Clinical trial NCT04027049: Biologic Mechanisms of Early Exercise After Intracerebral Hemorrhage
Official title: Biologic Mechanisms of Early Exercise After Intracerebral Hemorrhage: a Pilot Randomized Controlled Trial of Cycle Ergometry
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Intracerebral Hemorrhage
Acute Ischemic Stroke
Keywords: rehabilitation
cycle ergometry
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
First posted: 2019-07-19
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Pilot randomized parallel group design
Primary purpose: TREATMENT

Brief summary: This study aims to determine whether in-bed cycle ergometry, early in the hospital course after a brain hemorrhage could balance damaging and reparative inflammation in the brain. Inflammatory factors of two groups of patients with brain hemorrhage will be compared, one group will receive in-bed cycling beginning 3 days after hemorrhage plus usual care and the other group will receive usual care only.


Eligibility criteria: Inclusion Criteria:

* Supratentorial intracerebral hemorrhage with or without intraventricular hemorrhage
* Pre-morbid modified Rankin Score of 0-2
* Patient must be able to provide informed consent or have a legally authorized representative to provide consent on patient's behalf

Exclusion Criteria:

* Patients with known inflammatory conditions, infection requiring antibiotics or pregnancy
* Patients receiving daily anti-inflammatory medications including but not limited to prednisone, methotrexate, non-steroidal anti-inflammatory medications (ibuprofen, naproxen, indomethacin, celecoxib) and aspirin \>325mg
* Glasgow Coma Score (GCS) 3 48 hours after admission
* Patients in whom withdrawal of life support is being considered by surrogate decision makers
* Injury to the lower extremities, hips or pelvis, weight \>250 kg (weight limit of cycle), or body habitus precluding normal function of cycle

Primary outcomes:
measure: Change in Interleukin-1beta Level in Blood (Picogram/Milliliter)
timeFrame: Day 1, day 3 and day 7 of study
measure: Absolute Change in Interleukin-6 Level in Blood (Picogram/Milliliter)
timeFrame: Day 1, day 3 and day 7 of study
measure: Change in Tumor Necrosis Factor-alpha Level in Blood (Picogram/Milliliter)
timeFrame: Day 1, day 3 and day 7 of study
measure: Change in C Reactive Protein Level in Blood (Nanogram/Milliliter)
timeFrame: Day 1, day 3 and day 7 of study
measure: Absolute Change in Brain Derived Neurotrophic Factor Level in Blood (Picogram/Milliliter)
timeFrame: Day 1, day 3 and day 7 of study
measure: Change in Interleukin-1beta Level in Cerebrospinal Fluid (Picogram/Milliliter)
timeFrame: Day 1, day 3 and day 7 of study
measure: Absolute Change in Interleukin-6 Level in CSF (Picogram/Milliliter)
timeFrame: Day 1, day 3 and day 7 of study
measure: Change in Tumor Necrosis Factor (TNF) -Alpha Level in CSF (Picogram/Milliliter)
timeFrame: Day 1, day 3 and day 7 of study
measure: Change in C Reactive Protein Level in CSF (Nanogram/Milliliter)
timeFrame: Day 1, day 3 and day 7 of study
measure: Absolute Change in Brain Derived Neurotrophic Factor Level in CSF (Picogram/Milliliter)
timeFrame: Day 1, day 3 and day 7 of study
measure: Change in Salivary Cortisol Level (Microgram/Deciliter)
timeFrame: Day 1, day 3 and day 7 of study
Secondary outcomes:
measure: Absolute Change in Hand-held Dynamometry Score (Pounds)
timeFrame: Study days 1, 3, 7, day of transfer from the ICU or discharge, whichever comes first, assessed up to 60 days
measure: Global Pre-morbid Physical Health Status as Measured by the Promis Scale v1.2
timeFrame: Day 1 of study
measure: Global Pre-morbid Mental Health Status as Measured by the Promis Scale v1.2
timeFrame: Day 1 of study
measure: Functional Status as Assessed by the Modified Rankin Score (mRS)
timeFrame: Standard of care 90-day assessment
measure: Change in the Functional Status as Assessed by the Modified Rankin Score
timeFrame: Day of ICU transfer or discharge, 90 day assessment
measure: Change in Muscle Strength as Assessed by the Medical Research Council Sum (MRCS) Score
timeFrame: Study days 1, 3, 7, On transfer from the ICU or discharge from the hospital, whichever comes first, assessed up to 60 days, 30-day follow-up visit
measure: Ability to Perform Activities of Daily Living as Assessed by the Barthel Index
timeFrame: On transfer from the ICU or discharge from the hospital, whichever comes first, assessed up to 60 days, 30-day follow-up visit
measure: Health Status as Assessed by the Stroke Impact Scale Version 3.0
timeFrame: During the 30-day follow up visit
measure: Perception of Stroke Recovery as Assessed by the Stroke Impact Scale Version 3.0
timeFrame: During the 30-day follow up visit
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins University, Department of Neurology
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Elizabeth K Zink
role: PRINCIPAL_INVESTIGATOR
References:
citation: Amidei C, Sole ML. Physiological responses to passive exercise in adults receiving mechanical ventilation. Am J Crit Care. 2013 Jul;22(4):337-48. doi: 10.4037/ajcc2013284.
citation: Arafah BM, Nishiyama FJ, Tlaygeh H, Hejal R. Measurement of salivary cortisol concentration in the assessment of adrenal function in critically ill subjects: a surrogate marker of the circulating free cortisol. J Clin Endocrinol Metab. 2007 Aug;92(8):2965-71. doi: 10.1210/jc.2007-0181. Epub 2007 May 29.
citation: Burn JP. Reliability of the modified Rankin Scale. Stroke. 1992 Mar;23(3):438. No abstract available.
citation: Burtin C, Clerckx B, Robbeets C, Ferdinande P, Langer D, Troosters T, Hermans G, Decramer M, Gosselink R. Early exercise in critically ill patients enhances short-term functional recovery. Crit Care Med. 2009 Sep;37(9):2499-505. doi: 10.1097/CCM.0b013e3181a38937.
citation: Calabrese EJ. Pre- and post-conditioning hormesis in elderly mice, rats, and humans: its loss and restoration. Biogerontology. 2016 Aug;17(4):681-702. doi: 10.1007/s10522-016-9646-8. Epub 2016 Apr 13.
citation: Camargo Pires-Neto R, Fogaca Kawaguchi YM, Sayuri Hirota A, Fu C, Tanaka C, Caruso P, Park M, Ribeiro Carvalho CR. Very early passive cycling exercise in mechanically ventilated critically ill patients: physiological and safety aspects--a case series. PLoS One. 2013 Sep 9;8(9):e74182. doi: 10.1371/journal.pone.0074182. eCollection 2013.
citation: Chen J, Qin J, Su Q, Liu Z, Yang J. Treadmill rehabilitation treatment enhanced BDNF-TrkB but not NGF-TrkA signaling in a mouse intracerebral hemorrhage model. Neurosci Lett. 2012 Oct 31;529(1):28-32. doi: 10.1016/j.neulet.2012.09.021. Epub 2012 Sep 19.
citation: Cocks K, Torgerson DJ. Sample size calculations for pilot randomized trials: a confidence interval approach. J Clin Epidemiol. 2013 Feb;66(2):197-201. doi: 10.1016/j.jclinepi.2012.09.002. Epub 2012 Nov 27.
citation: Di Napoli M, Godoy DA, Campi V, Masotti L, Smith CJ, Parry Jones AR, Hopkins SJ, Slevin M, Papa F, Mogoanta L, Pirici D, Popa Wagner A. C-reactive protein in intracerebral hemorrhage: time course, tissue localization, and prognosis. Neurology. 2012 Aug 14;79(7):690-9. doi: 10.1212/WNL.0b013e318264e3be. Epub 2012 Aug 1.
citation: Duffy L, Gajree S, Langhorne P, Stott DJ, Quinn TJ. Reliability (inter-rater agreement) of the Barthel Index for assessment of stroke survivors: systematic review and meta-analysis. Stroke. 2013 Feb;44(2):462-8. doi: 10.1161/STROKEAHA.112.678615. Epub 2013 Jan 8.
citation: Fearon P, McArthur KS, Garrity K, Graham LJ, McGroarty G, Vincent S, Quinn TJ. Prestroke modified rankin stroke scale has moderate interobserver reliability and validity in an acute stroke setting. Stroke. 2012 Dec;43(12):3184-8. doi: 10.1161/STROKEAHA.112.670422. Epub 2012 Nov 13.
citation: Fogelholm R, Murros K, Rissanen A, Avikainen S. Long term survival after primary intracerebral haemorrhage: a retrospective population based study. J Neurol Neurosurg Psychiatry. 2005 Nov;76(11):1534-8. doi: 10.1136/jnnp.2004.055145.
citation: Gao Z, Wang J, Thiex R, Rogove AD, Heppner FL, Tsirka SE. Microglial activation and intracerebral hemorrhage. Acta Neurochir Suppl. 2008;105:51-3. doi: 10.1007/978-3-211-09469-3_11.
citation: Giraldo E, Garcia JJ, Hinchado MD, Ortega E. Exercise intensity-dependent changes in the inflammatory response in sedentary women: role of neuroendocrine parameters in the neutrophil phagocytic process and the pro-/anti-inflammatory cytokine balance. Neuroimmunomodulation. 2009;16(4):237-44. doi: 10.1159/000212384. Epub 2009 Apr 9.
citation: Gomez-Cabrera MC, Domenech E, Vina J. Moderate exercise is an antioxidant: upregulation of antioxidant genes by training. Free Radic Biol Med. 2008 Jan 15;44(2):126-31. doi: 10.1016/j.freeradbiomed.2007.02.001. Epub 2007 Feb 9.
citation: Guo YC, Song XK, Xu YF, Ma JB, Zhang JJ, Han PJ. The expression and mechanism of BDNF and NGB in perihematomal tissue in rats with intracerebral hemorrhage. Eur Rev Med Pharmacol Sci. 2017 Aug;21(15):3452-3458.
citation: Hanley DF. Intraventricular hemorrhage: severity factor and treatment target in spontaneous intracerebral hemorrhage. Stroke. 2009 Apr;40(4):1533-8. doi: 10.1161/STROKEAHA.108.535419. Epub 2009 Feb 26.
citation: 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 Apr;42(2):377-81. doi: 10.1016/j.jbi.2008.08.010. Epub 2008 Sep 30.
citation: Hemphill JC 3rd, Farrant M, Neill TA Jr. Prospective validation of the ICH Score for 12-month functional outcome. Neurology. 2009 Oct 6;73(14):1088-94. doi: 10.1212/WNL.0b013e3181b8b332. Epub 2009 Sep 2.
citation: Hermans G, Clerckx B, Vanhullebusch T, Segers J, Vanpee G, Robbeets C, Casaer MP, Wouters P, Gosselink R, Van Den Berghe G. Interobserver agreement of Medical Research Council sum-score and handgrip strength in the intensive care unit. Muscle Nerve. 2012 Jan;45(1):18-25. doi: 10.1002/mus.22219.
citation: Hodgson CL, Stiller K, Needham DM, Tipping CJ, Harrold M, Baldwin CE, Bradley S, Berney S, Caruana LR, Elliott D, Green M, Haines K, Higgins AM, Kaukonen KM, Leditschke IA, Nickels MR, Paratz J, Patman S, Skinner EH, Young PJ, Zanni JM, Denehy L, Webb SA. Expert consensus and recommendations on safety criteria for active mobilization of mechanically ventilated critically ill adults. Crit Care. 2014 Dec 4;18(6):658. doi: 10.1186/s13054-014-0658-y.
citation: Ishida A, Misumi S, Ueda Y, Shimizu Y, Cha-Gyun J, Tamakoshi K, Ishida K, Hida H. Early constraint-induced movement therapy promotes functional recovery and neuronal plasticity in a subcortical hemorrhage model rat. Behav Brain Res. 2015 May 1;284:158-66. doi: 10.1016/j.bbr.2015.02.022. Epub 2015 Feb 17.
citation: Ji LL, Gomez-Cabrera MC, Vina J. Exercise and hormesis: activation of cellular antioxidant signaling pathway. Ann N Y Acad Sci. 2006 May;1067:425-35. doi: 10.1196/annals.1354.061.
citation: Kimawi I, Lamberjack B, Nelliot A, Toonstra AL, Zanni J, Huang M, Mantheiy E, Kho ME, Needham DM. Safety and Feasibility of a Protocolized Approach to In-Bed Cycling Exercise in the Intensive Care Unit: Quality Improvement Project. Phys Ther. 2017 Jun 1;97(6):593-602. doi: 10.1093/ptj/pzx034.
citation: Kho ME, Martin RA, Toonstra AL, Zanni JM, Mantheiy EC, Nelliot A, Needham DM. Feasibility and safety of in-bed cycling for physical rehabilitation in the intensive care unit. J Crit Care. 2015 Dec;30(6):1419.e1-5. doi: 10.1016/j.jcrc.2015.07.025. Epub 2015 Jul 29.
citation: Kho ME, Molloy AJ, Clarke FJ, Ajami D, McCaughan M, Obrovac K, Murphy C, Camposilvan L, Herridge MS, Koo KK, Rudkowski J, Seely AJ, Zanni JM, Mourtzakis M, Piraino T, Cook DJ; Canadian Critical Care Trials Group. TryCYCLE: A Prospective Study of the Safety and Feasibility of Early In-Bed Cycling in Mechanically Ventilated Patients. PLoS One. 2016 Dec 28;11(12):e0167561. doi: 10.1371/journal.pone.0167561. eCollection 2016.
citation: Lei C, Lin S, Zhang C, Tao W, Dong W, Hao Z, Liu M, Wu B. High-mobility group box1 protein promotes neuroinflammation after intracerebral hemorrhage in rats. Neuroscience. 2013 Jan 3;228:190-9. doi: 10.1016/j.neuroscience.2012.10.023. Epub 2012 Oct 22.
citation: Mello RC, Sad EF, Andrade BC, Neves SP, Santos SM, Sarquis MM, Marik PE, Dias EP. Serum and salivary cortisol in the diagnosis of adrenal insufficiency and as a predictor of the outcome in patients with severe sepsis. Arq Bras Endocrinol Metabol. 2011 Oct;55(7):455-9. doi: 10.1590/s0004-27302011000700004.
citation: Mendelow AD, Gregson BA, Rowan EN, Murray GD, Gholkar A, Mitchell PM; STICH II Investigators. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet. 2013 Aug 3;382(9890):397-408. doi: 10.1016/S0140-6736(13)60986-1. Epub 2013 May 29.
citation: Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB, McGuire DK, Mohler ER 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2015 update: a report from the American Heart Association. Circulation. 2015 Jan 27;131(4):e29-322. doi: 10.1161/CIR.0000000000000152. Epub 2014 Dec 17. No abstract available.
citation: Ortega E. The
citation: Ovbiagele B, Goldstein LB, Higashida RT, Howard VJ, Johnston SC, Khavjou OA, Lackland DT, Lichtman JH, Mohl S, Sacco RL, Saver JL, Trogdon JG; American Heart Association Advocacy Coordinating Committee and Stroke Council. Forecasting the future of stroke in the United States: a policy statement from the American Heart Association and American Stroke Association. Stroke. 2013 Aug;44(8):2361-75. doi: 10.1161/STR.0b013e31829734f2. Epub 2013 May 22.
citation: Poon MT, Fonville AF, Al-Shahi Salman R. Long-term prognosis after intracerebral haemorrhage: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2014 Jun;85(6):660-7. doi: 10.1136/jnnp-2013-306476. Epub 2013 Nov 21.
citation: Quinn TJ, Dawson J, Walters MR, Lees KR. Reliability of the modified Rankin Scale: a systematic review. Stroke. 2009 Oct;40(10):3393-5. doi: 10.1161/STROKEAHA.109.557256. Epub 2009 Aug 13.
citation: Qureshi AI, Palesch YY, Barsan WG, Hanley DF, Hsu CY, Martin RL, Moy CS, Silbergleit R, Steiner T, Suarez JI, Toyoda K, Wang Y, Yamamoto H, Yoon BW; ATACH-2 Trial Investigators and the Neurological Emergency Treatment Trials Network. Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage. N Engl J Med. 2016 Sep 15;375(11):1033-43. doi: 10.1056/NEJMoa1603460. Epub 2016 Jun 8.
citation: Steins Bisschop CN, Courneya KS, Velthuis MJ, Monninkhof EM, Jones LW, Friedenreich C, van der Wall E, Peeters PH, May AM. Control group design, contamination and drop-out in exercise oncology trials: a systematic review. PLoS One. 2015 Mar 27;10(3):e0120996. doi: 10.1371/journal.pone.0120996. eCollection 2015.
citation: Takamatsu Y, Tamakoshi K, Waseda Y, Ishida K. Running exercise enhances motor functional recovery with inhibition of dendritic regression in the motor cortex after collagenase-induced intracerebral hemorrhage in rats. Behav Brain Res. 2016 Mar 1;300:56-64. doi: 10.1016/j.bbr.2015.12.003. Epub 2015 Dec 7.
citation: Franca EE, Ribeiro LC, Lamenha GG, Magalhaes IK, Figueiredo TG, Costa MJ, Elihimas UF Junior, Feitosa BL, Andrade MD, Correia MA Junior, Ramos FF, Castro CM. Oxidative stress and immune system analysis after cycle ergometer use in critical patients. Clinics (Sao Paulo). 2017 Mar;72(3):143-149. doi: 10.6061/clinics/2017(03)03.
citation: Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet. 1974 Jul 13;2(7872):81-4. doi: 10.1016/s0140-6736(74)91639-0. No abstract available.
citation: Thelandersson A, Nellgard B, Ricksten SE, Cider A. Effects of Early Bedside Cycle Exercise on Intracranial Pressure and Systemic Hemodynamics in Critically Ill Patients in a Neurointensive Care Unit. Neurocrit Care. 2016 Dec;25(3):434-439. doi: 10.1007/s12028-016-0278-2.
citation: Wang P, Li CG, Qi Z, Cui D, Ding S. Acute exercise stress promotes Ref1/Nrf2 signalling and increases mitochondrial antioxidant activity in skeletal muscle. Exp Physiol. 2016 Mar;101(3):410-20. doi: 10.1113/EP085493. Epub 2016 Jan 23.
citation: Wang XM, Zhang YG, Li AL, Long ZH, Wang D, Li XX, Xia JH, Luo SY, Shan YH. Expressions of serum inflammatory cytokines and their relationship with cerebral edema in patients with acute basal ganglia hemorrhage. Eur Rev Med Pharmacol Sci. 2016 Jul;20(13):2868-71.
citation: Wei P, You C, Jin H, Chen H, Lin B. Correlation between serum IL-1beta levels and cerebral edema extent in a hypertensive intracerebral hemorrhage rat model. Neurol Res. 2014 Feb;36(2):170-5. doi: 10.1179/1743132813Y.0000000292. Epub 2013 Dec 19.
citation: Winkelman C. Investigating activity in hospitalized patients with chronic obstructive pulmonary disease: a pilot study. Heart Lung. 2010 Jul-Aug;39(4):319-30. doi: 10.1016/j.hrtlng.2009.09.004. Epub 2010 Apr 8.
citation: Wu J, Yang S, Xi G, Song S, Fu G, Keep RF, Hua Y. Microglial activation and brain injury after intracerebral hemorrhage. Acta Neurochir Suppl. 2008;105:59-65. doi: 10.1007/978-3-211-09469-3_13.
citation: Xue M, Del Bigio MR. Comparison of brain cell death and inflammatory reaction in three models of intracerebral hemorrhage in adult rats. J Stroke Cerebrovasc Dis. 2003 May-Jun;12(3):152-9. doi: 10.1016/S1052-3057(03)00036-3.
citation: Yang X, Ren W, Zu H, Dong Q. Evaluate the serum cortisol in patients with intracerebral hemorrhage. Clin Neurol Neurosurg. 2014 Aug;123:127-30. doi: 10.1016/j.clineuro.2014.05.019. Epub 2014 Jun 5.
citation: Yang Z, Yu A, Liu Y, Shen H, Lin C, Lin L, Wang S, Yuan B. Regulatory T cells inhibit microglia activation and protect against inflammatory injury in intracerebral hemorrhage. Int Immunopharmacol. 2014 Oct;22(2):522-5. doi: 10.1016/j.intimp.2014.06.037. Epub 2014 Jul 4.
citation: Yong MS, Hwangbo K. Skilled reach training influences brain recovery following intracerebral hemorrhage in rats. J Phys Ther Sci. 2014 Mar;26(3):405-7. doi: 10.1589/jpts.26.405. Epub 2014 Mar 25.
citation: Yuan ZH, Jiang JK, Huang WD, Pan J, Zhu JY, Wang JZ. A meta-analysis of the efficacy and safety of recombinant activated factor VII for patients with acute intracerebral hemorrhage without hemophilia. J Clin Neurosci. 2010 Jun;17(6):685-93. doi: 10.1016/j.jocn.2009.11.020.
citation: Zhao X, Sun G, Ting SM, Song S, Zhang J, Edwards NJ, Aronowski J. Cleaning up after ICH: the role of Nrf2 in modulating microglia function and hematoma clearance. J Neurochem. 2015 Apr;133(1):144-52. doi: 10.1111/jnc.12974. Epub 2014 Nov 24.