Background —Patients with venous thromboembolism require initial treatment with an immediate-acting anticoagulant, low-molecular-weight heparin. We evaluated a novel synthetic factor Xa inhibitor ...(SR90107a/ORG31540) as an alternative treatment. Methods and Results —A randomized-parallel-group, phase II trial to assess the efficacy and safety of SR90107a/ORG31540 (5, 7.5, or 10 mg once daily) relative to low-molecular-weight heparin (dalteparin, 100 IU/kg twice daily) in symptomatic proximal deep vein thrombosis. The primary outcome measure was the change in thrombus mass, assessed by ultrasonography of the leg veins and perfusion lung scintigraphy, performed at baseline and day 7±1. A positive outcome was defined as improvement of the ultrasound and/or perfusion scan result without deterioration of either test. Other outcome measures included symptomatic, recurrent venous thromboembolism and major bleeding for a period of 3 months. All outcomes were interpreted with the observer unaware of treatment allocation. A positive primary outcome was observed in 46 of 100 (46%), 52 of 108 (48%), 48 of 115 (42%), and 56 of 115 (49%), respectively, of the subjects given 5, 7.5, or 10 mg SR90107a/ORG31540 or dalteparin. There were 8 recurrent thromboembolic complications (2.4%) in the 334 patients treated with SR90107a/ORG31540 and 6 (5.0%) in the 119 dalteparin patients, a difference of 2.6% in favor of SR90107a/ORG31540 (95% CI −2.1% to 10.1%). The incidence of bleeding was low and was similar among the groups. Conclusions —The factor Xa inhibitor SR90107a/ORG31540 appears to be an effective and safe treatment for patients with deep vein thrombosis across a wide range of doses. This synthetic compound merits evaluation in phase III studies.
The optimal osmotic agent to treat intracranial hypertension in patients with severe traumatic brain injury (TBI) remains uncertain. We aimed to test whether the choice of mannitol or hypertonic ...saline (HTS) as early (first 96 h) osmotherapy in these patients might be associated with a difference in mortality. We retrospectively analyzed data from 2015 from 14 tertiary intensive care units (ICUs) in Australia, UK, and Europe treating severe TBI patients with intracranial pressure (ICP) monitoring and compared mortality in those who received mannitol only versus HTS only. We performed multi-variable analysis adjusting for site and illness severity (Injury Severity Score, extended IMPACT score, and mean ICP over the first 96 h) using Cox proportional hazards regression. We collected data on 262 patients and compared patients who received early osmotherapy with mannitol alone (
= 46) with those who received HTS alone (
= 46). Mannitol patients were older (median age, 49.2 (19.2) vs. 40.5 (16.8) years;
= 0.02), with higher Injury Severity Scores (42 (15.9) vs. 32.1 11.3;
= 0.001), and IMPACT-TBI predicted 6-month mortality (34.5% 23-46 vs. 25% 13-38;
= 0.02), but had similar APACHE-II scores, and mean and maximum ICPs over the first 96 h. The unadjusted hazard ratio for in-hospital mortality in patients receiving only mannitol was 3.35 (95% confidence interval CI, 1.60-7.03;
= 0.001). After adjustment for key mortality predictors, the hazard ratio for in-hospital mortality in patients receiving only mannitol was 2.64 (95% CI, 0.96-7.30;
= 0.06). The choice of early osmotherapy in severe TBI patients may affect survival, or simply reflect clinician beliefs about their different roles, and warrants controlled investigation.
Delirium is frequently unrecognised. EEG shows slower frequencies (i.e. below 4 Hz) during delirium, which might be useful in improving delirium recognition. We studied the discriminative performance ...of a brief single-channel EEG recording for delirium detection in an independent cohort of patients.
In this prospective, multicentre study, postoperative patients aged ≥60 yr were included (n=159). Before operation and during the first 3 postoperative days, patients underwent a 5-min EEG recording, followed by a video-recorded standardised cognitive assessment. Two or, in case of disagreement, three delirium experts classified each postoperative day based on the video and chart review. Relative delta power (1–4 Hz) was based on 1-min artifact-free EEG. The diagnostic value of the relative delta power was evaluated by the area under the receiver operating characteristic curve (AUROC), using the expert classification as the gold standard.
Experts classified 84 (23.3%) postoperative days as either delirium or possible delirium, and 276 (76.7%) non-delirium days. The AUROC of the relative EEG delta power was 0.75 95% confidence interval (CI) 0.69–0.82. Exploratory analysis showed that relative power from 1 to 6 Hz had significantly higher AUROC (0.78, 95% CI 0.72–0.84, P=0.014).
Delirium/possible delirium can be detected in older postoperative patients based on a single-channel EEG recording that can be automatically analysed. This objective detection method with a continuous scale instead of a dichotomised outcome is a promising approach for routine detection of delirium.
NCT02404181.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Background
The role of haloperidol as treatment for ICU delirium and related symptoms remains controversial despite two recent large controlled trials evaluating its efficacy and safety. We ...sought to determine whether haloperidol when compared to placebo in critically ill adults with delirium reduces days with delirium and coma and improves delirium-related sequelae.
Methods
This multi-center double-blind, placebo-controlled randomized trial at eight mixed medical-surgical Dutch ICUs included critically ill adults with delirium (Intensive Care Delirium Screening Checklist ≥ 4 or a positive Confusion Assessment Method for the ICU) admitted between February 2018 and January 2020. Patients were randomized to intravenous haloperidol 2.5 mg or placebo every 8 h, titrated up to 5 mg every 8 h if delirium persisted until ICU discharge or up to 14 days. The primary outcome was ICU delirium- and coma-free days (DCFDs) within 14 days after randomization. Predefined secondary outcomes included the protocolized use of sedatives for agitation and related behaviors, patient-initiated extubation and invasive device removal, adverse drug associated events, mechanical ventilation, ICU length of stay, 28-day mortality, and long-term outcomes up to 1-year after randomization.
Results
The trial was terminated prematurely for primary endpoint futility on DSMB advice after enrolment of 132 (65 haloperidol; 67 placebo) patients mean age 64 (15) years, APACHE IV score 73.1 (33.9), male 68%. Haloperidol did not increase DCFDs (adjusted RR 0.98 95% CI 0.73–1.31,
p
= 0.87). Patients treated with haloperidol (vs. placebo) were less likely to receive benzodiazepines (adjusted OR 0.41 95% CI 0.18–0.89,
p
= 0.02). Effect measures of other secondary outcomes related to agitation (use of open label haloperidol OR 0.43 (95% CI 0.12–1.56) and other antipsychotics OR 0.63 (95% CI 0.29–1.32), self-extubation or invasive device removal OR 0.70 (95% CI 0.22–2.18)) appeared consistently more favorable with haloperidol, but the confidence interval also included harm. Adverse drug events were not different. Long-term secondary outcomes (e.g., ICU recall and quality of life) warrant further study.
Conclusions
Haloperidol does not reduce delirium in critically ill delirious adults. However, it may reduce rescue medication requirements and agitation-related events in delirious ICU patients warranting further evaluation.
Trial registration
: ClinicalTrials.gov (#NCT03628391), October 9, 2017.
IntroductionTo achieve an expert performance of care teams, adequate simulation-based team training courses with an effective instructional design are essential. As the importance of the ...instructional design becomes ever more clear, an objective assessment tool would be valuable for educators and researchers. Therefore, we aimed to develop an evidence-based and objective assessment tool for the evaluation of the instructional design of simulation-based team training courses.MethodsA validation study in which we developed an assessment tool containing an evidence-based questionnaire with Visual Analogue Scale (VAS) and a visual chart directly translating the results of the questionnaire. Psychometric properties of the assessment tool were tested using five descriptions of simulation-based team training courses. An expert-opinion-based ranking from poor to excellent was obtained. Ten independent raters assessed the five training courses twice, by using the developed questionnaire with an interval of 2 weeks. Validity and reliability analyses were performed by using the scores from the raters and comparing them with the expert’s ranking. Usability was assessed by an 11-item survey.ResultsA 42-item questionnaire, using VAS, and a propeller chart were developed. The correlation between the expert-opinion-based ranking and the evaluators’ scores (Spearman correlation) was 0.95, and the variance due to subjectivity of raters was 3.5% (VTraining*Rater). The G-coefficient was 0.96. The inter-rater reliability (intraclass correlation coefficient (ICC)) was 0.91 (95% CI 0.77 to 0.99), and intra-rater reliability for the overall score (ICC) was ranging from 0.91 to 0.99.ConclusionsWe developed an evidence-based and reliable assessment tool for the evaluation of the instructional design of a simulation-based team training: the ID-SIM. The ID-SIM is available as a free mobile application.
We aimed to develop a set of quality indicators for patients with traumatic brain injury (TBI) in intensive care units (ICUs) across Europe and to explore barriers and facilitators for implementation ...of these quality indicators.
A preliminary list of 66 quality indicators was developed, based on current guidelines, existing practice variation, and clinical expertise in TBI management at the ICU. Eight TBI experts of the Advisory Committee preselected the quality indicators during a first Delphi round. A larger Europe-wide expert panel was recruited for the next two Delphi rounds. Quality indicator definitions were evaluated on four criteria: validity (better performance on the indicator reflects better processes of care and leads to better patient outcome), feasibility (data are available or easy to obtain), discriminability (variability in clinical practice), and actionability (professionals can act based on the indicator). Experts scored indicators on a 5-point Likert scale delivered by an electronic survey tool.
The expert panel consisted of 50 experts from 18 countries across Europe, mostly intensivists (N = 24, 48%) and neurosurgeons (N = 7, 14%). Experts agreed on a final set of 42 indicators to assess quality of ICU care: 17 structure indicators, 16 process indicators, and 9 outcome indicators. Experts are motivated to implement this finally proposed set (N = 49, 98%) and indicated routine measurement in registries (N = 41, 82%), benchmarking (N = 42, 84%), and quality improvement programs (N = 41, 82%) as future steps. Administrative burden was indicated as the most important barrier for implementation of the indicator set (N = 48, 98%).
This Delphi consensus study gives insight in which quality indicators have the potential to improve quality of TBI care at European ICUs. The proposed quality indicator set is recommended to be used across Europe for registry purposes to gain insight in current ICU practices and outcomes of patients with TBI. This indicator set may become an important tool to support benchmarking and quality improvement programs for patients with TBI in the future.
IntroductionDelirium in critically ill adults is associated with prolonged hospital stay, increased mortality and greater cognitive and functional decline. Current practice guideline recommendations ...advocate the use of non-pharmacological strategies to reduce delirium. The routine use of scheduled haloperidol to treat delirium is not recommended given a lack of evidence regarding its ability to resolve delirium nor improve relevant short-term and longer-term outcomes. This study aims to evaluate the efficacy and safety of haloperidol for the treatment of delirium in adult critically ill patients to reduce days spent with coma or delirium.Methods and analysisEuRIDICE is a prospective, multi-centre, randomised, double-blind, placebo-controlled trial. Study population consists of adult intensive care unit (ICU) patients without acute neurological injury who have delirium based on a positive Intensive Care Delirium Screening Checklist (ICDSC) or Confusion Assessment Method for the ICU (CAM-ICU) assessment. Intervention is intravenous haloperidol 2.5 mg (or matching placebo) every 8 hours, titrated daily based on ICDSC or CAM-ICU positivity to a maximum of 5 mg every 8 hours, until delirium resolution or ICU discharge. Main study endpoint is delirium and coma-free days (DCFD) up to 14 days after randomisation. Secondary endpoints include (1) 28-day and 1-year mortality, (2) cognitive and functional performance at 3 and 12 months, (3) patient and family delirium and ICU experience, (4) psychological sequelae during and after ICU stay, (4) safety concerns associated with haloperidol use and (5) cost-effectiveness. Differences in DCFDs between haloperidol and placebo group will be analysed using Poisson regression analysis. Study recruitment started in February 2018 and continues.Ethics and disseminationThe study has been approved by the Medical Ethics Committee of the Erasmus University Medical Centre Rotterdam (MEC2017-511) and by the Institutional Review Boards of the participating sites. Its results will be disseminated via peer-reviewed publication and conference presentations.Trial registrationNCT03628391
To study variation in, and clinical impact of high Therapy Intensity Level (TIL) treatments for elevated intracranial pressure (ICP) in patients with traumatic brain injury (TBI) across European ...Intensive Care Units (ICUs).
We studied high TIL treatments (metabolic suppression, hypothermia (< 35 °C), intensive hyperventilation (PaCO
< 4 kPa), and secondary decompressive craniectomy) in patients receiving ICP monitoring in the ICU stratum of the CENTER-TBI study. A random effect logistic regression model was used to determine between-centre variation in their use. A propensity score-matched model was used to study the impact on outcome (6-months Glasgow Outcome Score-extended (GOSE)), whilst adjusting for case-mix severity, signs of brain herniation on imaging, and ICP.
313 of 758 patients from 52 European centres (41%) received at least one high TIL treatment with significant variation between centres (median odds ratio = 2.26). Patients often transiently received high TIL therapies without escalation from lower tier treatments. 38% of patients with high TIL treatment had favourable outcomes (GOSE ≥ 5). The use of high TIL treatment was not significantly associated with worse outcome (285 matched pairs, OR 1.4, 95% CI 1.0-2.0). However, a sensitivity analysis excluding high TIL treatments at day 1 or use of metabolic suppression at any day did reveal a statistically significant association with worse outcome.
Substantial between-centre variation in use of high TIL treatments for TBI was found and treatment escalation to higher TIL treatments were often not preceded by more conventional lower TIL treatments. The significant association between high TIL treatments after day 1 and worse outcomes may reflect aggressive use or unmeasured confounders or inappropriate escalation strategies.
Substantial variation was found in the use of highly intensive ICP-lowering treatments across European ICUs and a stepwise escalation strategy from lower to higher intensity level therapy is often lacking. Further research is necessary to study the impact of high therapy intensity treatments.
The core study was registered with ClinicalTrials.gov, number NCT02210221, registered 08/06/2014, https://clinicaltrials.gov/ct2/show/NCT02210221?id=NCT02210221&draw=1&rank=1 and with Resource Identification Portal (RRID: SCR_015582).
IntroductionThe use of different methods for introducing the scenario in simulation-based medical education has not been investigated before and may be a useful element to optimise the effectiveness ...of learning. The aim of this study was to compare an immersive video-assisted introduction to a minimal text-based one, with regard to emotional assessment of the situation.MethodsIn this pilot study, 39 students participated in a medical simulated scenario. The students were randomly assigned to an experimental group (video-assisted introduction) or a control group (minimal textual introduction) and both were followed by performing surgery on LapSim (Surgical Science, Gothenburg, Sweden). The emotional assessment of the situation, cognitive appraisal, was defined as the ratio of the demands placed by an individual’s environment (primary appraisal) to that person’s resources to meet the demands (secondary appraisal). Secondary outcomes were anxiety (State-Trait Anxiety Inventory), physiological parameters (heart rate, heart rate variability, skin conductance, salivary cortisol), engagement (Game Engagement Questionnaire), motivation (Intrinsic Motivation Inventory) and performance (mean score in percentage calculated by LapSim of predefined levels).ResultsParticipants in the immersive video group (n=17) were overloaded in terms of their perceived demands (a ratio of 1.17, IQR 0.30) compared with those in the control group (a ratio of 1.00, IQR 0.42, n=22) (P=0.01). No significant differences were found between the groups in secondary outcomes. Both groups showed an increase of anxiety after the introduction method. In the experimental group, this score increased from 9.0 to 11.0, and in the textual group from 7.5 to 10.5, both P<0.01.DiscussionThis study shows that the method of introducing a simulated scenario may influence the emotional assessment of the situation. It may be possible to make your simulation introduction too immersive or stimulating, which may interfere with learning. Further research will be necessary to investigate the impact and usefulness of these findings on learning in simulation-based medical education.
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