Ajmaline Challenge for the Diagnosis of Brugada Syndrome: Which Protocol?

Archives of Cardiovascular Disease (2010) 103, 570—578

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CLINICAL RESEARCH Ajmaline challenge for the diagnosis of Brugada syndrome: Which protocol?

Test à l’ajmaline pour le diagnostic du syndrome de Brugada: quel protocole?

Elise Arnalsteen-Dassonvalle a, Jean-Sylvain Hermida a,∗, Maciev Kubala a, Isabelle Six a, Serge Quenum a, Laurent Leborgne b, Geneviève Jarry b

a Centre d’activité de rythmologie, Amiens-Picardie University Hospital, 80054 Amiens cedex 1, France b Unité de Soins Intensifs de Cardiologie, Amiens-Picardie University Hospital, Amiens, France

Received 21 April 2010; received in revised form 6 October 2010; accepted 7 October 2010

KEYWORDS Summary Brugada syndrome; Background. — Ajmaline challenge is commonly used for the diagnosis of Brugada syndrome. A Ajmaline challenge; slow infusion rate has been recommended in view of the proarrhythmic risk, but the diagnostic Ventricular value of various infusion rates has not been investigated. arrhythmia; Aims. — To compare rapid and slow ajmaline infusion rates and to assess the proarrhythmic risk. Isoproterenol Methods. — The first part of this study prospectively compared rapid and slow infusion rates in terms of results and ventricular arrhythmias. Thirty-two patients (mean age 41 ± 12 years; 26 men) received the two ajmaline challenges on different days. According to randomization, ajmaline (1 mg/kg) was infused at 1 mg/sec or over 10 minutes. The second part of the study ret- rospectively assessed the prevalence of ventricular arrhythmia during 386 challenges performed at a rapid infusion rate. Results. — No differences were observed between rapid and slow tests. All patients diagnosed as positive or negative with one test obtained the same result with the other test. Ventricular premature beats were observed in five of 32 patients during the slow challenge and in four of 32 patients during the rapid challenge. No sustained ventricular arrhythmias were observed. Anal- ysis of the 386 tests revealed four episodes of ventricular arrhythmia (two complex ventricular premature beats, one non-sustained ventricular tachycardia and one ventricular fibrillation).

Abbreviations: BS, Brugada syndrome; ECG, electrocardiogram; NSVT, non-sustained ventricular tachycardia; VA, ventricular arrhythmia; VF, ventricular ﬁbrillation; VPB, ventricular premature beat; VT, ventricular tachycardia. ∗ Corresponding author. Fax: +33 3 22 45 56 61. E-mail addresses: [email protected], [email protected] (J.-S. Hermida).

Conclusion. — Slow and rapid infusions of ajmaline have identical diagnostic performances on suspected Brugada electrocardiograms. Owing to the risk of severe proarrhythmia, a slow infusion rate, allowing early discontinuation, should be recommended. © 2010 Elsevier Masson SAS. All rights reserved.

MOTS CLÉS Résumé Syndrome de Background. — Le test à l’ajmaline est couramment utilisé pour le diagnostic du syndrome Brugada ; de Brugada. Une administration lente de l’ajmaline est recommandée en raison du risque Test à l’ajmaline ; d’arythmie, mais sa valeur diagnostique n’a pas été évaluée. Arythmie Objectifs. — Comparer la valeur diagnostique des vitesses rapide et lente d’administration de ventriculaire ; l’ajmaline et évaluer le risque proarythmogène. Isoprénaline Méthodes. — La première partie de l’étude a consisté à comparer de façon prospective les résultats et le taux de survenue d’arythmie ventriculaire pour deux vitesses d’administration de l’ajmaline. Trente-deux patients (hommes = 26; moyenne d’âge 41 ± 12 ans) ont réalisé deux tests à l’ajmaline sur deux jours distincts. Selon la randomisation, l’ajmaline (1 mg/kg) a été administrée à la vitesse d’1 mg/s ou sur dix minutes. La seconde partie de l’étude a évalué de façon rétrospective la prévalence des arythmies ventriculaires de 386 tests réalisés avec un protocole rapide d’administration de l’ajmaline. Résultats. — Aucune différence n’a été observée entre le test rapid et le test long. Tous les patients ayant un test rapide positif (15/32 [47 %]), ont eu également un résultat positif pour le test long. Des extrasystoles ventriculaires isolées ont été observées chez cinq sur 32 patients durant le test long et chez quatre sur 32 patients lors du test rapide. Aucun épisode d’arythmie ventriculaire soutenue n’est survenu. L’analyse des 386 tests rapides a mis en évi- dence quatre épisodes d’arythmie ventriculaire (deux extrasystoles ventriculaires complexes, une tachycardie ventriculaire non soutenue, une fibrillation ventriculaire). Conclusion. — Les protocoles rapide et lent d’administration de l’ajmaline offrent les mêmes performances diagnostiques dans les suspicions d’ECG de Brugada. En raison du risque d’arythmie ventriculaire sévère, une administration plus lente, permettant l’arrêt précoce de l’injection, est préconisée. © 2010 Elsevier Masson SAS. Tous droits réservés.

Background 1 mg/kg over 10 minutes [4]. No randomized study has compared the sensitivity/specificity and risks associated with BS is associated with a risk of sudden death due to VF the various ajmaline administration protocols. Ajmaline [1]. ECG abnormalities include J point elevation by at induces concentration-dependent, frequency-independent least 0.2 mV and a coved pattern of the ST segment with and voltage-dependent sodium channel blockade [12], and a negative T wave in the right precordial leads. Right concentration-dependent and frequency-independent inhi- bundle branch block can also be associated with the syn- bition of the transient outward potassium current [13]. The drome [2]. These signs are sometimes intermittent. In rate of administration of ajmaline, by modifying the peak 1996, Miyasaki et al. showed that ST elevation can be plasma concentration, can alter potassium channel inacti- revealed by the use of sodium channel blocking agents vation and reactivation kinetics and modulate the intensity [3]. Ajmaline and flecainide have been used in Europe, and duration of sodium channel blockade. Furthermore, as procainamide in the USA and pilsicainide in Japan. The the time to onset of action of ajmaline is 2 to 3 minutes, various drugs have been compared, and ajmaline has the rapid injection of ajmaline (1 mg/sec for a dose of 1 mg/kg) highest sensitivity for detection of BS [4]. However, ajma- induces higher cardiac concentrations than the same dose line may have proarrhythmic effects and different infusion injected over 10 minutes. Rapid injection could accentuate rates have been recommended [2,5—8]. Administration of J point elevation during the first minutes to the detriment 1 mg/kg at the rate of 10 mg/min was proposed at the first of the specificity of the test. Inversely, the dose injected consensus conference [2]. Ajmaline challenge stopping cri- over 10 minutes could reduce the sensitivity of the test. The teria were defined in 2003 in order to avoid proarrhythmic objective of this study was to compare the electrocardio- effects. Fractionated administration of a dose of 10 mg every graphic effects of two rates of administration of ajmaline 2 minutes to reach a total dose of 1 mg/kg was proposed and to determine whether the diagnostic contribution is [8]. In 2005, the second consensus conference recommended modified by the ajmaline administration rate. Retrospec- a dose of 1 mg/kg over 5 minutes [9]. Other teams have tive evaluation of the prevalence of VA in a series of 386 reported their experience with protocols used to study tests performed with injection of 1 mg/sec was designed conduction disorders, i.e. 1 mg/kg at a rate of 1 mg/sec to estimate the proarrhythmic risk during rapid injection of [10,11]. Finally, other authors (such as Wolpert et al.) use ajmaline. 572 E. Arnalsteen-Dassonvalle et al.

Methods A paired Student’s t test was used to compare paired variables. Tests were considered to be significant for p < 0.05. Patients Statistical analysis was performed with SPSS software Ver- sion 11 (SPSS Inc., Chicago, IL, USA). The study was approved by the local ethics committee. Each subject signed an informed consent form. Between 2005 and 2008, 32 consecutive subjects with type 2 or 3 BS Results were prospectively included in the first phase of the study. In this population, ECG changes were disclosed after the Part I onset of symptoms, incidentally or in the context of family screening. Exclusion criteria were contraindications to Study population ajmaline (previous myocardial infarction, heart failure or Subjects had a mean age of 40.9 ± 12 years (range 19—69); impaired left ventricular ejection fraction, complete left the sex ratio was 4.3 (81.2% men). Patients had a type 2 ECG bundle branch block, bifascicular block, second- or third- in 22 (68.8%) cases and a type 3 ECG in 10 (31.2%) cases. degree atrioventricular block, use of a class I antiarrhythmic Symptoms consisted of syncope (n = 5), faintness (n =2) or agent, pregnancy or breastfeeding, children under the age palpitations (n = 11). The other subjects were asymptomatic of 15 years). (n = 14) and their ECG abnormality was found during a family The second phase of the study consisted of retrospec- screening (n = 7) or fortuitously (n = 7). tive evaluation of ajmaline challenges performed with the rapid injection protocol between January 2002 and July Test results 2009. This phase comprised 386 subjects in whom the test The concordance between rapid tests and slow tests was was performed for family screening of BS or sudden death, 100%. All patients diagnosed as positive or negative with one unexplained syncope, discovery of type 2 or 3 ECG, or test obtained the same result with the other test. No dif- resuscitated cardiac arrest. ECG recordings were reviewed ference in the results was observed between the two tests specifically for the analysis of VAs. Single VPBs, complex according to readings by the two observers (Fig. 1). The VPBs (frequent VPBs, polymorphic VPBs, bigeminy, cou- positive ajmaline challenge rate was 46.9% (15/32). Ajma- plets), NSVT and VF were notified. line challenges were more often positive for type 2 ECGs than for type 3 ECGs (p < 0.001). No significant difference in Ajmaline challenges the VPB rate was observed according to the protocol used (p = 0.51). VPBs occurred in three subjects during positive Ajmaline challenges were conducted in the electrophysi- tests and in five subjects during negative tests. No runs of ology laboratory, in the presence of a cardiologist. Each VPBs were observed during the 64 tests; ECG changes were patient underwent two ajmaline challenges, and the order identical for the two protocols (Table 1) and for both positive was determined by randomization, with a crossover design. and negative tests, except for the QTc interval (Table 2). The The two tests were performed on different days, < 1 month maximum variation of the amplitude of J point was observed apart. All tests were performed at the same time of the in lead V2 for the two tests, in 75 and 69% of cases, respec- day, in the late morning. Tests were preceded by echocar- tively. The peak changes in J point elevation, PR, RR, QRS diography and ␤-human chorionic gonadotropin if necessary. and QTc interval were observed 3 minutes after injection, The ajmaline injection was performed at a dose of 1 mg/kg, except in RR in the slow test (Figs. 2 and 3). either at an infusion rate of 1 mg/sec or over 10 minutes. Continuous 12-lead ECG monitoring, including leads V1 Part II and V2 in the second intercostal space, was performed on a computerized electrophysiology system (EP Med Systems, Study population NJ, USA). Measurements were performed with the software ± callipers, at a time-scale of 200 mm/sec at T0 (0 minutes), Subjects had a mean age of 42 15 years (range 15—81); T3 (T0 + 3 minutes), T5 (T0 + 5 minutes) and T10 (T0 + 55% were men. Tests were performed for family screening 10 minutes) after the end of injection for the two proto- in 290 (75%) cases. Sixteen (4.2%) patients had a history of cols, and at T0, T3 and T5 after the beginning of injection syncope and two (0.6%) had a history of resuscitated sudden for the slow test. ECGs were printed on paper at these dif- death. Fifty-five (14%) patients had a family history of sud- ferent times and recorded continuously on optical disk. The den death. The ECG was normal in 264 (68%) cases, transient presence of any arrhythmias was recorded. At the end of type 1 in 38 (10%) cases and type 2 or 3 in 84 (22%) cases. administration of ajmaline, the ECG recording continued until the reading returned to normal. The test results were Results and complications of ajmaline challenge evaluated by two independent, blinded observers. The test The ajmaline challenge was positive in 183 (47%) patients. was considered positive if more than one lead exhibited Two (0.5%) of the 386 patients presented runs of monomor- coved type with a J point elevation > 0.2 mV [2]. phic VT (a triplet of VPBs and a triplet of VPBs followed by a doublet), with no recurrence during subsequent ECG Statistics monitoring. Another two (0.5%) patients presented serious VAs. The first patient, a 29-year-old woman, presented poly- Variables are expressed as means and standard deviations. morphic NSVT of 15 complexes over 7 s, occurring 1 minute Comparisons between groups were performed by analysis of after the onset of a type 1 appearance on the ECG, i.e. variance or by using the Wilcoxon test for paired samples. 2 minutes after the end of the injection of the entire dose Ajmaline challenge for the diagnosis of Brugada syndrome: Which protocol? 573

Table 1 ECG variables: rapid vs slow infusion. Variable Rapid infusion (n = 32) Slow infusion (n = 32) pa Baseline 3 minutes (%) Baseline 10 minutes (%) PR (ms) 167 ± 28 219 ± 3 6 32.5 166 ± 32 217 ± 33 32.8 0.8 QRS (ms) 103 ± 14 134 ± 18 31.7 100 ± 13 132 ± 17 33.6 0.8 QTc (ms) 425 ± 37 481 ± 32 13.7 403 ± 24 470 ± 39 16.7 0.2 RR (ms) 847 ± 78 740 ± 10 —11.1 902 ± 133 754 ± 87 —15.5 0.06 J wave (mV) 0.28 ± 0.1 0.51 ± 0.17 95.0 0.26 ± 0.1 0.51 ± 0.22 96.8 0.5

a Comparison between infusion protocols.

Table 2 ECG variables: positive vs negative test. Variable Infusion rate Positive test (n = 15) Negative test (n = 17) p ms % ms % PR Rapid 58 ± 31 36.4 48 ± 24 29.1 0.3 Slow 48 ± 20 29.2 54 ± 29 36.0 0.3 QRS Rapid 34 ± 16 34.2 29 ± 15 29.5 0.3 Slow 33 ± 18 33.9 32 ± 14 33.3 0.8 QTc Rapid 69 ± 37 16.9 45 ± 28 10.9 0.05 Slow 70 ± 42 17.1 64 ± 31 16.4 0.4 RR Rapid —121 ± 109 —12.2 —94 ± 86 —10.1 0.5 Slow —125 ± 72 —13.4 —167 ± 124 —17.3 0.2

of ajmaline. Widening of the QRS and J point elevation was potentially fatal arrhythmias was 0.5% during the rapid test. observed before the run (Fig. 4). The test was performed in No studies evaluating the diagnostic performances of the the context of BS screening in a family of 15 cases of BS. The ajmaline challenge as a function of injection rates in BS have ECG before the test was normal. The second case occurred been published in the literature. Independently of injection in an asymptomatic 21-year-old woman also consulting in rate, the lengthening of QRS, PR and QTc intervals observed the context of family screening. The ECG before the test in this study was identical to that observed in previous stud- was normal. Three minutes after the end of the injection, ies [14,15], including in studies performed in BS patients a type 1 ECG pattern on lead V1 was observed, with widen- [5,8,16]. All ajmaline tests were performed at the same time ing of the QRS > 130%, followed by VF. Sinus rhythm was of the day to avoid spontaneous nycthemeral ECG fluctua- restored after 30 minutes of resuscitation, without neurolog- tions [17]. ical repercussion (Fig. 5). Resuscitation included repeated In the studies by Batchvarov et al. [5] and Veltmann et al. electrical shocks, infusion of sodium bicarbonate, a bolus of [16], only lengthening of the QTc interval (but not heart rate, adrenaline and isoproterenol. Intravenous isoproterenol was PR interval or QRS width) was slightly greater on positive administered as a continuous infusion of 0.06 mg/min for tests. These data are in line with those reported with the 15 minutes, and stopped a few minutes after sinus rhythm, rapid test in the first part of this study and confirm the good without recurrence of ventricular event. A Scarpa surgical ECG tolerance of this protocol. approach was done in preparation for circulatory support, Literature reports of the risk of VA during sodium chan- but was not necessary due to return to sinus rhythm. An nel blockade challenge in BS are summarized in Table 3. implantable cardioverter defibrillator was inserted a few Studies in which the presence of type 1 ECG was most fre- days later. Genetic analysis subsequently revealed an SCN5A quent reported the highest rates of proarrhythmias. This gene mutation (G1743R). appears to be true regardless of the type of sodium channel blocking agent used. However, it should be noted that a risk of VF was also observed when the ECG was strictly Discussion normal before the injection (Fig. 5), and when the injection was performed over 5 minutes [16]. In view of the risk No significant difference was observed between the slow of fatal arrhythmias, as recommended by Rolf et al. [8], test and the rapid test in terms of diagnostic performance, the injection of ajmaline should therefore be performed variation in ECG variables or the frequency of isolated VPBs. over 10 minutes and should be stopped in the case of sig- The development of isolated VPBs was not correlated with a nificant J point elevation or widening of the QRS by more positive ajmaline challenge. In contrast, runs of polymorphic than 130%. Ajmaline has the advantage of a shorter half-life VT were preceded by ECG changes typical of BS. The risk of and a briefer blocking effect on transient outward potassium 574 E. Arnalsteen-Dassonvalle et al. NSTV: 0.8 VF: 0.26 VF: 0.15 NSTV: 2 VT: 11 0 VT: 7.3 VF: 2.5 VT: 6.2 VT: 1.3 but 0 after protocol change VF: 1.3 with ajmaline VPBs: 14.1 Complex VPBs: 0.26 VPBs: 8.1 Complex VPBs: 4.7 VPBs: 7.1 VPBs: 6 Frequent VPBs: 0.6 reported VPBs: 9.2 reported VPBs: 4.7 rillation; VPB: ventricular premature 47.3 Single 39 VPB: 1.2 NSTVL 0.30 20.3 Single 40 Single 23.4 Not Testpositivity (%) VPB (%) VA (%) 100 Frequent 100 Not Syncope: 4.2 Syncope: 25.7 Syncope: 27.0 Syncope: 42.9 Syncope: 18.1 Syncope: 36.4 Syncope: 60.1 syncope (%) 386 9.8 SCD: 0.6 677 No SCD: 1.8 148 No SCD: 12.8 158 3.8 SCD: 13.3 106 32 > 32 42 Frequent Ajmaline 1 mg/sec Ajmaline 5 min Ajmaline 5 min Pilsicainide 28 64.3 SCD: 10.7 Pilsicainide 65 100 15.4 100 Frequent Flecainide 160 No SCD: 10.6 Flecainide 22(41 tests) 86.4 SCD: 9.1 Ajmaline 10 mg/2 min Drug usedAjmaline 5 min NFlecainide Procainamide Type 1ECG (%) SCD or Ventricular arrhythmias during sodium channel blockade challenge. [20] [8] Our study, part II Veltmann et al., 2009 [16] Batchvarov et al., 2009 [5] Chinushi et al., 2007 [21] Morita et al., 2003 [24] Meregalli, 2006 Gasparini et al., 2003 [19] Rolf et al., 2003 beat; VT: ventricular tachycardia. Table 3 Study reference Brugada et al., 2000 [18] ECG: electrocardiogram; NSVT: non-sustained ventricular tachycardia; SCD: sudden cardiac death; VA: ventricular arrhythmia; VF: ventricular fib Ajmaline challenge for the diagnosis of Brugada syndrome: Which protocol? 575

Figure 2. Kinetics of J point amplitude during slow and rapid tests, at 0 minutes (T0), 3 minutes (T3), 5 minutes (T5) and 10 minutes (T10) after the end of injection (means ± standard deviations).

current than other sodium channel blocking agents, and is therefore more rapidly reversible [13,22]. Predictive factors for the development of arrhythmia during sodium channel blockade challenge performed for the detection of BS are difficult to define because of the rarity of these events. According to Chinushi et al., the frequency of VPBs is higher in the presence of marked ST elevation before the test, but identical whether or not patients are symptomatic [21]. Batchvarov et al. emphasized the higher incidence of VAs during positive tests compared with negative tests [5], sug- gesting that the test should be stopped as soon as a positive response is observed. In our study, the two cases of severe polymorphic arrhythmia occurred in female patients with no personal or family history of sudden death and with a strictly normal baseline ECG. The risk of arrhythmia was assumed to be low. A G1743R mutation was demonstrated in one patient. This mutation, responsible for a marked reduction of the density of sodium current channels, has been previously reported by Valdivia et al. [23]. The other patient was not screened for SCN5A mutations. In view of the different morphology of the VPBs, Morita et al. [24] also proposed a different origin of the arrhythmia between subjects with or without SCN5A mutations, which could therefore explain the increased proarrhythmic risk in patients presenting such a mutation. A high rate of VA (43%) was reported during flecainide challenge in the presence of an SCN5A mutation in the studies by Gasparini et al. [19]. The presence of an SCN5A mutation may therefore be predictive of the development of proarrythmia. Isoprenaline efficiency had been described in the con- Figure 1. Bland and Altman plots of J wave amplitude (JWA) text of electrical storm in patients with BS [25—28], and changes with the two infusion protocols, at 0 minutes (T0), in cases of VA induced by drugs such as procainamide and 3 minutes (T3) and 5 minutes (T5) after the end of injection. The mean of J point elevation is represented by the abscissa (x-axis) pilsicainide [29,30]. It also seems to be effective in VA gen- value, and the difference between J point elevation by the ordi- erated by ajmaline. Isoproterenol is known to restore the nate (y-axis) value. The graph showed good agreement between dome of epicardial action potential and to normalize the ST the two protocols. segment by increasing the inward calcium current [31]. Its beta-adrenergic stimulation has been added in our clinical 576 E. Arnalsteen-Dassonvalle et al.

Figure 3. Kinetics of PR, QRS, QTc and RR intervals during slow and rapid tests, at 0 minutes (T0), 3 minutes (T3) and 5 minutes (T5) after the end of injection (means ± standard deviations).

Figure 4. Development of polymorphic non-sustained ventricular tachycardia at the third minute of a rapid ajmaline challenge. Ajmaline challenge for the diagnosis of Brugada syndrome: Which protocol? 577

Figure 5. Development of ventricular fibrillation 3 minutes after rapid intravenous administration of 60 mg of ajmaline in a 20-year-old woman. Panel A: 12-lead electrocardiogram before the test; no ST elevation in the right precordial leads. Panels B and C: progressive increase in the QRS duration and appearance of features of right bundle branch block with J point elevation (type 1 pattern) on lead V1. Panel D: polymorphic ventricular tachycardia then intractable ventricular fibrillation for 30 minutes despite 10 electrical shocks and intravenous administration of isoproterenol. Panel E: restoration of effective sinus rhythm after the 11th shock. case to an increased sympathetic activity due to adrenaline Conflict of interest statement injection. The isoproterenol concentrations that we used (0.06 mg/min) were larger than those usually described in None.Funding: This study was supported by a grant from the the electrical storms (0.1 to 1 ␮g/min) [25,26,28,30,32]. The Amiens-Picardie University Hospital. irreducible character of VF, despite electrical shocks, jus- tifies this high dose. Ablation of the triggering ventricular ectopies has been described in electrical storms in case of Acknowledgments failure of therapeutic options [33]. Our therapeutic option was cardiopulmonary ‘‘bypass’’ because of the emergency. The authors would like to thank Ms Beatrice Desachy and Heart transplantation has already been described as a last Christele Denturk for their technical contribution to the resort [34]. ajmaline challenge, and Mr Momar Diouf for his contribution One limitation is related to the power of the first part to statistical analysis. of our study. After a post-hoc calculation, a cohort of at least 80 patients would have been necessary to prove with a probability of 80% the absence of difference between the two tests. References

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