Serum Biomarkers of Delirium in Critical Illness
Abstract:
Delirium is a frequent and serious complication of critical illness, with up to 80% of ventilated ICU patients affected. This systematic review synthesized evidence from 28 studies assessing 54 serum biomarkers related to delirium, grouped into six mechanistic categories: CNS injury, immune activation, hormonal dysregulation, neurotransmission, coagulation, and amino acid metabolism. The review highlights methodological inconsistencies but identifies promising signals, especially for astrocytic and axonal injury markers.
Key Insights:
- Delirium in the ICU is linked to increased morbidity, mortality, and long-term cognitive impairment, with risk factors spanning patient-related predispositions and ICU-specific precipitants .
- Fifty-four unique serum biomarkers were studied, highlighting the broad search for biological correlates of delirium .
- CNS injury biomarkers such as S100β and neurofilament light chain (NfL) showed the strongest and most consistent associations with delirium presence and severity .
- Neurofilament heavy chain, GFAP, UCH-L1, tau, and NSE were studied less frequently but add to evidence of astrocytic and axonal injury as drivers of delirium pathogenesis .
- Inflammatory biomarkers including IL-6, CRP, and TNF-α were the most studied immune markers, but results were inconsistent, reflecting systemic inflammation’s non-specific role .
- Hormonal markers such as cortisol, prolactin, and leptin demonstrated preliminary promise, suggesting stress and endocrine dysregulation may contribute to delirium .
- Neurotransmitter-related biomarkers (serotonin, substance P, serum amyloid A) produced mixed results, challenging the classical neurotransmitter imbalance hypothesis of delirium .
- Coagulation-related markers (D-dimer, PAI-1, vWF) and amino acids (tryptophan, tyrosine, phenylalanine) were variably linked to delirium, underscoring metabolic complexity .
- Major limitations included heterogeneity in delirium assessment tools, biomarker sampling timelines, confounding adjustment, and lack of replication across cohorts .
- The authors propose a mechanistic “endotyping” framework that integrates biomarker profiles with clinical and neurophysiological data to identify biologically distinct delirium subtypes for future precision medicine .
Conclusion:
Serum biomarkers such as S100β and NfL hold potential for illuminating delirium pathogenesis in critical illness, especially regarding astrocytic and axonal injury. However, inconsistent findings and methodological heterogeneity limit clinical applicability. Progress will require harmonized biomarker protocols, longitudinal designs, and integration with EEG, imaging, and cognitive outcomes to enable mechanistic endotyping and precision-targeted delirium therapies.
Take-Home for Clinicians: Biomarkers of CNS injury currently show the greatest potential, but no serum marker is ready for clinical use in ICU delirium diagnosis. The future lies in multimodal profiling that can separate biological subtypes of delirium and match interventions to underlying mechanisms.
Discussion Question: Could biomarker-driven endotyping transform delirium care by enabling targeted pharmacologic and supportive interventions, or will the heterogeneity of critical illness always limit generalizability?
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