Association of early dexmedetomidine exposure with brain injury biomarker levels following moderate - Severe traumatic brain injury: A TRACK-TBI study.

BACKGROUND: Traumatic brain injury (TBI) triggers autonomic dysfunction and inflammatory response that can result in secondary brain injuries. Dexmedetomidine is an alpha-2 agonist that may modulate autonomic function and inflammation and has been increasingly used as a sedative agent for critically ill TBI patients. We aimed to investigate the association between early dexmedetomidine exposure and blood-based biomarker levels in moderate-to-severe TBI (msTBI). METHODS: We conducted a retrospective cohort study using data from the Transforming Clinical Research and Knowledge in Traumatic Brain Injury Study (TRACK-TBI), which enrolled acute TBI patients prospectively across 18 United States Level 1 trauma centers between 2014-2018. Our study population focused on adults with msTBI defined by Glasgow Coma Scale score 3-12 after resuscitation, who required mechanical ventilation and sedation within the first 48 h of ICU admission. The study's exposure was early dexmedetomidine utilization (within the first 48 h of admission). Primary outcome included brain injury biomarker levels measured from circulating blood on day 3 following injury, including glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neuron-specific enolase (NSE), S100 calcium-binding protein B (S100B) and the inflammatory biomarker C-reactive protein (CRP). Secondary outcomes assessed biomarker levels on days 5 and 14. Linear mixed-effects regression modelling of the log-transformed response variable was used to analyze the association of early dexmedetomidine exposure with brain injury biomarker levels. RESULTS: Among the 352 TRACK-TBI subjects that met inclusion criteria, 50 (14.2 %) were exposed to early dexmedetomidine, predominantly male (78 %), white (81 %), and non-Hispanic (81 %), with mean age of 39.8 years. Motor vehicle collisions (27 %) and falls (22 %) were common causes of injury. No significant associations were found between early dexmedetomidine exposure with day 3 brain injury biomarker levels (GFAP, ratio = 1.46, 95 % confidence interval [0.90, 2.34], P = 0.12; UCH-L1; ratio = 1.17 [0.89, 1.53], P = 0.26; NSE, ratio = 1.19 [0.92, 1.53], P = 0.19; S100B, ratio = 1.01 [0.95, 1.06], P = 0.82; hs-CRP, ratio = 1.29 [0.91, 1.83], P = 0.15). The hs-CRP level at day 14 in the dexmedetomidine group was higher than that of the non-exposure group (ratio = 1.62 [1.12, 2.35], P = 0.012). CONCLUSIONS: There were no significant associations between early dexmedetomidine exposure and day 3 brain injury biomarkers in msTBI. Our findings suggest that early dexmedetomidine use is not correlated with either decrease or increase in brain injury biomarkers following msTBI. Further research is necessary to confirm these findings.

Early Beta-Blocker Utilization in Critically Ill Patients With Moderate-Severe Traumatic Brain Injury: A Retrospective Cohort Study.

BACKGROUND: There is limited evidence that beta-blockers may provide benefit for patients with moderate-severe traumatic brain injury (TBI) during the acute injury period. Larger studies on utilization patterns and impact on outcomes in clinical practice are lacking. OBJECTIVE: The present study uses a large, national hospital claims-based dataset to examine early beta-blocker utilization patterns and its association with clinical outcomes among critically ill patients with moderate-severe TBI. METHODS: We conducted a retrospective cohort study of the administrative claims Premier Healthcare Database of adults (≥17 years) with moderate-severe TBI admitted to the intensive care unit (ICU) from 2016 to 2020. The exposure was receipt of a beta-blocker during day 1 or 2 of ICU stay (BB+). The primary outcome was hospital mortality, and secondary outcomes were: hospital length of stay (LOS), ICU LOS, discharge to home, and vasopressor utilization. In a sensitivity analysis, we explored the association of beta-blocker class (cardioselective and noncardioselective) with hospital mortality. We used propensity weighting methods to address possible confounding by treatment indication. RESULTS: A total of 109 665 participants met inclusion criteria and 39% (n = 42 489) were exposed to beta-blockers during the first 2 days of hospitalization. Of those, 42% received cardioselective only, 43% received noncardioselective only, and 14% received both. After adjustment, there was no association with hospital mortality in the BB+ group compared to the BB- group (adjusted odds ratio [OR] = 0.99, 95% confidence interval [CI] = 0.94, 1.04). The BB+ group had longer hospital stays, lower chance of discharged home, and lower risk of vasopressor utilization, although these difference were clinically small. Beta-blocker class was not associated with hospital mortality. CONCLUSION: In this retrospective cohort study, we found variation in use of beta-blockers and early exposure was not associated with hospital mortality. Further research is necessary to understand the optimal type, dose, and timing of beta-blockers for this population.

Association of Early Dexmedetomidine Utilization With Clinical Outcomes After Moderate-Severe Traumatic Brain Injury: A Retrospective Cohort Study.

BACKGROUND: Traumatic brain injury (TBI) is an expensive and common public health problem. Management of TBI oftentimes includes sedation to facilitate mechanical ventilation (MV) for airway protection. Dexmedetomidine has emerged as a potential candidate for improved patient outcomes when used for early sedation after TBI due to its potential modulation of autonomic dysfunction. We examined early sedation patterns, as well as the association of dexmedetomidine exposure with clinical and functional outcomes among mechanically ventilated patients with moderate-severe TBI (msTBI) in the United States. METHODS: We conducted a retrospective cohort study using data from the Premier dataset and identified a cohort of critically ill adult patients with msTBI who required MV from January 2016 to June 2020. msTBI was defined by head-neck abbreviated injury scale (AIS) values of 3 (serious), 4 (severe), and 5 (critical). We described early continuous sedative utilization patterns. Using propensity-matched models, we examined the association of early dexmedetomidine exposure (within 2 days of intensive care unit [ICU] admission) with the primary outcome of hospital mortality and the following secondary outcomes: hospital length of stay (LOS), days on MV, vasopressor use after the first 2 days of admission, hemodialysis (HD) after the first 2 days of admission, hospital costs, and discharge disposition. All medications, treatments, and procedures were identified using date-stamped hospital charge codes. RESULTS: The study population included 19,751 subjects who required MV within 2 days of ICU admission. The patients were majority male and white. From 2016 to 2020, the annual percent utilization of dexmedetomidine increased from 4.05% to 8.60%. After propensity score matching, early dexmedetomidine exposure was associated with reduced odds of hospital mortality (odds ratio [OR], 0.59; 95% confidence interval [CI], 0.47-0.74; P < .0001), increased risk for liberation from MV (hazard ratio [HR], 1.20; 95% CI, 1.09-1.33; P = .0003), and reduced LOS (HR, 1.11; 95% CI, 1.01-1.22; P = .033). Exposure to early dexmedetomidine was not associated with odds of HD (OR, 1.14; 95% CI, 0.73-1.78; P = .56), vasopressor utilization (OR, 1.10; 95% CI, 0.78-1.55; P = .60), or increased hospital costs (relative cost ratio, 1.98; 95% CI, 0.93-1.03; P = .66). CONCLUSIONS: Dexmedetomidine is being utilized increasingly as a sedative for mechanically ventilated patients with msTBI. Early dexmedetomidine exposure may lead to improved patient outcomes in this population.

Safety, Efficacy, and Clinical Outcomes of Dexmedetomidine for Sedation in Traumatic Brain Injury: A Scoping Review.

Dexmedetomidine is a promising alternative sedative agent for moderate-severe Traumatic brain injury (TBI) patients. Although the data are limited, the posited benefits of dexmedetomidine in this population are a reduction in secondary brain injury compared with current standard sedative regimens. In this scoping review, we critically appraised the literature to examine the effects of dexmedetomidine in patients with moderate-severe TBI to examine the safety, efficacy, and cerebral and systemic physiological outcomes within this population. We sought to identify gaps in the literature and generate directions for future research. Two researchers and a librarian queried PubMed, Embase, Scopus, and APA PsycINFO databases. Of 920 studies imported for screening, 11 were identified for inclusion in the review. The primary outcomes in the included studied were cerebral physiology, systemic hemodynamics, sedation levels and delirium, and the presence of paroxysmal sympathetic hyperactivity. Dexmedetomidine dosing ranged from 0.2 to 1 ug/kg/h, with 3 studies using initial boluses of 0.8 to 1.0 ug/kg over 10 minutes. Dexmedetomidine used independently or as an adjunct seems to exhibit a similar hemodynamic safety profile compared with standard sedation regimens, albeit with transient episodes of bradycardia and hypotension, decrease episodes of agitation and may serve to alleviate symptoms of sympathetic hyperactivity. This scoping review suggests that dexmedetomidine is a safe and efficacious sedation strategy in patients with TBI. Given its rapid onset of action and anxiolytic properties, dexmedetomidine may serve as a feasible sedative for TBI patients.

Association of Early Dexmedetomidine Utilization With Clinical and Functional Outcomes Following Moderate-Severe Traumatic Brain Injury: A Transforming Clinical Research and Knowledge in Traumatic Brain Injury Study.

OBJECTIVE: To examine early sedation patterns, as well as the association of dexmedetomidine exposure, with clinical and functional outcomes among mechanically ventilated patients with moderate-severe traumatic brain injury (msTBI). DESIGN: Retrospective cohort study with prospectively collected data. SETTING: Eighteen Level-1 Trauma Centers, United States. PATIENTS: Adult (age > 17) patients with msTBI (as defined by Glasgow Coma Scale < 13) who required mechanical ventilation from the Transforming Clinical Research and Knowledge in TBI (TRACK-TBI) study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Using propensity-weighted models, we examined the association of early dexmedetomidine exposure (within the first 5 d of ICU admission) with the primary outcome of 6-month Glasgow Outcomes Scale Extended (GOS-E) and the following secondary outcomes: length of hospital stay, hospital mortality, 6-month Disability Rating Scale (DRS), and 6-month mortality. The study population included 352 subjects who required mechanical ventilation within 24 hours of admission. The initial sedative medication was propofol for 240 patients (68%), midazolam for 59 patients (17%), ketamine for 6 patients (2%), dexmedetomidine for 3 patients (1%), and 43 patients (12%) never received continuous sedation. Early dexmedetomidine was administered in 77 of the patients (22%), usually as a second-line agent. Compared with unexposed patients, early dexmedetomidine exposure was not associated with better 6-month GOS-E (weighted odds ratio [OR] = 1.48; 95% CI, 0.98-2.25). Early dexmedetomidine exposure was associated with lower DRS (weighted OR = -3.04; 95% CI, -5.88 to -0.21). In patients requiring ICP monitoring within the first 24 hours of admission, early dexmedetomidine exposure was associated with higher 6-month GOS-E score (OR 2.17; 95% CI, 1.24-3.80), lower DRS score (adjusted mean difference, -5.81; 95% CI, -9.38 to 2.25), and reduced length of hospital stay (hazard ratio = 1.50; 95% CI, 1.02-2.20). CONCLUSION: Variation exists in early sedation choice among mechanically ventilated patients with msTBI. Early dexmedetomidine exposure was not associated with improved 6-month functional outcomes in the entire population, although may have clinical benefit in patients with indications for ICP monitoring.

Evaluation of endoscopic-assisted feline lateral bulla osteotomy: a cadaveric study.

OBJECTIVES: The aims of the study were to investigate if feline middle ear anatomy can be visualized using endoscopy via a lateral bulla approach and to determine if scope-assistance increases rates of successful entry into the hypotympanum during feline total ear canal ablation and lateral bulla osteotomy (TECA-LBO). METHODS: A total of 13 feline cadaver heads underwent CT to confirm the absence of pre-existing middle ear disease. For each head, an electronic coin toss was used to determine which ear would undergo endoscope-assisted TECA-LBO; a traditional TECA-LBO without the use of the scope was performed on the contralateral side. In endoscope-assisted procedures, a 1.9 mm scope was intermittently inserted into the tympanic bulla via a lateral bulla approach and used to identify middle ear structures, visualize the bony septum and confirm entry into the hypotympanum. After the bilateral TECA-LBO, the cadaver heads were imaged again and assessed for evidence of entry through the septum. RESULTS: Soft tissue and osseus structures of the middle ear were readily visualized with a 1.9 mm scope. Success rates for entry into the hypotympanum were high between both endoscope-assisted and traditional procedures, with entry confirmed for 12/13 ears in each group. CONCLUSIONS AND RELEVANCE: Endoscope assistance can facilitate the identification and examination of middle ear structures but does not appear to increase the success rate of entry into the hypotympanum during feline TECA-LBO, as entry through the bony septum was consistently accomplished even without scope-assisted visualization. Alternative benefits to scope assistance may exist, and future studies to elucidate its impact on rates of intraoperative trauma to middle ear structures are indicated.

Divergent projections from locus coeruleus to the corticobasal ganglia system and ventral tegmental area of the adult male zebra finch.

The locus coeruleus (LC) is a small noradrenergic brainstem nucleus that plays a central role in regulating arousal, attention, and performance. In the mammalian brain, individual LC neurons make divergent axonal projections to different brain regions, which are distinguished in part by which noradrenaline (NA) receptor subtypes they express. Here, we sought to determine whether similar organizational features characterize LC projections to corticobasal ganglia (CBG) circuitry in the zebra finch song system, with a focus on the basal ganglia nucleus Area X, the thalamic nucleus DLM, as well as the cortical nuclei HVC, LMAN, and RA. Single and dual retrograde tracer injections reveal that single LC-NA neurons make divergent projections to LMAN and Area X, as well as to the dopaminergic VTA/SNc complex that innervates this CBG circuit. Moreover, in situ hybridization revealed that differential expression of mRNA encoding α2A and α2C adrenoreceptors distinguishes LC-recipient CBG song nuclei. Therefore, LC-NA signaling in the zebra finch CBG circuit employs a similar strategy as in mammals, which could allow a relatively small number of LC neurons to exert widespread yet distinct effects across multiple brain regions.

Utilization and Outcomes of Extracorporeal Membrane Oxygenation Following Traumatic Brain Injury in the United States.

Objectives: Describe contemporary ECMO utilization patterns among patients with traumatic brain injury (TBI) and examine clinical outcomes among TBI patients requiring ECMO. Design: Retrospective cohort study. Setting: Premier Healthcare Database (PHD) between January 2016 to June 2020. Subjects: Adult patients with TBI who were mechanically ventilated and stratified by exposure to ECMO. Results: Among patients exposed to ECMO, we examined the following clinical outcomes: hospital LOS, ICU LOS, duration of mechanical ventilation, and hospital mortality. Of our initial cohort (n = 59,612), 118 patients (0.2%) were placed on ECMO during hospitalization. Most patients were placed on ECMO within the first 2 days of admission (54.3%). Factors associated with ECMO utilization included younger age (OR 0.96, 95% CI (0.95-0.97)), higher injury severity score (ISS) (OR 1.03, 95% CI (1.01-1.04)), vasopressor utilization (2.92, 95% CI (1.90-4.48)), tranexamic acid utilization (OR 1.84, 95% CI (1.12-3.04)), baseline comorbidities (OR 1.06, 95% CI (1.03-1.09)), and care in a teaching hospital (OR 3.04, 95% CI 1.31-7.05). A moderate degree (ICC = 19.5%) of variation in ECMO use was explained at the individual hospital level. Patients exposed to ECMO had longer median (IQR) hospital and ICU length of stay (LOS) [26 days (11-36) versus 9 days (4-8) and 19.5 days (8-32) versus 5 days (2-11), respectively] and a longer median (IQR) duration of mechanical ventilation [18 days (8-31) versus 3 days (2-8)]. Patients exposed to ECMO experienced a hospital mortality rate of 33.9%, compared to 21.2% of TBI patients unexposed to ECMO. Conclusions: ECMO utilization in mechanically ventilated patients with TBI is rare, with significant variation across hospitals. The impact of ECMO on healthcare utilization and hospital mortality following TBI is comparable to non-TBI conditions requiring ECMO. Further research is necessary to better understand the role of ECMO following TBI and identify patients who may benefit from this therapy.

Risk Factors and Neurological Outcomes Associated With Circulatory Shock After Moderate-Severe Traumatic Brain Injury: A TRACK-TBI Study.

BACKGROUND: Extracranial multisystem organ failure is a common sequela of severe traumatic brain injury (TBI). Risk factors for developing circulatory shock and long-term functional outcomes of this patient subset are poorly understood. OBJECTIVE: To identify emergency department predictors of circulatory shock after moderate-severe TBI and examine long-term functional outcomes in patients with moderate-severe TBI who developed circulatory shock. METHODS: We conducted a retrospective cohort study using the Transforming Clinical Research and Knowledge in TBI database for adult patients with moderate-severe TBI, defined as a Glasgow Coma Scale (GCS) score of <13 and stratified by the development of circulatory shock within 72 hours of hospital admission (Sequential Organ Failure Assessment score ≥2). Demographic and clinical data were assessed with descriptive statistics. A forward selection regression model examined risk factors for the development of circulatory shock. Functional outcomes were examined using multivariable regression models. RESULTS: Of our moderate-severe TBI population (n = 407), 168 (41.2%) developed circulatory shock. Our predictive model suggested that race, computed tomography Rotterdam scores <3, GCS in the emergency department, and development of hypotension in the emergency department were associated with developing circulatory shock. Those who developed shock had less favorable 6-month functional outcomes measured by the 6-month GCS-Extended (odds ratio 0.36, P = .002) and 6-month Disability Rating Scale score (Diff. in means 3.86, P = .002) and a longer length of hospital stay (Diff. in means 11.0 days, P < .001). CONCLUSION: We report potential risk factors for circulatory shock after moderate-severe TBI. Our study suggests that developing circulatory shock after moderate-severe TBI is associated with poor long-term functional outcomes.

Racial and Ethnic Differences in the Prevalence of Do-Not-Resuscitate Orders among Older Adults with Severe Traumatic Brain Injury.

BACKGROUND: Older adults suffering from traumatic brain injury (TBI) are subject to higher injury burden and mortality. Do Not Resuscitate (DNR) orders are used to provide care aligned with patient wishes, but they may not be equitably distributed across racial/ethnic groups. We examined racial/ethnic differences in the prevalence of DNR orders at hospital admission in older patients with severe TBI. METHODS: We conducted a retrospective cohort study using the National Trauma Databank (NTDB) between 2007 to 2016. We examined patients ≥ 65 years with severe TBI. For our primary aim, the exposure was race/ethnicity and outcome was the presence of a documented DNR at hospital admission. We conducted an exploratory analysis of hospital outcomes including hospital mortality, discharge to hospice, and healthcare utilization (intracranial pressure monitor placement, hospital LOS, and duration of mechanical ventilation). RESULTS: Compared to White patients, Black patients (OR 0.48, 95% CI 0.35-0.64), Hispanic patients (OR 0.54, 95% CI 0.40-0.70), and Asian patients (OR 0.63, 95% CI 0.44-0.90) had decreased odds of having a DNR order at hospital admission. Patients with DNRs had increased odds of hospital mortality (OR 2.16, 95% CI 1.94-2.42), discharge to hospice (OR 2.08, 95% CI 1.75-2.46), shorter hospital LOS (-2.07 days, 95% CI -3.07 to -1.08) and duration of mechanical ventilation (-1.09 days, 95% CI -1.52 to -0.67). There was no significant difference in the utilization of ICP monitoring (OR 0.94, 95% CI 0.78-1.12). CONCLUSIONS: We found significant racial and ethnic differences in the utilization of DNR orders among older patients with severe TBI. Additionally. DNR orders at hospital admission were associated with increased in-hospital mortality, increased hospice utilization, and decreased healthcare utilization. Future studies should examine mechanisms underlying race-based differences in DNR utilization.

Mechanical thrombectomy for perioperative ischemic stroke following elective inpatient surgery in the United States.

Perioperative ischemic stroke significantly increases morbidity and mortality in patients undergoing elective surgery. Mechanical thrombectomy can improve ischemic stroke outcomes, but frequency and trend of its utilization for treatment of perioperative ischemic stroke is not studied. We identified adults who underwent elective inpatient surgery from 2008 to 2018 and suffered from a perioperative ischemic stroke from the Premier Healthcare Database. The difference in mechanical thrombectomy usage before and after the updated recommendation inacute stroke guidelines was assessed in a univariate analysis using a chi-squared test. A segmented regression model was created to assess the change in rate over time.Of 6,349,668 patients with elective inpatient surgery, 12,507 (0.2%) had perioperative ischemic stroke. Mean age (and standard deviation) was 69.5 (11.7) years, and 48.8% were female. Mechanical thrombectomy was used in 1.7% patients and its use increased from 0.0% in 3rd quarter, 2008 to 4.4% in 4th quarter, 2018. Significant increase in the use of mechanical thrombectomy was seen after 3rd quarter, 2015 when its use was incorporated in acute stroke treatment guideline (1.14% before 3rd quarter, 2015 versus 3.07% after; p < 0.0001). Amongst patients with perioperative ischemic stroke, patients who received mechanical thrombectomy were more likely to have their surgery performed at a teaching institute (67.3% versus 53.9%). Although a significant increase in rates of utilization of mechanical thrombectomy was observed, rates of utilization remain low, especially in non-teaching hospitals. This highlights improvements in the management of perioperative ischemic strokes and further opportunities to improve outcomes.

Neural dynamics underlying birdsong practice and performance.

Musical and athletic skills are learned and maintained through intensive practice to enable precise and reliable performance for an audience. Consequently, understanding such complex behaviours requires insight into how the brain functions during both practice and performance. Male zebra finches learn to produce courtship songs that are more varied when alone and more stereotyped in the presence of females1. These differences are thought to reflect song practice and performance, respectively2,3, providing a useful system in which to explore how neurons encode and regulate motor variability in these two states. Here we show that calcium signals in ensembles of spiny neurons (SNs) in the basal ganglia are highly variable relative to their cortical afferents during song practice. By contrast, SN calcium signals are strongly suppressed during female-directed performance, and optogenetically suppressing SNs during practice strongly reduces vocal variability. Unsupervised learning methods4,5 show that specific SN activity patterns map onto distinct song practice variants. Finally, we establish that noradrenergic signalling reduces vocal variability by directly suppressing SN activity. Thus, SN ensembles encode and drive vocal exploration during practice, and the noradrenergic suppression of SN activity promotes stereotyped and precise song performance for an audience.