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Sex Differences in Cardiac and Cerebral Damage after Hypovolemic Cardiac Arrest
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Resuscitation from haemorrhagic shock and the subsequent circulatory arrest remains a major clinical challenge in the care of trauma patients. Numerous experimental studies in sexually mature animals have shown a gender dimorphism in response to trauma and haemorrhagic shock. The first study was designed to evaluate sex differences in outcome after resuscitation from hypovolemic circulatory arrest. We intended to examine innate sex differences, and chose to study sexually immature animals. The study showed that cerebral cortical blood flow was greater, blood-brain-barrier was better preserved and neuronal injury was smaller in female as compared to male piglets. The second study demonstrated that female sex was associated with enhanced haemodynamic response, cardioprotection, and better survival. This cardioprotective effect was observed despite comparable estradiol and testosterone levels in male and female animals, indicating an innate gender-related cardioprotection. In both studies (I and II) female sex was associated with a smaller increase in the cerebral expression of inducible and neuronal nitric oxide synthase (iNOS and nNOS). Thus in the study III we tested the hypothesis that exogenously administered 17β-estradiol (E2) could improve neurological outcome by NOS modulation. The results showed that compared with the control group, animals in the E2 group exhibited a significantly smaller increase in nNOS and iNOS expression, a smaller blood-brain-barrier disruption and a mitigated neuronal injury. There was also a significant correlation between nNOS and iNOS levels and neuronal injury. A hypothesis if female-specific cardioprotection may be attributed to a smaller NOS activity was tested in study IV. The animals received methylene blue (MB) during CPR, but were otherwise treated according to the same protocol as studies I-II. The female-specific cardioprotection could be attributed to a smaller NOS activity, but NOS inhibition with MB did not improve survival or myocardial injury, although it abated the difference between the sexes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2011. , 71 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 654
Keyword [en]
Cardiopulmonary resuscitation, sex, haemorrhage, neuronal damage, estradiol, hypertonic saline, nitric oxide, methylene blue
National Category
Medical and Health Sciences
Research subject
Anaesthesiology and Intensive Care
Identifiers
URN: urn:nbn:se:uu:diva-146314ISBN: 978-91-554-8028-8OAI: oai:DiVA.org:uu-146314DiVA: diva2:401116
Public defence
2011-04-28, Hedstrandsalen, Akademiska sjukhuset, entrance no. 70, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2011-04-08 Created: 2011-02-16 Last updated: 2011-05-05Bibliographically approved
List of papers
1. Sex differences in cerebral injury after severe haemorrhage and ventricular fibrillation in pigs
Open this publication in new window or tab >>Sex differences in cerebral injury after severe haemorrhage and ventricular fibrillation in pigs
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2010 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 54, no 3, 343-353 p.Article in journal (Refereed) Published
Abstract [en]

Background: Experimental studies of haemorrhagic shock have documented a superior haemodynamic response and a better outcome in female animals as compared with male controls. Such sexual dimorphism has, nevertheless, not been reported after circulatory arrest that follows exsanguination and shock. We aimed to study differences in cerebral injury markers after exsanguination cardiac arrest in pre-pubertal piglets. The hypothesis was that cerebral injury is less extensive in female animals, and that this difference is independent of sexual hormones or choice of resuscitative fluid. Methods: Thirty-two sexually immature piglets (14 males and 18 females) were subjected to 5 min of haemorrhagic shock followed by 2 min of ventricular fibrillation and 8 min of cardiopulmonary resuscitation, using three resuscitation fluid regimens (whole blood, hypertonic saline and dextran, or acetated Ringers' solution plus whole blood and methylene blue). Haemodynamic values, cellular markers of brain injury and brain histology were studied. Results: After successful resuscitation, female piglets had significantly greater cerebral cortical blood flow, tended to have lower S-100beta values and a lower cerebral oxygen extraction ratio. Besides, in female animals, systemic and cerebral venous acidosis were mitigated. Female piglets exhibited a significantly smaller increase in neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) expression in their cerebral cortex, smaller blood-brain-barrier (BBB) disruption and significantly smaller neuronal injury. Conclusion: After resuscitation from haemorrhagic circulatory arrest, cerebral reperfusion is greater, and BBB permeability and neuronal injury is smaller in female piglets. An increased cerebral cortical iNOS and nNOS expression in males implies a mechanistic relationship with post-resuscitation neuronal injury and warrants further investigation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-122756 (URN)10.1111/j.1399-6576.2009.02125.x (DOI)000274313000012 ()19764903 (PubMedID)
Available from: 2010-04-19 Created: 2010-04-19 Last updated: 2015-06-08Bibliographically approved
2. Sex differences in cardiac injury after severe haemorrhage and ventricular fibrillation in pigs
Open this publication in new window or tab >>Sex differences in cardiac injury after severe haemorrhage and ventricular fibrillation in pigs
2010 (English)In: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 81, no 12, 1718-1722 p.Article in journal (Refereed) Published
Abstract [en]

Aim of the study: Experimental studies have shown sex differences in haemodynamic response and outcome after trauma and haemorrhagic shock. We recently reported that female sex protects against cerebral injury after exsanguination cardiac arrest (CA), independent of sexual effects of hormones. The current study examines if female sex is also cardioprotective.

Methods: In this study 21 sexually immature piglets (12 males and 9 females) were subjected to 5min of haemorrhagic shock followed by 2min of ventricular fibrillation and 8min of cardiopulmonary resuscitation (CPR). Volume resuscitation was started during CPR with intravenous administration of 3mlkg−1 hypertonic saline-dextran (HSD) solution for 20min. Sexually immature animals were used to differentiate innate sex differences from the effects of sexual hormones. Sex differences in haemodynamics, myocardial injury (troponin I), and short-term survival (3-h) were evaluated.

Results: After resuscitation female animals had a higher blood pressure, lower heart rate, lower troponin I concentrations, and higher survival rate (100% and 63% in 3h) despite comparable sex hormone levels.

Conclusions: After resuscitation from haemorrhage and circulatory arrest, haemodynamic parameters are better preserved and myocardial injury is smaller in female piglets. This difference in outcome is independent of sexual hormones.

Keyword
Cardiopulmonary resuscitation, Haemorrhage, Hypertonic saline, Sex
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-146303 (URN)10.1016/j.resuscitation.2010.08.010 (DOI)000285815000023 ()20817375 (PubMedID)
Available from: 2011-02-16 Created: 2011-02-16 Last updated: 2011-05-05Bibliographically approved
3. Neuroprotective effects of 17-beta-estradiol after hypovolemic cardiac arrest in immature piglets: the role of nitric oxide and peroxidation
Open this publication in new window or tab >>Neuroprotective effects of 17-beta-estradiol after hypovolemic cardiac arrest in immature piglets: the role of nitric oxide and peroxidation
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2011 (English)In: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. 36, no 1, 30-37 p.Article in journal (Refereed) Published
Abstract [en]

We recently reported that cerebral and cardiac injuries are mitigated in immature female piglets after severe hemorrhage with subsequent cardiac arrest (CA) Female sex was also associated with a smaller increase in the cerebral expression of inducible and neuronal nitric oxide synthase (nNOS). In the current study, we tested the hypothesis that exogenously administered 17β-estradiol (E2) can improve neurological outcome by NOS modulation. Thirty nine sexually immature piglets were bled to a mean arterial pressure of 35 mmHg over 15 min. Fifty μg/kg of E2 was then administered to 10 male and 10 female animals (estradiol group), while control animals (n=10 males and 9 females) received equal volume of normal saline. The animals were then subjected to ventricular fibrillation (4 min) followed by up to 15 min of open chest CPR. Vasopressin 0.4 U/kg and amiodarone 0.5 mg/kg were given and 3 ml/kg of 7.5% saline with 6% dextran was administered over 20 min. All surviving animals were euthanized after 3hr and their brains examined for histological injury and NOS expression. No significant differences were observed in survival or hemodynamics between the groups. Compared with the control group, animals in the E2 group exhibited a significantly smaller increase in nNOS and iNOS expression, a smaller blood-brain-barrier disruption and a mitigated neuronal injury. There was a significant correlation between nNOS and iNOS levels and neuronal injury. Interestingly estradiol attenuated cerebral damage (including lower activation of nNOS and iNOS) both in male and female piglets. In conclusion, in our immature piglets model of hypovolemic cardiac arrest, E2 down-regulates iNOS and nNOS expression and results in decreased BBB permeability disruption and smaller neuronal injury.

National Category
Cardiac and Cardiovascular Systems Surgery Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-146312 (URN)10.1097/SHK.0b013e3182150f43 (DOI)000291675800006 ()21330940 (PubMedID)
Available from: 2011-02-16 Created: 2011-02-16 Last updated: 2014-08-15Bibliographically approved
4. Modulation of nitric oxide expression with methylene blue does not improve outcome after hypovolemic cardiac arrest
Open this publication in new window or tab >>Modulation of nitric oxide expression with methylene blue does not improve outcome after hypovolemic cardiac arrest
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2011 (English)In: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 82, no 10, 1344-1349 p.Article in journal (Refereed) Published
Abstract [en]

Aim of the study: We recently reported that female sex protects against cerebral and cardiac injury after hypovolemiccardiac arrest (CA), independent of sex hormone effects. As female sex was also associated with a smaller increase in inducible and neuronal nitric oxide synthase (NOS), we hypothesised that nitric oxide inhibition with methylene blue (MB) improves the outcome, primarily in male animals. Methods: Twenty sexually immature piglets (10 males and 10 females) were bled to mean arterial blood pressure of 35 mmHg, and were subjected to 2 min of untreated CA followed by 8 min of open chest cardiopulmonary resuscitation (CPR). Volume resuscitation was started during CPR with intravenous administration of 3 ml kg(-1) hypertonic saline-dextran. Methyleneblue was then administered as bolus of 2.5 mg kg(-1) over 20 min, followed by 1.5 mg kg(-1) infusion over 40 min. Historical data from 21 animals were used as control (no MB). Hemodynamic parameters, myocardial injury (troponin I), and short-term survival (3-h) were evaluated. Histopathological evaluation of heart specimens was performed. Results: There were no differences between male and female animals in survival or resuscitation rate. After CA female pigletshad significantly greater systolic and mean arterial pressures, and had lower troponin I plasma concentrations compared to malepiglets, with or without MB. No difference was observed in histopathological analysis of heart specimens between sexes. Conclusions: After resuscitation from hypovolemic CA, female sex protects against cardiac injury, independent of sex hormones. Modulation of NO expression with MB does not improve survival or myocardial histological injury in either sex. 

National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-146313 (URN)10.1016/j.resuscitation.2011.04.027 (DOI)000296168700020 ()21636201 (PubMedID)
Available from: 2011-02-16 Created: 2011-02-16 Last updated: 2014-08-15Bibliographically approved

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