Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin.

The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor-mediated nuclear factor κB signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor α-toxin. Naturally elicited antibodies against α-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to α-toxin in nonleukocytic cells.

Intraoperative dexamethasone and delirium after cardiac surgery: a randomized clinical trial.

BACKGROUND: Delirium is common after cardiac surgery and may be partly related to the systemic inflammatory response triggered by the surgery and the use of cardiopulmonary bypass. We hypothesized that intraoperative administration of high-dose dexamethasone, a drug with potent anti-inflammatory effects, would reduce the incidence of delirium at any time point during the first 4 postoperative days after cardiac surgery. METHODS: This was a single-center substudy within a larger, multicenter placebo-controlled randomized clinical trial, the Dexamethasone for Cardiac Surgery (DECS) trial that randomized patients ≥18 years, undergoing cardiac surgery with cardiopulmonary bypass, to receive, in a double-blind fashion, either dexamethasone 1 mg/kg or placebo at the induction of anesthesia. Over the first 4 postoperative days, we compared between groups the incidence of delirium (based on the Confusion Assessment Method adapted for the intensive care unit, or after intensive care unit discharge, by the Confusion Assessment Method, accompanied by chart review), restraint use, and administered haloperidol, benzodiazepines, and opioids. Data were analyzed according to the intention-to-treat principle. The proportion of patients with delirium in the dexamethasone versus the placebo group was compared using the odds ratio (OR) with a 95% confidence interval (CI). The proportion also was compared using logistic regression to adjust for common baseline variables that might confound the presence of delirium between the 2 groups. RESULTS: Of 768 eligible patients, 737 subjects (96.0%) had complete data. The incidence of delirium was similar between the dexamethasone (14.2%) and placebo (14.9%) groups (crude OR = 0.95, 95% CI, 0.63-1.43; adjusted OR = 0.85, 95% CI, 0.55-1.31). Among patients who developed delirium, the median (interquartile range) duration of delirium was similar between the dexamethasone and placebo groups (2 [1-3] vs 2 [1-2] days, respectively, P = 0.45; WMWodds 0.98, 95% CI, 0.83-1.17). Restraint use and the administration of haloperidol, benzodiazepines, and opioids were also similar between the 2 groups. CONCLUSIONS: The intraoperative administration of dexamethasone did not reduce the incidence or duration of delirium in the first 4 days after cardiac surgery.

Intensive care unit environment may affect the course of delirium.

PURPOSE: Delirium is a common disorder in intensive care unit (ICU) patients. It is unclear whether ICU environment affects delirium. We investigated the influence of ICU environment on the number of days with delirium during ICU admission. METHODS: In this prospective before-after study, ICU delirium was compared between a conventional ICU with wards and a single-room ICU with, among others, improved daylight exposure. We included patients admitted for more than 24 h between March and June 2009 (ICU with wards) or between June and September 2010 (single-room ICU). Patients who remained unresponsive throughout ICU admission were excluded. The presence of delirium in the preceding 24 h was assessed daily with the confusion assessment method for the ICU (CAM-ICU) by research physicians combined with evaluation of medical and nursing charts. The number of days with delirium was investigated with Poisson regression analysis. RESULTS: We included 55 patients (449 observation days) in the ICU with wards and 75 patients (468 observation days) in the single-room ICU. After adjusting for confounding, the number of days with delirium decreased by 0.4 days (95 % confidence interval 0.1-0.7) in the single-room ICU (p = 0.005). The incidence of delirium during ICU stay was similar in the ICU with wards (51 %) and in the single-room ICU (45 %, p = 0.53). CONCLUSIONS: This study is the first to show that ICU environment may influence the course of delirium in ICU patients.

Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicentre, double-blind, placebo-controlled randomised trial.

BACKGROUND: Delirium is frequently diagnosed in critically ill patients and is associated with adverse outcome. Impaired cholinergic neurotransmission seems to have an important role in the development of delirium. We aimed to establish the effect of the cholinesterase inhibitor rivastigmine on the duration of delirium in critically ill patients. METHODS: Patients (aged ≥18 years) who were diagnosed with delirium were enrolled from six intensive care units in the Netherlands, and treated between November, 2008, and January, 2010. Patients were randomised (1:1 ratio) to receive an increasing dose of rivastigmine or placebo, starting at 0·75 mL (1·5 mg rivastigmine) twice daily and increasing in increments to 3 mL (6 mg rivastigmine) twice daily from day 10 onwards, as an adjunct to usual care based on haloperidol. The trial pharmacist generated the randomisation sequence by computer, and consecutively numbered bottles of the study drug according to this sequence to conceal allocation. The primary outcome was the duration of delirium during hospital admission. Analysis was by intention to treat. Duration of delirium was censored for patients who died or were discharged from hospital while delirious. Patients, medical staff, and investigators were masked to treatment allocation. Members of the data safety and monitoring board (DSMB) were unmasked and did interim analyses every 3 months. This trial is registered with ClinicalTrials.gov, number NCT00704301. FINDINGS: Although a sample size of 440 patients was planned, after inclusion of 104 patients with delirium who were eligible for the intention-to-treat analysis (n=54 on rivastigmine, n=50 on placebo), the DSMB recommended that the trial be halted because mortality in the rivastigmine group (n=12, 22%) was higher than in the placebo group (n=4, 8%; p=0·07). Median duration of delirium was longer in the rivastigmine group (5·0 days, IQR 2·7-14·2) than in the placebo group (3·0 days, IQR 1·0-9·3; p=0·06). INTERPRETATION: Rivastigmine did not decrease duration of delirium and might have increased mortality so we do not recommend use of rivastigmine to treat delirium in critically ill patients. FUNDING: ZonMw, the Netherlands Brain Foundation, and Novartis.

Comparison of delirium assessment tools in a mixed intensive care unit.

OBJECTIVE: Delirium is a frequent problem in the intensive care unit (ICU) associated with poor prognosis. Delirium in the ICU is underdiagnosed by nursing and medical staff. Several detection methods have been developed for use in ICU patients. The aim of this study was to compare the value of three detection methods (the Confusion Assessment Method for the ICU [CAM-ICU], the Intensive Care Delirium Screening Checklist [ICDSC] and the impression of the ICU physician with the diagnosis of a psychiatrist, neurologist, or geriatrician). DESIGN: Prospective study. SETTING AND PATIENTS: During an 8-month period, 126 patients (mean age 62.4 years, sd 15.0; mean Acute Physiology and Chronic Health Evaluation II score 20.9, sd 7.5) admitted to a 32-bed mixed medical and surgical ICU were studied. MEASUREMENTS: The included patients were assessed independently by trained ICU nurses using either the CAM-ICU or the ICDSC. Furthermore, the ICU physician was asked whether a patient was delirious or not. A psychiatrist, geriatrician, or neurologist serving as reference rater diagnosed delirium using established criteria. MAIN RESULTS: The CAM-ICU showed superior sensitivity and negative predictive value (64% and 83%) compared with the ICDSC (43% and 75%). The ICDSC showed higher specificity and positive predictive value (95% and 82% vs. 88% and 72%). The sensitivity of the physicians view was only 29%. CONCLUSIONS: ICU physicians underdiagnose delirium in the ICU, which underlines the necessity of standard evaluation in all critically ill patients. In our mixed ICU population, the CAM-ICU had a higher sensitivity than the ICDSC.

Intensive care delirium monitoring and standardised treatment: a complete survey of Dutch Intensive Care Units.

OBJECTIVE: Delirium is a frequent and serious problem in the Intensive Care Unit (ICU). Several international guidelines recommend daily monitoring for ICU-delirium. The purpose of this article is to give an up-to-date overview of the current status of monitoring and treatment of ICU-delirium in the Netherlands. DESIGN: Nation-wide, telephone-based questionnaire survey. PARTICIPANTS: Head nurse of all ICUs and a random sample of intensivists. RESULTS: Only 14% (n=14) of all Dutch ICUs (n=103) monitored for ICU-delirium. Of these, only half (7%) used a tool that is validated in ICU patients. In 31% of Dutch ICUs, a protocol was used to treat ICU-delirium. Responses were obtained from 100% of ICUs. CONCLUSION: Despite an international guideline, not more than 7% of ICUs in our study routinely evaluated the presence of delirium with a validated instrument. Fewer than one-third of Dutch ICUs use a protocol to treat ICU-delirium.