Antiarrhythmic Drugs for Out-Of-Hospital Cardiac Arrest with Refractory Ventricular Fibrillation Takashi Tagami1,2*, Hideo Yasunaga2 and Hiroyuki Yokota3
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Tagami et al. Critical Care (2017) 21:59 DOI 10.1186/s13054-017-1639-8 REVIEW Open Access Antiarrhythmic drugs for out-of-hospital cardiac arrest with refractory ventricular fibrillation Takashi Tagami1,2*, Hideo Yasunaga2 and Hiroyuki Yokota3 in OHCA patients and that antiarrhythmic drugs can be Abstract used as advanced life support during cardiac arrest in This article is one of ten reviews selected from the patients with refractory ventricular dysrhythmias [5, 6]. Annual Update in Intensive Care and Emergency Refractory VF/pVT is generally defined as failure to ter- medicine 2017. Other selected articles can be found minate VF/pVT with one to three stacked shocks [5]. online at http://ccforum.com/series/ Antiarrhythmic drugs that may be used include amio- annualupdate2017. Further information about the darone, lidocaine, and nifekalant ([5, 6]; Table 1). The Annual Update in Intensive Care and Emergency ILCOR guidelines recommend the use of amiodarone as Medicine is available from http://www.springer.com/ first‐choice treatment for adult patients with refractory series/8901. VF/pVT to improve the rate of return of spontaneous circulation (ROSC) [5, 6]. Lidocaine and nifekalant are recommended as alternatives to amiodarone in the treat- Background ment of refractory VF/pVT in adult patients. However, ‐ ‐ Out of hospital cardiac arrest (OHCA) affects approxi- as mentioned in the knowledge gap section of the latest mately 300,000 people in the United States, 280,000 resuscitation guidelines [5], existing evidence is not people in Europe and 110,000 people in Japan each year enough to suggest that amiodarone is superior to lidocaine – [1 3]. Among all the presentations of cardiac arrest and/or nifekalant in terms of the critical outcome of sur- (asystole, pulseless electrical activity [PEA], ventricular vival to discharge. In a trial involving OHCA patients with fibrillation [VF], and pulseless ventricular tachycardia VF/pVT, Dorian et al. [7] reported that the rate of survival [pVT]), VF and pVT are considered the most treatment to admission was significantly higher in the amiodarone responsive, but the rate of survival to hospital discharge group than in the lidocaine group but found no significant – after OHCA remains markedly low [1 3]. To overcome difference in the rate of survival to discharge between the ‐ this time sensitive and severe condition that has a low two groups. More recently, Kudenchuk et al. [8] reported “ ” survival rate, the chain of survival concept was first in- survival data for patients with OHCA due to initial VF/ troduced by Newman [4] in the 1980s as follows: (1) pVT in the prehospital setting and found that survival early access to emergency medical care; (2) early cardio- rates with amiodarone or lidocaine administration were pulmonary resuscitation (CPR); (3) early defibrillation; not significantly higher than with placebo. and (4) early advanced cardiac life support. Even after Thus, the provision of amiodarone, lidocaine, or nife- three decades of accumulation of evidence, the 2015 kalant to OHCA patients with refractory VF/pVT is still International Liaison Committee on Resuscitation controversial in clinical practice. In this chapter, we (ILCOR) guidelines still recommend immediate defibril- review the recent evidence from randomized trials and lation with CPR as the treatment of choice for VF/pVT observational studies for the efficacy of antiarrhythmic drugs for OHCA patients with refractory VF/pVT. * Correspondence: [email protected] 1Department of Emergency and Critical Care Medicine, Nippon Medical School, Tama Nagayama Hospital, 2068512 Tama-shi, Tokyo, Japan Characteristics and evidence of the efficacy of 2Department of Clinical Epidemiology and Health Economics, The University antiarrhythmic drugs of Tokyo, School of Public Health, Graduate School of Medicine, 1138555 Bunkyo-ku, Tokyo, Japan Lidocaine was traditionally used as the drug of choice Full list of author information is available at the end of the article for the treatment of OHCA in patients with persistent © 2017 Tagami et al. Tagami et al. Critical Care (2017) 21:59 Page 2 of 6 Table 1 Classification and recommendations for the three antiarrhythmic drugs Amiodarone Lidocaine Nifekalant Vaughan Williams classification Class III Class Ib Class III 2015 ILCOR treatment Suggest use of amiodarone in adult Suggest use of lidocaine as an Suggest use of nifekalant as an recommendation [5] patients with refractory VF/pVT to alternative to amiodarone in adult alternative to amiodarone in adult improve rates of ROSC. patients with refractory VF/pVT. patients with refractory VF/pVT. Level of recommendation Weak recommendation, Weak recommendation, very‐ Weak recommendation, very‐low‐ moderate‐quality evidence low‐quality evidence quality evidence ILCOR International Liaison Committee on Resuscitation, VF ventricular fibrillation, pVT pulseless ventricular tachycardia VF/pVT until the early 2000s [9]. Lidocaine is classified as refractory VF/pVT [22–25]. Amino et al. [22] reported a class Ib agent in the Vaughan‐Williams classification. Al- no significant differences in the success rate of defibrilla- though lidocaine is low‐cost and simple to administer, evi- tion and rate of survival to discharge between nifekalant dence is not enough to suggest its superiority to other and amiodarone in OHCA patients with refractory VF/ antiarrhythmic drugs or placebo in terms of rate of survival pVT. However, they reported that the interval between to hospital discharge of OHCA patients with persistent VF/ antiarrhythmic drug administration and defibrillation pVT. One retrospective study suggested that lidocaine may success in the amiodarone group was significantly longer improve the success rate of resuscitation [10], contrary to than that in the nifekalant group [22]. This finding was the negative results reported in other studies [11, 12]. After also reported in a retrospective study by Harayama et al. the reports of two landmark studies on amiodarone [7, 13], [23], who found that nifekalant achieved faster ROSC resuscitation guidelines were revised with preference for after refractory VF/pVT than did amiodarone. More re- amiodarone over lidocaine in the treatment of cardiac ar- cently, Amino et al. [25] evaluated the results of a large rest patients with persistent VF/pVT [5, 6, 9]. multicenter prospective study (SOS‐KANTO 2012 [26]). Amiodarone and nifekalant are both classified as class These investigators retrospectively investigated nifeka- III antiarrhythmic agents (potassium channel blockers) lant potency and differential effects of two initial amio- in the Vaughan‐Williams classification [14, 15]. However, darone doses (150 or 300 mg) as compared with these two class III antiarrhythmic drugs have different lidocaine doses in the Japanese population. The odds ra- pharmacological characteristics. Amiodarone has several tios (ORs) for survival to admission were significantly effects on ion channels, receptors, and sympathetic ac- higher in the 150‐mg nifekalant or amiodarone group tivity, in addition to blocking the rapid components of than in the lidocaine group. The authors also reported delayed rectifier potassium currents, such as sodium and that 24‐hour survival was significantly higher in the nife- calcium channel‐blocking effects, and α‐ and β‐receptor kalant, 150‐mg amiodarone, or 300‐mg amiodarone blocking actions. In other words, amiodarone has nega- groups than in the lidocaine group. Amino et al. [27] tive inotropic and vasodilatory effects, which may nega- published another post hoc analysis from the SOS‐ tively affect hemodynamic status after ROSC in OHCA KANTO 2012 study. They evaluated the effect of adminis- patients. On the other hand, nifekalant is a pure potas- tration of antiarrhythmic drugs (defined as any one among sium channel blocker that specifically blocks the rapid or a combination of lidocaine, nifekalant, and amiodarone) component of delayed rectifier potassium currents with- during CPR on 1‐month outcome by using propensity out blocking sodium or calcium channels [16]. Labora- score analyses. Logistic regression with propensity scoring tory studies suggest that nifekalant has no negative demonstrated an OR of 1.92 for 1‐month survival in the inotropic effects and no effect on cardiac conduction antiarrhythmic drug group (p =0.01)and1.44forfavor- and hemodynamic status, whereas amiodarone has these able neurological outcome at 1 month (p =0.26). effects via its β‐blocking action [17, 18]. Although some animal model studies suggested that amiodarone did not The ROC‐ALPS study contribute to the decrease in defibrillation threshold, Recently, Resuscitation Outcomes Consortium (ROC) nifekalant was found to decrease the defibrillation investigators published the results of the Amiodarone, threshold of ventricular fibrillation [19–21]. Therefore, Lidocaine or Placebo Study (ALPS), a randomized nifekalant may have advantages over amiodarone for the double‐blind trial [8]. Amiodarone, lidocaine, or placebo treatment of refractory VF/pVT via defibrillation and was administered by paramedics in the prehospital set- post‐resuscitation hemodynamic management from a ting for OHCA patients with refractory VF/pVT in 10 pharmacological point of view. However, data from clin- North American sites. The investigators evaluated 3,026 ical studies have provided limited robust results [22, 23]. patients, of whom 974 were assigned to the amiodarone Only a few studies have compared the efficacy of ami- group, 993 to the lidocaine