ABSTRACT
Background
Electrical storm (ES) is a clinical syndrome characterized by densely clustered ventricular arrhythmias and associated with substantial morbidity and mortality. Autonomic dysfunction is thought to play key role in the pathophysiology of ES, with sympathetic blockade considered a therapeutic target. However, robust data supporting this treatment strategy remain limited. The objective of the SEDATE trial is to evaluate the effectiveness and safety of dexmedetomidine in the acute management of ES.
Methods and Design
SEDATE is a multicenter, double-blinded, randomized trial comparing dexmedetomidine to placebo in the acute treatment of patients with ES. A total of 192 participants admitted to an intensive care unit with ES will be randomized in a 1:1 fashion to receive either dexmedetomidine or placebo. Participants will undergo a study drug titration phase, followed by a 48-hour maintenance period and a subsequent study drug weaning phase. The primary outcome is a composite of all-cause in-hospital mortality and/or recurrent ventricular arrhythmia prompting intervention. All participants will be followed for the duration of their hospitalization.
Implication
The SEDATE clinical trial aims to determine whether early use of dexmedetomidine improves in-hospital outcomes in patients with ES.
Trial registration
clinicaltrials.gov NCT06281977.
ATP
anti-tachycardia pacing
ES
electrical storm
ICD
implantable cardioverter‐defibrillator
ICU
intensive care unit
VA
ventricular arrhythmia
VF
ventricular fibrillation
VT
ventricular tachycardia
Background and rationale
Electrical storm (ES) is a clinical syndrome characterized by densely clustered ventricular arrhythmias (VAs). Electrically defined as ≥3 treated and/or sustained VAs in a 24-hour period, ES is considered a medical emergency with significant short- and long-term morbidity and mortality. ,,, Patients with implantable cardioverter-defibrillators (ICDs) are among those at highest risk of developing ES, affecting an estimated 10% to 20% of such patients. ES is hypothesized to occur in the presence of a susceptible myocardial substrate, triggering event, and autonomic dysfunction. , Autonomic dysfunction, arising from an imbalance between sympathetic and parasympathetic inputs, can lead to the initiation and maintenance of VAs via multiple mechanisms, including enhanced automaticity and afterdepolarizations, and changes in action potential duration and repolarization. Chronic sympathetic dysregulation is common in patients with structural heart disease. , However, baseline autonomic dysregulation can be acutely exacerbated by sympathetic surges associated with VAs and their treatments, such as external shocks and ICD therapies. Sustained VAs can therefore promote further VAs, setting the stage for a cycle of worsening autonomic dysregulation and electrical instability that is characteristic of ES. ,
Methods to modulate the autonomic nervous system are often used in the treatment of ES. Beta blockade, preferably with a nonselective agent, is generally recommended in all patients with ES unless contraindicated. ,, Other therapies, such as deep sedation with mechanical ventilation and specialized procedures such as stellate ganglion blockade, are reserved for patients in “intractable” ES that is refractory to antiarrhythmic drug therapy. ,, Observational data suggest that deep sedation and stellate ganglion blockade can be effective in patients with ES, but they are associated with risks or require specific expertise, generally limiting their role to second-line strategies in current practice. ,,,
Alpha-2 agonism is an alternative method of sedation that can preserve spontaneous breathing and avoid the need for mechanical ventilation, rendering it an attractive strategy for the treatment of ES. , The intravenous formulation, dexmedetomidine, is widely used as a sedative in critical care settings and has favorable pharmacokinetics and pharmacodynamics for the treatment of ES due to its rapid onset (<15 minutes). Furthermore, it has purported antiarrhythmic properties thought to be mediated by increasing vagal tone, , reducing circulating catecholamines, , and direct effects on cardiac sodium and calcium ion channels with an overall reduction in spatial dispersion of repolarization. Clinically, dexmedetomidine has been reported to reduce the incidence of VAs in patients undergoing cardiac surgery ,, and more effectively than propofol. Although data to support dexmedetomidine’s impact on VAs is largely limited to the cardiac surgery population, the drug is commonly used in clinical practice in broader patient populations with ES and is recommended as a preferred sedating agent for treating refractory ES. ,, Dexmedetomidine’s purported benefits and relatively favorable safety profile render it a candidate not only as a second-line strategy but as an adjunct first-line treatment for ES.
The objective of the Study Evaluating Dexmedetomidine in the Acute Treatment of Electrical storm (SEDATE) trial is to determine if the use of early sedation with dexmedetomidine improves short-term clinical outcomes in patients with ES. We plan to test this with a multicenter, double-blinded, randomized placebo-controlled trial.
Methods
Study design and patient selection
SEDATE is a multicenter, double-blinded, randomized controlled trial that is expected to be conducted from May 2024 to May 2028. Patients aged ≥18 years admitted to an intensive care unit (ICU) with ES will be screened for recruitment. ES will be diagnosed as ≥3 VA episodes defined as sustained (estimated ≥30 seconds) ventricular tachycardia (VT), ventricular fibrillation (VF), or appropriate ICD therapies (including shocks and antitachycardia pacing [ATP]) or external defibrillation for VT/VF within a 24-hour window.
Exclusion criteria are listed in Table 1 . These criteria were selected to exclude clinical scenarios with poor prognoses irrespective of ES (such as refractory shock unrelated to VA events, Society for Cardiovascular Angiography & Interventions [SCAI] D or E cardiogenic shock, and cardiac arrest with prolonged cerebral hypoperfusion), scenarios in which ES may be due to a readily reversible etiology (such as ST-elevation myocardial infarction with evidence of active cardiac ischemia), and patients in whom dexmedetomidine may pose an elevated risk (such as marked bradycardia without a pacemaker in place or bradycardia-induced VA and ES).
Table 1
Eligibility criteria.
| Inclusion criteria: |
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| Exclusion criteria: |
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Abbreviations: ICU, intensive care unit; SCAI, society for cardiovascular angiography and interventions; VA, ventricular arrhythmia.
Enrollment and randomization
After obtaining informed consent from the patient or substitute decision maker (SDM), participants will be randomized to receive either dexmedetomidine or placebo in a 1:1 fashion using a computer-generated randomization sequence. Patients will be stratified by the presence of invasive mechanical ventilation in addition to study site. The participant, treating physicians, nursing team, and clinical pharmacists will remain blinded to treatment allocation.
Interventions
In the dexmedetomidine treatment arm, participants will start the study drug with a “dose titration phase” to minimize the risk of adverse events. This practice is consistent with current clinical care. A recommended titration protocol will be provided but can be modified at the treating team’s discretion as required ( Figure 2 , Supplementary material). The titration protocol recommends starting the study drug at a dose of 0.1 to 0.3 mcg/kg/h and titrating to a target dose of 1.0 mcg/kg/h. Once the participant has reached the target dose, or the maximum tolerated dose as per the treating team, participants will continue at this dose for the “maintenance phase”, which lasts 48 ± 6 hours. However, study drug dosing can be adjusted during this phase at the treating team’s discretion to account for changes in clinical status. After the “maintenance phase” is complete, participants will undergo a “weaning phase” to reduce the risk of rebound in sympathetic tone, which is recommended to be study drug down titration by 0.1 mcg/kg/h. Normal saline will be administered in an identical fashion in the placebo group ( Figure 1 ).
Study flow. ICU, intensive care unit, RASS, Richmond agitation-sedation scale.
Recommend study drug protocol. BPM, beats per minute, HR, heart rate, MAP, mean arterial pressure, RASS, Richmond agitation-sedation scale, RR, respiratory rate. *Criteria for titration in the nonmechanically ventilated participants.
Outcomes and endpoints
The primary outcome is a composite of all-cause in-hospital death and in-hospital VA requiring treatment after study drug initiation (defined as initiation or escalation of intravenous antiarrhythmic drug, ATP or shock from an ICD, external shock/cardioversion, endotracheal intubation/initiation of mechanical ventilation, or initiation of mechanical circulatory support by the treating team). If a participant meets the primary endpoint due to recurrent VA during the study drug intervention period, the study drug will continue, and usual care will continue as per the treating team. Several secondary outcomes are planned, including the individual components of the combined primary outcome ( Table 2 ). A blinded adjudication committee will assess the primary outcome and its individual components.
Table 2
Study endpoints and outcomes
| Primary endpoint: |
The primary outcome will be a composite of the following:
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Secondary outcomes:
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Abbreviations: ICU, intensive care unit; VA, ventricular arrhythmia.
Withdrawal from study/early termination
Participants may at any point withdraw from the study without any penalty or prejudice. The treating/research team may withdraw the participant from the study for any of the following reasons: (1) the participant fails to comply with the requirements of the study, (2) the healthcare team feels it is in the best interest of the participant to not continue in the study, or (3) the participant needs other treatment that would interfere with the study.
Ethics and informed consent
Local ethics approval will be obtained for all participating sites. This trial will be conducted in accordance with the good clinical practice standards and in accordance with the Declaration of Helsinki. Informed consent will be obtained from all participants or their SDM prior to enrolment. Participants’ confidentiality will be strictly maintained as per local and national regulations. The study has been registered on clinicaltrials.gov (NCT06281977). The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents.
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