Alia Marie O'Meara, MD
Pediatric Critical Care Med
Childrens Hospital of Richmond at VCU
Portsmouth, VA
Disclosure information not submitted.
Travis Sullivan, MD
Surgery Resident
Virginia Commonwealth University, Virginia, United States
Disclosure information not submitted.
Amanda Furman, BS, MS
Laboratory Technician
Virginia Commonwealth University, United States
Disclosure information not submitted.
Nikki Miller Ferguson, MD
Associate Professor
Virginia Commonwealth University Medical Center
Richmond, Virginia, United States
Disclosure information not submitted.
Carmen Sato-Bigbee, PhD
Associate Professor
Virginia Commonwealth University, United States
Disclosure information not submitted.
Gretchen Neigh, PhD
Associate Professor
Virginia Commonwealth University, United States
Disclosure information not submitted.
Title: Inflammation Combined with Analgesia and Sedation Alters Whisker Stimulation Response in Young Rats
Introduction: Despite prevalent neuromorbidity in pediatric critical illness, there are few if any preclinical models that elucidate causative mechanisms to guide practice change. Many illness and therapy factors are implicated, but inflammation and analgesia and sedation are common variables, and analgesia and sedation are potentially modifiable.
Hypothesis: Systemic exposure to escherichia coli lipopolysaccharide (LPS) combined with opioid and benzodiazepine sedation will increase markers of neuroinflammation (glial fibrillary acidic protein [GFAP] and ionized calcium-binding protein [Iba1]), and alter response to whisker stimulation.
Methods: Early childhood-approximate male and female Sprague Dawley rats (18-23 days old, n=64, ≥7/sex/group), were injected with LPS on study days 1, 3, and 5 and sedated twice daily with morphine and midazolam on days 2 through 6 (LPS+Mor/Mid). Controls were: Saline, LPS, and Mor/Mid. Whisker stimulation response was tested on day 6. On day 7 GFAP and Iba1 were assessed in the lateral cortex with western blot along with plasma cytokines by ELISA. Data were analyzed using 2-way ANOVA with Tukey’s HSD and are reported as mean±SEM.
Results: Scores for agitated or anxious responses to whisker stimulation were significantly higher for both sexes, but particularly females, in Mor/Mid (4.6±0.5, p< 0.01) and LPS+Mor/Mid (7.7±0.5, p< 0.001) vs Saline and LPS (1.9±0.6 and 2.2±1.2, respectively). Iba1 expression was 35% higher in LPS males vs Saline (p< 0.05) and 25% higher in LPS+Mor/Mid males and females (p< 0.01). Additionally, GFAP was increased by 36% in LPS+Mor/Mid females vs Saline or LPS (p< 0.001), while GFAP was 28% lower in both sexes Mor/Mid (p< 0.01). Animals were without “sick behaviors” on day 6 and there were no between-group differences in plasma cytokines.
Conclusions: Compared to all other groups, LPS+Mor/Mid had the most significant effect on abnormal whisker stimulation responses and increased Iba1 in the somatosensory-containing lateral cortex. This effect was greatest in females, in whom it was also associated with increased GFAP, a marker of astrocytes and brain injury. These results suggest an interactive effect of analgesia and sedation on neuroinflammation, astrocyte activity, and sensory processing which may contribute to neuromorbidity in critically ill children.