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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 9  |  Issue : 1  |  Page : 12-17

Use of ivabradine in postoperative junctional ectopic tachycardia: A systematic review of case series and case reports


1 Department of Cardiothoracic and Vascular Surgery, SMS Medical College and Attached Hospitals, J L N Marg, Jaipur, Rajasthan, India
2 Department of Paediatric Cardiac Surgery, Institute of Heart and Lung Transplant and Mechanical Circulatory Support, MGM Healthcare, Chennai, Tamil Nadu, India
3 Department of Pharmacology, SMS Medical College and Attached Hospitals, J L N Marg, Jaipur, Rajasthan, India
4 Department of Anatomy, SMS Medical College and Attached Hospitals, J L N Marg, Jaipur, Rajasthan, India

Date of Submission15-Oct-2020
Date of Decision02-Jan-2021
Date of Acceptance02-Feb-2021
Date of Web Publication30-Mar-2021

Correspondence Address:
Dr. Neha Sharma
Department of Pharmacology, SMS Medical College and Attached Hospitals, J L N Marg, Jaipur - 302 001, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/heartindia.heartindia_47_20

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  Abstract 


Purpose: When tachyarrhythmias originates from atrioventricular (AV) node, AV junction or bundle of His complex, they are termed “junctional ectopic tachycardia” (JET). Cardiac surgeries especially involving crux of the heart are mainly responsible for JET. Amiodarone and other pharmaco-therapeutic agents are tried as antiarrhythmics for the treatment of postoperative JET. Aim of this review was to discuss about role of ivabradine in the treatment of postoperative JET.
Materials and Methods: A search was carried out for this review article on the basis of literature available including scientific databases of PubMed, Embase, Scopus, Google Scholar, using keywords “Ivabradine,” “Postoperative junctional ectopic tachycardia,” “Arrhythmias,” “Funny currents,” from October 2011 to October 2020.
Results: After initial screening of 377 articles, 9 studies were included and discussed in detail in the present review article.
Conclusion: Treatment of choice of postoperative JET is still not well established. Although there are very few case reports and case series that have been reported on the use of ivabradine in JET, yet it seems to offer a promising use.

Keywords: Arrhythmias, funny currents, ivabradine, postoperative junctional ectopic tachycardia
Key points

  1. Junctions ectopic tachycardia (JET) is common tachyarrhythmia following pediatric cardiac surgery.
  2. Ivabradine seems to offer a promising use in treating JET arrhythmia in pediatric patients.
  3. Lack of intravenous formulation and unpredictable enteral absorption post-cardiac surgery is a drawback.
  4. More randomized controlled trials are need of the hour to asse


    How to cite this article:
    Sharma D, Subramaniam G, Sharma N, Sharma P. Use of ivabradine in postoperative junctional ectopic tachycardia: A systematic review of case series and case reports. Heart India 2021;9:12-7

    How to cite this URL:
    Sharma D, Subramaniam G, Sharma N, Sharma P. Use of ivabradine in postoperative junctional ectopic tachycardia: A systematic review of case series and case reports. Heart India [serial online] 2021 [cited 2021 Apr 17];9:12-7. Available from: https://www.heartindia.net/text.asp?2021/9/1/12/312488




      Introduction Top


    When tachyarrhythmias originate from atrioventricular (AV) node, AV junction, or bundle of His complex, they are termed as “junctional ectopic tachycardia” (JET). It is also known as “His bundle tachycardia” and “junctional automatic tachycardia.” The re-entry circuit is usually not involved in JET. Postoperative JET usually occurs within 72 h after pediatric cardiac surgery.[1],[2] On the basis of etiology, JET is classified as-congenital, postoperative, focal paroxysmal, focal nonparoxysmal, and JET associated with digitalis toxicity.[3] Amiodarone and other pharmaco-therapeutic agents have been tried for the treatment of postoperative JET.[1],[4] Aim of this review was to discuss the role of ivabradine in the treatment of postoperative JET. Thus current clinical evidence from case reports and case studies were explored.


      Materials and Methods Top


    A comprehensive search was carried out for this review article on the basis of literature available including scientific databases of PubMed, Embase, Scopus, Google Scholar, using keywords of “Ivabradine,” “Postoperative junctional ectopic tachycardia,” “Arrhythmias,” “Funny currents,” from October 2011 to October 2020. This systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.[5]

    All studies describing ivabradine as the potential frontier in the treatment of JET were eligible for inclusion. All study designs were eligible for inclusion. We excluded studies in other language other than English and when no translation was available. Duplicate studies were also excluded from the search. Various alterations in spelling and abbreviations were applied due to the pronounced heterogeneity of this research field.


      Results Top


    After the initial screening of the databases, we could find 377 articles (PubMed =12, other search engine =365). Further screening of title and abstract resulted in the exclusion of 127 duplicate articles. Full-text screening of the remaining 250 articles was done after the removal of duplicate records. Finally, 9 articles were included in the final systematic review. A flowchart demonstrating the search is presented in [Figure 1].
    Figure 1: Result of systematic review search

    Click here to view


    A case report of two siblings with JET associated with ventricular dysfunction revealed that both of them responded conclusively to ivabradine despite using multiple antiarrhythmic agents. After withdrawing other drugs gradually, both these patients were managed with ivabradine as monotherapy.[6] Boulos et al. portrayed the use of ivabradine in malignant JET in infants following congenital heart surgery. They used adenosine in a dose of 0.2 mg/kg and then Cordarone 500 mg/m2 by nasogastric tube, esmolol 50 μg/kg/min but, JET did not respond. The arrhythmia in their case of malignant JET was controlled only by oral Ivabradine f 0.1 mg/kg/day in bis in die after the failure of conventional therapy.[7]

    Another study mentioned the use of ivabradine in the treatment of automatic tachyarrhythmias among four children and young adults with increased automaticity. Ivabradine was found to be efficacious among 3 out of 4 patients treated.[8]

    Kumar et al. conducted a preliminary study and suggested the role of ivabradine as an adjunct for refractory JET following pediatric cardiac surgery. 20 out of 480 congenital heart surgery patients experienced JET in their study, while 5 out of 20 patients reported refractory JET. They used oral ivabradine in the dose range of 0.1–0.2 mg/kg/12 h as an adjunct to amiodarone to treat refractory JET. The rate reduction was gained in all five patients and sinus rhythm was achieved during a mean duration of 31.6 ± 13.6 h. Any recurrence of JET, hemodynamic derangement, or any other side effects attributable to oral ivabradine were not documented.[9]

    The use of ivabradine to be an effective alternative to Amiodarone in children with postoperative JET was registered in a study on eight patients with postoperative JET. It was noted that all eight patients responded to ivabradine. Recurrence of JET was found 10 h after ivabradine in one patient but, remission to sinus rhythm occurred after administering amiodarone along with the second dose of ivabradine.[10]

    Additionally, Holger et al. reported a case of an 1-year-old girl with ectopic atrial tachycardia that was successfully treated with a combination of beta-blocker and ivabradine. She presented with tachycardia (240 beats/min) and her N-terminal pro-brain natriuretic peptide was markedly elevated (maximum 2685 pg/ml, lab reference <130 pg/ml). Infusion of Flecainide (1 mg/kg/30 min), medical cardioversion, and amiodarone bolus was started but she developed second-degree AV-block (Wenckebach type). Esmolol infusion was then started and slowly increased to a maximum rate of 75 mcg/kg/min along with ivabradine in a dose of 0.25 mg (0.025 mg/kg) every 12 h and increased to 0.5 mg (0.05 mg/kg) per dose on the 2nd day. Sinus rhythm was confirmed on subsequent electrocardiogram (ECG) recordings. Beta-blocker therapy was then switched to metoprolol administered orally (1 mg/kg/d). No cardiac adverse effects attributable to ivabradine were noticed.[11]

    Details regarding the use of ivabradine[6],[9],[10],[12],[13],[14],[15],[16],[17],[18] in previously published literature are depicted in [Table 1].
    Table 1: Details regarding use of ivabradine in previously published literature

    Click here to view



      Discussion Top


    The review analysis identifies various research publications on the use of ivabradine in treating postoperative JET. Although randomized controlled trials (RCTs) were not yet reported the significant role of ivabradine in JET as published in some case reports and case series cannot be ignored. Appraisal of included studies was executed in consonance with their abstracts and titles in an unblinded consistent manner with the help of all coauthors. Detailed information regarding incidence and risk factors for JET, its etiopathogenesis, distinctive features of JET on 12-lead ECG, pharmacologic management, and role of ivabradine in JET was congregated.

    Incidence and risk factors for junctional ectopic tachycardia

    The incidence of JET in postoperative settings is 2%–10%, which increases with the complexity of the case, duration of cardiopulmonary bypass (CPB), and aortic cross-clamp time.[14],[18],[19],[20] Moreover, most units see a fall in the incidence of JET with increasing experience of the surgeon and the assistants.

    Protracted ischemia time and CPB time, hypoxia, electrolyte imbalance, younger age-group patients (mainly infants <6 months), surgery involving area near AV node, and the use of escalated doses of inotropic agents are common risk factors for the generation of JET.[14],[21]

    Impaired filling of the ventricles, loss of AV synchrony, and atrial contribution to cardiac output which is essential in patients with diastolic dysfunction of the right ventricle as in Tetralogy of Fallot (TOF) are hemodynamic consequences of JET development and can contribute to low cardiac output.[22] Cardiac surgeries, especially involving the crux of the heart are mainly responsible for JET.[1],[23],[24] It is common in the intracardiac repair of TOF and pulmonary stenosis, AV canal, and ventricular septal defect (VSD) repair, arterial switch operation with VSD, complex double outlet right ventricle.[23],[24] Reduced incidence of JET has been reported with the postoperative use of nitroprusside.[25]

    Although it is self-limiting, it can cause serious hemodynamic deterioration in the early postoperative period. It is very difficult to manage JET and if it persists, it can lead to ventricular dysfunction, heart failure, and high mortality.[6],[26] JET results in longer intensive care unit stay and hospital stay.

    Etio-pathogenesis of junctional ectopic tachycardia

    Expanded automaticity is caused within the bundle of His due to direct trauma or edema caused by sutures or infiltrative hemorrhage to the bundle of His and the AV node may be responsible for the pathogenesis of JET. The retraction exerted by the assistant for VSD exposure is well recognized but nonquantifiable risk factor. Furthermore, it can occur in patients of extracardiac Fontan operation and in cardiac transplantation recipients.[27]

    It typically starts within 24 h post-cardiac surgery mainly during the rewarming phase. In JET origination of impulse from AV node complex and bundle of His results in simultaneous activation of atrial and ventricles. This in turn leads to contraction of atria against closed AV valves which ultimately causes reduced filling of ventricles followed by reduction in cardiac output and hypotension.[1],[3]

    Distinctive features of junctional ectopic tachycardia on 12-lead electrocardiogram

    JET is characterized as heart rate >170 beats per min along with the baseline QRS complex.[21],[22]

    A narrow complex rhythm which is customarily characterized by AV dissociation or 1:1 pattern of retrograde atrial conduction is mostly seen in JET.

    It was documented in a study that the use of Lewis lead ECG placement in the case of JET with wide QRS has been recommended as a simple way to clearly visualize the P waves in the event atrial wires are unavailable.[22]

    Pharmacologic management of junctional ectopic tachycardia

    The main objective of treating JET is to reduce catecholaminergic stimuli along with hypothermia (32°C–34°C) either using extracorporeal cooling or intravenous cooling if needed.[21]

    Antiarrhythmic drugs such as propranolol, magnesium, digoxin, and flecainide have been used, alone or in combination to treat JET but showed suboptimal efficacy.[20]

    Amiodarone has been used as an antiarrhythmic for the treatment of postoperative JET. It works on dose-dependent manner and being used first as a loading dose then as continuous maintenance infusion. Hypotension, bradycardia, and AV block are potential adverse events that has been reported with its use.[28] Amiodarone and hypothermia are first-line treatment of JET.[29] Radiofrequency ablation is documented to be an effective procedure. However, it is difficult in small children and is not widely available.

    Despite all the available treatment modalities, managing JET is still challenging especially in the pediatric population.

    Role of ivabradine in junctional ectopic tachycardia

    Ivabradine was first approved on April 15, 2015, by the US Food and Drug Administration (FDA) to lessen the risk for hospitalization for worsening heart failure among patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤35%, who are in sinus rhythm with a resting heart rate of ≥70 beats per minute (bpm) and are taking maximally tolerated doses of beta-blockers or have a contraindication to beta-blockers. Depending on its potential to treat a life-threatening condition and fill an unmet medical need, ivabradine was granted a priority review and a fast-track review by the FDA.[30] Ivabradine is known to inhibit cardiac pacemaker cells. It has also established its distinctive role in the treatment of angina pectoris and inappropriate sinus tachycardia.[7],[31]

    It has been revealed in recent preclinical animal studies that, funny current channels (If current) play a significant role in originating junctional tachycardia. Hyperpolarization activated cyclic nucleotide-gated (HCN4) channels are known to be involved in the If current-related depolarization. Ivabradine selectively inhibits these channels. It has produced satisfactory results in treating JET.

    Because of its use dependence, it has a substantial effect on elevated heart rates. It is hemodynamically neutral and thus represents a potential frontier in treating tachyarrhythmias.[8]

    The absence of an IV formulation and the unknown effect of a postoperative low cardiac output state on drug absorption are major limitations of ivabradine in treating JET in the acute setting.[8],[17],[18]

    Although amiodarone is a competent drug for the control of sinus rhythm, its a porter of various adverse drug reactions, so its pros and cons should be meticulously assessed.[32]

    These adverse effects are minimal with ivabradine use. Moreover, there are very few case reports and case series that have been reported on the use of ivabradine in JET, yet it seems to offer a promising role.

    Limitations of the study

    Management of JET has been canvassed only in case reports and case series. In the hierarchy of epidemiological evidence, case reports and case series are usually conceived the lowest level of evidence, while RCTs, systematic reviews, and meta-analyses of RCTs are at the crown. Nevertheless, case studies and case series accommodate an authoritative position in the medical literature, particularly for the generation of hypothesis, recognizance of sentinel events, and studying outcomes of rare diseases or new treatments. Our study can help channelize decision-making for JET treatment by summing up the range of doses and time to outcomes antecedently went through, even when the limited nature of the data prevent the generation of summary statistics on efficacy.


      Conclusion Top


    Ivabradine appears to be a promising drug in the management of postoperative JET, while RCTs are needed assess its efficacy and safety in JET. In conclusion, there are a number of challenges to research on JET. Case reports and case series replete a significant role as the initial data source for such conditions, and when cautiously executed, systematic reviews of case reports and case series can render a utilitarian summation to evidence-based medicine.

    Ethical approval

    This manuscript represents a review article. Because this project involved no experimental design, the Institutional Review Board approval was not required. Applicable EQUATOR Network (http://www.equator-network.org) guidelines were followed.

    Authors' contributions

    SG, SD, SP and SN designed the study; all authors contributed to the model design; SG and SN implemented the model; all authors contributed to the data analysis and interpretation; SN, SP and SD drafted the manuscript and all authors critically revised it for important intellectual content and approved the final submitted version of the manuscript.

    Financial support and sponsorship

    Nil.

    Conflicts of interest

    There are no conflicts of interest.



     
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