Critical Care Alert: Survival by Time-to-administration of Amiodarone, Lidocaine, or Placebo in Shock-Refractory Out-of-hospital Cardiac Arrest

ARTICLE: Lupton JR, Neth MR, Sahni R, Jui J, Wittwer L, Newgard CD, Daya MR. Survival by time-to-administration of amiodarone, lidocaine, or placebo in shock-refractory out-of-hospital cardiac arrest. Acad Emerg Med. 2023;30(9):906-917.

OBJECTIVE

To determine how time from emergency medical services (EMS) arrival on scene to antiarrhythmic drug administration affects the efficacy of amiodarone and lidocaine on patient survival when compared to placebo for shock-refractory out-of-hospital cardiac arrest.

BACKGROUND

Out-of-hospital cardiac arrests (OHCA) are a leading cause of mortality with more than 80,000 patients having an initial shockable rhythm (VF/pVT).¹ It is known that patients with initial shockable rhythms have better survival when compared to non-shockable rhythms.¹ Current ACLS guidelines have either amiodarone or lidocaine as options for antiarrhythmics during shockable cardiac arrests, typically given after three defibrillation attempts, two rounds of CPR, and epinephrine administration.² However, quality evidence for the optimal timing of antiarrhythmics is lacking and administration timing can vary widely.

In 2016, the Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest (ALPS)³ trial was published. This was a large, multicentre, randomized control trial comparing these antiarrhythmics vs. placebo in refractory OHCA. This study ultimately found there was no survival benefit or increase in favorable neurological outcomes for amiodarone or lidocaine over placebo. However, the average time to antiarrhythmic administration was 19 minutes. At this length of time, there is a question of whether antiarrhythmics would have full effect given the likely significant physiologic derangements present at this stage of an arrest.

Six previous studies have shown that early administration of amiodarone and lidocaine increases the odds of return of spontaneous circulation (ROSC) and improves patient outcomes.⁴ However, these studies have been limited due to variability in timing of administration cutoffs, lack of controls for EMS arrival times, routes of administration, and not accounting for resuscitation time bias.

This secondary analysis of the ALPS data evaluates how time to administration of amiodarone or lidocaine affects survival to hospital discharge, survival to admission, and functional survival. This study gives a clear definition of administration timing (early vs late) of antiarrhythmics and attempts to account for resuscitation time bias and adjusted for potential confounders. This analysis is important as it provides more evidence for the early usage of antiarrhythmics for shockable rhythms in OHCA and may be generalizable for all shockable cardiac arrests. 

DESIGN

This study is a secondary analysis of the per-protocol arm of the ALPS trial. This was a large, double-blinded, randomized control trial on adults ≥ 18 from across 10 sites in North America and 55-EMS agencies. The original double-blind study compared administration of 300 mg amiodarone, 120 mg lidocaine, or placebo (normal saline) and subsequent doses of 150 mg of amiodarone or 60 mg of lidocaine in cardiac arrests with an initial shockable rhythm.

The secondary analysis stratified antiarrhythmic administration time for less than 8 minutes or greater than 8 minutes for the early and late groups, respectively. Time of drug administration was defined as time to administer the drug after ALS-capable EMS arrival on scene or time to administration if EMS witnessed the arrest. The 8-minute mark was chosen as the earliest reasonable interval for antiarrhythmic administration and from analysis of the primary ALPS data showing approximately one-third of patients would be included in the early group. In addition, a secondary sequence-of-care based analysis was completed for patients who received antiarrhythmics prior to or within 1 minutes of initial epinephrine dose (with-epinephrine group) and those who received it 1 minute or more after epinephrine (after-epinephrine group).

Finally, the study completed a multivariable analysis by adjusting variables associated with survival to discharge and time to drug administration without being on the causal pathway (ie, witnessed arrest, sex, location, bystander CPR, dispatch to first EMS vehicle arrival, etc). Downstream factors such as length of total arrest, need for advanced airway were not adjusted for as they could be on the causal pathway. The sensitivity analysis was also stratified by routes of administration (IV vs. IO).

INCLUSION CRITERIA

• Patients in the original ALPS trial who were adults 18 years or older with an initial, non-traumatic refractory VF/pVT OHCA on EMS evaluation and those who received the randomized study drug

EXCLUSION CRITERIA

• Initial non-shockable rhythm
• Achieving ROSC before administration of the study drugs

PRIMARY OUTCOME

• Survival to hospital discharge. This is the same as the primary outcome for the parent ALPS trial.

 SECONDARY OUTCOMES

• Survival to admission and functional survival
  • Functional survival was defined as a modified Rankin scale score ≤ 3 at hospital discharge. A modified Rankin scale of 3 is a patient with moderate disability requiring some external help but able to walk without the assistance of another individual. 

Both the primary and secondary outcomes were assessed for the early vs. late antiarrhythmic administration analysis and the sequence of care-based analysis of epinephrine administration.

KEY RESULTS

There were 2,802 patients that were included in the final per-protocol analysis. These patients were the per-protocol cohort of the ALPS population who received amiodarone, lidocaine, or placebo after having an initial shockable rhythm that had not yet achieved ROSC. Of these, 31.4% received the early administration of the study drug within 8 minutes of EMS arrival and 25.4% of patients received the study drug prior or within 1 minute of epinephrine administration.

Primary Outcome

Early amiodarone when compared to placebo had a higher survival to discharge (37.1% vs. 28.0%, p = 0.02; OR 1.56 [1.07-2.29]). This corresponds to a NNT for one additional survival to discharge of 11. 

Late amiodarone had no significant difference on survival to discharge when compared to placebo. There were no differences for survival to discharge for early or late lidocaine when compared to placebo.

In the with-epinephrine group, amiodarone had a higher survival to discharge compared to placebo (32.2% vs 23.5%, p = 0.038). There were no differences in amiodarone compared to placebo in the after-epinephrine group. There were no differences in outcomes for lidocaine compared to placebo for the with or after-epinephrine group.

Secondary Outcomes

Early amiodarone when compared to placebo had a higher survival to admission (62.0% vs. 48.5%, p = 0.001; OR 1.75 [1.24-2.50]) and functional survival (31.6% vs. 23.3%, p = 0.029; OR 1.55 [1.04-2.32]). This corresponds to a NNT for one additional survival to admission of 8 and a NNT for survivors with a good functional outcome of 12.

Late amiodarone had no significant difference on survival to admission or good functional outcome when compared to placebo. 

There were no statistically significant differences for survival to admission or functional survival for early or late lidocaine with the exception of late lidocaine for survival to admission (40.0% vs. 33.9%, p = 0.023; OR 1.35 [1.07-1.71]).

In the with-epinephrine group, amiodarone had a higher functional survival compared to placebo (27.0% vs 19.2%, p = 0.046). There were no differences in amiodarone compared to placebo in the after-epinephrine group. There were no differences in secondary outcomes for lidocaine compared to placebo for the with or after-epinephrine group with the exception of survival to admission for the after-epinephrine lidocaine group compared to placebo (45.7% vs 37.1%, p = 0.001).

LIMITATIONS

• This study was a secondary analysis of the parent ALPS trial, which was not originally designed to study the effects of medication timing
• Given this was a secondary analysis, potential limitations of the ALPS trial may apply for this study including selection bias and the enrollment of patients whose condition had little to no chance for survival
• The study was unable to adjust for clustering by agency or site as this data was not available in the ALPS data set. Although distributions were similar in the parent data, this study cannot evaluate if further timing stratification results in differences across the sites
• The parent data set does not have information on certain potential confounding factors that may be more applicable to this study, such as CPR fraction, CPR pauses, patient comorbidities, etc. 
• The study cannot account for possible inaccuracies of time measurement to drug administration that occurs in the field
• The dataset contains a small amount of IO delivery of medication which could affect the impact of antiarrhythmic efficacy

EM TAKE-AWAYS

This secondary analysis of one of the largest studies on shockable refractory OHCA demonstrated a survival benefit of early (<8 min) administration of amiodarone. Consider earlier administration of antiarrhythmics (particularly amiodarone) than typically given for shockable arrests in the prehospital or hospital setting.

REFERENCES

1. Tsao CW, Aday AW, Almarzooq ZI, et al. for the American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2022 update: a report from the American Heart Association. Circulation. 2022;145(8):e153-e639.
2. Merchant RM, Topjian AA, Panchal AR, et al. Part 1: Executive Summary: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020;142(16_suppl_2):S337-S357.
   
3. Kudenchuk PJ, Brown SP, Daya M, et al. Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest. N Engl J Med. 2016;374(18):1711-1722. 
4. Lupton JR, Neth MR, Sahni R, Jui J, Wittwer L, Newgard CD, Daya MR. Survival by time‐to‐administration of amiodarone, lidocaine, or placebo in shock‐refractory out‐of‐hospital cardiac arrest. Acad Emerg Med. 2023;30(9):906-917.