Assessment of [18F]PI-2620 Tau-PET Quantification via Non-Invasive Automatized Image Derived Input Function.

PURPOSE: [18F]PI-2620 positron emission tomography (PET) detects misfolded tau in progressive supranuclear palsy (PSP) and Alzheimer's disease (AD). We questioned the feasibility and value of absolute [18F]PI-2620 PET quantification for assessing tau by regional distribution volumes (VT). Here, arterial input functions (AIF) represent the gold standard, but cannot be applied in routine clinical practice, whereas image-derived input functions (IDIF) represent a non-invasive alternative. We aimed to validate IDIF against AIF and we evaluated the potential to discriminate patients with PSP and AD from healthy controls by non-invasive quantification of [18F] PET. METHODS: In the first part of the study, we validated AIF derived from radial artery whole blood against IDIF by investigating 20 subjects (ten controls and ten patients). IDIF were generated by manual extraction of the carotid artery using the average and the five highest (max5) voxel intensity values and by automated extraction of the carotid artery using the average and the maximum voxel intensity value. In the second part of the study, IDIF quantification using the IDIF with the closest match to the AIF was transferred to group comparison of a large independent cohort of 40 subjects (15 healthy controls, 15 PSP patients and 10 AD patients). We compared VT and VT ratios, both calculated by Logan plots, with distribution volume (DV) ratios using simplified reference tissue modelling and standardized uptake value (SUV) ratios. RESULTS: AIF and IDIF showed highly correlated input curves for all applied IDIF extraction methods (0.78 < r < 0.83, all p < 0.0001; area under the curves (AUC): 0.73 < r ≤ 0.82, all p ≤ 0.0003). Regarding the VT values, correlations were mainly found between those generated by the AIF and by the IDIF methods using the maximum voxel intensity values. Lowest relative differences (RD) were observed by applying the manual method using the five highest voxel intensity values (max5) (AIF vs. IDIF manual, avg: RD = -82%; AIF vs. IDIF automated, avg: RD = -86%; AIF vs. IDIF manual, max5: RD = -6%; AIF vs. IDIF automated, max: RD = -26%). Regional VT values revealed considerable variance at group level, which was strongly reduced upon scaling by the inferior cerebellum. The resulting VT ratio values were adequate to detect group differences between patients with PSP or AD and healthy controls (HC) (PSP target region (globus pallidus): HC vs. PSP vs. AD: 1.18 vs. 1.32 vs. 1.16; AD target region (Braak region I): HC vs. PSP vs. AD: 1.00 vs. 1.00 vs. 1.22). VT ratios and DV ratios outperformed SUV ratios and VT in detecting differences between PSP and healthy controls, whereas all quantification approaches performed similarly in comparing AD and healthy controls. CONCLUSION: Blood-free IDIF is a promising approach for quantification of [18F]PI-2620 PET, serving as correlating surrogate for invasive continuous arterial blood sampling. Regional [18F]PI-2620 VT show large variance, in contrast to regional [18F]PI-2620 VT ratios scaled with the inferior cerebellum, which are appropriate for discriminating PSP, AD and healthy controls. DV ratios obtained by simplified reference tissue modeling are similarly suitable for this purpose.

No substantial neurocognitive impact of COVID-19 across ages and disease severity: a multicenter biomarker study of SARS-CoV-2 positive and negative adult and pediatric patients with acute respiratory tract infections.

BACKGROUND: Compared to intensive care unit patients with SARS-CoV-2 negative acute respiratory tract infections, patients with SARS-CoV-2 are supposed to develop more frequently and more severely neurologic sequelae. Delirium and subsequent neurocognitive deficits (NCD) have implications for patients' morbidity and mortality. However, the extent of brain injury during acute COVID-19 and subsequent NCD still remain largely unexplored. Body-fluid biomarkers may offer valuable insights into the quantification of acute delirium, brain injury and may help to predict subsequent NCD following COVID-19. METHODS: In a multicenter, observational case-control study, conducted across four German University Hospitals, hospitalized adult and pediatric patients with an acute COVID-19 and SARS-CoV-2 negative controls presenting with acute respiratory tract infections were included. Study procedures comprised the assessment of pre-existing neurocognitive function, daily screening for delirium, neurological examination and blood sampling. Fourteen biomarkers indicative of neuroaxonal, glial, neurovascular injury and inflammation were analyzed. Neurocognitive functions were re-evaluated after three months. RESULTS: We enrolled 118 participants (90 adults, 28 children). The incidence of delirium [85 out of 90 patients (94.4%) were assessable for delirium) was comparable between patients with COVID-19 [16 out of 61 patients (26.2%)] and SARS-CoV-2 negative controls [8 out of 24 patients (33.3%); p > 0.05] across adults and children. No differences in outcomes as measured by the modified Rankin Scale, the Short-Blessed Test, the Informant Questionnaire on Cognitive Decline in the Elderly, and the pediatrics cerebral performance category scale were observed after three months. Levels of body-fluid biomarkers were generally elevated in both adult and pediatric cohorts, without significant differences between SARS-CoV-2 negative controls and COVID-19. In COVID-19 patients experiencing delirium, levels of GFAP and MMP-9 were significantly higher compared to those without delirium. CONCLUSIONS: Delirium and subsequent NCD are not more frequent in COVID-19 as compared to SARS-CoV-2 negative patients with acute respiratory tract infections. Consistently, biomarker levels of brain injury indicated no differences between COVID-19 cases and SARS-CoV-2 negative controls. Our data suggest that delirium in COVID-19 does not distinctly trigger substantial and persistent subsequent NCD compared to patients with other acute respiratory tract infections. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04359914; date of registration 24-APR 2020.

Development and validation of a new drug-focused predictive risk score for postoperative delirium in orthopaedic and trauma surgery patients.

BACKGROUND: Postoperative delirium (POD) is the most common complication following surgery in elderly patients. During pharmacist-led medication reconciliation (PhMR), a predictive risk score considering delirium risk-increasing drugs and other available risk factors could help to identify risk patients. METHODS: Orthopaedic and trauma surgery patients aged ≥ 18 years with PhMR were included in a retrospective observational single-centre study 03/2022-10/2022. The study cohort was randomly split into a development and a validation cohort (6:4 ratio). POD was assessed through the 4 A's test (4AT), delirium diagnosis, and chart review. Potential risk factors available at PhMR were tested via univariable analysis. Significant variables were added to a multivariable logistic regression model. Based on the regression coefficients, a risk score for POD including delirium risk-increasing drugs (DRD score) was established. RESULTS: POD occurred in 42/328 (12.8%) and 30/218 (13.8%) patients in the development and validation cohorts, respectively. Of the seven evaluated risk factors, four were ultimately tested in a multivariable logistic regression model. The final DRD score included age (66-75 years, 2 points; > 75 years, 3 points), renal impairment (eGFR < 60 ml/min/1.73m2, 1 point), anticholinergic burden (ACB-score ≥ 3, 1 point), and delirium risk-increasing drugs (n ≥ 2; 2 points). Patients with ≥ 4 points were classified as having a high risk for POD. The areas under the receiver operating characteristic curve of the risk score model were 0.89 and 0.81 for the development and the validation cohorts, respectively. CONCLUSION: The DRD score is a predictive risk score assessable during PhMR and can identify patients at risk for POD. Specific preventive measures concerning drug therapy safety and non-pharmacological actions should be implemented for identified risk patients.

Postoperative cognitive dysfunction after beach chair positioning compared to supine position in orthopaedic surgery in the elderly.

INTRODUCTION: Postoperative cognitive dysfunction (POCD) occurs in up to 26% of patients older than 60 years 1 week after non-cardiac surgery. Intraoperative beach chair positioning (BCP) is advantageous for some types of shoulder surgery. However, this kind of positioning leads to a downward bound redistribution of blood volume, with possible hypoperfusion of the brain. We hypothesized that patients > 60 years undergoing orthopaedic shoulder surgery in a BCP might experience more POCD than patients operated in the supine position (SP). MATERIAL AND METHODS: A single-centre, prospective observational trial of 114 orthopaedic patients was performed. Study groups were established according to the type of intraoperative positioning. Anaesthesiological management was carried out similarly in both groups, including types of anaesthetics and blood pressure levels. POCD was evaluated using the Trail Making Test, the Letter-Number Span and the Regensburger Word Fluency Test. The frequency of POCD 1 week after surgery was considered primary outcome. RESULTS: Baseline characteristics, including duration of surgery, were comparable in both groups. POCD after 1 week occurred in 10.5% of SP patients and in 21.1% of BCP patients (p = 0.123; hazard ratio 2.0 (CI 95% 0.794-5.038)). After 4 weeks, the incidence of POCD decreased (SP: 8.8% vs. BCP: 5.3%; p = 0.463). 12/18 patients with POCD showed changes in their Word Fluency Tests. Near-infrared spectroscopy (NIRS) values were not lower in patients with POCD compared to those without POCD (54% (50/61) vs. 57% (51/61); p = 0.671). CONCLUSION: POCD at 1 week after surgery tended to occur more often in patients operated in beach chair position compared to patients in supine position without being statistically significant.

Diagnostic accuracy of the 4AT for delirium detection in older adults: systematic review and meta-analysis.

OBJECTIVE: Detection of delirium in hospitalised older adults is recommended in national and international guidelines. The 4 'A's Test (4AT) is a short (<2 minutes) instrument for delirium detection that is used internationally as a standard tool in clinical practice. We performed a systematic review and meta-analysis of diagnostic test accuracy of the 4AT for delirium detection. METHODS: We searched MEDLINE, EMBASE, PsycINFO, CINAHL, clinicaltrials.gov and the Cochrane Central Register of Controlled Trials, from 2011 (year of 4AT release on the website www.the4AT.com) until 21 December 2019. Inclusion criteria were: older adults (≥65 years); diagnostic accuracy study of the 4AT index test when compared to delirium reference standard (standard diagnostic criteria or validated tool). Methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Pooled estimates of sensitivity and specificity were generated from a bivariate random effects model. RESULTS: Seventeen studies (3,702 observations) were included. Settings were acute medicine, surgery, a care home and the emergency department. Three studies assessed performance of the 4AT in stroke. The overall prevalence of delirium was 24.2% (95% CI 17.8-32.1%; range 10.5-61.9%). The pooled sensitivity was 0.88 (95% CI 0.80-0.93) and the pooled specificity was 0.88 (95% CI 0.82-0.92). Excluding the stroke studies, the pooled sensitivity was 0.86 (95% CI 0.77-0.92) and the pooled specificity was 0.89 (95% CI 0.83-0.93). The methodological quality of studies varied but was moderate to good overall. CONCLUSIONS: The 4AT shows good diagnostic test accuracy for delirium in the 17 available studies. These findings support its use in routine clinical practice in delirium detection. PROSPERO REGISTRATION NUMBER: CRD42019133702.

Functional testing of tranexamic acid effects in patients undergoing elective orthopaedic surgery.

Tranexamic acid (TXA) can reduce blood loss and transfusion rates in orthopaedic surgery. In this regard, a new viscoelastometric test (TPA-test, ClotPro), enables the monitoring of TXA effects. This prospective observational study evaluated and correlated TXA plasma concentrations (cTXA) following intravenous and oral administration in patients undergoing elective orthopaedic surgery with lysis variables of TPA-test. Blood samples of 42 patients were evaluated before TXA application and 2, 6, 12, 24 and 48 h afterwards. TPA-test was used to determine lysis time (LT) as well as maximum lysis (ML) and cTXA was measured using Ultra-High-Performance-Liquid-Chromatography/Mass-Spectrometry. Data are presented as median (min-max). LTTPA-test and MLTPA-test correlated with cTXA (r = 0.9456/r = 0.5362; p < 0.0001). 2 h after intravenous TXA administration all samples showed complete lysis inhibition (LTTPA-test prolongation: T1: 217 s (161-529) vs. T2: 4500 s (4500-4500);p < 0.0001), whereas after oral application high intraindividual variability was observed as some samples showed only moderate changes in LTTPA-test (T1: 236 s (180-360) vs. T2: 4500 s (460-4500); p < 0.0001). Nevertheless, statistically LTTPA-test did not differ between groups. MLTPA-test differed 2 h after application (i.v.: 9.0% (5-14) vs. oral: 31% (8-97); p = 0.0081). In 17/21 samples after oral and 0/21 samples after intravenous administration cTXA was < 10 µg ml-1 2 h after application. TPA-test correlated with cTXA. MLTPA-test differed between intravenous and oral application 2 h after application. Most patients with oral application had TXA plasma concentration < 10 µg ml-1. The duration of action did not differ between intravenous and oral application. Additional studies evaluating clinical outcomes and side-effects based on individualized TXA prophylaxis/therapy are required.

Implementation of strategies to prevent and treat postoperative delirium in the post-anesthesia caring unit : A German survey of current practice.

Postoperative delirium is associated with worse outcome. The aim of this study was to understand present strategies for delirium screening and therapy in German Post-Anesthesia-Caring-Units (PACU). We designed a German-wide web-based questionnaire which was sent to 922 chairmen of anesthesiologic departments and to 726 anesthetists working in ambulatory surgery. The response rate was 30% for hospital anesthesiologists. 10% (95%-confidence interval: 8-12) of the anesthesiologists applied a standardised screening for delirium. Even though not on a regular basis, in 44% (41-47) of the hospitals, a recommended and validated screening was used, the Nursing Delirium Screening Scale (NuDesc) or the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). If delirium was likely to occur, 46% (43-50) of the patients were examined using a delirium tool. 20% (17-23) of the patients were screened in intensive care units. For the treatment of delirium, alpha-2-agonists (83%, 80-85) were used most frequently for vegetative symptoms, benzodiazepines for anxiety in 71% (68-74), typical neuroleptics in 77% (71-82%) of patients with psychotic symptoms and in 20% (15-25) in patients with hypoactive delirium. 45% (39-51) of the respondents suggested no therapy for this entity. Monitoring of delirium is not established as a standard procedure in German PACUs. However, symptom-oriented therapy for postoperative delirium corresponds with current guidelines.

Functional Testing for Tranexamic Acid Duration of Action Using Modified Viscoelastometry.

INTRODUCTION: Tranexamic acid (TXA) is the standard medication to prevent or treat hyperfibrinolysis. However, prolonged inhibition of lysis (so-called "fibrinolytic shutdown") correlates with increased mortality. A new viscoelastometric test enables bedside quantification of the antifibrinolytic activity of TXA using tissue plasminogen activator (TPA). MATERIALS AND METHODS: Twenty-five cardiac surgery patients were included in this prospective observational study. In vivo, the viscoelastometric TPA test was used to determine lysis time (LT) and maximum lysis (ML) over 96 h after TXA bolus. Additionally, plasma concentrations of TXA and plasminogen activator inhibitor 1 (PAI-1) were measured. Moreover, dose effect curves from the blood of healthy volunteers were performed in vitro. Data are presented as median (25-75th percentile). RESULTS: In vivo TXA plasma concentration correlated with LT (r = 0.55; p < 0.0001) and ML (r = 0.62; p < 0.0001) at all time points. Lysis was inhibited up to 96 h (LTTPA-test: baseline: 398 s [229-421 s] vs. at 96 h: 886 s [626-2,175 s]; p = 0.0013). After 24 h, some patients (n = 8) had normalized lysis, but others (n = 17) had strong lysis inhibition (ML <30%; p < 0.001). The high- and low-lysis groups differed regarding kidney function (cystatin C: 1.64 [1.42-2.02] vs. 1.28 [1.01-1.52] mg/L; p = 0.002) in a post hoc analysis. Of note, TXA plasma concentration after 24 h was significantly higher in patients with impaired renal function (9.70 [2.89-13.45] vs.1.41 [1.30-2.34] µg/mL; p < 0.0001). In vitro, TXA concentrations of 10 µg/mL effectively inhibited fibrinolysis in all blood samples. CONCLUSIONS: Determination of antifibrinolytic activity using the TPA test is feasible, and individual fibrinolytic capacity, e.g., in critically ill patients, can potentially be measured. This is of interest since TXA-induced lysis inhibition varies depending on kidney function.

Natriuretic Peptides as a Prognostic Marker for Delirium in Cardiac Surgery-A Pilot Study.

Background and Objectives: Delirium is a common and major complication subsequent to cardiac surgery. Despite scientific efforts, there are no parameters which reliably predict postoperative delirium. In delirium pathology, natriuretic peptides (NPs) interfere with the blood-brain barrier and thus promote delirium. Therefore, we aimed to assess whether NPs may predict postoperative delirium and long-term outcomes. Materials and Methods: To evaluate the predictive value of NPs for delirium we retrospectively analyzed data from a prospective, randomized study for serum levels of atrial natriuretic peptide (ANP) and the precursor of C-type natriuretic peptide (NT-proCNP) in patients undergoing coronary artery bypass grafting (CABG) with or without cardiopulmonary bypass (off-pump coronary bypass grafting; OPCAB). Delirium was assessed by a validated chart-based method. Long-term outcomes were assessed 10 years after surgery by a telephone interview. Results: The overall incidence of delirium in the total cohort was 48% regardless of the surgical approach (CABG vs. OPCAB). Serum ANP levels >64.6 pg/mL predicted delirium with a sensitivity (95% confidence interval) of 100% (75.3-100) and specificity of 42.9% (17.7-71.1). Serum NT-proCNP levels >1.7 pg/mL predicted delirium with a sensitivity (95% confidence interval) of 92.3% (64.0-99.8) and specificity of 42.9% (17.7-71.1). Both NPs could not predict postoperative survival or long-term cognitive decline. Conclusions: We found a positive correlation between delirium and preoperative plasma levels of ANP and NT-proCNP. A well-powered and prospective study might identify NPs as biomarkers indicating the risk of delirium and postoperative cognitive decline in patients at risk for postoperative delirium.

Biomarkers and postoperative cognitive function: could it be that easy?

PURPOSE OF REVIEW: Neurocognitive dysfunction after surgery is highly relevant in the elderly. The multifactorial manner of this syndrome has made it hard to define an ideal biomarker to predict individual risk and assess diagnosis and severity of delirium [postoperative delirium (POD)] and subsequent postoperative cognitive decline (POCD). This review summarizes recent literature on blood biomarkers for POD/POCD. RECENT FINDINGS: Markers for delirium have been searched for in the cerebrospinal fluid to examine the pathologic cascade. However, cerebrospinal fluid cannot be easily obtained in the perioperative setting. Thus, attention shifts toward prediction markers from patients' blood to determine the individual risk. In this regard, three major groups of peripheral blood markers could be distinguished: first, global, but unspecific markers associated with POD/POCD; second, specific and established markers related to neurocognitive function; and third, upcoming or newly described markers with less evidence. Solely neuron-specific enolase is an adequate biomarker based on recent literature. SUMMARY: Single markers for postoperative cognitive impairment cannot predict POD/POCD in geriatric patients. However, a wisely arranged battery of promising biomarkers might achieve a satisfying sensitivity and specificity for the preoperative assessment of subsequent cognitive decline. Adequately powered studies to prove this hypothesis are required.

Preemptive volume therapy to prevent hemodynamic changes caused by the beach chair position: hydroxyethyl starch 130/0.4 versus Ringer's acetate-a controlled randomized trial.

BACKGROUND: Hemodynamic instability frequently occurs in beach chair positioning for surgery, putting patients at risk for cerebral adverse events. This study examined whether preoperative volume loading with crystalloids alone or with a crystalloid-colloid combination can prevent hemodynamic changes that may be causative for unfavorable neurologic outcomes. METHODS: The study randomly assigned 43 adult patients undergoing shoulder surgery to 3 study groups. Each group received an infusion of 500 mL of Ringer's acetate between induction of anesthesia and being placed in the beach chair position. The crystalloid group received an additional bolus of 1000 mL Ringer's acetate. The hydroxyethyl starch group was administered an additional bolus of 500 mL of 6% hydroxyethyl starch 130/0.4. Hemodynamic monitoring was accomplished via an esophageal Doppler probe. Cerebral oxygen saturation was examined with near-infrared spectroscopy. Changes in stroke volume variation between the prone and beach chair positions were defined as the primary outcome parameter. Secondary outcomes were changes in cardiac output and cerebral oxygen saturation. RESULTS: The control group was prematurely stopped after enrollment of 4 patients because of adverse events. In the hydroxyethyl starch group, stroke volume variation remained constant during positioning maneuvers (P = .35), whereas a significant increase was observed in the Ringer's acetate group (P < .01; P = .014 for intergroup comparison). This was also valid for changes in cardiac output. Cerebral oxygen saturation significantly decreased in both groups. CONCLUSIONS: Preprocedural boluses of 500 mL of 6% hydroxyethyl starch 130/0.4 as well as 1000 mL of Ringer's acetate were efficient in preserving hemodynamic conditions during beach chair position.

Preoperative Midazolam and Patient-Centered Outcomes of Older Patients: The I-PROMOTE Randomized Clinical Trial.

Importance: The effect of oral midazolam premedication on patient satisfaction in older patients undergoing surgery is unclear, despite its widespread use. Objective: To determine the differences in global perioperative satisfaction in patients with preoperative administration of oral midazolam compared with placebo. Design, Setting, and Participants: This double-blind, parallel-group, placebo-controlled randomized clinical trial was conducted in 9 German hospitals between October 2017 and May 2019 (last follow-up, June 24, 2019). Eligible patients aged 65 to 80 years who were scheduled for elective inpatient surgery for at least 30 minutes under general anesthesia and with planned extubation were enrolled. Data were analyzed from November 2019 to December 2020. Interventions: Patients were randomized to receive oral midazolam, 3.75 mg (n = 309), or placebo (n = 307) 30 to 45 minutes prior to anesthesia induction. Main Outcomes and Measures: The primary outcome was global patient satisfaction evaluated using the self-reported Evaluation du Vécu de l'Anesthésie Generale (EVAN-G) questionnaire on the first postoperative day. Key secondary outcomes included sensitivity and subgroup analyses of the primary outcome, perioperative patient vital data, adverse events, serious complications, and cognitive and functional recovery up to 30 days postoperatively. Results: Among 616 randomized patients, 607 were included in the primary analysis. Of these, 377 (62.1%) were male, and the mean (SD) age was 71.9 (4.4) years. The mean (SD) global index of patient satisfaction did not differ between the midazolam and placebo groups (69.5 [10.7] vs 69.6 [10.8], respectively; mean difference, -0.2; 95% CI, -1.9 to 1.6; P = .85). Sensitivity (per-protocol population, multiple imputation) and subgroup analyses (anxiety, frailty, sex, and previous surgical experience) did not alter the primary results. Secondary outcomes did not differ, except for a higher proportion of patients with hypertension (systolic blood pressure ≥160 mm Hg) at anesthesia induction in the placebo group. Conclusion and Relevance: A single low dose of oral midazolam premedication did not alter the global perioperative patient satisfaction of older patients undergoing surgery or that of patients with anxiety. These results may be affected by the low dose of oral midazolam. Further trials-including a wider population with commonplace low-dose intravenous midazolam and plasma level measurements-are needed. Trial Registration: ClinicalTrials.gov Identifier: NCT03052660.

Physiological levels of A-, B- and C-type natriuretic peptide shed the endothelial glycocalyx and enhance vascular permeability.

Atrial natriuretic peptide (ANP) is a peptide hormone released from the cardiac atria during hypervolemia. Though named for its well-known renal effect, ANP has been demonstrated to acutely increase vascular permeability in vivo. Experimentally, this phenomenon was associated with a marked shedding of the endothelial glycocalyx, at least for supraphysiological intravascular concentrations. This study investigates the impact and mechanism of action of physiological doses of ANP and related peptides on the vascular barrier. In isolated guinea pig hearts, prepared and perfused in a modified Langendorff mode with and without the intravascular presence of the colloid hydroxyethyl starch (HES), we measured functional changes in vascular permeability and glycocalyx shedding related to intracoronary infusion of physiological concentrations of A-, B- and C-type natriuretic peptide (ANP, BNP and CNP). Significant coronary venous washout of glycocalyx constituents (syndecan-1 and heparan sulfate) was observed. As tested for ANP, this effect was positively related to the intracoronary concentration. Intravascular shedding of the glycocalyx was morphologically confirmed by electron microscopy. Also, functional vascular barrier competence decreased, as indicated by significant increases in transudate formation and HES extravasation. Ortho-phenanthroline, a non-specific inhibitor of matrix metalloproteases, was able to reduce ANP-induced glycocalyx shedding. These findings suggest participation of natriuretic peptides in pathophysiological processes like heart failure, inflammation or sepsis. Inhibition of metalloproteases might serve as a basis for future therapeutical options.

[Postoperative delirium in the recovery room]. / Postoperatives Delir im Aufwachraum.

Postoperative delirium during emergence from anesthesia is the most frequent neuropsychiatric complication in the post-anesthesia care unit. In addition to increased medical and especially nursing care efforts, affected patients are threatened with delayed rehabilitation with a longer hospital stay and an increased mortality. It is therefore essential to identify risk factors at an early stage and to implement preventive measures; however, should a postoperative delirium occur in the post-anesthesia care unit despite the use of these preventive measures, it should be detected and treated at an early stage using suitable screening procedures. In this context, working instructions for delirium prophylaxis and standardized test procedures for detection of delirium have been shown to be useful. An additional drug treatment can be indicated when all nonpharmacological options have been exhausted.

Towards model-informed precision dosing of piperacillin: multicenter systematic external evaluation of pharmacokinetic models in critically ill adults with a focus on Bayesian forecasting.

PURPOSE: Inadequate piperacillin (PIP) exposure in intensive care unit (ICU) patients threatens therapeutic success. Model-informed precision dosing (MIPD) might be promising to individualize dosing; however, the transferability of published models to external populations is uncertain. This study aimed to externally evaluate the available PIP population pharmacokinetic (PopPK) models. METHODS: A multicenter dataset of 561 ICU patients (11 centers/3654 concentrations) was used for the evaluation of 24 identified models. Model performance was investigated for a priori (A) predictions, i.e., considering dosing records and patient characteristics only, and for Bayesian forecasting, i.e., additionally including the first (B1) or first and second (B2) therapeutic drug monitoring (TDM) samples per patient. Median relative prediction error (MPE) [%] and median absolute relative prediction error (MAPE) [%] were calculated to quantify accuracy and precision. RESULTS: The evaluation revealed a large inter-model variability (A: MPE - 135.6-78.3% and MAPE 35.7-135.6%). Integration of TDM data improved all model predictions (B1/B2 relative improvement vs. A: |MPE|median_all_models 45.1/67.5%; MAPEmedian_all_models 29/39%). The model by Kim et al. was identified to be most appropriate for the total dataset (A/B1/B2: MPE - 9.8/- 5.9/- 0.9%; MAPE 37/27.3/23.7%), Udy et al. performed best in patients receiving intermittent infusion, and Klastrup et al. best predicted patients receiving continuous infusion. Additional evaluations stratified by sex and renal replacement therapy revealed further promising models. CONCLUSION: The predictive performance of published PIP models in ICU patients varied considerably, highlighting the relevance of appropriate model selection for MIPD. Our differentiated external evaluation identified specific models suitable for clinical use, especially in combination with TDM.

Postoperative Delirium in Patients with Oral Cancer: Is Intraoperative Fluid Administration a Neglected Risk Factor?

Squamous cell carcinoma (SCC) is a malignant tumor derived from squamous cells and can be found in different localizations. In the oral cavity especially, it represents the most common type of malignant tumor. First-line therapy for oral squamous cell carcinoma (OSCC) is surgery, including tumor resection, neck dissection, and maybe reconstruction. Although perioperative mortality is low, complications such as delirium are very common, and may have long-lasting consequences on the patient's quality of life. This study examines if excessive fluid administration, among other parameters, is an aggravating factor for the development of postoperative delirium. A total of 198 patients were divided into groups concerning the reconstruction technique used: group A for primary wound closure or reconstruction with a local flap, and group B for microsurgical reconstruction. The patients with and without delirium in both groups were compared regarding intraoperative fluid administration, fluid balance, and other parameters, such as blood loss, duration of surgery and overall ventilation, alcohol consumption, and creatinine, albumin, natrium, and hematocrit levels. The logistic regression for group A shows that fluid intake (p = 0.02, OR = 5.27, 95% CI 1.27-21.8) and albumin levels (p = 0.036, OR = 0.22, CI 0.054-0.908) are independent predictors for the development of delirium. For group B, gender (p = 0.026, OR = 0.34, CI 0.133-0.879) with a protective effect for females, fluid intake (p = 0.003, OR = 3.975, CI 1.606-9.839), and duration of ventilation (p = 0.025, OR = 1.178, CI 1.021-1.359) are also independent predictors for delirium. An intake of more than 3000 mL for group A, and 4150 mL for group B, increases the risk of delirium by approximately five and four times, respectively. Fluid management should be considered carefully in patients with OSCC, in order to reduce the occurrence of postoperative delirium. Different factors may become significant for the development of delirium regarding different surgical procedures.