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Standardized experimental brain death model for studies of intracranial dynamics, organ preservation, and organ transplantation in the pig
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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2011 (English)In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 39, no 3, p. 512-517Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES:: Brain death impairs organ function and outcome after transplantation. There is a need for a brain death model to allow studies of organ viability and preservation. For neurointensive care research, it is also of interest to have a relevant brain death model for studies of intracranial dynamics and evaluation of cerebral monitoring devices. Therefore, the objective was to develop a standardized clinically relevant brain death model. METHODS:: Six pigs of both sexes (10-12 wks old; mean weight, 24.5 ± 1.4 kg) were included. Mean arterial blood pressure, heart rate, intracranial pressure, intracranial compliance, cerebral perfusion pressure, and brain tissue oxygenation (BtiPo2) were recorded during stepwise elevation of intracranial pressure by inflation of an epidural balloon catheter with saline (1 mL/20 mins). Brain death criteria were decided to be reached when cerebral perfusion pressure was <0 mm Hg for 60 mins and at least 10 mL saline was inflated epidurally. BtiPo2 and arterial injections of microspheres were used for confirmation of brain death. RESULTS:: A gradual volume-dependent elevation of intracranial pressure was observed. After 10 mL of balloon infusion, mean intracranial pressure was 89.8 ± 9.7 (sd) mm Hg. Intracranial compliance decreased from 0.137 ± 0.069 mL/mm Hg to 0.007 ± 0.001 mL/mm Hg. The mean arterial pressure decreased and the heart rate increased when the intracranial volume was increased to between 5 and 6 mL. All animals showed cerebral perfusion pressure ≤0 after 7 to 10 mL of infusion. In all animals, the criteria for brain death with negative cerebral perfusion pressure and BtiPo2 ∼0 mm Hg were achieved. Only a negligible amount of microspheres were found in the cerebrum, confirming brain death. The kidneys showed small foci of acute tubular necrosis. CONCLUSIONS:: The standardized brain death model designed in pigs simulates the clinical development of brain death in humans with a classic pressure-volume response and systemic cardiovascular reactions. Brain death was convincingly confirmed.

Place, publisher, year, edition, pages
2011. Vol. 39, no 3, p. 512-517
Keywords [en]
brain death, experimental animal model, intracranial pressure, cerebral perfusion pressure, brain tissue oxygenation, organ preservation
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-143532DOI: 10.1097/CCM.0b013e318206b824ISI: 000287480000013PubMedID: 21187748OAI: oai:DiVA.org:uu-143532DiVA, id: diva2:390368
Available from: 2011-01-21 Created: 2011-01-21 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Brain Tissue Oxygenation in Traumatic Brain Injury: Experimental and Clinical Studies
Open this publication in new window or tab >>Brain Tissue Oxygenation in Traumatic Brain Injury: Experimental and Clinical Studies
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Traumatic brain injury (TBI) is a major cause of death and disability. TBI is frequently followed by cerebral ischemia which is a great contributor to secondary brain damage. The main causes of cerebral ischemia are pathophysiological changes in cerebral blood flow and metabolism. Treatment of TBI patients is currently based on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) targeted treatment protocols. However, ICP and CPP alone do not provide information of the oxygen availability in the brain. Monitoring of brain tissue oxygenation (BtipO2) may give additional and valuable information about the risk for development of ischemia in TBI patients.

The aims of this thesis were to study BtipO2 monitoring devices in-vitro regarding accuracy and stability, to detect threshold level of cerebral ischemia in-vivo and finally to examine the cerebral oxygen levels and cerebral metabolism in TBI patients.

The BtipO2 probes performed with high accuracy and stability at different clinically relevant oxygen concentrations.

A pig TBI model was developed by step-wise intracranial volume/pressure increase. Volume increase resulted in a gradual increased ICP, decreased CPP, intracranial compliance and BtipO2, respectively. Brain death (BD) was confirmed by negative CPP and negligible amount of previously injected microspheres in the brain tissue. The model simulated the clinical development of BD in humans with a classical pressure-volume response and systemic cardiovascular reactions. The model should be suitable for studies of brain injury mechanisms.

From the same in-vivo model it was also possible to detect the threshold level of cerebral ischemia in the pig, where BtipO2 below 10 mmHg and CPP below 30 mmHg was associated with an impaired cerebral metabolism (microdialysis lactate to pyruvate ratio >30).

BtipO2 together with cerebral microdialysis were studied in 23 severe TBI patients. We observed different patterns of changes in BtipO2 and cerebral microdialysis biomarkers in focal and diffuse TBI.  Increased cerebral microdialysis levels of glutamate, glycerol or the lactate/pyruvate ratio were observed at BtipO2 < 5 mmHg, indicating increased vulnerability of the brain at this critical level of tissue oxygenation in TBI patients.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. p. 74
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 869
Keywords
Brain tissue oxygenation, Cerebral metabolism, Traumatic brain injury, Cerebral ischemia, Threshold levels, Neurovent-PTO, Microdialysis
National Category
Medical and Health Sciences Anesthesiology and Intensive Care Neurosciences
Research subject
Neurosurgery
Identifiers
urn:nbn:se:uu:diva-195867 (URN)978-91-554-8607-5 (ISBN)
Public defence
2013-04-19, Grönwallsalen, Akademiska sjukhuset, ingång 70, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2013-03-27 Created: 2013-02-28 Last updated: 2018-01-11Bibliographically approved
2. Management of Ischemia and Brain Death-Associated Injuries in Porcine Kidney Grafts
Open this publication in new window or tab >>Management of Ischemia and Brain Death-Associated Injuries in Porcine Kidney Grafts
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Organs from deceased donors after brain death (BD) remain the major source of organs for transplantation. The catastrophic event of BD and the inevitable consequences of ischemia reperfusion injury (IRI) are linked to impaired graft quality and transplantation outcome. The aim of this thesis was to create a BD model in pigs to assess early effects on IRI in kidneys preserved with an oxygenated solution and to evaluate the protective effects of coating the renal vessel walls with a heparin conjugate during hypothermic machine perfusion (HMP).

Brain death was achieved by raising the intracranial pressure (ICP) through stepwise increasing the volume of an epidurally placed balloon to the point of exceeding the mean arterial pressure (MAP) creating a negative cerebral perfusion pressure (CPP). This reproducible, clinically relevant experimental model makes evaluation of potential targeted methods to protect the organs possible. Kidneys retrieved from brain-dead pigs were preserved either in an oxygenated emulsion composed of 75% histidine-tryptophan-ketoglutarate (HTK) and 25% perfluorohexyloctane F6H8 or HTK alone. After 18h of cold storage the kidneys were transplanted into allogeneic pigs. F6H8 was associated with replenishment of adenosine triphosphate and lower gene expression of hypoxia inducible factor (HIF)-1a, vascular endothelial growth factor (VEGF), interleukin (IL)-1α and tumour necrosis factor (TNF)-α. F6H8 reduced early IRI at both the cellular and molecular level.

Kidneys from BD pigs were evaluated for the feasibility of coating the vessel walls with the heparin conjugate CHC (Corline Systems AB, Uppsala, Sweden) to restore glycocalyx. Porcine kidneys were preserved by HMP for 20h with 50 mg biotinylated CHC added to the perfusion solution. CHC was detected on the inner surface of the kidney vessels by immunofluorescence, and its uptake in kidneys was confirmed by reduced content in the perfusate. An ex vivo normothermic perfusion circuit was developed to assess kidney function. Perfusion with CHC during HMP was associated with lower creatinine levels, increased urine volume and reduced tubular injury. Modifying renal vessels walls using CHC during HMP improved early graft function. Preservation with the oxygenated F6H8 solution or CHC could be used to improve graft quality and ameliorate IRI in kidneys retrieved from deceased donors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. p. 77
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 993
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-222020 (URN)978-91-554-8939-7 (ISBN)
Public defence
2014-05-31, Gustavianum Auditorium Minus, Akademigatan 3, uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2014-05-08 Created: 2014-04-07 Last updated: 2014-06-30

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Lorant, TomasTufveson, GunnarWiklund, Lars

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NeurosurgeryTransplantation SurgeryDepartment of Medical Cell BiologyDepartment of Immunology, Genetics and PathologyAnaesthesiology and Intensive CareDepartment of Neuroscience
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