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Defibrillation Threshold Varies During Different Stages of Ventricular Fibrillation in Canine Hearts
ORIGINAL ARTICLE
Original Article
Defibrillation Threshold Varies During Different Stages of Ventricular Fibrillation in Canine Hearts Qi Jin, MD a,1 , Jian Zhou, MD a,1 , Ning Zhang, MD a , Changjian Lin, MD a , Yang Pang, MD a , Yangxun Xin, MD a , Jiajun Pan, MD b , Gang Gu, MD a , Weifeng Shen, MD, PhD a,∗ and Liqun Wu, MD, PhD a,∗ a
Department of Cardiology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, PR China b Department of Cardiology, Shanghai Luwan Hospital, Shanghai, PR China
Background: Recent studies have shown that short duration ventricular fibrillation (SDVF) and long duration ventricular fibrillation (LDVF) are maintained by different mechanisms. The objective of this study is to evaluate how the defibrillation threshold (DFT) varies over the duration of fibrillation since the mechanism of VF maintenance changes as VF progresses. Methods: Twelve canines were randomly divided into two groups (Group A and B, n = 6 each). DFTs were measured three times in each group: SDVF (20 s), LDVF (3 min in Group A and 7 min in Group B) and the first episode of refibrillation after successful defibrillation for LDVF. Two 64-electrode baskets used to globally map the endocardium were deployed into the left ventricle and right ventricle, respectively. Results: LDVF-DFT in Group A was significantly higher than that of Group B (628 ± 98 V vs 313 ± 81 V, P < 0.001). In Group B, the DFT of refibrillation was significantly increased compared with the LDVF-DFT (570 ± 199 V vs 313 ± 81 V, P = 0.035) but did not differ from the DFT of refibrillation in Group A (570 ± 199 V vs 638 ± 116 V, P = 0.39). Highly synchronised activation patterns on the left ventricular endocardium were observed between 3 and 7 min of LDVF in Group B but not within 3 min-LDVF in Group A or during refibrillation in each group. Conclusions: DFT varied during different stages of VF. The highly synchronised activation patterns exhibiting after 3 min VF might contribute to the decreased LDVF-DFT. (Heart, Lung and Circulation 2013;22:133–140) © 2012 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved. Keywords. Ventricular fibrillation; Defibrillation; Electrophysiology; Resuscitation
Introduction
R
ecent studies have shown that short duration ventricular fibrillation (SDVF; VF duration < 1 min) and long duration ventricular fibrillation (LDVF; VF duration > 1 min) can be maintained by different mechanisms [1–3]. Intramural reentry disappeared in the porcine left ventricle (LV) after the first 2–3 min of VF, while focal activity in the mid-wall increased during 10 min of VF [1]. Electrical mapping studies of global LV endocardium and regional transmural myocardium have demonstrated that after 3–7 min of LDVF, activations become highly organised and synchronised in the endocardium of canine Received 18 July 2012; received in revised form 9 August 2012; accepted 29 August 2012; available online 27 September 2012 ∗
Corresponding authors at: Department of Cardiology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, No. 197, Shanghai Ruijin Er Road, Shanghai 200025, PR China. Tel.: +86 021 64310871; fax: +86 021 64310871. E-mail addresses: [email protected] (W. Shen), [email protected] (L. Wu). 1 The first two authors contributed equally to this work.
hearts [4,5]. The more organised VF can be terminated by relatively less shock energy [6]. Wavefront synchronisation is also an important aspect preceding the termination of VF [7]. Thus, defibrillation mechanism and efficacy may differ during different stages of VF since the mechanism and activation patterns alter with the duration of VF [8,9]. While refibrillation is infrequent following SDVF, it is commonly seen after successful defibrillation for LDVF [9–12]. A clinical study has demonstrated that 79% patients with sudden cardiac arrest had at least one recurrence of VF with a median of two recurrences and that refibrillation significantly decreased the survival rate [12]. Therefore, the objective of this study was to evaluate how the defibrillation threshold (DFT) and refibrillation occurrence altered over the duration of fibrillation by simultaneously global endocardial mapping of right ventricle (RV) and LV in canine hearts.
Methods All animals were purchased from Shanghai Jiao Tong University Agriculture College of China and raised under
© 2012 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved.
1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2012.08.059
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controlled conditions in the Department of Animals for Scientific Research, Shanghai Jiao Tong University School of Medicine. All procedures were approved by the Animal Protection Committee of Shanghai Jiao Tong University. The investigation was carried out in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).
Animal Preparation Twelve beagles (11 ± 1.2 kg, mean ± SD) were injected intramuscularly with ketamine (10 mg/kg) and tropine (0.04 mg/kg) or anaesthetic induction. Anesthetisation was maintained intravenously with propofol (8–16 mg/kg/h) and the animal was ventilated in a restrained, dorsally recumbent position. To determine adequacy of anaesthesia, ventilation and oxygenation, arterial blood pressure, blood gases, cardiac electrical activity, body temperature and serum electrolytes were monitored and interdigital reflexes were tested throughout the entire study. After completion of data collection, the animal was terminated by an intravenous injection of potassium chloride. The heart was exposed through a median sternotomy and supported in a pericardial sling. A catheter (model 80993, IBI, St. Jude Medical) with the negative electrode into the RV apex and the positive electrode in the superior vena cava was inserted for defibrillation (Fig. 1).
Two Ventricular Endocardial Mapping with Basket Catheters A multielectrode basket (Constellation Catheter, model US8031U, Boston Scientific, Natick, MA) was introduced through a left carotid artery into LV. Another basket catheter was applied through right jugular vein into RV. Each catheter contained eight splines each with eight electrodes approximately 2 mm apart (Fig. 1). These two catheters were used to map the ventricles simultaneously.
Study Protocol DIFFERENT STAGES OF VF. Twelve dogs were randomly divided into two groups (Group A, n = 6; Group B, n = 6) (Fig. 2). VF was induced by a 30-Hz stimulation delivered (MicroPace III, EPS 320 Cardiac stimulator) through one of the basket electrodes in the RV. After the DFT of 20 s SDVF was measured, the DFTs of 3 min-LDVF (Group A) and 7 minLDVF (Group B) were determined, respectively. If return of spontaneous circulation (ROSC) was not observed within 10–20 s following defibrillation, direct cardiac compression would be initiated. ROSC was defined as an organised electrical rhythm with a systolic blood pressure of at least 80 mmHg for at least 1 min continuously at any time during the resuscitation effort [13]. Compression was interrupted briefly after 1 min for reassessment of spontaneous circulation. In the episodes where refibrillation occurred, defibrillation was performed after 1 min of compressions [14]. The DFT of the first refibrillation (R-DFT) would be measured (Fig. 2). Basket electrode recordings were then made for 15 min to document any refibrillation episodes.
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Refibrillation was defined as VF occurring more than 5 s after successful defibrillation of LDVF. DEFIBRILLATION THRESHOLD MEASUREMENT. The SDVF-DFT was determined with a three crossing bracketing protocol described in our previous study [15]. Biphasic shocks (6/4 ms) were delivered from a defibrillator (Teletronic Pacing Systems, 4510 Implant Support Device) via the defibrillating catheter. The leading edge voltage of the first shock was 400 V for the first animal. Depending on the success or failure of the shock, the leading edge voltage as decreased or increased by 40 V, respectively. The transition from failure to success or success to failure was recorded as the first data point. The up–down algorithm was continued until the third reversal of success to failure or failure to success was reached. The SDVF-DFT was determined by averaging the four shock strengths that formed the three reversals. At least 5 min elapsed after each SDVF episode to allow blood pressure and heart rate to return to normal. LDVF-DFT measurement was made as follows. The initial shock was given starting with 50% of the voltage of the SDVF-DFT. A shock was considered successful if no VF was observed within 5 s after the shock. More than 5 s asystole was defined as persistent asystole. If VF was not terminated, repeat shocks with escalation of voltage by 80 V increments were delivered until defibrillation success occurred. The lowest successful shock voltage was defined as the LDVF-DFT. The R-DFT of each group was measured with a similar ramp-up protocol as LDVF-DFT.
Data Acquisition and Analysis The two 64-electrodes of the basket catheter and the six limb-ECG leads were recorded with a 160 channel cardiac data acquisition system at a 2 kHz sampling rate and filtered with 0.5 Hz high pass and 500 Hz low pass filters. Ventricular activations were picked with a computer algorithm that selected the most negative peak in the temporal derivative during complexes that were more negative than −0.5 V/s and were verified by manual over-read. The activation rate was estimated by fast Fourier transform (FFT) analysis of VF at each electrode of basket catheter and the six limb leads of the body ECG. The frequency with the highest power between 1 and 20 Hz was taken as the activation rate. The VF cycle length (VF-CL) was defined as the reciprocal of the activation rate.
Definitions Activation was determined by visualisation of an animation of the first derivative (dV/dt) < −0.5 V/s of the unipolar electrograms recorded by the two 64-electrode baskets. Earliest activation was defined as the earliest activation front recorded after the shock that propagated throughout the myocardium, and the electrode that first recorded this activation front was labelled the earliest activation site [16]. The postshock interval was defined as the interval from the beginning of the shock until the first postshock activation at the earliest activation site. As previously described by Chen et al. [17], type A successful shocks were defined as shocks that terminated VF with a long isoelectric window (>130 ms) followed by
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Figure 1. Global electrical mapping of RV and LV endocardium. Panel I shows the fluoroscopic image of a posterior–anterior view of two basket catheters in LV and RV, and the RV defibrillation catheter. Panel II shows the display of the basket orientation in the LV and RV. R, right free wall; A, anterior free wall; L, left free wall; P, posterior free wall; and S, septum. Apical electrodes are towards the centre of the display, and basal electrodes are towards the periphery. Panel III shows the tracings of lead II of ECG, one of the basket electrodes of RV and LV recorded soon after VF onset.
Figure 2. Study design. Twelve dogs were divided into two groups. The DFTs were measured three times at SDVF, LDVF, and the first refibrillation after successful defibrillation following LDVF, respectively, in each group. In, induction of VF; DFT, defibrillation threshold; SDVF, short duration ventricular fibrillation; LDVF, long duration ventricular fibrillation; and Refib, refibrillation.
a nonshockable rhythm. Type B successful shocks were defined as shocks that terminated VF with earliest postshock electrical activity recorded ≤130 ms after the shock. Our mapping system can record the electrogram signal in 55 ms after a shock. Endocardial activations occurred synchronously during 40% or less of the cardiac cycle so that gaps with no endocardial activations were present 60% or more of the time. This activation pattern was called ventricular electrical synchrony (VES) [4]. Focal activation was defined as an activation sequence that spread in all directions centrifugally away from the origin of earliest activation. Nonfocal activation was defined as an activation sequence that spread in some directions but not others away from the origin of earliest activation.
Statistical Analysis Results were expressed as mean ± standard deviation (SD). ANOVA with repeated measurements was used to compare the DFT, VF-CL, and postshock interval
during different stages of VF. The percentage of type A/type B defibrillation and the incidence of early VF recurrence at different stages were evaluated by Chi-square test. For all analyses P < 0.05 was considered statistically significant.
Results Defibrillation Threshold During Different Stages of VF In Group A, LDVF-DFT (628 ± 98 V) was significantly higher than SDVF-DFT (473 ± 53 V) (P = 0.031, Fig. 3). There was no significant difference between the two SDVFDFTs from the two groups. In Group B, the mean DFT voltage obtained after 7 min-LDVF (313 ± 81 V) was significantly lower when compared with SDVF-DFT (483 ± 60 V) (P = 0.019) and R-DFT (570 ± 199 V) (P = 0.035). LDVF-DFT of Group B was nearly half of the DFT of 3 min-LDVF in Group A (P < 0.001) (Fig. 3). The number of shocks delivered in the same ramp-up protocol was 4.83 ± 0.98 and 2.33 ± 0.82 for 3 min-LDVF and 7 min-LDVF, respectively (P = 0.01), which indicated the decreased DFT of
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Figure 3. DFT varies over the duration of VF. Mean DFTs during different stages of VF are shown with the standard deviation indicated by an error bar. *P < 0.05 and # P < 0.01.
7 min-LDVF. The two DFTs of recurrent VF between Group A and Group B were not significantly different (Fig. 3).
Type A and B Successful Defibrillation Thirty-six successful shock episodes for SDVF (three episodes per animal) in Group A and Group B were used to analyse the postshock interval during the SDVFDFT measuring protocol. Each group had six successful shock episodes for LDVF to be analysed, respectively. Both types of successful defibrillation for SDVF were observed. Interestingly, only type A success was observed after successful shocks of 3 min-LDVF and 7 min-LDVF in the two groups. The percentage with type B defibrillation of LDVF (0 out of 12 successful shocks, 0%) was significantly lower than that of SDVF (16 out of 36 successful shocks, 44%). The postshock interval after 7 min-LDVF was significantly longer than that after 3 min LDVF (0.95 ± 0.81 s vs 5.1 ± 3.4 s, P = 0.029). None of persistent asystole with the duration more than 5 s occurred following successful shocks of 3 min-LDVF. However, three out of six hearts had persistent asystole with the mean duration of 8.1 s after successful defibrillation of 7-min LDVF.
Refibrillation Following Successful Defibrillation There was no refibrillation episode after successful defibrillation of SDVF in either two groups while early VF recurrence frequently occurred during different stages of
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LDVF. In Group A, refibrillation occurred in 5/6 successful defibrillation shocks after 3 min-LDVF. The refibrillation incidence of 3 min-LDVF after successful shock was significantly high compared with SDVF (0/18 vs 5/6, P < 0.01). In Group B, the incidence of early VF recurrence after successful defibrillation of 7 min-LDVF was much higher than that of SDVF (0/18 vs 6/6, P < 0.01). At least one refibrillation episode followed 7 min-LDVF in six animals of Group B. The number of refibrillation episodes per animal after 3 min LDVF (0.83 ± 0.41) was 36% of that for 7 min LDVF (2.3 ± 1.4, P = 0.027). All the first episode of refibrillation after 3 min and 7 min LDVF occurred within the first 3 min. Fig. 4 shows an early refibrillation following successful shock of 7 min-LDVF, which was immediately preceded by premature ventricular beats.
VES Exhibits During LDVF In Group A, VES was not observed during the first 3 min of LDVF. In Group B, at 4.8 ± 0.49 min of VF, highly synchronised activation pattern (VES) on the LV endocardium was first observed. Meanwhile, in either Group A or Group B, VES was not present in refibrillation, as measured during the 1 min of chest compressions that were performed prior to defibrillation of the refibrillation event. There was no significant difference between the mean of 10 VF-CLs of RV and LV endocardium before the exhibition of VES on the LV endocardium (Fig. 5A). The mean of 10 VFCLs of LV endocardium just after VES was longer than that of RV endocardium. The VF-CL of LV endocardium during VES was also markedly longer than that of LV endocardium without VES. The VF-CL of RV endocardium did not change significantly when VES began in the LV endocradium (Fig. 5A). Fig. 5B shows that the percentage gap only after VES began on the LV endocardium was more than 60% of VF-CL. There was no significant difference among three percentage gaps of RV and LV before VES and RV after VES. LV endocardium activation became only a small percentage of VF-CL during VES, which indicated that LV endocardial macro-reentry was not present. Isochronal map showed that LV endocardial activation during the VES cycles arose focally with no indication of reentry while RV endocardial activation appeared to be dissociated with activation of LV (Fig. 6).
Figure 4. Refibrillation after successful defibrillation following LDVF. VES can be observed on the LV endocardium before successful defibrillation after 7 min-LDVF. The shock (320 V in strength) initially terminates VF, followed by three ventricular escape beats (represented by ‘’). Early refibrillation (represented by ‘䊉’) occurs after the second and third cycles of ventricular escape beats (a couplet). The post shock interval is 8.02 s. Refib, refibrillation.
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Figure 5. VF-CL and percent gap before VES onset and during VES. Mean VF-CLs (Panel A) and percent gap (Panel B) of RV and LV are shown with the standard deviation indicated by an error bar before VES onset and during VES. VES, ventricular electrical synchrony; # P < 0.01.
Figure 6. An example of VES during 7 min-LDVF. Panel I-A and panel II-A show the tracings of lead I of ECG, one of the basket splines of RV and LV recorded at 20 s of SDVF and during VES at the 7 min of VF in one animal (data from #6). In panel II, activation rate of RV endocardium is faster than that of LV endocardium. The mean VF-CLs of RV and LV are 156 ms and 263 ms, respectively. The red lines in panel I-A and II-A represent the cardiac cycle with activation maps in panel B. Panel I-B and panel II-B show the isochronal maps of RV and LV endocardium at 20 s SDVF and during VES at 7 min-LDVF. Colours represent activation times of the 64-basket electrodes according to the time scale shown to the right. In panel II-B, activation on the LV endocardium during VES is present only a small part of the cycle length. A focal activity arises from the apical–posterior side. The orientation of the baskets in the RV and LV is given in Fig. 1. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
ECG Appearance During Different VF Stages As reported previously, the body ECG during the early stage of VF was highly irregular. FFT analysis of the limb leads of ECG showed that there was a significant difference in activation rate among VF onset, VF after 3 min and 7 min global ischaemia (11.6 ± 1.1 vs 4.1 ± 0.67 Hz, Group A, P < 0.001; 11.2 ± 1.1 vs 3.9 ± 0.59 Hz, Group B, P < 0.001). However, the body ECG continued to exhibit the disorganised pattern typical of VF although VES was present on the LV endocardium (Fig. 6).
Discussion The major findings of this study are as follows: (1) defibrillation threshold varied over the duration of VF. The DFT of 7 min-LDVF was significantly lower than that of 20 s SDVF and 3 min-LDVF; (2) refibrillation was commonly seen after successful defibrillation following 7 min-LDVF; (3) after the first 3 min of VF, a highly synchronised activation frequently occurred and arose focally on the LV endocardium; and (4) during the periods of VES, ECG
continued to exhibit a disorganised VF-like pattern because of the dissociation of RV and LV activation.
Alteration of DFT at Different Stages of VF The role of prolonged global ischaemia produced by LDVF in defibrillation efficacy is incompletely understood. Controversial results have been reported from a few mapping studies of LDVF using either internal or external defibrillation: acute prolonged global ischaemia has been reported to increase [15,18], cause no change [8,10,19] or even decrease [9,20] the LDVF-DFT when compared with SDVF-DFT. The mechanism underlying the alteration of DFT during different stages of VF in different studies is unclear, but may be related to different animals, experimental models, defibrillation waveforms, the location of defibrillation catheters, and time after VF induction. External defibrillation of LDVF during sudden cardiac arrest differs at least in two ways from internal defibrillation to halt SDVF. Firstly, the heart is in a different electrical and metabolic state [21]. Secondly, the distribution of the shock electric field throughout the heart is different. The tendency that DFT changes during the VF development may
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be similar for internal and external shock, but they could not replace each other. Tovar et al. reported that the DFT for a biphasic waveform was significantly lower after 1 min of LDVF than for SDVF (5 s). A previous optical mapping study found that DFT after 5 min ischaemia was significantly lower when compared with that at and after 10 min reperfusion. However, the above-mentioned two studies were performed in isolated rabbit hearts. In the present study, the DFT of 3 min-LDVF was significantly higher than SDVF (20 s) and the DFT became much lower during prolonged (7 min in duration) global ischaemia in in vivo canine hearts. This finding indicated that the shock energy to halt VF at the different stages did not change linearly. The DFTs of refibrillation in Groups A and B which continued 1 min for cardiac compression were not significantly different from the DFT of 3 min-LDVF but was higher than that of 7 min-LDVF (Fig. 3). Global dual ventricular endocardial mapping data of the current study showed that VF that lasted more than 3 min would be more synchronised in the LV endocardium (Figs. 5 and 6) than that within 3 min-LDVF and that within 1 min of refibrillation. Thus, the frequent occurrence of VF synchronisation and organisation may be an important regulator to affect the DFT at different stages of LDVF. Although the DFTs varied at different stages of LDVF, type A defibrillation successes were always observed after VF continued 3 min and 7 min. This finding is consistent with the idea that prolonged no-flow status suppresses postshock electrical activity. If there is no immediate postshock regeneration of VF, neither failed defibrillation nor type B defibrillation appears [17]. Because the diastolic interval appeared prolonged as VF progressed. The action potential of ventricular cells during LDVF may stay in phase 4 most of the time, which makes it unlikely that an electrical shock will fall into the repolarisation phase of the action potential and then trigger VF regeneration.
Synchronised Activation Patterns During LDVF VF in experimental models has been shown to progress through a series of stages [22,23]. Huang et al. found that VF epicardial activation exhibited an increased spatiotemporal organisation with a transient phase between 63 and 86 s after VF onset in dog hearts [22]. Global endocardial and regional transmural mapping studies in the LV indicated that highly organised and synchronous activations frequently occurred near the endocardium after around 3 min of LDVF in dogs [4,5]. However, none of the abovementioned three studies involves mapping of RV. In the current studies, we employed two 64-electrode baskets for simultaneous mapping of both LV and RV respectively. Synchronised activation pattern consistent with focal activity occurred in the LV endocardium but not in the RV (Figs. 5 and 6). VES was not occurred before the first 3 min of VF. Thus there was no VES in Group A. All six beagle hearts exhibited VES in Group B and continued until the measurement of 7 min LDVF-DFT. Thus the LDVFDFTs measured in Group B were VES related. The more organised VF can be terminated by relatively less shock
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energy [6]. Wavefront synchronisation and synchronisation of repolarisation have been shown to be important for VF termination [24–27]. A spatiotemporally controlled defibrillation strategy giving defibrillation shocks preceded by synchronised pacing can significantly improve defibrillation efficacy [27]. Thus, our data suggested that the synchronised activation in the LV endocardium might contribute to the decreased LDVF-DFT.
VF Recurrence Following Successful Defibrillation of LDVF Spontaneous refibrillation occurring about 1 min after successful defibrillation is common following LDVF but is rare following SDVF if acute ischaemia is absent. In our study, refibrillation was common after defibrillation of 3 min-LDVF (0.83 ± 0.41, episodes per animal) and 7 minLDVF (2.3 ± 1.4, episodes per animal) but not of SDVF in normal heart canine. The results suggested that early VF recurrence does not require previously diseased heart but can be caused solely by the effects of LDVF. Various factors may be related to the cause of refibrillation after successful LDVF conversion. One, mechanical stimuli can cause ventricular capture that can interact with a spontaneous activation and then lead to VF [14,28]. Another possible cause is reperfusion of global ischaemia myocardium after LDVF by compression or by ROSC. Ischaemia/reperfusion can lead to the genesis of ventricular premature beats and VF by the effects of transmembrane ionic imbalances and aberrant intracellular calcium handling [29]. Refibrillation has been shown to occur within the first minute after reperfusion of regional ischaemia in dogs [30]. All refibrillation in Groups A and B of this study occurred during the first 3 min after defibrillation (Fig. 4), which indicated that reperfusion after global ischaemia produced by LDVF may also cause these reperfusion arrhythmias.
ECG Appearance During LDVF Interestingly, the body ECG still exhibited the disorganised pattern of VF while endocardial activation on the LV endocardium was synchronous and organised during VES in this study. One possible reason of this ECG disorganisation was that activation of global RV endocardium appeared disorganised (Fig. 6) and had a different cycle length compared with LV endocardium during VES (Fig. 5). Also, the propagation of synchronous activations might be blocked when they conducted from endocardium to epicardium [5]. The different direction of propagation and the different location of activation block could lead to a complex pattern in the body ECG.
Clinical Significance There are several possible clinical implications from the current study. One, the DFT during different stages of VF did not alter linearly but appeared with a biphasic evolution. If the body ECG can be used to predict the stage of VF during cardiac resuscitation, especially for the onset of VF that is not witnessed, the rescuers could select the appropriate shock energy to halt VF based on the ECG information. As previously reported, the ischaemic
myocardium caused by LDVF is more sensitive to the damaging effects of shocks than is non-ischaemic myocardium [31]. Biphasic shocks with energies within the clinically applicable range (150–360 J) can still cause damage following LDVF [32]. Therefore, even though a single biphasic shock can terminate LDVF in most patients [33], it still may be necessary to reduce shock energy and shock episodes for defibrillation to reduce postshock damage and arrhythmias. Two, refibrillation is commonly seen after LDVF but not after SDVF in normal hearts in this study, suggesting that LDVF by itself can cause refibrillation without requiring previously diseased hearts. Electrical shock per se cannot eliminate the substrates of VF recurrence after prolonged global ischaemia. Electrical defibrillation combined with other treatment such as drugs or pacing that is to target these substrates may decrease the incidence of refibrillation during resuscitation. These ideas are required more experimental testing.
Limitations The limitations of this study are as follows. Firstly, although RV and LV endocardium were simultaneously mapped, our mapping technology cannot detect the micro-reentry in the endocardium. The basket electrodes were widely spaced so that fine details of endocardial activation sequence were not identified. Secondly, intramural recordings were not made. This study did not determine if the earliest refibrillation activation initiated from the specialised conduction system or the working myocardiocytes from epicardium and mid-wall. Thirdly, we only recorded the shock voltage and energy from the constant voltage device. It is well established that current levels are the primary determination of defibrillation effectiveness. However, previous studies have shown there were no significantly impedance changes for shocks delivered from a fixed lead configuration on individual animal. Another limitation of this study was that FFT was used to estimate the VF cycle lengths during VF, it may be more accurate if we direct counting the VF activation beat. The VF activation was directly counted in majority studies by maximum negative dV/dt. However, as VF continues, the maximum dV/dt becomes less negative. This also inhibits the accuracy in detecting VF activation.
Acknowledgements This work was supported by National Natural Science Foundation of China (nos. 81070266 and 81000081), Shanghai Science and Technology Committee Grants (10140903100 and 11ZR1422800) and by Programme for Innovative Research Team of Shanghai Municipal Education Commission.
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[19] Anastasiou-Nana MI, Tsagalou EP, Charitos C, Siafakas KX, Drakos S, Terrovitis JV, et al. Effects of transient myocardial ischemia on the ventricular defibrillation threshold. Pacing Clin Electrophysiol 2005;28(2):97–101. [20] Tovar OH, Jones JL. Electrophysiological deterioration during long-duration ventricular fibrillation. Circulation 2000;102(23):2886–91. [21] Worley SJ, Swain JL, Colavita PG, Smith WM, Ideker RE. Development of an endocardial–epicardial gradient of activation rate during electrically induced, sustained ventricular fibrillation in dogs. Am J Cardiol 1985;55(6):813–20. [22] Huang J, Rogers JM, Killingsworth CR, Singh KP, Smith WM, Ideker RE. Evolution of activation patterns during longduration ventricular fibrillation in dogs. Am J Physiol: Heart Circ Physiol 2004;286(3):H1193–200. [23] Huizar JF, Warren MD, Shvedko AG, Kalifa J, Moreno J, Mironov S, et al. Three distinct phases of VF during global ischemia in the isolated blood-perfused pig heart. Am J Physiol: Heart Circ Physiol 2007;293(3):H1617–28. [24] Kirchhof PF, Larissa Fabritz C, Franz MR. Phase angle convergence of multiple monophasic action potential recordings precedes spontaneous termination of ventricular fibrillation. Basic Res Cardiol 1998;93(5):412–21. [25] Dillon SM. Synchronized repolarization after defibrillation shocks. A possible component of the defibrillation process demonstrated by optical recordings in rabbit heart. Circulation 1992;85(5):1865–78. [26] Jones J, Noe W, Tovar O, Lin Y, Hsu W. Can shocks timed to action potentials in low-gradient regions improve both internal and out-of-hospital defibrillation? J Electrocardiol 1998;31(Suppl.):41–4.
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[27] Pak HN, Okuyama Y, Oh YS, Hayashi H, Liu YB, Chen PS, et al. Improvement of defibrillation efficacy with preshock synchronized pacing. J Cardiovasc Electrophysiol 2004;15(5):581–7. [28] Berdowski J, Tijssen JG, Koster RW. Chest compressions cause recurrence of ventricular fibrillation after the first successful conversion by defibrillation in out-of-hospital cardiac arrest. Circ Arrhythm Electrophysiol 2010;3(1):72–8. [29] Lakireddy V, Bub G, Baweja P, Syed A, Boutjdir M, El-Sherif N. The kinetics of spontaneous calcium oscillations and arrhythmogenesis in the in vivo heart during ischemia/reperfusion. HeartRhythm 2006;3(1):58–66. [30] Ideker RE, Klein GJ, Harrison L, Smith WM, Kasell J, Reimer KA, et al. The transition to ventricular fibrillation induced by reperfusion after acute ischemia in the dog: a period of organized epicardial activation. Circulation 1981;63(6):1371–9. [31] Tang W, Weil MH, Sun S, Yamaguchi H, Povoas HP, Pernat AM, et al. The effects of biphasic and conventional monophasic defibrillation on postresuscitation myocardial function. J Am Coll Cardiol 1999;34(3):815–22. [32] Tang W, Weil MH, Sun S, Jorgenson D, Morgan C, Klouche K, et al. The effects of biphasic waveform design on post-resuscitation myocardial function. J Am Coll Cardiol 2004;43(7):1228–35. [33] Schneider T, Martens PR, Paschen H, Kuisma M, Wolcke B, Gliner BE, et al. Multicenter, randomized, controlled trial of 150-J biphasic shocks compared with 200- to 360-J monophasic shocks in the resuscitation of out-of-hospital cardiac arrest victims. Optimized Response to Cardiac Arrest (ORCA) Investigators. Circulation 2000;102(15): 1780–7.
Original Article
Defibrillation Threshold Varies During Different Stages of Ventricular Fibrillation in Canine Hearts Qi Jin, MD a,1 , Jian Zhou, MD a,1 , Ning Zhang, MD a , Changjian Lin, MD a , Yang Pang, MD a , Yangxun Xin, MD a , Jiajun Pan, MD b , Gang Gu, MD a , Weifeng Shen, MD, PhD a,∗ and Liqun Wu, MD, PhD a,∗ a
Department of Cardiology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, PR China b Department of Cardiology, Shanghai Luwan Hospital, Shanghai, PR China
Background: Recent studies have shown that short duration ventricular fibrillation (SDVF) and long duration ventricular fibrillation (LDVF) are maintained by different mechanisms. The objective of this study is to evaluate how the defibrillation threshold (DFT) varies over the duration of fibrillation since the mechanism of VF maintenance changes as VF progresses. Methods: Twelve canines were randomly divided into two groups (Group A and B, n = 6 each). DFTs were measured three times in each group: SDVF (20 s), LDVF (3 min in Group A and 7 min in Group B) and the first episode of refibrillation after successful defibrillation for LDVF. Two 64-electrode baskets used to globally map the endocardium were deployed into the left ventricle and right ventricle, respectively. Results: LDVF-DFT in Group A was significantly higher than that of Group B (628 ± 98 V vs 313 ± 81 V, P < 0.001). In Group B, the DFT of refibrillation was significantly increased compared with the LDVF-DFT (570 ± 199 V vs 313 ± 81 V, P = 0.035) but did not differ from the DFT of refibrillation in Group A (570 ± 199 V vs 638 ± 116 V, P = 0.39). Highly synchronised activation patterns on the left ventricular endocardium were observed between 3 and 7 min of LDVF in Group B but not within 3 min-LDVF in Group A or during refibrillation in each group. Conclusions: DFT varied during different stages of VF. The highly synchronised activation patterns exhibiting after 3 min VF might contribute to the decreased LDVF-DFT. (Heart, Lung and Circulation 2013;22:133–140) © 2012 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved. Keywords. Ventricular fibrillation; Defibrillation; Electrophysiology; Resuscitation
Introduction
R
ecent studies have shown that short duration ventricular fibrillation (SDVF; VF duration < 1 min) and long duration ventricular fibrillation (LDVF; VF duration > 1 min) can be maintained by different mechanisms [1–3]. Intramural reentry disappeared in the porcine left ventricle (LV) after the first 2–3 min of VF, while focal activity in the mid-wall increased during 10 min of VF [1]. Electrical mapping studies of global LV endocardium and regional transmural myocardium have demonstrated that after 3–7 min of LDVF, activations become highly organised and synchronised in the endocardium of canine Received 18 July 2012; received in revised form 9 August 2012; accepted 29 August 2012; available online 27 September 2012 ∗
Corresponding authors at: Department of Cardiology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, No. 197, Shanghai Ruijin Er Road, Shanghai 200025, PR China. Tel.: +86 021 64310871; fax: +86 021 64310871. E-mail addresses: [email protected] (W. Shen), [email protected] (L. Wu). 1 The first two authors contributed equally to this work.
hearts [4,5]. The more organised VF can be terminated by relatively less shock energy [6]. Wavefront synchronisation is also an important aspect preceding the termination of VF [7]. Thus, defibrillation mechanism and efficacy may differ during different stages of VF since the mechanism and activation patterns alter with the duration of VF [8,9]. While refibrillation is infrequent following SDVF, it is commonly seen after successful defibrillation for LDVF [9–12]. A clinical study has demonstrated that 79% patients with sudden cardiac arrest had at least one recurrence of VF with a median of two recurrences and that refibrillation significantly decreased the survival rate [12]. Therefore, the objective of this study was to evaluate how the defibrillation threshold (DFT) and refibrillation occurrence altered over the duration of fibrillation by simultaneously global endocardial mapping of right ventricle (RV) and LV in canine hearts.
Methods All animals were purchased from Shanghai Jiao Tong University Agriculture College of China and raised under
© 2012 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved.
1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2012.08.059
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controlled conditions in the Department of Animals for Scientific Research, Shanghai Jiao Tong University School of Medicine. All procedures were approved by the Animal Protection Committee of Shanghai Jiao Tong University. The investigation was carried out in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).
Animal Preparation Twelve beagles (11 ± 1.2 kg, mean ± SD) were injected intramuscularly with ketamine (10 mg/kg) and tropine (0.04 mg/kg) or anaesthetic induction. Anesthetisation was maintained intravenously with propofol (8–16 mg/kg/h) and the animal was ventilated in a restrained, dorsally recumbent position. To determine adequacy of anaesthesia, ventilation and oxygenation, arterial blood pressure, blood gases, cardiac electrical activity, body temperature and serum electrolytes were monitored and interdigital reflexes were tested throughout the entire study. After completion of data collection, the animal was terminated by an intravenous injection of potassium chloride. The heart was exposed through a median sternotomy and supported in a pericardial sling. A catheter (model 80993, IBI, St. Jude Medical) with the negative electrode into the RV apex and the positive electrode in the superior vena cava was inserted for defibrillation (Fig. 1).
Two Ventricular Endocardial Mapping with Basket Catheters A multielectrode basket (Constellation Catheter, model US8031U, Boston Scientific, Natick, MA) was introduced through a left carotid artery into LV. Another basket catheter was applied through right jugular vein into RV. Each catheter contained eight splines each with eight electrodes approximately 2 mm apart (Fig. 1). These two catheters were used to map the ventricles simultaneously.
Study Protocol DIFFERENT STAGES OF VF. Twelve dogs were randomly divided into two groups (Group A, n = 6; Group B, n = 6) (Fig. 2). VF was induced by a 30-Hz stimulation delivered (MicroPace III, EPS 320 Cardiac stimulator) through one of the basket electrodes in the RV. After the DFT of 20 s SDVF was measured, the DFTs of 3 min-LDVF (Group A) and 7 minLDVF (Group B) were determined, respectively. If return of spontaneous circulation (ROSC) was not observed within 10–20 s following defibrillation, direct cardiac compression would be initiated. ROSC was defined as an organised electrical rhythm with a systolic blood pressure of at least 80 mmHg for at least 1 min continuously at any time during the resuscitation effort [13]. Compression was interrupted briefly after 1 min for reassessment of spontaneous circulation. In the episodes where refibrillation occurred, defibrillation was performed after 1 min of compressions [14]. The DFT of the first refibrillation (R-DFT) would be measured (Fig. 2). Basket electrode recordings were then made for 15 min to document any refibrillation episodes.
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Refibrillation was defined as VF occurring more than 5 s after successful defibrillation of LDVF. DEFIBRILLATION THRESHOLD MEASUREMENT. The SDVF-DFT was determined with a three crossing bracketing protocol described in our previous study [15]. Biphasic shocks (6/4 ms) were delivered from a defibrillator (Teletronic Pacing Systems, 4510 Implant Support Device) via the defibrillating catheter. The leading edge voltage of the first shock was 400 V for the first animal. Depending on the success or failure of the shock, the leading edge voltage as decreased or increased by 40 V, respectively. The transition from failure to success or success to failure was recorded as the first data point. The up–down algorithm was continued until the third reversal of success to failure or failure to success was reached. The SDVF-DFT was determined by averaging the four shock strengths that formed the three reversals. At least 5 min elapsed after each SDVF episode to allow blood pressure and heart rate to return to normal. LDVF-DFT measurement was made as follows. The initial shock was given starting with 50% of the voltage of the SDVF-DFT. A shock was considered successful if no VF was observed within 5 s after the shock. More than 5 s asystole was defined as persistent asystole. If VF was not terminated, repeat shocks with escalation of voltage by 80 V increments were delivered until defibrillation success occurred. The lowest successful shock voltage was defined as the LDVF-DFT. The R-DFT of each group was measured with a similar ramp-up protocol as LDVF-DFT.
Data Acquisition and Analysis The two 64-electrodes of the basket catheter and the six limb-ECG leads were recorded with a 160 channel cardiac data acquisition system at a 2 kHz sampling rate and filtered with 0.5 Hz high pass and 500 Hz low pass filters. Ventricular activations were picked with a computer algorithm that selected the most negative peak in the temporal derivative during complexes that were more negative than −0.5 V/s and were verified by manual over-read. The activation rate was estimated by fast Fourier transform (FFT) analysis of VF at each electrode of basket catheter and the six limb leads of the body ECG. The frequency with the highest power between 1 and 20 Hz was taken as the activation rate. The VF cycle length (VF-CL) was defined as the reciprocal of the activation rate.
Definitions Activation was determined by visualisation of an animation of the first derivative (dV/dt) < −0.5 V/s of the unipolar electrograms recorded by the two 64-electrode baskets. Earliest activation was defined as the earliest activation front recorded after the shock that propagated throughout the myocardium, and the electrode that first recorded this activation front was labelled the earliest activation site [16]. The postshock interval was defined as the interval from the beginning of the shock until the first postshock activation at the earliest activation site. As previously described by Chen et al. [17], type A successful shocks were defined as shocks that terminated VF with a long isoelectric window (>130 ms) followed by
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Figure 1. Global electrical mapping of RV and LV endocardium. Panel I shows the fluoroscopic image of a posterior–anterior view of two basket catheters in LV and RV, and the RV defibrillation catheter. Panel II shows the display of the basket orientation in the LV and RV. R, right free wall; A, anterior free wall; L, left free wall; P, posterior free wall; and S, septum. Apical electrodes are towards the centre of the display, and basal electrodes are towards the periphery. Panel III shows the tracings of lead II of ECG, one of the basket electrodes of RV and LV recorded soon after VF onset.
Figure 2. Study design. Twelve dogs were divided into two groups. The DFTs were measured three times at SDVF, LDVF, and the first refibrillation after successful defibrillation following LDVF, respectively, in each group. In, induction of VF; DFT, defibrillation threshold; SDVF, short duration ventricular fibrillation; LDVF, long duration ventricular fibrillation; and Refib, refibrillation.
a nonshockable rhythm. Type B successful shocks were defined as shocks that terminated VF with earliest postshock electrical activity recorded ≤130 ms after the shock. Our mapping system can record the electrogram signal in 55 ms after a shock. Endocardial activations occurred synchronously during 40% or less of the cardiac cycle so that gaps with no endocardial activations were present 60% or more of the time. This activation pattern was called ventricular electrical synchrony (VES) [4]. Focal activation was defined as an activation sequence that spread in all directions centrifugally away from the origin of earliest activation. Nonfocal activation was defined as an activation sequence that spread in some directions but not others away from the origin of earliest activation.
Statistical Analysis Results were expressed as mean ± standard deviation (SD). ANOVA with repeated measurements was used to compare the DFT, VF-CL, and postshock interval
during different stages of VF. The percentage of type A/type B defibrillation and the incidence of early VF recurrence at different stages were evaluated by Chi-square test. For all analyses P < 0.05 was considered statistically significant.
Results Defibrillation Threshold During Different Stages of VF In Group A, LDVF-DFT (628 ± 98 V) was significantly higher than SDVF-DFT (473 ± 53 V) (P = 0.031, Fig. 3). There was no significant difference between the two SDVFDFTs from the two groups. In Group B, the mean DFT voltage obtained after 7 min-LDVF (313 ± 81 V) was significantly lower when compared with SDVF-DFT (483 ± 60 V) (P = 0.019) and R-DFT (570 ± 199 V) (P = 0.035). LDVF-DFT of Group B was nearly half of the DFT of 3 min-LDVF in Group A (P < 0.001) (Fig. 3). The number of shocks delivered in the same ramp-up protocol was 4.83 ± 0.98 and 2.33 ± 0.82 for 3 min-LDVF and 7 min-LDVF, respectively (P = 0.01), which indicated the decreased DFT of
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Figure 3. DFT varies over the duration of VF. Mean DFTs during different stages of VF are shown with the standard deviation indicated by an error bar. *P < 0.05 and # P < 0.01.
7 min-LDVF. The two DFTs of recurrent VF between Group A and Group B were not significantly different (Fig. 3).
Type A and B Successful Defibrillation Thirty-six successful shock episodes for SDVF (three episodes per animal) in Group A and Group B were used to analyse the postshock interval during the SDVFDFT measuring protocol. Each group had six successful shock episodes for LDVF to be analysed, respectively. Both types of successful defibrillation for SDVF were observed. Interestingly, only type A success was observed after successful shocks of 3 min-LDVF and 7 min-LDVF in the two groups. The percentage with type B defibrillation of LDVF (0 out of 12 successful shocks, 0%) was significantly lower than that of SDVF (16 out of 36 successful shocks, 44%). The postshock interval after 7 min-LDVF was significantly longer than that after 3 min LDVF (0.95 ± 0.81 s vs 5.1 ± 3.4 s, P = 0.029). None of persistent asystole with the duration more than 5 s occurred following successful shocks of 3 min-LDVF. However, three out of six hearts had persistent asystole with the mean duration of 8.1 s after successful defibrillation of 7-min LDVF.
Refibrillation Following Successful Defibrillation There was no refibrillation episode after successful defibrillation of SDVF in either two groups while early VF recurrence frequently occurred during different stages of
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LDVF. In Group A, refibrillation occurred in 5/6 successful defibrillation shocks after 3 min-LDVF. The refibrillation incidence of 3 min-LDVF after successful shock was significantly high compared with SDVF (0/18 vs 5/6, P < 0.01). In Group B, the incidence of early VF recurrence after successful defibrillation of 7 min-LDVF was much higher than that of SDVF (0/18 vs 6/6, P < 0.01). At least one refibrillation episode followed 7 min-LDVF in six animals of Group B. The number of refibrillation episodes per animal after 3 min LDVF (0.83 ± 0.41) was 36% of that for 7 min LDVF (2.3 ± 1.4, P = 0.027). All the first episode of refibrillation after 3 min and 7 min LDVF occurred within the first 3 min. Fig. 4 shows an early refibrillation following successful shock of 7 min-LDVF, which was immediately preceded by premature ventricular beats.
VES Exhibits During LDVF In Group A, VES was not observed during the first 3 min of LDVF. In Group B, at 4.8 ± 0.49 min of VF, highly synchronised activation pattern (VES) on the LV endocardium was first observed. Meanwhile, in either Group A or Group B, VES was not present in refibrillation, as measured during the 1 min of chest compressions that were performed prior to defibrillation of the refibrillation event. There was no significant difference between the mean of 10 VF-CLs of RV and LV endocardium before the exhibition of VES on the LV endocardium (Fig. 5A). The mean of 10 VFCLs of LV endocardium just after VES was longer than that of RV endocardium. The VF-CL of LV endocardium during VES was also markedly longer than that of LV endocardium without VES. The VF-CL of RV endocardium did not change significantly when VES began in the LV endocradium (Fig. 5A). Fig. 5B shows that the percentage gap only after VES began on the LV endocardium was more than 60% of VF-CL. There was no significant difference among three percentage gaps of RV and LV before VES and RV after VES. LV endocardium activation became only a small percentage of VF-CL during VES, which indicated that LV endocardial macro-reentry was not present. Isochronal map showed that LV endocardial activation during the VES cycles arose focally with no indication of reentry while RV endocardial activation appeared to be dissociated with activation of LV (Fig. 6).
Figure 4. Refibrillation after successful defibrillation following LDVF. VES can be observed on the LV endocardium before successful defibrillation after 7 min-LDVF. The shock (320 V in strength) initially terminates VF, followed by three ventricular escape beats (represented by ‘’). Early refibrillation (represented by ‘䊉’) occurs after the second and third cycles of ventricular escape beats (a couplet). The post shock interval is 8.02 s. Refib, refibrillation.
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Figure 5. VF-CL and percent gap before VES onset and during VES. Mean VF-CLs (Panel A) and percent gap (Panel B) of RV and LV are shown with the standard deviation indicated by an error bar before VES onset and during VES. VES, ventricular electrical synchrony; # P < 0.01.
Figure 6. An example of VES during 7 min-LDVF. Panel I-A and panel II-A show the tracings of lead I of ECG, one of the basket splines of RV and LV recorded at 20 s of SDVF and during VES at the 7 min of VF in one animal (data from #6). In panel II, activation rate of RV endocardium is faster than that of LV endocardium. The mean VF-CLs of RV and LV are 156 ms and 263 ms, respectively. The red lines in panel I-A and II-A represent the cardiac cycle with activation maps in panel B. Panel I-B and panel II-B show the isochronal maps of RV and LV endocardium at 20 s SDVF and during VES at 7 min-LDVF. Colours represent activation times of the 64-basket electrodes according to the time scale shown to the right. In panel II-B, activation on the LV endocardium during VES is present only a small part of the cycle length. A focal activity arises from the apical–posterior side. The orientation of the baskets in the RV and LV is given in Fig. 1. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
ECG Appearance During Different VF Stages As reported previously, the body ECG during the early stage of VF was highly irregular. FFT analysis of the limb leads of ECG showed that there was a significant difference in activation rate among VF onset, VF after 3 min and 7 min global ischaemia (11.6 ± 1.1 vs 4.1 ± 0.67 Hz, Group A, P < 0.001; 11.2 ± 1.1 vs 3.9 ± 0.59 Hz, Group B, P < 0.001). However, the body ECG continued to exhibit the disorganised pattern typical of VF although VES was present on the LV endocardium (Fig. 6).
Discussion The major findings of this study are as follows: (1) defibrillation threshold varied over the duration of VF. The DFT of 7 min-LDVF was significantly lower than that of 20 s SDVF and 3 min-LDVF; (2) refibrillation was commonly seen after successful defibrillation following 7 min-LDVF; (3) after the first 3 min of VF, a highly synchronised activation frequently occurred and arose focally on the LV endocardium; and (4) during the periods of VES, ECG
continued to exhibit a disorganised VF-like pattern because of the dissociation of RV and LV activation.
Alteration of DFT at Different Stages of VF The role of prolonged global ischaemia produced by LDVF in defibrillation efficacy is incompletely understood. Controversial results have been reported from a few mapping studies of LDVF using either internal or external defibrillation: acute prolonged global ischaemia has been reported to increase [15,18], cause no change [8,10,19] or even decrease [9,20] the LDVF-DFT when compared with SDVF-DFT. The mechanism underlying the alteration of DFT during different stages of VF in different studies is unclear, but may be related to different animals, experimental models, defibrillation waveforms, the location of defibrillation catheters, and time after VF induction. External defibrillation of LDVF during sudden cardiac arrest differs at least in two ways from internal defibrillation to halt SDVF. Firstly, the heart is in a different electrical and metabolic state [21]. Secondly, the distribution of the shock electric field throughout the heart is different. The tendency that DFT changes during the VF development may
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be similar for internal and external shock, but they could not replace each other. Tovar et al. reported that the DFT for a biphasic waveform was significantly lower after 1 min of LDVF than for SDVF (5 s). A previous optical mapping study found that DFT after 5 min ischaemia was significantly lower when compared with that at and after 10 min reperfusion. However, the above-mentioned two studies were performed in isolated rabbit hearts. In the present study, the DFT of 3 min-LDVF was significantly higher than SDVF (20 s) and the DFT became much lower during prolonged (7 min in duration) global ischaemia in in vivo canine hearts. This finding indicated that the shock energy to halt VF at the different stages did not change linearly. The DFTs of refibrillation in Groups A and B which continued 1 min for cardiac compression were not significantly different from the DFT of 3 min-LDVF but was higher than that of 7 min-LDVF (Fig. 3). Global dual ventricular endocardial mapping data of the current study showed that VF that lasted more than 3 min would be more synchronised in the LV endocardium (Figs. 5 and 6) than that within 3 min-LDVF and that within 1 min of refibrillation. Thus, the frequent occurrence of VF synchronisation and organisation may be an important regulator to affect the DFT at different stages of LDVF. Although the DFTs varied at different stages of LDVF, type A defibrillation successes were always observed after VF continued 3 min and 7 min. This finding is consistent with the idea that prolonged no-flow status suppresses postshock electrical activity. If there is no immediate postshock regeneration of VF, neither failed defibrillation nor type B defibrillation appears [17]. Because the diastolic interval appeared prolonged as VF progressed. The action potential of ventricular cells during LDVF may stay in phase 4 most of the time, which makes it unlikely that an electrical shock will fall into the repolarisation phase of the action potential and then trigger VF regeneration.
Synchronised Activation Patterns During LDVF VF in experimental models has been shown to progress through a series of stages [22,23]. Huang et al. found that VF epicardial activation exhibited an increased spatiotemporal organisation with a transient phase between 63 and 86 s after VF onset in dog hearts [22]. Global endocardial and regional transmural mapping studies in the LV indicated that highly organised and synchronous activations frequently occurred near the endocardium after around 3 min of LDVF in dogs [4,5]. However, none of the abovementioned three studies involves mapping of RV. In the current studies, we employed two 64-electrode baskets for simultaneous mapping of both LV and RV respectively. Synchronised activation pattern consistent with focal activity occurred in the LV endocardium but not in the RV (Figs. 5 and 6). VES was not occurred before the first 3 min of VF. Thus there was no VES in Group A. All six beagle hearts exhibited VES in Group B and continued until the measurement of 7 min LDVF-DFT. Thus the LDVFDFTs measured in Group B were VES related. The more organised VF can be terminated by relatively less shock
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energy [6]. Wavefront synchronisation and synchronisation of repolarisation have been shown to be important for VF termination [24–27]. A spatiotemporally controlled defibrillation strategy giving defibrillation shocks preceded by synchronised pacing can significantly improve defibrillation efficacy [27]. Thus, our data suggested that the synchronised activation in the LV endocardium might contribute to the decreased LDVF-DFT.
VF Recurrence Following Successful Defibrillation of LDVF Spontaneous refibrillation occurring about 1 min after successful defibrillation is common following LDVF but is rare following SDVF if acute ischaemia is absent. In our study, refibrillation was common after defibrillation of 3 min-LDVF (0.83 ± 0.41, episodes per animal) and 7 minLDVF (2.3 ± 1.4, episodes per animal) but not of SDVF in normal heart canine. The results suggested that early VF recurrence does not require previously diseased heart but can be caused solely by the effects of LDVF. Various factors may be related to the cause of refibrillation after successful LDVF conversion. One, mechanical stimuli can cause ventricular capture that can interact with a spontaneous activation and then lead to VF [14,28]. Another possible cause is reperfusion of global ischaemia myocardium after LDVF by compression or by ROSC. Ischaemia/reperfusion can lead to the genesis of ventricular premature beats and VF by the effects of transmembrane ionic imbalances and aberrant intracellular calcium handling [29]. Refibrillation has been shown to occur within the first minute after reperfusion of regional ischaemia in dogs [30]. All refibrillation in Groups A and B of this study occurred during the first 3 min after defibrillation (Fig. 4), which indicated that reperfusion after global ischaemia produced by LDVF may also cause these reperfusion arrhythmias.
ECG Appearance During LDVF Interestingly, the body ECG still exhibited the disorganised pattern of VF while endocardial activation on the LV endocardium was synchronous and organised during VES in this study. One possible reason of this ECG disorganisation was that activation of global RV endocardium appeared disorganised (Fig. 6) and had a different cycle length compared with LV endocardium during VES (Fig. 5). Also, the propagation of synchronous activations might be blocked when they conducted from endocardium to epicardium [5]. The different direction of propagation and the different location of activation block could lead to a complex pattern in the body ECG.
Clinical Significance There are several possible clinical implications from the current study. One, the DFT during different stages of VF did not alter linearly but appeared with a biphasic evolution. If the body ECG can be used to predict the stage of VF during cardiac resuscitation, especially for the onset of VF that is not witnessed, the rescuers could select the appropriate shock energy to halt VF based on the ECG information. As previously reported, the ischaemic
myocardium caused by LDVF is more sensitive to the damaging effects of shocks than is non-ischaemic myocardium [31]. Biphasic shocks with energies within the clinically applicable range (150–360 J) can still cause damage following LDVF [32]. Therefore, even though a single biphasic shock can terminate LDVF in most patients [33], it still may be necessary to reduce shock energy and shock episodes for defibrillation to reduce postshock damage and arrhythmias. Two, refibrillation is commonly seen after LDVF but not after SDVF in normal hearts in this study, suggesting that LDVF by itself can cause refibrillation without requiring previously diseased hearts. Electrical shock per se cannot eliminate the substrates of VF recurrence after prolonged global ischaemia. Electrical defibrillation combined with other treatment such as drugs or pacing that is to target these substrates may decrease the incidence of refibrillation during resuscitation. These ideas are required more experimental testing.
Limitations The limitations of this study are as follows. Firstly, although RV and LV endocardium were simultaneously mapped, our mapping technology cannot detect the micro-reentry in the endocardium. The basket electrodes were widely spaced so that fine details of endocardial activation sequence were not identified. Secondly, intramural recordings were not made. This study did not determine if the earliest refibrillation activation initiated from the specialised conduction system or the working myocardiocytes from epicardium and mid-wall. Thirdly, we only recorded the shock voltage and energy from the constant voltage device. It is well established that current levels are the primary determination of defibrillation effectiveness. However, previous studies have shown there were no significantly impedance changes for shocks delivered from a fixed lead configuration on individual animal. Another limitation of this study was that FFT was used to estimate the VF cycle lengths during VF, it may be more accurate if we direct counting the VF activation beat. The VF activation was directly counted in majority studies by maximum negative dV/dt. However, as VF continues, the maximum dV/dt becomes less negative. This also inhibits the accuracy in detecting VF activation.
Acknowledgements This work was supported by National Natural Science Foundation of China (nos. 81070266 and 81000081), Shanghai Science and Technology Committee Grants (10140903100 and 11ZR1422800) and by Programme for Innovative Research Team of Shanghai Municipal Education Commission.
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