Abstract
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. 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. 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. 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.
Highlights
The immune system’s dysregulated response to infection remains a major public health threat
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
Development of management strategies aimed at altering the inflammatory response due to acute infection starts at understanding the host’s response to such triggers, as well as the subsequent sequelae that lead to life threatening organ dysfunction and death
Summary
The immune system’s dysregulated response to infection (sepsis) remains a major public health threat. Development of management strategies aimed at altering the inflammatory response due to acute infection starts at understanding the host’s response to such triggers, as well as the subsequent sequelae that lead to life threatening organ dysfunction (sepsis) and death Attempts at decoding such host-dependent changes using pre-clinical and early clinical trials have been repeatedly disappointing and have failed to translate in larger clinical trials [7]. Rodent-based studies have led to promising mechanistic findings, rodents are phylogenetically distant and biologically divergent from humans, limiting their relevance to the study of certain human diseases such as severe infection and sepsis [8,9,10,11,12,13] These models rarely simulate a natural timecourse where comprehensive data are collected from insult to the development of clinically relevant symptoms, and they do not permit easy investigation of the impact of standard therapies such as intravenous fluids, mechanical ventilation, or vasopressor administration over clinically relevant time periods.
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