The case for quinidine: Management of electrical storm in refractory ventricular fibrillation

Quinidine is regaining interest as a life-saving and possibly exclusive treatment for inherited arrhythmia syndromes presenting with ventricular fibrillation (VF). In December 2017, the pharmaceutical manufacturer Eli Lilly announced they would cease manufacturing intravenous (IV) quinidine gluconate, rendering it unavailable worldwide. In March 2019, all remaining drug supply expired. Here, we present a case of idiopathic VF (IVF) and electrical storm refractory to all antiarrhythmic therapies, successfully treated with IV quinidine. A previously healthy 27-year-old woman experienced witnessed out-of-hospital cardiac arrest, while at work. She was found in VF and return of spontaneous circulation was obtained 15 minutes later after multiple defibrillations and infusion of amiodarone and epinephrine. At admission, the electrocardiogram (ECG) (Figure 1) showed sinus rhythm at 100 beats per minute, with short-coupled premature ventricular contractions (PVCs). She demonstrated posturing of the extremities, hypokalemia, and lactic acidosis. Coronary angiography was unremarkable. Immediately after arrival to the intensive care unit she developed VF refractory to therapy with magnesium, amiodarone, lidocaine, and esmolol. She was placed on extracorporeal membrane oxygenation and hypothermia was induced (33°C). She remained in VF for another 8 hours with >20 failed cardioversion attempts. Following 2 boluses of quinidine 300 mg IV, sinus rhythm was restored with a single shock. The patient remained in sinus rhythm with no PVCs thereafter, continuing IV quinidine and finally transitioning to oral quinidine sulfate (300 mg 3 times a day). An implantable cardioverter-defibrillator was implanted for secondary prevention and magnetic resonance imaging 6 weeks later revealed normal cardiac function and absence of fibrosis. Genetic testing was uninformative, revealing 2 variants of unknown significance likely to be benign in the FLNC gene. She was ultimately discharged to home rehabilitative care. At 18 months follow-up she has not experienced arrhythmias and continues with oral quinidine therapy. The differential diagnosis for electrical storm in a patient without ischemia falls into 2 main categories: primarily electrical and toxic-metabolic. IVF, which has been associated with short-coupled PVCs originating from the distal Purkinje fibers,1Viskin S. Lesh M.D. Eldar M. et al.Mode of onset of malignant ventricular arrhythmias in idiopathic ventricular fibrillation.J Cardiovasc Electrophysiol. 1997; 8: 1115-1120Crossref PubMed Scopus (126) Google Scholar seemed the most likely diagnosis for the patient, considering all other negative findings. The short-coupled PVC noticed on presentation was compatible with a left posterior fascicle morphology (right bundle branch block, left anterior hemiblock), typical for Purkinje fibers supplying the posteromedial papillary muscle.2Pak H.N. Kim Y.H. Lim H.E. et al.Role of the posterior papillary muscle and purkinje potentials in the mechanism of ventricular fibrillation in open chest dogs and swine: effects of catheter ablation.J Cardiovasc Electrophysiol. 2006; 17: 777-783Crossref PubMed Scopus (72) Google Scholar IVF is a rare cause of sudden death, with an incidence between 1.2% and 6.8%.3Waldmann V. Bougouin W. Karam N. et al.Characteristics and clinical assessment of unexplained sudden cardiac arrest in the real-world setting: focus on idiopathic ventricular fibrillation.Eur Heart J. 2018; 39: 1981-1987Crossref PubMed Scopus (60) Google Scholar Haissaguerre and colleagues4Haissaguerre M. Cheniti G. Escande W. et al.Idiopathic ventricular fibrillation with repetitive activity inducible within the distal Purkinje system.Heart Rhythm. 2019; 16: 1268-1272Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar demonstrated that repetitive activity from the distal Purkinje fiber network may cause VF even with minimal or no PVCs at baseline. Quinidine is a class Ia sodium channel blocker that also reduces the inward and outward potassium currents IK1 and IKto.5Vitali Serdoz L. Rittger H. Furlanello F. et al.Quinidine - a legacy within the modern era of antiarrhythmic therapy.Pharmacol Res. 2019; 144: 257-263Crossref PubMed Scopus (18) Google Scholar This combined effect may make quinidine uniquely effective in controlling arrhythmias associated with action potential duration dispersion and phase 2 reentry, postulated in IVF. Particularly, Ito is highly expressed in Purkinje fibers, possibly explaining the unique effect of quinidine.6Han W. Wang Z. Nattel S. A comparison of transient outward currents in canine cardiac Purkinje cells and ventricular myocytes.Am J Physiol Heart Circ Physiol. 2000; 279: H466-H474Crossref PubMed Google Scholar Several studies have now demonstrated reduced incidence of ventricular arrhythmias in patients with IVF treated with quinidine.7Belhassen B. Pelleg A. Miller H.I. et al.Serial electrophysiological studies in a young patient with recurrent ventricular fibrillation.Pacing Clin Electrophysiol. 1981; 4: 92-99Crossref PubMed Scopus (25) Google Scholar,8Belhassen B. Glick A. Viskin S. Excellent long-term reproducibility of the electrophysiologic efficacy of quinidine in patients with idiopathic ventricular fibrillation and Brugada syndrome.Pacing Clin Electrophysiol. 2009; 32: 294-301Crossref PubMed Scopus (88) Google Scholar In addition to medical therapy, radiofrequency ablation has been shown to effectively suppress Purkinje fiber–triggered ectopy and IVF.9Cheniti G. Vlachos K. Meo M. et al.Mapping and ablation of idiopathic ventricular fibrillation.Front Cardiovasc Med. 2018; 5: 123Crossref PubMed Scopus (24) Google Scholar In our case, PVCs were not observed following the initiation of Quinidine therapy. Additional primary electrical etiologies of electrical storm include QT interval abnormalities (short and long QT syndrome), catecholaminergic polymorphic ventricular tachycardia, early repolarization syndrome,10Mizusawa Y. Bezzina C.R. Early repolarization pattern: its ECG characteristics, arrhythmogeneity and heritability.J Interv Card Electrophysiol. 2014; 39: 185-192Crossref PubMed Scopus (10) Google Scholar and Brugada syndrome. The latter may be elicited even in the presence of a normal baseline ECG by placing the precordial leads at an elevated sternal position or by administration of a sodium channel blocker such as procainamide or ajmaline.11Cheung C.C. Mellor G. Deyell M.W. et al.Comparison of ajmaline and procainamide provocation tests in the diagnosis of brugada syndrome.JACC Clin Electrophysiol. 2019; 5: 504-512Crossref PubMed Scopus (26) Google Scholar In our patient we did not observe a change to the ECG with these interventions. The worldwide discontinuation of IV quinidine is alarming. Its demonstrated effectiveness for various malignant ventricular arrhythmias expanded its in-hospital use, while availability kept decreasing progressively. Critically ill patients cannot easily absorb oral quinidine, and the lack of a parenteral option leaves them without access to a potentially life-saving medication. Our patient may not have survived her acute illness if IV quinidine was unavailable. Quinidine’s disappearance has impacted the infectious disease community as well. Owing to the lack of the drug, severe cases of malaria are now treated with IV artesunate, which is not yet approved by the Food and Drug Administration and must be obtained through the Centers for Disease Control. The restored availability of IV quinidine would hence serve different patients with life-threatening conditions and should be advocated by the medical community.Key Teaching Points•The differential diagnosis of an electrical storm includes idiopathic ventricular fibrillation (IVF).•IVF is elicited by automatic activity arising from Purkinje fibers, which may be manifested on the surface electrocardiogram by short-coupled PVCs.•Quinidine is a unique antiarrhythmic medication blocking both sodium and potassium channels. Its activity on the Ito current is effective in J-wave syndromes such as Brugada syndrome, early repolarization, and IVF.•Intravenous quinidine supply is limited. Efforts should be taken to ensure the continuation of this life-saving medication. •The differential diagnosis of an electrical storm includes idiopathic ventricular fibrillation (IVF).•IVF is elicited by automatic activity arising from Purkinje fibers, which may be manifested on the surface electrocardiogram by short-coupled PVCs.•Quinidine is a unique antiarrhythmic medication blocking both sodium and potassium channels. Its activity on the Ito current is effective in J-wave syndromes such as Brugada syndrome, early repolarization, and IVF.•Intravenous quinidine supply is limited. Efforts should be taken to ensure the continuation of this life-saving medication.