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Decreasing adrenergic or sympathetic hyperactivity after severe traumatic brain injury using propranolol and clonidine (DASH After TBI Study): study protocol for a randomized controlled trial.

ABSTRACT: Severe TBI, defined as a Glasgow Coma Scale???8, increases intracranial pressure and activates the sympathetic nervous system. Sympathetic hyperactivity after TBI manifests as catecholamine excess, hypertension, abnormal heart rate variability, and agitation, and is associated with poor neuropsychological outcome. Propranolol and clonidine are centrally acting drugs that may decrease sympathetic outflow, brain edema, and agitation. However, there is no prospective randomized evidence available demonstrating the feasibility, outcome benefits, and safety for adrenergic blockade after TBI.The DASH after TBI study is an actively accruing, single-center, randomized, double-blinded, placebo-controlled, two-arm trial, where one group receives centrally acting sympatholytic drugs, propranolol (1?mg intravenously every 6?h for 7?days) and clonidine (0.1?mg per tube every 12?h for 7?days), and the other group, double placebo, within 48?h of severe TBI. The study uses a weighted adaptive minimization randomization with categories of age and Marshall head CT classification. Feasibility will be assessed by ability to provide a neuroradiology read for randomization, by treatment contamination, and by treatment compliance. The primary endpoint is reduction in plasma norepinephrine level as measured on day 8. Secondary endpoints include comprehensive plasma and urine catecholamine levels, heart rate variability, arrhythmia occurrence, infections, agitation measures using the Richmond Agitation-Sedation Scale and Agitated Behavior scale, medication use (anti-hypertensive, sedative, analgesic, and antipsychotic), coma-free days, ventilator-free days, length of stay, and mortality. Neuropsychological outcomes will be measured at hospital discharge and at 3 and 12?months. The domains tested will include global executive function, memory, processing speed, visual-spatial, and behavior. Other assessments include the Extended Glasgow Outcome Scale and Quality of Life after Brain Injury scale. Safety parameters evaluated will include cardiac complications.The DASH After TBI Study is the first randomized, double-blinded, placebo-controlled trial powered to determine feasibility and investigate safety and outcomes associated with adrenergic blockade in patients with severe TBI. If the study results in positive trends, this could provide pilot evidence for a larger multicenter randomized clinical trial. If there is no effect of therapy, this trial would still provide a robust prospective description of sympathetic hyperactivity after TBI.ClinicalTrials.gov NCT01322048.

SUBMITTER: Patel MB

PROVIDER: S-EPMC3517360 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Decreasing adrenergic or sympathetic hyperactivity after severe traumatic brain injury using propranolol and clonidine (DASH After TBI Study): study protocol for a randomized controlled trial.

Patel Mayur B MB McKenna John W JW Alvarez JoAnn M JM Sugiura Ayaka A Jenkins Judith M JM Guillamondegui Oscar D OD Pandharipande Pratik P PP

Trials 20120926

<h4>Background</h4>Severe TBI, defined as a Glasgow Coma Scale ≤ 8, increases intracranial pressure and activates the sympathetic nervous system. Sympathetic hyperactivity after TBI manifests as catecholamine excess, hypertension, abnormal heart rate variability, and agitation, and is associated with poor neuropsychological outcome. Propranolol and clonidine are centrally acting drugs that may decrease sympathetic outflow, brain edema, and agitation. However, there is no prospective randomized e ...[more]

PMID: 23013802

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Project description:Background:Traumatic brain injury (TBI) correlated with increased sympathetic activity on the expense of parasympathetic system due to loss of cortical control after brain injury. Manifestations of sympathetic storm include tachycardia, hypertension, tachypnea, and hyperthermia. The neuroprotective effects via reducing cerebral metabolism and lowering O2 and glucose consumption are the targets early after trauma. Beta-blockers reduce sympathetic activity. Objectives:We suppose that using propranolol blunts the sympathetic storming phenomenon as it is a nonselective ? inhibitor and has a lipophilic property to steadily penetrate blood-brain barrier. Patients and Methods:Sixty patients allocated randomly into two groups, each consisting of 30 patients. Group A started propranolol and Group B received placebo within first 24 h. Primary outcome was catecholamine levels on day 7, and the secondary outcomes were physiological measures (heart rate [HR], respiratory rate [RR], mean arterial blood pressure [MABP], temperature, random blood sugar, and follow-up Glasgow coma score [GCS] and sedation score). Results:Analysis of outcomes demonstrated that Group A tended to have lower catecholamine levels in comparison to Group B in day 7 (norepinephrine 206.87 ± 44.44 vs. 529.33 ± 42.99 pg/ml, P = <0.001), epinephrine level (69.00 ± 8.66 vs. 190.73 ± 16.48 pg/ml, P < 0.001), and dopamine level (32.90 ± 4.57 vs. 78.00 ± 3.48 pg/ml P < 0.001). GCS of the patients in Group A improved and was statistically significant compared to Group B in day 7 (13 vs. 10, P = 0.006), with percent change interquartile range (20.0 vs. 8.33, P = 0.006). Regarding hemodynamic parameters between the two groups MABP, HR, RR, and temperature, there was no statistically significant difference on day 1, while on day 7, there is high statistical significance and significant percent change (P < 0.001). Conclusion:Early usage of propranolol after TBI controls hemodynamics and blood sugar with decreased catecholamine levels correlated with the improvement of GCS.

Project description:BackgroundParoxysmal sympathetic hyperactivity (PSH) results and aggravates in secondary brain injury, which seriously affects the prognosis of severe traumatic brain injury patients. Although several studies have focused on the treatment of PSH, few have concentrated on its prevention.MethodsNinety post-operation (post-op) severe traumatic brain injury (sTBI) patients admitted from October 2014 to April 2016 were chosen to participate in this study. Fifty of the post-op sTBI patients were sedated with dexmedetomidine and were referred as the "dexmedetomidine group" (admitted from May 2015 to April 2016). The other 40 patients (admitted from October 2014 to May 2015) received other sedations and were referred as the "control group." The two groups were then compared based on their PSH scores and the scores and ratios of those patients who met the criteria of "probable," "possible" and "unlikely" using the PSH assessment measure (PSH-AM) designed by Baguley et al. (2014). The durations of the neurosurgery intensive care unit (NICU) and hospital stays and the Glasgow outcome scale (GOS) values for the two groups were also compared to evaluate the therapeutic effects and the patients' prognosis.ResultsThe overall PSH score for the dexmedetomidine group was 5.26 ± 4.66, compared with 8.58 ± 8.09 for the control group. The difference between the two groups' PSH scores was significant (P = 0.017). The score of the patients who met the criterion of "probable" was 18.33 ± 1.53 in the dexmedetomidine group and 22.63 ± 2.97 in the control group, and the difference was statistically significant (P = 0.045). The ratio of patients who were classified as "unlikely" between the two groups was statistically significant (P = 0.028); that is, 42 (84%) in the dexmedetomidine group and 25 (62.5%) in the control group. The differences in NICU, hospital stays and GOS values between the two groups were not significant.ConclusionDexmedetomidine has a preventive effect on PSH in sTBI patients who have undergone surgery.

Project description:Severe traumatic brain injury (TBI) may result in a disorder of consciousness (DoC) and lead to substantial long-term disability. While level of independence with activities of daily living, especially for persons who recover consciousness during inpatient rehabilitation, generally improves over time, the degree of change in participation remains unknown. We determined level of participation among persons with TBI between 2005 and 2017 who were admitted to inpatient rehabilitation unable to follow commands and subsequently enrolled in the TBI Model Systems National Database. Participation on the Participation Assessment with Recombined Tools-Objective (PART-O) Productivity, Social Relations, and Out and About subscales was evaluated at 1-5 years post-injury. We used a mixed-effects model to longitudinally compare participation between persons who did and did not regain command-following during inpatient rehabilitation. We further explored the level of participation associated with increasing levels of functional independence (FIM). The analysis included 333 persons (229 recovered command-following during rehabilitation, mean age = 35.46 years, 74.9% male). Participation across groups, at all follow-up time points, on all PART-O subscales, was remarkably low (mean range = 0.021-1.91, maximum possible score = 5). Performance was highest on the Social Relations subscale and lowest on the Productivity subscale. Longitudinal analyses revealed no difference in level of participation or change in participation across time for persons who regained command-following during rehabilitation compared to those who did not. While productivity increased over time, social participation did not and participation outside the home increased more for younger than for older persons. Across all three PART-O subscales, FIM Motor scores positively predicted participation. FIM Cognitive scores positively predicted level of participation on the Productivity and Social Relations subscales. Exploratory analyses revealed that even persons who achieved independence on the FIM Motor and Cognitive subscales had low levels of participation across domains and follow-up years. In summary, persons with severe TBI who were admitted to inpatient rehabilitation unable to follow commands were found to be unlikely to participate in productive tasks, social endeavors, or activities outside of the home up to 5 years post-injury, even if functional independence was recovered.

Dataset Information

Decreasing adrenergic or sympathetic hyperactivity after severe traumatic brain injury using propranolol and clonidine (DASH After TBI Study): study protocol for a randomized controlled trial.

Publications

Decreasing adrenergic or sympathetic hyperactivity after severe traumatic brain injury using propranolol and clonidine (DASH After TBI Study): study protocol for a randomized controlled trial.

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