| 1. |
- Bahnasawy, Salma M., et al.
(författare)
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Predicting cytokine kinetics during sepsis; a modelling framework from a porcine sepsis model with live Escherichia coli
- 2023
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Ingår i: Cytokine. - : Elsevier BV. - 1043-4666 .- 1096-0023. ; 169
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Tidskriftsartikel (refereegranskat)abstract
- Background: Describing the kinetics of cytokines involved as biomarkers of sepsis progression could help to optimise interventions in septic patients. This work aimed to quantitively characterise the cytokine kinetics upon exposure to live E. coli by developing an in silico model, and to explore predicted cytokine kinetics at different bacterial exposure scenarios.Methods: Data from published in vivo studies using a porcine sepsis model were analysed. A model describing the time courses of bacterial dynamics, endotoxin (ETX) release, and the kinetics of TNF and IL-6 was developed. The model structure was extended from a published model that quantifies the ETX-cytokines relationship. An external model evaluation was conducted by applying the model to literature data. Model simulations were performed to explore the sensitivity of the host response towards differences in the input rate of bacteria, while keeping the total bacterial burden constant.Results: The analysis included 645 observations from 30 animals. The blood bacterial count was well described by a one-compartment model with linear elimination. A scaling factor was estimated to quantify the ETX release by bacteria. The model successfully described the profiles of TNF, and IL-6 without a need to modify the ETXcytokines model structure. The kinetics of TNF, and IL-6 in the external datasets were well predicted. According to the simulations, the ETX tolerance development results in that low initial input rates of bacteria trigger the lowest cytokine release.Conclusion: The model quantitively described and predicted the cytokine kinetics triggered by E. coli exposure. The host response was found to be sensitive to the bacterial exposure rate given the same total bacterial burden.
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| 2. |
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| 3. |
- Hanslin, Katja, et al.
(författare)
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The impact of the systemic inflammatory response on hepatic bacterial elimination in experimental abdominal sepsis
- 2019
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Ingår i: Intensive Care Medicine Experimental. - : Springer Science and Business Media LLC. - 2197-425X. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Bacterial translocation from the gut has been suggested to induce a systemic inflammatory response syndrome (SIRS) and organ dysfunction. The liver has a pivotal role in eliminating circulating bacteria entering from the gut. We investigated whether pre-existing inflammation affects hepatic bacterial elimination.METHODS: Fifteen anaesthetised piglets were infused with E. coli in the portal vein for 3 h. The naive group (n = 6) received the bacterial infusion without endotoxin exposure. SIRS (SIRS group, n = 6) was induced by endotoxin infusion 24 h before the bacterial infusion. For effects of anaesthesia, controls (n = 3) received saline instead of endotoxin for 24 h. Bacterial counts and endotoxin levels in the portal and hepatic veins were analysed during bacterial infusion.RESULTS: The bacterial killing rate was higher in the naive group compared with the SIRS group (p = 0.001). The ratio of hepatic to portal venous bacterial counts, i.e. the median bacterial influx from the splanchnic circulation, was 0.06 (IQR 0.01-0.11) in the naive group and 0.71 (0.03-1.77) in the SIRS group at 3 h, and a magnitude lower in the naive group during bacteraemia (p = 0.03). Similar results were seen for hepatic endotoxin elimination. Peak log tumour necrosis factor alpha was higher in the naive 4.84 (4.77-4.89) vs. the SIRS group 3.27 (3.26-3.32) mg/L (p < 0.001).CONCLUSIONS: Our results suggest that hepatic bacterial and endotoxin elimination is impaired in pigs with pre-existing SIRS while the inflammatory response to bacterial infusion is diminished. If similar mechanisms operate in human critical illness, the hepatic elimination of bacteria from the gut could be impaired by SIRS.
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| 4. |
- Lipcsey, Miklós, et al.
(författare)
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The time course of calprotectin liberation from human neutrophil granulocytes after Escherichia coli and endotoxin challenge
- 2019
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Ingår i: Innate Immunity. - : SAGE Publications. - 1753-4259 .- 1753-4267. ; 25:6, s. 369-373
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Tidskriftsartikel (refereegranskat)abstract
- Plasma calprotectin has previously been reported as a biomarker for sepsis. The aim of the present study was to elucidate the kinetics of calprotectin release from neutrophils exposed to Escherichia coli and endotoxin. Whole blood samples were exposed to E. coli bacteria or endotoxin in vitro. Blood samples were collected after 0, 1, 2, 3 and 4 h and plasma calprotectin was analysed by particle enhanced turbidimetric immunoassay while TNF-α, IL-6, neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) were analyzed by ELISA. When neutrophils were exposed to either E. coli or endotoxin, calprotectin levels began to increase within a couple of hours after the challenge. Calprotectin increases early in response to bacterial challenge. Given the logistic advantages of the calprotectin analysis, this may be of interest for early diagnosis of bacterial infections.
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| 5. |
- Otterbeck, Alexander, et al.
(författare)
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Bronchially instilled IgY-antibodies did not decrease pulmonary p. aeruginosa concentration in experimental porcine pneumonia
- 2021
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Ingår i: Acta Anaesthesiologica Scandinavica. - : John Wiley & Sons. - 0001-5172 .- 1399-6576. ; 65:5, s. 656-663
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundP. aeruginosa possesses antibiotic resistance, making treatment difficult. Polyclonal anti-P. aeruginosa IgY-antibodies (Pa-IgY) have antibacterial effects, but have not been studied in large animal pneumonia.ObjectivesTo test if Pa-IgY decreases the concentration of P. aeruginosa in bronchoalveolar lavage in experimental porcine pneumonia over 27 hours.MethodNorwegian landrace pigs were anesthetized, mechanically ventilated, and subject to invasive monitoring. The animals were randomized to receive either P. aeruginosa (control, n = 12) or P aeruginosa + Pa-IgY antibodies with a repeated dose of Pa-IgY after 12 hours (intervention, n = 12) in the right lower pulmonary lobe. Bronchoalveolar lavage (BAL) cultures and physiological measurements were obtained repeatedly for 27 hours after which the pigs were sacrificed.ResultsBAL bacterial concentration increased in both groups and peaked at 107.28 ± 100.21 CFU/mL in the intervention group vs 107.36 ± 100.50 CFU/mL in the control group (n.s.). BAL bacterial concentration decreased during the experiment to 105.35 ± 100.39 CFU/mL in the intervention group vs 105.19 ± 100.37 in the control group (n.s.). The intervention group had lower heart rate (P < .001), lower cardiac index (P < .01), and lower arterial lactate (P < .001) compared to the control group. The core temperature was lower in the intervention group than in the control group (P < .001).ConclusionThe chosen dose of Pa-IgY did not decrease concentrations of P. aeruginosa in BAL over 27 hours. We conclude that it is unlikely that there is a large effect of this specific dose and route of administration of Pa-IgY in this type of model.
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| 6. |
- Otterbeck, Alexander, et al.
(författare)
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Inhalation of specific anti-Pseudomonas aeruginosa IgY antibodies transiently decreases P. aeruginosa colonization of the airway in mechanically ventilated piglets
- 2019
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Ingår i: Intensive Care Medicine Experimental. - : SPRINGEROPEN. - 2197-425X. ; 7:24
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Tidskriftsartikel (refereegranskat)abstract
- Background: P. aeruginosa is a pathogen frequently resistant to antibiotics and a common cause of ventilator-associated pneumonia (VAP). Non-antibiotic strategies to prevent or treat VAP are therefore of major interest. Specific polyclonal avian IgY antibodies have previously been shown to be effective against pneumonia caused by P. aeruginosa in rodents and against P. aeruginosa airway colonization in patients.Objectives: To study the effect of specific polyclonal anti-P. aeruginosa IgY antibodies (Pa-IgY) on colonization of the airways in a porcine model.Method: The pigs were anesthetized, mechanically ventilated, and subject to invasive hemodynamic monitoring and allocated to either receive 10(9) CFU nebulized P. aeruginosa (control, n=6) or 10(9) CFU nebulized P. aeruginosa + 200 mg Pa-IgY antibodies (intervention, n=6). Physiological measurement, blood samples, and tracheal cultures were then secured regularly for 27 h, after which the pigs were sacrificed and lung biopsies were cultured.Results: After nebulization, tracheal growth of P. aeruginosa increased in both groups during the experiment, but with lower growth in the Pa-IgY-treated group during the experiment (p = 0.02). Tracheal growth was 4.6 x 10(3) (9.1 x 10(2)-3.1 x 10(4)) vs. 4.8 x 10(4) (7.5 x 10(3)-1.4 x 10(5)) CFU/mL in the intervention group vs. the control group at 1h and 5.0 x 10(0) (0.0 x 10(0)-3.8 x 10(2)) vs. 3.3 x 10(4) (8.0 x 10(3)-1.4 x 10(5)) CFU/mL at 12 h in the same groups. During this time, growth in the intervention vs. control group was one to two orders of ten lower. After 12 h, the treatment effect disappeared and bacterial growth increased in both groups. The intervention group had lower body temperature and cardiac index and higher static compliance compared to the control group.Conclusion: In this porcine model, Pa-IgY antibodies lessen bacterial colonization of the airways.
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| 7. |
- Otterbeck, Alexander, et al.
(författare)
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Intravenous anti-P. aeruginosa IgY-antibodies do not decrease pulmonary bacterial concentrations in a porcine model of ventilator-associated pneumonia
- 2022
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Ingår i: Innate Immunity. - : Sage Publications. - 1753-4259 .- 1753-4267. ; 28:7-8, s. 224-234
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Tidskriftsartikel (refereegranskat)abstract
- Ventilator associated pneumonia (VAP) caused by P. aeruginosa is a cause of morbidity and mortality in critically ill patients. The spread of pathogens with anti-microbial resistance mandates the investigation of novel therapies. Specific polyclonal anti-P. aeruginosa IgY-antibodies (Pa-IgY) might be effective for VAP caused by P. aeruginosa. The objective of this study was to investigate if intravenous Pa-IgY decreases the lower airway concentration of P. aeruginosa in VAP. We used a double blind randomized placebo controlled porcine model of VAP caused by P. aeruginosa. Eighteen pigs were randomized to either receive intravenous Pa-IgY or placebo. Repeated registration of physiological parameters and sampling was performed for 27 h. Concentration of P. aeruginosa in BAL-cultures was similar in both groups with 104.97 ± 102.09 CFU/mL in the intervention group vs 104.37 ± 102.62 CFU/mL in the control group at the end of the experiment. The intervention group had higher heart rate, cardiac index, oxygen delivery and arterial oxygen tension/fraction of inspired oxygen-ratio, but lower plasma lactate and blood hemoglobin levels than the control group. In summary, in an anesthetized and mechanically ventilated porcine model of VAP, Pa-IgY at the dose used did not decrease concentrations of P. aeruginosa in the lower airways.
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| 8. |
- Sancho Ferrando, Elena, et al.
(författare)
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Soluble TNF receptors predict acute kidney injury and mortality in critically ill COVID-19 patients : A prospective observational study
- 2021
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Ingår i: Cytokine. - : Springer Nature. - 1043-4666 .- 1096-0023. ; 149
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Although pneumonia is the hallmark of coronavirus disease 2019 (COVID-19), multiple organ failure may develop in severe disease. TNFα receptors in their soluble form (sTNFR) are involved in the immune cascade in other systemic inflammatory processes such as septic shock, and could mediate the inflammatory activation of distant organs. The aim of this study is to analyse plasma levels of sTNFR 1 and 2 in association with organ failure and outcome in critically ill patients with COVID-19.METHODS: After informed consent, we included 122 adult patients with PCR-confirmed COVID-19 at ICU admission. Demographic data, illness severity scores, organ failure and survival at 30 days were collected. Plasma sTNFR 1 and 2 levels were quantified during the first days after ICU admission. Twenty-five healthy blood donors were used as control group.RESULTS: Levels of sTNFR were higher in severe COVID-19 patients compared to controls (p < 0.001). Plasma levels of sTNFR were associated to illness severity scores (SAPS 3 and SOFA), inflammation biomarkers such as IL-6, ferritin and PCT as well as development of AKI during ICU stay. sTNFR 1 higher than 2.29 ng/mL and? sTNFR 2 higher than 11.7 ng/mL were identified as optimal cut-offs to discriminate survivors and non-survivors 30 days after ICU admission and had an area under the curve in receiver operating characteristic curve of 0.75 and 0.67 respectively.CONCLUSION: Plasma levels of sTNFR 1 and 2 were higher in COVID-19 patients compared to controls and were strongly associated with other inflammatory biomarkers, severity of illness and acute kidney injury development during ICU stay. In addition, sTNFR 1 was an independent predictor of 30-day mortality after adjustment for age and respiratory failure.
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| 9. |
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| 10. |
- von Seth, Magnus, et al.
(författare)
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Early decreased respiratory chain capacity in resuscitated experimental sepsis is a major contributor to lactate production
- 2023
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Ingår i: Shock. - : Wolters Kluwer. - 1073-2322 .- 1540-0514. ; 60:3, s. 461-468
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Tidskriftsartikel (refereegranskat)abstract
- Background: Increased plasma lactate levels in patients with sepsis may be due to insufficient oxygen delivery, but mitochondrial dysfunction or accelerated glycolysis may also contribute. We studied the effect of the latter on muscle metabolism by using microdialysis in a sepsis model with sustained oxygen delivery and decreased energy consumption or mitochondrial blockade.Methods: Pigs were subjected to continuous Escherichia coli infusion (sepsis group, n = 12) or saline infusion (sham group, n = 4) for 3 h. Protocolized interventions were applied to normalize the oxygen delivery and blood pressure. Microdialysis catheters were used to monitor muscle metabolism (naïve). The same catheters were used to block the electron transport chain with cyanide or the Na+/K+-ATPase inhibitor, ouabain locally.Results: All pigs in the sepsis group had positive blood cultures and a Sequential Organ Failure Assessment score increase by at least 2, fulfilling the sepsis criteria. Plasma lactate was higher in the sepsis group than in the sham group (P < 0.001), whereas muscle glucose was lower in the sepsis group (P < 0.01). There were no changes in muscle lactate levels over time but lactate to pyruvate ratio (LPR) was elevated in the sepsis versus the sham group (P < 0.05). Muscle lactate, LPR, and glutamate levels were higher in the sepsis group than in the sham group in the cyanide catheters (P < 0.001, all comparisons) and did not normalize in the former group.Conclusions: In this experimental study on resuscitated sepsis, we observed increased aerobic metabolism and preserved mitochondrial function. Sepsis and electron transport chain inhibition led to increased LPR, suggesting a decreased mitochondrial reserve capacity in early sepsis.
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| 11. |
- von Seth, Magnus, et al.
(författare)
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Mitochondrial stress in early experimental sepsis revealed by electron transport chain inhibition
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Increased plasma lactate in sepsis may not be due to insufficient oxygen delivery, but accelerated glycolysis and mitochondrial dysfunction may also contribute. To assess critical pathophysiological steps in non-ischemic lactate increase we studied the muscle metabolism with microdialysis in a sepsis model in pigs submitted to continuous E. coli infusion (sepsis group, n=12) for 3 hours (h). A control group (sham group, n=4) underwent the same procedures but did not receive E. coli. Protocolized interventions were applied to normalize oxygen delivery (DO2) and blood pressure. Metabolism was intervened locally via microdialysis catheters with the electron-transport chain inhibitor sodium cyanide and the inhibitor of the major energy consuming enzyme Na+/K+-ATPase ouabain. Results: All pigs in the sepsis group had positive blood cultures at 1 h. Median (range) Sequential Organ Failure Assessment (SOFA) score at 0 h was 0 (0-1) in both groups. At 3 h, SOFA increased to 6 (3-6) in the sepsis group but remained virtually unchanged in the sham group. Plasma lactate increased in the sepsis group despite that protocolized interventions maintained DO2. Sepsis accelerated glycolysis with a decrease in glucose, maintained or increased in lactate and pyruvate with a virtually normal lactate-to-pyruvate ratio (LPR) in microdialysate from catheters without intervention. The local cyanide intervention produced a severe energy crisis as evidenced by a dramatically elevated LPR, a lowered pyruvate and an increased lactate in both the sepsis and sham group. During sepsis, when the cyanide effect gradually diminished, this energy crisis normalized in the sham group but partly persisted in the sepsis group.Conclusions: Our findings suggest a reduction in mitochondrial oxidative capacity induced by sepsis, as revealed by cyanide inhibition. Decreasing energy consumption with a local ouabain intervention did not impact glucose and fat metabolism in sepsis or sham animals.
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| 12. |
- Wilske, Frida, et al.
(författare)
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Enhanced bacterial clearance in early secondary sepsis in a porcine intensive care model.
- 2023
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Early secondary sepsis (ESS), occurring after recent inflammatory activation is associated with a reduced inflammatory response. If this attenuation also is associated with decreased bacterial killing, the need for antibiotic efficacy might be greater than in primary sepsis (PS). This prospective, randomised interventional study compares bacterial killing in ESS and PS in a large animal intensive care sepsis model. 38 pigs were intravenously administered live Escherichia coli for 3 h. Before baseline ESS was pre-exposed to endotoxin 24 h, whereas PS was not. Bacterial growth was measured in organs immediately post-mortem, repeatedly during 6 h in blood in vivo and for blood intrinsic bactericidal capacity ex vivo. Splenic growth was lower in ESS animals, than in PS animals (3.31 ± 0.12, vs. 3.84 ± 0.14 log10 CFU/mL, mean ± SEM) (p < 0.01) with a similar trend in hepatic growth (p = NS). Blood bacterial count at 2 h correlated with splenic bacterial count in ESS (ESS: r = 0.71, p < 0.001) and to blood killing capacity in PS (PS: r = 0.69, p < 0.001). Attenuated inflammation in ESS is associated with enhanced antibacterial capacities in the spleen. In ESS blood bacterial count is related to splenic killing and in PS to blood bactericidal capacity. The results suggest no increased need for synergistic antibiotic combinations in ESS.
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