Unpacking the sepsis controversy.

Area of Science:

• Critical Care Medicine
• Infectious Diseases
• Pathophysiology

Background:

• The current definition of sepsis as 'life-threatening organ dysfunction caused by a dysregulated host response to infection' is widely accepted.
• However, this definition has led to numerous failed clinical trials and reliance on animal models that do not accurately represent human sepsis.
• Epidemiological data suggest sepsis is often associated with advanced age and pre-existing conditions, questioning the 'dysregulated host response' as the primary cause.

Purpose of the Study:

• To challenge the prevailing conceptual framework and definition of sepsis.
• To highlight the limitations of current animal models used in sepsis research.
• To argue that the current definition and models lead to ineffective clinical treatments.

Main Methods:

• Critical analysis of existing sepsis definitions and clinical guidelines.
• Review of epidemiological data from healthcare systems (e.g., NHS, USA).
• Evaluation of the suitability of host-centered, pathogen-agnostic animal models.

Main Results:

• The current sepsis definition and associated research paradigms are based on flawed assumptions.
• Animal models used in sepsis research frequently fail to recapitulate the human clinical condition.
• Sepsis-related mortality, particularly in older populations and those with comorbidities, suggests an association rather than a direct causal link to a 'dysregulated host response.'

Conclusions:

• The current definition of sepsis and the research methodologies employed are inadequate.
• There is a critical need to re-evaluate the conceptual basis of sepsis.
• A revised understanding is necessary to develop effective clinical treatments for sepsis.