Sex difference on neurological outcomes and post-cardiac arrest care in out-of-hospital cardiac arrest patients treated with targeted temperature management

doi:10.21203/rs.3.rs-1992890/v1

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Sex difference on neurological outcomes and post-cardiac arrest care in out-of-hospital cardiac arrest patients treated with targeted temperature management

https://doi.org/10.21203/rs.3.rs-1992890/v1

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Background: Conflicting results regarding sex-based differences in the outcomes of out-of-hospital cardiac arrest (OHCA) patients have been reported. Furthermore, no study has examined whether differences in in-hospital interventions and courses are driven by sex. This study evaluated the effect of sex on the in-hospital course as well as the survival rates and long-term neurological outcomes of OHCA patients treated with targeted temperature management.

Methods: We retrospectively analyzed the Korean Hypothermia Network Prospective Registry composed of data collected from 22 hospitals in Korea between October 2015 and December 2018. To evaluate the effect of sex on patient outcomes, we created various multivariate logistic regression models. Regarding the difference in in-hospital courses, we compared daily total and SOFA sub-scores between the sexes and analyzed whether the decision regarding early cardiac interventions and limitations in in-hospital care were associated with sex.

Results: The rate of good neurological outcomes after 6 months was higher in men (OR = 1.66, 95% CI: 1.26 2.17). However, when the results were adjusted using resuscitation variables and in-hospital variables were added, there was no significant difference between the two sexes (OR =1.22, 95% CI: 0.85 – 1.74; OR = 1.13, 95 CI: 0.76 – 1.68, respectively). There was no association between sex and outcome in patients of reproductive age and no interaction between age and sex. Regarding the in-hospital course, the daily total SOFA score was similar in both sexes whereas cardiovascular scores were higher in women on 2 and 3 days (on day 2, p = 0.006; on day 3, p = 0.017). The adjusted effect of sex was not associated with the clinician’s decision to perform early cardiac interventions except that men had more extracorporeal membrane oxygenation (ECMO) (OR=2.51, 95% CI: 1.11-5.66). The decision to discontinue life-sustaining treatment was determined by poor prognostic factors, not by sex.

Conclusions: The findings suggested that men had more favorable 6-month neurological outcomes. However, after adjusting for confounders, there was no difference between the sexes. The results regarding in-hospital course were similar in men and women.

Out-of-hospital cardiac arrest

Sex

In-hospital course

Targeted temperature management

Sex-based differences regarding disease prevalence, manifestation, and response to treatment are rooted in the genetic differences between men and women [1]. Especially, in cardiovascular disease, sex differences in symptoms and underlying pathophysiology have been increasingly recognized [2, 3], and have been used to improve health care. However, sex differences in survivors after out-of-hospital cardiac arrest (OHCA) remain unclear despite an increasing number of studies and the substantial public health burden[4].

Previous reports regarding sex differences have been conducted in heterogeneous populations, with the majority based on emergency medical service-attended OHCA [5-7], and others conducted on those who survived and were admitted to a hospital [8-10]. Consequently, the majority have mainly focused on outcomes at hospital discharge and the results regarding the association between sex and outcomes are conflicting. Several studies showed better outcomes in men or women [5, 6], some demonstrated comparable outcomes [7-10], and other studies reported better outcomes in women of reproductive age [11]. Surprisingly, these conflicting results exist in recent meta-analysis studies [12-14]. Post-cardiac arrest syndrome after OHCA is a heterogeneous disease entity with various causes and severities, and especially, the pre-hospital patient care and processes are uncontrolled. The in-hospital processes including disposition and therapeutic interventions that follow are also diverse. Although standard care including targeted temperature management (TTM) and early coronary angiography (CAG) is currently recommended for these patients [15], most previous reports could not adjust for various in-hospital interventions [16], which affect in-hospital interim outcomes and eventually, long-term neurological outcomes. Therefore, discrepancies in the outcomes among the published studies may be explained by different patient selection or incomplete analysis [6]. Furthermore, in-hospital death in OHCA patients usually results from the withdrawal of life-sustaining therapy (WLST) with or without a waiting period for neurological improvement [17]. While men and women may differ in their preference for life-sustaining treatments (LSTs) as a function of the specific type of illness for which LSTs are considered [18], limited studies have examined the differences in decisions regarding end-of-life in survivors of OHCA by sex. To determine the effect of sex differences, long-term neurological outcomes should be assessed after adjusting for pre-arrest and arrest characteristics and in-hospital processes, and comparisons of in-hospital conditions, resource consumption, and decisions regarding LST are essential.

In this study, we used a large prospective registry that recorded the details of post-cardiac arrest care and evaluated the effects of sex in comatose OHCA patients treated with TTM. Our primary aim was to evaluate the adjusted effect of sex on 6-month neurological outcomes. The secondary aim was to investigate the difference in in-hospital processes between men and women by comparing changes in daily Sequential Organ Failure Assessment (SOFA) scores, resource consumption, decisions regarding LST during hospitalization, and survival to discharge.

Study design and setting

This was a prospective, multicenter, observational cohort study based on the Korean Hypothermia Network Prospective Registry 1.0 (KORHN-PRO 1.0), which is a web-based registry of OHCA patients treated with TTM. From October 2015 to December 2018, 22 participating hospitals in South Korea enrolled 1373 adult OHCA patients (≥ 18 years old) who were unconscious after the return of spontaneous circulation (ROSC) and treated with TTM. The KORHN-PRO 1.0 protocol was approved by the Institutional Review Board of each hospital and was registered in the clinical trial registry platform (NCT02827422). Details on the KORHN-PRO 1.0 study design, protocol, and results have been published [19]. Informed consent was obtained from the patients’ legal relatives. The current study included all adult patients with sex information in the registry. The exclusion criterion was missing data on neurological outcomes after 6 months.

Variables

All variables were extracted from the KORHN-PRO 1.0 registry. Patient baseline characteristics, including sex information, age, and comorbidities such as acute myocardial infarction (AMI), angina pectoris, congestive heart failure (CHF), arrhythmia, stroke, hypertension, diabetes mellitus, chronic lung disease, chronic kidney disease (CKD), liver cirrhosis, and malignancy were collected. Each comorbidity was integrated into a modified comorbidity index (mCI) value based on the Charlson comorbidity index (CCI), which was validated as the degree of comorbidity in these patients by Winther et al [20].

The following resuscitation variables were collected: the location of the arrest, whether the arrest was witnessed, bystander cardiopulmonary resuscitation (CPR), initial arrest rhythm (shockable versus non-shockable), arrest etiology (cardiac versus non-cardiac), and arrest time (duration from collapse to ROSC).

As in-hospital variables, we investigated the initial electrocardiogram (ECG) after ROSC (ST-segment elevation myocardial infarction [STEMI]/LBBB [left bundle branch block] or not) and cardiac interventions (early CAG, percutaneous coronary intervention [PCI], intra-aortic balloon pumping [IABP] and echocardiography, and extracorporeal membrane oxygenation [ECMO]). Early intervention was defined as that performed within 24 h after ROSC. Whether the patients underwent the following prognostic tests were also determined: brainstem reflexes (both pupillary light reflex and corneal reflex) on day 4, brain computed tomography (CT) or diffusion-weighted image (DWI), electroencephalography (EEG), serum level of neuron-specific enolase (NSE), and somatosensory evoked potential (SSEP). The prognosis was considered poor when there was one abnormal result for any single predictor (the absence of brainstem reflexes, injury on brain CT or DWI, highly malignant EEG, high NSE level, and absence of the N20 wave on SSEP). We also used the multimodal algorithm recommended by the European Resuscitation Council/European Society of Intensive Care Medicine considering a combination of ≥ 2 abnormal results on any prognostic tests to indicate a poor outcome [15, 21].

Survival to hospital discharge, daily Sequential Organ Failure Assessment (SOFA) score, and six sub-scores (respiration, coagulation, liver, cardiovascular, central natural system, and renal) were assessed as interim outcomes [22]. We assessed whether there was any decision regarding LSTs, which consisted of WLST, withholding LST, do-not-perform essential tests, and do-not-attempt CPR (DNAR) orders, and were pre-defined as original KORHN-PRO variables.

Outcome measures

The primary outcome was a good neurological outcome defined as a Glasgow-Pittsburgh cerebral performance category (CPC) of 1 or 2 after 6 months. The secondary outcomes were in-hospital processes (early cardiac diagnostic and therapeutic interventions, prognostic tests, and decisions regarding LST) and interim outcomes (daily organ injury severity scores and survival to hospital discharge).

Statistical analysis

The categorical variables are presented as the total number of patients and the proportion of patients, and the continuous variables are reported as the mean ± standard deviation. To compare patient characteristics between the two groups, we used the chi-squared test and the Student’s t-test.

To evaluate the effect of sex differences on the primary outcome, logistic regression models were used to assess the factors independently associated with good neurological outcomes. Baseline characteristics, resuscitation, and in-hospital factors were sequentially adjusted to evaluate the effect of sex on the outcomes. After univariate analysis, the variables of interest or those with a possible predictive value (p < 0.05) were entered into a multivariate logistic regression analysis, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. An interaction term (age × sex) was included in the multivariate logistic regression model to compensate for the effect of age on outcomes. To determine whether there was a difference according to reproductive age, the two sexes were compared by dividing them into groups aged less than 50 and more than 50 years. To investigate the effect of sex differences on in-hospital processes and interim outcomes, multivariate logistic regression was also performed using covariates. We used analysis of covariance (ANCOVA) for the adjustment covariates to evaluate the effect of sex differences on the daily total SOFA scores and six sub-scores.

All statistical analyses were performed using IBM SPSS version 24 software (IBM, Armonk, NY, USA). All p-values were two-tailed, and p < 0.05 was considered significant.

Of 10,258 patients experiencing OHCA during the study period, 1373 were registered in the KORHN-PRO registry. Among these, 34 were excluded from the analysis due to missing 6-month neurological outcomes. Of the remaining 1339 patients, 952 (71.1%) were men and 387 (28.9%) were women. After 6 months, 412 (30.8%) had good neurological outcomes and the other 927 (69.2%) had poor outcomes (Fig. 1).

Comparison Of Patient Variables Between Men And Women

Table 1 shows the characteristics of the study participants according to sex. The mean age of the men and women was 58.2 ± 15.2 and 57.5 ± 17.0 years, respectively (p = 0.433). A history of AMI was more common in men (7.6% vs 3.6%, p = 0.008), and CHF and CKD were more common in women (2.9% vs. 5.9%, p = 0.009; 6.5% vs 10.3%, p = 0.017, respectively). However, in the analysis using mCI values, the comorbidity burden was similar between the sexes. In the arrest situation, men were more likely to experience witnessed cardiac arrest (72.3% vs. 62.3%, p < 0.001) and in places other than at home (48.0% vs. 59.4%, p < 0.001). The likelihood of shockable rhythm and cardiac etiology arrest was significantly higher in men (40.1% vs. 24.3%, p < 0.001; 65.8% vs. 52.5%, p < 0.001, respectively). In the hospital, STEMI or LBBB was more common in men (16.9% vs. 9.0%, p < 0.001), and early CAG and PCI, and ECMO were more frequently performed in men (31.0% vs. 19.8%, p < 0.001; 18.4% vs. 7.5%, p < 0.001; 5.8% vs 1.8%, p = 0.002, respectively). There were no differences between the sex groups in the rate of prognostic tests and other interventions. The rate of decisions regarding LSTs was similar in both sexes. The most common reason for limiting LST was DNAR orders in both sexes (165 cases [17.3%] in men and 71 cases [18.3%] in women), followed by withholding LST (n = 26), WLST (n = 12), and do not essential test (n = 9). Finally, the survival rate to hospital discharge was not different, but the rate of good neurological outcomes after 6 months was higher in men (33.7% vs. 23.5%, p < 0.001).

Table 1

Characteristics of the study participants by sex.
	Men (n = 952)	Women (n = 387)	p
Age, years	58.2 ± 15.2	57.5 ± 17.0	0.433
Comorbidity
Acute myocardial infarction	72 (7.6)	14 (3.6)	0.008
Angina pectoris	57 (6.0)	22 (5.7)	0.831
Congestive heart failure	28 (2.9)	23 (5.9)	0.009
Arrhythmia	49 (5.1)	16 (4.1)	0.434
Stroke	47 (4.9)	26 (6.7)	0.193
Hypertension	330 (34.7)	151 (39.0)	0.132
Diabetes mellitus	231 (24.3)	95 (24.5)	0.913
Chronic lung disease	63 (6.6)	24 (6.2)	0.779
Chronic renal disease	62 (6.5)	40 (10.3)	0.017
Liver cirrhosis	18 (1.9)	4 (1.0)	0.263
Malignancy	46 (4.8)	25 (6.5)	0.228
mCI
mCI 0	541 (56.8)	227 (58.7)	0.540
mCI 1	223 (23.4)	74 (19.1)	0.086
mCI 2	101 (10.6)	44 (11.4)	0.685
mCI 3	87 (9.1)	42 (10.9)	0.335
Arrest at home	457 (48.0)	230 (59.4)	< 0.001
Witnessed	688 (72.3)	241 (62.3)	< 0.001
Bystander CPR	591 (62.1)	231 (59.7)	0.415
Shockable rhythm	382 (40.1)	94 (24.3)	< 0.001
Cardiac cause	626 (65.8)	203 (52.5)	< 0.001
Arrest time, min*	27.0 ± 14.5	27.0 ± 14.9	0.894
GCS motor grade > 2	155 (16.4)	44 (11.4)	0.022
Brainstem reflex	162 (17.0)	54(14.0)	0.190
Shock on TTM	481 (50.5)	207 (53.5)	0.378
SOFA score on day 1			0.208
4–7	65 (6.8)	33 (8.5)
8–12	313 (32.9)	140 (36.2)
≥12	574 (60.3)	214 (55.3)
STEMI or new onset LBBB	161 (16.9)	35 (9.0)	< 0.001
Early coronary angiography	295 (31.0)	73 (19.8)	< 0.001
Early percutaneous coronary intervention	175 (18.4)	29 (7.5)	< 0.001
Early echocardiography	520 (54.6)	192 (49.6)	0.096
Extracorporeal membrane oxygenation	55 (5.8)	7 (1.8)	0.002
Intra-aortic balloon pumping	8 (0.8)	0 (0.0)	0.070
Brain computed tomography	874 (91.8)	364 (94.1)	0.158
Brain diffusion-weighted imaging	458 (48.1)	191 (49.4)	0.679
Electroencephalography	487 (51.1)	204 (52.4)	0.656
Somatosensory evoked potential	181 (19.0)	81 (20.8)	0.423
Neuron-specific enolase	411 (43.1)	153 (39.3)	0.201
Electrophysiology study	24 (2.5)	12 (3.1)	0.552
Implantable cardioverter-defibrillator	68 (7.1)	28 (7.2)	0.953
Limitations of active treatments	182 (19.1)	79 (20.4)	0.587
Withdrawal of life-sustaining therapy	10 (1.1)	2 (0.5)	0.348
Do-not-escalate	19 (2.0)	7 (1.8)	0.822
Do-not-essential-test	4 (0.4)	5 (1.3)	0.077
Do-not-attempt-CPR	165 (17.3)	71 (18.3)	0.659
Survival discharge	520 (54.6)	203 (52.5)	0.506
6-month survival	406 (42.6)	138 (35.7)	0.020
6-month good neurological outcome^†	321 (33.7)	91 (23.5)	< 0.001
*Collapse-to-ROSC interval.
^†Good neurological outcome is defined as cerebral performance category 1 or 2.
mCI, modified Charlson comorbidity index; CPR, cardiopulmonary resuscitation; GCS, Glasgow coma scale; TTM, targeted temperature management; SOFA, Sequential Organ Failure Assessment; STEMI, ST elevation myocardial infarction; LBBB, left bundle branch block.

Effect Of Sex On 6-month Good Neurological Outcomes And Survival To Discharge

Logistic regression models were used to compare the outcomes between men and women patients. The ORs for good neurological outcomes after 6 months and survival to discharge in men were calculated by univariate analysis and various multivariate models including the baseline characteristics, resuscitation, and in-hospital factors (Table 2). The details of the variables entered into each model are presented in additional file 1–6. The 6-month neurological outcomes seemed to be better in men before adjustment (OR = 1.66, 95% CI: 1.26–2.17). This effect of sex was still significant after adjusting for pre-arrest variables (age and mCI) in model 1 (OR = 1.78, 95% CI: 1.34–2.35). However, when the results were adjusted using resuscitation variables (model 2) and in-hospital variables were added (model 3), there was no significant difference between the two sexes (OR = 1.22, 95% CI: 0.85–1.74; OR = 1.10, 95 CI: 0.74–1.64, respectively).

In contrast, the effect of sex on survival to discharge was not significant in either univariate or multivariate analysis (all p-values > 0.05) (Table 2).

The interaction between sex and age was not significant for either good neurological outcomes or survival to discharge (all p-values > 0.05). We also performed a stratified analysis according to different age groups (less than 50 years of age and older than 50 years of age) (Table 3). The probability of better 6-month neurological outcomes in men was higher in both age groups (age < 50, OR = 1.80, 95% CI: 1.15–2.80, for age ≥ 50, OR = 1.72, 95% CI: 1.21–2.44) but this was not significant after adjusting for all covariates (OR = 1.49, 95% CI: 0.72– 3.06, p = 0.279; OR = 1.05, 95% CI: 0.62–1.76, p = 0.866, respectively). There was no sex difference in survival to discharge in either univariate or multivariate analysis.

Table 2

Odd ratio for men sex for 6-month good neurological outcome and survival at discharge by logistic regression.
	Univariate		Model 1		Model 2		Model 3
	OR (95% CI)	p	OR (95% CI)	p	OR (95% CI)	p	OR (95% CI)	p
Good neurological outcome	1.66 (1.26–2.17)	< 0.001	1.78 (1.34–2.35)	< 0.001	1.22 (0.85–1.74)	0.276	1.10 (0.74–1.64)	0.626
Survival discharge	1.09 (0.86–1.38)	0.471	1.12 (0.88–1.42)	0.363	0.87 (0.66–1.13)	0.284	0.82 (0.61–1.11)	0.205
Model 1: For a good neurological outcome, adjusted by baseline characteristics including men sex, age and modified Charlson comorbidity index. For a survival discharge, adjusted by basic characteristics including men sex, age and modified Charlson comorbidity index.
Model 2: For a good neurological outcome, adjusted by variables of model 1 and resuscitation variables including arrest at home, witnessed, bystander cardiopulmonary resuscitation, shockable rhythm, cardiac cause and arrest time. For a survival discharge, adjusted by variables of model 1 and resuscitation variables including arrest at home, witnessed, bystander cardiopulmonary resuscitation, shockable rhythm, cardiac cause and arrest time
Model 3: For a good neurological outcome, adjusted by variables of model 2 and in-hospital variables including initial ECG, early CAG, PCI, echocardiography, SOFA score on day 1, and limitations of active treatment. For a survival discharge, adjusted by variables of model 2 and in-hospital variables including initial ECG, early CAG, PCI, echocardiography, ECMO, SOFA score and limitations of active treatment.

Table 3

A good neurological outcome after targeted temperature management, stratified by sex and age.
	Age < 50 years (men = 260, women = 131)	p	Age ≥ 50 years (men = 692, women = 256)	p
Good neurological outcome
Women	41 (31.3)	0.009	50 (19.5)	0.002
Men	117 (45.0)		204 (29.5)
Crude OR (95% CI)	1.80 (1.15–2.80)	0.010	1.72 (1.21–2.44)	0.002
Adjusted OR^† (95% CI)	1.49 (0.72–3.06)	0.279	1.05 (0.62–1.76)	0.866
Survival discharge
Women	79 (60.3)	0.988	124 (48.4)	0.272
Men	157 (60.4)		363 (52.5)
Crude OR (95% CI)	1.00 (0.65–1.54)	0.988	1.18 (0.88–1.57)	0.272
Adjusted OR* (95% CI)	0.84 (0.47–1.51)	0.565	0.84 (0.57–1.22)	0.353
*ORs are adjusted for modified Charlson comorbidity index, arrest at home, witnessed, bystander CPR, shockable rhythm, cardiac cause, arrest time, initial ECG, early CAG, PCI, echocardiography, SOFA score and limitations of active treatment.
^†ORs are adjusted for modified Charlson comorbidity index, arrest at home, witnessed, bystander CPR, shockable rhythm, cardiac cause, arrest time, initial ECG, early CAG, PCI, echocardiography, ECMO, SOFA score and limitations of active treatment.

OR, odds ratio; CI, confidence interval.

Effect Of Sex On In-hospital Processes And Other Interim Outcomes

Among 829 patients with presumed cardiac etiology arrests, men more commonly underwent early CAG (OR = 1.61, 95% CI: 1.16–2.24) according to the univariate analysis results (Table 4). But after adjusting for confounders, the effect of the men sex was not significant (OR = 1.18, 95% CI: 0.82–1.69). In patients who underwent early CAG, PCI was more frequently performed in men (OR = 1.88, 95% CI: 1.10–3.21). However, this effect of sex was not significant when adjusting for confounders (OR = 1.25, 95% CI: 0.56–2.80). Early echocardiography was not associated with a specific sex in univariate or multivariate analysis (OR = 1.16, 95% CI: 0.89–1.51; OR = 1.02, 95% CI: 0.77–1.35, respectively) (Table 4). In contrast, the adjusted OR of men for ECMO was 2.51 (95% CI: 1.11–5.66).

Six hundred seventy-two patients underwent multimodal prognostic tests. Of these, we assessed the independent predictors for decisions regarding LST in two models that included single and multimodal predictors, respectively (Table 5). While older age, the absence of brainstem reflex and SSEP response, or abnormal results in more than two predictors were associated with decisions regarding LST, the men sex had no effect on these decisions in either model (OR = 1.20, 95% CI: 0.77–1.88, OR = 1.17, 95% CI: 0.76–1.82, respectively) (Table 5).

Daily total SOFA scores tended to gradually decrease in both sexes and there was no difference between the sexes. In the analysis of the six sub-scores, the mean values of several sub-scores were different between the sexes (Fig. 2). After adjusting for confounders such as age, comorbidities (mCI value), shockable rhythm, arrest time, cardiac etiology arrest, and STEMI/LBBB, we found that cardiovascular sub-scores on hospital days 2 and 3 were higher in women than those in men (on day 2, p = 0.006; on day 3, p = 0.017). Nonetheless, liver and renal sub-scores were higher in men than in women 3 days (all p-values < 0.05).

Table 4

Associating factors for undergoing early cardiac diagnostic and therapeutic interventions in out-of-hospital cardiac arrest patients with targeted temperature management.
	Early coronary angiography(n = 829)				Early PCI(n = 368)				Early echocardiography				ECMO
	Univariate		Multivariate		Univariate		Multivariate		Univariate		Multivariate		Univariate		Multivariate
	OR (95% CI)	P	OR (95% CI)	P	OR (95% CI)	P	OR (95% CI)	P	OR (95% CI)	P	OR (95% CI)	P	OR (95% CI)	P	OR (95% CI)	P
Men sex	1.61 (1.16–2.24)	0.005	1.18 (0.82–1.69)	0.373	1.88 (1.10–3.21)	0.021	1.25 (0.56–2.80)	0.584	1.16 (0.89–1.51)	0.278	1.02 (0.77–1.35)	0.888	3.33 (1.50–7.38)	0.003	2.51 (1.11–5.66)	0.027
Age, per year	1.00 (0.99–1.00)	0.273			1.02 (1.01–1.04)	0.004	1.01 (0.99–1.04)	0.363	1.00 (0.99–1.01)	0.915			0.99 (0.97–1.00)	0.057
mCI 0	Ref
mCI 1	0.89 (0.63–1.25)	0.502	0.97 (0.66–1.42)	0.868	0.92 (0.56–1.52)	0.755			0.96 (0.71–1.29)	0.768			0.88 (0.46–1.68)	0.696
mCI 2	0.61 (0.39–0.96)	0.034	0.69 (0.42–1.15)	0.154	0.66 (0.32–1.37)	0.263			0.96 (0.64–1.42)	0.820			0.83 (0.34–2.00)	0.677
mCI 3	0.45 (0.26–0.77)	0.004	0.76 (0.41–1.39)	0.365	1.45 (0.61–3.44)	0.402			1.13 (0.75–1.69)	0.563			0.78 (0.30–2.01)	0.599
Witnessed	1.07 (0.75–1.52)	< 0.001	0.83 (0.56–1.23)	0.351	2.03 (1.18–3.48)	0.010	1.24 (0.54–2.85)	0.615	1.65 (1.26–2.17)	< 0.001	1.34 (1.00–1.80)	0.049	1.40 (0.78–2.54)	0.263
Bystander CPR	1.11 (0.83–1.47)	0.100			0.95 (0.62–1.46)	0.817			1.17 (0.92–1.50)	0.209			1.15 (0.68–1.96)	0.605
Shockable rhythm	2.44 (1.83–3.25)	< 0.001	1.92 (1.37–2.67)	< 0.001	2.46 (1.57–3.85)	< 0.001	3.64 (1.83–7.27)	< 0.001	1.69 (1.33–2.16)	< 0.001	1.16 (0.85–1.56)	0.351	3.03 (1.80–5.15)	< 0.001	1.35 (0.75–2.41)	0.317
Arrest time, min*	1.00 (0.99–1.01)	0.701			0.99 (0.98–1.01)	0.285			0.99 (0.99–1.00)	0.166			1.01 (1.00–1.03)	0.104
Cardiac etiology arrest	NA				NA				2.07 (1.59–2.68)	< 0.001	1.64 (1.19–2.26)	0.002	9.52 (3.43–26.37)	< 0.001	5.51 (1.85–16.38)	0.002
Motor grade > 2	1.86 (1.32–2.63)	< 0.001	1.55 (1.03–2.34)	0.037	0.82 (0.51–1.32)	0.414			1.42 (1.03–1.96)	0.031	1.09 (0.92–1.82)	0.138	1.08 (0.54–2.17)	0.824
Brainstem reflex	1.77 (1.27–2.47)	0.001	1.16 (0.78–1.74)	0.467	1.40 (0.87–2.23)	0.163			1.22 (0.89–1.67)	0.215			1.71 (0.94–3.11)	0.080
STEMI or LBBB	4.99 (3.48–7.15)	< 0.001	4.76 (3.25–6.97)	< 0.001	5.62 (3.53–8.95)	< 0.001	3.81 (1.95–7.47)	< 0.001	1.70 (1.24–2.33)	0.001	1.29 (0.92–1.82)	0.138	5.44 (3.21–9.20)	< 0.001	3.24 (1.85–5.67)	< 0.001
Shock on TTM	1.23 (0.93–1.62)	0.144			0.89 (0.59–1.34)	0.585			0.77 (0.61–0.98)	0.032	0.81 (0.63–1.04)	0.101	2.22 (1.28–3.85)	0.005	2.64 (1.50–4.67)	0.001
Stenosis ≥ 50%^†	NA				197.64 (47.44–823.44)	< 0.001	171.26 (39.71–738.51)	< 0.001	NA				NA
*Time from arrest to ROSC, min
^† mCI, modified Charlson comorbidity index; CPR, cardiopulmonary resuscitation; GCS, Glasgow coma scale; STEMI, ST elevation myocardial infarction; LBBB, left bundle branch block; TTM, targeted temperature management; PCI; percutaneous coronary intervention, ECMO; extracorporeal membrane oxygenation.

Table 5

Associating factors with decision regarding life sustaining therapy in patients who underwent multimodal prognostic tests according to resuscitation guidelines (n = 672)
	Univariate analysis			Multivariate analysis
	OR	95% CI	P	OR	95% CI	P
Model 1
Age, per year	1.02	1.00–1.03	0.013	1.02	1.00–1.03	0.029
Men	1.15	0.75–1.78	0.523	1.20	0.77–1.88	0.419
mCI
mCI 0	Ref
mCI 1	1.38	0.84–2.27	0.204	1.17	0.69–1.98	0.560
mCI 2	1.50	0.80–2.82	0.207	1.32	0.67–2.59	0.418
mCI 3	1.76	0.95–3.23	0.071	1.58	0.83–3.01	0.168
Absence of brainstem reflexes	2.17	1.44–3.27	< 0.001	2.03	1.33–3.11	0.001
Injury on Brain CT or MRI	1.21	0.81–1.81	0.358
Highly malignant EEG	1.04	0.66–1.63	0.880
High NSE levels	1.25	0.84–1.87	0.274
Absent SEP	2.10	1.30–3.38	0.002	1.95	1.19–3.21	0.009
Model 2
Age, per year	1.02	1.00–1.03	0.013	1.02	1.00–1.03	0.033
Men	1.15	0.75–1.78	0.523	1.17	0.76–1.82	0.478
mCI
mCI 0	Ref
mCI 1	1.38	0.84–2.27	0.204	1.27	0.76–2.13	0.370
mCI 2	1.50	0.80–2.82	0.207	1.30	0.67–2.51	0.443
mCI 3	1.76	0.95–3.23	0.071	1.61	0.85–3.05	0.141
≥ two of poor predictors	1.81	1.17–2.82	0.008	2.00	1.28–3.13	0.002

In this multicenter registry-based study, we evaluated the effect of sex differences on long-term neurological outcomes, in-hospital processes including resource consumption, and other interim outcomes among adult OHCA patients treated with TTM. Although in univariate analysis it seemed that men had better 6-month neurological outcomes, when adjusted for confounders, the difference was not statistically significant. Resource consumption including prognostic tests and cardiac interventions except for ECMO and limiting LST was not different between the sexes. In contrast, we found sex differences in the daily injury severity scores of cardiovascular, liver, and renal organs.

Our final findings were consistent with those of previous studies and strengthen the evidence that sex has no effect on neurological outcomes in TTM patients after OHCA [8–10]. Although overall, men were significantly more likely to have a good neurological outcome after 6 months than women, there were several differences in pre-arrest, intra-arrest, and post-arrest factors between the sexes. Men had more AMI as comorbidity, whereas women had more CHF and CKD. A higher proportion of men experienced cardiac arrest in a public place, were witnessed, presented with shockable arrest rhythm, and had presumed cardiac etiology arrest. The effect of sex on neurological outcomes remained in multivariate logistic regression after adjusting for demographic variables. However, after adjusting for resuscitation and in-hospital confounding variables, sex did not influence neurological outcomes in these patients.

Several hypotheses could explain the conflicting results regarding the association between sex and outcomes following OHCA in previous studies [5–11]. Our study differed from most other studies in that we only included OHCA patients treated with TTM after ROSC, which allowed us to analyze various factors including in-hospital processes, and accordingly, adjust for these factors. In contrast, studies conducted on entire populations in which CPR was attempted seemed to show better outcomes in men compared to women. Interestingly, hospital-based studies and those only or predominantly including patients treated with TTM consistently demonstrated similar outcomes between sexes [8–10]. Estrogens can provide significant neuroprotective effects [23, 24]. Some clinical studies also demonstrated that women had good neurological outcomes compared to men, especially at reproductive ages [11]. One explanation might be that the neuroprotective effect of endogenous estrogen is attenuated or underestimated in the human TTM setting using clinical measures of neurological function. This can be partially explained that studies in which women have better outcome than men had lower TTM application rates[25]. Another possible cause is the age difference of the patients enrolled in the studies. However, our cohort was the youngest in the published literature, and sex did not influence the neurological outcomes in the stratified analysis or in interaction analysis with age. Nonetheless, our results cannot be extended to OHCA patients in which CPR was attempted because women usually have a higher rate of ROSC after OHCA considering unfavorable resuscitation factors [26, 27]. A future clinical trial of exogenous estrogen administration should be conducted to determine the effects of extra estrogen on a subgroup of reproductive age women.

As previous studies usually presented identifiable interim outcomes, we compared survival to discharge and daily total SOFA scores and six sub-scores between the sexes. To our knowledge, the present study was the first clinical report to describe the sex-specific impact on daily patient severity using organ severity scores. Several findings are interesting to clinicians. In contrast to total SOFA scores, several sub-scores differed between the sexes for 3 days after ROSC. In particular, cardiovascular instability on days 2 and 3 in women was driven by sex differences. Considering the wide range of cardiovascular sub-scores compared to other sub-scores, different management strategies are warranted according to sex.

This study had several strengths in understanding sex-based differences in these patients. In addition to the analysis of sex as a confounder influencing final outcomes, we investigated whether men and women were treated equally by analyzing in-hospital processes. First, we evaluated the rates of cardiac diagnostic and therapeutic interventions in both sexes. While coronary catheterization is currently used as the standard of care for post-cardiac arrest, previous studies showed that the adjusted rates of early CAG were significantly lower in women than in men [8, 28, 29]. In this study, early CAG and PCI were likely to be underutilized in women. However, these were explained by higher proportions of shockable rhythm, and STEMI/LBBB on ECG, or more severe obstruction findings on CAG. Considering that women had more CHF before OHCA and cardiovascular instability during early hospital care, early echocardiography and ECMO could be beneficial in women. However, our results showed that a higher proportion of men underwent ECMO. Second, irrespective of biological disparities, health disparities can be affected by differences in resource consumption according to social determinants such as sex. However, in our results, men and women did not experience inequity with respect to prognostic evaluations. Third, currently, little information is available regarding the rates of WLST and limiting LST in men and women. Some previous studies, which identified that women were less likely to survive to hospital discharge after OHCA, postulated that this was due to increased WLST [30, 31]. However, no study has included the results of prognostic tests to analyze the impact of sex on end-of-life decisions. In univariate analysis, women had rates of WLST and other limiting LST similar to those of men, which is in contrast to some previous studies but not others [8, 32]. When evaluating the independent factors of decisions regarding LST by multivariate logistic regression, the increase in age and the absence of brainstem reflex and an N20 peak on SSEP (or > 2 poor outcome predictors) were associated but not sex.

There were a number of limitations to this study. First, although our study included more in-depth investigation from pre-arrest to 6 months after ROSC, the nature of retrospective analysis inevitably leads to selection bias, information bias, and other confounders are unavoidable. Second, survival from OHCA to admission is an important interim outcome in understanding sex differences in OHCA, and consequently, the impact on long-term neurological outcomes. However, our registry did not include these details. Thus, the findings must be cautiously interpreted in comparison to other studies. Third, our data included few numbers of death after WLST, which was the most common mode of death in Western studies. Therefore, the cultural context of South Korea should be considered in interpreting our results regarding the effect of sex differences on end-of-life decisions. Fourth, healthcare costs, which could be an obstacle to appropriate in-hospital processes, were not considered in this study. Nonetheless, we tried to adjust for the identifiable differences in pre-arrest, intra-arrest characteristics, and all in-hospital processes, and our results could help decide treatment strategies according to sex.

In this registry-based study of comatose OHCA survivors treated with TTM, men and women patients differed in factors associated with outcomes, and men were likely to have good 6-month neurological outcomes. However, after adjustment for confounders, the men sex was not associated with good neurological outcomes. Among the interim outcomes, daily organ injury severity scores, especially cardiovascular, differed between the sexes after adjusting for covariates. The adjusted sex effect on resource consumption and decisions regarding LST was not significant except for the use of ECMO.

OHCA, out-of-hospital cardiac arrest; mCI, modified Charlson comorbidity index; CCI, Charlson comorbidity index; CPR, cardiopulmonary resuscitation; TTM, targeted temperature management; WLST, withdrawal of life-sustaining therapy; LSTs, life-sustaining treatments; DNAR, do-not-attempt CPR; ROSC, return of spontaneous circulation; AED, automated external defibrillator; GCS, Glasgow coma scale; ECG, electrocardiogram; AMI, acute myocardial infarction; CHF, congestive heart failure; SOFA, Sequential Organ Failure Assessment; CAG, coronary angiography; STEMI, ST elevation myocardial infarction; LBBB, left bundle branch block; CT, computed tomography; DWI, diffusion weighted image; EEG, electroencephalography; NSE, neuron-specific enolase; SSEP, somatosensory provoked potential; CPC, cerebral performance category; PCI, percutaneous coronary intervention; ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon pumping; KORHN-PRO: Korean Hypothermia Network of Prospective registry.

Ethics approval and consent to participate

The current study was approved by the institutional review board of each participating hospitals, and informed consent was obtained from all participants or relatives.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding authors on reasonable request.

Competing interests

All authors declare that they have no competing interests.

Funding

All authors received no specific funding for this work.

Authors’ contributions

SYP contributed to data analysis, interpretation and writing of the manuscript. SHO and SHK contributed to the study design, patient enrollment, data interpretation and writing of the manuscript. SHP and JHO contributed to patient enrollment and manuscript writing/editing. All authors read and approved the final manuscript.

Acknowledgements

The following investigators participated in the Korean Hypothermia Network. Network chair: Seung Pill Choi (The Catholic University of Korea, Eunpyeong St. Mary’s Hospital); principal investigators of each hospital: Kyu Nam Park (The Catholic University of Korea, Seoul St. Mary’s Hospital), Minjung Kathy Chae (Ajou University Medical Center), Won Young Kim (Asan Medical Center), Byung Kook Lee (Chonnam National University Hospital), Dong Hoon Lee (Chung-Ang University Hospital), Tae Chang Jang (Daegu Catholic University Medical Center), Jae Hoon Lee (Dong-A University Hospital), Yoon Hee Choi (Ewha Womans University Mokdong Hospital), Je Sung You (Gangnam Severance Hospital), Young Hwan Lee (Hallym University Sacred Heart Hospital), In Soo Cho (Hanil General Hospital), Su Jin Kim (Korea University Anam Hospital), Jong-Seok Lee (Kyung Hee University Medical Center), Yong Hwan Kim (Samsung Changwon Hospital), Min Seob Sim (Samsung Medical Center), Jonghwan Shin (Seoul Metropolitan Government Seoul National University Boramae Medical Center), Yoo Seok Park (Severance Hospital), Hyung Jun Moon (Soonchunhyang University Hospital Cheonan), Won Jung Jeong (The Catholic University of Korea, St. Vincent’s Hospital), Joo Suk Oh (The Catholic University of Korea, Uijeongbu St. Mary’s Hospital), Seung Pill Choi (The Catholic University of Korea, Eunpyeong St. Mary’s Hospital), Kyoung-Chul Cha (Wonju Severance Christian Hospital).

Statistical analysis was performed by biostatisticians Lee Min-joo employed by a contract research organization, Medical Excellence Inc.

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No competing interests reported.

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Sex difference on neurological outcomes and post-cardiac arrest care in out-of-hospital cardiac arrest patients treated with targeted temperature management

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Comparison Of Patient Variables Between Men And Women

Effect Of Sex On 6-month Good Neurological Outcomes And Survival To Discharge

Effect Of Sex On In-hospital Processes And Other Interim Outcomes

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