Cardiac Arrest in Acute Ischemic Stroke: Incidence, Predisposing Factors, and Clinical Outcomes

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Cardiac Arrest in Acute Ischemic Stroke: Incidence, Predisposing Factors, and Clinical Outcomes Raed A. Joundi, MD, DPhil,*† Alejandro A. Rabinstein, MD, FAHA,‡ Davar Nikneshan, MD, FRCPC,§ Jack V. Tu, MD, PhD, FRCPC,‖¶ Jiming Fang, PhD,‖ Robert Holloway, MD, FAHA,# and Gustavo Saposnik, MD, MSc, FAHA, FRCPC,*†‖** for the Stroke Outcomes Research Working Group (SORCan-www.sorcan.ca)

Background: Cardiac arrest is a devastating complication of acute ischemic stroke, but little is known about its incidence and characteristics. We studied a large ischemic stroke inpatient population and compared patients with and without cardiac arrest. Methods: We studied consecutive patients from the Ontario Stroke Registry who had an ischemic stroke between July 2003 and June 2008 at 11 tertiary care stroke centers in Ontario. Multivariable analyses were used to determine independent predictors of cardiac arrest and associated outcomes. Adjusted survival curves were computed, and hazard ratios for mortality at 30 days and 1 year were determined for cardiac arrest and other major outcomes. Results: Among the 9019 patients with acute ischemic stroke, 352 had cardiac arrest, for an overall incidence of 3.9%. In a sensitivity analysis with palliative patients removed, the incidence of cardiac arrest was 2.5%. Independent predictors of cardiac arrest were as follows: older age, greater stroke severity, preadmission dependence, and a history of diabetes, myocardial infarction, congestive heart failure, and atrial fibrillation. Systemic complications associated with cardiac arrest were as follows: myocardial infarction, pulmonary embolism, sepsis, gastrointestinal hemorrhage, and pneumonia. Patients with cardiac arrest had higher disability at discharge, and a markedly increased 30-day mortality of 82.1% compared with 9.3% without cardiac arrest. Conclusions: Cardiac arrest had a high incidence and was associated with poor outcomes after ischemic stroke, including multiple medical complications and very high mortality. Predictors of cardiac arrest identified in this study could help risk stratify ischemic stroke patients for cardiac investigations and prolonged cardiac monitoring. Key Words: Ischemic stroke—cardiac arrest—outcomes and process measures—stroke complications. © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

From the *Stroke Outcomes Research Unit, Division of Neurology, Department of Medicine, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; †Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; ‡Department of Neurology, Mayo Clinic, Rochester, Minnesota; §Calgary Stroke Program, Department of Clinical Neurosciences, Foothills Medical Centre, University of Calgary, Calgary, Alberta, Canada; ‖Institute for Clinical Evaluative Sciences (ICES), Toronto, Ontario, Canada; ¶Division of Cardiology, Sunnybrook Schulich Heart Centre, University of Toronto, Toronto, Ontario, Canada; #Department of Neurology, University of Rochester Medical Center, Rochester, New York; and **Neuroeconomics and Social Neuroscience, Department of Economics, University of Zurich, Zurich, Switzerland. Received November 29, 2015; revision received January 31, 2016; accepted March 8, 2016. Funding: Dr. Gustavo Saposnik is supported by the Distinguished Clinician Scientist Award from Heart and Stroke Foundation of Canada. Dr. Jack Tu holds a Tier 1 Canada Research Chair in Health Services Research. Address correspondence to Gustavo Saposnik, MD, MSc, FAHA, FRCPC, Department of Medicine (Neurology), St. Michael’s Hospital, University of Toronto, 55 Queen St E, Toronto, Ontario M5C 1R6, Canada. E-mail: [email protected]. 1052-3057/$ - see front matter © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.03.010

Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2016: pp ■■–■■

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Introduction Cardiac arrest (CA) may occur unexpectedly after an acute ischemic stroke. Cardiac complications after stroke span a wide range and include acute myocardial infarction (MI), bradyarrhythmia and tachyarrhythmia, congestive heart failure (CHF), and CA. Patients with pre-existing cardiac disease have a higher rate of cardiac events post stroke.1 However, even among those patients without overt heart disease, 20%-40% can develop silent myocardial ischemia after stroke. 2 Most bradyarrhythmias and tachyarrhythmias occur soon after stroke, with 74% of all arrhythmias detected within 24 hours of admission3; one fourth of these arrhythmias required urgent evaluation and treatment. Poststroke arrhythmias are hypothesized to result from abnormalities in autonomic control, causing release of catecholamines and dysregulated blood pressure and heart rate, particularly with insular lesions.4 Overall, 19% of ischemic stroke patients experience a serious adverse cardiac event,1 peaking between day 2 and day 3. In the first 1-2 weeks, cardiac death is the second most common cause of death of stroke after neurological causes,1,5 with a maximal rate at day 14.1 At 4 years, 7% of stroke patients have died of a primary cardiac cause.6 Despite the importance of CA, there is no large study to date identifying the incidence, patient characteristics, risk factors, outcomes, and overall impact of CA after stroke. Therefore, we conducted a registry-based study using the Ontario Stroke Registry (OSR) to identify patients who had suffered from “cardiac or respiratory arrest” after admission for stroke. The objectives of our study were as follows: (1) to determine the prevalence of CA in patients admitted to a tertiary care center after ischemic stroke; (2) to identify differences in baseline characteristics that may predispose to CA, and compare factors and outcomes associated with CA in patients admitted with ischemic stroke; and (3) to compare mortality between ischemic stroke patients with and without CA.

Methods We conducted a retrospective observational study using the OSR, a clinical database including patients who have experienced an acute stroke and admitted to the participating institutions. Participants were included in the study if they were admitted to any of 11 regional stroke centers in the province of Ontario, Canada, with first acute ischemic stroke between July 2003 and June 2008. The OSR was previously known as the Registry of the Canadian Stroke Network; further details can be obtained online.7 The study exclusion criteria were as follows: inhospital stroke, age less than 18 years, and stroke onset to emergency department arrival over 72 hours. All centers

are considered comprehensive or primary stroke centers. Patients with designation for palliative care, comfort measures, or do not resuscitate prior to the admission were excluded. Data were linked with the Registered Persons Database, which contains demographic information and vital status, to obtain long-term mortality.

Baseline Characteristics The following information was collected and assessed for differences between groups: demographics (age, gender, previous location, and preadmission independence), pre-existing medical conditions (including hypertension; hyperlipidemia; atrial fibrillation; previous angina, MI, coronary revascularization, CHF; diabetes; smoking; cancer; prior stroke or transient ischemic attack; Charlson comorbidity index), preadmission medications (antiplatelet, anticoagulant, and statin), acute treatment (thrombolysis), and stroke severity (based on the National Institutes of Health Stroke Scale [NIHSS] and Canadian Neurological Scale [CNS] scores). Stroke severity by CNS was categorized as mild (CNS >8), moderate (CNS 5-7), or severe (CNS <4). A CNS score of greater than or equal to 8 is equivalent to an NIHSS score of less than or equal to 8 (mild); a CNS score of 5-7 is equivalent to an NIHSS score of 9-13 (moderate); a CNS score of 1-4 is equivalent to an NIHSS score of 14-22 (severe); and a CNS score of 0 is equivalent to an NIHSS score of greater than or equal to 23. Stroke type was classified based on the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria8: small vessel disease, cardioembolic, large artery atherosclerotic disease, or undetermined etiology. Patients were also classified based on admission to general ward, intensive care unit (ICU), or stroke unit, where stroke unit was defined as designated ward where care was provided specifically to stroke patients by a multidisciplinary team.

Definition of Cardiac Arrest Cardiac arrest is an independent variable captured by the OSR database, defined as “cardiac or respiratory arrest within 30 days of admission for the hospital stay that was documented by a physician and identified from resuscitation records, progress reports, or consultant notes.” Data abstractors were also instructed to code for this variable when patients suffered sudden and unexpected death.

Main Outcome Measures The primary outcome was 30-day mortality. Secondary outcomes included 1-year mortality, medical complications during hospitalization (i.e., MI, pulmonary embolism, gastrointestinal [GI] hemorrhage, sepsis, and pneumonia), modified Rankin Scale (mRS) score at discharge, and location of discharge.

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Analysis Chi-square tests were used to compare categorical variables; t-test or Kruskal–Wallis test was used to compare mean and median differences for continuous variables. The primary analysis was conducted to evaluate the association between baseline factors and outcomes with CA. We included variables that were significant in the bivariate analyses in the multivariable logistic regression with backward selection to determine covariates that were independent predictors of CA. Adjustment was made for age, sex, stroke severity (CNS score), angina or coronary artery disease, pre-existent dependency, hypertension, atrial fibrillation, cancer, smoking, hyperlipidemia, peripheral vascular disease, asthma/chronic obstructive pulmonary disease (COPD), and diabetes. A similar analysis was completed for outcomes, including mortality. A sensitivity analysis was conducted in which we removed all patients who were made palliative during their time in the hospital, as this would impact on attempted resuscitation during CA. All tests were two tailed, and P values <.05 were considered significant. Survival analyses derived from Cox proportional hazard models were used to compare survival up to 1 year between patients with and without CA. Lastly, to determine the risk of CA in patients without pre-existing cardiovascular risk factors, we created a separate cohort of patients who did not have MI (previous or in-hospital MI), CHF, atrial fibrillation, hypertension, or diabetes, and measured rates of CA as well as hazard ratios for 30-day mortality.

Standard Protocol Approvals, Registrations, and Patient Consents The protocol was approved by the Research Ethics Board of St. Michael’s Hospital, Toronto. Patients’ informed consent was not obtained because the study was based on the OSR, which is a database that collects deidentified data from all patients’ medical records without obtaining consent but with appropriate confidentiality safeguards in place.9 The manuscript was approved by the OSR publication committee. Two cells in the data tables were suppressed as they had less than 6 subjects, in accordance with the confidentiality policy.

Results Overall, there were 9378 patients with an acute ischemic stroke that fulfilled our inclusion criteria. After excluding patients with missing data of stroke severity, glucose on admission, and mRS at discharge (n = 359), 9019 patients had complete data and were included in our study. Among those 9019 patients with an acute ischemic stroke, 352 (3.9%) had CA. Patients with CA were older than those without CA (mean age 77.3 versus 72.0; P < .0001, and age more than 80 years 50.9% versus 34.2%; P < .0001) (Table 1). There

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was no difference in gender (P > .05). They had more severe strokes (CNS <4 was 34.7% versus 12.6%; P < .0001, and mean NIHSS score was 16.5 versus 13; P = .0002). In terms of past medical history, CA patients were more likely to have a prior history of angina (32.1% versus 22.5%; P < .0001), MI (22.4% versus 14.9%; P = .0001), atrial fibrillation (32.1% versus 17.5%; P < .0001), and CHF (18.2% versus 8.7%, P < .0001). Fewer patients with CA were independent prior to admission (66.2% versus 81.4%; P < .0001) and more patients came from a nursing or retirement home (11.1% versus 6.3%; P = .0003). Fewer patients with CA were admitted to a stroke unit (45.2% versus 55.0%; P = .0003) and more patients were admitted to the ICU (25.6% versus 7.9%; P < .0001). More CA patients were made palliative during their admission (41.5% versus 8.4%; P < .0001). The most common stroke mechanism was cardioembolic among patients with CA (38.4% versus 24.4%, P > .0001), and there were less lacunar strokes (3.7% versus 16.3%; P < .0001). There was no difference in number of patients who received thrombolysis (P > .05). Neurological decline over the first 36 hours after thrombolysis was more common in patients who had CA (23.0% versus 6.2%; P < .0001). Symptomatic secondary intracranial hemorrhage was also more common in these patients (14.9% versus 6.2%; P < .0001), albeit the difference was not significant when only patients who received thrombolysis were considered. All baseline characteristics are displayed in Table 1.

Predictors of CA Multivariable logistic regression revealed that older age, preadmission dependence, diabetes, previous MI, CHF, atrial fibrillation, and greater stroke severity were independently associated with CA (Table 2). The strongest predictors were stroke severity (odds ratio of 3.8 when comparing moderate to mild, and 6.6 when comparing severe to mild) and age (odds ratio of 1.7 for age >80 years).

Outcome Measures: Mortality Patients with CA showed high 30-day mortality (82.1% versus 9.3%) and 1-year mortality (95.5% versus 19.9%) when compared to patients without CA. Table 2 shows clinical outcomes. Hazard ratio after CA for 30-day mortality was 6.03 (95% CI 5.16-7.03) and for 1-year mortality was 6.05 (95% CI 5.26-6.94). Figure 1 shows the adjusted survival curves derived from Cox regression analysis. Hazard ratios for 30-day and 1-year mortality using the baseline characteristics and complications that were significant in the multivariable analysis are displayed in Figure 2, A,B. Note the predictive value of older age, greater stroke severity, and CA for both 30-day and 1-year mortality.

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Table 1. Baseline characteristics

Variable Age, mean ± SD (n) Age groups 18-59 60-79 80+ Gender Female Male Preadmission independence (managing all activities of daily living) Arrived from Home Nursing or retirement home Inpatient rehabilitation/Other Previous comorbidities Hypertension Diabetes Hyperlipidemia Angina Previous MI Previous PCI or CABG CHF or pulmonary edema Atrial fibrillation Peripheral vascular disease Cancer Asthma/COPD Smoking Current smoker Ex-smoker Never Preadmission medications Antiplatelet Anticoagulant Statin Admission blood work, mean ± SD Creatinine Hemoglobin Glucose Stroke severity Mild (CNS ≥8 = NIHSS <9) Moderate (CNS 5-7 = NIHSS 9-13) Severe (CNS ≤4 = NIHSS >15) Coma (CNS 0 = NIHSS >23) NIHSS score, mean + SD Thrombolysis Neurological worsening in first 36 h after thrombolytic administration Intracranial hemorrhage within first 36 h after thrombolytic administration Symptomatic secondary ICH Admitted to ICU Medical ward Stroke unit Ischemic subtype Large artery atherosclerosis (e.g., carotid stenosis) Cardioembolic Lacunar Dissection/Other Undetermined

Overall (n = 9019), n (%)

Cardiac arrest (n = 352), n (%)

No cardiac arrest (n = 8667), n (%)

72.2 ± 13.8 (9019)

77.3 ± 12.0 (352)

72.0 ± 13.9 (8667)

1637 (18.2%) 4236 (47%) 3146 (34.9%)

32 (9.1%) 141 (40.1%) 179 (50.9%)

1605 (18.5%) 4095 (47.2%) 2967 (34.2%)

4304 (47.7%) 4715 (52.3%) 7284 (80.8%)

184 (52.3%) 168 (47.7%) 233 (66.2%)

4120 (47.5%) 4547 (52.5%) 7051 (81.4%)

7064 (78.3%) 583 (6.4%) 1357 (15.1%)

263 (74.7%) 39 (11.1%) 50 (14.2%)

6801 (78.5%) 544 (6.3%) 1307 (15.1%)

6145 (68.1%) 2247 (24.9%) 3113 (34.5%) 2066 (22.9%) 1374 (15.2%) 854 (9.5%) 820 (9.1%) 1626 (18%) 563 (6.2%) 862 (9.6%) 1164 (12.9%)

256 (72.7%) 107 (30.4%) 118 (33.5%) 113 (32.1%) 79 (22.4%) 40 (11.4%) 64 (18.2%) 113 (32.1%) 30 (8.5%) 40 (11.4%) 51 (14.5%)

5889 (67.9%) 2140 (24.7%) 2995 (34.6%) 1953 (22.5%) 1295 (14.9%) 814 (9.4%) 756 (8.7%) 1513 (17.5%) 533 (6.1%) 822 (9.5%) 1113 (12.8%)

1793 (19.9%) 1766 (19.6%) 5460 (60.5%)

50 (14.2%) 63 (17.9%) 239 (67.9%)

1743 (20.1%) 1703 (19.6%) 5221 (60.2%)

3679 (40.8%) 988 (11%) 2820 (31.3%)

138 (39.2%) 55 (15.6%) 111 (31.5%)

3541 (40.9%) 933 (10.8%) 2709 (31.3%)

P value <.0001 <.0001

.081 <.0001 .0084

.059 .015 .69 <.0001 .0001 .22 <.0001 <.0001 .071 .24 .37 .016

.54 .0042 .91

101.78 ± 62.89 (8986) 136.94 ± 17.97 (9011) 7.74 ± 3.45 (9019)

121.56 ± 84.89 (352) 129.97 ± 21.31 (352) 8.59 ± 3.92 (352)

100.98 ± 61.7 (8634) 137.22 ± 17.77 (8659) 7.7 ± 3.42 (8667)

5528 (61.3%) 2074 (23%) 1210 (13.4%) 207 (2.3%) 13.23 ± 5.92 (1284) 1596 (17.7%) 112 (7%)

77 (21.9%) 113 (32.1%) 122 (34.7%) 40 (11.4%) 15.7 ± 4.79 (66) 74 (21.0%) 17/74 (23.0%)

5451 (62.9%) 1961 (22.6%) 1088 (12.6%) 167 (1.9%) 13.09 ± 5.94 (1218) 1522 (17.6%) 95/1522 (6.2%)

.0005 .095 <.0001

194 (12.2%)

14/74 (18.9%)

180/1522 (11.8%)

.068

106 (6.6%)

11/74 (14.9%)

95/1522 (6.2%)

.0036 <.0001

778 (8.6%) 3260 (36.1%) 4925 (54.6%)

90 (25.6%) 100 (28.4%) 159 (45.2%)

688 (7.9%) 3160 (36.5%) 4766 (55.0%)

1468 (16.3%) 2246 (24.9%) 1428 (15.8%) 451 (5.0%) 3426 (38%)

42 (11.9%) 135 (38.4%) 13 (3.7%) 16 (4.6%) 146 (41.5%)

1426 (16.5%) 2111 (24.4%) 1415 (16.3%) 435 (5.0%) 3280 (37.8%)

<.0001 <.0001 <.0001 <.0001

<.0001

Abbreviations: CABG, coronary artery bypass grafting; CHF, congestive heart failure; CNS, Canadian Neurological Scale; COPD, chronic obstructive pulmonary disease; ICH, intracerebral hemorrhage; ICU, intensive care unit; MI, myocardial infarction; NIHSS, National Institutes of Health Stroke Scale; PCI, percutaneous coronary intervention; SD, standard deviation.

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Table 2. Predictors of cardiac arrest via logistic model with backward selection Effect

Odds ratio

Lower CL

Upper CL

P value

Age group (60-79 versus 18-59) Age group (80+ versus 18-59) CNS group (moderate 5-7 versus mild ≥8) CNS group (severe ≤4 versus mild ≥8) CNS group (coma 0 versus mild ≥8) Preadmission independence Diabetes Previous MI CHF or pulmonary edema Atrial fibrillation

1.27 1.70 3.76 6.57 14.61 .70 1.31 1.40 1.40 1.41

.85 1.13 2.80 4.87 9.61 .55 1.03 1.07 1.04 1.10

1.89 2.54 5.06 8.86 22.20 .90 1.68 1.84 1.90 1.81

.25 .011 <.0001 <.0001 <.0001 .0047 .028 .015 .029 .0064

Abbreviations: CHF, congestive heart failure; CL, confidence limit; CNS, Canadian Neurological Scale; MI, myocardial infarction.

Outcome Measures: Medical Complications MI (14.2% versus 2.1%, P < .0001), pulmonary embolism (2.8% versus .7%; P < .0001), sepsis (5.7% versus .9%; P < .0001), GI hemorrhage (5.7% versus 1.3%; P < .0001), and pneumonia (30.1% versus 6.0%; P < .0001) were more common in patients with CA (Table 3). After controlling for baseline factors with multivariable logistic regression, all these complications remained significantly associated with CA. The odds ratios ranged from 3.23 (GI hemorrhage) to 5.46 (MI) (Table 4). At discharge, patients with CA were much less likely to be alive and independent (mRS 0-2; 0%-1.7% versus 38.9%-39.0%; P < .0001; exact percentages suppressed as per confidentiality policy due to <6 subjects in cell).

Sensitivity Analysis: Palliative Care Overall, 146 of 352 patients (41.5%) in the CA group, and 728 of 8667 patients (8.4%) in the non-CA group were made palliative during their hospital stay. This left 206 patients with CA among a total of 8145 patients, giving a rate of CA of 2.5%. For this subgroup of CA patients who were not made palliative, mortality rates were 77.7%

at 30 days and 92.2% at 1 year (Table 5). In comparison, non-CA group had mortality rates of 3.7% at 30 days and 13.7% at 1 year. In summary, when removing palliative patients, there was a lower rate of CA but associations with outcomes were unaltered.

CA in Patients without Cardiovascular Risk Factors The rates of CA in a subcohort of patients without preexisting cardiovascular risk factors (previous or inhospital MI, CHF, atrial fibrillation, hypertension, or diabetes) stratified by age, gender, and stroke severity are shown in Table 6. Among a total of 1926 such patients, 43 had CA (2.23%). The lowest rate was among patients presenting with mild strokes (9 of 1263 patients, .7%), and the highest rate was among patients presenting in coma (11 of 43 patients, 25.6%). In this cohort, CA remained highly predictive of death, with a hazard ratio for 30-day mortality of 5.95 (95% CI 3.74-9.36) and for 1-year mortality of 7.06 (95% CI 4.6-10.74). Figure 2, C demonstrates the hazard ratios for 30-day mortality for factors that were significant in the multivariable analysis in this subcohort.

Discussion

Figure 1. Adjusted survival curves: 1-year survival. Vertical line denotes 30-day mark. Red: cardiac arrest. Blue: no cardiac arrest. (Color version of figure is available online.)

CA can be an unexpected and devastating outcome for stroke patients and their families. In the present study, we shed light on the impact of CA after an acute ischemic stroke using a large registry-based cohort of 9019 ischemic stroke patients. We showed that CA may affect up to 4% of patients admitted with an acute ischemic stroke. In a sensitivity analysis with palliative patients removed, the incidence was reduced to 2.5%. In a subcohort of patients without cardiovascular risk factors, the rate was 2.2%, with a low risk of .7% among mild strokes. CA carries a dramatic mortality, with 82% mortality at 30 days and 95.5% mortality at 1 year, and is also associated with multiple adverse in-hospital events and more severe disability at discharge.

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Figure 2. Forest plots of factors associated with (A) 30-day mortality and (B) 1-year mortality showing adjusted HR and lower and upper limits of 95% confidence intervals (lower CL and upper CL). Hazard ratios for 30-day mortality are also demonstrated for patients without cardiovascular risk factors (C). Abbreviations: CHF, congestive heart failure; CL, confidence limit; HR, hazard ratio; MI, myocardial infarction.

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Table 3. Outcome Measures

Variable 30-day mortality 1-year mortality Discharged to Home or rehabilitation Long-term care Other Length of stay (mean ± SD) mRS score at discharge 0-2 3-4 5 Myocardial infarction Pulmonary embolism GI hemorrhage Sepsis Pneumonia

Overall (n = 9019), n (%) 1096 (12.2%) 2059 (22.8%)

Cardiac arrest (n = 352), n (%) 289 (82.1%) 336 (95.5%)

No cardiac arrest (n = 8667), n (%) 807 (9.3%) 1723 (19.9%)

6383 (70.8%) 785 (8.7%) 837 (9.2%) 15.12 ± 21.87 (9016)

15 (4.3%) 7 (2.0%) 13 (3.7%) 16.75 ± 24.46 (352)

6368 (73.5%) 778 (9.0%) 824 (9.5%) 15.06 ± 21.76 (8664)

3377 (37.4%) 4170 (46.2%) 458 (5.1%) 228 (2.5%) 71 (.8%) 135 (1.5%) 102 (1.1%) 630 (7%)

<6 (0-1.7%)* 11 (3.1%) 20 (5.7%) 50 (14.2%) 10 (2.8%) 20 (5.7%) 20 (5.7%) 106 (30.1%)

3372-3377 (38.9-39.0%)* 4159 (48.0%) 438 (5.1%) 178 (2.1%) 61 (.7%) 115 (1.3%) 82 (.9%) 524 (6.0%)

P value <.0001 <.0001 <.0001

.16 <.0001

<.0001 <.0001 <.0001 <.0001 <.0001

Abbreviations: GI, gastrointestinal; mRS, modified Rankin Scale; SD, standard deviation. *Cells with less than 6 patients suppressed to maintain confidentiality as per ICES (Institute for Clinical Evaluative Sciences) policy.

The incidence of CA in our study (3.9%) was dramatically higher—almost tenfold—than that in the general inpatient population, recently reported as 4.02 per 1000 admissions, or .4%.10 Our high incidence may be an overrepresentation due to coding factors or inclusion of palliative patients, as discussed in our limitations section. With palliative patients removed, the incidence was lower but remained high at 2.5%. The fact that the CA rates are higher after stroke is perhaps not surprising, given the many comorbidities and complications associated with stroke—including sepsis, GI bleed, aspiration, and CHF.11 The association of CA with multiple complications is confirmed in our study. Our mortality rate is also consistent with a recent large study showing 18% survival rate of in-hospital CA in the general population.10 Stroke severity, older age, atrial fibrillation, MI, CHF, and diabetes were significant predictors of CA in our study, consistent with other studies,1,12 and suggesting that prolonged cardiac monitoring may be indicated in highrisk patients. Current guidelines by the American Heart

Association recommend cardiac monitoring for at least the first 24 hours after stroke,13 and European Stroke Initiative suggests that every stroke patient should have an electrocardiogram and that cardiac monitoring should be done to screen for atrial fibrillation.14 Prosser et al. recommended at least 72 hours of monitoring for high-risk patients as the rate of cardiac adverse events continues to rise in the third day. Prolonged cardiac monitoring may not be feasible for all patients, therefore predictors of CA identified in this study, such as stroke severity and age, could be used to risk stratify stroke patients for prolonged in-hospital cardiac monitoring after stroke. Our study has several limitations, mostly relating to the complexities of coding variables and interpreting results related to death. Firstly, our primary variable of interest was “cardiac or respiratory arrest,” and although data abstractors coded for this variable when specifically available in the chart, they were also instructed to include instants where patients suffered sudden and unexpected death. In addition, patients transitioned to palliative

Table 4. Medical complications associated with cardiac arrest after adjusting for baseline factors Outcome

Odds ratio

Lower CL

Upper CL

P value

MI Pulmonary embolism GI hemorrhage Sepsis Pneumonia

5.46 3.33 3.23 4.56 3.73

3.82 1.64 1.93 2.67 2.87

7.81 6.78 5.39 7.78 4.85

<.0001 .0009 <.0001 <.0001 <.0001

Abbreviations: CL, confidence limit; GI, gastrointestinal; MI, myocardial infarction.

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Table 5. Death and disability without palliative patients

Variable 30-day mortality 1-year mortality Discharged to Home or rehabilitation Long-term care Other modified Rankin Scale score at discharge among survivors 0-2 3-4 5

Overall (n = 8145), n (%)

Cardiac arrest (n = 206), n (%)

No cardiac arrest (n = 7939), n (%)

451 (5.5%) 1279 (15.7%)

160 (77.7%) 190 (92.2%)

291 (3.7%) 1089 (13.7%)

6306 (77.4%) 699 (8.6%) 770 (9.5%)

15 (7.3%) 6 (2.9%) 13 (6.3%)

6291 (79.2%) 693 (8.7%) 757 (9.5%)

P value <.0001 <.0001 <.0001

<.0001 3359 (41.2%) 4075 (50.0%) 341 (4.2%)

<6 (0-2.9%)* 11 (5.3%) 19 (9.2%)

3354-3359 (42.3%)* 4064 (51.2%) 322 (4.1%)

*Cells with less than 6 patients suppressed to maintain confidentiality as per ICES (Institute for Clinical Evaluative Sciences) policy.

care after the stroke may have had anticipated CA after de-escalation of therapeutic efforts. Both of these factors may partly explain our relatively high rate of CA of 3.9%. In our sensitivity analysis, palliative patients were removed, giving a lower and likely more accurate rate of 2.5%, and no significant change on the associations. Although this is still higher than the previously reported rate of 2%,11 our patients had a higher mean age and NIHSS score. Our rate may also have been driven partly by respiratory arrest. However, respiratory arrest comprises only the minority of cases of arrests; in an intensive care population, respiratory arrest accounted for 2.1% of all arrests, with the remaining 97.9% categorized as cardiac.15 Respiratory complications are common after stroke, in particular pneumonia, which is observed in 7% of ischemic stroke patients.16 Pulmonary embolism, pulmonary edema, and hypoxia are also known complications, al-

though respiratory failure and respiratory arrest were found to be uncommon occurrences in less than 1% of ischemic stroke patients.11 Nevertheless, this may be due to challenges in coding cause of death, for which the final event is often CA. We were unable to specifically capture respiratory failure in our dataset, and future registries should aim to more carefully distinguish cardiac from respiratory causes of death. Secondly, we have no data on cardiac function or biomarkers. Thirdly, we did not have temporal data on complications, and thus it was not possible to establish a causal relationship between CA and other medical complications. However, given the high mortality of CA, it is likely that in most cases medical complications preceded and led to cardiac complications and ultimately arrest. Finally, although we controlled for many confounders, there remains the possibility of unmeasured or unanticipated cofounding factors. For

Table 6. Rate of cardiac arrest among patients without cardiovascular risk factors (MI, CHF, atrial fibrillation, hypertension, or diabetes), stratified by age, gender, and stroke severity

Variable Age Age group (18-59) Age group (60-79) Age group (80+) Gender Female Male Stroke severity Mild stroke (CNS ≥8 = NIHSS <9) Moderate stroke (CNS 5-7 = NIHSS 9-13) Severe stroke (CNS ≤4 = NIHSS >15) Coma (CNS 0 = NIHSS >23)

Number of cardiac arrests/Total

%

11/721 14/747 18/458

1.5 1.9 3.9

26/867 17/1059

3.0 1.6

9/1263 11/417 12/203 11/43

.7 2.6 5.9 25.6

P value .017

.040 <.0001

Abbreviations: CHF, congestive heart failure; CNS, Canadian Neurological Scale; MI, myocardial infarction; NIHSS, National Institutes of Health Stroke Scale.

ARTICLE IN PRESS CARDIAC ARREST AND ACUTE ISCHEMIC STROKE

example, we only had data on patients who were made palliative, and not those in whom care was continued but were made “do not rescuscitate.” Some strengths of our study include a comprehensive inclusion of clinical factors known to affect stroke outcomes, assessment of cardiac risk factors and medical complications, and a near complete ascertainment of stroke severity and followup. Moreover, the registry is continuously monitored and audited to ensure outcome validation and data quality.7

Summary In conclusion, our study shows that between 2.5 and 4 out of 100 patients with an acute ischemic stroke may develop CA in the hospital. Pre-existing cardiovascular disease, older age, and greater stroke severity are the most common predisposing factors. Our study argues for prolonged cardiac monitoring post stroke, in particular when patients have additional risk factors. Our data also encourage frank discussions with the patient and families regarding the potential risk of CA and extremely poor long-term prognosis after stroke-related CA. Acknowledgments: The Ontario Stroke Registry (OSR) is funded by the Canadian Stroke Network (CSN) and the Ontario Ministry of Health and Long-Term Care (MOHLTC). The Institute for Clinical Evaluative Sciences (ICES) is supported by an operating grant from the Ontario MOHLTC. The opinions, results, and conclusions are those of the authors and should not be attributed to any supporting or sponsoring agencies. No endorsement by the CSN, ICES, or the Ontario MOHLTC is intended or should be inferred.

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