American Journal of Emergency Medicine xxx (2014) xxx–xxx

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Original Contribution

Sex differences in cardiac arrest survivors who receive therapeutic hypothermia☆,☆☆,★ Marna Rayl Greenberg, DO, MPH a,⁎, Amy M. Ahnert, MD b, Nainesh C. Patel, MD b, Courtney E. Bennett, DO b, Nicole Elliott, DO a, Mark Lundquist, MD a, Andrew Miller, DO a, Ellina C. Feiner, MD b, Anita Kurt, PhD, RN a, Bernadette Glenn-Porter, BS a, Mercedes Scott, BS b, David B. Burmeister, DO a a b

Department of Emergency Medicine, Lehigh Valley Hospital and Health Network, Allentown, PA 18103 Department of Medicine, Division of Cardiology, Lehigh Valley Hospital and Health Network, Allentown, PA 18103

a r t i c l e

i n f o

Article history: Received 6 January 2014 Received in revised form 30 January 2014 Accepted 4 February 2014 Available online xxxx

a b s t r a c t Objective: Sex differences have not been well defined for patients undergoing therapeutic hypothermia (TH). We aimed to determine sex differences in mortality and Cerebral Performance Category (CPC) scores at discharge among those receiving TH. Methods: This retrospective cohort study used data abstracted from an “ICE alert” database, an institutional protocol expediting mild TH for postarrest patients. Quality assurance variables (such as age, time to TH, CPC scores, and mortality) were reviewed and compared by sex. χ2 Test and Wilcoxon rank sum test were used. Stepwise logistic regression was used to assess the association between mortality and sex, while controlling for patient characteristics and clinical presentation of cardiac arrest. Results: Three hundred thirty subjects were analyzed, 198 males and 132 females. Subjects' mean age (SD) was 61.7 years (15.0); there was no significant sex difference in age. There were no statistically significant sex differences in history of coronary artery disease, congestive heart failure, arrhythmia, hypertension, chronic obstructive pulmonary disease, renal disease, type 1 and/or type 2 diabetes mellitus, or those previously healthy. Obesity (body mass index N 35 kg/m2) was more likely in females (37, 28.0%) than males (35, 17.7%); P = .03. Females (64, 49.6%) were more likely than males (71, 36.8%) to have shock; P = .02. There was no difference in arrest to initiating hypothermia, but there was a significant difference in time to target temperature (in median minutes, interquartile range): male (440, 270) vs female (310, 270), P = .003. There was no statistical difference in CPC at discharge. Crude mortality was not different between sexes: male, 67.7%; female, 70.5%; P = .594. However, after controlling for differences in age, obesity, shock, and other variables, females were less likely to die (odds ratio, 0.46; 95% confidence interval, 0.23-0.92; P = .03) than males. Conclusion: There is no statistically significant difference in CPC or crude mortality outcomes between sexes. After adjusting for confounders, females were 54% less likely to die than males. © 2014 Elsevier Inc. All rights reserved.

1. Introduction In the United States, implementation of “therapeutic hypothermia” (TH) programs in intensive care units has become the standard of care for patients that experience return of spontaneous circulation (ROSC)

☆ All authors are affiliated with Lehigh Valley Hospital and Health Network, Cedar Crest and I-78, Allentown, PA 18103. ☆☆ The authors have no outside support information, conflicts, or financial interest to disclose, and this work has not been presented elsewhere. ★ MG, AA, NP, AM, EF, and DB conceived the study, designed the trial, and obtained research funding. MG, AK, BP, and MS supervised the conduct of the trial and data collection. MS, BP, and AK managed the data, including quality control. MG, CB, NE, and ML drafted the manuscript, and all authors contributed substantially to its revision. MG takes responsibility for the study as a whole. ⁎ Corresponding author. 1909 Earls Court, Allentown, PA 18103. Tel.: +1 610 967 3140 (h); 610 360 4849 (c). E-mail address: [email protected] (M.R. Greenberg).

with coma after cardiac arrest. Studies have demonstrated the mortality benefit, improved outcomes, and improved long-term functioning of patients who receive this therapy [1-8]. Based on these initial studies, the American Heart Association has recommended that TH be considered in any comatose patient after cardiac arrest [9]. Patients are cooled to between 32°C and 34°C for 12 to 24 hours with the goal of appropriate neurologic recovery by decreasing the inflammatory process responsible for neurologic damage and slowing the brain's metabolic requirements [10]. It has been observed in the literature that there are sex differences in survival of cardiac arrest [11-13]. However, TH outcomes by sex have not been well defined. Patients undergoing TH have been reported as less likely to be male [14], and yet, most studies that evaluate outcomes include a minority of female participants [1,2,4,5,15]. We set out to determine sex differences in mortality and Cerebral Performance Category (CPC) scores at discharge among survivors of cardiac arrest who received TH.

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Please cite this article as: Greenberg MR, et al, Sex differences in cardiac arrest survivors who receive therapeutic hypothermia, Am J Emerg Med (2014), http://dx.doi.org/10.1016/j.ajem.2014.02.004

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M.R. Greenberg et al. / American Journal of Emergency Medicine xxx (2014) xxx–xxx

2. Methods This study was reviewed and approved by the hospital's institutional review board. This retrospective cohort study used abstracted data from an existing database of patients who had an ICE alert (an institutional protocol designed to expedite mild TH [goal 33°C] for post–cardiac arrest patients) from January 1, 2005, to September 19, 2013, at a level I trauma center with an annual adult emergency department (ED) census of 75 000, located in Pennsylvania. Patients were included in the database if they meet criteria for an ICE alert. Criteria for an ICE alert are defined as pulseless cardiac arrest with ROSC (pulses for 20 minutes continuously), persistent coma after ROSC (Glasgow Coma Scale score, ≤6), 18 years or older, time from arrest to ROSC less than 60 minutes, systolic blood pressure greater than 90 with mean arterial pressure greater than 60 mmHg for 30 minutes spontaneously or with vasopressors, and initiated within 6 hours of collapse. Patients are excluded from the registry if they have a do-not-resuscitate/do-not-intubate order or advanced medical illness precluding the possibility of meaningful recovery, persistent hypoxia with O2 saturation of less than 85% for more than 15 minutes after ROSC and before TH, initial body temperature of less than 30°C, known active bleeding, or coagulopathy (warfarin therapy is not an absolute contraindication). Therapeutic hypothermia induction is accomplished with the infusion of 2 L of 4°C normal saline solution, and maintenance is performed with the Artic Sun Temperature Management System (Medicance, Inc, Louisville, CO). The goal of the treatment protocol is to cool the patient to 33°C for 24 hours and then rewarm them 1°C every 4 to 6 hours. A database is maintained of the patients that undergo this protocol, and their outcomes are reviewed by a dedicated committee that includes physicians, nurses, and pharmacists. These outcome measurements include mortality, health performance measures, and brain injury. Brain injury is measured by the Glasgow-Pittsburgh CPC, a recognized outcome categorization tool for brain injury (see Table 1) [16]. We assessed standard quality assurance data points from the existing database, and these were reviewed and compared by sex. They included age, admission electrocardiogram, initial rhythm, time from arrest to ICE alert, time to TH set point, intensive care unit length of stay, mortality, and CPC scores. The distribution of the data for some of the points was markedly skewed by outliers with longer cooling times. Therefore, results were reported as percent or median minutes when applicable. Data analysis was completed using Pearson χ 2 test for categorical variables and Wilcoxon rank sum test for univariate comparisons of nonnormally distributed variables by patient sex. P values were used to report differences in therapies between the

Table 1 Cerebral performance categories 1. Good cerebral performance: Conscious, alert, and able to work and lead a normal life. Might have minor psychological or neurologic deficits (mild dysphasia, noncapacitating hemiparesis, or minor cranial nerve abnormalities). 2. Moderate cerebral disability: Conscious. Sufficient cerebral function for parttime work in a sheltered environment or independent activities of daily life (dress, travel by public transportation, food preparation). Such patients may have hemiplegia, seizures, ataxia, dysarthria, dysphasia, or permanent memory or mental changes. 3. Severe cerebral disability: Conscious; patient dependent on others for daily support (in an institution or at home with exceptional family effort) because of impaired brain function. Has at least limited cognition. This category includes a wide range of cerebral abnormalities, from patients who are ambulatory but have severe memory disturbance or dementia precluding independent existence to those who are paralyzed and can communicate only with their eyes, as in the locked-in syndrome. 4. Coma/vegetative state: Not conscious, unaware of surroundings, no cognition. No verbal and/or psychological interaction with environment. 5. Brain death: Certified brain dead or dead by traditional criteria.

Table 2 Cross-classification of patient characteristics by patient sex Variable

Overall, n = 330

Male, n = 198

Female, n = 132

P

Age, mean (SD), y

61.7 (15.0) n (%) 35 (10.6) 99 (30.0) 66 (20.0) 42 (12.7) 186 (56.4) 67 (20.3) 54 (16.4) 72 (21.8) 39 (11.8) 71 (21.5)

60.7 (15.4) n (%) 26 (13.1) 58 (29.3) 39 (19.7) 26 (13.1) 111 (56.1) 37 (18.7) 30 (15.1) 35 (17.7) 22 (11.1) 42 (21.2)

63.2 (14.3) n (%) 9 (6.8) 41 (31.1) 27 (20.4) 16 (12.1) 75 (56.8) 30 (22.7) 24 (18.2) 37 (28.0) 17 (12.9) 29 (22.0)

.14

Previously healthy Hx coronary disease Hx heart failure Hx arrhythmia Hypertension COPD Renal disease Obesity (BMI N35 kg/m2) Type 1 DM Type 2 DM

.07 .73 .87 .79 .89 .37 .47 .03 .63 .87

Abbreviations: Hx, history; COPD, chronic obstructive pulmonary disease; BMI, body mass index; DM, diabetes mellitus.

female and male groups, with significance set at .05. Stepwise logistic regression was used to assess the association between mortality and sex, while controlling for patient characteristics and clinical presentation of cardiac arrest. All data management and analyses were performed using Stata software (version 12.1; Stata Corporation, College Station, TX).

Table 3 Cross-classification of treatment characteristics by patient sex Variable

Coding

CPC prior

CPC-1 CPC-2 CPC-3 Unknown Admit ECG Abnormal, LBBB Abnormal, STEMI Abnormal, other ECG not done/unknown Normal Witnessed Yes Bystander CPR No Yes N/A (arrested with med person present) Shock Yes Initial rhythm PEA VT/VF VT/VF/AED-advised shock Asystole Unknown Angiography Yes Obey commands Yes CPC at discharge CPC-1 CPC-2 CPC-3 CPC-4 CPC-5 N/A

Male

Female

P

n (%)

n (%)

175 (88.4) 14 (7.1) 7 (3.5) 2 (1.0) 13 (7.1) 42 (22.8) 117 (63.6) 15 (7.6) 11 (5.6) 166 (84.7) 64 (33.2) 99 (51.3) 30 (15.5)

108 (81.8) 17 (12.9) 4 (3.0) 3 (2.3) 14 (10.6) 18 (13.6) 80 (60.6) 11 (8.3) 9 (6.8) 105 (80.2) 42 (33.3) 55 (43.7) 29 (23)

71 (36.8) 66 (33.3) 62 (31.3) 30 (15.2)

64 (49.6) 44 (33.3) 22 (16.7) 23 (17.4)

.02 1.0 .003 .58

37 (18.7) 3 (1.5) 99 (52.9) 60 (32.1) 28 (14.1) 20 (10.1) 12 (6.1) 6 (3) 77 (38.9) 55 (27.8)

40 (30.3) 3 (2.3) 35 (29.2) 35 (28) 12 (9.1) 15 (11.4) 7 (5.3) 5 (3.8) 55 (41.7) 38 (28.8)

.02 .61 b.001 .44 .82

.25

.19 .08 .78 .80 .64 .20

Median (IQR) Median (IQR) Arrest to hypothermia Time to target temperature ICU LOS

Time (min)

175 (157.5)

135 (160.0)

.07

Time (min)

440 (270)

310 (270)

.003

6 (6)

5 (6)

.14

Time (d)

Abbreviations: ECG, electrocardiogram; LBBB, left bundle-branch block; STEMI, STelevation myocardial infarction; CPR, cardiopulmonary resuscitation; N/A, not available; PEA, pulseless electrical activity; VT, ventricular tachycardia; VF, ventricular fibrillation; AED, automated external defibrillator; IQR, interquartile range; ICU, intensive care unit; LOS, length of stay.

Please cite this article as: Greenberg MR, et al, Sex differences in cardiac arrest survivors who receive therapeutic hypothermia, Am J Emerg Med (2014), http://dx.doi.org/10.1016/j.ajem.2014.02.004

M.R. Greenberg et al. / American Journal of Emergency Medicine xxx (2014) xxx–xxx

3. Results There were 330 subjects analyzed from the database in the defined period; 198 (60%) were male and 132 (40%) were female. The mean subject age was 61.7 years (SD, 15.0). There was no significant difference in age between men, 60.7 years (15.4), and women, 63.2 years (14.3); P = .14. Cross-classification of patient characteristics by sex can be viewed in Table 2. There were no statistically significant differences by sex in history of coronary artery disease, congestive heart failure, arrhythmia, hypertension, chronic obstructive pulmonary disease, renal disease, type 1 and/or type 2 diabetes mellitus, or those previously healthy. However, obesity (body mass index N35 kg/m 2) was more likely in women (37, 28.0%) than men (35, 17.7%); P = .03. Cross-classification of diagnostic and treatment characteristics by patient sex can be found in Table 3. Women (64, 49.6%) were more likely than men (71, 36.8%) to have shock; P = .02. Men (62, 31.3%) were more likely to have ventricular tachycardia/fibrillation as an initial rhythm than women (22, 16.7%); P = .003. Women (40, 30.3%) were more likely than men (37, 18.7%) to have an initial rhythm of asystole. Although there was no difference in arrest to initiating hypothermia, there was a significant difference in time to target temperature (in median minutes, interquartile range): men (440, 270) vs women (310, 270); P = .003. Overall, there was no statistical difference in CPC at discharge. Crude mortality did not differ by sex: males, 67.7%; females, 70.5%; P = .594. After controlling for differences in age, obesity, shock, and other variables, females were 54% less likely to die (odds ratio, 0.46; 95% confidence interval, 0.23-0.92; P = .03) from this cardiac event than males (Table 4). 4. Discussion In our study of cardiac arrest patients receiving TH after ROSC with persistent unresponsiveness, no significant difference in outcomes was found between male and female patients, with respect to either crude mortality (survival to discharge) or neurologic recovery (CPC

Table 4 The association between mortality and sex controlling for potential confounding factors Variable

Coding

OR

95% CI

P

Lower Upper Sex

Male Female Obese No Yes MI witnessed No Yes Bystander CPR No Yes Age Continuous Shock No Yes ECG Normal Abnormal, LBBB Abnormal, STEMI Abnormal, other Not performed Initial rhythm PEA VT/VF VT/VF/AED-advised shock Asystole Unknown Angiography performed No Yes

1.0 0.46 1.0 2.39 1.0 0.41 1.0 0.61 1.03 1.0 2.75 1.0 1.71 1.36 0.94 0.38 1.0 0.28 0.62

– 0.23 – 1.08 – 0.16 – 0.38 1.01 – 1.45 – 0.28 0.29 0.23 0.04 – 0.12 0.25

0.88 0.24 1.0 0.2

0.35 0.03 – 0.09



3

score at discharge). However, after univariate analysis, we observed several features associated with increased mortality, which were significantly more prevalent in the female subgroup. Examples of these were (a) the initial arrest rhythm (pulseless electrical activity or asystole versus ventricular tachycardia or ventricular fibrillation), (b) the development of shock, (c) the time required to reach target therapeutic temperature, and (d) cardiac catheterization. On multivariate analysis after controlling for differences in other study covariates, females had lower mortality. The clinical benefit of TH after cardiac arrest has come under scrutiny with the recent results reported by Nielsen et al [17] suggesting that hypothermia did not confer a benefit to unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause. We caution the interpretation of those results when evaluating the study for sex-specific outcomes. The characteristics of the population they studied were heavily skewed toward male patients with 393 (83%) of the 33°C group and 368 (79%) in the 36°C group being male [17]. Is it appropriate to decide the effectiveness of a treatment such as TH based on a sample with a minority of female patients? This presents a persistent obstacle when interpreting cardiac studies, and even the data we present are somewhat underrepresented by female patients (40%). Our data and analysis do not inform us as to the reasons for these differences between risk factors in our groups. However, this should inspire investigators to look more closely at the associated and/or causal etiologies of these differences in future studies. Certain limitations are inherent to the retrospective and observational design of our study. Even had this been a prospective study, certainly, the infeasibility of blinding providers and evaluators to our independent variable of patient sex would leave open the possibility of systematic differences in care leading to differences in outcome (such as, one could speculate, might have been the case with regard to the decision whether to proceed with cardiac catheterization). Our study is also limited by its small sample size as well as regional location. In multivariate analysis, we chose not to control for time to target temperature because the data were not available for a considerable proportion cohort. Further studies would optimally control for time to target temperature and be multisite and prospective in nature to evaluate a more robust number of patients and include a more “gender equal” population distribution. Finally, an important limitation of this study design is that all patients received the intervention being studied. Without randomization into treatment and nontreatment groups, we can only study sex-associated differences in outcome and cannot directly evaluate the question of sex-associated differential clinical benefit of TH treatment.

– 0.92



.03

5. Conclusion

– 5.26



.03 –

1.01 –

.05 –

0.95 1.05 – 5.19 – 10.37 6.43 3.84 3.39 – 0.65 1.52 2.17 2.18 – 0.42

.03 b.001 – b.001 – .56 .69 .94 .39 – b.001 .3 .78 .2 – b.001

Abbreviations: OR, odds ratio; CI, confidence interval; MI, myocardial infarction.

In this study, there is no statistically significant difference in crude mortality or CPC scores at discharge among survivors of cardiac arrest who received TH. However, after adjusting for confounders, females were less likely to die than males who received this treatment. Acknowledgment The authors thank Stephen W. Dusza, DrPH, for the statistical analysis. References [1] Van Der Wal G, Brinkman S, Bisschops L, et al. Influence of mild therapeutic hypothermia after cardiac arrest on hospital mortality. Crit Care Med 2011;39(1): 84–8. [2] Bernard S, Jones B, Horne M. Clinical trial of induced hypothermia in comatose survivors of out-of-hospital cardiac arrest. Ann Emerg Med 1997;30(2): 146–53.

Please cite this article as: Greenberg MR, et al, Sex differences in cardiac arrest survivors who receive therapeutic hypothermia, Am J Emerg Med (2014), http://dx.doi.org/10.1016/j.ajem.2014.02.004

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Please cite this article as: Greenberg MR, et al, Sex differences in cardiac arrest survivors who receive therapeutic hypothermia, Am J Emerg Med (2014), http://dx.doi.org/10.1016/j.ajem.2014.02.004

Sex differences in cardiac arrest survivors who receive therapeutic hypothermia.

Sex differences have not been well defined for patients undergoing therapeutic hypothermia (TH). We aimed to determine sex differences in mortality an...
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