Condensation of Ded1p Promotes a Translational Switch from Housekeeping to Stress Protein Production.

Cells sense elevated temperatures and mount an adaptive heat shock response that involves changes in gene expression, but the underlying mechanisms, particularly on the level of translation, remain unknown. Here we report that, in budding yeast, the essential translation initiation factor Ded1p undergoes heat-induced phase separation into gel-like condensates. Using ribosome profiling and an in vitro translation assay, we reveal that condensate formation inactivates Ded1p and represses translation of housekeeping mRNAs while promoting translation of stress mRNAs. Testing a variant of Ded1p with altered phase behavior as well as Ded1p homologs from diverse species, we demonstrate that Ded1p condensation is adaptive and fine-tuned to the maximum growth temperature of the respective organism. We conclude that Ded1p condensation is an integral part of an extended heat shock response that selectively represses translation of housekeeping mRNAs to promote survival under conditions of severe heat stress.

The RNA helicase Mtr4p modulates polyadenylation in the TRAMP complex.

Many steps in nuclear RNA processing, surveillance, and degradation require TRAMP, a complex containing the poly(A) polymerase Trf4p, the Zn-knuckle protein Air2p, and the RNA helicase Mtr4p. TRAMP polyadenylates RNAs designated for decay or trimming by the nuclear exosome. It has been unclear how polyadenylation by TRAMP differs from polyadenylation by conventional poly(A) polymerase, which produces poly(A) tails that stabilize RNAs. Using reconstituted S. cerevisiae TRAMP, we show that TRAMP inherently suppresses poly(A) addition after only 3-4 adenosines. This poly(A) tail length restriction is controlled by Mtr4p. The helicase detects the number of 3'-terminal adenosines and, over several adenylation steps, elicits precisely tuned adjustments of ATP affinities and rate constants for adenylation and TRAMP dissociation. Our data establish Mtr4p as a critical regulator of polyadenylation by TRAMP and reveal that an RNA helicase can control the activity of another enzyme in a highly complex fashion and in response to features in RNA.

The helicase Ded1p controls use of near-cognate translation initiation codons in 5' UTRs.

The conserved and essential DEAD-box RNA helicase Ded1p from yeast and its mammalian orthologue DDX3 are critical for the initiation of translation1. Mutations in DDX3 are linked to tumorigenesis2-4 and intellectual disability5, and the enzyme is targeted by a range of viruses6. How Ded1p and its orthologues engage RNAs during the initiation of translation is unknown. Here we show, by integrating transcriptome-wide analyses of translation, RNA structure and Ded1p-RNA binding, that the effects of Ded1p on the initiation of translation are connected to near-cognate initiation codons in 5' untranslated regions. Ded1p associates with the translation pre-initiation complex at the mRNA entry channel and repressing the activity of Ded1p leads to the accumulation of RNA structure in 5' untranslated regions, the initiation of translation from near-cognate start codons immediately upstream of these structures and decreased protein synthesis from the corresponding main open reading frames. The data reveal a program for the regulation of translation that links Ded1p, the activation of near-cognate start codons and mRNA structure. This program has a role in meiosis, in which a marked decrease in the levels of Ded1p is accompanied by the activation of the alternative translation initiation sites that are seen when the activity of Ded1p is repressed. Our observations indicate that Ded1p affects translation initiation by controlling the use of near-cognate initiation codons that are proximal to mRNA structure in 5' untranslated regions.

Changes of the nociceptive flexion reflex threshold in patients undergoing cardiac surgery-a prospective clinical pilot study.

Opioid dosage for general anaesthesia and sedation relies on surrogate parameters such as heartrate and blood pressure. This implies the risk of both under- and overdosing. A promising tool to provide target-oriented opioid dosing is measuring the nociceptive flexion reflex threshold (NFRT). The aim of this study was to investigate the individual trajectories and to determine this methods' clinical practicability in the perioperative setting of cardiac surgery. NFRT was measured preoperatively (twice as baseline), immediately after surgery and later in the general ward (primary outcomes). No intraoperative measurements were performed since neuromuscular blockade hinders NFRT assessment. Administered analgesics and pain scores were also recorded (secondary outcomes). Data were collected from August 2019 to March 2020. 264 patients scheduled for cardiac surgery were screened for eligibility. 55 patients were included, 30 rendered datasets for analysis. Thresholds after conclusion of surgery [TICU: median (IQR), 31.1 mA (21.5-50.0 mA)] were significantly higher than preoperatively [Tpre: 9.2 mA (5.4-13.4 mA); P < 0.001]. In 11 patients (36.7%), no immediate postoperative reflex response was elicited. Later, all reflexes returned, but thresholds remained significantly higher than preoperatively [Tpost: 11.9 mA (9.2-16.6 mA); P = 0.043]. NFRT values after surgery were higher compared to baseline measurements. Subsequently they decreased but did not reach their baseline levels. There was no corresponding dose-dependency, suggesting multimodal effects on the nociceptive system. Unless measurements are not prevented by technical issues NFRT-assessment appears to be a future tool to target analgesics in patients not able to self-report pain. Trial registration Study registration: DRKS00021617. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00021617 (registered retrospectively).

A helicase links upstream ORFs and RNA structure.

Upstream open reading frames (uORFs) in 5' UTRs of eukaryotic mRNAs are increasingly recognized as important elements that regulate cellular protein synthesis. Since uORFs can start from non-AUG codons, an enormous number of potential uORF initiation sites exists in 5'UTRs. However, only a subset of these sites is used and it has been unclear how actual start sites are selected. Studies of the DEAD-box helicase Ded1p from S. cerevisiae show that translation of uORFs with non-AUG initiation codons occurs upstream of mRNA structures that emerge with defective Ded1p. The data designate mRNA structure as important determinant for non-AUG initiation sites of uORFs. Ded1p can control this RNA structure and thereby regulate uORF translation.

Preoperative Depression and Plasma Cortisol Levels as Predictors of Delirium after Cardiac Surgery.

BACKGROUND: Delirium is common in old patients who undergo cardiac surgery, and it is associated with adverse outcomes. The genesis of delirium is thought to be multi-factorial, but it is still not well understood. Symptoms of depression and elevated cortisol level have been described in some previous studies as factors associated with delirium, suggesting a shared pathophysiology. AIMS: The objective of the present study was to determine whether preoperative depression symptoms and increased cortisol level represent risk factors for delirium after cardiac surgery. METHODS: We performed a prospective cohort study in 183 patients aged >50 years undergoing elective cardiac surgery. The Geriatric Depression Scale (GDS) was used to assess patients for depressive symptoms before surgery. Preoperative plasma cortisol levels were available in 145 participants. Delirium was diagnosed using the Confusion Assessment Method for Intensive Care Unit (CAM-ICU) during the first 7 days after surgery. Spearman correlation was used for correlations between GDS, Mini-Mental State Examination (MMSE), Charlson comorbidity index, and age. Binary logistic regression was used to determine whether GDS and cortisol levels predict postoperative delirium. RESULTS: Delirium occurred in 60 patients out of 183 (32.8%) included and lasted 2.3 days (SD 1.36). GDS was correlated with age (p = 0.001) and comorbidity index (p = 0.003) and inversely correlated with MMSE score (p < 0.001). Higher preoperative GDS scores were associated with incidence of delirium in the postoperative period (p = 0.002). The association was significant after controlling for age, MMSE score, history of stroke, and Charlson comorbidity index (p = 0.045). Preoperative cortisol level was not associated with the development of postoperative delirium. CONCLUSION: Our results suggest that a higher preoperative depression score is associated with an increased risk of postoperative delirium. On the other hand, preoperative plasma cortisol level does not seem to be a predictor of delirium after surgery. Further studies are needed to determine the potential of preoperative depression treatment to prevent postoperative delirium.

Hidden specificity in an apparently nonspecific RNA-binding protein.

Nucleic-acid-binding proteins are generally viewed as either specific or nonspecific, depending on characteristics of their binding sites in DNA or RNA. Most studies have focused on specific proteins, which identify cognate sites by binding with highest affinities to regions with defined signatures in sequence, structure or both. Proteins that bind to sites devoid of defined sequence or structure signatures are considered nonspecific. Substrate binding by these proteins is poorly understood, and it is not known to what extent seemingly nonspecific proteins discriminate between different binding sites, aside from those sequestered by nucleic acid structures. Here we systematically examine substrate binding by the apparently nonspecific RNA-binding protein C5, and find clear discrimination between different binding site variants. C5 is the protein subunit of the transfer RNA processing ribonucleoprotein enzyme RNase P from Escherichia coli. The protein binds 5' leaders of precursor tRNAs at a site without sequence or structure signatures. We measure functional binding of C5 to all possible sequence variants in its substrate binding site, using a high-throughput sequencing kinetics approach (HITS-KIN) that simultaneously follows processing of thousands of RNA species. C5 binds different substrate variants with affinities varying by orders of magnitude. The distribution of functional affinities of C5 for all substrate variants resembles affinity distributions of highly specific nucleic acid binding proteins. Unlike these specific proteins, C5 does not bind its physiological RNA targets with the highest affinity, but with affinities near the median of the distribution, a region that is not associated with a sequence signature. We delineate defined rules governing substrate recognition by C5, which reveal specificity that is hidden in cellular substrates for RNase P. Our findings suggest that apparently nonspecific and specific RNA-binding modes may not differ fundamentally, but represent distinct parts of common affinity distributions.

Helicase multitasking in ribosome assembly.

In this issue of Molecular Cell, Bohnsack et al. (2009) identify multiple binding sites of the RNA helicase Prp43 on preribosomal RNA. The target regions suggest distinct functions of Prp43 in ribosome biogenesis.

Patients prone for postoperative delirium: preoperative assessment, perioperative prophylaxis, postoperative treatment.

PURPOSE OF REVIEW: The aim of this study was to review current literature on identification of patients at risk for postoperative delirium (POD) and to summarize recent findings on prophylaxis and treatment. RECENT FINDINGS: Age and preoperative cognitive impairment are among the most important risk factors of POD. POD is the result of a complex interplay of predisposing and precipitating factors. Thus, both prophylaxis and treatment require multicomponent intervention programs. No single medication to prevent or treat POD is available. Avoiding too deep anesthesia, avoiding additional psychoactive substances including benzodiazepines and intravenous opioids, and effective pain management as well as early mobilization are essential. SUMMARY: An increase of the proportion of elderly patients undergoing surgery will lead to a higher incidence of POD. Preoperative assessment should facilitate identification of patients at high risk. Perioperative management should include monitoring depth of anesthesia, preference for nonopioid pain therapy, early regular delirium monitoring starting in the recovery room, avoiding ICU-sedation, early mobilization and exercise, and cognitive training.

Intraoperative burst suppression is associated with postoperative delirium following cardiac surgery: a prospective, observational study.

BACKGROUND: Postoperative delirium (POD) occurs frequently after cardiac surgery and is associated with increased morbidity and mortality. We analysed whether perioperative bilateral BIS monitoring may detect abnormalities before the onset of POD in cardiac surgery patients. METHODS: In a prospective observational study, 81 patients undergoing cardiac surgery were included. Bilateral Bispectral Index (BIS)-monitoring was applied during the pre-, intra- and postoperative period, and BIS, EEG Asymmetry (ASYM), and Burst Suppression Ratio (BSR) were recorded. POD was diagnosed according to the Confusion Assessment Method for the Intensive Care Unit, and patients were divided into a delirium and non-delirium group. RESULTS: POD was detected in 26 patients (32%). A trend towards a lower ASYM was observed in the delirium group as compared to the non-delirium group on the preoperative day (ASYM = 48.2 ± 3.6% versus 50.0 ± 4.7%, mean ± sd, p = 0.087) as well as before induction of anaesthesia, with oral midazolam anxiolysis (median ASYM = 49.5%, IQR [47.4;51.5] versus 50.6%, IQR [49.1;54.2], p = 0.081). Delirious patients remained significantly (p = 0.018) longer in a burst suppression state intraoperatively (107 minutes, IQR [47;170] versus 44 minutes, IQR [11;120]) than non-delirious patients. Receiver operating analysis revealed burst suppression duration (area under the curve = 0.73, p = 0.001) and BSR (AUC = 0.68, p = 0.009) as predictors of POD. CONCLUSIONS: Intraoperative assessment of BSR may identify patients at risk of POD and should be investigated in further studies. So far it remains unknown whether there is a causal relationship or rather an association between intraoperative burst suppression and the development of POD. TRIAL REGISTRATION: clinicaltrials.gov NCT01048775.

Percutaneous and surgical tracheostomy in critically ill adult patients: a meta-analysis.

INTRODUCTION: The aim of this study was to conduct a meta-analysis to determine whether percutaneous tracheostomy (PT) techniques are advantageous over surgical tracheostomy (ST), and if one PT technique is superior to the others. METHODS: Computerized databases (1966 to 2013) were searched for randomized controlled trials (RCTs) reporting complications as predefined endpoints and comparing PT and ST and among the different PT techniques in mechanically ventilated adult critically ill patients. Odds ratios (OR) and mean differences (MD) with 95% confidence interval (CI), and I(2) values were estimated. RESULTS: Fourteen RCTs tested PT techniques versus ST in 973 patients. PT techniques were performed faster (MD, -13.06 minutes (95% CI, -19.37 to -6.76 (P < 0.0001)); I(2) = 97% (P < 0.00001)) and reduced odds for stoma inflammation (OR, 0.38 (95% CI, 0.19 to 0.76 (P = 0.006)); I(2) = 2% (P = 0.36)), and infection (OR, 0.22 (95% CI, 0.11 to 0.41 (P < 0.00001)); I(2) = 0% (P = 0.54)), but increased odds for procedural technical difficulties (OR, 4.58 (95% CI, 2.21 to 9.47 (P < 0.0001)); I(2) = 0% (P = 0.63)). PT techniques reduced odds for postprocedural major bleeding (OR, 0.39 (95% CI, 0.15 to 0.97 (P = 0.04)); I(2) = 0% (P = 0.69)), but not when a single RCT using translaryngeal tracheostomy was excluded (OR, 0.58 (95% CI, 0.21 to 1.63 (P = 0.30)); I(2) = 0% (P = 0.89)). Eight RCTs compared different PT techniques in 700 patients. Multiple (MDT) and single step (SSDT) dilatator techniques are associated with the lowest odds for difficult dilatation or cannula insertion (OR, 0.30 (95% CI, 0.12 to 0.80 (P = .02)); I(2) = 56% (P = 0.03)) and major intraprocedural bleeding (OR, 0.29 (95% CI, 0.10 to 0.85 (P = 0.02)); I(2) = 0% (P = 0.72)), compared to the guide wire dilatation forceps technique. CONCLUSION: In critically ill adult patients, PT techniques can be performed faster and reduce stoma inflammation and infection but are associated with increased technical difficulties when compared to ST. Among PT techniques, MDT and SSDT were associated with the lowest intraprocedural risks and seem to be preferable.

RNA helicase IGHMBP2 regulates THO complex to ensure cellular mRNA homeostasis.

RNA helicases constitute a large protein family implicated in cellular RNA homeostasis and disease development. Here, we show that the RNA helicase IGHMBP2, linked to the neuromuscular disorder spinal muscular atrophy with respiratory distress type 1 (SMARD1), associates with polysomes and impacts translation of mRNAs containing short, GC-rich, and structured 5' UTRs. The absence of IGHMBP2 causes ribosome stalling at the start codon of target mRNAs, leading to reduced translation efficiency. The main mRNA targets of IGHMBP2-mediated regulation encode for components of the THO complex (THOC), linking IGHMBP2 to mRNA production and nuclear export. Accordingly, failure of IGHMBP2 regulation of THOC causes perturbations of the transcriptome and its encoded proteome, and ablation of THOC subunits phenocopies these changes. Thus, IGHMBP2 is an upstream regulator of THOC. Of note, IGHMBP2-dependent regulation of THOC is also observed in astrocytes derived from patients with SMARD1 disease, suggesting that deregulated mRNA metabolism contributes to SMARD1 etiology and may enable alternative therapeutic avenues.

Predisposing and precipitating factors of delirium after cardiac surgery: a prospective observational cohort study.

OBJECTIVE: To comprehensively assess pre-, intra-, and postoperative delirium risk factors as potential targets for intervention. BACKGROUND: Delirium after cardiac surgery is associated with longer intensive care unit (ICU) stay, and poorer functional and cognitive outcomes. Reports on delirium risk factors so far did not cover the full range of patients' presurgical conditions, intraoperative factors, and postoperative course. METHODS: After written informed consent, 221 consecutive patients ≥ 50 years scheduled for cardiac surgery were assessed for preoperative cognitive performance, and functional and physical status. Clinical and biochemical data were systematically recorded perioperatively. RESULTS: Of the 215 patients remaining for analysis, 31% developed delirium in the intensive care unit. Using logistic regression models, older age [73.3 (71.2-75.4) vs 68.5 (67.0-70.0); P = 0.016], higher Charlson's comorbidity index [3.0 (1.5-4.0) vs 2.0 (1.0-3.0) points; P = 0.009], lower Mini-Mental State Examination (MMSE) score (MMSE, [27 (23-29) vs 28 (27-30) points; P = 0.021], length of cardiopulmonary bypass (CPB) [CPB; 133 (112-163) vs 119 (99-143) min; P = 0.004], and systemic inflammatory response syndrome in the intensive care unit [25 (36.2%) vs 13 (8.9%); P = 0.001] were independently associated with delirium. Combining age, MMSE score, Charlson's comorbidity index, and length of CPB in a regression equation allowed for a prediction of postoperative delirium with a sensitivity of 71.19% and a specificity of 76.26% (receiver operating analysis, area under the curve: 0.791; 95% confidence interval: 0.727-0.845). CONCLUSIONS: Further research will evaluate if modification of these risk factors prevents delirium and improves outcomes.

The RNA helicase database.

RNA helicases are ubiquitous and essential enzymes that function in nearly all aspects of RNA metabolism. The RNA helicase database (www.rnahelicase.org) integrates the wealth of accumulating information on RNA helicases in a readily accessible format. The database is a portal that allows straightforward retrieval of comprehensive information on sequence, structure and on biochemical and cellular functions of all RNA helicases from the most widely used model organisms Escherichia coli, Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, mouse and human. Also included are RNA helicases from other organisms that are subject to specific investigation. The database is structured according to the most recent helicase classification into helicase superfamilies (SFs) and families, and thus emphasizes phyologenetic relations between RNA helicases as well. Information on individual RNA helicases can be accessed through various browsing routes or through text-based searches of the database.

ICU- and ventilator-free days with isoflurane or propofol as a primary sedative - A post- hoc analysis of a randomized controlled trial.

PURPOSE: To compare ICU-free (ICU-FD) and ventilator-free days (VFD) in the 30 days after randomization in patients that received isoflurane or propofol without receiving the other sedative. MATERIALS AND METHODS: A recent randomized controlled trial (RCT) compared inhaled isoflurane via the Sedaconda® anaesthetic conserving device (ACD) with intravenous propofol for up to 54 h (Meiser et al. 2021). After end of study treatment, continued sedation was locally determined. Patients were eligible for this post-hoc analysis only if they had available 30-day follow-up data and never converted to the other drug in the 30 days from randomization. Data on ventilator use, ICU stay, concomitant sedative use, renal replacement therapy (RRT) and mortality were collected. RESULTS: Sixty-nine of 150 patients randomized to isoflurane and 109 of 151 patients randomized to propofol were eligible. After adjusting for potential confounders, the isoflurane group had more ICU-FD than the propofol group (17.3 vs 13.8 days, p = 0.028). VFD for the isoflurane and propofol groups were 19.8 and 18.5 respectively (p = 0.454). Other sedatives were used more frequently (p < 0.0001) and RRT started in a greater proportion of patients in the propofol group (p = 0.011). CONCLUSIONS: Isoflurane via the ACD was not associated with more VFD but with more ICU-FD and less concomitant sedative use.

Tidal recruitment assessed by electrical impedance tomography and computed tomography in a porcine model of lung injury*.

OBJECTIVES: To determine the validity of electrical impedance tomography to detect and quantify the amount of tidal recruitment caused by different positive end-expiratory pressure levels in a porcine acute lung injury model. DESIGN: Randomized, controlled, prospective experimental study. SETTING: Academic research laboratory. SUBJECTS: Twelve anesthetized and mechanically ventilated pigs. INTERVENTIONS: Acute lung injury was induced by central venous oleic acid injection and abdominal hypertension in seven animals. Five healthy pigs served as control group. Animals were ventilated with positive end-expiratory pressure of 0, 5, 10, 15, 20, and 25 cm H2O, respectively, in a randomized order. MEASUREMENTS AND MAIN RESULTS: At any positive end-expiratory pressure level, electrical impedance tomography was obtained during a slow inflation of 12 mL/kg of body weight. Regional-ventilation-delay indices quantifying the time until a lung region reaches a certain amount of impedance change were calculated for lung quadrants and for every single electrical impedance tomography pixel, respectively. Pixel-wise calculated regional-ventilation-delay indices were plotted in a color-coded regional-ventilation-delay map. Regional-ventilation-delay inhomogeneity that quantifies heterogeneity of ventilation time courses was evaluated by calculating the scatter of all pixel-wise calculated regional-ventilation-delay indices. End-expiratory and end-inspiratory computed tomography scans were performed at each positive end-expiratory pressure level to quantify tidal recruitment of the lung. Tidal recruitment showed a moderate inter-individual (r = .54; p < .05) and intra-individual linear correlation (r = .46 up to r = .73 and p < .05, respectively) with regional-ventilation-delay obtained from lung quadrants. Regional-ventilation-delay inhomogeneity was excellently correlated with tidal recruitment intra- (r = .90 up to r = .99 and p < .05, respectively) and inter-individually (r = .90; p < .001). CONCLUSIONS: Regional-ventilation-delay can be noninvasively measured by electrical impedance tomography during a slow inflation of 12 mL/kg of body weight and visualized using ventilation delay maps. Our experimental data suggest that the impedance tomography-based analysis of regional-ventilation-delay inhomogeneity provides a good estimate of the amount of tidal recruitment and may be useful to individualize ventilatory settings.

Selective 5-HT(1A)-R-agonist repinotan prevents remifentanil-induced ventilatory depression and prolongs antinociception.

BACKGROUND: 5-HT(1A)-R-agonist repinotan was shown to counteract a morphine-induced ventilatory depression but had pronociceptive effects at small doses (0.2 µg/kg). It remained to be clarified (1) whether a moderate dose of repinotan, sufficient to stimulate spontaneous breathing, impairs antinociception if plasma concentration decreases over time, and if (2) moderate doses prevent ventilatory depression if given before the opioid. METHODS: A dose-response curve of the repinotan effects on spontaneous minute ventilation during continuous remifentanil infusion in anesthetized rats was established to identify moderate doses: (1) tail-flick reflex latencies to assess nociception were recorded until 60 min after cessation of a continuous remifentanil infusion with or without a concomitant moderate repinotan dose (10 µg/kg), and (2) remifentanil boluses (2.5 µg/kg) were given after repinotan (10 and 20 µg/kg). RESULTS: (1) Remifentanil-induced antinociception lasted only 5 min after infusion was stopped (tail-flick reflex latencies; median [interquartile range], 97 [54-100]% of maximum possible effect; P = 0.034), but was extended by repinotan (10 µg/kg) to 30 min (tail-flick reflex latencies, 100 [75-100]% of maximum possible effect; P = 0.031). Repinotan (10 µg/kg) alone did not have any significant antinociceptive effect. (2) The ventilatory depression by remifentanil boluses (2.5 µg/kg; minute ventilation, -65 [-81 to -56]%; P = 0.031, n = 5) was blunted by repinotan (20 µg/kg; minute ventilation, -24 [-53 to 13]%; P = 0.313, compared with the pretreatment level). CONCLUSIONS: Repinotan prevented remifentanil-induced ventilatory depression in spontaneously breathing, anesthetized rats. Although repinotan did not depress nociception itself, it prolonged the profound antinociception after discontinuation of remifentanil infusion.

[Disorientation and delirium assessment : A secondary analysis of a prospective, observational study]. / Bedeutung der Desorientierung bei der Delireinschätzung : Sekundäranalyse einer prospektiven, observationellen Studie.

Disorientation may present as a warning sign of developing delirium. The most commonly used delirium assessment tool in Germany, the Confusion Assessment Method for Intensive Care Unit (CAM-ICU), does not rate "disorientation", since intubated patients cannot communicate verbally. However, the majority of German ICU patients are not orally intubated, so they could be examined for their orientation. This study was carried out to investigate whether the delirium feature "disorientation" in extubated patients yields diverging findings in comparison to the CAM-ICU and whether the sensitivity of the CAM-ICU may be improved when combined with the feature "disorientation" (CAM-IMC). A total of 86 paired assessments were completed in 50 extubated patients. Delirium was found in 19.8% (N = 17). The CAM-ICU had a sensitivity of 71% (95% confidence interval [CI] 44-90%) and a specificity of 100% (95-100%). Disorientation, if taken as the only delirium feature, had a sensitivity of 77% (50-93%) and a specificity of 93% (89-100%). The CAM-IMC reached a sensitivity of 88% (64-99%) and a specificity of 100% (95-100%). The receiver operating characteristics (ROC) analyses found an area under the curve (AUC) of 0.941 (95%CI 0.851-1.000) for the CAM-IMC, which was the highest compared to the other delirium tests (CAM-ICU, AUC 0.853 [0.720-0.986]; disorientation, AUC 0.868 [0.745-0.991]). This research emphasizes the importance of the feature "disorientation" for delirium assessments in patients able to verbally communicate and explains some controversial delirium ratings in daily practice. The CAM-IMC appears to be an attractive tool for delirium assessment in nonintubated patients and deserves further research.

Isoflurane vs. propofol for sedation in invasively ventilated patients with acute hypoxemic respiratory failure: an a priori hypothesis substudy of a randomized controlled trial.

BACKGROUND: Acute hypoxemic respiratory failure (AHRF) is a leading concern in critically ill patients. Experimental and clinical data suggest that early sedation with volatile anesthestics may improve arterial oxygenation and reduce the plasma and alveolar levels of markers of alveolar epithelial injury and of proinflammatory cytokines. METHODS: An a priori hypothesis substudy of a multicenter randomized controlled trial (The Sedaconda trial, EUDRA CT Number 2016-004551-67). In the Sedaconda trial, 301 patients on invasive mechanical ventilation were randomized to 48 h of sedation with isoflurane or propofol in a 1:1 ratio. For the present substudy, patients with a ratio of arterial pressure of oxygen (PaO2) to inspired fraction of oxygen (FiO2), PaO2/FiO2, of ≤ 300 mmHg at baseline were included (n = 162). The primary endpoint was the change in PaO2/FiO2 between baseline and the end of study sedation. A subgroup analysis in patients with PaO2/FiO2 ≤ 200 mmHg was performed (n = 82). RESULTS: Between baseline and the end of study sedation (48 h), oxygenation improved to a similar extent in the isoflurane vs. the propofol group (isoflurane: 199 ± 58 to 219 ± 76 mmHg (n = 70), propofol: 202 ± 62 to 236 ± 77 mmHg (n = 89); p = 0.185). On day seven after randomization, PaO2/FiO2 was 210 ± 79 mmHg in the isoflurane group (n = 41) and 185 ± 87 mmHg in the propofol group (n = 44; p = 0.411). In the subgroup of patients with PaO2/FiO2 ≤ 200 mmHg, PaO2/FiO2 increase between baseline and end of study sedation was 152 ± 33 to 186 ± 54 mmHg for isoflurane (n = 37), and 150 ± 38 to 214 ± 85 mmHg for propofol (n = 45; p = 0.029). On day seven, PaO2/FiO2 was 198 ± 69 mmHg in patients randomized to isoflurane (n = 20) and 174 ± 106 mmHg in patients randomized to propofol (n = 20; p = 0.933). Both for the whole study population and for the subgroup with PaO2/FiO2 ≤ 200 mmHg, no significant between-group differences were observed for PaCO2, pH and tidal volume as well as 30-day mortality and ventilator-free days alive. CONCLUSIONS: In patients with AHRF, inhaled sedation with isoflurane for a duration of up to 48 h did not lead to improved oxygenation in comparison to intravenous sedation with propofol. Trial registration The main study was registered in the European Medicines Agency's EU Clinical Trial register (EudraCT), 2016-004551-67, before including the first patient. The present substudy was registered at German Clinical Trials Register (DRKS, ID: DRKS00018959) on January 7th, 2020, before opening the main study data base and obtaining access to study results.