Cracking the Code: Controversies in ACLS Pharmacotherapy

Basic life support (BLS) has the primary focus of high-quality CPR and early defibrillation. Advanced cardiac life support (ACLS) utilizes BLS and adds the layers of treatment of underlying causes, advanced airway management, and pharmacotherapy. BLS interventions of chest compressions and early defibrillation have been consistently associated with improvement in neurologic outcomes at hospital. While pharmacotherapy interventions are commonly utilized in ACLS, they have varying utility in achieving ROSC, survival to hospital admission, survival to hospital discharge, or survival with favorable neurologic outcomes.

In this post, we will discuss the literature surrounding pharmacotherapy interventions that can be utilized during advanced cardiac life support (ACLS). Specific topics covered include the role in therapy and clinical utility of epinephrine, the role of vasopressin (alone and in combination with steroids and epinephrine), and differences in outcomes when using amiodarone versus lidocaine in shockable arrests.

Epinephrine

Epinephrine is a combined alpha agonist (arterial vasoconstriction) and beta agonist (improved contractility). The alpha activity is proposed to augment both coronary and cerebral perfusion. Theoretically, this may result in improved rates of ROSC and neurologic function via cerebral perfusion. Potential adverse effects include the risk of beta-adrenergic stimulation resulting in enhanced arrhythmia risk and increasing myocardial oxygen demand.

Epinephrine has been historically recommended in the AHA guideline and ACLS algorithm to improve ROSC. In non-shockable rhythms, epinephrine should be given as soon as possible. In shockable rhythms, it is recommended to administer epinephrine after the second defibrillation attempt. The European guidelines defer epinephrine use until after the third defibrillation attempt. Epinephrine is administered at 1 mg IV or IO every 3-5 minutes, or with every other pulse check for ease.

PACA, published in 2001, was a single-center, double-blinded RCT evaluating outcomes associated with epinephrine use versus placebo in 534 OHCA patients. Approximately 45% of patients had an initial rhythm of VF or pVT, 30% PEA, and 24% asystole. Use of epinephrine was associated with improvement in pre-hospital ROSC (23.5% vs 8.4%, p <0.001) and survival to hospital admission (35.4% versus 13%, p< 0.001). There was no significant difference in survival to hospital discharge or favorable neurologic outcome among survivors. Of surviving patients, 82% of patients in the epinephrine group had favorable neurologic outcome compared to 100% in placebo, bringing into question whether improvement in survival was at the expense of neurologic harm.

In 2018, the PARAMEDIC 2 multicenter double-blind RCT evaluated epinephrine versus placebo in 8,014 OHCA patients. The median time to epinephrine administration was 21 minutes from EMS call and 79% of patients had a non-shockable rhythm (53% asystole). In the epinephrine group, there was higher survival at 30 days (3.2% vs 2.4%), pre-hospital ROSC (36.3% vs 11.7%), survival to hospital discharge (3.2% vs 2.3%). There were no differences in survival with favorable neurologic outcome with an OR of 1.19 (CI 0.84-1.68).

Holmberg and colleagues in 2019 completed a meta-analysis of epinephrine use in cardiac arrest patients. Sub-group analyses of initial rhythms found in shockable rhythms epinephrine was associated with improvement in ROSC, and in non-shockable rhythms epinephrine administration was associated with both ROSC and survival to hospital discharge. Earlier administration of epinephrine was associated with improved rates of ROSC.

Specifically in OHCA, every one minute delay from EMS arrival to epinephrine administration, the risk ratio of survival was decreased by 4.4% for non-shockable rhythms and 5.5% for shockable rhythms. For IHCA, non-shockable rhythms had improvement in survival with early epinephrine administration however in shockable rhythms, administration within the first two minutes is associated with decreased survival [1-11]

Based on the currently available evidence, epinephrine has demonstrated improvement in all of the following except?

• ROSC
• Survival to Hospital Admission
• Survival to Hospital Discharge
• Favorable Neurologic Survival

Vasopressin

Vasopressin is a V1-receptor agonist that can result in arterial vasoconstriction. Proposed mechanisms for the utility in cardiac arrest patients include the relative endogenous vasopressin deficiency that exists, and ability to avoid sympathetic adverse effects associated with epinephrine use. In the 2005 AHA Guidelines, vasopressin was recommended as a potential alternative to replace the first or second doses of epinephrine.

In 2015 the AHA removed the recommendation for vasopressin, citing no improvement in outcomes when compared to epinephrine. With the 2020 update, vasopressin was reintroduced to the algorithm with recommendations for use alone or in combination with epinephrine. This is presented with the stipulation that use offers no advantage as a substitute for epinephrine in cardiac arrest patients.

Wenzel et al (2004) evaluated the use of vasopressin in a multi-center double-blinded RCT in 1,186 patients with OHCA. The mean time to drug administration was 18 minutes, and 45% of patients were in asystole, 40% with VF or pVT and 15% PEA. There was an increase by 40% in survival to hospital admission in those with asystole, with no harm associated with the intervention.

In 2008, Geugniaud and colleagues compared vasopressin versus epinephrine in OHCA in a majority of asystole patients (83%) with mean drug administration at 21 minutes. There were no differences noted in survival to hospital admission, ROSC, survival to hospital discharge, or good neurologic recovery at discharge [12-13].

Which of the following statements accurately represents the current evidence for the use of vasopressin in cardiac arrest?

• 0%Vasopressin alone improves survival to discharge vs. epineph
• 0%Vasopressin + epinephrine is superior to epinephrine alone
• 0%Vasopressin is more effective in PEA than epinephrine
• 0%Vasopressin does not improve outcomes vs. epinephrine

Vasopressin, Steroids, and Epinephrine (VSE)

The role of steroids in a cardiac arrest patient are hypothesized to treat a relative adrenal insufficiency and attenuate the systemic inflammatory response. VSE pharmacotherapy was studied by Mentzelopoulus and colleagues in 2009 in IHCA patients comparing VSE therapy (methylprednisolone 40 mg IV once and combination of vasopressin 20 units and epinephrine 1 mg every 2-3 minutes (max five cycles)) to epinephrine with placebo. If ROSC was achieved, the VSE group received 300 mg of hydrocortisone over the course of each day (continuous infusion) for 7 days. The primary outcome of this trial was a composite of sustained ROSC for at least 15 minutes and survival to hospital discharge. The initial rhythm was 62% asystole, and 23% PEA with a mean time to ACLS of 1 minute. The VSE group lead to increased ROSC (81% vs. 52%, p = 0.003), increased survival to hospital discharge (18.8% vs. 3.8%, p = 0.02), a more rapid attainment of ROSC. Additionally, patients with post-resuscitation shock had increased survival with post-resuscitation steroids (29.6% vs. 0%, p = 0.02). This trials extrapolation was limited by small population, that it was completed in a single-center, and had no data on neurologic outcomes.

The same trial group published a multi-center RCT in 2013 in 268 patients. The same comparator groups were evaluated in this trial as prior, with a primary composite outcome of sustained ROSC for at least 20 minutes and survival to hospital discharge with a CPC 1 or 2. The initial rhythm was 65-70% asystole, and 15-20% PEA with a mean time to ACLS of 2 minute. Rates of TTM were similar in both groups (about 25%

in each). The VSE arm was associated with increased ROSC (83.9% vs. 65.9%, p = 0.005), increased survival to hospital discharge with favorable neurologic outcome (13.9% vs. 5.1%, p = 0.02), and decreased duration of ACLS (13 vs 19 minutes, p=0.01). The NNT for improvement in neurologic outcome for this study was 12, and this may be driven by the reduction in time to ROSC. This trial helped validate the prior published 2009 trial by being a multi-center trial in a larger patient population and evaluation of neurologic outcomes.

In 2021, the VMA-IHCA trial was published. This trial was a double-blinded, multi-center RCT in 501 IHCA patients that comparing VSE therapy to epinephrine plus placebo. The VSE protocol was a one-time dose of methylprednisolone 40 mg and vasopressin 20 units with epinephrine 1 mg every 3-5min up to 4 cycles. There was no protocol of post-arrest steroids. The primary outcome of this trial was sustained ROSC greater than 20 minutes. Most patients (90%) had non-shockable rhythms with 55% PEA and 25% asystole. The mean duration to trial drug was 8 minutes, and there was no difference in rates of TTM utilization. VSE was found to improve rates of ROSC, but failed to improve survival or favorable neurologic outcomes at 30 days. A sub-group analysis found higher rates of ROSC with faster drug administration (RR 1.46 if within 8 minutes) and in those with non-shockable rhythms. There is potential for selection bias as 170 patients were excluded for unknown reasons.

While use of vasopressin alone has no improvement in outcomes compared to epinephrine, VSE combination therapy compared to epinephrine across all trials consistently improved rates of ROSC. In certain trial, all from the same trial group, this was associated with improved survival to hospital discharge with favorable neurologic status. The benefit of combination therapy could potentially be driven by the use of steroids. VSE studies are the only pharmacotherapy interventions to demonstrate neurological survival benefit [14-22].

Which of the following outcomes was most consistently demonstrated with the Vasopressin, Steroids and Epinephrine trials?

• ROSC
• Survival to Hospital Admission
• Survival to Hospital Discharge
• Favorable Neurological Outcomes

Antiarrhythmic Drugs

Antiarrhythmic pharmacotherapy are utilized in patients with VF or pVT refractory to electrical cardioversion. The rationale for therapy is chemical cardioversion may restore a perfusing rhythm and lower the defibrillation threshold. Amiodarone, a class III antiarrhythmic, and lidocaine, a class 1b antiarrhythmic, are most commonly used. Previous AHA guidelines have recommended for the use of amiodarone over lidocaine in VF/pVT patients, however previously amiodarone was recommended preferentially.

In 1999, the ARREST trial was a multicenter, double-blind RCT in 504 patients comparing amiodarone bolus of 300 mg once versus placebo (poly-sorbate 80) in OHCA refractory to three shocks. Amiodarone increased survival to hospital admission (44% vs. 34%, p = 0.03), however had no difference in survival to hospital discharge or favorable neurologic outcomes, and there was an increase risk of hypotension (p < 0.02). Only a single dose of amiodarone was utilized and the average time to administration was after five shocks leading to the question if sooner use and additional dosing would have a greater effect.

In 2002, the ALIVE trial was published evaluating amiodarone 5 mg/kg followed by 2.5 mg/kg versus lidocaine 1.5 mg/kg followed by 1.5 mg/kg in a double-blind multi-center RCT in 347 patients. All

patients were OHCA refractory VF, defined by receipt of at least 4 shocks. The primary outcome was survival to hospital admission and was 22.8% in amiodarone group versus 12% in lidocaine (p=0.009) correlating to a number needed to treat of 10 patients. The odds of survival decreased by 12% for every minute delay between dispatch and drug administration (HR 0.88, p < 0.001). No data was provided on neurologic outcomes. As a result of this trial, guidelines began favoring amiodarone over lidocaine for routine administration in this patient population.

In 2016, ROC-ALPS was a multicenter, double-blind, RCT in 3,026 patients in OHCA with VF or pVT refractory to at least one shock. Trial drugs compared were amiodarone 300 mg followed by 150 mg or lidocaine 120 mg followed by 60 mg. 60% of patients received bystander CPR and the mean time to drug administration was 19.3 minutes after dispatch (faster than previous trials). The primary outcome was survival to hospital discharge with no difference between groups. Both amiodarone and lidocaine improved survival to hospital admission, however only lidocaine improved rates of ROSC at emergency department arrival. There was no difference in rates of favorable neurologic outcomes based on modified rankin score.

A secondary analysis of the ROC-ALPS trial in 2022 published by Rahimi looked at 2,994 patients to determine impact of timing of drug administration out efficacy. Rates of ROSC were decreased overall with delayed drug administration. Amiodarone led to increased ROSC with early administration but decreased rates when administered late (13.5 minutes when compared to lidocaine, and 19.5 minutes when compared to placebo). Lidocaine was associated with improvements in ROSC when compared to placebo irrespective of timing. Overall, earlier medication administration results in higher rates of ROSC, however amiodarone is less effective in prolonged arrests and lidocaine retains efficacy.

Wagner and colleagues in 2022 published a retrospective cohort of 14,630 patients comparing amiodarone versus lidocaine for IHCA. Lidocaine increased 24-hr survival (59.1% vs. 63.4%, p = 0.001), survival to hospital discharge (42.0% vs. 47.5%, p < 0.001) and favorable neurologic outcome (33.3% vs. 36.9%, p < 0.001) when compared to amiodarone. However, the patients in the lidocaine cohort have less comorbidities, were more likely to arrest during day shift, had less vasopressor and mechanical ventilator use, and shorter time to defibrillation when compared with amiodarone, limiting the wide application of these conclusions [23-28].

Conclusions from literature:

Amiodarone and Lidocaine appear to have comparable outcomes for patients with VF/VT arrest. While older studies indicated superior outcomes with amiodarone, more recent data lean towards lidocaine's effectiveness. One potential factor for positive outcomes is the early administration of antiarrhythmic drugs. From a personal standpoint, both amiodarone and lidocaine seem like reasonable options in ACLS, but current literature inclines me more towards lidocaine than previously. While there might be merit in considering earlier drug administration within the shockable algorithm, the absence of comprehensive data probably discourages deviations from the standard algorithm.

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