phase would make an anodal shock appear as a cathodal shock as the membrane potential would be reversed. That prediction is clearly supported by a study from the Ideker group which showed that waveforms with long second phases did better with a cathodal polarity. 29 Thus, we hypothesized that the rate of cathodal superiority may be related to the tilts used in the study. To test this hypothesis, we performed yet another subgroup analysis of the effects of polarity this time grouped by tilts. It was possible to ascertain the tilts used in seven of the eight studies. Three studies (n = 64) used 65/65% tilt waveforms and four studies (n = 133) used 60/50% tilt. The DFT reduction for the anodal polarity was 9.3% for the 60/50% tilt waveforms but 21.5% for the 65/65% waveforms (P = 0.020). The fraction of patients that did better with the cathodal polarity was 29/133 in the 60/50% tilt group but only 6/64 in the 65/65% tilt group (P = by Yates χ 2 ). Thus the waveform used appeared to have an impact on the impact of polarity. Clinical Implications While additional basic and applied research will continue to be useful, we believe that existing theoretical work and empiric data are now sufficient to establish the superiority of anodal stimulation in providing a lower DFT. In today s ICDs, the RV coil should typically be the anode. Since there is no theoretical explanation for a possible benefit of a cathodal shock, the minority of cases reported where a benefit of cathodal polarity appeared could reflect either biological noise due to the extreme variability of defibrillation, or a highly suboptimal biphasic waveform. Or, there is an as-yet-unknown mechanism by which some patients actually do better with the cathodal shock. Since the repeatability of DFT determination is mediocre (one study found that 8% of patients had a 20% change in DFT with an immediate repeat test), 39 it is possible that the majority of the apparent cathodal superiority cases were due to biological noise. As a corollary, implantations using inductions beginning with a cathodal polarity are most likely inappropriate, prolonging the procedure and subjecting high-dft patients to increased risks. We recommend an increasingly used approach of configuring an ICD to deliver anodal shocks before DFT testing. If an inadequate DFT obtains with the anodal shock, then one should be advised that only about 17% of patients would do better with a cathodal shock. In the rare case where two epicardial patches are required, we have only the guidance from older monophasic studies. This suggests that the left ventricular patch should be the anode, 40,41 perhaps since it directly affects more myocardium than the RV patch. Reversing the Nomenclature The occasional terminology of reverse and normal polarity is decidedly unhelpful, as the nominal polarity of the RV coil of one major manufacturer is anodal while it is cathodal for another. Finally, a third manufacturer has the nominal polarity anodal or cathodal depending on the model! One should strive to use universal terminology such as positive or anodal polarity. Another confusing practice is to describe the polarity by the direction of current in the body. While there is a physics convention that current always flows from the positive to the negative electrode, there are actually opposing currents of charge carriers inside the human body during a shock. Chlorine ions travel toward the positive electrode, while sodium, potassium, magnesium, and calcium ions travel toward the negative electrode. Finally, the routine reversal of polarity, in difficult cases, with ICD models that already have a positive nominal polarity, may be inappropriate depending on the type of ICD and its output flexibility. A cathodal polarity is unlikely to be of benefit with modern biphasic waveforms. However, if the device used lacks significant output programmable flexibility, then reversal (to cathodal) may present a better alternative to, for example, the installation of a subcutaneous array. Conclusion Primary use of anodal defibrillation would lower DFTs, providing effective therapy at reduced energy levels and improving the safety margin. Reduction of polarity changes as a variable in the empiric approach to defibrillation testing and optimization could minimize unnecessary fibrillation inductions and shocks and reduce the time required for ICD implantation. 890 August 2006 PACE, Vol. 29

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