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  • 51.
    Liu, X. L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Nozari, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Neurological outcome after experimental cardiopulmonary resuscitation: a result of delayed and potentially treatable neuronal injury?2002In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 46, no 5, p. 537-546Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In experimental cardiopulmonary resuscitation (CPR) aortic balloon occlusion, vasopressin, and hypertonic saline dextran administration improve cerebral blood flow. Free radical scavenger alpha-phenyl-N-tert-butyl-nitrone (PBN) and cyclosporine-A (CsA) alleviate neuronal damage after global ischemia. Combining these treatments, we investigated neurological outcome after experimental cardiac arrest.

    METHODS: Thirty anesthetized piglets, randomly allocated into three groups, were subjected to 8 min of ventricular fibrillation followed by 5 min of closed-chest CPR. The combined treatment (CT) group received all the above-mentioned modalities; group B was treated with balloon occlusion and epinephrine; and group C had sham balloon occlusion with epinephrine. Indicators of oxidative stress (8-iso-PGF(2 alpha)), inflammation (15-keto-dihydro-PGF(2 alpha)), energy crisis (hypoxanthine and xanthine), and anoxia/hypoxia (lactate) were monitored in jugular bulb venous blood. Neurological outcome was evaluated 24 h after CPR.

    RESULTS: Restoration of spontaneous circulation (ROSC) was more rapidly achieved and neurological outcome was significantly better in the CT group, although there was no difference in coronary perfusion pressure between groups. The jugular venous PCO2 and cerebral oxygen extraction ratio were lower in the CT group at 5-15 min after ROSC. Jugular venous 8-iso-PGF(2 alpha) and hypoxanthine after ROSC were correlated to 24 h neurological outcome

    CONCLUSIONS: A combination of cerebral blood flow promoting measures and administration of alpha-phenyl-N-tert-butyl-nitrone and cyclosporine-A improved 24 h neurological outcome after 8 min of experimental normothermic cardiac arrest, indicating an ongoing neuronal injury in the reperfusion phase.

  • 52.
    Liu, X. L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Nozari, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Differences in cerebral reperfusion and oxidative injury after cardiac arrest in pigs2003In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 47, no 8, p. 958-967Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: An investigation of the free radical scavenger sodium 2-sulfophenyl-N-tert-butyl nitrone (S-PBN) and the weak vasodilatator Tris buffer mixture (TBM) on cerebral cortical blood flow (CCBF) and the jugular bulb concentration of two eicosanoids, indicators of oxidative stress and inflammation, was undertaken in 30 anaesthetized piglets during cardiopulmonary resuscitation (CPR) and after restoration of spontaneous circulation (ROSC).

    METHODS: Thirty animals were subjected to 8 min of untreated circulatory arrest followed by 8 min of closed-chest CPR. During CPR, the animals were randomized to receive 60 mg/kg S-PBN, 1 mmol/kg TBM or 2 ml/kg normal saline (n = 10 in each group). Systemic haemodynamic variables, CCBF and jugular bulb plasma concentrations of 8-iso-PGF2alpha and 15-keto-dihydro-PGF2alpha were measured.

    RESULTS: The CCBF during reperfusion after ROSC was greater in the TBM group than in the S-PBN group, the regression coefficient between CCBF and mean arterial blood pressure being lower in the S-PBN group than in the TBM group. The jugular bulb plasma concentration of 8-iso-PGF2alpha during the first 30 min after ROSC was greater in the TBM group than in the S-PBN group. Administration of TBM after vasopressin did not attenuate the pressor effect of vasopressin.

    CONCLUSION: Administration of S-PBN during CPR results in less cerebral oxidative stress, possibly by promoting normal distribution of cerebral blood flow.

  • 53. Liu, Xiaoli
    et al.
    Nozari, Ala
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Buffer administration during CPR promotes cerebral reperfusion after return of spontaneous circulation and mitigates post-resuscitation cerebral acidosis.2002In: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 55, no 1, p. 45-55Article in journal (Refereed)
    Abstract [en]

    To explore the effects of alkaline buffers on cerebral perfusion and cerebral acidosis during and after cardiopulmonary resuscitation (CPR), 45 anaesthetized piglets were studied. The animals were subjected to 5 min non-interventional circulatory arrest followed by 7 min closed chest CPR and received either 1 mmol/kg of sodium bicarbonate, 1 mmol/kg of tris buffer mixture, or the same volume of saline (n=15 in all groups), adrenaline (epinephrine) boluses and finally external defibrillatory shocks. Systemic haemodynamic variables, cerebral cortical blood flow, arterial, mixed venous, and internal jugular bulb blood acid-base status and blood gases as well as cerebral tissue pH and PCO(2) were monitored. Cerebral tissue acidosis was recorded much earlier than arterial acidaemia. After restoration of spontaneous circulation, during and after temporary arterial hypotension, pH in internal jugular bulb blood and in cerebral tissue as well as cerebral cortical blood flow was lower after saline than in animals receiving alkaline buffer. Buffer administration during CPR promoted cerebral cortical reperfusion and mitigated subsequent post-resuscitation cerebral acidosis during lower blood pressure and flow in the reperfusion phase. The arterial alkalosis often noticed during CPR after the administration of alkaline buffers was caused by low systemic blood flow, which also results in poor outcome.

  • 54.
    Martijn, Cécile
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Effect of methylene blue on the genomic response to reperfusion injury induced by cardiac arrest and cardiopulmonary resuscitation in porcine brain2010In: BMC Medical Genomics, ISSN 1755-8794, Vol. 3, p. 27-Article in journal (Refereed)
    Abstract [en]

    Background: Cerebral ischemia/reperfusion injury is a common secondary effect of cardiac arrest which is largely responsible for postresuscitative mortality. Therefore development of therapies which restore and protect the brain function after cardiac arrest is essential. Methylene blue (MB) has been experimentally proven neuroprotective in a porcine model of global ischemia-reperfusion in experimental cardiac arrest. However, no comprehensive analyses have been conducted at gene expression level. Methods: Pigs underwent either untreated cardiac arrest (CA) or CA with subsequent cardiopulmonary resuscitation (CPR) accompanied with an infusion of saline or an infusion of saline with MB. Genome-wide transcriptional profiling using the Affymetrix porcine microarray was performed to 1) gain understanding of delayed neuronal death initiation in porcine brain during ischemia and after 30, 60 and 180 min following reperfusion, and 2) identify the mechanisms behind the neuroprotective effect of MB after ischemic injury (at 30, 60 and 180 min). Results: Our results show that restoration of spontaneous circulation (ROSC) induces major transcriptional changes related to stress response, inflammation, apoptosis and even cytoprotection. In contrast, the untreated ischemic and anoxic insult affected only few genes mainly involved in intra-/extracellular ionic balance. Furthermore, our data show that the neuroprotective role of MB is diverse and fulfilled by regulation of the expression of soluble guanylate cyclase and biological processes accountable for inhibition of apoptosis, modulation of stress response, neurogenesis and neuroprotection. Conclusions: Our results support that MB could be a valuable intervention and should be investigated as a therapeutic agent against neural damage associated with I/R injury induced by cardiac arrest.

  • 55.
    Martijn, Cécile
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zoerner, Frank
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Miclescu, Adriana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Effects of mild therapeutic hypothermia on genomic response to reperfusion injury after cardiac arrest and cardiopulmonary resuscitation in porcine brain2012In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 19, no S1, p. 565-565Article in journal (Other academic)
  • 56.
    Miclescu, Adriana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Cardio-cerebral and metabolic effects of methylene blue in hypertonic sodium lactate during experimental cardiopulmonary resuscitation2007In: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 75, no 1, p. 88-97Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Methylene blue (MB) administered with a hypertonic-hyperoncotic solution reduces the myocardial and cerebral damage due to ischaemia and reperfusion injury after experimental cardiac arrest and also increases short-term survival. As MB precipitates in hypertonic sodium chloride, an alternative mixture of methylene blue in hypertonic sodium lactate (MBL) was developed and investigated during and after cardiopulmonary resuscitation (CPR). METHODS: Using an experimental pig model of cardiac arrest (12 min cardiac arrest and 8 min CPR) the cardio-cerebral and metabolic effects of MBL (n=10), MB in normal saline (MBS; n=10) or in hypertonic saline dextran (MBHSD; n=10) were compared. Haemodynamic variables and cerebral cortical blood flow (CCBF) were recorded. Biochemical markers of cerebral oxidative injury (8-iso-PGF2alpha), inflammation (15-keto-dihydro-PGF2alpha), and neuronal damage (protein S-100beta) were measured in blood from the sagittal sinus, whereas markers of myocardial injury, electrolytes, and lactate were measured in arterial plasma. RESULTS: There were no differences between groups in survival, or in biochemical markers of cerebral injury. In contrast, the MBS group exhibited not only increased CKMB (P<0.001) and troponin I in comparison with MBHSD (P=0.019) and MBL (P=0.037), but also greater pulmonary capillary wedge pressure 120 min after return of spontaneous circulation (ROSC). Lactate administration had an alkalinizing effect started 120 min after ROSC. CONCLUSIONS: Methylene blue in hypertonic sodium lactate may be used against reperfusion injury during experimental cardiac arrest, having similar effects as MB with hypertonic saline-dextran, but in addition better myocardial protection than MB with normal saline. The neuroprotective effects did not differ.

  • 57.
    Miclescu, Adriana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Methylene blue added to a hypertonic-hyperoncotic solution increases short-term survival in experimental cardiac arrest2006In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 34, no 11, p. 2806-2813Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Methylene blue (MB), a free-radical scavenger inhibiting the production and actions of nitric oxide, may counteract excessive vasodilatation induced by nitric oxide during cardiac arrest. Effects of MB in cardiac arrest and cardiopulmonary resuscitation were investigated. DESIGN: Randomized, prospective, laboratory animal study. SETTING: University animal research laboratory. SUBJECTS: A total of 63 piglets of both sexes. INTERVENTIONS: A pig model of extended cardiac arrest (12 mins of untreated cardiac arrest and 8 mins of cardiopulmonary resuscitation) was employed to assess the addition or no addition of MB to a hypertonic saline-dextran solution. These two groups (MB and hypertonic saline-dextran group [MB group] and hypertonic saline-dextran-only group) of 21 animals were each compared with a group receiving isotonic saline (n = 21). MEASUREMENTS AND MAIN RESULTS: Although the groups were similar in baseline values, 4-hr survival in the MB group was increased (p = .02) in comparison with the isotonic saline group. Hemodynamic variables were somewhat improved at 15 mins after restoration of spontaneous circulation in the MB group compared with the other two groups. The jugular bulb levels of 8-isoprostane-prostaglandin F2alpha and 15-keto-dihydro-prostaglandin F2alpha (indicators of peroxidation and inflammation) were significantly decreased in the MB group compared with the isotonic saline group. Significant differences were recorded between the three groups in levels of protein S-100beta (indicator of neurologic injury), with lower levels in the MB group compared with the isotonic saline and hypertonic saline-dextran-only groups. Troponin I and myocardial muscle creatine kinase isoenzyme arterial concentrations (indicators of myocardial damage) were also significantly lower in the MB group. CONCLUSIONS: MB co-administered with a hypertonic-hyperoncotic solution increased 4-hr survival vs. saline in an experimental porcine model of cardiac arrest and reduced oxidative, inflammatory, myocardial, and neurologic injury.

  • 58.
    Miclescu, Adriana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Martijn, Cécile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Methylene blue administration during cardio-pulmonary resuscitation and early reperfusion protects against cortical blood-brain barrier disruptionManuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    Objective: The present study was designed to study the effects of cardiac arrest and cardiopulmonary resuscitation (CPR) on blood-brain barrier (BBB) permeability and subsequent neurological injury. It also tests the cerebral effects of MB on the maintenance of BBB integrity, the production of nitric oxide (NO) and regulation of nitric oxide synthases (NOS) in cerebral cortex.

    Intervention: The control group (CA, n=16) underwent 12 min cardiac arrest without subsequent CPR, after which the brain of the animals was removed immediately or after 15 and 30 min. The other two groups with 12 min cardiac arrest and subsequent 8 min CPR received either an infusion of saline (CA-MB group, n=10) or an infusion of saline with MB (CA+MB, n= 12) started one minute after the start of CPR and continued 50 min after return of spontaneous circulation (ROSC).  In both the latter (CA-MB and CA+MB) groups the brains were removed for histological analysis at the following time points: 30, 60, 180 min after ROSC.

    Main Results: In all the groups an increase of necrotic neurons and albumin immunoreactivity was demonstrated with increasing duration of ischemia and reperfusion time. The immunohistochemistry analysis indicated less blood brain barrier disruption in the animals receiving MB (CA+MB group) evidenced by decreased albumin leakage (P<0.01), water content (P=0.02), potassium (P=0.04), but also decreased neuronal injury (P<0.001) in this group in comparison with the group that was not treated with MB (CA-MB). Similarly, MB treatment reduced nitrite/nitrate ratio (P=0.02), iNOS expression (P<0.01), nNOS expression (P<0.01).

    Conclusion: Cerebral edema, increase BBB permeability and neurologic injury are observed early in ischemia induced by cardiac arrest. MB markedly reduced BBB disruption and subsequent neurologic injury. These cerebral cortical effects after the exposure to MB appear to be associated with a decrease of NO measured by nitrate/nitrite and different effects on NOS.

  • 59.
    Miclescu, Adriana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Martijn, Cécile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Methylene blue protects the cortical blood-brain barrier against ischemia/reperfusion-induced disruptions2010In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 38, no 11, p. 2199-2206Article in journal (Refereed)
    Abstract [en]

    Objectives: To investigate the effects of cardiac arrest and the reperfusion syndrome on blood-brain barrier permeability and evaluate whether methylene blue counteracts blood-brain barrier disruption in a pig model of controlled cardiopulmonary resuscitation. Design: Randomized, prospective, laboratory animal study. Setting: University-affiliated research laboratory. Subjects: Forty-five piglets. Interventions: Forty-five anesthetized piglets were subjected to cardiac arrest alone or 12-min cardiac arrest followed by 8 mins cardiopulmonary resuscitation. The first group (n = 16) was used to evaluate blood-brain barrier disruptions after untreated cerebral ischemia after 0, 15, or 30 mins after untreated cardiac arrest. The other two groups received either an infusion of saline (n = 10) or infusion of saline with methylene blue (n = 12) 1 min after the start of cardiopulmonary resuscitation and continued 50 mins after return of spontaneous circulation. In these groups, brains were removed for immunohistological analyses at 30, 60, and 180 mins after return of spontaneous circulation. Measurements and Main Results: An increase of injured neurons and albumin immunoreactivity was demonstrated with in-creasing duration of ischemia/reperfusion. Less blood-brain barrier disruption was observed in subjects receiving methylene blue as demonstrated by decreased albumin leakage (p<.01), water content (p<.05), and neuronal injury (p<.01). Methylene blue treatment reduced cerebral tissue nitrite/nitrate content (p<.05) and the number of inducible and neuronal nitric oxide synthase-activated cortical cells during administration (p<.01). Meanwhile, the number of cortical endothelial nitric oxide synthase-activated cells increased over time (p<.001). Conclusion: Cerebral tissue water content, blood-brain barrier permeability and neurologic injury were increased early in reperfusion after cardiac arrest. Methylene blue exerted neuroprotective effects against the brain damage associated with the ischemia/reperfusion injury and ameliorated the blood-brain barrier disruption by decreasing nitric oxide metabolites. (Crit Care Med 2010; 38: 2199-2206)

  • 60.
    Miclescu, Adriana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Crystalloid vs. hypertonic crystalloid-colloid solutions for induction of mild therapeutic hypothermia after experimental cardiac arrest2013In: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 84, no 2, p. 256-262Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    To compare cerebral and hemodynamic consequences of different volumes of cold acetated Ringer's solution or cold hypertonic saline dextran administered in order to achieve mild hypothermia after cardiac arrest (CA) in a pig model of experimental cardiopulmonary resuscitation (CPR).

    METHODS:

    Using an experimental pig model of 12min CA (followed by 8min CPR or no resuscitation) we compared four groups of piglets: a control group, a normothermic group and two groups with different solutions administered for induction of hypothermia. The control group of 5 piglets underwent 12min CA without subsequent CPR, after which the brain of the animals was removed immediately. After restoration of spontaneous circulation (ROSC) the resuscitated piglets were randomized into a normothermic group (NT group=10), and two hypothermic groups that received cold infusions of either 30mL/kg acetated Ringer's solution (Much fluid group, M, n=10) or 3mL/kg hypertonic saline dextran solution (Less fluid group, L, n=10), respectively, administered during 30min. Additional external cooling with ice packs was used in hypothermic groups. Sixty or 180min after ROSC the experiment was terminated. Immediately after arrest the brain was removed for histological analyses.

    RESULTS:

    The median time to reach the target core temperature of 34°C after ROSC was 51.5±7.8min in L group and 48.8±8.6min in M group. Less cerebral tissue content of water (p<0.001), sodium (p<0.0001), potassium (p<0.0001) and less central venous pressure (CVP) at 5 and 15min after ROSC were demonstrated in L group. Increased brain damage was demonstrated over time in NT group (p<0.001). Less neurologic damage and BBB disruptions (albumin leakage) was observed at 180min in M group in comparison with both NT and L groups (p<0.001).

    CONCLUSION:

    No statistical differences were observed between the hypothermic groups in the time to achieve mild hypothermia. Although inclusion of cold hypertonic crystalloid-colloidal solutions in the early resuscitation after ROSC may be more effective than cold crystalloids in reducing brain edema, this study demonstrates that mild hypothermia induced with small volumes of cold hypertonic crystalloid-colloids is less as effective as crystalloid's induced hypothermia in mitigating brain injury after cardiac arrest.

  • 61.
    Miclescu, Adriana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Methylene blue, an old drug with new indications?2010In: Jurnalul Roman de Anestezie Terapie Intaensiva, ISSN 1582-652X, Vol. 17, no 1, p. 35-41Article, review/survey (Other academic)
    Abstract [en]

    Just when we thought we finally understood methylene blue (MB) after it has been used clinically for more than a century, the old properties are revived and therefore possible new indications appears. Nitric oxide (NO) stimulates soluble guanylate cyclase, which converts guanosine triphosphate into cyclic guanosine monophosphate. Increases in cGMP concentration, in turn, through a cascade of protein kinases, induce smooth muscle relaxation and vasodilation. Methylene blue (MB) has direct inhibitory effects on nitric oxide synthases (NOS), both constitutive and inducible and blocks accumulation of cyclic guanosine monophosphate (cGMP) by inhibiting the enzyme guanylate cyclase. Also, MB blocks the iron-containing enzymes such as xanthine oxidase and has antioxidants effects. New indications are therefore described in relation with MB as in the vasoplegic syndrome following cardiopulmonary bypass in humans and in the settings of cardiac arrest in animals.

  • 62.
    Molnar, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Bergquist, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lennmyr, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Hyperglycaemia increases S100β after short experimental cardiac arrest2014In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 58, no 1, p. 106-113Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Hyperglycaemia is associated with aggravated ischaemic brain injury. The main objective of this study was to investigate the effects on cerebral perfusion of 5 min of cardiac arrest during hyperglycaemia and normoglycaemia.

    METHODS:

    Twenty triple-breed pigs (weight: 22-29 kg) were randomised and clamped at blood glucose levels of 8.5-10 mM [high (H)] or 4-5.5 mM [normal (N)] and thereafter subjected to alternating current-induced 5 min-cardiac arrest followed by 8 min of cardiopulmonary resuscitation and direct current shock to restore spontaneous circulation.

    RESULTS:

    Haemodynamics, laser Doppler measurements and regional venous oxygen saturation (HbO2 ) were monitored, and biochemical markers in blood [S100β, interleukin (IL)-6 and tumour necrosis factor (TNF)] quantified throughout an observation period of 3 h. The haemodynamics and physiological measurements were similar in the two groups. S100β increased over the experiment in the H compared with the N group (P < 0.05). IL-6 and TNF levels increased across the experiment, but no differences were seen between the groups.

    CONCLUSIONS:

    The enhanced S100β response is compatible with increased cerebral injury by hyperglycaemic compared with normoglycaemic 5 min of cardiac arrest and resuscitation. The inflammatory cytokines were similar between groups.

  • 63.
    Molnar, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lindblom, Rickard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Israelsson, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Fridman, Belinda
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lennmyr, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Differential regulation of cerebral metabolic genes after hyperglycemic and normoglycemic cardiac arrestManuscript (preprint) (Other academic)
  • 64.
    Mörtberg, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Cumming, Paul
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Cerebral metabolic rate of oxygen (CMRO2) in pig brain determined by PET after resuscitation from cardiac arrest2009In: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 80, no 6, p. 701-706Article in journal (Refereed)
    Abstract [en]

    AIM: To assess the regional vulnerability to ischemic damage and perfusion/metabolism mismatch of reperfused brain following restoration of spontaneous circulation (ROSC) after cardiac arrest. METHOD: We used positron emission tomography (PET) to map cerebral metabolic rate of oxygen (CMRO(2)), cerebral blood flow (CBF) and oxygen extraction fraction (OEF) in brain of young pigs at intervals after resuscitation from cardiac arrest. After obtaining baseline PET recordings, ventricular fibrillation of 10 min duration was induced, followed by mechanical closed-chest cardiopulmonary resuscitation (CPR) in conjunction with i.v. administration of 0.4 U/kg of vasopressin. After CPR, external defibrillatory shocks were applied to achieve restoration of spontaneous circulation (ROSC). CBF and CMRO(2) were mapped and voxelwise maps of OEF were calculated at times of 60, 180, and 300 min after ROSC. RESULTS: There was hypoperfusion throughout the telencephalon at 60 min, with a return towards baseline values at 300 min. In contrast, there was progressively increasing CBF in cerebellum throughout the observation period. The magnitude of CMRO(2) decreased globally after ROSC, especially in cerebral cortex. The magnitude of OEF in cerebral cortex was 60% at baseline, tended to increase at 60 min after ROSC, and declined to 50% thereafter, thus suggesting transition to an ischemic state. CONCLUSION: The cortical regions tended most vulnerable to the ischemic insult with an oligaemic pattern and a low CMRO(2) whereas the cerebellum instead showed a pattern of luxury perfusion.

  • 65.
    Mörtberg, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Cumming, Paul
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    A PET study of regional cerebral blood flow after experimental cardiopulmonary resuscitation2007In: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 75, no 1, p. 98-104Article in journal (Refereed)
    Abstract [en]

    Cerebral blood flow (CBF) during cardiopulmonary resuscitation and after restoration of spontaneous circulation (ROSC) from cardiac arrest has previously been measured with the microspheres and laser Doppler techniques. We used positron emission tomography (PET) with [15O]--water to map the haemodynamic changes after ROSC in nine young pigs. After the baseline PET recording, ventricular fibrillation of 5 min duration was induced, followed by closed-chest cardiopulmonary resuscitation (CPR) in conjunction with IV administration of three bolus doses of adrenaline (epinephrine). After CPR, external defibrillatory shocks were applied to achieve ROSC. CBF was measured at intervals during 4h after ROSC. Relative to the mean global CBF at baseline (32+/-5 ml hg(-1)min(-1)), there was a substantial global increase in CBF at 10 min, especially in the diencephalon. This was followed by an interval of cortical hypoperfusion and a subsequent gradual return to baseline values.

  • 66.
    Nahas, G
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Sutin, K
    Fermon, C
    Streat, S
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wahlander, S
    Yellin, P
    Brash, H
    Kanchuger, M
    Capan, L
    Manne, J
    Helwig, H
    Gaab, M
    Pfenninger, E
    Wetterberg, T
    Holmdahl, Martin H:son
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Turndorf, H
    Guidelines for the Treatment of Acidaemia with THAM.1998In: Drugs, Vol. 55, p. 191-Article in journal (Refereed)
  • 67.
    Nordgren, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Karlsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ammonium chloride and alpha-ketoglutaric acid increase glutamine availability in the early phase of induced acute metabolic acidosis2006In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 50, no 7, p. 840-847Article in journal (Refereed)
    Abstract [en]

    Background: Glutamine deficiency in critical illness is associated with increased morbidity and mortality. We hypothesized that ammonium chloride (NH4Cl) and alpha-ketoglutaric acid (alpha-KGA) infusions could increase glutamine availability possibly through de novo synthesis in the liver. Methods: Anesthetized post-absorptive pigs were allocated to four groups (n = 8). The study groups received either a 4-h intravenous infusion of alpha-KGA, 11.4 mu mol/kg/min and NH4+, 9.7 mu mol/kg/min (group 1), or alpha-KGA, 2.85 mu mol/kg/min and NH4+, 46.3 mu mol/kg/min (group 2), or alpha-KGA, 11.4 mu mol/kg/min (group 3), or isotonic saline (control group). Plasma concentrations of glutamine and glutamine exchange in liver, intestine and skeletal muscle were investigated. Results: Plasma glutamine concentrations in group 1 (58% increase) were greater (P < 0.05) compared with the control group (14% decrease) and group 3 (13% decrease), and in group 2 (91% increase) compared with the control group, group 3 (P < 0.0001) and group 1 (P < 0.05). Intestinal glutamine extractions in group 2 were significantly greater (P < 0.01) compared with all other groups. Neither the liver nor the hind leg increased its release of glutamine. Arterial pH decreased (all P < 0.001) to 7.39 +/- 0.01 in the control group, 7.30 +/- 0.01 in group 1, 7.19 +/- 0.01 in group 2 and 7.35 +/- 0.01 in group 3. Conclusion: Infusions of alpha-KGA and NH4Cl, to a pH range of 7.20-7.30, did not enhance hind leg or hepatic glutamine release. The increased plasma concentrations of glutamine were effects of NH4Cl, not alpha-KGA, and caused either by de novo synthesis or decreased degradation.

  • 68.
    Nordgren, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Karlsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Glutamine concentration and tissue exchange with intravenouslyadministered alpha-ketoglutaric acid and ammonium: a dose-response studyin the pig.2002In: Nutrition, Vol. 18, p. 496-Article in journal (Refereed)
  • 69.
    Nozari, A
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Rubertsson, S
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Gedeborg, R
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Wiklund, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Improved cerebral blood flow with hypertonic saline and dextran in combination with intra-aortic balloon occlusion during experimental CPR.1999In: Resuscitation, Vol. 40, no 1, p. 27-35Article in journal (Refereed)
  • 70.
    Nozari, A
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Differences in the pharmacodynamics of epinephrine and vasopressin duringand after experimental cardiopulmonary resuscitation.2001In: Resuscitation, Vol. 49, p. 59-Article in journal (Refereed)
  • 71. Nozari, A
    et al.
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Improved cerebral blood supply and oxygenation by aortic balloon occlusion combined with intra-aortic vasopressin administration during experimental cardiopulmonary resuscitation.2000In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 44, no 10, p. 1209-19Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Intravenous administration of vasopressin during cardiopulmonary resuscitation (CPR) has been shown to improve myocardial and cerebral blood flow. Aortic balloon occlusion during CPR may also augment myocardial and cerebral blood flow and can be used as a central route for the administration of resuscitative drugs. We hypothesized that, as compared with intravenously administered vasopressin, the administration of this drug above the site of an aortic balloon occlusion would result in a greater increase in cerebral perfusion and oxygenation during CPR and after restoration of spontaneous circulation (ROSC).

    METHODS: Twenty piglets were subjected to 5 min of ventricular fibrillation followed by 8 min of closed-chest CPR and were treated with 0.4 U kg(-1) boluses of vasopressin intravenously (the IV-vasopressin group with sham aortic balloon) or above the site for an aortic balloon occlusion (the balloon-vasopressin group). The aortic balloon catheter was inflated in the latter group 1 min after commencement of CPR and was deflated within 1 min after ROSC. Systemic blood pressures, cerebral cortical blood flow, cerebral tissue pH and PCO2 were monitored continuously and the cerebral oxygen extraction ratio was calculated.

    RESULTS: During CPR, arterial blood pressure and cerebral perfusion pressure were greater in the balloon-vasopressin group, as compared with the IV-vasopressin group. These pressures did not differ between the groups after ROSC. Cerebral cortical blood flow was not significantly greater in the balloon-vasopressin group during CPR, whereas significantly higher cortical blood flow levels were recorded after ROSC. Cerebral tissue pH decreased in the IV-vasopressin group during the post-resuscitation hypoperfusion period. In contrast, decreasing pressures during the hypoperfusion period did not result in increasing tissue acidosis in the balloon-vasopressin group.

    CONCLUSIONS: During CPR, intra-aortic vasopressin combined with aortic balloon occlusion resulted in significantly greater perfusion pressures but not in greater cerebral cortical blood flow. After ROSC, however, a greater increase in cortical blood flow was recorded in the balloon-vasopressin group, even though the aortic balloon was deflated and perfusion pressures did not differ between the groups. This suggests that vasopressin predominantly gives vasoconstrictive effects on cerebral cortical vessels during CPR, but results in cerebral cortical vasodilatation after ROSC.

  • 72.
    Nozari, A
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Improved cerebral blood supply and oxygenation by aortic balloon occlusioncombined with intra-aortic vasopressin administration during experimentalcardiopulmonary resuscitation.2000In: Acta Anaesthesiol. Scand., Vol. 44, p. 1209-Article in journal (Refereed)
  • 73.
    Purins, Karlis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lewén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Brain Tissue Oxygenation and Cerebral Perfusion Pressure Thresholds of Ischemia in a Standardized Pig Brain Death Model2012In: Neurocritical Care, ISSN 1541-6933, E-ISSN 1556-0961, Vol. 16, no 3, p. 462-469Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Neurointensive care of traumatic brain injury (TBI) patients is currently based on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) targeted protocols. Monitoring brain tissue oxygenation (B(ti)pO(2)) is of considerable clinical interest, but the exact threshold level of ischemia has been difficult to establish due to the complexity of the clinical situation. The objective of this study was to use the Neurovent-PTO (NV) probe, and to define critical cerebral oxygenation- and CPP threshold levels of cerebral ischemia in a standardized brain death model caused by increasing the ICP in pig. Ischemia was defined by a severe increase of cerebral microdialysis (MD) lactate/pyruvate ratio (L/P ratio > 30).

    METHODS:

    B(ti)pO(2), L/P ratio, Glucose, Glutamate, Glycerol and CPP were recorded using NV and MD probes during gradual increase of ICP by inflation of an epidural balloon catheter with saline until brain death was achieved.

    RESULTS:

    Baseline level of B(ti)pO(2) was 22.9 ± 6.2 mmHg, the L/P ratio 17.7 ± 6.1 and CPP 73 ± 17 mmHg. B(ti)pO(2) and CPP decreased when intracranial volume was added. The L/P ratio increased above its ischemic levels, (>30) when CPP decreased below 30 mmHg and B(ti)pO(2) to <10 mmHg.

    CONCLUSIONS:

    A severe increase of ICP leading to CPP below 30 mmHg and B(ti)pO(2) below 10 mmHg is associated with an increase of the L/P ratio, thus seems to be critical thresholds for cerebral ischemia under these conditions.

  • 74.
    Purins, Karlis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Sedigh, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Molnar, Christian
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Wennberg, Lars
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lewén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Standardized experimental brain death model for studies of intracranial dynamics, organ preservation, and organ transplantation in the pig2011In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 39, no 3, p. 512-517Article in journal (Refereed)
    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.

  • 75.
    Rubertsson, Sten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Grenvik, A
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Blood flow and perfusion pressure during open-chest versus closed-chest cardiopulmonary resuscitation in pigs.1995In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 23, no 4, p. 715-25Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate the blood flow and perfusion pressure differences observed during open- vs. closed-chest cardiopulmonary resuscitation (CPR), including the effects of epinephrine and sodium bicarbonate administration.

    DESIGN: Prospective, randomized, controlled trial.

    SETTING: Experimental animal laboratory in a university hospital.

    SUBJECTS: A total of 35 anesthetized piglets.

    INTERVENTIONS: After tracheostomy and insertion of arterial, right atrial, and pulmonary arterial catheters, thoracotomy was performed with placement of a pulmonary arterial flow probe and left atrial catheter. Ventricular fibrillation was induced and followed by 15 mins of either open-chest (n = 14) or closed-chest (n = 21) CPR. A 4-min infusion of 50 mmol of sodium bicarbonate or saline was added at the start of CPR. After 8 mins of CPR, 0.5 mg of epinephrine was given intravenously, and after 15 mins, direct current (DC) shocks were used to revert the heart to sinus rhythm.

    MEASUREMENTS AND MAIN RESULTS: Blood flow was studied using transit-time ultrasound flowmetry. In an extended group, intrathoracic pressure was measured for calculation of transmural pressure. Before epinephrine administration, mean pulmonary arterial flow (cardiac output) was reduced: a) during closed-chest CPR relatively more than pulmonary perfusion pressure but in proportion to systemic perfusion pressure; b) during open-chest CPR relatively less than pulmonary perfusion pressure but still in proportion to systemic perfusion pressure. Epinephrine administration temporarily increased systemic perfusion pressure during both closed- and open-chest CPR but temporarily decreased pulmonary perfusion pressure only during closed-chest CPR. After epinephrine administration, cardiac output temporarily decreased during both closed-and open-chest CPR.

    CONCLUSIONS: Open-chest CPR resulted in better cardiac output and systemic perfusion pressure than closed-chest CPR. However, cardiac output values obtained with both methods were much lower than previously reported. After epinephrine administration, cardiac output became extremely low with both methods.

  • 76.
    Rubertsson, Sten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Grenvik, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Zemgulis, Vitas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Systemic perfusion pressure and blood flow before and after administration of epinephrine during experimental cardiopulmonary resuscitation1995In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 23, no 12, p. 1984-1996Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To evaluate instantaneous blood flow variations in the compression and relaxation phases of cardiopulmonary resuscitation (CPR) and the effect of epinephrine administration.

    DESIGN: Prospective, randomized, controlled trial.

    SETTING: Experimental laboratory in a university hospital.

    SUBJECTS: Twenty-two anesthetized piglets.

    INTERVENTIONS: A tracheostomy was performed and arterial, central venous, and pulmonary arterial catheters were inserted, followed by thoracotomy with placement of pulmonary arterial, aortic, and left anterior descending coronary arterial (extended study group) flow probes and a left atrial catheter. Ventricular fibrillation for 2 mins was followed by 10 mins of either open-chest (n = 10) or closed-chest (n = 12) CPR. Seven minutes after the initiation of CPR, all piglets received 0.5 mg of epinephrine iv; at 12 mins, direct current shocks were applied.

    MEASUREMENTS AND MAIN RESULTS: Open-chest CPR generated greater systemic perfusion pressure than closed-chest CPR, especially during the relaxation phase, resulting in greater mean blood flow. With both open- and closed-chest CPR, antegrade pulmonary arterial and aortic blood flow occurred during compression, whereas antegrade left anterior descending coronary arterial blood flow occurred during relaxation. During relaxation, retrograde flow was found in the pulmonary artery and aorta. During compression, retrograde flow was found in the left anterior descending coronary artery. The administration of epinephrine had the following effects: a) increased the systemic perfusion pressure more during open- than closed-chest CPR; b) increased the systemic relaxation perfusion pressure more than the compression perfusion pressure; c) decreased mean pulmonary arterial and aortic blood flow, but substantially increased the mean left anterior descending coronary artery blood flow; and d) reduced the retrograde flow in the left anterior descending coronary artery.

    CONCLUSIONS: Open-chest CPR generated greater systemic perfusion pressure and blood flow than closed-chest CPR. Epinephrine increased left anterior descending coronary artery blood flow but decreased total cardiac output, such that cerebral perfusion might be endangered. This problem will be studied separately.

  • 77.
    Rubertsson, Sten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Karlsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Systemic oxygen uptake during experimental closed-chest cardiopulmonary resuscitation using air or pure oxygen ventilation.1998In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 42, no 1, p. 32-8Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Although clinical cardiopulmonary resuscitation always includes ventilation with pure oxygen, this kind of ventilation has been reported to be associated with worse neurological outcome than ventilation with air in experimental cardiopulmonary resuscitation (CPR). The aim of the present investigation was to compare the systemic oxygen uptake during experimental closed-chest CPR including ventilation with pure oxygen or ambient air and, furthermore, to elucidate possible mechanisms of action in the regulation of pulmonary gas exchange.

    METHODS: In 24 anesthetized piglets, 2 min of induced ventricular fibrillation and no ventilation was followed by 10 min of closed-chest CPR including i.v. administration of 0.5 mg adrenaline (at 8 min), and in one of the experimental groups alkaline buffer (at 5 min). The piglets were randomly divided into 3 groups: air ventilation during the entire CPR period with saline administration (n=8), air ventilation during the entire CPR period plus tris buffer mixture (n=8), and air ventilation for 3 min followed by 100% oxygen with saline administration (n= 8).

    RESULTS: In the group ventilated with air and treated with tris buffer mixture, cardiac output was significantly greater than in the group ventilated with pure oxygen. The arterial-mixed venous oxygen content difference was approximately 25% greater with pure oxygen than with air ventilation; however, there was no difference in systemic oxygen uptake. Systemic oxygen uptake increased after administration of tris buffer mixture in the group ventilated with air.

    CONCLUSIONS: Pulmonary hypoxic vasoconstriction appeared to be abolished during CPR including pure oxygen ventilation. Blood flow, not ventilation or pulmonary gas exchange, is the limiting factor during experimental closed-chest CPR.

  • 78.
    Semenas, Egidijus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Nozari, A.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sex differences in cerebral injury after severe haemorrhage and ventricular fibrillation in pigs2010In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 54, no 3, p. 343-353Article in journal (Refereed)
    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.

  • 79.
    Semenas, Egidijus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Nozari, Ala
    Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, 02114 Boston, Massachusetts, USA.
    Thiblin, Ingemar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Forensic Medicine.
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Modulation of nitric oxide expression with methylene blue does not improve outcome after hypovolemic cardiac arrest2011In: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 82, no 10, p. 1344-1349Article in journal (Refereed)
    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. 

  • 80.
    Semenas, Egidijus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Nozari, Ala
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sex differences in cardiac injury after severe haemorrhage and ventricular fibrillation in pigs2010In: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 81, no 12, p. 1718-1722Article in journal (Refereed)
    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.

  • 81.
    Semenas, Egidijus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Nozari, Ala
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Neuroprotective effects of 17-beta-estradiol after hypovolemic cardiac arrest in immature piglets: the role of nitric oxide and peroxidation2011In: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. 36, no 1, p. 30-37Article in journal (Refereed)
    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.

  • 82.
    Semenas, Egidijus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Adrenaline increases blood-brain-barrier permeability after haemorrhagic cardiac arrest in immature pigs2014In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 58, no 5, p. 620-629Article in journal (Refereed)
    Abstract [en]

    BackgroundAdrenaline (ADR) and vasopressin (VAS) are used as vasopressors during cardiopulmonary resuscitation. Data regarding their effects on blood-brain barrier (BBB) integrity and neuronal damage are lacking. We hypothesised that VAS given during cardiopulmonary resuscitation (CPR) after haemorrhagic circulatory arrest will preserve BBB integrity better than ADR. MethodsTwenty-one anaesthetised sexually immature male piglets (with a weight of 24.31.3kg) were bled 35% via femoral artery to a mean arterial blood pressure of 25mmHg in the period of 15min. Afterwards, the piglets were subjected to 8min of untreated ventricular fibrillation followed by 15min of open-chest CPR. At 9min of circulatory arrest, piglets received amiodarone 1.0mg/kg and hypertonic-hyperoncotic solution 4ml/kg infusions for 20min. At the same time, VAS 0.4U/kg was given intravenously to the VAS group (n=9) while the ADR group received ADR 20g/kg (n=12). Internal defibrillation was attempted from 11min of cardiac arrest to achieve restoration of spontaneous circulation. The experiment was terminated 3h after resuscitation. ResultsThe intracranial pressure (ICP) in the post-resuscitation phase was significantly greater in ADR group than in VAS group. VAS group piglets exhibited a significantly smaller BBB disruption compared with ADR group. Cerebral pressure reactivity index showed that cerebral blood flow autoregulation was also better preserved in VAS group. ConclusionsResuscitation with ADR as compared with VAS after haemorrhagic circulatory arrest increased the ICP and impaired cerebrovascular autoregulation more profoundly, as well as exerted an increased BBB disruption though no significant difference in neuronal injury was observed.

  • 83.
    Sharma, H S
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Gordh, T
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Wiklund, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Mohanty, S
    Sjöquist, P O
    Spinal cord injury induced heat shock protein expression is reduced by an antioxidant compound H-290/51. An experimental study using light and electron microscopy in the rat.2006In: J Neural Transm, ISSN 0300-9564, Vol. 113, no 4, p. 521-36Article in journal (Refereed)
  • 84.
    Sharma, H S
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Sjöquist, P O
    Mohanty, S
    Wiklund, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Post-injury treatment with a new antioxidant compound H-290/51 attenuates spinal cord trauma-induced c-fos expression, motor dysfunction, edema formation, and cell injury in the rat.2006In: Acta Neurochir Suppl, ISSN 0065-1419, Vol. 96, p. 322-8Article in journal (Refereed)
  • 85.
    Sharma, H S
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Skottner, A
    Lundstedt, T
    Flardh, M
    Wiklund, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Neuroprotective effects of melanocortins in experimental spinal cord injury. An experimental study in the rat using topical application of compounds with varying affinity to melanocortin receptors.2006In: J Neural Transm, ISSN 0300-9564, Vol. 113, no 4, p. 463-76Article in journal (Refereed)
  • 86.
    Sharma, Hari S
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Lundstedt, Torbjörn
    Faculty of Pharmacy, Department of Medicinal Chemistry. ORGFARM.
    Boman, Arne
    Lek, Per
    Seifert, Elisabeth
    Wiklund, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Ali, Syed F
    A potent serotonin-modulating compound AP-267 attenuates morphine withdrawal-induced blood-brain barrier dysfunction in rats.2006In: Ann N Y Acad Sci, ISSN 0077-8923, Vol. 1074, p. 482-96Article in journal (Refereed)
  • 87.
    Sharma, Hari Shanker
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Badgaiyan, Rajendra D.
    Alm, Per
    Mohanty, S.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Neuroprotective effects of nitric oxide synthase inhibitors in spinal cord injury-induced pathophysiology and motor functions: an experimental study in the rat2005In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1053, p. 422-434Article in journal (Refereed)
    Abstract [en]

    The role of nitric oxide (NO) in spinal cord injury (SCI)-induced motor dysfunction, breakdown of the blood-spinal cord barrier (BSCB), edema formation, and cell injury was examined using a pharmacological approach. We used three types of nitric oxide synthase (NOS) inhibitors: a nonselective blocker, L-NAME; an irreversible inhibitor of all isoforms of NOS, L-NMMA; and a long-term competitive inhibitor of neuronal NOS with equal potency to inhibit endothelial NOS, L-NNA. The compounds were administered once daily in separate groups of rats for 7 days. On the 8th day, SCI was performed by making a longitudinal incision into the right dorsal horn of the T10-11 segments, and the rats were allowed to survive 5 h after injury. Long-term treatment with L-NNA attenuated SCI-induced NOS upregulation, BSCB breakdown, edema formation, and cell injury, whereas comparatively less neuroprotection is offered by L-NMMA. The magnitude of neuroprotection is much less evident in injured animals that received L-NAME. Interestingly, SCI-induced motor dysfunction measured according to the Tarlov scale showed close correlation with the magnitude of neuroprotection. Thus, an improvement in motor function was seen in animals pretreated with L-NNA, whereas rats treated with L-NAME or L-NMMA did not show any influence on motor dysfunction after SCI. This observation suggests that inhibition of neuronal NOS is important for neuroprotection, and the disturbances in motor function following SCI are associated with the state of spinal cord pathology.

  • 88.
    Sharma, Hari Shanker
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lundstedt, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Flärdh, M.
    Skottner, A.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Neuroprotective effects of melanocortins in CNS injury2007In: Current pharmaceutical design, ISSN 1381-6128, E-ISSN 1873-4286, Vol. 13, no 19, p. 1929-1941Article, review/survey (Refereed)
    Abstract [en]

    New compounds having affinity to various melanocortin receptors have recently been identified as possible neuroprotective agents. This review is focused on the role of neuroprotective effects of melanocortins in CNS injury and repair mechanisms. Using selective non-peptidic compounds with varying affinity to melanocortin receptors, our laboratory has shown their anti-edematous effects in the spinal cord injury. This effect of the compounds is related with their ability to attenuate blood-spinal cord barrier permeability. The functional significance and possible therapeutic strategies of these compounds in CNS injury are discussed.

  • 89.
    Sharma, Hari Shanker
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Miclescu, Adriana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Cardiac arrest-induced regional blood-brain barrier breakdown, edema formation and brain pathology: a light and electron microscopic study on a new model for neurodegeneration and neuroprotection in porcine brain2011In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 118, no 1, p. 87-114Article in journal (Refereed)
    Abstract [en]

    Brief cardiac arrest and survival is often associated with marked neurological alterations related to cognitive and sensory motor functions. However, detail studies using selective vulnerability of brain after cardiac arrest in animal models are still lacking. We examined selective vulnerability of five brain regions in our well-established cardiac arrest model in pigs. Using light and electron microscopic techniques in combinations with immunohistochemistry, we observed that 5, 30, 60 and 180 min after cardiac arrest results in progressive neuronal damage that was most marked in the thalamus followed by cortex, hippocampus, hypothalamus and the brain stem. The neuronal damages are largely evident in the areas showing leakage of serum albumin in the neuropil. Furthermore, a tight correlation was seen between neuronal damage and increase in brain water content and Na(+) indicating vasogenic edema formation after cardiac arrest. Damage to myelinated fibers and loss of myelin as seen using Luxol fast blue and myelin basic protein (MBP) immunoreactivity is clearly evident in the brain areas exhibiting neuronal damage. Upregulation of GFAP positive astrocytes closely corresponds with neuronal damages in different brain areas after cardiac arrest. At the ultrastructural level, perivascular edema together with neuronal, glial and endothelia cell damages is frequent in the brain areas showing albumin leakage. Damage to both pre- and post-synaptic membrane is also common. Treatment with methylene blue, an antioxidant markedly reduced neuronal damage, leakage of albumin, overexpression of GFAP and damage to myelin following cardiac arrest. Taken together, these observations suggest that (a) cardiac arrest is capable to induce selective neuronal, glial and myelin damage in different parts of the pig brain, and (b) antioxidant methylene blue is capable to induce neuroprotection by reducing BBB disruption. These observations strongly suggest that the model could be used to explore new therapeutic agents to enhance neurorepair following cardiac arrest-induced brain damage for therapeutic purposes.

  • 90.
    Sharma, Hari Shanker
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, Dafin Fior
    Univ Med & Pharm, Dept Clin Neurosci, Cluj Napoca, Romania;RoNeuro Inst Neurol Res & Diagnost, Cluj Napoca, Romania.
    Nozari, Ala
    Massachusetts Gen Hosp, Anesthesia & Crit Care, Boston, MA 02114 USA.
    Castellani, Rudy J.
    Univ Maryland, Dept Pathol, Baltimore, MD 21201 USA.
    Dey, Prasanta Kumar
    Banaras Hindu Univ, Inst Med Sci, Dept Physiol, Neurophysiol Res Unit, Varanasi, Uttar Pradesh, India.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Anesthetics influence concussive head injury induced blood-brain barrier breakdown, brain edema formation, cerebral blood flow, serotonin levels, brain pathology and functional outcome2019In: 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.

  • 91.
    Sharma, Hari Shanker
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Patnaik, Ranjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Vicente Lafuente, Jose
    Univ Basque Country, Dept Neurosci, Bilbao, Spain..
    Miclescu, Adriana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Univ, Dept Surg Sci Anesthesiol & Intens Care Med, Lab Cerebrovasc Res, S-75185 Uppsala, Sweden..
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Cardiac Arrest Alters Regional Ubiquitin Levels in Association with the Blood-Brain Barrier Breakdown and Neuronal Damages in the Porcine Brain2015In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 52, no 2, p. 1043-1053Article in journal (Refereed)
    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.

  • 92.
    Sharma, Hari Shanker
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Patnaik, Ranjana
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    The contribution of glial cells and water channel aquaporin-4 in the neuropathology of cardiac arrest is still ignored2013In: CNS & Neurological Disorders: Drug Targets, ISSN 1871-5273, E-ISSN 1996-3181, Vol. 12, no 1, p. 3-3Article in journal (Refereed)
  • 93.
    Sharma, Hari Shanker
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, L.ars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Cardiac arrest induces widespread astrocytic activation, myelin degeneration and blood-brain barrier leakage in the areas exhibiting neuronal damage: Neuroprotection by methylene blue2012In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 19, no S1, p. 482-482Article in journal (Other academic)
  • 94.
    Sharma, Hari Shanker
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Badgaiyan, R. D.
    Mohanty, S.
    Alm, P.
    Intracerebral administration of neuronal nitric oxide synthase antiserum attenuates traumatic brain injury-induced blood-brain barrier permeability, brain edema formation, and sensory motor disturbances in the rat2006In: Acta neurochirurgica. Supplement, ISSN 0065-1419, Vol. 96, p. 288-294Article in journal (Refereed)
    Abstract [en]

    The role of nitric oxide (NO) in traumatic brain injury (TBI)-induced sensory motor function and brain pathology was examined using intracerebral administration of neuronal nitric oxide synthase (nNOS) antiserum in a rat model. TBI was produced by a making a longitudinal incision into the right parietal cerebral cortex limited to the dorsal surface of the hippocampus. Focal TBI induces profound edematous swelling, extravasation of Evans blue dye, and up-regulation of nNOS in the injured cerebral cortex and the underlying subcortical areas at 5 hours. The traumatized animals exhibited pronounced sensory motor deficit, as seen using Rota-Rod and grid-walking tests. Intracerebral administration of nNOS antiserum (1 : 20) 5 minutes and 1 hour after TBI significantly attenuated brain edema formation, Evans blue leakage, and nNOS expression in the injured cortex and the underlying subcortical regions. The nNOS antiserum-treated rats showed improved sensory motor functions. However, administration of nNOS antiserum 2 hours after TBI did not influence these parameters significantly. These novel observations suggest that NO participates in blood-brain barrier disruption, edema formation, and sensory motor disturbances in the early phase of TBI, and that nNOS antiserum has some potential therapeutic value requiring additional investigation.

  • 95. Shoemaker, W
    et al.
    Peitzman, A B
    Bellamy, R
    Bellomo, R
    Bruttig, S P
    Capone, A
    Dubick, M
    Kramer, G C
    McKenzie, J E
    Pepe, P E
    Safar, P
    Schlichtig, R
    Severinghaus, J W
    Tischerman, S A
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Resuscitation from severe hemorrhage.1996In: Crit Care Med., Vol. 24, p. 12-Article in journal (Refereed)
  • 96. Sommer, W
    et al.
    Moller, C
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Thorsell, A
    Rimondini, R
    Nissbrandt, H
    Heilig, M
    Local 5,7-dihydroxytryptamine lesions of rat amygdala: release of punisheddrinking, unaffected plus-maze behavior and ethanol consumption.2001In: Neuropsychopharmacology, Vol. 24, p. 430-Article in journal (Refereed)
  • 97.
    Spangberg, K
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Schwartz, S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Binding of the La autoantigen to the hepatitis C virus 3' untranslatedregion protects the RNA from rapid degradation in vitro.2001In: J Gen Virol, Vol. 82, p. 113-Article in journal (Refereed)
  • 98.
    Spangberg, K
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Schwartz, S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    HuR, a protein implicated in oncogene and growth factor mRNA decay, bindsto the 3' ends of hepatitis C virus RNA of both polarities.2000In: Virology, Vol. 274, p. 378-Article in journal (Refereed)
  • 99.
    Vahlquist, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ståhle, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Påhlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hällgren, Roger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Aquilonius, Sten-Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Alm, Albert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Betungande regler för klinisk forskning står inte i proportion till patientnyttan2005In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 102, no 23, p. 1832-1834Article in journal (Refereed)
  • 100.
    Vahlquist, Anders
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Westermark, Per
    Department of Genetics and Pathology.
    Ståhle, Elisabeth
    Venge, Per
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Påhlmarn, Lars
    Department of Surgical Sciences.
    Hällgren, Roger
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Rönnblom, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Kämpe, Olle
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Wiklund, Lars
    Department of Surgical Sciences.
    Aquilonius, Sten-Magnus
    Department of Neuroscience. Neurologi.
    Alm, Albert
    Department of Neuroscience.
    Betungande regler för klinisk prövning står inte i proportion till patientnyttan2005In: Läkartidningen, Vol. 102, no 23, p. 1832-1834Article in journal (Other (popular scientific, debate etc.))
123 51 - 100 of 129
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