|
1
|
Yang JY, Li LL, Fu SZ. Association analysis of sepsis progression to sepsis-induced coagulopathy: a study based on the MIMIC-IV database. BMC Infect Dis 2025; 25:573. [PMID: 40259248 PMCID: PMC12013014 DOI: 10.1186/s12879-025-10972-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 04/14/2025] [Indexed: 04/23/2025] Open
Abstract
BACKGROUND Sepsis-induced coagulopathy (SIC) is a severe complication of sepsis, characterized by poor prognosis and high mortality. However, the predictive factors for the development of SIC in sepsis patients remain to be determined. The aim of this study was to develop an easy-to-use and efficient nomogram for predicting the risk of sepsis patients developing SIC in the intensive care unit (ICU), based on common indicators and complications observed at admission. METHODS A total of 12, 455 sepsis patients from the MIMIC database were screened and randomly divided into training and validation cohorts. In the training cohort, LASSO regression was used for variable selection and regularization. The selected variables were then incorporated into a multivariable logistic regression model to construct the nomogram for predicting the risk of sepsis patients developing sepsis-induced coagulopathy (SIC). The model's predictive performance was evaluated using the area under the receiver operating characteristic curve (AUC), and its calibration was assessed through a calibration curve. Additionally, decision curve analysis (DCA) was performed to evaluate the clinical applicability of the model. External validation was conducted using data from the ICU database of Xingtai People's Hospital. RESULTS Among the 12, 455 sepsis patients, 5, 145 (41. 3%) developed SIC. The occurrence of SIC was significantly associated with the SOFA score, red blood cell count, red cell distribution width (RDW), white blood cell count, platelet count, INR, and lactate levels. Additionally, hypertension was identified as a potential protective factor. A nomogram was developed to predict the risk of SIC, which showed an AUC of 0. 81 (95% CI: 0. 79-0. 83) in the training set, 0. 83 (95% CI: 0. 82-0. 84) in the validation set, and 0. 79 (95% CI: 0. 74-0. 84) in the external validation. The calibration curve of the nomogram showed good consistency between the observed and predicted probabilities of SIC. CONCLUSIONS The novel nomogram demonstrates excellent predictive performance for the incidence of SIC in ICU patients with sepsis and holds promise for assisting clinicians in early identification and intervention of SIC. CLINICAL TRIAL Not applicable.
Collapse
Affiliation(s)
- Jian-Yue Yang
- Department of Critical Care Medicine, Xingtai People's Hospital, Hebei, 054001, China
| | - Li-Li Li
- Department of Critical Care Medicine, Xingtai People's Hospital, Hebei, 054001, China
| | - Su-Zhen Fu
- Department of Critical Care Medicine, Xingtai People's Hospital, Hebei, 054001, China.
| |
Collapse
|
|
2
|
Jose AM, Rafieezadeh A, Kirsch J, Ebanks M, Shnaydman I, Froula G, Prabhakaran K, Zangbar B. Unveiling the impact of trauma during pregnancy. Am J Surg 2025; 240:116124. [PMID: 39637602 DOI: 10.1016/j.amjsurg.2024.116124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 11/18/2024] [Accepted: 11/27/2024] [Indexed: 12/07/2024]
Abstract
BACKGROUND Pregnant trauma patients present unique challenges in terms of assessment and management. This study assesses the impact of traumatic injuries on pregnant patients using a national trauma database. METHODS ACS-TQIP (2020-2021) identified traumatically injured females aged ≥15 and ≤ 55. Propensity score matching compared pregnant and not-pregnant patients. Primary outcome was mortality, with secondary outcomes including length of stay (LOS), emergency department and discharge disposition, interventions, and complications. RESULTS Of 947,000 traumatically injured females, 8421 (0.9 %) were pregnant. Pregnant patients (6.0 %) sustained firearm injuries more than not-pregnant patients (5.4 %) (p = 0.02). Pregnant patients had more severe thoracic (47.2%vs.9.4 %) and abdominal injuries (7.1%vs.4.8 %) compared to not-pregnant patients (p < 0.001). Among pregnant patients, 5.6 % had preterm labor, 2.6 % had cesarean sections, and 1.9 % had abortions. After matching, there was no significant difference in mortality between both groups (p = 0.40). Pregnant patients had longer ICU LOS (p < 0.05) and higher rates of unplanned return to ICU (p < 0.05). CONCLUSIONS Pregnant patients are more often victims of firearm violence, sustaining critical thoracic and abdominal injuries. These injuries demand increased interventions, introduce complications, and can be fatal.
Collapse
Affiliation(s)
- Anna Mary Jose
- Westchester Medical Center, New York Medical College, Valhalla, NY, USA
| | - Aryan Rafieezadeh
- Westchester Medical Center, New York Medical College, Valhalla, NY, USA
| | - Jordan Kirsch
- Westchester Medical Center, New York Medical College, Valhalla, NY, USA
| | - Mikaiel Ebanks
- Westchester Medical Center, New York Medical College, Valhalla, NY, USA
| | - Ilya Shnaydman
- Westchester Medical Center, New York Medical College, Valhalla, NY, USA
| | - Gabriel Froula
- Westchester Medical Center, New York Medical College, Valhalla, NY, USA
| | | | - Bardiya Zangbar
- Westchester Medical Center, New York Medical College, Valhalla, NY, USA.
| |
Collapse
|
|
3
|
Lotfalla A, Halm JA, Schepers T, Giannakópoulos GF. Parameters influencing health-related quality of life after severe trauma: a systematic review (part II). Eur J Trauma Emerg Surg 2024; 50:93-106. [PMID: 37188975 PMCID: PMC10923745 DOI: 10.1007/s00068-023-02276-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 05/02/2023] [Indexed: 05/17/2023]
Abstract
INTRODUCTION It is increasingly recognized that health-related quality of life (HRQoL) is a relevant outcome to study in populations comprising severely injured patients. Although some studies have readily demonstrated a compromised HRQoL in those patients, evidence regarding factors that predict HRQoL is scarce. This hinders attempts to prepare patient-specific plans that may aid in revalidation and improved life satisfaction. In this review, we present identified predictors of HRQoL in patients that have suffered severe trauma. METHODS The search strategy included a database search until the 1st of January 2022 in the Cochrane Library, EMBASE, PubMed, and Web of Science, and reference checking. Studies were eligible for inclusion when (HR)QoL was studied in patients with major, multiple, or severe injury and/or polytrauma, as defined by authors by means of an Injury Severity Score (ISS) cut-off value. The results will be discussed in a narrative manner. RESULTS A total of 1583 articles were reviewed. Of those, 90 were included and used for analysis. In total, 23 possible predictors were identified. The following parameters predicted reduced HRQoL in severely injured patients and came forward in at least more than three studies: higher age, female gender, lower extremity injuries, higher rate of injury severity, lower achieved educational level, presence of (pre-existing) comorbidities and mental illness, longer duration of hospital stay, and high level of disability. CONCLUSION Age, gender, injured body region, and severity of injury were found to be good predictors of health-related quality of life in severely injured patients. A patient-centered approach, based on individual, demographic, and disease-specific predictors, is highly recommended.
Collapse
Affiliation(s)
- Annesimone Lotfalla
- Department of Trauma Surgery, Trauma Unit, Amsterdam University Medical Center, Location Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
| | - Jens Anthony Halm
- Department of Trauma Surgery, Trauma Unit, Amsterdam University Medical Center, Location Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Tim Schepers
- Department of Trauma Surgery, Trauma Unit, Amsterdam University Medical Center, Location Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Georgios Fredericus Giannakópoulos
- Department of Trauma Surgery, Trauma Unit, Amsterdam University Medical Center, Location Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| |
Collapse
|
|
4
|
Jiang W, Song L, Zhang Y, Ba J, Yuan J, Li X, Liao T, Zhang C, Shao J, Yu J, Zheng R. The influence of gender on the epidemiology of and outcome from sepsis associated acute kidney injury in ICU: a retrospective propensity-matched cohort study. Eur J Med Res 2024; 29:56. [PMID: 38229118 DOI: 10.1186/s40001-024-01651-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 01/08/2024] [Indexed: 01/18/2024] Open
Abstract
PURPOSES The influence of gender on the epidemiology of and outcome from SA-AKI in ICU has not been fully clarified. Our aim is to elucidate these differences. METHODS This study included adult patients with sepsis in MIMIC IV (V 2.2), and propensity matching analysis, cox regression and logistic regression were used to analyze gender differences in incidence, mortality and organ support rate. RESULTS Of the 24,467 patients included in the cohort, 18,128 were retained after propensity score matching. In the matched cohort, the incidence of SA-AKI in males is higher than that in females (58.6% vs. 56.2%; P = 0.001).males were associated with a higher risk of SA-AKI (OR:1.07(1.01-1.14), P = 0.026;adjusted OR:1.07(1.01-1.14), P < 0.033).In SA-AKI patients, males were associated with a lower risk of ICU mortality(HR:0.803(0.721-0.893), P < 0.001;adjusted HR:0.836(0.746-0.937), P = 0.002) and in-hospital mortality(HR: 0.820(0.748-0.899), P < 0.001;adjusted HR:0.853(0.775-0.938), P = 0.003).there were no statistically significant differences between male and female patients in 1-year all-cause mortality (36.9% vs. 35.8%, P = 0.12), kidney replacement therapy rate (7.8% vs.7.4%, P = 0.547), mechanical ventilation rate 64.8% vs.63.9%, P = 0.369), and usage of vasoactive drugs (55.4% vs. 54.6%, P = 0.418). CONCLUSIONS Gender may affect the incidence and outcomes of SA-AKI, further research is needed to fully understand the impact of gender on SA-AKI patients.
Collapse
Affiliation(s)
- Wei Jiang
- Medcial College, Yang Zhou University, Yangzhou, 225001, China
- Department of Critical Care Medicine, Clinical Medicine College, Yangzhou University & Intensive Care Unit, Northern Jiangsu People's Hospital, Yangzhou, 225001, China
| | - Lin Song
- Medcial College, Yang Zhou University, Yangzhou, 225001, China
- Department of Critical Care Medicine, Clinical Medicine College, Yangzhou University & Intensive Care Unit, Northern Jiangsu People's Hospital, Yangzhou, 225001, China
| | - Yaosheng Zhang
- School of Clinical and Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250000, China
| | - Jingjing Ba
- Department of Cardiology, the Second Affiliated Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271000, China
| | - Jing Yuan
- Department of Echocardiography, Northern Jiangsu People's Hospital, Yangzhou, 225001, China
| | - Xianghui Li
- Department of Critical Care Medicine, Clinical Medicine College, Yangzhou University & Intensive Care Unit, Northern Jiangsu People's Hospital, Yangzhou, 225001, China
| | - Ting Liao
- Medcial College, Yang Zhou University, Yangzhou, 225001, China
- Department of Critical Care Medicine, Clinical Medicine College, Yangzhou University & Intensive Care Unit, Northern Jiangsu People's Hospital, Yangzhou, 225001, China
| | - Chuanqing Zhang
- Medcial College, Yang Zhou University, Yangzhou, 225001, China
- Department of Critical Care Medicine, Clinical Medicine College, Yangzhou University & Intensive Care Unit, Northern Jiangsu People's Hospital, Yangzhou, 225001, China
| | - Jun Shao
- Medcial College, Yang Zhou University, Yangzhou, 225001, China
- Department of Critical Care Medicine, Clinical Medicine College, Yangzhou University & Intensive Care Unit, Northern Jiangsu People's Hospital, Yangzhou, 225001, China
| | - Jiangquan Yu
- Medcial College, Yang Zhou University, Yangzhou, 225001, China.
- Department of Critical Care Medicine, Clinical Medicine College, Yangzhou University & Intensive Care Unit, Northern Jiangsu People's Hospital, Yangzhou, 225001, China.
| | - Ruiqiang Zheng
- Medcial College, Yang Zhou University, Yangzhou, 225001, China.
- Department of Critical Care Medicine, Clinical Medicine College, Yangzhou University & Intensive Care Unit, Northern Jiangsu People's Hospital, Yangzhou, 225001, China.
| |
Collapse
|
|
5
|
Zwemer CH, Mohamed T, Wu S, Farag CM, Zebley J, Kartiko S. Do Females Have Worse Outcomes in Penetrating Trauma: A Single-Center Analysis. J Surg Res 2024; 293:632-638. [PMID: 37837819 DOI: 10.1016/j.jss.2023.09.045] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 08/15/2023] [Accepted: 09/03/2023] [Indexed: 10/16/2023]
Abstract
INTRODUCTION Penetrating trauma occurs less frequently in females than in males. Studies on penetrating injuries are conducted in predominantly male populations. We aim to elucidate the demographics and outcomes of penetrating trauma specifically in females to mitigate disparities of care in females. MATERIALS AND METHODS A retrospective review of hospitalized adult trauma patients suffering penetrating trauma from 2015 to 2021 was performed in an urban American College of Surgeon-verified level 1 trauma center. Patients were stratified by sex (females or males) and mechanism of injury (gun-related versus nongun-related). The primary outcome was mortality, and secondary outcomes included incidence of blood transfusion, incidence of surgical/interventional radiology (IR) interventions, hospital length of stay (LOS), and complications. Descriptive statistics were employed with a significance defined as P value <0.05. A multivariate logistic regression was used to determine the impact of sex on mortality, surgical/IR interventions, and hospital LOS. RESULTS Females with penetrating injury had lower Injury Severity Score (1 versus 4, P < 0.05) than males, but had similar mortality rates (4% versus 6%, P = 0.06). In multivariable logistic analysis adjusting for age and Injury Severity Score, while females experience 33% fewer OR/IR intervention, there was no statistically significant difference in mortality rates, hospital LOS, and complication rates between males and females. CONCLUSIONS Despite receiving fewer surgical/IR intervention, females with penetrating injuries have similar outcomes to their male counterparts. Further study is needed to study this discrepancy.
Collapse
Affiliation(s)
- Catherine H Zwemer
- Department of Surgery, Center for Trauma and Critical Care, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia
| | - Troy Mohamed
- Department of Surgery, Center for Trauma and Critical Care, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia
| | - Sophia Wu
- Department of Surgery, Center for Trauma and Critical Care, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia
| | - Christian M Farag
- Department of Surgery, Center for Trauma and Critical Care, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia
| | - James Zebley
- Department of Surgery, Center for Trauma and Critical Care, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia
| | - Susan Kartiko
- Department of Surgery, Center for Trauma and Critical Care, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia.
| |
Collapse
|
|
6
|
Zhang MQ, Macala KF, Fox-Robichaud A, Mendelson AA, Lalu MM. Sex- and Gender-Dependent Differences in Clinical and Preclinical Sepsis. Shock 2021; 56:178-187. [PMID: 33399356 DOI: 10.1097/shk.0000000000001717] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
ABSTRACT In this mini-review we provide an overview of sex- and gender-dependent issues in both clinical and preclinical sepsis. The increasing recognition for the need to account for sex and gender in biomedical research brings a unique set of challenges and requires researchers to adopt best practices when conducting and communicating sex- and gender-based research. This may be of particular importance in sepsis, given the potential contribution of sex bias in the failures of translational sepsis research in adults and neonates. Clinical evidence of sex-dependent differences in sepsis is equivocal. Since clinical studies are limited to observational data and confounded by a multitude of factors, preclinical studies provide a unique opportunity to investigate sex differences in a controlled, experimental environment. Numerous preclinical studies have suggested that females may experience favorable outcomes in comparison with males. The underlying mechanistic evidence for sex-dependent differences in sepsis and other models of shock (e.g., trauma-hemorrhage) largely centers around the beneficial effects of estrogen. Other mechanisms such as the immunosuppressive role of testosterone and X-linked mosaicism are also thought to contribute to observed sex- and gender-dependent differences in sepsis. Significant knowledge gaps still exist in this field. Future investigations can address these gaps through careful consideration of sex and gender in clinical studies, and the use of clinically accurate preclinical models that reflect sex differences. A better understanding of sex-and gender-dependent differences may serve to increase translational research success.
Collapse
Affiliation(s)
- Meng Qi Zhang
- Clinical Epidemiology Program, Blueprint Translational Group, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8M5
| | - Kimberly F Macala
- Departments of Critical Care Medicine and Anesthesiology and Pain Medicine, Royal Alexandra Hospital, University of Alberta, Edmonton, AB, Canada
| | - Alison Fox-Robichaud
- Department of Medicine and Thrombosis and Atherosclerosis Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada
| | - Asher A Mendelson
- Section of Critical Care Medicine, Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - Manoj M Lalu
- Clinical Epidemiology Program, Blueprint Translational Group, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, Ottawa, ON, Canada
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| |
Collapse
|
|
7
|
Lalonde CS, Mekawi Y, Ethun KF, Beurel E, Gould F, Dhabhar FS, Schultebraucks K, Galatzer-Levy I, Maples-Keller JL, Rothbaum BO, Ressler KJ, Nemeroff CB, Stevens JS, Michopoulos V. Sex Differences in Peritraumatic Inflammatory Cytokines and Steroid Hormones Contribute to Prospective Risk for Nonremitting Posttraumatic Stress Disorder. CHRONIC STRESS (THOUSAND OAKS, CALIF.) 2021; 5:24705470211032208. [PMID: 34595364 PMCID: PMC8477354 DOI: 10.1177/24705470211032208] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Women are at higher risk for developing posttraumatic stress disorder (PTSD) compared to men, yet little is known about the biological contributors to this sex difference. One possible mechanism is differential immunological and neuroendocrine responses to traumatic stress exposure. In the current prospective study, we aimed to identify whether sex is indirectly associated with the probability of developing nonremitting PTSD through pro-inflammatory markers and whether steroid hormone concentrations influence this effect. Female (n = 179) and male (n = 197) trauma survivors were recruited from an emergency department and completed clinical assessment within 24 h and blood samples within ∼three hours of trauma exposure. Pro-inflammatory cytokines (IL-6, IL-1 β , TNF, IFNγ), and steroid hormone (estradiol, testosterone, progesterone, cortisol) concentrations were quantified in plasma. Compared to men, women had a higher probability of developing nonremitting PTSD after trauma (p = 0.04), had lower pro-inflammatory cytokines and testosterone (p's<0.001), and had higher cortisol and progesterone (p's<0.001) concentrations. Estradiol concentrations were not different between the sexes (p = 0.24). Pro-inflammatory cytokines were a significant mediator in the relationship between sex and probability of developing nonremitting PTSD (p < 0.05), such that men had higher concentrations of pro-inflammatory cytokines which were associated with lower risk of nonremitting PTSD development. This effect was significantly moderated by estradiol (p < 0.05), as higher estradiol levels in men were associated with higher pro-inflammatory cytokine concentrations and lower risk for developing nonremitting PTSD. The current results suggest that sex differences in the pro-inflammatory cytokine response to trauma exposure partially mediate the probability of developing nonremitting PTSD, and that the protective ability to mount an pro-inflammatory cytokine response in men may depend on higher estradiol levels in the aftermath of trauma exposure.
Collapse
Affiliation(s)
- Chloe S. Lalonde
- Department of Medicine, Emory University School of
Medicine, Atlanta, Georgia, USA
| | - Yara Mekawi
- Department of Psychiatry and Behavioral Sciences, Emory University School of
Medicine, Atlanta, Georgia, USA
| | - Kelly F. Ethun
- Yerkes National Primate Research Center, Atlanta, Georgia, USA
- Department of Pathology and Laboratory Medicine, Emory University School of
Medicine, Atlanta, Georgia, USA
| | - Eleonore Beurel
- Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of
Medicine, Miami, Florida, USA
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of
Medicine, Miami, Florida, USA
| | - Felicia Gould
- Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of
Medicine, Miami, Florida, USA
| | - Firdaus S. Dhabhar
- Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of
Medicine, Miami, Florida, USA
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of
Medicine, Miami, Florida, USA
- Department of Psychology, University of Miami, Coral Gables,
Florida, USA
| | - Katharina Schultebraucks
- Department of Emergency Medicine, Columbia University Irving Medical
Center, New York, New York, USA
| | - Isaac Galatzer-Levy
- Department of Psychiatry, New York University School of
Medicine, New York, New York, USA
| | - Jessica L. Maples-Keller
- Department of Psychiatry and Behavioral Sciences, Emory University School of
Medicine, Atlanta, Georgia, USA
| | - Barbara O. Rothbaum
- Department of Psychiatry and Behavioral Sciences, Emory University School of
Medicine, Atlanta, Georgia, USA
| | - Kerry J. Ressler
- Department of Psychiatry and Behavioral Sciences, Emory University School of
Medicine, Atlanta, Georgia, USA
- Mclean Hospital, Harvard Medical School, Belmont, Massachusetts, USA
| | - Charles B. Nemeroff
- Department of Psychiatry and Behavioral Sciences, University of Texas at
Austin, Dell Medical School, Austin, Texas, USA
| | - Jennifer S. Stevens
- Department of Psychiatry and Behavioral Sciences, Emory University School of
Medicine, Atlanta, Georgia, USA
| | - Vasiliki Michopoulos
- Department of Psychiatry and Behavioral Sciences, Emory University School of
Medicine, Atlanta, Georgia, USA
- Yerkes National Primate Research Center, Atlanta, Georgia, USA
| |
Collapse
|
|
8
|
Abstract
Despite efforts in prevention and intensive care, trauma and subsequent sepsis are still associated with a high mortality rate. Traumatic injury remains the main cause of death in people younger than 45 years and is thus a source of immense social and economic burden. In recent years, the knowledge concerning gender medicine has continuously increased. A number of studies have reported gender dimorphism in terms of response to trauma, shock and sepsis. However, the advantageous outcome following trauma-hemorrhage in females is not due only to sex. Rather, it is due to the prevailing hormonal milieu of the victim. In this respect, various experimental and clinical studies have demonstrated beneficial effects of estrogen for the central nervous system, the cardiopulmonary system, the liver, the kidneys, the immune system, and for the overall survival of the host. Nonetheless, there remains a gap between the bench and the bedside. This is most likely because clinical studies have not accounted for the estrus cycle. This review attempts to provide an overview of the current level of knowledge and highlights the most important organ systems responding to trauma, shock and sepsis. There continues to be a need for clinical studies on the prevailing hormonal milieu following trauma, shock and sepsis.
Collapse
Affiliation(s)
- Florian Bösch
- Department of General, Visceral, and Transplant Surgery, Ludwig Maximilians-University Munich, 81377, Munich, Germany
| | - Martin K Angele
- Department of General, Visceral, and Transplant Surgery, Ludwig Maximilians-University Munich, 81377, Munich, Germany
| | - Irshad H Chaudry
- Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
| |
Collapse
|
|
9
|
Impact of Sexual Dimorphism on Trauma Patterns and Clinical Outcomes of Patients with a High-Risk Score of the Osteoporosis Self-Assessment Tool for Asians: A Propensity Score-Matched Analysis. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2018; 15:ijerph15030418. [PMID: 29495544 PMCID: PMC5876963 DOI: 10.3390/ijerph15030418] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 02/14/2018] [Accepted: 02/23/2018] [Indexed: 12/12/2022]
Abstract
The Osteoporosis Self-assessment Tool for Asians (OSTA) is a validated index based on age and weight to predict the risk of osteoporosis in women. This cross-sectional study was designed to evaluate the impact of sexual dimorphism on the trauma patterns and the clinical outcomes of patients with high-risk OSTA scores. Trauma data of patients with high-risk OSTA scores between 1 January 2009 and 31 December 2015 were retrieved from the trauma registry system of a level I trauma center. A total of 2248 patients including 1585 women and 663 men were included in this study. In-hospital mortality was assessed as the primary outcome in the propensity score-matched analyses of the female and male patients, which were created in a 1:1 ratio under the adjustment of potential confounders, including age, co-morbidity, mechanism and injury-severity score (ISS). Female patients with a high-risk OSTA score had significantly lower mortality rates than their male counterparts. Among the propensity score-matched population, female patients had lower odds of having cerebral contusion and pneumothorax, but higher odds of presenting with radial, ulnar and femoral fractures than male patients. In addition, the female patients still had significantly lower odds of mortality (odds ratio (OR), 0.5; 95% confidence interval (CI), 0.29-0.90; p = 0.019) than the male patients. However, no significant differences were noted in the length of stay (LOS) in hospital, intensive-care unit (ICU) admission, and LOS in the ICU between the sexes. Female patients with high-risk OSTA scores showed different injury patterns and significantly lower mortality rates than their male counterparts, even after controlling for potential confounding factors.
Collapse
|
|
10
|
Abstract
Several lines of evidence indicate that female sex is a protective factor in trauma and hemorrhage. In both clinical and experimental studies, proestrus females have been shown to have better chances of survival and reduced rates of posttraumatic sepsis. Estrogen receptors are expressed in a variety of tissues and exert genomic, as well as nongenomic effects. By improving cardiac, pulmonary, hepatic, and immune function, estrogens have been shown to prolong survival in animal models of hemorrhagic shock. Despite encouraging results from experimental studies, retrospective clinical studies have not clearly pointed to advantages of estrogens following trauma-hemorrhage, which may be due to insufficient study design. Therefore, this review aims to give an overview on the current evidence and emphasizes on the importance of further clinical investigation on estrogens following trauma.
Collapse
|
|
11
|
Al-Tarrah K, Moiemen N, Lord JM. The influence of sex steroid hormones on the response to trauma and burn injury. BURNS & TRAUMA 2017; 5:29. [PMID: 28920065 PMCID: PMC5597997 DOI: 10.1186/s41038-017-0093-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 07/19/2017] [Indexed: 12/24/2022]
Abstract
Trauma and related sequelae result in disturbance of homeostatic mechanisms frequently leading to cellular dysfunction and ultimately organ and system failure. Regardless of the type and severity of injury, gender dimorphism in outcomes following trauma have been reported, with females having lower mortality than males, suggesting that sex steroid hormones (SSH) play an important role in the response of body systems to trauma. In addition, several clinical and experimental studies have demonstrated the effects of SSH on the clinical course and outcomes following injury. Animal studies have reported the ability of SSH to modulate immune, inflammatory, metabolic and organ responses following traumatic injury. This indicates that homeostatic mechanisms, via direct and indirect pathways, can be maintained by SSH at local and systemic levels and hence result in more favourable prognosis. Here, we discuss the role and mechanisms by which SSH modulates the response of the body to injury by maintaining various processes and organ functions. Such properties of sex hormones represent potential novel therapeutic strategies and further our understanding of current therapies used following injury such as oxandrolone in burn-injured patients.
Collapse
Affiliation(s)
- K Al-Tarrah
- Institute of Inflammation and Ageing, Birmingham University Medical School, B15 2TT, Birmingham, UK.,Scar Free Foundation Centre for Burns Research, University Hospital Birmingham Foundation Trust, B15 2WB, Birmingham, UK
| | - N Moiemen
- Scar Free Foundation Centre for Burns Research, University Hospital Birmingham Foundation Trust, B15 2WB, Birmingham, UK
| | - J M Lord
- Institute of Inflammation and Ageing, Birmingham University Medical School, B15 2TT, Birmingham, UK
| |
Collapse
|
|
12
|
Flores-Espinosa P, Preciado-Martínez E, Mejía-Salvador A, Sedano-González G, Bermejo-Martínez L, Parra-Covarruvias A, Estrada-Gutiérrez G, Vega-Sánchez R, Méndez I, Quesada-Reyna B, Olmos-Ortiz A, Zaga-Clavellina V. Selective immuno-modulatory effect of prolactin upon pro-inflammatory response in human fetal membranes. J Reprod Immunol 2017; 123:58-64. [PMID: 28938125 DOI: 10.1016/j.jri.2017.09.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 09/06/2017] [Accepted: 09/13/2017] [Indexed: 02/08/2023]
Abstract
During pregnancy, prolactin (PRL) is a neuro-immuno-cytokine that contributes actively to the crosstalk between the immune and endocrine systems and, thus, to the creation of an immune-privileged milieu. This work aims to analyze the capacity of PRL to modulate the synthesis and secretion of pro-inflammatory markers associated with labor. Studies were conducted using human fetal membranes at term mounted in a model of two independent chambers. The choriodecidual region was stimulated with 500-ng/mL lipopolysaccharide (LPS), and the amnion and choriodecidual region were co-simulated with different concentrations of PRL that can arise during pregnancy: 250, 500, 1000, and 4000ng/mL. Following these co-treatments, the tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10 levels were measured in both compartments. As expected, treatment with LPS induced all cytokines to increase. Co-stimulation with the highest tested concentration of PRL induced significant decreases in TNF-α in the choriodecidual region and IL-1β in both regions of the fetal membranes. PRL did not modified the IL-6 and IL-10 secretion profile. These findings, coupled with clinical evidence, suggest that the high level of PRL in the amniotic cavity is involved the mechanism by which the fetal-placental unit regulates the equilibrium between pro- and anti-inflammatory modulators.
Collapse
Affiliation(s)
- Pilar Flores-Espinosa
- Inmunobiochemistry Branch, Instituto Nacional de Perinatología, Isidro Espinosa de los Reyes, Mexico City, 11000, Mexico
| | - Eduardo Preciado-Martínez
- Inmunobiochemistry Branch, Instituto Nacional de Perinatología, Isidro Espinosa de los Reyes, Mexico City, 11000, Mexico
| | - Araceli Mejía-Salvador
- Inmunobiochemistry Branch, Instituto Nacional de Perinatología, Isidro Espinosa de los Reyes, Mexico City, 11000, Mexico
| | - Gabriela Sedano-González
- Inmunobiochemistry Branch, Instituto Nacional de Perinatología, Isidro Espinosa de los Reyes, Mexico City, 11000, Mexico
| | - Luisa Bermejo-Martínez
- Inmunobiochemistry Branch, Instituto Nacional de Perinatología, Isidro Espinosa de los Reyes, Mexico City, 11000, Mexico
| | - Adalberto Parra-Covarruvias
- Endocrinology Branch, Instituto Nacional de Perinatología, Isidro Espinosa de los Reyes, Mexico City, 11000, Mexico
| | - Guadalupe Estrada-Gutiérrez
- Inmunobiochemistry Branch, Instituto Nacional de Perinatología, Isidro Espinosa de los Reyes, Mexico City, 11000, Mexico
| | - Rodrigo Vega-Sánchez
- Nutrition and Bioprogramation Branch, Instituto Nacional de Perinatología, Isidro Espinosa de los Reyes, Mexico City, 11000, Mexico
| | - Isabel Méndez
- Cellular and Molecular Neurobiology Branch, Instituto de Neurobiología, Campus UNAM-Juriquilla, Querétaro, 76230, Mexico
| | - Braulio Quesada-Reyna
- Gyneco-Obstetric Division, Hospital de Gineco-Obstetricia No. 4, Luis Castelazo Ayala‖ (HGOLCA), Mexico City, 06720, Mexico
| | - Andrea Olmos-Ortiz
- Inmunobiochemistry Branch, Instituto Nacional de Perinatología, Isidro Espinosa de los Reyes, Mexico City, 11000, Mexico
| | - Veronica Zaga-Clavellina
- Inmunobiochemistry Branch, Instituto Nacional de Perinatología, Isidro Espinosa de los Reyes, Mexico City, 11000, Mexico.
| |
Collapse
|
|
13
|
Feng Q, Ai YH, Gong H, Wu L, Ai ML, Deng SY, Huang L, Peng QY, Zhang LN. Characterization of Sepsis and Sepsis-Associated Encephalopathy. J Intensive Care Med 2017; 34:938-945. [PMID: 28718340 DOI: 10.1177/0885066617719750] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Sepsis and sepsis-associated encephalopathy (SAE) are common intensive care unit (ICU) diseases; the morbidity and mortality are high. The present study analyzed the sensitivity of different diagnostic criteria of sepsis 1.0 and 3.0, epidemiological characteristics of sepsis and SAE, and explored its risk factors for death, short-term, and long-term prognosis. METHODS The retrospective study included patients in ICU from January 2015 to June 2016. After excluding 58 patients, 175 were assigned to either an SAE or a non-SAE group (patients with sepsis but no encephalopathy). The sensitivity of the diagnostic criteria was compared between sepsis 1.0 and 3.0, respectively. Between-group differences in baseline data, Acute Physiology and Chronic Health Evaluation II score (APACHE II score), Sequential Organ Failure Assessment score (SOFA score), etiological data, biochemical indicators, and 28-day and 180-day mortality rates were analyzed. Survival outcomes and long-term prognosis were observed, and risk factors for death were analyzed through 180-day follow-up. RESULTS The sensitivity did not differ significantly between the diagnostic criteria of sepsis 1.0 and 3.0 (P = .286). The 42.3% incidence of SAE presented a significantly high APACHE II and SOFA scores as well as 28-day mortality and 180-day mortality (all P < .001). The incidence of death was 37.1%. The multivariate stepwise regression analysis demonstrated that the risk of death in SAE group was significantly higher than the non-SAE group (P < .001). Sepsis-associated encephalopathy is a risk factor for sepsis-related death (relative risk [RR] = 2.868; 95% confidence interval: 1.730-4.754; P < .001). Although males showed a significantly high rate of 28-day and 180-day mortality (P = .035 and .045), it was not an independent risk factor for sepsis-related death (P = .072). The long-term prognosis of patients with sepsis was poor with decreased quality of life. No significant difference was observed in prognosis between the SAE and non-SAE groups (P > .05). CONCLUSION Both diagnostic criteria cause misdiagnosis, and the sensitivity did not differ significantly. The incidence of SAE was high, and 28-day and 180-day mortality rates were significantly higher than those without SAE. Sepsis-associated encephalopathy is a risk factor for poor outcome. The overall long-term prognosis of patients with sepsis was poor, and the quality of life decreased.
Collapse
Affiliation(s)
- Qing Feng
- Department of Intensive Care Unit, Xiangya Hospital, Central South University, Changsha, China
| | - Yu-Hang Ai
- Department of Intensive Care Unit, Xiangya Hospital, Central South University, Changsha, China
| | - Hua Gong
- Department of Intensive Care Unit, Xiangya Hospital, Central South University, Changsha, China
| | - Long Wu
- Department of Intensive Care Unit, Xiangya Hospital, Central South University, Changsha, China
| | - Mei-Lin Ai
- Department of Intensive Care Unit, Xiangya Hospital, Central South University, Changsha, China
| | - Song-Yun Deng
- Department of Intensive Care Unit, Xiangya Hospital, Central South University, Changsha, China
| | - Li Huang
- Department of Intensive Care Unit, Xiangya Hospital, Central South University, Changsha, China
| | - Qian-Yi Peng
- Department of Intensive Care Unit, Xiangya Hospital, Central South University, Changsha, China
| | - Li-Na Zhang
- Department of Intensive Care Unit, Xiangya Hospital, Central South University, Changsha, China
| |
Collapse
|
|
14
|
Wu Y, Chung CS, Chen Y, Monaghan SF, Patel S, Huang X, Heffernan DS, Ayala A. A Novel Role for Programmed Cell Death Receptor Ligand-1 (PD-L1) in Sepsis-Induced Intestinal Dysfunction. Mol Med 2016; 22:830-840. [PMID: 27782294 DOI: 10.2119/molmed.2016.00150] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 10/14/2016] [Indexed: 12/24/2022] Open
Abstract
Studies imply that intestinal barrier dysfunction is a key contributor to morbid events associated with sepsis. Recently, co-inhibitory molecule, programmed death-ligand1 (PD-L1) has been shown to be involved in the regulation of intestinal immune tolerance and/or inflammation. Our previous studies showed that PD-L1 gene deficiency reduced sepsis-induced intestinal injury morphologically. However, it isn't known how PD-L1 expression impacts intestinal barrier dysfunction during sepsis. Here we tested the hypothesis that PD-L1 expressed on intestinal epithelial cells (IECs) has a role in sepsis-induced intestinal barrier dysfunction. To address this, C57BL/6 or PD-L1 gene knockout mice were subjected to experimental sepsis and PD-L1 expression, intestinal permeability, tissue cytokine levels were assessed. Subsequently, septic or non-septic patient colonic samples (assigned by pathology report) were immunohistochemically stained for PD-L1 I a blinded fashion. Finally, human Caco2 cells were used for in vitro studies. The results demonstrated that PD-L1 was constitutively expressed and sepsis significantly up-regulates PD-L1 in IECs from C57BL/6 mice. Concurrently, we observed an increased PD-L1 expression in colon tissue samples from septic patients. PD-L1 gene deficiency reduced ileal permeability, tissue levels of IL-6, TNF-α and MCP-1, and prevented ileal tight junction protein loss compared to WT after sepsis. Comparatively, while Caco2 cell monolayers responded to inflammatory cytokine stimulation also with elevated PD-L1 expression, increased monolayer permeability and altering/decreasing monolayer tight junction protein morphology/expression; these changes were reversed by PD-L1 blocking antibody. Together these data indicate that ligation of ICE PD-L1 plays a novel role in mediating the pathophysiology of sepsis-induced intestinal barrier dysfunction.
Collapse
Affiliation(s)
- Youping Wu
- Department of Anesthesiology, Changhai Hospital, Second Military Medical University, Shanghai, 200433, PR China
| | - Chun-Shiang Chung
- Department of Surgery, Division of Surgical Research, the Alpert School of Medicine at Brown University/Rhode Island Hospital, Providence, RI 02903, USA
| | - Yaping Chen
- Department of Surgery, Division of Surgical Research, the Alpert School of Medicine at Brown University/Rhode Island Hospital, Providence, RI 02903, USA
| | - Sean Farrell Monaghan
- Department of Surgery, Division of Surgical Research, the Alpert School of Medicine at Brown University/Rhode Island Hospital, Providence, RI 02903, USA
| | - Sima Patel
- Department of Biochemistry and Molecular Biology, Brown University, Providence, RI 02912, USA
| | - Xin Huang
- Department of Surgery, Division of Surgical Research, the Alpert School of Medicine at Brown University/Rhode Island Hospital, Providence, RI 02903, USA
| | - Daithi Seamus Heffernan
- Department of Surgery, Division of Surgical Research, the Alpert School of Medicine at Brown University/Rhode Island Hospital, Providence, RI 02903, USA
| | - Alfred Ayala
- Department of Surgery, Division of Surgical Research, the Alpert School of Medicine at Brown University/Rhode Island Hospital, Providence, RI 02903, USA
| |
Collapse
|
|
15
|
Albertsmeier M, Pratschke S, Chaudry I, Angele MK. Gender-Specific Effects on Immune Response and Cardiac Function after Trauma Hemorrhage and Sepsis. VISZERALMEDIZIN 2015; 30:91-6. [PMID: 26288583 PMCID: PMC4513799 DOI: 10.1159/000360149] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Background Studies in human as well as animal models indicate a gender-specific responsiveness of the immune and organ systems with regard to shock, trauma, and sepsis. Methods A literature review was performed. Results Cell-mediated immune responses and cardiovascular functions are suppressed in males following trauma hemorrhage, whereas they are maintained or even enhanced in females in the proestrus state of the estrus cycle. Experimental studies have demonstrated that divergent immune responses in males and females following adverse circulatory conditions are mediated by the gender-specific hormones testosterone and estrogen. Several clinical trials, however, failed to demonstrate a significant association of gender and inflammatory response. This may be explained by the heterogeneity of the population in terms of their hormonal status at the time of injury. Conclusions With regard to the underlying mechanisms, receptors for sex hormones have been identified on various immune cells, suggesting direct effects of these hormones on immune function. Alternatively, indirect effects of sex steroids such as changes in cardiovascular responses or androgen- and estrogen-synthesizing enzymes might contribute to gender-specific immune responses. Clinical studies suggest that sex hormones, such as dehydroepiandrosterone, modulate the function of peripheral blood mononuclear cells also following abdominal surgery. Thus, sex hormones, receptor antagonists, and sex steroid-synthesizing enzymes might be useful in the future for modulating the complex immune responses after trauma hemorrhage and sepsis.
Collapse
Affiliation(s)
- Markus Albertsmeier
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Ludwig Maximilian University, Munich, Germany
| | - Sebastian Pratschke
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Ludwig Maximilian University, Munich, Germany
| | - Irshad Chaudry
- Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Martin K Angele
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Ludwig Maximilian University, Munich, Germany
| |
Collapse
|
|
16
|
Weniger M, D'Haese JG, Angele MK, Chaudry IH. Potential therapeutic targets for sepsis in women. Expert Opin Ther Targets 2015; 19:1531-43. [PMID: 26083575 DOI: 10.1517/14728222.2015.1057570] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
INTRODUCTION Gender is increasingly recognized as a key factor in trauma and sepsis. Multiple clinical and experimental studies on sepsis have shown a distinct advantage of females in the proestrus cycle to survive sepsis compared with age-matched males. In addition, estrogen treatment is beneficial in non-proestrus cycles and also in ovarectomized females. In this manuscript, the effects of gender and sex hormones in sepsis are summarized and potential gender-specific therapeutic strategies in women are evaluated. AREAS COVERED This review comprises current clinical studies on the effect of gender in sepsis and gives an overview on gender and sex hormone-related effects on immune cells and organ function. Based on clinical and experimental data, potential therapeutic targets are presented. EXPERT OPINION Estrogens and estrogen-receptor agonists have been extensively shown to be beneficial in the setting of sepsis. Clinical data, however, do not clearly support their therapeutic use. This discrepancy appears to be mainly due to insufficient study design in clinical trials conducted up to now. Therefore, improved study protocols with exact analysis of the patients' hormonal status are needed to clarify the role of gender and sex hormones in trauma and sepsis.
Collapse
Affiliation(s)
- Maximilian Weniger
- a 1 Ludwig Maximilians-University, Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Campus Grosshadern , Munich, Germany
| | - Jan G D'Haese
- b 2 Ludwig Maximilians-University, Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Campus Grosshadern , Munich, Germany
| | - Martin K Angele
- c 3 Ludwig Maximilians-University, Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Campus Grosshadern , Munich, Germany
| | - Irshad H Chaudry
- d 4 University of Alabama at Birmingham, Center for Surgical Research and Department of Surgery , G094 Volker Hall, 1670 University Boulevard, Birmingham, AL 35294, USA +1 205 975 2195 ; +1 205 975 9719 ;
| |
Collapse
|
|
17
|
El-Menyar A, El-Hennawy H, Al-Thani H, Asim M, Abdelrahman H, Zarour A, Parchani A, Peralta R, Latifi R. Traumatic injury among females: does gender matter? J Trauma Manag Outcomes 2014; 8:8. [PMID: 25089153 PMCID: PMC4118222 DOI: 10.1186/1752-2897-8-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Accepted: 07/22/2014] [Indexed: 06/03/2023]
Abstract
BACKGROUND Trauma remains one of the leading causes of morbidity and mortality worldwide. Generally, the incidence of traumatic injuries is disproportionately high in males. However, trauma in females is underreported. AIM To study the epidemiology and outcome of different mechanisms and types of traumatic injuries in women. METHODS We conducted a traditional narrative review using PubMed, MEDLINE and EMBASE, searching for English-language publications for gender-specific trauma between January 1993 and January 2013 using key words "trauma", "gender", "female" and "women". RESULTS Among 1150 retrieved articles, 71 articles were relevant over 20 years. Although it is an important public health problem, traumatic injuries among females remain under-reported. CONCLUSION There is a need for further research and evaluation of the exact burden of traumatic injuries among females together with the implementation of effective community based preventive programs.
Collapse
Affiliation(s)
- Ayman El-Menyar
- Clinical Research, Trauma Surgery Section, Hamad General Hospital, PO Box 3050, Doha, Qatar
- Clinical Medicine, Weill Cornell Medical School, Doha, Qatar
- Internal Medicine, Ahmed Maher Teaching Hospital, Cairo, Egypt
| | | | | | - Mohammad Asim
- Clinical Research, Trauma Surgery Section, Hamad General Hospital, PO Box 3050, Doha, Qatar
| | | | - Ahmad Zarour
- Trauma Surgery Section, Hamad General Hospital, Doha, Qatar
| | - Ashok Parchani
- Trauma Surgery Section, Hamad General Hospital, Doha, Qatar
| | - Ruben Peralta
- Trauma Surgery Section, Hamad General Hospital, Doha, Qatar
| | - Rifat Latifi
- Trauma Surgery Section, Hamad General Hospital, Doha, Qatar
- Department of Surgery, Arizona University, Tucson, AZ, USA
| |
Collapse
|
|
18
|
Jin H, Liu Z, Xiao Y, Fan X, Yan J, Liang H. Prediction of sepsis in trauma patients. BURNS & TRAUMA 2014; 2:106-13. [PMID: 27602370 PMCID: PMC5012019 DOI: 10.4103/2321-3868.135479] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Revised: 04/14/2014] [Accepted: 06/10/2014] [Indexed: 02/07/2023]
Abstract
Trauma is one of the leading causes of death worldwide. Approximately 39.5% of deaths occur in the hospital, and the mortality rate of delayed death caused by septic complications is still high. Early prediction of the development of sepsis can help promote early intervention and treatment for patients and contribute to improving patient outcomes. Thus so far, biomarkers, patient demographics and injury characteristics are the main methods used for predicting sepsis in trauma patients. However, studies that verify their predictive value are limited, and the results are still controversial. More work should be conducted to explore more efficient and accurate ways to predict post-traumatic sepsis.
Collapse
Affiliation(s)
- He Jin
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing, 400042 China
| | - Zheng Liu
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing, 400042 China
| | - Ya Xiao
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing, 400042 China
| | - Xia Fan
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing, 400042 China
| | - Jun Yan
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing, 400042 China
| | - Huaping Liang
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing, 400042 China
| |
Collapse
|
|
19
|
Role for gender in colorectal cancer risk: a Taiwan population-based study. Int J Colorectal Dis 2013; 28:1001-8. [PMID: 23371332 DOI: 10.1007/s00384-013-1647-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/21/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Gender differences in the prognosis of colorectal cancer (CRC) remain controversial. The aim of this study was to complete a comprehensive analysis of gender differences in CRC survival derived from population registries in Taiwan. MATERIALS AND METHODS We analyzed survival data for patients diagnosed with CRC between 1998 and 2005 derived from the Taiwan Cancer Registry database. During this time period, 65,113 patients were registered, and 62,060 patients were eligible. Gender differences in overall survival and cancer-specific survival were analyzed by use of the Kaplan-Meier method. We then modeled the risk in different genders by use of a multivariate proportional hazard (Cox) model adjusting for possible confounders of survival. RESULTS The 5-year period overall and cancer-specific survivals were significantly higher in women than in men [51.84% (95% confidence interval (CI), 51.22-52.46) vs. 47.68% (95% CI, 47.14-48.22), log-rank p < 0.001; and 56.44% (95% CI, 55.82-57.07) vs. 53.47 % (95 % CI, 52.92-54.01), log-rank p < 0.001, respectively]. Subgroup analysis revealed higher overall and cancer-specific survivals in women between 50 and 80 years age and those with adenocarcinomas (p < 0.001). By use of Cox modeling, we noted a decreased hazard ratio (HR) for death from CRC in women compared with men (HR, 0.820-0.971), especially in the 50-80-year age group. All estimated HRs, after adjusting for age, tumor histology, and tumor site, had significant trends of a decreasing risk of death from CRC in women. CONCLUSIONS Our findings suggest that overall and cancer-specific survival advantage was most evident in women between 50 and 80 years of age.
Collapse
|
|
20
|
Sakr Y, Elia C, Mascia L, Barberis B, Cardellino S, Livigni S, Fiore G, Filippini C, Ranieri VM. The influence of gender on the epidemiology of and outcome from severe sepsis. Crit Care 2013; 17:R50. [PMID: 23506971 PMCID: PMC3733421 DOI: 10.1186/cc12570] [Citation(s) in RCA: 129] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2012] [Revised: 02/12/2013] [Accepted: 03/08/2013] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION The impact of gender on outcome in critically ill patients is unclear. We investigated the influence of gender on the epidemiology of severe sepsis and associated morbidity and mortality in a large cohort of ICU patients in the region of Piedmont in Italy. METHODS This was a post-hoc analysis of data from a prospective, multicenter, observational study in which all patients admitted to one of 24 participating medical and/or surgical ICUs between 3 April 2006 and 29 September 2006 were included. RESULTS Of the 3,902 patients included in the study, 63.5% were male. Female patients were significantly older than male patients (66±16 years vs. 63±16 years, P<0.001). Female patients were less likely to have severe sepsis and septic shock on admission to the ICU and to develop these syndromes during the ICU stay. ICU mortality was similar in men and women in the whole cohort (20.1% vs. 19.8%, P=0.834), but in patients with severe sepsis was significantly greater in women than in men (63.5% vs. 46.4%, P=0.007). In multivariate logistic regression analysis with ICU outcome as the dependent variable, female gender was independently associated with a higher risk of ICU death in patients with severe sepsis (odds ratio=2.33, 95% confidence interval=1.23 to 4.39, P=0.009) but not in the whole cohort (odds ratio=1.07, 95% confidence interval=0.87 to 1.34). CONCLUSION In this large regional Italian cohort of ICU patients, there were more male than female admissions. The prevalence of severe sepsis was lower in women than in men, but female gender was independently associated with a higher risk of death in the ICU for patients with severe sepsis.
Collapse
Affiliation(s)
- Yasser Sakr
- Department of Anesthesiology and Intensive Care, Friedrich-Schiller-University,
Erlanger Allee 103, 07743 Jena, Germany
| | - Cristina Elia
- Department of Anesthesiology and Intensive Care, San Giovanni Battista-Molinette
Hospital, University of Turin, corso Dogliotti 14, 10126 Turin, Italy
| | - Luciana Mascia
- Department of Anesthesiology and Intensive Care, San Giovanni Battista-Molinette
Hospital, University of Turin, corso Dogliotti 14, 10126 Turin, Italy
| | - Bruno Barberis
- Department of Anesthesiology and Intensive Care, Ospedale degli Infermi, via
Rivalta 29, 10128 Rivoli (TO), Italy
| | - Silvano Cardellino
- Department of Anesthesiology and Intensive Care, Ospedale Cardinal Massaia, corso
Dante 202, 14100 Asti, Italy
| | - Sergio Livigni
- Department of Anesthesiology and Intensive Care, Ospedale Giovanni Bosco, piazza
Donatore di sangue n° 3, 10154 Turin, Italy
| | - Gilberto Fiore
- Department of Anesthesiology and Intensive Care, Ospedale Santa Croce, Piazza A.
Ferdinando n° 3, 10024 Moncalieri (TO), Italy
| | - Claudia Filippini
- Department of Anesthesiology and Intensive Care, San Giovanni Battista-Molinette
Hospital, University of Turin, corso Dogliotti 14, 10126 Turin, Italy
| | - Vito Marco Ranieri
- Department of Anesthesiology and Intensive Care, San Giovanni Battista-Molinette
Hospital, University of Turin, corso Dogliotti 14, 10126 Turin, Italy
| |
Collapse
|
|
21
|
Khaksari M, Keshavarzi Z, Gholamhoseinian A, Bibak B. The effect of female sexual hormones on the intestinal and serum cytokine response after traumatic brain injury: different roles for estrogen receptor subtypes. Can J Physiol Pharmacol 2013; 91:700-7. [PMID: 23984641 DOI: 10.1139/cjpp-2012-0359] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The purpose of this study was to evaluate the effect of female sexual hormones on intestinal and serum cytokines following traumatic brain injury (TBI). Adult female rats were ovariectomized and distributed among the following 9 groups: (i) sham trauma, (ii) TBI (Marmarou's method), (iii) vehicle (dimethylsulfoxide) treated, (iv) estrogen (E2) treated, (v) progesterone (P) treated, (vi) treated with E2+P, (vii) propylpyrazole triol (PPT) treated, (viii) diarylpropionitrile (DPN) treated, and (ix) control. PPT and DPN are estrogen receptor αand β agonists, respectively. Serum and intestinal levels of interleukin (IL)-1β were increased by TBI (P < 0.001). The level of intestinal IL-1β was increased in the group treated with E2 (P < 0.001). There was a reduction in serum IL-1β (P < 0.01) and an increase in intestinal IL-1β level (P < 0.001) in the PPT-treated group compared with the vehicle-treated group. TBI reduced serum IL-6 (P < 0.01) and increased intestinal IL-6 (P < 0.001). Serum IL-6 was increased in the group treated with E2 (P < 0.001), P (P < 0.001), E2+P (P < 0.01), and DPN (P < 0.001) after TBI; however, intestinal IL-6 was higher in the E2-treated group compared with the vehicle-treated group (P < 0.01). Intestinal tumor necrosis factor α (TNF-α) was increased by TBI (P < 0.001). Progesterone decreased serum TNF-α (P < 0.01). Intestinal TNF-α in the E2 (P < 0.01), E2+P (P < 0.001), and PPT (P < 0.001) treatment groups was less than in the vehicle-treated group. In conclusion, estrogen influences the intestinal levels of proinflammatory cytokines, in particular TNF-α, mediated through estrogen receptor α.
Collapse
Affiliation(s)
- Mohammad Khaksari
- Neuroscience Research Center, Kerman University of Medical Sciences, Kerman 76175-113, Iran
| | | | | | | |
Collapse
|
|
22
|
Gatson JW, Liu MM, Abdelfattah K, Wigginton JG, Smith S, Wolf S, Simpkins JW, Minei JP. Estrone is neuroprotective in rats after traumatic brain injury. J Neurotrauma 2012; 29:2209-19. [PMID: 22435710 DOI: 10.1089/neu.2011.2274] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
In various animal and human studies, early administration of 17β-estradiol, a strong antioxidant, anti-inflammatory, and anti-apoptotic agent, significantly decreases the severity of injury in the brain associated with cell death. Estrone, the predominant estrogen in postmenopausal women, has been shown to be a promising neuroprotective agent. The overall goal of this project was to determine if estrone mitigates secondary injury following traumatic brain injury (TBI) in rats. Male rats were given either placebo (corn oil) or estrone (0.5 mg/kg) at 30 min after severe TBI. Using a controlled cortical impact device in rats that underwent a craniotomy, the right parietal cortex was injured using the impactor tip. Non-injured control and sham animals were also included. At 72 h following injury, the animals were perfused intracardially with 0.9% saline followed by 10% phosphate-buffered formalin. The whole brain was removed, sliced, and stained for TUNEL-positive cells. Estrone decreased cortical lesion volume (p<0.01) and neuronal injury (p<0.001), and it reduced cerebral cortical levels of TUNEL-positive staining (p<0.0001), and decreased numbers of TUNEL-positive cells in the corpus callosum (p<0.03). We assessed the levels of β-amyloid in the injured animals and found that estrone significantly decreased the cortical levels of β-amyloid after brain injury. Cortical levels of phospho-ERK1/2 were significantly (p<0.01) increased by estrone. This increase was associated with an increase in phospho-CREB levels (p<0.021), and brain-derived neurotrophic factor (BDNF) expression (p<0.0006). In conclusion, estrone given acutely after injury increases the signaling of protective pathways such as the ERK1/2 and BDNF pathways, decreases ischemic secondary injury, and decreases apoptotic-mediated cell death. These results suggest that estrone may afford protection to those suffering from TBI.
Collapse
Affiliation(s)
- Joshua W Gatson
- D/FW Center for Resuscitation Research, Department of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9160, USA.
| | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Clond MA, Mirocha J, Singer MB, Bukur M, Salim A, Marguiles DR, Ley EJ. Gender influences outcomes in trauma patients with elevated systolic blood pressure. Am J Surg 2012; 202:823-7; discussion 828. [PMID: 22137141 DOI: 10.1016/j.amjsurg.2011.06.044] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2011] [Revised: 06/28/2011] [Accepted: 06/28/2011] [Indexed: 10/14/2022]
Abstract
BACKGROUND This analysis explored the association between gender and systolic blood pressure (SBP) in trauma patients and then established how gender influenced outcomes in those with elevated SBP. METHODS Demographics and outcomes were compared using the Los Angeles County Trauma System Database and multivariable modeling determined predictors for SBP, pneumonia, and mortality. RESULTS Age and male sex were significant predictors for increased SBP, whereas the Injury Severity Score (ISS) ≥16 was a significant predictor for decreased SBP. In both male and female TBI patients, SBP ≥160 mmHg was associated with increased pneumonia (Adjusted odds ratio [AOR] = 1.74, P = .002 and AOR = 2.37, P = .046, respectively), whereas SBP ≥160 mmHg was a predictor for mortality only among male TBI patients (AOR = 1.48, P = .03). In non-TBI patients, SBP ≥160 mmHg was not a predictor for pneumonia or mortality in either sex. CONCLUSIONS In this retrospective review of trauma registry data, men presented with higher SBP. In patients with TBI, regardless of gender, increased SBP was associated with increased pneumonia, and in men with TBI increased SBP was associated with increased mortality. The cause and relevance of these epidemiological findings require further investigation.
Collapse
Affiliation(s)
- Morgan A Clond
- Department of Surgery, Division of Trauma and Critical Care, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | | | | | | | | | | | | |
Collapse
|
|
24
|
Han S, Martin GS, Maloney JP, Shanholtz C, Barnes KC, Murray S, Sevransky JE. Short women with severe sepsis-related acute lung injury receive lung protective ventilation less frequently: an observational cohort study. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2011; 15:R262. [PMID: 22044724 PMCID: PMC3388675 DOI: 10.1186/cc10524] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2011] [Revised: 07/22/2011] [Accepted: 11/01/2011] [Indexed: 01/11/2023]
Abstract
Introduction Lung protective ventilation (LPV) has been shown to improve survival and the duration of mechanical ventilation in acute lung injury (ALI) patients. Mortality of ALI may vary by gender, which could result from treatment variability. Whether gender is associated with the use of LPV is not known. Methods A total of 421 severe sepsis-related ALI subjects in the Consortium to Evaluate Lung Edema Genetics from seven teaching hospitals between 2002 and 2008 were included in our study. We evaluated patients' tidal volume, plateau pressure and arterial pH to determine whether patients received LPV during the first two days after developing ALI. The odds ratio of receiving LPV was estimated by a logistic regression model with robust and cluster options. Results Women had similar characteristics as men with the exception of lower height and higher illness severity, as measured by Acute Physiology and Chronic Health Evaluation (APACHE) II score. 225 (53%) of the subjects received LPV during the first two days after ALI onset; women received LPV less frequently than men (46% versus 59%, P < 0.001). However, after adjustment for height and severity of illness (APACHE II), there was no difference in exposure to LPV between men and women (P = 0.262). Conclusions Short people are less likely to receive LPV, which seems to explain the tendency of clinicians to adhere to LPV less strictly in women. Strategies to standardize application of LPV, independent of differences in height and severity of illness, are necessary.
Collapse
Affiliation(s)
- SeungHye Han
- Critical Care Medicine Department, National Institute of Health, 10 Center Drive, Bethesda, MD 20892, USA.
| | | | | | | | | | | | | |
Collapse
|
|
25
|
An assessment of the impact of pregnancy on trauma mortality. Surgery 2011; 149:94-8. [DOI: 10.1016/j.surg.2010.04.019] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2010] [Accepted: 04/16/2010] [Indexed: 11/18/2022]
|
|
26
|
Gatson JW, Simpkins JW, Yi KD, Idris AH, Minei JP, Wigginton JG. Aromatase is increased in astrocytes in the presence of elevated pressure. Endocrinology 2011; 152:207-13. [PMID: 21047944 PMCID: PMC3033056 DOI: 10.1210/en.2010-0724] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2010] [Accepted: 10/01/2010] [Indexed: 11/19/2022]
Abstract
After traumatic brain injury (TBI), a progressive injury and death of neurons and glia leads to decreased brain function. Endogenous and exogenous estrogens may protect these vulnerable cells. In this study, we hypothesized that increased pressure leads to an increase in aromatase expression and estrogen production in astrocytes. In this study, we subjected rat glioma (C6) cells and primary cortical astrocytes to increased pressure (25 mm Hg) for 1, 3, 6, 12, 24, 48, and 72 h. Total aromatase protein and RNA levels were measured using Western analysis and RT-PCR, respectively. In addition, we measured aromatase activity by assaying estrone levels after administration of its precursor, androstenedione. We found that increased pressure applied to the C6 cells and primary cortical astrocytes resulted in a significant increase in both aromatase RNA and protein. To extend these findings, we also analyzed aromatase activity in the primary astrocytes during increased pressure. We found that increased pressure resulted in a significant (P < 0.01) increase in the conversion of androstenedione to estrone. In conclusion, we propose that after TBI, astrocytes sense increased pressure, leading to an increase in aromatase production and activity in the brain. These results may suggest mechanisms of brain estrogen production after increases in pressure as seen in TBI patients.
Collapse
Affiliation(s)
- J W Gatson
- Department of Surgery, University of Texas Southern Medical Center Dallas, Texas 75390-8579, USA.
| | | | | | | | | | | |
Collapse
|
|
27
|
Rationale for routine and immediate administration of intravenous estrogen for all critically ill and injured patients. Crit Care Med 2010; 38:S620-9. [DOI: 10.1097/ccm.0b013e3181f243a9] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
|
|
28
|
Probst C, Zelle B, Panzica M, Lohse R, Sitarro NA, Krettek C, Pape HC. Clinical Re-Examination 10 or More Years After Polytrauma: Is There a Gender Related Difference? ACTA ACUST UNITED AC 2010; 68:706-11. [DOI: 10.1097/ta.0b013e3181a8b21c] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|
|
29
|
Abstract
Even if trauma patients initially avoid death after trauma (due to massive blood volume loss, primary severe brain injury), they are still at risk for multiple organ failure. Thus, it is crucial to elucidate the underlying pathophysiological mechanisms of trauma/hemorrhagic shock and the immune response involved. As of now, many hemorrhagic shock/trauma studies have used various types of animal models. Despite a large number of results from these efforts, some authors have argued that animal model results are difficult to translate directly into the clinical scenario. This review summarizes the advantages and the disadvantages of using animal models in trauma/hemorrhagic shock studies and discusses the relevance of various animal studies to the clinical scenario.
Collapse
|
|
30
|
Raju R, Chaudry IH. Sex steroids/receptor antagonist: their use as adjuncts after trauma-hemorrhage for improving immune/cardiovascular responses and for decreasing mortality from subsequent sepsis. Anesth Analg 2008; 107:159-66. [PMID: 18635483 DOI: 10.1213/ane.0b013e318163213d] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Studies in human as well as animal models demonstrate that females in the proestrus cycle (i.e., with high estrogen) tolerate trauma-hemorrhage and sepsis far better than males. The female sex steroid, estrogen, is the significant factor contributing to this observed gender difference in outcome. One reason for the lack of significant gender association in some clinical studies is the possibility of heterogeneity of the population in terms of their hormonal status at the time of injury. Several experimental investigations have revealed that androgens produce immune and cardiovascular depression after trauma-hemorrhage. However, the use of an androgen receptor antagonist after trauma-hemorrhage has salutary effects of immune and cardiovascular function. Likewise, estrogen produces beneficial effects on immune and cardiovascular function after trauma-hemorrhage and significantly decreases mortality rates from subsequent sepsis. The salutary effects of estrogen after trauma-hemorrhage have been shown to be due to both genomic and nongenomic effects. Thus, the use of an estrogen or androgen receptor antagonist as an adjunct after trauma-hemorrhage is a safe and novel approach for restoring immune and cardiovascular function after trauma-hemorrhage and for decreasing the mortality from subsequent sepsis.
Collapse
Affiliation(s)
- Raghavan Raju
- Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019, USA
| | | |
Collapse
|
|
31
|
Angele MK, Schneider CP, Chaudry IH. Bench-to-bedside review: latest results in hemorrhagic shock. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2008; 12:218. [PMID: 18638356 PMCID: PMC2575549 DOI: 10.1186/cc6919] [Citation(s) in RCA: 135] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Hemorrhagic shock is a leading cause of death in trauma patients worldwide. Bleeding control, maintenance of tissue oxygenation with fluid resuscitation, coagulation support, and maintenance of normothermia remain mainstays of therapy for patients with hemorrhagic shock. Although now widely practised as standard in the USA and Europe, shock resuscitation strategies involving blood replacement and fluid volume loading to regain tissue perfusion and oxygenation vary between trauma centers; the primary cause of this is the scarcity of published evidence and lack of randomized controlled clinical trials. Despite enormous efforts to improve outcomes after severe hemorrhage, novel strategies based on experimental data have not resulted in profound changes in treatment philosophy. Recent clinical and experimental studies indicated the important influences of sex and genetics on pathophysiological mechanisms after hemorrhage. Those findings might provide one explanation why several promising experimental approaches have failed in the clinical arena. In this respect, more clinically relevant animal models should be used to investigate pathophysiology and novel treatment approaches. This review points out new therapeutic strategies, namely immunomodulation, cardiovascular maintenance, small volume resuscitation, and so on, that have been introduced in clinics or are in the process of being transferred from bench to bedside. Control of hemorrhage in the earliest phases of care, recognition and monitoring of individual risk factors, and therapeutic modulation of the inflammatory immune response will probably constitute the next generation of therapy in hemorrhagic shock. Further randomized controlled multicenter clinical trials are needed that utilize standardized criteria for enrolling patients, but existing ethical requirements must be maintained.
Collapse
Affiliation(s)
- Martin K Angele
- Department of Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University, Marchionistrasse 15, 81377 Munich, Germany
| | | | | |
Collapse
|
|
32
|
Characterization of the gender dimorphism after injury and hemorrhagic shock: are hormonal differences responsible? Crit Care Med 2008; 36:1838-45. [PMID: 18496363 DOI: 10.1097/ccm.0b013e3181760c14] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To characterize the gender dimorphism after injury with specific reference to the reproductive age of the women (young, <48 yrs of age, vs. old, >52 yrs of age) in a cohort of severely injured trauma patients for which significant variation in postinjury care is minimized. DESIGN Secondary data analysis of an ongoing prospective multicenter cohort study. SETTING Academic, level I trauma and intensive care unit centers. PATIENTS Blunt-injured adults with hemorrhagic shock. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Separate Cox proportional hazard regression models were formulated based on all patients to evaluate the effects of gender on mortality, multiple organ failure, and nosocomial infection, after controlling for all important confounders. These models were then used to characterize the effect of gender in young and old age groups. Overall mortality, multiple organ failure, and nosocomial infection rates for the entire cohort (n = 1,036) were 20%, 40%, and 45%, respectively. Mean Injury Severity Score was 32 +/- 14 (mean +/- SD). Men (n = 680) and women (n = 356) were clinically similar except that men required higher crystalloid volumes, more often had a history of alcoholism and liver disease, and had greater ventilatory and intensive care unit requirements. Female gender was independently associated with a 43% and 23% lower risk of multiple organ failure and nosocomial infection, respectively. Gender remained an independent risk factor in young and old subgroup analysis, with the protection afforded by female gender remaining unchanged. CONCLUSIONS The independent protective effect of female gender on multiple organ failure and nosocomial infection rates remains significant in both premenopausal and postmenopausal women when compared with similarly aged men. This is contrary to previous experimental studies and the known physiologic sex hormone changes that occur after menopause in women. These results suggest that factors other than sex hormones may be responsible for gender-based differences after injury.
Collapse
|
|
33
|
Bird MD, Karavitis J, Kovacs EJ. Sex differences and estrogen modulation of the cellular immune response after injury. Cell Immunol 2008; 252:57-67. [PMID: 18294625 PMCID: PMC2544631 DOI: 10.1016/j.cellimm.2007.09.007] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2007] [Accepted: 09/01/2007] [Indexed: 11/22/2022]
Abstract
Cell-mediated immunity is extremely important for resolution of infection and for proper healing from injury. However, the cellular immune response is dysregulated following injuries such as burn and hemorrhage. Sex hormones are known to regulate immunity, and a well-documented dichotomy exists in the immune response to injury between the sexes. This disparity is caused by differences in immune cell activation, infiltration, and cytokine production during and after injury. Estrogen and testosterone can positively or negatively regulate the cellular immune response either by aiding in resolution or by compounding the morbidity and mortality. It is apparent that the hormonal dysregulation is dependent not only on the type of injury sustained but also the amount of circulating hormones. Therefore, it may be possible to design sex-specific therapies to improve immunological function and patient outcome.
Collapse
Affiliation(s)
- Melanie D Bird
- Department of Surgery, Loyola University Medical Center, Maywood, IL 60153, USA
| | | | | |
Collapse
|
|
34
|
Influence of surgical trauma on the mRNA expression of sex hormone receptors in PBMCs in male and female patients. Langenbecks Arch Surg 2008; 393:871-6. [PMID: 18297304 DOI: 10.1007/s00423-008-0304-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2007] [Accepted: 01/31/2008] [Indexed: 11/27/2022]
Abstract
INTRODUCTION Gender-specific immune responses have been found after trauma-hemorrhage. Male and female sex hormones seem to be responsible for this gender dimorphism. Alterations in sex hormone receptor expression in mice appear to contribute to the immunomodulatory effect of sex hormones after blood loss. The effect of surgical trauma on the expression of sex hormone receptors in peripheral blood mononuclear cells (PBMCs) from patients, however, remains unknown. MATERIALS AND METHODS PBMCs were obtained from 14 patients (7 men and 7 women) undergoing major abdominal surgery preoperatively and 2 h postoperatively. The expression of the androgen and the estrogen alpha- and beta- receptors were determined by reverse transcriptase polymerase chain reaction (RT-PCR). beta-Actin was used as housekeeping gene. RESULTS The results indicate that surgical trauma has no influence on the expression of the androgen receptor and the estrogen receptors alpha and beta in male and female patients. DISCUSSION The data demonstrate that, in contrast to mice, no alterations in the expression of androgen and estrogen hormone receptors were evident after surgery in patients. Thus, differences in the expression of sex hormone receptors do not appear to be responsible for the gender-specific immune response after surgery.
Collapse
|
|
35
|
Abstract
Trauma with multiple injuries is a leading cause of death. It presents a diversity of challenges and requires many healthcare workers to care for its victims. Advances continue in the organization of pre-hospital care, the techniques of trauma surgery and critical care, and understanding the pathophysiology of traumatic injuries.
Collapse
Affiliation(s)
- R E Johnstone
- Department of Anesthesiology, West Virginia University, Morgantown, West Virginia 26506, USA.
| | | |
Collapse
|
|
36
|
Suzuki T, Shimizu T, Yu HP, Hsieh YC, Choudhry MA, Bland KI, Chaudry IH. Estrogen receptor-alpha predominantly mediates the salutary effects of 17beta-estradiol on splenic macrophages following trauma-hemorrhage. Am J Physiol Cell Physiol 2007; 293:C978-84. [PMID: 17553937 DOI: 10.1152/ajpcell.00092.2007] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Although 17beta-estradiol administration following trauma-hemorrhage prevents the suppression in splenic macrophage cytokine production, it remains unknown whether the salutary effects are mediated via estrogen receptor (ER)-alpha or ER-beta and which signaling pathways are involved in such 17beta-estradiol effects. Utilizing ER-alpha- or ER-beta-specific agonists, this study examined the role of ER-alpha and ER-beta in 17beta-estradiol-mediated restoration of macrophage cytokine production following trauma-hemorrhage. In addition, since MAPK and NF-kappaB are known to regulate macrophage cytokine production, we also examined the activation of those signaling molecules. Male rats underwent trauma-hemorrhage (mean arterial pressure of 40 mmHg for 90 min) and fluid resuscitation. The ER-alpha agonist propyl pyrazole triol (PPT; 5 microg/kg), the ER-beta agonist diarylpropionitrile (DPN; 5 microg/kg), 17beta-estradiol (50 microg/kg), or vehicle (10% DMSO) was injected subcutaneously during resuscitation. Twenty-four hours thereafter, splenic macrophages were isolated, and their IL-6 and TNF-alpha production and activation of MAPK and NF-kappaB were measured. Macrophage IL-6 and TNF-alpha production and MAPK activation were decreased, whereas NF-kappaB activity was increased, following trauma-hemorrhage. PPT or 17beta-estradiol administration after trauma-hemorrhage normalized those parameters. DPN administration, on the other hand, did not normalize the above parameters. Since PPT but not DPN administration following trauma-hemorrhage was as effective as 17beta-estradiol in preventing the suppression in macrophage cytokine production, it appears that ER-alpha plays the predominant role in mediating the salutary effects of 17beta-estradiol on macrophage cytokine production following trauma-hemorrhage and that such effects are likely mediated via normalization of MAPK but not NF-kappaB signaling pathways.
Collapse
Affiliation(s)
- Takao Suzuki
- Center for Surgical Research and Dept. of Surgery, Univ. of Alabama, at Birmingham, 1670 Univ. Blvd., Volker Hall, Rm. G094, Birmingham, AL 35294-0019, USA
| | | | | | | | | | | | | |
Collapse
|
|
37
|
Hsieh YC, Frink M, Kawasaki T, Thobe BM, Choudhry MA, Schwacha MG, Bland KI, Chaudry IH. Downregulation of TLR4-dependent ATP production is critical for estrogen-mediated immunoprotection in Kupffer cells following trauma-hemorrhage. J Cell Physiol 2007; 211:364-70. [PMID: 17219405 DOI: 10.1002/jcp.20943] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Toll-like receptor 4 (TLR4) mediates mitochondrial DNA (mtDNA) damage and biogenic responses. Mitochondrial transcription factor A (Tfam) is an essential regulator for mtDNA transcription and ATP production. Increased ATP levels were associated with normalization of immune function following trauma-hemorrhage. Moreover, administration of 17beta-estradiol following trauma-hemorrhage upregulates cardiac Tfam and ATP levels. We therefore hypothesized that the salutary effect of 17beta-estradiol on Kupffer cell function following trauma-hemorrhage is mediated via negative regulation of TLR4, which downregulates iNOS, upregulates Tfam and mtDNA-encoded gene cytochrome c oxidase I (mtCOI), and consequently increases cellular ATP levels. Male C3H/HeN, C3H/HeOuJ (intact TLR4), and C3H/HeJ (TLR4 mutant) mice were subjected to trauma-hemorrhage (mean BP 35 +/- 5 mmHg approximately 90 min, then resuscitation) or sham operation. At the beginning of resuscitation, mice received 17beta-estradiol (25 microg/25 g) or vehicle intravenously and were sacrificed 2 h thereafter. Kupffer cell TLR4, iNOS, IL-6 and TNF-alpha production capacities were increased, and ATP, Tfam, and mtCOI levels were decreased following trauma-hemorrhage. Administration of 17beta-estradiol following trauma-hemorrhage prevented the increase in Kupffer cell TLR4, iNOS, and cytokine production. This was accompanied by normalized ATP, Tfam, and mtCOI levels. Furthermore, the decreased Kupffer cell ATP and mtCOI levels were not observed in TLR4 mutant mice following trauma-hemorrhage. Taken together, these findings suggest that downregulation of TLR4-dependent ATP production is critical to 17beta-estradiol-mediated immunoprotection in Kupffer cells following trauma-hemorrhage.
Collapse
MESH Headings
- Adenosine Triphosphate/metabolism
- Animals
- Cells, Cultured
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/metabolism
- Disease Models, Animal
- Down-Regulation/drug effects
- Electron Transport Complex IV/genetics
- Electron Transport Complex IV/metabolism
- Estradiol/administration & dosage
- Femoral Artery/surgery
- High Mobility Group Proteins/genetics
- High Mobility Group Proteins/metabolism
- Injections, Intravenous
- Interleukin-6/metabolism
- Kupffer Cells/drug effects
- Kupffer Cells/immunology
- Kupffer Cells/metabolism
- Male
- Mice
- Mice, Inbred C3H
- Mice, Transgenic
- Mitochondria, Liver/drug effects
- Mitochondria, Liver/metabolism
- Mutation
- Nitric Oxide Synthase Type II/genetics
- Nitric Oxide Synthase Type II/metabolism
- RNA/metabolism
- Shock, Hemorrhagic/immunology
- Shock, Hemorrhagic/metabolism
- Shock, Hemorrhagic/prevention & control
- Time Factors
- Toll-Like Receptor 4/genetics
- Toll-Like Receptor 4/metabolism
- Transcription, Genetic/drug effects
- Tumor Necrosis Factor-alpha/metabolism
Collapse
Affiliation(s)
- Ya-Ching Hsieh
- Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Hsieh YC, Frink M, Thobe BM, Hsu JT, Choudhry MA, Schwacha MG, Bland KI, Chaudry IH. 17Beta-estradiol downregulates Kupffer cell TLR4-dependent p38 MAPK pathway and normalizes inflammatory cytokine production following trauma-hemorrhage. Mol Immunol 2007; 44:2165-2172. [PMID: 17182102 PMCID: PMC2366161 DOI: 10.1016/j.molimm.2006.11.019] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2006] [Revised: 10/28/2006] [Accepted: 11/18/2006] [Indexed: 01/19/2023]
Abstract
Although studies have shown that 17beta-estradiol (estradiol) normalized Kupffer cell function following trauma-hemorrhage, the mechanism by which E2 maintains immune function remains unclear. Activation of Toll-like receptor 4 (TLR4) initiates an inflammatory cascade, involving activation of p38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and nuclear factor-kappaB (NF-kappaB). This leads to the release of proinflammatory cytokines. Thus, we hypothesized that the salutary effects of estradiol on Kupffer cell function following trauma-hemorrhage are mediated via negative regulation of TLR4-dependent p38 MAPK and NF-kappaB. TLR4 mutant (C3H/HeJ) and wild type (C3H/HeOuJ) mice were subjected to trauma-hemorrhage (mean BP 35+/-5 mmHg approximately 90 min, then resuscitation) or sham operation. Administration of estradiol following trauma-hemorrhage in wild type mice decreased Kupffer cell TLR4 expression as well as prevented the phosphorylation of p38 MAPK and NF-kappaB. This was accompanied by normalization of Kupffer cell production capacities of IL-6, TNF-alpha, macrophage inflammatory protein (MIP)-1alpha, and MIP-2 and the decrease in plasma cytokine levels. In contrast, TLR4 mutant mice did not exhibit the increase in Kupffer cell p38 MAPK and NF-kappaB activation, cytokine production, or the increase in circulating cytokine levels following trauma-hemorrhage. No difference was observed in activation of PI3K among groups. These results suggest that the protective effect of estradiol on Kupffer cell function is mediated via downregulation of TLR4-dependent p38 MAPK and NF-kappaB signaling following trauma-hemorrhage, which prevents the systemic release of cytokines.
Collapse
Affiliation(s)
- Ya-Ching Hsieh
- Center for Surgical Research and Department of Surgery University of Alabama at Birmingham Birmingham, AL 35294
| | - Michael Frink
- Center for Surgical Research and Department of Surgery University of Alabama at Birmingham Birmingham, AL 35294
| | - Bjoern M. Thobe
- Center for Surgical Research and Department of Surgery University of Alabama at Birmingham Birmingham, AL 35294
| | - Jun-Te Hsu
- Center for Surgical Research and Department of Surgery University of Alabama at Birmingham Birmingham, AL 35294
| | - Mashkoor A. Choudhry
- Center for Surgical Research and Department of Surgery University of Alabama at Birmingham Birmingham, AL 35294
| | - Martin G. Schwacha
- Center for Surgical Research and Department of Surgery University of Alabama at Birmingham Birmingham, AL 35294
| | - Kirby I. Bland
- Center for Surgical Research and Department of Surgery University of Alabama at Birmingham Birmingham, AL 35294
| | - Irshad H. Chaudry
- Center for Surgical Research and Department of Surgery University of Alabama at Birmingham Birmingham, AL 35294
| |
Collapse
|
|
39
|
Suzuki T, Shimizu T, Yu HP, Hsieh YC, Choudhry MA, Schwacha MG, Chaudry IH. Tissue compartment-specific role of estrogen receptor subtypes in immune cell cytokine production following trauma-hemorrhage. J Appl Physiol (1985) 2007; 102:163-8. [PMID: 17023568 DOI: 10.1152/japplphysiol.00964.2006] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Although 17β-estradiol administration following trauma-hemorrhage attenuates plasma cytokines and alteration in immune cell cytokine production, it is not known whether the salutary effects are mediated via estrogen receptor (ER)-α or ER-β. Accordingly, we examined which ER subtype predominantly mediates the salutary effects of 17β-estradiol on systemic inflammatory response/immune cell cytokine production in various tissues following trauma-hemorrhage. Male rats underwent trauma-hemorrhage (mean blood pressure: 40 mmHg for 90 min) and fluid resuscitation. The ER-α agonist propyl pyrazole triol (PPT; 5 μg/kg), the ER-β agonist diarylpropionitrile (DPN; 5 μg/kg), 17β-estradiol (50 μg/kg), or vehicle (10% DMSO) was injected subcutaneously during resuscitation, and various measurements were made 24 h thereafter. 17β-Estradiol or PPT administration following trauma-hemorrhage prevented the increase in plasma IL-6 and IL-10 levels that were observed in vehicle-treated animals. IL-6 and TNF-α production by Kupffer cells increased; however, splenic macrophages (SMΦ), alveolar macrophages (AMΦ), and peripheral blood mononuclear cells (PBMC) had decreased release of these cytokines after trauma-hemorrhage. IL-10 production, however, increased in all macrophage populations. Administration of 17β-estradiol following trauma-hemorrhage prevented all of these alterations. PPT had the same effects as 17β-estradiol on IL-6 and TNF-α production by Kupffer cells and SMΦ, and DPN had the same effects on AMΦ and PBMC. The same effects as 17β-estradiol on IL-10 production were observed by PPT on Kupffer cells and DPN on PBMC. Both agonists were equally effective on SMΦ and AMΦ. Thus ER subtypes have tissue compartment-specific roles in mediating the effects of 17β-estradiol on immune cell functions following trauma-hemorrhage.
Collapse
Affiliation(s)
- Takao Suzuki
- Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, 1670 Univ. Blvd., Volker Hall, Rm. G094, Birmingham, AL 35294-0019, USA
| | | | | | | | | | | | | |
Collapse
|
|
40
|
Yang R, Tibbs BM, Chang B, Nguyen C, Woodall C, Steppacher R, Helling T, Morrison DC, Van Way CW. Effect of DHEA on the Hemodynamic Response to Resuscitation in a Porcine Model of Hemorrhagic Shock. ACTA ACUST UNITED AC 2006; 61:1343-9. [PMID: 17159675 DOI: 10.1097/01.ta.0000222955.14191.08] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Hemorrhagic shock is a major cause of death from trauma. Pharmacologic treatment has not been satisfactory. The objective of this study was to use a porcine model of hemorrhagic shock and resuscitation to access the hemodynamic effects of dehydroepiandrosterone (DHEA), an adrenal steroid hormone reported to improve cardiac function in patients. METHODS Hemorrhagic shock was produced in 20- to 30-kg male Yorkshire pigs anesthetized with 2% isoflurane by withdrawing blood through a carotid cannula to a mean arterial pressure (MAP) of 40 to 45 mm Hg and maintaining that level for 60 minutes by further removals of blood. Resuscitation was with 21 mL/kg Ringer's lactate (LR), with (n = 6) or without (n = 6) DHEA (4 mg/kg) dissolved in propylene glycol. The animals were killed after 7 days. Continuous cardiac output (CCO) was recorded using a modified Swan-Ganz catheter system. MAP, heart rate (HR), central venous pressure (CVP), and pulmonary arterial pressure (PAP) were measured every 5 minutes until 60 minutes postresuscitation. From MAP, CCO, HR, and CVP, we calculated total peripheral resistance (TPR), stroke volume (SV), and left ventricular stroke work (SW). RESULTS The MAP, CCO, SV, and SW decreased significantly during hemorrhagic shock, and then gradually increased to baseline levels during and 1 hour after resuscitation. The TPR was increased during hemorrhagic shock, and then gradually decreased to baseline levels during and after resuscitation. DHEA administration was associated with no significant improvement. CONCLUSION DHEA when added to standard fluid resuscitation showed no added benefit as resumed by the hemodynamic response.
Collapse
Affiliation(s)
- Rongjie Yang
- Department of Surgery, Shock/Trauma Research Center, University of Missouri Kansas City, Kansas City, MO 64108, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Angele MK, Frantz MC, Chaudry IH. Gender and sex hormones influence the response to trauma and sepsis: potential therapeutic approaches. Clinics (Sao Paulo) 2006; 61:479-88. [PMID: 17072448 DOI: 10.1590/s1807-59322006000500017] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2006] [Accepted: 08/07/2006] [Indexed: 11/22/2022] Open
Abstract
Several clinical and experimental studies have demonstrated gender dimorphism in immune and organ responsiveness and in the susceptibility to and morbidity from shock, trauma, and sepsis. In this respect, cell-mediated immune responses have been shown to be depressed in males following trauma-hemorrhage, whereas they were aintained/enhanced in proestrus females. Furthermore, sex hormones have been shown to be responsible for this gender-specific immune response following adverse circulatory conditions. More specifically, studies indicate that androgens produce immunodepression following trauma-hemorrhage in males. In contrast, female sex steroids appear to exhibit immunoprotective properties following trauma and severe blood loss. With regard to the underlying mechanisms, receptors for sex hormones have been identified on various immune cells suggesting direct effects of these hormones on the immune cells. Alternatively, indirect effects of sex hormones, ie, modulation of cardiovascular responses or androgen- and estrogen-synthesizing enzymes, might contribute to gender-specific immune responses. Recent studies indicate that sex hormones, eg, dehydroepiandrosterone (DHEA), also modulate the function of peripheral blood mononuclear cells in surgical patients. Thus, the immunomodulatory properties of sex hormones/receptor antagonists/sex steroid synthesizing enzymes following trauma-hemorrhage suggests novel therapeutic strategies for the treatment of immunodepression in surgical patients.
Collapse
Affiliation(s)
- Martin K Angele
- Department of Surgery, Klinikum Grosshadern, Munich, Germany
| | | | | |
Collapse
|
|
42
|
Choudhry MA, Schwacha MG, Hubbard WJ, Kerby JD, Rue LW, Bland KI, Chaudry IH. GENDER DIFFERENCES IN ACUTE RESPONSE TO TRAUMA-HEMORRHAGE. Shock 2005; 24 Suppl 1:101-6. [PMID: 16374381 DOI: 10.1097/01.shk.0000191341.31530.5e] [Citation(s) in RCA: 119] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
To understand the pathogenesis of a disease, experimental models are needed. A good experimental model is the one that simulates responses observed in the clinical setting. In recent years, clinical studies have indicated that gender might be a factor that plays a significant role in the outcome of patients with shock, trauma, and sepsis. These observations are now being evaluated in experimental setting. Studies performed in a rodent model of trauma-hemorrhage have concluded that alterations in immune and cardiac functions after trauma-hemorrhage are more markedly depressed in adult males, and ovariectomized and aged females. However, both are maintained in castrated males and in proestrus females. Moreover, the survival rate of proestrus females subjected to sepsis after trauma-hemorrhage is significantly higher than age-matched males or ovariectomized females. Although these observations suggest gender-specific response after trauma-hemorrhage, the mechanisms responsible for gender specificity remain largely unknown. Furthermore, in other injuries such as burn, experimental studies dealing with sexual dimorphism are limited. Therefore, more studies in clinical and experimental settings are required to determine whether gender-specific responses are global across the injuries or are observed in specific injury situations. Studies are also needed to delineate underlying mechanisms responsible for differences between males and females after trauma-hemorrhage. The information gained from the experimental studies will help in designing innovative therapeutic approaches for the treatment of trauma patients.
Collapse
Affiliation(s)
- Mashkoor A Choudhry
- Department of Surgery, University of Alabama, Birmingham, AL 35294-0019, USA.
| | | | | | | | | | | | | |
Collapse
|
|
43
|
Abstract
Aging in men is associated with a progressive decline in the production of several hormones, including androgens. The extent to which an age-dependent decline in androgen levels lead to health problems or can affect quality of life remains under debate. Clinical results on replacement therapy do not yet provide a definitive clue on the benefit/risk balance. A sexual dimorphism of the immune system is well established, and the differences between female and male immune responses under normal, as well as pathological, conditions are generally attributed to the influence of estrogens, progestins, and androgens. The suppressive effects of male sex hormones on immune functions have been observed in a wide variety of disease processes and appear to be testosterone-mediated. Endogenous testosterone inhibits skin wound healing response in males and is associated with an enhanced inflammatory response. Although there are no known gender-related differences in permeability barrier function in adults, estrogens accelerates--whereas testosterone retards--barrier development in fetal skin, and male fetuses demonstrate slower barrier development than female littermates.
Collapse
Affiliation(s)
- S Fimmel
- Department of Dermatology, Charité Universitaetsmedizin Berlin, Berlin, Germany
| | | |
Collapse
|
|
44
|
Angele MK, Chaudry IH. Surgical trauma and immunosuppression: pathophysiology and potential immunomodulatory approaches. Langenbecks Arch Surg 2005; 390:333-41. [PMID: 15995884 DOI: 10.1007/s00423-005-0557-4] [Citation(s) in RCA: 96] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2005] [Accepted: 04/11/2005] [Indexed: 11/27/2022]
Abstract
BACKGROUND Several studies indicate that organ failure is the leading cause of death in the postoperative phase after major surgery. An excessive inflammatory response followed by a dramatic depression of cell-mediated immunity after major surgery appears to be responsible for the increased susceptibility to subsequent sepsis. In view of this, most of the scientific and medical research has been directed towards measuring the progression and interrelationship of mediators after major surgery. Furthermore, the effect of those mediators on cell-mediated immune responses has been studied. OBJECTIVE This article focuses on the effect of surgical injury and blood loss on cell-mediated immune responses in experimental studies utilizing models of trauma and hemorrhagic shock. The findings from those experimental studies will also be correlated with data from surgical patients. RESULTS Recently, a gender-dimorphic immune and organ responsiveness in the susceptibility to and morbidity from shock, trauma, and sepsis has been found. Androgens have been shown to be responsible for the immunosuppression after trauma-hemorrhage in males. In contrast, female sex steroids exhibit immunoprotective properties after trauma and severe blood loss. CONCLUSION In view of these findings, clinically relevant therapeutic strategies have been developed using the testosterone receptor blocker flutamide and/or estrogen or agents with estrogenic effects, i.e., dehydroepiandrosterone, which might yield safe and useful therapeutic approaches for the treatment of immune depression in surgical patients.
Collapse
Affiliation(s)
- Martin K Angele
- Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA
| | | |
Collapse
|
|
45
|
Lü P, Liu F, Wang CY, Chen DD, Yao Z, Tian Y, Zhang JH, Wu YH. Gender differences in hepatic ischemic reperfusion injury in rats are associated with endothelial cell nitric oxide synthase-derived nitric oxide. World J Gastroenterol 2005; 11:3441-5. [PMID: 15948251 PMCID: PMC4316000 DOI: 10.3748/wjg.v11.i22.3441] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: This study was designed to examine the hypothesis that gender differences in I/R injury are associated with endothelial cell nitric oxide synthase (eNOS)-derived nitric oxide (NO).
METHODS: Wistar rats were randomized into seven experimental groups (12 animals per group). Except for the sham operated groups, all rats were subjected to total liver ischemia for 40 min followed by reperfusion. All experimental groups received different treatments 45 min before the laparotomy. For each group, half of the animals (six) were used to investigate the survival; blood samples and liver tissues were obtained in the remaining six animals after 3 h of reperfusion to assess serum NO, alanine aminotransferase (ALT) and TNF-α levels, liver tissue malondialdehyde (MDA) content, and severity of hepatic I/R injury.
RESULTS: Basal serum NO levels in female sham operated (FS) group were nearly 1.5-fold of male sham operated (MS) group (66.7±11.0 μmol/L vs 45.3±10.1 μmol/L, P<0.01). Although serum NO levels decreased significantly after hepatic I/R (P<0.01, vs sham operated groups), they were still significantly higher in female rat (F) group than in male rat (M) group (47.8±8.6 μmol/L vs 23.8±4.7 μmol/L, P<0.01). Serum ALT and TNF-α levels, and liver tissue MDA content were significantly lower in F group than in M group (370.5±46.4 U/L, 0.99±0.11 μg/L and 0.57±0.10 μmol/g vs 668.7±78.7 U/L, 1.71±0.18 μg/L and 0.86±0.11 μmol/g, respectively, P<0.01). I/R induced significant injury to the liver both in M and F groups (P<0.01 vs sham operated groups). But the degree of hepatocyte injury was significantly milder in F group than in M group (P<0.05 and P<0.01). The median survival time was six days in F group and one day in M group. The overall survival rate was significantly higher in F group than in M group (P<0.05). When compared with male rats pretreated with saline (M group), pretreatment of male rats with 17-β-estradiol (E2) (M+E2 group) significantly increased serum NO levels and significantly decreased serum ALT and TNF-α levels, and liver tissue MDA content after I/R (P<0.01). The degree of hepatocyte injury was significantly decreased and the overall survival rate was significantly improved in M+E2 group than in M group (P<0.01 and P<0.05). The NOS inhibitor Nw-nitro-L-arginine methyl ester (L-NAME) treatment could completely abolish the protective effects of estrogen in both male and female rats.
CONCLUSION: The protective effects afforded to female rats subjected to hepatic I/R are associated with eNOS-derived NO.
Collapse
Affiliation(s)
- Ping Lü
- Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China.
| | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Perl M, Gebhard F, Brückner UB, Ayala A, Braumüller S, Büttner C, Kinzl L, Knöferl MW. Pulmonary contusion causes impairment of macrophage and lymphocyte immune functions and increases mortality associated with a subsequent septic challenge*. Crit Care Med 2005; 33:1351-8. [PMID: 15942355 DOI: 10.1097/01.ccm.0000166352.28018.a9] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE AND DESIGN Pulmonary contusion is frequently followed by acute respiratory distress syndrome, pneumonia, and sepsis. However, immunologic alterations of circulating and resident immune cell populations contributing to the posttraumatic immunosuppression are poorly understood. We therefore characterized the influence of pulmonary contusion on peripheral blood mononuclear cells, peritoneal macrophages, splenocytes, and splenic macrophages. To address the significance of the immunosuppression associated with lung contusion, we investigated how the consecutive addition of moderate or severe sepsis affected survival after blunt chest trauma. SUBJECTS Male C3H/HeN mice (n = 10 per group) were anesthetized and subjected to chest trauma or sham procedure. MEASUREMENTS The cytokine release of cultured peripheral blood mononuclear cells, peritoneal macrophages, splenocytes, and splenic macrophages and plasma levels of tumor necrosis factor-alpha and interleukin-6 from those animals were quantified. Sepsis was induced via cecal ligation and puncture 24 hrs after lung contusion. MAIN RESULTS Two hours after blunt chest trauma, plasma tumor necrosis factor-alpha and interleukin-6 were markedly increased, as was peripheral blood mononuclear cell cytokine production, lung myeloperoxidase activity, and lung chemokine concentrations. At 24 hrs and, in part, already at 2 hrs, cytokine release from peritoneal macrophages, splenic macrophages, and splenocytes was significantly suppressed. Furthermore, pulmonary contusion when followed by moderate sepsis significantly diminished survival rate when compared with chest trauma or moderate sepsis alone. CONCLUSIONS These results indicate that pulmonary contusion causes severe immunodysfunction of splenocytes, macrophages, and monocytes in different local compartments and systemically. Moreover, this immunosuppression is associated with an increased susceptibility to infectious complications, which results in a decreased survival rate if blunt chest trauma is followed by a septic insult.
Collapse
Affiliation(s)
- Mario Perl
- Department of Trauma, Hand, and Reconstructive Surgery, University of Ulm, Germany
| | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Matsutani T, Samy TSA, Rue LW, Bland KI, Chaudry IH. Transgenic prolactin−/− mice: effect of trauma-hemorrhage on splenocyte functions. Am J Physiol Cell Physiol 2005; 288:C1109-16. [PMID: 15601751 DOI: 10.1152/ajpcell.00478.2004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Prolactin (PRL) is involved in the regulation of immune functions under normal and pathological conditions. Trauma-hemorrhage (T-H) produces profound immunosuppression in male mice but not in proestrus female mice. Administration of PRL in males after T-H, however, restores immune functions. In this study, PRL+/+ and transgenic (PRL−/−) male and female mice were used to assess immune suppression after T-H and to determine the reasons for the hormone's beneficial effect. In vitro lymphoproliferation assay with Nb2 cells showed complete absence of PRL in the circulation of the transgenic PRL−/− mice of both sexes, whereas very high levels of the hormone were detected in the wild-type PRL+/+ mice of both sexes. Moreover, T-H resulted in the appearance of significant levels of the hormone in circulation, but only in PRL+/+ mice. Splenocyte proliferation in male PRL−/− mice was significantly lower than in PRL+/+ mice after T-H. Marginal differences between PRL+/+ and PRL−/− mice were observed in the release of IL-2 and IFN-γ by splenocytes, while the release of IL-10 was significantly higher in PRL−/− than in PRL+/+ mice. A significant observation of our study is the release of a ∼25-kDa protein in the concanavalin A-stimulated splenocytes of male PRL+/+ and PRL−/− mice that was active in the in vitro lymphoproliferation assay with Nb2 cells. It is unlikely that this protein is PRL because it is also present in the splenocyte extracts of PRL−/− transgenic mice. Nonetheless, because control of lymphoid cell proliferation is considered one of the characteristics of the immune system, the local release of this protein may be significant in the differences observed in splenocyte cytokine release after T-H in wild-type as well as transgenic mice.
Collapse
Affiliation(s)
- Takeshi Matsutani
- Center for Surgical Research and Dept. of Surgery, Univ. of Alabama at Birmingham, Volker Hall G094, 1670 University Blvd., Birmingham, AL 35294-0019, USA
| | | | | | | | | |
Collapse
|
|
48
|
Inaba K, Suzuki S, Ihara H, Sakaguchi T, Baba S, Urano T, Konno H, Nakamura S. Sexual dimorphism in endotoxin susceptibility after partial hepatectomy in rats. J Hepatol 2005; 42:719-27. [PMID: 15826722 DOI: 10.1016/j.jhep.2004.12.026] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2004] [Revised: 11/17/2004] [Accepted: 12/24/2004] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS Liver failure due to endotoxemia after hepatectomy is a fatal complication. Little is known regarding the gender influence on this pathophysiological condition. This study was conducted to investigate whether a gender difference exists in the endotoxin susceptibility after hepatectomy. METHODS Sexually mature male and female rats received an intravenous administration of lipopolysaccharide (LPS), as endotoxin, 48h after a two-thirds hepatectomy. RESULTS The 24-h survival rate after LPS administration was significantly higher in females (75%) than in males (38%). Ovariectomy reduced the survival rate in females to 44%. Plasma tumor necrosis factor-alpha levels 1h after LPS were significantly elevated in males and ovariectomized females. The inducible nitric oxide synthase (iNOS) gene expression in liver and spleen, and consequent nitric oxide production 3h after LPS were significantly enhanced in males and ovariectomized females when compared to females, in addition to less functional and structural liver damage in females. CONCLUSIONS Our results indicate a gender difference in the susceptibility to endotoxemia in the early phase after hepatectomy. Female tolerance to these conditions may be mediated by an inhibition of excessive inflammatory response in the liver and the spleen, partially via the suppression of iNOS gene up-regulation.
Collapse
Affiliation(s)
- Keisuke Inaba
- Second Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan.
| | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Wang M, Baker L, Tsai BM, Meldrum KK, Meldrum DR. Sex differences in the myocardial inflammatory response to ischemia-reperfusion injury. Am J Physiol Endocrinol Metab 2005; 288:E321-6. [PMID: 15367393 DOI: 10.1152/ajpendo.00278.2004] [Citation(s) in RCA: 118] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The myocardium generates inflammatory mediators during ischemia-reperfusion (I/R), and these mediators contribute to cardiac functional depression and apoptosis. The great majority of these data have been derived from male animals and humans. Sex has a profound effect over many inflammatory responses; however, it is unknown whether sex affects the cardiac inflammatory response to acute myocardial I/R. We hypothesized the existence of inherent sex differences in myocardial function, expression of inflammatory cytokines, and activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway after I/R. Isolated rat hearts from age-matched adult males and females were perfused (Langendorff), and myocardial contractile function was continuously recorded. After I/R, myocardium was assessed for expression of TNF-alpha, IL-1beta, and IL-6 (RT-PCR, ELISA); IL-1alpha and IL-10 mRNA (RT-PCR); and activation of p38 MAPK (Western blot). All indexes of postischemic myocardial function [left ventricular developed pressure, left ventricular end-diastolic pressure, and maximal positive (+dP/dt) and negative (-dP/dt) values of the first derivative of pressure] were significantly improved in females compared with males. Compared with males, females had decreased myocardial TNF-alpha, IL-1beta, and IL-6 (mRNA, protein) and decreased activation of p38 MAPK pathway. These data demonstrate that hearts from age-matched adult females are relatively protected against I/R injury, possibly due to a diminished inflammatory response.
Collapse
Affiliation(s)
- Meijing Wang
- Department of Cellular Physiology, Indiana University School of Medicine, 545 Barnhill Drive, Emerson Hall 215, Indianapolis, IN 46202, USA
| | | | | | | | | |
Collapse
|
|
50
|
Eisenmenger SJ, Wichmann MW, Angele P, Faist E, Hatz R, Chaudry IH, Jauch KW, Angele MK. Differences in the expression of LPS-receptors are not responsible for the sex-specific immune response after trauma and hemorrhagic shock. Cell Immunol 2005; 230:17-22. [PMID: 15541715 DOI: 10.1016/j.cellimm.2004.08.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2004] [Accepted: 08/13/2004] [Indexed: 10/26/2022]
Abstract
Several studies demonstrated a sex-specific cytokine secretion by macrophages following trauma-hemorrhage (T-H) and incubation with lipopolysaccharide A (LPS). Although LPS is known to act via the receptors CD14 and TLR4 on macrophages, it remains unknown whether differences in LPS receptor expression in males and females may be responsible for the gender-specific LPS induced cytokine response following (T-H). To study this, male and proestrus female mice (C3H/HeN) were subjected to trauma (laparotomy) followed by hemorrhage or sham operation. At 2 h thereafter, SMphi and PMphi were harvested and cultured for 2 h. The expression of CD14 and TLR4 was measured by flow cytometry on unstimulated SMphi and PMphi as well as after LPS stimulation. The results indicate that the expression of CD14 and TLR4 on SMphi and PMphi from female and male mice was similar in sham-operated animals and after (T-H). Incubation of macrophages with LPS did not alter CD14 and TLR4 expression in the study groups. Thus, the sex specific LPS induced cytokine secretion after (T-H) is not caused by differences in LPS receptor expression on Mphi of male and female mice.
Collapse
Affiliation(s)
- S J Eisenmenger
- Department of Surgery, Klinikum Grosshadern Ludwig-Maximilians University, Marchioninistr. 15, D-81377 Munich, Germany
| | | | | | | | | | | | | | | |
Collapse
|