Clinical trial NCT03207100: Analgesia-first Minimal Sedation for Spontaneous Intracerebral Hemorrhage Early Antihypertensive Treatment
Official title: Clinical Study of the Safety and Efficacy of Analgesia-first Minimal Sedation as an Early Antihypertensive Treatment for Spontaneous Intracerebral Hemorrhage
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Early Systolic Blood Pressure Control Rate
Hematoma Growth
Blood Pressure Variability
Healthcare Worker Satisfaction
Duration of ICU Treatment and Mechanical Ventilation
Keywords: Intracerebral hemorrhage
Early antihypertensive treatment
Analgesia-first
Sedation
Lead sponsor: The Third Affiliated Hospital of Southern Medical University
Sponsor class: OTHER_GOV
Collaborators: name: Xuanwu Hospital, Beijing
name: Qilu Hospital of Shandong University
name: First Affiliated Hospital of Kunming Medical University
name: First Affiliated Hospital of Xinjiang Medical University
name: Second Affiliated Hospital of Third Military Medical University
name: Henan Provincial People's Hospital
name: The Second Hospital University of South China
name: Shenzhen Second People's Hospital
name: People's Hospital of Guangxi Zhuang Autonomous Region
name: Department of Biostatistics, Southern Medical University
name: LanZhou University
name: The First Affiliated Hospital of HuNan University of Medicine
name: Guangdong 999 Brain Hospital
name: Maoming People's Hospital
name: The Fifth Affiliated Hospital of Southern Medical University
name: Zhongshan People's Hospital, Guangdong, China
name: Fifth Affiliated Hospital, Sun Yat-Sen University
First posted: 2017-07-02
Enrollment: 338
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Systolic BP control rate at 1h post-treatment initiation
timeFrame: 1h post-treatment initiation
Secondary outcomes:
measure: Hematoma growth at 24 h
timeFrame: 24h of treatment
measure: BP variability
timeFrame: Up to 7 days
measure: Neurologic function
timeFrame: Up to 7 days
measure: Duration of ICU treatment and mechanical ventilation
timeFrame: Up to 7 days
measure: Healthcare worker satisfaction
timeFrame: 7 day or discharge from ICU (if patients discharge from ICU in 7 days)
measure: cerebral tissue oxygenation index (TOI)
timeFrame: Up to 7 days and around sputum aspiration
measure: 28-day mortality and disability rate
timeFrame: 28 days
measure: 90-day mortality and disability rate
timeFrame: 90 days
Other outcomes:
Locations:
city: Beijing
country: China
facility: Xuanwu Hospital Capital Medical University
state: Beijing
city: Chongqing
country: China
facility: Xinqiao Hospital of Army Medical University
state: Chongqing
city: Lanzhou
country: China
facility: The First Hospital of Lanzhou University
state: Gansu
city: Guangzhou
country: China
facility: Guangdong 999 Brain Hospital
state: Guangdong
city: Guangzhou
country: China
facility: The Third Affiliated Hospital of Southern Medical University
state: Guangdong
city: Guangzhou
country: China
facility: The Fifth Affiliated Hospital of Southern Medical University
state: Guangdong
city: Maoming
country: China
facility: MaoMing People's Hospital
state: Guangdong
city: Shenzhen
country: China
facility: The Second People's Hospital of Shenzhen
state: Guangdong
city: Zhongshan
country: China
facility: Zhongshan People's Hospital
state: Guangdong
city: Zhuhai
country: China
facility: The Fifth Affiliated Hospital Sun-yet sen University
state: Guangdong
city: Nanning
country: China
facility: The People's Hospital of Guangxi Zhuang Autonomous Region
state: Guangxi
city: Zhengzhou
country: China
facility: Henan Provincial People's Hospital
state: Henan
city: Hengyang
country: China
facility: The Second Hospital University of South China
state: Hunan
city: Huaihua
country: China
facility: The First Affiliated Hospital of HuNan University of Medicine
state: Hunan
city: Qingdao
country: China
facility: Qilu Hospital of Shandong University
state: Shandong
city: Ürümqi
country: China
facility: The First Affiliated Hospital of Xinjiang Medical University
state: Xinjiang
city: Kunming
country: China
facility: The First Affiliated Hospital of Kuming Medical University
state: Yunnan
Study officials:
affiliation: Xuanwu Hospital, Beijing
name: Wen-Jin Chen
role: STUDY_CHAIR
affiliation: The Third Affiliated Hospital of Southern Medical University
name: Hong Yang, Dr
role: STUDY_CHAIR
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