Personalized decision-making for aneurysm treatment of aneurysmal subarachnoid hemorrhage: development and validation of a clinical prediction tool.

BACKGROUND: In patients with aneurysmal subarachnoid hemorrhage suitable for endovascular coiling and neurosurgical clip-reconstruction, the aneurysm treatment decision-making process could be improved by considering heterogeneity of treatment effect and durability of treatment. We aimed to develop and validate a tool to predict individualized treatment benefit of endovascular coiling compared to neurosurgical clip-reconstruction. METHODS: We used randomized data (International Subarachnoid Aneurysm Trial, n = 2143) to develop models to predict 2-month functional outcome and to predict time-to-rebleed-or-retreatment. We modeled for heterogeneity of treatment effect by adding interaction terms of treatment with prespecified predictors and with baseline risk of the outcome. We predicted outcome with both treatments and calculated absolute treatment benefit. We described the patient characteristics of patients with ≥ 5% point difference in the predicted probability of favorable functional outcome (modified Rankin Score 0-2) and of no rebleed or retreatment within 10 years. Model performance was expressed with the c-statistic and calibration plots. We performed bootstrapping and leave-one-cluster-out cross-validation and pooled cluster-specific c-statistics with random effects meta-analysis. RESULTS: The pooled c-statistics were 0.72 (95% CI: 0.69-0.75) for the prediction of 2-month favorable functional outcome and 0.67 (95% CI: 0.63-0.71) for prediction of no rebleed or retreatment within 10 years. We found no significant interaction between predictors and treatment. The average predicted benefit in favorable functional outcome was 6% (95% CI: 3-10%) in favor of coiling, but 11% (95% CI: 9-13%) for no rebleed or retreatment in favor of clip-reconstruction. 134 patients (6%), young and in favorable clinical condition, had negligible functional outcome benefit of coiling but had a ≥ 5% point benefit of clip-reconstruction in terms of durability of treatment. CONCLUSIONS: We show that young patients in favorable clinical condition and without extensive vasospasm have a negligible benefit in functional outcome of endovascular coiling - compared to neurosurgical clip-reconstruction - while at the same time having a substantially lower probability of retreatment or rebleeding from neurosurgical clip-reconstruction - compared to endovascular coiling. The SHARP prediction tool ( https://sharpmodels.shinyapps.io/sharpmodels/ ) could support and incentivize a multidisciplinary discussion about aneurysm treatment decision-making by providing individualized treatment benefit estimates.

Targeted temperature control following traumatic brain injury: ESICM/NACCS best practice consensus recommendations.

AIMS AND SCOPE: The aim of this panel was to develop consensus recommendations on targeted temperature control (TTC) in patients with severe traumatic brain injury (TBI) and in patients with moderate TBI who deteriorate and require admission to the intensive care unit for intracranial pressure (ICP) management. METHODS: A group of 18 international neuro-intensive care experts in the acute management of TBI participated in a modified Delphi process. An online anonymised survey based on a systematic literature review was completed ahead of the meeting, before the group convened to explore the level of consensus on TTC following TBI. Outputs from the meeting were combined into a further anonymous online survey round to finalise recommendations. Thresholds of ≥ 16 out of 18 panel members in agreement (≥ 88%) for strong consensus and ≥ 14 out of 18 (≥ 78%) for moderate consensus were prospectively set for all statements. RESULTS: Strong consensus was reached on TTC being essential for high-quality TBI care. It was recommended that temperature should be monitored continuously, and that fever should be promptly identified and managed in patients perceived to be at risk of secondary brain injury. Controlled normothermia (36.0-37.5 °C) was strongly recommended as a therapeutic option to be considered in tier 1 and 2 of the Seattle International Severe Traumatic Brain Injury Consensus Conference ICP management protocol. Temperature control targets should be individualised based on the perceived risk of secondary brain injury and fever aetiology. CONCLUSIONS: Based on a modified Delphi expert consensus process, this report aims to inform on best practices for TTC delivery for patients following TBI, and to highlight areas of need for further research to improve clinical guidelines in this setting.

Haloperidol for the treatment of delirium in critically ill patients: an updated systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Haloperidol is frequently used in critically ill patients with delirium, but evidence for its effects has been sparse and inconclusive. By including recent trials, we updated a systematic review assessing effects of haloperidol on mortality and serious adverse events in critically ill patients with delirium. METHODS: This is an updated systematic review with meta-analysis and trial sequential analysis of randomised clinical trials investigating haloperidol versus placebo or any comparator in critically ill patients with delirium. We adhered to the Cochrane handbook, the PRISMA guidelines and the grading of recommendations assessment, development and evaluation statements. The primary outcomes were all-cause mortality and proportion of patients with one or more serious adverse events or reactions (SAEs/SARs). Secondary outcomes were days alive without delirium or coma, delirium severity, cognitive function and health-related quality of life. RESULTS: We included 11 RCTs with 15 comparisons (n = 2200); five were placebo-controlled. The relative risk for mortality with haloperidol versus placebo was 0.89; 96.7% CI 0.77 to 1.03; I2 = 0% (moderate-certainty evidence) and for proportion of patients experiencing SAEs/SARs 0.94; 96.7% CI 0.81 to 1.10; I2 = 18% (low-certainty evidence). We found no difference in days alive without delirium or coma (moderate-certainty evidence). We found sparse data for other secondary outcomes and other comparators than placebo. CONCLUSIONS: Haloperidol may reduce mortality and likely result in little to no change in the occurrence of SAEs/SARs compared with placebo in critically ill patients with delirium. However, the results were not statistically significant and more trial data are needed to provide higher certainty for the effects of haloperidol in these patients. TRIAL REGISTRATION: CRD42017081133, date of registration 28 November 2017.

Efficacy of haloperidol to decrease the burden of delirium in adult critically ill patients: the EuRIDICE randomized clinical trial.

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.

Early predictors of functional outcome in poor-grade aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis.

BACKGROUND: Patients with poor-grade aneurysmal subarachnoid hemorrhage (aSAH) often receive delayed or no aneurysm treatment, although recent studies suggest that functional outcome following early aneurysm treatment has improved. We aimed to systematically review and meta-analyze early predictors of functional outcome in poor-grade aSAH patients.  METHODS: We included studies investigating the association of early predictors and functional outcome in adult patients with confirmed poor-grade aSAH, defined as World Federation of Neurological Surgeons (WFNS) grade or Hunt and Hess (H-H) grade IV-V. Studies had to use multivariable regression analysis to estimate independent predictor effects of favorable functional outcome measured with the Glasgow Outcome Scale or modified Rankin Scale. We calculated pooled adjusted odds ratios (aOR) and 95% confidence intervals (CI) with random effects models.  RESULTS: We included 27 studies with 3287 patients. The likelihood of favorable outcome increased with WFNS grade or H-H grade IV versus V (aOR 2.9, 95% CI 1.9-4.3), presence of clinical improvement before aneurysm treatment (aOR 3.3, 95% CI 2.0-5.3), and intact pupillary light reflex (aOR 2.9, 95% CI 1.6-5.1), and decreased with older age (aOR 0.7, 95% CI 0.5-1.0, per decade), increasing modified Fisher grade (aOR 0.4, 95% CI 0.3-0.5, per grade), and presence of intracerebral hematoma on admission imaging (aOR 0.4, 95% CI 0.2-0.8). CONCLUSIONS: We present a summary of early predictors of functional outcome in poor-grade aSAH patients that can help to discriminate between patients with favorable and with unfavorable prognosis and may aid in selecting patients for early aneurysm treatment.

Delirium in older COVID-19 patients: Evaluating risk factors and outcomes.

OBJECTIVES: A high incidence of delirium has been reported in older patients with Coronavirus disease 2019 (COVID-19). We aimed to identify determinants of delirium, including the Clinical Frailty Scale, in hospitalized older patients with COVID-19. Furthermore, we aimed to study the association of delirium independent of frailty with in-hospital outcomes in older COVID-19 patients. METHODS: This study was performed within the framework of the multi-center COVID-OLD cohort study and included patients aged ≥60 years who were admitted to the general ward because of COVID-19 in the Netherlands between February and May 2020. Data were collected on demographics, co-morbidity, disease severity, and geriatric parameters. Prevalence of delirium during hospital admission was recorded based on delirium screening using the Delirium Observation Screening Scale (DOSS) which was scored three times daily. A DOSS score ≥3 was followed by a delirium assessment by the ward physician In-hospital outcomes included length of stay, discharge destination, and mortality. RESULTS: A total of 412 patients were included (median age 76, 58% male). Delirium was present in 82 patients. In multivariable analysis, previous episode of delirium (Odds ratio [OR] 8.9 [95% CI 2.3-33.6] p = 0.001), and pre-existent memory problems (OR 7.6 [95% CI 3.1-22.5] p < 0.001) were associated with increased delirium risk. Clinical Frailty Scale was associated with increased delirium risk (OR 1.63 [95%CI 1.40-1.90] p < 0.001) in univariable analysis, but not in multivariable analysis. Patients who developed delirium had a shorter symptom duration and lower levels of C-reactive protein upon presentation, whereas vital parameters did not differ. Patients who developed a delirium had a longer hospital stay and were more often discharged to a nursing home. Delirium was associated with mortality (OR 2.84 [95% CI1.71-4.72] p < 0.001), but not in multivariable analyses. CONCLUSIONS: A previous delirium and pre-existent memory problems were associated with delirium risk in COVID-19. Delirium was not an independent predictor of mortality after adjustment for frailty.

Comparative effectiveness of intracranial hypertension management guided by ventricular versus intraparenchymal pressure monitoring: a CENTER-TBI study.

OBJECTIVE: To compare outcomes between patients with primary external ventricular device (EVD)-driven treatment of intracranial hypertension and those with primary intraparenchymal monitor (IP)-driven treatment. METHODS: The CENTER-TBI study is a prospective, multicenter, longitudinal observational cohort study that enrolled patients of all TBI severities from 62 participating centers (mainly level I trauma centers) across Europe between 2015 and 2017. Functional outcome was assessed at 6 months and a year. We used multivariable adjusted instrumental variable (IV) analysis with "center" as instrument and logistic regression with covariate adjustment to determine the effect estimate of EVD on 6-month functional outcome. RESULTS: A total of 878 patients of all TBI severities with an indication for intracranial pressure (ICP) monitoring were included in the present study, of whom 739 (84%) patients had an IP monitor and 139 (16%) an EVD. Patients included were predominantly male (74% in the IP monitor and 76% in the EVD group), with a median age of 46 years in the IP group and 48 in the EVD group. Six-month GOS-E was similar between IP and EVD patients (adjusted odds ratio (aOR) and 95% confidence interval [CI] OR 0.74 and 95% CI [0.36-1.52], adjusted IV analysis). The length of intensive care unit stay was greater in the EVD group than in the IP group (adjusted rate ratio [95% CI] 1.70 [1.34-2.12], IV analysis). One hundred eighty-seven of the 739 patients in the IP group (25%) required an EVD due to refractory ICPs. CONCLUSION: We found no major differences in outcomes of patients with TBI when comparing EVD-guided and IP monitor-guided ICP management. In our cohort, a quarter of patients that initially received an IP monitor required an EVD later for ICP control. The prevalence of complications was higher in the EVD group. PROTOCOL: The core study is registered with ClinicalTrials.gov , number NCT02210221, and the Resource Identification Portal (RRID: SCR_015582).

Use and impact of high intensity treatments in patients with traumatic brain injury across Europe: a CENTER-TBI analysis.

PURPOSE: 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). METHODS: We studied high TIL treatments (metabolic suppression, hypothermia (< 35 °C), intensive hyperventilation (PaCO2 < 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. RESULTS: 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. CONCLUSION: 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. TAKE HOME MESSAGE: 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. TRIAL REGISTRATION: 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).

Variability in Serum Sodium Concentration and Prognostic Significance in Severe Traumatic Brain Injury: A Multicenter Observational Study.

BACKGROUND/OBJECTIVE: Dysnatremia is common in severe traumatic brain injury (TBI) patients and may contribute to mortality. However, serum sodium variability has not been studied in TBI patients. We hypothesized that such variability would be independently associated with mortality. METHODS: We collected 6-hourly serum sodium levels for the first 7 days of ICU admission from 240 severe TBI patients in 14 neurotrauma ICUs in Europe and Australia. We evaluated the association between daily serum sodium standard deviation (dNaSD), an index of variability, and 28-day mortality. RESULTS: Patients were 46 ± 19 years of age with a median initial GCS of 6 [4-8]. Overall hospital mortality was 28%. Hypernatremia and hyponatremia occurred in 64% and 24% of patients, respectively. Over the first 7 days in ICU, serum sodium standard deviation was 2.8 [2.0-3.9] mmol/L. Maximum daily serum sodium standard deviation (dNaSD) occurred at a median of 2 [1-4] days after admission. There was a significant progressive decrease in dNaSD over the first 7 days (coefficient - 0.15 95% CI [- 0.18 to - 0.12], p < 0.001). After adjusting for baseline TBI severity, diabetes insipidus, the use of osmotherapy, the occurrence of hypernatremia, and hyponatremia and center, dNaSD was significantly independently associated with 28-day mortality (HR 1.27 95% CI (1.01-1.61), p = 0.048). CONCLUSIONS: Our study demonstrates that daily serum sodium variability is an independent predictor of 28-day mortality in severe TBI patients. Further prospective investigations are necessary to confirm the significance of sodium variability in larger cohorts of TBI patients and test whether attenuating such variability confers outcome benefits to such patients.

Quality indicators for patients with traumatic brain injury in European intensive care units: a CENTER-TBI study.

BACKGROUND: The aim of this study is to validate a previously published consensus-based quality indicator set for the management of patients with traumatic brain injury (TBI) at intensive care units (ICUs) in Europe and to study its potential for quality measurement and improvement. METHODS: Our analysis was based on 2006 adult patients admitted to 54 ICUs between 2014 and 2018, enrolled in the CENTER-TBI study. Indicator scores were calculated as percentage adherence for structure and process indicators and as event rates or median scores for outcome indicators. Feasibility was quantified by the completeness of the variables. Discriminability was determined by the between-centre variation, estimated with a random effect regression model adjusted for case-mix severity and quantified by the median odds ratio (MOR). Statistical uncertainty of outcome indicators was determined by the median number of events per centre, using a cut-off of 10. RESULTS: A total of 26/42 indicators could be calculated from the CENTER-TBI database. Most quality indicators proved feasible to obtain with more than 70% completeness. Sub-optimal adherence was found for most quality indicators, ranging from 26 to 93% and 20 to 99% for structure and process indicators. Significant (p < 0.001) between-centre variation was found in seven process and five outcome indicators with MORs ranging from 1.51 to 4.14. Statistical uncertainty of outcome indicators was generally high; five out of seven had less than 10 events per centre. CONCLUSIONS: Overall, nine structures, five processes, but none of the outcome indicators showed potential for quality improvement purposes for TBI patients in the ICU. Future research should focus on implementation efforts and continuous reevaluation of quality indicators. TRIAL REGISTRATION: The core study was registered with ClinicalTrials.gov, number NCT02210221, registered on August 06, 2014, with Resource Identification Portal (RRID: SCR_015582).

High Early Fluid Input After Aneurysmal Subarachnoid Hemorrhage: Combined Report of Association With Delayed Cerebral Ischemia and Feasibility of Cardiac Output-Guided Fluid Restriction.

BACKGROUND: Guidelines on the management of aneurysmal subarachnoid hemorrhage (aSAH) recommend euvolemia, whereas hypervolemia may cause harm. We investigated whether high early fluid input is associated with delayed cerebral ischemia (DCI), and if fluid input can be safely decreased using transpulmonary thermodilution (TPT). METHODS: We retrospectively included aSAH patients treated at an academic intensive care unit (2007-2011; cohort 1) or managed with TPT (2011-2013; cohort 2). Local guidelines recommended fluid input of 3 L daily. More fluids were administered when daily fluid balance fell below +500 mL. In cohort 2, fluid input in high-risk patients was guided by cardiac output measured by TPT per a strict protocol. Associations of fluid input and balance with DCI were analyzed with multivariable logistic regression (cohort 1), and changes in hemodynamic indices after institution of TPT assessed with linear mixed models (cohort 2). RESULTS: Cumulative fluid input 0 to 72 hours after admission was associated with DCI in cohort 1 (n=223; odds ratio [OR] 1.19/L; 95% confidence interval 1.07-1.32), whereas cumulative fluid balance was not. In cohort 2 (23 patients), using TPT fluid input could be decreased from 6.0 ± 1.0 L before to 3.4 ± 0.3 L; P = .012), while preload parameters and consciousness remained stable. CONCLUSION: High early fluid input was associated with DCI. Invasive hemodynamic monitoring was feasible to reduce fluid input while maintaining preload. These results indicate that fluid loading beyond a normal preload occurs, may increase DCI risk, and can be minimized with TPT.

Influence of sedation on delirium recognition in critically ill patients: A multinational cohort study.

BACKGROUND: Guidelines advocate intensive care unit (ICU) patients be regularly assessed for delirium using either the Confusion Assessment Method for the ICU (CAM-ICU) or the Intensive Care Delirium Screening Checklist (ICDSC). Single-centre studies, primarily with the CAM-ICU, suggest level of sedation may influence delirium screening results. OBJECTIVE: The objective of this study was to determine the association between level of sedation and delirium occurrence in critically ill patients assessed with either the CAM-ICU or the ICDSC. METHODS: This was a secondary analysis of a multinational, prospective cohort study performed in nine ICUs from seven countries. Consecutive ICU patients with a Richmond Agitation-Sedation Scale (RASS) of -3 to 0 at the time of delirium assessment where a RASS ≤ 0 was secondary to a sedating medication. Patients were assessed with either the CAM-ICU or the ICDSC. Logistic regression analysis was used to account for factors with the potential to influence level of sedation or delirium occurrence. RESULTS: Among 1660 patients, 1203 patients underwent 5741 CAM-ICU assessments [9.6% were delirium positive; at RASS = 0 (3.3% were delirium positive), RASS = -1 (19.3%), RASS = -2 (35.1%); RASS = -3 (39.0%)]. The other 457 patients underwent 3210 ICDSC assessments [11.6% delirium positive; at RASS = 0 (4.9% were delirium positive), RASS = -1 (15.8%), RASS = -2 (26.6%); RASS = -3 (20.6%)]. A RASS of -3 was associated with more positive delirium evaluations (odds ratio: 2.31; 95% confidence interval: 1.34-3.98) in the CAM-ICU-assessed patients (vs. the ICDSC-assessed patients). At a RASS of 0, assessment with the CAM-ICU (vs. the ICDSC) was associated with fewer positive delirium evaluations (odds ratio: 0.58; 95% confidence interval: 0.43-0.78). At a RASS of -1 or -2, no association was found between the delirium assessment method used (i.e., CAM-ICU or ICDSC) and a positive delirium evaluation. CONCLUSIONS: The influence of level of sedation on a delirium assessment result depends on whether the CAM-ICU or ICDSC is used. Bedside ICU nurses should consider these results when evaluating their sedated patients for delirium. Future research is necessary to compare the CAM-ICU and the ICDSC simultaneously in sedated and nonsedated ICU patients. TRIAL REGISTRATION: ClinicalTrials.gov; NCT02518646.

Improved Guideline Adherence and Reduced Brain Dysfunction After a Multicenter Multifaceted Implementation of ICU Delirium Guidelines in 3,930 Patients.

OBJECTIVES: Implementation of delirium guidelines at ICUs is suboptimal. The aim was to evaluate the impact of a tailored multifaceted implementation program of ICU delirium guidelines on processes of care and clinical outcomes and draw lessons regarding guideline implementation. DESIGN: A prospective multicenter, pre-post, intervention study. SETTING: ICUs in one university hospital and five community hospitals. PATIENTS: Consecutive medical and surgical critically ill patients were enrolled between April 1, 2012, and February 1, 2015. INTERVENTIONS: Multifaceted, three-phase (baseline, delirium screening, and guideline) implementation program of delirium guidelines in adult ICUs. MEASUREMENTS AND MAIN RESULTS: The primary outcome was adherence changes to delirium guidelines recommendations, based on the Pain, Agitation and Delirium guidelines. Secondary outcomes were brain dysfunction (delirium or coma), length of ICU stay, and hospital mortality. A total of 3,930 patients were included. Improvements after the implementation pertained to delirium screening (from 35% to 96%; p < 0.001), use of benzodiazepines for continuous sedation (from 36% to 17%; p < 0.001), light sedation of ventilated patients (from 55% to 61%; p < 0.001), physiotherapy (from 21% to 48%; p < 0.001), and early mobilization (from 10% to 19%; p < 0.001). Brain dysfunction improved: the mean delirium duration decreased from 5.6 to 3.3 days (-2.2 d; 95% CI, -3.2 to -1.3; p < 0.001), and coma days decreased from 14% to 9% (risk ratio, 0.5; 95% CI, 0.4-0.6; p < 0.001). Other clinical outcome measures, such as length of mechanical ventilation, length of ICU stay, and hospital mortality, did not change. CONCLUSIONS: This large pre-post implementation study of delirium-oriented measures based on the 2013 Pain, Agitation, and Delirium guidelines showed improved health professionals' adherence to delirium guidelines and reduced brain dysfunction. Our findings provide empirical support for the differential efficacy of the guideline bundle elements in a real-life setting and provide lessons for optimization of guideline implementation programs.

External Validation of Two Models to Predict Delirium in Critically Ill Adults Using Either the Confusion Assessment Method-ICU or the Intensive Care Delirium Screening Checklist for Delirium Assessment.

OBJECTIVES: To externally validate two delirium prediction models (early prediction model for ICU delirium and recalibrated prediction model for ICU delirium) using either the Confusion Assessment Method-ICU or the Intensive Care Delirium Screening Checklist for delirium assessment. DESIGN: Prospective, multinational cohort study. SETTING: Eleven ICUs from seven countries in three continents. PATIENTS: Consecutive, delirium-free adults admitted to the ICU for greater than or equal to 6 hours in whom delirium could be reliably assessed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The predictors included in each model were collected at the time of ICU admission (early prediction model for ICU delirium) or within 24 hours of ICU admission (recalibrated prediction model for ICU delirium). Delirium was assessed using the Confusion Assessment Method-ICU or the Intensive Care Delirium Screening Checklist. Discrimination was determined using the area under the receiver operating characteristic curve. The predictive performance was determined for the Confusion Assessment Method-ICU and Intensive Care Delirium Screening Checklist cohort, and compared with both prediction models' original reported performance. A total of 1,286 Confusion Assessment Method-ICU-assessed patients and 892 Intensive Care Delirium Screening Checklist-assessed patients were included. Compared with the area under the receiver operating characteristic curve of 0.75 (95% CI, 0.71-0.79) in the original study, the area under the receiver operating characteristic curve of the early prediction model for ICU delirium was 0.67 (95% CI, 0.64-0.71) for delirium as assessed using the Confusion Assessment Method-ICU and 0.70 (95% CI, 0.66-0.74) using the Intensive Care Delirium Screening Checklist. Compared with the original area under the receiver operating characteristic curve of 0.77 (95% CI, 0.74-0.79), the area under the receiver operating characteristic curve of the recalibrated prediction model for ICU delirium was 0.75 (95% CI, 0.72-0.78) for assessing delirium using the Confusion Assessment Method-ICU and 0.71 (95% CI, 0.67-0.75) using the Intensive Care Delirium Screening Checklist. CONCLUSIONS: Both the early prediction model for ICU delirium and recalibrated prediction model for ICU delirium are externally validated using either the Confusion Assessment Method-ICU or the Intensive Care Delirium Screening Checklist for delirium assessment. Per delirium prediction model, both assessment tools showed a similar moderate-to-good statistical performance. These results support the use of either the early prediction model for ICU delirium or recalibrated prediction model for ICU delirium in ICUs around the world regardless of whether delirium is evaluated with the Confusion Assessment Method-ICU or Intensive Care Delirium Screening Checklist.

Sudden unresponsive patient with normal vital signs: what is going on?

PURPOSE OF REVIEW: To summarize the differential diagnosis and diagnostic approach of sudden unresponsiveness with normal vital signs in various settings, including the ICU. RECENT FINDINGS: Sudden unresponsiveness may be either transient or persistent, and may result from primary brain diseases or nonstructural systemic conditions. Life-threatening causes should always be discriminated from those more benign. Regional epidemiology, for example regarding intoxications, and evolving therapeutic management, for example for ischemic stroke, should always be taken into account for optimal opportunity for rapid diagnosis and best management. SUMMARY: Sudden unresponsiveness with normal vital signs should trigger immediate and focused diagnostic evaluation to find or exclude those conditions requiring urgent, and possibly life-saving, management.

Development of a quality indicator set to measure and improve quality of ICU care for patients with traumatic brain injury.

BACKGROUND: 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. METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.

Common Data Elements for Unruptured Intracranial Aneurysms and Aneurysmal Subarachnoid Hemorrhage: Recommendations from the Working Group on Hospital Course and Acute Therapies-Proposal of a Multidisciplinary Research Group.

INTRODUCTION: The Common Data Elements (CDEs) initiative is a National Institute of Health/National Institute of Neurological Disorders and Stroke (NINDS) effort to standardize naming, definitions, data coding, and data collection for observational studies and clinical trials in major neurological disorders. A working group of experts was established to provide recommendations for Unruptured Aneurysms and Aneurysmal Subarachnoid Hemorrhage (SAH) CDEs. METHODS: This paper summarizes the recommendations of the Hospital Course and Acute Therapies after SAH working group. Consensus recommendations were developed by assessment of previously published CDEs for traumatic brain injury, stroke, and epilepsy. Unruptured aneurysm- and SAH-specific CDEs were also developed. CDEs were categorized into "core", "supplemental-highly recommended", "supplemental" and "exploratory". RESULTS: We identified and developed CDEs for Hospital Course and Acute Therapies after SAH, which included: surgical and procedure interventions; rescue therapy for delayed cerebral ischemia (DCI); neurological complications (i.e. DCI; hydrocephalus; rebleeding; seizures); intensive care unit therapies; prior and concomitant medications; electroencephalography; invasive brain monitoring; medical complications (cardiac dysfunction; pulmonary edema); palliative comfort care and end of life issues; discharge status. The CDEs can be found at the NINDS Web site that provides standardized naming, and definitions for each element, and also case report form templates, based on the CDEs. CONCLUSION: Most of the recommended Hospital Course and Acute Therapies CDEs have been newly developed. Adherence to these recommendations should facilitate data collection and data sharing in SAH research, which could improve the comparison of results across observational studies, clinical trials, and meta-analyses of individual patient data.

Induced Hypertension for Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: A Randomized Clinical Trial.

BACKGROUND AND PURPOSE: Induced hypertension is widely used to treat delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage, but a literature review shows that its presumed effectiveness is based on uncontrolled case-series only. We here report clinical outcome of aneurysmal subarachnoid hemorrhage patients with DCI included in a randomized trial on the effectiveness of induced hypertension. METHODS: Aneurysmal subarachnoid hemorrhage patients with clinical symptoms of DCI were randomized to induced hypertension or no induced hypertension. Risk ratios for poor outcome (modified Rankin Scale score >3) at 3 months, with 95% confidence intervals, were calculated and adjusted for age, clinical condition at admission and at time of DCI, and amount of blood on initial computed tomographic scan with Poisson regression analysis. RESULTS: The trial aiming to include 240 patients was ended, based on lack of effect on cerebral perfusion and slow recruitment, when 21 patients had been randomized to induced hypertension, and 20 patients to no hypertension. With induced hypertension, the adjusted risk ratio for poor outcome was 1.0 (95% confidence interval, 0.6-1.8) and the risk ratio for serious adverse events 2.1 (95% confidence interval, 0.9-5.0). CONCLUSIONS: Before this trial, the effectiveness of induced hypertension for DCI in aneurysmal subarachnoid hemorrhage patients was unknown because current literature consists only of uncontrolled case series. The results from our premature halted trial do not add any evidence to support induced hypertension and show that this treatment can lead to serious adverse events. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01613235.

Brain death and postmortem organ donation: report of a questionnaire from the CENTER-TBI study.

BACKGROUND: We aimed to investigate the extent of the agreement on practices around brain death and postmortem organ donation. METHODS: Investigators from 67 Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study centers completed several questionnaires (response rate: 99%). RESULTS: Regarding practices around brain death, we found agreement on the clinical evaluation (prerequisites and neurological assessment) for brain death determination (BDD) in 100% of the centers. However, ancillary tests were required for BDD in 64% of the centers. BDD for nondonor patients was deemed mandatory in 18% of the centers before withdrawing life-sustaining measures (LSM). Also, practices around postmortem organ donation varied. Organ donation after circulatory arrest was forbidden in 45% of the centers. When withdrawal of LSM was contemplated, in 67% of centers the patients with a ventricular drain in situ had this removed, either sometimes or all of the time. CONCLUSIONS: This study showed both agreement and some regional differences regarding practices around brain death and postmortem organ donation. We hope our results help quantify and understand potential differences, and provide impetus for current dialogs toward further harmonization of practices around brain death and postmortem organ donation.