Beta-adrenergic blockade for attenuation of catecholamine surge after traumatic brain injury: a randomized pilot trial

Abstract

BackgroundBeta-blockers have been proven in multiple studies to be beneficial in patients with traumatic brain injury. Few prospective studies have verified this and no randomized controlled trials. Additionally, most studies do not titrate the dose of beta-blockers to therapeutic effect. We hypothesize that propranolol titrated to effect will confer a survival benefit in patients with traumatic brain injury.MethodsA randomized controlled pilot trial was performed during a 24-month period. Patients with traumatic brain injury were randomized to propranolol or control group for a 14-day study period. Variables collected included demographics, injury severity, physiologic parameters, urinary catecholamines, and outcomes. Patients receiving propranolol were compared with the control group.ResultsOver the study period, 525 patients were screened, 26 were randomized, and 25 were analyzed. Overall, the mean age was 51.3 years and the majority were male with blunt mechanism. The mean Injury Severity Score was 21.8 and median head Abbreviated Injury Scale score was 4. Overall mortality was 20.0%. Mean arterial pressure was higher in the treatment arm as compared with control (p=0.021), but no other differences were found between the groups in demographics, severity of injury, severity of illness, physiologic parameters, or mortality (7.7% vs. 33%; p=0.109). No difference was detected over time in any variables with respect to treatment, urinary catecholamines, or physiologic parameters. Glasgow Coma Scale (GCS), Sequential Organ Failure Assessment, and Acute Physiology and Chronic Health Evaluation scores all improved over time. GCS at study end was significantly higher in the treatment arm (11.7 vs. 8.9; p=0.044). Finally, no difference was detected with survival analysis over time between groups.ConclusionsDespite not being powered to show statistical differences between groups, GCS at study end was significantly improved in the treatment arm and mortality was improved although not at a traditional level of significance. The study protocol was safe and feasible to apply to an appropriately powered larger multicenter study.Level of evidenceLevel 2—therapeutic.

Long-Term Analysis of Functional Outcomes in Traumatic Brain Injury Patients

“…1,9 While few interventions have shown to improve mortality in this population, recent studies suggest that BB may be of benefit during the initial hospitalization. [4][5][6][7][8] The index study demonstrated that the odds of mortality were reduced by 77% in multivariable analysis in the cohort of patients that received propranolol. 4 A prospective randomized pilot trial examining propranolol in TBI also showed a protective effect of this medication as the propranolol group had a higher end-study GCS (11.7 vs 8.9; P = .044) despite that study not being powered to show differences.…”

“…4 A prospective randomized pilot trial examining propranolol in TBI also showed a protective effect of this medication as the propranolol group had a higher end-study GCS (11.7 vs 8.9; P = .044) despite that study not being powered to show differences. 6 Few studies in the trauma literature address long-term outcomes of TBI patients after discharge from the initial hospitalization. Interestingly, while propranolol was found to be protective in the index study that did not hold true after discharge in this analysis.…”

“…2,3 Beta-adrenergic blockade has shown promise during the acute phase for this population in multiple studies but limited data are available regarding outcomes associated with beta-blockers (BB) after discharge from the index hospitalization. [4][5][6][7][8] Severe TBI carries extensive mortality during the index admission of up to 79% and the long-term mortality, even in those that survive the index admission, is also considerable with a rate of up to 52%. [9][10][11][12][13][14][15] For those patients that do survive the initial hospitalization, a proportion will continue to improve for up to 10 years postdischarge.…”

Management and Challenges of Severe Traumatic Brain Injury

“…[133][134][135][136][137][138][139][140] There have been only two RCTs evaluating the impact of adrenergic blockade on TBI outcomes. 141,142 Schroeppel et al 141 performed a pilot RCT comparing propranolol (starting dose of 20 mg in every 8 hours) to placebo whose primary outcomes were in-hospital mortality and plasma/urine catecholamine levels. Though underpowered to detect a mortality benefit, it did find trends toward higher GCS at 14 days or hospital discharge in the treatment arm, (which was not the primary outcome).…”

“…Though underpowered to detect a mortality benefit, it did find trends toward higher GCS at 14 days or hospital discharge in the treatment arm, (which was not the primary outcome). 141 Our group performed the decreasing adrenergic or sympathetic hyperactivity (DASH) after severe TBI study, 142 an RCT evaluating the α-agonist clonidine in combination with the nonselective α-blocker propranolol given parenterally compared with placebo. The primary outcome was ventilator-free days, and secondary outcomes included plasma and urine catecholamine levels, delirium/coma-free days, ICU/hospital length of stay, PSH CFS scale, arousal and sedation, GCS, as well as long-term outcomes such as global cognition, functional status, and quality of life.…”