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The influence of female gender on cardiac arrest outcomes: a systematic review of the literature a
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Omar F. Hasan , Jassim Al Suwaidi , Anas A. Omer , Wissam Ghadban , Hani Alkilani , Abdurrazzak Gehani a
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& Amar M. Salam
Cardiology Section, Al-Khor Hospital, Hamad Medical City DohaQatar
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Department of Cardiology and Cardiovascular Surgery, Hamad General Hospital, Hamad Medical City DohaQatar c
The Heart Hospital, Hamad Medical Corporation DohaQatar
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Medicine Department, Hamad Medical Corporation DohaQatar
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Accident & Emergency Department, Hamad Medical Corporation DohaQatar Published online: 26 May 2015.
To cite this article: Omar F. Hasan, Jassim Al Suwaidi, Anas A. Omer, Wissam Ghadban, Hani Alkilani, Abdurrazzak Gehani & Amar M. Salam (2014) The influence of female gender on cardiac arrest outcomes: a systematic review of the literature, Current Medical Research and Opinion, 30:11, 2169-2178 To link to this article: http://dx.doi.org/10.1185/03007995.2014.936552
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Current Medical Research & Opinion 0300-7995 doi:10.1185/03007995.2014.936552
Vol. 30, No. 11, 2014, 2169–2178
Article ST-0358.R1/936552 All rights reserved: reproduction in whole or part not permitted
Review The influence of female gender on cardiac arrest outcomes: a systematic review of the literature Omar F. Hasan Downloaded by [Stockholm University Library] at 13:21 13 August 2015
Cardiology Section, Al-Khor Hospital, Hamad Medical City, Doha, Qatar
Jassim Al Suwaidi Department of Cardiology and Cardiovascular Surgery, Hamad General Hospital, Hamad Medical City, Doha, Qatar The Heart Hospital, Hamad Medical Corporation, Doha, Qatar
Abstract Background: Sudden cardiac arrest is an important cause of cardiovascular mortality. The impact of gender on the outcome of cardiac arrest is not clear and data about that is limited. Objective: Understanding the influence of gender on cardiac arrest through a systematic review of the published literature.
Anas A. Omer Cardiology Section, Al-Khor Hospital, Hamad Medical City, Doha, Qatar Department of Cardiology and Cardiovascular Surgery, Hamad General Hospital, Hamad Medical City, Doha, Qatar
Methods: A search of all published studies in English between January 1970 and May 2013 was performed using the electronic databases PubMed and MEDLINE, using the key words ‘cardiac arrest’, ‘outcome’, and ‘gender’.
Wissam Ghadban
Results: Eleven studies were included in this review, all of which were observational studies conducted using national-based database registries of cardiac arrest. A total of 548,440 patients were enrolled in these studies with 220,646 (40.3%) of them being female patients. In general, there was a lower percentage of women in the reported studies compared to men. Women were older in age and more likely to have nonshockable rhythms as the initial rhythm. Women also had a lower rate of witnessed arrest, a lower rate of bystander resuscitation, a higher rate of survival until hospital admission and a lower rate of in-hospital survival compared to men. Women also had a more favorable one month survival and neurological outcome.
Medicine Department, Hamad Medical Corporation, Doha, Qatar
Hani Alkilani Accident & Emergency Department, Hamad Medical Corporation, Doha, Qatar
Abdurrazzak Gehani Department of Cardiology and Cardiovascular Surgery, Hamad General Hospital, Hamad Medical City, Doha, Qatar The Heart Hospital, Hamad Medical Corporation, Doha, Qatar
Amar M. Salam Cardiology Section, Al-Khor Hospital, Hamad Medical City, Doha, Qatar Department of Cardiology and Cardiovascular Surgery, Hamad General Hospital, Hamad Medical City, Doha, Qatar Address for correspondence: Amar M. Salam MBBS FRCP (London) FACC, Assistant Professor of Clinical Medicine, Weill Cornell Medical College–Qatar, Senior Consultant Cardiologist, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar. Tel.: +974 447 45408; Fax: +974 447 45616; [email protected] Keywords: Cardiac arrest – Gender – Outcome – Survival Accepted: 10 June 2014; published online: 12 August 2014 Citation: Curr Med Res Opin 2014; 30:2169–78
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Conclusion: In the reported literature female gender seems to offer survival and outcome advantages following outof-hospital cardiac arrest over male gender. This is in contrast to most other aspects of heart disease in which women tend to have a worse prognosis.
Introduction The relationship between gender and the incidence and prognosis of many cardiovascular disorders has been studied extensively, including coronary artery disease (CAD), heart failure, valvular heart disease and atrial fibrillation. Coronary artery disease and the risk of male gender was the most thoroughly studied issue and it became a fact that male gender is a non-modifiable risk factor for the development of coronary artery disease. Cardiac arrest is an important cause of cardiovascular mortality in women and can be the presenting manifestation of cardiovascular events1. Although the influence of gender on cardiac arrest outcome was raised with several epidemiological and clinical studies1, the results were inconsistent and poorly understood. Some but not all studies reported higher success rates in the treatment of women with cardiac arrest when compared to men; however, the survival to hospital discharge was equivalent to men or even lower2,3,4,5. Gender and cardiac arrest outcomes Hasan et al.
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The aim of this review was to review the available literature to have a better understanding of the influence of gender on the incidence, survival rate and neurological outcome of cardiac arrest.
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Methods A search was done on all literature published using the main electronic databases, PubMed and MEDLINE, using the key words ‘cardiac arrest’, ‘outcome’, and ‘gender difference’. Initially found articles were searched to find additional relevant articles. The literature was reviewed carefully with the main attention being paid to study design and interpretation of the results. We focused our search on all studies published in English language in peer-reviewed journals since 1970 up to the writing of this review. The studies that are included in this review are all observational and epidemiological studies that studied the influence of gender on the outcome of cardiac arrest, and the studies that reported on this issue. For each study, characteristics (type of study, duration of follow up and methods), baseline demographics, survival till discharge, and quality of life after discharge were analyzed. The primary analysis of this review was aimed at evaluating the impact of gender on survival and quality of life after cardiac arrest.
nationwide study done in Japan, and included all cardiac arrest cases aged from 20 to 89 years over a 3 year period. The study found that 171,970 (62.4%) out of the total of 276,590 patients included were males compared to 104,620 (37.6%) female patients. Another nationwide study also done in Japan but including fewer patients (58,889 patients), conducted by Matsui et al. (2010)7, showed the same percentage of gender with a male to female ratio of 64% vs. 36%. Merchant et al. (2011)8 conducted a nationwide study in the USA on Medicare beneficiary cardiac arrest patients over a period of 7 years and included a total of 69,115 cardiac arrest patients; they reported that females constituted 46% of the patients. Pell et al.9 studied all the community based cardiac arrest cases reported in Scotland from 1988 to 1997. They enrolled a total of 22,161 cardiac arrest cases and found that 15,437 (70%) occurred in men compared to 6724 (30%) in women. A South Korean nationwide study enrolling 13,922 adults with out-of-hospital cardiac arrest over a period of 1 year (2008) showed significantly more male than female patients (62.9% vs. 37.1%)10. An observational study conducted by Bray et al.15 using population-based data from the south-eastern state of Victoria (Australia) obtained from the Victorian Ambulance Cardiac Arrest Registry (VACAR) enrolled 24,469 adults with out-of-hospital cardiac arrest; 36% of the patients were females.
Age difference
Results Eleven major studies that evaluated the influence of gender on the incidence and outcome of out-of-hospital cardiac arrest were identified. Five of these studied were nationwide6,7,8,9,10 and the other six studies were at district or city wide level2,11,12,13,14,15. All studies were observational, prospective and performed on database registries of cardiac arrest. The number of patients enrolled in each study was widely variable. The duration of different studies was also widely variable as some of them were done over a period of 16 years while others were over a 1 year period (Table 1 and 2).
Gender percentage The eleven major studies enrolled 548,440 reported patients with cardiac arrest. The number of male patients significantly exceeded that of female patients (327,794 [59.7%] versus 220,646 [40.3%], P50.001). The gender percentage was variable in different studies but in all of them the percentage of male patients significantly exceeded that of female patients. A study done by Akahane et al. (2011)6 was the largest study that addressed the gender difference in cardiac arrest outcome. It was a 2170
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All the studies showed that the mean age of women was significantly higher than that of men. Akahane et al.6 found that the mean age of men was significantly lower than that of women (67.9 years vs. 72.7 years). Also Matsui et al.7 showed that the mean age of women was significantly higher than that of men (78.7 years vs. 70.1 years). In Scotland, analysis done by Pell and colleagues9 showed that women were significantly older than men (69 years vs. 65 years, P50.0001). Ahn et al. found that the mean age of men was significantly lower than the mean age of women (63.7 years vs. 72.4 years, P50.001)10. Bray et al. found that women with out-of-hospital cardiac arrest were significantly older than men (78 years vs. 71 years, P50.001)15. Zheng and colleagues16 analyzed the United States vital statistics mortality data from 1989 to 1998. They included 456,076 cases defined as sudden cardiac death and found that the age of women (82.4 years) was significantly higher than the age of men (70 years).
Incidence of cardiac arrest Studies that addressed the incidence of cardiac arrest in the general population showed a widely variable incidence regardless of the gender. Akahane et al.6 was one of those www.cmrojournal.com ! 2014 Informa UK Ltd
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Gender and cardiac arrest outcomes Hasan et al.
4401
270,590
65,563
58,889
95,852
4147
10,139
22,161
10,879
13,922
24,469
Perers et al.2
Akahane et al.6
Merchant et al.8
Matsui et al.7
Topjian et al.11
Wigginton et al.12
Iwami et al.13
Pell et al.9
Kim et al.14
Ahn et al.10
Bray et al.15
36%
5158
3810 (35%)
6724 (30%)
40%
42%
21,423 (36%)
46%
37.8% (104,620)
28%
Females
2003–2010
2008
1990–1998
October 1988–October 1997
1 May 1998–30 April 2000
6 yrs
1 January 2000 through 31 July 2008
1 January 2005–31 December 2008
January 2000–December 2006
January 2005–December 2007
1980–1996
Duration of FU
74/69
72.4/63.7
68.5
65.5
68.7/61.7
15–44 yrs and 56 yrs or older
78.1/77.4
67.9/72.7
Mean age women/men (years)
Women differ from men in being older, receiving bystander CPR less frequently, having cardiac etiology of the arrest less frequently and being found in ventricular fibrillation less often. Female gender is an independent predictor for patients being hospitalized alive. Men have a higher 1 month survival rate after out-of-hospital cardiac arrest. The rate of survival with favorable neurologic outcome was significantly higher for women than men in the group aged 40 to 59 years. Among patients with cardiac arrest who were initially resuscitated and hospitalized, gender and race disparities in survival to hospital discharge were not explained by variation in age, pre-existing comorbidities, or concurrent diagnoses during the index hospitalization. Male patients were significantly younger and had VF or pulseless VT more frequently than female patients. Before hospital arrival, male patients tended to have more ALS procedures such as tracheal tube insertion, defibrillation, intravenous line insertion, and/or intravenous medication administration, and had better outcome than female patients. Women of child-bearing age were more likely than comparably aged men to survive to hospital discharge after in-hospital cardiac arrest, even after controlling for etiology of arrest and other important variables. Women have significantly better resuscitation rates than men, especially when controlling for age, particularly among women with non-ventricular fibrillation/ ventricular tachycardia presentations. There was an exponential increase in the incidence rate of out-of-hospital cardiac arrests with age in both sexes and a higher incidence rate in men in every age group. Most of the witnessed VF cases were found to be of cardiac etiology, and showed a peak for men in their 70 s. Many of the arrest cases with VF of cardiac etiology were observed in men in their 50 s, 60 s, and 70 s. Women had a poorer risk profile than men. They were older and less likely to have shockable rhythms. Despite this, they were more likely to survive to admission. However, thereafter, women were more likely to die in hospital. There was no significant difference between the sexes in overall case-fatality rates to discharge. The incidence of out-of-hospital cardiac arrest in women was about half that of men. Women had lower unadjusted resuscitation and survival rates compared with men, primarily because of their lower incidence of VF. Females did not have equal access to resuscitation efforts such as BLS and use of an AED during prehospital care. Survival to discharge was not different between sexes after adjusting for potential risk factors. After adjusting for differences in pre-hospital factors, women were more likely to survive to hospital arrival than men (OR 3.47, 95% CI: 2.19–5.50). Both younger men and younger women were more likely to survive to hospital discharge compared to older men and women.
Conclusion
AED ¼ automated external defibrillator; ALS ¼ advanced life support; BLS ¼ basic life support; CPR ¼ cardiopulmonary resuscitation; FU ¼ follow up; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia
No. of patients
Authors
Table 1. Summary of the major studies on gender and outcome of cardiac arrest.
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who studied the incidence of cardiac arrest in the general population and they found that the incidence is significantly higher in men (120/100,000) than women (70/ 100,000). Iwami et al.13 in their study found that the annual incidence rate of out-of-hospital cardiac arrests in Osaka Prefecture was 55 per 100,000 population and men showed a higher annual incidence rate than women in every age group. They also found that in both sexes the incidence increased exponentially with age and the incidence rate for women by age was approximately equal to that for men 10 years younger. Kim et al.14 conducted a study in Seattle over a period of 8 years (1990–1998) and included a total of 10,879 adults with out-of-hospital cardiac arrest (OHCA) and found that women had a lower annual rate of cardiac arrest than men (0.085% versus 0.16%, P50.0001). A systematic review17 that addressed the global incidence and survival in 67 prospective studies showed that the incidence of out-of-hospital cardiac arrest is widely variable and ranged from 24/100,000 in the East Bohemian region, Czech Republic18 and up to 186/ 100,000 in Rochester, NY, USA19. The Becker et al. study20 done on the CPR Chicago Project also found that the incidence was significantly higher in men and in both sexes the incidence increases in the older age groups.
(VF/VT) rhythm was significantly higher in men than women (22% vs. 9%, P50.001).
Location of cardiac arrest The studies that analyzed this fact showed women suffering cardiac arrest while they were at home or admitted in nursing homes. On the other side, men suffered arrest while they were at work or in a public place. Bray et al.15 found that men tend to suffer arrest in public places more than women (15% vs. 5%, P50.001), while women are more prone to arrest at home (76% vs. 68%, P50.001) or nursing home (13% vs. 6%, P50.001). The nationwide South Korean observational study conducted by Ahn et al.10 found that men are more prone to arrest in public places than women (18.4% vs. 9.5%, P50.001). Kim et al.14 in the Seattle study found that women are less likely to collapse in public places (10% vs. 23%, P50.0001) and more likely to collapse at home (75% vs. 70%, P50.0001) or nursing home (14% vs. 6%, P50.0001) than men. The Kitamura et al. study21 which is an observational study that enrolled all patients who suffered out-of-hospital cardiac arrest (OHCA) before emergency medical services (EMS) arrival in the Osaka Prefecture showed that women are more prone to arrest at home and in healthcare facilities than men, while men suffered arrest more at workplaces and public places than women.
The initial rhythm All the reviewed studies showed that men were more prone to have ventricular tachycardia/ventricular fibrillation (VT/VF) as initial rhythm while women were more likely to present with asystole or pulseless electrical activity (PEA) as initial rhythm. The nationwide Japanese study conducted by Akahane et al.6 found that the rate of initial VF/VT rhythm was higher in men (10.1%) than women (4.7%). This significant difference in the initial rhythm as VF/VT remained higher in men than women (8.3% vs. 4.7%) even after adjusting for age. A similar tendency was observed when witnessed cases of out-of hospital cardiac arrest were examined separately (male: 14.5% vs. female: 8.4% after age adjustment), indicating that men had a substantially increased rate of presentation with initial VF/VT rhythm. Wigginton et al.12 reported that women’s rate of asystole was 42% compared with the men’s rate of 37%, and women were more prone to PEA on presentation than men (24% vs. 18%) (P50.001 for both). In contrast, women were found in VF/VT only 30% of the time, compared with 41% of men (P50.001). In the Seattle study14 the rate of VF as initial rhythm was significantly higher in men than women (43% vs. 25%, P50.0001), while PEA/asystole was higher among women (73% vs. 55%, P50.0001). The Australian study done by Bray et al.15 reported that initial shockable 2172
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Witnessed cardiac arrest Generally the rate of witnessed cardiac arrest was lower in women than men, but this difference was not significant in all published studies. The Akahane et al. study reported that cardiac arrest was witnessed in men more than in women (42.1% vs. 36.9%, P50.001)6. This finding was also observed in the Scotland study done by Pell et al.9 (63% vs. 58%, P50.0001), by Kim et al.14 (54% vs. 48%, P50.0001), Bray et al.15 (63% vs. 57%, P50.001), and Kitamura et al.21. In the Sweden study conducted in the city of Go¨teborg by Perers et al.2, men had a higher incidence of witnessed cardiac arrest than women but it was not significant (73% vs. 70%, P ¼ 0.056). Similar results were reported in the Ahn et al. study (46.9% vs. 45%, P ¼ 0.358)10.
Rate of bystander CPR The results related to this fact were not comparable in all the studies. The results were affected by the study design and method of analysis of these studies. In the Perers et al. study, women were less likely to receive bystander cardiopulmonary resuscitation (CPR) than men (15% vs. 11%, P ¼ 0.002) and this difference remained even after www.cmrojournal.com ! 2014 Informa UK Ltd
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adjustment for the type of initial rhythm but was less significant in the non-shockable rhythm group (7% vs. 10%, P ¼ 0.04)2. Akahane et al. reported that women received more bystander cardio-pulmonary resuscitation (CPR) than men at all age groups, but after adjustment for witnessed arrest, men were more likely to receive bystander CPR than women in witnessed collapse cases6. Ahn et al.10 found that women were less likely to receive basic life support (BLS) than men (70.8% vs. 77.5%, P50.001) and less likely to receive advanced cardiac life support (ACLS) in the emergency department than men (42.2% vs. 49.2%, P50.001). In addition after adjustment for age, location of arrest, witnessed status, response and transport time, the odds of women receiving bystander BLS was lower than men (OR 0.91, 95% CI, 0.84–0.99), but there was no difference in ACLS rate in the emergency department. The study by Kim et al.14 showed that the unadjusted rate of resuscitation in women was lower than that in men but, after adjustment for the presence of VF, women had a greater odds of resuscitation (OR, 1.13; 95% CI, 1.03– 1.25) and women in VF had a higher unadjusted resuscitation rate than men in VF, whereas women and men with pulseless electrical activity (PEA)/asystole had similar unadjusted resuscitation rates. Another fact observed by this study was the significant interaction between sex and age in VF patients, suggesting that the relation between sex and pre-hospital resuscitation was not constant across all age groups, and after stratification of men and women by age in decades, younger women in VF had a higher odds of resuscitation and hospital admission than younger men in VF after adjustment for witnessed arrest, location of arrest, CPR, and response intervals. This difference between men and women progressively declined as women aged and women and men 460 years of age had similar adjusted odds of resuscitation. This interaction between sex and age was not present in patients with PEA/asystole. Bray et al. found that men were more likely to receive bystander CPR than women (52% vs. 48%, P50.001)15. Kitamura et al.21, in their study that included all outof-hospital cardiac arrests presumably of cardiac etiology that happened in Osaka, reported that the rate of bystander CPR was not different between men and women below the age of 50 years, while above the age of 50 years men received more bystander CPR than women.
In general women had a higher rate of survival till hospital admission after being resuscitated from cardiac arrest. The Pell et al. study9 reported that women were less likely to die at the scene and more likely to be admitted alive than men. Kim et al.14 found that successful resuscitation and survival till hospital admission was higher in men than women (32% vs. 29%, P50.0001) but after adjustment for the initial rhythm, survival to hospital admission was higher in women if the initial rhythm was VF (57% vs. 51%, P ¼ 0.001). On the other hand no significant difference in survival till admission was found with PEA/asystole rhythm. Two studies addressed the influence of age on survival rate till hospital admission in both genders. Bray et al.15 found that the overall survival till admission was higher in women than men (30% vs. 29%) and this difference becomes clearer after adjustment for other confounding factors (adjusted OR 3.47, 95% CI, 2.19–5.50, P ¼ 0.003). This difference was even more significant in the age group of 30–49 years and it increased after stratification according to initial rhythm. The study conducted by Kitamura et al.21 reached similar results to Bray et al. and showed that women below the age of 50 years had a significantly higher survival and admission rate than that of men (21.6% vs. 15.9%) (1.45, 95% CI, 1.15–1.84, P ¼ 0.002) and this difference remained significant even after adjustment for other confounding factors (2.09, 95% CI, 1.60–2.72, P50.001). In those older than 50 years men’s survival till admission was higher than women (19.9% vs. 17.3%) (0.84, 95% CI, 0.79–0.90, P50.001), but after adjustment for other confounding factors there was no significant difference in survival rate till admission (1.05, 95% CI, 0.98–1.13, P ¼ 0.102).
The incidence of cardiac etiology
Survival till hospital discharge
The included studies followed the Utstein style for the diagnosis of cardiac etiology of cardiac arrest. Accordingly, men had a significantly higher incidence of cardiovascular problems especially coronary artery disease than women did. The Perers et al. study2, which divided
The influence of gender on the survival rate till hospital discharge was also one of the poorly understood facts. Pell et al. reported similar survival rates until hospital discharge in both genders (7% for each)9. Bray et al.15 showed that the overall in-hospital survival and discharge alive was
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the enrolled patients according to the initial rhythm, reported that incidence of cardiac etiology for cardiac arrest was higher in men than women. Iwami et al.13 reported in their study that 62.1% of the included cases were defined as of cardiac etiology according to the Utstein style and the incidence rates of cardiac etiology were higher for men than women in every age group. In addition this incidence of cardiac etiology increased with age when they were evaluated by cardiac or non-cardiac etiology separately.
Survival till admission
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higher in men than women (11% vs. 7%, P50.001), but after adjustment for other confounding factors (age, witnessed arrest, bystander CPR, year of arrest, rural vs. public location, emergency medical services [EMS] response time and initial rhythm), there was no difference in survival and discharge rate (OR 1.11, 95% CI, 0.92–1.33, P ¼ 0.27). This absence of difference in in-hospital survival and discharge rate was more clear in the young age group (550 years) even before adjustment for other factors (17% for both genders, P ¼ 0.34) (adjusted OR 1.17, 95% CI: 0.71– 1.95, P ¼ 0.53). Another finding was that both younger men and younger women were more likely to survive to hospital discharge compared to older men and women (men adjusted OR 1.87, 95% CI: 1.42–2.47, P50.001; women adjusted OR 2.59, 95% CI: 1.64–4.11, P50.001).
Iwami et al.13 studied the 1 year survival for patients with out-of-hospital cardiac arrest over a 2 year period in Osaka, Japan and found that women’s survival at 30–60 years was higher than that of men but this favorable survival of women disappeared in older age groups. Kitamura et al.21 studied the effect of female age on outcome and survival in out-of-hospital cardiac arrest and found that neurologically intact 1 month survival in witnessed OHCA for the age group of 13–49 years was significantly higher in females than males (9.7 vs. 8.2%) (adjusted OR, 2.08; 95% CI, 1.16–3.73, P ¼ 0.006). Also he found that among OHCA patients of presumed cardiac etiology, females aged 13–49 years had a significantly higher neurologically intact 1 month survival than males (4.9 vs. 4.4%; adjusted OR, 2.00; 95% CI 1.21–3.32, P ¼ 0.005).
Long term survival, neurological outcome and quality of life
Discussion
The results of the studies that addressed this part and gender influence were variable. Akahane et al.6 in their study found that the unadjusted 1 month survival rates of men were higher than women (5.2% vs. 4.3%, P50.001) (OR 1.24; 95% CI, 1.20–1.28). However, for witnessed cases, age-adjusted 1 month survival rates between genders were similar (male: 8.4% vs. female: 8.1%, OR 1.04; 95% CI, 0.99–1.09). They also found that the survival rate of men was lower than women in the group aged 30 to 39 years (5.4% vs. 6.4), while the rate in the group aged 50 to 69 years was higher for men (7 % vs. 5.6%) and this higher rate disappeared when VF/VT cases were excluded. In addition, when he analyzed the gender difference in 1 month survival in patients with non-shockable rhythm as initial rhythm, he found that the rate was higher in women below the age of 50 years, while in older patients the survival rate was similar in both genders. The same study6 found that the unadjusted favorable neurologic outcome rate for men was significantly higher than for women (2.5% vs. 1.7%, P50.001) (OR 1.49; 95% CI, 1.41–1.58). Overall, favorable neurologic outcome was significantly associated with younger age, female sex, witnessed events, bystander cardiopulmonary resuscitation, and attempted defibrillation. After examination of the rates of favorable neurologic outcomes in each age group, it was revealed that the rate of favorable neurologic outcomes is higher in women aged 30 to 49 years compared with men in this age range (3.7% vs. 3.1%) and this difference disappears with the increase in the patients’ age and becomes similar in elderly patients. Among patients with out-of-hospital cardiac arrest initially presenting with VF/VT rhythms, women aged 30 to 79 years showed a higher 1 month survival rate than men in the same age range. The rate of favorable neurologic outcomes also was higher in women aged 40 to 59 years compared with men within this age range.
The selected studies were major studies that included large numbers of patients reported in nationwide health registries (Table 1). The results of our review will raise important questions on the influence of gender on the outcome of cardiac arrest resuscitation. Some epidemiological findings were similar and consistent in all the studies conducted on this subject. In general the number of men with reported out-of-hospital cardiac arrest (OHCA) significantly exceeded the number of women. There was no clear explanation for this finding. Coronary artery disease is the most common cause for sudden cardiac death and it is more prevalent in men, while the incidence in women lags behind by 10 years22. This will give a partial explanation for the mean age of women being significantly higher than that of men, which was consistent in all the registries of out-of-hospital cardiac arrest. In addition, women are less likely and later in seeking medical advice when they have symptoms of chest pain and reporting to their general practitioner instead of EMS2. The real incidence of cardiac arrest is not known and it was widely variable among different registries. This difference came from the fact that the demographic distribution of the population was not the same in all countries. A systematic review by Berdowski et al.17 to assess the global incidence of cardiac arrest showed that the incidence varies greatly around the globe and increases as the mean population age increases. A study by Malcom et al.23 concluded that higher population density was associated with decreased incidence of out-of-hospital cardiac arrest and a higher incidence of cardiac arrest occurring outside the house. The difference in incidence of cardiac arrest between both genders was clearer and comparable in all registries as it was significantly higher in men than women. But as the patients get older this difference
2174
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Gender and cardiac arrest outcomes Hasan et al.
2175
10,453
13,922
4147
95,852
58,889
22,161
276,590
4401
68,115
10,879
Male Female Male Female Male Female Male Female Male Female Male Female Male Female Male Female Male Female Male Female Male Female
Gender
14,009 10,440 7069 3810 36,794 31,321 3158 1243 171,970 104,620 15,437 (70) 6724 (30) 37,466 21,423 (36) 53,639 42,213 (44) 2405 1742 8764 (63) 5158 (37) 7345 (70) 3108 (30)
Number per gender
61.7 (17) 68.7 (18) 63.7 (14.8) 72.4 (15.4) 71 (21) 78 (19)
69 73 67.9 72.7 65 69 70.1 (14.6) 78.7 (13.6)
72 78.7 66 71
Mean age (SD)
120/100,000 70/100,000
98.5/100,000 50.1/100,000
Incidence
6291 (71.8) 4270 (82.8) 5033 (68) 2358 (76)
7493 (55) 4051 (67)
9836 (70.4) 7823 (75.1) 4936 (70) 2848 (75)
Arrest at home
(34.4) (32.3) 4114 (46.9) 2320 (45.0) 4613 (63) 1774 (57)
(73) 7 (0) 72,459 (42.1) 38,602 (36.9) 10,207 (66) 4273 (63.5)
5668 (40.5) 3505 (33.6) 3825 (54) 1841 (48)
Witnessed
CPR ¼ cardiopulmonary resuscitation; OHCA ¼ out-of hospital cardiac arrest; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia
Bray et al.15
Ahn et al.
10
Wigginton et al.12
Topjian et al.
11
Matsui et al.7
Pell et al.
9
Akahane et al.6
Perers et al.
2
Merchant et al.8
Kim et al.
24,449
Kitamura et al.21
14
Total number
Authors
Table 2. The results of the major studies on the influence of gender on the incidence and outcome of OHCA.
6789 (77.5) 3652 (70.8) 3618 (52) 1399 (48)
16,835 (44.9) 10,678 (49.8)
(15) (11) 56,365 (32.8) 40,084 (38.3)
3899 (27.8) 3571 (34.2) 3971 (56) 2141 (56.2)
Bystander CPR
896 (41) 522 (30) 470 (5.4) 177 (3.4) 3319 (45) 778 (26)
11,073 (29.6) 2794 (13)
1400 (44) 346 (28) 17,417 (10.1) 4872 (4.7)
1873 (13.4) 588 (5.7) 3025 (43) 939 (25)
VF/VT as initial rhythm
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2507 (16) 1277 (19) 4070 (10.9) 1583 (7.4) 26,018 (48.5) 21,977 (52) 259 (10.7) 234 (13.5) 1074 (12.3) 609 (11.8) (29) (30)
(23) (24)
2788 (19.9) 1810 (17.3) 2282 (32) 1094 (29)
Admitted
274 (3.1) 94 (1.8) (11) (7)
9817 (18) 7593 (18)
1113 (7) 422 (7)
1056 (15) 403 (11) 12,973 (37) 9187 (31) (10) (8)
Discharge
9017 (5.2) 4478 (4.3)
733 (5.2) 360 (3.4)
1 month survival
7462 (14) 5782 (13.7)
4285 (2.5) 1769 (1.7)
312 (2.2) 139 (1.3)
Favorable neurological outcome
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becomes less and less until the age of 90 years when it becomes nearly comparable6,13,14,21. Interestingly, VT/VF cardiac arrest was significantly higher in men than women2,6,13,14. Men are more prone to have underlying CAD and structural heart disease with primary cardiac origin of cardiac arrest resulting in higher prevalence of VF/VT cardiac arrest. On the other hand, women are older in age and have other medical comorbidities and relatively normal heart, resulting in higher incidence of PEA/asystole cardiac arrest than VF/VT. Several autopsy studies showed that men with cardiac arrest had a higher prevalence of left ventricular (LV) hypertrophy and CAD. In addition, women had a higher chance of cardiac arrest while they were at home or being admitted to a nursing home, while men had arrests in public and work places2,6,13. This could be an expected finding as women suffered arrest at a relatively higher age and usually had multiple comorbidities making them less active or productive and being more housebound and dependent in their care on other people. This may explain the finding in some studies that women received more bystander CPR than men as they had more chance of being attended by their relatives or the people who were taking care of them. The results of the studies that included the rate of bystander CPR among both genders were not similar in all these registries. It is not clearly understood or explainable. One of the reasons is that although many studies used the Utstein style24, it was not uniformly used in all the studies. A study by Cone et al.25 showed that 6 years after the release of the Utstein style, less than 60% of published studies used this style, making it difficult to compare the results among different regions. Another factor responsible for this inconsistency in the results is the difference in age distribution of the patients in different studies. A study by Kim et al.14 showed that bystander CPR was significantly higher in young women than young men even after adjustment for witnessed arrest, location of arrest, CPR, and response intervals, and this difference will progressively decline as the patients get older. The fact that resuscitation protocols of EMS are not the same in all countries is also a reasonable explanation for this difference, as for example the practice in Japan is to initiate resuscitation in all arrest patients regardless of age, sex or the duration of the arrest state6. The studies that examined the rate of bystander CPR in different age groups among both genders showed that younger women were more likely to receive bystander CPR, even more than young men. It is clear that the rate of bystander CPR strongly related to the rate of witness and location of the arrest state and the victims are more likely to receive resuscitation when they are witnessed or when the arrest happens in public areas or at the workplace. Young women are at a higher chance of having an arrest outside the house 2176
Gender and cardiac arrest outcomes Hasan et al.
and have a higher chance of being witnessed and resuscitated than older women and is comparable to men. The female endogenous estrogen and progesterone have a proven neuroprotective effect and decrease the incidence of acute cardiovascular events. This effect on the focal and generalized hypoxic damage on the neuron cell was studied in many experimental and observational studies. A review by McCullough and Hurm26 found that estrogen is a potent neuroprotectant, demonstrating cell salvage from ischemic death pathways. Another experimental randomized study on mice27 showed that 17bestradiol has a critical dosing effect on neuronal survival, and physiologic levels of 17b-estradiol were neuroprotective after cardiac arrest and cardiopulmonary resuscitation. This neuroprotective effect of female gender and female sex hormones can explain the favorable women’s survival rate and higher chance of remaining alive at the scene and admission rate than men. Earlier studies found that women had a higher mortality rate during hospital course, but more recent and larger studies including a larger number of patients and evaluating the outcome after adjustment for other confounding factors found that female gender had a favorable effect on survival rate in the hospital course and discharge rate6,28,29. In addition, Herlitz et al.28, after multivariate analysis, concluded that female sex was an independent predictor for patients being hospitalized alive and for being alive after 1 month. Moreover, Perers et al.29 found that female gender was a significant predictor for patients being brought to hospital alive, both among the total series and among patient found in either ventricular fibrillation or asystole, but this significant association was not evident for survival on discharge. Earlier studies have indicated an increased survival among patients having an OHCA in a public place, which is probably due to higher rates of bystander cardiopulmonary resuscitation, higher rate of witnessed arrests and less comorbidities30–34. The impact of gender on neurological outcome was one of the complex issues to understand as the results of different studies were not consistent. And this was the same for long term survival. One important reason for this conflict is the age of female patients who are included in the studies, which is affected by the age of the population and is not similar in all populations. This was supported by several studies that analyzed the outcome in women among different age groups which revealed that the best favorable 1 month survival and neurological outcome was in females of child bearing age (30–50 years)8,9,21. The protective role of female hormones was therefore raised including its favorable influence on the lipid profile. Iwami et al.13 found that long term survival dropped significantly as patients get older regardless of sex and survival after 1 year will be similar in both sexes. A study assessing the influence of female gender in different age groups on the outcome of cardiac arrest found that women in the www.cmrojournal.com ! 2014 Informa UK Ltd
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Current Medical Research & Opinion Volume 30, Number 11
reproductive age group (i.e. before menopause) had more favorable long term survival and neurological outcome than men and older women21. A large observational study from Japan6 included all the cardiac arrest cases during the period from January 2005 to December 2007 and studied the influence of sex on the outcome of cardiac arrest. The results were not biased by low EMS response as they have to respond and initiate CPR in all cardiac arrest cases regardless of the age, sex of patients or the duration of the arrest state. This study showed that higher rates of survival and favorable neurologic status were significantly associated with younger age, female sex, witnessed events, bystander cardiopulmonary resuscitation, and attempted defibrillation. Interestingly, Lang et al.35 reviewed the results of the experimental studies on the effect of female sex on the extent of hypoxic damage on the neuronal and cardiac cells and concluded that there is a dichotomous response between male and female animals that is independent of sex hormones. In addition, a study by Kuilman et al.36 on patients discharged after cardiac arrest and followed for 8 years showed that age, female gender and cardiac etiology were independent and significant predictors of long term survival.
Conclusions Our current systematic review shows that female gender seems to offer survival and outcome advantages following out-of-hospital cardiac arrest over male gender after adjustment for age and other risk factors. This is in contrast to most other aspects of heart disease in which women tend to have a worse prognosis. The specific effects of female hormones on different types of rhythms encountered in cardiac arrest warrants further investigations.
Transparency Declaration of funding This study was not funded. Declaration of financial/other relationships A.F.H., J.A.S., A.A.O., W.G., H.A., A.G., and A.M.S. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
References 1. Albert CM, McGovern BA, Newell JB, et al. Sex differences in cardiac arrest survivors. Circulation 1996;93:1170-6
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2. Perers E, Abrahamsson P, Bang A. There is a difference in characteristics and outcome between women and men who suffer out of hospital cardiac arrest. Resuscitation 1999;41:133-40 3. Ritter G, Wolfe R, Goldstein S, et al. The effect of bystander CPR on survival of out-of-hospital cardiac arrest victims. Am Heart J 1985;110:932-7 4. Weston C, Wilson R, Jones S. Predicting survival from out-of-hospital cardiac arrest: a multivariate analysis. Resuscitation 1997;34:27-34 5. Hallstrom A, Cobb L, Swain M, et al. Predictors of hospital mortality after out-of-hospital cardiopulmonary resuscitation. Crit Care Med 1993; 13:927-9 6. Akahane M, Ogawa T, Koike S, Tanabe S. The effects of sex on out-of-hospital cardiac arrest outcomes. Am J Med 2011;124:325-333 7. Matsui K, Kojima S, Seino Y, Ogawa H. Gender difference and outcome of witnessed patients with out-of-hospital cardiac arrest: impact of the administered ALS procedures before hospital arrival. Circulation 2010;122:A258 8. Merchant RM, Becker LB, Groeneveld PW, et al. Race and gender disparities in survival to hospital discharge after cardiac arrest. Am Heart J 2011;16:705-11 9. Pell JP, Sirel J, Marsden AK, Cobbe SM. Sex differences in outcome following community-based cardiopulmonary arrest. Eur Heart J 2000;21: 239-44 10. Ahn KO, Shin SD, Huang SS. Sex disparity in resuscitation efforts and outcomes in out-of-hospital cardiac arrest. Am J Emerg Med 2012;30:1810-16 11. Topjian AA, Localio AR, Berg RA. Women of child-bearing age have better inhospital cardiac arrest survival outcomes than do equal-aged men. Crit Care Med 2010;38:1254-60 12. Wigginton JG, Pepe PE, Bedolla JP, et al. Sex-related differences in the presentation and outcome of out-of-hospital cardiopulmonary arrest: a multiyear, prospective, population-based study. Crit Care Med 2002;30:S131-6 13. Iwami T, Hiraide A, Nakanishi N, et al. Age and sex analyses of out-of-hospital cardiac arrest in Osaka, Japan. Resuscitation 2003;57:145-52 14. Kim C, Fahrenbruch CE, Cobb LA, Eisenberg MS. Out-of-hospital cardiac arrest in men and women. Circulation 2001;104:2699-703 15. Bray JE, Stub D, Bernard S, Smith K. Exploring gender differences and the ‘oestrogen effect’ in an Australian out-of-hospital cardiac arrest population. Resuscitation 2013;84:957-63 16. Zheng ZJ, Croft JB, Giles WH, Mensah GA. Sudden cardiac death in the United States, 1989 to 1998. Circulation 2001;104:2158-63 17. Berdowski J, Bergb RA, Tijssena JGP, Koster RW. Global incidences of out-ofhospital cardiac arrest and survival rates: systematic review of 67 prospective studies. Resuscitation 2010;81:1479-87 18. Pleskot M, Babu A, Kajzr J, et al. Characteristics and short-term survival of individuals with out-of-hospital cardiac arrests in the East Bohemian region. Resuscitation 2006;68:209-20 19. Fairbanks RJ, Shah MN, Lerner EB, et al. Epidemiology and outcomes of out-of-hospital cardiac arrest in Rochester, New York. Resuscitation 2007;72:415-24 20. Becker LB, Han BH, Meyer PM, et al.; and the CPR Chicago Project. Racial differences in the incidence of cardiac arrest and subsequent survival. N Engl J Med 1993;329:600-6 21. Kitamura T, Iwami T, Nichol G, et al. Reduction in incidence and fatality of outof-hospital cardiac arrest in females of the reproductive age. Eur Heart J 2010;31:1365-72 22. Lerner DJ, Kannel WB. Patterns of coronary heart disease morbidity and mortality in the sexes: a 26 year follow-up of the Framingham population. Am Heart J 1986;111:383-90 23. Malcom GE, Thompsom TM, Coule PL. The location and incidence of out-ofhospital cardiac arrest in Georgia: implications for placement of automated external defibrillators. Prehospital Emergency Care 2004;8:10-14 24. Cummins RO, Chamberlain DA, Abramson NS, et al. Recommended guidelines for uniform reporting of data from out-of-hospital cardiac arrest: the Utstein style. A statement for health professionals from a task force of the American Heart Association, the European Resuscitation Council, the Heart and Stroke Foundation of Canada, and the Australian Resuscitation Council. Circulation 1991;84:960-75
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fatality of 3991 events in men and 1551 events in women. Circulation 1996;93:1981-92 Eisenberg MS, Hadas E, Nuri I, et al. Sudden cardiac arrest in Israel: factors associated with successful resuscitation. Am J Emerg Med 1988;6:319-23 Ritter G, Wolfe RA, Goldstein S, et al. The effect of bystander CPR on survival of out-of-hospital cardiac arrest victims. Am Heart J 1985;110:932-7 Litwin PE, Eisenberg MS, Hallstrom AP, Cummins RO. The location of collapse and its effect on survival from cardiac arrest. Ann Emerg Med 1987;16:787-91 Albert CM, Chae CU, Grodstein F, et al. Prospective study of sudden cardiac death among women in the United States. Circulation 2003;107:2096-101 Lang JT, McCullough LD. Pathways to ischemic neuronal cell death: are sex differences relevant? Journal Transl Med 2008;6:33-43 Kuilman M, Bleeker JK, Hartman JAM, Simoons ML. Long-term survival after out-of-hospital cardiac arrest: an 8-year follow-up. Resuscitation 1999;41:25-31
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25. Cone DC, Jaslow DS, Brabson TA. Now that we have the Utstein style, are we using it? Acad Emerg Med 1999;6:923-8 26. McCullough LD, Hurm PD. Estrogen and ischemic neuroprotection: an integrated view. Trends Endocrinol Metab 2003;14:228-35 27. Noppens RR, Kofler J, Hurn PD, Traystman RJ. Dose-dependent neuroprotection by 17beta-estradiol after cardiac arrest and cardiopulmonary resuscitation. Crit Care Med 2005;33:1595-602 28. Herlitz J, Engdahl J, Svensson L, et al. Is female sex associated with increased survival after out-of-hospital cardiac arrest? Resuscitation 2004;60:197-203 29. Perers E, Abrahamsson P, Ba˚ng A, et al. Outcomes of patients hospitalized after out-of-hospital cardiac arrest in relation to sex. Coron Artery Dis 1999;10:509-14 30. Tunstall-Pedoe H, Morrison C, Woodward M, et al. Sex differences in myocardial infarction and coronary deaths in the Scottish MONICA population of Glasgow 1985 to 1991. Presentation, diagnosis, treatment, and 28-day case
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The influence of female gender on cardiac arrest outcomes: a systematic review of the literature a
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Omar F. Hasan , Jassim Al Suwaidi , Anas A. Omer , Wissam Ghadban , Hani Alkilani , Abdurrazzak Gehani a
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& Amar M. Salam
Cardiology Section, Al-Khor Hospital, Hamad Medical City DohaQatar
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Department of Cardiology and Cardiovascular Surgery, Hamad General Hospital, Hamad Medical City DohaQatar c
The Heart Hospital, Hamad Medical Corporation DohaQatar
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Medicine Department, Hamad Medical Corporation DohaQatar
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Accident & Emergency Department, Hamad Medical Corporation DohaQatar Published online: 26 May 2015.
To cite this article: Omar F. Hasan, Jassim Al Suwaidi, Anas A. Omer, Wissam Ghadban, Hani Alkilani, Abdurrazzak Gehani & Amar M. Salam (2014) The influence of female gender on cardiac arrest outcomes: a systematic review of the literature, Current Medical Research and Opinion, 30:11, 2169-2178 To link to this article: http://dx.doi.org/10.1185/03007995.2014.936552
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Review The influence of female gender on cardiac arrest outcomes: a systematic review of the literature Omar F. Hasan Downloaded by [Stockholm University Library] at 13:21 13 August 2015
Cardiology Section, Al-Khor Hospital, Hamad Medical City, Doha, Qatar
Jassim Al Suwaidi Department of Cardiology and Cardiovascular Surgery, Hamad General Hospital, Hamad Medical City, Doha, Qatar The Heart Hospital, Hamad Medical Corporation, Doha, Qatar
Abstract Background: Sudden cardiac arrest is an important cause of cardiovascular mortality. The impact of gender on the outcome of cardiac arrest is not clear and data about that is limited. Objective: Understanding the influence of gender on cardiac arrest through a systematic review of the published literature.
Anas A. Omer Cardiology Section, Al-Khor Hospital, Hamad Medical City, Doha, Qatar Department of Cardiology and Cardiovascular Surgery, Hamad General Hospital, Hamad Medical City, Doha, Qatar
Methods: A search of all published studies in English between January 1970 and May 2013 was performed using the electronic databases PubMed and MEDLINE, using the key words ‘cardiac arrest’, ‘outcome’, and ‘gender’.
Wissam Ghadban
Results: Eleven studies were included in this review, all of which were observational studies conducted using national-based database registries of cardiac arrest. A total of 548,440 patients were enrolled in these studies with 220,646 (40.3%) of them being female patients. In general, there was a lower percentage of women in the reported studies compared to men. Women were older in age and more likely to have nonshockable rhythms as the initial rhythm. Women also had a lower rate of witnessed arrest, a lower rate of bystander resuscitation, a higher rate of survival until hospital admission and a lower rate of in-hospital survival compared to men. Women also had a more favorable one month survival and neurological outcome.
Medicine Department, Hamad Medical Corporation, Doha, Qatar
Hani Alkilani Accident & Emergency Department, Hamad Medical Corporation, Doha, Qatar
Abdurrazzak Gehani Department of Cardiology and Cardiovascular Surgery, Hamad General Hospital, Hamad Medical City, Doha, Qatar The Heart Hospital, Hamad Medical Corporation, Doha, Qatar
Amar M. Salam Cardiology Section, Al-Khor Hospital, Hamad Medical City, Doha, Qatar Department of Cardiology and Cardiovascular Surgery, Hamad General Hospital, Hamad Medical City, Doha, Qatar Address for correspondence: Amar M. Salam MBBS FRCP (London) FACC, Assistant Professor of Clinical Medicine, Weill Cornell Medical College–Qatar, Senior Consultant Cardiologist, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar. Tel.: +974 447 45408; Fax: +974 447 45616; [email protected] Keywords: Cardiac arrest – Gender – Outcome – Survival Accepted: 10 June 2014; published online: 12 August 2014 Citation: Curr Med Res Opin 2014; 30:2169–78
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Conclusion: In the reported literature female gender seems to offer survival and outcome advantages following outof-hospital cardiac arrest over male gender. This is in contrast to most other aspects of heart disease in which women tend to have a worse prognosis.
Introduction The relationship between gender and the incidence and prognosis of many cardiovascular disorders has been studied extensively, including coronary artery disease (CAD), heart failure, valvular heart disease and atrial fibrillation. Coronary artery disease and the risk of male gender was the most thoroughly studied issue and it became a fact that male gender is a non-modifiable risk factor for the development of coronary artery disease. Cardiac arrest is an important cause of cardiovascular mortality in women and can be the presenting manifestation of cardiovascular events1. Although the influence of gender on cardiac arrest outcome was raised with several epidemiological and clinical studies1, the results were inconsistent and poorly understood. Some but not all studies reported higher success rates in the treatment of women with cardiac arrest when compared to men; however, the survival to hospital discharge was equivalent to men or even lower2,3,4,5. Gender and cardiac arrest outcomes Hasan et al.
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The aim of this review was to review the available literature to have a better understanding of the influence of gender on the incidence, survival rate and neurological outcome of cardiac arrest.
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Methods A search was done on all literature published using the main electronic databases, PubMed and MEDLINE, using the key words ‘cardiac arrest’, ‘outcome’, and ‘gender difference’. Initially found articles were searched to find additional relevant articles. The literature was reviewed carefully with the main attention being paid to study design and interpretation of the results. We focused our search on all studies published in English language in peer-reviewed journals since 1970 up to the writing of this review. The studies that are included in this review are all observational and epidemiological studies that studied the influence of gender on the outcome of cardiac arrest, and the studies that reported on this issue. For each study, characteristics (type of study, duration of follow up and methods), baseline demographics, survival till discharge, and quality of life after discharge were analyzed. The primary analysis of this review was aimed at evaluating the impact of gender on survival and quality of life after cardiac arrest.
nationwide study done in Japan, and included all cardiac arrest cases aged from 20 to 89 years over a 3 year period. The study found that 171,970 (62.4%) out of the total of 276,590 patients included were males compared to 104,620 (37.6%) female patients. Another nationwide study also done in Japan but including fewer patients (58,889 patients), conducted by Matsui et al. (2010)7, showed the same percentage of gender with a male to female ratio of 64% vs. 36%. Merchant et al. (2011)8 conducted a nationwide study in the USA on Medicare beneficiary cardiac arrest patients over a period of 7 years and included a total of 69,115 cardiac arrest patients; they reported that females constituted 46% of the patients. Pell et al.9 studied all the community based cardiac arrest cases reported in Scotland from 1988 to 1997. They enrolled a total of 22,161 cardiac arrest cases and found that 15,437 (70%) occurred in men compared to 6724 (30%) in women. A South Korean nationwide study enrolling 13,922 adults with out-of-hospital cardiac arrest over a period of 1 year (2008) showed significantly more male than female patients (62.9% vs. 37.1%)10. An observational study conducted by Bray et al.15 using population-based data from the south-eastern state of Victoria (Australia) obtained from the Victorian Ambulance Cardiac Arrest Registry (VACAR) enrolled 24,469 adults with out-of-hospital cardiac arrest; 36% of the patients were females.
Age difference
Results Eleven major studies that evaluated the influence of gender on the incidence and outcome of out-of-hospital cardiac arrest were identified. Five of these studied were nationwide6,7,8,9,10 and the other six studies were at district or city wide level2,11,12,13,14,15. All studies were observational, prospective and performed on database registries of cardiac arrest. The number of patients enrolled in each study was widely variable. The duration of different studies was also widely variable as some of them were done over a period of 16 years while others were over a 1 year period (Table 1 and 2).
Gender percentage The eleven major studies enrolled 548,440 reported patients with cardiac arrest. The number of male patients significantly exceeded that of female patients (327,794 [59.7%] versus 220,646 [40.3%], P50.001). The gender percentage was variable in different studies but in all of them the percentage of male patients significantly exceeded that of female patients. A study done by Akahane et al. (2011)6 was the largest study that addressed the gender difference in cardiac arrest outcome. It was a 2170
Gender and cardiac arrest outcomes Hasan et al.
All the studies showed that the mean age of women was significantly higher than that of men. Akahane et al.6 found that the mean age of men was significantly lower than that of women (67.9 years vs. 72.7 years). Also Matsui et al.7 showed that the mean age of women was significantly higher than that of men (78.7 years vs. 70.1 years). In Scotland, analysis done by Pell and colleagues9 showed that women were significantly older than men (69 years vs. 65 years, P50.0001). Ahn et al. found that the mean age of men was significantly lower than the mean age of women (63.7 years vs. 72.4 years, P50.001)10. Bray et al. found that women with out-of-hospital cardiac arrest were significantly older than men (78 years vs. 71 years, P50.001)15. Zheng and colleagues16 analyzed the United States vital statistics mortality data from 1989 to 1998. They included 456,076 cases defined as sudden cardiac death and found that the age of women (82.4 years) was significantly higher than the age of men (70 years).
Incidence of cardiac arrest Studies that addressed the incidence of cardiac arrest in the general population showed a widely variable incidence regardless of the gender. Akahane et al.6 was one of those www.cmrojournal.com ! 2014 Informa UK Ltd
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Gender and cardiac arrest outcomes Hasan et al.
4401
270,590
65,563
58,889
95,852
4147
10,139
22,161
10,879
13,922
24,469
Perers et al.2
Akahane et al.6
Merchant et al.8
Matsui et al.7
Topjian et al.11
Wigginton et al.12
Iwami et al.13
Pell et al.9
Kim et al.14
Ahn et al.10
Bray et al.15
36%
5158
3810 (35%)
6724 (30%)
40%
42%
21,423 (36%)
46%
37.8% (104,620)
28%
Females
2003–2010
2008
1990–1998
October 1988–October 1997
1 May 1998–30 April 2000
6 yrs
1 January 2000 through 31 July 2008
1 January 2005–31 December 2008
January 2000–December 2006
January 2005–December 2007
1980–1996
Duration of FU
74/69
72.4/63.7
68.5
65.5
68.7/61.7
15–44 yrs and 56 yrs or older
78.1/77.4
67.9/72.7
Mean age women/men (years)
Women differ from men in being older, receiving bystander CPR less frequently, having cardiac etiology of the arrest less frequently and being found in ventricular fibrillation less often. Female gender is an independent predictor for patients being hospitalized alive. Men have a higher 1 month survival rate after out-of-hospital cardiac arrest. The rate of survival with favorable neurologic outcome was significantly higher for women than men in the group aged 40 to 59 years. Among patients with cardiac arrest who were initially resuscitated and hospitalized, gender and race disparities in survival to hospital discharge were not explained by variation in age, pre-existing comorbidities, or concurrent diagnoses during the index hospitalization. Male patients were significantly younger and had VF or pulseless VT more frequently than female patients. Before hospital arrival, male patients tended to have more ALS procedures such as tracheal tube insertion, defibrillation, intravenous line insertion, and/or intravenous medication administration, and had better outcome than female patients. Women of child-bearing age were more likely than comparably aged men to survive to hospital discharge after in-hospital cardiac arrest, even after controlling for etiology of arrest and other important variables. Women have significantly better resuscitation rates than men, especially when controlling for age, particularly among women with non-ventricular fibrillation/ ventricular tachycardia presentations. There was an exponential increase in the incidence rate of out-of-hospital cardiac arrests with age in both sexes and a higher incidence rate in men in every age group. Most of the witnessed VF cases were found to be of cardiac etiology, and showed a peak for men in their 70 s. Many of the arrest cases with VF of cardiac etiology were observed in men in their 50 s, 60 s, and 70 s. Women had a poorer risk profile than men. They were older and less likely to have shockable rhythms. Despite this, they were more likely to survive to admission. However, thereafter, women were more likely to die in hospital. There was no significant difference between the sexes in overall case-fatality rates to discharge. The incidence of out-of-hospital cardiac arrest in women was about half that of men. Women had lower unadjusted resuscitation and survival rates compared with men, primarily because of their lower incidence of VF. Females did not have equal access to resuscitation efforts such as BLS and use of an AED during prehospital care. Survival to discharge was not different between sexes after adjusting for potential risk factors. After adjusting for differences in pre-hospital factors, women were more likely to survive to hospital arrival than men (OR 3.47, 95% CI: 2.19–5.50). Both younger men and younger women were more likely to survive to hospital discharge compared to older men and women.
Conclusion
AED ¼ automated external defibrillator; ALS ¼ advanced life support; BLS ¼ basic life support; CPR ¼ cardiopulmonary resuscitation; FU ¼ follow up; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia
No. of patients
Authors
Table 1. Summary of the major studies on gender and outcome of cardiac arrest.
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who studied the incidence of cardiac arrest in the general population and they found that the incidence is significantly higher in men (120/100,000) than women (70/ 100,000). Iwami et al.13 in their study found that the annual incidence rate of out-of-hospital cardiac arrests in Osaka Prefecture was 55 per 100,000 population and men showed a higher annual incidence rate than women in every age group. They also found that in both sexes the incidence increased exponentially with age and the incidence rate for women by age was approximately equal to that for men 10 years younger. Kim et al.14 conducted a study in Seattle over a period of 8 years (1990–1998) and included a total of 10,879 adults with out-of-hospital cardiac arrest (OHCA) and found that women had a lower annual rate of cardiac arrest than men (0.085% versus 0.16%, P50.0001). A systematic review17 that addressed the global incidence and survival in 67 prospective studies showed that the incidence of out-of-hospital cardiac arrest is widely variable and ranged from 24/100,000 in the East Bohemian region, Czech Republic18 and up to 186/ 100,000 in Rochester, NY, USA19. The Becker et al. study20 done on the CPR Chicago Project also found that the incidence was significantly higher in men and in both sexes the incidence increases in the older age groups.
(VF/VT) rhythm was significantly higher in men than women (22% vs. 9%, P50.001).
Location of cardiac arrest The studies that analyzed this fact showed women suffering cardiac arrest while they were at home or admitted in nursing homes. On the other side, men suffered arrest while they were at work or in a public place. Bray et al.15 found that men tend to suffer arrest in public places more than women (15% vs. 5%, P50.001), while women are more prone to arrest at home (76% vs. 68%, P50.001) or nursing home (13% vs. 6%, P50.001). The nationwide South Korean observational study conducted by Ahn et al.10 found that men are more prone to arrest in public places than women (18.4% vs. 9.5%, P50.001). Kim et al.14 in the Seattle study found that women are less likely to collapse in public places (10% vs. 23%, P50.0001) and more likely to collapse at home (75% vs. 70%, P50.0001) or nursing home (14% vs. 6%, P50.0001) than men. The Kitamura et al. study21 which is an observational study that enrolled all patients who suffered out-of-hospital cardiac arrest (OHCA) before emergency medical services (EMS) arrival in the Osaka Prefecture showed that women are more prone to arrest at home and in healthcare facilities than men, while men suffered arrest more at workplaces and public places than women.
The initial rhythm All the reviewed studies showed that men were more prone to have ventricular tachycardia/ventricular fibrillation (VT/VF) as initial rhythm while women were more likely to present with asystole or pulseless electrical activity (PEA) as initial rhythm. The nationwide Japanese study conducted by Akahane et al.6 found that the rate of initial VF/VT rhythm was higher in men (10.1%) than women (4.7%). This significant difference in the initial rhythm as VF/VT remained higher in men than women (8.3% vs. 4.7%) even after adjusting for age. A similar tendency was observed when witnessed cases of out-of hospital cardiac arrest were examined separately (male: 14.5% vs. female: 8.4% after age adjustment), indicating that men had a substantially increased rate of presentation with initial VF/VT rhythm. Wigginton et al.12 reported that women’s rate of asystole was 42% compared with the men’s rate of 37%, and women were more prone to PEA on presentation than men (24% vs. 18%) (P50.001 for both). In contrast, women were found in VF/VT only 30% of the time, compared with 41% of men (P50.001). In the Seattle study14 the rate of VF as initial rhythm was significantly higher in men than women (43% vs. 25%, P50.0001), while PEA/asystole was higher among women (73% vs. 55%, P50.0001). The Australian study done by Bray et al.15 reported that initial shockable 2172
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Witnessed cardiac arrest Generally the rate of witnessed cardiac arrest was lower in women than men, but this difference was not significant in all published studies. The Akahane et al. study reported that cardiac arrest was witnessed in men more than in women (42.1% vs. 36.9%, P50.001)6. This finding was also observed in the Scotland study done by Pell et al.9 (63% vs. 58%, P50.0001), by Kim et al.14 (54% vs. 48%, P50.0001), Bray et al.15 (63% vs. 57%, P50.001), and Kitamura et al.21. In the Sweden study conducted in the city of Go¨teborg by Perers et al.2, men had a higher incidence of witnessed cardiac arrest than women but it was not significant (73% vs. 70%, P ¼ 0.056). Similar results were reported in the Ahn et al. study (46.9% vs. 45%, P ¼ 0.358)10.
Rate of bystander CPR The results related to this fact were not comparable in all the studies. The results were affected by the study design and method of analysis of these studies. In the Perers et al. study, women were less likely to receive bystander cardiopulmonary resuscitation (CPR) than men (15% vs. 11%, P ¼ 0.002) and this difference remained even after www.cmrojournal.com ! 2014 Informa UK Ltd
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adjustment for the type of initial rhythm but was less significant in the non-shockable rhythm group (7% vs. 10%, P ¼ 0.04)2. Akahane et al. reported that women received more bystander cardio-pulmonary resuscitation (CPR) than men at all age groups, but after adjustment for witnessed arrest, men were more likely to receive bystander CPR than women in witnessed collapse cases6. Ahn et al.10 found that women were less likely to receive basic life support (BLS) than men (70.8% vs. 77.5%, P50.001) and less likely to receive advanced cardiac life support (ACLS) in the emergency department than men (42.2% vs. 49.2%, P50.001). In addition after adjustment for age, location of arrest, witnessed status, response and transport time, the odds of women receiving bystander BLS was lower than men (OR 0.91, 95% CI, 0.84–0.99), but there was no difference in ACLS rate in the emergency department. The study by Kim et al.14 showed that the unadjusted rate of resuscitation in women was lower than that in men but, after adjustment for the presence of VF, women had a greater odds of resuscitation (OR, 1.13; 95% CI, 1.03– 1.25) and women in VF had a higher unadjusted resuscitation rate than men in VF, whereas women and men with pulseless electrical activity (PEA)/asystole had similar unadjusted resuscitation rates. Another fact observed by this study was the significant interaction between sex and age in VF patients, suggesting that the relation between sex and pre-hospital resuscitation was not constant across all age groups, and after stratification of men and women by age in decades, younger women in VF had a higher odds of resuscitation and hospital admission than younger men in VF after adjustment for witnessed arrest, location of arrest, CPR, and response intervals. This difference between men and women progressively declined as women aged and women and men 460 years of age had similar adjusted odds of resuscitation. This interaction between sex and age was not present in patients with PEA/asystole. Bray et al. found that men were more likely to receive bystander CPR than women (52% vs. 48%, P50.001)15. Kitamura et al.21, in their study that included all outof-hospital cardiac arrests presumably of cardiac etiology that happened in Osaka, reported that the rate of bystander CPR was not different between men and women below the age of 50 years, while above the age of 50 years men received more bystander CPR than women.
In general women had a higher rate of survival till hospital admission after being resuscitated from cardiac arrest. The Pell et al. study9 reported that women were less likely to die at the scene and more likely to be admitted alive than men. Kim et al.14 found that successful resuscitation and survival till hospital admission was higher in men than women (32% vs. 29%, P50.0001) but after adjustment for the initial rhythm, survival to hospital admission was higher in women if the initial rhythm was VF (57% vs. 51%, P ¼ 0.001). On the other hand no significant difference in survival till admission was found with PEA/asystole rhythm. Two studies addressed the influence of age on survival rate till hospital admission in both genders. Bray et al.15 found that the overall survival till admission was higher in women than men (30% vs. 29%) and this difference becomes clearer after adjustment for other confounding factors (adjusted OR 3.47, 95% CI, 2.19–5.50, P ¼ 0.003). This difference was even more significant in the age group of 30–49 years and it increased after stratification according to initial rhythm. The study conducted by Kitamura et al.21 reached similar results to Bray et al. and showed that women below the age of 50 years had a significantly higher survival and admission rate than that of men (21.6% vs. 15.9%) (1.45, 95% CI, 1.15–1.84, P ¼ 0.002) and this difference remained significant even after adjustment for other confounding factors (2.09, 95% CI, 1.60–2.72, P50.001). In those older than 50 years men’s survival till admission was higher than women (19.9% vs. 17.3%) (0.84, 95% CI, 0.79–0.90, P50.001), but after adjustment for other confounding factors there was no significant difference in survival rate till admission (1.05, 95% CI, 0.98–1.13, P ¼ 0.102).
The incidence of cardiac etiology
Survival till hospital discharge
The included studies followed the Utstein style for the diagnosis of cardiac etiology of cardiac arrest. Accordingly, men had a significantly higher incidence of cardiovascular problems especially coronary artery disease than women did. The Perers et al. study2, which divided
The influence of gender on the survival rate till hospital discharge was also one of the poorly understood facts. Pell et al. reported similar survival rates until hospital discharge in both genders (7% for each)9. Bray et al.15 showed that the overall in-hospital survival and discharge alive was
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the enrolled patients according to the initial rhythm, reported that incidence of cardiac etiology for cardiac arrest was higher in men than women. Iwami et al.13 reported in their study that 62.1% of the included cases were defined as of cardiac etiology according to the Utstein style and the incidence rates of cardiac etiology were higher for men than women in every age group. In addition this incidence of cardiac etiology increased with age when they were evaluated by cardiac or non-cardiac etiology separately.
Survival till admission
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higher in men than women (11% vs. 7%, P50.001), but after adjustment for other confounding factors (age, witnessed arrest, bystander CPR, year of arrest, rural vs. public location, emergency medical services [EMS] response time and initial rhythm), there was no difference in survival and discharge rate (OR 1.11, 95% CI, 0.92–1.33, P ¼ 0.27). This absence of difference in in-hospital survival and discharge rate was more clear in the young age group (550 years) even before adjustment for other factors (17% for both genders, P ¼ 0.34) (adjusted OR 1.17, 95% CI: 0.71– 1.95, P ¼ 0.53). Another finding was that both younger men and younger women were more likely to survive to hospital discharge compared to older men and women (men adjusted OR 1.87, 95% CI: 1.42–2.47, P50.001; women adjusted OR 2.59, 95% CI: 1.64–4.11, P50.001).
Iwami et al.13 studied the 1 year survival for patients with out-of-hospital cardiac arrest over a 2 year period in Osaka, Japan and found that women’s survival at 30–60 years was higher than that of men but this favorable survival of women disappeared in older age groups. Kitamura et al.21 studied the effect of female age on outcome and survival in out-of-hospital cardiac arrest and found that neurologically intact 1 month survival in witnessed OHCA for the age group of 13–49 years was significantly higher in females than males (9.7 vs. 8.2%) (adjusted OR, 2.08; 95% CI, 1.16–3.73, P ¼ 0.006). Also he found that among OHCA patients of presumed cardiac etiology, females aged 13–49 years had a significantly higher neurologically intact 1 month survival than males (4.9 vs. 4.4%; adjusted OR, 2.00; 95% CI 1.21–3.32, P ¼ 0.005).
Long term survival, neurological outcome and quality of life
Discussion
The results of the studies that addressed this part and gender influence were variable. Akahane et al.6 in their study found that the unadjusted 1 month survival rates of men were higher than women (5.2% vs. 4.3%, P50.001) (OR 1.24; 95% CI, 1.20–1.28). However, for witnessed cases, age-adjusted 1 month survival rates between genders were similar (male: 8.4% vs. female: 8.1%, OR 1.04; 95% CI, 0.99–1.09). They also found that the survival rate of men was lower than women in the group aged 30 to 39 years (5.4% vs. 6.4), while the rate in the group aged 50 to 69 years was higher for men (7 % vs. 5.6%) and this higher rate disappeared when VF/VT cases were excluded. In addition, when he analyzed the gender difference in 1 month survival in patients with non-shockable rhythm as initial rhythm, he found that the rate was higher in women below the age of 50 years, while in older patients the survival rate was similar in both genders. The same study6 found that the unadjusted favorable neurologic outcome rate for men was significantly higher than for women (2.5% vs. 1.7%, P50.001) (OR 1.49; 95% CI, 1.41–1.58). Overall, favorable neurologic outcome was significantly associated with younger age, female sex, witnessed events, bystander cardiopulmonary resuscitation, and attempted defibrillation. After examination of the rates of favorable neurologic outcomes in each age group, it was revealed that the rate of favorable neurologic outcomes is higher in women aged 30 to 49 years compared with men in this age range (3.7% vs. 3.1%) and this difference disappears with the increase in the patients’ age and becomes similar in elderly patients. Among patients with out-of-hospital cardiac arrest initially presenting with VF/VT rhythms, women aged 30 to 79 years showed a higher 1 month survival rate than men in the same age range. The rate of favorable neurologic outcomes also was higher in women aged 40 to 59 years compared with men within this age range.
The selected studies were major studies that included large numbers of patients reported in nationwide health registries (Table 1). The results of our review will raise important questions on the influence of gender on the outcome of cardiac arrest resuscitation. Some epidemiological findings were similar and consistent in all the studies conducted on this subject. In general the number of men with reported out-of-hospital cardiac arrest (OHCA) significantly exceeded the number of women. There was no clear explanation for this finding. Coronary artery disease is the most common cause for sudden cardiac death and it is more prevalent in men, while the incidence in women lags behind by 10 years22. This will give a partial explanation for the mean age of women being significantly higher than that of men, which was consistent in all the registries of out-of-hospital cardiac arrest. In addition, women are less likely and later in seeking medical advice when they have symptoms of chest pain and reporting to their general practitioner instead of EMS2. The real incidence of cardiac arrest is not known and it was widely variable among different registries. This difference came from the fact that the demographic distribution of the population was not the same in all countries. A systematic review by Berdowski et al.17 to assess the global incidence of cardiac arrest showed that the incidence varies greatly around the globe and increases as the mean population age increases. A study by Malcom et al.23 concluded that higher population density was associated with decreased incidence of out-of-hospital cardiac arrest and a higher incidence of cardiac arrest occurring outside the house. The difference in incidence of cardiac arrest between both genders was clearer and comparable in all registries as it was significantly higher in men than women. But as the patients get older this difference
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2175
10,453
13,922
4147
95,852
58,889
22,161
276,590
4401
68,115
10,879
Male Female Male Female Male Female Male Female Male Female Male Female Male Female Male Female Male Female Male Female Male Female
Gender
14,009 10,440 7069 3810 36,794 31,321 3158 1243 171,970 104,620 15,437 (70) 6724 (30) 37,466 21,423 (36) 53,639 42,213 (44) 2405 1742 8764 (63) 5158 (37) 7345 (70) 3108 (30)
Number per gender
61.7 (17) 68.7 (18) 63.7 (14.8) 72.4 (15.4) 71 (21) 78 (19)
69 73 67.9 72.7 65 69 70.1 (14.6) 78.7 (13.6)
72 78.7 66 71
Mean age (SD)
120/100,000 70/100,000
98.5/100,000 50.1/100,000
Incidence
6291 (71.8) 4270 (82.8) 5033 (68) 2358 (76)
7493 (55) 4051 (67)
9836 (70.4) 7823 (75.1) 4936 (70) 2848 (75)
Arrest at home
(34.4) (32.3) 4114 (46.9) 2320 (45.0) 4613 (63) 1774 (57)
(73) 7 (0) 72,459 (42.1) 38,602 (36.9) 10,207 (66) 4273 (63.5)
5668 (40.5) 3505 (33.6) 3825 (54) 1841 (48)
Witnessed
CPR ¼ cardiopulmonary resuscitation; OHCA ¼ out-of hospital cardiac arrest; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia
Bray et al.15
Ahn et al.
10
Wigginton et al.12
Topjian et al.
11
Matsui et al.7
Pell et al.
9
Akahane et al.6
Perers et al.
2
Merchant et al.8
Kim et al.
24,449
Kitamura et al.21
14
Total number
Authors
Table 2. The results of the major studies on the influence of gender on the incidence and outcome of OHCA.
6789 (77.5) 3652 (70.8) 3618 (52) 1399 (48)
16,835 (44.9) 10,678 (49.8)
(15) (11) 56,365 (32.8) 40,084 (38.3)
3899 (27.8) 3571 (34.2) 3971 (56) 2141 (56.2)
Bystander CPR
896 (41) 522 (30) 470 (5.4) 177 (3.4) 3319 (45) 778 (26)
11,073 (29.6) 2794 (13)
1400 (44) 346 (28) 17,417 (10.1) 4872 (4.7)
1873 (13.4) 588 (5.7) 3025 (43) 939 (25)
VF/VT as initial rhythm
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2507 (16) 1277 (19) 4070 (10.9) 1583 (7.4) 26,018 (48.5) 21,977 (52) 259 (10.7) 234 (13.5) 1074 (12.3) 609 (11.8) (29) (30)
(23) (24)
2788 (19.9) 1810 (17.3) 2282 (32) 1094 (29)
Admitted
274 (3.1) 94 (1.8) (11) (7)
9817 (18) 7593 (18)
1113 (7) 422 (7)
1056 (15) 403 (11) 12,973 (37) 9187 (31) (10) (8)
Discharge
9017 (5.2) 4478 (4.3)
733 (5.2) 360 (3.4)
1 month survival
7462 (14) 5782 (13.7)
4285 (2.5) 1769 (1.7)
312 (2.2) 139 (1.3)
Favorable neurological outcome
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becomes less and less until the age of 90 years when it becomes nearly comparable6,13,14,21. Interestingly, VT/VF cardiac arrest was significantly higher in men than women2,6,13,14. Men are more prone to have underlying CAD and structural heart disease with primary cardiac origin of cardiac arrest resulting in higher prevalence of VF/VT cardiac arrest. On the other hand, women are older in age and have other medical comorbidities and relatively normal heart, resulting in higher incidence of PEA/asystole cardiac arrest than VF/VT. Several autopsy studies showed that men with cardiac arrest had a higher prevalence of left ventricular (LV) hypertrophy and CAD. In addition, women had a higher chance of cardiac arrest while they were at home or being admitted to a nursing home, while men had arrests in public and work places2,6,13. This could be an expected finding as women suffered arrest at a relatively higher age and usually had multiple comorbidities making them less active or productive and being more housebound and dependent in their care on other people. This may explain the finding in some studies that women received more bystander CPR than men as they had more chance of being attended by their relatives or the people who were taking care of them. The results of the studies that included the rate of bystander CPR among both genders were not similar in all these registries. It is not clearly understood or explainable. One of the reasons is that although many studies used the Utstein style24, it was not uniformly used in all the studies. A study by Cone et al.25 showed that 6 years after the release of the Utstein style, less than 60% of published studies used this style, making it difficult to compare the results among different regions. Another factor responsible for this inconsistency in the results is the difference in age distribution of the patients in different studies. A study by Kim et al.14 showed that bystander CPR was significantly higher in young women than young men even after adjustment for witnessed arrest, location of arrest, CPR, and response intervals, and this difference will progressively decline as the patients get older. The fact that resuscitation protocols of EMS are not the same in all countries is also a reasonable explanation for this difference, as for example the practice in Japan is to initiate resuscitation in all arrest patients regardless of age, sex or the duration of the arrest state6. The studies that examined the rate of bystander CPR in different age groups among both genders showed that younger women were more likely to receive bystander CPR, even more than young men. It is clear that the rate of bystander CPR strongly related to the rate of witness and location of the arrest state and the victims are more likely to receive resuscitation when they are witnessed or when the arrest happens in public areas or at the workplace. Young women are at a higher chance of having an arrest outside the house 2176
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and have a higher chance of being witnessed and resuscitated than older women and is comparable to men. The female endogenous estrogen and progesterone have a proven neuroprotective effect and decrease the incidence of acute cardiovascular events. This effect on the focal and generalized hypoxic damage on the neuron cell was studied in many experimental and observational studies. A review by McCullough and Hurm26 found that estrogen is a potent neuroprotectant, demonstrating cell salvage from ischemic death pathways. Another experimental randomized study on mice27 showed that 17bestradiol has a critical dosing effect on neuronal survival, and physiologic levels of 17b-estradiol were neuroprotective after cardiac arrest and cardiopulmonary resuscitation. This neuroprotective effect of female gender and female sex hormones can explain the favorable women’s survival rate and higher chance of remaining alive at the scene and admission rate than men. Earlier studies found that women had a higher mortality rate during hospital course, but more recent and larger studies including a larger number of patients and evaluating the outcome after adjustment for other confounding factors found that female gender had a favorable effect on survival rate in the hospital course and discharge rate6,28,29. In addition, Herlitz et al.28, after multivariate analysis, concluded that female sex was an independent predictor for patients being hospitalized alive and for being alive after 1 month. Moreover, Perers et al.29 found that female gender was a significant predictor for patients being brought to hospital alive, both among the total series and among patient found in either ventricular fibrillation or asystole, but this significant association was not evident for survival on discharge. Earlier studies have indicated an increased survival among patients having an OHCA in a public place, which is probably due to higher rates of bystander cardiopulmonary resuscitation, higher rate of witnessed arrests and less comorbidities30–34. The impact of gender on neurological outcome was one of the complex issues to understand as the results of different studies were not consistent. And this was the same for long term survival. One important reason for this conflict is the age of female patients who are included in the studies, which is affected by the age of the population and is not similar in all populations. This was supported by several studies that analyzed the outcome in women among different age groups which revealed that the best favorable 1 month survival and neurological outcome was in females of child bearing age (30–50 years)8,9,21. The protective role of female hormones was therefore raised including its favorable influence on the lipid profile. Iwami et al.13 found that long term survival dropped significantly as patients get older regardless of sex and survival after 1 year will be similar in both sexes. A study assessing the influence of female gender in different age groups on the outcome of cardiac arrest found that women in the www.cmrojournal.com ! 2014 Informa UK Ltd
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reproductive age group (i.e. before menopause) had more favorable long term survival and neurological outcome than men and older women21. A large observational study from Japan6 included all the cardiac arrest cases during the period from January 2005 to December 2007 and studied the influence of sex on the outcome of cardiac arrest. The results were not biased by low EMS response as they have to respond and initiate CPR in all cardiac arrest cases regardless of the age, sex of patients or the duration of the arrest state. This study showed that higher rates of survival and favorable neurologic status were significantly associated with younger age, female sex, witnessed events, bystander cardiopulmonary resuscitation, and attempted defibrillation. Interestingly, Lang et al.35 reviewed the results of the experimental studies on the effect of female sex on the extent of hypoxic damage on the neuronal and cardiac cells and concluded that there is a dichotomous response between male and female animals that is independent of sex hormones. In addition, a study by Kuilman et al.36 on patients discharged after cardiac arrest and followed for 8 years showed that age, female gender and cardiac etiology were independent and significant predictors of long term survival.
Conclusions Our current systematic review shows that female gender seems to offer survival and outcome advantages following out-of-hospital cardiac arrest over male gender after adjustment for age and other risk factors. This is in contrast to most other aspects of heart disease in which women tend to have a worse prognosis. The specific effects of female hormones on different types of rhythms encountered in cardiac arrest warrants further investigations.
Transparency Declaration of funding This study was not funded. Declaration of financial/other relationships A.F.H., J.A.S., A.A.O., W.G., H.A., A.G., and A.M.S. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
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2. Perers E, Abrahamsson P, Bang A. There is a difference in characteristics and outcome between women and men who suffer out of hospital cardiac arrest. Resuscitation 1999;41:133-40 3. Ritter G, Wolfe R, Goldstein S, et al. The effect of bystander CPR on survival of out-of-hospital cardiac arrest victims. Am Heart J 1985;110:932-7 4. Weston C, Wilson R, Jones S. Predicting survival from out-of-hospital cardiac arrest: a multivariate analysis. Resuscitation 1997;34:27-34 5. Hallstrom A, Cobb L, Swain M, et al. Predictors of hospital mortality after out-of-hospital cardiopulmonary resuscitation. Crit Care Med 1993; 13:927-9 6. Akahane M, Ogawa T, Koike S, Tanabe S. The effects of sex on out-of-hospital cardiac arrest outcomes. Am J Med 2011;124:325-333 7. Matsui K, Kojima S, Seino Y, Ogawa H. Gender difference and outcome of witnessed patients with out-of-hospital cardiac arrest: impact of the administered ALS procedures before hospital arrival. Circulation 2010;122:A258 8. Merchant RM, Becker LB, Groeneveld PW, et al. Race and gender disparities in survival to hospital discharge after cardiac arrest. Am Heart J 2011;16:705-11 9. Pell JP, Sirel J, Marsden AK, Cobbe SM. Sex differences in outcome following community-based cardiopulmonary arrest. Eur Heart J 2000;21: 239-44 10. Ahn KO, Shin SD, Huang SS. Sex disparity in resuscitation efforts and outcomes in out-of-hospital cardiac arrest. Am J Emerg Med 2012;30:1810-16 11. Topjian AA, Localio AR, Berg RA. Women of child-bearing age have better inhospital cardiac arrest survival outcomes than do equal-aged men. Crit Care Med 2010;38:1254-60 12. Wigginton JG, Pepe PE, Bedolla JP, et al. Sex-related differences in the presentation and outcome of out-of-hospital cardiopulmonary arrest: a multiyear, prospective, population-based study. Crit Care Med 2002;30:S131-6 13. Iwami T, Hiraide A, Nakanishi N, et al. Age and sex analyses of out-of-hospital cardiac arrest in Osaka, Japan. Resuscitation 2003;57:145-52 14. Kim C, Fahrenbruch CE, Cobb LA, Eisenberg MS. Out-of-hospital cardiac arrest in men and women. Circulation 2001;104:2699-703 15. Bray JE, Stub D, Bernard S, Smith K. Exploring gender differences and the ‘oestrogen effect’ in an Australian out-of-hospital cardiac arrest population. Resuscitation 2013;84:957-63 16. Zheng ZJ, Croft JB, Giles WH, Mensah GA. Sudden cardiac death in the United States, 1989 to 1998. Circulation 2001;104:2158-63 17. Berdowski J, Bergb RA, Tijssena JGP, Koster RW. Global incidences of out-ofhospital cardiac arrest and survival rates: systematic review of 67 prospective studies. Resuscitation 2010;81:1479-87 18. Pleskot M, Babu A, Kajzr J, et al. Characteristics and short-term survival of individuals with out-of-hospital cardiac arrests in the East Bohemian region. Resuscitation 2006;68:209-20 19. Fairbanks RJ, Shah MN, Lerner EB, et al. Epidemiology and outcomes of out-of-hospital cardiac arrest in Rochester, New York. Resuscitation 2007;72:415-24 20. Becker LB, Han BH, Meyer PM, et al.; and the CPR Chicago Project. Racial differences in the incidence of cardiac arrest and subsequent survival. N Engl J Med 1993;329:600-6 21. Kitamura T, Iwami T, Nichol G, et al. Reduction in incidence and fatality of outof-hospital cardiac arrest in females of the reproductive age. Eur Heart J 2010;31:1365-72 22. Lerner DJ, Kannel WB. Patterns of coronary heart disease morbidity and mortality in the sexes: a 26 year follow-up of the Framingham population. Am Heart J 1986;111:383-90 23. Malcom GE, Thompsom TM, Coule PL. The location and incidence of out-ofhospital cardiac arrest in Georgia: implications for placement of automated external defibrillators. Prehospital Emergency Care 2004;8:10-14 24. Cummins RO, Chamberlain DA, Abramson NS, et al. Recommended guidelines for uniform reporting of data from out-of-hospital cardiac arrest: the Utstein style. A statement for health professionals from a task force of the American Heart Association, the European Resuscitation Council, the Heart and Stroke Foundation of Canada, and the Australian Resuscitation Council. Circulation 1991;84:960-75
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