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Impact of Emergency Coronary Angiography on In-Hospital Outcome of Unconscious Survivors After Out-of-Hospital Cardiac Arrest
Impact of Emergency Coronary Angiography on In-Hospital Outcome of Unconscious Survivors After Out-of-Hospital Cardiac Arrest Davide Zanuttini, MDa, Ilaria Armellini, MDa, Gaetano Nucifora, MDa,*, Elio Carchietti, MDb, Giulio Trillò, MDb, Leonardo Spedicato, MDa, Guglielmo Bernardi, MDa, and Alessandro Proclemer, MDa Acute coronary thrombotic occlusion is the most common trigger of cardiac arrest. The aim of the present study was to assess the impact of an invasive strategy characterized by emergency coronary angiography and subsequent percutaneous coronary intervention (PCI), if indicated, on in-hospital survival of resuscitated patients with out-of-hospital cardiac arrest (OHCA) and no obvious extracardiac cause who do not regain consciousness soon after recovery of spontaneous circulation. Ninety-three consecutive patients (67 ⴞ 12 years old, 76% men) were included in the study. Clinical characteristics and coronary angiographic and in-hospital outcome data were retrospectively collected. Multivariate Cox proportional-hazards analysis was performed to identify independent determinants of in-hospital survival. Coronary angiography was performed in 66 patients (71%). Fortyeight patients underwent emergency coronary angiography; in the remaining 18 patients, mean time from OHCA to coronary angiography was 13 ⴞ 10 days. In patients referred to emergency coronary angiography, successful emergency PCI of a culprit coronary lesion was performed in 25 patients (52%). In-hospital survival rate was 54%. At multivariate analysis, emergency coronary angiography (hazard ratio 2.32, 95% confidence interval 1.23 to 4.38, p ⴝ 0.009) and successful emergency PCI (hazard ratio 2.54, 95% confidence interval 1.35 to 4.8, p ⴝ 0.004) were independently related to in-hospital survival in the overall study population; delay in performing coronary angiography (hazard ratio 0.95, 95% confidence interval 0.92 to 0.99, p ⴝ 0.013) was independently related to in-hospital mortality in patients referred to coronary angiography. In conclusion, an invasive strategy characterized by emergency coronary angiography and subsequent PCI, if indicated, seems to improve in-hospital outcome of resuscitated but unconscious patients with OHCA without obvious extracardiac cause. © 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110:1723–1728) Acute coronary thrombotic occlusion is the most common trigger of cardiac arrest.1,2 Few recent retrospective studies and prospective registries have suggested a beneficial effect of emergency coronary angiography and percutaneous coronary intervention (PCI) on the outcome of resuscitated patients with out-of-hospital cardiac arrest (OHCA).3–19 The benefit seems to be well established in patients who regain consciousness soon after recovery of spontaneous circulation (ROSC).3 Conversely, whether emergency coronary angiography and PCI improve survival in patients who remain unconscious after ROSC remains unknown. Therefore, the aim of the present study was to assess the impact of an invasive strategy characterized by emergency coronary angiography and subsequent PCI, if indicated, on in-hospital survival of resuscitated unconscious patients with OHCA without obvious extracardiac cause.
a Division of Cardiology, University Hospital “Santa Maria della Misericordia”, Udine, Italy; bUdine 118 Operative Station, Udine, Italy. Manuscript received June 20, 2012; revised manuscript received and accepted August 8, 2012. *Corresponding author: Tel: 39-0432-552441; fax: 39-0432-482353. E-mail address: [email protected] (G. Nucifora).
0002-9149/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2012.08.006
Methods The Province of Udine including urban, suburban, and rural areas has approximately 550,000 inhabitants and is served by a centrally coordinated ambulance system (118 Operative Station). For established OHCA, resuscitation is delivered by an emergency team. Patients in whom ROSC is achieved are then referred to our institution, which is a tertiary center with intensive care units, a coronary care unit, and a coronary intervention facility available 24 hours a day, 7 days a week. In this retrospective analysis, the clinical characteristics and outcome of consecutive unconscious patients resuscitated from OHCA without obvious extracardiac cause and admitted to the intensive care unit of our institution from 2008 through 2011 were evaluated. Patients were included in the study if they fulfilled the following inclusion criteria: (1) age ⬎18 years; (2) sustained ROSC, defined as ⬎20 minutes; (3) persistent unconscious state at hospital admission; and (4) absence of any obvious extracardiac cause (such as respiratory failure, brain injury, metabolic disorder, hemorrhage, drug overdose). For each patient fulfilling the inclusion criteria, medical records were reviewed to document the presence of coronary risk factors and history of coronary artery disease www.ajconline.org
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Table 1 Characteristics of study population Variable
Age (years) ⱕ60 ⬎60 Men Smoker Hypertension Diabetes mellitus Dyslipidemia* Known coronary artery disease Preceding symptoms Witnessed arrest Bystander cardiopulmonary resuscitation Initial rhythm Pulseless electrical activity or asystole Ventricular tachycardia or ventricular fibrillation Time from collapse to recovery of spontaneous circulation ⱕ20 minutes ⬎20 minutes Electrocardiogram after recovery of spontaneous circulation ST-segment elevation Other electrocardiographic pattern†
All Patients (n ⫽ 93)
Emergency Coronary Angiography (n ⫽ 48)
Delayed or No Coronary Angiography (n ⫽ 45)
27 (29%) 66 (71%) 71 (76%) 48 (52%) 59 (63%) 19 (20%) 21 (23%) 30 (32%) 25 (27%) 78 (84%) 53 (57%)
18 (38%) 30 (62%) 38 (79%) 25 (52%) 30 (63%) 8 (17%) 12 (25%) 17 (35%) 15 (31%) 40 (83%) 24 (50%)
9 (20%) 36 (80%) 33 (73%) 23 (51%) 29 (64%) 11 (24%) 9 (20%) 13 (29%) 10 (22%) 38 (84%) 29 (64%)
33 (35%) 60 (65%)
12 (25%) 36 (75%)
21 (47%) 24 (53%)
47 (51%) 46 (49%)
23 (48%) 25 (52%)
24 (53%) 21 (47%)
32 (34%) 61 (66%)
28 (58%) 20 (42%)
4 (9%) 41 (91%)
p Value
0.063
0.51 0.34 0.85 0.35 0.56 0.50 0.33 0.88 0.16 0.029
0.60
⬍0.001
Data are expressed as number (percentage). * Defined as total cholesterol level ⱖ240 mg/dl and/or triglyceride level ⬎150 mg/dl. † In patients with another electrocardiographic pattern, 7 had left bundle branch block (3 patients referred to emergency coronary angiography and 4 patients with delayed or no coronary angiography).
(CAD). A history of CAD was defined as previous acute coronary syndrome, percutaneous or surgical coronary revascularization, and/or ⱖ1 angiographically documented coronary stenosis with ⱖ50% luminal diameter. Data related to the early phase of OHCA were collected according to Utstein recommendations20 and included symptoms preceding collapse (i.e., chest pain, dyspnea, of syncope), witnessed cardiac arrest, bystander resuscitation, initial arrest rhythm (i.e., ventricular fibrillation/ventricular tachycardia, or pulseless electrical activity/asystole), time from collapse to ROSC ⬎20 minutes, and post-ROSC electrocardiographic (ECG) pattern (i.e., ST-segment elevation or other ECG patterns). Coronary angiographic data were also collected. Of note, during the study period the decision to perform emergency or delayed coronary angiography was taken by the treating cardiologist based on clinical judgment and according to existing guidelines.21–23 Coronary lesions resulting in ⱖ50% decrease in luminal diameter were considered significant. Thrombotic occlusion and irregular eccentric stenoses with a narrow neck, acute angles or craters, and thrombotic apposition were judged to represent acute or recent culprit coronary lesions12; in these cases, PCI was subsequently performed. PCI was deemed successful if it resulted in residual stenosis of ⬍50% with Thrombolysis In Myocardial Infarction grade 3 flow. The outcome of the study was survival at time of hospital discharge. Neurologic status at that time was also assessed using the Cerebral Performance Categories scale20; a Cerebral Performance Categories score ⱕ2 indicates recovery without major neurologic impairment.
Continues variables are expressed as mean ⫾ SD when normally distributed and as median and interquartile range when non-normally distributed. Categorical data are presented as absolute number and percentage. Differences in continuous variables were assessed using Student’s t test or Mann–Whitney U test as appropriate. Chi-square test or Fisher exact test, if appropriate, was computed to assess differences in categorical variables. Mantel–Haenszel test for time-to-event data with respect to the primary outcome was used for statistical comparison between patients referred to emergency coronary angiography and the remaining study population. Multivariate Cox proportional-hazards analysis was performed to identify the independent determinants of outcome in the overall study population and in patients referred to coronary angiography. Variables with a p value ⬍0.2 at univariate analysis were entered as covariates in the multivariate analysis using the stepwise backward likelihood ratio selection method. For each variable, the hazard ratio and 95% confidence interval were calculated. All statistical analyses were performed using SPSS 20 for Windows (SPSS, Inc., Chicago, Illinois). A 2-tailed p value ⬍0.05 was considered statistically significant. Results Ninety-three patients fulfilled the inclusion criteria and were entered in the study. Demographic and clinical characteristics of the study population are presented in Table 1. Table 2 presents differences between patients with and without known CAD. Mean age was 67 ⫾ 12 years; 71 (76%) patients were men. Coronary angiography during
Coronary Artery Disease/Emergency Coronary Angiography in Unconscious OHCA Survivors
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Table 2 Differences between patients with and without known coronary artery disease Variable
Patients With Known CAD (n ⫽ 30)
Patients Without Known CAD (n ⫽ 63)
7 (23%) 23 (77%) 24 (80%) 12 (40%) 19 (63%) 7 (23%) 12 (40%) 12 (40%) 26 (87%) 19 (63%)
20 (32%) 43 (68%) 47 (75%) 36 (57%) 40 (64%) 12 (19%) 9 (14%) 13 (21%) 52 (83%) 34 (54%)
11 (37%) 19 (63%)
22 (35%) 41 (65%)
15 (50%) 15 (50%)
32 (51%) 31 (49%)
11 (37%) 19 (63%)
21 (33%) 42 (67%)
17 (57%) 13 (43%)
31 (49%) 32 (51%)
Age (years) ⱕ60 ⬎60 Men Smoker Hypertension Diabetes mellitus Dyslipidemia* Preceding symptoms Witnessed arrest Bystander cardiopulmonary resuscitation Initial rhythm Pulseless electrical activity or asystole Ventricular tachycardia or ventricular fibrillation Time from collapse to recovery of spontaneous circulation ⱕ20 minutes ⬎20 minutes Electrocardiogram after recovery of spontaneous circulation ST-segment elevation Other electrocardiographic pattern Coronary angiography Emergency Delayed or not performed
p Value 0.40
0.57 0.12 0.99 0.63 0.006 0.049 0.77 0.39 0.87
0.94
0.75
0.50
Data are expressed as number (percentage). * Defined as total cholesterol level ⱖ240 mg/dl and/or triglyceride level ⬎150 mg/dl. Table 3 Univariate analysis to identify variables significantly related to survival Variable
All Patients (n ⫽ 93)
Age ⬎60 years Male gender Smoking Hypertension Diabetes Dyslipidemia* Known coronary artery disease Preceding symptoms Witnessed arrest Bystander cardiopulmonary resuscitation Pulseless electrical activity or asystole as initial rhythm Time from collapse to recovery of spontaneous circulation ⬎20 minutes ST-segment elevation on electrocardiogram after recovery of spontaneous circulation Emergency coronary angiography Delay in coronary angiography (days) Successful emergency percutaneous coronary intervention
Patients Referred to Coronary Angiography (n ⫽ 66)
HR (95% CI)
p Value
HR (95% CI)
p Value
0.51 (0.28–0.90) 1.54 (0.78–3.01) 1.14 (0.65–2.00) 0.99 (0.55–1.79) 0.85 (0.40–1.81) 0.97 (0.50–1.87) 1.36 (0.74–2.49) 1.26 (0.65–2.45) 0.45 (0.16–1.28) 1.12 (0.63–2.02) 0.46 (0.21–1.02) 0.65 (0.35–1.19) 1.11 (0.61–2.02) 2.05 (1.11–3.79) — 2.42 (1.29–4.52)
0.021 0.21 0.65 0.99 0.67 0.93 0.32 0.50 0.13 0.70 0.056 0.16 0.74 0.022 — 0.006
0.57 (0.32–1.02) 1.24 (0.63–2.44) 1.08 (0.60–1.94) 1.08 (0.58–2.00) 0.79 (0.37–1.70) 1.10 (0.57–2.13) 1.12 (0.60–2.08) 1.62 (0.81–3.25) 0.46 (0.16–1.32) 1.21 (0.67–2.19) 0.85 (0.38–1.92) 0.70 (0.37–1.31) 1.11 (0.60–2.04) — 0.96 (0.93–0.99) 2.11 (1.12–4.00)
0.057 0.54 0.79 0.81 0.55 0.79 0.72 0.17 0.15 0.54 0.70 0.26 0.75 — 0.023 0.022
* Defined as total cholesterol level ⱖ240 mg/dl and/or triglyceride level ⬎150 mg/dl. CI ⫽ confidence interval; HR ⫽ hazard ratio.
hospitalization was performed in 66 patients (71%). Fortyeight patients underwent emergency coronary angiography; in the remaining 18 patients, mean time from OHCA to coronary angiography was 13 ⫾ 10 days. In patients referred to coronary angiography, significant CAD was observed in 57 patients (86%). No significant difference in prevalence of significant CAD was present between patients
with ventricular fibrillation/ventricular tachycardia and those with pulseless electrical activity/asystole as initial arrest rhythm (n ⫽ 43, 84%, vs n ⫽ 14, 93%, p ⫽ 0.45); a trend toward a higher prevalence of significant CAD was observed in patients with ST-segment elevation compared to those with other ECG patterns on post-ROSC electrocardiogram (n ⫽ 27, 96%, vs n ⫽ 30, 79%, p ⫽ 0.067).
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In patients referred to emergency coronary angiography, successful emergency PCI of a culprit coronary lesion was performed in 25 patients (52%); in patients referred to delayed coronary angiography, successful PCI of a presumed culprit coronary lesion was performed in 6 patients (33%). In-hospital survival was 54% (n ⫽ 50 patients); of these, 36 patients (72%) reached a Cerebral Performance Categories level of 1 or 2, indicating a favorable neurologic outcome. Median time from OHCA to hospital discharge for survivor patients was 19 days (interquartile range 12 to 44). In patients referred to emergency coronary angiography, 29 patients (60%) were discharged alive after a median time from OHCA of 18 days (interquartile range 11 to 28). Twenty-one patients (47%) with delayed or no coronary angiography were discharged alive after a median time from OHCA of 38 days (interquartile range 15 to 64, p ⫽ 0.018, compared to patients referred to emergency coronary angiography). Table 3 and Figure 1 present results of univariate and multivariate analyses performed to determine independent correlates of survival at time of hospital discharge. In the overall study population (n ⫽ 93), age ⬎60 years, emergency coronary angiography, and successful emergency PCI were independently related to outcome (Figure 1). In patients referred to coronary angiography (n ⫽ 66), age ⬎60 years and delay in coronary angiography were found as independent determinants of outcome (Figure 1). Discussion
Figure 1. Multivariate analysis performed to determine independent correlates of survival at time of hospital discharge in the overall study population (n ⫽ 93) in models 1 (A) and 2 (B) and in patients referred to coronary angiography (n ⫽ 66) (C). Two different multivariate models were computed for the overall study population including emergency coronary angiography (A) or successful emergency percutaneous coronary intervention (B). CI ⫽ confidence interval; HR ⫽ hazard ratio.
An acute or recent culprit coronary lesion was observed in 38 patients (58%). No significant difference in the prevalence of culprit coronary lesion was present between patients with ventricular fibrillation/ventricular tachycardia and those with pulseless electrical activity/ asystole as initial arrest rhythm (n ⫽ 31, 61%, vs n ⫽ 7, 47%, p ⫽ 0.38); conversely, culprit coronary lesions were more frequently observed in patients with ST-segment elevation compared to those with other ECG patterns on postROSC electrocardiogram (n ⫽ 22, 79%, vs n ⫽ 16, 42%, p ⫽ 0.005).
Results of the present study can be summarized as follows: (1) significant CAD and acute or recent culprit coronary lesions are present in most resuscitated unconscious patients with OHCA without obvious extracardiac cause; (2) significant CAD and acute or recent culprit coronary lesions are observed in most patients with ST-segment elevation and in a nonnegligible proportion of patients with other ECG patterns on post-ROSC electrocardiogram; and (3) emergency coronary angiography and successful emergency PCI are independently related to in-hospital survival after OHCA. In the present study, significant CAD was observed in 57 patients (86%) referred to coronary angiography; of note, significant CAD was frequently found in patients with STsegment elevation and in patients with other ECG patterns on post-ROSC electrocardiogram (96% and 79%, respectively). Moreover, culprit coronary lesions were found in most patients with ST-segment elevation (79%), as expected, and in a significant proportion of patients with other ECG patterns on post-ROSC electrocardiogram (42%). These results are in line with those previously reported by postmortem examinations of patients after sudden cardiac death and in vivo studies of resuscitated patients after OHCA.1,2,10,12 According to these observations, electrocardiogram should not be considered a strict selection criterion for performing emergency coronary angiography in resuscitated patients with OHCA without obvious extracardiac cause; even in the absence of ST-segment elevation on post-ROSC electrocardiogram, acute culprit coronary lesions may indeed be present and considered the trigger of cardiac arrest. Besides assessing the prevalence of acute coronary lesions in patients with OHCA, the present study specifically evaluated the in-hospital outcome and prognostic value of
Coronary Artery Disease/Emergency Coronary Angiography in Unconscious OHCA Survivors
an emergency invasive strategy (i.e., emergency coronary angiography followed by PCI) in patients who did not regain consciousness after ROSC. Of note, a high in-hospital survival rate (54%) was observed and a favorable neurological recovery was obtained in 72% of survivors. More importantly, emergency coronary angiography and successful emergency PCI were independently related to in-hospital survival. Recent advances in cardiopulmonary resuscitation and medical management and a more frequent use of an invasive strategy including coronary angiography and PCI have led to a significant improvement in survival of patients with OHCA.6,7,11,24,25 In particular, the prognostic value of emergency coronary angiography and PCI has been consistently demonstrated by previous studies including conscious and comatose patients after ROSC.3–10 The retrospective registry of Strote et al14 confirmed a higher survival rate in patients undergoing emergency coronary angiography compared to patients not referred to coronary angiography or undergoing delayed coronary angiography. In another recent retrospective study, Reynolds et al9 observed that early coronary angiography (performed ⬍24 hours after admission) was an independent predictor of in-hospital survival. The independent relation between primary PCI and in-hospital survival has been recently demonstrated also by the prospective Parisian Region Out of Hospital Cardiac Arrest (PROCAT) registry.10 The present study extends these previous observations, confirming the benefit of an invasive emergency strategy specifically in patients with OHCA who remain unconscious after ROSC, who are commonly considered a subgroup with worse prognosis and frequently excluded from invasive emergency therapeutic strategies.11–19 The positive effect of emergency coronary angiography on in-hospital survival is probably related to timely identification and treatment of patients with acute coronary syndrome; the independent relation between delay in performing coronary angiography and worse outcome observed in this study seems to reinforce this hypothesis. This strategy appears to be also cost– effective because it allowed not only an improvement of survival but also a shorter hospital stay. However, further studies are needed to specifically address this issue. According to these observations, emergency coronary angiography and PCI, when indicated, should be performed in OHCA survivors regardless of ECG findings and state of consciousness. The benefit of this emergency invasive strategy appears to be greater especially in young subjects because increasing age seems to be a factor independently related to worse outcome. This study has some limitations that should be acknowledged. First, a selection bias may have been introduced because the study population included patients who presented to a tertiary referral center, which may differ from an unselected group of patients. Second, it is a retrospective study, the limitations of which are well known. In addition, the study population was relatively small; consequently, multivariate analysis was exploratory and its result needs to be confirmed by larger prospective studies. Third, CAD was ruled out by invasive coronary angiography only in selected patients.
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1. Davies MJ. Anatomic features in victims of sudden coronary death. Coronary artery pathology. Circulation 1992;85:I19 –I24. 2. Spaulding CM, Joly LM, Rosenberg A, Monchi M, Weber SN, Dhainaut JF, Carli P. Immediate coronary angiography in survivors of out-of-hospital cardiac arrest. N Engl J Med 1997;336:1629 –1633. 3. Gorjup V, Radsel P, Kocjancic ST, Erzen D, Noc M. Acute STelevation myocardial infarction after successful cardiopulmonary resuscitation. Resuscitation 2007;72:379 –385. 4. Knafelj R, Radsel P, Ploj T, Noc M. Primary percutaneous coronary intervention and mild induced hypothermia in comatose survivors of ventricular fibrillation with ST-elevation acute myocardial infarction. Resuscitation 2007;74:227–234. 5. Garot P, Lefevre T, Eltchaninoff H, Morice MC, Tamion F, Abry B, Lesault PF, Le Tarnec JY, Pouges C, Margenet A, Monchi M, Laurent I, Dumas P, Garot J, Louvard Y. Six-month outcome of emergency percutaneous coronary intervention in resuscitated patients after cardiac arrest complicating ST-elevation myocardial infarction. Circulation 2007;115:1354 –1362. 6. Sunde K, Pytte M, Jacobsen D, Mangschau A, Jensen LP, Smedsrud C, Draegni T, Steen PA. Implementation of a standardised treatment protocol for post resuscitation care after out-of-hospital cardiac arrest. Resuscitation 2007;73:29 –39. 7. Werling M, Thorén AB, Axelsson C, Herlitz J. Treatment and outcome in post-resuscitation care after out-of-hospital cardiac arrest when a modern therapeutic approach was introduced. Resuscitation 2007;73:40 – 45. 8. Anyfantakis ZA, Baron G, Aubry P, Himbert D, Feldman LJ, Juliard JM, Ricard-Hibon A, Burnod A, Cokkinos DV, Steg PG. Acute coronary angiographic findings in survivors of out-of-hospital cardiac arrest. Am Heart J 2009;157:312–318. 9. Reynolds JC, Callaway CW, El Khoudary SR, Moore CG, Alvarez RJ, Rittenberger JC. Coronary angiography predicts improved outcome following cardiac arrest: propensity-adjusted analysis. J Intensive Care Med 2009;24:179 –186. 10. Dumas F, Cariou A, Manzo-Silberman S, Grimaldi D, Vivien B, Rosencher J, Empana JP, Carli P, Mira JP, Jouven X, Spaulding C. 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. 11. Stub D, Hengel C, Chan W, Jackson D, Sanders K, Dart AM, Hilton A, Pellegrino V, Shaw JA, Duffy SJ, Bernard S, Kaye DM. Usefulness of cooling and coronary catheterization to improve survival in out-ofhospital cardiac arrest. Am J Cardiol 2011;107:522–527. 12. Radsel P, Knafelj R, Kocjancic S, Noc M. Angiographic characteristics of coronary disease and postresuscitation electrocardiograms in patients with aborted cardiac arrest outside a hospital. Am J Cardiol 2011;108:634 – 638. 13. Cronier P, Vignon P, Bouferrache K, Aegerter P, Charron C, Templier F, Castro S, El Mahmoud R, Lory C, Pichon N, Dubourg O, VieillardBaron A. Impact of routine percutaneous coronary intervention after out-of-hospital cardiac arrest due to ventricular fibrillation. Crit Care 2011;15:R122. 14. Strote JA, Maynard C, Olsufka M, Nichol G, Copass MK, Cobb LA, Kim F. Comparison of role of early (less than six hours) to later (more than six hours) or no cardiac catheterization after resuscitation from out-of-hospital cardiac arrest. Am J Cardiol 2012;109:451– 454. 15. Nanjayya VB, Nayyar V. Immediate coronary angiogram in comatose survivors of out-of-hospital cardiac arrest—an Australian study. Resuscitation 2012;83:699 –704. 16. Noc M. Urgent coronary angiography and percutaneous coronary intervention as a part of postresuscitation management. Crit Care Med 2008;36(suppl):S454 –S457. 17. Noc M, Radsel P. Urgent invasive coronary strategy in patients with sudden cardiac arrest. Curr Opin Crit Care 2008;14:287–291. 18. Bangalore S, Hochman JS. A routine invasive strategy for out-ofhospital cardiac arrest survivors: are we there yet? Circ Cardiovasc Interv 2010;3:197–199. 19. Stub D, Bernard S, Duffy SJ, Kaye DM. Post cardiac arrest syndrome: a review of therapeutic strategies. Circulation 2011;123:1428 –1435. 20. Jacobs I, Nadkarni V, Bahr J, Berg RA, Billi JE, Bossaert L, Cassan P, Coovadia A, D’Este K, Finn J, Halperin H, Handley A, Herlitz J, Hickey R, Idris A, Kloeck W, Larkin GL, Mancini ME, Mason P, Mears G, Monsieurs K, Montgomery W, Morley P, Nichol G, Nolan J, Okada K, Perlman J, Shuster M, Steen PA, Sterz F, Tibballs J, Timerman S, Truitt
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T, Zideman D; International Liaison Committee on Resusitation. Cardiac arrest and cardiopulmonary resuscitation outcome reports: update and simplification of the Utstein templates for resuscitation registries. A statement for healthcare professionals from a task force of the International Liaison Committee on Resuscitation (American Heart Association, European Resuscitation Council, Australian Resuscitation Council, New Zealand Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Southern Africa). Resuscitation 2004;63:233–249. 21. ECC Committee, Subcommittees and Task Forces of the American Heart Association. 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2005;112(suppl):IV1–IV203. 22. Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, Zimmerman JL, Donnino M, Gabrielli A, Silvers SM, Zaritsky AL, Merchant R, Vanden Hoek TL, Kronick SL. Part 9: post-cardiac arrest care: 2010
American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2010;122(suppl): S768 –S786. 23. O’Connor RE, Brady W, Brooks SC, Diercks D, Egan J, Ghaemmaghami C, Menon V, O’Neil BJ, Travers AH, Yannopoulos D. Part 10: acute coronary syndromes: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2010;122(suppl):S787–S817. 24. Sasson C, Rogers MA, Dahl J, Kellermann AL. Predictors of survival from out-of-hospital cardiac arrest: a systematic review and metaanalysis. Circ Cardiovasc Qual Outcomes 2010;3:63– 81. 25. Kudenchuk PJ, Redshaw JD, Stubbs BA, Fahrenbruch CE, Dumas F, Phelps R, Blackwood J, Rea TD, Eisenberg MS. Impact of changes in resuscitation practice on survival and neurological outcome after outof-hospital cardiac arrest resulting from nonshockable arrhythmias. Circulation 2012;125:1787–1794.
a Division of Cardiology, University Hospital “Santa Maria della Misericordia”, Udine, Italy; bUdine 118 Operative Station, Udine, Italy. Manuscript received June 20, 2012; revised manuscript received and accepted August 8, 2012. *Corresponding author: Tel: 39-0432-552441; fax: 39-0432-482353. E-mail address: [email protected] (G. Nucifora).
0002-9149/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2012.08.006
Methods The Province of Udine including urban, suburban, and rural areas has approximately 550,000 inhabitants and is served by a centrally coordinated ambulance system (118 Operative Station). For established OHCA, resuscitation is delivered by an emergency team. Patients in whom ROSC is achieved are then referred to our institution, which is a tertiary center with intensive care units, a coronary care unit, and a coronary intervention facility available 24 hours a day, 7 days a week. In this retrospective analysis, the clinical characteristics and outcome of consecutive unconscious patients resuscitated from OHCA without obvious extracardiac cause and admitted to the intensive care unit of our institution from 2008 through 2011 were evaluated. Patients were included in the study if they fulfilled the following inclusion criteria: (1) age ⬎18 years; (2) sustained ROSC, defined as ⬎20 minutes; (3) persistent unconscious state at hospital admission; and (4) absence of any obvious extracardiac cause (such as respiratory failure, brain injury, metabolic disorder, hemorrhage, drug overdose). For each patient fulfilling the inclusion criteria, medical records were reviewed to document the presence of coronary risk factors and history of coronary artery disease www.ajconline.org
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Table 1 Characteristics of study population Variable
Age (years) ⱕ60 ⬎60 Men Smoker Hypertension Diabetes mellitus Dyslipidemia* Known coronary artery disease Preceding symptoms Witnessed arrest Bystander cardiopulmonary resuscitation Initial rhythm Pulseless electrical activity or asystole Ventricular tachycardia or ventricular fibrillation Time from collapse to recovery of spontaneous circulation ⱕ20 minutes ⬎20 minutes Electrocardiogram after recovery of spontaneous circulation ST-segment elevation Other electrocardiographic pattern†
All Patients (n ⫽ 93)
Emergency Coronary Angiography (n ⫽ 48)
Delayed or No Coronary Angiography (n ⫽ 45)
27 (29%) 66 (71%) 71 (76%) 48 (52%) 59 (63%) 19 (20%) 21 (23%) 30 (32%) 25 (27%) 78 (84%) 53 (57%)
18 (38%) 30 (62%) 38 (79%) 25 (52%) 30 (63%) 8 (17%) 12 (25%) 17 (35%) 15 (31%) 40 (83%) 24 (50%)
9 (20%) 36 (80%) 33 (73%) 23 (51%) 29 (64%) 11 (24%) 9 (20%) 13 (29%) 10 (22%) 38 (84%) 29 (64%)
33 (35%) 60 (65%)
12 (25%) 36 (75%)
21 (47%) 24 (53%)
47 (51%) 46 (49%)
23 (48%) 25 (52%)
24 (53%) 21 (47%)
32 (34%) 61 (66%)
28 (58%) 20 (42%)
4 (9%) 41 (91%)
p Value
0.063
0.51 0.34 0.85 0.35 0.56 0.50 0.33 0.88 0.16 0.029
0.60
⬍0.001
Data are expressed as number (percentage). * Defined as total cholesterol level ⱖ240 mg/dl and/or triglyceride level ⬎150 mg/dl. † In patients with another electrocardiographic pattern, 7 had left bundle branch block (3 patients referred to emergency coronary angiography and 4 patients with delayed or no coronary angiography).
(CAD). A history of CAD was defined as previous acute coronary syndrome, percutaneous or surgical coronary revascularization, and/or ⱖ1 angiographically documented coronary stenosis with ⱖ50% luminal diameter. Data related to the early phase of OHCA were collected according to Utstein recommendations20 and included symptoms preceding collapse (i.e., chest pain, dyspnea, of syncope), witnessed cardiac arrest, bystander resuscitation, initial arrest rhythm (i.e., ventricular fibrillation/ventricular tachycardia, or pulseless electrical activity/asystole), time from collapse to ROSC ⬎20 minutes, and post-ROSC electrocardiographic (ECG) pattern (i.e., ST-segment elevation or other ECG patterns). Coronary angiographic data were also collected. Of note, during the study period the decision to perform emergency or delayed coronary angiography was taken by the treating cardiologist based on clinical judgment and according to existing guidelines.21–23 Coronary lesions resulting in ⱖ50% decrease in luminal diameter were considered significant. Thrombotic occlusion and irregular eccentric stenoses with a narrow neck, acute angles or craters, and thrombotic apposition were judged to represent acute or recent culprit coronary lesions12; in these cases, PCI was subsequently performed. PCI was deemed successful if it resulted in residual stenosis of ⬍50% with Thrombolysis In Myocardial Infarction grade 3 flow. The outcome of the study was survival at time of hospital discharge. Neurologic status at that time was also assessed using the Cerebral Performance Categories scale20; a Cerebral Performance Categories score ⱕ2 indicates recovery without major neurologic impairment.
Continues variables are expressed as mean ⫾ SD when normally distributed and as median and interquartile range when non-normally distributed. Categorical data are presented as absolute number and percentage. Differences in continuous variables were assessed using Student’s t test or Mann–Whitney U test as appropriate. Chi-square test or Fisher exact test, if appropriate, was computed to assess differences in categorical variables. Mantel–Haenszel test for time-to-event data with respect to the primary outcome was used for statistical comparison between patients referred to emergency coronary angiography and the remaining study population. Multivariate Cox proportional-hazards analysis was performed to identify the independent determinants of outcome in the overall study population and in patients referred to coronary angiography. Variables with a p value ⬍0.2 at univariate analysis were entered as covariates in the multivariate analysis using the stepwise backward likelihood ratio selection method. For each variable, the hazard ratio and 95% confidence interval were calculated. All statistical analyses were performed using SPSS 20 for Windows (SPSS, Inc., Chicago, Illinois). A 2-tailed p value ⬍0.05 was considered statistically significant. Results Ninety-three patients fulfilled the inclusion criteria and were entered in the study. Demographic and clinical characteristics of the study population are presented in Table 1. Table 2 presents differences between patients with and without known CAD. Mean age was 67 ⫾ 12 years; 71 (76%) patients were men. Coronary angiography during
Coronary Artery Disease/Emergency Coronary Angiography in Unconscious OHCA Survivors
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Table 2 Differences between patients with and without known coronary artery disease Variable
Patients With Known CAD (n ⫽ 30)
Patients Without Known CAD (n ⫽ 63)
7 (23%) 23 (77%) 24 (80%) 12 (40%) 19 (63%) 7 (23%) 12 (40%) 12 (40%) 26 (87%) 19 (63%)
20 (32%) 43 (68%) 47 (75%) 36 (57%) 40 (64%) 12 (19%) 9 (14%) 13 (21%) 52 (83%) 34 (54%)
11 (37%) 19 (63%)
22 (35%) 41 (65%)
15 (50%) 15 (50%)
32 (51%) 31 (49%)
11 (37%) 19 (63%)
21 (33%) 42 (67%)
17 (57%) 13 (43%)
31 (49%) 32 (51%)
Age (years) ⱕ60 ⬎60 Men Smoker Hypertension Diabetes mellitus Dyslipidemia* Preceding symptoms Witnessed arrest Bystander cardiopulmonary resuscitation Initial rhythm Pulseless electrical activity or asystole Ventricular tachycardia or ventricular fibrillation Time from collapse to recovery of spontaneous circulation ⱕ20 minutes ⬎20 minutes Electrocardiogram after recovery of spontaneous circulation ST-segment elevation Other electrocardiographic pattern Coronary angiography Emergency Delayed or not performed
p Value 0.40
0.57 0.12 0.99 0.63 0.006 0.049 0.77 0.39 0.87
0.94
0.75
0.50
Data are expressed as number (percentage). * Defined as total cholesterol level ⱖ240 mg/dl and/or triglyceride level ⬎150 mg/dl. Table 3 Univariate analysis to identify variables significantly related to survival Variable
All Patients (n ⫽ 93)
Age ⬎60 years Male gender Smoking Hypertension Diabetes Dyslipidemia* Known coronary artery disease Preceding symptoms Witnessed arrest Bystander cardiopulmonary resuscitation Pulseless electrical activity or asystole as initial rhythm Time from collapse to recovery of spontaneous circulation ⬎20 minutes ST-segment elevation on electrocardiogram after recovery of spontaneous circulation Emergency coronary angiography Delay in coronary angiography (days) Successful emergency percutaneous coronary intervention
Patients Referred to Coronary Angiography (n ⫽ 66)
HR (95% CI)
p Value
HR (95% CI)
p Value
0.51 (0.28–0.90) 1.54 (0.78–3.01) 1.14 (0.65–2.00) 0.99 (0.55–1.79) 0.85 (0.40–1.81) 0.97 (0.50–1.87) 1.36 (0.74–2.49) 1.26 (0.65–2.45) 0.45 (0.16–1.28) 1.12 (0.63–2.02) 0.46 (0.21–1.02) 0.65 (0.35–1.19) 1.11 (0.61–2.02) 2.05 (1.11–3.79) — 2.42 (1.29–4.52)
0.021 0.21 0.65 0.99 0.67 0.93 0.32 0.50 0.13 0.70 0.056 0.16 0.74 0.022 — 0.006
0.57 (0.32–1.02) 1.24 (0.63–2.44) 1.08 (0.60–1.94) 1.08 (0.58–2.00) 0.79 (0.37–1.70) 1.10 (0.57–2.13) 1.12 (0.60–2.08) 1.62 (0.81–3.25) 0.46 (0.16–1.32) 1.21 (0.67–2.19) 0.85 (0.38–1.92) 0.70 (0.37–1.31) 1.11 (0.60–2.04) — 0.96 (0.93–0.99) 2.11 (1.12–4.00)
0.057 0.54 0.79 0.81 0.55 0.79 0.72 0.17 0.15 0.54 0.70 0.26 0.75 — 0.023 0.022
* Defined as total cholesterol level ⱖ240 mg/dl and/or triglyceride level ⬎150 mg/dl. CI ⫽ confidence interval; HR ⫽ hazard ratio.
hospitalization was performed in 66 patients (71%). Fortyeight patients underwent emergency coronary angiography; in the remaining 18 patients, mean time from OHCA to coronary angiography was 13 ⫾ 10 days. In patients referred to coronary angiography, significant CAD was observed in 57 patients (86%). No significant difference in prevalence of significant CAD was present between patients
with ventricular fibrillation/ventricular tachycardia and those with pulseless electrical activity/asystole as initial arrest rhythm (n ⫽ 43, 84%, vs n ⫽ 14, 93%, p ⫽ 0.45); a trend toward a higher prevalence of significant CAD was observed in patients with ST-segment elevation compared to those with other ECG patterns on post-ROSC electrocardiogram (n ⫽ 27, 96%, vs n ⫽ 30, 79%, p ⫽ 0.067).
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In patients referred to emergency coronary angiography, successful emergency PCI of a culprit coronary lesion was performed in 25 patients (52%); in patients referred to delayed coronary angiography, successful PCI of a presumed culprit coronary lesion was performed in 6 patients (33%). In-hospital survival was 54% (n ⫽ 50 patients); of these, 36 patients (72%) reached a Cerebral Performance Categories level of 1 or 2, indicating a favorable neurologic outcome. Median time from OHCA to hospital discharge for survivor patients was 19 days (interquartile range 12 to 44). In patients referred to emergency coronary angiography, 29 patients (60%) were discharged alive after a median time from OHCA of 18 days (interquartile range 11 to 28). Twenty-one patients (47%) with delayed or no coronary angiography were discharged alive after a median time from OHCA of 38 days (interquartile range 15 to 64, p ⫽ 0.018, compared to patients referred to emergency coronary angiography). Table 3 and Figure 1 present results of univariate and multivariate analyses performed to determine independent correlates of survival at time of hospital discharge. In the overall study population (n ⫽ 93), age ⬎60 years, emergency coronary angiography, and successful emergency PCI were independently related to outcome (Figure 1). In patients referred to coronary angiography (n ⫽ 66), age ⬎60 years and delay in coronary angiography were found as independent determinants of outcome (Figure 1). Discussion
Figure 1. Multivariate analysis performed to determine independent correlates of survival at time of hospital discharge in the overall study population (n ⫽ 93) in models 1 (A) and 2 (B) and in patients referred to coronary angiography (n ⫽ 66) (C). Two different multivariate models were computed for the overall study population including emergency coronary angiography (A) or successful emergency percutaneous coronary intervention (B). CI ⫽ confidence interval; HR ⫽ hazard ratio.
An acute or recent culprit coronary lesion was observed in 38 patients (58%). No significant difference in the prevalence of culprit coronary lesion was present between patients with ventricular fibrillation/ventricular tachycardia and those with pulseless electrical activity/ asystole as initial arrest rhythm (n ⫽ 31, 61%, vs n ⫽ 7, 47%, p ⫽ 0.38); conversely, culprit coronary lesions were more frequently observed in patients with ST-segment elevation compared to those with other ECG patterns on postROSC electrocardiogram (n ⫽ 22, 79%, vs n ⫽ 16, 42%, p ⫽ 0.005).
Results of the present study can be summarized as follows: (1) significant CAD and acute or recent culprit coronary lesions are present in most resuscitated unconscious patients with OHCA without obvious extracardiac cause; (2) significant CAD and acute or recent culprit coronary lesions are observed in most patients with ST-segment elevation and in a nonnegligible proportion of patients with other ECG patterns on post-ROSC electrocardiogram; and (3) emergency coronary angiography and successful emergency PCI are independently related to in-hospital survival after OHCA. In the present study, significant CAD was observed in 57 patients (86%) referred to coronary angiography; of note, significant CAD was frequently found in patients with STsegment elevation and in patients with other ECG patterns on post-ROSC electrocardiogram (96% and 79%, respectively). Moreover, culprit coronary lesions were found in most patients with ST-segment elevation (79%), as expected, and in a significant proportion of patients with other ECG patterns on post-ROSC electrocardiogram (42%). These results are in line with those previously reported by postmortem examinations of patients after sudden cardiac death and in vivo studies of resuscitated patients after OHCA.1,2,10,12 According to these observations, electrocardiogram should not be considered a strict selection criterion for performing emergency coronary angiography in resuscitated patients with OHCA without obvious extracardiac cause; even in the absence of ST-segment elevation on post-ROSC electrocardiogram, acute culprit coronary lesions may indeed be present and considered the trigger of cardiac arrest. Besides assessing the prevalence of acute coronary lesions in patients with OHCA, the present study specifically evaluated the in-hospital outcome and prognostic value of
Coronary Artery Disease/Emergency Coronary Angiography in Unconscious OHCA Survivors
an emergency invasive strategy (i.e., emergency coronary angiography followed by PCI) in patients who did not regain consciousness after ROSC. Of note, a high in-hospital survival rate (54%) was observed and a favorable neurological recovery was obtained in 72% of survivors. More importantly, emergency coronary angiography and successful emergency PCI were independently related to in-hospital survival. Recent advances in cardiopulmonary resuscitation and medical management and a more frequent use of an invasive strategy including coronary angiography and PCI have led to a significant improvement in survival of patients with OHCA.6,7,11,24,25 In particular, the prognostic value of emergency coronary angiography and PCI has been consistently demonstrated by previous studies including conscious and comatose patients after ROSC.3–10 The retrospective registry of Strote et al14 confirmed a higher survival rate in patients undergoing emergency coronary angiography compared to patients not referred to coronary angiography or undergoing delayed coronary angiography. In another recent retrospective study, Reynolds et al9 observed that early coronary angiography (performed ⬍24 hours after admission) was an independent predictor of in-hospital survival. The independent relation between primary PCI and in-hospital survival has been recently demonstrated also by the prospective Parisian Region Out of Hospital Cardiac Arrest (PROCAT) registry.10 The present study extends these previous observations, confirming the benefit of an invasive emergency strategy specifically in patients with OHCA who remain unconscious after ROSC, who are commonly considered a subgroup with worse prognosis and frequently excluded from invasive emergency therapeutic strategies.11–19 The positive effect of emergency coronary angiography on in-hospital survival is probably related to timely identification and treatment of patients with acute coronary syndrome; the independent relation between delay in performing coronary angiography and worse outcome observed in this study seems to reinforce this hypothesis. This strategy appears to be also cost– effective because it allowed not only an improvement of survival but also a shorter hospital stay. However, further studies are needed to specifically address this issue. According to these observations, emergency coronary angiography and PCI, when indicated, should be performed in OHCA survivors regardless of ECG findings and state of consciousness. The benefit of this emergency invasive strategy appears to be greater especially in young subjects because increasing age seems to be a factor independently related to worse outcome. This study has some limitations that should be acknowledged. First, a selection bias may have been introduced because the study population included patients who presented to a tertiary referral center, which may differ from an unselected group of patients. Second, it is a retrospective study, the limitations of which are well known. In addition, the study population was relatively small; consequently, multivariate analysis was exploratory and its result needs to be confirmed by larger prospective studies. Third, CAD was ruled out by invasive coronary angiography only in selected patients.
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