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Clinical paper| Volume 164, P54-61, July 2021

Coronary angiography findings in patients with shock-resistant ventricular fibrillation cardiac arrest

Open AccessPublished:May 20, 2021DOI:https://doi.org/10.1016/j.resuscitation.2021.05.006

      Abstract

      Introduction

      Shock-resistant ventricular fibrillation (VF) poses a therapeutic challenge during out-of-hospital cardiac arrest (OHCA). For these patients, new treatment strategies are under active investigation, yet underlying trigger(s) and substrate(s) have been poorly characterised, and evidence on coronary angiography (CAG) data is often limited to studies without a control group.

      Methods

      In our OHCA-registry, we studied CAG-findings in OHCA-patients with VF who underwent CAG after hospital arrival. We compared baseline demographics, arrest characteristics, CAG-findings and outcomes between patients with VF that was shock-resistant (defined as >3 shocks) or not shock-resistant (≤3 shocks).

      Results

      Baseline demographics, arrest location, bystander resuscitation and AED-use did not differ between 105 patients with and 196 patients without shock-resistant VF. Shock-resistant VF-patients required more shocks, with higher proportions endotracheal intubation, mechanical CPR, amiodaron and epinephrine. In both groups, significant coronary artery disease (≥1 stenosis >70%) was highly prevalent (78% vs. 77%, p = 0.76). Acute coronary occlusions (ACOs) were more prevalent in shock-resistant VF-patients (41% vs. 26%, p = 0.006). Chronic total occlusions did not differ between groups (29% vs. 33%, p = 0.47). There was an association between increasing numbers of shocks and a higher likelihood of ACO. Shock-resistant VF-patients had lower proportions 24-h survival (75% vs. 93%, p < 0.001) and survival to discharge (61% vs. 78%, p = 0.002).

      Conclusion

      In this cohort of OHCA-patients with VF and CAG after transport, acute coronary occlusions were more prevalent in patients with shock-resistant VF compared to VF that was not shock-resistant, and their clinical outcome was worse. Confirmative studies are warranted for this potentially reversible therapeutic target.

      Keywords

      Introduction

      Ventricular fibrillation (VF) is frequently observed as initial rhythm in out-of-hospital cardiac arrest (OHCA).
      • Berdowski J.
      • Berg R.A.
      • Tijssen J.G.
      • Koster R.W.
      Global incidences of out-of-hospital cardiac arrest and survival rates: systematic review of 67 prospective studies.
      An important subset of these patients have VF that is resistant to multiple defibrillation attempts, i.e. VF that persists or recurs despite shock delivery. This so-called shock-resistant VF is most commonly defined as requiring >3 shocks.
      • Yannopoulos D.
      • Bartos J.A.
      • Raveendran G.
      • et al.
      Coronary artery disease in patients with out-of-hospital refractory ventricular fibrillation cardiac arrest.
      • Yannopoulos D.
      • Bartos J.A.
      • Aufderheide T.P.
      • et al.
      The evolving role of the cardiac catheterization laboratory in the management of patients with out-of-hospital cardiac arrest: a scientific statement from the american heart association.
      • Kudenchuk P.J.
      • Brown S.P.
      • Daya M.
      • et al.
      Amiodarone, Lidocaine, or Placebo in out-of-hospital cardiac arrest.
      These patients with prolonged arrest duration are at high risk of mortality and poor neurologic outcome, and have gained increasing interest in recent years.
      • Berdowski J.
      • ten Haaf M.
      • Tijssen J.G.
      • Chapman F.W.
      • Koster R.W.
      Time in recurrent ventricular fibrillation and survival after out-of-hospital cardiac arrest.
      • Eilevstjonn J.
      • Kramer-Johansen J.
      • Sunde K.
      Shock outcome is related to prior rhythm and duration of ventricular fibrillation.
      A wide range of treatment strategies has been studied for shock-resistant VF, ranging from experimental studies to a pilot randomised trial on dual sequential defibrillation and a large randomised trial on amiodarone.
      • Kudenchuk P.J.
      • Brown S.P.
      • Daya M.
      • et al.
      Amiodarone, Lidocaine, or Placebo in out-of-hospital cardiac arrest.
      • Bartos J.A.
      • Voicu S.
      • Matsuura T.R.
      • et al.
      Role of epinephrine and extracorporeal membrane oxygenation in the management of ischemic refractory ventricular fibrillation: a randomized trial in pigs.
      • Cheskes S.
      • Dorian P.
      • Feldman M.
      • et al.
      Double sequential external defibrillation for refractory ventricular fibrillation: the DOSE VF pilot randomized controlled trial.
      Recently, more invasive protocols such as early coronary angiography and extra-corporeal life support have gained attention.
      • Yannopoulos D.
      • Bartos J.A.
      • Raveendran G.
      • et al.
      Coronary artery disease in patients with out-of-hospital refractory ventricular fibrillation cardiac arrest.
      • Bartos J.A.
      • Carlson K.
      • Carlson C.
      • et al.
      Surviving refractory out-of-hospital ventricular fibrillation cardiac arrest: Critical care and extracorporeal membrane oxygenation management.
      • Stub D.
      • Bernard S.
      • Pellegrino V.
      • et al.
      Refractory cardiac arrest treated with mechanical CPR, hypothermia, ECMO and early reperfusion (the CHEER trial).
      • Yannopoulos D.
      • Bartos J.
      • Raveendran G.
      • et al.
      Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): a phase 2, single centre, open-label, randomised controlled trial.
      As of yet, only the use of anti-arrhythmic drugs has been incorporated in cardiopulmonary resuscitation (CPR) guidelines as routine treatment.
      • Soar J.
      • Nolan J.P.
      • Bottiger B.W.
      • et al.
      European resuscitation council guidelines for resuscitation 2015: section 3. Adult advanced life support.
      However, despite the growing interest in the optimal therapeutic strategy for these patients, the underlying myocardial substrate has scarcely been described. Importantly, detailed analyses on underlying etiology may reveal potential therapeutic targets.
      One recently published study investigated a treatment strategy with immediate coronary angiography (CAG) in patients with VF that was refractory to ≥3 shocks without intermittent return of spontaneous circulation (ROSC).
      • Yannopoulos D.
      • Bartos J.A.
      • Raveendran G.
      • et al.
      Coronary artery disease in patients with out-of-hospital refractory ventricular fibrillation cardiac arrest.
      This study revealed that significant coronary artery disease (CAD) was present in 82% of the patients with refractory VF, with acute thrombotic lesions in 64%. However, that study was limited in patient numbers (n = 55) and there was no description of CAG-findings in a control group.
      Given the high prevalence of coronary artery disease in VF-patients in general, additional study is warranted to identify coronary substrate that is specific for shock-resistant VF.
      • Dumas F.
      • Cariou A.
      • Manzo-Silberman S.
      • et al.
      Immediate percutaneous coronary intervention is associated with better survival after out-of-hospital cardiac arrest: insights from the PROCAT (Parisian Region Out of hospital Cardiac ArresT) registry.
      • Spaulding C.M.
      • Joly L.M.
      • Rosenberg A.
      • et al.
      Immediate coronary angiography in survivors of out-of-hospital cardiac arrest.
      • Lemkes J.S.
      • Janssens G.N.
      • van der Hoeven N.W.
      • et al.
      Coronary angiography after cardiac arrest without ST-Segment elevation.
      Such analyses may provide impetus for further study on treatment specifically targeted towards this substrate, which in turn may contribute to improved outcomes in these high-risk patients. Therefore, we studied coronary angiography findings in cardiac arrest patients with VF that was shock-resistant vs. VF that was not shock-resistant.

      Methods

      Patient population

      We studied patients from the Nijmegen area OHCA-cohort (Gelderland-Zuid, the Netherlands).
      • Nas J.
      • Thannhauser J.
      • Herrmann J.J.
      • et al.
      Changes in automated external defibrillator use and survival after out-of-hospital cardiac arrest in the Nijmegen area.
      We included patients ≥18 years with a non-traumatic OHCA and a shockable first observed rhythm (defined as either an ECG-confirmed initial rhythm of VF or pulseless ventricular tachycardia, or a shockable rhythm as indicated by the automated external defibrillator [AED] if the first shock was administered by the AED), resuscitated between 1 January 2013 and 1 July 2018, transported to our tertiary hospital and undergoing CAG. Appreciating the non-interventional study design, written informed consent was not necessary to obtain (Dutch Act on Medical Research involving Human Subjects).
      • Thannhauser J.
      • Nas J.
      • van Grunsven P.M.
      The ventricular fibrillation waveform in relation to shock success in early vs. late phases of out-of-hospital resuscitation.

      Emergency medical services

      Gelderland-Zuid (population 530,000 residents, 1040 square kilometers) includes (sub)urban and rural areas. The emergency medical service (EMS) system is activated by calling 112. Paramedics will give instructions to the caller to initiate CPR, and usually two ambulances are dispatched to the OHCA-location. Ambulances are staffed by a driver and a paramedic, who is professionally trained to perform advanced life support. CPR was performed according to the prevailing European Resuscitation Council guidelines at the time of the OHCA.
      • Soar J.
      • Nolan J.P.
      • Bottiger B.W.
      • et al.
      European resuscitation council guidelines for resuscitation 2015: section 3. Adult advanced life support.

      Data acquisition

      Baseline characteristics and outcome data were collected using EMS-records, hospital records and data from municipal registries, following Utstein style definitions.
      • Perkins G.D.
      • Jacobs I.G.
      • Nadkarni V.M.
      • et al.
      Cardiac arrest and cardiopulmonary resuscitation outcome reports: update of the Utstein Resuscitation Registry Templates for Out-of-Hospital Cardiac Arrest: a statement for healthcare professionals from a task force of the International Liaison Committee on Resuscitation (American Heart Association, European Resuscitation Council, Australian and New Zealand Council on Resuscitation, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Southern Africa, Resuscitation Council of Asia); and the American Heart Association Emergency Cardiovascular Care Committee and the Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation.

      Coronary angiography

      A dedicated angiography committee (1 senior, 1 fellow interventional cardiologist) reviewed all CAG-images specifically for research purposes, using a predefined template including the angiographic parameters of interest.
      • Guidelines for percutaneous transluminal coronary angioplasty
      A report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Subcommittee on Percutaneous Transluminal Coronary Angioplasty).
      • Gibson C.M.
      • Cannon C.P.
      • Daley W.L.
      • et al.
      TIMI frame count: a quantitative method of assessing coronary artery flow.
      A random sample of 20% of all evaluated CAGs was used to calculate inter-observer agreement. In concordance with previous studies, a kappa of >0.80 was used as a cut-off to decide whether the initial evaluations would be used for final reporting, or if a systematic evaluation of all CAGs by a third reader would be required.
      • Nas J.
      • Thannhauser J.
      • Vart P.
      • et al.
      Effect of face-to-face vs virtual reality training on cardiopulmonary resuscitation quality: a randomized clinical trial.
      It was hospital policy to perform CAG in all patients with VF that regained ROSC and had no contraindication for CAG, but the final decision to perform CAG was left to the discretion of the treating physician. From January 2017 we participated in the Coronary Angiography after Cardiac Arrest (COACT) trial, in which patients with ROSC after shockable cardiac arrest without ST-elevation were randomised to immediate or delayed CAG.
      • Lemkes J.S.
      • Janssens G.N.
      • van der Hoeven N.W.
      • et al.
      Coronary angiography after cardiac arrest without ST-Segment elevation.
      Patients that were randomised in the COACT study were also included in the present study.
      In accordance with previous studies we used the following definitions:
      • Significant stenosis: stenosis >70%.
        • Yannopoulos D.
        • Bartos J.A.
        • Raveendran G.
        • et al.
        Coronary artery disease in patients with out-of-hospital refractory ventricular fibrillation cardiac arrest.
      • Significant coronary artery disease: at least one stenosis >70%.
        • Yannopoulos D.
        • Bartos J.A.
        • Raveendran G.
        • et al.
        Coronary artery disease in patients with out-of-hospital refractory ventricular fibrillation cardiac arrest.
      • Acute coronary occlusion: a presumably new obstructive lesion (i.e. the ability to pass a guidewire easily through the occlusion if angioplasty was attempted) with TIMI 0-I flow.
        • Spaulding C.M.
        • Joly L.M.
        • Rosenberg A.
        • et al.
        Immediate coronary angiography in survivors of out-of-hospital cardiac arrest.
        • Gibson C.M.
        • Cannon C.P.
        • Daley W.L.
        • et al.
        TIMI frame count: a quantitative method of assessing coronary artery flow.
      • Chronic total occlusion (CTO): complete occlusion of one of the main coronary artery branches, deemed >3 months old.
        • Brilakis E.S.
        • Mashayekhi K.
        • Tsuchikane E.
        • et al.
        Guiding principles for chronic total occlusion percutaneous coronary intervention.

      Study groups

      Patients were categorised as having either shock-resistant VF or VF that was not shock-resistant. In line with previous studies and an American Heart Association consensus document, we used a cut-off of >3 shocks.
      • Yannopoulos D.
      • Bartos J.A.
      • Raveendran G.
      • et al.
      Coronary artery disease in patients with out-of-hospital refractory ventricular fibrillation cardiac arrest.
      • Yannopoulos D.
      • Bartos J.A.
      • Aufderheide T.P.
      • et al.
      The evolving role of the cardiac catheterization laboratory in the management of patients with out-of-hospital cardiac arrest: a scientific statement from the american heart association.
      Patients with >3 shocks were categorised as shock-resistant VF, whereas patients with VF requiring ≤3 shocks were categorised as patients with VF that was not shock-resistant. For this categorisation, both AED and EMS shocks were taken into account.
      • Kudenchuk P.J.
      • Brown S.P.
      • Daya M.
      • et al.
      Amiodarone, Lidocaine, or Placebo in out-of-hospital cardiac arrest.

      Outcome measure

      Primary outcome measures were CAG-findings as described above. Secondarily, we calculated the proportions of ROSC, 24-h survival and survival to discharge.

      Statistical analysis

      Categorical data were expressed as frequencies (percentages) and compared using Chi-squared tests. Continuous data were tested for normal distribution and reported as means (standard deviations) or medians (interquartile ranges) and compared using student t-tests or Mann-Whitney U tests, whichever appropriate. A p-value <0.05 was considered statistically significant. Analyses were performed using SPSS (Version 25, IBM Corp., USA).

      Results

      Entire patient population

      Baseline and arrest characteristics

      During the study period, 571 patients were transported to our hospital with OHCA. A total of 301 patients was included in the present analysis, with exclusion mainly related to presentation with a non-shockable rhythm (Supplement 1).
      The majority was male (82%) and median age was 63 (53−70) years (Table 1). Of all arrests, 58% occurred at a public location, 88% was witnessed, of which 8% by the EMS. Bystander CPR was performed in 79% of the non EMS-witnessed cases. AED use before EMS-arrival occurred in 54% of the patients. For the entire study population, the median total number of shocks was 2 (1−4) shocks.
      Table 1Clinical and baseline variables.
      Shock-resistant VF
      OverallYes (>3 shocks) (n = 105)No (≤3 shocks)

      (n = 196)
      p-value
      Male246 (82%)89 (85%)157 (80%)0.32
      Age63 (53−70)63 (54−71)63 (53−70)0.72
      Prior MI (n = 288)66 (23%)23 (24%)43 (23%)0.82
      Previous cardiac disease125 (43%)43 (43%)82 (43%)0.88
      Arrest characteristics
      Public location166 (58%)56 (54%)110 (60%)0.32
      Witnessed249 (88%)89 (86%)160 (88%)0.62
       Bystander226 (80%)83 (81%)143 (79%)0.53
       EMS23 (8%)6 (6%)17 (9%)
      Bystander CPR*215 (79%)75 (78%)140 (80%)0.72
      AED used before EMS arrival*151 (54%)57 (57%)94 (52%)0.42
      EMS response time (min)7 (5−10)9 (5−15)6 (5−10)0.08
      Shocks by EMS220 (73%)98 (93%)122 (62%)<0.001
      Total nr of shocks2 (1−4)5 (4−8)2 (1−2)<0.001
      Autopulse used45 (16%)27 (28%)18 (10%)<0.001
      Endotracheal intubation166 (60%)68 (72%)98 (54%)0.006
      Patients receiving amiodarone96 (33%)70 (70%)26 (15%)<0.001
      Patients receiving epinephrine120 (42%)74 (74%)46 (25%)<0.001
      ST-elevation on ECG170 (60%)66 (71%)104 (55%)0.009
      Clinical and baseline characteristics in patients with shock-resistant vs. non-shock-resistant VF. * Of all cases not witnessed by the EMS. VF = Ventricular fibrillation, MI = Myocardial infarction; CPR = Cardiopulmonary resuscitation; AED = Automated external defibrillator; EMS = Emergency medical services; ECG = Electrocardiogram; ROSC = Return of spontaneous circulation.

      Coronary angiography findings

      The blinded secondary review resulted in an inter-observer agreement of 93% for acute coronary occlusion, of 93% for no acute coronary occlusion and a kappa of 0.83. Given this high level of agreement, we report on the CAG-reviews of the first observer in all cases.
      Of all patients, 77% had significant coronary artery disease, with 40% of all patients having 1-vessel disease and 37% having ≥2-vessel disease (Table 2). An acute coronary occlusion was present in 31% of all patients. The localization of these acute occlusions can be found in Table 2. Of all patients, 31% had a chronic total occlusion (CTO), of which the localization can be found in Table 2.
      Table 2Coronary angiography data.
      Shock-resistant VF
      OverallYes (>3 shocks) (n = 105)No (≤3 shocks) (n = 196)p-value
      Immediate CAG277 (92%)102 (97%)175 (89%)0.02
      Coronary angiography without ROSC12 (4%)9 (9%)3 (2%)0.004
      Re-arrest in the cath-lab15 (5%)8 (8%)7 (4%)0.12
      Coronary artery disease
      Significant CAD232 (77%)82 (78%)150 (77%)0.76
       1 vessel119 (40%)50 (48%)69 (35%)0.17
       2 vessel64 (21%)19 (18%)45 (23%)
       3 vessel49 (16%)13 (12%)36 (18%)
      Location of significant stenosis
      LM21 (7%)6 (6%)15 (8%)0.53
      LAD142 (47%)49 (47%)93 (47%)0.90
      RCx115 (38%)33 (31%)82 (42%)0.08
      RCA132 (44%)44 (42%)88 (45%)0.67
      Acute coronary occlusions
      ≥1 ACO93 (31%)43 (41%)50 (26%)0.006
       ACO LAD47 (16%)22 (21%)25 (13%)0.06
       ACO RCx27 (9%)9 (9%)18 (9%)0.86
       ACO RCA26 (9%)15 (14%)11 (6%)0.01
      Chronic total occlusion
      ≥1 CTO94 (31%)30 (29%)64 (33%)0.47
       CTO LAD22 (7%)4 (4%)18 (9%)0.09
       CTO RCx38 (13%)11 (11%)27 (14%)0.42
       CTO RCA68 (23%)23 (22%)45 (23%)0.85
      Percutaneous coronary intervention
      ≥1 lesion treated with PCI169 (56%)66 (63%)103 (53%)0.09
       LM12 (4%)5 (5%)7 (4%)0.62
       LAD83 (28%)33 (31%)50 (26%)0.27
       RCx50 (17%)18 (17%)32 (16%)0.86
       RCA56 (19%)24 (23%)32 (16%)0.15
      Coronary angiography data in patients with shock-resistant vs. non-shock-resistant VF. VF = Ventricular fibrillation; CAG = Coronary angiography; ROSC = Return of spontaneous circulation; CAD = Coronary artery disease; LM = Left main; LAD = Left anterior descending artery; RCx = Ramus circumflex; RCA = Right coronary artery; ACO = Acute coronary occlusion; CTO = Chronic total occlusion; PCI = Percutaneous coronary intervention.

      Outcomes

      Of all patients, 83% was transported with sustained ROSC, 87% survived for at least 24 h and 72% survived to hospital discharge.

      Comparisons between study groups

      Of all patients, 105 (35%) received >3 shocks and were thus classified as shock-resistant VF, while the remaining 196 (65%) patients were classified as patients with VF that was not shock-resistant.

      Baseline and arrest characteristics

      Baseline demographics did not differ between the two groups (Table 1). There were no differences in arrest location, bystander CPR and AED use. Patients with shock-resistant VF more often received shocks by the EMS, more often underwent endotracheal intubation, and more frequently received epinephrine and amiodarone. There was a significantly higher proportion of ST-segment elevation on the post-arrest ECG among patients with shock-resistant VF (71% vs. 55%, p = 0.009).

      Coronary angiography findings

      Comparisons between both study groups are shown in Table 2. The proportion with immediate CAG (i.e. immediately after admission) was high, and significantly higher in patients with than without shock-resistant VF (97% vs. 89%, p = 0.02).
      There was no difference in the occurrence of significant CAD between the two groups (78% vs. 77%, p = 0.76).
      An acute coronary occlusion occurred significantly more often in patients with compared to those without shock-resistant VF (41% vs. 26%, p = 0.006). There was a statistically significant association between the number of shocks and the proportion of patients with an acute coronary occlusion (Fig. 1). There was a trend towards a higher proportion of acute occlusions in the LAD and a significantly higher proportion of acute occlusions in the RCA in patients with shock-resistant VF.
      Fig. 1
      Fig. 1The association between number of shocks and occurrence of an acute coronary occlusion.
      Figure demonstrating the association between number of shocks and occurrence of an ACO. ACO = Acute coronary occlusion.
      There was no difference in the occurrence of CTOs between patients with vs. without shock-resistant VF (29% vs. 33%, p = 0.47), and a trend towards a higher proportion of patients undergoing PCI in the shock-resistant VF group (63% vs. 53%, p = 0.09). Lesions in patients undergoing PCI are described in Supplement 2.

      Outcomes

      Proportions of sustained ROSC, 24-h survival and survival to discharge were lower in patients with compared to patients without shock-resistant VF (Fig. 2).
      Fig. 2
      Fig. 2Outcomes in patients with and without shock-resistant VF.
      Outcomes in shock-resistant vs. non-shock-resistant VF. These are all patients that were transported to the hospital. VF = Ventricular fibrillation, ROSC = Return of spontaneous circulation.

      Discussion

      We compared coronary angiography findings between cardiac arrest patients with VF that was shock-resistant (>3 shocks) and patients with VF that was not shock-resistant (≤3 shocks), and found that significant coronary artery disease was present in >75% of patients in both groups. Notably, we found 1.5 times as many acute coronary occlusions among shock-resistant VF-patients and a significant association between the number of shocks and the proportion of acute coronary occlusions. Outcomes were also poorer in case of shock-resistant VF. Larger registries that confirm our angiographic and clinical outcome data could provide impetus randomised controlled studies on the potential benefit of an early invasive approach in patients with shock-resistant VF.

      Coronary angiography findings

      We found significant CAD (≥1 stenosis >70%) in 78% of patients with shock-resistant VF, which is comparable to findings reported in a previous study with 55 patients with VF refractory to >3 shocks, without intermittent ROSC.
      • Yannopoulos D.
      • Bartos J.A.
      • Raveendran G.
      • et al.
      Coronary artery disease in patients with out-of-hospital refractory ventricular fibrillation cardiac arrest.
      However, as in that report a control group without refractory VF was lacking, it was unclear whether those findings were exclusive to VF requiring multiple shocks, particularly given the high prevalence of CAD in VF-patients in general.
      • Dumas F.
      • Cariou A.
      • Manzo-Silberman S.
      • et al.
      Immediate percutaneous coronary intervention is associated with better survival after out-of-hospital cardiac arrest: insights from the PROCAT (Parisian Region Out of hospital Cardiac ArresT) registry.
      • Spaulding C.M.
      • Joly L.M.
      • Rosenberg A.
      • et al.
      Immediate coronary angiography in survivors of out-of-hospital cardiac arrest.
      • Lemkes J.S.
      • Janssens G.N.
      • van der Hoeven N.W.
      • et al.
      Coronary angiography after cardiac arrest without ST-Segment elevation.
      • Kern K.B.
      • Lotun K.
      • Patel N.
      • et al.
      Outcomes of comatose cardiac arrest survivors with and without ST-segment elevation myocardial infarction: importance of coronary angiography.
      We now demonstrate that significant CAD is also often present in VF that is not shock-resistant (77%). The extent of CAD, in terms of number of vessels affected, was also similar between both groups. We did, however, find a higher proportion of acute coronary occlusions in the group of patients with shock-resistant VF. This is in line with the fact that we also found more ST-elevation in this group, as ST-elevation is a strong predictor for ACO.
      • De Luca G.
      • Ernst N.
      • Zijlstra F.
      • et al.
      Preprocedural TIMI flow and mortality in patients with acute myocardial infarction treated by primary angioplasty.
      Our observations could indicate that an ACO in itself may be a trigger or a sustaining substrate of shock-resistant VF.
      It could also be hypothesised that an ACO triggers VF, and that VF becomes shock-resistant in case of a persisting acute occlusion, while VF that is not shock-resistant occurs in case of reperfusion before CAG. Studies on primary PCI show that reperfusion before PCI occurs in 15–30% of patients.
      • Liem A.
      • Zijlstra F.
      • Ottervanger J.P.
      • et al.
      High dose heparin as pretreatment for primary angioplasty in acute myocardial infarction: the Heparin in Early Patency (HEAP) randomized trial.
      Our findings also corroborate with animal studies, which show that VF induced by a persistent acute coronary occlusion on average requires more shocks before regaining ROSC than VF without persistent coronary occlusion.
      • Niemann J.T.
      • Rosborough J.P.
      • Youngquist S.
      • Thomas J.
      • Lewis R.J.
      Is all ventricular fibrillation the same? A comparison of ischemically induced with electrically induced ventricular fibrillation in a porcine cardiac arrest and resuscitation model.
      • Indik J.H.
      • Allen D.
      • Gura M.
      • Dameff C.
      • Hilwig R.W.
      • Kern K.B.
      Utility of the ventricular fibrillation waveform to predict a return of spontaneous circulation and distinguish acute from post myocardial infarction or normal Swine in ventricular fibrillation cardiac arrest.
      In terms of PCI-performance, Table 1 shows that there is a significant difference in acute coronary occlusions but not in the proportion of patients undergoing a PCI, implying that there are relatively many patients without shock-resistant VF group with lesions that are not persistently occluded, but in whom PCI has been performed.
      Regarding the infarct related artery, acute occlusion of the RCA was significantly more frequent in case of shock-resistant VF. Based on mechanistic studies, there is a complex interplay between the extent of ischemia, the presence of prior infarction, genetic predisposition and conduction disturbances in the initiation of ventricular arrhythmias.
      • Lemmert M.E.
      • de Jong J.S.
      • van Stipdonk A.M.
      • et al.
      Electrocardiographic factors playing a role in ischemic ventricular fibrillation in ST elevation myocardial infarction are related to the culprit artery.
      • Pascale P.
      • Schlaepfer J.
      • Oddo M.
      • Schaller M.D.
      • Vogt P.
      • Fromer M.
      Ventricular arrhythmia in coronary artery disease: limits of a risk stratification strategy based on the ejection fraction alone and impact of infarct localization.
      • Dekker L.R.
      • Bezzina C.R.
      • Henriques J.P.
      • et al.
      Familial sudden death is an important risk factor for primary ventricular fibrillation: a case-control study in acute myocardial infarction patients.
      As for CTOs, data in OHCA-patients is scarce.
      • Shinouchi K.
      • Ueda Y.
      • Kato T.
      • et al.
      Relation of Chronic total occlusion to in-hospital mortality in the patients with sudden cardiac arrest due to acute coronary syndrome.
      Our findings indicate no association between CTO and shock-resistant VF. It should be noted that patients with CTO form a heterogeneous group, where in some the CTO is related to prior infarction, whereas in others there may be no signs of myocardial scar. Importantly, previous studies did not specifically study the role of CTOs in shock-resistant VF, and to our knowledge we describe the first study on CAG-findings in this patient category with a control group without shock-resistant VF.

      Baselines, arrest characteristics and outcomes

      Baseline characteristics and key prognostic arrest characteristics (e.g. public location, bystander CPR, AED use) did not differ between both study groups. This provides additional support to the hypothesis that the underlying substrate is a major contributing factor to the shock-resistancy of VF. To further explore this, we studied and confirmed the association between increasing numbers of required defibrillation attempts and a higher likelihood of an acute coronary occlusion (Fig. 1).
      We found a trend towards a longer response time in shock-resistant VF-patients, which might have contributed to VF becoming shock-resistant, given the association between longer VF-duration and lower shock success.
      • Berdowski J.
      • ten Haaf M.
      • Tijssen J.G.
      • Chapman F.W.
      • Koster R.W.
      Time in recurrent ventricular fibrillation and survival after out-of-hospital cardiac arrest.
      • Eilevstjonn J.
      • Kramer-Johansen J.
      • Sunde K.
      Shock outcome is related to prior rhythm and duration of ventricular fibrillation.
      In an exploratory post-hoc logistic regression analysis we corrected for response time, and the association of an acute coronary occlusion with shock-resistant VF remained significant (adjusted odds ratio 2.20, p = 0.045). However, this analysis should be considered hypothesis generating as our study was not designed to identify predictors of shock-resistant VF.
      In the current cohort, overall survival is high, which could have several reasons. First, we selected only VF-patients transported to the hospital and undergoing routine CAG. In a previous report from our registry, we studied all, non-selected OHCA-cases and found survival to discharge rate of 15%.
      • Verhaert D.V.
      • Bonnes J.L.
      • Nas J.
      • et al.
      Termination of resuscitation in the prehospital setting: A comparison of decisions in clinical practice vs. recommendations of a termination rule.
      Importantly, the present data corroborate with previous studies using similar inclusion criteria.
      • Hidano D.
      • Coult J.
      • Blackwood J.
      • et al.
      Ventricular fibrillation waveform measures and the etiology of cardiac arrest.
      • Hulleman M.
      • Salcido D.D.
      • Menegazzi J.J.
      Predictive value of amplitude spectrum area of ventricular fibrillation waveform in patients with acute or previous myocardial infarction in out-of-hospital cardiac arrest.
      Second, we defined shock-resistant VF according to the number of defibrillation shocks, in line with previous studies.
      • Delorenzo A.
      • Nehme Z.
      • Yates J.
      • Bernard S.
      • Smith K.
      Double sequential external defibrillation for refractory ventricular fibrillation out-of-hospital cardiac arrest: a systematic review and meta-analysis.
      As such, included patients may have had intermittent organised rhythm or output between shocks. Other studies, such as Yannopoulos et al., exclusively focused on patients with refractory VF without intermittent ROSC, with poorer outcomes.
      • Yannopoulos D.
      • Bartos J.A.
      • Raveendran G.
      • et al.
      Coronary artery disease in patients with out-of-hospital refractory ventricular fibrillation cardiac arrest.
      • Yannopoulos D.
      • Bartos J.
      • Raveendran G.
      • et al.
      Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): a phase 2, single centre, open-label, randomised controlled trial.
      Third, we found a markedly high proportion of bystander AED-use, which is common in the Dutch setting.
      • Blom M.T.
      • Beesems S.G.
      • Homma P.C.
      • et al.
      Improved survival after out-of-hospital cardiac arrest and use of automated external defibrillators.
      In the Netherlands, AED-use has been widely advertised and we previously reported on rising numbers of AED-use and survival in our region.
      • Nas J.
      • Thannhauser J.
      • Herrmann J.J.
      • et al.
      Changes in automated external defibrillator use and survival after out-of-hospital cardiac arrest in the Nijmegen area.

      Implications

      The high proportion of acute coronary occlusions in shock-resistant VF implies that these may be a trigger or substrate for difficult-to-defibrillate VF. In the context of these findings, and the current possibilities of transport with mechanical resuscitation and extracorporeal membrane oxygenation programs, our data support future initiatives to investigate the impact of immediate catheterization in patients with shock-resistant VF.
      • Yannopoulos D.
      • Bartos J.A.
      • Aufderheide T.P.
      • et al.
      The evolving role of the cardiac catheterization laboratory in the management of patients with out-of-hospital cardiac arrest: a scientific statement from the american heart association.
      • Bartos J.A.
      • Carlson K.
      • Carlson C.
      • et al.
      Surviving refractory out-of-hospital ventricular fibrillation cardiac arrest: Critical care and extracorporeal membrane oxygenation management.
      • Yannopoulos D.
      • Bartos J.
      • Raveendran G.
      • et al.
      Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): a phase 2, single centre, open-label, randomised controlled trial.
      Two recently published randomised trials (COACT and PEARL) found that early CAG is not beneficial for patients without ST-elevation and without ongoing resuscitation. The present study focusses on all VF-patients transported to the hospital and undergoing CAG, regardless of the ECG-pattern and whether or not ROSC is reached before CAG, and can therefore be interpreted as complementary to COACT and PEARL.
      • Lemkes J.S.
      • Janssens G.N.
      • van der Hoeven N.W.
      • et al.
      Coronary angiography after cardiac arrest without ST-Segment elevation.
      • Kern K.B.
      • Radsel P.
      • Jentzer J.C.
      • et al.
      Randomized Pilot clinical trial of early coronary angiography versus no early coronary angiography after cardiac arrest without ST-segment elevation: The PEARL study.
      Our findings implicate that the need for multiple shocks might indicate a high likelihood of acute coronary occlusion. Whether or not such patients benefit from early invasive strategies is an interesting topic for further study. Prerequisite for future intervention studies is that our angiographic and clinical outcomes are corroborated by additional studies. Importantly, pevious reports indeed demonstrated favorable outcomes in case of early transportation to the cath-lab in patients with refractory VF, both in observational as well as in pilot randomised studies.
      • Yannopoulos D.
      • Bartos J.A.
      • Raveendran G.
      • et al.
      Coronary artery disease in patients with out-of-hospital refractory ventricular fibrillation cardiac arrest.
      • Yannopoulos D.
      • Bartos J.
      • Raveendran G.
      • et al.
      Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): a phase 2, single centre, open-label, randomised controlled trial.
      The downside of an early-invasive strategy for shock-resistant VF is that several shocks have to be awaited before deciding to transport the patient, as the patient only then fulfils the criteria for shock-resistant VF. Longer VF- duration is associated with worse outcomes.
      • Berdowski J.
      • ten Haaf M.
      • Tijssen J.G.
      • Chapman F.W.
      • Koster R.W.
      Time in recurrent ventricular fibrillation and survival after out-of-hospital cardiac arrest.
      • Eilevstjonn J.
      • Kramer-Johansen J.
      • Sunde K.
      Shock outcome is related to prior rhythm and duration of ventricular fibrillation.
      Thus, it would be helpful to either predict the chance of VF becoming shock-resistant, or identify a coronary occlusion earlier, i.e. at the moment of arrival at the patient. With regard to the former, we found no baseline characteristics associated with shock-resistant VF, which precludes predicting of the occurrence of shock-resistant VF using such characteristics. Regarding the latter, experimental studies suggest that there may be a role for analysis of the morphology of the VF-waveform itself in early identification of acute coronary occlusions.
      • Thannhauser J.
      • Nas J.
      • Rebergen D.J.
      • et al.
      Computerized analysis of the ventricular fibrillation waveform allows identification of myocardial infarction: a proof-of-concept study for smart defibrillator applications in cardiac arrest.
      Animal and human studies demonstrate that the VF-signal is markedly altered in case of an underlying coronary occlusion.
      • Indik J.H.
      • Allen D.
      • Gura M.
      • Dameff C.
      • Hilwig R.W.
      • Kern K.B.
      Utility of the ventricular fibrillation waveform to predict a return of spontaneous circulation and distinguish acute from post myocardial infarction or normal Swine in ventricular fibrillation cardiac arrest.
      • Hulleman M.
      • Salcido D.D.
      • Menegazzi J.J.
      Predictive value of amplitude spectrum area of ventricular fibrillation waveform in patients with acute or previous myocardial infarction in out-of-hospital cardiac arrest.
      This should be investigated further, preferably using prospective studies, which are currently lacking.

      Limitations

      As stated, we used a cut-off of >3 shocks for defining shock-resistant VF, in accordance with the scientific statement of the American Heart Association and previous studies.
      • Yannopoulos D.
      • Bartos J.A.
      • Raveendran G.
      • et al.
      Coronary artery disease in patients with out-of-hospital refractory ventricular fibrillation cardiac arrest.
      • Yannopoulos D.
      • Bartos J.A.
      • Aufderheide T.P.
      • et al.
      The evolving role of the cardiac catheterization laboratory in the management of patients with out-of-hospital cardiac arrest: a scientific statement from the american heart association.
      This does not necessarily mean that VF has actually persisted through all shocks as we cannot exclude the possibility of intermittent return of organised rhythm and VF-recurrence. This is a problem frequently encountered in studies on VF requiring multiple shocks, as defibrillator read-out is not routinely performed.
      • Delorenzo A.
      • Nehme Z.
      • Yates J.
      • Bernard S.
      • Smith K.
      Double sequential external defibrillation for refractory ventricular fibrillation out-of-hospital cardiac arrest: a systematic review and meta-analysis.
      This hampers comparing (outcome) data between different cohorts. Future studies should aim for a more uniform methodology to define shock-resistant VF, as we previously demonstrated that the type of VF (recurrent or persisting) may impact patient outcomes.
      • Nas J.
      • Thannhauser J.
      • Bonnes J.L.
      • Brouwer M.A.
      Importance of the distinction between recurrent and shock-resistant ventricular fibrillation: Call for a uniform definition of refractory VF.
      Although selection bias cannot be excluded, during the study period it was hospital policy to perform immediate CAG in all resuscitated VF patients that regained ROSC. Arguments not to perform catheterization are shown in Supplement 2: no ROSC at any point during CPR was the main reason (67%). Exclusion of the 8% with delayed (i.e. not immediately after presentation at the emergency room, but still during the same hospital admission) CAG did not alter the results, as can be seen in Supplement 3. Importantly, the present study was designed to assess CAG-findings and not to provide in-depth analyses on outcome. As such, those findings should be considered hypothesis generating.

      Conclusions

      In VF-cardiac arrest patients transported to our hospital and undergoing coronary angiography, we found significantly more acute coronary occlusions in case VF was shock-resistant (>3 shocks) compared to when VF was not shock-resistant (≤3 shocks). Shock-resistant VF-patients had adverse outcome. Larger confirmative registries are warranted and the collective evidence may provide impetus for randomised controlled trials on the potential benefit of an early invasive approach in patients with shock-resistant VF.

      Disclosures

      Niels van Royen received research grants from Abbott, Biotronik, AstraZeneca and Philips, and professional fees from Abbott, Microport, Amgen and Medtronic. Peter Damman has received consultancy fees from Philips and Abbott, and research grants from Philips and AstraZeneca. Marleen van Wely has received proctor fees from Zoll Medical. The other authors have no conflicts of interest to declare

      Funding

      None.

      Conflicts of interest

      Niels van Royen received research grants from Abbott, Biotronik, AstraZeneca and Philips, and professional fees from Abbott, Microport, Amgen and Medtronic. Peter Damman has received consultancy fees from Philips and Abbott, and research grants from Philips and AstraZeneca. Marleen van Wely has received proctor fees from Zoll Medical. The other authors have no conflicts of interest to declare.

      CRediT authorship contribution statement

      J Nas, JL Bonnes, T ten Cate, MA Brouwer: Conception and design. J Nas, J Thannhauser, EGJA van Dijk, C Verkroost, P Damman, M van Wely, T ten Cate, MA Brouwer: Collection and assembly of data. J Nas, J Thannhauser, RJ van Geuns, N van Royen, MJ de Boer, JL Bonnes, T ten Cate, MA Brouwer: Analysis and interpretation of data. J Nas, T ten Cate, MA Brouwer: Drafting of the manuscript. J Thannhauser, EGJA van Dijk, C Verkroost, P Damman, M van Wely, RJ van Geuns, N van Royen, MJ de Boer, JL Bonnes: Critical revising.
      Final approval of the manuscript
      All authors mentioned above.

      Acknowledgement

      None.

      Appendix A. Supplementary data

      The following is Supplementary data to this article:

      References

        • Berdowski J.
        • Berg R.A.
        • Tijssen J.G.
        • Koster R.W.
        Global incidences of out-of-hospital cardiac arrest and survival rates: systematic review of 67 prospective studies.
        Resuscitation. 2010; 81: 1479-1487
        • Yannopoulos D.
        • Bartos J.A.
        • Raveendran G.
        • et al.
        Coronary artery disease in patients with out-of-hospital refractory ventricular fibrillation cardiac arrest.
        J Am Coll Cardiol. 2017; 70: 1109-1117
        • Yannopoulos D.
        • Bartos J.A.
        • Aufderheide T.P.
        • et al.
        The evolving role of the cardiac catheterization laboratory in the management of patients with out-of-hospital cardiac arrest: a scientific statement from the american heart association.
        Circulation. 2019; 139: e530-e552
        • Kudenchuk P.J.
        • Brown S.P.
        • Daya M.
        • et al.
        Amiodarone, Lidocaine, or Placebo in out-of-hospital cardiac arrest.
        N Engl J Med. 2016; 374: 1711-1722
        • Berdowski J.
        • ten Haaf M.
        • Tijssen J.G.
        • Chapman F.W.
        • Koster R.W.
        Time in recurrent ventricular fibrillation and survival after out-of-hospital cardiac arrest.
        Circulation. 2010; 122: 1101-1108
        • Eilevstjonn J.
        • Kramer-Johansen J.
        • Sunde K.
        Shock outcome is related to prior rhythm and duration of ventricular fibrillation.
        Resuscitation. 2007; 75: 60-67
        • Bartos J.A.
        • Voicu S.
        • Matsuura T.R.
        • et al.
        Role of epinephrine and extracorporeal membrane oxygenation in the management of ischemic refractory ventricular fibrillation: a randomized trial in pigs.
        JACC Basic Transl Sci. 2017; 2: 244-253
        • Cheskes S.
        • Dorian P.
        • Feldman M.
        • et al.
        Double sequential external defibrillation for refractory ventricular fibrillation: the DOSE VF pilot randomized controlled trial.
        Resuscitation. 2020; 150: 178-184
        • Bartos J.A.
        • Carlson K.
        • Carlson C.
        • et al.
        Surviving refractory out-of-hospital ventricular fibrillation cardiac arrest: Critical care and extracorporeal membrane oxygenation management.
        Resuscitation. 2018; 132: 47-55
        • Stub D.
        • Bernard S.
        • Pellegrino V.
        • et al.
        Refractory cardiac arrest treated with mechanical CPR, hypothermia, ECMO and early reperfusion (the CHEER trial).
        Resuscitation. 2015; 86: 88-94
        • Yannopoulos D.
        • Bartos J.
        • Raveendran G.
        • et al.
        Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): a phase 2, single centre, open-label, randomised controlled trial.
        Lancet. 2020; 396: 1807-1816
        • Soar J.
        • Nolan J.P.
        • Bottiger B.W.
        • et al.
        European resuscitation council guidelines for resuscitation 2015: section 3. Adult advanced life support.
        Resuscitation. 2015; 95: 100-147
        • Dumas F.
        • Cariou A.
        • Manzo-Silberman S.
        • et al.
        Immediate percutaneous coronary intervention is associated with better survival after out-of-hospital cardiac arrest: insights from the PROCAT (Parisian Region Out of hospital Cardiac ArresT) registry.
        Circ Cardiovasc Interv. 2010; 3: 200-207
        • Spaulding C.M.
        • Joly L.M.
        • Rosenberg A.
        • et al.
        Immediate coronary angiography in survivors of out-of-hospital cardiac arrest.
        N Engl J Med. 1997; 336: 1629-1633
        • Lemkes J.S.
        • Janssens G.N.
        • van der Hoeven N.W.
        • et al.
        Coronary angiography after cardiac arrest without ST-Segment elevation.
        N Engl J Med. 2019; 380: 1397-1407
        • Nas J.
        • Thannhauser J.
        • Herrmann J.J.
        • et al.
        Changes in automated external defibrillator use and survival after out-of-hospital cardiac arrest in the Nijmegen area.
        Neth Heart J. 2018; 26: 600-605
        • Thannhauser J.
        • Nas J.
        • van Grunsven P.M.
        The ventricular fibrillation waveform in relation to shock success in early vs. late phases of out-of-hospital resuscitation.
        Resuscitation. 2019; 139: 99-105
        • Perkins G.D.
        • Jacobs I.G.
        • Nadkarni V.M.
        • et al.
        Cardiac arrest and cardiopulmonary resuscitation outcome reports: update of the Utstein Resuscitation Registry Templates for Out-of-Hospital Cardiac Arrest: a statement for healthcare professionals from a task force of the International Liaison Committee on Resuscitation (American Heart Association, European Resuscitation Council, Australian and New Zealand Council on Resuscitation, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Southern Africa, Resuscitation Council of Asia); and the American Heart Association Emergency Cardiovascular Care Committee and the Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation.
        Circulation. 2015; 132: 1286-1300
        • Guidelines for percutaneous transluminal coronary angioplasty
        A report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Subcommittee on Percutaneous Transluminal Coronary Angioplasty).
        J Am Coll Cardiol. 1988; 12: 529-545
        • Gibson C.M.
        • Cannon C.P.
        • Daley W.L.
        • et al.
        TIMI frame count: a quantitative method of assessing coronary artery flow.
        Circulation. 1996; 93: 879-888
        • Nas J.
        • Thannhauser J.
        • Vart P.
        • et al.
        Effect of face-to-face vs virtual reality training on cardiopulmonary resuscitation quality: a randomized clinical trial.
        JAMA Cardiol. 2020; 5: 328-335
        • Brilakis E.S.
        • Mashayekhi K.
        • Tsuchikane E.
        • et al.
        Guiding principles for chronic total occlusion percutaneous coronary intervention.
        Circulation. 2019; 140: 420-433
        • Kern K.B.
        • Lotun K.
        • Patel N.
        • et al.
        Outcomes of comatose cardiac arrest survivors with and without ST-segment elevation myocardial infarction: importance of coronary angiography.
        JACC Cardiovasc Interv. 2015; 8: 1031-1040
        • De Luca G.
        • Ernst N.
        • Zijlstra F.
        • et al.
        Preprocedural TIMI flow and mortality in patients with acute myocardial infarction treated by primary angioplasty.
        J Am Coll Cardiol. 2004; 43: 1363-1367
        • Liem A.
        • Zijlstra F.
        • Ottervanger J.P.
        • et al.
        High dose heparin as pretreatment for primary angioplasty in acute myocardial infarction: the Heparin in Early Patency (HEAP) randomized trial.
        J Am Coll Cardiol. 2000; 35: 600-604
        • Niemann J.T.
        • Rosborough J.P.
        • Youngquist S.
        • Thomas J.
        • Lewis R.J.
        Is all ventricular fibrillation the same? A comparison of ischemically induced with electrically induced ventricular fibrillation in a porcine cardiac arrest and resuscitation model.
        Crit Care Med. 2007; 35: 1356-1361
        • Indik J.H.
        • Allen D.
        • Gura M.
        • Dameff C.
        • Hilwig R.W.
        • Kern K.B.
        Utility of the ventricular fibrillation waveform to predict a return of spontaneous circulation and distinguish acute from post myocardial infarction or normal Swine in ventricular fibrillation cardiac arrest.
        Circ Arrhythm Electrophysiol. 2011; 4: 337-343
        • Lemmert M.E.
        • de Jong J.S.
        • van Stipdonk A.M.
        • et al.
        Electrocardiographic factors playing a role in ischemic ventricular fibrillation in ST elevation myocardial infarction are related to the culprit artery.
        Heart Rhythm. 2008; 5: 71-78
        • Pascale P.
        • Schlaepfer J.
        • Oddo M.
        • Schaller M.D.
        • Vogt P.
        • Fromer M.
        Ventricular arrhythmia in coronary artery disease: limits of a risk stratification strategy based on the ejection fraction alone and impact of infarct localization.
        Europace. 2009; 11: 1639-1646
        • Dekker L.R.
        • Bezzina C.R.
        • Henriques J.P.
        • et al.
        Familial sudden death is an important risk factor for primary ventricular fibrillation: a case-control study in acute myocardial infarction patients.
        Circulation. 2006; 114: 1140-1145
        • Shinouchi K.
        • Ueda Y.
        • Kato T.
        • et al.
        Relation of Chronic total occlusion to in-hospital mortality in the patients with sudden cardiac arrest due to acute coronary syndrome.
        Am J Cardiol. 2019; 123: 1915-1920
        • Verhaert D.V.
        • Bonnes J.L.
        • Nas J.
        • et al.
        Termination of resuscitation in the prehospital setting: A comparison of decisions in clinical practice vs. recommendations of a termination rule.
        Resuscitation. 2016; 100: 60-65
        • Hidano D.
        • Coult J.
        • Blackwood J.
        • et al.
        Ventricular fibrillation waveform measures and the etiology of cardiac arrest.
        Resuscitation. 2016; 109: 71-75
        • Hulleman M.
        • Salcido D.D.
        • Menegazzi J.J.
        Predictive value of amplitude spectrum area of ventricular fibrillation waveform in patients with acute or previous myocardial infarction in out-of-hospital cardiac arrest.
        Resuscitation. 2017; 120: 125-131
        • Delorenzo A.
        • Nehme Z.
        • Yates J.
        • Bernard S.
        • Smith K.
        Double sequential external defibrillation for refractory ventricular fibrillation out-of-hospital cardiac arrest: a systematic review and meta-analysis.
        Resuscitation. 2019; 135: 124-129
        • Blom M.T.
        • Beesems S.G.
        • Homma P.C.
        • et al.
        Improved survival after out-of-hospital cardiac arrest and use of automated external defibrillators.
        Circulation. 2014; 130: 1868-1875
        • Kern K.B.
        • Radsel P.
        • Jentzer J.C.
        • et al.
        Randomized Pilot clinical trial of early coronary angiography versus no early coronary angiography after cardiac arrest without ST-segment elevation: The PEARL study.
        Circulation. 2020; 142: 2002-2012
        • Thannhauser J.
        • Nas J.
        • Rebergen D.J.
        • et al.
        Computerized analysis of the ventricular fibrillation waveform allows identification of myocardial infarction: a proof-of-concept study for smart defibrillator applications in cardiac arrest.
        J Am Heart Assoc. 2020; (e016727)
        • Nas J.
        • Thannhauser J.
        • Bonnes J.L.
        • Brouwer M.A.
        Importance of the distinction between recurrent and shock-resistant ventricular fibrillation: Call for a uniform definition of refractory VF.
        Resuscitation. 2019; 138: 312-313