First Results of Our Local Practice Guide Used During the Late Phase of Resuscitation in Patients with Refractory VF in Out of Hospital Cardiac Arrest

Introduction

Approximately 4–5% of all cardiac arrests and 20% of shockable arrests (pulseless ventricular tachycardia and ventricular fibrillation) are patients with refractory ventricular fibrillation (rVF).^1,2 This is defined by the contemporary European Resuscitation Council (ERC) Advanced Life Support (ALS) guideline as “ventricular fibrillation that persists after three defibrillations”.¹ The duration of rVF is associated with poor outcome^3–6 and given the exponential decline in survival, early and effective treatment is crucial.^3,7

Treatment recommendations in the ALS guideline consist of optimizing standard defibrillation, using an escalating energy level or considering antero-posterior defibrillation pad position.¹ Acknowledging that repeating previous unsuccessful therapies does not contribute to favorable neurological outcome,⁴ other treatment opportunities might be considered whenever the standard ALS algorithm falls short. Therapeutic options described in the literature can be categorized as follows:

Alternative defibrillation strategies, either a “vector change” (VC) to antero-posterior defibrillation resulting in a possible larger portion of the ventricles being depolarized or “dual synchronized external defibrillation” (DSED) with the delivery of more energy as well as a “conditioning shock” phenomenon, can increase the success rate of defibrillation.^8–12 Reduction of adrenergic catecholamine drive, can be achieved by the reduction of epinephrine administration,^13–15 beta-adrenergic blockade^16–19 and/or sedation.²⁰ Concerns around epinephrine in rVF focus on the negative effects mediated through beta-receptors and platelet’s function, resulting in an increased myocardial oxygen demand, reduced subendocardial perfusion and exacerbated ischemic injury of the heart and brain.^21–24 Administration of epinephrine does not improve survival with good neurological outcome^2,15,25–27 and norepinephrine has therefore been studied as an alternative vasopressor.^22,28–32 Mitigating ischemic effects from phosphodiesterase inhibitors in (prolonged) cardiac arrest can benefit the cardiac function.^33–39 Niemann, Garner, Khaleeli and Lewis³⁶ compared the effects of milrinone and saline in an animal study, finding that milrinone facilitated resuscitation from rVF and attenuated left ventricular dysfunction. Evidence of additional antiarrhythmic drugs is limited, although lidocaine could be beneficial after ineffective administration of amiodarone in VF patients with Brugada syndrome.⁴⁰ Magnesium was reported successful in certain rVF cases,^41,42 although larger studies were unable to reproduce these findings.^43,44 Finally, Extracorporeal-CardioPulmonary Resuscitation (E-CPR) can be a “bridging” option in carefully selected patients,^45–49 eg until coronary revascularization is obtained.

Objective

We distilled a local practice guide from the available literature and introduced this as standard care for the later stage of VF by our HEMS service in March 2022. This analysis reports the results of our first patients and associated outcome data of this local practice guide. A comparison is made with reference data from the literature to analyze the outcome results and to check for non-inferiority.

Methods and Materials

Study Design

This was a database study evaluating standard of care using a local practice guide in patients with persisting VF beyond the fifth ALS shock-block in the presence of helicopter emergency medical service (HEMS).

Local Practice Guide

The initial draft of the local practice guide was designed according to the available literature by two anesthesiologists/HEMS physicians (CS, LM) and subsequently discussed with all HEMS physicians until expert consensus was reached. Additional content validity was obtained by an independent cardiologist. The local practice guide includes alternating blocks with bolus administration of esmolol (0.5mg/kg) and “cardio-mixture” (norepinephrine 0.5mg, combined with enoximone 25mg), coupled with alternative defibrillation strategies and optional use of magnesium and/or lidocaine (Figure 1). This local practice guide was introduced as standard HEMS care in March 2022 for the prolonged phase of patients in persisting VF.

Figure 1 Local practice guide for the treatment of persistent Ventricular Fibrillation by the Helicopter Emergency Medical Service Lifeliner. Advanced Life Support (ALS) resuscitation block 1–5 according to contemporary ALS guideline. *Dichotomous weight-based dosing 0.5mg/25mg (>50kg), 0.25mg/12.5mg (<50kg).

In- and Exclusion

All primary HEMS deployments for cardiac arrest between 1-3-2022 until 31-12-2023 were included in this analysis. Inclusion was set to adult patients (≥18 years) suffering from an out-of-hospital cardiac arrest (OHCA) with both an initial and persistent shockable rhythm beyond the fifth ALS block and presence of HEMS. If HEMS would arrive before the fifth ALS block, treatment would be continued according to the contemporary ALS guideline until after the fifth ALS block ensuring that at least five antero-lateral defibrillations, 450mg of amiodarone and 2mg of epinephrine had been administered before initializing the local practice guide.

Cardiac arrests resulting from obvious traumatic etiology or intoxication were excluded. Patients in VF in whom E-CPR was performed were also excluded from the study.

Data Extraction

All receiving hospitals were contacted for relevant outcome data, being part of standard procedure after a HEMS deployment. Patient selection and data extraction from HEMS database was performed between 20^th – 24^th December 2023 by two independent researchers (CS, LM). Any discrepancies were discussed until consensus was reached. The final cohort was subsequently verified by an independent physician. During data collection age and date of resuscitation and hospital were known. The name and date of birth (only age remains) of our patients disappears out of our database after 24 hours. This is how we maintain and comply with relevant data protection and privacy regulations.

Outcome Parameters

The primary outcome was defined as “sustained return of spontaneous circulation” (ROSC) until hospital admission. The deceased group was defined as patient declared dead either on-scene or at the emergency department. Secondary outcomes were defined as survival to hospital discharge and associated cerebral performance category (CPC). Survival to hospital discharge was compared to reference data from the literature using the systematic review by Mandigers, Boersma, den Uil et al.⁵⁰ As a tertiary outcome, we reported local practice guide adherence.

Reported resuscitation time was derived from the number of ALS blocks, starting from the first documented defibrillation and stopped when resuscitation was terminated either because the patient was declared dead or ROSC had occurred.

Statistical Analysis

Data were analyzed using IBM Statistic Package for the Social Sciences (IBM Corp.^© SPSS Statistics for Windows, Version 28.0.0.0). Continuous variables were reported as median and interquartile range (IQR), dichotomous variables as counts and percentages unless otherwise specified. Differences between those who died and those with sustained ROSC were tested using the Mann–Whitney U-test or Fisher’s exact test for continuous and dichotomous variables, respectively. The exact binomial test with exact Clopper-Pearson 95% CI and univariable and multivariable logistic regression analysis was used to test hospital survival against the reference literature data.

Ethical Consideration

The Institutional Ethical Review Board, METC Oost-Nederland, approved the study of our local practice guide in patients with prolonged rVF in prehospital care (2023–16616) and waived the need for informed consent as the study was not subjected to Medical Research Involving Human Subjects (WMO). Study complies with the Declaration of Helsinki.

Results

During a 21-month period, 716 hEMS deployments for an OHCA occurred. In 24 cases VF persistent beyond the fifth ALS block in the presence of HEMS crew. Five cases were excluded for E-CPR as our HEMS service participates in the on scene trial (On-Scene trial – The First Nationwide PreHospital ECPR program), leaving 19 patients to be included in this analysis (Figure 2). Patient demographics and resuscitation details are shown in Table 1 and individual patient treatments are included in Figure 3.

Table 1 Patient Demographics and Resuscitation Details

Figure 2 Overview of patients.

Figure 3 Individual patient treatments.

Primary Outcome

Most cardiac arrest were witnessed (79%), had bystander CPR (63%) and had an Automated External Defibrillator (AED) applied (53%). The overall median [IQR] age was 52.0 [10] All patients receiving ROSC did so prehospitally. The median [IQR] HEMS flight time was 16.0 [5] minutes, resulting in HEMS arrival in the 8^th [2] ALS block. The overall median [IQR] resuscitation time was 22.0 [16]. All patients had been given amiodarone and epinephrine according to the contemporary ALS guideline before initiation of the local practice guide. Nine out of 19 patients (47%) arrived at hospital with ROSC.

Secondary Outcome

Of the nine patients admitted to hospital, one was diagnosed with a cerebral etiology for the arrest and treatment was withdrawn. Of the remaining eight patients (42% of the total population), all were discharged from hospital with good neurological outcome (CPC 1 or 2).

The expected hospital survival derived from a median resuscitation time of 22min according to the systematic review by Mandigers, Boersma, den Uil et al⁵⁰ was 17% for adults suffering an OHCA due to a shockable rhythm. An exact binomial test with exact Clopper-Pearson 95% CI showed a significant higher survival (42%) in our sample with a 95% CI of 20.3% to 66.5%, p = 0.009. Logistic regression analysis revealed an OR of 8.7 (95% CI 1.2–61.5), p = 0.030 for survival with good neurology with additional care, according to the local practice guide (Figure 4). The effect of the local practice guide adjusted for age and gender resulted in an OR of 6.8 (95% CI 0.45–101.7), p = 0.165. These results suggest non- inferiority of the local practice guide.

Figure 4 Forest plot survival with good neurology following Out of Hospital Cardiac Arrest. Forest plot for studies comparing out-of-hospital cardiac arrest survival with good neurology (CPC ≤ 2). Fourteen studies were included, n = 441.693 cases comparing standard ALS guideline care (n = 441.674) with additional local practice guideline care (n = 19). The size of the grey square reflects its weight in the analysis the grey diamond is the overall results of the meta-analysis. The horizontal lines represent confidential intervals. Abbreviation: CI, confidence interval.

Tertiary Outcome

Withholding epinephrine was achieved in 84% of patients. Esmolol and cardio-mixture were administered in 79% and 90% of patients respectively. Four patients were withheld esmolol because of intermittent underlying bradycardia or VF was already terminated after preceding drug administration (magnesium or norepinephrine/enoximone). A total of 42% of patients received magnesium and 15% were given lidocaine. Alternative defibrillation positions were indicated in 18 patients but applied in only 6 (33%).

Discussion

Local Practice Guide Design Reflection

Given the a priori expected low survival in extended resuscitations, we chose a parallel approach with alternating medications and defibrillations per ALS block. Given the reported effects of esmolol,^18,51 we put extra emphasis on beta-blockade administration. The observed effect in our study was, however, much smaller compared to the initial studies^18,51 and more in line with the recent published beta-arrest trial.⁵² Both findings led to a more stringent indication and dose reduction for future patients.

Despite the study by Lindner and Ahnefeld³¹ showing comparative effects of norepinephrine and epinephrine, we were concerned that high-dose norepinephrine could be deleterious to the ischemic heart when given without inotropic support in the late resuscitation phase. Given the reported positive effects of milrinone,^{33,35–37,39} we therefore combined norepinephrine with enoximone, a phosphodiesterase-inhibitor that can be administer as a push dose.⁵³

Contrary to case-reports, larger studies failed to demonstrate the benefit of magnesium in rVF,^43,44 which was the reason we placed magnesium optionally at the end of our local practice guide. A rather large portion of patients was given magnesium, which resulted from HEMS physicians’ interpretation of polymorphic ventricular tachycardia as Torsades de Pointes.

Primary and Secondary Outcome Reflection

Survival with good neurology from VF declines rapidly to approximately 7% at 30min and 1–2% at 45min.^3,6,7,50,54 As inclusion was set to cases of persisting VF beyond the fifth ALS block, selection bias was inevitable present. The natural course of VF is, however, gradual with 40% of untreated cardiac arrests patients still in VF after 20 minutes.³ Although in theory, E-CPR would not have to preclude additional rVF treatments, we did not combine these interventions and therefore E-CPR prevailed above the local practice guide, thereby excluding five rVF cases. Given the stringent criteria for E-CPR within our service (age 18–50 years, witnessed and shockable arrest with adequate bystander CPR, etCO2 > 10mmHg and time to initiation of E-CPR <45min after collapse), this selection was likely to attenuate survival.

Survival rates differ between true refractory and recurrent VF.^9,55 Given the high workload in the prehospital setting, limited diagnostic opportunities and often short intervals of terminated VF in recurrent cases, we could not differentiate between these two entities.^56,57 The majority of persisting VF, according to the ALS guideline definition, appears to be recurrent VF with only 4% being truly refractory VF.⁵⁷ Acknowledging this distribution, searching for alternative medication strategies as suggested in the local practice guide might be even more important compared to achieving alternative defibrillation positions.

To limit the overestimation of the effect, we purposefully derived the resuscitation time from the actual number of ALS blocks as AEDs and ambulance monitors keep track of time in an objective manner. This is, however, an underrepresentation of the actual resuscitation time as it does not incorporate no-flow and low-flow time before the first defibrillation.⁵⁸

Tertiary Outcome Reflection

The pharmacological interventions from the local practice guide appear to be well implemented in the prehospital setting.¹⁷ Alternative defibrillation on the other hand, seems much more difficult to achieve. Other observational studies achieved success rates of 78–89%.^10,12 Hypotheses for this discrepancy might be the concomitant tasks-/workload, the administration of alternative medications, the unavailability of equipment, unfamiliarity with the procedure and/or technical difficulty. The later might be particularly relevant to the Netherlands where, compared to the other studies, mechanical CPR is regularly used prehospitally.

Limitations

This study incorporated alternative pharmacological and defibrillation options for the later stage of shockable arrest. The well-organized resuscitation system in the Netherlands with eg dispatch-center initiated CPR instructions, the activation of citizen assistance (“near-bystander”) CPR and public availability of AEDs are relevant to the survival outcome in this study. This study has limitations regarding sample size, data omissions and selection bias. We tried to minimize these by using independent researchers, by analyzing all HEMS deployments and by combining data from multiple sources as well as by providing detailed individual patient information. Furthermore, we calculated duration of resuscitation in a restrictive manner, thereby attenuating the effects of the local practice guide. We acknowledge the shortcomings of this study and underscore the necessity of more robust future research for confirmation of the study results.

Conclusions

In this study on patients with persisting VF despite full amiodaron administration and multiple standard defibrillation attempts, a multifaceted, bundle of care approach shows promising results regarding survival with favorable neurological outcome and requires further research. Alternative pharmacologic interventions seem feasible in the prehospital environment, although alternative defibrillation strategies pose more of a challenge and require further exploration.