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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Clinical Study of the Safety and Efficacy of Analgesia-first Minimal Sedation as an Early Antihypertensive Treatment for Spontaneous Intracerebral Hemorrhage

Conditions
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Early Systolic Blood Pressure Control Rate, Hematoma Growth, Blood Pressure Variability, Healthcare Worker Satisfaction, Duration of ICU Treatment and Mechanical Ventilation

Intervention / Treatment
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* Combination Product: Analgesia-first minimal sedation
* Combination Product: Antihypertensive treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Definitive diagnosis of ICH-induced acute brain injury by CT; Systolic BP ≥150 mmHg for at least twice; >18 years old; Feasible for emergency antihypertensive treatment and real-time BP monitoring; Disease onset is within 24h; ICU or stroke unit admission within 24h. Exclusion Criteria: Subject has contraindications for emergency intensified antihypertensive treatment; Intracranial hemorrhage secondary to intracranial tumor, recent trauma, cerebral infarction and thrombolytic therapy; History of ischemic stroke within 30 days before disease onset; Clinical or imaging examination reveals an expected high mortality in subject within the next 24h; Presence of dementia or significant post-stroke disability; Coagulation disorder caused by drugs or hematologic diseases; Allergy to opioids; Interference test result, assessment and follow-up of comorbidity; Presence of sinus arrest, borderline rhythm, grade II and above atrioventricular block and malignant arrhythmia; Individual is pregnant or lactating; Currently participating in other drug studies or clinical trials; 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; 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Analgesia-first minimal sedation group<br>Using analgesia-first minimal sedation strategy to implement antihypertensive therapy. | Combination Product: Analgesia-first minimal sedation<br>* 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.<br>|
| Active Comparator: Antihypertensive drug treatment group<br>Using routine antihypertensive drugs to implement antihypertensive therapy. | Combination Product: Antihypertensive treatment<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Systolic BP control rate at 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. | 1h post-treatment initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematoma growth at 24 h | 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). | 24h of treatment | 
| BP variability | 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). | Up to 7 days | 
| Neurologic function | 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). | Up to 7 days | 
| Duration of ICU treatment and mechanical ventilation | Duration of ICU treatment and mechanical ventilation | Up to 7 days | 
| Healthcare worker satisfaction | Questionnaire is designed based on the Copenhagen Psychosocial Questionnaire, with a parameter for self-assessed workload. | 7 day or discharge from ICU (if patients discharge from ICU in 7 days) | 
| cerebral tissue oxygenation index (TOI) | Assess changes in the TOI after sputum aspiration in mechanical ventilation patients | Up to 7 days and around sputum aspiration | 
| 28-day mortality and disability rate | 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) | 28 days | 
| 90-day mortality and disability rate | 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) | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intracerebral hemorrhage, Early antihypertensive treatment, Analgesia-first, Sedation