Expression of HO1 and PER2 can predict the incidence of delirium in trauma patients with concomitant brain injury

Abstract

Intensive care unit (ICU)-acquired delirium is associated with adverse outcome in trauma patients with concomitant traumatic brain injury (TBI), but diagnosis remains challenging. Quantifying circadian disruption by analyzing expression of the circadian gene period circadian regulator 2 (PER2) and heme oxygenase 1 (HO1), which determines heme turnover, may prove to be potential diagnostic tools. Expression of PER2 and HO1 was quantified using qPCR from blood samples 1 day and 7 days after trauma. Association analysis was performed comparing mRNA expression levels with parameters of trauma (ISS—injury severity score), delirium, acute kidney injury (AKI) and length of ICU stay. 48 polytraumatized patients were included (equal distribution of TBI versus non-TBI) corrected for ISS, age and gender using a matched pairs approach. Expression levels of PER2 and HO1 were independent of age (PER2: P = 0.935; HO1: P = 0.988), while expression levels were significantly correlated with trauma severity (PER2: P = 0.009; HO1: P < 0.001) and longer ICU length of stay (PER2: P = 0.018; HO1: P < 0.001). High expression levels increased the odds of delirium occurrence (PER2: OR = 4.32 [1.14–13.87]; HO1: OR = 4.50 [1.23–14.42]). Patients with TBI showed a trend towards elevated PER2 (OR = 3.00 [0.84–9.33], P = 0.125), but not towards delirium occurrence (P = 0.556). TBI patients were less likely to develop AKI compared to non-TBI (P = 0.022). Expression levels of PER2 and HO1 correlate with the incidence of delirium in an age-independent manner and may potentially improve diagnostic algorithms when used as delirium biomarkers.Trial registration: German Clinical Trials Register (Trial-ID DRKS00008981; Universal Trial Number U1111-1172-6077; Jan. 18, 2018).

Sleep Fragmentation, Electroencephalographic Slowing, and Circadian Disarray in a Mouse Model for Intensive Care Unit Delirium

“…4–6 In aged mice subjected to ASI, sleep was interrupted by frequent arousals, awake EEG activity was characterized by loss of high frequencies, and awake EEG slowing was strongly correlated with behavioral quiescence. In addition, ASI mice failed to synchronize their sleep-wake activity with external light cues, and their expression of key molecular components of the brain circadian clock 22–27 was decreased relative to controls.…”

“…Given their inability to align their sleep-wake state with light cues, we next asked whether the expression of core clock genes necessary for normal circadian function was impaired in ASI mice. [22][23][24][25][26][27] Brains were collected at the same time for all animals at the end of simulated ICU conditions. Indeed, we found that mRNA levels of CLOCK, BMAL1, PER1, PER2, PER3, www.anesthesia-analgesia.org 217 CRY1, and CRY2 genes were significantly decreased in ASI mice relative to controls (BMAL1: −1.3-fold; CLOCK: −1.2; CRY1: −1.4; CRY2: −1.2; PER1: −1.2; PER2: −1.4; and PER3: −1.3; Figure 7A).…”

The effect of dexmedetomidine on the postoperative recovery of patients with severe traumatic brain injury undergoing craniotomy treatment: a retrospective study

“…Delirium, an acute mental state change, is characterized by inattention, arousal disorders and mental disorders [ 28 ]. However, the presence of delirium caused irreversible damage to the brain function of patients, significantly increased the total length of hospital stay, significantly increased the cost of hospitalization, and even seriously affected the prognosis [ 28 , 29 ]. Delirium is highly common in patients with severe TBI and can occur at any time during a patient's hospital stay, and studies suggest that up to 70% of patients present during a hospital stay [ 28 , 30 ].…”

Delirium in trauma ICUs: a review of incidence, risk factors, outcomes, and management

“…Although clinical scoring systems have been around for many years, in the last few years, novel laboratory markers have been shown to predict those at highest risk for delirium among trauma patients. In a small study, Steimer et al [30 ▪ ] in 2021 showed that expression of circadian gene period regulators (PER2) and heme oxygenase 1 (HO1) early in the hospital stay in trauma patients correlated with development of delirium in an age-independent fashion. With more widespread use and availability, biomarkers like these may serve as useful predictors allowing more targeted assessment and prevention.…”