ASSICHH: Analgesia-first Minimal Sedation for Spontaneous Intracerebral Hemorrhage Early Antihypertensive Treatment

• Sponsor: Hong Yang (Other)
• Overall Status: Completed
• CT.gov ID: NCT03207100
• Collaborator: Xuanwu Hospital, Beijing (Other), Qilu Hospital of Shandong University (Other), The First Affiliated Hospital of Kunming Medical College (Other), First Affiliated Hospital of Xinjiang Medical University (Other), Second Affiliated Hospital of Third Military Medical University (Other), Henan Provincial People's Hospital (Other), The Second Hospital University of South China (Other), Shenzhen Second People's Hospital (Other), People's Hospital of Guangxi (Other), Department of Biostatistics, Southern Medical University (Other), LanZhou University (Other), The First Affiliated Hospital of HuNan University of Medicine (Other), Guangdong 999 Brain Hospital (Other), Maoming People's Hospital (Other), The Fifth Affiliated Hospital of Southern Medical University (Other), Zhongshan People's Hospital, Guangdong, China (Other), Fifth Affiliated Hospital, Sun Yat-Sen University (Other)
• Enrollment: 305
• Locations: 17
• Arms: 2
• Actual Duration (Months): 41.3
• Patients Per Site: 17.9
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This study evaluates safety and efficacy of analgesia-first minimal sedation as an early antihypertensive treatment for spontaneous intracerebral hemorrhage. The analgesia-first minimal sedation strategy relies on the remifentanil-mediated alleviation of pain-induced stress response and the antisympathetic activity of dexmedetomidine to restore the elevated blood pressure to normal level in patients with spontaneous intracerebral hemorrhage. This strategy allows rapid stabilization of blood pressure, and its use as a pre-treatment for patients on mechanical ventilation prior to painful procedures reduces blood pressure variability and thereby results in etiologic treatment. It is more effective in blood pressure control than conventional symptomatic antihypertensive treatment, reduces the incidence of early hematoma expansion and improves prognosis, ,lowers healthcare workers workload, increases patient adherence, and improves healthcare worker satisfaction.

Condition or Disease	Intervention/Treatment	Phase
Early Systolic Blood Pressure Control Rate; Hematoma Growth; Blood Pressure Variability; Healthcare Worker Satisfaction; Duration of ICU Treatment and Mechanical Ventilation	Combination Product: Analgesia-first minimal sedation; Combination Product: Antihypertensive treatment	N/A

Detailed Description

Spontaneous intracerebral hemorrhage (ICH) is hemorrhage in the brain parenchyma caused by non-traumatic spontaneous rupture of cerebral artery, arteriole, vein and capillary in adults. ICH is a common problem, with subarachnoid hemorrhage. About 90% ICH patients have increased blood pressure (BP) that usually occurs immediately after disease onset. BP elevation in the acute phase of ICH is associated with poor prognosis, and its mechanism of action includes the local increase of initial hemorrhage, early hematoma expansion at hemorrhagic sites, the increased risk of early recurrent hemorrhage, serious cerebral edema, and recurrent stroke, this affects the most within the few hours following the onset of the disease. The current American Heart Association guidelines recommended early antihypertensive treatment and suggested that rapid decrease of BP to 140 mmHg is safe in ICH patients with no obvious antihypertensive contraindications. However, the significant differences between large studies conducted in recent years have led to great controversy on the effect of early antihypertensive treatment in acute ICH and disease prognosis. A meta-analysis of early antihypertensive treatment for ICH showed that differences in early BP control rate and BP increase variability are also the major causes of inconsistency between these studies. There is currently no consensus on the best antihypertensive regimen as it is difficult to reach the optimal BP level timely. Some studies have shown that stress response, pain, ICP increase and pre-onset BP elevation are factors that cause acute BP increase in ICH patients. In particular, restlessness, sleep deprivation, and stress due to intolerable pain can lead to dramatic BP and intracranial pressure (ICP) increases, further lead to secondary intracerebral hematoma expansion and subsequently cause neurologic degeneration and cerebral tissue damage. Therefore, the primary principles of ICH acute BP increase treatment are to keep quiet, restore BP to normal level, stably reduce BP, decrease BP variability, lower the chance of recurrent hemorrhage, and thereby improve long-term prognosis. Traditional antihypertensive treatment can only resolve the issue of BP elevation but not the root cause of disease. Analgesia and sedation is a critical component of and a global consensus in the clinical management of ICH patients. Remifentanil is a fentanyl μ-type opioid receptor agonist with strong and fast-acting analgesic effects, does not induce ICP elevation and can alleviate pain induced by sputum aspiration, body turning and back clapping in severe patients. A randomized trial on patients with craniocerebral injury has indicated that a remifentanil-based sedation strategy can significantly reduce the amount of sedative used and shorten the time of mechanical ventilation without affecting the functional assessment of the nervous system. Dexmedetomidine is an α2-adrenergic agonist that inhibits sympathetic activity by activating the pre-synaptic α2-receptor in the locus coeruleus, which in turn reduces norepinephrine release, that only slightly affects consciousness and breathing and helps patients with craniocerebral injury stay conscious while under sedation, allowing real-time functional assessment of the nervous system. Therefore, the research group developed a treatment strategy in which sufficient analgesia is applied in combination with a minimal sedation program as an effective and safe early an- tihypertensive treatment.We hypothesize that applying sufficient analgesia in combination with a minimal sedation program will involve the use of remifentanil for pain relief and dexmedetomidine for antisympathetic activity to restore elevated BP to normal levels in patients with spontaneous ICH, and we further hypothesize that this strategy will be more effective than conventional symptomatic antihypertensive treatment for controlling BP.

Study Design

• Study Type: Interventional
• Actual Enrollment: 305 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Subjects are grouped into the analgesia-first minimal sedation group (experimental group) or antihypertensive drug treatment group (control group) using the central randomization system upon enrollment. Antihypertensive intervention is performed on the subjects in accordance to the protocol of each group.Subjects are grouped into the analgesia-first minimal sedation group (experimental group) or antihypertensive drug treatment group (control group) using the central randomization system upon enrollment. Antihypertensive intervention is performed on the subjects in accordance to the protocol of each group.
• Masking: Single (Participant)
• Masking Description: This study uses a single-blinded design in which only the investigators and not the subjects know the method of intervention.
• Primary Purpose: Treatment
• Official Title: Clinical Study of the Safety and Efficacy of Analgesia-first Minimal Sedation as an Early Antihypertensive Treatment for Spontaneous Intracerebral Hemorrhage
• Actual Study Start Date: Dec 6, 2017
• Actual Primary Completion Date: Feb 14, 2021
• Actual Study Completion Date: May 15, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Analgesia-first minimal sedation group Using analgesia-first minimal sedation strategy to implement antihypertensive therapy.	Combination Product: Analgesia-first minimal sedation; Remifentanil will be administered by IV infusion and maintained at a dose of 0.025 μg/kg/min in non-mechanically ventilated patients and a dose of 0.05 μg/kg/min in mechanically ventilated patients. BP will be measured after 10 min of continuous infusion.If systolic BP is still ≥ 140 mmHg, then dexmedetomidine will be applied using an infusion pump at a dose of 0.2 μg/kg/h. BP will be measured again after 15 min of continuous infusion of dexmedetomidine. If systolic BP is still ≥ 140 mmHg, the dose of dexmedetomidine can be increased 0.1 μg/kg/h to the maximum of 0.6 μg/kg/h.If the maximum dose of dexmedetomidine does not lower blood pressure, use routine blood pressure reduction programs in each center to reduce blood pressure to the target range. Mechanically ventilated patients will be given a rapid remifentanil (0.5 μg/kg) infusion to reduce procedure-related pain.
Active Comparator: Antihypertensive drug treatment group Using routine antihypertensive drugs to implement antihypertensive therapy.	Combination Product: Antihypertensive treatment; Routine antihypertensive treatment will be performed in accordance with the protocol of each respective research center. Urapidil, nicardipine, and labetalol will be used in this group. Urapidil will be used as follows: a slow IV injection of 10-15 mg and then IV pumping for maintenance at an initial rate of 2 mg/min, adjusted according to BP to a maximum of 9 mg/min. Nicardipine will be used as follows: IV pumping at 0.5μg/kg/min adjusted according to BP to a maximum of 6μg/kg/min. Labetalol will be used as follows: IV infusion for maintenance at 1-4 mg/min until the aim is reached.The mechanically ventilated patients in the control group will be administered a rapid physiological saline infusion as a controlled pretreatment.

Outcome Measures

Primary Outcome Measures

1. Systolic BP control rate at 1h post-treatment initiation [1h post-treatment initiation]

   The number of patients who systolic BP decreased to <140 mmHg at 1h post-treatment initiation compared to the total number of each group.

Secondary Outcome Measures

1. Hematoma growth at 24 h [24h of treatment]

   Head CT re-examination is required for the subjects after 24h of treatment.Hematoma expansion is defined as V2-V1≥12.5 cm³ or (V2-V1)/V1>33% (V1 and V2 represent the hematoma volume in the two CT scans, respectively).

2. BP variability [Up to 7 days]

   BPs are also recorded every hour from hour 2 to 24 post-treatment, and monitored on d2-d7 of treatment of recorded every 6h daily (4 times per day); BP Coefficient of Variation (CV) = (standard deviation of BP/mean of systolic BP).

3. Neurologic function [Up to 7 days]

   Assessed once every morning using the National Institutes of Health Stroke Scale (NIHSS), Glasgow Coma Scale scores (GCS), Richmond Agitation-Sedation Scale (RASS), Nonverbal Adult Pain Assessment Scale (NVPS), Reaction Level Scale (RLS).

4. Duration of ICU treatment and mechanical ventilation [Up to 7 days]

   Duration of ICU treatment and mechanical ventilation

5. Healthcare worker satisfaction [7 day or discharge from ICU (if patients discharge from ICU in 7 days)]

   Questionnaire is designed based on the Copenhagen Psychosocial Questionnaire, with a parameter for self-assessed workload.

6. cerebral tissue oxygenation index (TOI) [Up to 7 days and around sputum aspiration]

   Assess changes in the TOI after sputum aspiration in mechanical ventilation patients

7. 28-day mortality and disability rate [28 days]

   Using a binary indicator of the patient's death or dependency at 28 days, with dependency being defined by a score of 3 to 5 on the modified Rankin Score (mRS)

8. 90-day mortality and disability rate [90 days]

   Using a binary indicator of the patient's death or dependency at 90 days, with dependency being defined by a score of 3 to 5 on the modified Rankin Score (mRS)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Definitive diagnosis of ICH-induced acute brain injury by CT;

2. Systolic BP ≥150 mmHg for at least twice;

3. 18 years old;

4. Feasible for emergency antihypertensive treatment and real-time BP monitoring;

5. Disease onset is within 24h;

6. ICU or stroke unit admission within 24h.

Exclusion Criteria:

1. Subject has contraindications for emergency intensified antihypertensive treatment;

2. Intracranial hemorrhage secondary to intracranial tumor, recent trauma, cerebral infarction and thrombolytic therapy;

3. History of ischemic stroke within 30 days before disease onset;

4. Clinical or imaging examination reveals an expected high mortality in subject within the next 24h;

5. Presence of dementia or significant post-stroke disability;

6. Coagulation disorder caused by drugs or hematologic diseases;

7. Allergy to opioids;

8. Interference test result, assessment and follow-up of comorbidity;

9. Presence of sinus arrest, borderline rhythm, grade II and above atrioventricular block and malignant arrhythmia;

10. Individual is pregnant or lactating;

11. Currently participating in other drug studies or clinical trials;

12. Subject or guardian is unwilling to provide his/her informed consent form, or subject is highly unable to persist with the study and follow-up;

13. Subject's participation in the study will increase his/her study-related risk, and other reasons that make the subject unsuitable for the study as determined by the investigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Xuanwu Hospital Capital Medical University	Beijing	Beijing	China	100053
2	Xinqiao Hospital of Army Medical University	Chongqing	Chongqing	China	400037
3	The First Hospital of Lanzhou University	Lanzhou	Gansu	China	730000
4	Guangdong 999 Brain Hospital	Guangzhou	Guangdong	China	510000
5	The Third Affiliated Hospital of Southern Medical University	Guangzhou	Guangdong	China	510630
6	The Fifth Affiliated Hospital of Southern Medical University	Guangzhou	Guangdong	China	510900
7	MaoMing People's Hospital	Maoming	Guangdong	China	525000
8	The Second People's Hospital of Shenzhen	Shenzhen	Guangdong	China	518035
9	Zhongshan People's Hospital	Zhongshan	Guangdong	China	528400
10	The Fifth Affiliated Hospital Sun-yet sen University	Zhuhai	Guangdong	China	519000
11	The People's Hospital of Guangxi Zhuang Autonomous Region	Nanning	Guangxi	China	530021
12	Henan Provincial People's Hospital	Zhengzhou	Henan	China	450003
13	The Second Hospital University of South China	Hengyang	Hunan	China	421001
14	The First Affiliated Hospital of HuNan University of Medicine	Huaihua	Hunan	China	418000
15	Qilu Hospital of Shandong University	Qingdao	Shandong	China	266035
16	The First Affiliated Hospital of Xinjiang Medical University	Ürümqi	Xinjiang	China	830054
17	The First Affiliated Hospital of Kuming Medical University	Kunming	Yunnan	China	650032

Sponsors and Collaborators

• Hong Yang
• Xuanwu Hospital, Beijing
• Qilu Hospital of Shandong University
• The First Affiliated Hospital of Kunming Medical College
• First Affiliated Hospital of Xinjiang Medical University
• Second Affiliated Hospital of Third Military Medical University
• Henan Provincial People's Hospital
• The Second Hospital University of South China
• Shenzhen Second People's Hospital
• People's Hospital of Guangxi
• Department of Biostatistics, Southern Medical University
• LanZhou University
• The First Affiliated Hospital of HuNan University of Medicine
• Guangdong 999 Brain Hospital
• Maoming People's Hospital
• The Fifth Affiliated Hospital of Southern Medical University
• Zhongshan People's Hospital, Guangdong, China
• Fifth Affiliated Hospital, Sun Yat-Sen University

Investigators

• Study Chair: Wen-Jin Chen, Xuanwu Hospital, Beijing
• Study Chair: Hong Yang, Dr, The Third Affiliated Hospital of Southern Medical University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Arakawa S, Saku Y, Ibayashi S, Nagao T, Fujishima M. Blood pressure control and recurrence of hypertensive brain hemorrhage. Stroke. 1998 Sep;29(9):1806-9.
• Barr J, Fraser GL, Puntillo K, Ely EW, Gélinas C, Dasta JF, Davidson JE, Devlin JW, Kress JP, Joffe AM, Coursin DB, Herr DL, Tung A, Robinson BR, Fontaine DK, Ramsay MA, Riker RR, Sessler CN, Pun B, Skrobik Y, Jaeschke R; American College of Critical Care Medicine. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the Intensive Care Unit: executive summary. Am J Health Syst Pharm. 2013 Jan 1;70(1):53-8.
• 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 Jul;24(7):987-93.
• Broderick JP, Brott TG, Tomsick T, Barsan W, Spilker J. Ultra-early evaluation of intracerebral hemorrhage. J Neurosurg. 1990 Feb;72(2):195-9.
• Chen ST, Chen SD, Hsu CY, Hogan EL. Progression of hypertensive intracerebral hemorrhage. Neurology. 1989 Nov;39(11):1509-14.
• Kasner SE. Clinical interpretation and use of stroke scales. Lancet Neurol. 2006 Jul;5(7):603-12. Review.
• Kazui S, Naritomi H, Yamamoto H, Sawada T, Yamaguchi T. Enlargement of spontaneous intracerebral hemorrhage. Incidence and time course. Stroke. 1996 Oct;27(10):1783-7.
• Koskinen LO, Olivecrona M, Grände PO. Severe traumatic brain injury management and clinical outcome using the Lund concept. Neuroscience. 2014 Dec 26;283:245-55. doi: 10.1016/j.neuroscience.2014.06.039. Epub 2014 Jun 25. Review.
• 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 May 5;20(1):128. doi: 10.1186/s13054-016-1294-5. Review.
• Pejtersen JH, Kristensen TS, Borg V, Bjorner JB. The second version of the Copenhagen Psychosocial Questionnaire. Scand J Public Health. 2010 Feb;38(3 Suppl):8-24. doi: 10.1177/1403494809349858.
• Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage. N Engl J Med. 2001 May 10;344(19):1450-60. Review.
• Stålhammar D, Starmark JE, 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 (Wien). 1988;90(3-4):73-80.
• Stocchetti N, Pagan F, Calappi E, Canavesi K, Beretta L, Citerio G, Cormio M, Colombo A. Inaccurate early assessment of neurological severity in head injury. J Neurotrauma. 2004 Sep;21(9):1131-40.
• 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 Aug;13(8):844-54. doi: 10.1016/S1474-4422(14)70120-6. Review. Erratum in: Lancet Neurol. 2014 Sep;13(9):863.
• van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988 May;19(5):604-7.

• Responsible Party: Hong Yang, Doctor of Medicine (M.D.)；Associate Senior Doctor, The Third Affiliated Hospital of Southern Medical University
• ClinicalTrials.gov Identifier: NCT03207100
• Other Study ID Numbers: 201704004
• First Posted: Jul 2, 2017
• Last Update Posted: Jul 21, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Hong Yang, Doctor of Medicine (M.D.)；Associate Senior Doctor, The Third Affiliated Hospital of Southern Medical University: Intracerebral hemorrhage; Early antihypertensive treatment; Analgesia-first; Sedation
• Additional relevant MeSH terms: Cerebral Hemorrhage; Hemorrhage; Hematoma; Antihypertensive Agents

Study Results

No Results Posted as of Jul 21, 2021