Top

Published in:

Open Access 01-12-2020 | Central Nervous System Trauma | Study protocol

Use of olanzapine to treat agitation in traumatic brain injury: study protocol for a randomised controlled trial

Authors: Ruby K Phyland, Adam McKay, John Olver, Mark Walterfang, Malcolm Hopwood, Amelia J Hicks, Duncan Mortimer, Jennie L Ponsford

Published in: Trials | Issue 1/2020

Abstract

Background

Agitation is common in the early stages of recovery from traumatic brain injury (TBI), when patients are in post-traumatic amnesia (PTA). Agitation is associated with risk of harm to patients and caregivers. Recent guidelines recommend that agitation during PTA is managed using environmental modifications. Agitation is also frequently treated pharmacologically, with the use of atypical antipsychotics such as olanzapine among the most common. This is despite a lack of well-designed studies to support the use of antipsychotics within this context. This study will be a double-blind, placebo-controlled randomised controlled trial. We will examine the efficacy, safety, cost-effectiveness and outcomes associated with the use of olanzapine for reducing agitation in patients in PTA following TBI over and above recommended environmental management.

Methods

Fifty-eight TBI rehabilitation inpatients who are in PTA and are agitated will receive olanzapine or placebo for the duration of PTA. All participants will additionally receive optimal environmental management for agitation. Measures of agitation, PTA and health will be undertaken at baseline. Treatment administration will begin at a dose of 5 mg daily and may be escalated to a maximum dose of 20 mg per day. Throughout the treatment period, agitation and PTA will be measured daily, and adverse events monitored weekly. Efficacy will be assessed by treatment group comparison of average Agitated Behaviour Scale scores during PTA. Participants will cease treatment upon emergence from PTA. Agitation levels will continue to be monitored for a further 2 weeks, post-treatment measures of health will be undertaken and cognitive and functional status will be assessed. Level of agitation and functional health will be assessed at hospital discharge. At 3 months post-discharge, functional outcomes and health service utilisation will be measured.

Discussion

This trial will provide crucial evidence to inform the management of agitation in patients in PTA following TBI. It will provide guidance as to whether olanzapine reduces agitation over and above recommended environmental management or conversely whether it increases or prolongs agitation and PTA, increases length of inpatient hospitalisation and impacts longer term cognitive and functional outcomes. It will also speak to the safety and cost-effectiveness of olanzapine use in this population.

Trial registration

ANZCTR ACTRN12619000284167. Registered on 25 February 2019

Available only for authorised users

Helps Y, Henley G, Harrison JE (Research Centre for Injury Studies, Flinders University, Adelaide, AU). Hospital separations due to traumatic brain injury, Australia 2004–05. Adelaide: Australian Institute of Health and Welfare; 2008. Report No.: 45.

Faul M, Xu L, Wald MM, Coronado V, Dellinger AM. Traumatic brain injury in the United States: national estimates of prevalence and incidence, 2002–2006. Inj Prev. 2010;16(Suppl 1):A268. https://doi.org/10.1136/ip.2010.029215.951.CrossRef

World Health Organization. Neurological disorders: public health challenges. Geneva: World Health Organisation; 2006. Report No.: 92 4 156336 2.

Ahmed S, Bierley R, Sheikh JI, Date ES. Post-traumatic amnesia after closed head injury: a review of the literature and some suggestions for further research. Brain Inj. 2000;14(9):765–80. https://doi.org/10.1080/026990500421886.CrossRefPubMed

Corrigan JD, Mysiw WJ. Agitation following traumatic head injury: equivocal evidence for a discrete stage of cognitive recovery. Arch Phys Med Rehabil. 1988;69(7):487–92.PubMed

Corrigan JD, Mysiw WJ, Gribble MW, Chock SK. Agitation, cognition and attention during post-traumatic amnesia. Brain Inj. 1992;6(2):155–60. https://doi.org/10.3109/02699059209029653.CrossRefPubMed

Ponsford J, Janzen S, McIntyre A, Bayley M, Velikonja D, Tate R. INCOG recommendations for management of cognition following traumatic brain injury, part I: posttraumatic amnesia/delirium. J Head Trauma Rehabil. 2014;29(4):307–20. https://doi.org/10.1097/HTR.0000000000000074.CrossRefPubMed

Nott MT, Chapparo C, Baguley IJ. Agitation following traumatic brain injury: an Australian sample. Brain Inj. 2006;20(11):1175–82. https://doi.org/10.1080/02699050601049114.CrossRefPubMed

Nygren DeBoussard C, Lannsjö M, Stenberg M, Stålnacke BM, Godbolt AK. Behavioural problems in the first year after severe traumatic brain injury: a prospective multicentre study. Clin Rehabil. 2017;31(4):555–66. https://doi.org/10.1177/0269215516652184.CrossRefPubMed

10.

Weir N, Doig EJ, Fleming JM, Wiemers A, Zemljic C. Objective and behavioural assessment of the emergence from post-traumatic amnesia (PTA). Brain Inj. 2006;20(9):927–35. https://doi.org/10.1080/02699050600832684.CrossRefPubMed

11.

Bogner J, Corrigan JD. Epidemiology of agitation following brain injury. NeuroRehabilitation. 1995;5(4):293–7. https://doi.org/10.3233/NRE-1995-5403.CrossRefPubMed

12.

Fugate LP, Spacek LA, Kresty LA, Levy CE, Johnson JC, Mysiw WJ. Definition of agitation following traumatic brain injury: i. a survey of the Brain Injury Special Interest Group of the American Academy of Physical Medicine and Rehabilitation. Arch Phys Med Rehabil. 1997;78(9):917–23. https://doi.org/10.1016/s0003-9993(97)90050-2.CrossRefPubMed

13.

Mysiw WJ, Sandel ME. The agitated brain injured patient. Part 2: pathophysiology and treatment. Arch Phys Med Rehabil. 1997;78(2):213–20. https://doi.org/10.1016/s0003-9993(97)90266-5.CrossRefPubMed

14.

Bogner JA, Corrigan JD, Fugate L, Mysiw WJ, Clinchot D. Role of agitation in prediction of outcomes after traumatic brain injury. Am J Phys Med Rehabil. 2001;80(9):636–44. https://doi.org/10.1097/00002060-200109000-00002.CrossRefPubMed

15.

McNeny R, Benjamin J. Agitation in the therapy setting: managing the patient with brain injury. NeuroRehabilitation. 1995;5(3):211–7. https://doi.org/10.3233/NRE-1995-5304.CrossRefPubMed

16.

Silver JM, Yudofsky SC. Neuropsychiatry of traumatic brain injury. Washington: American Psychiatric Press; 2004. Chapter 10, Aggressive disorders. p. 313–53.

17.

Lequerica AH, Rapport LJ, Loeher K, Axelrod BN, Vangel SJ Jr, Hanks RA. Agitation in acquired brain injury: impact on acute rehabilitation therapies. J Head Trauma Rehabil. 2007;22(3):177–83. https://doi.org/10.1097/01.HTR.0000271118.96780.bc.CrossRefPubMed

18.

McNett M, Sarver W, Wilczewski P. The prevalence, treatment and outcomes of agitation among patients with brain injury admitted to acute care units. Brain Inj. 2012;26(9):1155–62. https://doi.org/10.3109/02699052.2012.667587.CrossRefPubMed

19.

Hicks AJ, Clay FJ, Hopwood M, James AC, Jayaram M, Batty R, Perry LA, Ponsford JL. The efficacy and harms of pharmacological interventions for neurobehavioral symptoms in post traumatic amnesia after traumatic brain injury: a systematic review. J Neurotrauma. 2018;35(23):2755–75. https://doi.org/10.1089/neu.2018.5738.CrossRefPubMed

20.

Fleminger S, Greenwood RJ, Oliver DL. Pharmacological management for agitation and aggression in people with acquired brain injury. Cochrane Database Syst Rev. 2006;4:i-25. https://doi.org/10.1002/14651858.CD003299.pub2.CrossRef

21.

Kalra ID, Watanabe TK. Mood stabilizers for traumatic brain injury-related agitation. J Head Trauma Rehabil. 2017;32(6):E61–4. https://doi.org/10.1097/HTR.0000000000000359.CrossRefPubMed

22.

Lombard LA, Zafonte RD. Agitation after traumatic brain injury: considerations and treatment options. Am J Phys Med Rehabil. 2005;84(10):797–812. https://doi.org/10.1097/01.phm.0000179438.22235.08.CrossRefPubMed

23.

Luauté J, Plantier D, Wiart L, Tell L; SOMFER group. Care management of the agitation or aggressiveness crisis in patients with TBI. Systematic review of the literature and practice recommendations. Ann Phys Rehabil Med 2016;59(1):58–67. doi:https://doi.org/10.1016/j.rehab.2015.11.001.

24.

Levy M, Berson A, Cook T, Bollegala N, Seto E, Tursanski S, Kim J, Sockalingam S, Rajput A, Krishnadev N, Feng C, Bhalerao S. Treatment of agitation following traumatic brain injury: a review of the literature. NeuroRehabilitation. 2005;20(4):279–306. https://doi.org/10.3233/NRE-2005-20405.CrossRefPubMed

25.

Francisco GE, Walker WC, Zasler ND, Bouffard MH. Pharmacological management of neurobehavioural sequelae of traumatic brain injury: a survey of current physiatric practice. Brain Inj. 2007;21(10):1007–14. https://doi.org/10.1080/02699050701559558.CrossRefPubMed

26.

McKay A, Love J, Trevena-Peters J, Gracey J, Ponsford J. The relationship between agitation and impairments of orientation and memory during the PTA period after traumatic brain injury. Neuropsychol Rehabil. 2018:1–12. https://doi.org/10.1080/09602011.2018.

27.

Hoffman AN, Cheng JP, Zafonte RD, Kline AE. Administration of haloperidol and risperidone after neurobehavioral testing hinders the recovery of traumatic brain injury-induced deficits. Life Sci. 2008;83(17–18):602–7. https://doi.org/10.1016/j.lfs.2008.08.007.CrossRefPubMedPubMedCentral

28.

Phelps TI, Bondi CO, Ahmed RH, Olugbade YT, Kline AE. Divergent long-term consequences of chronic treatment with haloperidol, risperidone, and bromocriptine on traumatic brain injury–induced cognitive deficits. J Neurotrauma. 2015;32(8):590–7. https://doi.org/10.1089/neu.2014.3711.CrossRefPubMedPubMedCentral

29.

Wilson MS, Gibson CJ, Hamm RJ. Haloperidol, but not olanzapine, impairs cognitive performance after traumatic brain injury in rats. Am J Phys Med Rehabil. 2003;82(11):871–9. https://doi.org/10.1097/01.PHM.0000091982.33232.CB.

30.

Goldstein LB, Bullman S. Differential effects of haloperidol and clozapine on motor recovery after sensorimotor cortex injury in rats. Neurorehabil Neural Repair. 2002;16(4):321–5. https://doi.org/10.1177/154596830201600402.CrossRefPubMed

31.

Anderson RL, Birrer KL, Liu-DeRyke X. Haloperidol use in acute traumatic brain injury: a safety analysis. J Intensive Crit Care. 2016;2(2):1–6.CrossRef

32.

Rao N, Jellinek HM, Woolston DC. Agitation in closed head injury: haloperidol effects on rehabilitation outcome. Arch Phys Med Rehabil. 1985;66(1):30–4.PubMed

33.

Mysiw WJ, Bogner JA, Corrigan JD, Fugate LP, Clinchot DM, Kadyan V. The impact of acute care medications on rehabilitation outcome after traumatic brain injury. Brain Inj. 2006;20(9):905–11. https://doi.org/10.1080/02699050600743972.CrossRefPubMed

34.

Feeney DM, Gonzalez A, Law WA. Amphetamine, haloperidol, and experience interact to affect rate of recovery after motor cortex injury. Science. 1982;217(4562):855–7. https://doi.org/10.1126/science.7100929.CrossRefPubMed

35.

Kline AE, Hoffman AN, Cheng JP, Zafonte RD, Massucci JL. Chronic administration of antipsychotics impede behavioral recovery after experimental traumatic brain injury. Neurosci Lett. 2008;448(3):263–7. https://doi.org/10.1016/j.neulet.2008.10.076.CrossRefPubMedPubMedCentral

36.

Flanagan SR, Elovic EP, Sandel E. Managing agitation associated with traumatic brain injury: behavioral versus pharmacologic interventions? PM R. 2009;1:76–80. https://doi.org/10.1016/j.pmrj.2008.10.013.CrossRefPubMed

37.

Kooda K, Aho J, Weber D, Brown A. The effect of antipsychotic use post-traumatic brain injury on duration of post-traumatic amnesia. Crit Care Med. 2015;43(Suppl 12):289. https://doi.org/10.1097/01.ccm.0000474980.38145.7b.CrossRef

38.

Breier A, Meehan K, Birkett M, David S, Ferchland I, Sutton V, Taylor CC, Palmer R, Dossenbach M, Kiesler G, Brook S, Wright P. A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch Gen Psychiatry. 2002;59(5):441–8. https://doi.org/10.1001/archpsyc.59.5.441.CrossRefPubMed

39.

Centorrino F, Meyers AL, Ahl J, Cincotta SL, Zun L, Gulliver AH, Kinon BJ, Houston JP. An observational study of the effectiveness and safety of intramuscular olanzapine in the treatment of acute agitation in patients with bipolar mania or schizophrenia/schizoaffective disorder. Hum Psychopharmacol. 2007;22(7):455–62. https://doi.org/10.1002/hup.870.CrossRefPubMed

40.

Katagiri H, Fujikoshi S, Suzuki T, Fujita K, Sugiyama N, Takahashi M, Gomez JC. A randomized, double-blind, placebo-controlled study of rapid-acting intramuscular olanzapine in Japanese patients for schizophrenia with acute agitation. BMC Psychiatry. 2013;13:1–8. https://doi.org/10.1186/1471-244X-13-20.CrossRef

41.

Kishi T, Matsunaga S, Iwata N. Intramuscular olanzapine for agitated patients: a systematic review and meta-analysis of randomized controlled trials. J Psychiatr Res. 2015;68:198–209. https://doi.org/10.1016/j.jpsychires.2015.07.005.CrossRefPubMed

42.

Noé E, Ferri J, Trénor C, Chirivella J. Efficacy of ziprasidone in controlling agitation during post-traumatic amnesia. Behav Neurol. 2007;18:7–11. https://doi.org/10.1155/2007/529076.CrossRefPubMedPubMedCentral

43.

Harmsen M, Geurts AC, Fasotti L, Bevaart BJ. Positive behavioural disturbances in the rehabilitation phase after severe traumatic brain injury: an historic cohort study. Brain Inj. 2004;18(8):787–96. https://doi.org/10.1080/02699050410001671757.CrossRefPubMed

44.

Shores EA, Marosszeky JE, Sandanam J, Batchelor J. Preliminary validation of a clinical scale for measuring the duration of post-traumatic amnesia. Med J Aust. 1986;144(11):569–72.CrossRefPubMed

45.

Shores EA. Further concurrent validity data on the Westmead PTA Scale. Appl Neuropsychol. 1995;2(3–4):167–9. https://doi.org/10.1080/09084282.1995.9645356.CrossRefPubMed

46.

Australian Register of Therapeutic Goods [Internet]. [Canberra (AU)]: Therapeutic goods administration. [date unknown] - . Record No. 77390, Australian product information Zyprexa (Olanzapine); [updated 2019 Sep 28; cited 2020 Mar 14]; [23 p.]. Available from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2011-PI-02804-3.

47.

Rosenberger WF, Lachin JM. Randomization in clinical trials: theory and practice. 2nd ed. Hoboken: Wiley; 2015. p. 254.

48.

Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c332. https://doi.org/10.1136/bmj.c332.CrossRefPubMedPubMedCentral

49.

Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand. 1970;212:11–9. https://doi.org/10.1111/j.1600-0447.1970.tb02066.x.CrossRef

50.

Schmidt M. Rey auditory verbal learning test: a handbook. Los Angeles: Western Psychological Services; 1996.

51.

Smith A. Symbol digit modalities test. Los Angeles: Western Psychological Services; 1973.

52.

Granger CV, Hamilton BB, Keith RA, Zielezny M, Sherwin FS. Advances in functional assessment for medical rehabilitation. Top Geriatr Rehabil. 1986;1(3):59–74.CrossRef

53.

Ware J Jr, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care. 1996;34(3):220–33. https://doi.org/10.1097/00005650-199603000-00003.CrossRefPubMed

54.

Ware JE Jr, Kosinski M, Turner-Bowker DM, Sundaram M, Gandek B, Maruish ME. User's manual for the SF-12v2 Health Survey second edition. Lincoln: QualityMetric Incorporated; 2009.

55.

Malec JF. The Mayo-Portland adaptability inventory [internet]. San Jose: The Center for Outcome Measurement in Brain Injury; 2005. [cited 2020 Mar 14]. Available from: http://www.tbims.org/mpai/.

56.

Bogner J, Barrett RS, Hammond FM, Horn SD, Corrigan JD, Rosenthal J, Beaulieu CL, Waszkiewicz M, Shea T, Reddin CJ, Cullen N, Giuffrida GC, Young J, Garmoe W. Predictors of agitated behavior during inpatient rehabilitation for traumatic brain injury. Arch Phys Med Rehabil. 2015;96(Suppl 8):S274–81. https://doi.org/10.1016/j.apmr.2015.04.020.CrossRefPubMed

57.

Corrigan JD. Development of a scale for assessment of agitation following traumatic brain injury. J Clin Exp Neuropsychol. 1989;11(2):261–77. https://doi.org/10.1080/01688638908400888.CrossRefPubMed

58.

Corrigan JD, Bogner JA. Factor structure of the Agitated Behavior Scale. J Clin Exp Neuropsychol. 1994;16(3):386–92. https://doi.org/10.1080/01688639408402649.CrossRefPubMed

59.

Bogner JA, Corrigan JD, Bode RK, Heinemann AW. Rating scale analysis of the Agitated Behavior Scale. J Head Trauma Rehabil. 2000;15(1):656–69. https://doi.org/10.1097/00001199-200002000-00005.CrossRefPubMed

60.

Bogner JA, Corrigan JD, Stange M, Rabold D. Reliability of the Agitated Behavior Scale. J Head Trauma Rehabil. 1999;14(1):91–6. https://doi.org/10.1097/00001199-199902000-00012.CrossRefPubMed

61.

Geffen G, Bishop K, Connell J, Hopkins P. Inter-rater reliability of the Westmead Post-Traumatic Amnesia (PTA) Scale. Aust Occup Ther J. 1994;41(1):31–6. https://doi.org/10.1111/j.1440-1630.1994.tb01809.x.CrossRef

62.

Draper K, Ponsford J. Cognitive functioning ten years following traumatic brain injury and rehabilitation. Neuropsychology. 2008;22(5):618–25. https://doi.org/10.1037/0894-4105.22.5.618.CrossRefPubMed

63.

Wilde EA, Whiteneck GG, Bogner J, Bushnik T, Cifu DX, Dikmen S, French L, Giacino JT, Hart T, Malec JF, Millis SR, Novack TA, Sherer M, Tulsky DS, Vanderploeg RD, von Steinbuechel N. Recommendations for the use of common outcome measures in traumatic brain injury research. Arch Phys Med Rehabil. 2010;91(11):1650–60.e17. https://doi.org/10.1016/j.apmr.2010.06.033.CrossRefPubMed

64.

Jaywant A, Barredo J, Ahern DC, Resnik L. Neuropsychological assessment without upper limb involvement: a systematic review of oral versions of the Trail Making Test and Symbol-Digit Modalities Test. Neuropsychol Rehabil. 2018;28(7):1055–77. https://doi.org/10.1080/09602011.2016.1240699.CrossRefPubMed

65.

Ottenbacher KJ, Hsu Y, Granger CV, Fiedler RC. The reliability of the functional independence measure: a quantitative review. Arch Phys Med Rehabil. 1996;77(12):1226–32. https://doi.org/10.1016/s0003-9993(96)90184-7.CrossRefPubMed

66.

Corrigan JD, Smith-Knapp K, Granger CV. Validity of the Functional Independence Measure for persons with traumatic brain injury. Arch Phys Med Rehabil. 1997;78(8):828–34. https://doi.org/10.1016/s0003-9993(97)90195-7.CrossRefPubMed

67.

Nichol AD, Higgins AM, Gabbe BJ, Murray LJ, Cooper DJ, Cameron PA. Measuring functional and quality of life outcomes following major head injury: common scales and checklists. Injury. 2011;42(3):281–7. https://doi.org/10.1016/j.injury.2010.11.047.CrossRefPubMed

68.

Malec JF, Hammond FM. Minimal clinically important difference for the Rasch Neuropsychiatric Inventory Irritability and Aggression Scale for Traumatic Brain Injury. Arch Phys Med Rehabil. 2018;99(3):603–6.e1. https://doi.org/10.1016/j.apmr.2017.06.038.CrossRefPubMed

69.

Department of Health. Manual of resource items and their associated unit costs - December 2016 [Internet]. Canberra: Department of Health; 2016. [cited 2020 Mar 14]. Available from: http://www.pbs.gov.au/info/industry/useful-resources/manual.

70.

Norman R, Viney R, Brazier J, Burgess L, Cronin P, King M, Ratcliffe J, Street D. Valuing SF-6D health states using a discrete choice experiment. Med Decis Mak. 2014;34(6):773–86. https://doi.org/10.1177/0272989X13503499.CrossRef

71.

Teare MD, Dimairo M, Shephard N, Hayman A, Whitehead A, Walters SJ. Sample size requirements to estimate key design parameters from external pilot randomised controlled trials: a simulation study. Trials. 2014;15:264. https://doi.org/10.1186/1745-6215-15-264.CrossRefPubMedPubMedCentral

72.

Brown H, Prescott R. Applied mixed models in medicine. 3rd ed. Chichester: Wiley; 2014.CrossRef

73.

McKenzie DP, Sim MR, Clarke DM, Forbes AB, Ikin JF, Kelsall HL. Developing a brief depression screen and identifying associations with comorbid physical and psychological illness in Australian Gulf War veterans. J Psychosom Res. 2015;79(6):566–73. https://doi.org/10.1016/j.jpsychores.2015.08.003.CrossRefPubMed

74.

Cameron CM, Purdie D, Kliewer EV, McClure RJ. Ten-year outcomes following traumatic brain injury: a population-based cohort. Brain Inj. 2008;22(6):437–49. https://doi.org/10.1080/02699050802060621.CrossRefPubMed

75.

Sullivan TR, White IR, Salter AB, Ryan P, Lee KJ. Should multiple imputation be the method of choice for handling missing data in randomized trials? Stat Methods Med Res. 2018;27(9):2610–26. https://doi.org/10.1177/0962280216683570.CrossRefPubMed

76.

Mackinnon A. The use and reporting of multiple imputation in medical research - a review. J Intern Med. 2010;268(6):586–93. https://doi.org/10.1111/j.1365-2796.2010.02274.x.CrossRefPubMed

77.

Glick HA, Doshi JA, Sonnad SS, Polsky D. Economic evaluation in clinical trials. 2nd ed. Oxford: Oxford University Press; 2014. 272 p.

78.

Buntin MB, Zaslavsky AM. Too much ado about two-part models and transformation? Comparing methods of modeling Medicare expenditures. J Health Econ. 2004;23(3):525–42. https://doi.org/10.1016/j.jhealeco.2003.10.005.CrossRefPubMed

79.

International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals: writing and editing for biomedical publication. J Pharmacol Pharmacother. 2010;1:42–58.

Title: Use of olanzapine to treat agitation in traumatic brain injury: study protocol for a randomised controlled trial
Authors: Ruby K Phyland
Adam McKay
John Olver
Mark Walterfang
Malcolm Hopwood
Amelia J Hicks
Duncan Mortimer
Jennie L Ponsford
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Central Nervous System Trauma
Amnesia
Agitation
Olanzapine
Published in: Trials / Issue 1/2020
Electronic ISSN: 1745-6215
DOI: https://doi.org/10.1186/s13063-020-04553-2

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Use of olanzapine to treat agitation in traumatic brain injury: study protocol for a randomised controlled trial

Abstract

Background

Methods

Discussion

Trial registration

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Discussion

Trial registration

Please log in to get access to this content

Other articles of this Issue 1/2020

Tailored, psychological intervention for anxiety or depression in people with chronic obstructive pulmonary disease (COPD), TANDEM (Tailored intervention for ANxiety and DEpression Management in COPD): protocol for a randomised controlled trial

Effect of hydroxychloroquine on prevention of COVID-19 virus infection among healthcare professionals: a structured summary of a study protocol for a randomised controlled trial

“Early transfusion of convalescent plasma in older patients with COVID-19 to prevent disease progression: A structured summary of a study protocol for a randomised controlled trial”

Correction to: Pakistan Randomized and Observational Trial to Evaluate Coronavirus Treatment (PROTECT) of Hydroxychloroquine, Oseltamivir and Azithromycin to treat newly diagnosed patients with COVID-19 infection: A structured summary of a study protocol for a randomized controlled trial

Effects of Licorice on clinical symptoms and laboratory signs in moderately ill patients with pneumonia from COVID-19: A structured summary of a study protocol for a randomized controlled trial

Development of a core outcome set for oral health services research involving dependent older adults (DECADE): a study protocol