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Thorsted, A., Bouchene, S., Tano, E., Castegren, M., Lipcsey, M., Sjölin, J., . . . Nielsen, E. I. (2019). A non-linear mixed effect model for innate immune response: In vivo kinetics of endotoxin and its induction of the cytokines tumor necrosis factor alpha and interleukin-6. PLoS ONE, 14(2), Article ID e0211981.
Open this publication in new window or tab >>A non-linear mixed effect model for innate immune response: In vivo kinetics of endotoxin and its induction of the cytokines tumor necrosis factor alpha and interleukin-6
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2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 2, article id e0211981Article in journal (Refereed) Published
Abstract [en]

Endotoxin, a component of the outer membrane of Gram-negative bacteria, has been extensively studied as a stimulator of the innate immune response. However, the temporal aspects and exposure-response relationship of endotoxin and resulting cytokine induction and tolerance development is less well defined. The aim of this work was to establish an in silico model that simultaneously captures and connects the in vivo time-courses of endotoxin, tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and associated tolerance development. Data from six studies of porcine endotoxemia in anesthetized piglets (n = 116) were combined and used in the analysis, with purified endotoxin (Escherichia coli O111: B4) being infused intravenously for 1-30 h in rates of 0.063-16.0 mu g/kg/h across studies. All data were modelled simultaneously by means of importance sampling in the non-linear mixed effects modelling software NONMEM. The infused endotoxin followed one-compartment disposition and non-linear elimination, and stimulated the production of TNF-alpha to describe the rapid increase in plasma concentration. Tolerance development, observed as declining TNF-alpha concentration with continued infusion of endotoxin, was also driven by endotoxin as a concentration-dependent increase in the potency parameter related to TNF-alpha production (EC50). Production of IL-6 was stimulated by both endotoxin and TNF-a, and four consecutive transit compartments described delayed increase in plasma IL-6. A model which simultaneously account for the time-courses of endotoxin and two immune response markers, the cytokines TNF-alpha and IL-6, as well as the development of endotoxin tolerance, was successfully established. This model-based approach is unique in its description of the time-courses and their interrelation and may be applied within research on immune response to bacterial endotoxin, or in pre-clinical pharmaceutical research when dealing with study design or translational aspects.

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-379038 (URN)10.1371/journal.pone.0211981 (DOI)000459330800014 ()30789941 (PubMedID)
Funder
Swedish Foundation for Strategic Research
Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-11Bibliographically approved
Marchesi, S., Ortiz-Nieto, F., Ahlgren, K. M., Roneus, A., Feinstein, R., Lipcsey, M., . . . Hedenstierna, G. (2019). Abdominal organ perfusion and inflammation in experimental sepsis: a magnetic resonance imaging study. American Journal of Physiology - Gastrointestinal and Liver Physiology, 316(1), G187-G196
Open this publication in new window or tab >>Abdominal organ perfusion and inflammation in experimental sepsis: a magnetic resonance imaging study
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2019 (English)In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 316, no 1, p. G187-G196Article in journal (Refereed) Published
Abstract [en]

Diffusion-weighted magnetic resonance imaging (DW-MRI) uses water as contrast and enables the study of perfusion in many organs simultaneously in situ. We used DW-MRI in a sepsis model, comparing abdominal organs perfusion with global hemodynamic measurements and inflammation. Sixteen anesthetized piglets were randomized into 3 groups: HighMAP (mean arterial pressure, MAP > 65 mmHg), LowMAP (MAP between 50 and 60 mmHg) and Healthy Controls (HC). Sepsis was obtained with endotoxin and the desired MAP maintained with noradrenaline. After 6 hours DW-MRI was performed. Acute inflammation was assessed with IL-6 and TNFα in abdominal organs, ascites, and blood and by histology of intestine (duodenum). Perfusion of abdominal organs was reduced in the LowMAP group compared to the HighMAP group and HC. Liver perfusion was still reduced by 25% in the HighMAP group compared with HC. Intestinal perfusion did not differ significantly between the study groups. Cytokines concentration were generally higher in the LowMAP group but did not correlate with global hemodynamics. However, cytokines correlated with regional perfusion and, for liver and intestine, also with intra-abdominal pressure. Histopathology of intestine worsened with decreasing perfusion. In conclusion, although a low MAP (≤60 mmHg) indicated impeded abdominal perfusion in experimental sepsis, it did not predict inflammation, nor did other global measures of circulation. Decreased abdominal perfusion predicted partially inflammation but intestine, occupying most of the abdomen, and liver, were also affected by intra-abdominal pressure.

Keywords
Abdominal organs, inflammation, magnetic resonance, perfusion, sepsis
National Category
Surgery Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-364356 (URN)10.1152/ajpgi.00151.2018 (DOI)000455670700012 ()30335473 (PubMedID)
Funder
Swedish Heart Lung FoundationSwedish Research Council
Available from: 2018-10-25 Created: 2018-10-25 Last updated: 2019-02-05Bibliographically approved
Frithiof, R., Bandert, A., Larsson, A., Lipcsey, M. & Smekal, D. (2019). Central Venous Line and Dialysis Catheter Position Affects Drug Clearance during Continuous Renal Replacement Therapy in an Animal Model.. ASAIO journal (1992), 65(4), 408-413
Open this publication in new window or tab >>Central Venous Line and Dialysis Catheter Position Affects Drug Clearance during Continuous Renal Replacement Therapy in an Animal Model.
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2019 (English)In: ASAIO journal (1992), ISSN 1058-2916, E-ISSN 1538-943X, Vol. 65, no 4, p. 408-413Article in journal (Refereed) Published
Abstract [en]

In intensive care, drugs are commonly administered through central venous catheters (CVC). These catheters and central venous dialysis catheters (CVDC) are often placed in the same vessel for practical reasons. The aim of this experimental study was to investigate if the position of CVC and CVDC influences the elimination of infused drugs, during continuous renal replacement therapy (CRRT). In a randomized, cross-over model, anesthetized piglets received both a CVC and a CVDC in a jugular vein. Another CVDC was placed in a femoral vein for comparison. After baseline measurements, CRRT was performed in either of the CVDC, each CRRT-period separated by another baseline period. Hypotension was induced by peripherally given sodium nitroprusside. In the CVC, both gentamicin and noradrenaline were administered. Noradrenaline was titrated to reach a target blood pressure. When CRRT was performed using the CVDC in the same vessel as the drugs were infused, the plasma concentration of gentamicin was reduced compared with when the infusion and CVDC were in different vessels (5.66 [standard deviation (SD) ± 1.23] vs. 7.76 [SD ± 2.30] mg/L [p = 0.02]). The noradrenaline infusion rate needed to reach the target blood pressure was more than doubled (0.32 [SD ± 0.16] vs. 0.15 [SD ± 0.08] µg/kg/min [p = 0.006]). This experimental study indicates that the removal of drugs is increased if infusion is in close vicinity of the CVDC, during CRRT.

National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-353342 (URN)10.1097/MAT.0000000000000839 (DOI)000466791000022 ()29863633 (PubMedID)
Funder
Swedish Research Council, 523-2014-2569
Available from: 2018-10-18 Created: 2018-10-18 Last updated: 2019-05-29Bibliographically approved
Strandberg, G., Larsson, A., Lipcsey, M. & Eriksson, M. (2019). Comparison of Intraosseous, Arterial, and Venous Blood Sampling for Laboratory Analysis in Hemorrhagic Shock. Clinical Laboratory, 65(7), 1169-1177
Open this publication in new window or tab >>Comparison of Intraosseous, Arterial, and Venous Blood Sampling for Laboratory Analysis in Hemorrhagic Shock
2019 (English)In: Clinical Laboratory, ISSN 1433-6510, Vol. 65, no 7, p. 1169-1177Article in journal (Refereed) Published
Abstract [en]

Background: Intraosseous (IO) access is often indicated for administration of drugs and fluids in emergencies when venous access is challenging. There is no consensus regarding whether and which laboratory analyses may be performed on IO aspirates, and research on hemodynamically unstable subjects is limited.

Methods: Twelve anesthetized pigs were sampled from IO, venous, and arterial accesses during stable circulation and after hemorrhage corresponding to 20% and 40% of the blood volume. Samples were analyzed for blood gases and acid-base status, electrolytes, hematocrit, creatinine, glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (γ-GT), alkaline phosphatase (ALP), and creatine kinase (CK).

Results: Average differences of blood gases and acid-base parameters, sodium, creatinine, hematocrit, ALT, and γ-GT and between IO and venous samples were small at baseline and after hemorrhage while differences for lactate and glucose increased with hypovolemia. Both IO-arterial and venoarterial differences in acid-base parameters increased with hypovolemia. Dispersions of differences were often large.

Conclusions: Average levels of blood gases, acid base parameters, hematocrit, CK, AST, γ-GT, creatinine, and ALT, but not lactate and glucose, were similar in IO and venous samples in hypovolemia. However, precision was limited, indicating that IO test results should be confirmed when other vascular access is established, and that analysis of IO samples should be limited to acute situations and not used for detailed diagnostics in this setting.

Keywords
analysis, blood drawing, intraosseous sampling, laboratory, precision, shock
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-321402 (URN)10.7754/Clin.Lab.2019.181214 (DOI)000475700400006 ()31307157 (PubMedID)
Note

Title in thesis list of papers: Comparison of Intraosseous, Arterial and Venous Blood Sampling for Laboratory Analysis in Haemorrhagic Shock

Available from: 2017-05-04 Created: 2017-05-04 Last updated: 2019-08-26Bibliographically approved
Otterbeck, A., Hanslin, K., Lidberg Lantz, E., Larsson, A., Stålberg, J. & Lipcsey, M. (2019). Correction to: Inhalation of specific anti-Pseudomonas aeruginosa IgY antibodies transiently decreases P. aeruginosa colonization of the airway in mechanically ventilated piglets.. Intensive Care Medicine Experimental, 7, Article ID 24.
Open this publication in new window or tab >>Correction to: Inhalation of specific anti-Pseudomonas aeruginosa IgY antibodies transiently decreases P. aeruginosa colonization of the airway in mechanically ventilated piglets.
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2019 (English)In: Intensive Care Medicine Experimental, ISSN 1646-2335, E-ISSN 2197-425X, Vol. 7, article id 24Article in journal (Refereed) Published
Abstract [en]

Following publication of the original article, the authors flagged that an incorrect piece of data is given in the Materials and Methods section of the article.

National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-383249 (URN)10.1186/s40635-019-0253-2 (DOI)000467648200001 ()31073811 (PubMedID)
Note

This correction refers to: https://doi.org/10.1186/s40635-019-0246-1

Available from: 2019-05-11 Created: 2019-05-11 Last updated: 2019-06-10Bibliographically approved
Otterbeck, A., Hanslin, K., Lantz, E. L., Larsson, A., Stålberg, J. & Lipcsey, M. (2019). Inhalation of specific anti-Pseudomonas aeruginosa IgY antibodies transiently decreases P. aeruginosa colonization of the airway in mechanically ventilated piglets. Intensive Care Medicine Experimental, 7, Article ID 21.
Open this publication in new window or tab >>Inhalation of specific anti-Pseudomonas aeruginosa IgY antibodies transiently decreases P. aeruginosa colonization of the airway in mechanically ventilated piglets
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2019 (English)In: Intensive Care Medicine Experimental, ISSN 1646-2335, E-ISSN 2197-425X, Vol. 7, article id 21Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
SPRINGEROPEN, 2019
Keywords
Pneumonia, Nosocomial, VAP, HAP
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-382562 (URN)10.1186/s40635-019-0246-1 (DOI)000464186100001 ()30963317 (PubMedID)
Funder
Vinnova, 2016-04083
Available from: 2019-05-03 Created: 2019-05-03 Last updated: 2019-05-03Bibliographically approved
Lipcsey, M., Aronsson, A., Larsson, A., Renlund, H. & Gedeborg, R. (2019). Multivariable models using administrative data and biomarkers to adjust for case mix in the ICU. Acta Anaesthesiologica Scandinavica, 63(6), 751-760
Open this publication in new window or tab >>Multivariable models using administrative data and biomarkers to adjust for case mix in the ICU
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2019 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 63, no 6, p. 751-760Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Routinely collected laboratory biomarkers could improve control of confounding from disease severity in non-interventional studies of general intensive care unit (ICU) patients. Their ability to predict both short- and long-term mortality was evaluated.

METHODS: The performance of age, sex, Charlson co-morbidity index, and baseline values of ten predefined blood biomarkers as predictors of 30-day and 1-year mortality was evaluated in 5505 general ICU stays.

RESULTS: Regression models based on age, sex, Charlson index, and biomarkers were somewhat less accurate in predicting 30-day mortality (c-index 0.83, Brier score 0.27) compared to the SAPS II score (c-index = 0.88, Brier score = 0.09) and in predicting 1-year mortality (c-index = 0.82, Brier score = 0.31) compared to the SAPS II score (c-index = 0.85, Brier score = 0.13). Cystatin C improved predictive ability slightly compared to creatinine, but age and Charlson comorbidity index were more important predictors. Using multiple imputation to replace missing biomarker values notably improved predictive ability of the models.

CONCLUSIONS: Automatically collected baseline variables are almost as predictive of both short- and long-term mortality in general ICU patients, as the SAPS II score. This can facilitate internal control of confounding in non-interventional studies of mortality using administrative data.

Keywords
creatinine, cystatin C, intensive care, logistic models, mortality
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-377642 (URN)10.1111/aas.13338 (DOI)000472664500008 ()30734281 (PubMedID)
Available from: 2019-02-23 Created: 2019-02-23 Last updated: 2019-09-12Bibliographically approved
Larsson, A., Carlsson, L., Karlsson, B. & Lipcsey, M. (2019). Rapid testing of red blood cell parameters in primary care patients using HemoScreen™ point of care instrument. BMC Family Practice, 20(1), Article ID 77.
Open this publication in new window or tab >>Rapid testing of red blood cell parameters in primary care patients using HemoScreen™ point of care instrument
2019 (English)In: BMC Family Practice, ISSN 1471-2296, E-ISSN 1471-2296, Vol. 20, no 1, article id 77Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Patients with anemia are frequently encountered in primary care. Once anemia is detected, it is essential to define the type and identify the underlying cause prior to initiation of treatment. In most cases, the cause can be determined using information from the patient history, physical exam, and complete blood counts (CBC). Point of care testing of blood cell counts would speed up the work up of anemia patients. The aim of the present study was to evaluate if the HemoScreen™ instrument (PixCell Medical, Yokneam Ilit, Israel) could be used for primary care samples. It is a POCT instrument that utilizes single sample cuvettes and image analysis of full blood count including RBC, Hemoglobin, MCV, MCH, platelets, WBC, and WBC 5-part differential.

METHODS: We compared the HemoScreen™ and the Sysmex XN instrument results of 100 primary care patient samples focusing on the total white blood cells, red blood cell parameters RBC, Hemoglobin, MCH, MCV and platelets.

RESULTS: Deming correlations between the HemoScreen™ and the Sysmex XN instruments for the CBC were WBCHemoScreen™ = 1.016* WBCSysmex + 0.34; r = 0.981, RBCHemoScreen™ = 0.988* RBCSysmex + 0.015; r = 0.974, HemoglobinHemoScreen™ = 1.081* HemoglobinSysmex - 11.25; r = 0.964, MCHHemoScreen™ = 0.978* MCHSysmex + 0.78; r = 0.939, MCVHemoScreen™ = 0.963* MCVSysmex + 8.68; r = 0.946, PlateletsHemoScreen™ = 0.964* PlateletsSysmex + 25.7; r = 0.953.

CONCLUSION: The HemoScreen™ instrument could provide rapid and accurate test results for evaluation of the red blood cell parameters in primary care. This new technology is interesting as it allows the analysis red blood cell parameters also at small primary care centers.

Place, publisher, year, edition, pages
BioMed Central, 2019
Keywords
Anemia, Iron deficiency, red blood cells, Method evaluation, Point of care testing, Primary care
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-385060 (URN)10.1186/s12875-019-0971-2 (DOI)000470712600001 ()31174471 (PubMedID)
Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-06-26Bibliographically approved
Eriksson, M. B., Larsson, A., Lipcsey, M. & Strandberg, G. (2019). The effect of hemorrhagic shock and intraosseous adrenaline injection on the delivery of a subsequently administered drug - an experimental study. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, 27, Article ID 29.
Open this publication in new window or tab >>The effect of hemorrhagic shock and intraosseous adrenaline injection on the delivery of a subsequently administered drug - an experimental study
2019 (English)In: Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, ISSN 1757-7241, E-ISSN 1757-7241, Vol. 27, article id 29Article in journal (Refereed) Published
Abstract [en]

Background: Intraosseous (IO) access is a recommended method when venous access cannot be rapidly established in an emergency. Experimental data suggest that major hemorrhage and catecholamine administration both reduce bone marrow blood flow. We studied the uptake of gentamicin as a tracer substance administered IO following adrenaline administration in hemorrhagic shock and in cardiac arrest.

Methods: Twenty anesthetized pigs underwent hemorrhage corresponding to 50% of the blood volume. They then received injections of either; adrenaline IO (n=5), saline IO n=5), adrenaline IO during cardiac arrest and cardiopulmonary resuscitation (CPR, n=5), or intravenous adrenaline. The injections were followed by an injection of gentamicin by the same route. Doses and volumes were equivalent among the groups. In all animals, mixed venous antibiotic concentrations were analyzed at 5, 15 and 30min after administration.

Results: Mean (SD) plasma gentamicin concentrations (mg x L-1) at 5min were 26.4 (2.3) in the group with previous IO adrenaline administration, 26.6 (4.5) in the IO saline group, 31. 2 (12) in the IO adrenaline + CPR group and 23 (4.5) in the IV group. Concentrations in the CPR group were significantly higher than the others.

Conclusions: No impairment of drug uptake with IO administration after recent IO adrenaline exposure was demonstrable in this shock model.

Place, publisher, year, edition, pages
BMC, 2019
Keywords
Adrenaline, Cardiac arrest, CPR, Intraosseous, Pig, Shock
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-379890 (URN)10.1186/s13049-018-0569-z (DOI)000460797900001 ()30850019 (PubMedID)
Available from: 2019-03-25 Created: 2019-03-25 Last updated: 2019-03-25Bibliographically approved
Hanslin, K., Sjölin, J., Skorup, P., Wilske, F., Frithiof, R., Larsson, A., . . . Lipcsey, M. (2019). The impact of the systemic inflammatory response on hepatic bacterial elimination in experimental abdominal sepsis. Intensive Care Medicine Experimental, 7(1), Article ID 52.
Open this publication in new window or tab >>The impact of the systemic inflammatory response on hepatic bacterial elimination in experimental abdominal sepsis
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2019 (English)In: Intensive Care Medicine Experimental, ISSN 2197-425X, Vol. 7, no 1, article id 52Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
Animal models, Bacterial translocation, Endotoxins, Escherichia coli, Mononuclear phagocyte system, Sepsis
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-392098 (URN)10.1186/s40635-019-0266-x (DOI)000483360800001 ()31456116 (PubMedID)
Funder
Swedish Society of Medicine, SLS-409831
Available from: 2019-08-29 Created: 2019-08-29 Last updated: 2019-10-18Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-1976-4129

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