Expression of Glucocorticoid Receptors in the Early Period After the Return of Spontaneous Circulation Among Patients Who Experienced Cardiac Arrest : A Retrospective Observational Study

Expression of Glucocorticoid Receptors in the Early Period After the Return of Spontaneous Circulation Among Patients Who Experienced Cardiac Arrest : A Retrospective Observational Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Original research Expression of Glucocorticoid Receptors in the Early Period After the Return of Spontaneous Circulation Among Patients Who Experienced Cardiac Arrest : A Retrospective Observational Study Yanan Yu, Ziren Tang, Jiabao Li, Miaorong Xie, Chenchen Hang, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-278830/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Rapid changes in glucocorticoid (GC) levels and adrenal insufficiency are related to the development of post-cardiac arrest syndrome. However, changes in glucocorticoid receptors (GR) have not been studied. Hence, this study aimed to investigate the association of early changes in GR and prognosis and immune response in patients who experienced cardiac arrest (CA). Methods: In this observational single-center case-control study, we enrolled patients who were in the early period of return of spontaneous circulation after CA and were admitted to the emergency department of the Beijing Chaoyang Hospital between October 2018 and October 2019. Age- and sex-matched healthy individuals were recruited for the control group after a physical examination. GR expression and cell counts of circulatory T and B lymphocytes, natural killer, and regulatory T (Treg) cells were assessed. Plasma total cortisol and adrenocorticotrophic hormone (ACTH) levels were tested. Since the data for total cortisol and ACTH levels had a skewed distribution, we compared our results with the natural logarithmic conversion values after adding 1 (ln [total cortisol+ 1], ln [ACTH+ 1]). Measurement data with a skewed distribution are expressed as medians (25th and 75th percentiles). The Mann–Whitney U test was used to compare variables between groups. The qualitative parameters in the 2 × 2 contingency table were used for analysis. Results: Overall, 85 patients who experienced CA and 40 healthy individuals were enrolled. All cell counts were lower and plasma total cortisol levels were higher (P<0.001) in patients who experienced CA than those in the healthy control group. GR expression in Treg cells and CD3 + CD4 + T lymphocytes was not significantly different, but the mean fluorescence intensity and GR expression in other cells were lower in patients who experienced CA (P<0.05) than those in the healthy control group. ACTH levels did not show any difference. There were no significant differences between survivors and non-survivors. Conclusion: Our findings provide insights into GC sensitivity and immunosuppressive status in these patients, and a new perspective for GC targeted treatment. Critical Care & Emergency Medicine Glucocorticoid immunosuppression cortisol ACTH pituitary–adrenal axis Figures Figure 1 Figure 2 Figure 3 Background Cardiac arrest (CA) is an important health problem globally; about 356,500 people experience medical emergencies due to CA in the United States, and over 544,000 people die from sudden CA in China annually [ 1 – 3 ]. The systemic ischemia-reperfusion response in patients who experienced CA can present as post-cardiac arrest syndrome (PCAS), systematic inflammatory response syndrome (SIRS), which increases the risk of multiple organ failure and infection and affect the inflammatory response and the prognosis of patients [ 4 – 7 ] after return of spontaneous circulation (ROSC). CA is the most intense among acute stress events, which seriously affects the function of the pituitary and adrenal axis [ 8 ]. Studies have shown that abnormal cortisol levels and relative adrenocortical insufficiency after ROSC in patients who experienced CA are related to their prognosis [ 8 – 12 ]. However, the clinical application of glucocorticoids (GCs) is controversial. In the 2015 International Cardiopulmonary Resuscitation Guidelines, the routine use of GCs is not recommended for resuscitation of patients with in-hospital or out-of-hospital cardiac arrest [ 13 ]. Recent clinical studies have shown that early administration of corticosteroids after CA can improve the success rate of ROSC, nervous system functional outcome, and prognosis, which is speculated to be related to its influence on hemodynamics, SIRS response, and other mechanisms [ 14 – 18 ]. Therefore, the role of glucocorticoids in the occurrence and development of PCAS needs to be studied further. GCs combine with intracellular glucocorticoid receptors (GRs) to exert anti-inflammatory and immunosuppressive effects, and reduce the production as well as the release of inflammatory cytokines [ 19 , 20 ]. The affinity of GRs to GC in circulating monocytes is decreased in patients with acquired immunodeficiency syndrome [ 21 ]. The expression of GR is decreased in critical illness [ 22 ], pediatric septic shock, and patients with high serum cortisol [ 23 ]. However, hitherto, no study has reported on the GR expression after ROSC in patients who experienced CA. Previous studies have found that the count of circulating B and T lymphocytes, regulatory T (Treg) cells, monocytes, and the human leukocyte antigen DR (HLA-DR) expression on circulatory monocytes and B and T lymphocytes were reduced [ 24 , 25 ]. Hence, this study aimed to investigate the relationship between GR expression and immune alteration in the early period after ROSC in patients who experienced CA by observing the GR expression in circulatory T and B lymphocytes, NK cells, and Treg cells, their cell counts, and plasma total cortisol and ACTH levels. Methods Study participants This was an observational single-center case-control study conducted in the Emergency Department (ED) of Beijing Chaoyang Hospital in China. This study was approved by the Medical Ethics Committee of Beijing Chaoyang Hospital. Due to the observational, non-interventional nature of the study, which was based on residual blood samples taken every morning after measuring the levels of routine biomarkers, we did not obtain informed consent from the patients. Following the 2015 International Cardiopulmonary Resuscitation Guidelines [ 26 ], we enrolled patients who were in the early period of ROSC after CA, and were admitted to the ED of Beijing Chaoyang Hospital between October 2018 and October 2019. The inclusion criteria were (a) ROSC 6 h after CA and (b) a Glasgow coma scale score of < 8 after ROSC. The exclusion criteria were (a) < 18 years of age, (b) terminal stage of disease (malignant cancer of any type, acquired immunodeficiency syndrome), (c) corticosteroid treatment within the past 3 months, (d) administration of corticosteroids, and (e) adrenal insufficiency. All patients were treated according to the 2015 International Cardiopulmonary Resuscitation Consensus [ 13 ]. Age- and sex-matched healthy individuals were recruited for the control group after a physical examination. Data collection We collected data on demographics, resuscitation (initial heart rhythm, ROSC time, and cumulative adrenaline [epinephrine] dose), as well as laboratory findings (routine blood cell, blood gas, and blood biochemical tests performed 6 h after ROSC). Acute Physiology and Chronic Health Evaluation (APACHE) II and the Sequential Organ Failure Assessment (SOFA) were used to determine disease severity. Residual samples of blood, with heparin anticoagulant, from routine clinical tests or physical health examinations were collected, maintained at 4°C during transport and storage, and used to determine GR expression in circulatory T and B lymphocytes, NK cells, and Treg cells and their cell counts. The plasma was maintained at -80°C during storage and used to determine total cortisol and ACTH levels. During follow-up, 28-day survival data were also collected. Additional file 1, shows the workflow of this study. Flow cytometry Expression of GR was measured on T and B lymphocytes, NK cells, and Treg cells. Briefly, a 100-µL peripheral blood sample was stained for 20 min with surface antibodies (CD3, CD4, CD8, CD19, CD16, CD56, CD25, and CD127) in a dark place. Erythrocytes were lysed for 15 min, and the debris was washed away. Before intracellular GR staining, surface-stained cells were fixed and permeabilized using the BD Transcription Factor Buffer Set (BD Pharmingen™, Catalogue No. 562574). Monoclonal antibodies and their isotype controls were all purchased from BD Biosciences (San Jose, CA, USA). Details of all antibodies are shown in additional file 2. According to the manufacturers’ recommendations, all antibodies and their isotype controls were used in the concentration of 1 µL per 100 µL whole blood. Samples were measured using the Gallios flow cytometer (Beckman Coulter, Brea, CA) and analyzed on the Gallios Software version 1.0 (Beckman Coulter). Cells were stained for 20 min; thresholds were defined using the manufacturer’s recommended isotype controls. T cells were gated by CD3 + CD4 + or CD3 + CD8 + ; B cells were gated by CD3 − CD19 + ; NK cells were gated by CD16 + CD56 + ; Tregs were gated by CD4 + CD25 high CD127 low . At least 10,000 events were collected in the lymphocyte cell gate for each sample. Results are expressed as percentages and mean fluorescence intensity (MFI) values. Absolute CD3 + and CD4 + lymphocytes, NK cell, and Treg cell counts were obtained using Flow-Count fluorospheres (Beckman Coulter, Catalogue No. 7547053), according to the manufacturer’s instructions. B, CD3 + CD4 + T, CD3 + CD8 + T, and Treg cell counts were calculated by their percentages in CD3 + or CD4 + lymphocytes multiplied by CD3 + or CD4 + lymphocyte counts. Determination of plasma total cortisol and ACTH levels after ROSC Venous blood samples were collected in ethylenediaminetetraacetic acid tubes, centrifuged, and then stored at -80°C. Plasma total cortisol (IMMULITE2000 Cortisol, L2KCO2, United Kingdom) and ACTH (IMMULITE2000 ACTH, L2KAC2, United Kingdom) were assayed using a chemiluminescent immunoassay on a Siemens automated analyzer (Immulite® 2000 XPi; Siemens Healthcare Diagnostics, Erlangen, Germany). The lower detection limit of total cortisol was 2.00 ng/mL, and that of ACTH was 5.00 pg/mL. Statistical analyses All data were analyzed using SPSS version 22.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism version 8.0 (GraphPad Software). For normally distributed data, continuous variables are expressed as means with standard deviations. Since the data for total cortisol and ACTH levels had a skewed distribution, we compared our results with the natural logarithmic conversion values after adding 1 (ln [total cortisol + 1], ln [ACTH + 1]). Measurement data with a skewed distribution are expressed as medians (25th and 75th percentiles). The Mann–Whitney U test was used to compare variables between groups. The qualitative parameters in the 2 × 2 contingency table were used for analysis. All statistical tests were two-tailed, and a P-value of < 0.05 was considered statistically significant. Follow-up Patients who experienced CA were classified into survivor and non-survivor groups according to the 28-day survival end-point. Those with all-cause mortality within the follow-up period were considered as non-survivors. Results Patient characteristics In total, 40 healthy individuals and 85 patients who experienced CA were analyzed. The demographics and clinical characteristics of both groups are shown in Table 1 . In this study, acute cardiac and brain events were the main causes of CA. Other causes of CA included poisoning (including carbon monoxide poisoning) and hypokalemia. Sex and age were not significantly different between the CA and healthy control groups. The comparisons of clinical characteristics of the survivor and non-survivor groups based on 28-day survival are shown in additional file 3. The APACHE II and SOFA scores were significantly different between the CA and healthy control groups (P < 0.001 for all) and the survivor and non-survivor groups (P < 0.001 and P = 0.011, respectively). Table 1 Patient Characteristics at Admission Characteristics Healthy Control Group (n = 40) Successful Resuscitation Group (n = 85) P-Value Age (years), median [IQR] 64.0 (54.3–69.8) 65.0 (55.0–74.0) 0.209 Male/Female (n) 23/17 58/27 0.241 Previous medical history, n (%) Hypertension Diabetes Coronary heart disease Chronic lung disease Chronic kidney disease 5 (12.5%) 3 (7.5%) 2 (5.0%) 1 (2.5%) 0 38 (44.7%) 27 (31.8%) 29 (34.1%) 9 (10.6%) 9 (10.6%) < 0.001 0.003 < 0.001 0.230 0.077 Cardiac arrest cause (n, %) Cardiac Respiratory Cerebral Others Unknow 34 (40.0%) 20 (23.5%) 23 (27.1%) 7 (8.2%) 1 (1.2%) Initial resuscitation Time to ROSC (min), median [IQR] 20.0 (10.0–30.0) Adrenaline (mg), median [IQR] 2.0 (0.0–5.0) Initial rhythm VF/VT, n (%) 30 (35.3%) MAP (mmHg), median [IQR]95.7 (86.0-103.2) 74.3 (56.2–97.2) < 0.001 White cell count (×10 9 /L), median [IQR] 5.81 (4.85–6.53) 13.56 (10.84–18.29) < 0.001 APACHE Ⅱ score, mean ± SD 0 32.9 ± 6.5 < 0.001 SOFA score, median [IQR] 0 11.5 (8.5–14.0) < 0.001 28-day mortality, n (%) 65(76.5%) 28-day CPC 1–2, n (%) 14 (16.5%) Data are presented as mean ± SD or interquartile range (IQR) as appropriate. The p-value represents comparison between groups. Abbreviations: ROSC: return of spontaneous circulation; VF: ventricular fibrillation; VT: ventricular tachycardia; MAP: mean arterial pressure; APACHE Ⅱ: acute physiology and chronic health evaluation; SOFA: sequential organ failure assessment; CPC: cerebral performance category. Changes in circulatory T and B lymphocyte, NK cell, and Treg cell counts after ROSC Compared with those of the healthy controls, the T and B lymphocyte, NK cell, and Treg cell counts were significantly lower after ROSC in patients who experienced CA (P < 0.001 for all). Compared with those of the healthy controls, the CD3 + CD4 + /T lymphocyte, CD3 + CD8 + /T lymphocyte, and Treg cell/CD4 + T lymphocyte ratios were also significantly reduced after ROSC in patients who experienced CA (P 0.05 for all) (Additional file 5). GR expression in circulatory T and B lymphocytes, NK cells, and Treg cells after ROSC Compared with those in healthy individuals, the MFI and percentages of GR expression in B and T lymphocytes, NK cells, and CD3 + CD8 + T lymphocytes decreased significantly after ROSC in patients who experienced CA (P < 0.01 for all) (Figs. 2 A–D, G, H, K, L). There were also significant reductions in the MFI of GR expression in Treg cells and CD3 + CD4 + T lymphocytes (P 0.05 for all) (Figs. 2 F, J; Additional file 6). However, there were no significant differences in the MFI and percentages of GR expression in these cells between survivors and non-survivors (P > 0.05 for all) (Additional file 7). Changes in plasma total cortisol and ACTH levels after ROSC We measured the plasma total cortisol and ACTH levels of the 40 healthy individuals and 85 CA patients (two samples were excluded because their total cortisol levels were not measured). Compared with those in healthy controls, plasma total cortisol levels were significantly higher in patients who experienced CA (P 0.05 for all) (Figs. 3 B, D). Discussion This study explored the relationship between GR expression and immune alteration in the early period after ROSC in patients who experienced CA, by observing GR expression in circulatory T and B lymphocytes, NK cells, and Treg cells and changes in cell counts and plasma total cortisol and ACTH levels. We found that GR expression, cell counts, and ratios rapidly decreased and plasma total cortisol levels increased in these patients. After ROSC, the immune response of patients who experienced CA is impaired, and the systemic inflammatory response is increased [ 7 , 27 ]. In this study, the T and B lymphocyte, NK cell, and Treg cell counts as well as the CD3 + CD4 + /T, CD3 + CD8 + /T, and Treg cell/CD4 + T lymphocyte ratios were significantly reduced after ROSC. NK cells, which are special innate immune cells that have cytotoxic functions similar to CD3 + CD8 + T lymphocytes, mainly distinguish infected and stressed cells from healthy cells and eliminate intracellular infection as well as dysfunctional cells [ 28 , 29 ]. T lymphocytes are also important because of their function as adaptive immune cells for the control and elimination of infection [ 28 ]. Moreover, B and T lymphocytes mediate humoral and cellular immunity, respectively. Compared with previous studies, this study further performed an earlier and more comprehensive assessment of the immune system of patients who experienced CA, and our findings more substantially supported the rapid emergence of immune dysfunction in these patients after ROSC compared to that of previous reports. The effectiveness of GC use in these patients during and after resuscitation has been controversial due to insufficient evidence. However, the use of GC during resuscitation improves the survival rate of patients who experienced CA due to its direct anti-inflammatory, immunosuppressive effects, hemodynamic, and positive inotropic effects. All of this ultimately leads to increased stress capacity of the body [ 19 , 20 ]. GC can activate GRs in cells when the body is under stress, thereby increasing both the effectiveness of resuscitation and the discharge survival rate. This study is the first to explore GR expression in circulating immune cells in patients who experienced CA after ROSC. We observed that GR expression in B and T lymphocytes, NK cells, and CD3 + CD8 + T lymphocytes decreased significantly in patients who experienced CA, while the percentage of GR + Treg cells and CD3 + CD4 + T lymphocytes showed a slight decrease. Moreover, we observed a more significant decrease in the MFI of GR expression in Treg cells and CD3 + CD4 + T lymphocytes but none in the percentage of GR expression. Previous studies have found decreased expression of GRs in peripheral polymorphonuclear cells in critically ill patients [ 22 ], and antagonism to GRs aggravates viral and bacterial infections [ 30 ]. The results of this study suggest that the decrease in intracellular GR expression in patients who experienced CA may be one of the causes of GC resistance, due to insufficient binding of GRs and GCs, GC insensitivity, and the inability of GCs to effectively exert anti-inflammatory and immunosuppressive effects. These findings may also explain why different results of the clinical application of GCs have appeared in previous studies and support the possibility of using GCs in the clinical treatment of patients who experienced CA. In this study, we also found that the total plasma cortisol levels were significantly higher in patients who experienced CA but ACTH levels were not. High levels of inflammatory cytokines inhibit ACTH release [ 19 ]. During critical illness, the body does not sufficiently metabolize cortisol [ 31 ]. In addition, the continuous increase in plasma cortisol levels may trigger the negative feedback pathway of the hypothalamic-pituitary-adrenal axis, inhibiting the release of ACTH and cortisol and eventually leading to adrenal insufficiency. These factors may explain the opposite trends of plasma ACTH and cortisol levels in the patients who were included in this study and experienced CA. Notably, this result suggests that low GR expression levels cannot be matched with high plasma total cortisol levels. Previous studies have found that GC use during resuscitation may benefit patients who experienced CA [ 14 – 17 ]. The benefits, such as direct anti-inflammatory and anti-shock effects, improvement of vascular endothelial permeability, and other mechanisms may be related to the effects of using a high dose of GC, or GCs may work through other non-GR pathways. It is also possible that the immune function of patients who experienced CA is suppressed due to ischemia-reperfusion injury, which requires a large dose of GC to stimulate GRs to function. This study did not provide data on plasma GC levels and GR expression in a group of patients who were administered GCs and successfully resuscitated; therefore, further studies are required to explore the exact mechanisms of GCs. Our study has several limitations. First, to assess obvious changes, we only enrolled patients who experienced CA and had obvious signs of systemic ischemic hypoxia, such as GCS < 8 after ROSC. The patients were not stratified by age, gender, occurrence of comorbidities or mild systemic ischemic hypoxia. Second, since this was a preliminary observational study, we were only observing early changes. A dynamic observation for a longer duration would be helpful to understand the significance of GR expression in evolving immunity during the clinical course of CA after ROSC. Third, the samples used in this study were from the clinical laboratory, so the plasma total cortisol and ACTH in the samples were at a risk of degradation before we collected the samples. Finally, we did not discuss the changes in and the roles of GR isoforms, free cortisol, and corticosteroid-binding globulin. Therefore, future studies on these aspects are warranted to better understand the immunosuppressive effects of ROSC among patients who experienced CA. Conclusion In conclusion, this study revealed that GR expression, cell counts, and ratios rapidly decreased, while plasma total cortisol levels increased in the early period after ROSC among patients who experienced CA. These findings may provide important information about GC sensitivity and immunosuppressive status in these patients. In addition, this study provides a new perspective for clinical targeted treatment using GCs and high-quality prognosis in patients who experienced CA. Abbreviations GC: Glucocorticoids; GR: Glucocorticoid receptors; CA: Cardiac arrest; Treg: Regulatory T cells; ACTH: Adrenocorticotrophic hormone; PCAS: Post cardiac arrest syndrome; SIRS: Systematic inflammatory response syndrome; ROCS: Return of spontaneous circulation; HLA-DR: Human leukocyte antigen DR; ED: Emergency department; APACHE: Acute Physiology and Chronic Health Evaluation; SOFA: Sequential Organ Failure Assessment; MFI: Mean fluorescence intensity; NK: Natural killer cells Declarations Ethics approval: This study was approved by the Medical Ethics Committee of Beijing Chaoyang Hospital, Capital Medical University (2013-KE-1). Consent to participate: Due to the observational, non-interventional nature of the study, which was based on residual blood samples taken every morning after measuring the levels of routine biomarkers, we did not obtain informed consent from the patients. Consent to publish: Not applicable Availability of data and materials: All data generated or analysed during this study are included in this published article and its supplementary information files. Competing interests: The authors declare that they have no competing interests. Funding: None Author contributions: CL designed the study and reviewed the manuscript. YNY searched literatures, contributed to experimental studies, date analysis and writing this manuscript. ZRT, CCH and LA collected and analyzed data. JBL and MRX helped with statistical analysis. All authors have read and approved the final manuscript. Acknowledgements: We thank all the researchers who participated in this study and all colleagues in the emergency department who provided support. References Myat A, Song KJ, Rea T. Out-of-hospital cardiac arrest: current concepts. Lancet. 2018;391:970–9. Writing Group M, Mozaffarian D, Benjamin EJ, Go AS, Arnett TK, Blaha MJ, et al. 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Boonen E, Vervenne H, Meersseman P, Andrew R, Mortier L, Declercq PE, et al. Reduced cortisol metabolism during critical illness. N Engl J Med. 2013;368:1477–88. Tables Table 1. Patient Characteristics at Admission Characteristics Healthy Control Group (n=40) Successful Resuscitation Group (n=85) P-Value Age (years), median [IQR] 64.0 (54.3-69.8) 65.0 (55.0-74.0) 0.209 Male/Female (n) 23/17 58/27 0.241 Previous medical history, n (%) Hypertension Diabetes Coronary heart disease Chronic lung disease Chronic kidney disease 5 (12.5%) 3 (7.5%) 2 (5.0%) 1 (2.5%) 0 38 (44.7%) 27 (31.8%) 29 (34.1%) 9 (10.6%) 9 (10.6%) <0.001 0.003 <0.001 0.230 0.077 Cardiac arrest cause (n, %) Cardiac Respiratory Cerebral Others Unknow 34 (40.0%) 20 (23.5%) 23 (27.1%) 7 (8.2%) 1 (1.2%) Initial resuscitation Time to ROSC (min), median [IQR] 20.0 (10.0-30.0) Adrenaline (mg), median [IQR] 2.0 (0.0-5.0) Initial rhythm VF/VT, n (%) 30 (35.3%) MAP (mmHg), median [IQR] 95.7 (86.0-103.2) 74.3 (56.2-97.2) <0.001 White cell count (×10 9 /L), median [IQR] 5.81 (4.85-6.53) 13.56 (10.84-18.29) <0.001 APACHE Ⅱ score, mean±SD 0 32.9±6.5 <0.001 SOFA score, median [IQR] 0 11.5 (8.5-14.0) <0.001 28-day mortality, n (%) 65（76.5%） 28-day CPC 1–2, n (%) 14 (16.5%) Data are presented as mean±SD or interquartile range (IQR) as appropriate. The p-value represents comparison between groups. Abbreviations: ROSC: return of spontaneous circulation; VF: ventricular fibrillation; VT: ventricular tachycardia; MAP: mean arterial pressure; APACHE Ⅱ: acute physiology and chronic health evaluation; SOFA: sequential organ failure assessment; CPC: cerebral performance category. Supplementary Files Electronicsupplementalmaterial.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-278830","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Original research","associatedPublications":[],"authors":[{"id":15619174,"identity":"d81681de-e437-454c-8953-7eb66b7b51f6","order_by":0,"name":"Yanan Yu","email":"","orcid":"","institution":"Capital Medical University, Beijing Chaoyang Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yanan","middleName":"","lastName":"Yu","suffix":""},{"id":15619175,"identity":"041ac426-1a50-44c9-a26a-1d84eaaf6106","order_by":1,"name":"Ziren Tang","email":"","orcid":"","institution":"Capital Medical University, Beijing Chaoyang Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ziren","middleName":"","lastName":"Tang","suffix":""},{"id":15619176,"identity":"e9560f05-a137-4302-ae44-9b22413112d8","order_by":2,"name":"Jiabao Li","email":"","orcid":"","institution":"Capital Medical University, Capital Medical University Affiliated Beijing Friendship Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jiabao","middleName":"","lastName":"Li","suffix":""},{"id":15619177,"identity":"1861d0df-8246-4fa5-a807-c845434001d8","order_by":3,"name":"Miaorong Xie","email":"","orcid":"","institution":"Capital Medical University, Capital Medical University Affiliated Beijing Friendship Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Miaorong","middleName":"","lastName":"Xie","suffix":""},{"id":15619178,"identity":"bb6137b4-c8d1-4215-8408-6318ad63af14","order_by":4,"name":"Chenchen Hang","email":"","orcid":"","institution":"Capital Medical University, Beijing Chaoyang Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chenchen","middleName":"","lastName":"Hang","suffix":""},{"id":15619179,"identity":"c898922e-c5ac-4212-982d-4372388586d8","order_by":5,"name":"Le An","email":"","orcid":"","institution":"Capital Medical University, Beijing Chaoyang Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Le","middleName":"","lastName":"An","suffix":""},{"id":15619180,"identity":"afb01e9c-4f1b-44e4-802e-d9add39d00d8","order_by":6,"name":"Chunsheng Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAArklEQVRIiWNgGAWjYBACPigtx8befoA4LWxQ2piP50wCaVoS50k4GBCphf34w8+8bYfT2yQYEhh+VGwjQgtPjrE0UEtum3TjAcaeM7eJ0CLBw8YM1iJzIIGZsY0oLezPQFrS2SQSDIjVwmAG0pJAghagXyTnnEs3bAMG8kGi/MIPDLEPb8qs5eXb2w8++FFBhBYQYOJlawYzDhCnHggYf/ypI1rxKBgFo2AUjEAAAJ2TNaKlnFDuAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-3161-4457","institution":"Capital Medical University Affiliated Beijing Friendship Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Chunsheng","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2021-02-26 06:52:38","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-278830/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-278830/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":6978878,"identity":"b9877131-af19-4a53-91e8-1db7470702db","added_by":"auto","created_at":"2021-03-15 19:57:15","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":648077,"visible":true,"origin":"","legend":"Changes in circulatory T and B lymphocyte, NK cell, and Treg cell counts, and CD3+CD4+/T, CD3+CD8+/T, and Treg/CD4+T lymphocyte ratios between the healthy control group and CA group. The CA group showed significant differences compared with the healthy control group (P\u003c0.001). CA, cardiac arrest; NK, natural killer; Treg, regulatory T.","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-278830/v1/b09cda48ccc2bb3625ab9629.png"},{"id":6978503,"identity":"40d5aefe-2977-4cf7-ae9b-cb267ed819a2","added_by":"auto","created_at":"2021-03-15 19:54:15","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":851819,"visible":true,"origin":"","legend":"Expression of GRs in circulatory T and B lymphocytes, NK cells, and Treg cells in the healthy control group and CA group. The CA group showed significant differences compared with the healthy control group (P\u003c0.05). CA, cardiac arrest; GR, glucocorticoid receptor; NK, natural killer; ROSC, return of spontaneous circulation; Treg, regulatory T.","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-278830/v1/3731921fc7e1374b8ea8b8fa.png"},{"id":6978881,"identity":"b1eaaaa5-6bea-44f2-afb8-85bdd20efa83","added_by":"auto","created_at":"2021-03-15 19:57:16","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":171600,"visible":true,"origin":"","legend":"(A, B) The (ln+1) values of plasma total cortisol and ACTH levels after ROSC in the healthy control group and CA group. (C, D) The (ln+1) values of plasma total cortisol and ACTH levels in survivors and non-survivors after ROSC. The CA group showed significant differences compared with the healthy control group (P\u003c0.05). ACTH, adrenocorticotrophic hormone; CA, cardiac arrest; ROSC, return of spontaneous circulation.","description":"","filename":"OnlineFigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-278830/v1/2414b53b2850fe5cca3d4b3a.png"},{"id":13679818,"identity":"1d2426da-8dc8-4668-943e-2f49ee4de5cf","added_by":"auto","created_at":"2021-09-17 11:45:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":958656,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-278830/v1/a574d70e-7d76-4e49-8c62-d82a2314b3d7.pdf"},{"id":6978879,"identity":"af042864-4949-49cc-afbc-1aa5dd2d3bf5","added_by":"auto","created_at":"2021-03-15 19:57:15","extension":"docx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":57519,"visible":true,"origin":"","legend":"","description":"","filename":"Electronicsupplementalmaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-278830/v1/29688389d8f03c6960288eae.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eExpression of Glucocorticoid Receptors in the Early Period After the Return of Spontaneous Circulation Among Patients Who Experienced Cardiac Arrest : A Retrospective Observational Study\u003c/p\u003e","fulltext":[{"header":"Background","content":" \u003cp\u003eCardiac arrest (CA) is an important health problem globally; about 356,500 people experience medical emergencies due to CA in the United States, and over 544,000 people die from sudden CA in China annually [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The systemic ischemia-reperfusion response in patients who experienced CA can present as post-cardiac arrest syndrome (PCAS), systematic inflammatory response syndrome (SIRS), which increases the risk of multiple organ failure and infection and affect the inflammatory response and the prognosis of patients [\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] after return of spontaneous circulation (ROSC).\u003c/p\u003e \u003cp\u003eCA is the most intense among acute stress events, which seriously affects the function of the pituitary and adrenal axis [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Studies have shown that abnormal cortisol levels and relative adrenocortical insufficiency after ROSC in patients who experienced CA are related to their prognosis [\u003cspan additionalcitationids=\"CR9 CR10 CR11\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, the clinical application of glucocorticoids (GCs) is controversial. In the 2015 International Cardiopulmonary Resuscitation Guidelines, the routine use of GCs is not recommended for resuscitation of patients with in-hospital or out-of-hospital cardiac arrest [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Recent clinical studies have shown that early administration of corticosteroids after CA can improve the success rate of ROSC, nervous system functional outcome, and prognosis, which is speculated to be related to its influence on hemodynamics, SIRS response, and other mechanisms [\u003cspan additionalcitationids=\"CR15 CR16 CR17\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Therefore, the role of glucocorticoids in the occurrence and development of PCAS needs to be studied further.\u003c/p\u003e \u003cp\u003eGCs combine with intracellular glucocorticoid receptors (GRs) to exert anti-inflammatory and immunosuppressive effects, and reduce the production as well as the release of inflammatory cytokines [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The affinity of GRs to GC in circulating monocytes is decreased in patients with acquired immunodeficiency syndrome [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The expression of GR is decreased in critical illness [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], pediatric septic shock, and patients with high serum cortisol [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. However, hitherto, no study has reported on the GR expression after ROSC in patients who experienced CA. Previous studies have found that the count of circulating B and T lymphocytes, regulatory T (Treg) cells, monocytes, and the human leukocyte antigen DR (HLA-DR) expression on circulatory monocytes and B and T lymphocytes were reduced [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Hence, this study aimed to investigate the relationship between GR expression and immune alteration in the early period after ROSC in patients who experienced CA by observing the GR expression in circulatory T and B lymphocytes, NK cells, and Treg cells, their cell counts, and plasma total cortisol and ACTH levels.\u003c/p\u003e "},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy participants\u003c/h2\u003e\u003cp\u003eThis was an observational single-center case-control study conducted in the Emergency Department (ED) of Beijing Chaoyang Hospital in China. \u003cdiv class=\"Ethics-ToolTip\"\u003eThis study was approved by the Medical Ethics Committee of Beijing Chaoyang Hospital.\u003c/div\u003e\u003cdiv class=\"Ethics-ToolTip\"\u003eDue to the observational, non-interventional nature of the study, which was based on residual blood samples taken every morning after measuring the levels of routine biomarkers, we did not obtain informed consent from the patients.\u003c/div\u003e Following the 2015 International Cardiopulmonary Resuscitation Guidelines [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], we enrolled patients who were in the early period of ROSC after CA, and were admitted to the ED of Beijing Chaoyang Hospital between October 2018 and October 2019. The inclusion criteria were (a) ROSC 6 h after CA and (b) a Glasgow coma scale score of \u0026lt;\u0026thinsp;8 after ROSC. The exclusion criteria were (a)\u0026thinsp;\u0026lt;\u0026thinsp;18 years of age, (b) terminal stage of disease (malignant cancer of any type, acquired immunodeficiency syndrome), (c) corticosteroid treatment within the past 3 months, (d) administration of corticosteroids, and (e) adrenal insufficiency. All patients were treated according to the 2015 International Cardiopulmonary Resuscitation Consensus [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Age- and sex-matched healthy individuals were recruited for the control group after a physical examination.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003eData collection\u003c/h2\u003e\u003cp\u003eWe collected data on demographics, resuscitation (initial heart rhythm, ROSC time, and cumulative adrenaline [epinephrine] dose), as well as laboratory findings (routine blood cell, blood gas, and blood biochemical tests performed 6 h after ROSC). Acute Physiology and Chronic Health Evaluation (APACHE) II and the Sequential Organ Failure Assessment (SOFA) were used to determine disease severity. Residual samples of blood, with heparin anticoagulant, from routine clinical tests or physical health examinations were collected, maintained at 4\u0026deg;C during transport and storage, and used to determine GR expression in circulatory T and B lymphocytes, NK cells, and Treg cells and their cell counts. The plasma was maintained at -80\u0026deg;C during storage and used to determine total cortisol and ACTH levels. During follow-up, 28-day survival data were also collected. Additional file 1, shows the workflow of this study.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eFlow cytometry\u003c/h2\u003e\u003cp\u003eExpression of GR was measured on T and B lymphocytes, NK cells, and Treg cells. Briefly, a 100-\u0026micro;L peripheral blood sample was stained for 20 min with surface antibodies (CD3, CD4, CD8, CD19, CD16, CD56, CD25, and CD127) in a dark place. Erythrocytes were lysed for 15 min, and the debris was washed away. Before intracellular GR staining, surface-stained cells were fixed and permeabilized using the BD Transcription Factor Buffer Set (BD Pharmingen\u0026trade;, Catalogue No. 562574). Monoclonal antibodies and their isotype controls were all purchased from BD Biosciences (San Jose, CA, USA). Details of all antibodies are shown in additional file 2. According to the manufacturers\u0026rsquo; recommendations, all antibodies and their isotype controls were used in the concentration of 1 \u0026micro;L per 100 \u0026micro;L whole blood. Samples were measured using the Gallios flow cytometer (Beckman Coulter, Brea, CA) and analyzed on the Gallios Software version 1.0 (Beckman Coulter). Cells were stained for 20 min; thresholds were defined using the manufacturer\u0026rsquo;s recommended isotype controls. T cells were gated by CD3\u003csup\u003e+\u003c/sup\u003e CD4\u003csup\u003e+\u003c/sup\u003e or CD3\u003csup\u003e+\u003c/sup\u003e CD8\u003csup\u003e+\u003c/sup\u003e; B cells were gated by CD3\u003csup\u003e\u0026minus;\u003c/sup\u003e CD19\u003csup\u003e+\u003c/sup\u003e; NK cells were gated by CD16\u003csup\u003e+\u003c/sup\u003e CD56\u003csup\u003e+\u003c/sup\u003e; Tregs were gated by CD4\u003csup\u003e+\u003c/sup\u003eCD25\u003csup\u003ehigh\u003c/sup\u003eCD127\u003csup\u003elow\u003c/sup\u003e. At least 10,000 events were collected in the lymphocyte cell gate for each sample. Results are expressed as percentages and mean fluorescence intensity (MFI) values.\u003c/p\u003e\u003cp\u003eAbsolute CD3\u003csup\u003e+\u003c/sup\u003e and CD4\u003csup\u003e+\u003c/sup\u003e lymphocytes, NK cell, and Treg cell counts were obtained using Flow-Count fluorospheres (Beckman Coulter, Catalogue No. 7547053), according to the manufacturer\u0026rsquo;s instructions. B, CD3\u003csup\u003e+\u003c/sup\u003eCD4\u003csup\u003e+\u003c/sup\u003eT, CD3\u003csup\u003e+\u003c/sup\u003eCD8\u003csup\u003e+\u003c/sup\u003eT, and Treg cell counts were calculated by their percentages in CD3\u003csup\u003e+\u003c/sup\u003e or CD4\u003csup\u003e+\u003c/sup\u003e lymphocytes multiplied by CD3\u003csup\u003e+\u003c/sup\u003e or CD4\u003csup\u003e+\u003c/sup\u003e lymphocyte counts.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eDetermination of plasma total cortisol and ACTH levels after ROSC\u003c/h2\u003e\u003cp\u003eVenous blood samples were collected in ethylenediaminetetraacetic acid tubes, centrifuged, and then stored at -80\u0026deg;C. Plasma total cortisol (IMMULITE2000 Cortisol, L2KCO2, United Kingdom) and ACTH (IMMULITE2000 ACTH, L2KAC2, United Kingdom) were assayed using a chemiluminescent immunoassay on a Siemens automated analyzer (Immulite\u0026reg; 2000 XPi; Siemens Healthcare Diagnostics, Erlangen, Germany). The lower detection limit of total cortisol was 2.00 ng/mL, and that of ACTH was 5.00 pg/mL.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analyses\u003c/h2\u003e\u003cp\u003eAll data were analyzed using SPSS version 22.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism version 8.0 (GraphPad Software). For normally distributed data, continuous variables are expressed as means with standard deviations. Since the data for total cortisol and ACTH levels had a skewed distribution, we compared our results with the natural logarithmic conversion values after adding 1 (ln [total cortisol\u0026thinsp;+\u0026thinsp;1], ln [ACTH\u0026thinsp;+\u0026thinsp;1]). Measurement data with a skewed distribution are expressed as medians (25th and 75th percentiles). The Mann\u0026ndash;Whitney U test was used to compare variables between groups. The qualitative parameters in the 2 \u0026times; 2 contingency table were used for analysis. All statistical tests were two-tailed, and a P-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eFollow-up\u003c/h2\u003e\u003cp\u003ePatients who experienced CA were classified into survivor and non-survivor groups according to the 28-day survival end-point. Those with all-cause mortality within the follow-up period were considered as non-survivors.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":" \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eIn total, 40 healthy individuals and 85 patients who experienced CA were analyzed. The demographics and clinical characteristics of both groups are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. In this study, acute cardiac and brain events were the main causes of CA. Other causes of CA included poisoning (including carbon monoxide poisoning) and hypokalemia. Sex and age were not significantly different between the CA and healthy control groups. The comparisons of clinical characteristics of the survivor and non-survivor groups based on 28-day survival are shown in additional file 3. The APACHE II and SOFA scores were significantly different between the CA and healthy control groups (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for all) and the survivor and non-survivor groups (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and P\u0026thinsp;=\u0026thinsp;0.011, respectively).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient Characteristics at Admission\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHealthy Control\u003c/p\u003e \u003cp\u003eGroup (n\u0026thinsp;=\u0026thinsp;40)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSuccessful Resuscitation Group (n\u0026thinsp;=\u0026thinsp;85)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years), median [IQR]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64.0 (54.3\u0026ndash;69.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.0 (55.0\u0026ndash;74.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.209\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale/Female (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23/17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58/27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.241\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious medical history, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003cp\u003eDiabetes\u003c/p\u003e \u003cp\u003eCoronary heart disease\u003c/p\u003e \u003cp\u003eChronic lung disease\u003c/p\u003e \u003cp\u003eChronic kidney disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (12.5%)\u003c/p\u003e \u003cp\u003e3 (7.5%)\u003c/p\u003e \u003cp\u003e2 (5.0%)\u003c/p\u003e \u003cp\u003e1 (2.5%)\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38 (44.7%)\u003c/p\u003e \u003cp\u003e27 (31.8%)\u003c/p\u003e \u003cp\u003e29 (34.1%)\u003c/p\u003e \u003cp\u003e9 (10.6%)\u003c/p\u003e \u003cp\u003e9 (10.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003e0.003\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003e0.230\u003c/p\u003e \u003cp\u003e0.077\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac arrest cause (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac\u003c/p\u003e \u003cp\u003eRespiratory\u003c/p\u003e \u003cp\u003eCerebral\u003c/p\u003e \u003cp\u003eOthers\u003c/p\u003e \u003cp\u003eUnknow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (40.0%)\u003c/p\u003e \u003cp\u003e20 (23.5%)\u003c/p\u003e \u003cp\u003e23 (27.1%)\u003c/p\u003e \u003cp\u003e7 (8.2%)\u003c/p\u003e \u003cp\u003e1 (1.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial resuscitation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to ROSC (min), median [IQR]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20.0 (10.0\u0026ndash;30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdrenaline (mg), median [IQR]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.0 (0.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eInitial rhythm VF/VT, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (35.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMAP (mmHg), median [IQR]95.7 (86.0-103.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74.3 (56.2\u0026ndash;97.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhite cell count (\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L), median [IQR]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.81 (4.85\u0026ndash;6.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.56 (10.84\u0026ndash;18.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPACHE Ⅱ score, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32.9\u0026thinsp;\u0026plusmn;\u0026thinsp;6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSOFA score, median [IQR]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.5 (8.5\u0026ndash;14.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e28-day mortality, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65(76.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e28-day CPC 1\u0026ndash;2, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (16.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or interquartile range (IQR) as appropriate. The p-value represents comparison between groups. Abbreviations: ROSC: return of spontaneous circulation; VF: ventricular fibrillation; VT: ventricular tachycardia; MAP: mean arterial pressure; APACHE Ⅱ: acute physiology and chronic health evaluation; SOFA: sequential organ failure assessment; CPC: cerebral performance category.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eChanges in circulatory T and B lymphocyte, NK cell, and Treg cell counts after ROSC\u003c/h2\u003e \u003cp\u003eCompared with those of the healthy controls, the T and B lymphocyte, NK cell, and Treg cell counts were significantly lower after ROSC in patients who experienced CA (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for all). Compared with those of the healthy controls, the CD3\u003csup\u003e+\u003c/sup\u003eCD4\u003csup\u003e+\u003c/sup\u003e/T lymphocyte, CD3\u003csup\u003e+\u003c/sup\u003eCD8\u003csup\u003e+\u003c/sup\u003e/T lymphocyte, and Treg cell/CD4\u003csup\u003e+\u003c/sup\u003e T lymphocyte ratios were also significantly reduced after ROSC in patients who experienced CA (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for all) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e; Additional file 4). However, there were no significant differences in these cell counts and ratios between survivors (n\u0026thinsp;=\u0026thinsp;20) and non-survivors (n\u0026thinsp;=\u0026thinsp;65) (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05 for all) (Additional file 5).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eGR expression in circulatory T and B lymphocytes, NK cells, and Treg cells after ROSC\u003c/h2\u003e \u003cp\u003eCompared with those in healthy individuals, the MFI and percentages of GR expression in B and T lymphocytes, NK cells, and CD3\u003csup\u003e+\u003c/sup\u003eCD8\u003csup\u003e+\u003c/sup\u003e T lymphocytes decreased significantly after ROSC in patients who experienced CA (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01 for all) (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA\u0026ndash;D, G, H, K, L). There were also significant reductions in the MFI of GR expression in Treg cells and CD3\u003csup\u003e+\u003c/sup\u003eCD4\u003csup\u003e+\u003c/sup\u003e T lymphocytes (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 for all) (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE, I) but none in the percentages of GR expression (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05 for all) (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eF, J; Additional file 6). However, there were no significant differences in the MFI and percentages of GR expression in these cells between survivors and non-survivors (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05 for all) (Additional file 7).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eChanges in plasma total cortisol and ACTH levels after ROSC\u003c/h2\u003e \u003cp\u003eWe measured the plasma total cortisol and ACTH levels of the 40 healthy individuals and 85 CA patients (two samples were excluded because their total cortisol levels were not measured). Compared with those in healthy controls, plasma total cortisol levels were significantly higher in patients who experienced CA (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) but ACTH levels were not (Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA, C). No statistical differences in ln (total cortisol\u0026thinsp;+\u0026thinsp;1) and ln (ACTH\u0026thinsp;+\u0026thinsp;1) values were observed between survivors and non-survivors (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05 for all) (Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB, D).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e "},{"header":"Discussion","content":" \u003cp\u003eThis study explored the relationship between GR expression and immune alteration in the early period after ROSC in patients who experienced CA, by observing GR expression in circulatory T and B lymphocytes, NK cells, and Treg cells and changes in cell counts and plasma total cortisol and ACTH levels. We found that GR expression, cell counts, and ratios rapidly decreased and plasma total cortisol levels increased in these patients.\u003c/p\u003e \u003cp\u003eAfter ROSC, the immune response of patients who experienced CA is impaired, and the systemic inflammatory response is increased [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In this study, the T and B lymphocyte, NK cell, and Treg cell counts as well as the CD3\u003csup\u003e+\u003c/sup\u003eCD4\u003csup\u003e+\u003c/sup\u003e/T, CD3\u003csup\u003e+\u003c/sup\u003eCD8\u003csup\u003e+\u003c/sup\u003e/T, and Treg cell/CD4\u003csup\u003e+\u003c/sup\u003eT lymphocyte ratios were significantly reduced after ROSC. NK cells, which are special innate immune cells that have cytotoxic functions similar to CD3\u003csup\u003e+\u003c/sup\u003eCD8\u003csup\u003e+\u003c/sup\u003e T lymphocytes, mainly distinguish infected and stressed cells from healthy cells and eliminate intracellular infection as well as dysfunctional cells [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. T lymphocytes are also important because of their function as adaptive immune cells for the control and elimination of infection [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Moreover, B and T lymphocytes mediate humoral and cellular immunity, respectively. Compared with previous studies, this study further performed an earlier and more comprehensive assessment of the immune system of patients who experienced CA, and our findings more substantially supported the rapid emergence of immune dysfunction in these patients after ROSC compared to that of previous reports.\u003c/p\u003e \u003cp\u003eThe effectiveness of GC use in these patients during and after resuscitation has been controversial due to insufficient evidence. However, the use of GC during resuscitation improves the survival rate of patients who experienced CA due to its direct anti-inflammatory, immunosuppressive effects, hemodynamic, and positive inotropic effects. All of this ultimately leads to increased stress capacity of the body [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. GC can activate GRs in cells when the body is under stress, thereby increasing both the effectiveness of resuscitation and the discharge survival rate. This study is the first to explore GR expression in circulating immune cells in patients who experienced CA after ROSC. We observed that GR expression in B and T lymphocytes, NK cells, and CD3\u003csup\u003e+\u003c/sup\u003eCD8\u003csup\u003e+\u003c/sup\u003e T lymphocytes decreased significantly in patients who experienced CA, while the percentage of GR\u003csup\u003e+\u003c/sup\u003e Treg cells and CD3\u003csup\u003e+\u003c/sup\u003eCD4\u003csup\u003e+\u003c/sup\u003e T lymphocytes showed a slight decrease. Moreover, we observed a more significant decrease in the MFI of GR expression in Treg cells and CD3\u003csup\u003e+\u003c/sup\u003eCD4\u003csup\u003e+\u003c/sup\u003e T lymphocytes but none in the percentage of GR expression. Previous studies have found decreased expression of GRs in peripheral polymorphonuclear cells in critically ill patients [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], and antagonism to GRs aggravates viral and bacterial infections [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. The results of this study suggest that the decrease in intracellular GR expression in patients who experienced CA may be one of the causes of GC resistance, due to insufficient binding of GRs and GCs, GC insensitivity, and the inability of GCs to effectively exert anti-inflammatory and immunosuppressive effects. These findings may also explain why different results of the clinical application of GCs have appeared in previous studies and support the possibility of using GCs in the clinical treatment of patients who experienced CA.\u003c/p\u003e \u003cp\u003eIn this study, we also found that the total plasma cortisol levels were significantly higher in patients who experienced CA but ACTH levels were not. High levels of inflammatory cytokines inhibit ACTH release [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. During critical illness, the body does not sufficiently metabolize cortisol [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. In addition, the continuous increase in plasma cortisol levels may trigger the negative feedback pathway of the hypothalamic-pituitary-adrenal axis, inhibiting the release of ACTH and cortisol and eventually leading to adrenal insufficiency. These factors may explain the opposite trends of plasma ACTH and cortisol levels in the patients who were included in this study and experienced CA. Notably, this result suggests that low GR expression levels cannot be matched with high plasma total cortisol levels. Previous studies have found that GC use during resuscitation may benefit patients who experienced CA [\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The benefits, such as direct anti-inflammatory and anti-shock effects, improvement of vascular endothelial permeability, and other mechanisms may be related to the effects of using a high dose of GC, or GCs may work through other non-GR pathways. It is also possible that the immune function of patients who experienced CA is suppressed due to ischemia-reperfusion injury, which requires a large dose of GC to stimulate GRs to function. This study did not provide data on plasma GC levels and GR expression in a group of patients who were administered GCs and successfully resuscitated; therefore, further studies are required to explore the exact mechanisms of GCs.\u003c/p\u003e \u003cp\u003eOur study has several limitations. First, to assess obvious changes, we only enrolled patients who experienced CA and had obvious signs of systemic ischemic hypoxia, such as GCS\u0026thinsp;\u0026lt;\u0026thinsp;8 after ROSC. The patients were not stratified by age, gender, occurrence of comorbidities or mild systemic ischemic hypoxia. Second, since this was a preliminary observational study, we were only observing early changes. A dynamic observation for a longer duration would be helpful to understand the significance of GR expression in evolving immunity during the clinical course of CA after ROSC. Third, the samples used in this study were from the clinical laboratory, so the plasma total cortisol and ACTH in the samples were at a risk of degradation before we collected the samples. Finally, we did not discuss the changes in and the roles of GR isoforms, free cortisol, and corticosteroid-binding globulin. Therefore, future studies on these aspects are warranted to better understand the immunosuppressive effects of ROSC among patients who experienced CA.\u003c/p\u003e "},{"header":"Conclusion","content":" \u003cp\u003eIn conclusion, this study revealed that GR expression, cell counts, and ratios rapidly decreased, while plasma total cortisol levels increased in the early period after ROSC among patients who experienced CA. These findings may provide important information about GC sensitivity and immunosuppressive status in these patients. In addition, this study provides a new perspective for clinical targeted treatment using GCs and high-quality prognosis in patients who experienced CA.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003eGC: Glucocorticoids; GR: Glucocorticoid receptors; CA: Cardiac arrest; Treg: Regulatory T cells; ACTH: Adrenocorticotrophic hormone; PCAS: Post cardiac arrest syndrome; SIRS: Systematic inflammatory response syndrome; ROCS: Return of spontaneous circulation; HLA-DR: Human leukocyte antigen DR; ED: Emergency department; APACHE: Acute Physiology and Chronic Health Evaluation; SOFA: Sequential Organ Failure Assessment; MFI: Mean fluorescence intensity; NK: Natural killer cells\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e This study was approved by the Medical Ethics Committee of Beijing Chaoyang Hospital, Capital Medical University (2013-KE-1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u003c/strong\u003e Due to the observational, non-interventional nature of the study, which was based on residual blood samples taken every morning after measuring the levels of routine biomarkers, we did not obtain informed consent from the patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish:\u003c/strong\u003e Not applicable\u003cstrong\u003eAvailability of data and materials: \u003c/strong\u003eAll data generated or analysed during this study are included in this published article and its supplementary information files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests: \u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding: \u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions: \u003c/strong\u003eCL designed the study and reviewed the manuscript. YNY searched literatures, contributed to experimental studies, date analysis and writing this manuscript. ZRT, CCH and LA collected and analyzed data. JBL and MRX helped with statistical analysis. All authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements: \u003c/strong\u003eWe thank all the researchers who participated in this study and all colleagues in the emergency department who provided support.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMyat A, Song KJ, Rea T. Out-of-hospital cardiac arrest: current concepts. Lancet. 2018;391:970\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWriting Group M, Mozaffarian D, Benjamin EJ, Go AS, Arnett TK, Blaha MJ, et al. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation. 2016;133:e38\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhang S. Sudden cardiac death in China: current status and future perspectives. Europace. 2015;17(Suppl 2):ii14\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNolan JP, Neumar RW, Adrie C, Aibiki M, Berg RA, Bottiger BW, et al. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke. Resuscitation. 2008;79:350\u0026ndash;79.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSu CP, Wu JH, Yang MC, Liao CH, Hsu HY, Chang CH, et al. Demographics and Clinical Features of Postresuscitation Comorbidities in Long-Term Survivors of Out-of-Hospital Cardiac Arrest: A National Follow-Up Study. Biomed Res Int. 2017;2017:9259182.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTsai MS, Chiang WC, Lee CC, Hsieh CC, Ko PC, Hsu CY, et al. Infections in the survivors of out-of-hospital cardiac arrest in the first 7 days. Intensive Care Med. 2005;31:621\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAdrie C, Adib-Conquy M, Laurent I, Monchi M, Vinsonneau C, Fitting C, et al. Successful cardiopulmonary resuscitation after cardiac arrest as a \"sepsis-like\" syndrome. Circulation. 2002;106:562\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ede Jong MF, Beishuizen A, de Jong MJ, Girbes AR, Groeneveld ABJ. The pituitary-adrenal axis is activated more in non-survivors than in survivors of cardiac arrest, irrespective of therapeutic hypothermia. Resuscitation. 2008;78:281\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHall ED. Neuroprotective actions of glucocorticoid and nonglucocorticoid steroids in acute neuronal injury. Cell Mol Neurobiol. 1993;13:415\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMosaddegh R, Kianmehr N, Mahshidfar B, Rahmani Z, Aghdam H, Mofidi M. Serum cortisol level and adrenal reserve as a predictor of patients' outcome after successful cardiopulmonary resuscitation. J Cardiovasc Thorac Res. 2016;8:61\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHekimian G, Baugnon T, Thuong M, Monchi M, Dabbane H, Jaby D, et al. Cortisol levels and adrenal reserve after successful cardiac arrest resuscitation. Shock. 2004;22:116\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTavakoli N, Bidari A, Shams Vahdati S. Serum Cortisol Levels as a Predictor of Neurologic Survival in Successfully Resuscitated Victims of Cardiopulmonary Arrest. J Cardiovasc Thorac Res. 2012;4:107\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSoar J, Callaway CW, Aibiki M, Bottiger BW, Brooks SC, Deakin CD, et al. Part 4: Advanced life support: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation. 2015;95:e71\u0026ndash;120.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMentzelopoulos SD, Malachias S, Chamos C, Konstantopoulos D, Ntaidou T, Papastylianou A, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest: a randomized clinical trial. JAMA. 2013;310:270\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTsai MS, Chuang PY, Yu PH, Huang CH, Tang CH, Chang WT, et al. Glucocorticoid use during cardiopulmonary resuscitation may be beneficial for cardiac arrest. Int J Cardiol. 2016;222:629\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNiimura T, Zamami Y, Koyama T, Izawa-Ishizawa Y, Miyake M, Koga T, et al. Hydrocortisone administration was associated with improved survival in Japanese patients with cardiac arrest. Sci Rep. 2017;7:17919.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChalkias A, Xanthos T. Post-cardiac arrest syndrome: Mechanisms and evaluation of adrenal insufficiency. World J Crit Care Med. 2012;1:4\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBuddineni JP, Callaway C, Huang DT. Epinephrine, vasopressin and steroids for in-hospital cardiac arrest: the right cocktail therapy? Crit Care. 2014;18:308.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVarvarousi G, Stefaniotou A, Varvaroussis D, Xanthos T. Glucocorticoids as an emerging pharmacologic agent for cardiopulmonary resuscitation. Cardiovasc Drugs Ther. 2014;28:477\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKadmiel M, Cidlowski JA. Glucocorticoid receptor signaling in health and disease. Trends Pharmacol Sci. 2013;34:518\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNorbiato G, Bevilacqua M, Vago T, Baldi G, Chebat E, Bertora P, et al. Cortisol resistance in acquired immunodeficiency syndrome. J Clin Endocrinol Metab. 1992;74:608\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVassiliou AG, Floros G, Jahaj E, Stamogiannos G, Gennimata S, Vassiliadi DA, et al. Decreased glucocorticoid receptor expression during critical illness. Eur J Clin Invest. 2019;49:e13073.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlder MN, Opoka AM, Wong HR. The glucocorticoid receptor and cortisol levels in pediatric septic shock. Crit Care. 2018;22:244.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eQi Z, Liu Q, Zhang Q, Liu B, Li C. Overexpression of programmed cell death-1 and human leucocyte antigen-DR on circulatory regulatory T cells in out-of-hospital cardiac arrest patients in the early period after return of spontaneous circulation. Resuscitation. 2018;130:13\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eQi Z, An L, Liu B, Zhang Q, Yin W, Yu H, et al. Patients with out-of-hospital cardiac arrest show decreased human leucocyte antigen-DR expression on monocytes and B and T lymphocytes after return of spontaneous circulation. Scand J Immunol. 2018;88:e12707.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePerkins GD, Travers AH, Berg RA, Castren M, Considine J, Escalante R, et al. Part 3: Adult basic life support and automated external defibrillation: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation. 2015;95:e43\u0026ndash;69.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBeurskens CJ, Horn J, de Boer AM, Schultz MJ, Leeuwen EM, Vroom MB, et al. Cardiac arrest patients have an impaired immune response, which is not influenced by induced hypothermia. Crit Care. 2014;18:R162.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLanier LL. NK cell recognition. Annu Rev Immunol. 2005;23:225\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol. 2008;9:503\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWebster JI, Sternberg EM. Role of the hypothalamic-pituitary-adrenal axis, glucocorticoids and glucocorticoid receptors in toxic sequelae of exposure to bacterial and viral products. J Endocrinol. 2004;181:207\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBoonen E, Vervenne H, Meersseman P, Andrew R, Mortier L, Declercq PE, et al. Reduced cortisol metabolism during critical illness. N Engl J Med. 2013;368:1477\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Patient Characteristics at Admission\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" width=\"0\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"287\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e\u003cstrong\u003eHealthy Control\u0026nbsp; \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGroup (n=40)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e\u003cstrong\u003eSuccessful Resuscitation\u003c/strong\u003e \u003cstrong\u003eGroup (n=85)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eP-Value\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"287\"\u003e\n\u003cp\u003eAge (years), median [IQR]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e64.0 (54.3-69.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e65.0 (55.0-74.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e0.209\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"287\"\u003e\n\u003cp\u003eMale/Female (n)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e23/17\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e58/27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e0.241\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"287\"\u003e\n\u003cp\u003ePrevious medical history, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"287\"\u003e\n\u003cp\u003eHypertension\u003c/p\u003e\n\u003cp\u003eDiabetes\u003c/p\u003e\n\u003cp\u003eCoronary heart disease\u003c/p\u003e\n\u003cp\u003eChronic lung disease\u003c/p\u003e\n\u003cp\u003eChronic kidney disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e5 (12.5%)\u003c/p\u003e\n\u003cp\u003e3 (7.5%)\u003c/p\u003e\n\u003cp\u003e2 (5.0%)\u003c/p\u003e\n\u003cp\u003e1 (2.5%)\u003c/p\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e38 (44.7%)\u003c/p\u003e\n\u003cp\u003e27 (31.8%)\u003c/p\u003e\n\u003cp\u003e29 (34.1%)\u003c/p\u003e\n\u003cp\u003e9 (10.6%)\u003c/p\u003e\n\u003cp\u003e9 (10.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n\u003cp\u003e0.003\u003c/p\u003e\n\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n\u003cp\u003e0.230\u003c/p\u003e\n\u003cp\u003e0.077\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"287\"\u003e\n\u003cp\u003eCardiac arrest cause (n, %)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"287\"\u003e\n\u003cp\u003eCardiac\u003c/p\u003e\n\u003cp\u003eRespiratory\u003c/p\u003e\n\u003cp\u003eCerebral\u003c/p\u003e\n\u003cp\u003eOthers\u003c/p\u003e\n\u003cp\u003eUnknow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e34 (40.0%)\u003c/p\u003e\n\u003cp\u003e20 (23.5%)\u003c/p\u003e\n\u003cp\u003e23 (27.1%)\u003c/p\u003e\n\u003cp\u003e7 (8.2%)\u003c/p\u003e\n\u003cp\u003e1 (1.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"287\"\u003e\n\u003cp\u003eInitial resuscitation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"287\"\u003e\n\u003cp\u003eTime to ROSC (min), median [IQR]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e20.0 (10.0-30.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"287\"\u003e\n\u003cp\u003eAdrenaline (mg), median [IQR]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e2.0 (0.0-5.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"420\"\u003e\n\u003cp\u003eInitial rhythm VF/VT, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e30 (35.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"420\"\u003e\n\u003cp\u003eMAP (mmHg), median [IQR]\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; 95.7 (86.0-103.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e74.3 (56.2-97.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"287\"\u003e\n\u003cp\u003eWhite cell count (\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L), median [IQR]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e5.81 (4.85-6.53)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e13.56 (10.84-18.29)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"287\"\u003e\n\u003cp\u003eAPACHE Ⅱ score, mean\u0026plusmn;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e32.9\u0026plusmn;6.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"287\"\u003e\n\u003cp\u003eSOFA score, median [IQR]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e11.5 (8.5-14.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"287\"\u003e\n\u003cp\u003e28-day mortality, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e65（76.5%）\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"287\"\u003e\n\u003cp\u003e28-day CPC 1\u0026ndash;2, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"161\"\u003e\n\u003cp\u003e14 (16.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eData are presented as mean\u0026plusmn;SD or interquartile range (IQR) as appropriate. The p-value represents comparison between groups. Abbreviations: ROSC: return of spontaneous circulation; VF: ventricular fibrillation; VT: ventricular tachycardia; MAP: mean arterial pressure; APACHE Ⅱ: acute physiology and chronic health evaluation; SOFA: sequential organ failure assessment; CPC: cerebral performance category.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Glucocorticoid, immunosuppression, cortisol, ACTH, pituitary–adrenal axis","lastPublishedDoi":"10.21203/rs.3.rs-278830/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-278830/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Rapid changes in glucocorticoid (GC) levels and adrenal insufficiency are related to the development of post-cardiac arrest syndrome. However, changes in glucocorticoid receptors (GR) have not been studied. Hence, this study aimed to investigate the association of early changes in GR and prognosis and immune response in patients who experienced cardiac arrest (CA). \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e In this observational single-center case-control study, we enrolled patients who were in the early period of return of spontaneous circulation after CA and were admitted to the emergency department of the Beijing Chaoyang Hospital between October 2018 and October 2019. Age- and sex-matched healthy individuals were recruited for the control group after a physical examination.\u003c/p\u003e\u003cp\u003eGR expression and cell counts of circulatory T and B lymphocytes, natural killer, and regulatory T (Treg) cells were assessed. Plasma total cortisol and adrenocorticotrophic hormone (ACTH) levels were tested. Since the data for total cortisol and ACTH levels had a skewed distribution, we compared our results with the natural logarithmic conversion values after adding 1 (ln [total cortisol+ 1], ln [ACTH+ 1]). Measurement data with a skewed distribution are expressed as medians (25th and 75th percentiles). The Mann–Whitney U test was used to compare variables between groups. The qualitative parameters in the 2 × 2 contingency table were used for analysis.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eOverall, 85 patients who experienced CA and 40 healthy individuals were enrolled. All cell counts were lower and plasma total cortisol levels were higher (P\u0026lt;0.001) in patients who experienced CA than those in the healthy control group. GR expression in Treg cells and CD3\u003csup\u003e+\u003c/sup\u003eCD4\u003csup\u003e+\u003c/sup\u003e T lymphocytes was not significantly different, but the mean fluorescence intensity and GR expression in other cells were lower in patients who experienced CA (P\u0026lt;0.05) than those in the healthy control group. ACTH levels did not show any difference. There were no significant differences between survivors and non-survivors. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e Our findings provide insights into GC sensitivity and immunosuppressive status in these patients, and a new perspective for GC targeted treatment.\u003c/p\u003e","manuscriptTitle":"Expression of Glucocorticoid Receptors in the Early Period After the Return of Spontaneous Circulation Among Patients Who Experienced Cardiac Arrest : A Retrospective Observational Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-03-15 19:54:13","doi":"10.21203/rs.3.rs-278830/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"57119657-53b3-4286-b604-d5bb5e086b91","owner":[],"postedDate":"March 15th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":2949897,"name":"Critical Care \u0026 Emergency Medicine"}],"tags":[],"updatedAt":"2021-03-29T14:06:13+00:00","versionOfRecord":[],"versionCreatedAt":"2021-03-15 19:54:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-278830","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-278830","identity":"rs-278830","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}