Examining the Relationship Between Systemic Inflammatory Biomarkers and Delirium among Surgical Pediatric Critically Ill Patients.

Abstract

Pediatric critically ill patients with delirium experience worse outcomes compared to those without delirium. Despite ongoing efforts to identify patients with delirium, daily delirium screening using validated screening tools remains a challenge. Delirium is hypothesized to have an underlying neuroinflammatory mechanism. According to the neuroinflammatory hypothesis, systemic inflammation triggered by an infection or injury may prompt an inflammatory response in the brain. This response can activate brain parenchymal cells, increase blood-brain barrier (BBB) permeability, and ultimately contribute to neuroinflammation and delirium. To evaluate the most reported, associated, and clinically accessible serum inflammatory biomarkers, a state-of-the-science review was conducted. Among studies reviewed, which are mostly in adults, most evidence establishing a relationship between several inflammatory biomarkers and delirium has come from surgical patients. C-reactive protein (CRP), interleukin-6 (IL-6), and neutrophil-to-lymphocyte ratio (NLR) were among the most commonly reported, with positive associations with delirium. Researchers in the studies reviewed recommend that future work target specific populations to better understand these relationships. Among the most studied serum inflammatory biomarkers, C-reactive protein (CRP) and the Neutrophil-to-Lymphocyte Ratio (NLR) are also readily accessible in clinical practice. To further evaluate the neuroinflammatory relationship among pediatric patients, a multi-aim study was conducted to determine whether there are similar associations between systemic inflammatory biomarkers and delirium among surgical PICU and CICU patients, and whether biomarkers can predict delirium in this population and further support detection alongside bedside delirium screening. To evaluate the association and predictive performance of pre-operative C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR), a retrospective cohort study was conducted at a quaternary, free-standing, academic children’s hospital in Seattle, WA. Surgical patients aged 0 to 21 years admitted post-operatively to a PICU or CICU between 2017 and 2025 with at least one pre-operative biomarker within 14 days prior to surgery, and delirium assessment were included in the study. Multivariable logistic regression models, adjusted for age, sex, developmental delay, and American Society of Anesthesiologists (ASA) status, showed no significant association between pre-operative CRP or NLR and post-operative delirium. The discriminative performance was poor for CRP, NLR, and the combined models, with an area under the receiver operating characteristic curve of 0.55 for the combined model. Diagnostic sensitivity was low across all models, limiting their clinical utility for delirium risk stratification. Furthermore, a sub-cohort study was conducted to determine whether the relative change in pre- and post-operative inflammatory biomarkers (CRP, NLR) predicted delirium in surgical PICU and CICU patients who had at least one pre- and one post-operative biomarker of the same type. Delirium was defined as CAPD greater than or equal to 9 within the first seven post-operative days. Percent change in CRP and NLR from pre-operative to post-operative values was calculated, censoring biomarker measurements obtained after delirium onset. To examine the relationship between inflammatory biomarkers and incident delirium, a multivariable modified Poisson and generalized linear model (GLM) were used, adjusted for age, sex, developmental delay, and American Society of Anesthesiologists (ASA) class. Delirium occurred in 51.1% of the NLR cohort (n=45) and 53.3% of the CRP cohort (n=15). Percent change in NLR and CRP was not associated with delirium risk. In both studies, CRP and NLR were not associated with post-operative delirium among PICU and CICU patients. Several limitations reduced the power of the study results, including the cohort size and the variable timing of biomarker measurements relative to the surgery date and time. Future prospective studies with larger sample sizes, narrower pre-operative laboratory measurement windows, and improved temporal assessment of inflammatory processes, including additional systemic inflammatory biomarkers (e.g. IL-6), are needed to clarify the relationship between perioperative inflammation and post-operative pediatric delirium.