In septic shock (SS), hydrogen peroxide (H2O2) and other reactive oxygen species (ROS) are released by inflammatory cells and have been implicated in tissue damage and inflammation. Recently, H2O2 has been established as an important signaling molecule and an important component of SS. The pathways involved in this process are not completely understood, but the formation of hydroperoxides (HPs), arachidonic acid (AA) metabolites and potassium (K+) channels have been implicated. In this study, we used a canine carotid ring preparation as a bioassay to determine the role of peroxyacetic acid (POX), a hydroperoxide (HP), in causing vasodilation and elucidate the subsequent pathways involved. We removed internal carotid artery segments from dogs and placed them in an organ bath. The segments were preconstricted after which we added POX to the preparation. We found that POX produced an endothelium and nitric oxide independent vasodilation in the carotid artery ring preparation. This decrease in tension could be prevented by high concentrations of K+ in the bath. This suggested that K+ channels were involved in POX’s action. Further investigation showed that the particular K+ channels implicated were the combination of small (SKCa) and intermediate conductance calcium activated K+ channels (IKCa). In addition we found that the prostaglandin H synthase (PGHS) inhibitor, indomethacin, could block POX’s mechanism of action. This finding indicates that PGHS takes part in the vasodilation caused by POX. Our results suggest that HPs that are released from inflammatory cells in sepsis could stimulate the PGHS pathway leading to prostaglandin synthesis and subsequently activating SKCa and IKCa to produce vasodilation. Inhibition of this pathway may be important component in the treatment of SS.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 4 uppsatser.

Ulm, Univ., Diss., 2008.

Ulm, Univ., Diss., 2008.

Regensburg, Univ., Diss., 2009.

Bakgrund: Sepsis är ett globalt hälsoproblem med oacceptabelt hög mortalitet. Som omvårdnadsansvarig har sjuksköterskan ett viktigt arbete i att identifiera patienten med sepsis för att behandling skall kunna ges i tid. Syfte: Syftet med litteraturstudien var att beskriva faktorer som påverkar sjuksköterskors identifiering av sepsis. Metod: Studien var en litteraturstudie och utformades enligt Polit och Becks (2017) flödesschema i nio steg. Databassökning genomfördes i CINAHL och PubMed. Litteraturstudiens resultat baserades på tio vetenskapliga artiklar som genomgick systematisk urvalsprocess innan kvalitetsgranskning. Resultat: Databearbetning och analys resulterade i tre huvudkategorier; klinisk kunskap, arbetsmiljö, utbildning och två underkategorier; erfarenhet, hjälpmedel i klinisk verksamhet.  Slutsats: Många faktorer påverkar sjuksköterskan i identifieringen av sepsis. Kunskapsbrist, hög arbetsbelastning, brist på utbildning och frånvaro av adekvata hjälpmedel var de vanligaste faktorerna som framkom i litteraturstudiens resultat. Kliniskt verksamma sjuksköterskor behöver fler hjälpmedel och mer utbildning för att öka kunskapen om sepsis.

Following the TLR-dependent initiation phase of acute systemic proinflammatory responses such as sepsis, an adaptive phase represses or activates a specific pattern of gene expression until the inflammation resolves. Here, we used the THP-1 sepsis cell model of bacterial LPS/endotoxin tolerance to show that TLR4- induced miR-146a supports the feed-forward adaptive processes that silence transcription and disrupt translation of acute proinflammatory genes. First, we found that miR-146a regulates a pathway that promotes the binding of transcription repressor RelB to the TNF-α promoter, a step known to precede histone and DNA modifications, which generate facultative heterochromatin to silence acute proinflammatory genes. However, once RelB binding occurred, miR-146a inhibition could not reverse compacted chromatin, and endotoxin tolerance persisted. Second, we observed that miR- 146a regulates a pathway that supports assembly of the translation repressor complex of TNF-α by preventing the interaction of the RNA-binding protein effector Ago2 and RBM4. We also determined that once endotoxin tolerance is established, and specific genes have been reprogrammed, transcription and translation disruption can be reversed only by simultaneously depleting RelB and inhibiting miR-146a. Thus, miR-146a induction supports the TLR4-dependent shift from initiation to gene-specific repression at two levels. Our results also imply that therapies designed to reverse endotoxin tolerance as potential therapies for sepsis should be directed at the transcription and translation pathways of reprogramming.

No description available.

Bakgrund: Sepsis är ett livshotande tillstånd med hög mortalitet. Upptäckten av tillståndet kompliceras av att kroppens reaktion mot den bakomliggande infektionen börjar innan kliniska symtom uppkommer vilket försvårar identifiering. Tidig upptäckt och omedelbara åtgärder är avgörande för framgångsrik handläggning av patienter med sepsis. Sjuksköterskan har en central roll i identifiering av sepsis vilket är en komplex och utmanande uppgift. Uppsatsens teoretiska referensram för att undersöka sjuksköterskans handläggning av patienter med sepsis var personcentrerad vård.  Syftet: Att kartlägga faktorer som var av betydelse för handläggningen av patienter med sepsis på akutmottagning.Metod: Litteraturöversikten som inkluderade 12 vetenskapliga artiklar med kvantitativ ansats, analyserades enligt Fribergs fyra steg.  Resultat: Tre kategorier identifierades: bedömning, diagnostisering och behandling. Resultatet visade att sjuksköterskans handläggande av sepsis är komplext och påverkades av identifieringstid, teamarbete, provtagning av laktat samt tid till administration av antibiotika. Förutom detta framkom det även att sepsisutbildning och bedömningsinstrument behövdes för att öka sjuksköterskornas kunskap om sepsis.  Slutsats: Litteraturöversikten lyfte fram faktorer av betydelse för handläggande av patienter med sepsis såsom vikten av tidiga insatser och att sjuksköterskor behöver mer kunskap om handläggandet vid sepsis och på det sättet stärka sitt kliniska handläggande. Därtill krävs bedömningsinstrument och tydliga protokoll. Förslag på vidare forskning är att studera hur en kombination av dessa faktorer kan påverka mortaliteten vid sepsis.  Nyckelord: Hantering, Kompetens, Sepsis, Sjuksköterska / Title: Important factors in the management of sepsis in the emergency department Background: Sepsis is a life-threatening condition with a high mortality rate. Discovery of the condition is complicated and is aggravated by the fact that the body ́s reaction to the infection begins before clinical symptoms appear which makes identification more difficult. Early identification and the initiation of rapid measurements are critical to successful management of patients with sepsis. The nurse’s role in identifying signs of sepsis is a complex and challenging task. In this thesis, the chosen theoretical frame of reference, to investigate nurses’ management of sepsis was person-centered care.  Aim: To chart factors that was of importance for management of patients with sepsis in the emergency department.Method: The literature review which included 12 scientific articles with quantitative approach, were were analysed according to Friberg’s method of four-step analysis. Results: Three categories were identified, assessment, diagnostics and treatment. The results show that the nurses’ management of sepsis is complex and influenced by time to identification, teamwork, measuring of lactate and time span before the initiation of antibiotics. Additionally, the study showed that education on sepsis and well- established assessment instruments are needed to increase nurses’ knowledge of sepsis.  Conclusion: The literature review highlights factors of importance for the management of patients with sepsis such as the need of further education and an in- depth knowledge for nurses about sepsis and how to properly handle patients at an early stage. Increased competence, improved assessment instruments as well as clear protocols are needed. Suggestions for further research are to study how the identified factors can affect mortality.  Key words: Competence, Management, Nurse, Sepsis

Sepsis ist eine dysregulierte Reaktion des Organismus auf eine Infektion. Bei Sepsis werden oft Blutungs- und Thromboseereignisse beobachtet, welche in einer Disseminierten Intravasalen Gerinnung (DIG) gipfeln können. Thrombozyten sind die Schlüsselzellen von Thrombose und Hämostase. Bei Sepsis und DIG kommt es häufig zu einem Abfall der Thrombozytenzahl, doch Blutungs- und Thromboseereignisse können unabhängig von der Thrombozytenzahl auftreten, was zusätzlich eine Veränderung der Thrombozytenfunktion nahelegt. In dieser Arbeit wurde deshalb die Thrombozytenfunktion bei 15 Patienten mit Sepsis zu drei Zeitpunkten im Krankheitsverlauf untersucht. Es konnte bei unauffälliger Rezeptorexpression keine Voraktivierung der Thrombozyten mittels Durchflusszytometrie festgestellt werden. Jedoch war die Aktivierung nach Stimulation mit multiplen Agonisten signifikant reduziert. Besonders ausgeprägt war die Hyporeaktivität bei Stimulation des Kollagen-Rezeptors GPVI mit dem Agonisten CRP-XL. Es wurde gezeigt, dass nach GPVI-Stimulation eine reduzierte Phosphorylierung der nachgeschalteten Proteine Syk und LAT im Vergleich zum Gesundspender induziert wird. In Kreuzinkubationsexperimenten hatte die (Co )Inkubation von Thrombozyten in Plasma von Sepsispatienten oder mit Bakterienisolaten aus Sepsis-Blutkulturen keinen Effekt auf die Thrombozytenreaktivität. Allerdings konnte durch Sepsis-Vollblut eine signifikante GPVI-Hyporeaktivität in Thrombozyten von gesunden Probanden induziert werden, was einen zellulären Mediator als Ursache des Defekts nahelegt. In dieser Arbeit wurde gezeigt, dass insbesondere die GPVI-Signalkaskade bei Sepsis massiv beeinträchtigt ist. Der Immunorezeptor GPVI ist ein vielversprechendes Zielmolekül, um die Pathogenese der Sepsis, des Capillary Leak und die immunregulatorische Rolle von Thrombozyten besser zu verstehen. Die GPVI-Hyporeaktivität könnte als zukünftiger Biomarker für die Sepsis-Frühdiagnose genutzt werden. / Sepsis is the dysregulated immune response of a host to infection and the leading cause for intensive care unit (ICU) treatment worldwide. Patients often suffer from bleeding and thrombotic events, which can escalate to a disseminated intravasal coagulation (DIC). Platelets are important regulators of hemostasis and thrombocytopenia is a hallmark of sepsis and DIC. However, bleeding and thrombosis are observed independently from thrombocytopenia suggesting that altered platelet function might contribute. While platelet number has been investigated in multiple studies and is an integral part of the diagnostic SOFA-score, platelet function during sepsis remains ill-defined. We assessed platelet function in 15 patients with sepsis in a single center study at three times during disease: I intensive care unit (ICU) admission day; II day 5-7 at ICU; III day of ICU discharge. Platelets of all patients at time point I and II had an overall unaltered receptor expression shown by flow cytometry, were not preactivated, but showed a markedly impaired response upon stimulation with multiple agonists. The defect was most prominent upon stimulation of the collagen receptor GPVI with the selective agonist CRP-XL. Sepsis platelets failed to induce phosphorylation of downstream effectors Syk and LAT, as shown by immunoblotting. Next, we asked which factor(s) in patients can induce GPVI hyporeactivity. Incubation of platelets from healthy individuals in plasma of sepsis patients did not cause pre-activation or altered platelet responsiveness. However, platelet incubation in sepsis whole blood diminished CRP-XL reactivity, suggesting the contribution of a cellular component. Co incubation of healthy platelets with bloodborne heat-inactivated bacteria or antibiotics did neither lead to platelet preactivation nor impaired platelet reactivity upon GPVI stimulation. Taken together, our results imply that GPVI function is highly deficient in sepsis patients. GPVI is a promising target, which can pave the way for a better understanding of platelet function in innate immunity and the regulation of vascular integrity. GPVI hyporeactivity might serve as a robust biomarker for the early identification of sepsis patients in the future.