National Preclinical Sepsis Platform: developing a framework for accelerating innovation in Canadian sepsis research

Abstract

Despite decades of preclinical research, no experimentally derived therapies for sepsis have been successfully adopted into routine clinical practice. Factors that contribute to this crisis of translation include poor representation by preclinical models of the complex human condition of sepsis, bias in preclinical studies, as well as limitations of single-laboratory methodology. To overcome some of these shortcomings, multicentre preclinical studies—defined as a research experiment conducted in two or more research laboratories with a common protocol and analysis—are expected to maximize transparency, improve reproducibility, and enhance generalizability. The ultimate objective is to increase the efficiency and efficacy of bench-to-bedside translation for preclinical sepsis research and improve outcomes for patients with life-threatening infection. To this end, we organized the first meeting of the National Preclinical Sepsis Platform (NPSP). This multicentre preclinical research collaboration of Canadian sepsis researchers and stakeholders was established to study the pathophysiology of sepsis and accelerate movement of promising therapeutics into early phase clinical trials. Integrated knowledge translation and shared decision-making were emphasized to ensure the goals of the platform align with clinical researchers and patient partners. 29 participants from 10 independent labs attended and discussed four main topics: (1) objectives of the platform; (2) animal models of sepsis; (3) multicentre methodology and (4) outcomes for evaluation. A PIRO model (predisposition, insult, response, organ dysfunction) for experimental design was proposed to strengthen linkages with interdisciplinary researchers and key stakeholders. This platform represents an important resource for maximizing translational impact of preclinical sepsis research.

Sex-based analysis of treatment responses in animal models of sepsis: a preclinical systematic review protocol

“…Our systematic review is informed by an 'integrated knowledge translation' approach [ 23 ], where knowledge users will contribute to the research. Specficially, members of Sepsis Canada's NPSP are involved in the design and execution of this systematic review and will contribute to the dissemination of findings.…”

“…Specficially, members of Sepsis Canada's NPSP are involved in the design and execution of this systematic review and will contribute to the dissemination of findings. Indeed, findings from this systematic review will directly impact the design and conduct of a planned multicenter preclinical study by the NPSP to investigate sex-dependent differences in preclinical sepsis [ 23 ]. Our systematic review will provide a comprehensive assessment of male versus female differences in response to a variety of sepsis therapies and provide insight into “baseline” sex-dependent differences between untreated male and female septic animals, reflecting the natural progression of sepsis.…”

“…Findings from this proposed systematic review will directly impact the design and focus of a planned multicenter preclinical study by National Preclinical Sepsis Platform (NPSP; funded by Sepsis Canada) to investigate sex-dependent differences in preclinical sepsis [ 23 ]. We anticipate the publication of our systematic review in a peer-reviewed, open-access journal at the conclusion of this project.…”

On the same page? A qualitative study protocol on collaboration in a multi-laboratory preclinical study

“…The National Preclinical Sepsis Platform (NPSP) is a scientific consortium undertaking Canada’s first multi-laboratory preclinical study, as part of the Sepsis Canada Research Network funded by the Canadian Institutes for Health Research. The NPSP brings together six independent labs from three Canadian provinces (Ontario, Alberta, and Manitoba) to collaboratively conduct an experiment using a shared protocol [ 2 ]. The objective of their first study is to explore the influence of biological sex on host response and treatment effect from fluid resuscitation and antibiotics using a fecal-induced peritonitis (FIP) model of murine sepsis.…”

“…Medical advancements are often slowed due to difficulties in translating preclinical and clinical studies to the patient bedside. Multi-laboratory preclinical studies are a promising new strategy for addressing the methodological deficiencies that weaken the translational impact of single laboratory studies [ 1 , 2 ]. These types of studies involve two or more research labs collaborating on study design, execution, and analysis using a shared protocol [ 3 ].…”