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Sharma, H. S., Muresanu, D. F., Nozari, A., Castellani, R. J., Dey, P. K., Wiklund, L. & Sharma, A. (2019). Anesthetics influence concussive head injury induced blood-brain barrier breakdown, brain edema formation, cerebral blood flow, serotonin levels, brain pathology and functional outcome. In: Sharma, HS Sharma, A (Ed.), New Therapeutic Strategies for Brain Edema and Cell Injury: (pp. 45-81). Elsevier
Open this publication in new window or tab >>Anesthetics influence concussive head injury induced blood-brain barrier breakdown, brain edema formation, cerebral blood flow, serotonin levels, brain pathology and functional outcome
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2019 (English)In: New Therapeutic Strategies for Brain Edema and Cell Injury / [ed] Sharma, HS Sharma, A, Elsevier, 2019, p. 45-81Chapter in book (Refereed)
Abstract [en]

Several lines of evidences show that anesthetics influence neurotoxicity and neuroprotection. The possibility that different anesthetic agents potentially influence the pathophysiological and functional outcome following neurotrauma was examined in a rat model of concussive head injury (CHI). The CHI was produced by an impact of 0.224N on the right parietal bone by dropping a weight of 114.6g from a 20cm height under different anesthetic agents, e.g., inhaled ether anesthesia or intraperitoneally administered ketamine, pentobarbital, equithesin or urethane anesthesia. Five hour CHI resulted in profound volume swelling and brain edema formation in both hemispheres showing disruption of the blood-brain barrier (BBB) to Evans blue and radio-iodine. A marked decrease in the cortical CBF and a profound increase in plasma or brain serotonin levels were seen at this time. Neuronal damages were present in several parts of the brain. These pathological changes were most marked in CHI under ether anesthesia followed by ketamine (35mg/kg, i.p.), pentobarbital (50 mg/kg, i.p.), equithesin (3 mL/kg, i.p.) and urethane (1 g/kg, i.p.). The functional outcome on Rota Rod performances or grid walking tests was also most adversely affected after CHI under ether anesthesia followed by pentobarbital, equithesin and ketamine. Interestingly, the plasma and brain serotonin levels strongly correlated with the development of brain edema in head injured animals in relation to different anesthetic agents used. These observations suggest that anesthetic agents are detrimental to functional and pathological outcomes in CHI probably through influencing the circulating plasma and brain serotonin levels, not reported earlier. Whether anesthetics could also affect the efficacy of different neuroprotective agents in CNS injuries is a new subject that is currently being examined in our laboratory.

Place, publisher, year, edition, pages
Elsevier, 2019
Series
International Review of Neurobiology, ISSN 0074-7742 ; 146
National Category
Anesthesiology and Intensive Care Neurosciences
Identifiers
urn:nbn:se:uu:diva-401923 (URN)10.1016/bs.irn.2019.06.006 (DOI)000501592100003 ()31349932 (PubMedID)978-0-12-816754-0 (ISBN)
Funder
Swedish Research Council, 2710Göran Gustafsson Foundation for Research in Natural Sciences and MedicineAstraZenecaNIH (National Institute of Health), R01 AG028679
Available from: 2020-01-10 Created: 2020-01-10 Last updated: 2020-01-10Bibliographically approved
Wiklund, L., Patnaik, R., Sharma, A., Miclescu, A. & Sharma, H. S. (2018). Cerebral Tissue Oxidative Ischemia-Reperfusion Injury in Connection with Experimental Cardiac Arrest and Cardiopulmonary Resuscitation: Effect of Mild Hypothermia and Methylene Blue. Molecular Neurobiology, 55(1), 115-121
Open this publication in new window or tab >>Cerebral Tissue Oxidative Ischemia-Reperfusion Injury in Connection with Experimental Cardiac Arrest and Cardiopulmonary Resuscitation: Effect of Mild Hypothermia and Methylene Blue
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2018 (English)In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 55, no 1, p. 115-121Article in journal (Refereed) Published
Abstract [en]

The present investigation is an expansion of previous studies which all share a basic experimental protocol of a porcine-induced cardiac arrest (CA) of 12 min followed by 8 min of cardiopulmonary resuscitation (CPR), different experimental treatments (immediate as well as postponed induced mild hypothermia and administration of much or less cool intravenous fluids), and a follow-up period of 3 h after which the animals were sacrificed. Another group of animals was studied according to the same protocol after 12-min CA and Bstandard CPR.^ After death (within 1 min), the brains were harvested and frozen in liquid nitrogen awaiting analysis. Control brains of animals were collected in the same way after short periods of untreated CA (0 min, 5 min, and 15–30 min). Previous studies concerning chiefly neuropathological changes were now expanded with analyses of different tissue indicators (glutathione, luminol, leucigenin, malonialdehyde, and myeloperoxidase) of cerebral oxidative injury. The results indicate that a great part of oxidative injury occurs within the first 5 min after CA. Immediate cooling by administration of much intravenous fluid results in less cerebral oxidative injury compared to less intravenous fluid administration. A 30-min postponement of induction of hypothermia results in a cerebral oxidative injury comparable to that of Bstandard CPR^ or the oxidative injury found after 5 min of untreated CA. Intravenous administration of methylene blue (MB) during and immediately after CPR in combination with postponed cooling resulted in no statistical difference in any of the indicators of oxidative injury, except myeloperoxidase, and glutathione, when this treatment was compared with the negative controls, i.e., animals subjected to anesthesia alone.

Place, publisher, year, edition, pages
Humana Press, 2018
Keywords
Cardiac arrest, Oxidative injury, Ischemia reperfusion, Methylene blue
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-337384 (URN)10.1007/s12035-017-0723-z (DOI)000424702600012 ()28895060 (PubMedID)
Available from: 2017-12-24 Created: 2017-12-24 Last updated: 2019-01-25Bibliographically approved
Lindblom, R. P., Molnar, M., Israelsson, C., Röjsäter, B., Wiklund, L. & Lennmyr, F. (2018). Hyperglycemia Alters Expression of Cerebral Metabolic Genes after Cardiac Arrest. Journal of Stroke & Cerebrovascular Diseases, 27(5), 1200-1211
Open this publication in new window or tab >>Hyperglycemia Alters Expression of Cerebral Metabolic Genes after Cardiac Arrest
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2018 (English)In: Journal of Stroke & Cerebrovascular Diseases, ISSN 1052-3057, E-ISSN 1532-8511, Vol. 27, no 5, p. 1200-1211Article in journal (Refereed) Published
Abstract [en]

Background: Survivors of cardiac arrest often experience neurologic deficits. To date, treatment options are limited. Associated hyperglycemia is believed to further worsen the neurologic outcome. The aim with this study was to characterize expression pathways induced by hyperglycemia in conjunction with global brain ischemia.

Methods: Pigs were randomized to high or normal glucose levels, as regulated by glucose and insulin infusions with target levels of 8.5-10 mM and 4-5.5 mM, respectively. The animals were subjected to 5-minute cardiac arrest followed by 8 minutes of cardiopulmonary resuscitation and direct-current shock to restore spontaneous circulation. Global expression profiling of the cortex using microarrays was performed in both groups.

Results: A total of 102 genes differed in expression at P<.001 between the hyperglycemic and the normoglycemic pigs. Several of the most strongly differentially regulated genes were involved in transport and metabolism of glucose. Functional clustering using bioinformatics tools revealed enrichment of multiple biological processes, including membrane processes, ion transport, and glycoproteins.

Conclusions: Hyperglycemia during cardiac arrest leads to differential early gene expression compared with normoglycemia. The functional relevance of these expressional changes cannot be deduced from the current study; however, the identified candidates have been linked to neuroprotective mechanisms and constitute interesting targets for further studies.

Keywords
Cerebral, ischemia-reperfusion, gene expression, glucose, hyperglycemia, microarray, pigs
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-351620 (URN)10.1016/j.jstrokecerebrovasdis.2017.11.036 (DOI)000428778400016 ()29306595 (PubMedID)
Funder
Erik, Karin och Gösta Selanders Foundation
Available from: 2018-06-13 Created: 2018-06-13 Last updated: 2018-06-13Bibliographically approved
Wiklund, L., Sharma, A. & Sharma, H. S. (2016). Neuroprotection by Methylene Blue in Cerebral Global Ischemic Injury Induced Blood-Brain Barrier Disruption and Brain Pathology: A Review. CNS & Neurological Disorders: Drug Targets, 15(9), 1181-1187
Open this publication in new window or tab >>Neuroprotection by Methylene Blue in Cerebral Global Ischemic Injury Induced Blood-Brain Barrier Disruption and Brain Pathology: A Review
2016 (English)In: CNS & Neurological Disorders: Drug Targets, ISSN 1871-5273, E-ISSN 1996-3181, Vol. 15, no 9, p. 1181-1187Article, review/survey (Refereed) Published
Abstract [en]

Transient global ischemic cerebral injury is a consequence of cardiac arrest and accounts for approximately 450,000 annual deaths with a mortality of approximately 90%. Serious morbidity follows for many of the survivors and up to 16% of patients achieving restoration of spontaneous circulation develop brain death. Other survivors are left with persistent cognitive impairment such as memory and sensimotor deficits, reducing quality of life and resulting in heavy costs on society. Many studies over the years have been devoted to improving outcome after cardiac arrest and have, to a certain degree succeeded, especially locally in areas where improvement of ambulance organizations have been effective. In spite of this serious problems remain and the chances of cerebral survival need to increase if over-all results, i.e. survival as well as cognitive function, are to improve. Methylene blue, a textile dye synthesized in the late 19th century has also been used in medicine for different purposes. One of its effects is to increase systemic blood pressure, but other effects have been documented, among which are its neuroprotective effects well-noted during the last few years. In this review we have appraised these findings in relation to global ischemic injury.

Keywords
Global ischemia, cardiac arrest, neuronal cell injury, glial cell activation, ubiquitin expression, methylene blue, neuroprotection, blood-brain barrier
National Category
Neurology Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-311092 (URN)10.2174/1871527315666160915114516 (DOI)000387125600013 ()27633785 (PubMedID)
Available from: 2016-12-21 Created: 2016-12-21 Last updated: 2018-01-13Bibliographically approved
Helliksson, F., Wernerman, J., Wiklund, L., Rosell, J. & Karlsson, M. (2016). The combined use of three widely available biochemical markers as predictor of organ failure in critically ill patients. Scandinavian Journal of Clinical and Laboratory Investigation, 76(6), 479-485
Open this publication in new window or tab >>The combined use of three widely available biochemical markers as predictor of organ failure in critically ill patients
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2016 (English)In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 76, no 6, p. 479-485Article in journal (Refereed) Published
Abstract [en]

Background: We hypothesized that lactate dehydrogenase, LDH/albumin ratio in combination with or without magnesium (Mg2+) could predict organ failure in critically ill adult patients. The aim of this study was to describe a new risk index for organ failure or mortality in critically ill patients based on a combination of these routinely available biochemical plasma biomarkers.Methods: Patients18 years admitted to the intensive care unit (ICU) were screened. Albumin and LDH were analyzed at the time of admission to ICU (n=347). Organ failure assessed with Sequential Organ Failure Assessment' (SOFA) score was used, and 30-day mortality was recorded. The predictive value of the test was calculated using the areas under the receiving operating characteristic (ROC) curve.Results: The LDH/albumin ratio was higher in patients who developed organ failure as compared to those who did not (p<0.001). The areas under the ROC curve were 0.77 both for prediction of multiple organ failure and for 30-day mortality. In a subgroup of patients (n=183) admitted to ICU from the emergency department, the predictive values were 0.86 and 0.80, respectively.Conclusion: The LDH/albumin ratio at ICU admission was associated with the development of multiple organ failure and 30-day mortality in this prospective study. The clinical value of this biomarker as a predictor of organ failure in critically ill patients is yet to be defined.

Keywords
Biomarkers, critical care, lactate dehydrogenases, multiple organ failure, organ dysfunction scores
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-305962 (URN)10.1080/00365513.2016.1201850 (DOI)000384305800007 ()27362714 (PubMedID)
Available from: 2016-10-31 Created: 2016-10-24 Last updated: 2017-11-29Bibliographically approved
Kaisdotter Andersson, A., Kron, J., Castren, M., Muntlin Athlin, Å., Hök, B. & Wiklund, L. (2015). Assessment of the breath alcohol concentration in emergency care patients with different level of consciousness. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, 23(1), Article ID 11.
Open this publication in new window or tab >>Assessment of the breath alcohol concentration in emergency care patients with different level of consciousness
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2015 (English)In: Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, ISSN 1757-7241, E-ISSN 1757-7241, Vol. 23, no 1, article id 11Article in journal (Refereed) Published
Abstract [en]

Background

Many patients seeking emergency care are under the influence of alcohol, which in many cases implies a differential diagnostic problem. For this reason early objective alcohol screening is of importance not to falsely assign the medical condition to intake of alcohol and thus secure a correct medical assessment.

Objective

At two emergency departments, demonstrate the feasibility of accurate breath alcohol testing in emergency patients with different levels of cooperation.

Method

Assessment of the correlation and ratio between the venous blood alcohol concentration (BAC) and the breath alcohol concentration (BrAC) measured in adult emergency care patients. The BrAC was measured with a breathalyzer prototype based on infrared spectroscopy, which uses the partial pressure of carbon dioxide (pCO2) in the exhaled air as a quality indicator.

Result

Eighty-eight patients enrolled (mean 45 years, 53 men, 35 women) performed 201 breath tests in total. For 51% of the patients intoxication from alcohol or tablets was considered to be the main reason for seeking medical care. Twenty-seven percent of the patients were found to have a BAC of <0.04 mg/g. With use of a common conversion factor of 2100:1 between BAC and BrAC an increased agreement with BAC was found when the level of pCO2 was used to estimate the end-expiratory BrAC (underestimation of 6%, r = 0.94), as compared to the BrAC measured in the expired breath (underestimation of 26%, r = 0.94). Performance of a forced or a non-forced expiration was not found to have a significant effect (p = 0.09) on the bias between the BAC and the BrAC estimated with use of the level of CO2. A variation corresponding to a BAC of 0.3 mg/g was found between two sequential breath tests, which is not considered to be of clinical significance.

Conclusion

With use of the expired pCO2 as a quality marker the BrAC can be reliably assessed in emergency care patients regardless of their cooperation, and type and length of the expiration.

National Category
Other Clinical Medicine
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-243624 (URN)10.1186/s13049-014-0082-y (DOI)000350846000001 ()
Available from: 2015-02-11 Created: 2015-02-11 Last updated: 2017-12-04Bibliographically approved
Sharma, H. S., Patnaik, R., Sharma, A., Vicente Lafuente, J., Miclescu, A. & Wiklund, L. (2015). Cardiac Arrest Alters Regional Ubiquitin Levels in Association with the Blood-Brain Barrier Breakdown and Neuronal Damages in the Porcine Brain. Molecular Neurobiology, 52(2), 1043-1053
Open this publication in new window or tab >>Cardiac Arrest Alters Regional Ubiquitin Levels in Association with the Blood-Brain Barrier Breakdown and Neuronal Damages in the Porcine Brain
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2015 (English)In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 52, no 2, p. 1043-1053Article in journal (Refereed) Published
Abstract [en]

The possibility that ubiquitin expression is altered in cardiac arrest-associated neuropathology was examined in a porcine model using immunohistochemical and biochemical methods. Our observations show that cardiac arrest induces progressive increase in ubiquitin expression in the cortex and hippocampus in a selective and specific manner as compared to corresponding control brains using enzyme-linked immunoassay technique (enzyme-linked immunosorbent assay (ELISA)). Furthermore, immunohistochemical studies showed ubiquitin expression in the neurons exhibiting immunoreaction in the cytoplasm and karyoplasm of distorted or damaged cells. Separate Nissl and ubiquitin staining showed damaged and distorted neurons and in the same cortical region ubiquitin expression indicating that ubiquitin expression after cardiac arrest represents dying neurons. The finding that methylene blue treatment markedly induced neuroprotection following identical cardiac arrest and reduced ubiquitin expression strengthens this view. Taken together, our observations are the first to show that cardiac arrest enhanced ubiquitin expression in the brain that is related to the magnitude of neuronal injury and the finding that methylene blue reduced ubiquitin expression points to its role in cell damage, not reported earlier.

Keywords
Cardiac arrest, Ubiquitin expression, Brain pathology, Neuroprotection, Methylene blue, Transmission electron microscopy, Immunohistochemistry, ELISA
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-263424 (URN)10.1007/s12035-015-9254-7 (DOI)000360687200023 ()26108181 (PubMedID)
Funder
Swedish Research Council, 2710-HSSSwedish Foundation for Strategic Research AstraZeneca
Available from: 2015-10-13 Created: 2015-09-30 Last updated: 2017-12-01Bibliographically approved
Wiklund, L., Johansson, H. & Karlsson, T. (2015). Martin H: son Holmdahl.. Upsala Journal of Medical Sciences, 120(2)
Open this publication in new window or tab >>Martin H: son Holmdahl.
2015 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 2Article in journal (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-266753 (URN)10.3109/03009734.2015.1044055 (DOI)25941864 (PubMedID)
Available from: 2015-11-10 Created: 2015-11-10 Last updated: 2017-12-01
Zoerner, F., Lennmyr, F., Wiklund, L., Martijn, C. & Semenas, E. (2015). Milrinone and esmolol decrease cardiac damage after resuscitation from prolonged cardiac arrest. Acta Anaesthesiologica Scandinavica, 59(4), 465-474
Open this publication in new window or tab >>Milrinone and esmolol decrease cardiac damage after resuscitation from prolonged cardiac arrest
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2015 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 59, no 4, p. 465-474Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Long-term survival after cardiac arrest (CA) due to shock-refractory ventricular fibrillation (VF) is low. Clearly, there is a need for new pharmacological interventions in the setting of cardiopulmonary resuscitation (CPR) to improve outcome. Here, hemodynamic parameters and cardiac damage are compared between the treatment group (milrinone, esmolol and vasopressin) and controls (vasopressin only) during resuscitation from prolonged CA in piglets.

METHODS: A total of 26 immature male piglets were subjected to 12-min VF followed by 8-min CPR. The treatment group (n = 13) received i.v. (intravenous) boluses vasopressin 0.4 U/kg, esmolol 250 μg/kg and milrinone 25 μg/kg after 13 min, followed by i.v. boluses esmolol 375 μg/kg and milrinone 25 μg/kg after 18 min and continuous esmolol 15 μg/kg/h infusion during 180 min reperfusion, whereas controls (n = 13) received equal amounts of vasopressin and saline. A 200 J monophasic counter-shock was delivered to achieve resumption of spontaneous circulation (ROSC) after 8 min CPR. If ROSC was not achieved, another 200 J defibrillation and bolus vasopressin 0.4 U/kg would be administered in both groups. Direct current shocks at 360 J were applied as one shot per minute over maximally 5 min. Hemodynamic variables and troponin I as a marker of cardiac injury were recorded.

RESULTS: Troponin I levels after 180 min reperfusion were lower in the treatment group than in controls (P < 0.05). The treatment group received less norepinephrine (P < 0.01) and had greater diuresis (P < 0.01). There was no difference in survival between groups.

CONCLUSION: The combination of milrinone, esmolol and vasopressin decreased cardiac injury compared with vasopressin alone.

National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-251850 (URN)10.1111/aas.12480 (DOI)000351537900008 ()25790148 (PubMedID)
Available from: 2015-04-24 Created: 2015-04-24 Last updated: 2017-12-04Bibliographically approved
Halvorsen, P., Sharma, H. S., Basu, S. & Wiklund, L. (2015). Neural injury after use of vasopressin and adrenaline during porcine cardiopulmonary resuscitation. Upsala Journal of Medical Sciences, 120(1), 11-19
Open this publication in new window or tab >>Neural injury after use of vasopressin and adrenaline during porcine cardiopulmonary resuscitation
2015 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 1, p. 11-19Article in journal (Refereed) Published
Abstract [en]

Background. Our aim was to investigate cerebral and cardiac tissue injury subsequent to use of vasopressin and adrenaline in combination compared with vasopressin alone during cardiopulmonary resuscitation (CPR). Methods. In a randomized, prospective, laboratory animal study 28 anesthetized piglets were subject to a 12-min untreated cardiac arrest and subsequent CPR. After 1 min of CPR, 10 of the piglets received 0.4 U/kg of arg(8)-vasopressin (V group), and 10 piglets received 0.4 U/kg of arg(8)-vasopressin, 1 min later followed by 20 mu g/kg body weight of adrenaline, and another 1 min later continuous administration (10 mu g/kg/min) of adrenaline (VA group). After 8 min of CPR, the piglets were defibrillated and monitored for another 3 h. Then they were killed and the brain immediately removed pending histological analysis. Results. During CPR, the VA group had higher mean blood pressure and cerebral cortical blood flow (CCBF) but similar coronary perfusion pressure. After restoration of spontaneous circulation there was no difference in the pressure variables, but CCBF tended to be (36% +/- 16%) higher in the V group. Neuronal injury and signs of a disrupted blood-brain barrier (BBB) were greater, 20% +/- 4% and 21% +/- 4%, respectively, in the VA group. In a background study of repeated single doses of adrenaline every third minute after 5 min arrest but otherwise the same protocol, histological measurements showed even worse neural injury and disruption of the BBB. Conclusion. Combined use of vasopressin and adrenaline caused greater signs of cerebral and cardiac injury than use of vasopressin alone during experimental cardiopulmonary resuscitation.

Keywords
Adrenaline, cardiopulmonary resuscitation, cerebral anoxia-ischemia, heart arrest, ischemia, vasopressin
National Category
Other Medical Sciences not elsewhere specified
Identifiers
urn:nbn:se:uu:diva-251516 (URN)10.3109/03009734.2015.1010665 (DOI)000350984700002 ()25645317 (PubMedID)
Available from: 2015-04-23 Created: 2015-04-20 Last updated: 2017-12-04Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8700-5610

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