Understanding sedative effects within the context of acute neuroinflammation in the developing brain: Potential induction of delirium-like behaviors.

Neurologic morbidity is highly prevalent in pediatric critical illness, and the use of benzodiazepines and/or opioids is a risk factor for delirium and post-discharge sequelae. However, little is known about how multidrug sedation with these medications interacts with inflammation in the developing brain, a frequent condition during childhood critical illness that has not been extensively studied. In weanling rats, mild-moderate inflammation was induced with lipopolysaccharide (LPS) on postnatal day (P)18 and combined with 3 days repeated opioid and benzodiazepine sedation using morphine and midazolam (MorMdz) between P19-21. Delirium-like behaviors including abnormal response to whisker stimulation, wet dog shakes, and delay in finding buried food were induced in male and female rat pups treated with LPS, MorMdz, or LPS/MorMdz (n ≥ 17/group) and were compared using a z-score composite. Composite behavior scores were significantly increased in LPS, MorMdz, and LPS/MorMdz groups compared to saline control (F = 38.1, p < 0.0001). Additionally, expression of glial-associated neuroinflammatory markers ionized calcium-binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP) in western blots of P22 brain homogenate were significantly higher after LPS than after LPS/MorMdz (Iba1, p < 0.0001; GFAP, p < 0.001). Likewise, proinflammatory cytokines were increased in brains of LPS-treated pups versus Saline (p = 0.002), but not LPS/MorMdz-treated pups (p = 0.16). These results are of potential interest during pediatric critical illness, as inflammation is ubiquitous and the effects of multidrug sedation on homeostatic neuroimmune responses need to be considered along with neurodevelopmental effects.