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Updated: Aug 30, 2026
A Reproducible Intensive Care Unit-Oriented Endotoxin Model in Rats
Published on: February 20, 2021
[Animal models for sepsis]
Kaoru Koike1, Kazuhiko Sekine, Tomoyuki Endo
1Department of Emergency and Critical Care Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
Abstract:
When new immunomodulatory agents are developed for the treatment of sepsis, the efficacy is usually tested in animal models before going to clinical trials. However, despite promising preclinical evidence, dozens of new agents have failed to demonstrate clinical efficacy. One of the reasons may be that the preclinical trials were conducted using animal models that did not adequately reflect clinical realities. Various kinds of experiments utilized for the development of new agents were carried where bolus or short term continuous infusions of large doses of bacteria or endotoxin were administered intravenously. Massive i.v. bolus models using bacteria or endotoxin generally produce a rapid hypodynamic cardiovascular response with the animals dying within hours. The serum cytokine response is transient and is much greater in magnitude than that observed in septic patients. For the preclinical testing of agents, 1) i.v. bacteria and endotoxin models in which the total challenge dose of adequate bacteria or endotoxin is reduced and/or the length of administration time is increased, and 2) peritonitis models, e.g., cecal ligation and puncture and peritoneal implantation of bacteria or endotoxin, will become reasonable choices. The animals are also required to receive volume resuscitation and adjuvant antibiotic therapy.
Insights
Preclinical sepsis models often fail to predict clinical efficacy of immunomodulatory agents. Revised animal models, including modified intravenous and peritonitis approaches with supportive care, may offer better translation to human sepsis treatment.
Area of Science:
- Sepsis research
- Immunomodulatory agents
- Preclinical animal models
Context:
- Developing novel immunomodulatory agents for sepsis requires reliable preclinical testing.
- Many promising agents fail in clinical trials despite positive results in animal models.
- Current animal models may not accurately reflect human sepsis pathophysiology.
Purpose:
- To identify more clinically relevant animal models for testing immunomodulatory agents in sepsis.
- To propose modifications to existing models and suggest alternative approaches.
- To improve the predictive value of preclinical sepsis studies.
Summary:
- Intravenous (IV) bolus models with high bacterial/endotoxin doses induce rapid, transient responses unlike human sepsis.
- Modified IV models with reduced doses or prolonged infusion times are suggested.
- Peritonitis models, such as cecal ligation and puncture, are proposed as more relevant alternatives.
- Supportive care, including fluid resuscitation and antibiotics, is crucial in these revised models.
Impact:
- More accurate preclinical models can reduce the failure rate of sepsis therapeutics in clinical trials.
- Improved translation from animal studies to human treatment outcomes.
- Facilitates the development of effective immunomodulatory therapies for sepsis patients.
