AN INFLAMMATORY SIGNATURE OF POSTOPERATIVE DELIRIUM

Abstract Delirium is a common, morbid, and costly geriatric syndrome, yet its pathophysiology remains poorly understood. In a nested matched case-control study within the Successful Aging after Elective Surgery (SAGES) study, a cohort of adults age ≥70 without dementia undergoing major non-cardiac surgery, we previously identified inflammatory proteins to be associated with delirium. Using the entire SAGES cohort, the current study examines the independent associations of these inflammatory proteins with postoperative delirium. Plasma was collected preoperatively (PREOP) and on postoperative day 2 (POD2). Neuroinflammatory marker chitinase-3-like protein [CHI3l1 or YKL-40]; PREOP and POD2) and systemic inflammatory markers interleukin [IL]-6 (POD2 only) and C-reactive protein (CRP; PREOP and POD2) were measured using enzyme-linked immunosorbent assays. Generalized linear models were used to determine the independent (multivariable) associations between the inflammatory markers, measured in sample-based quartiles (Q). All models adjusted for age, sex, baseline cognition, surgery type, Charlson comorbidity index, and medical complications. Among the 555 patients (mean age 77 years, standard deviation, SD 5.2), 58% were female and 86% underwent orthopedic surgeries. Postoperative delirium occurred in 24%. High YKL-40 PREOP and IL-6 at POD2 (Q4 vs. Q1) were significantly associated with an increased risk of delirium: relative risk (RR) [95% confidence interval (CI)] 2.2[1.1-4.4] and 2.7[1.3-5.7], respectively. CRP (PREOP and POD2) was not significantly associated with delirium (p=0.37 and p=0.73, respectively). This work underscores the importance of inflammation (YKL-40 and IL-6) in the pathophysiology of postoperative delirium.

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Apolipoprotein E Genotype and the Relationship Between Chitinase 3–Like Protein 1 and Postoperative Delirium

Innovation in Aging ◽

10.1093/geroni/igaa057.803 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 249-249

Author(s):

Sarinnapha Vasunilashorn ◽

Long Ngo ◽

Sharon Inouye ◽

Tamara Fong ◽

Richard Jones ◽

...

Keyword(s):

Apolipoprotein E ◽

Postoperative Delirium ◽

Linear Models ◽

Inflammatory Marker ◽

Apoe Genotype ◽

Confusion Assessment Method ◽

Assessment Method ◽

Reactive Protein ◽

Increased Risk ◽

The Relationship

Abstract Apolipoprotein E (APOE) ɛ4 does not confer increased risk of delirium in older surgical patients; however, ɛ4 status modifies the relationship of C-reactive protein (CRP) with delirium: increased risk for delirium in ɛ4 carriers with high CRP. We examine whether APOE genotype modifies the established association between inflammatory marker chitinase-3-like protein-1 (CHI3LI/YKL-40) and delirium in patients without dementia age≥70 undergoing major non-cardiac surgery. We performed APOE genotyping using PCR, considering APOE ɛ4 vs. non-ɛ4 carriers. Plasma YKL-40, measured on postoperative day 2 by ELISA, was examined using sample-based quartiles (Q1-Q4). Delirium status was determined with daily interviews rating the Confusion Assessment Method, augmented by a validated chart review. We used generalized linear models adjusted for age, sex, surgery type, and stratified by APOE ɛ4 status. Among the 557 patients, 19% were APOE ɛ4 carriers, and 24% developed postoperative delirium. The YKL-40-delirium relationship differed by APOE status. Among APOE non-ɛ4 carriers, we found a significant relationship between YKL-40 and delirium (relative risk [RR](95% confidence interval [CI] for YKL-40 Q4 vs. Q1: 2.6(1.4-4.9) and Q3 vs. Q1: 2.3(1.2-4.5); p-trend<.01). Among APOE ɛ4 carriers, YKL-40 was not significantly associated with delirium (RR(95% CI) for YKL-40 Q4 vs. Q1: 2.0(0.6-6.6) and Q3 vs. Q1:1.1(0.3-3.5); p-trend=0.37). APOE non-ɛ4 carriers may have increased risk of delirium conferred by post-surgical inflammation specific to the type 2 immune response (high YKL-40). These results differ from prior results with CRP, and raise the possibility that APOE genotype may interact at different points in the inflammatory pathway leading to delirium.

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Proteome-Wide Analysis Using SOMAscan Identifies and Validates Chitinase-3-Like Protein 1 as a Risk and Disease Marker of Delirium Among Older Adults Undergoing Major Elective Surgery

The Journals of Gerontology Series A ◽

10.1093/gerona/glaa326 ◽

2021 ◽

Author(s):

Sarinnapha M Vasunilashorn ◽

Simon T Dillon ◽

Noel Y Chan ◽

Tamara G Fong ◽

Marie Joseph ◽

...

Keyword(s):

Older Adults ◽

Successful Aging ◽

Postoperative Delirium ◽

Linear Models ◽

Elective Surgery ◽

Protein Modeling ◽

Full Cohort ◽

Validation Data ◽

Age Related

Abstract Background Delirium (an acute change in cognition) is a common, morbid, and costly syndrome seen primarily in aging adults. Despite increasing knowledge of its epidemiology, delirium remains a clinical diagnosis with no established biomarkers to guide diagnosis or management. Advances in proteomics now provide opportunities to identify novel markers of risk and disease progression for postoperative delirium and its associated long-term consequences (eg, long-term cognitive decline and Alzheimer’s disease [AD]). Methods In a nested matched case–control study (18 delirium/no-delirium pairs) within the Successful Aging after Elective Surgery study (N = 556), we evaluated the association of 1305 plasma proteins preoperatively [PREOP] and on postoperative day 2 [POD2]) with delirium using SOMAscan. Generalized linear models were applied to enzyme-linked immunosorbant assay (ELISA) validation data of one protein across the full cohort. Multi-protein modeling included delirium biomarkers identified in prior work (C-reactive protein, interleukin-6 [IL6]). Results We identified chitinase-3-like-protein-1 (CHI3L1/YKL-40) as the sole delirium-associated protein in both a PREOP and a POD2 predictor model, a finding confirmed by ELISA. Multi-protein modeling found high PREOP CHI3L1/YKL-40 and POD2 IL6 increased the risk of delirium (relative risk [95% confidence interval] Quartile [Q]4 vs Q1: 2.4[1.2–5.0] and 2.1[1.1–4.1], respectively). Conclusions Our identification of CHI3L1/YKL-40 in postoperative delirium parallels reports of CHI3L1/YKL-40 and its association with aging, mortality, and age-related conditions including AD onset and progression. This highlights the type 2 innate immune response, involving CHI3L1/YKL-40, as an underlying mechanism of postoperative delirium, a common, morbid, and costly syndrome that threatens the independence of older adults.

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Antirheumatic therapy is not associated with changes in circulating N-terminal pro-brain natriuretic peptide levels in patients with autoimmune arthritis

PLoS ONE ◽

10.1371/journal.pone.0253793 ◽

2021 ◽

Vol 16 (6) ◽

pp. e0253793

Author(s):

Thao H. P. Nguyen ◽

Morten Wang Fagerland ◽

Gia Deyab ◽

Gunnbjørg Hjeltnes ◽

Ivana Hollan ◽

...

Keyword(s):

Brain Natriuretic Peptide ◽

Natriuretic Peptide ◽

Inflammatory Markers ◽

Heart Function ◽

Autoimmune Arthritis ◽

Antirheumatic Therapy ◽

Modest Improvement ◽

Reactive Protein ◽

Increased Risk ◽

The Impact

Background Patients with autoimmune arthritis (AA) are at increased risk for impaired cardiac function and heart failure. This may be partly due to the effect of inflammation in heart function. The impact of antirheumatic drugs on cardiac dysfunction in AA remains controversial. Therefore, we aimed to examine effects of antirheumatic treatment on serum N-terminal pro-brain natriuretic peptide (NT-proBNP) in AA patients and its relationship to inflammatory markers. Methods We examined 115 patients with AA (64 rheumatoid arthritis (RA), 31 psoriatic arthritis and 20 ankylosis spondylitis) starting with methotrexate (MTX) monotherapy or tumor necrosis factor inhibitors (TNFi) with or without MTX co-medication. NT-proBNP (measured in serum by ECLIA from Roche Diagnostics), and other clinical and laboratory parameters were evaluated at baseline, after 6 weeks and 6 months of treatment. Results NT-proBNP levels did not change significantly after 6 weeks and 6 months of antirheumatic therapy (pbaseline-6weeks = 0.939; pbaseline-6months = 0.485), although there was a modest improvement from 6 weeks to 6 months in the MTX only treatment group (median difference = -18.2 [95% CI = -32.3 to -4.06], p = 0.013). There was no difference in the effects of MTX monotherapy and TNFi regimen on NT-proBNP levels. The changes in NT-proBNP after antirheumatic treatment positively correlated with changes in C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Baseline NT-proBNP levels were related to baseline CRP and ESR levels, and some other established markers of disease activities in crude analyses. Conclusion Circulating levels of NT-proBNP were related to established inflammatory markers at baseline, and the changes in NT-proBNP after antirheumatic treatment were positively related to these markers. Nevertheless, antirheumatic therapy did not seem to affect NT-proBNP levels compared to baseline, even though inflammatory markers significantly improved.

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Smoking Status Effect on Inflammatory Markers in a Randomized Trial of Current and Former Heavy Smokers

International Journal of Inflammation ◽

10.1155/2015/439396 ◽

2015 ◽

Vol 2015 ◽

pp. 1-6 ◽

Cited By ~ 22

Author(s):

Sami Aldaham ◽

Janet A. Foote ◽

H.-H. Sherry Chow ◽

Iman A. Hakim

Keyword(s):

Inflammatory Markers ◽

Smoking Status ◽

Smoking History ◽

Smoking Intensity ◽

Reactive Protein ◽

The Metabolic Syndrome ◽

Status Effect ◽

Increased Risk ◽

Gender Specific Differences ◽

Former Smokers

Background. The level of systemic inflammation as measured by circulating levels of C-reactive protein (CRP) and interleukin-6 (IL-6) is linked to an increased risk for cardiovascular diseases (CVD) and cancer.Methods. We recruited 154 current and former smokers between 40 and 80 years of age with 25 or more pack-years of smoking history to study the relationship between inflammatory markers (CRP and IL-6) and smoking status.Results. Our results show that male smokers had significantly higher levels of serum IL-6 compared to male former smokers. We did not find any gender specific differences for smoking and CRP levels but the IL-6 levels were slightly lower in females compared to males. Additionally, our results show that CRP is significantly associated with IL-6 regardless of smoking status. Modelling indicates that the significant predictors of CRP levels were biomarkers of the metabolic syndrome while the significant predictors of IL-6 levels were age and plasma triglycerides among former smokers and the numbers of smoked packs of cigarettes per year among smokers.Conclusions. In conclusion, our study showed that CRP levels were not associated with markers of smoking intensity. However, IL-6 levels were significantly associated with smoking especially among current smokers.

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Targeted metabolomics analysis of postoperative delirium

Scientific Reports ◽

10.1038/s41598-020-80412-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Bridget A. Tripp ◽

Simon T. Dillon ◽

Min Yuan ◽

John M. Asara ◽

Sarinnapha M. Vasunilashorn ◽

...

Keyword(s):

Successful Aging ◽

Postoperative Delirium ◽

Elective Surgery ◽

Acid Synthesis ◽

Major Surgery ◽

Amino Acid Synthesis ◽

Citrate Cycle ◽

Plasma Metabolome ◽

Matched Case ◽

Univariate Analyses

AbstractPostoperative delirium is the most common complication among older adults undergoing major surgery. The pathophysiology of delirium is poorly understood, and no blood-based, predictive markers are available. We characterized the plasma metabolome of 52 delirium cases and 52 matched controls from the Successful Aging after Elective Surgery (SAGES) cohort (N = 560) of patients ≥ 70 years old without dementia undergoing scheduled major non-cardiac surgery. We applied targeted mass spectrometry with internal standards and pooled controls using a nested matched case-control study preoperatively (PREOP) and on postoperative day 2 (POD2) to identify potential delirium risk and disease markers. Univariate analyses identified 37 PREOP and 53 POD2 metabolites associated with delirium and multivariate analyses achieved significant separation between the two groups with an 11-metabolite prediction model at PREOP (AUC = 83.80%). Systems biology analysis using the metabolites with differential concentrations rendered “valine, leucine, and isoleucine biosynthesis” at PREOP and “citrate cycle” at POD2 as the most significantly enriched pathways (false discovery rate < 0.05). Perturbations in energy metabolism and amino acid synthesis pathways may be associated with postoperative delirium and suggest potential mechanisms for delirium pathogenesis. Our results could lead to the development of a metabolomic delirium predictor.

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Preoperative prognostic factors associated with postoperative delirium in older people undergoing surgery: protocol for a systematic review and individual patient data meta-analysis

10.21203/rs.3.rs-41459/v1 ◽

2020 ◽

Author(s):

Tayler A Buchan ◽

Behnam Sadeghirad ◽

Nayeli Schmutz ◽

Nicolai Goettel ◽

Farid Foroutan ◽

...

Keyword(s):

Risk Factors ◽

Systematic Review ◽

Elderly Patients ◽

Postoperative Delirium ◽

Individual Patient Data ◽

Elective Surgery ◽

Meta Analysis ◽

Patient Data ◽

Factors Associated ◽

Increased Risk

Abstract Background: Early identification of patients at risk for postoperative delirium is essential because adequate well-timed interventions could reduce the occurrence of delirium and the related detrimental outcomes.Methods: We will conduct a systematic review and individual patient data (IPD) meta-analysis of prognostic studies evaluating the predictive value of risk factors associated with an increased risk of postoperative delirium in elderly patients undergoing elective surgery. We will identify eligible studies through systematic search of MEDLINE, EMBASE, and CINAHL from their inception to May 2020. Eligible studies will enroll older adults (≥ 50 years) undergoing elective surgery and assess pre-operative prognostic risk factors for delirium and incidence of delirium measured by a trained individual using a validated delirium assessment tool. Pairs of reviewers will, independently and in duplicate, screen titles and abstracts of identified citations, review the full texts of potentially eligible studies. We will contact chief investigators of eligible studies requesting to share the IPD to a secured repository. We will use one-stage approach for IPD meta-analysis and will assess certainty of evidence using the GRADE approach.Discussion: Since we are using existing anonymized data, ethical approval is not required for this study. Our results can be used to guide clinical decisions about the most efficient way to prevent postoperative delirium in elderly patients.

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Postoperative Delirium and Postoperative Cognitive Dysfunction

Anesthesiology ◽

10.1097/aln.0000000000002729 ◽

2019 ◽

Vol 131 (3) ◽

pp. 477-491 ◽

Cited By ~ 22

Author(s):

Lori A. Daiello ◽

Annie M. Racine ◽

Ray Yun Gou ◽

Edward R. Marcantonio ◽

Zhongcong Xie ◽

...

Keyword(s):

Relative Risk ◽

Cognitive Dysfunction ◽

Successful Aging ◽

Postoperative Delirium ◽

Elective Surgery ◽

Postoperative Cognitive Dysfunction ◽

Significant Risk ◽

International Study ◽

Neurocognitive Deficits

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Postoperative delirium and postoperative cognitive dysfunction share risk factors and may co-occur, but their relationship is not well established. The primary goals of this study were to describe the prevalence of postoperative cognitive dysfunction and to investigate its association with in-hospital delirium. The authors hypothesized that delirium would be a significant risk factor for postoperative cognitive dysfunction during follow-up. Methods This study used data from an observational study of cognitive outcomes after major noncardiac surgery, the Successful Aging after Elective Surgery study. Postoperative delirium was evaluated each hospital day with confusion assessment method–based interviews supplemented by chart reviews. Postoperative cognitive dysfunction was determined using methods adapted from the International Study of Postoperative Cognitive Dysfunction. Associations between delirium and postoperative cognitive dysfunction were examined at 1, 2, and 6 months. Results One hundred thirty-four of 560 participants (24%) developed delirium during hospitalization. Slightly fewer than half (47%, 256 of 548) met the International Study of Postoperative Cognitive Dysfunction-defined threshold for postoperative cognitive dysfunction at 1 month, but this proportion decreased at 2 months (23%, 123 of 536) and 6 months (16%, 85 of 528). At each follow-up, the level of agreement between delirium and postoperative cognitive dysfunction was poor (kappa less than .08) and correlations were small (r less than .16). The relative risk of postoperative cognitive dysfunction was significantly elevated for patients with a history of postoperative delirium at 1 month (relative risk = 1.34; 95% CI, 1.07–1.67), but not 2 months (relative risk = 1.08; 95% CI, 0.72–1.64), or 6 months (relative risk = 1.21; 95% CI, 0.71–2.09). Conclusions Delirium significantly increased the risk of postoperative cognitive dysfunction in the first postoperative month; this relationship did not hold in longer-term follow-up. At each evaluation, postoperative cognitive dysfunction was more common among patients without delirium. Postoperative delirium and postoperative cognitive dysfunction may be distinct manifestations of perioperative neurocognitive deficits.

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Preoperative prognostic factors associated with postoperative delirium in older people undergoing surgery: protocol for a systematic review and individual patient data meta-analysis

10.21203/rs.3.rs-41459/v2 ◽

2020 ◽

Author(s):

Tayler A Buchan ◽

Behnam Sadeghirad ◽

Nayeli Schmutz ◽

Nicolai Goettel ◽

Farid Foroutan ◽

...

Keyword(s):

Risk Factors ◽

Systematic Review ◽

Elderly Patients ◽

Postoperative Delirium ◽

Individual Patient Data ◽

Elective Surgery ◽

Meta Analysis ◽

Patient Data ◽

Factors Associated ◽

Increased Risk

Abstract Background: Early identification of patients at risk for postoperative delirium is essential because adequate well-timed interventions could reduce the occurrence of delirium and the related detrimental outcomes.Methods: We will conduct a systematic review and individual patient data (IPD) meta-analysis of prognostic studies evaluating the predictive value of risk factors associated with an increased risk of postoperative delirium in elderly patients undergoing elective surgery. We will identify eligible studies through systematic search of MEDLINE, EMBASE, and CINAHL from their inception to May 2020. Eligible studies will enroll older adults (³ 50 years) undergoing elective surgery and assess pre-operative prognostic risk factors for delirium and incidence of delirium measured by a trained individual using a validated delirium assessment tool. Pairs of reviewers will, independently and in duplicate, screen titles and abstracts of identified citations, review the full texts of potentially eligible studies. We will contact chief investigators of eligible studies requesting to share the IPD to a secured repository. We will use one-stage approach for IPD meta-analysis and will assess certainty of evidence using the GRADE approach.Discussion: Since we are using existing anonymized data, ethical approval is not required for this study. Our results can be used to guide clinical decisions about the most efficient way to prevent postoperative delirium in elderly patients. Systematic review registration: CRD42020171366

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Preliminary results of clinical use of colchicine in COVID-19 treatment

BMJ Case Reports ◽

10.1136/bcr-2021-244482 ◽

2021 ◽

Vol 14 (7) ◽

pp. e244482

Author(s):

Rafael Silvestre Knack ◽

Luis Carlos Losso ◽

Renata Silvestre Knack ◽

Talie Hanada

Keyword(s):

Inflammatory Markers ◽

Treatment Initiation ◽

Clinical Use ◽

Cytokine Storm ◽

C Reactive Protein ◽

Protein Levels ◽

Reactive Protein ◽

Increased Risk ◽

Pulmonary Impairment ◽

Experimental Use

We report a case of the use of colchicine in a patient infected with SARS-CoV-2 virus. A 37-year-old man with COVID-19 presented with moderate symptoms, mild pulmonary impairment and elevated inflammatory markers, suggesting an increased risk of cytokine storm and possible worsening of clinical condition. Experimental use of colchicine resulted in an 85% decrease in C reactive protein levels 3 days after treatment initiation and a 182.6% decrease in interleukin-6 levels 8 days after treatment initiation. Due to the lack of effective therapies, it is important to search for potential compounds and compounds that focus on controlling the danger caused by systemic inflammation in COVID-19. Although further research is needed in the area of colchicine and viral infection, preliminary efficacy was observed.

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