Characteristics of thrombin generation in a fulminant porcine sepsis model

Tóth, Judit; Debreceni, Ildikó Beke; Deák, Ádám; Pető, Károly; Berhés, Mariann; Hajdú, Endre; Szabó, Judit; Németh, Norbert; Fülesdi, Béla; Kappelmayer, János

doi:10.1016/j.thromres.2017.07.030

Cited by 9 publications

(8 citation statements)

References 39 publications

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“…more routine use of large animal models for the study of sepsis is emerging [14]. However, current attempts using sheep and swine to model sepsis have mainly utilized endotoxemia [15,16], peritonitis [17,18], or direct bacterial IV inoculation [19]. Although these investigations produced valuable insight, they may not be particularly clinically applicable and may not mirror the development and progression of the disease over time.…”

Section: Plos Onementioning

confidence: 99%

“…Other conditions such as soft tissue, pulmonary, and GI tract infection are arduous to model in large animals due to the larger size of the organs, complexity of the microbiome, and the time needed for the manifestation of illness. These modifications make our model novel and distinct from other porcine models of sepsis particularly since, to date, most have induced sepsis via peritonitis [17,18,40,42,43] or by direct intravenous infusion of either a pathogen [19,44] or endotoxin [41]. In summary, our model is closely aligned with the current MQTiPPS review Part II recommendations which advocate for the discontinuation of endotoxin challenge models as well as "modeling sepsis syndromes that are initiated at sites other than the peritoneal cavity (e.g., lung, urinary tract, brain)" [47].…”

Section: Plos Onementioning

confidence: 99%

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A comprehensive assessment of multi-system responses to a renal inoculation of uropathogenic E. coli in swine

et al. 2020

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Background The systemic responses to infection and its progression to sepsis remains poorly understood. Progress in the field has been stifled by the shortcomings of experimental models which include poor replication of the human condition. To address these challenges, we developed and piloted a novel large animal model of severe infection that is capable of generating multi-system clinically relevant data. Methods Male swine (n = 5) were anesthetized, mechanically ventilated, and surgically instrumented for continuous hemodynamic monitoring and serial blood sampling. Animals were inoculated with uropathogenic E. coli by direct injection into the renal parenchyma and were maintained until a priori endpoints were met. The natural history of the infection was studied. Animals were not resuscitated. Multi-system data were collected hourly to 6 hours; all animals were euthanized at predetermined physiologic endpoints. Results Core body temperature progressively increased from mean (SD) 37.9(0.8)°C at baseline to 43.0(1.2)°C at experiment termination (p = 0.006). Mean arterial pressure did not begin to decline until 6h post inoculation, dropping from 86(9) mmHg at baseline to 28(5) mmHg (p = 0.005) at termination. Blood glucose progressively declined but lactate levels did not elevate until the last hours of the experiment. There were also temporal changes in whole blood concentrations of a number of metabolites including increases in the catecholamine precursors, tyrosine (p = 0.005) and phenylalanine (p = 0.005). Lung, liver, and kidney function parameters worsened as infection progressed and at study termination there was histopathological evidence of injury in these end-organs. Conclusion We demonstrate a versatile, multi-system, longitudinal, swine model of infection that could be used to further our understanding of the mechanisms that underlie infection-induced multi-organ dysfunction and failure, optimize resuscitation protocols and test therapeutic interventions. Such a model could improve translation of findings from the bench to the bedside, circumventing a significant obstacle in sepsis research.

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Section: Plos Onementioning

confidence: 99%

Section: Plos Onementioning

confidence: 99%

A comprehensive assessment of multi-system responses to a renal inoculation of uropathogenic E. coli in swine

et al. 2020

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“…However, it is essential to get further insights on the time course of platelet activation during sepsis, on the consequences of sepsis on platelet prothrombotic properties at arterial shear rate and to evaluate the impact of platelet PI3Kβ inhibition. Only a few studies have investigated platelet activation during sepsis in humans 13 , 23 – 26 or in experimental animal models 27 , 28 . Recently, a study of platelet activation dynamics during the progression of a streptococcus pyogenes infection has proposed that monitoring platelet activation may provide prognostic information in this type of sepsis 29 .…”

Section: Introductionmentioning

confidence: 99%

Platelet activation and prothrombotic properties in a mouse model of peritoneal sepsis

Vardon-Bounes

Mémier

Marcaud

et al. 2018

Sci Rep

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Sepsis is associated with thrombocytopenia and microvascular thrombosis. Studies have described platelets implication in this pathology but their kinetics of activation and behavior remain poorly known. We show in a mouse model of peritonitis, the appearance of platelet-rich thrombi in organ microvessels and organ damage. Complementary methods are necessary to characterize platelet activation during sepsis as circulating soluble markers and platelet-monocyte aggregates revealed early platelet activation, while surface activation markers were detected at later stage. A microfluidic based ex-vivo thrombosis assay demonstrated that platelets from septic mice have a prothrombotic behavior at shear rate encountered in microvessels. Interestingly, we found that even though phosphoinositide-3-kinase β−deficient platelet mice formed less thrombi in liver microcirculation, peritoneal sepsis activates a platelet alternative pathway to compensate the otherwise mandatory role of this lipid-kinase to form stable thrombi at high shear rate. Platelets are rapidly activated during sepsis. Thrombocytopenia can be attributed in part to platelet-rich thrombi formation in capillaries and platelet-leukocytes interactions. Platelets from septic mice have a prothrombotic phenotype at a shear rate encountered in arterioles. Further studies are necessary to unravel molecular mechanisms leading to this prothrombotic state of platelets in order to guide the development of future treatments of polymicrobial sepsis.

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“…As a consequence of this hypodynamic circulatory response, an immediate microcirculatory impairment was observed in an early phase of the bacterial injection [12], whereas cerebral autoregulation remained unaffected [13]. It has been also documented that due to this hemodynamic collapse, lactate levels got elevated followed by the increased appearance of nucleated red blood cells, indicating tissue hypoxia [14]. Thus, intravenous infusion of E. coli results in a fulminant hypodynamic sepsis leading to tissue hypoperfusion and hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Hemodynamic consequences of intravenously given E. coli suspension: observations in a fulminant sepsis model in pigs, a descriptive case–control study

et al. 2019

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BackgroundThe aim of the present work was to assess systemic hemodynamic changes using PiCCo monitoring in a porcine model of E. coli-induced fulminant sepsis.MethodsThirty-one healthy female Hungahib pigs were randomly assigned into control (n = 15) or septic groups (n = 16). In the sepsis group Escherichia coli culture was intravenously administrated in a continuously increasing manner according to the following protocol: 2 ml of bacterial culture suspended in physiological saline was injected in the first 30 min, then 4 ml of bacterial culture was administered within 30 min, followed by infusion of 32 ml bacterial culture for 2 h. Control animals received identical amount of saline infusion. Systemic hemodynamic parameters were assessed by PiCCo monitoring in both groups.ResultsResting hemodynamic parameters were identical in the two groups. In control animals, systemic hemodynamic variables were relatively stable during the entire procedure. In septic animals shock developed in 165 (IQR: 60–255) min after starting the injection of E. coli solution. Blood pressure values gradually decreased, whereas pulse rate increased. A decrease in cardiac index, an increased systemic vascular resistance, and a decreased stroke volume variation were observed.ConclusionsThese results may serve as additional pathophysiological information of hemodynamic changes occurring during hypodynamic sepsis and may contribute to a better understanding of the pathomechanism of septic multiple organ failure.

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Characteristics of thrombin generation in a fulminant porcine sepsis model

Cited by 9 publications

References 39 publications

A comprehensive assessment of multi-system responses to a renal inoculation of uropathogenic E. coli in swine

A comprehensive assessment of multi-system responses to a renal inoculation of uropathogenic E. coli in swine

Platelet activation and prothrombotic properties in a mouse model of peritoneal sepsis

Hemodynamic consequences of intravenously given E. coli suspension: observations in a fulminant sepsis model in pigs, a descriptive case–control study

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