| 1. |
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| 2. |
- Näsström, Thomas, et al.
(författare)
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The lipid peroxidation products 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote the formation of α-synuclein oligomers with distinct biochemical, morphological, and functional properties
- 2011
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Ingår i: Free Radical Biology & Medicine. - : Elsevier BV. - 0891-5849 .- 1873-4596. ; 50:3, s. 428-437
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Tidskriftsartikel (refereegranskat)abstract
- Oxidative stress has been implicated in the etiology of neurodegenerative disorders with alpha-synuclein pathology. Lipid peroxidation products such as 4-oxo-2-nonenal (ONE) and 4-hydroxy-2-nonenal (HNE) can covalently modify and structurally alter proteins. Herein, we have characterized ONE- or HNE-induced alpha-synuclein oligomers. Our results demonstrate that both oligomers are rich in beta-sheet structure and have a molecular weight of about 2000 kDa. Atomic force microscopy analysis revealed that ONE-induced alpha-synuclein oligomers were relatively amorphous, with a diameter of 40-80 nm and a height of 4-8 nm. In contrast, the HNE-induced alpha-synuclein oligomers had a protofibril-like morphology with a width of 100-200 nm and a height of 2-4 nm. Furthermore, neither oligomer type polymerized into amyloid-like fibrils despite prolonged incubation. Although more SDS and urea stable, because of a higher degree of cross-linking, ONE-induced alpha-synuclein oligomers were less compact and more sensitive to proteinase K treatment. Finally, both ONE- and HNE-induced alpha-synuclein oligomers were cytotoxic when added exogenously to a neuroblastoma cell line, but HNE-induced alpha-synuclein oligomers were taken up by the cells to a significantly higher degree. Despite nearly identical chemical structures, ONE and HNE induce the formation of off-pathway alpha-synuclein oligomers with distinct biochemical, morphological, and functional properties.
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| 3. |
- Barbu, Mikael
(författare)
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Cardiopulmonary bypass: Clinical studies in cardiac surgery patients
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUND: Cardiopulmonary bypass (CPB) is necessary to facilitate most cardiac operations. Although the vast majority of patients tolerate CPB physiology in conjunction with cardiac surgery well, there is risks of adverse outcomes. Optimal CPB perfusion is not defined, and may vary according to operation and patient specific factors. AIMS: The project aims to study different aspects of CPB management and risk in adult cardiac surgery. The first part of the project investigates the efficacy and safety of dextran 40 based colloid prime compared to crystalloid prime. The second part aimed to describe the dynamics of brain injury markers in peripheral blood after routine cardiac surgery. Lastly, we aimed to identify manageable CPB variables associated to risk of acute kidney injury (AKI). METHODS: We conducted a prospective, randomized, double-blinded, single-center study to compare dextran 40 based colloid prime with ringer acetate with added mannitol prime in elective adult cardiac surgery patients. Serum colloid osmotic pressure was measured before, during, and after CPB. Biochemical markers for organ injury, inflammation, hemolysis, hemostasis, pulmonary function, and brain injury markers were measured before and after CPB. Fluid balance, bleeding and transfusion requirements were recorded during and after operation. To analyze risk of AKI in relation to CPB management, we conducted a registry based study combining prospectively collected outcome data from the SWEDEHEART registry with our institutions automated CPB registry. RESULTS: Dextran 40 based prime was better at maintaining serum colloid osmotic pressure during and shortly after CPB, and also improved total fluid balance compared to crystalloid prime. Although dextran treated patients had a measurable effect on laboratory and functional coagulation values, it did not increase the risk of bleeding or transfusion. Acute renal tubular injury and hemolysis was less pronounced in dextran prime patients, however, there were no difference in AKI rates. In adjusted observational data, we identified an association between risk of AKI and time on CPB, aortic clamp time, compromised flow, and nadir hematocrit during CPB, along with several patient specific risk factors. Markers of brain injury in serum and plasma were all significantly elevated in the first 24 hours after CPB compared to preoperative baseline values. The individual markers had different temporal distribution and large variability in magnitude and inter-individual differences. The increase was independent of blood-brain barrier damage, and levels were correlated with patient age, CPB duration, and/or hemolysis. CONCLUSION: CPB prime with dextran 40 is safe and effective in adult cardiac surgery, and seems to attenuate CPB induced renal tubular injury and hemolysis. To reduce the risk of cardiac surgery associated AKI, it is important to keep the time on CPB and aortic cross clamp short, and to maintain hematocrit and pump flow during CPB. There is a release of brain injury biomarkers in peripheral blood after cardiac surgery that is not attributed to evident neurologic damage or blood-brain barrier dysfunction.
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| 4. |
- Barbu, Mikael, et al.
(författare)
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Cardiopulmonary bypass management and acute kidney injury in cardiac surgery patients.
- 2024
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Ingår i: Acta anaesthesiologica Scandinavica. - 1399-6576. ; 68:3, s. 328-336
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Tidskriftsartikel (refereegranskat)abstract
- Cardiopulmonary bypass (CPB) ensures tissue oxygenation during cardiac surgery. New technology allows continuous registration of CPB variables during the operation. The aim of the present investigation was to study the association between CPB management and the risk of postoperative acute kidney injury (AKI).This observational study based on prospectively registered data included 2661 coronary artery bypass grafting and/or valve patients operated during 2016-2020. Individual patient characteristics and postoperative outcomes collected from the SWEDEHEART registry were merged with CPB variables automatically registered every 20s during CPB. Associations between CPB variables and AKI were analyzed with multivariable logistic regression models adjusted for patient characteristics.In total, 387 patients (14.5%) developed postoperative AKI. After adjustments, longer time on CPB and aortic cross-clamp, periods of compromised blood flow during aortic cross-clamp time, and lower nadir hematocrit were associated with the risk of AKI, while mean blood flow, bladder temperature, central venous pressure, and mixed venous oxygen saturation were not. Patient characteristics independently associated with AKI were advanced age, higher body mass index, hypertension, diabetes mellitus, atrial fibrillation, lower left ventricular ejection fraction, estimated glomerular filtration rate<60 or>90mL/min/m2 , and preoperative hemoglobin concentration below or above the normal sex-specific range.To reduce the risk of AKI after cardiac surgery, aortic clamp time and CPB time should be kept short, and low hematocrit and periods of compromised blood flow during aortic cross-clamp time should be avoided if possible.
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| 5. |
- Barbu, Mikael, et al.
(författare)
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Dextran- versus crystalloid-based prime in cardiac surgery: A prospective randomized pilot study.
- 2020
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Ingår i: The Annals of thoracic surgery. - : Elsevier BV. - 1552-6259 .- 0003-4975. ; 110:5, s. 1541-7
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Tidskriftsartikel (refereegranskat)abstract
- The optimum priming fluid for the cardiopulmonary bypass (CPB) circuit is still debated. We compared a new hyperoncotic priming solution containing dextran 40, which has an electrolyte composition that mimics extracellular fluid, with a standard crystalloid-based prime.Eighty cardiac surgery patients were included in this double-blind randomized single-centre study. The patients were randomized to either a dextran-based prime or a crystalloid prime containing Ringer acetate and mannitol. The primary endpoint was colloid oncotic pressure (COP) in serum during CPB. Secondary endpoints included fluid balance, bleeding and transfusion requirements, pulmonary function, hemolysis, systemic inflammation, and markers of renal, hepatic, myocardial, and brain injury. Blood samples were collected before, during, and after CPB.COP was higher in the dextran group than in the crystalloid prime group on CPB (18.8±2.9 vs. 16.4±2.9 mmHg, p<0.001) and 10 min after CPB (19.2±2.7 vs. 16.8±2.9 mmHg, p<0.001). Patients in the dextran group required less intravenous fluid during CPB (1090±499 vs. 1437±543 ml; p=0.003) and net fluid balance was less positive 12h after surgery (+1,431±741 vs. +1,901±922 ml; p=0.014). Plasma free hemoglobin was significantly lower in the dextran group 2h after CPB (0.18±0.11 vs 0.41±0.33, p=0.001). There were no significant differences in bleeding, transfusion requirements, organ function, systemic inflammation, or brain and myocardial injury markers between the groups at any time point.Our results suggest that a hyperoncotic dextran-based priming solution preserves intraoperative COP compared to crystalloid prime. Larger studies with clinically valid endpoints are necessary to evaluate hyperoncotic prime solutions further.
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| 6. |
- Barbu, Mikael, et al.
(författare)
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Hemostatic effects of a dextran-based priming solution for cardiopulmonary bypass: A secondary analysis of a randomized clinical trial
- 2023
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Ingår i: Thrombosis Research. - : Elsevier BV. - 0049-3848. ; 223, s. 139-145
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Intravascular fluids administered to patients may influence hemostasis. In patients undergoing cardiac surgery with cardiopulmonary bypass, the heart-lung machine is primed with 1300 ml of fluid. We assessed postoperative coagulation and platelet function in patients randomized to two different priming solu-tions, one colloid-based (dextran 40) and one crystalloid-based.Materials and methods: Eighty-four elective cardiac surgery patients were randomized to either a dextran-based prime or Ringer's acetate with added mannitol. Blood samples were collected before, and 2 and 24 h after cardiopulmonary bypass. Coagulation was assessed by standard coagulation tests and rotational thromboelas-tometry. Platelet function was assessed with impedance aggregometry. Bleeding volumes and transfusion re-quirements were recorded.Results: Comparing the groups 2 h after bypass, the dextran group showed lower hemoglobin concentration, hematocrit, platelet count, and fibrinogen concentration, and higher INR and aPTT, as well as longer clot for-mation time (+41 +/- 21 % vs. +8 +/- 18 %, p < 0.001) and a larger reduction in fibrinogen-dependent clot strength (-37 +/- 12 % vs.-7 +/- 20 %, p < 0.001). Adenosine diphosphate-dependent platelet activation was reduced in the dextran group but not in the crystalloid group 2 h after bypass (-14 +/- 29 % vs.-1 +/- 41 %, p = 0.041). No significant between-group differences in hemostatic variables remained after 24 h, and no significant differences in perioperative bleeding volumes, re-explorations for bleeding, or transfusion rates were observed.Conclusions: Compared to a crystalloid solution, a dextran-based prime had measurable negative impact on he-mostatic variables but no detectable increase in bleeding volume or transfusion requirements in cardiac surgery patients.
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| 7. |
- Barbu, Mikael, et al.
(författare)
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Serum biomarkers of brain injury after uncomplicated cardiac surgery: Secondary analysis from a randomized trial
- 2022
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Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 66:4, s. 447-453
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Tidskriftsartikel (refereegranskat)abstract
- Background: Postoperative cognitive dysfunction is common after cardiac surgery. Postoperative measurements of brain injury biomarkers may identify brain damage and predict cognitive dysfunction. We describe the release patterns of five brain injury markers in serum and plasma after uncomplicated cardiac surgery. Methods: Sixty-one elective cardiac surgery patients were randomized to undergo surgery with either a dextran-based prime or a crystalloid prime. Blood samples were taken immediately before surgery, and 2 and 24h after surgery. Concentrations of the brain injury biomarkers S100B, glial fibrillary acidic protein (GFAP), tau, neurofilament light (NfL) and neuron-specific enolase (NSE)) and the blood–brain barrier injury marker β-trace protein were analyzed. Concentrations of brain injury biomarkers were correlated to patients’ age, operation time, and degree of hemolysis. Results: No significant difference in brain injury biomarkers was observed between the prime groups. All brain injury biomarkers increased significantly after surgery (tau +456% (25th–75th percentile 327%−702%), NfL +57% (28%−87%), S100B +1145% (783%−2158%), GFAP +17% (−3%−43%), NSE +168% (106%−228%), while β-trace protein was reduced (−11% (−17−3%). Tau, S100B, and NSE peaked at 2h, NfL and GFAP at 24h. Postoperative concentrations of brain injury markers correlated to age, operation time, and/or hemolysis. Conclusion: Uncomplicated cardiac surgery with cardiopulmonary bypass is associated with an increase in serum/plasma levels of all the studied injury markers, without signs of blood–brain barrier injury. The biomarkers differ markedly in their levels of release and time course. Further investigations are required to study associations between perioperative release of biomarkers, postoperative cognitive function and clinical outcome. © 2022 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.
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| 8. |
- Hansson, Emma C., 1985, et al.
(författare)
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Coronary artery bypass grafting-related bleeding complications in patients treated with ticagrelor or clopidogrel : a nationwide study
- 2016
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 37:2, s. 189-197
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Tidskriftsartikel (refereegranskat)abstract
- AIMS:Excessive bleeding impairs outcome after coronary artery bypass grafting (CABG). Current guidelines recommend withdrawal of clopidogrel and ticagrelor 5 days (120 h) before elective surgery. Shorter discontinuation would reduce the risk of thrombotic events and save hospital resources, but may increase the risk of bleeding. We investigated whether a shorter discontinuation time before surgery increased the incidence of CABG-related major bleeding complications and compared ticagrelor- and clopidogrel-treated patients.METHODS AND RESULTS:All acute coronary syndrome patients in Sweden on dual antiplatelet therapy with aspirin and ticagrelor (n = 1266) or clopidogrel (n = 978) who underwent CABG during 2012-13 were included in a retrospective observational study. The incidence of major bleeding complications according to the Bleeding Academic Research Consortium-CABG definition was 38 and 31%, respectively, when ticagrelor/clopidogrel was discontinued <24 h before surgery. Within the ticagrelor group, there was no significant difference between discontinuation 72-120 or >120 h before surgery [odds ratio (OR) 0.93 (95% confidence interval, CI, 0.53-1.64), P = 0.80]. In contrast, clopidogrel-treated patients had a higher incidence when discontinued 72-120 vs. >120 h before surgery (OR 1.71 (95% CI 1.04-2.79), P = 0.033). The overall incidence of major bleeding complications was lower with ticagrelor [12.9 vs. 17.6%, adjusted OR 0.72 (95% CI 0.56-0.92), P = 0.012].CONCLUSION:The incidence of CABG-related major bleeding was high when ticagrelor/clopidogrel was discontinued <24 h before surgery. Discontinuation 3 days before surgery, as opposed to 5 days, did not increase the incidence of major bleeding complications with ticagrelor, but increased the risk with clopidogrel. The overall risk of major CABG-related bleeding complications was lower with ticagrelor than with clopidogrel.
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| 9. |
- Jónsson, Kristján, et al.
(författare)
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Perioperative stroke and survival in coronary artery bypass grafting patients: a SWEDEHEART study
- 2022
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Ingår i: European Journal of Cardio-Thoracic Surgery. - : Oxford University Press (OUP). - 1010-7940 .- 1873-734X. ; 62:4
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES Perioperative stroke is a severe complication of cardiac surgery. We assessed the incidence of stroke over time, the association between stroke and mortality and identified preoperative factors independently associated with perioperative stroke, in a large nationwide cardiac surgery population. METHODS All patients who underwent coronary artery bypass grafting in Sweden 2006-2017 were included in a registry-based observational cohort study based on prospectively collected data. Multivariable logistic and Cox regression models were used to assess associations between perioperative stroke and mortality and to identify factors associated with stroke. The median follow-up was 6 years (range 0-12). RESULTS There were 441 perioperative strokes in 36 898 patients. The mean incidence was 1.2% and decreased marginally over time [adjusted odds ratio (OR) 0.97 per year (95% confidence interval 0.94-1.00), P = 0.035]. Stroke patients had a higher overall mortality risk during follow-up [adjusted hazard ratio 2.30 (2.00-2.64), P < 0.001], with the highest risk during the first 30 postoperative days [adjusted hazard ratio (7.29 (5.58-9.54), P < 0.001]. The strongest independent preoperative factors associated with stroke were prior cardiac surgery [adjusted OR 2.89 (1.40-5.96)], critical preoperative condition [adjusted OR 2.55 (1.73-3.76)], previous stroke [adjusted OR 1.77 (1.35-2.33)], preoperative angina requiring intravenous nitrates [adjusted OR 1.67 (1.28-2.17)], peripheral vascular disease [OR 1.63 (1.25-2.13)] and advanced age [OR 1.05 (1.03-1.06) per year]. CONCLUSIONS The incidence of perioperative stroke after coronary artery bypass grafting has remained stable. Patients with perioperative stroke had a markedly higher adjusted risk of death early after surgery. The risk declined over time but remained higher during the entire follow-up period.
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| 10. |
- Kolsrud, Oscar, et al.
(författare)
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Dextran-based priming solution during cardiopulmonary bypass attenuates renal tubular injury-A secondary analysis of randomized controlled trial in adult cardiac surgery patients
- 2022
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Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 66:1, s. 40-47
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Tidskriftsartikel (refereegranskat)abstract
- Background Acute kidney injury (AKI) is a well-known complication after cardiac surgery and cardiopulmonary bypass (CPB). In the present secondary analysis of a blinded randomized controlled trial, we evaluated the effects of a colloid-based versus a conventional crystalloid-based prime on tubular injury and postoperative renal function in patients undergoing cardiac surgery with CPB. Methods Eighty-four adult patients undergoing cardiac surgery with CPB were randomized to receive either a crystalloid- or colloid- (dextran 40) based CPB priming solution. The crystalloid solution was based on Ringer-Acetate plus mannitol. The tubular injury biomarker, N-acetyl-b-D-glucosaminidase (NAG), serum creatinine and diuresis were measured before, during and after CPB. The incidence of AKI was assessed according to the KDIGO criteria. Results The urinary-NAG/urinary-creatinine ratio rose in both groups during and after CPB, with a more pronounced increase in the crystalloid group (p = .038). One hour after CPB, the urinary-NAG/urinary-creatinine ratio was 88% higher in the crystalloid group (4.7 +/- 6.3 vs. 2.5 +/- 2.7, p = .045). Patients that received the dextran 40-based priming solution had a significantly lower intraoperative diuresis (p < .001) compared to the crystalloid group. The incidence of AKI was 18% in the colloid and 22% in the crystalloid group (p = .66). Postoperative serum creatinine did not differ between groups. Conclusions In patients undergoing cardiac surgery with CPB, colloid-based priming solution (dextran 40) induced less renal tubular injury compared to a crystalloid-based priming solution. Whether a colloid-based priming solution will improve renal outcome in high-risk cardiac surgery, or not, needs to be evaluated in future studies on higher risk cardiac surgery patients.
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