Pathophysiological, Inflammatory and Haemostatic Responses to Various Endotoxaemic Patterns : An Experimental Study in the Pig

Septic shock is frequently seen in intensive care units and is associated with significant mortality. Endotoxin – a major mediator of the pathophysiologic responses – is released during lysis of Gram-negative bacteria. These responses can be mimicked in the endotoxaemic pig. This thesis focuses on the following topics: the inflammatory and pathophysiological responses to various endotoxin doses and infusion patterns; covariations between endotoxin induced inflammatory and pathophysiological responses; whether the biological effects of endotoxin can be modulated by clopidogrel and whether tobramycin or ceftazidime reduce plasma cytokine levels. Endotoxin induced linear log-log cytokine and F2-isoprostane responses. Leukocyte and platelet responses, pulmonary compliance, circulatory variables as well as indicators of plasma leakage and hypoperfusion exhibited log-linear responses to the endotoxin dose. Biological responses to endotoxaemia such as inflammation, hypotension, hypoperfusion and organ dysfunction were more expressed when the organism was exposed to endotoxin at a higher rate. These results may facilitate the possibility to choose relevant endotoxin administration, when experiments are set up in order to evaluate certain responses to endotoxaemia. Correlation studies between cytokines, leukocytes, platelets and the endotoxin dose were in agreement with the well-known ability of endotoxin to induce cytokine expression and to activate both primary haemostasis and leukocytes. Free radical mediated lipid peroxidation and COX-mediated inflammation correlated to cytokine expression and organ dysfunction in endotoxaemic shock. Endotoxaemic pigs pretreated with clopidogrel, exhibited a trend towards less expressed deterioration of renal function, although blocking of ADP-induced primary haemostasis is not a key mediator of endotoxin induced deterioration of renal function. Tobramycin did not neutralise the biological effects of endotoxin or the plasma levels of endotoxin, suggesting that these antibiotics do not bind to endotoxin. Reduction in IL-6 was greater in pigs treated with ceftazidime and tobramycin as compared with those given saline, indicating a possible anti-inflammatory effect of both antibiotics

Pathophysiological, Inflammatory and Haemostatic Responses to Various Endotoxaemic Patterns : An Experimental Study in the Pig

Septic shock is frequently seen in intensive care units and is associated with significant mortality. Endotoxin – a major mediator of the pathophysiologic responses – is released during lysis of Gram-negative bacteria. These responses can be mimicked in the endotoxaemic pig. This thesis focuses on the following topics: the inflammatory and pathophysiological responses to various endotoxin doses and infusion patterns; covariations between endotoxin induced inflammatory and pathophysiological responses; whether the biological effects of endotoxin can be modulated by clopidogrel and whether tobramycin or ceftazidime reduce plasma cytokine levels. Endotoxin induced linear log-log cytokine and F2-isoprostane responses. Leukocyte and platelet responses, pulmonary compliance, circulatory variables as well as indicators of plasma leakage and hypoperfusion exhibited log-linear responses to the endotoxin dose. Biological responses to endotoxaemia such as inflammation, hypotension, hypoperfusion and organ dysfunction were more expressed when the organism was exposed to endotoxin at a higher rate. These results may facilitate the possibility to choose relevant endotoxin administration, when experiments are set up in order to evaluate certain responses to endotoxaemia. Correlation studies between cytokines, leukocytes, platelets and the endotoxin dose were in agreement with the well-known ability of endotoxin to induce cytokine expression and to activate both primary haemostasis and leukocytes. Free radical mediated lipid peroxidation and COX-mediated inflammation correlated to cytokine expression and organ dysfunction in endotoxaemic shock. Endotoxaemic pigs pretreated with clopidogrel, exhibited a trend towards less expressed deterioration of renal function, although blocking of ADP-induced primary haemostasis is not a key mediator of endotoxin induced deterioration of renal function. Tobramycin did not neutralise the biological effects of endotoxin or the plasma levels of endotoxin, suggesting that these antibiotics do not bind to endotoxin. Reduction in IL-6 was greater in pigs treated with ceftazidime and tobramycin as compared with those given saline, indicating a possible anti-inflammatory effect of both antibiotics

Pathophysiological, Inflammatory and Haemostatic Responses to Various Endotoxaemic Patterns : An Experimental Study in the Pig

Septic shock is frequently seen in intensive care units and is associated with significant mortality. Endotoxin – a major mediator of the pathophysiologic responses – is released during lysis of Gram-negative bacteria. These responses can be mimicked in the endotoxaemic pig. This thesis focuses on the following topics: the inflammatory and pathophysiological responses to various endotoxin doses and infusion patterns; covariations between endotoxin induced inflammatory and pathophysiological responses; whether the biological effects of endotoxin can be modulated by clopidogrel and whether tobramycin or ceftazidime reduce plasma cytokine levels. Endotoxin induced linear log-log cytokine and F2-isoprostane responses. Leukocyte and platelet responses, pulmonary compliance, circulatory variables as well as indicators of plasma leakage and hypoperfusion exhibited log-linear responses to the endotoxin dose. Biological responses to endotoxaemia such as inflammation, hypotension, hypoperfusion and organ dysfunction were more expressed when the organism was exposed to endotoxin at a higher rate. These results may facilitate the possibility to choose relevant endotoxin administration, when experiments are set up in order to evaluate certain responses to endotoxaemia. Correlation studies between cytokines, leukocytes, platelets and the endotoxin dose were in agreement with the well-known ability of endotoxin to induce cytokine expression and to activate both primary haemostasis and leukocytes. Free radical mediated lipid peroxidation and COX-mediated inflammation correlated to cytokine expression and organ dysfunction in endotoxaemic shock. Endotoxaemic pigs pretreated with clopidogrel, exhibited a trend towards less expressed deterioration of renal function, although blocking of ADP-induced primary haemostasis is not a key mediator of endotoxin induced deterioration of renal function. Tobramycin did not neutralise the biological effects of endotoxin or the plasma levels of endotoxin, suggesting that these antibiotics do not bind to endotoxin. Reduction in IL-6 was greater in pigs treated with ceftazidime and tobramycin as compared with those given saline, indicating a possible anti-inflammatory effect of both antibiotics

The effect of hemorrhagic shock and intraosseous adrenaline injection on the delivery of a subsequently administered drug - an experimental study

Abstract 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 30 min after administration. Results Mean (SD) plasma gentamicin concentrations (mg x L− 1) at 5 min 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

Risk of malignant disease in 1-year sepsis survivors, a registry-based nationwide follow-up study

BACKGROUND: Cancer and sepsis share risk factors, and sepsis patients may have impaired immune response and increased morbidity long after intensive care. This study aimed to assess whether sepsis survivors are at increased risk for cancer. Our objective was to assess the incidence of new cancer in 1-year sepsis survivors and test the hypothesis that it is higher than that of the general population. METHODS: We obtained data on ICU admissions of adult patients from Swedish Intensive care registry (SICR) from 2005 to 2017. We included patients with an explicit ICD-10 code for sepsis for the primary ICU admission. We obtained data on cancer diagnoses (2001-2018), death (2005-2018) and emigration (2005-2018) from Cancer and Cause of death and National Patient Registry databases of the National Board of Health and Welfare; age and sex-specific cancer incidence rates in Sweden from NORDCAN registry from 2006 to 2018. One-year survivors formed the final cohort, that was followed for new cancer diagnoses until death, emigration, or end of 2018, whichever came first. The main outcome measure was standardized incidence rate ratio (SIR) to compare the incidence of cancer in 1-year sepsis survivors to that in the general population (NORDCAN). We also performed several sensitivity analyses. RESULTS: In a cohort of 18,550 1-year survivors, 75,427 person years accumulated during a median follow-up (FU) of 3.36 years (IQR 1.72-5.86), 6366 (34.3%) patients died, and 1625 (8.8%) patients were diagnosed with a new cancer after a median FU of 2.51 (IQR 1.09-4.48) years. The incidence ratio of any new cancer over the whole FU was 1.31 (95% CI 1.23-1.40) for men and 1.74 (95% CI 1.61-1.88) for women. The difference in incidence rates persisted in several sensitivity analyses. The SIRs were highest in cancers of gastrointestinal tract, genital organs, and skin. CONCLUSION AND RELEVANCE: Compared to general population, incidence of cancer is increased in 1-year sepsis survivors. Variation in the findings depending on follow-up time suggests that factors other than sepsis alone are involved. Surveillance for malignant disease may be warranted in sepsis survivors

The Use of Diffusion Weighted Imaging and Intravoxel Incoherent Motion to Assess Edema and Perfusion in Abdominal Organs during Endotoxemia

Diffusion weighted magnetic resonance imaging (DW-MRI) technique probing the microscopic movement of water molecules in tissue, allows for the quantification of water diffusivity and the contribution of perfusion to the total amount of water. In the last decades, its use in organs other than the brain has increased and it has successfully been applied to abdominal organs; otherwise the use of DWI for the assessment of perfusion (by measuring perfusion fraction and edema (by measuring the apparent diffusion coefficient—ADC) of entire organs is not a clinical standard. The aim of this paper is to assess whether DWI, specifically IVIM, can accurately assess edema (the amount of water contained in a tissue) and perfusion in abdominal organs (liver, spleen, intestine and kidneys) in an endotoxemic porcine model. Endotoxemia was induced in 20 piglets and they were divided into three groups: HM group (HighMAP, mean arterial pressure was maintained >65 mmHg by noradrenaline infusion), LM group (LowMAP, MAP was maintained between 50 and 60 mmHg) and LTD (the thoracic duct was ligated to increase abdominal edema). In addition, a fourth group of healthy controls (four animals) underwent MRI. Edema was also assessed by wet–dry weight in liver, spleen and intestine; and perfusion was assessed by hemodynamics, lactate concentration and SvO2. ADC was found to be higher in the intestine of the LTD group compared with the other groups, in accordance with wet–dry weight. In addition, ADC in kidneys was found to be correlated to glomerular filtration rate. f was correlated with hemodynamics in kidneys and liver. The presented data show that there is a potential for clinical use of the technique in septic patients

Rapid testing of red blood cell parameters in primary care patients using HemoScreen™ point of care instrument

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

A nationwide study of the long-term prevalence of dementia and its risk factors in the Swedish intensive care cohort

BackgroundDeveloping dementia is feared by many for its detrimental effects on cognition and independence. Experimental and clinical evidence suggests that sepsis is a risk factor for the later development of dementia. We aimed to investigate whether intensive care-treated sepsis is an independent risk factor for a later diagnosis of dementia in a large cohort of intensive care unit (ICU) patients.MethodsWe identified adult patients admitted to an ICU in 2005 to 2015 and who survived without a dementia diagnosis 1year after intensive care admission using the Swedish Intensive Care Registry, collecting data from all Swedish general ICUs. Comorbidity, the diagnosis of dementia and mortality, was retrieved from the Swedish National Patient Registry, the Swedish Dementia Registry, and the Cause of Death Registry. Sepsis during intensive care served as a covariate in an extended Cox model together with age, sex, and variables describing comorbidities and acute disease severity.ResultsOne year after ICU admission 210,334 patients were alive and without a diagnosis of dementia; of these, 16,115 (7.7%) had a diagnosis of sepsis during intensive care. The median age of the cohort was 61years (interquartile range, IQR 43-72). The patients were followed for up to 11years (median 3.9years, IQR 1.7-6.6). During the follow-up, 6312 (3%) patients were diagnosed with dementia. Dementia was more common in individuals diagnosed with sepsis during their ICU stay (log-rank p<0.001), however diagnosis of sepsis during critical care was not an independent risk factor for a later dementia diagnosis in an extended Cox model: hazard ratio (HR) 1.01 (95% confidence interval 0.91-1.11, p=0.873). Renal replacement therapy and ventilator therapy during the ICU stay were protective. High age was a strong risk factor for later dementia, as was increasing severity of acute illness, although to a lesser extent. However, the severity of comorbidities and the length of ICU and hospital stay were not independent risk factors in the model.ConclusionAlthough dementia is more common among patients treated with sepsis in the ICU, sepsis was not an independent risk factor for later dementia in the Swedish national critical care cohort.Trial registrationThis study was registered a priori with the Australian and New Zeeland Clinical Trials Registry (registration no. ACTRN12618000533291)

Mortality after Severe Sepsis and Septic Shock in Swedish Intensive Care Units 2008-2016 : A nationwide observational study

Background Recent studies have reported substantially decreased hospital mortality for sepsis, but data are scarcer on outcomes after hospital discharge. We studied mortality up to 1 year in Swedish intensive care unit (ICU) patients with and without sepsis. Methods Demographic and medical data for all registered adult general ICU patients admitted between 01‐01‐2008 and 30‐09‐2016 were retrieved from the Swedish Intensive Care Registry and linked with the National Patient Register for comorbidity data and the Cause of Death Register for death dates. The population was divided in two cohorts; (a) Patients with a diagnosis of severe sepsis or septic shock and (b) All other ICU patients. Crude yearly mortality was calculated, and logistic regression was used to analyse predictors of mortality. Results 28 886 sepsis and 221 941 nonsepsis ICU patients were identified. In the sepsis cohort, in 2008 unadjusted mortality was 32.6% at hospital discharge, 32.7% at 30 days, 39% at 90 days and 46.8% at 365 days. In 2016, mortality was 30.5% at hospital discharge, 31.9% at 30 days and 38% at 90 days. Mortality at 365 days was 45.3% in 2015. Corresponding nonsepsis mortality was 15.4%, 16.2%, 20% and 26% in 2008 and 15.6%, 17.1%, 20.7% and 26.7% in 2016/2015. No consistent decrease in odds of mortality was seen in the adjusted analysis. Conclusions Mortality in severe sepsis and septic shock is high, with more than one in three patients not surviving three months after ICU admission, and adjusted mortality has not decreased convincingly in Sweden 2008‐2016