What are the options for treating refractory ventricular fibrillation in the ED?

 In the original amiodarone and lidocaine trials (1,2), it meant no return of spontaneous circulation (ROSC) after 3 shocks. In more recent studies, it means no ROSC after one shock (3). And upon review the AHA guidelines:

“Refractory VF/pVT [ventricular fibrillation or pulseless VT] refers to VF or pVT that persists or recurs after one or more shocks.”(4)

It’s also important to recognize that this is distinct from electrical storm which is 3 episodes of sustained VF/VT and shocks from an AICD within a 24 hour period. There is a lot of overlap in terms of pathophysiology and treatment between refractory VF and electrical storm but ultimately the biggest difference is that electrical storm patients may not be undergoing active CPR and this allows them to be amenable to a different time course and range of interventions such as stellate ganglion block (5).

 Well, in general, the mechanisms involved in ventricular dysrhythmias (and really all dysrhythmias) follow some basic concepts (6).

The first mechanism is abnormal automaticity or “firing before you should”.

Why does this happen? Normally, during phase 4, pacemaker cells have leaky sodium/calcium channels that allow for slow depolarization, and when threshold potential is reached, boom – phase 0 rapid depolarization ensues. Well, in the acute phase of an MI or during transient ischemia, cell membrane Na-K ATPase pumps become dysfunctional leading to increased extracellular potassium and a less negative resting membrane potential. This depressed membrane potential may create injury currents between the injured and healthy myocardium and result in spontaneous, pacemaking activity (6). Basically, this injured myocardial tissue turns into an ectopic pacemaker and is called abnormal automaticity. (When adrenergic stimulation results in a steeper phase 4 within the conducting system, for example the purkinje fibers, it is called enhanced normal automaticity.) Automatic dysrhythmias will not terminate with direct current cardioversion.

 

The second mechanism is triggered activity.

If your calcium or sodium channels are dysfunctional, say from a genetic condition like Brugada Syndrome or in catecholaminergic VT, during phase 2 (plateau) and phase 3 (repolarization), your sodium channels may reopen too early. Early or late afterdepolarizations cause a “double bounce”. This is traditionally known as the “R on T” phenomenon. Polymorphic VT (and Torsades de Pointes) is typically associated with triggered activity, but degeneration to VF may occur without prompt defibrillation.

https://pocketdentistry.com/24-antiarrhythmic-drugs/

 

To be complete, the third mechanism for ventricular dysrhythmia is re-entry. This process usually underlies VT (with a pulse) in people with known heart disease (not refractory VF/pulseless VT). There are some subtleties in how exactly re-entry propagates, but it is depicted below. Normal conduction splits down into a normal pathway and a slow-conducting pathway (myocardial scar usually provides the slowly conducting pathway). The slowly conducting pathway is also characterized by a short refractory period setting up a pathway for retrograde conduction (blue arrow) and then a self-propagating circuit. Reentrant dysrhythmias will typically terminate with direct current cardioversion.

https://www.cvphysiology.com/Arrhythmias/A008c

Our understanding of the pathophysiology of refractory VF comes from animal studies in an attempt to create a cellular model (7). Ultimately, the thinking is that patients have increased cellular susceptibility to automaticity and triggered activity from both genetic and environmental factors.

Ok, so going in sequence with ACLS. We’ve addressed the basics. The guy got shocked, and it didn’t work.

 Possibly… There is concept called Dual Sequential Defibrillation (DSD):

Two sets of pads placed both anterior-posterior and R anterosuperior-L inferolateral with the shocks delivered < 0.4 sec apart.

There are 3 main ideas underlying DSD:

1. More energy ( maybe electricity is not the same dose for everyone and some people need more)
2. More vectors! (maybe we need to get more of the heart directly in the “path” of the electricity)
3. More time exposed to the shock

The evidence for DSD mainly comes from small case studies and retrospective trials (8,9,10,11). Recently there was a study that batched a bunch these case studies together for an N of 39 (12). ROSC was achieved in 53.9% of patients. Of those who achieved ROSC with DSD, about one third died within 24 hours. Overall, 28.2% of the patients who got DSD survived with favorable neuro outcome at discharge (CPC score < 2). Of note, the people who did better had bystander CPR (maybe early CPR was the reason?) and got DSD earlier. Ultimately though, these are all small retrospectives studies without statistical analysis, and the main driver of this technique is the theoretical basis behind how and why it should work.

 Also a maybe.

Mechanical CPR has been suggested, but the trials and meta-analysis have not shown clear statistical benefit or harm (13,14). Active Compression Decompression (ACD) / Impedance Threshold Device (ITD) CPR has a long story in the literature. For those who don’t know, it’s the combination of two augmentations to CPR. ACD CPR involves putting a suction cup on the chest to pull more blood into the heart. Allegedly, we only provide 25% ejection fraction with our CPR, and maybe we can make that better by increasing venous return with active decompression. (This idea was kick started because of a case report of someone doing CPR with a plunger). Despite being a good idea, ACD CPR was found to have no benefit in a 2013 Cochrane review (15).

Along the same line as ACD CPR is the implementation of an impedance threshold device (ITD). This is basically the opposite of a PEEP valve. During normal CPR, the negative intrathoracic pressure generated by chest recoil will pull blood into the heart and air into the lungs by passive ventilation. By preventing passive ventilation with the ITD, the intrathoracic pressure will be reduced. This may allow greater venous return and therefore increase cardiac output. Unfortunately, a large study in 2011 in the NEJM found no mortality benefit (16).

The weird thing is there was a 2011 RCT in Lancet that found when you combined the two interventions (ACD and ITD), there was a 3% increase to hospital survival with good neuro outcome (~6% vs. ~9%, p=0.03) (16). Additionally, a 2015 meta-analysis of either ACD or ITD  found no benefit but when adjusted for witnessed arrest and response time, there was a trend toward improved survival to hospital discharge with either device (17).

There was also a post hoc analysis of the 2011 NEJM study that showed when you excluded people in both groups who received poor CPR (depth and rate as captured by electrical impedance device), there was about a 3% mortality benefit. When CPR was performed poorly, patients with the ITD did worse (18). These findings were even more impressive when the study was limited to the approximately 4,000 patients who had witnessed cardiac arrest (19). Thus, it is possible that when compressions are given appropriately (correct rate/depth,) ITD works as intended and improves ROSC. There was no benefit detected in the original trial (16) because too many patients did not receive appropriate CPR.

There have been some indications in the literature that epinephrine may not be as useful as once thought. A recent large RCT, PARAMEDIC 2 (20), found that epinephrine increased the chance of ROSC in patients with out-of-hospital-cardiac arrests but did not increase the chance of survival with good neurological outcome. For additional reading, consider:

http://www.thennt.com/nnt/epinephrine-hospital-cardiac-arrest-2/

http://rebelem.com/rebel-cast-ep56-paramedic-2-time-to-abandon-epinephrine-in-ohca/

https://emcrit.org/emnerd/em-nerd-the-case-of-the-costly-compound/

The benefits of epinephrine administration may turn out to depend on timing, dose, and initial arrest rhythm (shockable or non-shockable). There were two studies (21,22) examining a vasopressin-steroid-epinephrine (VSE) bundle for inpatient arrests; in these cases, epinephrine will be given earlier. The treatment group was made up of inpatients with VF/VT refractory to two defibrillations or asystole/PEA. The intervention group was given 20 IU of vasopressin mixed with 1 mg epinephrine for all cycles of CPR, 40 mg methylprednisolone (VSE) after the first cycle of CPR, and if there was post-ROSC shock, stress-dose hydrocortisone. The control group received epinephrine and normal saline placebo. The VSE group had significantly increased survival to hospital discharge 19% vs 4%. The study was then repeated as a multicenter RCT across 3 centers (n=268). The findings were similar with the VSE group again demonstrating significantly improved survival to hospital discharge with CPC score 1-2: 13.9% vs 5.1%. However, only approximately 17% of each group had documented VF/VT; therefore, most of the patients had a non-shockable rhythm. This drug combination has shown promise and warrants further investigation. Interestingly, in the 2015 ACLS guidelines, VSE actually carries the same level of recommendation as amiodarone (4). A recent network meta-analysis also concluded that VSE was associated with improved survival with good neurologic outcome compared to any other drug or placebo, particularly in in-hospital cardiac arrest (23). This same meta-analysis found that there was no significant evidence to support or discourage the use of epinephrine in cardiac arrest.

 

Similarly, antidysrhythmics have been associated with increased rates of ROSC and hospital admission, but none have yet been proven to increase long-term survival or survival with good neurologic outcome. The majority of evidence referenced in the 2015 ACLS guidelines are from smaller RCTs that did not look at survival to discharge as a primary outcome (1,2). The best current evidence is from the 2016 Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest Study (ROC-ALPS). ROC-ALPS compared amiodarone, lidocaine, and placebo for out-of-hospital cardiac arrest in 3,000 patients and found no mortality benefit (3). However, among 1,934 patients with bystander-witnessed arrest, the survival rate was higher with amiodarone (27.7%) or lidocaine (27.8%) than with placebo (22.7%). This absolute risk difference was significant for amiodarone or lidocaine versus placebo separately but did not differ significantly between amiodarone and lidocaine. So, perhaps antidysrhythmic use soon after arrest (i.e. for inpatient arrests) may have benefit.

Venturing outside the guidelines, beta-blockade has been making its way into the literature. It seems like a weird idea, but it makes sense as a way of mitigating the instigators of VF and the negative consequences of epinephrine. From a pathophysiological perspective, epinephrine (whether endogenous or exogenous) may exacerbate dysrhythmia via direct mediators on channel sensitivity as well as by increasing oxygen demand (6). These effects have to be balanced against the theoretical hemodynamic benefits of increased coronary and cerebral perfusion. Beta blockade should blunt the dysrhythmogenic effects while preserving the hemodynamic benefits. In cardiac arrest, there have only been small retrospective studies which did show mortality benefit, but this is far from high-level evidence (24,25).

 

It is also worth noting that in the age of ECMO, increasing ROSC and survival to hospital admission may translate to as yet unproven better outcomes. For more on ECMO see:

http://blog.clinicalmonster.com/2016/10/ccm-ecmo/

It is beyond the scope of this post to address post-arrest management but it should be noted that there is a strong association with VF arrest and acute MI, so all these patients should be evaluated for urgent PCI (26).

There is a lot of info here but ultimately it’s useful to divide up our interventions based on what we are treating. Cardiac arrest follows a pathophysiology:

Weisfeldt ML and Becker LB (2002). DOI: 10.1001/jama.288.23.3035 (26)

Accordingly, I’ve lined up our interventions by which phase they treat. For the electrical phase, it’s really shocking in all its different forms, and although the evidence isn’t there, maybe try amiodarone or beta-blocker: basically anything to stop the underlying mechanism of the dysrhythmia and increase the chance of defibrillation to work. In the circulatory phase, we are trying to artificially also optimize myocardial response to another shock. This can be thought as cellular resuscitation: we artificially pump blood (with oxygen, glucose, etc.) to myocardium with CPR (traditional or modified), try to augment flow with vasopressors (i.e. epinephrine perhaps at lower than currently recommended doses), and maybe minimize drug-related harm with beta-blockers. Lastly, we may anticipate post-resuscitation shock and try steroids.