Narrowing the Gap: Preclinical Trauma/Sepsis model with Increased Clinical Relevance

Author(s):
Jennifer Munley; Lauren Kelly; Gwendolyn Gillies; Preston Coldwell; Erick Pons; Kolenkode Kannan; Letitia Bible; Philip Efron; Alicia Mohr

Background:

Overall outcomes for trauma patients have improved over time. However, 10% of severely injured patients develop sepsis, which is associated with worse outcomes and increased mortality. The use of relevant preclinical studies remains necessary to understand mechanistic changes following injury and sepsis at the cellular and molecular level.

Hypothesis:

We hypothesized that a preclinical rodent model of multicompartmental injury with postinjury pneumonia and chronic stress would replicate inflammation and organ injury similar to trauma patients in the intensive care unit (ICU).

Methods:

Male and proestrus female Sprague-Dawley rats (n=8/group) aged 9-11 weeks were subjected to either polytrauma (PT) (lung contusion, hemorrhagic shock, cecectomy, and bifemoral pseudofracture), PT with daily chronic restraint stress (PT/CS), PT with postinjury day 1 pseudomonas pneumonia (PT+PNA), PT/CS with pneumonia (PT/CS+PNA) or naïve controls. Weight, hemoglobin, white blood cell count (WBC), serum creatinine, plasma toll-like receptor 4 (TLR4), and urine norepinephrine (NE) were evaluated on day 2. ANOVA with pairwise comparisons were performed with significance defined as *p < 0.05.

Results:

Rats who underwent PT+PNA and PT/CS+PNA lost more weight compared to their those without sepsis (PT, PT/CS) and naïve rats (*p<0.03). PT/CS+PNA exhibited worse acute kidney injury with elevated serum creatinine compared to PT, PT/CS (*p<0.01). Both pneumonia groups had a leukocytosis greater than uninfected (PT, PT/CS) (*p<0.004). Each experimental group exhibited severe anemia compared to naïve rats (*p<0.0001). Plasma TLR4 was elevated in PT+PNA compared to uninfected counterparts (*p=0.01). Urine NE was elevated in PT+PNA and PT/CS+PNA compared to naïve (*p<0.02), with PT/CS+PNA exhibiting the highest levels.

Conclusions:

Sepsis, with postinjury pneumonia, induced significant systemic inflammation, acute kidney injury, leukocytosis, and anemia following polytrauma and chronic stress. Advanced animal models that replicate the critically ill human condition will help overcome the classic limitations of previous experimental models and enhance their translational value.