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

Mayur B Patel, John W McKenna, JoAnn M Alvarez, Ayaka Sugiura, Judith M Jenkins, Oscar D Guillamondegui, Pratik P Pandharipande, Mayur B Patel, John W McKenna, JoAnn M Alvarez, Ayaka Sugiura, Judith M Jenkins, Oscar D Guillamondegui, Pratik P Pandharipande

Abstract

Background: 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.

Methods/design: 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.

Discussion: 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.

Trial registration: ClinicalTrials.gov NCT01322048.

Figures

Figure 1
Figure 1
Conceptual model of sympathetichyperactivity after severe TBI.
Figure 2
Figure 2
CONSORT diagram of theDASH After TBI Study.
Figure 3
Figure 3
Current sample size vs. power for Δ plasma norepinephrine on day 8.

References

    1. Maas AIR, Marmarou A, Murray GD, Teasdale SGM, Steyerberg EW. Prognosis and clinical trial design in traumatic brain injury: the IMPACT study. J Neurotrauma. 2007;24:232–238. doi: 10.1089/neu.2006.0024.
    1. Menon DK, Zahed C. Prediction of outcome in severe traumatic brain injury. Curr Opin Crit Care. 2009;15:437–441. doi: 10.1097/MCC.0b013e3283307a26.
    1. Tran TY, Dunne IE, German JW. Beta blockers exposure and traumatic brain injury: a literature review. Neurosurg Focus. 2008;25:E8.
    1. Woolf PD, Hamill RW, Lee LA, Cox C, McDonald JV. The predictive value of catecholamines in assessing outcome in traumatic brain injury. J Neurosurg. 1987;66:875–882. doi: 10.3171/jns.1987.66.6.0875.
    1. Woolf PD, Hamill RW, Lee LA, McDonald JV. Free and total catecholamines in critical illness. Am J Physiol. 1988;254:E287–E291.
    1. Hamill RW, Woolf PD, McDonald JV, Lee LA, Kelly M. Catecholamines predict outcome in traumatic brain injury. Ann Neurol. 1987;21:438–443. doi: 10.1002/ana.410210504.
    1. Woolf PD, McDonald JV, Feliciano DV, Kelly MM, Nichols D, Cox C. The catecholamine response to multisystem trauma. Arch Surg. 1992;127:899–903. doi: 10.1001/archsurg.1992.01420080033005.
    1. Perkes I, Baguley IJ, Nott MT, Menon DK. A review of paroxysmal sympathetic hyperactivity after acquired brain injury. Ann Neurol. 2010;68:126–135. doi: 10.1002/ana.22066.
    1. Riordan WP, Cotton BA, Norris PR, Waitman LR, Jenkins JM, Morris JA. Beta-blocker exposure in patients with severe traumatic brain injury (TBI) and cardiac uncoupling. J Trauma. 2007;63:503–510. doi: 10.1097/TA.0b013e3181271c34. discussion 510–511.
    1. Mowery NT, Norris PR, Riordan W, Jenkins JM, Williams AE, Morris JA. Cardiac uncoupling and heart rate variability are associated with intracranial hypertension and mortality: a study of 145 trauma patients with continuous monitoring. J Trauma. 2008;65:621–627. doi: 10.1097/TA.0b013e3181837980.
    1. Heffernan DS, Inaba K, Arbabi S, Cotton BA. Sympathetic hyperactivity after traumatic brain injury and the role of beta-blocker therapy. J Trauma. 2010;69:1602–1609. doi: 10.1097/TA.0b013e3181f2d3e8.
    1. Rabinstein AA, Benarroch EE. Treatment of paroxysmal sympathetic hyperactivity. Curr Treat Options Neurol. 2008;10:151–157. doi: 10.1007/s11940-008-0016-y.
    1. Kim E, Lauterbach EC, Reeve A, Arciniegas DB, Coburn KL, Mendez MF, Rummans TA, Coffey EC. ANPA Committee on Research. Neuropsychiatric complications of traumatic brain injury: a critical review of the literature (a report by the ANPA Committee on Research) J Neuropsychiatry Clin Neurosci. 2007;19:106–127. doi: 10.1176/appi.neuropsych.19.2.106.
    1. Brooke MM, Patterson DR, Questad KA, Cardenas D, Farrel-Roberts L. The treatment of agitation during initial hospitalization after traumatic brain injury. Arch Phys Med Rehabil. 1992;73:917–921.
    1. Nott MT, Chapparo C, Baguley IJ. Agitation following traumatic brain injury: an Australian sample. Brain Inj. 2006;20:1175–1182. doi: 10.1080/02699050601049114.
    1. Nott MT, Chapparo C, Heard R, Baguley IJ. Patterns of agitated behaviour during acute brain injury rehabilitation. Brain Inj. 2010;24:1214–1221. doi: 10.3109/02699052.2010.506858.
    1. Baguley IJ, Slewa-Younan S, Heriseanu RE, Nott MT, Mudaliar Y, Nayyar V. The incidence of dysautonomia and its relationship with autonomic arousal following traumatic brain injury. Brain Inj. 2007;21:1175–1181. doi: 10.1080/02699050701687375.
    1. Liu MY. Protective effects of propranolol on experimentally head-injured mouse brains. J Formos Med Assoc. 1995;94:386–390.
    1. Ley EJ, Park R, Dagliyan G, Palestrant D, Miller CM, Conti PS, Margulies DR, Salim A. In vivo effect of propranolol dose and timing on cerebral perfusion after traumatic brain injury. J Trauma. 2010;68:353–356. doi: 10.1097/TA.0b013e3181c8269a.
    1. Ley EJ, Scehnet J, Park R, Schroff S, Dagliyan G, Conti PS, Margulies DR, Salim A. The in vivo effect of propranolol on cerebral perfusion and hypoxia after traumatic brain injury. J Trauma. 2009;66:154–159. doi: 10.1097/TA.0b013e31819388be. discussion 159–161.
    1. Greendyke RM, Kanter DR, Schuster DB, Verstreate S, Wootton J. Propranolol treatment of assaultive patients with organic brain disease. A double-blind crossover, placebo-controlled study. J Nerv Ment Dis. 1986;174:290–294. doi: 10.1097/00005053-198605000-00005.
    1. Fleminger S, Greenwood RJ, Oliver DL. Pharmacological management for agitation and aggression in people with acquired brain injury. Cochrane Database Syst Rev. 2006;4:CD003299.
    1. Hinson HE, Sheth KN. Manifestations of the hyperadrenergic state after acute brain injury. Curr Opin Crit Care. 2012;18:139–145. doi: 10.1097/MCC.0b013e3283513290.
    1. Inaba K, Teixeira PGR, David J-S, Chan LS, Salim A, Brown C, Browder T, Beale E, Rhee P, Demetriades D. Beta-blockers in isolated blunt head injury. J Am Coll Surg. 2008;206:432–438. doi: 10.1016/j.jamcollsurg.2007.10.005.
    1. Arbabi S, Campion EM, Hemmila MR, Barker M, Dimo M, Ahrns KS, Niederbichler AD, Ipaktchi K, Wahl WL. Beta-blocker use is associated with improved outcomes in adult trauma patients. J Trauma. 2007;62:56–61. doi: 10.1097/TA.0b013e31802d972b. discussion 61–62.
    1. Cotton BA, Snodgrass KB, Fleming SB, Carpenter RO, Kemp CD, Arbogast PG, Morris JA. Beta-blocker exposure is associated with improved survival after severe traumatic brain injury. J Trauma. 2007;62:26–33. doi: 10.1097/TA.0b013e31802d02d0. discussion 3335.
    1. Pandharipande PP, Pun BT, Herr DL, Maze M, Girard TD, Miller RR, Shintani AK, Thompson JL, Jackson JC, Deppen SA, Stiles RA, Dittus RS, Bernard GR, Ely EW. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA. 2007;298:2644–2653. doi: 10.1001/jama.298.22.2644.
    1. Chan AKM, Cheung CW, Chong YK. Alpha-2 agonists in acute pain management. Expert Opin Pharmacother. 2010;11:2849–2868. doi: 10.1517/14656566.2010.511613.
    1. Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, Whitten P, Margolis BD, Byrne DW, Ely EW, Rocha MG. SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009;301:489–499. doi: 10.1001/jama.2009.56.
    1. Hoffman WE, Cheng MA, Thomas C, Baughman VL, Albrecht RF. Clonidine decreases plasma catecholamines and improves outcome from incomplete ischemia in the rat. Anesth Analg. 1991;73:460–464.
    1. Payen D, Quintin L, Plaisance P, Chiron B, Lhoste F. Head injury: clonidine decreases plasma catecholamines. Crit Care Med. 1990;18:392–395. doi: 10.1097/00003246-199004000-00008.
    1. Asgeirsson B, Grände PO, Nordström CH, Berntman L, Messeter K, Ryding E. Effects of hypotensive treatment with alpha 2-agonist and beta 1-antagonist on cerebral haemodynamics in severely head injured patients. Acta Anaesthesiol Scand. 1995;39:347–351. doi: 10.1111/j.1399-6576.1995.tb04075.x.
    1. Nordström C-H. Physiological and biochemical principles underlying volume-targeted therapy–the “Lund concept”. Neurocrit Care. 2005;2:83–95. doi: 10.1385/NCC:2:1:083.
    1. Grände PO, Asgeirsson B, Nordström CH. Physiologic principles for volume regulation of a tissue enclosed in a rigid shell with application to the injured brain. J Trauma. 1997;Suppl 5:S23–S31.
    1. Dizdarevic K, Hamdan A, Omerhodzic I, Kominlija-Smajic E. Modified Lund concept versus cerebral perfusion pressure-targeted therapy: A randomised controlled study in patients with secondary brain ischaemia. Clin Neurol Neurosurg. 2012;114:142–148. doi: 10.1016/j.clineuro.2011.10.005.
    1. Choi Y, Novak JC, Hillier A, Votolato NA, Beversdorf DQ. The effect of alpha-2 adrenergic agonists on memory and cognitive flexibility. Cogn Behav Neurol. 2006;19:204–207. doi: 10.1097/01.wnn.0000213919.95266.0d.
    1. Schneider JS, Tinker JP, Decamp E. Clonidine improves attentional and memory components of delayed response performance in a model of early Parkinsonism. Behav Brain Res. 2010;211:236–239. doi: 10.1016/j.bbr.2010.03.040.
    1. Kroes MCW, Strange BA, Dolan RJ. Beta-adrenergic blockade during memory retrieval in humans evokes a sustained reduction of declarative emotional memory enhancement. J Neurosci. 2010;30:3959–3963. doi: 10.1523/JNEUROSCI.5469-09.2010.
    1. Oei NYL, Tollenaar MS, Elzinga BM, Spinhoven P. Propranolol reduces emotional distraction in working memory: a partial mediating role of propranolol-induced cortisol increases? Neurobiol Learn Mem. 2010;93:388–395. doi: 10.1016/j.nlm.2009.12.005.
    1. Schulz KF, Altman DG, Moher D, Group C. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMC Med. 2010;8:18. doi: 10.1186/1741-7015-8-18.
    1. Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics. 1975;31:103–115. doi: 10.2307/2529712.
    1. Marshall LF, Marshall SB, Klauber MR, Van Berkum Clark M, Eisenberg H, Jane JA, Luerssen TG, Marmarou A, Foulkes MA. The diagnosis of head injury requires a classification based on computed axial tomography. J Neurotrauma. 1992;Suppl 1:S287–S292.
    1. R Development Core Team. R: A language and environment for statistical computing. 2140th. Vienna: R Foundation for Statistical Computing; 2011.
    1. Horner J. rApache: Web application development with R and Apache. 2012.
    1. Duhaime A-C, Gean AD, Haacke EM, Hicks R, Wintermark M, Mukherjee P, Brody D, Latour L, Riedy G. Common Data Elements Neuroimaging Working Group Members, Pediatric Working Group Members. Common data elements in radiologic imaging of traumatic brain injury. Arch Phys Med Rehabil. 2010;91:1661–1666. doi: 10.1016/j.apmr.2010.07.238.
    1. Maas AI, Harrison-Felix CL, Menon D, Adelson PD, Balkin T, Bullock R, Engel DC, Gordon W, Langlois Orman J, Lew HL, Robertson C, Temkin N, Valadka A, Verfaellie M, Wainwright M, Wright DW, Schwab K. Common data elements for traumatic brain injury: recommendations from the interagency working group on demographics and clinical assessment. Arch Phys Med Rehabil. 2010;91:1641–1649. doi: 10.1016/j.apmr.2010.07.232.
    1. He HB, Deegan RJ, Wood M, Wood AJ. Optimization of high-performance liquid chromatographic assay for catecholamines. Determination of optimal mobile phase composition and elimination of species-dependent differences in extraction recovery of 3,4-dihydroxybenzylamine. J Chromatogr. 1992;574:213–218. doi: 10.1016/0378-4347(92)80032-L.
    1. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42:377–381. doi: 10.1016/j.jbi.2008.08.010.
    1. Dupont WD, Plummer WD. Power and sample size calculations. A review and computer program. Control Clin Trials. 1990;11:116–128. doi: 10.1016/0197-2456(90)90005-M.
    1. Maas AIR, Steyerberg EW, Marmarou A, McHugh GS, Lingsma HF, Butcher I, Lu J, Weir J, Roozenbeek B, Murray GD. IMPACT recommendations for improving the design and analysis of clinical trials in moderate to severe traumatic brain injury. Neurotherapeutics. 2010;7:127–134. doi: 10.1016/j.nurt.2009.10.020.
    1. Lv L-Q, Hou L-j, Yu M-k, Qi X-Q, Chen H-R, Chen J-X, Hu G-H, Luo C, Lu Y-C. Prognostic influence and magnetic resonance imaging findings in paroxysmal sympathetic hyperactivity after severe traumatic brain injury. J Neurotrauma. 2010;27:1945–1950. doi: 10.1089/neu.2010.1391.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi