Sepsis after trauma—evolving paradigms in stress biology and host response failure

Severe trauma is often complicated by subsequent infection and organ dysfunction, with sepsis being a major mortality risk factor. Factors such as barrier destruction, wound contamination, invasive procedures, injury severity, and shock were traditionally considered primary predisposing elements for post-trauma sepsis. However, recent advances in stress biology have revealed a more nuanced understanding of the body's response to trauma. Organisms have evolved adaptive responses to various noxious stimuli that follow a biphasic pattern: Low to moderate stress levels can increase resilience, while overwhelming insults, both acute and chronic, overstrain the body’s coping mechanisms and are known as allostatic overload, hallmarked by maladaptive responses. An illustrative example of this concept is the body's response to iron ion exposure following trauma, transfusion, or haemolysis. Iron ions, at low levels, induce adaptive Nrf2-dependent responses, such as haem oxygenase gene expression. However, high concentrations or prolonged exposure can lead to cellular damage and organ failure, e.g. through the production of highly reactive free radicals. This biphasic pattern highlights the complex interplay between protective and harmful responses in post-trauma physiology. Whereas tools such as the SOFA score allow to measure severity of organ dysfunction, no metrics for quantifying the intensity of ‘stress’ over time are available. As cumulative stress is a crucial outcome-associated factor in trauma care, the development of adequate indicators could significantly enhance our understanding and management of post-trauma complications, arising from secondary surgical interventions, transfusion management, or metabolic derangements. This evolving perspective on stress biology in the severely injured host underscores the need for a more comprehensive approach to patient assessment and treatment in critical care settings, to identify and to decrease stress load with the aim to prevent life-threatening complications, such as sepsis, and ultimately improve outcomes.