A Review of Selected Treatment Options in Refractory Ventricular Fibrillation

October 5, 2021
Ethan Deckert, MD

Tones ring out and dispatch announces a 9-Echo call in your district: an approximately 35-year-old male was found lying on the sidewalk, with bystanders currently receiving instructions to start CPR. You arrive on scene to find a sweaty 35-year-old male in running clothes, unresponsive and pulseless. Your crew takes over CPR and places him on the monitor which shows ventricular fibrillation (Vfib). You defibrillate the patient and recheck rhythm which is still Vfib. After three defibrillation attempts, the patient remains in Vfib. You restart CPR and a rookie on your team looks to you with confusion on his face and says, “What do we do now…?”

Shock-refractory ventricular arrhythmia is commonly defined as ventricular tachycardia (Vtach) or Vfib that persists after either one or (more commonly) three attempted defibrillations.1 It is important to note that refractory Vfib is when Vfib rhythm persists despite intervention, while recurrent Vfib is when a patient is converted out of Vfib to another rhythm, but then returns to Vfib later in the resuscitation. Refractory Vfib can be a perplexing problem for EMS because the topic is not specifically addressed in the current American Heart Association (AHA) cardiac arrest algorithm2 and because of a paucity of high-quality literature to inform our decision making. This lack of high-quality evidence results in part from the lack of standardized EMS protocols and guidelines to treat this condition and from the challenges of conducting robust prehospital research in cardiac arrest.

There is, however, sufficient evidence to make informed decisions to positively impact patient care. The first-line medication class for rVfib is vasopressors, such as epinephrine. An in-depth discussion of epinephrine dosing and timing in prehospital management of cardiac arrest is a topic for another day. However, another pharmacologic strategy – anti-arrhythmic agents – is necessary when vasopressors alone are ineffective. The use of anti-arrhythmics is presumed to facilitate subsequent defibrillation attempts rather than directly converting the ventricular tachydysrhythmia. Currently, the most studied in-hospital antiarrhythmic agents are amiodarone, lidocaine, magnesium sulfate (MgSO4), and (more recently) esmolol.

Related

There is some preliminary evidence from the U.K. suggesting procainamide may be stepping into this group, as it was shown to be superior to amiodarone (in-hospital) for converting ventricular tachycardia.3,4 But this was not isolated to refractory Vfib cases and more evidence needs to be available before leading to changes in current recommendations. These antiarrhythmics are making their way into the prehospital setting as well, and more research is being completed to better inform our understanding of the role of each anti-arrhythmic for EMS. Other strategies include vector changes, double sequential defibrillation and extracorporeal membrane oxygenation (ECMO). So, what does the literature say?

An important preliminary note is necessary before discussing the literature in more detail. Many prehospital and hospital studies of the treatment of refractory Vfib arrest report outcomes such as return of spontaneous circulation (ROSC) and/or survival to hospital/ICU admission. These are short-term outcomes with unclear patient benefit. If a patient lives to ICU admission, but has severe anoxic brain injury, then ICU admission is not a very good marker of therapeutic superiority. Most studies have failed to show improvement in long-term outcomes such as neurologically intact survival or survival to hospital discharge. These are much more meaningful, patient-centered outcomes to guide our standards of practice. Unfortunately, to the best of our knowledge, adequately powered studies reporting these outcomes for prehospital refractory Vfib are few and far between, but this article explores the current literature, focusing on the quality of evidence to best inform your practice.

Magnesium has been studied for treatment of ventricular arrhythmias as far back as the 1960s.5 And, of course, MgSO4 has long been a staple of treatment for torsades de pointes as established by many studies in the late 1980s and early 1990s.6,7,8 There are also many case reports suggesting conversion of shock-refractory ventricular arrhythmias after magnesium administration.9,10,11 However, several more recent studies have suggested no benefit to using magnesium sulfate for this indication. In 2001, Allegra et al. published a prospective, double-blind, placebo-controlled, prehospital trial of magnesium sulfate.12 Adults with out-of-hospital cardiac arrest (OHCA) and ventricular arrhythmias refractory to three defibrillations were randomized to receive either two grams of MgSO4 or a placebo. MgSO4 showed no benefit over placebo in short term outcomes (ROSC and survival to ICU admission) or long-term outcomes (survival to discharge from the hospital).

Similarly, a 1997 study of in-hospital cardiac arrest showed no improvement in ROSC, survival to admission, or survival to hospital discharge with MgSO4.13 These results mirror those from 2002 a study by Hassan et al. which also compared MgSO4 to placebo.14 This study was a randomized, double-blinded, placebo-controlled trial comparing two grams and four grams of MgSO4 to placebo in adult OHCA patients in refractory Vfib. This study also showed no improvement in the MgSO4-treated groups for the proportion of patients with ROSC or survival to hospital discharge. Unfortunately, all these studies were inadequately powered to evaluate long-term, patient-centered outcomes. Some would assert that MgSO4+ administration may optimize the intravascular environment, particularly in dialysis patients, alcoholic patients or in the setting of other comorbidities that often alter circulating potassium or magnesium levels. However, no prospective studies to date have shown benefit of magnesium when used as an antiarrhythmic in shock refractory Vfib.

This is reflected in the 2020 AHA CPR/ECC guidelines which do not recommend the use of magnesium sulfate in cardiac arrest.2 Additionally, similar findings were reported in the 2017 meta-analysis (a meta-analysis is a review and re-analysis of data from multiple existing studies) by Khan et al.15 This statistically sophisticated analysis of existing antiarrhythmic trials for refractory Vfib showed no benefit for MgSO4 when compared to placebo. However, this study did suggest considerable improvement in ROSC and survival to hospital discharge for other anti-arrhythmics (amiodarone or lidocaine) when compared to MgSO4 or placebo.

Amiodarone is one of the most common antiarrhythmics used in the prehospital setting today. Importantly, amiodarone has been studied in several formulations, most commonly mixed with a diluent of polysorbate, Captisol® or cyclodextrin.16,17 The polysorbate containing formulation, often called “Cordarone®,” is still the most widely used in prehospital applications. Cordarone is vasoactive, sometimes resulting in hypotension which is an important considering when giving this medication. Despite its vasoactivity, two landmark articles (the ARREST trial in 1999 and the ALIVE trial in 2002) established amiodarone in polysorbate (Coradrone®) as an effective treatment for shock-refractory ventricular arrhythmias with improvements in survival to hospital admission when compared with placebo and lidocaine.18,19 These randomized trials initially established amiodarone as the AHA preferred choice for refractory tachyarrhythmias. However, with further study in recent years, the AHA has added lidocaine as an equivalent option that can be reasonably used instead of amiodarone.20 That being said, the 2020 AHA CPR/ECC guidelines still only give a level 2b recommendation for amiodarone.2

Randomized trials support initial IV/IO dosing of 300mg of amiodarone, followed by repeat IV/IO dosing of 150mg, if required.21 The Resuscitation Outcomes Consortium (ROC) ALPS trial was a large, prospective, randomized controlled, prehospital trial reported by Kudenchuk et al. in 2016. This study reported no difference in survival to hospital discharge or neurological outcome between amiodarone in Captisol® when compared with lidocaine and placebo.18 Within the ALPS trial, a subgroup analysis of patients with witnessed OHCA and bystander CPR suggested that amiodarone and lidocaine were both associated with improvements in survival to hospital discharge over placebo. But this subgroup analysis was performed within the context of an insignificant difference for the overall analysis, thus limiting its applicability.22,23 This is one of the few articles with any evidence of improved long-term outcomes with amiodarone or lidocaine, and it is weak at best. Most of this evidence points to improved short-term outcomes with amiodarone over placebo, with comparable short-term outcome improvements reported for lidocaine.

Lidocaine has been a familiar drug to EMS professionals for decades and is a commonly used antiarrhythmic agent. The recommended dosing for lidocaine is 1.0-1.5 mg/kg, IV/IO with evidence supporting repeat IV/IO dosing at 0.5-0.75 mg/kg if required.21 The ALPS trial, noted previously, suggested improvement in ROSC with lidocaine compared to placebo.18 Survival to hospital admission was significantly improved with both lidocaine and amiodarone over placebo as well. Unfortunately, there was not significant improvement in survival to hospital discharge and neurologic outcomes were not assessed. The previously mentioned meta-analysis by Khan et al. in 2017 likewise showed lidocaine to be either superior or equivalent to amiodarone in survival to hospital discharge, (both of which were superior to MgSO4 and placebo).15

Unfortunately, the only two RCTs included in this meta-analysis were statistically underpowered. Neither independently demonstrated improvement in long-term outcomes. Thus, the significance of the results of the meta-analysis is questionable, given the absence of consistent statistically significant differences in long-term outcomes like survival to hospital discharge or good neurologic outcomes between lidocaine, amiodarone, MgSO4 and placebo. In the context of equivocal science currently supporting these antiarrhythmics, more recent studies have investigated beta-blockade as an option for shock-refractory Vtach/Vfib.

Beta-blockade, specifically with esmolol, has been studied with increasing frequency in the past few years and low-quality preliminary evidence suggests that esmolol may be effective in converting refractory Vtach/Vfib.24,25 Beta blockade may reduce the catecholamine surge suspected of perpetuating Vfib despite attempted defibrillation.26 Epinephrine directly contributes to this high concentration of catecholamines that could be preventing effective defibrillation. Therefore, the continued use of epinephrine while administering beta blockers for refractory Vfib is counterproductive. There is accumulating evidence, mostly observational, but several studies including the PARAMEDIC-2 trial suggest that typical epinephrine dosing and frequency may be excessive and that the therapy is often given long after it is likely to be effective (during the late metabolic phase of cardiac arrest).27,28,29,30

This evidence is not clear enough to change epinephrine dosing recommendations as they stand, but if the trend of current evidence continues, changes to epinephrine dosing recommendations would be a natural next step. With that in mind, several studies support the use of esmolol in refractory Vfib. There are many case studies supporting this theory with weak anecdotal evidence.31,32,33,34 However, no consistent, adequately powered, randomized, prospective studies have been produced supporting esmolol use in this scenario.

Miraglia et al. reported in 2020 a systematic review and meta-analysis showing low-grade evidence for improved survival to hospital discharge and better neurologic outcomes in refractory Vfib patients treated with esmolol.35 Similar evidence showing improvements with esmolol was present for both ROSC and survival to hospital admission. Unfortunately, the statistical analysis suggested that this was inconclusive and warranted further investigation to clarify the possible role of esmolol in this setting. Generally, for cardiac arrest patients, a loading dose of 500 mcg/kg over one minute has been administered prior to a maintenance infusion dose of 0–100 mg/kg/min.(25)(35) Esmolol could be considered for prehospital use in shock-refractory ventricular arrhythmia after lidocaine or amiodarone has proven ineffective, but considerable investigation needs to be done before this would become the standard practice. If the evidence supporting anti-arrhythmics is weak, what other strategies could be used for refractory Vfib?

Vector changing is simply the process of changing the pad positioning if the ventricular arrhythmia is not responding to defibrillation with the initial (usually anterolateral) pad placement.36,37 Double sequential defibrillation (DSD) is the use of two defibrillators and two sets of pads to provide two sequential defibrillations in rapid succession.

Figure 1: This is an image demonstrating DSD pad placement. Standard anterolateral placement is shown in red with the second set of pads in an anterioposterior position in blue. For more detailed information on this defibrillation strategy, see the DOSE-VF trial by Cheskes et al.36
Figure 1: This is an image demonstrating DSD pad placement. Standard anterolateral placement is shown in red with the second set of pads in an anterioposterior position in blue. For more detailed information on this defibrillation strategy, see the DOSE-VF trial by Cheskes et al.36 Image created by the author.

This strategy has been shown to be feasible and some studies suggest it is safe.36 Importantly, this strategy remains controversial and generally voids the manufacturer’s warranty on the defibrillator, as some defibrillators have been damaged or destroyed by this strategy. That being said there are several primary theories for how DSD works.36

  1. Increased energy from two shocks allows defibrillation of a larger amount of myocardium which is more effective in overcoming refractory Vfib.
  2. The first shock lowers the defibrillation threshold, improving the effectiveness of the second shock.
  3. Multiple simultaneous vectors allow energy to reach areas of myocardium that would be ineffectively defibrillated by standard anterolateral pad position.  

It is not clear how much, each of these theories contributes to the effect of DSD. Timing seems to be one of the most important factors for DSD effectiveness. Evidence suggests that DSD is more effective during shocks four through eight rather than after defibrillation attempt eight.36 However, DSD does not seem to be effective in patients that have already received a large number of shocks. Several studies looking at DSD suggest it safe and may improve at least short-term outcomes. Other studies criticize the use of DSD, suggesting the support for its use is weak, and the risks may still outweigh the benefits.36,38 The AHA 2020 ECC guidelines currently give DSD a 2b recommendation, which is not strong support.2 It’s also important to consider that other very simple strategies may improve the effectiveness of defibrillation, such as replacing the pads, drying/shaving the chest before defibrillation, applying pressure to the pads on the chest with a gloved hand during shock delivery and basic vector changes. Ultimately, a larger prospective study with clinically meaningful outcomes – such as neurologically intact survival – will be needed before making DSD a standard of care in refractory Vfib.38

ECMO is an advanced reperfusion strategy that has shown promise in improving meaningful long-term outcomes in refractory Vfib. ECMO provides oxygenation and circulation of the blood on an external circuit. This allows the underlying cause of the refractory Vfib to be addressed while the patient is sustained on external support. There are some systems that have established prehospital ECMO cannulation teams, and most systems with ECMO capabilities rely on cannulation within the hospital. The latter strategy of in-hospital ECMO cannulation shifts the focus of OHCA management for EMS from on-scene resuscitation to resuscitation during rapid transport to the hospital to minimize the time to reperfusion that occurs with ECMO cannulation. The ARREST trial in 2020 showed significant improvement in survival to hospital discharge for patients meeting ECMO criteria, when compared to standard ACLS algorithms.39 There are several other studies supporting the use of ECMO in refractory Vfib.23,40,41

These studies suggest that ECMO is a good option for selected prehospital patients with refractory Vfib and suggest a positive impact on long-term survival outcomes. However, not only is the process of ECMO cannulation is very time and resource intensive, it requires enormous and often prohibitive system/regional resources, training, coordination and commitment to implement and maintain an ECMO program. The vast majority of EMS agencies and even hospitals don’t yet have the resources or training available to be able to support ECMO cannulation within their systems.

In Summary

  1. Magnesium sulfate lacks substantial supporting evidence for its use in shock-refractory Vfib/Vtach and is not recommended for routine use at this time. In the absence of strong evidence showing that it is harmful, magnesium sulfate could be reasonably used in last-ditch efforts when other therapies are failing or if torsades de pointes is suspected. It should not, however, be prioritized over alternative strategies such as vasopressors, lidocaine, amiodarone or vector changes during defibrillation.
  2. Lidocaine and amiodarone have been shown to be more effective than both MgSO4+ and placebo for achieving short-term resolution of refractory vFib, but the level of evidence is not robust and they are only 2b recommendation by the AHA in 2020.2 There is no consistent evidence supporting the use of one of these two agents over the other, especially in terms of clinically-meaningful outcomes. Operational EMS considerations should be carefully considered when deciding on these antiarrhythmics, since similar patient outcomes have been demonstrated with either medication. Cost, familiarity for EMS clinicians, supply chain considerations, medical director preference, and other factors may influence the choice of one or the other for a given EMS agency/system.
  3. Esmolol may be effective, e.g., as a second-line pharmacologic treatment when amiodarone or lidocaine is not effective for refractory VFib. While some EMS agencies have adopted it in their protocols, more robust data from rigorous prehospital studies will be needed to determine its true role in this setting.
  4. Defibrillation vector changes and other measures to increase defibrillation effectiveness are a great option for refractory ventricular arrhythmia. These adjustments are feasible, safe and do not require a second defibrillator. If vector changes and antiarrhythmics are ineffective, DSD can be considered, although robust data from rigorous clinical trials is not yet available. DSD is not currently the standard of care, and the risk to the defibrillator (and its warranty) should be considered before adding it to your guidelines.
  5. ECMO initiated in the field or early transport to an ED with eCPR capability are both excellent options in selected OHCA patients in refractory Vfib who meet the inclusion criteria for ECMO cannulation, if the necessary system and community resources are in place. Until ECMO availability becomes more widespread, it will not be an option for most EMS agencies due to cost, training, time and/or distance restrictions rendering it impractical.

*This is by no means an exhaustive list of all data informing the decision for treatment in refractory ventricular arrhythmias, but this covers the relevant landmark studies and the highest quality evidence sources that were found in a literature review, which have been referenced below to help with personal medical knowledge acquisition and EMS agency guideline development.

Disclaimer: This article reflects the views and opinions of the author and not necessarily those of the University of New Mexico EMS Consortium or any affiliated agencies.

Support: There was no financial support for this literature review.

Disclosures: The author has no disclosures to report.

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