Association of age with death and withdrawal of life-sustaining therapy after severe traumatic brain injury.

BACKGROUND: Compared to younger age, older age (≥ 65 yr) is associated with worse outcomes after severe traumatic brain injury (TBI). We sought to describe the association of older age with in-hospital death and aggressiveness of intervention. METHODS: We conducted a retrospective cohort study of adult (age ≥ 16 yr) patients with severe TBI admitted to a single academic tertiary care neurotrauma centre between January 2014 and December 2015. We collected data through chart review as well as from our institutional administrative database. We provided descriptive statistics and used multivariable logistic regression to evaluate the independent association of age with the primary outcome, in-hospital death. The secondary outcome was early withdrawal of life-sustaining therapy. RESULTS: There were 126 adult patients (median age 67 yr [Q1-Q3, 33-80 yr]) with severe TBI during the study period who met our eligibility criteria. The most common mechanism was high-velocity blunt injury (55 patients [43.6%]). The median Marshall score was 4 (Q1-Q3, 2-6), and the median Injury Severity Score was 26 (Q1-Q3, 25-35). After controlling for confounders including clinical frailty, pre-existing comorbidity, injury severity, Marshall score and neurologic examination at admission, we observed that older patients were more likely than younger patients to die in hospital (odds ratio 5.10, 95% confidence interval 1.65-15.78). Older patients were also more likely to experience early withdrawal of life-sustaining therapy and less likely to receive invasive interventions. CONCLUSION: After controlling for confounding factors relevant to older patients, we observed that age was an important and independent predictor of in-hospital death and early withdrawal of life-sustaining therapy. The mechanism by which age influences clinical decision-making independent of global and neurologic injury severity, clinical frailty and comorbidities remains unclear.

Tspan18 is a novel regulator of the Ca2+ channel Orai1 and von Willebrand factor release in endothelial cells.

Ca2+ entry via Orai1 store-operated Ca2+ channels in the plasma membrane is critical to cell function, and Orai1 loss causes severe immunodeficiency and developmental defects. The tetraspanins are a superfamily of transmembrane proteins that interact with specific 'partner proteins' and regulate their trafficking and clustering. The aim of this study was to functionally characterize tetraspanin Tspan18. We show that Tspan18 is expressed by endothelial cells at several-fold higher levels than most other cell types analyzed. Tspan18-knockdown primary human umbilical vein endothelial cells have 55-70% decreased Ca2+ mobilization upon stimulation with the inflammatory mediators thrombin or histamine, similar to Orai1-knockdown. Tspan18 interacts with Orai1, and Orai1 cell surface localization is reduced by 70% in Tspan18-knockdown endothelial cells. Tspan18 overexpression in lymphocyte model cell lines induces 20-fold activation of Ca2+ -responsive nuclear factor of activated T cell (NFAT) signaling, in an Orai1-dependent manner. Tspan18-knockout mice are viable. They lose on average 6-fold more blood in a tail-bleed assay. This is due to Tspan18 deficiency in non-hematopoietic cells, as assessed using chimeric mice. Tspan18-knockout mice have 60% reduced thrombus size in a deep vein thrombosis model, and 50% reduced platelet deposition in the microcirculation following myocardial ischemia-reperfusion injury. Histamine- or thrombin-induced von Willebrand factor release from endothelial cells is reduced by 90% following Tspan18-knockdown, and histamine-induced increase of plasma von Willebrand factor is reduced by 45% in Tspan18-knockout mice. These findings identify Tspan18 as a novel regulator of endothelial cell Orai1/Ca2+ signaling and von Willebrand factor release in response to inflammatory stimuli.

Validation of the Critical Care Pain Observation Tool in Critically Ill Patients With Delirium: A Prospective Cohort Study.

OBJECTIVES: The 2013 clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the ICU suggest that pain be routinely assessed using a validated pain assessment tool. Currently available tools have only been evaluated in nondelirious critically ill patients, yet delirium can affect as many as 80% of ICU patients. The validated pain assessment tool adopted by our institution is the Critical Care Pain Observation Tool, and the objective of this study was to investigate the validity of this tool in patients with evidence of delirium. DESIGN: Prospective cohort study. SETTING: Two ICUs within a Canadian tertiary healthcare center. PATIENTS: Forty consecutive adult patients deemed delirious on the day of enrollment using the Confusion Assessment Method for ICU. MEASUREMENTS AND MAIN RESULTS: Serial Critical Care Pain Observation Tool assessments were conducted simultaneously by study personnel and objective nurses at baseline and after nonpainful and painful stimuli. Subjective opinions about pain and objective physical variables (including mean arterial pressure, heart rate, respiratory rate, and oxygen saturation) were collected at the same time points. Discriminant validity was described using paired t tests, whereas internal consistency was described using the Cronbach α statistic. Responsiveness of the Critical Care Pain Observation Tool was measured by effect size, and reliability was described as the agreement between raters. Comparisons between the Critical Care Pain Observation Tool and the subjective assessments and objective measurements were based on positive and negative percent agreement. Critical Care Pain Observation Tool demonstrated excellent discriminant validity as evidenced by a highly statistically and clinically significant change in mean Critical Care Pain Observation Tool scores between baseline and painful procedures (mean difference, 3.13 ± 1.56; p < 0.001; Cohen D, 2.0). Interrater agreement was also excellent (κ > 0.6), and scores between raters were highly correlated (r = 0.957). The Critical Care Pain Observation Tool possessed a high level of internal consistency (overall Cronbach α, 0.778). Percent agreement was found to be greater between the Critical Care Pain Observation Tool and the nurse's subjective opinion of the presence or absence of pain when compared with that between the Critical Care Pain Observation Tool and physiologic variables (80.5% vs 67.5%, respectively). CONCLUSIONS: The Critical Care Pain Observation Tool is a valid pain assessment tool in noncomatose, delirious adult ICU patients who are unable to reliably self-report the presence or absence of pain.

Systematic review of physical and chemical compatibility of commonly used medications administered by continuous infusion in intensive care units.

OBJECTIVE: To quantify the physical and chemical stability data published for commonly used continuously infused medications in the intensive care unit and to evaluate the quality of the studies providing these data. DATA SOURCES AND STUDY SELECTION: We conducted a systematic electronic literature search of MEDLINE, EMBASE, and International Pharmaceutical Abstracts as well as the references of electronic drug compatibility textbooks for all English and French language research publications evaluating the physical compatibility or chemical stability of the 820 possible two-drug combinations of 41 commonly used drugs in an adult intensive care unit. DATA EXTRACTION AND SYNTHESIS: A total of 93 studies comprised of 86 (92%) studies evaluating physical compatibility and 35 (38%) studies evaluating chemical compatibility of at least one drug combination of interest were included. Physical and/or chemical compatibility data exist for only 441 of the possible 820 two-drug combinations (54%), whereas chemical compatibility data exist for only 75 (9%) of the possible combinations. Of the 441 combinations for which compatibility data are available, 67 (15%) represent incompatible combinations and 39 (9%) had conflicting data in which both compatible and incompatible data were identified. CONCLUSIONS: Physical compatibility studies that provide the basis for y-site compatibility are lacking for commonly used medications in intensive care unit patients and may contribute to unsafe medication practices. Furthermore, the heterogeneity in the methodology of these studies likely contributes to the common finding of conflicting data for specific combinations of drugs. Future studies should apply similar methodologic and reporting principles to be able to reproduce and compare outcomes both clinically and in the laboratory.