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  • 301.
    Retamal, Jaime
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet. Pontificia Univ Catolica Chile, Dept Med Intensiva, Fac Med, Santiago, Chile..
    Bugedo, G.
    Pontificia Univ Catolica Chile, Dept Med Intensiva, Fac Med, Santiago, Chile..
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Bruhn, A.
    Pontificia Univ Catolica Chile, Dept Med Intensiva, Fac Med, Santiago, Chile..
    High PEEP levels are associated with overdistension and tidal recruitment/derecruitment in ARDS patients2015Ingår i: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 59, nr 9, s. 1161-1169Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BackgroundPositive end-expiratory pressure (PEEP) improves gas exchange and respiratory mechanics, and it may decrease tissue injury and inflammation. The mechanisms of this protective effect are not fully elucidated. Our aim was to determine the intrinsic effects of moderate and higher levels of PEEP on tidal recruitment/derecruitment, hyperinflation, and lung mechanics, in patients with acute respiratory distress syndrome (ARDS). MethodsNine patients with ARDS of mainly pulmonary origin were ventilated sequential and randomly using two levels of PEEP: 9 and 15cmH(2)O, and studied with dynamic computed tomography at a fix transversal lung region. Tidal recruitment/derecruitment and hyperinflation were determined as non-aerated tissue and hyperinflated tissue variation between inspiration and expiration, expressed as percentage of total weight. We also assessed the maximal amount of non-aerated and hyperinflated tissue weight. ResultsPEEP 15cmH(2)O was associated with decrease in non-aerated tissue in all the patients (P<0.01). However, PEEP 15cmH(2)O did not decrease tidal recruitment/derecruitment compared to PEEP 9cmH(2)O (P=1). In addition, PEEP 15cmH(2)O markedly increased maximal hyperinflation (P<0.01) and tidal hyperinflation (P<0.05). Lung compliance decreased with PEEP 15cmH(2)O (P<0.001). ConclusionIn this series of patients with ARDS of mainly pulmonary origin, application of high levels of PEEP did not decrease tidal recruitment/derecruitment, but instead consistently increased tidal and maximal hyperinflation.

  • 302.
    Retamal, Jaime
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Hurtado, Daniel
    Villarroel, Nicolas
    Bruhn, Alejandro
    Bugedo, Guillermo
    Amato, Marcelo
    Costa, Eduardo
    Hedenstierna, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Borges, Joao Batista
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Regional pulmonary deformation is positively correlated with regional lung inflammation assessed by 18F-FDG positron emission tomography / computed tomographyManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Objective: Lung deformation beyond of physiological capacity is associated with cell death and inflammation. Lung strain has been estimated as a global strain, but uneven strain distribution may lead to regional stress concentrations and lung damage. Local lung inflammation can be estimated using PET imaging of [18F]fluoro-2-deoxy-D-glucose. We hypothesized that local lung deformation correlates well with local inflammation. The aim of this study was to assess local tidal deformations by using a new mathematical model of finite-elements to analyze CT images, and to correlate them with local inflammation in a porcine experimental model of early acute respiratory distress syndrome.

    Design: Retrospective images analysis, laboratory investigation.

    Setting: University animal research laboratory.

    Subjects: Seven piglets submitted to experimental ventilator-induced lung injury and five healthy ventilated controls.

    Intervention: Lung injury was induced by repeated lung lavages and 210 minutes of injurious mechanical ventilation using low positive end-expiratory pressure and high inspiratory pressures. All animals were subsequently studied with dynamic PET imaging of [18F]fluoro-2-deoxy-D-glucose. CT scans were acquired at end expiration and end inspiration. Then maps of deformation were constructed and regional deformation was estimated. We divided the lung parenchyma in 10 horizontal ROIs, and correlations of local volumetric strain and [18F]fluoro-2-deoxy-D-glucose uptake were analyzed in each ROI.

    Measurements and Main Results: The deformation maps showed a heterogeneous distribution with a greater concentration in the intermediate gravitational regions. We found a strong correlation between local strain and inflammation (R2 > 0.5) for the whole lung, when we eliminate the 3/10 dorsal ROIs R2 increased until>0.8.

    Conclusion: the present findings suggest that the greater local stretches were mainly concentrated in the intermediate gravitational zones of injured heterogeneous lungs. Additionally, local lung deformations correlated well with local inflammation in this experimental model of VILI. And the new proposed image-based estimation of regional volumetric strain based on finite element interpolations has the potential to give new insights of local pathogenic mechanisms of VILI and how best design protective-ventilations strategies.

  • 303.
    Retamal, Jaime
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Departamento de Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
    Hurtado, Daniel
    Villarroel, Nicolás
    Bruhn, Alejandro
    Bugedo, Guillermo
    Amato, Marcelo Britto Passos
    Costa, Eduardo Leite Vieira
    Hedenstierna, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Batista Borges, João
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet. Pulmonary Division, Heart Institute (InCor), Hospital das Clinicas, University of São Paulo, São Paulo, Brazil.
    Does Regional Lung Strain Correlate With Regional Inflammation in Acute Respiratory Distress Syndrome During Nonprotective Ventilation?: An Experimental Porcine Study2018Ingår i: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 46, nr 6, s. e591-e599Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: It is known that ventilator-induced lung injury causes increased pulmonary inflammation. It has been suggested that one of the underlying mechanisms may be strain. The aim of this study was to investigate whether lung regional strain correlates with regional inflammation in a porcine model of acute respiratory distress syndrome.

    DESIGN: Retrospective analysis of CT images and positron emission tomography images using [18F]fluoro-2-deoxy-D-glucose.

    SETTING: University animal research laboratory.

    SUBJECTS: Seven piglets subjected to experimental acute respiratory distress syndrome and five ventilated controls.

    INTERVENTIONS: Acute respiratory distress syndrome was induced by repeated lung lavages, followed by 210 minutes of injurious mechanical ventilation using low positive end-expiratory pressures (mean, 4 cm H2O) and high inspiratory pressures (mean plateau pressure, 45 cm H2O). All animals were subsequently studied with CT scans acquired at end-expiration and end-inspiration, to obtain maps of volumetric strain (inspiratory volume - expiratory volume)/expiratory volume, and dynamic positron emission tomography imaging. Strain maps and positron emission tomography images were divided into 10 isogravitational horizontal regions-of-interest, from which spatial correlation was calculated for each animal.

    MEASUREMENTS AND MAIN RESULTS: The acute respiratory distress syndrome model resulted in a decrease in respiratory system compliance (20.3 ± 3.4 to 14.0 ± 4.9 mL/cm H2O; p < 0.05) and oxygenation (PaO2/FIO2, 489 ± 80 to 92 ± 59; p < 0.05), whereas the control animals did not exhibit changes. In the acute respiratory distress syndrome group, strain maps showed a heterogeneous distribution with a greater concentration in the intermediate gravitational regions, which was similar to the distribution of [18F]fluoro-2-deoxy-D-glucose uptake observed in the positron emission tomography images, resulting in a positive spatial correlation between both variables (median R2 = 0.71 [0.02-0.84]; p < 0.05 in five of seven animals), which was not observed in the control animals.

    CONCLUSION: In this porcine acute respiratory distress syndrome model, regional lung strain was spatially correlated with regional inflammation, supporting that strain is a relevant and prominent determinant of ventilator-induced lung injury.

  • 304.
    Retamal Montes, Jaime
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Aspects on ventilation induced stress and strain on regional and global inflammation in experimental acute respiratory distress syndrome2016Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Mechanical ventilation (MV) is a life-saving therapy in acute respiratory distress syndrome (ARDS), a condition that affects 3000 patients/year in Sweden with a mortality rate of about 40%. However, MV may induce or worsen lung injury causing “ventilator-induced lung injury (VILI)”. From a mechanical perspective strain (deformation, or relative change in lung volume) and stress (tension) have been postulated as main determinants of VILI. High respiratory rate is potentially another factor that may exacerbate VILI by amplifying the total energy transmitted to the lungs during MV. In this thesis in animal ARDS models the hypotheses were that 1) lung parenchyma inhomogeneities concentrate stress and amplify lung damage and inflammation, 2) higher respiratory rates increase lung inflammation and lung edema in heterogeneous ARDS, and 3) local lung deformation is related to local inflammation.

    First, in a rat model the effect on inflammation and structural damage of regional lung collapse on the healthy surrounding lung tissue was assessed. Second, in porcine models the effect of respiratory rate on lung edema and inflammation was studied during two ventilatory modes; a) a permissive collapse mode and b) a homogenized lung parenchyma mode. Finally, lung deformation was correlated with lung inflammation assessed by positron emission tomography using 18F-FDG uptake.

    It was found that; 1) local inhomogeneities can act as stress amplifiers, increasing lung tissue inflammation and damage in the healthy surrounded lung. 2) high respiratory rate increases lung edema but decreases lung inflammation when permissive lung collapse is used and that these effects are prevented with lung parenchyma homogenization; 3) local lung deformation and inflammation are well correlated.

    In conclusion, lung inhomogeneities may aggravate VILI, respiratory rate may affect in different ways VILI progression depending on the ventilatory strategy, and finally, lung deformation is closely related to lung inflammation. With the caveat that the studies are performed in animal models, the results suggest that using ventilator strategies that homogenize the lungs, i.e., open collapsed lung regions and prevent re-collapse in ARDS will reduce VILI and in the end may decrease morbidity and the high mortality in this condition.

    Delarbeten
    1. Non-lobar atelectasis generates inflammation and structural alveolar injury in the surrounding healthy tissue during mechanical ventilation
    Öppna denna publikation i ny flik eller fönster >>Non-lobar atelectasis generates inflammation and structural alveolar injury in the surrounding healthy tissue during mechanical ventilation
    Visa övriga...
    2014 (Engelska)Ingår i: Critical Care, ISSN 1364-8535, E-ISSN 1466-609X, Vol. 18, nr 5, s. 505-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Introduction

    When alveoli collapse the traction forces exerted on their walls by adjacent expanded units may increase and concentrate. These forces may promote its re-expansion at the expense of potentially injurious stresses at the interface between the collapsed and the expanded units. We developed an experimental model to test the hypothesis that a local non-lobar atelectasis can act as a stress concentrator, contributing to inflammation and structural alveolar injury in the surrounding healthy lung tissue during mechanical ventilation.

    Methods

    A total of 35 rats were anesthetized, paralyzed and mechanically ventilated. Atelectasis was induced by bronchial blocking: after five minutes of stabilization and pre-oxygenation with FIO2 = 1.0, a silicon cylinder blocker was wedged in the terminal bronchial tree. Afterwards, the animals were randomized between two groups: 1) Tidal volume (VT) = 10 ml/kg and positive end-expiratory pressure (PEEP) = 3 cmH2O (VT10/PEEP3); and 2) VT = 20 ml/kg and PEEP = 0 cmH2O (VT20/zero end-expiratory pressure (ZEEP)). The animals were then ventilated during 180 minutes. Three series of experiments were performed: histological (n = 12); tissue cytokines (n = 12); and micro-computed tomography (microCT; n = 2). An additional six, non-ventilated, healthy animals were used as controls.

    Results

    Atelectasis was successfully induced in the basal region of the lung of 26 out of 29 animals. The microCT of two animals revealed that the volume of the atelectasis was 0.12 and 0.21 cm3. There were more alveolar disruption and neutrophilic infiltration in the peri-atelectasis region than the corresponding contralateral lung (control) in both groups. Edema was higher in the peri-atelectasis region than the corresponding contralateral lung (control) in the VT20/ZEEP than VT10/PEEP3 group. The volume-to-surface ratio was higher in the peri-atelectasis region than the corresponding contralateral lung (control) in both groups. We did not find statistical difference in tissue interleukin-1β and cytokine-induced neutrophil chemoattractant-1 between regions.

    Conclusions

    The present findings suggest that a local non-lobar atelectasis acts as a stress concentrator, generating structural alveolar injury and inflammation in the surrounding lung tissue.

    Nationell ämneskategori
    Klinisk medicin
    Forskningsämne
    Klinisk fysiologi
    Identifikatorer
    urn:nbn:se:uu:diva-233429 (URN)10.1186/s13054-014-0505-1 (DOI)000351850600024 ()25200702 (PubMedID)
    Tillgänglig från: 2014-10-03 Skapad: 2014-10-03 Senast uppdaterad: 2017-12-05Bibliografiskt granskad
    2. High respiratory rate is associated with early reduction of lung edema clearance in an experimental model of ARDS
    Öppna denna publikation i ny flik eller fönster >>High respiratory rate is associated with early reduction of lung edema clearance in an experimental model of ARDS
    Visa övriga...
    2016 (Engelska)Ingår i: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 60, nr 1, s. 79-92Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    BACKGROUND: The independent impact of respiratory rate on ventilator-induced lung injury has not been fully elucidated. The aim of this study was to investigate the effects of two clinically relevant respiratory rates on early ventilator-induced lung injury evolution and lung edema during the protective ARDSNet strategy. We hypothesized that the use of a higher respiratory rate during a protective ARDSNet ventilation strategy increases lung inflammation and, in addition, lung edema associated to strain-induced activation of transforming growth factor beta (TGF-β) in the lung epithelium.

    METHODS: Twelve healthy piglets were submitted to a two-hit lung injury model and randomized into two groups: LRR (20 breaths/min) and HRR (40 breaths/min). They were mechanically ventilated during 6 h according to the ARDSNet strategy. We assessed respiratory mechanics, hemodynamics, and extravascular lung water (EVLW). At the end of the experiment, the lungs were excised and wet/dry ratio, TGF-β pathway markers, regional histology, and cytokines were evaluated.

    RESULTS: No differences in oxygenation, PaCO2 levels, systemic and pulmonary arterial pressures were observed during the study. Respiratory system compliance and mean airway pressure were lower in LRR group. A decrease in EVLW over time occurred only in the LRR group (P < 0.05). Wet/dry ratio was higher in the HRR group (P < 0.05), as well as TGF-β pathway activation. Histological findings suggestive of inflammation and inflammatory tissue cytokines were higher in LRR.

    CONCLUSION: HRR was associated with more pulmonary edema and higher activation of the TGF-β pathway. In contrast with our hypothesis, HRR was associated with less lung inflammation.

    Nationell ämneskategori
    Anestesi och intensivvård
    Forskningsämne
    Anestesiologi och intensivvård
    Identifikatorer
    urn:nbn:se:uu:diva-264211 (URN)10.1111/aas.12596 (DOI)000368139400010 ()26256848 (PubMedID)
    Forskningsfinansiär
    Hjärt-LungfondenVetenskapsrådet, K2015-99X-22731-01-4
    Tillgänglig från: 2015-10-07 Skapad: 2015-10-07 Senast uppdaterad: 2017-12-01Bibliografiskt granskad
    3. Open lung approach ventilation abolishes the negative effects of respiratory rate in experimental lung injury
    Öppna denna publikation i ny flik eller fönster >>Open lung approach ventilation abolishes the negative effects of respiratory rate in experimental lung injury
    Visa övriga...
    2016 (Engelska)Ingår i: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 60, nr 8, s. 1131-1141Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    BACKGROUND: We recently reported that a high respiratory rate was associated with less inflammation than a low respiratory rate, but caused more pulmonary edema in a model of ARDS when an ARDSNet ventilatory strategy was used. We hypothesized that an open lung approach (OLA) strategy would neutralize the independent effects of respiratory rate on lung inflammation and edema. This hypothesis was tested in an ARDS model using two clinically relevant respiratory rates during OLA strategy.

    METHODS: Twelve piglets were subjected to an experimental model of ARDS and randomized into two groups: LRR (20 breaths/min) and HRR (40 breaths/min). They were mechanically ventilated for 6 h according to an OLA strategy. We assessed respiratory mechanics, hemodynamics, and extravascular lung water (EVLW). At the end of the experiment, wet/dry ratio, regional histology, and cytokines were evaluated.

    RESULTS: After the ARDS model was established, Cdyn,rs decreased from 21 ± 3.3 to 9.0 ± 1.8 ml/cmH2 O (P < 0.0001). After the lung recruitment maneuver, Cdyn,rs increased to the pre-injury value. During OLA ventilation, no differences in respiratory mechanics, hemodynamics, or EVLW were observed between groups. Wet/dry ratio and histological scores were not different between groups. Cytokine quantification was similar and showed a homogeneous distribution throughout the lung in both groups.

    CONCLUSION: Contrary to previous findings with the ARDSNet strategy, respiratory rate did not influence lung inflammatory response or pulmonary edema during OLA ventilation in experimental ARDS. This indicates that changing the respiratory rate when OLA ventilation is used will not exacerbate lung injury.

    Nationell ämneskategori
    Anestesi och intensivvård
    Identifikatorer
    urn:nbn:se:uu:diva-296932 (URN)10.1111/aas.12735 (DOI)000380960400012 ()27110871 (PubMedID)
    Forskningsfinansiär
    Hjärt-LungfondenVetenskapsrådet, K2015-99X-22731-01-4
    Tillgänglig från: 2016-06-20 Skapad: 2016-06-20 Senast uppdaterad: 2018-11-12Bibliografiskt granskad
    4. Regional pulmonary deformation is positively correlated with regional lung inflammation assessed by 18F-FDG positron emission tomography / computed tomography
    Öppna denna publikation i ny flik eller fönster >>Regional pulmonary deformation is positively correlated with regional lung inflammation assessed by 18F-FDG positron emission tomography / computed tomography
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Objective: Lung deformation beyond of physiological capacity is associated with cell death and inflammation. Lung strain has been estimated as a global strain, but uneven strain distribution may lead to regional stress concentrations and lung damage. Local lung inflammation can be estimated using PET imaging of [18F]fluoro-2-deoxy-D-glucose. We hypothesized that local lung deformation correlates well with local inflammation. The aim of this study was to assess local tidal deformations by using a new mathematical model of finite-elements to analyze CT images, and to correlate them with local inflammation in a porcine experimental model of early acute respiratory distress syndrome.

    Design: Retrospective images analysis, laboratory investigation.

    Setting: University animal research laboratory.

    Subjects: Seven piglets submitted to experimental ventilator-induced lung injury and five healthy ventilated controls.

    Intervention: Lung injury was induced by repeated lung lavages and 210 minutes of injurious mechanical ventilation using low positive end-expiratory pressure and high inspiratory pressures. All animals were subsequently studied with dynamic PET imaging of [18F]fluoro-2-deoxy-D-glucose. CT scans were acquired at end expiration and end inspiration. Then maps of deformation were constructed and regional deformation was estimated. We divided the lung parenchyma in 10 horizontal ROIs, and correlations of local volumetric strain and [18F]fluoro-2-deoxy-D-glucose uptake were analyzed in each ROI.

    Measurements and Main Results: The deformation maps showed a heterogeneous distribution with a greater concentration in the intermediate gravitational regions. We found a strong correlation between local strain and inflammation (R2 > 0.5) for the whole lung, when we eliminate the 3/10 dorsal ROIs R2 increased until>0.8.

    Conclusion: the present findings suggest that the greater local stretches were mainly concentrated in the intermediate gravitational zones of injured heterogeneous lungs. Additionally, local lung deformations correlated well with local inflammation in this experimental model of VILI. And the new proposed image-based estimation of regional volumetric strain based on finite element interpolations has the potential to give new insights of local pathogenic mechanisms of VILI and how best design protective-ventilations strategies.

    Nationell ämneskategori
    Anestesi och intensivvård
    Identifikatorer
    urn:nbn:se:uu:diva-296945 (URN)
    Tillgänglig från: 2016-06-20 Skapad: 2016-06-20 Senast uppdaterad: 2016-08-25Bibliografiskt granskad
  • 305.
    Retamal Montes, Jaime
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Pontificia Univ Catolica Chile, Dept Med Intens, Santiago, Chile.
    Borges, João Batista
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet. Univ Sao Paulo, Cardiopulm Dept, Pulm Div, Heart Inst Incor, Sao Paulo, Brazil.
    Bruhn, Alejandro
    Pontificia Univ Catolica Chile, Dept Med Intens, Santiago, Chile.
    Feinstein, Ricardo
    Natl Vet Inst, Dept Pathol & Wildlife Dis, Uppsala, Sweden.
    Hedenstierna, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi.
    Suarez-Sipmann, Fernando
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Open lung approach ventilation abolishes the negative effects of respiratory rate in experimental lung injury2016Ingår i: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 60, nr 8, s. 1131-1141Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: We recently reported that a high respiratory rate was associated with less inflammation than a low respiratory rate, but caused more pulmonary edema in a model of ARDS when an ARDSNet ventilatory strategy was used. We hypothesized that an open lung approach (OLA) strategy would neutralize the independent effects of respiratory rate on lung inflammation and edema. This hypothesis was tested in an ARDS model using two clinically relevant respiratory rates during OLA strategy.

    METHODS: Twelve piglets were subjected to an experimental model of ARDS and randomized into two groups: LRR (20 breaths/min) and HRR (40 breaths/min). They were mechanically ventilated for 6 h according to an OLA strategy. We assessed respiratory mechanics, hemodynamics, and extravascular lung water (EVLW). At the end of the experiment, wet/dry ratio, regional histology, and cytokines were evaluated.

    RESULTS: After the ARDS model was established, Cdyn,rs decreased from 21 ± 3.3 to 9.0 ± 1.8 ml/cmH2 O (P < 0.0001). After the lung recruitment maneuver, Cdyn,rs increased to the pre-injury value. During OLA ventilation, no differences in respiratory mechanics, hemodynamics, or EVLW were observed between groups. Wet/dry ratio and histological scores were not different between groups. Cytokine quantification was similar and showed a homogeneous distribution throughout the lung in both groups.

    CONCLUSION: Contrary to previous findings with the ARDSNet strategy, respiratory rate did not influence lung inflammatory response or pulmonary edema during OLA ventilation in experimental ARDS. This indicates that changing the respiratory rate when OLA ventilation is used will not exacerbate lung injury.

  • 306.
    Rhodin, Annica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Long-term Effects of Opioids in the Treatment of Chronic Pain: Investigation of Problems and Hazards on Clinical, Biochemical, Cellular and Genetic Levels2010Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    After two decades of liberal prescribing of opioids, there has been an increasing recognition of problems connected to the prolonged use of opioids for chronic pain.

    The aim of my thesis was to explore some consequences of long-term opioid treatment for chronic pain such as problematic opioid use, endocrine disorders, tolerance and genetic variations in pain and opioid response.

    Sixty patients with severe pain and problematic opioid use were treated with a structured methadone programme. Risk factors were musculoskeletal pain, psychiatric co-morbidity and previous addiction. Treatment resulted in good pain relief and improved quality of life, but function was impaired by side effects indicating endocrine dysregulation.

    The possibility of opioid-induced endocrine dysfunction was explored in the second paper, where 40 pain patients treated with strong opioids and 20 pain patients without treatment of strong opioids were investigated. The opioid-treated patients had significantly higher incidence of endocrine disturbance affecting gonadal and adrenal function and prolactin levels.

    The functionality of the μ-receptor after long-term treatment with morphine, saline and naloxone was explored in a cell-line expressing the μ-receptor. After one and four weeks of treatment the binding was tested with morphine, methadone, fentanyl and DAMGO and function measured by GTP γ-assay. The binding of DAMGO was significantly diminished after 4 weeks in cells treated with morphine compared with saline and naloxone.

    Genetic variation in three genes with functional impact on opioid response and pain sensitivity was investigated in 80 patients with chronic low-back pain and differential opioid sensitivity and in 56 healthy controls. The results indicated a higher incidence of opioid-related side effects and gender differences in patients with the minor allele of the ABCB1 gene, a correlation between increased opioid sensitivity and the major CACNA2D2 allele and a possible relationship between intrinsic protection against chronic pain and the minor allele of OPRM1.

    Delarbeten
    1. Methadone treatment of chronic non-malignant pain and opioid dependence - A long-term follow-up.
    Öppna denna publikation i ny flik eller fönster >>Methadone treatment of chronic non-malignant pain and opioid dependence - A long-term follow-up.
    2006 (Engelska)Ingår i: European Journal of Pain, ISSN 1090-3801, Vol. 10, nr 3, s. 271-8Artikel i tidskrift (Refereegranskat) Published
    Identifikatorer
    urn:nbn:se:uu:diva-78409 (URN)15972261 (PubMedID)
    Tillgänglig från: 2008-06-29 Skapad: 2008-06-29 Senast uppdaterad: 2011-01-14
    2. Combined analysis of circulating β-endorphin with gene polymorphisms in OPRM1, CACNAD2 and ABCB1 reveals correlation with pain, opioid sensitivity and opioid-related side effects
    Öppna denna publikation i ny flik eller fönster >>Combined analysis of circulating β-endorphin with gene polymorphisms in OPRM1, CACNAD2 and ABCB1 reveals correlation with pain, opioid sensitivity and opioid-related side effects
    Visa övriga...
    2013 (Engelska)Ingår i: Molecular Brain, ISSN 1756-6606, Vol. 6, s. 8-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background

    Opioids are associated with wide inter-individual variability in the analgesic response and a narrow therapeutic index. This may be partly explained by the presence of single nucleotide polymorphisms (SNPs) in genes encoding molecular entities involved in opioid metabolism and receptor activation. This paper describes the investigation of SNPs in three genes that have a functional impact on the opioid response: OPRM1, which codes for the μ-opioid receptor; ABCB1 for the ATP-binding cassette B1 transporter enzyme; and the calcium channel complex subunit CACNA2D2. The genotyping was combined with an analysis of plasma levels of the opioid peptide β-endorphin in 80 well-defined patients with chronic low back pain scheduled for spinal fusion surgery, and with differential sensitivity to the opioid analgesic remifentanil. This patient group was compared with 56 healthy controls.

    Results

    The plasma β-endorphin levels were significantly higher in controls than in pain patients.

    A higher incidence of opioid-related side effects and sex differences was found in patients with the minor allele of the ABCB1 gene. Further, a correlation between increased opioid sensitivity and the major CACNA2D2 allele was confirmed. A tendency of a relationship between opioid sensitivity and the minor allele of OPRM1 was also found.

    Conclusions

    Although the sample cohort in this study was limited to 80 patients it appears that it was possible to observe significant correlations between polymorphism in relevant genes and various items related to pain sensitivity and opioid response. Of particular interest is the new finding of a correlation between increased opioid sensitivity and the major CACNA2D2 allele. These observations may open for improved strategies in the clinical treatment of chronic pain with opioids.

    Nyckelord
    chronic pain, opioid sensitivity, beta-endorphin, mu-1-opioid receptor (OPRM1), calcium channel subunit 2 (CACNA2D2), ATP-binding cassette B1 (ABCB1)
    Nationell ämneskategori
    Anestesi och intensivvård Medicin och hälsovetenskap Neurovetenskaper
    Forskningsämne
    Anestesiologi
    Identifikatorer
    urn:nbn:se:uu:diva-129623 (URN)10.1186/1756-6606-6-8 (DOI)000316319900001 ()23402298 (PubMedID)
    Tillgänglig från: 2010-08-19 Skapad: 2010-08-19 Senast uppdaterad: 2018-01-12
    3. The effects of long-term morphine oncbinding and functionality of different opioids in C-6 cells expressing the OPRM-1 receptor
    Öppna denna publikation i ny flik eller fönster >>The effects of long-term morphine oncbinding and functionality of different opioids in C-6 cells expressing the OPRM-1 receptor
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nyckelord
    lontg-term morphine, OPRM 1-receptor, receptor functionality, [35 S] GTPg-assay
    Nationell ämneskategori
    Anestesi och intensivvård
    Forskningsämne
    Anestesiologi
    Identifikatorer
    urn:nbn:se:uu:diva-129619 (URN)
    Tillgänglig från: 2010-08-19 Skapad: 2010-08-19 Senast uppdaterad: 2011-01-14
    4. Opioid endocrinopathy: a clinical problem in patients with chronic pain and long-term opioid treatment
    Öppna denna publikation i ny flik eller fönster >>Opioid endocrinopathy: a clinical problem in patients with chronic pain and long-term opioid treatment
    2010 (Engelska)Ingår i: The Clinical Journal of Pain, ISSN 0749-8047, E-ISSN 1536-5409, Vol. 26, nr 5, s. 374-380Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background:

    The use of strong opioids for treatment of noncancer chronic pain has increased. However, strong evidence for sustained pain relief and improved function is lacking. Controversy prevails, whether hormonal changes are induced by long-term treatment with opioids. The purpose of this study was to investigate the occurrence of endocrine dysfunction in chronic pain patients on long-term opioid treatment.

    Methods:

    A study group of 39 chronic pain patients treated with strong oral opioids for more than 1 year was compared with a control group of 20 chronic pain patients without opioid treatment. Basic levels of prolactin and function of the hypothalamic-pituitary-thyroid-, hypothalamic-pituitary-adrenal-axis, and hypothalamic-pituitary-growth-hormone - and hypothalamic-pituitary-gonadal-axis were measured. Quality-of-life and side effects were estimated with EORTC-QLQ-C30.

    Results:

    In the opioid-treated group, the patients had signs of pituitary dysfunction affecting all axes. Significant differences were shown in hypofunction of the hypothalamic-pituitary-gonadal -axis, hyperfunction of the hypothalamic-pituitary-adrenal -axis, and higher prolactin levels in the opioid-treated group, compared with the control group. The degree of pain was rated the same in both groups, but the opioid-treated group reported more side effects and lower quality of life.

    Conclusions:

    Long-term treatment of chronic pain with strong opioids causes side effects that can be attributed to hormonal abnormalities caused by opioid-induced inhibition of hypothalamic-pituitary function. Hormone substitution can be indicated to treat symptoms. Decreasing the opioid dose or stopping the opioid treatment can reverse endocrine dysfunction. This needs to be recognized by all practitioners treating chronic pain patients with opioids.

    Nyckelord
    oral opioid treatment, chronic pain, pituitary dysfunction, opioid endocrinopathy
    Nationell ämneskategori
    Anestesi och intensivvård
    Forskningsämne
    Anestesiologi och intensivvård
    Identifikatorer
    urn:nbn:se:uu:diva-129512 (URN)10.1097/AJP.0b013e3181d1059d (DOI)000278073100003 ()20473043 (PubMedID)
    Projekt
    Long-term effects of opioids
    Tillgänglig från: 2010-08-19 Skapad: 2010-08-17 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
  • 307.
    Rhodin, Annica
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet.
    Grönbladh, Alfhild
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet.
    Hallberg, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet.
    The effects of long-term morphine oncbinding and functionality of different opioids in C-6 cells expressing the OPRM-1 receptorManuskript (preprint) (Övrigt vetenskapligt)
  • 308.
    Rhodin, Annica
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    Gröndbladh, Alfhild
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet.
    Ginya, Harumi
    Precision System Science Japan.
    NIlsson, Kent W
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    Rosenblad, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    Zhou, Qin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Enlund, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    Hallberg, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Division of Biological Research on Drug Dependence.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Combined analysis of circulating β-endorphin with gene polymorphisms in OPRM1, CACNAD2 and ABCB1 reveals correlation with pain, opioid sensitivity and opioid-related side effects2013Ingår i: Molecular Brain, ISSN 1756-6606, Vol. 6, s. 8-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Opioids are associated with wide inter-individual variability in the analgesic response and a narrow therapeutic index. This may be partly explained by the presence of single nucleotide polymorphisms (SNPs) in genes encoding molecular entities involved in opioid metabolism and receptor activation. This paper describes the investigation of SNPs in three genes that have a functional impact on the opioid response: OPRM1, which codes for the μ-opioid receptor; ABCB1 for the ATP-binding cassette B1 transporter enzyme; and the calcium channel complex subunit CACNA2D2. The genotyping was combined with an analysis of plasma levels of the opioid peptide β-endorphin in 80 well-defined patients with chronic low back pain scheduled for spinal fusion surgery, and with differential sensitivity to the opioid analgesic remifentanil. This patient group was compared with 56 healthy controls.

    Results

    The plasma β-endorphin levels were significantly higher in controls than in pain patients.

    A higher incidence of opioid-related side effects and sex differences was found in patients with the minor allele of the ABCB1 gene. Further, a correlation between increased opioid sensitivity and the major CACNA2D2 allele was confirmed. A tendency of a relationship between opioid sensitivity and the minor allele of OPRM1 was also found.

    Conclusions

    Although the sample cohort in this study was limited to 80 patients it appears that it was possible to observe significant correlations between polymorphism in relevant genes and various items related to pain sensitivity and opioid response. Of particular interest is the new finding of a correlation between increased opioid sensitivity and the major CACNA2D2 allele. These observations may open for improved strategies in the clinical treatment of chronic pain with opioids.

  • 309.
    Rhodin, Annica
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    Stridsberg, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk endokrinologi.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Opioid endocrinopathy: a clinical problem in patients with chronic pain and long-term opioid treatment2010Ingår i: The Clinical Journal of Pain, ISSN 0749-8047, E-ISSN 1536-5409, Vol. 26, nr 5, s. 374-380Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background:

    The use of strong opioids for treatment of noncancer chronic pain has increased. However, strong evidence for sustained pain relief and improved function is lacking. Controversy prevails, whether hormonal changes are induced by long-term treatment with opioids. The purpose of this study was to investigate the occurrence of endocrine dysfunction in chronic pain patients on long-term opioid treatment.

    Methods:

    A study group of 39 chronic pain patients treated with strong oral opioids for more than 1 year was compared with a control group of 20 chronic pain patients without opioid treatment. Basic levels of prolactin and function of the hypothalamic-pituitary-thyroid-, hypothalamic-pituitary-adrenal-axis, and hypothalamic-pituitary-growth-hormone - and hypothalamic-pituitary-gonadal-axis were measured. Quality-of-life and side effects were estimated with EORTC-QLQ-C30.

    Results:

    In the opioid-treated group, the patients had signs of pituitary dysfunction affecting all axes. Significant differences were shown in hypofunction of the hypothalamic-pituitary-gonadal -axis, hyperfunction of the hypothalamic-pituitary-adrenal -axis, and higher prolactin levels in the opioid-treated group, compared with the control group. The degree of pain was rated the same in both groups, but the opioid-treated group reported more side effects and lower quality of life.

    Conclusions:

    Long-term treatment of chronic pain with strong opioids causes side effects that can be attributed to hormonal abnormalities caused by opioid-induced inhibition of hypothalamic-pituitary function. Hormone substitution can be indicated to treat symptoms. Decreasing the opioid dose or stopping the opioid treatment can reverse endocrine dysfunction. This needs to be recognized by all practitioners treating chronic pain patients with opioids.

  • 310.
    Rhodin, Annika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    von Ehren, Michaela
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Skottheim, B
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Grönbladh, Alfhild
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Ortiz-Nieto, Francisco
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Raininko, Raili
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Recombinant human growth hormone improves cognitive capacity in a pain patient exposed to chronic opioids2014Ingår i: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 58, nr 6, s. 759-765Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During recent decades, the increasing use of opioids for chronic non-cancer pain has raised concerns regarding tolerance, addiction, and importantly cognitive dysfunction. Current research suggests that the somatotrophic axis could play an important role in cognitive function. Administration of growth hormone (GH) to GH-deficient humans and experimental animals has been shown to result in significant improvements in cognitive capacity. In this report, a patient with cognitive disabilities resulting from chronic treatment with opioids for neuropathic pain received recombinant human growth hormone (rhGH) replacement therapy. A 61-year-old man presented with severe cognitive dysfunction after long-term methadone treatment for intercostal neuralgia and was diagnosed with GH insufficiency by GH releasing hormone-arginine testing. The effect of rhGH replacement therapy on his cognitive capacity and quality of life was investigated. The hippocampal volume was measured using magnetic resonance imaging, and the ratios of the major metabolites were calculated using proton magnetic resonance spectroscopy. Cognitive testing revealed significant improvements in visuospatial cognitive function after rhGH. The hippocampal volume remained unchanged. In the right hippocampus, the N-acetylaspartate/creatine ratio (reflecting nerve cell function) was initially low but increased significantly during rhGH treatment, as did subjective cognitive, physical and emotional functioning. This case report indicates that rhGH replacement therapy could improve cognitive behaviour and well-being, as well as hippocampal metabolism and functioning in opioid-treated patients with chronic pain. The idea that GH could affect brain function and repair disabilities induced by long-term exposure to opioid analgesia is supported.

  • 311.
    Rosenberg, Sofia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Patienters upplevelse av smärta vid venportsinläggning2012Självständigt arbete på avancerad nivå (magisterexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Studiens syfte var att jämföra hur patienter som skall få en subkutan venport

    inlagd och lokalbedövas enligt en lokalbedövningsmodell, skattade smärta under

    ingreppet, samt att undersöka om det fanns något samband mellan preoperativ

    oro och smärta under ingrepp.

    Studien var en deskriptiv, jämförande studie och utfördes med en kvantitativ

    metod, med hjälp av enkäter, där patienterna bland annat fick skatta oro och

    smärta med hjälp av Numeric Rating Scale. Studien genomfördes på patienter,

    vilka skulle få en subkutan venport inlagd. Fyrtiofem patienter deltog i studien.

    Tolv patienter av totalt 45, (27 %), skattade sin oro över tre på NRS. Antal

    patienter vilka skattade sin smärta över tre på de olika momenten var på bedövningsmomentet

    13 patienter, (29 %), på dilatationsmomentet 21 patienter, (47

    %) och på momentet borttagande av operationstejp 13 patienter, (29 %). Ingen

    signifikant skillnad kunde mätas mellan momenten, inget signifikant samband

    mellan oro och smärta kunde mätas och ingen signifikant skillnad i smärta mellan

    inneliggande patienter och polikliniska patienter kunde mätas.

    Patienterna skattade smärtan under ingreppet relativt lågt men nästan hälften

    av patienterna skattade smärtan över tre på dilatationsmomentet. Det finns

    utrymme för verksamheten att göra förbättringar vad gäller smärtlindring.

     

  • 312.
    Rosjo, Helge
    et al.
    Akershus Univ Hosp, Div Med, Sykehusveien 25, N-1478 Lorenskog, Norway;Univ Oslo, Inst Clin Med, Ctr Heart Failure Res, Oslo, Norway.
    Masson, Serge
    IRCCS Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy.
    Caironi, Pietro
    Azienda Osped Univ S Luigi Gonzaga, Dept Anesthesia & Crit Care, Orbassano, Italy;Univ Torino, Dipartimento Oncol, Turin, Italy.
    Stridsberg, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk endokrinologi.
    Magnoli, Michela
    IRCCS Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy.
    Christensen, Geir
    Inst Expt Med Res, Ulleval, Norway;Univ Oslo, Inst Clin Med, Ctr Heart Failure Res, Oslo, Norway.
    Moise, Gabriella
    Osped Citta Sesto San Giovanni, Dept Anesthesia & Crit Care, Sesto San Giovanni, Italy.
    Urbano, Maria Cristina
    Osped Misericordia, Grosseto, Italy.
    Gattinoni, Luciano
    Univ Gottingen, Dept Anesthesiol Emergency & Intens Care Med, Gottingen, Germany.
    Pesenti, Antonio
    Fdn IRCCS Ca Granda Osped Maggiore Policlin, Dipartimento Anestesia, Milan, Italy;Univ Milan, Dipartimento Fisiopatol Med Chirurg & Trapianti, Milan, Italy.
    Latini, Roberto
    IRCCS Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy.
    Omland, Torbjorn
    Akershus Univ Hosp, Div Med, Sykehusveien 25, N-1478 Lorenskog, Norway;Univ Oslo, Inst Clin Med, Ctr Heart Failure Res, Oslo, Norway.
    Prognostic Value of Secretoneurin in Patients With Severe Sepsis and Septic Shock: Data From the Albumin Italian Outcome Sepsis Study2018Ingår i: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 46, nr 5, s. E404-E410Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives: Secretoneurin directly influences cardiomyocyte calcium handling, and circulating secretoneurin levels seem to improve risk prediction in patients with myocardial dysfunction by integrating information on systemic stress, myocardial function, and renal function. Accordingly, in this study, we hypothesized that secretoneurin would improve risk prediction in patients with sepsis and especially in patients with septic shock as these patients are more hemodynamically unstable. Design: Multicenter, interventional randomized clinical trial. Setting: Multicenter, pragmatic, open-label, randomized, prospective clinical trial testing fluid administration with either 20% human albumin and crystalloids or crystalloid solutions alone in patients with severe sepsis or septic shock (The Albumin Italian Outcome Sepsis). Patients or Subjects: In total, 540 patients with septic shock and 418 patients with severe sepsis. Interventions: Either 20% human albumin and crystalloids or crystalloid solutions alone. Measurements and Main Results: We measured secretoneurin on days 1, 2, and 7 after randomization and compared the prognostic value of secretoneurin for ICU and 90-day mortality with established risk indices and cardiac biomarkers in septic shock and severe sepsis. High secretoneurin levels on day 1 were associated with age and serum concentrations of lactate, bilirubin, creatinine, and N-terminal pro-B-type natriuretic peptide. Adjusting for established risk factors and cardiovascular biomarkers, secretoneurin levels on day 1 were associated with ICU (odds ratio, 2.27 [95% CI, 1.05-4.93]; p = 0.04) and 90-day mortality (2.04 [1.02-4.10]; p = 0.04) in patients with septic shock, but not severe sepsis without shock. Secretoneurin levels on day 2 were also associated with ICU (3.11 [1.34-7.20]; p = 0.008) and 90-day mortality (2.69 [1.26-5.78]; p = 0.01) in multivariate regression analyses and improved reclassification in patients with septic shock, as assessed by the net reclassification index. Randomized albumin administration did not influence the associations between secretoneurin and outcomes. Conclusions: Secretoneurin provides early and potent prognostic information in septic patients with cardiovascular instability.

  • 313.
    Rostami, Elham
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Glucose and the injured brain-monitored in the neurointensive care unit2014Ingår i: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 5, artikel-id 91Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Brain has a continuous demand for energy that is met by oxidative metabolism of oxygen and glucose. This demand is compromised in the injured brain and if the inadequate supply persists it will lead to permanent tissue damage. Zero values of cerebral glucose have been associated with infarction and poor neurological outcome. Furthermore, hyperglycemia is common in patients with neurological insults and associated with poor outcome. Intensive insulin therapy (IIT) to control blood glucose has been suggested and used in neurointensive care with conflicting results. This review covers the studies reporting on monitoring of cerebral glucose with microdialysis in patients with traumatic brain injury (TBI), subarachnoid hemorrhage (SAH) and ischemic stroke. Studies investigating IIT are also discussed. Available data suggest that low cerebral glucose in patients with TBI and SAH provides valuable information on development of secondary ischemia and has been correlated with worse outcome. There is also indication that the location of the catheter is important for correlation between plasma and brain glucose. In conclusion considering catheter location, monitoring of brain glucose in the neurointensive care not only provides information on imminent secondary ischemia it also reveals the effect of peripheral treatment on the injured brain.

  • 314. Rostami, Elham
    Microdialysis in neurointensive care.2004Ingår i: Current pharmaceutical design, ISSN 1381-6128, E-ISSN 1873-4286, Vol. 10, nr 18, s. 2145-2152Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Microdialysis is a technique for sampling the chemistry of the interstitial fluid of tissues and organs in animal and man. It is minimally invasive and simple to perform in a clinical setting. Although microdialysis samples essentially all small molecular substances present in the interstitial fluid the use of microdialysis in neurointensive care has focused on markers of ischemia and cell damage. The lactate / pyruvate ratio is a well-known marker of changes in the redox state of cells caused by ischemia Glycerol is an integral component of cell membranes. Loss of energy due to ischemia eventually leads to an influx of calcium and a decomposition of cell membranes, which liberates glycerol into the interstitial fluid. Thus the lactate / pyruvate ratio and glycerol have become the most important markers of ischemia and cell membrane damage. While the primary insult at the site of the accident is beyond our control, secondary insults during intensive care should be avoided by all means. Therefore, the single most important finding from microdialysis studies is the dramatic difference in the vulnerability of the penumbra surrounding a lesion as compared to normal brain tissue allowing early detection of secondary insults after traumatic brain injury as well as the onset of vasospasm after subarachnoid hemorrhage.

  • 315. Rostami, Elham
    Traumatic brain injury in humans and animal models2012Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
  • 316.
    Rostami, Elham
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Engquist, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Enblad, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Imaging of cerebral blood flow in patients with severe traumatic brain injury in the neurointensive care2014Ingår i: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 5, artikel-id 114Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ischemia is a common and deleterious secondary injury following traumatic brain injury (TBI). A great challenge for the treatment of TBI patients in the neurointensive care unit (NICU) is to detect early signs of ischemia in order to prevent further advancement and deterioration of the brain tissue. Today, several imaging techniques are available to monitor cerebral blood flow (CBF) in the injured brain such as positron emission tomography (PET), single-photon emission computed tomography, xenon computed tomography (Xenon-CT), perfusion-weighted magnetic resonance imaging (MRI), and CT perfusion scan. An ideal imaging technique would enable continuous non-invasive measurement of blood flow and metabolism across the whole brain. Unfortunately, no current imaging method meets all these criteria. These techniques offer snapshots of the CBF. MRI may also provide some information about the metabolic state of the brain. PET provides images with high resolution and quantitative measurements of CBF and metabolism; however, it is a complex and costly method limited to few TBI centers. All of these methods except mobile Xenon-CT require transfer of TBI patients to the radiological department. Mobile Xenon-CT emerges as a feasible technique to monitor CBF in the NICU, with lower risk of adverse effects. Promising results have been demonstrated with Xenon-CT in predicting outcome in TBI patients. This review covers available imaging methods used to monitor CBF in patients with severe TBI.

  • 317.
    Rostami, Elham
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Rocksen, David
    Ekberg, Neda R.
    Goiny, Michel
    Ungerstedt, Urban
    Brain metabolism and oxygenation in healthy pigs receiving hypoventilation and hyperoxia2013Ingår i: Respiratory Physiology & Neurobiology, ISSN 1569-9048, E-ISSN 1878-1519, Vol. 189, nr 3, s. 537-542Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Modulation in ventilatory settings is one of the approaches and interventions used to treat and prevent secondary brain damage after traumatic brain injury (TBI). Here we investigate the effect of hyperoxia in combination with hypoventilation on brain oxygenation, metabolism and intracranial pressure. Twelve pigs were divided into three groups; groupl-100% hyperoxia (n=4), group 2-100% hyperoxia and 20% decrease in minute volume (MV) (n=4) and group 3-100% hyperoxia and 50% decrease in MV (n=4). Neither of the ventilator settings affected the lactate/pyruvate ratio significantly. However, there was a significant decrease of brain lactate (2.6+/-1.7 to 1.8+/-1.6 mM) and a rapid and marked increase in brain oxygenation (7.9+/-0.7 to 61.3+/-17.6 mmHg) in group 3. Intracranial pressure (ICP) was not significantly affected in this group, however, the ICP increased significantly in group 2 with 100% hyperoxia plus 20% reduction in minute volume. We conclude that hyperoxia in combination with 50% decrease in MV showed pronounced increase in partial brain oxygen tension (pbrO(2)) and decrease in brain lactate. The ventilatory modification, used in this study should be considered for further investigation as a possible therapeutic intervention for TBI patients.

  • 318.
    Rubertsson, Sten
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Lindgren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Smekal, David
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Östlund, Ollie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Silfverstolpe, Johan
    Lichtveld, Robert A
    Boomars, Rene
    Bruins, Wendy
    Ahlstedt, Björn
    Skoog, Gunnar
    Kastberg, Robert
    Halliwell, David
    Box, Martyn
    Herlitz, Johan
    Karlsten, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Per-Protocol and Pre-Defined population analysis of the LINC study2015Ingår i: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 96, s. 92-99Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: To perform two predefined sub-group analyses within the LINC study and evaluate if the results were supportive of the previous reported intention to treat (ITT) analysis.

    METHODS: Predefined subgroup analyses from the previously published LINC study were performed. The Per-Protocol population (PPP) included the randomized patients included in the ITT-population but excluding those with violated inclusion or exclusion criteria and those that did not get the actual treatment to which the patient was randomized. In the Pre-Defined population (PDP) analyses patients were also excluded if the dispatch time to ambulance arrival at the address exceeded 12min, there was a non-witnessed cardiac arrest, or if it was not possible to determine whether the arrest was witnessed or not, and those cases where LUCAS was not brought to the scene at the first instance.

    RESULTS: After exclusion from the 2589 patients within the ITT-population, the Per-Protocol analysis was performed in 2370 patients and the Pre-Defined analysis within 1133 patients. There was no significant difference in 4-h survival of patients between the mechanical-CPR group and the manual-CPR group in the Per-Protocol population; 279 of 1172 patients (23.8%) versus 281 of 1198 patients (23.5%) (risk difference -0.35%, 95% C.I. -3.1 to 3.8, p=0.85) or in the Pre-Defined population; 176 of 567 patients (31.0%) versus 192 of 566 patients (33.9%) (risk difference -2.88%, 95% C.I. -8.3 to 2.6, p=0.31). There was no difference in any of the second outcome variables analyzed in the Pre-Protocol or Pre-Defined populations.

    CONCLUSIONS: The results from these predefined sub-group analyses of the LINC study population did not show any difference in 4h survival or in secondary outcome variables between patients treated with mechanical-CPR or manual-CPR. This is consistent with the previously published ITT analysis.

  • 319.
    Ruozi, Barbara
    et al.
    Univ Modena & Reggio Emilia, Dept Life Sci, Lab Pharmaceut Technol, I-41125 Modena, Italy..
    Belletti, Daniela
    Univ Modena & Reggio Emilia, Dept Life Sci, Lab Pharmaceut Technol, I-41125 Modena, Italy..
    Sharma, Hari Shanker
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Sharma, Aruna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Muresanu, Dafin F.
    Univ Med & Pharm, Univ Hosp, Dept Clin Neurosci, Cluj Napoca, Romania..
    Moessler, Herbert
    Ever Neuro Pharma, Oberburgau, Austria..
    Forni, Flavio
    Univ Modena & Reggio Emilia, Dept Life Sci, Lab Pharmaceut Technol, I-41125 Modena, Italy..
    Vandelli, Maria Angela
    Univ Modena & Reggio Emilia, Dept Life Sci, Lab Pharmaceut Technol, I-41125 Modena, Italy..
    Tosi, Giovanni
    Univ Modena & Reggio Emilia, Dept Life Sci, Lab Pharmaceut Technol, I-41125 Modena, Italy..
    PLGA Nanoparticles Loaded Cerebrolysin: Studies on Their Preparation and Investigation of the Effect of Storage and Serum Stability with Reference to Traumatic Brain Injury2015Ingår i: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 52, nr 2, s. 899-912Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cerebrolysin is a peptide mixture able to ameliorate symptomatology and delay progression of neurological disorders such as Alzheimer's disease and dementia. The administration of this drug in humans presents several criticisms due to its short half-life, poor stability, and high doses needed to achieve the effect. This paper investigates the potential of polylactic-co-glycolide (PLGA) nanoparticles (NPs) as sustained release systems for iv administration of cerebrolysin in normal and brain injured rats. NPs were prepared by water-in-oil-in-water (w/o/w) double emulsion technique and characterized by light scattering for mean size and zeta potential and by scanning electron microscopy (SEM) for surface morphology. The NPs produced by double sonication under cooling at 60 W for 45 s, 12 mL of 1 % w:v of PVA, and 1:0.6 w:w drug/PLGA ratio (C-NPs4) displayed an adequate loading of drug (24 +/- 1 mg/100 mg of NPs), zeta potential value (-13 mV), and average diameters (ranged from 250 to 330 nm) suitable to iv administration. SEM images suggested that cerebrolysin was molecularly dispersed into matricial systems and partially adhered to the NP surface. A biphasic release with an initial burst effect followed by sustained release over 24 h was observed. Long-term stability both at room and at low temperature of freeze-dried NPs was investigated. To gain deeper insight into NP stability after in vivo administration, the stability of the best NP formulation was also tested in serum. These PLGA NPs loaded with cerebrolysin were able to reduce brain pathology following traumatic brain injury. However, the size, the polydispersivity, and the surface properties of sample were significantly affected by the incubation time and the serum concentration.

  • 320. Sainio, Marko
    et al.
    Hellevuo, Heidi
    Huhtala, Heini
    Hoppu, Sanna
    Eilevstjonn, Joar
    Tenhunen, Jyrki
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Olkkola, Klaus T.
    Effect of mattress and bed frame deflection on real chest compression depth measured with two CPR sensors2014Ingår i: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 85, nr 6, s. 840-843Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim: Implementation of chest compression (CC) feedback devices with a single force and deflection sensor (FDS) may improve the quality of CPR. However, CC depth may be overestimated if the patient is on a compliant surface. We have measured the true CC depth during in-hospital CPR using two FDSs on different bed and mattress types. Methods: This prospective observational study was conducted at Tampere University Hospital between August 2011 and September 2012. During in-hospital CPR one FDS was placed between the rescuer's hand and the patient's chest, with the second attached to the backboard between the patient's back and the mattress. The real CC depth was calculated as the difference between the total depth from upper FDS to lower FDS. Results: Ten cardiac arrests on three different bed and mattress types yielded 10,868 CCs for data analyses. The mean (SD) mattress/bed frame effect was 12.8 (4) mm on a standard hospital bed with a gel mattress, 12.4 (4) mm on an emergency room stretcher with a thin gel mattress and 14.1 (3) mm on an ICU bed with an emptied air mattress. The proportion of CCs with an adequate depth (>= 50 mm) decreased on all mattress types after compensating for the mattress/bed frame effect from 94 to 64%, 98 to 76% and 91 to 17%, in standard hospital bed, emergency room stretcher and ICU bed, respectively (p < 0.001). Conclusion: The use of FDS without real-time correction for deflection may result in CC depth not reaching the recommended depth of 50 mm.

  • 321.
    Sainio, Marko
    et al.
    Tampere Univ Hosp, Dept Intens Care Med, Crit Care Med Res Grp, FI-33521 Tampere, Finland.;Turku Univ Hosp, Dept Emergency Med, Emergency Med Serv, FI-20521 Turku, Finland..
    Hoppu, Sanna
    Tampere Univ Hosp, Dept Intens Care Med, Crit Care Med Res Grp, FI-33521 Tampere, Finland..
    Huhtala, Heini
    Univ Tampere, Sch Hlth Sci, FI-33014 Tampere, Finland..
    Eilevstjonn, Joar
    Laerdal Med AS, N-4002 Stavanger, Norway..
    Olkkola, Klaus T.
    Univ Helsinki, Dept Anaesthesiol Intens Care Emergency Care & Pa, FI-00029 Helsinki, Finland.;Univ Helsinki, Cent Hosp, Meilahti Hosp, FI-00029 Helsinki, Finland..
    Tenhunen, Jyrki
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Tampere Univ Hosp, Dept Intens Care Med, Crit Care Med Res Grp, FI-33521 Tampere, Finland..
    Simultaneous beat-to-beat assessment of arterial blood pressure and quality of cardiopulmonary resuscitation in out-of-hospital and in-hospital settings2015Ingår i: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 96, s. 163-169Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: The current recommendation for depth and rate of chest compression (CC) during cardiopulmonary resuscitation (CPR) is based on limited hemodynamic data recorded during human CPR. We have evaluated the possible association between CC depth and rate and continuously measured arterial blood pressure during adult CPR. Methods: This prospective study included data from 104 patients resuscitated inside or outside hospital. Adequate data on continuously measured invasive arterial blood pressure (BP) and the quality of CPR from a defibrillator capable recording CPR quality parameters was successful in 39 patients. We used logistic regression and mixed effects modeling to identify CC depths and rates associated with systolic blood pressure (SBP) >= 85 mmHg and diastolic blood pressure (DBP) >= 30 mmHg. Results: We analyzed 41,575 compression-BP pairs. The values for blood pressure varied greatly between the patients. SBP varied from 25 to 225 mmHg and DBP from 2 to 59 mmHg. CC rate 100-120/min and CC depth >= 60 mm (without mattress deflection correction) was associated with DBP >= 30 mmHg in both femoral (OR 1.14; 95% CI 1.03, 1.26; p < 0.05) and radial (OR 4.70; 95% CI 3.92, 5.63; p < 0.001) recordings. For any given subject there was a weak upward trend in blood pressure as CC depth increased. Conclusion: Deeper CC does not equal higher BP in every patient. The heterogeneity of patients creates a challenge to find the optimal way to resuscitate patients individually.

  • 322.
    Salah, Heba
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Muscle Wasting in a Rat ICU Model: Underlying Mechanisms and Specific Intervention Strategies2017Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Critical care has undergone several developments in the recent years leading to improved survival. However, acquired muscle weakness in the intensive care unit (ICU) is an important complication that affects severely ill patients and can prolong their ICU stay. Critical illness myopathy (CIM) is the progressive decline in the function and mass of the limb muscles in response to exposure to the ICU condition, while ventilator-induced diaphragm dysfunction (VIDD) is the time dependent decrease in the diaphragm function after the initiation of mechanical ventilation. Since the complete underlying mechanisms for CIM and VIDD are not completely understood, there is a compelling need for research on the mechanisms of CIM and VIDD to develop intervention strategies targeting these mechanisms. The aim of this thesis was to investigate the effects of several intervention strategies and rehabilitation programs on muscle wasting associated with ICU condition. Moreover, muscle specific differences in response to exposure to the ICU condition and different interventions was investigated. Hence, a rodent ICU model was used to address the mechanistic and therapeutic aspects of CIM and VIDD. The effects of heat shock protein 72 co-inducer (HSP72), BGP-15, on diaphragm and soleus for rats exposed to different durations of ICU condition was investigated. We showed that 5 and 10 days treatment with BGP-15 improved diaphragm fiber and myosin function, protected myosin from posttranslational modification, induced HSP72 and improved mitochondrial function. Moreover, BGP-15 treatment for 5 days improved soleus muscle fibers function, improved mitochondrial structure and reduced the levels of some ubiquitin ligases. In addition to BGP-15 treatment, passive mechanical loading of the limb muscles was investigated during exposure to the ICU condition. We showed that mitochondrial dynamics and mitophagy gene expression was affected by Mechanical silencing while mechanical loading counteracted these effects. Our investigation for other pathways that can be involved in muscle wasting associated with ICU condition showed that the Janus kinase 2/ Signal transducer and activator of transcription 3 (JAK2/STAT3) pathway is differentially activated in plantaris, intercostals and diaphragm. However, further studies are required with JAK2/STAT3 inhibitors to fully examine the role of this pathway in the pathogenesis of CIM and VIDD prior to translation to clinical research.

    Delarbeten
    1. The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction
    Öppna denna publikation i ny flik eller fönster >>The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction
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    2016 (Engelska)Ingår i: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 8, nr 350, artikel-id 350ra103Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Ventilation-induced diaphragm dysfunction (VIDD) is a marked decline in diaphragm function in response to mechanical ventilation, which has negative consequences for individual patients' quality of life and for the health care system, but specific treatment strategies are still lacking. We used an experimental intensive care unit (ICU) model, allowing time-resolved studies of diaphragm structure and function in response to long-term mechanical ventilation and the effects of a pharmacological intervention (the chaperone co-inducer BGP-15). The marked loss of diaphragm muscle fiber function in response to mechanical ventilation was caused by post-translational modifications (PTMs) of myosin. In a rat model, 10 days of BGP-15 treatment greatly improved diaphragm muscle fiber function (by about 100%), although it did not reverse diaphragm atrophy. The treatment also provided protection from myosin PTMs associated with HSP72 induction and PARP-1 inhibition, resulting in improvement of mitochondrial function and content. Thus, BGP-15 may offer an intervention strategy for reducing VIDD in mechanically ventilated ICU patients.

    Nationell ämneskategori
    Cell- och molekylärbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-303060 (URN)10.1126/scitranslmed.aaf7099 (DOI)000380780000005 ()
    Externt samarbete:
    Forskningsfinansiär
    Stiftelsen för internationalisering av högre utbildning och forskning (STINT)Vetenskapsrådet, 8651; 4423; 4870; 3074EU, Europeiska forskningsrådet, CT-223756; COST CM1001Karolinska Institutets ForskningsstiftelseStockholms läns landstingNovo Nordisk, 100193
    Tillgänglig från: 2016-09-14 Skapad: 2016-09-14 Senast uppdaterad: 2018-01-10Bibliografiskt granskad
    2. Does chaperone co-inducer BGP-15 mitigate the contractile dysfunction of the soleus muscle in a rat ICU model?
    Öppna denna publikation i ny flik eller fönster >>Does chaperone co-inducer BGP-15 mitigate the contractile dysfunction of the soleus muscle in a rat ICU model?
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    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Anestesi och intensivvård
    Identifikatorer
    urn:nbn:se:uu:diva-328594 (URN)
    Tillgänglig från: 2017-08-28 Skapad: 2017-08-28 Senast uppdaterad: 2017-08-31
    3. Mechano-signalling pathways in an experimental intensive critical illness myopathy model
    Öppna denna publikation i ny flik eller fönster >>Mechano-signalling pathways in an experimental intensive critical illness myopathy model
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    2016 (Engelska)Ingår i: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793Artikel i tidskrift (Refereegranskat) Published
    Nationell ämneskategori
    Klinisk medicin
    Identifikatorer
    urn:nbn:se:uu:diva-322821 (URN)
    Tillgänglig från: 2017-08-21 Skapad: 2017-08-21 Senast uppdaterad: 2017-08-31
    4. Muscle specific differences in activation of the Janus kinase 2/ Signal Transducer and Activator of Transcription 3 following long-term mechanical ventilation and immobilization in rats
    Öppna denna publikation i ny flik eller fönster >>Muscle specific differences in activation of the Janus kinase 2/ Signal Transducer and Activator of Transcription 3 following long-term mechanical ventilation and immobilization in rats
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    (Engelska)Ingår i: Artikel i tidskrift (Refereegranskat) Submitted
    Nationell ämneskategori
    Anestesi och intensivvård
    Identifikatorer
    urn:nbn:se:uu:diva-328592 (URN)
    Tillgänglig från: 2017-08-28 Skapad: 2017-08-28 Senast uppdaterad: 2017-08-31
  • 323.
    salah, heba
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Fury, Wen
    Gromada, Jesper
    Bai, Yu
    Tchkonia, Tamar
    Kirkland, James
    Larsson, Lars
    Muscle specific differences in activation of the Janus kinase 2/ Signal Transducer and Activator of Transcription 3 following long-term mechanical ventilation and immobilization in ratsIngår i: Artikel i tidskrift (Refereegranskat)
  • 324. Sander, C. Hallsjo
    et al.
    Hallbaeck, M.
    Sipmann, Fernando Suarez
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet.
    Wallin, M.
    Oldner, A.
    Bjorne, H.
    A novel continuous capnodynamic method for cardiac output assessment in a porcine model of lung lavage2015Ingår i: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 59, nr 8, s. 1022-1031Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BackgroundWe have evaluated a new method for continuous monitoring of effective pulmonary blood flow (COEPBF), i.e. cardiac output (CO) minus intra-pulmonary shunt, during mechanical ventilation. The method has shown good trending ability during severe hemodynamic challenges in a porcine model with intact lungs. In this study, we further evaluate the COEPBF method in a model of lung lavage. MethodsCO(EPBF) was compared to a reference method for CO during hemodynamic and PEEP alterations, 5 and 12cmH(2)O, before and after repeated lung lavages in 10 anaesthetised pigs. Bland-Altman, four-quadrant and polar plot methodologies were used to determine agreement and trending ability. ResultsAfter lung lavage at PEEP 5cmH(2)O, the ratio of arterial oxygen partial pressure related to inspired fraction of oxygen significantly decreased. The mean difference (limits of agreement) between methods changed from 0.2 (-1.1 to 1.5) to -0.9 (-3.6 to 1.9)l/min and percentage error increased from 34% to 70%. Trending ability remained good according to the four-quadrant plot (concordance rate 94%), whereas mean angular bias increased from 4 degrees to -16 degrees when using the polar plot methodology. ConclusionBoth agreement and precision of COEPBF were impaired in relation to CO when the shunt fraction was increased after lavage at PEEP 5cmH(2)O. However, trending ability remained good as assessed by the four-quadrant plot, whereas the mean polar angle, calculated by the polar plot, was wide.

  • 325.
    Sander, Caroline Hällsjö
    et al.
    Karolinska Univ Hosp, Dept Anesthesiol Surg Serv & Intens Care Med, S-17176 Stockholm, Sweden.;Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Lönnqvist, Per-Arne
    Karolinska Univ Hosp, Astrid Lindgrens Childrens Hosp, Paediat Anesthesia & Intens Care, Stockholm, Sweden..
    Hallbäck, Magnus
    Maquet Crit Care AB, Solna, Sweden..
    Suarez Sipmann, Fernando
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet. Inst Carlos III, CIBERES, CIBER Enfermedades Resp, Madrid, Spain..
    Wallin, Mats
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.;Maquet Crit Care AB, Solna, Sweden..
    Oldner, Anders
    Karolinska Univ Hosp, Dept Anesthesiol Surg Serv & Intens Care Med, S-17176 Stockholm, Sweden.;Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Björne, Håkan
    Karolinska Univ Hosp, Dept Anesthesiol Surg Serv & Intens Care Med, S-17176 Stockholm, Sweden.;Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Capnodynamic assessment of effective lung volume during cardiac output manipulations in a porcine model2016Ingår i: Journal of clinical monitoring and computing, ISSN 1387-1307, E-ISSN 1573-2614, Vol. 30, nr 6, s. 761-769Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A capnodynamic calculation of effective pulmonary blood flow includes a lung volume factor (ELV) that has to be estimated to solve the mathematical equation. In previous studies ELV correlated to reference methods for functional residual capacity (FRC). The aim was to evaluate the stability of ELV during significant manipulations of cardiac output (CO) and assess the agreement for absolute values and trending capacity during PEEP changes at different lung conditions. Ten pigs were included. Alterations of alveolar carbon dioxide were induced by cyclic reoccurring inspiratory holds. The Sulphur hexafluoride technique for FRC measurements was used as reference. Cardiac output was altered by preload reduction and inotropic stimulation at PEEP 5 and 12 cmH(2)O both in normal lung conditions and after repeated lung lavages. ELV at baseline PEEP 5 was [mean (SD)], 810 (163) mL and decreased to 400 (42) mL after lavage. ELV was not significantly affected by CO alterations within the same PEEP level. In relation to FRC the overall bias (limits of agreement) was -35 (-271 to 201) mL, and percentage error 36 %. A small difference between ELV and FRC was seen at PEEP 5 cmH(2)O before lavage and at PEEP 12 cmH(2)O after lavage. ELV trending capability between PEEP steps, showed a concordance rate of 100 %. ELV was closely related to FRC and remained stable during significant changes in CO. The trending capability was excellent both before and after surfactant depletion.

  • 326.
    Santos, Arnoldo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet.
    Hemodynamic Effects of Lung Function Optimization in Experimental Acute Respiratory Distress Syndrome2018Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Acute Respiratory Distress Syndrome (ARDS) is a severe pulmonary inflammation affecting thousands of patients every year in Sweden and has a mortality of 30-50%. Mechanical ventilation (MV) is usually necessary, but could per se augment the inflammation and contribute to mortality. MV strategies protective for the lung parenchyma have been developed but without considering the pulmonary circulation or the right heart ventricle (RV) that also are affected in ARDS. MV should ideally be optimized to protect both the lung parenchyma and the RV/pulmonary vasculature. My hypothesis was that MV that prevents alveolar collapse and overdistension, i.e., the “open lung approach (OLA)” would be optimal. The aims of this project were 1) to carefully describe the pulmonary vascular mechanics (PVM) in ARDS compared with healthy lungs, 2) to assess how different ventilatory methods influence PVM, and 3) to propose a ventilatory method that protects both lung parenchyma and circulation.

    In a porcine model, high fidelity pressure and flow sensors were applied directly on the main pulmonary artery to evaluate steady and oscillatory components of PVM.  In this way a complete PVM description was obtained for normal and injured lungs at different MV. In particular, the effects of OLA were compared with standard MV and, in addition, with MV methods where overdistension or collapse were present.

    Results: 1) Compared with collapse or overdistension, OLA provided better PVM. 2) The effects on PVM of OLA and the standard protective MV were similar. 3) Early ARDS augmented the effects of pulse wave reflection on PVM leading to a situation in which the RV had to increase its work to maintain adequate blood flow. Thus, a part of this work was wasted by the effect of wave reflections, making the RV/pulmonary vasculature inefficient. 4) Tidal breathing affected PVM cyclically and this effect was enhanced in ARDS compared with healthy lungs.

    In conclusion, ARDS and different ventilatory methods, as well as tidal ventilation per se, affected PVM. OLA improved PVM compared with other MV settings where significant collapse and overdistension were allowed. However, OLA was not superior to standard protective MV.

    Delarbeten
    1. The Open Lung Approach Improves Pulmonary Vascular Mechanics in an Experimental Model of Acute Respiratory Distress Syndrome
    Öppna denna publikation i ny flik eller fönster >>The Open Lung Approach Improves Pulmonary Vascular Mechanics in an Experimental Model of Acute Respiratory Distress Syndrome
    Visa övriga...
    2017 (Engelska)Ingår i: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 45, nr 3, s. e298-e305Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    OBJECTIVE: To test whether positive end-expiratory pressure consistent with an open lung approach improves pulmonary vascular mechanics compared with higher or lower positive end-expiratory pressures in experimental acute respiratory distress syndrome.

    DESIGN: Experimental study.

    SETTING: Animal research laboratory.

    SUBJECTS: Ten pigs, 35 ± 5.2 kg.

    INTERVENTIONS: Acute respiratory distress syndrome was induced combining saline lung lavages with injurious mechanical ventilation. The positive end-expiratory pressure level resulting in highest compliance during a decremental positive end-expiratory pressure trial after lung recruitment was determined. Thereafter, three positive end-expiratory pressure levels were applied in a random order: hyperinflation, 6 cm H2O above; open lung approach, 2 cm H2O above; and collapse, 6 cm H2O below the highest compliance level. High fidelity pressure and flow sensors were placed at the main pulmonary artery for measuring pulmonary artery resistance (Z0), effective arterial elastance, compliance, and reflected pressure waves.

    MEASUREMENTS AND MAIN RESULTS: After inducing acute respiratory distress syndrome, Z0 and effective arterial elastance increased (from 218 ± 94 to 444 ± 115 dyn.s.cm and from 0.27 ± 0.14 to 0.62 ± 0.22 mm Hg/mL, respectively; p < 0.001), vascular compliance decreased (from 2.76 ± 0.86 to 1.48 ± 0.32 mL/mm Hg; p = 0.003), and reflected waves arrived earlier (0.23 ± 0.07 vs 0.14 ± 0.05, arbitrary unit; p = 0.002) compared with baseline. Comparing the three positive end-expiratory pressure levels, open lung approach resulted in the lowest: 1) Z0 (297 ± 83 vs 378 ± 79 dyn.s.cm, p = 0.033, and vs 450 ± 119 dyn.s.cm, p = 0.002); 2) effective arterial elastance (0.37 ± 0.08 vs 0.50 ± 0.15 mm Hg/mL, p = 0.04, and vs 0.61 ± 0.12 mm Hg/mL, p < 0.001), and 3) reflection coefficient (0.35 ± 0.17 vs 0.48 ± 0.10, p = 0.024, and vs 0.53 ± 0.19, p = 0.005), comparisons with hyperinflation and collapse, respectively.

    CONCLUSIONS: In this experimental setting, positive end-expiratory pressure consistent with the open lung approach resulted in the best pulmonary vascular mechanics compared with higher or lower positive end-expiratory pressure settings.

    Nyckelord
    Fluid responsiveness, Spontaneous breathing, Head-up tilt, Pulse pressure variation, Stroke volume variation, Systolic pressure variation
    Nationell ämneskategori
    Anestesi och intensivvård
    Identifikatorer
    urn:nbn:se:uu:diva-307915 (URN)10.1097/CCM.0000000000002082 (DOI)27763913 (PubMedID)
    Tillgänglig från: 2016-11-22 Skapad: 2016-11-22 Senast uppdaterad: 2018-12-05Bibliografiskt granskad
    2. Effects on Pulmonary Vascular Mechanics of Two Different Lung-Protective Ventilation Strategies in an Experimental Model of Acute Respiratory Distress Syndrome
    Öppna denna publikation i ny flik eller fönster >>Effects on Pulmonary Vascular Mechanics of Two Different Lung-Protective Ventilation Strategies in an Experimental Model of Acute Respiratory Distress Syndrome
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    2017 (Engelska)Ingår i: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 45, nr 11, s. e1157-e1164Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    OBJECTIVES: To compare the effects of two lung-protective ventilation strategies on pulmonary vascular mechanics in early acute respiratory distress syndrome.

    DESIGN: Experimental study.

    SETTING: University animal research laboratory.

    SUBJECTS: Twelve pigs (30.8 ± 2.5 kg).

    INTERVENTIONS: Acute respiratory distress syndrome was induced by repeated lung lavages and injurious mechanical ventilation. Thereafter, animals were randomized to 4 hours ventilation according to the Acute Respiratory Distress Syndrome Network protocol or to an open lung approach strategy. Pressure and flow sensors placed at the pulmonary artery trunk allowed continuous assessment of pulmonary artery resistance, effective elastance, compliance, and reflected pressure waves. Respiratory mechanics and gas exchange data were collected.

    MEASUREMENTS AND MAIN RESULTS: Acute respiratory distress syndrome led to pulmonary vascular mechanics deterioration. Four hours after randomization, pulmonary vascular mechanics was similar in Acute Respiratory Distress Syndrome Network and open lung approach: resistance (578 ± 252 vs 626 ± 153 dyn.s/cm; p = 0.714), effective elastance, (0.63 ± 0.22 vs 0.58 ± 0.17 mm Hg/mL; p = 0.710), compliance (1.19 ± 0.8 vs 1.50 ± 0.27 mL/mm Hg; p = 0.437), and reflection index (0.36 ± 0.04 vs 0.34 ± 0.09; p = 0.680). Open lung approach as compared to Acute Respiratory Distress Syndrome Network was associated with improved dynamic respiratory compliance (17.3 ± 2.6 vs 10.5 ± 1.3 mL/cm H2O; p < 0.001), driving pressure (9.6 ± 1.3 vs 19.3 ± 2.7 cm H2O; p < 0.001), and venous admixture (0.05 ± 0.01 vs 0.22 ± 0.03, p < 0.001) and lower mean pulmonary artery pressure (26 ± 3 vs 34 ± 7 mm Hg; p = 0.045) despite of using a higher positive end-expiratory pressure (17.4 ± 0.7 vs 9.5 ± 2.4 cm H2O; p < 0.001). Cardiac index, however, was lower in open lung approach (1.42 ± 0.16 vs 2.27 ± 0.48 L/min; p = 0.005).

    CONCLUSIONS: In this experimental model, Acute Respiratory Distress Syndrome Network and open lung approach affected pulmonary vascular mechanics similarly. The use of higher positive end-expiratory pressures in the open lung approach strategy did not worsen pulmonary vascular mechanics, improved lung mechanics, and gas exchange but at the expense of a lower cardiac index.

    Nationell ämneskategori
    Lungmedicin och allergi
    Identifikatorer
    urn:nbn:se:uu:diva-334177 (URN)10.1097/CCM.0000000000002701 (DOI)000417107000007 ()28872540 (PubMedID)
    Forskningsfinansiär
    Vetenskapsrådet, K2015-99X-22731-01-4Hjärt-LungfondenEU, FP7, Sjunde ramprogrammet, 291820
    Tillgänglig från: 2017-11-21 Skapad: 2017-11-21 Senast uppdaterad: 2018-03-09Bibliografiskt granskad
    3. Acute Respiratory Distress Syndrome deteriorates pulmonary vascular efficiency and increases cardiac energy wasting in a porcine model.
    Öppna denna publikation i ny flik eller fönster >>Acute Respiratory Distress Syndrome deteriorates pulmonary vascular efficiency and increases cardiac energy wasting in a porcine model.
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    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Background: Right ventricle failure worsen outcomes in acute respiratory distress syndrome (ARDS). However, the pathophysiology of right ventricle failure and vascular dysfunction in ARDS is not completely understood. In this study we aim to evaluate the effects of early ARDS on pulmonary vascular efficiency for transmission of flow and pressure in an experimental animal model.  

    Methods: ARDS was induced in 10 pigs (32.5±4.3 kg) combining saline lung-lavages with injurious mechanical ventilation. Pressure and flow sensors were placed at the main pulmonary artery for pulmonary vascular function evaluation, including arterial load parameters, cardiac power and energy transmission ratio.

    Results: Compared to baseline healthy conditions, ARDS increased pulmonary vascular resistance (199±62 versus 524±154 dyn.s.cm-5, p <0.001), effective arterial elastance (0.65±0.26 versus 1.13±0.36 mmHg/ml, p <0.001) and total hydraulic power (195±60 to 266±87 mW, p =0.015), decreased pulmonary arterial compliance (from 2.34±0.86 to 1.00±0.25 ml/mmHg, p <0.001) and energy transmission ratio (68±15 versus 55±14%, p = 0.014), whereas oscillatory power did not change (17±6 versus 16±6%, p = 0.359).

    Conclusions: In this experimental ARDS model, an increase in pulmonary arterial load was associated with a higher cardiac power and a decrease in the energy transmission ratio. These results suggest that right ventricle energy consumption is increased and part of this energy is wasted in pulmonary circulation worsening pulmonary vascular efficiency in the early course of ARDS. These findings may help to explain primary mechanisms leading to right ventricle dysfunction in ARDS.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-337402 (URN)
    Tillgänglig från: 2017-12-25 Skapad: 2017-12-25 Senast uppdaterad: 2018-01-12
    4. Cyclic Changes of Pulmonary Vascular Mechanics During mechanical ventilation in acute respiratory distress syndrome. A porcine experimental model.
    Öppna denna publikation i ny flik eller fönster >>Cyclic Changes of Pulmonary Vascular Mechanics During mechanical ventilation in acute respiratory distress syndrome. A porcine experimental model.
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    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Objective: To test the hypothesis that acute respiratory syndrome (ARDS) worsens pulmonary vascular mechanics during the respiratory cycle under mechanical ventilation in an animal model.  

    Design: Experimental study.

    Setting: Animal research laboratory.

    Subjects: 6 pigs, 31.7 ± 5.4 kg.

    Interventions: ARDS was induced by combining saline lung-lavages with injurious mechanical ventilation. Pressure and flow sensors were placed at the main pulmonary artery (PA) and signals were collected simultaneously with airway pressure and flow. Pulmonary vascular mechanics and cardiac function parameters were calculates beat by beat during 2-3 minutes. We designed a novel method to quantify how the calculated variables behave during the whole respiratory cycle, i.e., during expiration and during inspiration. Results are expressed as the mean value during the corresponding phase of the respiratory cycle.

    Measurements and Main Results: During the whole respiratory cycle and at expiration ARDS decreased SV and arterial compliance while increased mean and pulse PA pressure, effective arterial elastance and Dp/Dtmax when compared to baseline. At baseline and after ARDS, inspiration in positive pressure ventilation caused a decrease in stroke volume (-3±1ml, p<0.001 and -3±1ml, p<0.001), pulmonary mean (-0.5±0.3, p=0.007 and -0.7±0.3mmHg, p=0.002) and pulse pressure (-0.8±0.4, p=0.003 and -1,5±0.7mmHg, p=0.003) and compliance (-0.07±0.04 and -0.04±0.00ml/mmHg, p<0.001) and an increase in resistance (34±13, p=0.001 and 50±32dyn.s.cm-5, p=0.012) and in effective arterial elastance (0.04±0.01, p=0.001 and 0.08±0.04mmHg/ml, p=0.003). ARDS produced a more pronounced inspiratory increase in effective arterial elastance (p=0.041) when compared to baseline. Positive pressure ventilation caused a decrease in Dp/Dtmax at baseline (-15±9mmHg/s, p=0.010) but this was not significant during ARDS (-27±28mmHg/s, p=0.068).  

    Conclusions: We found in this experimental model that MV induced tidal increase in arterial load and that this effect was higher during ARDS. This finding if transferred to patients, might partly explain the high rate of right heart failure clinically in ARDS.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-337405 (URN)
    Tillgänglig från: 2017-12-25 Skapad: 2017-12-25 Senast uppdaterad: 2018-01-12
  • 327.
    Santos, Arnoldo
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet.
    Lucchetta, Luca
    Monge-Garcia, M Ignacio
    Batista Borges, João
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet.
    Tusman, Gerardo
    Hedenstierna, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Suarez-Sipmann, Fernando
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet.
    The Open Lung Approach Improves Pulmonary Vascular Mechanics in an Experimental Model of Acute Respiratory Distress Syndrome2017Ingår i: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 45, nr 3, s. e298-e305Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: To test whether positive end-expiratory pressure consistent with an open lung approach improves pulmonary vascular mechanics compared with higher or lower positive end-expiratory pressures in experimental acute respiratory distress syndrome.

    DESIGN: Experimental study.

    SETTING: Animal research laboratory.

    SUBJECTS: Ten pigs, 35 ± 5.2 kg.

    INTERVENTIONS: Acute respiratory distress syndrome was induced combining saline lung lavages with injurious mechanical ventilation. The positive end-expiratory pressure level resulting in highest compliance during a decremental positive end-expiratory pressure trial after lung recruitment was determined. Thereafter, three positive end-expiratory pressure levels were applied in a random order: hyperinflation, 6 cm H2O above; open lung approach, 2 cm H2O above; and collapse, 6 cm H2O below the highest compliance level. High fidelity pressure and flow sensors were placed at the main pulmonary artery for measuring pulmonary artery resistance (Z0), effective arterial elastance, compliance, and reflected pressure waves.

    MEASUREMENTS AND MAIN RESULTS: After inducing acute respiratory distress syndrome, Z0 and effective arterial elastance increased (from 218 ± 94 to 444 ± 115 dyn.s.cm and from 0.27 ± 0.14 to 0.62 ± 0.22 mm Hg/mL, respectively; p < 0.001), vascular compliance decreased (from 2.76 ± 0.86 to 1.48 ± 0.32 mL/mm Hg; p = 0.003), and reflected waves arrived earlier (0.23 ± 0.07 vs 0.14 ± 0.05, arbitrary unit; p = 0.002) compared with baseline. Comparing the three positive end-expiratory pressure levels, open lung approach resulted in the lowest: 1) Z0 (297 ± 83 vs 378 ± 79 dyn.s.cm, p = 0.033, and vs 450 ± 119 dyn.s.cm, p = 0.002); 2) effective arterial elastance (0.37 ± 0.08 vs 0.50 ± 0.15 mm Hg/mL, p = 0.04, and vs 0.61 ± 0.12 mm Hg/mL, p < 0.001), and 3) reflection coefficient (0.35 ± 0.17 vs 0.48 ± 0.10, p = 0.024, and vs 0.53 ± 0.19, p = 0.005), comparisons with hyperinflation and collapse, respectively.

    CONCLUSIONS: In this experimental setting, positive end-expiratory pressure consistent with the open lung approach resulted in the best pulmonary vascular mechanics compared with higher or lower positive end-expiratory pressure settings.

  • 328.
    Scaramuzzo, Gaetano
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet. Univ Ferrara, Dept Morphol Surg & Expt Med, Ferrara, Italy.
    Broche, Ludovic
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet. European Synchrotron Radiat Facil, Grenoble, France;Grenoble Alpes Univ, Synchrotron Radiat Biomed STROBE Lab, INSERM UA7, Amiens, France.
    Pellegrini, Mariangela
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Porra, Liisa
    Univ Helsinki, Fac Math & Nat Sci, Dept Phys, Helsinki, Finland;Univ Helsinki, Cent Hosp, Helsinki, Finland.
    Derosa, Savino
    Univ Bari Aldo Moro, Dept Emergency & Organ Transplant, Bari, Italy.
    Tannoia, Angela Principia
    Univ Bari Aldo Moro, Dept Emergency & Organ Transplant, Bari, Italy.
    Marzullo, Andrea
    Univ Bari Aldo Moro, Dept Emergency & Organ Transplant, Bari, Italy.
    Batista Borges, João
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet. Kings Coll London, Fac Sci & Med, Ctr Human & Appl Physiol Sci, London, England.
    Bayat, Sam
    Grenoble Alpes Univ, Synchrotron Radiat Biomed STROBE Lab, INSERM UA7, Amiens, France.
    Bravin, Alberto
    European Synchrotron Radiat Facil, Grenoble, France.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet.
    Perchiazzi, Gaetano
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Regional Behavior of Airspaces During Positive Pressure Reduction Assessed by Synchrotron Radiation Computed Tomography2019Ingår i: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 10, artikel-id 719Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: The mechanisms of lung inflation and deflation are only partially known. Ventilatory strategies to support lung function rely upon the idea that lung alveoli are isotropic balloons that progressively inflate or deflate and that lung pressure/volume curves derive only by the interplay of critical opening pressures, critical closing pressures, lung history, and position of alveoli inside the lung. This notion has been recently challenged by subpleural microscopy, magnetic resonance, and computed tomography (CT). Phase-contrast synchrotron radiation CT (PC-SRCT) can yield in vivo images at resolutions higher than conventional CT.

    Objectives: We aimed to assess the numerosity (ASden) and the extension of the surface of airspaces (ASext) in healthy conditions at different volumes, during stepwise lung deflation, in concentric regions of the lung. Methods: The study was conducted in seven anesthetized New Zealand rabbits. They underwent PC-SRCT scans (resolution of 47.7 mu m) of the lung at five decreasing positive end expiratory pressure (PEEP) levels of 12, 9, 6, 3, and 0 cmH(2)O during end-expiratory holds. Three concentric regions of interest (ROIs) of the lung were studied: subpleural, mantellar, and core. The images were enhanced by phase contrast algorithms. ASden and ASext were computed by using the Image Processing Toolbox for MatLab. Statistical tests were used to assess any significant difference determined by PEEP or ROI on ASden and ASext.

    Results: When reducing PEEP, in each ROI the ASden significantly decreased. Conversely, ASext variation was not significant except for the core ROI. In the latter, the angular coefficient of the regression line was significantly low.

    Conclusion: The main mechanism behind the decrease in lung volume at PEEP reduction is derecruitment. In our study involving lung regions laying on isogravitational planes and thus equally influenced by gravitational forces, airspace numerosity and extension of surface depend on the local mechanical properties of the lung.

  • 329.
    Schell, Carl Otto
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Castegren, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Lugazia, Edwin
    Blixt, Jonas
    Mulungu, Moses
    Konrad, David
    Baker, Tim
    Severely deranged vital signs as triggers for acute treatment modifications on an intensive care unit in a low-income country2015Ingår i: BMC Research Notes, ISSN 1756-0500, E-ISSN 1756-0500, Vol. 8, artikel-id 313Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Critical care saves lives of the young with reversible disease. Little is known about critical care services in low-income countries. In a setting with a shortage of doctors the actions of the nurse bedside are likely to have a major impact on the outcome of critically ill patients with rapidly changing physiology. Identification of severely deranged vital signs and subsequent treatment modifications are the basis of modern routines in critical care, for example goal directed therapy and rapid response teams. This study assesses how often severely deranged vital signs trigger an acute treatment modification on an Intensive Care Unit (ICU) in Tanzania.

    METHODS: A medical records based, observational study. Vital signs (conscious level, respiratory rate, oxygen saturation, heart rate and systolic blood pressure) were collected as repeated point prevalences three times per day in a 1-month period for all adult patients on the ICU. Severely deranged vital signs were identified and treatment modifications within 1 h were noted.

    RESULTS: Of 615 vital signs studied, 126 (18%) were severely deranged. An acute treatment modification was in total indicated in 53 situations and was carried out three times (6%) (2/32 for hypotension, 0/8 for tachypnoea, 1/6 for tachycardia, 0/4 for unconsciousness and 0/3 for hypoxia).

    CONCLUSIONS: This study suggests that severely deranged vital signs are common and infrequently lead to acute treatment modifications on an ICU in a low-income country. There may be potential to improve outcome if nurses are guided to administer acute treatment modifications by using a vital sign directed approach. A prospective study of a vital sign directed therapy protocol is underway.

  • 330.
    Schell, Carl Otto
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Karolinska Inst, Dept Publ Hlth Sci, Global Hlth Hlth Syst & Policy, Stockholm, Sweden.
    Warnberg, Martin Gerdin
    Karolinska Inst, Dept Publ Hlth Sci, Global Hlth Hlth Syst & Policy, Stockholm, Sweden.
    Hvarfner, Anna
    Uppsala Univ, Fac Med, Uppsala, Sweden.
    Hoog, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Baker, Ulrika
    Karolinska Inst, Dept Publ Hlth Sci, Global Hlth Hlth Syst & Policy, Stockholm, Sweden;Coll Med, Blantyre, Malawi.
    Castegren, Markus
    Karolinska Univ Hosp, Perioperat Med & Intens Care PMI, Stockholm, Sweden.
    Baker, Tim
    Karolinska Inst, Dept Publ Hlth Sci, Global Hlth Hlth Syst & Policy, Stockholm, Sweden;Coll Med, Blantyre, Malawi;Karolinska Univ Hosp, Perioperat Med & Intens Care PMI, Stockholm, Sweden.
    The global need for essential emergency and critical care2018Ingår i: Critical Care, ISSN 1364-8535, E-ISSN 1466-609X, Vol. 22, artikel-id 284Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Critical illness results in millions of deaths each year. Care for those with critical illness is often neglected due to a lack of prioritisation, co-ordination, and coverage of timely identification and basic life-saving treatments. To improve care, we propose a new focus on essential emergency and critical care (EECC)care that all critically ill patients should receive in all hospitals in the world. Essential emergency and critical care should be part of universal health coverage, is appropriate for all countries in the world, and is intended for patients irrespective of age, gender, underlying diagnosis, medical specialty, or location in the hospital. Essential emergency and critical care is pragmatic and low-cost and has the potential to improve care and substantially reduce preventable mortality.

  • 331. Schilling, Thomas
    et al.
    Kozian, Alf
    Huth, Christof
    Bühling, Frank
    Kretzschmar, Moritz
    Welte, Tobias
    Hachenberg, Thomas
    The pulmonary immune effects of mechanical ventilation in patients undergoing thoracic surgery2005Ingår i: Anesthesia and Analgesia, ISSN 0003-2999, E-ISSN 1526-7598, Vol. 101, nr 4, s. 957-965Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mechanical ventilation (MV) may induce an inflammatory alveolar response. One-lung ventilation (OLV) with tidal volumes (Vt) as used during two-lung ventilation is a suggested algorithm but may impose mechanical stress of the dependent lung and potentially aggravate alveolar mediator release. We studied whether ventilation with different Vt modifies pulmonary immune function, hemodynamics, and gas exchange. Thirty-two patients undergoing open thoracic surgery were randomized to receive either MV with Vt = 10 mL/kg (n = 16) or Vt = 5 mL/kg (n = 16) adjusted to normal Pa(CO2) during and after OLV. Fiberoptic bronchoalveolar lavage of the ventilated lung was performed, and cells, protein, tumor necrosis factor (TNF)-alpha, interleukin (IL)-8, soluble intercellular adhesion molecule (sICAM)-1, IL-10, and elastase were determined in the bronchoalveolar lavage. Data were analyzed by parametric or nonparametric tests, as indicated. In all patients, an increase of proinflammatory variables was found. The time courses of intra-alveolar cells, protein, albumin, IL-8, elastase, and IL-10 did not differ between the groups after OLV and postoperatively. TNF-alpha (8.4 versus 5.0 microg/mL) and sICAM-1 (52.7 versus 27.5 microg/mL) concentrations were significantly smaller after OLV with Vt = 5 mL/kg. These results indicate that MV may induce epithelial damage and a proinflammatory response in the ventilated lung. Reduction of tidal volume during OLV may reduce alveolar concentrations of TNF-alpha and of sICAM-1. IMPLICATIONS: Reductions of tidal volume, with subsequently decreased peak airway pressures, may reduce some alveolar inflammatory responses seen with mechanical ventilation.

  • 332. Schneider, Antoine G
    et al.
    Lipcsey, Miklós
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Bailey, Michael
    Pilcher, David V
    Bellomo, Rinaldo
    Simple translational equations to compare illness severity scores in intensive care trials2013Ingår i: Journal of critical care, ISSN 0883-9441, E-ISSN 1557-8615, Vol. 28, nr 5, s. 885.e1-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE:

    Comparison of illness severity for intensive care unit populations assessed according to different scoring systems should increase our ability to compare and meta-analyze past and future trials but is currently not possible. Accordingly, we aimed to establish a methodology to translate illness severity scores obtained from one system into another.

    MATERIALS AND METHODS:

    Using the Australian and New-Zealand intensive care adult patient database, we obtained simultaneous admission Acute Physiology and Chronic Health Evaluation (APACHE) II and APACHE III scores and Simplified Acute Physiology Score (SAPS) II in 634428 patients admitted to 153 units between 2001 and 2010. We applied linear regression analyses to create models enabling translation of one score into another. Sensitivity analyses were performed after removal of diagnostic categories excluded from the original APACHE database, after matching for similar risk of death, after splitting data according to country of origin (Australia or New Zealand) and after splitting admissions occurring before or after 2006.

    RESULTS:

    The translational models were APACHE III = 3.08 × APACHE II + 5.75; APACHE III = 1.47 × SAPS II + 8.6; and APACHE II = 0.36 × SAPS II + 4.4. The area under the receiver operating curve for mortality prediction was 0.853 (95% confidence interval, 0.851-0.855) for the "APACHE II derived APACHE III" score and 0.854 (0.852-0.855) for the "SAPS II derived APACHE III" vs 0.854 (0.852-0.855) for the original APACHE III score. Similarly, it was 0.841 (0.839-0.843) for the "SAPS II derived APACHE II score" vs 0.842 (0.840-0.843) for the original APACHE II score. Correlation coefficients as well as intercepts remained very similar in all subgroups analyses.

    CONCLUSIONS:

    Simple and robust translational formulas can be developed to allow clinicians to compare illness severity between studies involving critically ill patients. Further studies in other countries and health care systems are needed to confirm the generalizability of these results.

  • 333. Schollin Borg, M
    et al.
    Nordin, P
    Zetterström, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Johansson, J
    Blood lactate is a useful indicator for the Medical Emergency Team2016Ingår i: Critical Care Research and Practice, ISSN 2090-1305, E-ISSN 2090-1313, artikel-id 5765202Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lactate has been thoroughly studied and found useful for stratification of patients with sepsis, in the Intensive Care Unit, and trauma care. However, little is known about lactate as a risk-stratification marker in the Medical Emergency Team- (MET-) call setting. We aimed to determine whether the arterial blood lactate level at the time of a MET-call is associated with increased 30-day mortality. This is an observational study on a prospectively gathered cohort at a regional secondary referral hospital. All MET-calls during the two-year study period were eligible. Beside blood lactate, age and vital signs were registered at the call. Among the 211 calls included, there were 64 deaths (30.3%). Median lactate concentration at the time of the MET-call was 1.82 mmol/L (IQR 1.16–2.7). We found differences between survivors and nonsurvivors for lactate and oxygen saturation, a trend for age, but no significant correlations between mortality and systolic blood pressure, respiratory rate, and heart rate. As compared to normal lactate (<2.44 mmol/L), OR for 30-day mortality was 3.54 (p < 0.0006) for lactate 2.44–5.0 mmol/L and 4.45 (p < 0.0016) for lactate > 5.0 mmol/L. The present results support that immediate measurement of blood lactate in MET call patients is a useful tool in the judgment of illness severity.

  • 334.
    Schumann, S.
    et al.
    Univ Freiburg, Fac Med, Med Ctr, Dept Anesthesiol & Crit Care, Freiburg, Germany.
    Vimlati, Laszlo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Kawati, Rafael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Guttmann, J.
    Univ Freiburg, Fac Med, Med Ctr, Dept Anesthesiol & Crit Care, Freiburg, Germany.
    Lichtwarck-Aschoff, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Cardiogenic oscillations to detect intratidal derecruitment and overdistension in a porcine model of healthy and atelectatic lungs2018Ingår i: British Journal of Anaesthesia, ISSN 0007-0912, E-ISSN 1471-6771, Vol. 121, nr 4, s. 928-935Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Low positive end-expiratory pressure (PEEP) can result in alveolar derecruitment, and high PEEP or high tidal volume (V-T) in lung overdistension. We investigated cardiogenic oscillations (COS) in the airway pressure signal to investigate whether these oscillations can assess unfavourable intratidal events. COS induce short instantaneous compliance increases within the pressure-volume curve, and consequently in the compliance-volume curve. We hypothesised that increases in COS-induced compliance reflect non-linear intratidal respiratory system mechanics. Methods: In mechanically ventilated anaesthetised pigs with healthy (n = 13) or atelectatic (n = 12) lungs, pressure-volume relationships and the ECG were acquired at a PEEP of 0, 5, 10, and 15 cm H2O. During inspiration, the peak compliance of successive COS (C-COS) was compared with intratidal respiratory system compliance (C-RS) within incremental volume steps up to the full V-T of 12 ml kg(-1). We analysed whether C-COS variation corresponded with systolic arterial pressure variation. Results: C-COS-volume curves showed characteristic intratidal patterns depending on the PEEP level and on atelectasis. Increasing C-RS- or C-COS-volume patterns were associated with intratidal derecruitment with low PEEP, and decreasing patterns above 6 ml kg(-1) and high PEEP showed overdistension. C-COS was not associated with systolic arterial pressure variations. Conclusions: Heartbeat-induced oscillations within the course of the inspiratory pressure-volume curve reflect nonlinear intratidal respiratory system mechanics. The analysis of these cardiogenic oscillations can be used to detect intratidal derecruitment and overdistension and, hence, to guide PEEP and V-T settings that are optimal for respiratory system mechanics.

  • 335. Seder, David B.
    et al.
    Sunde, Kjetil
    Rubertsson, Sten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Mooney, Michael
    Stammet, Pascal
    Riker, Richard R.
    Kern, Karl B.
    Unger, Barbara
    Cronberg, Tobias
    Dziodzio, John
    Nielsen, Niklas
    Neurologic Outcomes and Postresuscitation Care of Patients With Myoclonus Following Cardiac Arrest2015Ingår i: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 43, nr 5, s. 965-972Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives: To evaluate the outcomes of cardiac arrest survivors with myoclonus receiving modern postresuscitation care. Design: Retrospective review of registry data. Setting: Cardiac arrest receiving centers in Europe and the United States from 2002 to 2012. Patients: Two thousand five hundred thirty-two cardiac arrest survivors 18 years or older enrolled in the International Cardiac Arrest Registry. Interventions: None. Measurements and Main Results: Eighty-eight percent of patients underwent therapeutic hypothermia and 471 (18%) exhibited myoclonus. Patients with myoclonus had longer time to professional cardiopulmonary resuscitation (8.6 vs 7.0 min; p < 0.001) and total ischemic time (25.6 vs 22.3 min; p < 0.001) and less often presented with ventricular tachycardia/ventricular fibrillation, a witnessed arrest, or had bystander cardiopulmonary resuscitation. Electroencephalography demonstrated myoclonus with epileptiform activity in 209 of 374 (55%), including status epilepticus in 102 of 374 (27%). Good outcome (Cerebral Performance Category 1-2) at hospital discharge was noted in 9% of patients with myoclonus, less frequently in myoclonus with epileptiform activity (2% vs 15%; p < 0.001). Patients with myoclonus with good outcome were younger (53.7 vs 62.7 yr; p < 0.001), had more ventricular tachycardia/ventricular fibrillation (81% vs 46%; p < 0.001), shorter ischemic time (18.9 vs 26.4 min; p = 0.003), more witnessed arrests (91% vs 77%; p = 0.02), and fewer "do-not-resuscitate" orders (7% vs 78%; p < 0.001). Life support was withdrawn in 330 of 427 patients (78%) with myoclonus and poor outcome, due to neurological futility in 293 of 330 (89%), at 5 days (3-8 d) after resuscitation. With myoclonus and good outcome, median ICU length of stay was 8 days (5-11 d) and hospital length of stay was 14.5 days (9-22 d). Conclusions: Nine percent of cardiac arrest survivors with myoclonus after cardiac arrest had good functional outcomes, usually in patients without associated epileptiform activity and after prolonged hospitalization. Deaths occurred early and primarily after withdrawal of life support. It is uncertain whether prolonged care would yield a higher percentage of good outcomes, but myoclonus of itself should not be considered a sign of futility.

  • 336.
    Semenas, Egidijus
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Sharma, Hari Shanker
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Nozari, Ala
    Basu, Samar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Wiklund, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Neuroprotective effects of 17-beta-estradiol after hypovolemic cardiac arrest in immature piglets: the role of nitric oxide and peroxidation2011Ingår i: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. 36, nr 1, s. 30-37Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 337.
    Semenas, Egidijus
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Sharma, Hari Shanker
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Wiklund, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Adrenaline increases blood-brain-barrier permeability after haemorrhagic cardiac arrest in immature pigs2014Ingår i: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 58, nr 5, s. 620-629Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 338. Serpa Neto, Ary
    et al.
    Hemmes, Sabrine N T
    Barbas, Carmen S V
    Beiderlinden, Martin
    Biehl, Michelle
    Binnekade, Jan M
    Canet, Jaume
    Fernandez-Bustamante, Ana
    Futier, Emmanuel
    Gajic, Ognjen
    Hedenstierna, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi.
    Hollmann, Markus W
    Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands .
    Jaber, Samir
    Kozian, Alf
    Licker, Marc
    Lin, Wen-Qian
    Maslow, Andrew D
    Memtsoudis, Stavros G
    Reis Miranda, Dinis
    Moine, Pierre
    Ng, Thomas
    Paparella, Domenico
    Putensen, Christian
    Ranieri, Marco
    Scavonetto, Federica
    Schilling, Thomas
    Schmid, Werner
    Selmo, Gabriele
    Severgnini, Paolo
    Sprung, Juraj
    Sundar, Sugantha
    Talmor, Daniel
    Treschan, Tanja
    Unzueta, Carmen
    Weingarten, Toby N
    Wolthuis, Esther K
    Wrigge, Hermann
    Gama de Abreu, Marcelo
    Pelosi, Paolo
    Schultz, Marcus J
    Protective versus Conventional Ventilation for Surgery: A Systematic Review and Individual Patient Data Meta-analysis2015Ingår i: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 123, nr 1, s. 66-78Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Recent studies show that intraoperative mechanical ventilation using low tidal volumes (VT) can prevent postoperative pulmonary complications (PPCs). The aim of this individual patient data meta-analysis is to evaluate the individual associations between VT size and positive end-expiratory pressure (PEEP) level and occurrence of PPC.

    METHODS: Randomized controlled trials comparing protective ventilation (low VT with or without high levels of PEEP) and conventional ventilation (high VT with low PEEP) in patients undergoing general surgery. The primary outcome was development of PPC. Predefined prognostic factors were tested using multivariate logistic regression.

    RESULTS: Fifteen randomized controlled trials were included (2,127 patients). There were 97 cases of PPC in 1,118 patients (8.7%) assigned to protective ventilation and 148 cases in 1,009 patients (14.7%) assigned to conventional ventilation (adjusted relative risk, 0.64; 95% CI, 0.46 to 0.88; P < 0.01). There were 85 cases of PPC in 957 patients (8.9%) assigned to ventilation with low VT and high PEEP levels and 63 cases in 525 patients (12%) assigned to ventilation with low VT and low PEEP levels (adjusted relative risk, 0.93; 95% CI, 0.64 to 1.37; P = 0.72). A dose-response relationship was found between the appearance of PPC and VT size (R = 0.39) but not between the appearance of PPC and PEEP level (R = 0.08).

    CONCLUSIONS: These data support the beneficial effects of ventilation with use of low VT in patients undergoing surgery. Further trials are necessary to define the role of intraoperative higher PEEP to prevent PPC during nonopen abdominal surgery.

  • 339.
    Sharma, Aruna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Muresanu, Dafin F.
    Univ Med & Pharm, Univ Hosp, Dept Clin Neurosci, Cluj Napoca, Romania..
    Lafuente, Jose V.
    Univ Basque Country, Dept Neurosci, Bilbao, Spain..
    Patnaik, Ranjana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Banaras Hindu Univ, Indian Inst Technol, Dept Biomat, Sch Biomed Engn, Varanasi 221005, Uttar Pradesh, India..
    Tian, Z. Ryan
    Univ Arkansas, Dept Chem & Biochem, Fayetteville, AR 72701 USA..
    Buzoianu, Anca D.
    Univ Med & Pharm, Fac Med, Dept Pharmacol, Cluj Napoca, Romania..
    Sharma, Hari Shanker
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Sleep Deprivation-Induced Blood-Brain Barrier Breakdown and Brain Dysfunction are Exacerbated by Size-Related Exposure to Ag and Cu Nanoparticles. Neuroprotective Effects of a 5-HT3 Receptor Antagonist Ondansetron2015Ingår i: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 52, nr 2, s. 867-881Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Military personnel are often subjected to sleep deprivation (SD) during combat operations. Since SD is a severe stress and alters neurochemical metabolism in the brain, a possibility exists that acute or long-term SD will influence blood-brain barrier (BBB) function and brain pathology. This hypothesis was examined in young adult rats (age 12 to 14 weeks) using an inverted flowerpot model. Rats were placed over an inverted flowerpot platform (6.5 cm diameter) in a water pool where the water levels are just 3 cm below the surface. In this model, animals can go to sleep for brief periods but cannot achieve deep sleep as they would fall into water and thus experience sleep interruption. These animals showed leakage of Evans blue in the cerebellum, hippocampus, caudate nucleus, parietal, temporal, occipital, cingulate cerebral cortices, and brain stem. The ventricular walls of the lateral and fourth ventricles were also stained blue, indicating disruption of the BBB and the blood-cerebrospinal fluid barrier (BCSFB). Breakdown of the BBB or the BCSFB fluid barrier was progressive in nature from 12 to 48 h but no apparent differences in BBB leakage were seen between 48 and 72 h of SD. Interestingly, rats treated with metal nanoparticles, e.g., Cu or Ag, showed profound exacerbation of BBB disruption by 1.5- to 4-fold, depending on the duration of SD. Measurement of plasma and brain serotonin showed a close correlation between BBB disruption and the amine level. Repeated treatment with the serotonin 5-HT3 receptor antagonist ondansetron (1 mg/kg, s.c.) 4 and 8 h after SD markedly reduced BBB disruption and brain pathology after 12 to 24 h SD but not following 48 or 72 h after SD. However, TiO2-nanowired ondansetron (1 mg/kg, s.c) in an identical manner induced neuroprotection in rats following 48 or 72 h SD. However, plasma and serotonin levels were not affected by ondansetron treatment. Taken together, our observations are the first to show that (i) SD could induce BBB disruption and brain pathology, (ii) nanoparticles exacerbate SD-induced brain damage, and (iii) serotonin 5-HT3 receptor antagonist ondansetron is neuroprotective in SD that is further potentiated byTiO2-nanowired delivery, not reported earlier.

  • 340.
    Sharma, Aruna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Muresanu, Dafin Fior
    Moessler, Herbert
    Sharma, Hari Shanker
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Superior Neuroprotective Effects of Cerebrolysin in Nanoparticle-Induced Exacerbation of Hyperthermia-Induced Brain Pathology2012Ingår i: CNS & Neurological Disorders - Drug Targets, ISSN 1871-5273, Vol. 11, nr 1, s. 7-25Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    In recent years, the incidence of heat stroke and associated brain pathology are increasing Worldwide. More than half of the world's population are living in areas associated with high environmental heat especially during the summer seasons. Thus, new research is needed using novel drug targets to achieve neuroprotection in heat-induced brain pathology. Previous research from our laboratory showed that the pathophysiology of brain injuries following heat stroke are exacerbated by chronic intoxication of engineered nanoparticles of small sizes (50-60 nm) following identical heat exposure in rats. Interestingly, in nanoparticle-intoxicated animals the known neuroprotective agents in standard doses failed to induce effective neuroprotection. This suggests that the dose-response of the drugs either requires modification or new therapeutic agents are needed to provide better neuroprotection in nanoparticle-intoxicated animals after heat stroke. This review is focused on the use of cerebrolysin, a mixture of several neurotrophic factors and active peptide fragments, in relation to other neuroprotective agents normally used to treat ischemic stroke in clinics in nanoparticle-induced exacerbation of brain damage in heat stroke. It appears that cerebrolysin exerts the most superior neuroprotective effects in heat stress as compared to other neuroprotective agents on brain pathology in normal rats. Interestingly, to induce effective neuroprotection in nanoparticle-induced exacerbation of brain pathology a double dose of cerebrolysin is needed. On the other hand, double doses of the other drugs were quite ineffective in reducing brain damage. These observations suggest that the drug type and doses are important factors in attenuating nanoparticle-induced exacerbation of brain pathology in heat stroke. The functional significance and possible mechanisms of drug-induced neuroprotection in nanoparticle-treated, heat-stressed rats are discussed.

  • 341.
    Sharma, Hari S.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Ali, Syed F.
    Hussain, Saber M.
    Schlager, John J.
    Sharma, Aruna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Influence of Engineered Nanoparticles from Metals on the Blood-Brain Barrier Permeability, Cerebral Blood Flow, Brain Edema and Neurotoxicity: An Experimental Study in the Rat and Mice Using Biochemical and Morphological Approaches2009Ingår i: Journal of Nanoscience and Nanotechnology, ISSN 1533-4880, E-ISSN 1533-4899, Vol. 9, nr 8, s. 5055-5072Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Influence of nanoparticles on brain function following in vivo exposures is not well known. Depending on the magnitude and intensity of nanoparticle exposure from the environment, food and/or water source, neuronal function could be affected and may lead to neurotoxicity and neuropathology. This hypothesis was examined in present investigation using systemic or intracerebroventricular administration of engineered nanoparticles from metals, i.e., Al, Ag and Cu (approximate to 50 to 60 nm) on neurotoxicity in rats and mice. Intraperitoneal (50 mg/kg), intravenous (30 mg/kg), intracarotid (2.5 mg/kg) or intracerebroventricular administration (20 mu g) of nanoparticles significantly altered the blood-brain barrier (BBB) function to Evans blue and radioiodine in several regions of the brain and spinal cord at 24 h after their administration. Marked decreases in local cerebral blood flow (CBF) and pronounced brain edema was seen in regional areas associated with BBB leakage. Neuronal cell injuries, glial cell activation, heat shock protein (HSP) upregulation and loss of myelinated fibers are quite common in effected brain areas. The observed pathological changes were most pronounced in mice compared to rats. Exposures to Cu and Ag nanoparticles showed most marked effects on brain pathology when administered into systemic circulation or into the brain ventricular spaces as compared to Al nanoparticles. Our results are the first to show that nanoparticles from metals are able to induce selective and specific neurotoxicity that depends on the type of metals, route of administration and the species used.

  • 342.
    Sharma, Hari Shanker
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    A combination of tumor necrosis factor-α and neuronal nitric oxide synthase antibodies applied topically over the traumatized spinal cord enhances neuroprotection and functional recovery in the rat2010Ingår i: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1199, s. 175-185Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The possibility that neutralization of nitric oxide synthase and tumor necrosis factor alpha (TNF-alpha) in the cord using their antiserum will induce neuroprotection and improve functional outcome following spinal cord injury (SCI) was examined in a rat model. The SCI was induced in rats by a unilateral incision of the right dorsal horn at the T10-11 segments under equithesin anesthesia. TNF-alpha and/or neuronal nitric oxide synthase (nNOS) antibodies were applied over the traumatized spinal cord at 10-90 minutes after injury and functional recovery and cord pathophysiology were examined at five hours. Topical application of TNF-alpha antiserum at 10 min followed by NOS antiserum at 20 min after SCI significantly improved functional recovery and attenuated blood-spinal cord barrier (BSCB) disturbances, edema formation, and cord pathology. These neuroprotective effects were also seen when the NOS antiserum was applied 10 min after injury followed by TNF-alpha antiserum at 30 min after trauma. However, when TNF-alpha antiserum was applied 1 h after injury and NOS antiserum was given either before or after TNF-alpha antiserum, no neuroprotective effects were observed. Interestingly, neuronal injury was tightly correlated with nNOS expression in the cord in antibody treated groups. These novel observations suggest that early blockade of TNF-alpha and nNOS expression within 20-30 min after SCI is beneficial in nature. This indicates that TNF-alpha. and nitric oxide play synergistic roles in the pathophysiology of SCI and combined antibodies therapy has added neuroprotective values in spinal trauma.

  • 343.
    Sharma, Hari Shanker
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Ali, Syed F.
    Tian, Z. Ryan
    Hussain, Saber M.
    Schlager, John J.
    Sjöquist, Per-Ove
    Sharma, Aruna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Muresanu, Datin F.
    Chronic Treatment with Nanoparticles Exacerbate Hyperthermia Induced Blood-Brain Barrier Breakdown, Cognitive Dysfunction and Brain Pathology in the Rat: Neuroprotective Effects of Nanowired-Antioxidant Compound H-290/512009Ingår i: Journal of Nanoscience and Nanotechnology, ISSN 1533-4880, E-ISSN 1533-4899, Vol. 9, nr 8, s. 5073-5090Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The possibility that chronic exposure of nanoparticles may alter stress reaction and brain pathology following hyperthermia was examined in a rat model. Engineered nanoparticles from Ag or M Cu (approximate to 50-60 nm) were administered (30 mg/kg, i.p.) once daily for 1 week in young male rats. M On the 8th day these animals were subjected to 4 h heat stress at 38 degrees C in a BOD incubator. In these animals stress symptoms, blood-brain barrier (BBB) permeability, cognitive and motor functions and brain pathology were examined. Subjection of nanoparticle treated rats to heat stress showed exacerbation of stress symptoms i.e., hyperthermia, salivation and prostration and exhibited greater BBB disruption, brain edema formation, impairment of cognitive and motor functions M and brain damage compared to normal animals. This enhanced brain pathology in heat stress was most marked in animals that received Ag nanoparticles compared to Cu treatment. Treatment with antioxidant compound H-290/51 either 30 min or 60 min after heat stress did not alter hyperthermia M induce brain pathology in nanoparticle treated rats. Whereas, administration of nanowired-H-290/51 after 30 min or 60 min heat stress markedly attenuated BBB disruption, sensory motor function and brain pathology. These results suggest that chronic nanoparticles treatment exacerbate hyperthermia induced brain pathology that is significantly attenuated by nanowired but not normal H-290/51 compound. Taken together, our observations suggest that nano-wired drug delivery of H-290/51 is a promising approach to induce neuroprotection in hyperthermia induced brain pathology, not reported earlier.

  • 344.
    Sharma, Hari Shanker
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Hussain, Saber
    Schlager, John
    Ali, Syed F.
    Sharma, Aruna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Influence of Nanoparticles on Blood-Brain Barrier Permeability and Brain Edema Formation in Rats2010Ingår i: Brain Edema XIV / [ed] Zbigniew Czernicki et al., Vienna: Springer , 2010, Vol. 106, s. 359-364Konferensbidrag (Refereegranskat)
    Abstract [en]

    Nanoparticles are small sized (1-100 nm) particles derived from transition metals, silver, copper, aluminum, silicon, carbon and metal oxides that can easily cross the blood-brain barrier (BBB) and/or produce damage to the barrier integrity by altering endothelial cell membrane permeability. However, the influence of nanoparticles on BBB integrity is still not well-known. In this investigation, effect of nanoparticles derived from Ag, Al and Cu (50-60 nm) on BBB permeability in relation to brain edema formation was examined in a rat model. Intravenous (30 mg/kg), intraperitoneal (50 mg/kg) or intracerebral (20 mu g in 10 mu L) administration of Ag, Cu or AI nanoparticles disrupted the BBB function to Evans blue albumin (EBA) and radioiodine in rats 24 h after administration and induced brain edema formation. The leakage of Evans blue dye was observed largely in the ventral surface of brain and in the proximal frontal cortex. The dorsal surfaces of cerebellum showed mild to moderate EBA staining. These effects were most pronounced in animals that received Ag or Cu nanoparticles compared to Al nanoparticles through intravenous routes. These observations are the first to suggest that nanoparticles can induce brain edema formation by influencing BBB breakdown in vivo.

  • 345.
    Sharma, Hari Shanker
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Kiyatkin, Eugene A.
    NIDA, Vivo Electrophysiol Unit, Behav Neurosci Branch, IRP,NIH, Baltimore, MD USA..
    Patnaik, Ranjana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Lafuente, Jose Vicente
    Univ Basque Country, Dept Neurosci, Bilbao, Spain..
    Muresanu, Dafin F.
    Univ Med & Pharm, Univ Hosp, Dept Clin Neurosci, Cluj Napoca, Romania..
    Sjoquist, Per-Ove
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Div Cardiol, Stockholm, Sweden..
    Sharma, Aruna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Exacerbation of Methamphetamine Neurotoxicity in Cold and Hot Environments: Neuroprotective Effects of an Antioxidant Compound H-290/512015Ingår i: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 52, nr 2, s. 1023-1033Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this study, we examined the influence of cold and hot environments on methamphetamine (METH) neurotoxicity in both drug-naive rats and animals previously exposed to different types of nanoparticles (NPs). Since METH induces oxidative stress, we also examined how a potential chain-breaking antioxidant H-290/51 (Astra-Zeneca, Molndal, Sweden) affects METH-induced neurotoxicity. Exposure of drug-naive rats to METH (9 mg/kg, s.c.) at 4, 21, or 34 A degrees C for 3 h resulted in breakdown of the blood-brain barrier (BBB), brain edema, and neuronal injuries, which all differed in severity depending upon ambient temperatures. The changes were moderate at 21 A degrees C, 120-180 % larger at 34 A degrees C, and almost absent at 4 A degrees C. In rats chronically treated with NPs (SiO2, Cu, or Ag; 50-60 nm, 50 mg/kg, i.p. for 7 days), METH-induced brain alterations showed a two- to fourfold increase at 21 A degrees C, a four- to sixfold increase at 34 A degrees C, and three- to fourfold increase at 4 A degrees C. SiO2 exposure showed the most pronounced METH-induced brain pathology at all temperatures followed by Ag and Cu NPs. Pretreatment with a potent antioxidant compound H-290/51 (50 mg/kg, p.o., 30 min before METH) significantly reduced brain pathology in naive animals exposed to METH at 21 and 34 A degrees C. In NPs-treated animals, however, attenuation of METH-induced brain pathology occurred only after repeated exposure of H-290/51 (-30 min, 0 min, and +30 min). These observations are the first to show that NPs exacerbate METH-induced brain pathology in both cold and hot environments and demonstrate that timely intervention with antioxidant H-290/51 could have neuroprotective effects.

  • 346.
    Sharma, Hari Shanker
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Muresanu, D.
    Nozari, A.
    Patnaik, R.
    Moessler, H.
    Sharma, Aruna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Nanoparticles Aggravate Cardiac Arrest-Induced Blood-Brain Barrier Breakdown, Edema Formation, and Neuronal Injuries: Neuroprotective Effects of a Multimodal Drug Cerebrolysin2014Ingår i: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 23, nr 6, s. 782-783Artikel i tidskrift (Övrigt vetenskapligt)
  • 347.
    Sharma, Hari Shanker
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Muresanu, Dafin F.
    Univ Med & Pharm Cluj Napoca, Univ Hosp, Dept Clin Neurosci, Cluj Napoca, Romania.;RoNeuro Inst Neurol Res & Diagnost, Cluj Napoca 400364, Romania..
    Lafuente, Jose V.
    Univ Basque Country, Dept Neurosci, LaNCE, Bilbao, Spain.;Univ Autonoma Chile, Fac Hlth Sci, Santiago, Chile..
    Sjoquist, Per-Ove
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Div Cardiol, Stockholm, Sweden..
    Patnaik, Ranjana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Banaras Hindu Univ, Indian Inst Technol, Sch Biomed Engn, Dept Biomat, Varanasi 221005, Uttar Pradesh, India..
    Sharma, Aruna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Nanoparticles Exacerbate Both Ubiquitin and Heat Shock Protein Expressions in Spinal Cord Injury: Neuroprotective Effects of the Proteasome Inhibitor Carfilzomib and the Antioxidant Compound H-290/512015Ingår i: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 52, nr 2, s. 882-898Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Increased levels of ubiquitin and heat shock protein (HSP) 72 kD are often seen in spinal cord injury (SCI). However, their roles in cell injury or survival are not well known. Thus, we have investigated the possible relationship between ubiquitin and HSP expressions in relation to cell injury in healthy animals, or following nanoparticle (NP) intoxication in SCI animals. A focal SCI was inflicted on the T10-11 segments over the right dorsal horn; animals were allowed to survive from 5 to 8 h after trauma. Separate groups of rats were exposed to SiO2, Ag, or Cu NPs for 7 days and subjected to SCI on the eighth day. A marked increase in ubiquitin or HSP immunoreactive cells occurred in the T9 to T12 segments 5 h after the injury, which further extended to the T4 and L5 after 8 h of survival. At this time, a marked increase in blood-spinal cord barrier (BSCB) permeability to Evans blue and radioiodine, accompanied by an intense edema formation, was observed. Changes were further exacerbated in NP-treated traumatized rats. The most marked expressions of ubiquitin and HSP in SCI were seen in rats treated with SiO2, followed by Ag, and Cu NPs. Treatment with H-290/51 (50 mg/kg p.o., 30 to 60 min after injury) or carfilzomib (1 mg/kg, i.v., 30 to 60 min after trauma) significantly reduced the ubiquitin or HSP expressions, as well as the BSCB breakdown, the edema formation, and the cell injury in the cord both 5 and 8 h after the injury, in normal animals. However, a double dose of H-290/51 (100 mg/kg) or carfilzomib (2 mg/kg) is needed to reduce cord pathology or ubiquitin and HSP expressions in traumatized animals treated with NPs. H-290/51 showed superior beneficial effects in reducing cord pathology in SCI than carfilzomib. These observations are the first to demonstrate that (i) NP-treated traumatized animals induce a widespread BSCB leakage, edema formation, and cord pathology as well as an overexpression of ubiquitin and HSP, (ii) high doses of antioxidant compounds or proteasome inhibitors are required for neuroprotection in the NP-exposed traumatized group, and (iii) ubiquitin and HSP expressions play a key role in neuronal injury in SCI, not reported earlier.

  • 348.
    Sharma, Hari Shanker
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Muresanu, Dafin Fior
    Tian, Z. Ryan
    Ozkizlicik, Asya
    Lafuente, Jose Vicente
    Moessler, Herbert
    Sharma, Aruna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    TiO2 Nanowired Cerebrolysin Attenuates Overexpression of Ubiquitin and Nitric Oxide Synthase and Induces Neuroprotection Following Spinal Cord Trauma2015Ingår i: The journal of head trauma rehabilitation, ISSN 0885-9701, E-ISSN 1550-509X, Vol. 30, nr 3, s. E80-E81Artikel i tidskrift (Övrigt vetenskapligt)
  • 349.
    Sharma, Hari Shanker
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Muresanu, Dafin
    Sharma, Aruna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Zimmermann-Meinzingen, Sibilla
    Cerebrolysin treatment attenuates heat shock protein overexpression in the brain following heat stress: An experimental study using immunohistochemistry at light and electron microscopy in the rat2010Ingår i: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1199, s. 138-148Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The possibility that overexpression of heat shock proteins (HSPs) in the CNS represents a neurodestructive signal following hyperthermia was examined in a rat model using a potent neuroprotective drug, Cerebrolysin (Ebewe Pharma, Austria). Rats subjected to four hours of heat stress in a biological oxygen demand incubator at 38 degrees C developed profound hyperthermia (41.23 +/- 0.14 degrees C) and overexpressed HSP 72 kD in several brain regions: cerebral cortex, hippocampus, cerebellum, thalamus, hypothalamus, brain stem, and spinal cord compared to controls. This HSP overexpression closely correlated with the leakage of blood-brain barrier permeability and vasogenic edema formation in these brain areas. HSP positive cells are largely confined in the edematous brain regions showing Evans blue leakage. Pretreatment with Cerebrolysin (5 mL/kg, i.v.) 30 minutes before heat stress markedly attenuated hyperthermia (39.48 +/- 0.23 degrees C, P < 0.01) and the induction of HSP to all the brain regions examined. Leakage of Evans blue albumin and increase in brain water content in these brain areas are also markedly reduced with Cerebrolysin pretreatment. These results are the first to show that Cerebrolysin, if administered before heat stress, attenuates hyperthermia induced stress reaction and HSP 72 kD induction. Taken together, these novel observations suggest that upregulation of HSP 72 kD in brain represents neurodestructive signals and a reduction in cellular stress mechanisms leading to decline in HSP expression is neuroprotective in nature.

  • 350.
    Sharma, Hari Shanker
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Patnaik, Ranjana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Sharma, Aruna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Vicente Lafuente, Jose
    Univ Basque Country, Dept Neurosci, Bilbao, Spain..
    Miclescu, Adriana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Uppsala Univ, Dept Surg Sci Anesthesiol & Intens Care Med, Lab Cerebrovasc Res, S-75185 Uppsala, Sweden..
    Wiklund, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Cardiac Arrest Alters Regional Ubiquitin Levels in Association with the Blood-Brain Barrier Breakdown and Neuronal Damages in the Porcine Brain2015Ingår i: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 52, nr 2, s. 1043-1053Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

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