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1
Radhakrishnan, Jayachandran. "Functional genomics of severe sepsis and septic shock." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:2b2afd65-82e0-4847-b7ae-960635b7e884.
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Sepsis is the systemic inflammatory response to an infection. Severe sepsis with multi organ failure is one of the commonest causes of admission to intensive care units, and is associated with poor early and late outcomes. The pathophysiology of sepsis is complex, and poorly understood. This is reflected in the limited and contentious treatment options for sepsis. Genetic factors have been shown to be associated with the risk of and subsequent outcomes from infection. However, clear associations with bacterial sepsis are rare, and even when associations are present their functional effects are often unknown. Gene expression signatures in sepsis are investigated in this project using serial samples obtained from patients admitted to intensive care units with community-acquired pneumonia or faecal peritonitis. The evolving gene expression signatures that define the response to sepsis were identified with large changes seen in genes coding for ribosomal proteins RPS4Y1 and RPS26P54. The differences in the sepsis response between the two diagnostic classes were examined. The gene expression predictors of mortality in sepsis were determined and include genes from the class II MHC HLA-DRB4, HLA-DRB5 and the T cell differentiation protein MAL. The effects of important covariates on gene expression were investigated and their impact on survival related expression determined. The findings were confirmed in a validation cohort. A novel clustering of samples representing distinct inflammatory patterns in a clinically homogeneous population of sepsis patients was identified and related to differences in clinical behaviour. The biological relevance of the differentially expressed genes was ascertained by identifying enriched gene sets. The gene expression changes in sepsis were examined in the context of related clinically relevant immune phenomena: the sterile systemic inflammatory response in patients undergoing elective cardiac surgery and the phenomenon of endotoxin tolerance in PBMCs derived from healthy volunteers. The results highlight the complexities of clinical sepsis and identify hypotheses for future investigations.
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Furebring, Mia. "C5a Receptor Expression in Severe Sepsis and Septic Shock." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-5832.
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Jones, K. J. "Mediators of gram-positive septic shock." Thesis, Aston University, 2003. http://publications.aston.ac.uk/12349/.
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Gram-positive bacteria are increasingly becoming more prevalent especially Staphylococcus epidermidis in association with indwelling devices. Lipopolysaccaride (LPS) is the key Gram-negative component involved in this process, but it is not clear which components of Gram-positive bacteria are responsible for progression of this often fatal disease. The aim of this thesis was to investigate the effect of bacterial components on the immune systems. Lipid S, a short chain form of lipoteichoic acid (LTA) found to be excreted from bacteria during growth in culture medium was examined along with other Gram-positive cell wall components: LTA, peptidoglycan (PG) and wall teichoic acids (WTA) and LPS from Gram-negative bacteria. Lipid S, LTA, PG and LPS but not WTA all stimulated murine macrophages and cell lines to produce significant amounts of NO, TNF-a, IL-6 and IL-1 and would induce fever and tissue damage seen in inflammatory diseases. Lipid S proved to be the most potent out of the Gram-positive samples tested. IgG antibodies in patients serum were found to bind to and cross react with lipid S and LTA. Anti-inflammatory antibiotics, platelet activating factor (PAF), PAF receptor antagonists and monoclonal antibodies (mAbs) directed to LTA, CD14 and toll-like receptors were utilised to modulate cytokine and NO production. In cell culture the anti-LTA and the anti-CD14 mAbs failed to markedly attenuate the production of NO, TNF-a, IL-6 or IL-1, the anti-TLR4 antibody did greatly inhibit the ability of LPS to stimulate cytokine production but not lipid S. The tetracyclines proved to be the most effective compounds, many were active at low concentrations and showed efficacy to inhibit both lipid S and LPS stimulated macrophages to produce NO.
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Braga, D. "TRANSCRIPTOMIC ANALYSIS IN SEPTIC SHOCK PATIENTS." Doctoral thesis, Università degli Studi di Milano, 2017. http://hdl.handle.net/2434/473670.
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Introduction
Septic shock, also defined as distributive shock, is a complication of sepsis, characterized by pronounced hypotension, followed by anomalous distribution of blood at vessels, organs and tissues. The hemodynamic, cellular and metabolic alterations described in septic shock patients lead to a mortality that is at present around 40%. Septic shock patients develop dysfunctions or failure to multiple organs (MOF) but the molecular mechanisms triggering tissue injury remain largely undetermined and a specific treatment for septic shock is still not available.
Aim
This work is part of the European Project ShockOmics, a multicentric, prospective, observational study, whose aim is to identify with a multiscale approach, molecular biomarkers in septic shock patients who develop acute heart failure. The specific aim of the present Research project is to investigate the modifications induced by septic shock on transcriptional profile, using blood cells as RNA source. This investigation is performed at different timepoints starting from admission of the patient to the intensive care unit (ICU).
Materials and Methods
Septic shock patients were recruited in the ICUs of Geneva and Bruxelles University Hospitals, that are Partners of ShockOmics Project. Blood samples were collected in the acute phase of the disease at ICU admission (T1), after the appropriate pharmacological intervention (T2 ) and at steady state on day 7 of the ICU stay (T3). RNA was extracted from whole blood and RNA sequencing was used to evaluate the expression level of genes, long non coding RNAs and microRNAs. We explored the dataset using PCA and unsupervised hierarchical clustering and we identified differentially expressed genes and microRNAs across conditions. Gene Ontology analysis was used to identify relevant biological processes involved in shock. We identified microRNA regulatory targets with an in silico target prediction.
Results
We identified two main gene expression profiles corresponding to the acute phase of shock and to the condition of steady state. Between the acute phase of shock (day 1) and the steady state condition (day 7) we observed in patients at day 7 a downregulation of pathways of the innate immune response (Toll-like receptor and C-type lectin receptors pathways) and of acute inflammation (IL-1 receptor family and alarmins) and the upregulation in the same patients of genes of the adaptive immunity related to B and T lymphocytes activation. A transcriptional regulation was observed also for genes with antimicrobial function and protease activity and for genes involved in carbohydrate metabolism, lipid inflammatory pathway, transport of vesicles and protein synthesis. miR-125a-5p and miR-150-5p, with a predicted regulatory role in the MAPK pathway, and miR-193a-3p were differentially expressed in the acute and steady state condition.
Conclusion
We observed a significant modulation of multiple classes of genes involved in defense response to pathogens, immunity, inflammation and metabolism. From these results it appears that in septic shock a relevant change in the transcriptomic profile of blood cells is induced, in order to counteract the pathogens and as a consequence of the hemodynamic changes underlying the circulatory failure. The transcriptomic profile of septic shock patients showed inter patient variability reflecting the complexity of the shock condition and of the individual response to treatment. Specific signatures could turn out by combining clinical data and expression profile and could be used to better classify septic shock patients.
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Saha, Dhanonjoy C. "The effects of endotoxin and monophosphoryl lipid A on monocyte activity." Thesis, University of Surrey, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337003.
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Wilson, Susan. "Lipopolysaccharide-activated signal transduction in cardiac and vascular smooth cells." Thesis, University of Strathclyde, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367047.
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Darwiche, Aiman A. "Machine Learning Methods for Septic Shock Prediction." Diss., NSUWorks, 2018. https://nsuworks.nova.edu/gscis_etd/1051.
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Sepsis is an organ dysfunction life-threatening disease that is caused by a dysregulated body response to infection. Sepsis is difficult to detect at an early stage, and when not detected early, is difficult to treat and results in high mortality rates. Developing improved methods for identifying patients in high risk of suffering septic shock has been the focus of much research in recent years. Building on this body of literature, this dissertation develops an improved method for septic shock prediction. Using the data from the MMIC-III database, an ensemble classifier is trained to identify high-risk patients. A robust prediction model is built by obtaining a risk score from fitting the Cox Hazard model on multiple input features. The score is added to the list of features and the Random Forest ensemble classifier is trained to produce the model. The Cox Enhanced Random Forest (CERF) proposed method is evaluated by comparing its predictive accuracy to those of extant methods.
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MacKenzie, Iain M. J. "Nitric oxide synthesis and human septic shock." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301763.
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Bagley, John Sorrell. "The beta adrenergic receptor in septic shock." Thesis, University of Aberdeen, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.305466.
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The myocardial depression found during septic shock has been a subject of intense study for many years. Many theories exist as to the precise cause of this condition but in this thesis the role of the β-adrenergic receptor is examined. Some investigators have found reduced response to β-adrenergic stimulation in models of septic shock in animals. This is of interest to the clinician since adrenergic stimulation is a key manipulation in the management of septic shock. An animal model of septic shock was established using a comparatively small dose of <i>Escherichia coli</i> endotoxin infused into the male Sprague-Dawley rat. Heart function and response to isoprenaline, a β1-agonist, were measured in an <i>in vitro</i> organ bath. A reduction in the force of contraction was found together with a shift in the response curve to the right. These findings were associated with an increase in the number of β-receptors in the ventricular tissue from the same hearts, a measurement made using radioligand binding with I<sup>125</sup>-(-)-Iodocyanopindolol, a β1-antagonist. The finding of more β-receptors in the context of septic shock raises interesting questions discussed in the thesis. When forskolin, a plant alkaloid that stimulates the adenyl cyclase enzyme, was used to stimulate the atria <i>in vitro</i> the same response was found in the endotoxin treated and the normal groups. This is strong evidence that endotoxin causes a myocardial depressant effect mediated prior to adenylcyclase in the β-receptor transduction cascade.
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Barrett, L. K. "Mechanisms of vasopressin hypersensitivity in septic shock." Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/1445995/.
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Patients in prolonged, catecholamine-refractory septic shock have plasma vasopressin levels inappropriately low for their hypotension, yet show enhanced responses to exogenously administered hormone. I hypothesised that altered vasopressin signalling within vascular smooth muscle is responsible for this heightened sensitivity. Both vasopressin and the catecholamine, norepinephrine vasoconstrict via sarcolemmal G protein- coupled receptors. Diversity in the calcium signalling pathways downstream of these receptors may explain the differential effect of sepsis on vascular reactivity to the two hormones. To investigate this, I characterised a long-term fluid-resuscitated, rat model of faecal peritonitis, and examined in-vivo reactivity to these vasopressors. In subsequent ex-vivo studies performed on mesenteric resistance arteries taken from these animals, I compared concentration-response characteristics, calcium mobilisation pathways, and calcium-tension relationships for the two agonists, using wire myography and fluorescence microscopy. I also measured hormone levels in a cohort of septic and non-septic intensive care patients and undertook preliminary myography studies on human small mesenteric arteries. In prolonged illness, vasopressin levels were not elevated in either the septic rats or in septic patients, despite hypotension and organ dysfunction. Pressor responses to norepinephrine, but not vasopressin, were diminished in septic rats. This pattern of reactivity was mirrored ex-vivo, with decreased efficacy of norepinephrine, but increased potency of vasopressin. Differences were apparent in the calcium mobilisation pathways contributing to norepinephrine- and vasopressin-induced responses in septic vessels, with a greater reliance on store-operated calcium channels with vasopressin, compared to voltage- gated calcium channels with norepinephrine. The norepinephrine calcium- tension relationship was similar in sham and septic vessels but, for vasopressin, there was evidence of agonist-specific increased calcium sensitivity of the contractile apparatus in the septic tissues. In conclusion, my long-term septic model was able to satisfactorily mimic the clinical scenario. I demonstrated increased vasoconstriction to vasopressin suggesting enhanced receptor coupling to calcium signalling. Vasopressin, but not norepinephrine, may be able to both effectively mobilise calcium in septic vascular smooth muscle and sensitise the contractile apparatus to its effect. In addition to providing insight into the phenomenon of vasopressin hypersensitivity in septic shock, this work supports modulation of calcium mobilisation channels and/or sensitisation pathways as a potential new therapeutic paradigm.
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Smith, Fiona Susan. "The regulation of hepatic nitric oxide synthesis and inhibition of glucose output during endotoxic shock." Thesis, University of Sussex, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.263207.
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Szabo, Csaba. "Role of nitric oxide in circulatory shock." Thesis, Queen Mary, University of London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283567.
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Konrad, David. "Cardiac function in experimental septic and non-septic conditions with special reference to the endothelin system /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-984-X/.
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Su, FUHONG. "Adjunctive therapies in an ovine model of septic shock due to fecal peritonitis." Doctoral thesis, Universite Libre de Bruxelles, 2007. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210580.
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Sepsis remains a severe issue in critically ill patients. Adjunctive therapies might play important role to decrease morbidity and mortality. The aim of this thesis is to investigate new adjunctive therapies role in the treatment of sepsis and septic shock.<br>Doctorat en Sciences biomédicales et pharmaceutiques<br>info:eu-repo/semantics/nonPublished
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Wu, Chin-Chen. "Role of inducible nitric oxide synthase in septic shock." Thesis, Queen Mary, University of London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362801.
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Stalets, Erika L. M. D. "Time to antibiotics and outcomes in pediatric septic shock." University of Cincinnati / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1377870939.
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Bertsche, Joseph. "Histone Deacetylase Inhibitors and Innate Immunity in Septic Shock." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/2011.
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Innate immunity depends on pattern recognition receptors, which recognize pathogen associated molecular patterns (PAMPS), such as Toll-like receptor 4 (TLR4), which detects the gram-negative bacterial toxin, lipopolysaccharide. Engagement of TLR4 by LPS sets off a cascade ending in the activation of pro-inflammatory cytokines and interferon-β (IFN-β) which alerts the host to the infection. However, these responses can be mal-adaptive, especially in the context of bacterial sepsis, where a "cytokine storm" results in death of the host. Pharmacological modulation of these responses may therefore be a promising treatment modality. Inhibition of classic pro-inflammatory cytokines such as IL-1β and TNF-α has been the (largely unfruitful) focus of much research. However it has recently emerged that mice with defects in type I IFN signaling are also substantially resistant to challenge with endotoxin. We therefore wish to investigate pharmacological inhibition of IFN signaling as a potential means to control sepsis. We analyzed the effects of Trichostatin A (TSA) and Suberoylanilide hydroxamic acid (SAHA) (both broad spectrum HDAC inhibitors) and ST-2-92 (HDAC6 specific inhibitor) on IFN regulation and endotoxic shock. We created an in vivo mouse model for this treatment with TSA and SAHA (which are well tolerated in mouse and human) to look for possible alteration in the survival rate following endotoxin challenge. We as well as others found that treatment with SAHA (50mg/kg) significantly improves survival rate. We also characterized in-vitro modulation of IFN responses through SAHA by mouse DNA microarray. We noticed a decreased expression of many innate immune regulated genes in the SAHA and LPS treated condition compared to the LPS treatment alone. Additionally we observed a decrease in protein levels of IFN-β IL-1β, IL-6, IL-12p40, RANTES and TNF-α in cell culture supernatants treated with SAHA or ST-2-92 and LPS compared to LPS only treatment. These results show the ability of broad spectrum HDACi through SAHA to increase mouse survival following LPS challenge as well as modulate the induction of innate immune responsive genes in vitro. Furthermore we have shown that HDAC specific inhibition through ST-2-92 can decrease pro-inflammatory transcript as well as protein levels.
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Rosten, Patricia Melanie. "The role of toxic shock syndrome toxin-1 in the pathogenesis of toxic shock syndrome." Thesis, University of British Columbia, 1986. http://hdl.handle.net/2429/26527.
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Toxic shock syndrome toxin-1 (TSST-1), an exoprotein produced by some strains of Staphylococcus aureus, is implicated in the pathogenesis of menstrual TSS. However, its role in nonmenstrual TSS is less certain. In order to study the pathogenetic role of TSST-1 in TSS, three approaches were taken: a) to develop an ELISA for detection of TSST-1 in biologic fluids in order to verify TSST-1 production in vivo in TSS patients, b) to quantitate TSST-1 specific antibodies in the serum of TSS patients and controls to determine whether such antibodies are protective, and c) to attempt to identify other staphylococcal products which may be implicated in some forms of TSS.
A sensitive and specific noncompetitive enzyme-linked immunosorbent assay (ELISA) capable of detecting TSST-1 at concentrations from 0.5 to 16 ng/ml was developed. This assay did not detect other staphylococcal enterotoxins including A, B, C₁, C₂, C₃, D and E. Possible interference by protein A was readily eliminated by pretreatment of test samples with 10% nonimmune rabbit serum. The assay was adapted for rapid screening of TSST-1 production by S. aureus isolates in culture supernatants in vitro, and for the detection of TSST-1 in vaginal washings and urine of TSS patients and healthy controls in vivo. All 35 S. aureus isolates confirmed to be TSST-1 positive by Ouchterlony immunodiffusion, and 59 of 60 isolates confirmed to be TSST-1 negative, gave concordant results by ELISA. Interestingly, toxigenic S. aureus strains isolated from TSS patients quantitatively produced significantly more toxin in vitro compared to toxigenic control strains (p<0.05, Mann-Whitney rank sum test). TSST-1 could be detected by ELISA in 3 of 4 vaginal washings collected within 3 days of hospitalization from 3 women with acute menstrual TSS, compared to 0 of 17 washings from 9 TSS women collected greater than 3 days after hospitalization (p=0.003, Fisher's exact test) and 1 of 15 washings from 14 healthy control women (p=0.016). TSST-1 was not detected in the urine of 4 acute TSS patients, 2 convalescent TSS patients or in 3 control urine tested.
A sensitive and reproducible ELISA was also developed for the quantitation of TSST-1 specific IgG in serum. Anti-TSST-1 was assessed in acute and convalescent sera from 16 nonmenstrual (9 female, 7 male) and 14 menstrual TSS patients, and from 87 healthy women and 66 healthy men as controls. Quantitative levels of anti-TSST-1 in the study groups were calculated as the percent of standard activity (POSA) relative to a medium titre reference serum standard. ELISA titers in acute sera from menstrual TSS (26.2 ± 5.2, mean POSA ± S.E.M.), but not nonmenstrual TSS women (71.8 ± 18.6), were significantly lower than in healthy controls (78.9 ± 7.3) (p<0.01, Mam-Whitney test). Titers from menstrual TSS patients remained low (25.2 ± 10.7) even during late convalescence (mean duration 20 months after illness onset), compared to healthy female controls (p<0.05). Acute titers in males with TSS (37.0 ± 15.6) were also significantly lower than those in control men (114.6 + 11.0) (p<0.05). An inverse relationship of recovery of toxigenic S. aureus and anti-TSST-1 titers in acute sera of TSS patients was observed. Interestingly, antibody titers in control men were significantly higher than in control women (p<0.001). No age-dependent effects or interactive effects of age and sex on ELISA titers were observed.
To enable immunoblot analyses, TSST-1 was produced and partially purified using column chromatography techniques. Percent recovery of TSST-1 from culture supernatant through to the final procedure was approximately 15.5%. The relative purity of TSST-1 (TSST-l/total protein, w/w) was increased from 0.21% in culture supernatants to 94.4% in the final product. Ouchterlony immunoprecipitation against reference rabbit antitoxin demonstrated identity with reference TSST-1 as well as with TSST-1 prepared in other laboratories. Physical characterization demonstrated a molecular weight of 24 kd and a pi of 7.0. Using pooled normal human serum as a first antibody probe, several bands in addition to the 24 kd TSST-1 band were visualized by immunoblot against our partially purified toxin as well as similar preparations obtained from other investigators. To determine whether any of the additional bands might be implicated in TSS, acute and convalescent sera from TSS patients were used to probe for immunoreactive bands in our partially purified TSST-1 as well as a commercially obtained preparation. Seroconversion was demonstrated to the 24 kd TSST-1 protein in 7 of 10 TSS patients from whom toxigenic S. aureus was isolated. In addition, seroconversion was noted to a 49 kd band in 4 patients, to a 21 kd band in 3 patients, to a 28 kd band in 1 patient and to a 32 kd band in 2 patients.
In conclusion: 1) the ability to measure TSST-1 in biologic fluids lends stronger support for the role of TSST-1 in menstrual TSS patients; 2) the serologic data support the etiologic role of TSST-1 in menstrual TSS and in nonmenstrual TSS patients from whom toxigenic S. aureus could be cultured, but not for nonmenstrual TSS women from whom toxigenic S. aureus was not isolated; 3) immunoblotting results with acute and convalescent sera from TSS and control patients, not only add further support to the role of TSST-1 in patients from whom toxigenic S. aureus could be isolated, but also indicate that there may be several other staphylococcal products implicated in TSS, particularly in whom antibody to TSST-1 pre-existed in acute sera. The nonresponsiveness or lack of seroconversion to TSST-1 in some patients could suggest either: a) TSST-1 was not the etiologic agent for such patients; b) TSST-1 was the etiologic agent, but the exposure was sufficient for an immune response (similar to tetanus), or; c) some immunologic defect may be present. Future studies are required to clarify these possibilities.<br>Science, Faculty of<br>Microbiology and Immunology, Department of<br>Graduate
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Bhat, Sundeep Ram. "Lactate Clearance Predicts 28-Day Survival Among Patients with Severe Sepsis and Septic Shock." Yale University, 2009. http://ymtdl.med.yale.edu/theses/available/etd-03182009-143432/.
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Severe sepsis and septic shock comprise a significant number of emergency department (ED) admissions annually. With the advent of early goal directed therapies, early identification and intervention have become paramount in this population. Few studies, however, have examined the role of serum lactate as a predictor of mortality or endpoint to resuscitation among this population. We aimed to show that improved lactate clearance is associated with decreased 28-day in-hospital mortality. We retrospectively examined data from the Yale Sepsis Registry for patients with severe sepsis or septic shock who had lactate levels that were measured initially in the ED and subsequently when the patient arrived on the floor. This study received institutional review board approval. Lactate clearance was calculated as a percentage, and comparison between patients who cleared lactate and those who did not were made for mortality data as well as baseline characteristics and interventions required between the two groups. 207 patients (110 male) with mean age and standard deviation (SD) of 63.17 ± 17.9 years were examined. 136 patients (65.7%) were diagnosed with severe sepsis and 71 patients (34.3%) had septic shock. Of those with identified sources of infection, pneumonia was the most common (54 patients, 26.1%). There were 171 patients in the clearance group and 36 patients in the non-clearance group, all of whom had a mean time of 9 hours 8 minutes ± 4 hours 6 minutes between lactate measurements. 28-day mortality rates were 15.2% (26 patients) in the lactate clearance group and 36.1% (13 patients) in the non-clearance group (p<0.01). Vasopressor support within 72 hours of admission was initiated among 61.1% (22 patients) in the non-clearance group compared with 36.8% (63 patients) in the clearance group (p<0.01). Mechanical ventilation was required for 36.3% (62 patients) in the clearance group and 66.7% (24 patients) in the non-clearance group (p=0.001). Rates of severe sepsis, mean number of SIRS and organ dysfunction criteria, and initial creatinine were similar between the two groups; however, only 86.1% (31 patients) in the non-clearance group received intravenous fluids in the ED compared with 98.8% (169 patients) in the clearance group (p=0.002). 33.3% (12 patients) in the non-clearance group had chronic obstructive pulmonary disease (COPD) compared with 15.2% (26 patients) in the clearance group (p<0.05). The mean Mortality in Emergency Department Sepsis (MEDS) scores were 8.78 ± 3.96 for the clearance group and 10.4 ± 4.48 for the non-clearance group (95% CI, -3.1 to -.14, p<0.05). These results show significantly higher mortality rates among patients who do not clear their lactate in the ED. Additionally, these patients require vasopressor support and mechanical ventilation more often. Lactate clearance was significantly associated with receipt of fluids and may also reflect lower MEDS score. Our findings suggest lactate clearance could be used as an endpoint for ED resuscitation and in stratifying mortality risk among patients with severe sepsis or septic shock. Future studies might seek to prospectively validate these findings and incorporate multivariate analysis to determine factors affecting lactate clearance.
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Weinberg, Julius Rolf. "A study of the circulatory responses to fever with and without hypertension." Thesis, University of Oxford, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.258154.
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Martin, Joelma Gonçalves [UNESP]. "Interlucina 12, procalcitonina e protína C - reativa em crianças com sepse e choque séptico." Universidade Estadual Paulista (UNESP), 2009. http://hdl.handle.net/11449/102628.
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martin_jg_dr_botfm.pdf: 229557 bytes, checksum: 8ac04c0bae3f323bc75baa932f60ad46 (MD5)<br>Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)<br>Problemas com diagnóstico de sepse são indicativos da necessidade de enfocar mediadores bioquímicos capazes, não somente de distinguir as diferentes causas de inflamação, mas também de indicar a gravidade dos pacientes. Avaliar o comportamento da Interleucina-12 (IL-12), proteína C-reativa (PCR), e procalcitonina (PCT) e sua utilidade em diferenciar crianças com sepse e quadros correlatos. Crianças sépticas foram incluídas prospectivamente e divididas em dois subgrupos: sepse (GS; n=46) e choque séptico (GCS; n=41). IL-12, PCR e PCT foram medidas à admissão (T0) e 12 horas mais tarde (T12h). Valores de PCT foram classificados como: sepse improvável, sepse possível, infecção bacteriana complicada por inflamção sistêmica e choque séptico. A gravidade da doença foi medida pelo escore PRISM. Em T0, houve uma maior frequência de crianças com choque séptico com níveis mais elevados de PCT, quando comparados com o grupo sepse [GCS: 30 (69,7%) > GS: 14 (29,8%); p < 0,05], o mesmo ocorrendo em T12h. PRISM foi maior para os pacientes do GCS do que do GS. Em T12h, os níveis de IL-12 foram maiores no GCS [T12: 1,32 (0-61.0) > T0: 0,24 (0-226,43; p= 0,018]. Os níveis de PCR não foram diferentes entre os grupos ou tempos de coleta. PCT parece ser útil no diagnóstico precoce de sepse e choque séptico, sendo relacionada com a gravidade da doença. PCR e IL-12 não diferenciaram sepse e choque séptico.<br>Problems with sepsis diagnosis are indications of the need to focus on biochemical mediators capable not only of distinguishing the different causes of inflammation, but also of indicating the severity of patients. Objectives: To examine the behavior of interleukin-12 (IL-12), C-reactive protein (CRP), and procalcitonin (PCT) and the utility of them to differentiate children with septic conditions. Methods: Septic children, prospectively enrolled, were divided into sepsis (SG; n = 47) and septic shock (SSG; n = 43) groups. IL-12, PCT and CRP were measured at admission (T0) and 12 hours later (T12). Values of PCT were ranked as: unlikely sepsis; possible sepsis; systemic inflammation; septic shock. Disease severity was assessed by PRISM score. Results: At T0, there was a higher frequency of SSG with higher PCT compared with SG [SSG: 30 (69.7%) > SG: 14 (29.8%); p < 0.05], similarly at T12h. PRISM was higher for SSG patients with higher PCT than SG patients. At T12, IL-12 levels were higher in SSG [T12: 1,32 (0 – 61,0) > T0: 0,24 (0 – 226,43); p = 0,018]. CRP levels were not different for groups and moments. Conclusions: PCT appears to be helpful in early diagnosis of pediatric septic conditions, being related to disease severity. CRP and IL-12 did not differentiate septic conditions.
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Pathan, Nazima. "Characterisation of a myocardial depressant factor in meningococcal septic shock." Thesis, Imperial College London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.412281.
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Shavdia, Dewang. "Septic shock : providing early warnings through multivariate logistic regression models." Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/42338.
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Includes bibliographical references (leaves 87-89).<br>Thesis (M. Eng.)--Harvard-MIT Division of Health Sciences and Technology, 2007.<br>(cont.) The EWS models were then tested in a forward, casual manner on a random cohort of 500 ICU patients to mimic the patients' stay in the unit. The model with the highest performance achieved a sensitivity of 0.85 and a positive predictive value (PPV) of 0.70. Of the 35 episodes of hypotension despite fluid resuscitation present in the random patient dataset, the model provided early warnings for 29 episodes with a mean early warning time of 582 ± 355 minutes.<br>Early goal-directed therapy (EGDT) in severe sepsis and septic shock has shown to provide substantial benefits in patient outcomes. However, these preventive therapeutic interventions are contingent upon an early detection or suspicion of the underlying septic etiology. Detection of sepsis in the early stages can be difficult, as the initial pathogenesis can occur while the patient is still displaying normal vital signs. This study focuses on developing an early warning system (EWS) to provide clinicians with a forewarning of an impending hypotensive crisis-thus allowing for EGDT intervention. Research was completed in three main stages: (1) generating an annotated septic shock dataset, (2) constructing multivariate logistic regression EWS models using the annotated dataset, and (3) testing the EWS models in a forward, causal manner on a random cohort of patients to simulate performance in a real-life ICU setting. The annotated septic shock dataset was created using the Multi-parameter Intelligent Monitoring for Intensive Care II (MIMIC II) database. Automated pre-annotations were generated using search criteria designed to identify two patient types: (1) sepsis patients who do not progress to septic shock, and (2) sepsis patient who progress to septic shock. Currently, manual review by expert clinicians to verify the pre-annotations has not been completed. Six separate EWS models were constructed using the annotated septic shock dataset. The multivariate logistic regression EWS models were trained to differentiate between 107 high-risk sepsis patients of whom 39 experienced a hypotensive crisis and 68 who remained stable. The models were tested using 7-fold cross validation; the mean area under the receiver operating characteristic (ROC) curve for the best model was 0.940 ± 0.038.<br>by Dewang Shavdia.<br>M.Eng.
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Ihendyane, Nahla. "Pathogenesis and immunotherapy of streptococcal septicemia and shock /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-599-9/.
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Clark, Megan Frances. "Effects of endotoxin on cationic amino acid transport in peripheral blood mononuclear cells." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298251.
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Waller, John. "Cardiovascular regulatory mechanisms in endotoxaemia." Thesis, University of Nottingham, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307806.
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Wileman, Samantha Mary. "Induction of L-arginine transport and nitric oxide synthase by pro-inflammatory cytokines and bacterial lipopolysaccharide in vascular smooth muscle cells." Thesis, King's College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338774.
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Lee, Peggy S. P. "Measured metabolic requirement for septic shock patients before and after liberation from mechanical ventilation." Thesis, University of Bath, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.665433.
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Objectives: Negative energy balance can impair regeneration of the respiratory epithelium and limit the functionality of respiratory muscles, which can prolong mechanical ventilation. The present study sought to quantify and identify deviation in energy requirements of patients with septic shock during and upon liberation from mechanical ventilation. Methods: Patients admitted into intensive care with initial diagnosis of septic shock and mechanical ventilation-dependent were recruited. Their metabolic requirements before and after liberation from mechanical ventilation were measured by indirect calorimetry. Paired t-test was used to examine the variance between the two modes of breathing and Spearman rho correlation coefficient to examine relationship of selected indicators. Results: Thirty-five patients, 20 males and 15 females mean age 69 ±10 years, body height of 1.58 ±0.08 meters, and ideal body weight 59.01 ±7.63 kg were recruited. Median APACHEII score was 22, length of stay in the intensive care was 45 ±65 days and duration on mechanical ventilation was 24 ±25 days. Measured energy expenditure during ventilation was 2090 ±489 kcal∙d-1 upon liberation from ventilation was 1910 ±579 kcal∙d-1, and actual caloric intake was 1148 ±495 kcal∙d-1. Paired-t test showed that measured energy expenditure (p=0.02), actual calories provision and energy expenditure with (p=0.00) and without (p=0.00) ventilator support were all significantly different. Mean carbohydrate oxidation was 0.17 ±0.09 g·min-1 when patients were on mechanical ventilation compared to 0.14 ±0.08 g·min-1 upon liberalization from it, however, the results were not statistically significant. Furthermore, mean lipid oxidation was 0.08 ±0.05 g·min-1 during mechanical ventilation and 0.09±0.07 g·min-1 upon liberalization from it and the mean difference was not statistically significant. Spearman correlation coefficient showed a positive relationship between actual calorie provision and duration of stay in intensive care (r=0.41 and p=0.01) and duration on mechanical ventilation (r=0.55 and p=0.00). Oxygen consumption (r=0.49 and p=0.00) and carbon dioxide production (r=0.4 and p=0.02) were moderately strong and positive during and upon liberation from mechanical ventilation. Correlation between lipid oxidation and oxygen consumption during ventilation (r=0.74, p=0.00) and after ventilation (r=0.82, p=0.00) as well as lipid oxidation and carbon dioxide production during ventilation (r=0.37, p=0.03) and liberation from ventilator (r=0.91, p=0.00) were significantly correlated with each other in grams per minute only. Conclusions: This is a pioneering study to examine energy expenditure and substrate utilization and oxidation within a single cohort of patients. The lower measured energy expenditure upon liberation from mechanical ventilation among critically ill patients could result from positive pressure support from ventilation, the repeated cycle of “rest” and “work” during weaning from ventilators and the asynchronization between self-initiated breathing effort and the ventilatory support. The positive relationship in duration on mechanical ventilation and length of stay with calorie consumption could be longer stay led to more time for progression to reach nutrition targets. . Any discrepancy in energy expenditure and substrate utilization with and without ventilatory support should be monitored. Future studies are important to examine whether matching energy expenditure with energy intake could promote positive clinical outcomes.
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Kapoor, Amar. "Role of peroxisome proliferator-activated receptor-β/δ in acute myocardial infarction, septic shock and sepsis". Thesis, Queen Mary, University of London, 2011. http://qmro.qmul.ac.uk/xmlui/handle/123456789/688.
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Peroxisome Proliferator-Activated Receptors (PPARs) are ligand activated transcription factors that belong to the nuclear hormone receptor family. In this thesis, I have investigated the anti-inflammatory role of PPAR-β/δ in animal models of regional myocardial ischaemia and reperfusion (I/R) injury and multiple organ injury/dysfunction associated with endotoxaemia and septic shock. Using a selective PPAR-β/δ agonist, GW0742, I have demonstrated that selective activation of PPAR-β/δ protects the rat heart against injury caused by regional I/R when administered, as late as, on reperfusion of the previously ischaemic myocardium. Additionally, I have demonstrated that genetic deletion of PPAR-β/δ greatly exacerbates the multiple organ injury/dysfunction caused by endotoxaemia in the mouse. Moreover, treatment of wild-type mice with GW0742 attenuated the multiple organ injury/dysfunction caused by endotoxaemia. Thus, activation of PPAR-β/δ affords a protective effect against multiple organ injury/dysfunction in endotoxic shock. I extended the above study by investigating the effect of PPAR-β/δ activation in a clinically relevant model of caecal ligation and puncture (CLP)-induced polymicrobial sepsis by evaluating survival in mice over 10 days. I demonstrated that treatment with GW0742, several hours after the induction of polymicrobial sepsis, improved survival. Furthermore, I have demonstrated this organ protective effect of PPAR-β/δ activation in a rat model of severe acute endotoxaemia. Finally, I have shown that the protective effects of PPAR-β/δ activation in animal models of acute regional myocardial I/R injury and endotoxic shock are secondary to an anti-inflammatory mechanism involving the activation of the phosphatidylinositol 3-kinase (PI3K)-Akt signalling pathway, which leads to the inhibition of the activation of glycogen synthase kinase (GSK)-3β and nuclear factor (NF)-B activity, subsequently reducing the expression of NF-B-driven gene transcription of a number of pro-inflammatory mediators. Thus, in this thesis, I have demonstrated an anti-inflammatory protective role for PPAR-β/δ in models of regional myocardial I/R injury, septic shock and systemic inflammation.
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Somell, Anna. "Endothelin receptor antagonism and hypertonic solutions in experimental endotoxin shock /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-209-5/.
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Wang, Zhen. "Adjunctive therapies in a clinical revelant ovine model of septic shock." Doctoral thesis, Universite Libre de Bruxelles, 2009. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210196.
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Sepsis has been defined as a systemic response to an infection. With an incidence of 3 per 1000 population per year or about 750 000 cases a year, this syndrome ranks as the 10th leading cause of death in the United States (1). Increasing severity of sepsis correlates with increasing mortality, which rises from 30-40% for severe sepsis up to 40-60% for septic shock. This thesis examines the effectiveness of adjunctive therapies, including activated protein C, hypercapnia and acidosis, and sodium selenite, in a clinically relevant ovine model of septic shock. The results from these studies can provide valuable information for future clinical trials on sepsis.<p>This thesis is divided into four sections: 1) sepsis overview; 2) an autologous fecal peritonitis model in sheep and its evaluation; 3) the series of studies on adjunctive therapeutics; and 4) ongoing studies and future perspective.<p>In the first section, a broad overview gives a rough introduction to delineate many aspects of sepsis syndrome such as terminology, etiology, epidemiology, pathophysiology and current guidelines for management. Hemodynamics in sepsis are especially elaborated since these are major observations throughout the studies presented later.<p>In the second section, the general characteristics of the sepsis models used in this thesis are elucidated. Data on hemodynamics, lung mechanics, gas exchange, etc. are presented to feature the ovine peritonitis model. The results of laboratory examinations for hematology, coagulation, bacteriology, biochemistry and hormonology are also presented. And then, I review currently used sepsis models with regards to their advantages and disadvantages.<p>The third section discusses three studies with their objectives, the methods used, the major findings, and the potential clinical implications.<p>9<p>1) Beneficial effects of recombinant human activated protein C in experimental septic shock. Activated protein C has a multitude of beneficial effects in severe sepsis and septic shock, including anti-inflammation, anti-coagulation, profibrinolysis, anti-apoptosis and endothelial protection. A clinical Phase III trial demonstrated that the administration of recombinant human activated protein C improved survival in patients with severe sepsis. However, doubts on the protective effects of activated protein C have persisted and been refueled by the recently published negative trials in less severely ill patients and in children. In the light of these ambiguities and uncertainties, we reinvestigated the effects of activated protein C in experimental septic shock.<p>2) Acute hypercapnia improves indices of tissue oxygenation more than dobutamine in septic shock. Hepercapnia has been found to possess beneficial effects in diverse acute inflammatory states independent of protective lung mechanics. To prove the hypothesis that acute hypercapnia has similar or superior hemodynamic effects to those of a dobutamine infusion, which may be particularly relevant in the presence of hemodynamic instability associated with respiratory failure, we investigated the effects of hypercapnia, which induced by inspiring extrinsic carbon dioxide in experimental septic shock.<p>3) High bolus dose of sodium selenite prolongs survival in an ovine model of septic shock. Selenite has both pro- and anti-oxidant effects. The administration of high dose sodium selenite may improve survival in septic shock patients. The benefit may be greater with the administration of a bolus (to achieve higher concentrations) rather than a continuous infusion. To test this hypothesis, we examined the effects of a high dose bolus administration of sodium selenite in experimental septic shock.<p>The fourth and final section talks about currently ongoing studies and offers some perspective on future direction.<br>Doctorat en Sciences médicales<br>info:eu-repo/semantics/nonPublished
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Kengatharan, Muralitharan. "Studies of the cause and mechanism of gram-positive septic shock." Thesis, Queen Mary, University of London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265704.
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Hanage, William Paul. "Host microbial interactions in the pathogenesis of Viridans streptococcal septic shock." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272512.
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Lai, Choi-hung, and 賴彩紅. "Beta adrenergic stimulation and intracellular cAMP levels: changes in septic shock." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B45011242.
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De, Geer Lina. "Cardiac dysfunction in septic shock : Observational studies on characteristics and outcome." Doctoral thesis, Linköpings universitet, Institutionen för medicin och hälsa, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-122759.
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Background: Cardiac dysfunction is a well-known complication of sepsis, but its characteristics and consequences, especially on a longer term, remain unclear. The aim of this thesis was to study the characteristics and the implications of cardiac dysfunction for outcome in intensive care unit (ICU) patients with septic shock. Purpose: First, to assess the ability of a cardiac biomarker to predict outcome in ICU patients. Second, to characterise cardiac dysfunction in septic shock using speckle tracking echocardiography. Third, to investigate the reliability of echocardiographic methods used to describe cardiac dysfunction in septic shock. Fourth, to study long-term cardiac outcome in severe sepsis and septic shock patients. Materials and methods: The cardiac biomarker amino-terminal pro-brain natriuretic peptide (NTproBNP) was collected in 481 patients on ICU admission and its ability to predict death was assessed. In 50 patients with septic shock, echocardiography was performed on ICU admission and was repeated during and after ICU stay. Measurements of cardiac strain using speckle tracking echocardiography were assessed in relation to other echocardiographic function parameters, NT-proBNP and severity of illness scores, and their change over time was analysed. Echocardiograms from patients with septic shock were independently evaluated by two physicians and the results analysed regarding measurement variability. A nationwide-registry-based open cohort of 9,520 severe sepsis and septic shock ICU patients discharged alive from the ICU was analysed together with a non-septic control group matched for age, sex and severity of illness. In patients who died after ICU discharge, information on causes of death was collected. Results: A discriminatory level of significance of NT-proBNP on ICU admission was identified at ≥1,380 ng/L, above which NT-proBNP was an independent predictor of death. With increasing levels of NT-proBNP, patients were more severely ill, had a longer ICU stay and were more often admitted with septic shock. Cardiac strain was frequently impaired in septic shock patients but was not superior to other echocardiographic measurements in detecting cardiac dysfunction. Cardiac strain correlated with other echocardiographic function parameters and with NT-proBNP, and was the least user-dependent echocardiographic parameter in septic shock patients. Cardiac strain remained unchanged over time, did not differ between survivors and non-survivors and could not predict an increased risk of death. During a follow-up of up to nearly 6 years after ICU discharge, 3,954 (42%) of sepsis patients died, 654 (17%) with cardiac failure as the cause of death. With increasing severity of illness on admission, the risk of death with cardiac failure as the cause of death after ICU discharge increased. In comparison to other ICU patients with similar severity of illness, however, the risk of death due to cardiac was not increased in patients with severe sepsis or septic shock. Conclusions: Laboratory or echocardiographic signs of cardiac dysfunction are commonly seen in ICU patients in general and in septic shock patients in particular. The assessment of cardiac dysfunction in patients with septic shock is, however, complicated by pre-existing comorbidities, by treatment given in the ICU and by critical illness in itself. Signs of cardiac dysfunction, and the increasing risk of death related to cardiac failure seen after remission of sepsis, may therefore be reflections of critical illness per se, rather than of sepsis.
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Wei, Chaojie. "Mechanism of action of a β1 blocker in experimental septic shock". Thesis, Université de Lorraine, 2016. http://www.theses.fr/2016LORR0259/document.
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Le choc septique est associé non seulement à une réponse immunitaire excessive et inappropriée contre l'infection, mais aussi à une augmentation de l'activité nerveuse sympathique, à une augmentation des catécholamines circulantes et à un dysfonctionnement autonome. Le blocage de la bêta 1-adrénergique a montré une protection cardiovasculaire et une amélioration de la survie pendant le choc septique dans les études expérimentales et cliniques, ce qui semble être dû à ses effets anti-inflammatoires. Cependant, les effets de la réduction du rythme cardiaque (HRR) d'un bloqueur des adrénorécepteurs bêta 1 sur la fonction cardiovasculaire et les voies inflammatoires restent peu clairs. En utilisant un médicament pur de réduction du rythme cardiaque, Ivabradine, dans un modèle de choc septique polymicrobien induit par CLP, nous avons constaté que la réduction de la fréquence cardiaque : 1) n'était associé à aucune amélioration des fonctions cardiaques ou vasculaires; 2) n'avait aucun impact sur les niveaux circulants de TNF-a, IL-6 ou IL-10; 3) n'a eu aucune influence sur l'expression d'iNOS et NF-κB cardiovasculaires, les rapports P-akt / akt et P-eNOS / eNOS et la dégradation d'IκBα dans ce contexte aigu. En utilisant un bloqueur bêta 1-adrénergique, Esmolol, dans un modèle de choc septique polymicrobien induit par CLP, nous avons constaté que de faibles doses d'Esmolol, ne diminuant pas la fréquence cardiaque 1) a aussi amélioré la fonction cardiaque évaluée par échocardiographie et la vasoréactivité évaluée par myographie ; 2) les bénéfices ont été associés avec la modulation des voies inflammatoire au niveau systémique et tissulaire. Ces résultats ouvrent de nouvelles perspectives dans le traitement clinique du choc septique avec des bloqueurs adrénergiques bêta 1<br>Septic shock is associated with not only an excessive and an inappropriate immune response against infection, but also with increased sympathetic nerve activity, elevated circulating catecholamines and autonomic dysfunction. Beta 1-adrenergic blockade has shown to provide cardiovascular protection and survival improvement during septic shock in experimental and clinical studies, which seems due to its anti-inflammatory effects. However, the effects of heart rate reduction (HRR) of a beta 1-adrenoreceptor blocker on cardiovascular function and inflammatory pathways remain unclear. By using a pure heart rate-lowering drug, Ivabradine, in a polymicrobial septic shock model induced by CLP, we found isolated heart rate reduction 1) was not associated with any improvement in cardiac or vascular functions; 2) has no impact on circulating levels of TNF-a, IL-6 or IL-10; 3) had no influence in cardiovascular iNOS and NF-κB expression, P-akt/akt and P-eNOS/eNOS ratio and IκBα degradations in this acute setting. By using a beta 1-adrenergic blocker, Esmolol, in a polymicrobial septic shock model induced by CLP, we found that a low dose of Esmolol, which didn’t induce HRR, also 1) improved cardiac function evaluated by echocardiography and vasoreactivity tested by myograph; 2) beneficial effects were associated with the modulation of inflammatory pathways at both the systemic and the tissue levels. These results open up new perspectives in clinical treatment of septic shock with beta 1 adrenergic blockers
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Darenberg, Jessica. "Streptococcus pyogenes infections and toxic shock syndrome : molecular epidemiology and immunotherapy /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-676-X/.
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Scully, Timothy Graeme. "The use of intravenous fluids and the role of haemodynamic monitoring in the management of patients in septic shock." Thesis, University of Sydney, 2020. https://hdl.handle.net/2123/22879.
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Over the past 20 years, multiple studies have illustrated the association between positive fluid balance and poor outcomes in septic shock. Advanced haemodynamic monitoring and judging whether a patient is fluid responsive has become the gold standard to guide fluid therapy in septic shock. Most studies in this field do not address whether the ability to determine a patient’s fluid responsiveness leads to any meaningful change in decisions regarding the volume of intravenous fluids used in the treatment of the septic patient. This thesis aims to explore the effect of using advanced haemodynamic monitoring and fluid responsiveness led protocols on fluid balance, morbidity and mortality outcomes. A systematic review was conducted to assess the current body of evidence for transpulmonary thermodilution monitoring in septic shock with regards to outcomes on fluid therapy. Transpulmonary thermodilution devices led to a reduced fluid balance in septic shock patients when compared to the use of central venous pressures and early goal-directed therapy. We conducted a pilot randomised controlled trial comparing a transpulmonary thermodilution device to standard monitoring practices in patients in shock admitted to our Intensive Care Unit. In contrast to the systematic review, there was no trend to suggest that the use of advanced haemodynamic monitoring leads to lower intravascular fluid use in patients in septic shock. We established that doctors are still reliant on clinical examination and other techniques with poor sensitivity for determining fluid status, even when advanced haemodynamic monitoring is present. Together, these results show that it is difficult to derive any meaningful outcomes from research regarding fluid therapy in septic shock unless issues around study design are addressed and the impact of the microvascular system is investigated further.
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Harral, Kristine Lynette. "Implementing a Sepsis Protocol in a Long-term Care Hospital." ScholarWorks, 2019. https://scholarworks.waldenu.edu/dissertations/6900.
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Sepsis is life-threatening organ dysfunction caused by a response to infection that causes multiorgan failure. This condition causes high mortality and morbidity rates and leaves permanent disabilities. The purpose of this project was to create a sepsis protocol and an education training program for clinical staff in a hospital setting where no sepsis protocol was in place. The practice-focused question examined whether an educational program would improve clinical staff perception of their knowledge of the early recognition and management of sepsis. A literature review was conducted to identify an evidence-based practice protocol; the results were used to develop the education program for the clinical staff at the site. Malcolm Knowles's theory of adult learning framed the project that included a team of 9 content experts consisting of physicians, physician assistants, and an educator who reviewed and approved the protocol and education program prior to implementation. The education program was then presented to 45 staff members including physicians, licensed vocational nurses, registered nurses, physician assistants, and nurse practitioners. Results of a 14-item knowledge test before and after the education program were examined for percent correct; results were compared using a paired-samples t test. Participant knowledge increased significantly (p <.05) from 20% correctly answering 10 of the 14 questions on the pretest to 87% answering all of the posttest questions correctly. The results of this project may promote positive social change by supporting clinical staff in early recognition and treatment of sepsis thereby reducing the morbidity and mortality that accompanies sepsis.
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Armero, Garrigós Eva Mª. "Implementación de una estrategia en formato código para mejorar el manejo de la sepsis grave comunitaria en hospitales comarcales sin UCI." Doctoral thesis, Universitat Autònoma de Barcelona, 2014. http://hdl.handle.net/10803/285142.
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Introducción: La sepsis grave comunitaria es una enfermedad de alta letalidad que aumenta su incidencia cada año e implica gran coordinación de diferentes ámbitos por la variedad de formas de presentación y recursos que puede requerir para su diagnóstico y tratamiento. Se han hecho grandes esfuerzos por simplificar y homogeneizar su manejo, utilizando estrategias como la Early Goal Directed Theraphy, o los paquetes de recomendaciones (bundles) de la Sepsis Surviving Campaign (SSC). Las peculiaridades del sistema sanitario catalán podrían dificultar la implementación de las guías y el continuo asistencial en su manejo por la existencia de numerosos centros comarcales sin unidades de cuidados intensivos. Otras patologías con riesgo vital han sabido identificar las maniobras esenciales para la estabilización y la optimización del tiempo en formato “código sepsis” que podría ser extrapolable.
Objetivo: Se pretende implementar una estrategia en formato código para mejorar la adherencia a las guías clínicas de la SS/SG en el servicio de urgencias de hospitales comarcales.
Método: Estudio antes y después de realizar una estrategia formativa para mejorar la adherencia a las guías clínicas existentes en un hospital comarcal.
Resultados: Se estima una incidencia de 1’4-1’5 por mil habitantes/año. La adherencia a las bundles de la SSC en hospitales comarcales es menor del 1%, consiguiéndose una mejora de hasta el 18’3% tras la aplicación del código. La letalidad del proceso es de un 20’6% que disminuye a un 13’3% en los pacientes sin limitación del esfuerzo terapéutico. El índice de Charlson, la edad, la puntuación de SOFA y la administración de drogas vasoactivas se relacionan con el aumento de la letalidad. La administración de antibióticos en el menor tiempo posible, la identificación de pacientes de alto riesgo (por comorbilidad y/o gravedad de presentación) y su traslado a centros de mayor complejidad, se relacionan con la mayor supervivencia.
Conclusiones: La incidencia global de la SS/SG es alta comparada con otras patologías con riesgo vital. La adherencia a las guías propuestas por la SSC es baja y se puede mejorar con estrategias de formación y coordinación intrahospitalarias entre los centros implicados.<br>Introduction: Community severe sepsis is a highly fatal disease that increases its incidence every year and involves great coordination of different areas by the variety of forms of presentation and resources that may be required for diagnosis and treatment. They have made great efforts to streamline and standardize their management, using strategies like Early Goal Directed therapy, recommendations or packages (bundles) Surviving Sepsis Campaign (SSC). The peculiarities of the Catalan health system could hinder the implementation of the guidelines and the continuum of care in its handling by the existence of numerous regional centers without intensive care units . Other life-threatening diseases have managed to identify the maneuvers essential for the stabilization and optimization of the code which could be extrapolated format. Objective: To implement a strategy in code format that reduces the lethality of these patients at community hospital without UCI. Methods: A before and after a training strategy to improve adherence to existing clinical guidelines in a community hospital. Results: The incidence of 1'4 - 1'5 per 1000 / year is estimated. Adherence to the SSC bundles in regional hospitals is less than 1%, achieving an improvement of up to 18'3 % after the implementation of the code. The lethality of the process is a 20'6 % decreasing to 13'3 % in patients without limitation of therapeutic effort. The Charlson index, age, SOFA score and the administration of vasoactive drugs are associated with increased mortality. The administration of antibiotics in the shortest time possible, the identification of patients at high risk (comorbidity and/or severity of presentation) and moving to more complex centers, are associated with longer survival. Conclusions: The overall incidence of SS / SG is high compared with other life-threatening diseases. Adherence to the guidelines proposed by the SSC is low and can be improved with training strategies and interhospital coordination between the institutions involved.
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Zhang, Haibo. "Oxygen extraction capabilities in low cardiac output and septic shock: possible interventions." Doctoral thesis, Universite Libre de Bruxelles, 1995. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/212475.
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Shi, Weiwei. "KATP Channel Action in Vascular Tone Regulation During Septic Shock: Beyond Physiology." unrestricted, 2009. http://etd.gsu.edu/theses/available/etd-02252009-205655/.
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Thesis (Ph. D.)--Georgia State University, 2009.<br>Title from file title page. Chun Jiang, committee chair; Walter William Walthall, Delon W. Barfuss, Deborah Baro, committee members. Description based on contents viewed July 28, 2009. Includes bibliographical references. (p. 121-143)
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Horton, Robert Arthur. "An investigation into the role of nitric oxide in the inhibition of hepatic gluconeogenesis by bacterial endotoxin." Thesis, University of Sussex, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.262635.
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Okeke, Emeka B. "Regulation of Sepsis and Endotoxic Shock by Regulatory T cells." Wolters Kluwer Health Lippincott Williams & Wilkins, 2013. http://hdl.handle.net/1993/31580.
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One of the major challenges facing clinicians is how to effectively manage excessive host immune response to pathogenic insults resulting in sepsis. This is demonstrated by the fact that despite over half-century research efforts, sepsis and its spectrum of diseases (severe sepsis and septic shock) are still associated with poor clinical outcome. Currently, sepsis is a leading cause of death in intensive care units.
The immune system protects the host against pathogens and is therefore armed with an arsenal of deadly ammunitions (including chemicals, cells and proteins) necessary for the elimination of microbes. It is therefore paramount that the immune system must develop mechanisms necessary to prevent destruction of the host it is designed to protect. A good example of such a mechanism is found in the subset of lymphocytes known as regulatory T cells (Tregs). There is unequivocal experimental evidence of the role of Tregs in the maintenance of immune homeostasis and self tolerance and aberrant Treg function has been linked with several inflammatory diseases. Since sepsis is a disease marked by a hyper-inflammatory state, I investigated the possible role of Tregs in dampening sepsis-induced excessive inflammation.
Using a murine model of lipopolysaccharide (LPS) infusion and bacterial infection, I show that Tregs are essential for survival during sepsis because their depletion leads to acute death to an otherwise non-lethal dose of LPS. This enhanced susceptibility to LPS following Treg depletion was also observed using live E. coli infection. Next, I probed the mechanism by which Tregs protect against LPS challenge. I found that defective Treg function leads to exaggerated activity of two immune cells – CD4+ effector T cells and neutrophils in response to LPS, leading to severe inflammatory response. Hence, this work successfully illustrates the critical role of Tregs in regulating other immune cells and the catastrophic consequences of defective Treg function during an immune response.
Overall, this work highlights the significant role of Tregs in the regulation of bacteria associated inflammatory processes. The findings hold implications for the successful management of sepsis and have potential for use in development of adequate therapeutic intervention for sepsis.<br>October 2016
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Isopo, Elyse Diana. "Disseminating the Sepsis Bundle: Evaluating an Evidence-Based Education Module." ScholarWorks, 2018. https://scholarworks.waldenu.edu/dissertations/4792.
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Due to increasing incidence and noncompliance with sepsis at a local hospital, an educational deficit was identified on the sepsis bundle in the medical intensive care unit. The purpose of this project was to develop and validate a sepsis bundle education program for all frontline staff in the MICU at a local University Hospital. The goal was for the educational tool to be validated by a multidisciplinary team to increase awareness, education, and ultimately, compliance with the severe sepsis and septic shock guidelines. The diffusion of innovation theory was utilized to support the process of change by encouraging the use of screening tools and best practice guidelines. The research question asked whether the education program meets critical care expert panel standards to educate frontline MICU staff on the sepsis bundle. The research design included a 5-member panel of experts in critical care, utilizing the Likert scale to review the proposed educational project on the sepsis bundle. Results are averaged from each reviewer. Results from the review included a unanimous '5' rating on every issue identified, equating to strongly agree on the Likert scale. This rating supported the validity of the educational project, the use of evidence-based practice and that the educational material was clear and easy to follow. Utilizing this validated tool will guide the education of sepsis, severe sepsis, and septic shock and promote social change by increasing education, awareness, recognition and early deployment of the sepsis bundle to improve patient outcomes.
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Gordon, Anthony Christopher. "Genetic polymorphisms of the innate immune system : influence on susceptibility and outcome in severe sepsis and septic shock." Thesis, Queen Mary, University of London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.430022.
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Cartwright, Neil. "The innate immune system in blood vessels and its relevance to septic shock." Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.487991.
Full textAbstract:
Septic shock is a common condition with a high mortality rate. The pathophysiology of sepsis is complex, although inappropriate vasodilation, leading to a fall in systemic vascular resistance (SVR), is pivotal to the development of shock and multi-organ dysfunction syndrome (MODS). The molecular pathways and mediators underlying this vascular dysfunction are not clearly understood. . I investigate the role of pattern-recognition receptors, including Toll-like receptors (TLRs) and NOD domain containing proteins with a leucine rich repeat (NLRs), in blood vessels and their contribution to vascular dysfunction. I show that Gram positive Staphylococcus aureus signals exclusively through a TLR2I6 heterodimer in murine vessels to induce nitric oxide synthase (NOS) II, through a MyD88 and tumor necrosis factor a. (TNFa.) dependent pathway. Lipopolysaccharide (LPS) signals through TLR4, but signalling is not exclusively dependent on MyD88/Mal, TRIF or TNFa. Escherichia coli induced NOSII in blood vessels is partially independent of TLR4: this may be due to peptidoglycan, which is sensed through NOD1. I show that, in rats, NOD1 agonists cause shock in vivo and induction of NOSII in blood vessels. The shock caused by NOD1 agonists differ from that caused by LPS as it has a different cytokine profile and causes less end organ injury. NOD1 agonists do not directly activate macrophages and other immune cells: I investigate the role of stromal versus radiosensitive cells in a chimeric mouse model of LPS induced systemic inflammation and show that stromal cells play an important role in the induction of cytokines and development of systemic inflammatory response. Blood vessels sense pathogens through different pathways than macrophages. These differences may be exploited in the development of new drugs for sepsis and other vascular diseases.
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Shan, Qixian, and 單綺嫻. "The role of nitric oxide and adrenomedullin in cardiovascular failure in septic shock." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2001. http://hub.hku.hk/bib/B31242261.
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Windbichler, Michaela. "Role of the lectin pathway of complement activation in septic and anaphylactic shock." Thesis, University of Leicester, 2005. http://hdl.handle.net/2381/27819.
Full textAbstract:
The complement system constitutes an important part of innate host defence. Complement activation can be initiated via the classical, lectin or alternative pathway. This work focuses on the role of the lectin pathway in mouse models of septic and anaphylactic shock. As a model of septic shock cecal ligation and puncture (CLP) was used. Complement activation is crucial for survival as mouse strains deficient in C I q and factors Band C2 show a higher mortality than complement-sufficient controls. H2-Bƒ/C2-/- mice also demonstrate an impaired bacterial clearance. The involvement of the lectin pathway can be seen in a rapid and long lasting decrease of serum MBL levels. mRNA expression was not altered during the course of infection. Furthermore, MBL deposition was demonstrated on the abscess that forms after peritoneal infection. Activation of the complement system also occurs during anaphylactic shock. It is believed that the classical pathway is responsible for complement activation, as serum C1q levels decrease during shock. This work shows also an involvement of the lectin pathway with serum MBL levels being diminished after antigen challenge. The mechanism leading to this decrease was investigated. To find out whether complement activation is of pathophysiological consequence in anaphylactic shock, several mouse strains with selective deficiencies in complement components, as well as mast-cell deficient mice were tested. Only mast cell deficient mice were protected from anaphylaxis and showed no decrease in serum MBL levels, indicating that cell derived mediators and not the complement system are crucial for the induction of anaphylaxis. Taken together, these results demonstrate a clear need for the complement system in combating bacterial infections during septic shock. In the case of anaphylaxis, however, complement activation is not causative of the symptoms.
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Reade, Michael Charles. "Arginine transport and other determinants of nitric oxide production in human septic shock." Thesis, University of Oxford, 2002. http://ora.ox.ac.uk/objects/uuid:abf881fc-3c9a-40b4-89e1-07b8df2067d1.
Full textAbstract:
The arterial vasodilation seen in human septic shock is conventionally attributed to increased nitric oxide (NO) production, primarily by extrapolation of animal and cellular studies. Little is known of the cellular source of NO in human septic shock. Other mediators, such as carbon monoxide (CO), may modulate NO production, and could also directly contribute to vasodilation. This study has examined the NO and CO synthetic pathways in peripheral blood mononuclear cells and mesenteric arterial smooth muscle from patients with septic shock, and from non-septic controls. Peripheral blood mononuclear cells from septic patients had increased NO production, though this was perhaps more modest than expected. The transport of arginine, the substrate for NO synthase, into these cells was increased; this was due to an increase in the activity of one transporter system, y<sup>+</sup>. mRNA for a protein encoding y<sup>+</sup> activity, CAT2B, was increased in these cells. However, mRNA and protein for inducible and endothelial NO synthase was decreased in sepsis, while inducible heme oxygenase (the enzyme responsible for CO production) mRNA and protein was increased. NO production in arterial smooth muscle from septic patients was reduced, as was mRNA for inducible and endothelial NO synthase, and the arginine transporter CAT1. There was no increase in inducible NO synthase protein, though there were small increases in endothelial NO synthase protein and NO synthase activity. In contrast, both mRNA and protein for inducible heme oxygenase were increased. These results challenge the assumption that NO is central to the pathogenesis of human sepsis. Negative feedback systems for NO production have been demonstrated in cell models. These may be relatively more important in human sepsis. In addition to forming one of these feedback systems, it may be that CO, more than NO, is responsible for the hypotension observed in these patients.