Foundations of circadian medicine.

The circadian clock is an evolutionarily highly conserved endogenous timing program that structures physiology and behavior according to the time of day. Disruption of circadian rhythms is associated with many common pathologies. The emerging field of circadian medicine aims to exploit the mechanisms of circadian physiology and clock-disease interaction for clinical diagnosis, treatment, and prevention. In this Essay, we outline the principle approaches of circadian medicine, highlight the development of the field in selected areas, and point out open questions and challenges. Circadian medicine has unambiguous health benefits over standard care but is rarely utilized. It is time for clock biology to become an integrated part of translational research.

An exploratory research report on brain mineralization in postoperative delirium and cognitive decline.

Delirium is a severe postoperative complication associated with poor overall and especially neurocognitive prognosis. Altered brain mineralization is found in neurodegenerative disorders but has not been studied in postoperative delirium and postoperative cognitive decline. We hypothesized that mineralization-related hypointensity in susceptibility-weighted magnetic resonance imaging (SWI) is associated with postoperative delirium and cognitive decline. In an exploratory, hypothesis-generating study, we analysed a subsample of cognitively healthy patients ≥65 years who underwent SWI before (N = 65) and 3 months after surgery (N = 33). We measured relative SWI intensities in the basal ganglia, hippocampus and posterior basal forebrain cholinergic system (pBFCS). A post hoc analysis of two pBFCS subregions (Ch4, Ch4p) was conducted. Patients were screened for delirium until the seventh postoperative day. Cognitive testing was performed before and 3 months after surgery. Fourteen patients developed delirium. After adjustment for age, sex, preoperative cognition and region volume, only pBFCS hypointensity was associated with delirium (regression coefficient [90% CI]: B = -15.3 [-31.6; -0.8]). After adjustments for surgery duration, age, sex and region volume, perioperative change in relative SWI intensities of the pBFCS was associated with cognitive decline 3 months after surgery at a trend level (B = 6.8 [-0.9; 14.1]), which was probably driven by a stronger association in subregion Ch4p (B = 9.3 [2.3; 16.2]). Brain mineralization, particularly in the cerebral cholinergic system, could be a pathomechanism in postoperative delirium and cognitive decline. Evidence from our studies is limited because of the small sample and a SWI dataset unfit for iron quantification, and the analyses presented here should be considered exploratory.

Determinants of Subjective Mental and Functional Health of Critical Illness Survivors: Comparing Pre-ICU and Post-ICU Status.

OBJECTIVES: To compare ICU survivors' subjective mental and functional health before ICU admission and after discharge and to assess determinants of subjective health decline or improvement. DESIGN: Secondary analysis of the multicenter cluster-randomized Enhanced Recovery after Intensive Care trial ( ClinicalTrials.gov : NCT03671447). SETTING: Ten ICU clusters in Germany. PATIENTS: Eight hundred fifty-five patients with 1478 follow-up assessments. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At two patient follow-ups scheduled 3 and 6 months after ICU discharge, patients rated their subjective mental and functional/physical health on two separate visual analog scales from 0 (worst) to 10 (best) in the previous week and before ICU admission. We compared pre-ICU and post-ICU subjective health and used mixed-effects regression to assess determinants of a health decline or improvement. At the first follow-up, 20% ( n = 165/841) and 30% ( n = 256/849) of patients reported a decline in subjective mental and functional health of at least three points, respectively; 16% ( n = 133/841 and n = 137/849) outlined improvements of mental and functional health. For 65% ( n = 543/841) and 54% ( n = 456/849), mental and functional health did not change three points or more at the first follow-up. Multivariable mixed-effects logistic regressions revealed that the ICU length of stay was a predictor of mental (adjusted odds ratio [OR] per ICU day, 1.04; 95% CI, 1.00-1.09; p = 0.038) and functional health (adjusted OR per ICU day, 1.06; 95% CI, 1.01-1.12; p = 0.026) decline. The odds of a mental health decline decreased with age (adjusted OR per year, 0.98; 95% CI, 0.96-0.99; p = 0.003) and the odds of a functional health decline decreased with time after discharge (adjusted OR per month, 0.86; 95% CI, 0.79-0.94; p = 0.001). CONCLUSIONS: The majority of ICU survivors did not experience substantial changes in their subjective health status, but patients with long ICU stays were prone to subjective mental and functional health decline. Hence, post-ICU care in post-ICU clinics could focus on these patients.

Modification in ICU Design May Affect Delirium and Circadian Melatonin: A Proof of Concept Pilot Study.

OBJECTIVES: Nonpharmacologic delirium management is recommended by current guidelines, but studies on the impact of ICU design are still limited. The study's primary purpose was to determine if a multicomponent change in room design prevents ICU delirium. Second, the influence of lighting conditions on serum melatonin was assessed. DESIGN: Prospective observational cohort pilot study. SETTING: The new design concept was established in two two-bed ICU rooms of a university hospital. Besides modifications aimed at stress relief, it includes a new dynamic lighting system. PATIENTS: Seventy-four adult critically ill patients on mechanical ventilation with an expected ICU length of stay of at least 48 hours, treated in modified or standard rooms. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The clinical examination included a prospective assessment for depth of sedation, delirium, and pain every 8 hours using validated scores. Blood samples for serum melatonin profiles were collected every 4 hours for a maximum of three 24-hour periods. Seventy-four patients were included in the analysis. Seventy-six percent ( n = 28) of patients in the standard rooms developed delirium compared with 46% of patients ( n = 17) in the modified rooms ( p = 0.017). Patients in standard rooms (vs. modified rooms) had a 2.3-fold higher delirium severity (odds ratio = 2.292; 95% CI, 1.582-3.321; p < 0.0001). Light intensity, calculated using the measure of circadian effective irradiance, significantly influenced the course of serum melatonin ( p < 0.0001). Significant interactions ( p < 0.001) revealed that differences in serum melatonin between patients in standard and modified rooms were not the same over time but varied in specific periods of time. CONCLUSIONS: Modifications in ICU room design may influence the incidence and severity of delirium. Dedicated light therapy could potentially influence delirium outcomes by modulating circadian melatonin levels.

Electroencephalogram Biomarkers from Anesthesia Induction to Identify Vulnerable Patients at Risk for Postoperative Delirium.

BACKGROUND: Postoperative delirium is a common complication in elderly patients undergoing anesthesia. Even though it is increasingly recognized as an important health issue, the early detection of patients at risk for postoperative delirium remains a challenge. This study aims to identify predictors of postoperative delirium by analyzing frontal electroencephalogram at propofol-induced loss of consciousness. METHODS: This prospective, observational single-center study included patients older than 70 yr undergoing general anesthesia for a planned surgery. Frontal electroencephalogram was recorded on the day before surgery (baseline) and during anesthesia induction (1, 2, and 15 min after loss of consciousness). Postoperative patients were screened for postoperative delirium twice daily for 5 days. Spectral analysis was performed using the multitaper method. The electroencephalogram spectrum was decomposed in periodic and aperiodic (correlates to asynchronous spectrum wide activity) components. The aperiodic component is characterized by its offset (y intercept) and exponent (the slope of the curve). Computed electroencephalogram parameters were compared between patients who developed postoperative delirium and those who did not. Significant electroencephalogram parameters were included in a binary logistic regression analysis to predict vulnerability for postoperative delirium. RESULTS: Of 151 patients, 50 (33%) developed postoperative delirium. At 1 min after loss of consciousness, postoperative delirium patients demonstrated decreased alpha (postoperative delirium: 0.3 µV2 [0.21 to 0.71], no postoperative delirium: 0.55 µV2 [0.36 to 0.74]; P = 0.019] and beta band power [postoperative delirium: 0.27 µV2 [0.12 to 0.38], no postoperative delirium: 0.38 µV2 [0.25 to 0.48]; P = 0.003) and lower spectral edge frequency (postoperative delirium: 10.45 Hz [5.65 to 15.04], no postoperative delirium: 14.56 Hz [9.51 to 16.65]; P = 0.01). At 15 min after loss of consciousness, postoperative delirium patients displayed a decreased aperiodic offset (postoperative delirium: 0.42 µV2 (0.11 to 0.69), no postoperative delirium: 0.62 µV2 [0.37 to 0.79]; P = 0.004). The logistic regression model predicting postoperative delirium vulnerability demonstrated an area under the curve of 0.73 (0.69 to 0.75). CONCLUSIONS: The findings suggest that electroencephalogram markers obtained during loss of consciousness at anesthesia induction may serve as electroencephalogram-based biomarkers to identify at an early time patients at risk of developing postoperative delirium.

Value of hemophagocytosis in the diagnosis of hemophagocytic lymphohistiocytosis in critically ill patients.

BACKGROUND: Ferritin is an established biomarker in the diagnosis of secondary hemophagocytic lymphohistiocytosis (HLH), which is diagnosed by the HLH-2004 criteria. Among these criteria, detection of hemophagocytosis through invasive procedures may delay early life saving treatment. Our aim was to investigate the value of hemophagocytosis in diagnosing HLH in critically ill patients. METHODS: In this secondary analysis of a retrospective observational study, we included all patients aged ≥18 years and admitted to any adult ICU at Charité-Universitätsmedizin Berlin between January 2006 and August 2018, who had hyperferritinemia (≥500 µg/L) and underwent bone marrow biopsy during their ICU course. RESULTS: Two hundred fifty-two patients were included, of whom 31 (12.3%) showed hemophagocytosis. In multivariable logistic regression analysis, maximum ferritin was independently associated with hemophagocytosis. By removing hemophagocytosis from HLH-2004 criteria and HScore, prediction accuracy for HLH diagnosis was only marginally decreased compared to the original scores. CONCLUSIONS: Our results strengthen the diagnostic value of ferritin and underline the importance of considering HLH diagnosis in patients with high ferritin but only four fulfilled HLH-2004 criteria, when hemophagocytosis was not assessed or not detectable. Proof of hemophagocytosis is not required for a reliable HLH diagnosis.

The Association of Plasma Leptin, Soluble Leptin Receptor and Total and High-Molecular Weight Adiponectin With the Risk of Perioperative Neurocognitive Disorders.

BACKGROUND: Perioperative neurocognitive disorders (NCD) are poorly characterized in terms of their risk factor profiles. Leptin and adiponectin are adipose-tissue-derived hormones with a role in inflammation and atherosclerosis whose function in perioperative NCD is unclear. Here, we used a cohort of older adults to examine the association of preoperative plasma concentrations of these biomarkers with the risk of perioperative NCD. METHODS: Prospective analysis of 768 participants aged ≥ 65 years of the BioCog study. Blood was collected before surgery for measurement of plasma total and high-molecular-weight (hmw) adiponectin, leptin, and soluble leptin receptor (sOB-R). The free leptin index (FLI, leptin:sOB-R) was calculated. Postoperative delirium (POD) was assessed twice daily until postoperative day 7/discharge. Five hundred twenty-six patients (68.5%) returned for 3-month follow-up and provided data on postoperative cognitive dysfunction (POCD). POCD was defined as a decline on six neuropsychological tests that exceeded that of a nonsurgical control group. Logistic regression analyses examined the associations of each exposure with POD and POCD risk, in separate models adjusted for age, sex, fasting, surgery type, and body mass index (BMI). RESULTS: Of 768 patients, 152 (19.8%) developed POD. Of 526 attendants of the follow-up, 54 (10.3%) had developed POCD. Leptin, sOB-R, and total and hmw adiponectin were each not associated with POD. For POCD, we observed reduced risk in patients in FLI quartile 4 compared with quartile 1 (odds ratio, 0.26; 95% CI 0.08, 0.89). Sensitivity analyses for the outcome POD revealed statistically significant interaction terms of sOB-R and total adiponectin with obesity (BMI≥30kg/m2 versus BMI<30kg/m2). For the outcome POCD, a higher sOB-R was associated with an increased risk in the obese subgroup (odds ratio, 4.00; 95% CI 1.01, 15.86). CONCLUSIONS: We did not find consistent evidence for the role of leptin, its receptor, and total and hmw adiponectin in POD and POCD risk. Future research should be used to support or refute our findings and to fully characterize any differences in the associations of these hormones with POD/POCD between obese and nonobese individuals.

Understanding the biases to sepsis surveillance and quality assurance caused by inaccurate coding in administrative health data.

PURPOSE: Timely and accurate data on the epidemiology of sepsis are essential to inform policy decisions and research priorities. We aimed to investigate the validity of inpatient administrative health data (IAHD) for surveillance and quality assurance of sepsis care. METHODS: We conducted a retrospective validation study in a disproportional stratified random sample of 10,334 inpatient cases of age ≥ 15 years treated in 2015-2017 in ten German hospitals. The accuracy of coding of sepsis and risk factors for mortality in IAHD was assessed compared to reference standard diagnoses obtained by a chart review. Hospital-level risk-adjusted mortality of sepsis as calculated from IAHD information was compared to mortality calculated from chart review information. RESULTS: ICD-coding of sepsis in IAHD showed high positive predictive value (76.9-85.7% depending on sepsis definition), but low sensitivity (26.8-38%), which led to an underestimation of sepsis incidence (1.4% vs. 3.3% for severe sepsis-1). Not naming sepsis in the chart was strongly associated with under-coding of sepsis. The frequency of correctly naming sepsis and ICD-coding of sepsis varied strongly between hospitals (range of sensitivity of naming: 29-71.7%, of ICD-diagnosis: 10.7-58.5%). Risk-adjusted mortality of sepsis per hospital calculated from coding in IAHD showed no substantial correlation to reference standard risk-adjusted mortality (r = 0.09). CONCLUSION: Due to the under-coding of sepsis in IAHD, previous epidemiological studies underestimated the burden of sepsis in Germany. There is a large variability between hospitals in accuracy of diagnosing and coding of sepsis. Therefore, IAHD alone is not suited to assess quality of sepsis care.

Causes, Consequences, and Treatments of Sleep and Circadian Disruption in the ICU: An Official American Thoracic Society Research Statement.

Background: Sleep and circadian disruption (SCD) is common and severe in the ICU. On the basis of rigorous evidence in non-ICU populations and emerging evidence in ICU populations, SCD is likely to have a profound negative impact on patient outcomes. Thus, it is urgent that we establish research priorities to advance understanding of ICU SCD. Methods: We convened a multidisciplinary group with relevant expertise to participate in an American Thoracic Society Workshop. Workshop objectives included identifying ICU SCD subtopics of interest, key knowledge gaps, and research priorities. Members attended remote sessions from March to November 2021. Recorded presentations were prepared and viewed by members before Workshop sessions. Workshop discussion focused on key gaps and related research priorities. The priorities listed herein were selected on the basis of rank as established by a series of anonymous surveys. Results: We identified the following research priorities: establish an ICU SCD definition, further develop rigorous and feasible ICU SCD measures, test associations between ICU SCD domains and outcomes, promote the inclusion of mechanistic and patient-centered outcomes within large clinical studies, leverage implementation science strategies to maximize intervention fidelity and sustainability, and collaborate among investigators to harmonize methods and promote multisite investigation. Conclusions: ICU SCD is a complex and compelling potential target for improving ICU outcomes. Given the influence on all other research priorities, further development of rigorous, feasible ICU SCD measurement is a key next step in advancing the field.

Influence of a chronic beta-blocker therapy on perioperative opioid consumption - a post hoc secondary analysis.

BACKGROUND: Beta-blocker (BB) therapy plays a central role in the treatment of cardiovascular diseases. An increasing number of patients with cardiovascular diseases undergoe noncardiac surgery, where opioids are an integral part of the anesthesiological management. There is evidence to suggest that short-term intravenous BB therapy may influence perioperative opioid requirements due to an assumed cross-talk between G-protein coupled beta-adrenergic and opioid receptors. Whether chronic BB therapy could also have an influence on perioperative opioid requirements is unclear. METHODS: A post hoc analysis of prospectively collected data from a multicenter observational (BioCog) study was performed. Inclusion criteria consisted of elderly patients (≥ 65 years) undergoing elective noncardiac surgery as well as total intravenous general anesthesia without the use of regional anesthesia and duration of anesthesia ≥ 60 min. Two groups were defined: patients with and without BB in their regular preopreative medication. The administered opioids were converted to their respective morphine equivalent doses. Multiple regression analysis was performed using the morphine-index to identify independent predictors. RESULTS: A total of 747 patients were included in the BioCog study in the study center Berlin. 106 patients fulfilled the inclusion criteria. Of these, 37 were on chronic BB. The latter were preoperatively significantly more likely to have arterial hypertension (94.6%), chronic renal failure (27%) and hyperlipoproteinemia (51.4%) compared to patients without BB. Both groups did not differ in terms of cumulative perioperative morphine equivalent dose (230.9 (BB group) vs. 214.8 mg (Non-BB group)). Predictive factors for increased morphine-index were older age, male sex, longer duration of anesthesia and surgery of the trunk. In a model with logarithmised morphine index, only gender (female) and duration of anesthesia remained predictive factors. CONCLUSIONS: Chronic BB therapy was not associated with a reduced perioperative opioid consumption. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov ( NCT02265263 ) on the 15.10.2014 with the principal investigator being Univ.-Prof. Dr. med. Claudia Spies.

Facilitators and barriers to the implementation of prehabilitation for frail patients into routine health care: a realist review.

BACKGROUND: Despite evidence supporting the effectiveness of prehabilitation as a new preoperative care pathway to optimise perioperative outcomes, its implementation into routine health care is widely pending. Frail patients might particularly benefit from prehabilitation interventions, but facilitating and hindering factors need to be considered in the implementation process. Thus, our aim was to derive a programme theory on what prehabilitation programmes work for frail patients in what circumstances and why. METHODS: Following Pawson's realist review approach, preliminary programme theories on facilitators and barriers were established. General and topic-specific databases were searched systematically for facilitators and barriers to the implementation of prehabilitation for frail patients. Articles were included if they dealt with multimodal prehabilitation programmes prior to surgery in a frail population and if they contained information on facilitators and barriers during the implementation process in the full text. Based on these articles, refined programme theories were generated. RESULTS: From 2,609 unique titles, 34 were retained for the realist synthesis. Facilitating factors included the individualisation of prehabilitation programmes to meet the patients' needs and abilities, multimodality, adaption to the local setting and health care system, endorsement by an ambassador and sharing of responsibilities among a multidisciplinary team. Central barriers for frail patients were transportation, lack of social support, and inadequate, overwhelming information provision. CONCLUSIONS: Implementing prehabilitation as a new care pathway for frail patients requires organisational readiness and adaptability to the local setting. On an individual level, a clear understanding of responsibilities and of the intervention's goal among patients and providers are necessary. Added attention must be paid to the individualisation to fit the needs and restrictions of frail patients. This makes prehabilitation a resource-intense, but promising intervention for frail surgery patients. TRIAL REGISTRATION: PROSPERO (CRD42022335282).

Barriers and facilitators to the implementation of prehabilitation for elderly frail patients prior to elective surgery: a qualitative study with healthcare professionals.

BACKGROUND: Prehabilitation aims to enhance functional capacity before surgery, minimise complications and achieve a better postoperative outcome. This can be particularly useful for older, frail patients to better tolerate surgery. The aim of this study was to identify what barriers and facilitators healthcare professionals in Germany experienced in the implementation and delivery of the multimodal prehabilitation programme "PRAEP-GO" for (pre-)frail adults aged 70 years and older to inform the implementation of prehabilitation into standard care. METHODS: A nested descriptive qualitative study was conducted using semi-structured face-to-face interviews with healthcare professionals involved in the PRAEP-GO trial from the Berlin and Brandenburg region in Germany. Transcripts were analysed using Kuckartz' qualitative content analysis. Results were interpreted and synthesised using the Consolidated Framework for Implementation Research, a theoretical framework to allow their application to a more general context. RESULTS: A total of 14 interviews were conducted. Seven therapists (physio-, ergo-, sports therapy), five physicians and two employees from other professions with mainly administrative and organisational tasks in the project. All identified barriers and facilitating factors could be assigned to the themes of organisation, prehabilitation, cooperation and communication between healthcare professionals and with patients. Much optimisation potential was found regarding organisational aspects, e.g. addressing perceived staff shortages and optimising the patient pathway. Furthermore, it became apparent that communication and cooperation between professionals but also with patients need to be improved. More evidence regarding prehabilitation should be provided to convince professionals more. Prehabilitation should be multimodal and individualised, including the programme duration. Officially introducing prehabilitation into standard care would facilitate its delivery. DISCUSSION: These findings underscore the fact that successful implementation of prehabilitation programmes, such as PRAEP-GO, requires sufficient organisational infrastructure, human resources, access to knowledge, an adaptable and individualised programme design as well as good communication among professionals and with patients. The transferability of the findings is limited by the absence of nutritionists and resulting overrepresentation of other therapists in the sample. To further convince professionals and patients of the concept of prehabilitation, more research is needed to build a solid evidence base that will ensure greater awareness and, thus, more motivation and cooperation among professionals and patients. TRIAL REGISTRATION: Open Science Framework (osf.io/ksfgj).

Update of the European Society of Anaesthesiology and Intensive Care Medicine evidence-based and consensus-based guideline on postoperative delirium in adult patients.

Postoperative delirium (POD) remains a common, dangerous and resource-consuming adverse event but is often preventable. The whole peri-operative team can play a key role in its management. This update to the 2017 ESAIC Guideline on the prevention of POD is evidence-based and consensus-based and considers the literature between 01 April 2015, and 28 February 2022. The search terms of the broad literature search were identical to those used in the first version of the guideline published in 2017. POD was defined in accordance with the DSM-5 criteria. POD had to be measured with a validated POD screening tool, at least once per day for at least 3 days starting in the recovery room or postanaesthesia care unit on the day of surgery or, at latest, on postoperative day 1. Recent literature confirmed the pathogenic role of surgery-induced inflammation, and this concept reinforces the positive role of multicomponent strategies aimed to reduce the surgical stress response. Although some putative precipitating risk factors are not modifiable (length of surgery, surgical site), others (such as depth of anaesthesia, appropriate analgesia and haemodynamic stability) are under the control of the anaesthesiologists. Multicomponent preoperative, intra-operative and postoperative preventive measures showed potential to reduce the incidence and duration of POD, confirming the pivotal role of a comprehensive and team-based approach to improve patients' clinical and functional status.

Structural disconnectivity in postoperative delirium: A perioperative two-center cohort study in older patients.

BACKGROUND: Structural disconnectivity was found to precede dementia. Global white matter abnormalities might also be associated with postoperative delirium (POD). METHODS: We recruited older patients (≥65 years) without dementia that were scheduled for major surgery. Diffusion kurtosis imaging metrics were obtained preoperatively, after 3 and 12 months postoperatively. We calculated fractional anisotropy (FA), mean diffusivity (MD), mean kurtosis (MK), and free water (FW). A structured and validated delirium assessment was performed twice daily. RESULTS: Of 325 patients, 53 patients developed POD (16.3%). Preoperative global MD (standardized beta 0.27 [95% confidence interval [CI] 0.21-0.32] p < 0.001) was higher in patients with POD. Preoperative global MK (-0.07 [95% CI -0.11 to (-0.04)] p < 0.001) and FA (0.07 [95% CI -0.10 to (-0.04)] p < 0.001) were lower. When correcting for baseline diffusion, postoperative MD was lower after 3 months (0.05 [95% CI -0.08 to (-0.03)] p < 0.001; n = 183) and higher after 12 months (0.28 [95% CI 0.20-0.35] p < 0.001; n = 45) among patients with POD. DISCUSSION: Preoperative structural disconnectivity was associated with POD. POD might lead to white matter depletion 3 and 12 months after surgery.

Allogeneic Blood Transfusion and Risk of Postoperative Complications in Patients with Mild and Moderate Anemia of Any Cause? A Retrospective Cohort Study in Total Revision Hip Surgery.

Introduction: Patients undergoing revision total hip surgery (RTHS) have a high prevalence of mild and moderate preoperative anemia, associated with adverse outcomes. The aim of this study was to investigate the association of perioperative allogeneic blood transfusions (ABT) and postoperative complications in preoperatively mild compared to moderate anemic patients undergoing RTHS who did not receive a diagnostic anemia workup and treatment before surgery. Methods: We included 1,765 patients between 2007 and 2019 at a university hospital. Patients were categorized according to their severity of anemia using the WHO criteria of mild, moderate, and severe anemia in the first Hb level of the case. Patients were grouped as having received no ABT, 1-2 units of ABT, or more than 2 units of ABT. Need for intraoperative ABT was assessed in accordance with institutional standards. Primary endpoint was the compound incidence of postoperative complications. Secondary outcomes included major/minor complications and length of hospital and ICU stay. Results: Of the 1,765 patients, 31.0% were anemic of any cause before surgery. Transfusion rates were 81% in anemic patients and 41.2% in nonanemic patients. The adjusted risks for compound postoperative complication were significantly higher in patients with moderate anemia (OR 4.88, 95% CI: 1.54-13.15, p = 0.003) but not for patients with mild anemia (OR 1.93, 95% CI: 0.85-3.94, p < 0.090). Perioperative ABT was associated with significantly higher risks for complications in nonanemic patients and showed an increased risk for complications in all anemic patients. In RTHS, perioperative ABT as a treatment for moderate preoperative anemia of any cause was associated with a negative compound effect on postoperative complications, compared to anemia or ABT alone. Discussion: ABT is associated with adverse outcomes of patients with moderate preoperative anemia before RTHS. For this reason, medical treatment of moderate preoperative anemia may be considered.

Subjective Ratings of Mental and Physical Health Correlate With EQ-5D-5L Index Values in Survivors of Critical Illness: A Construct Validity Study.

OBJECTIVES: Survivors of critical illness commonly show impaired health-related quality of life (HrQoL). We investigated if HrQoL can be approximated by brief, easily applicable items to be used in primary care. DESIGN: Secondary analysis of data from the multicenter, cluster-randomized controlled Enhanced Recovery after Intensive Care trial ( ClinicalTrials.gov : NCT03671447) and construct validity study. SETTING: Ten participating clusters of ICUs in the metropolitan area of Berlin, Germany. PATIENTS: Eight hundred fifty ICU survivors enrolled in a mixed, medical or surgical ICU when they had an expected ICU length of stay of at least 24 hours, were at least 18 years old, and had statutory health insurance coverage. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients received follow-ups scheduled 3 and 6 months after ICU discharge. HrQoL was assessed with the EuroQol 5-Dimension 5-Level (EQ-5D-5L), and patients were asked to rate their current mental and physical health state from 0 (worst) to 10 (best). We fitted prediction models for the EQ-5D-5L index value using these two items and additional covariates, applying stepwise regression and adaptive lasso. Subjective mental health (Spearman: 0.59) and subjective physical health (Spearman: 0.68) correlated with EQ-5D-5L index values and were better predictors of EQ-5D-5L index values in the two-item regression (normalized root mean squared error [nRMSE] 0.164; normalized mean absolute error [nMAE] 0.118; R2adj 0.43) than the EQ-5D Visual Analog Scale (nRMSE 0.175; nMAE 0.124; R2adj 0.35). Stepwise regression with additional covariates further increased prediction performance (nRMSE 0.133; nMAE 0.1; R2adj 0.51). CONCLUSIONS: Asking patients to rate their subjective mental and physical health can be an easily applicable tool for a first impression of the HrQoL in primary care settings.

Deep Isoflurane Anesthesia Is Associated with Alterations in Ion Homeostasis and Specific Na+/K+-ATPase Impairment in the Rat Brain.

BACKGROUND: Maintenance of ion homeostasis is essential for normal brain function. Inhalational anesthetics are known to act on various receptors, but their effects on ion homeostatic systems, such as sodium/potassium-adenosine triphosphatase (Na+/K+-ATPase), remain largely unexplored. Based on reports demonstrating global network activity and wakefulness modulation by interstitial ions, the hypothesis was that deep isoflurane anesthesia affects ion homeostasis and the key mechanism for clearing extracellular potassium, Na+/K+-ATPase. METHODS: Using ion-selective microelectrodes, this study assessed isoflurane-induced extracellular ion dynamics in cortical slices of male and female Wistar rats in the absence of synaptic activity, in the presence of two-pore-domain potassium channel antagonists, during seizures, and during spreading depolarizations. The specific isoflurane effects on Na+/K+-ATPase function were measured using a coupled enzyme assay and studied the relevance of the findings in vivo and in silico. RESULTS: Isoflurane concentrations clinically relevant for burst suppression anesthesia increased baseline extracellular potassium (mean ± SD, 3.0 ± 0.0 vs. 3.9 ± 0.5 mM; P < 0.001; n = 39) and lowered extracellular sodium (153.4 ± 0.8 vs. 145.2 ± 6.0 mM; P < 0.001; n = 28). Similar changes in extracellular potassium and extracellular sodium and a substantial drop in extracellular calcium (1.5 ± 0.0 vs. 1.2 ± 0.1 mM; P = 0.001; n = 16) during inhibition of synaptic activity and two-pore-domain potassium suggested a different underlying mechanism. After seizure-like events and spreading depolarization, isoflurane greatly slowed extracellular potassium clearance (63.4 ± 18.2 vs. 196.2 ± 82.4 s; P < 0.001; n = 14). Na+/K+-ATPase activity was markedly reduced after isoflurane exposure (greater than 25%), affecting specifically the α2/3 activity fraction. In vivo, isoflurane-induced burst suppression resulted in impaired extracellular potassium clearance and interstitial potassium accumulation. A computational biophysical model reproduced the observed effects on extracellular potassium and displayed intensified bursting when Na+/K+-ATPase activity was reduced by 35%. Finally, Na+/K+-ATPase inhibition with ouabain induced burst-like activity during light anesthesia in vivo. CONCLUSIONS: The results demonstrate cortical ion homeostasis perturbation and specific Na+/K+-ATPase impairment during deep isoflurane anesthesia. Slowed potassium clearance and extracellular accumulation might modulate cortical excitability during burst suppression generation, while prolonged Na+/K+-ATPase impairment could contribute to neuronal dysfunction after deep anesthesia.

Representation of evidence-based clinical practice guideline recommendations on FHIR.

BACKGROUND: Various formalisms have been developed to represent clinical practice guideline recommendations in a computer-interpretable way. However, none of the existing formalisms leverage the structured and computable information that emerge from the evidence-based guideline development process. Thus, we here propose a FHIR-based format that uses computer-interpretable representations of the knowledge artifacts that emerge during the process of evidence-based guideline development to directly serve as the basis of evidence-based recommendations. METHODS: We identified the information required to represent evidence-based clinical practice guideline recommendations and reviewed the knowledge artifacts emerging during the evidence-based guideline development process. We then conducted a consensus-based design process with domain experts to develop an information model for guideline recommendation representation that is structurally aligned to the evidence-based guideline recommendation development process and a corresponding representation based on FHIR resources developed for evidence-based medicine (EBMonFHIR). The resulting recommendations were modelled and represented in conformance with the FHIR Clinical Guidelines (CPG-on-FHIR) implementation guide. RESULTS: The information model of evidence-based clinical guideline recommendations and its EBMonFHIR-/CPG-on-FHIR-based representation contain the clinical contents of individual guideline recommendations, a set of metadata for the recommendations, the ratings for the recommendations (e.g., strength of recommendation, certainty of overall evidence), the ratings of certainty of evidence for individual outcomes (e.g., risk of bias) and links to the underlying evidence (systematic reviews based on primary studies). We created profiles and an implementation guide for all FHIR resources required to represent the knowledge artifacts generated during evidence-based guideline development and their re-use as the basis for recommendations and used the profiles to implement an exemplary clinical guideline recommendation. CONCLUSIONS: The FHIR implementation guide presented here can be used to directly link the evidence assessment process of evidence-based guideline recommendation development, i.e. systematic reviews and evidence grading, and the underlying evidence from primary studies to the resulting guideline recommendations. This not only allows the evidence on which recommendations are based on to be evaluated transparently and critically, but also enables guideline developers to leverage computable evidence in a more direct way to facilitate the generation of computer-interpretable guideline recommendations.

Metabolic syndrome and the risk of postoperative delirium and postoperative cognitive dysfunction: a multi-centre cohort study.

BACKGROUND: Metabolic syndrome and its components are risk factors for cognitive impairment, but their contribution to perioperative neurocognitive disorders is unknown. We examined their associations with the risk of postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) in older patients. METHODS: In 765 male and female participants aged ≥65 years, we measured preoperative metabolic parameters and screened for POD for 7 days or until discharge. POCD was defined through comparison of cognitive change on six neuropsychological tests with non-surgical controls. Multiple logistic regression analyses examined the association of metabolic parameters with risk of POD and POCD with adjustment for age, sex, and surgery type. RESULTS: A total of 149 patients (19.5% of 765) developed POD and 53 (10.1% of 520 attendees) had POCD at 3 months. Patients with metabolic syndrome were at 1.85-fold higher risk of POD (95% confidence interval [CI] 1.26-2.70). Each 1 mM higher high-density lipoprotein cholesterol (HDL-C) was associated with a 0.47-fold lower POD risk (95% CI 0.30-0.74). Each 1 kg m-2 higher body mass index (BMI) was associated with a 1.09-fold higher POCD risk (95% CI 1.02- 1.16). CONCLUSIONS: Older surgical patients with metabolic syndrome were at increased risk of POD. Only reduced HDL-C was significantly associated with POD. For POCD, a higher preoperative BMI was identified as a risk factor. These findings add to mounting evidence of a distinct epidemiology of POD and POCD. Screening programmes taking advantage of HDL-C and BMI measurements and of metabolic interventions in reducing perioperative neurocognitive disorders should be evaluated. CLINICAL TRIAL REGISTRATION: NCT02265263.

Functional brain network and trail making test changes following major surgery and postoperative delirium: a prospective, multicentre, observational cohort study.

BACKGROUND: Delirium is a frequent complication after surgery in older adults and is associated with an increased risk of long-term cognitive impairment and dementia. Disturbances in functional brain networks were previously reported during delirium. We hypothesised that alterations in functional brain networks persist after remission of postoperative delirium and that functional brain network alterations are associated with long-term cognitive impairment. METHODS: In this prospective, multicentre, observational cohort study, we included older patients who underwent clinical assessments (including the Trail Making Test B [TMT-B]) and resting-state functional MRI (rs-fMRI) before and 3 months after elective surgery. Delirium was assessed on the first seven postoperative days. RESULTS: Of the 554 enrolled patients, 246 remained after strict motion correction, of whom 38 (16%) developed postoperative delirium. The rs-fMRI functional connectivity strength increased 3 months after surgery in the total study population (ß=0.006; 95% confidence interval [CI]: 0.001-0.011; P=0.013), but it decreased after postoperative delirium (ß=-0.015; 95% CI: -0.028 to 0.002; P=0.023). No difference in TMT-B scores was found at follow-up between patients with and without postoperative delirium. Patients with decreased functional connectivity strength declined in TMT-B scores compared with those who did not (ß=11.04; 95% CI: 0.85-21.2; P=0.034). CONCLUSIONS: Postoperative delirium was associated with decreased brain functional connectivity strength after 3 months, suggesting that delirium has a long-lasting impact on brain networks. The decreased connectivity strength was associated with significant cognitive deterioration after major surgery. CLINICAL TRIAL REGISTRATION: NCT02265263.