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.

Pain, depression, and quality of life in adults with MOG-antibody-associated disease.

BACKGROUND AND PURPOSE: Myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) is an inflammatory autoimmune condition of the central nervous system. However, data on pain and depression have remained scarce. The aim of this study was to assess features of chronic pain and depression as well as their impact on health-related quality of life (hr-QoL) in MOGAD. METHODS: Patients with MOGAD were identified in the Neuromyelitis Optica Study Group registry. Data were acquired by a questionnaire, including clinical, demographic, pain (PainDetect, Brief Pain Inventory-Short Form, McGill Pain Questionnaire-Short Form), depression (Beck Depression Inventory-II), and hr-QoL (Short Form-36 Health Survey) items. RESULTS: Twenty-two of 43 patients suffered from MOGAD-related pain (11 nociceptive, eight definite neuropathic, three possible neuropathic) and 18 from depression. Patients with neuropathic pain had the highest pain intensity and most profound activities of daily living (ADL) impairment. Fifteen patients reported spasticity-associated pain, including four with short-lasting painful tonic spasms. Later disease onset, profound physical impairment, and depression were associated with chronic pain. Physical QoL was more affected in pain sufferers (p < 0.001) than in pain-free patients, being most severely reduced by neuropathic pain (p = 0.016). Pain severity, visual impairment, and gait impairment independently predicted lower physical QoL. Depression was the only factor reducing mental QoL. Twelve patients still suffering from moderate pain (pain severity 4.6 ± 2.3) received pain medication. Only four out of 10 patients with moderate to severe depression took antidepressants. CONCLUSIONS: Being highly prevalent, pain and depression strongly affect QoL and ADL in MOGAD. Both conditions remain insufficiently controlled in real-life clinical practice.

Physostigmine for prevention of postoperative delirium and long-term cognitive dysfunction in liver surgery: A double-blinded randomised controlled trial.

BACKGROUND: Anecdotally, cholinergic stimulation has been used to treat delirium and reduce cognitive dysfunction. OBJECTIVE: The aim of this investigation was to evaluate whether physostigmine reduced the incidence of postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) in patients undergoing liver resection. DESIGN: This was a double-blind, randomised, placebo-controlled trial. Between 11 August 2009 and 3 March 2016, patients were recruited at the Charité - Universitätsmedizin Berlin in Germany. Follow-ups took place at 1 week (T1), 90 days (T2) and 365 days (T3) after surgery. SETTING: This single-centre study was conducted at an academic medical centre. PARTICIPANTS: In total, 261 participants aged at least 18 years scheduled for elective liver surgery were randomised. The protocol also included 45 non-surgical matched controls to provide normative data for POCD and neurocognitive deficit (NCD). INTERVENTION: Participants were allocated to receive either intravenous physostigmine, as a bolus of 0.02 mg kg-1 body weight followed by 0.01 mg kg-1 body weight per hour (n = 130), or placebo (n = 131), for 24 h after induction of anaesthesia. MAIN OUTCOMES AND MEASURES: Primary outcomes were POD, assessed using the Diagnostic and Statistical Manual of Mental Disorders (DSM-4-TR) twice daily up to day 7 after surgery, and POCD assessed via the CANTAB neuropsychological test battery, and two paper pencil tests on the day before surgery, and on postoperative days 7, 90 and 365. RESULTS: In total, 261 patients were randomised, 130 to the physostigmine and 131 to the placebo group. The incidence of POD did not differ significantly between the physostigmine and placebo groups (20 versus 15%; P = 0.334). Preoperative cognitive impairment and POCD frequencies did not differ significantly between the physostigmine and placebo groups at any time. Lower mortality rates were found in the physostigmine group compared with placebo at 3 months [2% (95% confidence interval (CI), 0 to 4) versus 11% (95% CI, 6 to 16), P = 0.002], and 6 months [7% (95% CI, 3 to 12) versus 16% (95% CI, 10 to 23), P = 0.012] after surgery. CONCLUSION: Physostigmine had no effect on POD and POCD when applied after induction of anaesthesia up to 24 h. TRIAL REGISTRATION: DOI 10.1186/ISRCTN18978802, EudraCT 2008-007237-47, Ethics approval ZS EK 11 618/08 (15 January 2009).

Influence of Sedation Level and Ventilation Status on the Diagnostic Validity of Delirium Screening Tools in the ICU-An International, Prospective, Bi-Center Observational Study (IDeAS).

Background and objectives: The use of delirium screening instruments (DSIs) is recommended in critical care practice for a timely detection of delirium. We hypothesize that the patient-related factors "level of sedation" and "mechanical ventilation" impact test validity of DSIs. Materials and Methods: This is a prospective, bi-center observational study (clinicaltrials.gov: NCT01720914). Critically ill patients were screened for delirium daily for up to seven days after enrollment using the Nursing Delirium Screening Scale (Nu-DESC), Intensive Care Delirium Screening Checklist (ICDSC), and Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Reference standard for delirium diagnosis was the neuropsychiatric examination using the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Immediately before delirium assessment, ventilation status and sedation levels were documented. Results: 160 patients were enrolled and 151 patients went into final analysis. Delirium incidence was 23.2%. Nu-DESC showed a sensitivity and specificity of 88.5%, a positive predictive value (PPV) of 71.9%, and a negative predictive value (NPV) of 95.8%. ICDSC had a sensitivity of 62.5%, a specificity of 92.4%, a PPV of 71.4%, and a NPV of 89.0%. CAM-ICU showed a sensitivity of 75.0%, a specificity of 94.7%, a PPV of 85.7%, and a NPV of 90.0%. For Nu-DESC and ICDSC, test validity was significantly better for non-sedated patients (Richmond Agitation Sedation Scale (RASS) 0/-1), whereas test validity for CAM-ICU in a severity scale version showed no significant differences for different sedation levels. No DSI showed a significant difference in test validity between noninvasively and invasively ventilated patients. Conclusions: Test validities of DSIs were comparable to previous studies. The observational scores ICDSC and Nu-DESC showed a significantly better performance in awake and drowsy patients (RASS 0/-1) when compared with other sedation levels. Physicians should refrain from sedation whenever possible to avoid suboptimal performance of DSIs.

Relevance of peripheral cholinesterase activity on postoperative delirium in adult surgical patients (CESARO): A prospective observational cohort study.

BACKGROUND: The cholinergic system is considered to play a key role in the development of postoperative delirium (POD), which is a common complication after surgery. OBJECTIVES: To determine whether peri-operative acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities are associated with the development of POD in in-hospital surgical patients, and raise hypotheses on cholinergic regulatory mechanisms in POD. DESIGN: A prospective multicentre observational study by the Peripheral Cholinesterase-activity on Neurocognitive Dysfunctions in Surgical Patients (CESARO) study group. SETTING: Nine German hospitals. PATIENTS: Patients of at least 18 years of age scheduled for inpatient elective surgery for a variety of surgical procedures. A total of 650 patients (mean age 61.5 years, 52.8% male) were included. METHODS: Clinical variables, and peripheral AChE and BuChE activities, were assessed throughout the peri-operative period using bedside point-of-care measurements (one pre-operative and two postoperative measurements). POD screening was conducted postoperatively for at least 24 h and up to the third postoperative day using a validated screening tool (nursing delirium screening scale). RESULTS: In all, 179 patients (27.5%) developed POD within the early postoperative phase. There was a lower BuChE activity in patients with delirium compared with patients without delirium pre-operatively (Cohen's r = 0.07, P = 0.091), on postoperative day 1 (Cohen's r = 0.12, P = 0.003) and on postoperative day 2 (Cohen's r = 0.12, P = 0.002). In contrast, there was a significantly higher AChE activity in patients with delirium compared with patients without delirium pre-operatively (Cohen's r = 0.10, P = 0.012), on postoperative day 1 (Cohen's r = 0.11, P = 0.004) and on postoperative day 2 (Cohen's r = 0.13, P = 0.002). After adjusting for covariates in multiple logistic regression, a significant association between both BuChE and AChE activities and POD was not found. However, in the multivariable analysis using the Generalized Estimating Equation, cholinesterase activities showed that a decrease of BuChE activity by 100 U L increased the risk of a delirium by approximately 2.1% (95% CI 1.6 to 2.8%) and for each 1 U g of haemoglobin increase in AChE activity, there was a 1.4% (95% CI 0.6 to 2.2%) increased risk of POD. CONCLUSION: Peri-operative peripheral cholinesterase activities may be related to the development of POD, but the clinical implications remain unclear. Further studies, in homogeneous patient groups with a strict protocol for measurement time points, are needed to investigate the relationship between cholinesterase activities and POD. TRIAL REGISTRATION: www.clinicaltrials.gov. Identifier NCT01964274.

The growth of uterine myomas in untreated women: influence factors and ultrasound monitoring.

PURPOSE: Until now there are no systematic studies about the long-term course of myoma growth. Therefore, the aims of the present study were: (1) ultrasound monitoring of the natural course of growth of uterine leiomyomas; (2) assessment of whether the growth of myomas depends on the age of the patients, the location, or the initial size (possible co-factors/predictor criteria for increase of growth); influence of oral contraceptives (OC). METHODS: Patient records (2010-May 2016) were retrospectively and systematically evaluated in regards to their growth and clinical course. The patients received a follow-up questionnaire by mail about the further history. Linear regression analysis and generalized regression analysis were performed to determine the influence of various factors on the growth of myomas. RESULTS: Overall, 152 met the further inclusion criteria. Most of the myomas increased in size but 10% of the myomas became smaller without therapy. There is a significant dependency between the initial myoma size, and the first and second measurements, but not between those measures and myoma localization. In regression analysis, there was also a significant association between the growth of the myomas and the initial size but no association with age, complaint symptoms, and use of OC. However, the use of OC waas significantly associated with myoma growth in GEE. CONCLUSIONS: The course of growth of myomas has large variance, so this should not be taken as a sign for a malignant event (sarcoma or the so-called STUMP). The growth takes place with considerable individual variability and ultimately is not predictable.

Emergence delirium in children is related to epileptiform discharges during anaesthesia induction: An observational study.

BACKGROUND: Epileptiform discharges frequently occur in children during induction of anaesthesia. However, studies analysing the impact of epileptiform discharges on postoperative emergence delirium in children are still scarce. The aim of this study is to correlate the incidence of epileptiform activity during anaesthesia induction with the occurrence of emergence delirium during stay in the recovery room. OBJECTIVES: Prospective, observational cohort study in children 0.5 to 8 years old undergoing planned surgery. Bifrontal electroencephalogram electrodes were placed before induction of anaesthesia. Visual electroencephalogram analysis was performed from start of anaesthetic agent administration until intubation with regard to epileptiform patterns: rhythmic polyspikes; periodic epileptiform discharges; delta with spikes; and suppression with spikes. Emergence delirium was assessed during stay in the recovery room using the Pediatric Assessment of Emergence Delirium Score. DESIGN: Prospective, observational cohort study. SETTING: University hospital - Germany/Berlin. Children were included between September 2015 and February 2017. PATIENTS: A total of 62 Children, aged 0.5 to 8 years old undergoing planned surgery were included. MAIN OUTCOME MEASURES: Primary outcome was emergence delirium. Secondary outcomes, peri-operative Electroencephalography (EEG) data analysis. The presented study analysed an association between emergence delirium and the occurrence of epileptiform discharges during anaesthesia induction. RESULTS: A total of 43.5% of the children developed emergence delirium and 56.5% did not. Epileptiform discharges were observed more often in children developing emergence delirium (63%) compared with children not developing emergence delirium (43%). But only the occurrence of interictal spike events - such as rhythmic polyspikes; periodic epileptiform discharges and delta with spikes - were significantly related to emergence delirium (emergence delirium-group 48% vs. nonemergence delirium-group 14%, OR = 5.6 [95% CI: 1.7 to 18.7]; P = 0.004). CONCLUSION: Emergence delirium in children is significantly related to interictal spike events occurring during induction of anaesthesia. CLINICAL TRIAL: NCT02481999.

Observational clinical study on organ dysfunction associated with dosing of antibiotics in a Pediatric Intensive Care Unit.

BACKGROUND: Medication errors are of concern especially in pediatric patients. This study investigates impact of dosing errors of antibiotics on outcome in critically ill pediatric patients. METHODS: Retrospective study including all consecutive patients admitted to one university pediatric intensive care unit (PICU) in 2010 with length of PICU stay >24 hrs, age <18 years and antibiotic therapy. Antibiotic dosages were evaluated for compliance with recommended dosing individually adapted for bodyweight, age and organ function. Primary endpoint was organ dysfunction defined as occurrence of liver injury (LI) or acute kidney injury (AKI) after initiation of antibiotic therapy. AKI was defined as reduced estimated glomerular filtration below 50 mL/min or renal replacement therapy. LI was defined as more than two-fold elevation of liver enzymes. Additionally, duration of PICU stay, ventilation and all-cause PICU mortality were investigated. RESULTS: Altogether 305 patients were evaluated with 2577 patient PICU days and 4021 antibiotic dosages. Overall 38.6% of dosages were incorrect according to recommendations and were applied in 130 patients (low-adherence-group). 175 children received antibiotic dosing according to recommendations (high-adherence-group). Patients in the low-adherence-group showed a 7-fold increase in adjusted risk to develop new-onset organ dysfunction (95% CI: 2.1-26.4), needed longer median PICU treatment (7 versus 3 days, P<0.001) and prolonged duration of mechanical ventilation (8 versus 2 days, P<0.001). In subgroup analyses, organ dysfunction and PICU mortality were associated with non-adherence to recommendations. CONCLUSIONS: Adherence to a bodyweight- and age-adapted dosage-protocol is associated with less organ dysfunction and a more favorable clinical outcome in pediatric patients.

Patient Empowerment Reduces Pain in Geriatric Patients After Gynecologic Onco-Surgery: Subgroup Analysis of a Prospective Randomized Controlled Clinical Trial.

PURPOSE: This study aimed to determine the effect of patient empowerment on acute postoperative pain. This research was part of the Patient Empowerment and Risk-Assessed Treatment to Improve Outcome in the Elderly After Onco-Surgery Trial. DESIGN: This research was a prospective randomized controlled interventional study. METHODS: Patients who underwent gynecologic onco-surgery were included in this analysis of demographic data, basic characteristics, pain intensity by numeric rating scale, and mode of pain therapy. The intervention included provision of detailed information booklet and patient diary. FINDINGS: Ninety-one patients were enrolled (treatment group, n = 51; control group, n = 40). With the same medications, pain on the first postoperative day was significantly less severe in the treatment group than in the control group (P = .03). On multivariate logistic regression, patient empowerment had a significant effect on pain intensity (odds ratio, 3.46; 95% confidence interval, 1.35 to 8.86; P = .01). The number needed to treat to decrease pain from severe to mild (numeric rating scale, 5 to 10 to 0 to 4) was 4.35. CONCLUSIONS: Patient empowerment significantly reduces postoperative pain in elderly patients undergoing gynecologic cancer surgery.

Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses.

OBJECTIVE: Neuromyelitis optica (NMO) attacks often are severe, are difficult to treat, and leave residual deficits. Here, we analyzed the frequency, sequence, and efficacy of therapies used for NMO attacks. METHODS: A retrospective review was made of patient records to assess demographic/diagnostic data, attack characteristics, therapies, and the short-term remission status (complete remission [CR], partial remission [PR], no remission [NR]). Inclusion criteria were NMO according to Wingerchuk's 2006 criteria or aquaporin-4 antibody-positive NMO spectrum disorder (NMOSD). Remission status was analyzed with generalized estimating equations (GEEs), a patient-based statistical approach. RESULTS: A total of 871 attacks in 185 patients (142 NMO/43 NMOSD, 82% female) were analyzed. The 1,153 treatment courses comprised high-dose intravenous steroids (HD-S; n = 810), plasma exchange (PE; n = 192), immunoadsorption (IA; n = 38), other (n = 80), and unknown (n = 33) therapies. The first treatment course led to CR in 19.1%, PR in 64.5%, and NR in 16.4% of attacks. Second, third, fourth, and fifth treatment courses were given in 28.2%, 7.1%, 1.4%, and 0.5% of attacks, respectively. This escalation of attack therapy significantly improved outcome (p < 0.001, Bowker test). Remission rates were higher for isolated optic neuritis versus isolated myelitis (p < 0.001), and for unilateral versus bilateral optic neuritis (p = 0.020). Isolated myelitis responded better to PE/IA than to HD-S as first treatment course (p = 0.037). Predictors of CR in multivariate GEE analysis were age (odds ratio [OR] = 0.97, p = 0.011), presence of myelitis (OR = 0.38, p = 0.002), CR from previous attack (OR = 6.85, p < 0.001), and first-line PE/IA versus HD-S (OR = 4.38, p = 0.006). INTERPRETATION: Particularly myelitis and bilateral optic neuritis have poor remission rates. Escalation of attack therapy improves outcome. PE/IA may increase recovery in isolated myelitis.

Influence of female sex and fertile age on neuromyelitis optica spectrum disorders.

BACKGROUND: Gender and age at onset are important epidemiological factors influencing prevalence, clinical presentation, and treatment response in autoimmune diseases. OBJECTIVE: To evaluate the impact of female sex and fertile age on aquaporin-4-antibody (AQP4-ab) status, attack localization, and response to attack treatment in patients with neuromyelitis optica (NMO) and its spectrum disorders (neuromyelitis optica spectrum disorder (NMOSD)). METHODS: Female-to-male ratios, diagnosis at last visit (NMO vs NMOSD), attack localization, attack treatment, and outcome were compared according to sex and age at disease or attack onset. RESULTS: A total of 186 NMO/SD patients (82% female) were included. In AQP4-ab-positive patients, female predominance was most pronounced during fertile age (female-to-male ratio 23:1). Female patients were more likely to be positive for AQP4-abs (92% vs 55%; p < 0.001). Interval between onset and diagnosis of NMO/SD was longer in women than in men (mean 54 vs 27 months; p = 0.023). In women, attacks occurring ⩽40 years of age were more likely to show complete remission ( p = 0.003) and better response to high-dose intravenous steroids ( p = 0.005) compared to woman at >40 years. CONCLUSION: Our data suggest an influence of sex and age on susceptibility to AQP4-ab-positive NMO/SD. Genetic and hormonal factors might contribute to pathophysiology of NMO/SD.

Whole-body vibration to prevent intensive care unit-acquired weakness: safety, feasibility, and metabolic response.

BACKGROUND: Intensive care unit (ICU)-acquired weakness in critically ill patients is a common and significant complication affecting the course of critical illness. Whole-body vibration is known to be effective muscle training and may be an option in diminishing weakness and muscle wasting. Especially, patients who are immobilized and not available for active physiotherapy may benefit. Until now whole-body vibration was not investigated in mechanically ventilated ICU patients. We investigated the safety, feasibility, and metabolic response of whole-body vibration in critically ill patients. METHODS: We investigated 19 mechanically ventilated, immobilized ICU patients. Passive range of motion was performed prior to whole-body vibration therapy held in the supine position for 15 minutes. Continuous monitoring of vital signs, hemodynamics, and energy metabolism, as well as intermittent blood sampling, took place from the start of baseline measurements up to 1 hour post intervention. We performed comparative longitudinal analysis of the phases before, during, and after intervention. RESULTS: Vital signs and hemodynamic parameters remained stable with only minor changes resulting from the intervention. No application had to be interrupted. We did not observe any adverse event. Whole-body vibration did not significantly and/or clinically change vital signs and hemodynamics. A significant increase in energy expenditure during whole-body vibration could be observed. CONCLUSIONS: In our study the application of whole-body vibration was safe and feasible. The technique leads to increased energy expenditure. This may offer the chance to treat patients in the ICU with whole-body vibration. Further investigations should focus on the efficacy of whole-body vibration in the prevention of ICU-acquired weakness. TRIAL REGISTRATION: Applicability and Safety of Vibration Therapy in Intensive Care Unit (ICU) Patients. ClinicalTrials.gov NCT01286610 . Registered 28 January 2011.

Readiness to change and therapy outcomes of an innovative psychotherapy program for surgical patients: results from a randomized controlled trial.

BACKGROUND: Readiness to change is a pivotal construct for psychotherapy research and a major target of motivational interventions. Our primary objective was to examine whether pre-treatment readiness to change moderated therapy effects of Bridging Intervention in Anesthesiology (BRIA), an innovative psychotherapy approach for surgical patients. This stepped care program aims at motivating and supporting surgical patients with mental disorders to engage in psychosocial mental health care. METHODS: The major steps of BRIA are two motivational interventions with different intensity. The first step of the program consists of preoperative computer-assisted psychosocial self-assessment including screening for psychological distress and automatically composed computerized brief written advice (BWA). In the second step, patients participate in postoperative psychotherapy sessions combining motivational interviewing with cognitive behavioural therapy (BRIA psychotherapy sessions). We performed regression-based moderator analyses on data from a recent randomized controlled trial published by our research group. The sample comprised 220 surgical patients with diverse comorbid mental disorders according to ICD-10. The most frequent disorders were mood, anxiety, substance use and adjustment disorders. The patients had a mean age of 43.31 years, and 60.90% were women. In a regression model adjusted for pre-treatment psychological distress, we investigated whether readiness to change moderated outcome differences between (1) the BRIA psychotherapy sessions and (2) no psychotherapy / BWA only. RESULTS: Multiple regression analyses showed that readiness to change moderated treatment effects regarding the primary outcomes "Participation in psychosocial mental health care options at month 6" (p = 0.03) and "Having approached psychosocial mental health care options at month 6" (p = 0.048) but not regarding the secondary outcome "Change of general psychological distress between baseline assessment and month 6" (p = 0.329). Probing the moderation effect with the Johnson-Neyman technique revealed that BRIA psychotherapy sessions were superior to BWA in patients with low to moderate readiness, but not in those with high readiness. CONCLUSIONS: Readiness to change may act as moderator of the efficacy of psychosocial therapy. Combinations of motivational interviewing and cognitive behavioural therapy may be effective particularly in patients with a variety of mental disorders and low readiness to change. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01357694.

In vivo application of Granulocyte-Macrophage Colony-stimulating Factor enhances postoperative qualitative monocytic function.

BACKGROUND: Granulocyte macrophage colony-stimulating factor (GM-CSF) can be used as a potent stimulator for immune suppressed patients as defined by a decrease of human leukocyte antigen-D related expression on monocytes (mHLA-DR) after surgery. However, the exact role of GM-CSF on monocytic and T cell function is unclear. METHODS: In this retrospective randomized controlled trial (RCT) subgroup analysis, monocytic respectively T cell function and T cell subspecies of 20 immune suppressed (i.e. mHLA-DR levels below 10,000 monoclonal antibodies (mAb) per cell at the first day after surgery) patients after esophageal or pancreatic resection were analyzed. Each 10 patients received either GM-CSF (250 µg/m²/d) or placebo for a maximum of three consecutive days if mHLA-DR levels remained below 10,000 mAb per cell. mHLA-DR and further parameters of immune function were measured preoperatively (od) until day 5 after surgery (pod5). Statistical analyses were performed using nonparametric statistical procedures. RESULTS: In multivariate analysis, mHLA-DR significantly differed between the groups (p < 0.001). mHLA-DR was increased on pod2 (p < 0.001) and pod3 (p = 0.002) after GM-CSF application. Tumor necrosis factor-α (TNF-α) release of lipopolysaccharide (LPS) stimulated monocytes multivariately significantly differed between the groups (p < 0.008) and was increased in the GM-CSF group on pod2 (p < 0.001) and pod3 (p = 0.046). Th17/regulatory T (Treg) cell ratio was higher after GM-CSF treatment on pod2 (p = 0.041). No differences were seen in lymphocytes and T helper cell (Th)1/Th2 specific cytokine production after T cell stimulation with Concanavalin (Con) A between the groups. CONCLUSIONS: Postoperative application of GM-CSF significantly enhanced qualitative monocytic function by increased mHLA-DR and TNF-α release after LPS stimulation and apparently enhanced Th17/Treg ratio. Clinical trial registered with www.controlled-trials.com (ISRCTN27114642) 05 December 2008.

In vitro and ex vivo Measurement of Prophylactic Dabigatran Concentrations with a New Ecarin-Based Thromboelastometry Test.

BACKGROUND: An increasing number of oral anticoagulants has been approved, including dabigatran etexilate (DE). DE is a direct thrombin inhibitor that requires no routine monitoring, but, if necessary (e.g. urgent surgery etc.), the diluted thrombin time measured with Hemoclot® has shown reliable results. So far, no point-of-care (PoC) assay is available to measure DE effects. The EcaTEM assay uses ecarin to initiate the coagulation cascade at the step of thrombin generation and measures the clotting time (CT) by thromboelastometry. METHODS: This study investigated the correlation of the EcaTEM with standard laboratory assays in dabigatran-treated patients. Ten patients undergoing total hip or knee arthroplasty were included in the study. DE for thromboprophylaxis was started 4 h after surgery. Blood samples were taken before surgery as well as 2, 6 and 12 h after ingestion on the 3rd postoperative day. Dabigatran concentration (Hemoclot), activated partial thromboplastin time, thrombin time and CT EcaTEM were measured. RESULTS: Only CT EcaTEM and Hemoclot showed a correlation > 0.75 for all measurements. CONCLUSION: CT EcaTEM appears a valid PoC method parameter to detect thrombin inhibition and thus the presence of dabigatran beside diluted thrombin time at different concentration levels. This may represent an opportunity to identify the presence of dabigatran, e.g., in emergency situations.

Validity of Different Delirium Assessment Tools for Critically Ill Children: Covariates Matter.

OBJECTIVES: To evaluate test validity of the Pediatric Confusion Assessment Method for the ICU, the Pediatric Anesthesia Emergence Delirium scale, and the newly developed severity scale for the Pediatric Confusion Assessment Method for the ICU; to prospectively assess covariates and their influence on test validity of the scores. DESIGN: Prospective observational cohort study. SETTING: PICU of a tertiary care medical center. PATIENTS: Critically ill patients 5 years old or older ventilated or nonventilated with an ICU length of stay of at least 24 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were scored with the Pediatric Confusion Assessment Method for the ICU and the Pediatric Anesthesia Emergence Delirium scale once daily for a maximum of 21 days. Validity was determined by comparing scoring results with the evaluations of the delirium experts who used the criteria of the Diagnostic and Statistical Manual, 4th Edition, Text Revision, for delirium diagnosis. Sixty-four patients were enrolled and 214 assessments were conducted and included in data analysis. The first assessments within each patient revealed sensitivities of 69.2% for the Pediatric Anesthesia Emergence Delirium scale, 76.9% for the Pediatric Confusion Assessment Method for the ICU, and 84.9% for the severity scale for the Pediatric Confusion Assessment Method for the ICU. Specificities were 98% for all scores. Considering repeated measurements, sensitivities decreased to 35.9% for the Pediatric Anesthesia Emergence Delirium scale and to 52.3% for the Pediatric Confusion Assessment Method for the ICU. The sensitivity of the severity scale for the Pediatric Confusion Assessment Method for the ICU dropped to 71.8%, which was significantly higher compared to the Pediatric Anesthesia Emergence Delirium scale (p = 0.0008). Receiver operator characteristic regression unveiled that sedation and mechanical ventilation had a significant negative effect on the validity of the Pediatric Anesthesia Emergence Delirium scale and the severity scale for the Pediatric Confusion Assessment Method for the ICU. Age and gender had a significant impact on the receiver operator characteristic curve of the severity scale for the Pediatric Confusion Assessment Method for the ICU. CONCLUSIONS: The severity scale for the Pediatric Confusion Assessment Method for the ICU showed the best test validity when used in critically ill children of 5 years old or older. Nevertheless, validity of delirium screening itself depends on patient specific factors. These factors should be taken into consideration when choosing a delirium screening instrument.

End-of-life decisions in surgical intensive care medicine - the relevance of blood transfusions.

BACKGROUND: End-of-life decisions (EOLDs) are common in the intensive care unit (ICU). EOLDs underlie a dynamic process and limitation of ICU-therapies is often done sequentially. Questionnaire-based and observational studies on medical ICUs and in palliative care reveal blood transfusions as the first therapy physicians withhold as an EOLD. METHODS: To test whether this practice also applies to surgical ICU-patients, in an observational study, all deceased patients (n = 303) admitted to an academic surgical ICU in a three-year period were analyzed for the process of limiting ICU-therapies. RESULTS: Restriction of further surgery (85.4%) and limiting doses of vasopressors (75.8%) were the most frequent forms of limitations in surgical ICU therapies. Surgical patients, who had blood transfusions withheld (44.6%), had more ICU-therapies withheld or withdrawn simultaneously than patients who had transfusions maintained (5 ± 2 vs. 2 ± 1, p < 0.001). Secondary EOLDs and subsequent limitations occurred less frequently in patients who had transfusions withheld with their first EOLD (17.1% vs. 35.6%, p < 0.05). CONCLUSION: Limitation orders for blood transfusions are not a prioritized decision in EOLDs of surgical ICU patients. Withholding blood transfusions correlates with discontinuation of further significant life-support therapies. This suggests that EOLDs to withhold blood transfusions are part of the most advanced limitations of therapy on the surgical ICU.

Predictors of survival in critically ill patients with acute respiratory distress syndrome (ARDS): an observational study.

BACKGROUND: Currently there is no ARDS definition or classification system that allows optimal prediction of mortality in ARDS patients. This study aimed to examine the predictive values of the AECC and Berlin definitions, as well as clinical and respiratory parameters obtained at onset of ARDS and in the course of the first seven consecutive days. METHODS: The observational study was conducted at a 14-bed intensive care unit specialized on treatment of ARDS. Predictive validity of the AECC and Berlin definitions as well as PaO2/FiO2 and FiO2/PaO2*Pmean (oxygenation index) on mortality of ARDS patients was assessed and statistically compared. RESULTS: Four hundred forty two critically-ill patients admitted for ARDS were analysed. Multivariate Cox regression indicated that the oxygenation index was the most accurate parameter for mortality prediction. The third day after ARDS criteria were met at our hospital was found to represent the best compromise between earliness and accuracy of prognosis of mortality regarding the time of assessment. An oxygenation index of 15 or greater was associated with higher mortality, longer length of stay in ICU and hospital and longer duration of mechanical ventilation. In addition, non-survivors had a significantly longer length of stay and duration of mechanical ventilation in referring hospitals before admitted to the national reference centre than survivors. CONCLUSIONS: The oxygenation index is suggested to be the most suitable parameter to predict mortality in ARDS, preferably assessed on day 3 after admission to a specialized centre. Patients might benefit when transferred to specialized ICU centres as soon as possible for further treatment.

Four-phase rhinomanometry: a multicentric retrospective analysis of 36,563 clinical measurements.

Rhinomanometry can still be considered as the standard technique for the objective assessment of the ventilatory function of the nose. Reliable technical requirements are given by fast digital sensors and modern information technology. However, the xyimaging of the pressure-flow relation typically shows loops as a sign of hysteresis, with the need for resolution of the breath in four phases. The three pillars of 4-phase rhinomanometry (4PR) are the replacement of estimations by measurements, the introduction of parameters related to the subjective sensing of obstruction, and the graphical information regarding the disturbed function of the nasal valve. In a meta-analysis of 36,563 clinical measurements, we analyze the errors of the "classic" parameters (flow in 150 Pa) and reject the further use of these parameters as obsolete, because they correspond to an inaccurate estimation rather than proper measurement. In a pre-study of 1580 measurements, the logarithmic effective resistance (Reff) was found to have the highest correlation with values obtained from a visual analog scale. Next, we classify the inspiratory effective resistance in 20,069 measurements without treatment and 16,494 measurements after decongestion with xylometazoline 0.1 % spray in 20 % percentiles. The gradation of obstruction delivers not only "normal" values but also indications for the severity of the obstruction in adult Caucasian noses. Adoption of the distribution for the growing nose and analysis of the total nasal resistance is addressed, and typical findings of nasal valve phenomena are outlined.