The Safety of Intravenous Lipopolysaccharide for the Study of Systemic Inflammation in Humans: A Scoping Review

Background and Objective This review was conducted to evaluate the safety of intravenous lipopolysaccharide (IV LPS) for human immunology research through a scoping assessment of published clinical trials and pertinent case reports. As a collection of case studies reporting rare instances of sinus pauses following IV LPS had been reported in 2005, along with suggested approaches to minimize them, we limited our review to articles published since 2005 in order to focus on contemporary safety. Method PRISMA Extension for Scoping Reviews (PRISMA-ScR) guidelines were followed. English language articles meeting inclusion criteria were identified in PubMed through February 2025. Results From 234 articles we identified 155 distinct studies, with the majority (n=113) limiting enrollment to males only. These studies included a total of 3,551 volunteers, almost exclusively healthy volunteers, with an estimated mean age of 26.0 (range 20 to 56). In all studies, IV LPS elicited a dose-dependent inflammatory response characterized by elevations of heart rate, body temperature, and influenza-like symptoms that typically resolved by 8 hours post dosing. The only unanticipated serious adverse events identified were 2 cases of mild syncope associated with 4-5 second sinus pauses that both occurred in a single study. Conclusion The rarity of adverse events across the 155 studies reviewed suggests that the LPS model of systemic inflammation in humans is safe and well tolerated, although precautions should be taken to minimize vagally induced sinus pauses. Keywords lipopolysaccharide, immunology, safety, bradycardia, systemic inflammation, endotoxemia