Expression of microRNA induced by postoperative delirium-like behavior is associated with long-term default mode network disruption: Sequencing and a secondary analysis of resting-state fMRI data.

AIMS: Resting state functional magnetic resonance imaging (rs-fMRI) has been widely used in studying default mode network (DMN) changes in postoperative delirium (POD). Reproducibility and interpretability of the analyzing results remain insufficiently studied. METHODS: Delirium-like behavior was induced by tibial fixation surgery under isoflurane anesthesia. Firstly, we evaluated delirium-like behavior and inflammatory responses in hippocampus and systemic level. Then the expressions of microRNA (miRNA) and target gene were sequenced and validated. Afterwards the functional connectivity (FC) in DMN was analyzed. Finally, results were correlated with DMN changes. RESULTS: POD-like behavior caused significant changes of miR-34b-5p, miR-328-5p, and miR-3505 in miRNA level and Nos1, Tubb3, and Gys1 in the gene level. The FC in left and right hippocampus (L-Hip and R-Hip) and right auditory cortex (R-AC) was found significantly changed. Significant correlations were found in FCL-Hip/R-AC and FCR-Hip/R-AC for miR-34b-5p and miR-3505, as well as Nos1 and Tubb3. For miR-328-5p, no significant correlations were found. CONCLUSION: Our study demonstrates that POD-like behavior induced significant miRNA and gene expression changes were associated with hippocampus related long-term FC disruption in DMN. The results increased reproducibility and interpretability for standardized rs-fMRI data analysis, as well as providing potential targets for postoperative delirium treatment.

Epigenetic signals associated with delirium replicated across four independent cohorts.

Delirium is risky and indicates poor outcomes for patients. Therefore, it is crucial to create an effective delirium detection method. However, the epigenetic pathophysiology of delirium remains largely unknown. We aimed to discover reliable and replicable epigenetic (DNA methylation: DNAm) markers that are associated with delirium including post-operative delirium (POD) in blood obtained from patients among four independent cohorts. Blood DNA from four independent cohorts (two inpatient cohorts and two surgery cohorts; 16 to 88 patients each) were analyzed using the Illumina EPIC array platform for genome-wide DNAm analysis. We examined DNAm differences in blood between patients with and without delirium including POD. When we compared top CpG sites previously identified from the initial inpatient cohort with three additional cohorts (one inpatient and two surgery cohorts), 11 of the top 13 CpG sites showed statistically significant differences in DNAm values between the delirium group and non-delirium group in the same directions as found in the initial cohort. This study demonstrated the potential value of epigenetic biomarkers as future diagnostic tools. Furthermore, our findings provide additional evidence of the potential role of epigenetics in the pathophysiology of delirium including POD.

The Genome-wide DNA methylation changes in gastrointestinal surgery patients with and without postoperative delirium: Evidence of immune process in its pathophysiology.

AIM: The pathophysiological mechanisms of postoperative delirium (POD) are still unclear, and there is no reliable biomarker to distinguish between those with and without POD. Our aim was to discover DNAm markers associated with POD in blood collected from patients before and after gastrointestinal surgery. METHOD: We collected blood samples from 16 patients including 7 POD patients at three timepoints; before surgery (pre), the first and third postoperative days (day1 and day3). We measured differences in DNA methylation between POD and control groups between pre and day1 as well as between pre and day3 using the Illumina EPIC array method. Besides, enrichment analysis with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes terms were also performed after excluding influence of common factors related to surgery and anesthesia. RESULT: The results showed that pre and day1 comparisons showed that immune and inflammatory signals such as 'T-cell activation' were significantly different, consistent with our previous studies with non-Hispanic White subjects. In contrast, we found that these signals were not significant any more when pre was compared with day3. CONCLUSION: These results provide strong evidence for the involvement of inflammatory and immune-related epigenetic signals in the pathogenesis of delirium, including POD, regardless of ethnic background. These findings also suggest that DNAm, which is involved in inflammation and immunity, is dynamically altered in patients with POD. In summary, the present results indicate that these signals may serve as a new diagnostic tool for POD.

DNA methylation in the inflammatory genes after neurosurgery and diagnostic ability of post-operative delirium.

The pathophysiological mechanisms of postoperative delirium (POD) are still not clear, and no reliable biomarker is available to differentiate those with and without POD. Pre- and post-surgery blood from epilepsy subjects undergoing neurosurgery were collected. DNA methylation (DNAm) levels of the TNF gene, IL1B gene, and IL6 gene by the Illumina EPIC array method, and DNAm levels of the TNF gene by pyrosequencing, were analyzed. Blood from 37 subjects were analyzed by the EPIC array method, and blood from 27 subjects were analyzed by pyrosequencing. Several CpGs in the TNF gene in preoperative blood showed a negative correlation between their DNAm and age both in the POD group and in the non-POD group. However, these negative correlations were observed only in the POD group after neurosurgery. Neurosurgery significantly altered DNAm levels at 17 out of 24 CpG sites on the TNF gene, 8 out of 14 CpG sites on the IL1B gene, and 4 out of 14 CpG sites on the IL6 gene. Furthermore, it was found that the Inflammatory Methylation Index (IMI), which was based on the post-surgery DNAm levels at the selected five CpG sites, can be a potential detection tool for delirium with moderate accuracy; area under the curve (AUC) value was 0.84. The moderate accuracy of this IMI was replicated using another cohort from our previous study, in which the AUC was 0.79. Our findings provide further evidence of the potential role of epigenetics and inflammation in the pathophysiology of delirium.

Association between genetic variants of the cholinergic system and postoperative delirium and cognitive dysfunction in elderly patients.

BACKGROUND: Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) are frequent and serious complications after surgery. We aim to investigate the association between genetic variants in cholinergic candidate genes according to the Kyoto encyclopedia of genes and genomes - pathway: cholinergic neurotransmission with the development of POD or POCD in elderly patients. METHODS: This analysis is part of the European BioCog project ( www.biocog.eu ), a prospective multicenter observational study with elderly surgical patients. Patients with a Mini-Mental-State-Examination score ≤ 23 points were excluded. POD was assessed up to seven days after surgery using the Nursing Delirium Screening Scale, Confusion Assessment Method and a patient chart review. POCD was assessed three months after surgery with a neuropsychological test battery. Genotyping was performed on the Illumina Infinium Global Screening Array. Associations with POD and POCD were analyzed using logistic regression analysis, adjusted for age, comorbidities and duration of anesthesia (for POCD analysis additionally for education). Odds ratios (OR) refer to minor allele counts (0, 1, 2). RESULTS: 745 patients could be included in the POD analysis, and 452 in the POCD analysis. The rate of POD within this group was 20.8% (155 patients), and the rate of POCD was 10.2% (46 patients). In a candidate gene approach three genetic variants of the cholinergic genes CHRM2 and CHRM4 were associated with POD (OR [95% confidence interval], rs8191992: 0.61[0.46; 0.80]; rs8191992: 1.60[1.22; 2.09]; rs2067482: 1.64[1.10; 2.44]). No associations were found for POCD. CONCLUSIONS: We found an association between genetic variants of CHRM2 and CHRM4 and POD. Further studies are needed to investigate whether disturbances in acetylcholine release and synaptic plasticity are involved in the development of POD. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02265263.

DNA methylation in the TNF-alpha gene decreases along with aging among delirium inpatients.

It has been suggested that aging and inflammation play key roles in the development of delirium. In the present study, we investigated the differences of the DNAm patterns in the TNF gene between patients with delirium and without. The data and samples derived from previous and ongoing cohort studies were analyzed. DNAm levels of the TNF gene were analyzed using the Illumina EPIC array genome-wide method and pyrosequencing method. Correlations between age and DNAm levels of each CpG were calculated. Several CpG in the TNF gene in blood showed negative correlation between their DNAm and age in delirium cases both with the EPIC array and by the pyrosequencing method. However, there was no CpG that had significant correlation between their DNAm and age regardless of delirium status among buccal samples. On the other hand, among peripheral blood mononuclear cells samples, it was found that several CpG showed negative correlation between their DNAm and age in delirium cases. The evidence of DNAm change in the TNF gene among delirious subjects was demonstrated.

Scopolamine promotes neuroinflammation and delirium-like neuropsychiatric disorder in mice.

Postoperative delirium is a common neuropsychiatric syndrome resulting a high postsurgical mortality rate and decline in postdischarge function. Extensive research has been performed on both human and animal delirium-like models due to their clinical significance, focusing on systematic inflammation and consequent neuroinflammation playing a key role in the pathogenesis of postoperative cognitive dysfunctions. Since animal models are widely utilized for pathophysiological study of neuropsychiatric disorders, this study aimed at examining the validity of the scopolamine-induced delirium-like mice model with respect to the neuroinflammatory hypothesis of delirium. Male C57BL/6 mice were treated with intraperitoneal scopolamine (2 mg/kg). Neurobehavioral tests were performed to evaluate the changes in cognitive functions, including learning and memory, and the level of anxiety after surgery or scopolamine treatment. The levels of pro-inflammatory cytokines (IL-1ß, IL-18, and TNF-α) and inflammasome components (NLRP3, ASC, and caspase-1) in different brain regions were measured. Gene expression profiles were also examined using whole-genome RNA sequencing analyses to compare gene expression patterns of different mice models. Scopolamine treatment showed significant increase in the level of anxiety and impairments in memory and cognitive function associated with increased level of pro-inflammatory cytokines and NLRP3 inflammasome components. Genetic analysis confirmed the different expression patterns of genes involved in immune response and inflammation and those related with the development of the nervous system in both surgery and scopolamine-induced mice models. The scopolamine-induced delirium-like mice model successfully showed that analogous neuropsychiatric changes coincides with the neuroinflammatory hypothesis for pathogenesis of delirium.

Preoperative MRI brain phenotypes are related to postoperative delirium in older individuals.

The underlying structural correlates of predisposition to postoperative delirium remain largely unknown. A combined analysis of preoperative brain magnetic resonance imaging (MRI) markers could improve our understanding of the pathophysiology of delirium. Therefore, we aimed to identify different MRI brain phenotypes in older patients scheduled for major elective surgery, and to assess the relation between these phenotypes and postoperative delirium. Markers of neurodegenerative and neurovascular brain changes were determined from MRI brain scans in older patients (n = 161, mean age 71, standard deviation 5 years), of whom 24 (15%) developed delirium. A hierarchical cluster analysis was performed. We found six distinct groups of patients with different MRI brain phenotypes. Logistic regression analysis showed a higher odds of developing postoperative delirium in individuals with multi-burden pathology (n = 15 (9%), odds ratio (95% confidence interval): 3.8 (1.1-13.0)). In conclusion, these results indicate that different MRI brain phenotypes are related to a different risk of developing delirium after major elective surgery. MRI brain phenotypes could assist in an improved understanding of the structural correlates of predisposition to postoperative delirium.

Preoperative Circulating MiR-210, a Risk Factor for Postoperative Delirium Among Elderly Patients with Gastric Cancer Undergoing Curative Resection.

BACKGROUND: Postoperative delirium (POD) is a very common complication in elderly patients with gastric cancer (GC) and associated with poor prognosis. MicroRNAs (miRNAs) serve as key post-transcriptional regulators of gene expression via targeting mRNAs and play important roles in the nervous system. This study aimed to investigate the potential predictive role of miRNAs for POD. METHODS: Elderly GC patients who were scheduled to undergo elective curative resection were consequently enrolled in this study. POD was assessed at 1 day before surgery and 1-7 days after surgery following the guidance of the 5th edition of Diagnostic and Statistical Manual of Mental Disorders (DSM V, 2013). The demographics, clinicopathologic characteristics and preoperative circulating miRNAs by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were compared between patients with or without POD. Risk factors for POD were assessed via univariate and multivariate logistic regression analyses. RESULTS: A total of 370 participants were enrolled, of which 63 had suffered from POD within postoperative 7 days with an incidence of 17.0%. Preoperative miR-210 was a predictor for POD with an area under the curve (AUC) of 0.921, a cut-off value of 1.67, a sensitivity of 95.11%, and a specificity of 92.06%, (P<0.001). In the multivariate logistic regression model, the relative expression of serum miR-210 was an independent risk factor for POD (OR: 3.37, 95%CI: 1.98-5.87, P=0.003). CONCLUSIONS: In conclusion, the present study highlighted that preoperative miR-210 could serve as a potential predictor for POD in elderly GC patients undergoing curative resection.

Systems pharmacogenomics - gene, disease, drug and placebo interactions: a case study in COMT.

Disease, drugs and the placebos used as comparators are inextricably linked in the methodology of the double-blind, randomized controlled trial. Nonetheless, pharmacogenomics, the study of how individuals respond to drugs based on genetic substrate, focuses primarily on the link between genes and drugs, while the link between genes and disease is often overlooked and the link between genes and placebos is largely ignored. Herein, we use the example of the enzyme catechol-O-methyltransferase to examine the hypothesis that genes can function as pharmacogenomic hubs across system-wide regulatory processes that, if perturbed in andomized controlled trials, can have primary and combinatorial effects on drug and placebo responses.

Genome-wide association study of myocardial infarction, atrial fibrillation, acute stroke, acute kidney injury and delirium after cardiac surgery - a sub-analysis of the RIPHeart-Study.

BACKGROUND: The aim of our study was the identification of genetic variants associated with postoperative complications after cardiac surgery. METHODS: We conducted a prospective, double-blind, multicenter, randomized trial (RIPHeart). We performed a genome-wide association study (GWAS) in 1170 patients of both genders (871 males, 299 females) from the RIPHeart-Study cohort. Patients undergoing non-emergent cardiac surgery were included. Primary endpoint comprises a binary composite complication rate covering atrial fibrillation, delirium, non-fatal myocardial infarction, acute renal failure and/or any new stroke until hospital discharge with a maximum of fourteen days after surgery. RESULTS: A total of 547,644 genotyped markers were available for analysis. Following quality control and adjustment for clinical covariate, one SNP reached genome-wide significance (PHLPP2, rs78064607, p = 3.77 × 10- 8) and 139 (adjusted for all other outcomes) SNPs showed promising association with p < 1 × 10- 5 from the GWAS. CONCLUSIONS: We identified several potential loci, in particular PHLPP2, BBS9, RyR2, DUSP4 and HSPA8, associated with new-onset of atrial fibrillation, delirium, myocardial infarction, acute kidney injury and stroke after cardiac surgery. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov NCT01067703, prospectively registered on 11 Feb 2010.

The Association Between C-Reactive Protein and Postoperative Delirium Differs by Catechol-O-Methyltransferase Genotype.

OBJECTIVE: Catechol-O-methyltransferase (COMT), a key enzyme in degrading catecholamines associated with the stress response, may influence susceptibility to delirium. Individuals with the COMT (rs4680) Val/Val genotype (designated "warriors") withstand the onset of neuropsychiatric disorders and cognitive decline, whereas individuals with Met/Met and Val/Met genotypes ("nonwarriors") are more susceptible to these conditions. We evaluated whether COMT genotype modifies the established association between acute phase reactant (stress marker) C-reactive protein (CRP) and postoperative delirium. METHODS: This was a prospective cohort study conducted at two academic medical centers. The study involved 547 patients aged 70 or older undergoing major noncardiac surgery. We collected blood, extracted DNA, and performed COMT genotyping using allele-specific polymerase chain reaction assays, considering warriors versus nonwarriors. High plasma CRP, measured on postoperative day 2 using enzyme-linked immunosorbent assay, was defined by the highest sample-based quartile (≥234.12 mg/L). Delirium was determined using the Confusion Assessment Method, augmented by a validated chart review. We used generalized linear models adjusted for age, sex, surgery type, and race/ethnicity, stratified by COMT genotype, to determine whether the association between CRP and delirium differed by COMT. RESULTS: Prevalence of COMT warriors was 26%, and postoperative delirium occurred in 23%. Among COMT warriors, high CRP was not associated with delirium (relative risk [RR] 1.0, 95% confidence interval [CI] 0.4-2.6). In contrast, among nonwarriors, we found the expected relationship of high CRP and delirium (RR 1.5, 95% CI 1.1-2.2). CONCLUSION: COMT warriors may be protected against the increased risk of delirium associated with high CRP on postoperative day 2. With further confirmation, COMT genotype may help target interventions for delirium prevention in the vulnerable nonwarrior group.

Does the melatonin receptor 1B gene polymorphism have a role in postoperative delirium?

INTRODUCTION: Patients undergoing cardiac surgery are at high risk for postoperative delirium, which is associated with longer hospital and intensive care lengths of stays, increased morbidity and mortality. Because sleep disturbances are common in delirium, melatonin has been an area of interest in the treatment of delirium. The rs10830963 single nucleotide polymorphism of the melatonin receptor 1B gene can cause pathological dysfunction of this receptor and is associated with delayed morning offset of melatonin. We hypothesized patients undergoing aortic cardiac surgery who have the risk genotype of a melatonin receptor 1B polymorphism would have a higher incidence of postoperative delirium. METHODS: Ninety-eight patients undergoing aortic root or valve surgery underwent analysis for melatonin receptor 1B single nucleotide polymorphism, rs10830963. Using a validated method, CHART-DEL, all charts were retrospectively reviewed and scored for the presence of delirium while blinded to the results of the melatonin receptor 1B gene polymorphism. RESULTS: Genotyping for melatonin receptor 1B polymorphism was acceptable in 76 subjects of European descent of which 18 (23.7%) had delirium. Four of seven subjects with the risk genotype had delirium versus only 20.3% of subjects without the risk genotype. This carried an odds ratio of 5.2 (1.0, 26.1), p = 0.050. CONCLUSION: This observation suggests a role of the risk genotype of a melatonin receptor 1B polymorphism in the development of postoperative delirium. These hypotheses generating results warrant further prospective studies in a larger cohort group with delirium, circadian rhythm and melatonin assessments.

Whole-Genome mRNA Gene Expression Differs Between Patients With and Without Delirium.

OBJECTIVE: To identify differences in gene expression between patients with in-hospital delirium from a known etiology (urinary tract infection [UTI]) and patients with delirium from an unknown etiology, as well as from nondelirious patients. METHODS: Thirty patients with delirium (8 with UTI) and 21 nondelirious patients (11 with UTI) were included in this prospective case-control study. Transcriptomic profiles from messenger RNA sequencing of peripheral blood were analyzed for gene expression and disease-specific pathway enrichment patterns, correcting for systemic inflammatory response syndrome. Genes and pathways with significant differential activity based on Fisher exact test ( P < .05, |Z score| >2) are reported. RESULTS: Patients with delirium with UTI, compared to patients with delirium without UTI, exhibited significant activation of interferon signaling, upstream cytokines, and transcription regulators, as well as significant inhibition of actin cytoskeleton, integrin, paxillin, glioma invasiveness signaling, and upstream growth factors. All patients with delirium, compared to nondelirious patients, had significant complement system activation. Among patients with delirium without UTI, compared to nondelirious patients without UTI, there was significant activation of elF4 and p7056 K signaling. CONCLUSIONS: Differences exist in gene expression between delirious patients due to UTI presence, as well as due to the presence of delirium alone. Transcriptional profiling may help develop etiology-specific biomarkers for patients with delirium.

Observational cohort study examining apolipoprotein E status and preoperative neuropsychological performance as predictors of post-operative delirium in an older elective arthroplasty population.

Introduction: delirium following surgery is common and is associated with negative outcomes. Preoperative cognitive impairment has been shown to be a risk factor for post-operative delirium. Often the cognitive tests used are cumbersome. This study tests the hypothesis that the quantification of brain vulnerability, using Apolipoprotein E (ApoE) status and neuropsychological tests, both traditional and more easily administered, can quantify the risk of post-operative delirium following elective primary arthroplasty surgery. Methods: this observational cohort study recruited participants aged 65 years or older admitted prior to elective primary hip or knee arthroplasty. Baseline data was collected and participants underwent neuropsychological testing and had blood taken for ApoE genotyping preoperatively. Post-operatively participants were assessed daily for delirium using the Confusion Assessment Method (CAM) and charts were reviewed where possible for reports of delirium. Univariate and multivariate analyses of preoperative factors were undertaken to identify independent predictors of delirium. Results: between March 2012 and October 2014, 315 participants completed the study with an overall incidence of post-operative delirium of 40/315 (12.7%). Of these 18 fulfilled the CAM criteria for delirium and 22 were deemed delirious by consensus decision based on chart review. ApoE genotype was not associated with post-operative delirium in this cohort. Time taken to complete Colour Trails 2, errors in mini mental state examination and level of pain preoperatively were independent predictors of post-operative delirium. Conclusions: this study challenges the assertion that ApoE4 genotype predicts post-operative delirium. It replicates previous work suggesting cognitive impairment predicts post-operative delirium and shows for the 1st time that simple cognitive tests can be as effective as more detailed tests.

Does Apolipoprotein E Genotype Increase Risk of Postoperative Delirium?

OBJECTIVE: To determine whether apolipoprotein E (ApoE) is associated with postoperative delirium incidence, severity, and duration in older patients free of dementia at baseline. METHODS: The authors examined 557 nondemented patients aged 70 years or older undergoing major noncardiac surgery enrolled in the Successful Aging after Elective Surgery Study. Three ApoE measures were considered: ε2, ε4 carriers versus noncarriers, and a three-category ApoE measure. Delirium was determined using the Confusion Assessment Method (CAM) and chart review. We used generalized linear models to estimate the association between ApoE and delirium incidence, severity (peak CAM Severity [CAM-S] score), and days. RESULTS: ApoE ε2 and ε4 was present in 15% and 19%, respectively, and postoperative delirium occurred in 24%. Among patients with delirium, the mean peak CAM-S score was 8.0 (standard deviation: 4), with most patients experiencing 1 or 2 delirium days (51% or 28%, respectively). After adjusting for age, sex, surgical procedure, and preoperative cognitive function, ApoE ε4 and ε2 carrier status were not associated with postoperative delirium: RR for ε4=1.0, 95% CI: 0.7-1.5 and RR for ε2=0.9, 95% CI: 0.6-1.4. No association between ApoE and delirium severity or number of delirium days was observed. CONCLUSION: In older surgery patients free of dementia, our findings do not support the hypothesis that the ApoE genotype does not confer either risk or protection in postoperative delirium incidence, severity, or duration. Thus, an important genetic risk factor for Alzheimer disease does not affect risk of delirium.

The assessment of the T102C polymorphism of the 5HT2a receptor gene, 3723G/A polymorphism of the NMDA receptor 3A subunit gene (GRIN3A) and 421C/A polymorphism of the NMDA receptor 2B subunit gene (GRIN2B) among cardiac surgery patients with and without delirium.

OBJECTIVE: The studies regarding the role of genes polymorphism in development of postoperative delirium are extremely rare. Therefore, we investigated the potential association of polymorphism in 5HT2a receptor gene and N-methyl-d-aspartate (NMDA) receptor 3A and 2B subunits genes with postoperative delirium. METHOD: We conducted a prospective, nested, case-control study. For analysis, 3723 G/A (rs3739722) polymorphism in the GRIN3A gene, 421 C/A (rs3764028) polymorphism in the GRIN2B gene and T102C (rs6313) polymorphism in the 5HT2A gene were selected. RESULTS: Genetic analysis confirmed that there were significant differences in genotype frequencies for 3723 G/A between delirium patients and controls. No other significant associations were observed. Moreover, according to the multivariate conditional logistic regression analysis the presence of AG haplotype of GRIN3A gene was independently associated with postoperative delirium. CONCLUSIONS: These findings suggest that the genetic variations of NR3A subunit of NMDA receptor may be a predisposing factor to delirium among the Polish population of cardiac surgery patients.

Interleukin 6 and apolipoprotein E as predictors of acute brain dysfunction and survival in critical care patients.

BACKGROUND: Delirium occurs in up to 80% of intensive care patients and is associated with poor outcomes. The biological cause of delirium remains elusive. OBJECTIVES: To determine if delirium and recovery are associated with serum levels of interleukins and apolipoprotein E over time and with apolipoprotein E genotype. METHODS: The sample consisted of 77 patients with no previous cognitive deficits who required mechanical ventilation for 24 to 96 hours. Daily serum samples were obtained for enzyme-linked immunosorbent assay measurements of interleukins 6, 8, and 10 and apolipoprotein E. DNA extracted from blood was analyzed for apolipoprotein E genotyping. The Confusion Assessment Method for the Intensive Care Unit was administered daily on days 2 through 9. RESULTS: Among the 77 patients, 23% had no delirium, 46% experienced delirium, and 31% experienced coma. Additionally, 77% had delirium or coma (acute brain dysfunction), and compared with other patients, had fewer ventilator-free days (P = .03), longer stay (P = .04), higher care needs at discharge (P = .001), higher mortality (P = .02), and higher levels of interleukin 6 (P = .03), and the APOE*3/*3 apolipoprotein E genotype (P = .05). Serum levels of apolipoprotein E correlated with levels of interleukins 8 and 10. Patients with the E4 allele of apolipoprotein E had shorter duration of delirium (P = .02) and lower mortality (P = .03) than did patients without this allele. CONCLUSIONS: Apolipoprotein E plays a complex role in illness response and recovery in critically ill patients. The relationship between apolipoprotein E genotype and brain dysfunction and survival is unclear.

Factors predisposing to coma and delirium: fentanyl and midazolam exposure; CYP3A5, ABCB1, and ABCG2 genetic polymorphisms; and inflammatory factors.

BACKGROUND: Delirium and sedative-induced coma are described as incremental manifestations of cerebral dysfunction. Both may be associated with sedative or opiate doses and pharmacokinetic or pharmacogenetic variables, such as drug plasma levels (exposure), drug metabolism, and/or their transport across the blood-brain barrier. OBJECTIVES: To compare biological and drug treatment characteristics in patients with coma and/or delirium while in the ICU. PATIENTS AND MEASUREMENTS: In 99 patients receiving IV fentanyl, midazolam, or both, we evaluated drug doses, covariates likely to influence drug effects (age, body mass index, and renal and hepatic dysfunction); delirium risk factors; concomitant administration of CYP3A and P-glycoprotein substrates/inhibitors; ABCB1, ABCG2, and CYP3A5 genetic polymorphisms; and fentanyl and midazolam plasma levels. Delirium and coma were evaluated daily. In patients with only coma (n=15), only delirium (n=7), and neither ever (n=14), we measured plasma levels of tumor necrosis factor-α, interleukin (IL)-1ß, IL-1RA, IL-6, IL-8, IL-10, IL-17,macrophage inflammatory protein-1ß, and monocyte chemotactic protein-1. RESULTS: Time to first coma was associated with fentanyl and midazolam doses (p=0.03 and p=0.01, respectively). The number of days in coma was associated with the number of days of coadministration of CYP3A inhibitors (r=0.30; p=0.006). Plasma levels of fentanyl were higher in patients with clinical coma (3.7±4.7 vs. 2.0±1.8 ng/mL, p=0.0001) as were midazolam plasma levels (1050±2232 vs. 168±249 ng/mL, p=0.0001). Delirium occurrence was unrelated to midazolam administration, cumulative doses, or serum levels. Days with delirium were associated with days of coadministration of P-glycoprotein inhibitor (r=0.35; p=0.0004). Delirious patients had higher levels of the inflammatory mediator IL-6 than comatose patients (129.3 vs. 35.0 pg/mL, p=0.05). CONCLUSIONS: Coma is associated with fentanyl and midazolam exposure; delirium is unrelated to midazolam and may be linked to inflammatory status. These data suggest that iatrogenic coma and delirium are not mechanistically linked.