Safety and efficacy of applying sufficient analgesia combined with a minimal sedation program as an early antihypertensive treatment for spontaneous intracerebral hemorrhage: a randomized controlled trial

Rui Dong, Fen Li, Ying Xu, Pingyan Chen, Marc Maegele, Hong Yang, Wenjin Chen, Rui Dong, Fen Li, Ying Xu, Pingyan Chen, Marc Maegele, Hong Yang, Wenjin Chen

Abstract

Background: Spontaneous intracerebral hemorrhage (ICH) is a serious threat to human health. Although early blood pressure (BP) elevation is closely associated with a poor prognosis, the optimal antihypertensive regimen for acute-phase ICH remains controversial. In ICH, pain, sleep deprivation, and stress are usually the main causes of dramatic BP increases. While traditional antihypertensive treatment resolves the increased BP, it does not address the root cause of the disease. Remifentanil relieves pain and, when combined with dexmedetomidine's antisympathetic action, can restore elevated BP to normal levels. Here, we seek to validate the efficacy and safety of applying sufficient analgesia in combination with a minimal sedation program versus antihypertensive drug therapy for the early and rapid stabilization of BP in ICH patients.

Methods/design: We are conducting a multicenter, prospective, randomized controlled, single-blinded, superiority clinical trial across 15 hospitals. We will enroll 354 subjects in mainland China, and all subjects will be randomized into experimental and control groups in which they will be given remifentanil combined with dexmedetomidine or antihypertensive drugs (urapidil, nicardipine, and labetalol). The primary endpoint will be the systolic BP control rate within 1 h of treatment initiation, and the efficacy and safety of the antihypertensive regimens will be compared between the two groups. Secondary endpoints include the incidence rate of early hemorrhage growth, neurological function, duration of intensive care unit (ICU) stay, and staff satisfaction with the treatment process.

Discussion: We hypothesize that applying sufficient analgesia in combination with minimal sedation will act as an effective and safe antihypertensive strategy in ICH and that this treatment strategy could, therefore, be widely used as an ICH acute-phase therapy.

Trial registration: ClinicalTrials.gov, ID: NCT03207100 . Registered on 22 July 2017.

Keywords: Clinical trial; Early antihypertensive treatment; Intracerebral hemorrhage; Minimal sedation; Sufficient analgesia.

Conflict of interest statement

Ethics approval and consent to participate

The Institutional Ethics Committee of The Third Affiliated Hospital of Southern Medical University has approved our study for the various centers (reference number: 201711009). All enrolled subjects will sign an informed consent form (ICF).

Consent for publication

Each participant will provide consent to publish individual patient data.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Flow diagram of the study
Fig. 2
Fig. 2
Schedule of assessments/data collection

References

    1. Wang WJ, Wang CX, Yang ZH, Liu LP, Lu JJ, Wang AX, Zhao XQ. Management and variables associated with case fatality of intracerebral haemorrhage in China. Chin J Stroke. 2013;8(9):703–711.
    1. Chinese Society of Neurosurgery. Chinese College of Emergency Physicians. Stroke Screening Prevention Project Committee, National Health Family Planning Commission, P. R. China Multidisciplinary expert consensus on the diagnosis and treatment of spontaneous intracerebral hemorrhage in China. Chin J Neurosurg. 2015;31(12):1189–1194.
    1. Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage. N Engl J Med. 2001;344:1450–1460. doi: 10.1056/NEJM200105103441907.
    1. Eastern Stroke and Coronary Heart Disease Collaborative Research Group Blood pressure, cholesterol and stroke in eastern Asia. Lancet. 1998;352:1801–1807. doi: 10.1016/S0140-6736(98)03454-0.
    1. Asia Pacific Cohort Studies Collaboration Blood pressure and cardiovascular diseases in the Asia-Pacific region. J Hypertens. 2003;21(4):707–716. doi: 10.1097/00004872-200304000-00013.
    1. Wallace JD, Levy LL. Blood pressure after stroke. JAMA. 1981;246:2177–2180. doi: 10.1001/jama.1981.03320190035023.
    1. Harper G, Castleden CM, Potter JF. Factors affecting changes in blood pressure after acute stroke. Stroke. 1994;25:1726–1729. doi: 10.1161/01.STR.25.9.1726.
    1. Ong TZ, Raymond AA. Risk factors for stroke and predictors of one-month mortality. Singap Med J. 2002;43(10):517–521.
    1. Becker KJ, Baxter AB, Bybee HM, Tirschwell DL, Abouelsaad T, Cohen WA. Extravasation of radiographic contrast is an independent predictor of death in primary intracerebral hemorrhage. Stroke. 1999;30:2025–2032. doi: 10.1161/01.STR.30.10.2025.
    1. Mayer SA, Sacco RL, Shi T, Mohr JP. Neurologic deterioration in noncomatose patients with supratentorial intracerebral hemorrhage. Neurology. 1994;44:1379–1384. doi: 10.1212/WNL.44.8.1379.
    1. Chen ST, Chen SD, Hsu CY, Hogan EL. Progression of hypertensive intracerebral hemorrhage. Neurology. 1989;39:1509–1514. doi: 10.1212/WNL.39.11.1509.
    1. Broderick JP, Brott TG, Tomsick T, Barsan W, Spilker J. Ultra-early evaluation of intracerebral hemorrhage. J Neurosurg. 1990;72:195–199. doi: 10.3171/jns.1990.72.2.0195.
    1. Zhou JF, Wang JY, Luo YE, Chen HH. Influence of hypertension, lipometabolism disorders, obesity and other lifestyles on spontaneous intracerebral hemorrhage. Biomed Environ Sci. 2003;16(3):295–303.
    1. Kazui S, Minematsu K, Yamamoto H, Sawada T, Yamaguchi T. Predisposing factors to enlargement of spontaneous intracerebral hematoma. Stroke. 1997;28:2370–2375. doi: 10.1161/01.STR.28.12.2370.
    1. Gebel JM, Jauch EC, Brott TG, Khoury J, Sauerbeck L, Salisbury S, et al. Natural history of perihematomal edema in patients with hyperacute spontaneous intracerebral hemorrhage. Stroke. 2002;33:2631–2635. doi: 10.1161/01.STR.0000035284.12699.84.
    1. Carhuapoma JR, Hanley DF, Banerjee M, Beauchamp NJ. Brain edema after human cerebral hemorrhage: a magnetic resonance imaging volumetric analysis. J Neurosurg Anesth. 2003;15:230–233. doi: 10.1097/00008506-200307000-00010.
    1. Arakawa S, Saku Y, Ibayashi S, Nagao T, Fujishima M. Blood pressure control and recurrence of hypertensive brain hemorrhage. Stroke. 1998;29:1806–1809. doi: 10.1161/01.STR.29.9.1806.
    1. Terayama Y, Tanahashi N, Fukuuchi Y, Gotoh F. Prognostic value of admission blood pressure in patients with intracerebral hemorrhage: Keio Cooperative Stroke Study. Stroke. 1997;28:1185–1188. doi: 10.1161/01.STR.28.6.1185.
    1. Hemphill JR, Greenberg SM, Anderson CS, Becker K, Bendok BR, Cushman M, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46:2032–2060. doi: 10.1161/STR.0000000000000069.
    1. Anderson CS, Heeley E, Huang Y, Wang J, Stapf C, Delcourt C, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med. 2013;368:2355–2365. doi: 10.1056/NEJMoa1214609.
    1. Manning L, Hirakawa Y, Arima H, Wang X, Chalmers J, Wang J, et al. Blood pressure variability and outcome after acute intracerebral haemorrhage: a post-hoc analysis of INTERACT2, a randomised controlled trial. Lancet Neurol. 2014;13:364–373. doi: 10.1016/S1474-4422(14)70018-3.
    1. Anderson CS, Huang Y, Wang JG, Arima H, Neal B, Peng B, et al. Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Lancet Neurol. 2008;7:391–399. doi: 10.1016/S1474-4422(08)70069-3.
    1. Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) investigators Antihypertensive treatment of acute cerebral hemorrhage. Crit Care Med. 2010;38:637–648. doi: 10.1097/CCM.0b013e3181b9e1a5.
    1. 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. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. N Engl J Med. 2016;375(11):1033–1043. doi: 10.1056/NEJMoa1603460.
    1. Kate MP, Hansen MB, Mouridsen K, Østergaard L, Choi V, Gould BE, et al. Blood pressure reduction does not reduce perihematoma oxygenation: a CT perfusion study. J Cereb Blood Flow Metab. 2014;34:81–86. doi: 10.1038/jcbfm.2013.164.
    1. Boulouis G, Morotti A, Goldstein JN, Charidimou A. Intensive blood pressure lowering in patients with acute intracerebral haemorrhage: clinical outcomes and haemorrhage expansion. Systematic review and meta-analysis of randomised trials. J Neurol Neurosurg Psychiatry. 2017;88:339–345. doi: 10.1136/jnnp-2016-315346.
    1. Egawa S, Hifumi T, Kawakita K, Okauchi M, Shindo A, Kawanishi M, Tamiya T, Kuroda Y. Impact of neurointensivist-managed intensive care unit implementation on patient outcomes after aneurysmal subarachnoid hemorrhage. J Crit Care. 2016;32:52–55. doi: 10.1016/j.jcrc.2015.11.008.
    1. Rodriguezluna D, Piñeiro S, Rubiera M, Ribo M, Coscojuela P, Pagola J, et al. Impact of blood pressure changes and course on hematoma growth in acute intracerebral hemorrhage. Eur J Neurol. 2013;20:1277–1283. doi: 10.1111/ene.12180.
    1. Tanaka E, Koga M, Kobayashi J, Kario K, Kamiyama K, Furui E, et al. Blood pressure variability on antihypertensive therapy in acute intracerebral hemorrhage: the Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-intracerebral hemorrhage study. Stroke. 2014;45:2275–2279. doi: 10.1161/STROKEAHA.114.005420.
    1. Steiner T, Alshahi SR, Beer R, Christensen H, Cordonnier C, Csiba L, et al. European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage. Int J Stroke. 2014;9:840–855. doi: 10.1111/ijs.12309.
    1. Oddo M, Crippa IA, Mehta S, Menon D, Payen JF, Taccone FS, Citerio G. Optimizing sedation in patients with acute brain injury. Crit Care. 2016;20:128. doi: 10.1186/s13054-016-1294-5.
    1. Swieten JCV, Koudstaal PJ, Visser MC, Schouten HJ, Gijn JV. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19:604–607. doi: 10.1161/01.STR.19.5.604.
    1. De Leyn P, Bedert L, Delcroix M, Depuydt P, Lauwers G, Sokolov Y. Tracheotomy: clinical review and guidelines. Eur J Cardiothorac Surg. 2007;32(3):412–421. doi: 10.1016/j.ejcts.2007.05.018.
    1. Brott T, Broderick J, Kothari R, Barsan W, Tomsick T, Sauerbeck L, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke. 1997;28:1–5. doi: 10.1161/01.STR.28.1.1.
    1. Broderick JP, Diringer MN, Hill MD, Brun NC, Mayer SA, Steiner T, et al. Determinants of intracerebral hemorrhage growth an exploratory analysis. Stroke. 2007;38:1072–1075. doi: 10.1161/01.STR.0000258078.35316.30.
    1. Broderick JP, Brott TG, Duldner JE, Tomsick T, Huster G. Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality. Stroke. 1993;24:987–993. doi: 10.1161/01.STR.24.7.987.
    1. Kothari RU, Brott T, Broderick JP, Barsan WG, Sauerbeck LR, Zuccarello M, Khoury J. The ABCs of measuring intracerebral hemorrhage volumes. Stroke. 1996;27:1304–1305. doi: 10.1161/01.STR.27.8.1304.
    1. Kazui S, Naritomi H, Yamamoto H, Sawada T, Yamaguchi T. Enlargement of spontaneous intracerebral hemorrhage. Incidence and time course. Stroke. 1996;27:1783–1787. doi: 10.1161/01.STR.27.10.1783.
    1. Andreas K, Kostas M, Spiros S, Apostolos K, Jens S, Ben S, Kirkham Andrew JT. Safety and efficacy of analgesia-based sedation with remifentanil versus standard hypnotic-based regimens in intensive care unit patients with brain injuries: a randomised, controlled trial [ISRCTN50308308] Crit Care. 2004;8(4):R268–R280. doi: 10.1186/cc2896.
    1. Yokota H, Yokoyama K, Noguchi H, Nishioka T, Umegaki O, Komatsu H, Sakaki T. Post-operative dexmedetomidine-based sedation after uneventful intracranial surgery for unruptured cerebral aneurysm: comparison with propofol-based sedation. Neurocrit Care. 2011;14:182–187. doi: 10.1007/s12028-010-9485-4.
    1. Grof TM, Bledsoe KA. Evaluating the use of dexmedetomidine in neurocritical care patients. Neurocrit Care. 2010;12:356–361. doi: 10.1007/s12028-008-9156-x.
    1. Brott T, Adams HP, Jr, Olinger CP, Marler JR, Barsan WG, Biller J, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke. 1989;20:864–870. doi: 10.1161/01.STR.20.7.864.
    1. Kasner SE. Clinical interpretation and use of stroke scales. Lancet Neurol. 2006;5:603–612. doi: 10.1016/S1474-4422(06)70495-1.
    1. Teasdale G, Maas A, Lecky F, Manley G, Stocchetti N, Murray G. The Glasgow Coma Scale at 40 years: standing the test of time. Lancet Neurol. 2014;13:844–854. doi: 10.1016/S1474-4422(14)70120-6.
    1. Barr J, Fraser GL, Puntillo K, Ely EW, Gélinas C, Dasta JF, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the Intensive Care Unit. Crit Care Med. 2013;41:263–306. doi: 10.1097/CCM.0b013e3182783b72.
    1. Topolovec-Vranic J, Canzian S, Innis J, Pollmann-Mudryj MA, Mcfarlan AW, Baker AJ. Patient satisfaction and documentation of pain assessments and management after implementing the adult nonverbal pain scale. Am J Crit Care. 2010;19:345–354. doi: 10.4037/ajcc2010247.
    1. Starmark JE, Stålhammar D, Holmgren E, Eriksson N, Nordström CH, Fedders O, Rosander B. Assessment of responsiveness in acute cerebral disorders. A multicentre study on the Reaction Level Scale (RLS 85) Acta Neurochir. 1988;90:73–80. doi: 10.1007/BF01560558.
    1. Pejtersen JH, Kristensen TS, Borg V, Bjorner JB. The second version of the Copenhagen Psychosocial Questionnaire. Scand J Public Health. 2010;38:8–24. doi: 10.1177/1403494809349858.
    1. Ferrari M, Quaresima V. A brief review on the history of human functional near-infrared spectroscopy (fNIRS) development and fields of application. NeuroImage. 2012;63:921–935. doi: 10.1016/j.neuroimage.2012.03.049.
    1. Scholkmann F, Kleiser S, Metz AJ, Zimmermann R, Mata Pavia J, Wolf U, Wolf M. A review on continuous wave functional near-infrared spectroscopy and imaging instrumentation and methodology. Neuroimage. 2014;85 Pt 1:6–27. doi: 10.1016/j.neuroimage.2013.05.004.
    1. Coleman RM, Tousignant-Laflamme Y, Ouellet P, Parenteau-Goudreault É, Cogan J, Bourgault P. The use of the bispectral index in the detection of pain in mechanically ventilated adults in the intensive care unit: A review of the literature. Pain Res Manag. 2015;20:e33–e37. doi: 10.1155/2015/981419.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する