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  • 1.
    Aarnio, Mikko
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Visualization of Peripheral Pain Generating Processes and Inflammation in Musculoskeletal Tissue using [11C]-D-deprenyl PET2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    An objective visualization and quantification of pain-generating processes in the periphery would alter pain diagnosis and represent an important paradigm shift in pain research. Positron emission tomography (PET) radioligand [11C]-D-deprenyl has shown an elevated uptake in painful inflammatory arthritis and whiplash-associated disorder. However, D-Deprenyl’s molecular binding target and uptake mechanism in inflammation and musculoskeletal injuries are still unknown. The present thesis aimed to gain insight into the mechanisms of D-deprenyl binding and uptake and to verify whether pain-associated sites and inflammation in acute musculoskeletal injury could be visualized, objectively quantified and followed over time with [11C]-D-deprenyl PET-computed tomography (PET/CT).

    To identify the D-deprenyl binding target, a high-throughput analysis and competitive radioligand binding studies were performed. D-deprenyl inhibited monoamine oxidase A (MAO-A) activity by 55%, MAO-B activity by 99% and angiotensin-converting enzyme (ACE) by 70%, which identified these enzymes as higher-affinity targets. Furthermore, radioligand receptor binding assays pointed favorably towards the concept of MAO-B as the primary target. To investigate the biochemical characteristics of the binding site, we used radioligand binding assays to assess differences in the binding profile in inflamed human synovial membranes exhibiting varying levels of inflammation. D-deprenyl bound to a single, saturable population of membrane-bound protein in synovial membrane homogenates and the level of inflammation correlated with an increase in D-deprenyl binding affinity.

    To verify whether D-deprenyl can visualize pain-generating processes, patients with musculoskeletal injuries were investigated and followed-up with [11C]-D-deprenyl PET/CT. In the study of eight patients with ankle sprain, the molecular aspects of inflammation and tissue injury could be visualized, objectively quantified and followed over time with [11C]-D-deprenyl PET/CT. The pain coexisted with increased [11C]-D-deprenyl uptake. In the study of 16 whiplash patients, an altered [11C]-D-deprenyl uptake in the cervical bone structures and facet joints was associated with subjective pain levels and self-rated disability.

    To further evaluate D-Deprenyl’s usefulness as a marker of inflammation, three PET tracers were compared in an animal PET/CT study. Preliminary findings showed that [11C]-D-deprenyl had an almost identical uptake pattern when compared with [11C]-L-deprenyl. The two deprenyl enantiomers showed no signs of specific binding or trapping and therefore may not be useful to study further in models of inflammatory pain, surgical pain, or both.

    This thesis demonstrates that D-deprenyl visualizes painful inflammation in musculoskeletal injuries and that the probable underlying mechanism of [11C]-D-deprenyl uptake is binding to MAO.

    List of papers
    1. High-throughput screening and radioligand binding studies reveal monoamine oxidase-B as the primary binding target for D-deprenyl
    Open this publication in new window or tab >>High-throughput screening and radioligand binding studies reveal monoamine oxidase-B as the primary binding target for D-deprenyl
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    2016 (English)In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 152, p. 231-237Article in journal (Refereed) Published
    Abstract [en]

    Aims: D-deprenyl is a useful positron emission tomography tracer for visualization of inflammatory processes. Studies with [C-11]-D-deprenyl showed robust uptake in peripheral painful sites of patients with rheumatoid arthritis or chronic whiplash injury. The mechanism of preferential D-deprenyl uptake is not yet known, but the existence of a specific binding site was proposed. Thus, in the present study, we sought to identify the binding site for D-deprenyl and verify the hypothesis about the possibility of monoamine oxidase enzymes as major targets for this molecule. Main methods: A high-throughput analysis of D-deprenyl activity towards 165 G-protein coupled receptors and 84 enzyme targets was performed. Additionally, binding studies were used to verify the competition of [H-3]D-deprenyl with ligands specific for targets identified in the high-throughput screen. Key findings: Our high-throughput investigation identified monoamine oxidase-B, monoamine oxidase-A and angiotensin converting enzyme as potential targets for D-deprenyl. Further competitive [3H] D-deprenyl binding studies with specific inhibitors identified monoamine oxidase-B as the major binding site. No evident high-affinity hits were identified among G-protein coupled receptors. Significance: Our study was the first to utilize a high-throughput screening approach to identify putative D-deprenyl targets. It verified 249 candidate proteins and confirmed the role of monoamine oxidase - B in D-deprenyl binding. Our results add knowledge about the possible mechanism of D-deprenyl binding, which might aid in explaining the increased uptake of this compound in peripheral inflammation. Monoamine oxidase-B will be further investigated in future studies utilizing human inflamed synovium.

    Keywords
    D-deprenyl High-throughput screening Binding site
    National Category
    Pharmaceutical Sciences Clinical Medicine
    Identifiers
    urn:nbn:se:uu:diva-291492 (URN)10.1016/j.lfs.2016.03.058 (DOI)000375728500028 ()27058977 (PubMedID)
    Funder
    Berzelii Centre EXSELENT, 2013-01495
    Available from: 2016-05-03 Created: 2016-05-03 Last updated: 2018-04-09Bibliographically approved
    2. Characterization of the binding site for d-deprenyl in human inflamed synovial membrane.
    Open this publication in new window or tab >>Characterization of the binding site for d-deprenyl in human inflamed synovial membrane.
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    2018 (English)In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 194, p. 26-33Article in journal (Refereed) Published
    Abstract [en]

    Aims: D-Deprenyl when used as a positron emission tomography tracer visualizes peripheral inflammation. The major aim of the current study was to identify and investigate the properties of the binding target for D-deprenyl in synovial membrane explants from arthritic patients.

    Main methods: Thirty patients diagnosed with arthritis or osteoarthritis were enrolled into the study. Homologous and competitive radioligand binding assays utilizing [H-3]D-deprenyl were performed to investigate the biochemical characteristics of the binding site and assess differences in the binding profile in synovial membranes exhibiting varying levels of inflammation.

    Key findings: The [H-3]D-deprenyl binding assay confirmed the existence of a single, saturable population of membrane-bound protein binding sites in synovial membrane homogenates. The macroscopically determined level of inflammation correlated with an increase in [H-3]D-deprenyl binding affinity, without significant alterations in binding site density. Selective monoamine oxidase B inhibitor, selegiline competed for the same site as [H-3]D-deprenyl, but failed to differentiate the samples with regard to their inflammation grade. A monoamine oxidase A inhibitor, pirlindole mesylate showed only weak displacement of [H-3]D-deprenyl binding. No significant alterations in monoamine oxidase B expression was detected, thus it was not confirmed whether it could serve as a marker for ongoing inflammation.

    Significance: Our study was the first to show the biochemical characteristics of the [H-3]D-deprenyl binding site in inflamed human synovium. We confirmed that d-deprenyl could differentiate between patients with varying severity of synovitis in the knee joint by binding to a protein target distinct from monoamine oxidase B.

    Keywords
    Arthritis, Binding target, Monoamine oxidase B, Synovium, d-Deprenyl
    National Category
    Pharmaceutical Sciences
    Research subject
    Pharmaceutical Biochemistry; Medical Biochemistry
    Identifiers
    urn:nbn:se:uu:diva-347601 (URN)10.1016/j.lfs.2017.12.003 (DOI)000425052000004 ()29221756 (PubMedID)
    Funder
    Swedish Research Council, 9459
    Available from: 2018-04-04 Created: 2018-04-04 Last updated: 2018-04-18Bibliographically approved
    3. Visualization of painful inflammation in patients with pain after traumatic ankle sprain using [(11)C]-D-deprenyl PET/CT.
    Open this publication in new window or tab >>Visualization of painful inflammation in patients with pain after traumatic ankle sprain using [(11)C]-D-deprenyl PET/CT.
    Show others...
    2017 (English)In: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 17, p. 418-424Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND AND AIMS: Positron emission tomography (PET) with the radioligand [(11)C]-D-deprenyl has shown increased signal at location of pain in patients with rheumatoid arthritis and chronic whiplash injury. The binding site of [(11)C]-D-deprenyl in peripheral tissues is suggested to be mitochondrial monoamine oxidase in cells engaged in post-traumatic inflammation and tissue repair processes. The association between [(11)C]-D-deprenyl uptake and the transition from acute to chronic pain remain unknown. Further imaging studies of musculoskeletal pain at the molecular level would benefit from establishing a clinical model in a common and well-defined injury in otherwise healthy and drug-naïve subjects. The aim of this study was to investigate if [(11)C]-D-deprenyl uptake would be acutely elevated in unilateral ankle sprain and if tracer uptake would be reduced as a function of healing, and correlated with pain localizations and pain experience.

    METHODS: Eight otherwise healthy patients with unilateral ankle sprain were recruited at the emergency department. All underwent [(11)C]-D-deprenyl PET/CT in the acute phase, at one month and 6-14 months after injury.

    RESULTS: Acute [(11)C]-D-deprenyl uptake at the injury site was a factor of 10.7 (range 2.9-37.3) higher than the intact ankle. During healing, [(11)C]-D-deprenyl uptake decreased, but did not normalize until after 11 months. Patients experiencing persistent pain had prolonged [(11)C]-D-deprenyl uptake in painful locations.

    CONCLUSIONS AND IMPLICATIONS: The data provide further support that [(11)C]-D-deprenyl PET can visualize, quantify and follow processes in peripheral tissue that may relate to soft tissue injuries, inflammation and associated nociceptive signaling. Such an objective correlate would represent a progress in pain research, as well as in clinical pain diagnostics and management.

    Keywords
    Ankle injuries, Carbon-11, Deprenyl, Inflammation, PET, Pain
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-333782 (URN)10.1016/j.sjpain.2017.10.008 (DOI)000419851500070 ()29126847 (PubMedID)
    Available from: 2017-11-16 Created: 2017-11-16 Last updated: 2018-04-09Bibliographically approved
    4. Whiplash injuries associated with experienced pain and disability can be visualized with [11C]-D-deprenyl PET/CT
    Open this publication in new window or tab >>Whiplash injuries associated with experienced pain and disability can be visualized with [11C]-D-deprenyl PET/CT
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The understanding of etiological mechanisms of whiplash associated disorder is still inadequate. Objective visualization and quantification of peripheral musculoskeletal injury and possible painful inflammation in whiplash associated disorder would facilitate diagnosis, strengthen patients’ subjective pain reports and aid clinical decisions eventually leading to better treatments. In the current study, we further evaluated the potential to use [11C]D-deprenyl PET/CT to visualize inflammation after whiplash injury. Sixteen patients with whiplash injury grade II were recruited at the emergency department and underwent [11C]D-deprenyl PET/CT in the acute phase and at 6 months after injury. Subjective pain levels, self rated neck disability and active cervical range of motion were recorded at each imaging session. Results showed that the molecular aspects of inflammation and possible tissue injuries after acute whiplash injury could be visualized, objectively quantified and followed over time with [11C]-D-deprenyl PET/CT. An altered [11C]D-deprenyl uptake in the cervical bone structures and facet joints was associated with subjective pain levels and self rated disability during both imaging occasions. These findings may contribute to a better understanding of affected peripheral structures in whiplash injury and strengthens the idea that PET/CT detectable organic lesions in peripheral tissue may be relevant for the development of persistent pain and disability in whiplash injury.

    Perspective: This article presents a novel way of objectively visualizing possible structural damage and inflammation that cause pain and disability in whiplash injury. This PET method can bring an advance in pain research and eventually would facilitate the clinical management of patients in pain.

    Keywords
    Whiplash; deprenyl; inflammation; pain; PET; carbon-11
    National Category
    Medical and Health Sciences
    Research subject
    Molecular Medicine; Medical Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-347602 (URN)
    Available from: 2018-04-04 Created: 2018-04-04 Last updated: 2018-04-12
    5. Evaluation of  PET tracers [11C]D-deprenyl, [11C]L-dideuteriumdeprenyl and [18F]FDG for Visualization of Acute Inflammation in a Rat Model of Pain - Preliminary Findings.
    Open this publication in new window or tab >>Evaluation of  PET tracers [11C]D-deprenyl, [11C]L-dideuteriumdeprenyl and [18F]FDG for Visualization of Acute Inflammation in a Rat Model of Pain - Preliminary Findings.
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Purpose: Positron emission tomography with the radioligand [11C]D-deprenyl has shown an increased signal at the location of pain in patients with ankle sprains, rheumatoid arthritis and chronic whiplash injury, but the mechanism of this tracer uptake and its exact binding site in inflammation or tissue injury is still unclear. The aim of this study was to further evaluate [11C]D-deprenyl´s usefulness as a marker of acute inflammation.

    Methods: An animal PET/CT study was performed three days after the induction of a rat model of inflammatory or surgical pain. Fourteen adult male Sprague-Dawley rats and three tracers [11C]D-deprenyl, [11C]L-dideuterumdeprenyl and [18F]fluorodeoxyglucose were used.

    Results: No [11C]D-deprenyl accumulation was seen in a rat model of musculoskeletal pain. In the rat model of inflammatory pain all three ligands were shown to visualize the inflamed ankle joint with much lower uptake in the control ankle joint. The uptake was largest with [11C]D-deprenyl and [11C]L- dideuteriumdeprenyl, where approximately 1 % of the injected dose could be found in the affected ankle joint during the first minutes, whereas the uptake of [18F]FDG was approximately 0.5 % of the injected dose. However, the ratio of uptake of the injected ankle joint versus the control ankle joint was much higher for [18F]FDG (around 10 fold increase) than for the two deprenyl enantiomers (2 – 3 fold increase). The uptake pattern of [11C]D-deprenyl and [11C]L-dideuteriumdeprenyl did not show signs of specific binding or irreversible trapping.

    Conclusions: Contrary to our expectations, of the three tracers only [18F]FDG may be used as markers of peripheral inflammation in a rat model of inflammatory pain. However, as a high site-specificity is required, [11C]D-deprenyl and [11C]L-dideyteriumdeprenyl deserve further exploration regarding sensitivity, specificity and uptake mechanisms in human pain syndromes.

    Keywords
    deprenyl; inflammation; pain; PET; carbon-11
    National Category
    Medical and Health Sciences
    Research subject
    Anaesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:uu:diva-347604 (URN)
    Available from: 2018-04-04 Created: 2018-04-04 Last updated: 2018-04-12
  • 2.
    Aarnio, Mikko
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Fredriksson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Karolinska Inst, Dept Neurosci, Stockholm, Sweden.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wolf, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Eriksson, Måns
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Peterson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Linnman, Clas
    Visualization of painful inflammation in patients with pain after traumatic ankle sprain using [(11)C]-D-deprenyl PET/CT.2017In: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 17, p. 418-424Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Positron emission tomography (PET) with the radioligand [(11)C]-D-deprenyl has shown increased signal at location of pain in patients with rheumatoid arthritis and chronic whiplash injury. The binding site of [(11)C]-D-deprenyl in peripheral tissues is suggested to be mitochondrial monoamine oxidase in cells engaged in post-traumatic inflammation and tissue repair processes. The association between [(11)C]-D-deprenyl uptake and the transition from acute to chronic pain remain unknown. Further imaging studies of musculoskeletal pain at the molecular level would benefit from establishing a clinical model in a common and well-defined injury in otherwise healthy and drug-naïve subjects. The aim of this study was to investigate if [(11)C]-D-deprenyl uptake would be acutely elevated in unilateral ankle sprain and if tracer uptake would be reduced as a function of healing, and correlated with pain localizations and pain experience.

    METHODS: Eight otherwise healthy patients with unilateral ankle sprain were recruited at the emergency department. All underwent [(11)C]-D-deprenyl PET/CT in the acute phase, at one month and 6-14 months after injury.

    RESULTS: Acute [(11)C]-D-deprenyl uptake at the injury site was a factor of 10.7 (range 2.9-37.3) higher than the intact ankle. During healing, [(11)C]-D-deprenyl uptake decreased, but did not normalize until after 11 months. Patients experiencing persistent pain had prolonged [(11)C]-D-deprenyl uptake in painful locations.

    CONCLUSIONS AND IMPLICATIONS: The data provide further support that [(11)C]-D-deprenyl PET can visualize, quantify and follow processes in peripheral tissue that may relate to soft tissue injuries, inflammation and associated nociceptive signaling. Such an objective correlate would represent a progress in pain research, as well as in clinical pain diagnostics and management.

  • 3.
    Acosta, Cecilia M.
    et al.
    Hosp Privado Comunidad Mar Del Plata, Dept Anesthesia, Cordoba 4545, RA-7600 Buenos Aires, DF, Argentina..
    Tusman, Gerardo
    Hosp Privado Comunidad Mar Del Plata, Dept Anesthesia, Cordoba 4545, RA-7600 Buenos Aires, DF, Argentina..
    Costantini, Mauro
    Hosp Privado Comunidad Mar Del Plata, Dept Anesthesia, Cordoba 4545, RA-7600 Buenos Aires, DF, Argentina..
    Echevarria, Camila
    Hosp Privado Comunidad Mar Del Plata, Dept Radiol, Buenos Aires, DF, Argentina..
    Pollioto, Sergio
    Hosp Privado Comunidad Mar Del Plata, Dept Pediat Surg, Buenos Aires, DF, Argentina..
    Abrego, Diego
    Hosp Privado Comunidad Mar Del Plata, Dept Pediat Surg, Buenos Aires, DF, Argentina..
    Suarez-Sipmann, Fernando
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain..
    Bohm, Stephan H.
    Swisstom AG, Landquart, Switzerland..
    Doppler images of intra-pulmonary shunt within atelectasis in anesthetized children2016In: Critical Ultrasound Journal, ISSN 2036-3176, E-ISSN 2036-7902, Vol. 8, article id 19Article in journal (Refereed)
    Abstract [en]

    Background: Doppler images of pulmonary vessels in pulmonary diseases associated with subpleural consolidations have been described. Color Doppler easily identifies such vessels within consolidations while spectral Doppler analysis allows the differentiation between pulmonary and bronchial arteries. Thus, Doppler helps in diagnosing the nature of consolidations. To our knowledge, Doppler analysis of pulmonary vessels within anesthesia-induced atelectasis has never been described before. The aim of this case series is to demonstrate the ability of lung ultrasound to detect the shunting of blood within atelectatic lung areas in anesthetized children.

    Findings: Three anesthetized and mechanically ventilated children were scanned in the supine position using a high-resolution linear probe of 6-12 MHz. Once subpleural consolidations were detected in the most dependent posterior lung regions, the probe was rotated such that its long axis followed the intercostal space. In this oblique position, color Doppler mapping was performed to detect blood flow within the consolidation. Thereafter, pulsed waved spectral Doppler was applied in the previously identified vessels during a short expiratory pause, which prevented interferences from respiratory motion. Different flow patterns were identified which corresponded to both, pulmonary and bronchial vessels. Finally, a lung recruitment maneuver was performed which leads to the complete resolution of the aforementioned consolidation thereby confirming the pathophysiological entity of anesthesia-induced atelectasis.

    Conclusions: Lung ultrasound is a non-invasive imaging tool that not only enables the diagnosis of anesthesia-induced atelectasis in pediatric patients but also analysis of shunting blood within this consolidation.

  • 4.
    Adamski, Jan
    et al.
    Satakunta Dist Hosp, Dept Anaesthesia & Intens Care, Pori, Finland..
    Nowakowski, Piotr
    Czerniakowski Hosp, Dept Anaesthesiol & Intens Therapy, Warsaw, Poland..
    Gorynski, Pawel
    Ctr Monitoring Populat Hlth Status, Dept Hyg, Natl Inst Publ Hlth, Warsaw, Poland..
    Onichimowski, Dariusz
    Reg Specialist Hosp, Dept Anaesthesiol & Intens Therapy, Olsztyn, Poland..
    Weigl, Wojciech
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Incidence of in-hospital cardiac arrest in Poland2016In: ANAESTHESIOLOGY INTENSIVE THERAPY, ISSN 1642-5758, Vol. 48, no 5, p. 288-293Article in journal (Refereed)
    Abstract [en]

    Background: In-hospital cardiac arrest with its poor prognosis is a challenging problem in hospitals. The aim of this study was to evaluate in Polish hospitals the frequency of in-hospital cardiac arrests with the subsequent mortality, with special emphasis on the type of unit at which the event occurred, and the patient's demographic data, such as age and sex.

    Methods: The study was a retrospective analysis of data for 2012 registered in the Polish General Hospital Morbidity Study. This research covered all Polish hospitals, excluding only government and psychiatric hospitals. The study inclusion criterion was the incidence of cardiac arrest in any hospital ward, recorded by the respective ICD-10 diagnosis code.

    Results: Of the 7,775,553 patients hospitalized, the diagnosis of cardiac arrest was reported in a total of 22,602 patients, which included 22,317 adults (98.7% of all patients) and 285 children (1.3%). Overall mortality after cardiac arrest among adults was 74.2%, and in children 46.7%. In both absolute numbers and as percentages of all documented cases, cardiac arrests occurred most often at the departments of intensive care, internal medicine, cardiology and emergency medicine. The accompanying mortality was lower than average at the departments of intensive care, cardiology, cardiology high dependency unit and emergency medicine. The median age of patients with cardiac arrest who died in the hospital was higher than the median age of those who survived (72 vs. 64; P < 0.05). Although cardiac arrests were reported more often among men than women (58.2% vs. 41.8%; P < 0.001), the hospital mortality was higher among women (79.2% vs. 71.6%; P < 0.001).

    Conclusion: The frequency of in-hospital cardiac arrests in Polish hospitals and the subsequent mortality is not substantially different from that observed in other countries. However, our study, based on ICD-10 diagnosis codes, gives only limited information about the patients and circumstances of this event. An in-depth analysis of the causes, prognoses, and outcome of in-hospital cardiac arrests could be facilitated by the creation of a national registry.

  • 5. Aliverti, A.
    et al.
    Kostic, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lo Mauro, Antonella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Andersson-Olerud, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Quaranta, M.
    Pedotti, A.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Frykholm, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Effects of propofol anaesthesia on thoraco-abdominal volume variations during spontaneous breathing and mechanical ventilation2011In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 55, no 5, p. 588-596Article in journal (Refereed)
    Abstract [en]

    Background Anaesthesia based on inhalational agents has profound effects on chest wall configuration and breathing pattern. The effects of propofol are less well characterised. The aim of the current study was to evaluate the effects of propofol anaesthesia on chest wall motion during spontaneous breathing and positive pressure ventilation. Methods We studied 16 subjects undergoing elective surgery requiring general anaesthesia. Chest wall volumes were continuously monitored by opto-electronic plethysmography during quiet breathing (QB) in the conscious state, induction of anaesthesia, spontaneous breathing during anaesthesia (SB), pressure support ventilation (PSV) and pressure control ventilation (PCV) after muscle paralysis. Results The total chest wall volume decreased by 0.41 +/- 0.08 l immediately after induction by equal reductions in the rib cage and abdominal volumes. An increase in the rib cage volume was then seen, resulting in total chest wall volumes 0.26 +/- 0.09, 0.24 +/- 0.10, 0.22 +/- 0.10 l lower than baseline, during SB, PSV and PCV, respectively. During QB, rib cage volume displacement corresponded to 34.2 +/- 5.3% of the tidal volume. During SB, PSV and PCV, this increased to 42.2 +/- 4.9%, 48.2 +/- 3.6% and 46.3 +/- 3.2%, respectively, with a corresponding decrease in the abdominal contribution. Breathing was initiated by the rib cage muscles during SB. Conclusion Propofol anaesthesia decreases end-expiratory chest wall volume, with a more pronounced effect on the diaphragm than on the rib cage muscles, which initiate breathing after apnoea.

  • 6.
    Alström, Ulrica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Granath, Fredrik
    Friberg, Orjan
    Ekbom, Anders
    Ståhle, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Risk factors for re-exploration due to bleeding after coronary artery bypass grafting2012In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 46, no 1, p. 39-44Article in journal (Refereed)
    Abstract [en]

    Objective. The study aimed to investigate relevant clinical risk factors for re-exploration due to bleeding after primary coronary artery bypass graft (CABG) surgery, and to evaluate the influence of antiplatelet and antifibrinolytic drugs. Design. Three retrospective analyses were performed on patients who underwent CABG: (1) Logistic regression was used to identify clinical risk factors for re-exploration (n = 3000). (2) A case-control study (n = 228) was used to obtain information on exposure of antithrombotic and hemostatic therapy. (3) Based on exposure to antiplatelet and antifibrinolytic therapy, and odds ratios (ORs) in multivariate logistic models, the proportion of re-explorations attributed to these drugs was calculated. Results. A receiver operating characteristic curve was created for clinical risk factors. The C-index was 0.64, indicating limited ability to predict re-exploration for bleeding. Clopidogrel was the only drug influencing the risk of re-exploration (OR 3.2, 95% CI 1.7-5.9). The harmful effect of clopidogrel was confirmed in multivariate model (OR 4.7, 95% CI 2.2-9.9), and aprotinin had a protective effect of the same magnitude (OR 0.2, 95% CI 0.1-0.6). Conclusions. Clopidogrel is an essential risk factor for re-exploration due to bleeding, and attributable to at least one-quarter of surveyed cases. Aside from pharmaceuticals, there are no strong clinical risk factors.

  • 7.
    Alström, Ulrica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Granath, Fredrik
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ståhle, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Tydén, Hans
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Platelet inhibition assessed with VerifyNow, flow cytometry and PlateletMapping in patients undergoing heart surgery2009In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 124, no 5, p. 572-577Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: A substantial number of patients with coronary artery disease undergo cardiac surgery within five days of discontinuing anti-platelet treatment with aspirin and clopidogrel. The aims of this study were to describe the degree of platelet inhibition in patients with dual anti-platelet treatment scheduled for coronary artery bypass graft (CABG) surgery and to investigate whether the measured platelet inhibition correlated to intra- and postoperative risk for bleeding and transfusion requirements. MATERIAL AND METHODS: Sixty patients were included. Platelet inhibition was analysed with flow cytometry including phosphorylation status of the vasodilator-stimulated phosphoprotein (VASP-assay) and two bed-side analyzers, VerifyNow-System and PlateletMapping, a modified thrombelastograph. All 60 patients were analysed with VerifyNow and PlateletMapping, and 48 were analysed with flow cytometry and VASP-assay. RESULTS: There was a correlation between the ADP-receptor inhibition as measured by VASP-assay and VerifyNowP2Y(12) (r = -0.29, p<0.05), and between VASP-assay and the expression of P-selectin (r = 0.29, p<0.05) as measured by flow cytometry when platelets were stimulated with 5 microM ADP. VerifyNowP2Y(12) was the only measurement of platelet inhibition correlated to total blood loss (Spearman r = 0.29, p=0.03) and red blood cell transfusion (Spearman r = 0.43, p<0.01) requirements, although this might be confounded by aprotinin treatment. CONCLUSION: We found a modest agreement between the methods for preoperative platelet inhibition, though not for PlateletMapping-MA(ADP). There was a correlation between preoperative platelet inhibition measured by VerifyNowP2Y(12) and surgical blood loss or transfusion requirements. However, for the individual patient, preoperative use of VerifyNowP2Y(12) as an instrument to decide bleeding and transfusion risk does not seem helpful.

  • 8.
    Alström, Ulrica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Levin, L-Å
    Ståhle, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Svedjeholm, R
    Friberg, Ö
    Cost analysis of re-exploration for bleeding after coronary artery bypass graft surgery2012In: British Journal of Anaesthesia, ISSN 0007-0912, E-ISSN 1471-6771, Vol. 108, no 2, p. 216-222Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Re-exploration for bleeding after cardiac surgery is an indicator of substantial haemorrhage and is associated with increased hospital resource utilization. This study aimed to analyse the costs of re-exploration and estimate the costs of haemostatic prophylaxis.

    METHODS:

    A total of 4232 patients underwent isolated, first-time, coronary artery bypass graft (CABG) surgery during 2005-8. Each patient re-explored for bleeding (n=127) was matched with two controls not requiring re-exploration (n=254). Cost analysis was based on resource utilization from completion of CABG until discharge. A mean cost per patient for re-exploration was calculated. Based on this, the net cost of prophylactic treatment with haemostatic drugs for preventing re-exploration was calculated.

    RESULTS:

    Patients undergoing re-exploration had higher exposure to clopidogrel before operation, prolonged stays in the intensive care unit, and more blood transfusions than controls. The mean incremental cost for re-exploration was (sic)6290 [95% confidence interval (CI) (sic)3408-(sic)9173] per patient, of which 48% [(sic)3001 (95% CI (sic)249-(sic)2147)] was due to prolonged stay, 31% [(sic)1928 (95% CI (sic)1710-(sic)2147)] to the cost of surgery/anaesthesia, 20% [(sic)1261 (95% CI (sic)1145-(sic)1378)] to the increased number of blood transfusions, and <2% [(sic)100 (95% CI (sic)39-(sic)161)] to the cost of haemostatic drugs. A cost model, at an estimated 50% efficacy for recombinant activated clotting factor VIIa and a 50% expected risk for re-exploration without prophylaxis, demonstrated that to be cost neutral, prophylaxis of four patients needed to result in one avoided re-exploration.

    CONCLUSIONS:

    The resource utilization costs were substantially higher in patients requiring re-exploration for bleeding. From a strict cost-effectiveness perspective, clinical interventions to prevent haemorrhage might be underutilized.

  • 9.
    Anderberg, S. B.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Luther, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Frithiof, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Physiological aspects of Toll-like receptor 4 activation in sepsis-induced acute kidney injury2017In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 219, no 3, p. 575-590Article, review/survey (Refereed)
    Abstract [en]

    Sepsis-induced acute kidney injury (SI-AKI) is common and associated with high mortality. Survivors are at increased risk of chronic kidney disease. The precise mechanism underlying SI-AKI is unknown, and no curative treatment exists. Toll-like receptor 4 (TLR4) activates the innate immune system in response to exogenous microbial products. The result is an inflammatory reaction aimed at clearing a potential infection. However, the consequence may also be organ dysfunction as the immune response can cause collateral damage to host tissue. The purpose of this review is to describe the basis for how ligand binding to TLR4 has the potential to cause renal dysfunction and the mechanisms by which this may take place in gram-negative sepsis. In addition, we highlight areas for future research that can further our knowledge of the pathogenesis of SI-AKI in relation to TLR4 activation. TLR4 is expressed in the kidney. Activation of TLR4 causes cytokine and chemokine release as well as renal leucocyte infiltration. It also results in endothelial and tubular dysfunction in addition to altered renal metabolism and circulation. From a physiological standpoint, inhibiting TLR4 in large animal experimental SI-AKI significantly improves renal function. Thus, current evidence indicates that TLR4 has the ability to mediate SI-AKI by a number of mechanisms. The strong experimental evidence supporting a role of TLR4 in the pathogenesis of SI-AKI in combination with the availability of pharmacological tools to target TLR4 warrants future human studies.

  • 10.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Frykholm, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Introducing the 6-4-0 fasting regimen and the incidence of prolonged preoperative fasting in children2018In: Pediatric Anaesthesia, ISSN 1155-5645, E-ISSN 1460-9592, Vol. 28, no 1, p. 46-52Article in journal (Refereed)
    Abstract [en]

    Background

    Children often starve for longer than recommended by current preoperative fasting guidelines.

    Aims

    We studied the effects of implementing a more lenient fasting regimen on the duration of clear fluid fasting, as well as the incidence of extended fasting in children.

    Methods

    Preoperative duration of clear fluid fasting was recorded for patients scheduled for procedures in a unit applying the standard 6-4-2 fasting regimen. This group was compared with a cohort in the same unit 1year after transitioning to a 6-4-0 fasting regimen. The latter includes no limitations on clear fluid intake until the child is called to theater. A third cohort from a unit in which the 6-4-0 fasting regimen has been implemented for over a decade was also studied for comparison.

    Results

    Patients fasting according to the 6-4-2 fasting regimen (n=66) had a median fasting time for clear fluids of 4.0h and a 33.3% incidence of fasting more than 6h. After transitioning to the 6-4-0 fasting regimen (n=64), median duration of fasting for clear fluids decreased to 1.0h, and the incidence of fasting more than 6h decreased to 6.3%. In the second unit (n=73), median fasting time was 2.2h and the proportion of patients fasting more than 6h was 21.9%.

    Conclusion

    The introduction and implementation of the 6-4-0 fasting regimen reduces median fluid fasting duration and the number of children subjected to extended fasting.

  • 11.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Schmitz, Achim
    Univ Childrens Hosp Zürich, Dept Anesthesiol, Zürich, Switzerland.
    Frykholm, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Preoperative fasting guidelines in pediatric anesthesia: are we ready for a change?2018In: Current Opinion in Anaesthesiology, ISSN 0952-7907, E-ISSN 1473-6500, Vol. 31, no 3, p. 342-348Article, review/survey (Refereed)
    Abstract [en]

    Purpose of review: Study after study shows that prolonged fasting before anesthesia is common in children. Pediatric anesthesiologists around the world are concerned that the current guidelines may be part of the problem. This review focuses on what can be done about it.

    Recent findings: We discuss new insights into the physiology of gastric emptying of different categories of food and drink. The evidence for negative effects of prolonged fasting occurring in spite of implementation of the current guidelines is examined. We also critically appraise the concept of a strict association between fasting time and the risk of aspiration and discuss recent studies in which children have been allowed clear fluids less than 2 h before anesthesia induction.

    Summary: Accumulating evidence indicates that changes of the current guidelines for preoperative fasting should be considered for children undergoing elective procedures.

    Video abstract: http://links.lww.com/COAN/A50

  • 12.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Zarén, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Frykholm, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Low incidence of pulmonary aspiration in children allowed intake of clear fluids until called to the operating suite2015In: Pediatric Anaesthesia, ISSN 1155-5645, E-ISSN 1460-9592, Vol. 25, no 8, p. 770-777Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: International guidelines recommend 2 h of clear fluid fasting prior to general anesthesia. The pediatric anesthesia unit of Uppsala University Hospital has been implementing a more liberal fasting regime for more than a decade; thus, children scheduled for elective procedures are allowed to drink clear fluids until called to the operating suite.

    AIM: To determine the incidence of perioperative pulmonary aspiration in pediatric patients allowed unlimited intake of clear fluids prior to general anesthesia.

    METHOD: Elective pediatric procedures between January 2008 and December 2013 were examined retrospectively by reviewing anesthesia charts and discharge notes in the electronic medical record system. All notes from the care event and available chest x-rays were examined for cases showing vomiting, regurgitation, and/or aspiration. Pulmonary aspiration was defined as radiological findings consistent with aspiration and/or postoperative symptoms of respiratory distress after vomiting during anesthesia.

    RESULTS: Of the 10 015 pediatric anesthetics included, aspiration occurred in three (0.03% or 3 in 10 000) cases. No case required cancellation of the surgical procedure, intensive care or ventilation support, and no deaths attributable to aspiration were found. Pulmonary aspiration was suspected, but not confirmed by radiology or continuing symptoms, in an additional 14 cases.

    CONCLUSION: Shortened fasting times may improve the perioperative experience for parents and children with a low risk of aspiration.

  • 13. Antonen, Jaakko
    et al.
    Leppanen, Ilona
    Tenhunen, Jyrki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Arvola, Pertti
    Makela, Satu
    Vaheri, Antti
    Mustonen, Jukka
    A severe case of Puumala hantavirus infection successfully treated with bradykinin receptor antagonist icatibant2013In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 45, no 6, p. 494-496Article in journal (Refereed)
    Abstract [en]

    A patient with severe capillary leakage syndrome caused by a Puumala hantavirus infection was treated with a single dose of icatibant, a bradykinin receptor antagonist, with a dramatic positive response. We suggest that this drug should be tested in a larger number of patients with severe hantavirus infection.

  • 14.
    Arakelian, Erebouni
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Gunningberg, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Larsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Health Services Research.
    Norlén, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Factors influencing early postoperative recovery after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy2011In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 37, no 10, p. 897-903Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) can prolong survival in selected patients with peritoneal carcinomatosis (PC). However, there is little data on patients' recovery process after this complex treatment. This study aimed to describe the in-hospital postoperative recovery and factors related to the recovery of patients who undergo CRS and HIPEC.

    METHOD:

    A retrospective audit of the electronic health record (EHR) was undertaken for 76 PC patients (42 women, 34 men) treated primarily with CRS and HIPEC between 2005 and 2006 in Sweden.

    RESULTS:

    Oral intake, regaining bowel functions and mobilisation usually occurred between 7 and 11 days postoperatively. Patients experienced nausea for up to 13 days postoperatively. Forty-two patients were satisfied with their pain management, which usually took the form of epidural anaesthesia and which continued for about one week post-surgery. Sleep disturbance was observed in 51 patients and psychological problems in 49 patients during the first three postoperative weeks. Tumour burden, stoma formation, use of CPAP, primary diagnosis, and the length of stay in the ICU were factors related to an early recovery process.

    CONCLUSION:

    Drinking, eating, regaining bowel functions and mobilisation were re-established within 11 days of CRS and HIPEC. Tumour burden, stoma formation, use of CPAP, primary diagnosis and the length of stay in the ICU all had an impact on postoperative recovery, and should be discussed with the patients preoperatively and taken into consideration in designing an individualised patient care plan, in order to attain a more efficient recovery.

  • 15.
    Arakelian, Erebouni
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Torkzad, Michael R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Bergman, Antonina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Pulmonary influences on early postoperative recovery in patients after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy treatment2011In: Anesthesia and Analgesia, ISSN 0003-2999, E-ISSN 1526-7598Article in journal (Other academic)
  • 16.
    Arakelian, Erebouni
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Education in Nursing.
    Torkzad, Michael R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Bergman, Antonina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Pulmonary influences on early post-operative recovery in patients after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy treatment: a retrospective study2012In: World Journal of Surgical Oncology, ISSN 1477-7819, E-ISSN 1477-7819, Vol. 10, p. 258-Article in journal (Refereed)
    Abstract [en]

    Background: The combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a curative treatment option for peritoneal carcinomatosis (PC). There have been few studies on the pulmonary adverse events (AEs) affecting patient recovery after this treatment, thus this study investigated these factors. Methods: Between January 2005 and December 2006, clinical data on all pulmonary AEs and the recovery progress were reviewed for 76 patients with after CRS and HIPEC. Patients with pulmonary interventions (thoracocenthesis and chest tubes) were compared with the non-intervention patients. Two senior radiologists, blinded to the post-operative clinical course, separately graded the occurrence of pulmonary AEs. Results: Of the 76 patients, 6 had needed thoracocentesis and another 6 needed chest tubes. There were no differences in post-operative recovery between the intervention and non-intervention groups. The total number of days on mechanical ventilation, the length of stay in the intensive care unit, total length of hospital stay, tumor burden, and an American Society of Anesthesiologists (ASA) grade of greater than 2 were correlated with the occurrence of atelectasis and pleural effusion. Extensive atelectasis (grade 3 or higher) was seen in six patients, major pleural effusion (grade 3) in seven patients, and signs of heart failure (grade 1-2) in nine patients. Conclusions: Clinical and radiological post-operative pulmonary AEs are common after CRS and HIPEC. However, most of the pulmonary AEs did not affect post-operative recovery.

  • 17. Arbeus, Mikael
    et al.
    Axelsson, Birger
    Friberg, Orjan
    Magnuson, Anders
    Bodin, Lennart
    Hultman, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Milrinone Increases Flow in Coronary Artery Bypass Grafts After Cardiopulmonary Bypass: A Prospective, Randomized, Double-Blind, Placebo-Controlled Study2009In: Journal of Cardiothoracic and Vascular Anesthesia, ISSN 1053-0770, E-ISSN 1532-8422, Vol. 23, no 1, p. 48-53Article in journal (Refereed)
    Abstract [en]

    Objective: To compare the effects of a bolus of milrinone, 50 mu g/kg, versus placebo on flow in coronary artery bypass grafts after cardiopulmonary bypass (CPB). Design: A prospective, randomized, double-blind study. Setting: A university hospital. Participants: Forty-four patients with stable angina and left ventricular ejection fraction > 30% scheduled for elective coronary artery bypass graft (CABG) surgery were included. Intervention: Patients were randomized to receive 50 mu g/kg of milrinone (n = 22) or placebo (n = 22) after aortic declamping. Measurements and Main Results: The flow in coronary artery bypass grafts was measured with a transit time flow meter at 10 minutes and 30 minutes after termination of CPB. The hemodynamic evaluation included transesophageal echocardiography, mean arterial pressure (MAP), heart rate, and intracavitary measurement of left ventricular end-diastolic pressure (LVEDP). The flow in the saphenous vein grafts was significantly higher in the milrinone group when compared with the placebo group both at 10 and 30 minutes after termination of CPB (p < 0.001). At 10 minutes, the flow was 64.5 +/- 37.4 mL/min (mean +/- standard deviation) and 43.6 +/- 25.7 mL/min in nonsequential vein grafts for milrinone and placebo, respectively. Corresponding values at 30 minutes were 54.8 +/- 29.9 mL/min and 35.3 +/- 22.4 mL/min. The left internal thoracic artery (LITA) flow was higher in the milrinone group but did not reach statistical significance. The fractional area change was higher, and the MAP and calculated pressure gradient (MAP-LVEDP) were lower at 10 minutes in the milrinone group. Conclusion: Milrinone significantly increases the flow in anastomosed saphenous vein grafts after CPB, and has beneficial effects on left ventricular function.

  • 18.
    Arnell, Kai
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Koskinen, Lars-Owe D.
    Malm, Jan
    Eklund, Anders
    Evaluation of Strata NSC and Codman Hakim adjustable cerebrospinal fluid shunts and their corresponding antisiphon devices2009In: Journal of neurosurgery. Pediatrics, ISSN 1933-0707, Vol. 3, no 3, p. 166-72Article in journal (Refereed)
    Abstract [en]

    OBJECT: The authors investigated and compared the in vitro characteristics of 2 CSF shunts, the Strata NSC and the Codman Hakim, and their corresponding antisiphon devices (ASDs). METHODS: Six new CSF shunts and the corresponding ASDs for each model were tested in an automated, computerized experimental setup based on pressure regulation. Opening pressure accuracy, resistance, sensitivity to abdominal pressure, antisiphon effect, and the influence of different ASD positions were determined. RESULTS: In general the shunts performed according to the manufacturers' specifications. However, at the lowest setting, the opening pressure of the Strata NSC was close to 0, and in the Codman Hakim shunt, it was higher than specified. The resistance in the Codman Hakim shunt (5.4 mm Hg/ml/min) was much higher than that in the Strata NSC (3.6 mm Hg/ml/min). Abdominal pressure affected opening pressure in both valves. Positioning the Strata ASD above or below the ventricular catheter tip resulted in higher and lower opening pressures, respectively, than when it was placed in line with the catheter. The positioning of the Codman Hakim ASD did not influence the opening pressure. CONCLUSIONS: Both CSF shunts work properly, but at the lowest setting the opening pressure of the Strata NSC was near 0 and in the Codman Hakim it was twice the manufacturer's specifications. The resistance in the Strata NSC was below the normal physiological range, and in the Codman Hakim device it was in the lower range of normal. The ASD did not change the shunt characteristics in the lying position and therefore might not do so in children. If this is the case, then a shunt system with an integrated ASD could be implanted at the first shunt insertion, thus avoiding a second operation and the possibility of infection.

  • 19.
    Arnell, Kai
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Olsen, L.
    Wester, T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Paediatric Surgery.
    Hydrocephalus2008In: Pediatric surgery: Diagnosis and management, Berlin: Springer Verlag , 2008, p. 418-426Chapter in book (Other (popular science, discussion, etc.))
  • 20. Artigas, Antonio
    et al.
    Noël, Julie-Lyn
    Brochard, Laurent
    Busari, Jamiu O
    Dellweg, Dominic
    Ferrer, Miguel
    Geiseler, Jens
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Nava, Stefano
    Navalesi, Paolo
    Orfanos, Stylianos
    Palange, Paolo
    Pelosi, Paolo
    Rohde, Gernot
    Schoenhofer, Bernd
    Vassilakopoulos, Theodoros
    Simonds, Anita K
    Defining a training framework for clinicians in respiratory critical care2014In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 44, no 3, p. 572-577Article in journal (Refereed)
  • 21. Artigas, Antonio
    et al.
    Pelosi, Paolo
    Dellweg, Dominic
    Brochard, Laurent
    Ferrer, Miguel
    Geiseler, Jens
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Nava, Stefano
    Navalesi, Paolo
    Noel, Julie-Lyn
    Orfanos, Stylianos
    Palange, Paolo
    Schoenhofer, Bernd
    Vassilakopoulos, Theodoros
    Simonds, Anita
    Respiratory critical care HERMES syllabus: defining competencies for respiratory doctors2012In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 39, no 6, p. 1294-1297Article in journal (Other academic)
  • 22.
    Arvidson, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Kildal, Morten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Linde, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gedeborg, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Toxic epidermal necrolysis and hemolytic uremic syndrome after allogeneic stem-cell transplantation2007In: Pediatric Transplantation, ISSN 1397-3142, E-ISSN 1399-3046, Vol. 11, no 6, p. 689-693Article in journal (Refereed)
    Abstract [en]

    TEN and HUS are challenging complications with excessive mortality after HSCT. We report the development of these two conditions in combination in a nine-yr-old boy after HSCT from an unrelated donor. TEN with skin detachment of more than 90% of body surface area developed after initial treatment for GvHD. Within a few days of admission to the burns unit, the patient developed severe hemolysis, hypertension, thrombocytopenia, and acute renal failure consistent with HUS, apparently caused by CSA. The management included intensive care in a burns unit, accelerated drug removal using plasmapheresis, and a dedicated multi-disciplinary team approach to balance immunosuppression and infections management in a situation with extensive skin detachment. The patient survived and recovered renal function but requires continued treatment for severe GvHD. Suspecting and identifying causative drugs together with meticulous supportive care in the burns unit is essential in the management of these patients and long-term survival is possible.

  • 23.
    Ata, KA
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lennmyr, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lennmyr, F
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Funa, K
    Olsson, Y
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Olsson, Y
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Terent, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Terent, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Expression of transforming growth factor-beta 1, 2, 3 isoforms and type I and II receptors in acute focal cerebral ischemia: an immunohistochemical study in rat after transient and permanent occlusion1999In: Acta Neuropathol., Vol. 97, p. 447-Article in journal (Refereed)
  • 24. Backes, Yara
    et al.
    van der Sluijs, Koenraad F
    Mackie, David P
    Tacke, Frank
    Koch, Alexander
    Tenhunen, Jyrki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Schultz, Marcus J
    Usefulness of suPAR as a biological marker in patients with systemic inflammation or infection: a systematic review2012In: Intensive Care Medicine, ISSN 0342-4642, E-ISSN 1432-1238, Vol. 38, no 9, p. 1418-1428Article, review/survey (Refereed)
    Abstract [en]

    PURPOSE:

    Systemic levels of soluble urokinase-type plasminogen activator receptor (suPAR) positively correlate with the activation level of the immune system. We reviewed the usefulness of systemic levels of suPAR in the care of critically ill patients with sepsis, SIRS, and bacteremia, focusing on its diagnostic and prognostic value.

    METHODS:

    A PubMed search on suPAR was conducted, including manual cross-referencing. The list of papers was narrowed to original studies of critically ill patients. Ten papers on original studies of critically ill patients were identified that report on suPAR in sepsis, SIRS, or bacteremia.

    RESULTS:

    Systematic levels of suPAR have little diagnostic value in critically ill patients with sepsis, SIRS, or bacteremia. Systemic levels of suPAR, however, have superior prognostic power over other commonly used biological markers in these patients. Mortality prediction by other biological markers or severity-of-disease classification system scores improves when combining them with suPAR. Systemic levels of suPAR correlate positively with markers of organ dysfunction and severity-of-disease classification system scores. Finally, systemic levels of suPAR remain elevated for prolonged periods after admission and only tend to decline after several weeks. Notably, the type of assay used to measure suPAR as well as the age of the patients and underlying disease affect systemic levels of suPAR.

    CONCLUSIONS:

    The diagnostic value of suPAR is low in patients with sepsis. Systemic levels of suPAR have prognostic value, and may add to prognostication of patients with sepsis or SIRS complementing severity-of-disease classification systems and other biological markers.

  • 25.
    Backryd, Emmanuel
    et al.
    Linkoping Univ, Dept Med & Hlth Sci, Pain & Rehabil Ctr, Linkoping, Sweden..
    Tanum, Lars
    Akershus Univ Hosp, Dept R&D Mental Hlth, Lorenskog, Norway..
    Lind, Anne-Li
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to the cerebrospinal fluid and to plasma2017In: Journal of Pain Research, ISSN 1178-7090, E-ISSN 1178-7090, Vol. 10Article in journal (Refereed)
    Abstract [en]

    In addition to central hyperexcitability and impaired top-down modulation, chronic inflammation probably plays a role in the pathophysiology of fibromyalgia (FM). Indeed, on the basis of both animal experiments and human studies involving the analysis of cytokines and other inflammation-related proteins in different body fluids, neuroinflammatory mechanisms are considered to be central to the pathophysiology of many chronic pain conditions. However, concerning FM, previous human plasma/serum and/or cerebrospinal fluid (CSF) cytokine studies have looked only at a few predetermined cytokine candidates. Instead of analyzing only a few substances at a time, we used a new multiplex protein panel enabling simultaneous analysis of 92 inflammation-related proteins. Hence, we investigated the CSF and plasma inflammatory profiles of 40 FM patients compared with CSF from healthy controls (n= 10) and plasma from blood donor controls (n= 46). Using multivariate data analysis by projection, we found evidence of both neuroinflammation (as assessed in CSF) and chronic systemic inflammation (as assessed in plasma). Two groups of proteins (one for CSF and one for plasma) highly discriminating between patients and controls are presented. Notably, we found high levels of CSF chemokine CX3CL1 (also known as fractalkine). In addition, previous findings concerning IL-8 in FM were replicated, in both CSF and plasma. This is the first time that such an extensive inflammatory profile has been described for FM patients. Hence, FM seems to be characterized by objective biochemical alterations, and the lingering characterization of its mechanisms as essentially idiopathic or even psychogenic should be seen as definitively outdated.

  • 26. Bagge, L.
    et al.
    Borowiec, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Thelin, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hultman, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Haemostasis at low heparin dosage during cardiopulmonary bypass with heparin-coated circuits pigs1997In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 31, no 6, p. 275-281Article, book review (Other academic)
    Abstract [en]

    Cardiopulmonary bypass (CPB) causes activation of cascade systems. Although heparin coating of CPB circuits improves biocompatibility, the effects on coagulation remain controversial. Theoretically, heparin coating should permit the reduction of systemic anticoagulation during CPB. We investigated influences on haemostatic variables in animal CPB, comparing heparin-coated circuits and reduced systemic heparinization (group HC) with uncoated circuits and full heparinization (group C). Twenty pigs underwent 2-h CPB. Seven (HC, n = 4; C, n = 3) were weaned from CPB and studied for up to 4 h. Total administered heparin was 470 +/- 6 IU/kg (mean +/- SEM) in group C and 100 +/- 0 IU/kg in group HC. Protamine dosage was significantly reduced in group HC. In group C, levels of prothrombin complex, factor VIII and adhesive platelets were reduced significantly during CPB, and postoperatively there were significantly lower values of prothrombin complex, fibrinogen antithrombin III, factor VIII and adhesive platelets but a significantly increased concentration of von Willebrand factor and cumulative bleeding after 4 h. In conclusion, heparin-coated CPB circuits combined with lowered heparin dosage reduced coagulation factor consumption and preserved platelet function, possibly contributing to improved postoperative haemostasis.

  • 27. Barklin, A
    et al.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Vestergaard, C
    Koefoed-Nielsen, J
    Bach, A
    Nyboe, R
    Wogensen, L
    Tønnesen, E
    Does brain death induce a pro-inflammatory response at the organ level in a porcine model?2008In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 52, no 5, p. 621-627Article in journal (Refereed)
    Abstract [en]

    Background:

    Organs from brain-dead donors have a poorer prognosis after transplantation than organs from living donors. A possible explanation for this is that brain death might initiate a systemic inflammatory response, elicited by a metabolic stress response or brain ischemia. The aim of this study was to investigate the effect of brain death on the cytokine content in the heart, liver, and kidney. In addition, the metabolic and hemodynamic response caused by brain death was carefully registered.

    Methods:

    Fourteen pigs (35–40 kg) were randomized into two groups (1) eight brain-dead pigs and (2) six pigs only sham operated. Brain death was induced by inflation of an epidurally placed balloon. Blood samples for insulin, glucose, catecholamine, free fatty acids (FAA), and glucagon were obtained during the experimental period of 360 min. At the conclusion of the experiment, biopsies were taken from the heart, liver, and kidney and were analyzed for cytokine mRNA and proteins [tumor necrosis factor α (TNF-α), interleukin (IL)-6, and IL-10).

    Results:

    We found a dramatic response to brain death on plasma levels of epinephrine (P=0.004), norepinephrine (P=0.02), FAA (P=0.0001), and glucagon (P=0.0003) compared with the sham group. There was no difference in cytokine content in any organ between the groups.

    Conclusion:

    In this porcine model, brain death induced a severe metabolic response in peripheral blood. At the organ level, however, there was no difference in the cytokine response between the groups.

  • 28. Barklin, Anne
    et al.
    Theodorsson, Elvar
    Tyvold, Stig S.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Granfeldt, Asger
    Sloth, Erik
    Tonnesen, Else
    Alteration of neuropeptides in the lung tissue correlates brain death-induced neurogenic edema2009In: The Journal of Heart and Lung Transplantation, ISSN 1053-2498, E-ISSN 1557-3117, Vol. 28, no 7, p. 725-32Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Increased intracranial pressure induces neurogenic pulmonary edema (NPE), potentially explaining why only lungs from less than 20% of brain dead organ donors can be used for transplantation. This study investigated the underlying mechanisms of NPE, focusing on neuropeptides, which potently induce vasoconstriction, vasodilatation, and neurogenic inflammation. METHODS: Brain death was induced in 10 pigs by increasing the intracranial pressure. Eight additional pigs served as controls. Neuropeptide Y (NPY), calcitonin gene-related peptide (CGRP), and substance P were analyzed in plasma, bronchoalveolar lavage (BAL) fluid, and homogenized lung tissue 6 hours after brain death. Pulmonary oxygen exchange was estimated using partial pressure of arterial oxygen (Pao2)/fraction of inspired oxygen (Fio2), and pulmonary edema by wet/dry weight ratio. RESULTS: Brain death induced a decrease in Pao(2)/Fio2 (p < 0.001) and increased the wet/dry weight of both apical (p = 0.01) and basal lobes (p = 0.03). NPY and CGRP concentrations were higher in the BAL fluid of brain-dead animals compared with controls (p = 0.02 and p = 0.02) and were positively correlated with the wet/dry weight ratio. NPY content in lung tissue was lower in brain-dead animals compared with controls (p = 0.04) and was negatively correlated with the wet/dry weight ratio. There were no differences in substance P concentrations between the groups. CONCLUSION: NPY was released from the lung tissue of brain-dead pigs, and its concentration was related to the extent of pulmonary edema. NPY may be one of several crucial mediators of neurogenic pulmonary edema, raising the possibility of treatment with NPY-antagonists to increase the number of available lung donors.

  • 29.
    Bartha, Erzsebet
    et al.
    Karolinska Univ Hosp, Huddinge, Sweden..
    Helleberg, Johan
    Karolinska Univ Hosp, Huddinge, Sweden..
    Ahlstrand, Rebecca
    Orebro Univ Hosp, Orebro, Sweden..
    Bell, Max
    Karolinska Univ Hosp, Solna, Sweden..
    Bjorne, Hakan
    Karolinska Univ Hosp, Solna, Sweden..
    Brattstrom, Olof
    Karolinska Univ Hosp, Solna, Sweden..
    Nilsson, Lena
    Univ Hosp Linkoping, Linkoping, Sweden..
    Semenas, Egidijus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Andreas
    Karolinska Univ Hosp, Solna, Sweden..
    Kalman, Sigridur
    Karolinska Univ Hosp, Huddinge, Sweden..
    Performance of prediction models of postoperative mortality in high-risk surgical patients in swedish university hospitals: Predictors, Risk factors and Outcome Following major Surgery study (PROFS study NCT02626546)2017In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 61, no 8, p. 1056-1057Article in journal (Other academic)
  • 30. Basnet, A.
    et al.
    Butler, Stephen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Honore, P. H.
    Butler, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Gordh, Torsten E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Kristensen, K.
    Bjerrum, O. J.
    Donepezil provides positive effects to patients treated with gabapentin for neuropathic pain: an exploratory study2014In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 58, no 1, p. 61-73Article in journal (Refereed)
    Abstract [en]

    BackgroundThe first-line medication gabapentin and the acetylcholinesterase inhibitor donepezil represent a new promising combination to improve treatment outcomes for patients with severe neuropathic pain. The drugs have previously shown synergism following co-administration in nerve-injured rats. MethodsThe clinical relevance of adding donepezil to existing gabapentin treatment in patients with post-traumatic neuropathic pain was explored in this open-label study. The study comprised two consecutive periods of minimum 6 weeks: (1) titration of gabapentin to the highest tolerable dose or maximum 2400mg daily, and (2) addition of donepezil 5mg once daily to the fixed gabapentin dose. Efficacy and tolerability were assessed by ratings of pain intensity, questionnaires for pain and health-related quality of life, and reporting of adverse events. Pain scores were also analysed using mixed-effects analysis with the software NONMEM to account for intersubject variability. ResultsEight patients commenced treatment with donepezil, of which two withdrew because of adverse events. Addition of donepezil resulted in clinically relevant reductions of pain (>11 units on a 0-100 scale) and improved mental wellness in three of six patients. The remaining three patients had no obvious supplemental effect. Mixed-effects analysis revealed that pain scores were significantly lower during co-administration (P<0.0001 combination vs. monotherapy). ConclusionDonepezil may provide additional analgesia to neuropathic pain patients with insufficient pain relief from gabapentin as monotherapy. The promising results support controlled clinical trials of the drug combination. The usefulness of mixed-effects analysis in small-scale trials and/or for data with high intersubject variability was also demonstrated.

  • 31.
    Basu, Samar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Mattsson, Christer
    Eriksson, Örjan
    Kiiski, Ritva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Nordgren, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Eriksson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Effects of melagatran, a novel direct thrombin inhibitor, during experimental septic shock2000In: Expert Opinion on Investigational Drugs, ISSN 1354-3784, E-ISSN 1744-7658, Vol. 9, no 5, p. 1129-1137Article in journal (Refereed)
    Abstract [en]

    Sepsis and endotoxaemia initiate the generation of thrombin, which is responsible for the conversion of fibrinogen to fibrin, platelet aggregation and acts as an inflammatory mediator affecting numerous types of cells, including myocardial, smooth muscle and endothelial cells. Human Gram-negative septic shock, frequently seen in intensive care units, is a condition with high mortality. This condition can be replicated in the endotoxaemic pig. As many of the toxic effects of sepsis are due to thrombin generation, it was of interest to study, using this porcine experimental septic shock model, whether inhibition of thrombin could alleviate the effects of endotoxaemia. For this purpose melagatran, a direct synthetic thrombin inhibitor with a molecular weight of 429 Da, was employed. Melagatran does not significantly interact with any other enzymes in the coagulation cascade or fibrinolytic enzymes aside from thrombin. Furthermore, melagatran does not require endogenous co-factors such as antithrombin or heparin co-Factor II for its antithrombin effect, which is important, as these inhibitors are often consumed in septic patients. We have shown that melagatran exerts a beneficial effect on renal function, as evaluated by plasma creatinine and urinary output, during experimental septic shock. These effects were most pronounced during the later phase of the experimental period, after the infusion of melagatran had been discontinued. Prevention of intrarenal coagulation may be attributable to this finding. In addition, melagatran had beneficial effects on systemic haemodynamics (left ventricular stroke work index, pulmonary capillary wedge pressure and systemic vascular resistance index) in endotoxaemic pigs. This result may be explained by the ability of melagatran to inhibit thrombin, thereby counteracting thrombin's cellular effects. Thus, it can be seen, using this experimental model of septic shock, that melagatran may help to alleviate some of the damaging effects of endotoxaemia, although more research is required to test this further.

  • 32.
    Basu, Samar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Liu, Xiaoli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Nozari, Ala
    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.
    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.
    Evidence for Time-dependent Maximum Increase ofFree Radical Damage and Eicosanoid Formation in theBrain as Related to Duration of Cardiac Arrest andCardio-pulmonary Resuscitation2003In: Free radical research, ISSN 1071-5762, E-ISSN 1029-2470, Vol. 37, no 3, p. 251-256Article in journal (Refereed)
    Abstract [en]

    Recovery of neurological function in patients following cardiac arrest and cardiopulmonary resuscitation (CPR) is a complex event. Free radical induced oxidative stress is supposed to be involved in this process. We studied levels of 8-iso-PGF2alpha (indicating oxidative injury) and 15-keto-dihydro-PGF2alpha (indicating inflammatory response) in venous plasma obtained from the jugular bulb in a porcine model of experimental cardiopulmonary resuscitation (CPR) where 2, 5, 8, 10 or 12 min of ventricular fibrillation (VF) was followed by 5 or 8 min of closed-chest CPR. A significant increase of 8-iso-PGF2alpha was observed immediately following restoration of spontaneous circulation in all experiments of various duration of VF and CPR. No such increase was seen in a control group. When compared between the groups there was a duration-dependent maximum increase of 8-iso-PGF2alpha which was greatest in animals subjected to the longest period (VF12 min + CPR8 min) of no or low blood flow. In contrast, the greatest increase of 15-keto-dihydro-PGF2alpha was observed in the 13 min group (VF8 min + CPR5 min). Thus, a time-dependent cerebral oxidative injury occurs in conjunction which cardiac arrest and CPR.

  • 33.
    Basu, Samar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation.
    Miclescu, Adriana
    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.
    Propofol mitigates systemic oxidative injury during experimental cardiopulmonary cerebral resuscitation2011In: Prostaglandins, Leukotrienes and Essential Fatty Acids, ISSN 0952-3278, E-ISSN 1532-2823, Vol. 84, no 5-6, p. 123-130Article in journal (Refereed)
    Abstract [en]

    Effects of propofol, an intravenous anesthetic agent that exerts potent antioxidant properties, were investigated in an experimental model of cardiac arrest and cardiopulmonary resuscitation. An extended cardiac arrest with 15 randomized piglets was studied to assess the effect of propofol or its solvent intralipid as the control group. Oxidative stress (as measured by a major F(2)-isoprostane) and inflammation (a major metabolite of PGF(2α)) were evaluated in addition to the hemodynamic evaluation, protein S-100β and in situ tissue brain damage by immunochemistry at sacrifice after 3h of reperfusion following cardiac arrest and restoration of spontaneous circulation (ROSC). ROSC increased jugular bulb plasma levels of F(2)-isoprostane and PGF(2α) metabolite significantly more in controls than in the propofol-treated group. In situ tissue damage after ischemia-reperfusion was variable among the pigs at sacrifice, but tended to be greater in the control than the propofol-treated group. Propofol significantly reduced an ROSC-mediated oxidative stress in the brain.

  • 34.
    Basu, Samar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Mutschler, Diana K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Larsson, Anders O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kiiski, Ritva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Nordgren, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Eriksson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Propofol (Diprivan-EDTA) counteracts oxidative injury and deterioration of the arterial oxygen tension during experimental septic shock2001In: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 50, no 3, p. 341-348Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Human septic shock can be replicated in the endotoxaemic pig. Endotoxaemia causes a multitude of events, including reduced PaO(2) and increased lipid peroxidation. This study was designed to evaluate the possible effects of a commonly used anaesthetic drug with known antioxidant properties (propofol) during porcine endotoxaemia.

    METHODS: Ten pigs were anaesthetised and given a 6 h E. coli endotoxin infusion. The animals received, randomly, a supplementary continuous infusion of propofol emulsion (containing 0.005% EDTA) or the corresponding volume of vehicle (controls). Pathophysiologic responses were determined. Non-enzymatic (by measuring plasma 8-iso-PGF(2 alpha) and enzymatic (by measuring plasma 15-keto-dihydro-PGF(2 alpha)) lipid peroxidations were evaluated. Plasma levels of the endogenous antioxidants alpha- and gamma-tocopherols, were also analysed.

    RESULTS: Endotoxaemia increased plasma levels of 8-iso-PGF(2 alpha) (1st-4th h) and 15-keto-dihydro-PGF(2 alpha) (1st-4th h) significantly more in controls than in the propofol+endotoxin group. PaO(2) was significantly less affected by endotoxin in the propofol treated animals (2nd-4th h). Mean arterial pressure (4th-6th h) and systemic vascular resistance (6th h) were reduced significantly more by endotoxin among the propofol-treated animals. Vitamin E (alpha-tocopherol) increased in all animals, significantly more in the propofol+endotoxin group (1/2-6th h) than in the control group.

    CONCLUSIONS: Propofol reduced endotoxin-induced free radical mediated and cyclooxygenase catalysed lipid peroxidation significantly. The implication is that propofol counteracts endotoxin-induced deterioration of PaO(2).

  • 35.
    Basu, Samar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Nozari, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Liu, X. L.
    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.
    Development of a novel biomarker of free radical damage in reperfusion injury after cardiac arrest2000In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 470, no 1, p. 1-6Article in journal (Refereed)
    Abstract [en]

    In a porcine model of cardiopulmonary resuscitation (CPR), we investigated changes in the plasma levels of 8-iso-PGF(2alpha), a marker for oxidative injury, and 15-keto-dihydro-PGF(2alpha), an inflammatory response indicator during the post-resuscitation period after cardiac arrest. Twelve piglets were subjected to either 2 or 5 min (VF2 and VF5 group) of ventricular fibrillation (VF) followed by 5 min of closed-chest CPR. Six piglets without cardiac arrest were used as controls. In VF5 group, 8-iso-PGF(2alpha) in the jugular bulb plasma (draining the brain) increased four-fold. Jugular bulb 8-iso-PGF(2alpha) in the control group remained unchanged. The 15-keto-dihydro-PGF(2alpha) also increased four-fold in the VF5 group. Thus, 8-iso-PGF(2alpha) and 15-keto-dihydro-PGF(2alpha) measurements in jugular bulb plasma may be used as biomarkers for quantification of free radical catalyzed oxidative brain injury and inflammatory response in reperfusion injury

  • 36.
    Batista Borges, João
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Univ Sao Paulo, Sao Paulo, Brazil.
    The Plausibility of "Bronchiolotrauma"2018In: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 197, no 8, p. 1086-1087Article in journal (Refereed)
  • 37.
    Batista Borges, João
    et al.