Evaluating dopamine D2 receptor gene polymorphisms and peripheral inflammatory cytokines in ICU delirium: a two-stage exploratory observational study.

BACKGROUND

Delirium is a prevalent form of acute brain dysfunction in the Intensive Care Unit (ICU). Its pathogenesis is multifactorial, involving neurotransmitter imbalance and neuroinflammation. While Dopamine D2 receptor (DRD2) signaling is central to delirium pathophysiology, the association between specific DRD2 single nucleotide polymorphisms (SNPs) and ICU delirium remains understudied in Chinese populations. This study aimed to investigate the association of DRD2 polymorphisms (rs6275, rs6277) and inflammatory cytokines with the development of delirium in critically ill patients.

METHODS

This prospective observational study enrolled 200 adult patients admitted to the ICU of Lanzhou University Second Hospital between January 2021 and May 2022. Patients were screened for delirium twice daily using the Confusion Assessment Method for the ICU (CAM-ICU). Genomic DNA was extracted to genotype DRD2 SNPs (rs6275 and rs6277). In a subset of 100 patients, serum inflammatory markers (IL-6, IL-8, and TNF-ɑ) were quantified by ELISA. Multivariate logistic regression was performed to identify independent risk factors, and a nomogram was constructed to visualize risk prediction.

RESULTS

Of the 200 patients, 28 (14.0%) developed delirium. Genotyping revealed no significant difference in rs6275 distribution between groups. However, the rs6277 genotype distribution differed significantly (P = 0.019), with the CC genotype associated with a higher risk of delirium (OR=2.851, 95% CI: 1.149-6.703, P = 0.009). In the inflammatory subset, serum TNF-ɑ levels were significantly higher in delirious patients compared to non-delirious patients (P = 0.037), whereas IL-6 and IL-8 showed no significant differences. Multivariable logistic regression framework revealed that mechanical ventilation strongly correlated with increased delirium risk (adjusted OR = 6.842, 95% CI: 1.895-24.712, P = 0.003). The DRD2 rs6277 CC genotype also maintained a significant independent correlation with higher odds of delirium onset under full clinical adjustment (adjusted OR = 2.615, 95% CI: 1.038-6.694, P = 0.039). Conversely, dexmedetomidine administration was independently associated with lower odds of delirium development (adjusted OR = 0.371, 95% CI: 0.141-0.938, P = 0.036). A nomogram based on these factors showed good discrimination (AUC = 0.796).

CONCLUSION

The DRD2 rs6277 CC genotype is associated with ICU delirium risk in our primary cohort, while elevated serum TNF-ɑ represents a correlated inflammatory marker in a separate validation subgroup. These parallel findings independently support the genetic and neuroinflammatory hypotheses of delirium. However, larger integrated cohorts are required to confirm their potential intersecting mechanistic pathways.