Lidocaine
Intravenous sodium-channel blockers (lidocaine, procainamide) are minimally effective in suppressing shock-resistant VT/VF and ES (Credner et al, 1996 and Nademanee et al, 2000). Lidocaine binds to fast sodium channels in a use-dependent fashion. Binding increases under cellular conditions that are common in ischemic VT, such as reduced pH, faster stimulation rate and reduced membrane potential. However, lidocaine has relatively weak antiarrhythmic properties outside the ischemic setting: conversion rates from VT to sinus rhythm range from 8% to 30%. In one study enrolling patients with out-of-hospital, shock-resistant VT or VF, only 12% of those randomized to lidocaine survived to hospital admission, versus 23% who received amiodarone. On the basis of this and other findings, amiodarone has replaced lidocaine as first line therapy for refractory VT and VF. Actual recommendations suggest intravenous lidocaine only in the treatment of polymorphic VT associated with acute ischemia. If lidocaine is used, it should be administered as an intravenous bolus of 0.5 to 0.75 mg/kg that is repeated every 5 to 10 min as needed. A continuous intravenous infusion of 1 to 4 mg/ min maintains therapeutic levels. The maximum total dose is 3 mg/kg over 1 hr.
Procainamide
Procainamide blocks fast sodium channels in a use-dependent fashion and is metabolized to N-acetylprocainamide, which in turn blocks potassium channels and accounts for much of the antiarrhythmic effect in vivo. When given as a loading dose of 100 mg over 5 min, procainamide is a reasonable choice for terminating monomorphic VT. In patients with depressed systolic function procainamide can cause hypotension or prolong QRS width by more than 50%, either of which would necessitate discontinuation of the drug. Procainamide prolongs the QT interval and therefore could cause torsade de pointes. Its use is contraindicated in patients with impaired renal function, because N-acetylprocainamide is excreted by the kidneys.
Azimilide
Azimilide is an experimental class III antiarrhythmic drug that blocks calcium channels and prolongs the energy potential and refractory periods. The recently published SHIELD trial showed that azimilide is effective and helps to reduce the number of ICD discharges, though not mortality (Stefan et al, 2006). A secondary analysis of the SHIELD data found that during a prospective one-year follow up azimilide significantly reduced the incidence of ES in comparison with placebo. Azimilide could become an alternative for the treatment of ES whenever it becomes commercially available.
Polypharmacological approach
Optimization of 3-blocker therapy is the first important step, particularly when the electrical storm is triggered by ischemia or increased sympathetic tone. The next step is initiating anti-arrhythmic therapy if patient still experiences ES. In the absence of contraindications (such as QT lengthening or polymorphic ventricular tachycardia), amiodarone is generally the antiarrhythmic drug of choice and has been validated in numerous clinical trials (Kowey et al, 1995 and Wood et al, 1995). Most of the time, optimized 3-blocker therapy plus intravenous amiodarone will control the electrical storm within 24 to 48 hours. This appears to be the most effective therapy for electrical storm. If the intravenous combination of amiodarone and 3-blockers proves inefficacious, the addition of lidocaine is a reasonable option. Although controlled data are not available, combination of anti-arrhythmic drug allows lower and better tolerated doses of individual drugs, and offers the potential of synergistic effects.
Sedation
The physical and emotional stress that patients experience in association with electrical storm and multiple electrical cardioversions increases adrenergic tone and often perpetuatesarrhythmias. All patients who have electrical storm should be sedated. Sedation or general anesthesia are needed in resistant cases where repeated shocks or anti-tachicardia transthoracic pacing are needed. Short-acting anesthetics such as propofol, benzodiazepines, and some agents of general anesthesia have been associated with the conversion and suppression of VT (Burjorjee & Milne, 2002). Left stellate ganglion blockade and thoracic epidural anesthesia have also suppressed electrical storms that were refractory to multiple antiarrhythmic agents and P blockade (Nademanee et al, 2000). These therapeutic approaches directly target nerve fibers that innervate the myocardium, and a reduced adrenergic tone is most likely responsible for the reported efficacy. Is currently unknown whether sedative and anesthetic agents may have direct antiarrhythmic effects.
Implantable defibrillators: First-line therapy and first-line diagnostic?
ES is quite common in ICD recipients. In different studies the incidence of ES in patients with an ICD ranges from 10 to 60% when ICDs are implanted for secondary prevention (Arya A et al, 2005) and 4% to 7% when ICDs are implanted for primary prevention (Sesselberg et al, 2007). A higher incidence of ES in ICD patients is related to an higher cardiovascular mortality and morbidity among ICD recipients. As previously said the presence of ICD allows the physician to recognize more arrhythmias and the patient to survive the arrhythmia and hence manifest more episodes.
Occurrence of ES after ICD implant has changed over time. A paper from the late 1990s reported the peak of incidence of ES between 4 and 5 months after implant (Credner et al, 1998). On the other hand recent evidences pushed the onset of ES to 26 months after implant (Streitner et al, 2011). Total number of episodes varied over time too: as much as 55 mean episodes per patient have been reported (Greene et al, 2000), whereas more recent papers describe far less VT/VF per single patient (Streitner et al, 2011). Both these findings could be explained by changes in antiarrhythmic therapy and ICD technology occurred in this last decade which in turn led to fewer total arrhythmic episodes and improved overall prognosis. There is a multitude of etiologies of ES in ICD patients: hypokalemia or other electrolytic imbalance, drugs (diuretics, b-adrenergic drugs, alcohol), ischemia, medication noncompliance and less common causes such as fever or stress (Huang et al, 2005 and Israel et al, 2007). The most common cause of ES in ICD patients is exacerbation of heart failure, as underlying ischemic or idiopathic dilated cardiomyopathy could progress despite medical therapy and arrhythmic prevention. Nevertheless, most ES have no clear etiology and even an exhaustive search for acute cause may prove fruitless.
Clinical presentation can vary dramatically depending on arrhythmias typology (monomorphic VT, polymorphic VT or VF) and patient’s characteristics (EF, NYHA class, comorbidities). The presence of syncope associated with arrhythmia depends both on hemodynamic factors and on ICD settings (mostly shock charging time). The most important acute consequence related to ES is hospitalization that is required in more than 80% of patients, particularly when shocks are delivered (Bansch et al, 2000). ICD patients presenting ES have higher morbidity and mortality, hence determination of predictors is needed to identify high risk patients.
Data on risk factors of ES are far from comprehensive or conclusive but most studies consider low EF and secondary prevention as major risk factors for developing ES in ICD recipients. High NT-proBNP and hs-CRP, history of atrial fibrillation before implant or single/dual chamber pacing over CRT are also described as predisposing to ES (Streitner et al, 2011).
ICD patients who experienced a first ES are also more likely to experience one or more ES recurrence. Recurrence rate is as high as 80% within 12 months after the first episode, according to Steinert, who described LVEF < 30%, age > 65 years, chronic obstructive pulmonary disease and lack of ACE inhibitors therapy as independent predictors of ES recurrence (Steinert et al, 2011).
Most authors report poor prognosis associated whit ES with a risk of death increased from 1.9 to 17.8 fold. Death rate is usually low during hospitalization and acute episode but increases afterward, particularly during the first year after ES.
Lately, new tools have become available to detect and manage ES in ICD patients. All major ICD companies now offer some sort of home or remote monitoring along with their devices. Home monitoring offers the physician reports for arrhythmic events, device battery and parameters status in real-time. Asymptomatic or lightly symptomatic ES could be then promptly recognized and the patient immediately called in for a check-up without the need to wait for the next programmed ambulatory visit. Figure 1 shows how an ES looks like on auto-generated home monitoring report: the patient experienced 37 arrhythmic episodes in less than 24 hours, 36 VT terminated with a shock after ATP sequence was ineffective and 1 VF episode terminated with ATP.
Figure 2 shows how EGM can be seen and interpreted via remote monitoring. In this EGM VT has been correctly detected and treated by ICD shock.
Is cardiac resynchronization therapy useful in preventing electrical storm?
Cardiac resynchronization therapy (CRT) is a well established therapy for treatment of moderate to severe heart failure. Several studies assessed benefits from biventricular pacing resulting in prevention of left ventricular remodeling and improvement of hemodynamic, ejection fraction, NYHA class, quality of life, morbidity and mortality (Cleeland et al, 2005). Effects of CRT on ventricular arrhythmias are less well established. Some evidence suggests that pacing itself might cause arrhythmias and some authors reported an increase in incidence of atrial fibrillations, ventricular arrhythmias or even electrical storms after biventricular pacing (Kantharia et al, 2006). However, currently available large-scale trials showed no significant proarrhythmic effects of CRT. On the other hand, there is no strong evidence of a direct antiarrhythmic effect of CRT over single or dual chamber pacing either. Nordbeck et al. compared incidence of ES in 168 CRT and 561 ICD patients. They found significant lower incidence of ES in CRT group (0.6% versus 7%), suggesting that, beside the well known hemodynamic improvements, cardiac resynchronization therapy may reduce the arrhythmia burden in heart failure patients (Nordbeck et al, 2010). An Italian group found a higher incidence of ES (11.3% vs 5.3%) in patients non responder to CRT therapy, defined as minor improvement in NYHA class and ejection fraction (Gasparini et al, 2008). These data support the hypothesis that CRT may have an indirect antiarrhythmic effect, due to factors which are still unclear. Nordbeck suggests that the reduction of arrhythmic burden could be due to improvement of cardiac output and ejection fraction from CRT, as ejection fraction is a known risk factor for ventricular arrhythmias. Another hypothesis by Kowal found some evidences in clinical cases reporting a specific role of cardiac pacing site in development or suppression of VT. He hypothesized that the mechanism of arrhythmia suppression under biventricular pacing could be ascribed to preexcitation of the area of slow conduction responsible for the reentrant arrhythmia (Kowal et al, 2004). Nevertheless, electrophysiologic effects of CRT are still poorly understood. Biventricular pacing remains a major therapeutic tool in the treatment of heart failure but additional data are required to assess its efficacy as antiarrhythmic therapy.
Fig. 1. 78 year-old patient with dilated idiopathic cardiomyopathy. In this report the patient experienced 37 arrhythmic episodes in less than 24 hours. Physicians can check the report directly online in real time, allowing fast diagnosis of ES and, hence, immediate treatment of ES.
Fig. 2. One of the arrhythmic episodes reported in Fig.1. In this EGM a ventricular tachycardia in VT zone starts abruptly following a premature ventricular contraction. Atrio-venticular dissociation is easily visible. ATP was ineffective whereas 15J delivered shock successfully terminated VT.
Specific therapy in congenital pro-arrhythmic diseases
Although electrical storm associated with Brugada syndrome is exceptional, it is a major and life threatening event that requires rapid and effective treatment. In most cases presented to date, infusion of isoproterenol (as a 1-2 ^g bolus injection followed by continuous infusion at 0.15 ^g/min, or at a rate of about 0.003 ^g/kg/min tritated to result in a 20% increase in heart rate), was used to terminate electrical storm. Other cases reported intravenous orciprenaline infusion or quinidine as effective in terminating ES. Direct 3 adrenergic stimulation by isoproterenol and orciprenaline increases the L-type calcium current, which restores the epicardial action potential dome, normalizes ST segment elevations and suppresses ventricular arrhythmias. It should be emphasized that orciprenaline or quinidine use as last resort approach in ES is limited to cases of confirmed Brugada syndrome, while in the majority of ES associated with ischemic or dilated cardiomyopathy, orciprenaline or quinidine application may result in fatal outcome. In the congenital long QT syndrome, high dose 3-blockers can suppress the occurrence of ES and frequent ICD discharges. In refractory cases, left cardiac sympathetic denervation results in marked reduction in ES incidence.
In the ES associated with the short-coupled variant of torsade de pointes ventricular tachycardia, verapamil or the combination of verapamil and mexiletine is somewhat effective. Intravenous magnesium and overdrive pacing are the treatment of choice for drug-induced torsade de pointes.
Arrhythmogenic right ventricular cardiomyopathy and myocardial non-compaction deeply modify heart structure, and ES associated with these conditions is usually resistant to medical therapy. Heart transplantation represents nowadays the only viable option for terminating recurrent, haemodynamically destabilizing arrhythmias in these patients.
Last resource therapies. Radio-frequency ablation and heart transplantation
Radio-frequency ablation
Although radiofrequency catheter ablation (CA) has an established role in the treatment of recurrent VT, only recently it has been suggested as a method of choice in management of ES, especially when pharmacological and ICD therapies fail. The best candidates for CA are those ventricular arrhythmias in which the initiating beat or premature ventricular contractions morphologically identical to the initiating beat can be localized with electroanatomical mapping. In patients affected with ischemic cardiomyopathy the typical site of the initiating beat is around the border zone of the scar tissue. The procedure can be performed under light anesthesia or deep sedation, according to the hemodynamic state of the patient. If the VT is not incessant, a stimulation protocol from right and left ventricle and up to three extrastimuli is usually applied to induce clinical VT and determine its characteristics. Mapping and ablation is usually performed by an irrigated-tip catheter introduced into the right ventricle or left ventricle by direct femoral vein approach or retrograde transaortic or transseptal approach, respectively. Electroanatomical mapping is nowadays the standard of care, being safe and effective.
The largest series of patients undergoing CA for refractory ES has been described by Carbucicchio and coworkers. Solid electrophysiological evidence of the effective treatment of the presenting VT was achieved in 89% of patients, whereas a transient effect of CA causing short-term stabilization but ineffective in long-term ES prevention was observed in the remaining 11% of patients (Carbucicchio et al, 2008). In this latter group, CA acted only as a temporary bailout, with no impact on ES recurrence. In a recent Czech study RF ablation proved effective in suppression of ES in 84% of cases; however, repeated procedures were necessary in 1 out of 4 patients (Kozeluhova et al, 2011). Severely depressed left ventricular ejection fraction, highly-dilated left ventricle, renal insufficiency, and ES recurrence after previous ablation procedure were independently associated with adverse outcome within the first 6 months after the procedure. Is it still unclear whether inducibility testing of the VT at the end of the study is predictive of mortality and arrhythmic recurrences, as currently available data are controversial.
Successful CA of refractory ES in the absence of a detectable trigger has also been described. Schreieck and colleagues reported a case series of 5 ischemic patients with unmappable recurrent VTs, in which CA was attempted targeting delayed local potentials guided by voltage mapping and pace mapping (Schreieck et al, 2004). These isolated delayed potentials are found exclusively in areas of dense scar, making this kind of technique ineffective in idiopathic dilated cardiomyopathy.
On a side note, patients with pseudo-storm due to inappropriate ICD shocks induced by atrial tachyarrhythmias can benefit from CA of atrial flutter, atrial fibrillation or even AV node ablation.
Heart transplantation
Patients with no significant comorbidities except for recurrent ES who experienced no improvements from pharmacological, device-related and surgical treatment should be considered for cardiac transplantation. Patients with refractory ES associated with a genetic arrhythmia syndromes may also be reasonable candidates for heart transplantation as these patients are typically young, otherwise healthy individuals with good quality of life and prognosis.
In haemodynamically instable patients, intraaortic balloon pump and cardiac assist devices should be used as bridge-to-transplant, as potentially lifesaving.
