Background

Although it has been established that elevated blood pressure and its variability worsen outcomes in spontaneous intracerebral hemorrhage, antihypertensives use during the acute phase still lacks robust evidence. A blood pressure–lowering regimen using remifentanil and dexmedetomidine might be a reasonable therapeutic option given their analgesic and antisympathetic effects. The objective of this superiority trial was to validate the efficacy and safety of this blood pressure–lowering strategy that uses remifentanil and dexmedetomidine in patients with acute intracerebral hemorrhage.

Methods

In this multicenter, prospective, single-blinded, superiority randomized controlled trial, patients with intracerebral hemorrhage and systolic blood pressure (SBP) 150 mmHg or greater were randomly allocated to the intervention group (a preset protocol with a standard guideline management using remifentanil and dexmedetomidine) or the control group (standard guideline-based management) to receive blood pressure–lowering treatment. The primary outcome was the SBP control rate (less than 140 mmHg) at 1 h posttreatment initiation. Secondary outcomes included blood pressure variability, neurologic function, and clinical outcomes.

Results

A total of 338 patients were allocated to the intervention (n = 167) or control group (n = 171). The SBP control rate at 1 h posttreatment initiation in the intervention group was higher than that in controls (101 of 161, 62.7% vs. 66 of 166, 39.8%; difference, 23.2%; 95% CI, 12.4 to 34.1%; P < 0.001). Analysis of secondary outcomes indicated that patients in the intervention group could effectively reduce agitation while achieving lighter sedation, but no improvement in clinical outcomes was observed. Regarding safety, the incidence of bradycardia and respiratory depression was higher in the intervention group.

Conclusions

Among intracerebral hemorrhage patients with a SBP 150 mmHg or greater, a preset protocol using a remifentanil and dexmedetomidine–based standard guideline management significantly increased the SBP control rate at 1 h posttreatment compared with the standard guideline-based management.

Editor’s Perspective
What We Already Know about This Topic
  • In patients who have suffered spontaneous intracerebral hemorrhage, excessively high blood pressure is associated with worse outcomes

  • Existing blood pressure lowering regimens involve administration of various antihypertensive drugs, but the optimal choice of treatment is unknown

What This Article Tells Us That Is New
  • For this patient group, the use of dexmedetomidine and remifentanil results in a higher proportion of patients achieving good systolic blood pressure control at 1 h after admission than is seen in the control group

  • Dexmedetomidine and remifentanil produced less agitation, but occasionally resulted in treatable bradycardia and respiratory depression

  • There was no difference in hematoma growth and long-term stroke outcomes between the groups

Spontaneous intracerebral hemorrhage is the most serious and least treatable form of acute stroke, affecting approximately 2 million people worldwide each year, with risk disparities between patients in low- and middle-income countries and those in high-income countries.1–4  The patient’s blood pressure often becomes elevated after intracerebral hemorrhage,5  frequently reaching very high levels, and elevated blood pressure is an independent predictor of poor clinical outcomes.6–9  Moreover, previous studies have shown that high systolic blood pressure (SBP) variability during the hyperacute and acute phases of intracerebral hemorrhage is closely related to poor outcomes.10–12 

The current guidelines recommend initiating smooth and sustained SBP lowering (e.g., a target of 140 mmHg) as soon as possible in acute intracerebral hemorrhage patients because early lowering of blood pressure might be beneficial to the recovery of neurologic function and the reduction of major disabilities and death in patients with intracerebral hemorrhage.13,14  In terms of acute blood pressure reduction, the choice of antihypertensives is limited, although the use of labetalol, hydralazine, nicardipine, and/or enalapril has been recommended by the Canadian Stroke Best Practice Recommendations.15  In addition, some antihypertensives could induce rebound hypertension and increased intracranial pressure (ICP),16,17  which limits their application in acute blood pressure–lowering in intracerebral hemorrhage patients. Remarkably, an early rise in blood pressure is associated not only with premorbid acute or persistent hypertension but also with a variety of factors, including stress, pain, stimulation, and increased ICP.13,18,19  Thus, a blood pressure–lowering strategy based on analgesia, sedation, and antisympathetic treatment might theoretically achieve favorable effects. Given the potent fast- and short-acting analgesic effects of remifentanil and the arousable sedation and antisympathetic effects of dexmedetomidine, the combination of remifentanil and dexmedetomidine could achieve the purpose of a rapid and smooth blood pressure–lowering effect and facilitate consciousness assessment.

Therefore, it is hypothesized that remifentanil and dexmedetomidine–based blood pressure treatment for patients with acute intracerebral hemorrhage would contribute to a rapid and stable decrease in blood pressure. To test this hypothesis, we designed a multicenter, prospective, superiority randomized controlled trial to evaluate the efficacy and safety of a preset protocol using a remifentanil and dexmedetomidine–based standard guideline management and compared this new protocol with the standard guideline-based management for early intensive blood pressure–lowering among patients with intracerebral hemorrhage.

Study Design

This multicenter, prospective, parallel-group, single-blinded, superiority randomized controlled trial was conducted in the intensive care units (ICUs) of 14 tertiary hospitals in China. The study protocol, which had been published in detail previously,20  was designed following the Consolidated Standards of Reporting Trials statement21  and was approved by the Institutional Review Board of the Third Affiliated Hospital of Southern Medical University (Guangzhou, China; No. 201711009). Informed written consent, following the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice, was obtained from each patient or their legal surrogate before study entry. The registered information of the protocol can be found on the ClinicalTrials.gov website (https://clinicaltrials.gov; registration No., NCT03207100; principal investigator, Hong Yang; date of registration, June 30, 2017). Notably, modifications were made to the original protocol before formal enrollment commenced. Initially intended to investigate remifentanil’s and dexmedetomidine’s clinical efficacy in intracerebral hemorrhage patients, the study design, including inclusion criteria, interventions, and outcome measures underwent significant adjustments. This change was prompted by the recognized benefits of remifentanil combined with dexmedetomidine in blood pressure management outcomes.22–24  Formal subject enrollment commenced subsequently. Furthermore, due to the COVID-19 pandemic, some hospitals ceased patient recruitment after January 2020. Consequently, study units were modified to ensure ongoing patient recruitment. Detailed information on these changes is available on ClinicalTrials.gov.

Participants

Based on the study protocol, the inclusion criteria were as follows: patients (1) older than 18 yr; (2) with acute intracerebral hemorrhage confirmed by a computed tomography scan; (3) who had a symptom onset within 24 h (if the time of onset is unknown, the last known time is selected); (4) with a SBP 150 mmHg or greater at least twice (based on brachial artery pressure measured in the nonparetic arm in two measurements conducted 2 min or more apart); (5) who are feasible for emergency antihypertensive treatment and real-time blood pressure monitoring; and (6) who had ICU or stroke unit admission within 24 h. Participants who met any of the following criteria were excluded: (1) existing contraindications for emergency blood pressure–lowering treatment (such as severe carotid, vertebral, or cerebral artery stenosis or severe kidney failure); (2) intracerebral hemorrhage secondary to an intracranial tumor, recent trauma, or cerebral infarction and thrombolytic therapy; (3) history of ischemic stroke within 30 days before disease onset; (4) a clinical or imaging examination revealing a high chance of mortality within the next 24 h (e.g., Glasgow Coma Scale score 3 to 5, hemorrhage-induced midline shift, or sustained deep coma [the absence of any limb or body movements response to nociceptive stimulus]); (5) presence of dementia or significant poststroke disability (modified Rankin Scale 3 points or more ); (6) presence of a coagulation disorder caused by drugs or hematological disease; (7) allergy to opioids; (8) an interfering test result, assessment, or follow-up comorbidity (such as malignant tumor and respiratory diseases); (9) presence of sinus arrest, borderline rhythm, grade II or higher atrioventricular block or malignant arrhythmia; (10) pregnant or lactating; (11) currently participating in another study; (12) unwilling to provide informed consent, or unlikely to persist with the study and follow-up; and (13) participants who were considered ineligible by the investigator (participants with severe systemic disorders or sleep-disordered breathing). Given the urgency of the condition, all the patients were enrolled and randomized within 2 h of ICU admission, including those who underwent surgery directly from the emergency department. If the patient was expected to undergo surgery as soon as possible after enrollment, the intervention would be performed concurrently with preoperative preparations.

Randomization

Randomization was performed in a 1:1 ratio using blocks of four via a centralized Web-based randomization system to ensure a balance of the treatment and coagulation factors (including surgical intervention within 24 h, the use of antiplatelet or anticoagulant drugs in the past week, and the use of mechanical ventilation) that might affect the early blood pressure–lowering effect and poor prognosis of intracerebral hemorrhage. The randomization process was handled by the Clinical Trial Service (Guangzhou) Co., Ltd. (Guangzhou, China), and the random allocation sequence was generated by the company’s programmers (not trial statisticians). To preserve the allocation concealment, the randomization center did not reveal the randomization sequence, block numbers, or block sizes. After patient eligibility was confirmed, randomization was completed by the site investigator using a Web-based application.

Blinding

The participants were blinded, but the investigators could not be blinded because of opioid management. After obtaining the randomization number, the doctor issued a drug prescription, and the nurse configured and administered the medication according to the protocol. The patients, but not the researchers, remained blinded to the treatment status.

Trial Intervention

The goal of treatment was to reduce the patient’s SBP to a range of 110 mmHg and 140 mmHg within 1 h of the initiation of treatment and to maintain this level during the patient’s ICU stay but at most for 7 days. The patients who were allocated to the intervention group were initially treated with remifentanil combined with dexmedetomidine to provide sufficient analgesia and sedation. For the patients who were randomly assigned to the control group, urapidil, nicardipine, or any other intravenous antihypertensive agents were used following the guidelines and expert consensus recommendations.15  To achieve the SBP target rapidly, blood pressure was measured at least every 10 min to facilitate drug titration during the initial treatment phase. In the intervention group, remifentanil was administered intravenously and maintained at doses of 0.025 μg · kg-1 · min-1 and 0.05 μg · kg-1 · min-1 in nonmechanically ventilated and mechanically ventilated patients, respectively. Dexmedetomidine was continuously infused intravenously at a dose ranging from 0.2 μg · kg-1 · h-1 to 0.6 μg · kg-1 · h-1 if remifentanil failed to reduce the patient’s SBP to 140 mmHg or lower. When the maximum dexmedetomidine was reached and if achieving the SBP target had failed, conventional antihypertensives were used according to the guidelines. Meanwhile, considering blood pressure fluctuations during sputum suctioning, the mechanically ventilated patients in the intervention group were administered a rapid remifentanil (0.5 μg/kg) infusion before the procedure to reduce the blood pressure variation caused by the malignant stimulation. The patients who were allocated to the control group were treated with routine antihypertensives. Notably, the medications used in the intervention group could result in apnea or bradycardia. In such cases, the remifentanil and dexmedetomidine administration would then be reduced or interrupted or the patient would be switched to antihypertensives. Sedatives and analgesics were administered to the control group if pain or agitation developed, and remifentanil and dexmedetomidine were strictly prohibited in this group. In the event of acute agitation and/or acute blood pressure elevation, remifentanil was the primary medication used for control in the intervention group, while the control group received midazolam or propofol. Antihypertensive medications were only administered when a subject experienced nonagitation-induced acute blood pressure elevation, with this being particularly true in the intervention group. The supplemental table (Supplemental Digital Content 1, https://links.lww.com/ALN/D506) provides further details regarding the standard treatment protocol for intracerebral hemorrhage.

Trial Assessment Data

Once the patients were enrolled, the following information was collected: (1) baseline demographics and clinical characteristics, including age, sex, body mass index, history of smoking, alcohol abuse, and vital signs (including blood pressure, heart rate, respiratory rate, and oxygen saturation); (2) medical histories (hypertension, previous intracerebral hemorrhage, ischemic stroke, acute coronary event, diabetes mellitus, dyslipidemia, gout,25  allergy, and antiplatelet or anticoagulant agent treatment); and (3) clinical efficacy, including SBP control rate, blood pressure variability, hematoma growth, analgesic and sedative scores, neurologic scores, length of mechanical ventilation and ICU stay, major disabilities, and death at 28 days and 90 days. To assess hematoma growth, noncontrast head computed tomography scans were evaluated at baseline and 24 h after the initiation of treatment (6 h earlier or later was allowed), and the scans were reviewed by senior radiologists who were blinded to this study. The patients’ analgesic and sedative scores were evaluated via the Richmond Agitation-Sedation Scale and Nonverbal Adult Pain Assessment Scale. The National Institutes of Health (Bethesda, Maryland) Stroke Scale, Glasgow Coma Scale, and Reaction Level Scale were used to assess neurologic scores from baseline to discharge from the ICU. Major disabilities and death of all participants were followed up in person or by telephone at 28 days and 90 days by trained local staff who were unaware of the group assignments.

Outcome Measures

In this study, all blood pressure levels were recorded in the nonparetic arm in a supine position using an automated device with an appropriate size cuff. The primary outcome was the SBP control rate at 1 h posttreatment initiation, defined as the proportion of participants with controlled SBP (less than 140 mmHg measured twice with an interval of 2 min or more) at 1 h posttreatment initiation. The secondary outcomes included the blood pressure variability (especially the variability after sputum suctioning), hematoma growth, analgesic and sedative scores, neurologic scores, the length of mechanical ventilation and ICU stay, and the major disability and mortality rate at 28 days and 90 days. Blood pressure variability, expressed as the coefficient of variation (defined as SD divided by the mean), was calculated from all blood pressure values obtained during the ICU stay but at most 7 days (excluded values during surgery). Hematoma growth was defined as V2 − V1 ≥ 12.5 cm3 or (V2 − V1)/V1 > 33% (V1 and V2 represent the hematoma volume at baseline and 24 h after the treatment initiation). The analgesic and sedative scores were calculated by the Nonverbal Adult Pain Assessment Scale and the Richmond Agitation-Sedation Scale after treatment. The neurologic scores were assessed at ICU discharge or on day 28 of the ICU stay using the Glasgow Coma Scale, National Institutes of Health Stroke Scale, and Reaction Level Scale. Concurrently, the length of mechanical ventilation and ICU stay were recorded. Major disability was defined as a modified Rankin Scale score of 3 to 5 at day 28 and day 90 after randomization. Importantly, the inclusion of major disability and mortality rates at days 28 and 90 in the secondary outcomes was introduced after the formal enrollment began, with the aim of further exploring clinical outcome differences. Additionally, the Bispectral Index and cerebral tissue oxygenation index, originally planned in the study design, were excluded from the final outcome due to equipment configuration imbalances arising from the inclusion of additional participating hospitals.

We assessed adverse events, including serious adverse events, on the basis of occurrence of side effects from the study drug. Unexpected endotracheal intubation, unintentional extubation, pressure ulcers, deep vein thromboses, and ICU-acquired muscle weakness related to side effects from the procedure were also documented. Multiple adverse events per patient were analyzed as a single event.

Data Management

The data collection and management in this study were performed using an electronic data capture system that allowed for Web-based data entry. Each participating hospital could capture and enter data at each site using an electronic signature (unique user and password), and all changes made after the electronic signing had an electronic audit trail with a signature and a date. An independent Data and Safety Monitoring Board consisting of clinicians and biostatisticians monitored the safety and progress of the trial. The board reviewed all data obtained in both treatment groups, in addition to the dropout and event rates at the end of the study.

Sample Size

The primary efficacy measure of the trial, the SBP control rate at 1 h posttreatment initiation, was expected to be 33.4% in the control group based on the second Intensive Blood Pressure Reduction in Acute Cerebral hemorrhage Trial26  results and was expected to be 51% in the intervention group based on our unpublished results. Two-tailed tests were performed with a significance level of 0.05, a test power of 80%, a parallel design, and a less than 20% dropout rate. The sample size was calculated as 165 participants per group with a total of 330 participants using nQuery Advisor + nTerim 4.0 (Statsols, USA).

Statistical Methods

Categorical variables were presented as counts or percentages and were compared using the chi-square test, continuity correction, or Fisher exact test, as appropriate. Continuous variables are expressed as mean ± SD or as median with interquartile range. We tested continuous variables for normal distribution using the Kolmogorov–Smirnov test. Normal continuous variables were compared by Student’s t test, while skewed distribution continuous variables were compared by a nonparametric test. Logistic regression was used to evaluate the difference between the groups regarding the SBP control rates at 1 h after the posttreatment initiation, and the 95% CI for the difference in control rate between the groups was calculated by the Delta method. A post hoc subgroup analysis for the primary outcome was performed on subgroups determined from the baseline variables, namely, age, hypertension history, baseline SBP, Glasgow Coma Scale score, hematoma volume, hematoma location, surgical intervention in the first 24 h, and intraventricular extension.

The analysis dataset was selected based on the intention-to-treat set, full analysis set, per-protocol set, and safety analysis set. Specifically, the primary analysis was performed on the intention-to-treat set, whereas the efficacy analysis was performed on the full analysis set and per-protocol set. The intention-to-treat set consisted of all randomized patients and the full analysis set patients within the intention-to-treat set who received at least one infusion of the study drug. The per-protocol set included all randomized patients who completed the trial and did not have major protocol violations. The safety analysis was based on the safety analysis set, which included all patients who received at least one infusion of the study drug. For validity and safety data, missing values were not filled in, but for the data from a laboratory test, missing values were handled according to the established protocol if necessary.

Statistical significance was considered two-sided at a nominal 5%. SAS statistics software (version 9.4, SAS Institute Inc., USA) was utilized for statistical analyses. The study protocol and statistical analysis plan are available in the supplemental files (Supplemental Digital Content 2, https://links.lww.com/ALN/D507; Supplemental Digital Content 3, https://links.lww.com/ALN/D508).

Study Population

Of the 789 patients assessed for eligibility from June 2018 to February 2021, 338 patients were enrolled in the study and were randomly assigned to the intervention or control group. A total of 338 patients (167 in the intervention group and 171 in the control group) were included in the intention-to-treat set. Among these patients, eight in the intervention group and nine in the control group did not receive treatment due to withdrawn consent, rapid deterioration, or confirmed ineligible. Hence, 159 and 162 patients in the intervention and control groups were included in the full analysis set and safety analysis set, respectively. In addition, 6 patients violated the protocol in the intervention group (they were not treated with remifentanil or dexmedetomidine or received dezocine), while 15 patients violated the protocol in the control group (received remifentanil or dexmedetomidine). Therefore, 153 patients in the intervention group and 147 patients in the control group were included in the per-protocol set. However, 11 patients in the intention-to-treat set (6 in the intervention group and 5 in the control group) were identified as missing data for the primary outcome due to premature discontinuation of treatment for reasons such as reconfirmed ineligibility for enrollment or family requirements. Thus, 161 patients in the intervention group and 166 patients in the control group had data available on the primary outcome and were included in the primary analysis of intention-to-treat set (fig. 1). No participants withdrew from the trial due to medication side effects.

Fig. 1.

Study flow chart. Other reasons for exclusion include presence of coagulation disorder, malignant tumor, sinus arrest, grade II or higher atrioventricular block, or currently participating in another study. SBP, systolic blood pressure.

Fig. 1.

Study flow chart. Other reasons for exclusion include presence of coagulation disorder, malignant tumor, sinus arrest, grade II or higher atrioventricular block, or currently participating in another study. SBP, systolic blood pressure.

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As shown in table 1, both groups tended to be middle-aged. Of all the patients, 31.4% were women, and 63.6% had a medical history of hypertension. Of the 215 patients with a history of hypertension, treatment was administered to only 38. Furthermore, no significant difference was observed in the utilization of various antihypertensive medication types between the two groups. The mean ± SD SBP at baseline was 176.2 ± 23.1 mmHg in the intervention group and 176.0 ± 26.3 mmHg in the control group. The baseline median Glasgow Coma Scale score was 10. The most common location of hemorrhage was the basal ganglia, with an incidence of 54.1% and a median hematoma volume of 20 ml.

Table 1.

Baseline Demographic and Clinical Characteristics of the Patients from Intention-to-treat Set

Baseline Demographic and Clinical Characteristics of the Patients from Intention-to-treat Set
Baseline Demographic and Clinical Characteristics of the Patients from Intention-to-treat Set

Management of Patients within the First 24 h after Treatment

Within 24 h of treatment initiation, 125 patients (74.8%) in the intervention group received the remifentanil and dexmedetomidine combination, 27 (16.2%) received remifentanil alone, 3 (1.8%) received dexmedetomidine alone, and 12 (7.2%) received neither medication. Among those who received treatment, 76 (47.8%) in the intervention group required additional antihypertensive medication, while 92 (56.8%) patients in the control group required additional analgesic therapy (table 2). The two groups were comparable in terms of neurosurgical interventions, use of mechanical ventilation, and antiepileptic medications (tables 1 and 2). The therapeutic doses and duration are detailed in the supplemental table (Supplemental Digital Content 4, https://links.lww.com/ALN/D509).

Table 2.

Number of Patients Requiring Additional Medications between the Two Groups

Number of Patients Requiring Additional Medications between the Two Groups
Number of Patients Requiring Additional Medications between the Two Groups

Primary Outcome

For the primary outcome in the intention-to-treat set, the SBP control rate at 1 h posttreatment initiation was 62.7% (101 of 161; 95% CI, 54.8 to 70.2%) in the intervention group compared to 39.8% (66 of 166; 95% CI, 32.3 to 47.6%) in the control group, with a statistically significant increase (difference, 23.2%; 95% CI, 12.4 to 34.1%; odds ratio, 2.59 [95% CI, 1.66 to 4.1]; P < 0.001; see table 3 and Supplemental Digital Content 5, https://links.lww.com/ALN/D510, showing frequency distribution histogram of SBP at 1 h posttreatment initiation in two groups). Similarly, in full analysis set and per-protocol set populations, the SBP control rate in the intervention group was higher than that in the control group (table 3). Regarding blood pressure maintenance, the trend in SBP control during the first 24 h posttreatment was consistent across both groups (see Supplemental Digital Content 6, https://links.lww.com/ALN/D511, showing SBP levels in the first 24 h). Overall, the mean SBP in both groups remained stable within the range of 130 to 140 mmHg. However, transient drops in SBP less than 110 mmHg might occur in patients receiving the combination of remifentanil and dexmedetomidine (see Supplemental Digital Content 7, https://links.lww.com/ALN/D512, listing patients with SBP less than 110 mmHg in the first 24 h).

Table 3.

Primary and Secondary Outcomes According to Treatment Groups

Primary and Secondary Outcomes According to Treatment Groups
Primary and Secondary Outcomes According to Treatment Groups

Secondary Outcomes

As presented in table 3, the coefficient of variation for blood pressure after sputum suctioning, including SBP, diastolic blood pressure, and mean arterial pressure, showed a significant reduction in the intervention group for the intention-to-treat set (SBP, 10.1 ± 3.4% vs. 12.5 ± 3.5%, P < 0.001; diastolic blood pressure, 12.0 ± 4.2% vs. 14.0 ± 5.1%, P = 0.034; mean arterial pressure, 10.3 ± 3.3% vs. 12.6 ± 4.0%, P = 0.002), full analysis set, and per-protocol set analyses, although differences in the coefficient of variation for blood pressure between the two groups were insignificant. In terms of the analgesic and sedative scores, the intervention group showed a significant difference in their Richmond Agitation-Sedation Scale scores compared with those in the control group for the intention-to-treat set (+2 to + 4 scores, 0.6% vs. 6.3%; –2 to + 1 scores, 73.4% vs. 59.1%; –5 to –3 scores, 26.0% vs. 34.6%, P = 0.003; odds ratio of + 2 to + 4 scores compared with –5 to –3 scores, 0.138 [95% CI, 0.017 to 1.12]; odds ratio of –2 to + 1 scores compared with –5 to –3 scores, 1.65 [95% CI, 1.01 to 2.70]), full analysis set, and per-protocol set analyses, despite both groups obtaining similar results in the Nonverbal Adult Pain Assessment Scale. Regarding the neurologic outcomes, there were no statistically significant differences between the two groups in hematoma growth, Glasgow Coma Scale score, National Institutes of Health Stroke Scale score, or Reaction Level Scale grade. The median length of ICU stay and mechanical ventilation and the mortality and major disability rates at 28 and 90 days were not different between the groups (table 3).

Post Hoc Analysis

As shown in the forest plots (fig. 2), the analyses for the SBP control rate at 1 h posttreatment initiation for the important subgroups was generally consistent with the overall study results (except for the patients with baseline SBP 180 mmHg or greater and who had a hematoma location consistent with subarachnoid hemorrhage).

Fig. 2.

Post hoc analysis of the primary outcome. The primary outcome of the study was the systolic blood pressure control rate at 1 h posttreatment initiation, using the number of patients in whom systolic blood pressure decreased to less than 140 mmHg at 1 h posttreatment initiation compared to the total number in each group of patients. Each percentage is based on the number of people in that subgroup. Glasgow Coma Scale ranges from 3 to 15; 15 is considered fully conscious, and 3 is considered deep coma.

Fig. 2.

Post hoc analysis of the primary outcome. The primary outcome of the study was the systolic blood pressure control rate at 1 h posttreatment initiation, using the number of patients in whom systolic blood pressure decreased to less than 140 mmHg at 1 h posttreatment initiation compared to the total number in each group of patients. Each percentage is based on the number of people in that subgroup. Glasgow Coma Scale ranges from 3 to 15; 15 is considered fully conscious, and 3 is considered deep coma.

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Safety

According to the safety analysis set results, several adverse events and serious adverse events were recorded during the study. No significant differences were observed in the incidence of any events between the intervention group and control group according to all documented complications from the drugs and procedure-related side effects (table 4). However, the incidence of bradycardia and respiratory depression was higher in the intervention group compared to the control group. Among the 15 patients in the intervention group who experienced bradycardia, the condition resolved through dose reduction in 9 patients and suspension of remifentanil and dexmedetomidine in 6 patients. Notably, nine of these patients subsequently required a combination or switch to antihypertensive medications to maintain stable blood pressure. Of the four patients who experienced respiratory depression, three recovered with a dose reduction, while one patient required mechanical ventilation. No procedure-related side effects occurred except for unplanned endotracheal intubation in 18 patients (5.6%), unintentional extubation in 3 patients (0.9%), deep vein thrombosis in 19 patients (5.9%), pressure ulcers in 8 patients (2.5%), and ICU-acquired weakness in 3 patients (0.9%). No patient withdrew from the study because of adverse events, and no treatment-related deaths occurred during our study.

Table 4.

Safety Outcome in Patients with Intracranial Hemorrhage

Safety Outcome in Patients with Intracranial Hemorrhage
Safety Outcome in Patients with Intracranial Hemorrhage

In this superiority trial involving patients with intracerebral hemorrhage, a preset protocol using remifentanil and dexmedetomidine–based standard guideline management demonstrated a significant rapid, stable, and effective blood pressure reduction without an increase in mortality compared to the standard guideline-based management.15  This study contributes valuable evidence supporting early intensive blood pressure–lowering therapy, emphasizing the benefits of analgesia and antisympathetic effects. Addressing existing guideline gaps, our innovative approach not only rapidly achieves recommended SBP control within 1 h14  but also minimizes acute blood pressure fluctuations from procedural pain. Apart from this, it enables light sedation, offering a favorable option to meet SBP reduction targets in intracerebral hemorrhage patients, presenting a potentially groundbreaking method for effective and timely intervention.

The major guidelines14,27  are in high agreement that early intensive blood pressure–lowering (e.g., target to 140 mmHg) is safe because it does not increase the rates of death or severe disability, although the improvement in functional outcomes remains controversial.16,26,28  However, there is still a lack of solid evidence to guide the initial choice of rapid antihypertensive agents. Although the Canadian Stroke Best Practice Recommendations suggest the use of labetalol, hydralazine, nicardipine, and enalapril for acute blood pressure reduction,15  more substantial evidence is still needed to support their widespread clinical application.29  Simultaneously, we cannot deny that there are defects in antihypertensives, which lead to rebound hypertension, elevated ICP, and even worse prognosis of intracerebral hemorrhage patients.30  To address these deficiencies, new frontiers of blood pressure–lowering management, not only focusing on antihypertensives but also considering medications other than antihypertensives, need to be explored. This integrated strategy involving remifentanil and dexmedetomidine brings new prospects for improving the prognosis of critical intracerebral hemorrhage.

Remifentanil, characterized as an ultrashort-acting opioid receptor agonist, exhibits rapid onset and metabolism, pronounced analgesic effect, and minimal respiratory depression.31,32  Widely employed in clinical general anesthesia and for the analgesia in critically ill patients, remifentanil’s unique properties facilitate frequent awakening, enabling the assessment of neurologic function.31,33  Its potential neurophysiological benefits in patients with craniocerebral injuries may arise from a reduction in oxidative metabolism and ICP, coupled with minimal impact on cerebral blood flow and cerebral perfusion pressure.34,35  Dexmedetomidine, a highly selective α2-adrenergic receptor agonist, boasts rapid distribution and elimination without accumulation. It provide anxiolysis and cooperative sedation without inducing respiratory depression, making it particularly suitable for conducting reliable neurologic examinations in acute brain injury patients.31,36  Studies have indicated that continuous infusion of remifentanil and dexmedetomidine could maintain hemodynamic stability, including heart rate and blood pressure.37–39  Additionally, this combination strategy reduces the dose dependence of calcium channel blockers like nimodipine by attenuating the sympathetic response.40  This establishes a scientific foundation for the integrated approach and elucidates why this strategy could contribute to early intensive blood pressure–lowering.

Beyond early intensive blood pressure–lowering, maintaining continuous, smooth, and sustained control of blood pressure, particularly avoiding peaks and large variability in SBP, represents a crucial approach for enhancing functional outcomes in patients with acute intracerebral hemorrhage.10,14,41–43  However, in severely ill patients, inevitable nociceptive procedures during treatment, such as endotracheal sputum suctioning, have the potential to induce a sudden elevation in SBP via the stimulation of cough-associated neurons and activation of the sympathetic nervous system.33,44–46  The findings of this study highlight that this innovative blood pressure–lowering strategy, when pretreated with remifentanil, can effectively manage the increase in blood pressure variability induced by endotracheal sputum suctioning. This observation serves as a foundational element for addressing iatrogenic pain in patients with intracerebral hemorrhage.

Our findings revealed a significantly higher proportion of patients with light sedation in the intervention group compared to the control group. In recent years, there has been a growing recognition of the neuroprotective effects associated with the continuous infusion of sedative and opioid agents during the acute phase (initial 24 to 48 h) in patients with acute brain injuries.36  Light sedation, in contrast to deep sedation, not only facilitates patient arousal and conscious level assessment but also contributes to shorter extubation times and reduced tracheostomy rates.33,47–49  Therefore, this strategy based on remifentanil and dexmedetomidine seems to have particular value for patients with mild to moderate brain injuries, presenting an alternative to commonly used sedatives such as midazolam and propofol.31 

An exploratory post hoc subgroup analysis was conducted to further investigate the results, and the findings from this analysis align with the overall efficacy results, demonstrating consistency within the trial. This underscores the robustness of the preset protocol of remifentanil and dexmedetomidine-based standard guideline management for treating acute intracerebral hemorrhage. It should be noted that this strategy did not exhibit a sufficient advantage for early blood pressure control in two specific subgroups: patients with subarachnoid hemorrhage and those with a baseline SBP greater than 180 mmHg. This may be attributed to pain and stress not being the primary factors leading to increased blood pressure in patients with ruptured aneurysms or severe hypertension, emphasizing the need for further exploration and identification of more adaptive populations. In addition, it is crucial to acknowledge the limitations of the subgroup analysis. The results should be considered as reference points for exploration rather than definitive conclusions, as the subgroup did not adhere to the randomness principle, the sample size was insufficient, and the level of certainty was low.

Regarding safety, although there was no significant difference in overall adverse events in this study, the intervention group experienced higher incidences of bradycardia and respiratory depression, likely associated with the use of dexmedetomidine and remifentanil.31  Therefore, it is recommended that the intervention in this study be carried out under close monitoring of electrocardiogram and respiration. It is crucial to be vigilant and responsive to potential cardiovascular and respiratory effects. However, it is important to highlight that most adverse events in this trial, including bradycardia and respiratory depression, were classified as mild to moderate. Furthermore, these events were reversible upon the suspension of treatment, indicating that the blood pressure–lowering protocol involving remifentanil and dexmedetomidine is safe and feasible for this patient population when administered under adequate intensive care conditions.

Our findings also suggest that an early intensive blood pressure–lowering strategy does not provide a therapeutic benefit in the rate of the secondary outcomes, including the occurrence of hematoma expansion and the improvement of neurologic function. This contrasts with the results of secondary analyses in previous studies.10,41,50  The disparity can be attributed to the primary focus of the study design on adhering to the blood pressure–lowering target and time window recommended by the guidelines rather than explicitly targeting neuroprotection, hematoma expansion, and functional recovery. Meanwhile, the limited sample size in this trial restricted the power to demonstrate potential interactions between the intervention and prognostic outcomes. Thus, further large-sample studies with careful prospective evaluations to limit confounding factors are needed to verify the use of this strategy to improve hematoma expansion, neural prognosis, and mortality.

Several limitations of this study should be noted. First, while the goals of blood pressure control differ for intracerebral hemorrhage,27  we did not exclude patients with subarachnoid hemorrhage. This inclusion stems from the possibility that stress may elevate blood pressure in both conditions. However, our post hoc subgroup analyses revealed that these patients did not experience the same benefits from the intervention as the overall population. This discrepancy might lead to an overestimation or underestimation of the actual intervention effect, but it also provides a basis for further research. Second, the use of various drug therapies and the inclusion of surgical patients introduce complexity into the outcome analysis. Uncontrolled postoperative pain or persistent sedation could potentially elevate or lower blood pressure responses. Third, the single-blinded assignment of the interventions, necessitated by limitations related to opioid administration, might have led to more stringent blood pressure monitoring and dosage adjustments than conventional blood pressure reduction methods. Consequently, the outcomes may have been influenced by differences in management strategies used for the two groups after randomization rather than documented ones. Moreover, while the results of blood pressure variability support the efficacy of opioid premedication for procedural pain, the use of a placebo in the control group may introduce potential bias. Finally, since the range of SBP maintenance was not conclusively determined at the time of study design, the study’s goal for SBP maintenance differs from current guideline updates.14  Nevertheless, this strategy remains instructive for policymakers aiming to achieve excellent blood pressure control.

To summarize, this study provided a novel and promising therapeutic option for early intensive blood pressure–lowering in patients with acute intracerebral hemorrhage. Priority application of remifentanil combined with dexmedetomidine rapidly and consistently lowers blood pressure, although its impact on overall outcomes in intracerebral hemorrhage patients lacks sufficient evidence. Larger-scale studies are needed to further assess this intervention’s effectiveness in the existing literature.

Acknowledgments

The authors are immensely grateful to their patients with intracerebral hemorrhage and their families for helping in our efforts to improve care and outcomes for patients with hemorrhagic stroke. They also thank the China Neurocritical (Beijing, China) study group for their support of study design and execution; Guangzhou Hipower Pharmaceutical R&D Co., Ltd. (Guangzhou, China), for their support of the data monitoring; and Clinical Trial Service (Guangzhou) Co., Ltd. (Guangzhou, China), for their contribution to statistics and randomization process.

Research Support

This study was supported by the China International Medical Foundation (to Dr. Yang, grant No. Z2018351902; Beijing, China) and Clinical Research Startup Program of Southern Medical University by the High-level University Construction Funding of Guangdong Provincial Department of Education (to Dr. Yang, grant No. LC2019ZD017; Guangzhou, China). The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Competing Interests

The authors declare no competing interests.

Reproducible Science

Full protocol available at: yhicu_1103@163.com. Raw data available at: yhicu_1103@163.com.

Supplemental Digital Content

Supplemental Digital Content 1. Standard care bundle of intracerebral hemorrhage, https://links.lww.com/ALN/D506

Supplemental Digital Content 2. Study protocol, https://links.lww.com/ALN/D507

Supplemental Digital Content 3. Statistical analysis plan, https://links.lww.com/ALN/D508

Supplemental Digital Content 4. Blood pressure lowering agents, analgesics, and sedatives used in the first 24 h posttreatment between the two groups, https://links.lww.com/ALN/D509

Supplemental Digital Content 5. Frequency distribution histogram of the systolic blood pressure at 1 h posttreatment initiation in two groups, https://links.lww.com/ALN/D510

Supplemental Digital Content 6. Mean systolic blood pressure during the first 24 h posttreatment in the intervention group or control group, https://links.lww.com/ALN/D511

Supplemental Digital Content 7. Number of patients with systolic blood pressure less than 110 mmHg during 24 h posttreatment in both groups, https://links.lww.com/ALN/D512

1.
Poon
MT
,
Fonville
AF
,
Al-Shahi Salman
R
:
Long-term prognosis after intracerebral haemorrhage: Systematic review and meta-analysis.
J Neurol Neurosurg Psychiatry
2014
;
85
:
660
7
2.
An
SJ
,
Kim
TJ
,
Yoon
BW
:
Epidemiology, risk factors, and clinical features of intracerebral hemorrhage: An update.
J Stroke
2017
;
19
:
3
10
3.
Qureshi
AI
,
Tuhrim
S
,
Broderick
JP
,
Batjer
HH
,
Hondo
H
,
Hanley
DF
:
Spontaneous intracerebral hemorrhage.
N Engl J Med
2001
;
344
:
1450
60
4.
Feigin
VL
,
Lawes
CM
,
Bennett
DA
,
Barker-Collo
SL
,
Parag
V
:
Worldwide stroke incidence and early case fatality reported in 56 population-based studies: A systematic review.
Lancet Neurol
2009
;
8
:
355
69
5.
Qureshi
AI
,
Ezzeddine
MA
,
Nasar
A
et al
.:
Prevalence of elevated blood pressure in 563,704 adult patients with stroke presenting to the ED in the United States.
Am J Emerg Med
2007
;
25
:
32
8
6.
Zhang
Y
,
Reilly
KH
,
Tong
W
et al
.:
Blood pressure and clinical outcome among patients with acute stroke in Inner Mongolia, China.
J Hypertens
2008
;
26
:
1446
52
7.
Okumura
K
,
Ohya
Y
,
Maehara
A
,
Wakugami
K
,
Iseki
K
,
Takishita
S
:
Effects of blood pressure levels on case fatality after acute stroke.
J Hypertens
2005
;
23
:
1217
23
8.
Vemmos
KN
,
Tsivgoulis
G
,
Spengos
K
et al
.:
U-shaped relationship between mortality and admission blood pressure in patients with acute stroke.
J Intern Med
2004
;
255
:
257
65
9.
Ohwaki
K
,
Yano
E
,
Nagashima
H
,
Hirata
M
,
Nakagomi
T
,
Tamura
A
:
Blood pressure management in acute intracerebral hemorrhage: Relationship between elevated blood pressure and hematoma enlargement.
Stroke
2004
;
35
:
1364
7
10.
Moullaali
TJ
,
Wang
X
,
Martin
RH
et al
.:
Blood pressure control and clinical outcomes in acute intracerebral haemorrhage: A preplanned pooled analysis of individual participant data.
Lancet Neurol
2019
;
18
:
857
64
11.
Meeks
JR
,
Bambhroliya
AB
,
Meyer
EG
et al
.:
High in-hospital blood pressure variability and severe disability or death in primary intracerebral hemorrhage patients.
Int J Stroke
2019
;
14
:
987
95
12.
Divani
AA
,
Liu
X
,
Di Napoli
M
et al
.:
Blood pressure variability predicts poor in-hospital outcome in spontaneous intracerebral hemorrhage.
Stroke
2019
;
50
:
2023
9
13.
Hemphill
JC
, 3rd
,
Greenberg
SM
,
Anderson
CS
et al
.;
American Heart Association Stroke Council
:
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
60
14.
Greenberg
SM
,
Ziai
WC
,
Cordonnier
C
et al
.;
American Heart Association/American Stroke Association
:
2022 Guideline for the management of patients with spontaneous intracerebral hemorrhage: A guideline from the American Heart Association/American Stroke Association.
Stroke
2022
;
53
:
e282
361
15.
Shoamanesh
A
,
Patrice Lindsay
M
,
Castellucci
LA
et al
.:
Canadian stroke best practice recommendations: Management of spontaneous intracerebral hemorrhage, 7th edition update 2020.
Int J Stroke
2021
;
16
:
321
41
16.
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
45
17.
Suri
MF
,
Vazquez
G
,
Ezzeddine
MA
,
Qureshi
AI
:
A multicenter comparison of outcomes associated with intravenous nitroprusside and nicardipine treatment among patients with intracerebral hemorrhage.
Neurocrit Care
2009
;
11
:
50
5
18.
Ko
SB
,
Yoon
BW
:
Blood pressure management for acute ischemic and hemorrhagic stroke: The evidence.
Semin Respir Crit Care Med
2017
;
38
:
718
25
19.
Myers
MG
,
Norris
JW
,
Hachniski
VC
,
Sole
MJ
:
Plasma norepinephrine in stroke.
Stroke
1981
;
12
:
200
4
20.
Dong
R
,
Li
F
,
Xu
Y
et al
.:
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.
Trials
2018
;
19
:
607
21.
Moher
D
,
Hopewell
S
,
Schulz
KF
et al
.:
CONSORT 2010 explanation and elaboration: Updated guidelines for reporting parallel group randomised trials.
BMJ
2010
;
340
:
c869
22.
Hogue
CW
, Jr.
,
Bowdle
TA
,
O’Leary
C
et al
.:
A multicenter evaluation of total intravenous anesthesia with remifentanil and propofol for elective inpatient surgery.
Anesth Analg
1996
;
83
:
279
85
23.
Guy
J
,
Hindman
BJ
,
Baker
KZ
et al
.:
Comparison of remifentanil and fentanyl in patients undergoing craniotomy for supratentorial space-occupying lesions.
Anesthesiology
1997
;
86
:
514
24
24.
Bhana
N
,
Goa
KL
,
McClellan
KJ
:
Dexmedetomidine.
Drugs
2000
;
59
:
263
8; discussion 269
25.
Song
J
,
Jin
C
,
Shan
Z
,
Teng
W
,
Li
J
:
Prevalence and risk factors of hyperuricemia and gout: A cross-sectional survey from 31 provinces in Mainland China.
J Transl Int Med
2022
;
10
:
134
45
26.
Anderson
CS
,
Heeley
E
,
Huang
Y
et al
.;
INTERACT2 Investigators
:
Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage.
N Engl J Med
2013
;
368
:
2355
65
27.
Hoh
BL
,
Ko
NU
,
Amin-Hanjani
S
et al
.:
2023 Guideline for the management of patients with aneurysmal subarachnoid hemorrhage: A guideline from the American Heart Association/American Stroke Association.
Stroke
2023
;
54
:
e314
70
28.
Qureshi
AI
,
Palesch
YY
,
Barsan
WG
et al
.;
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
;
375
:
1033
43
29.
Minhas
JS
,
Moullaali
TJ
,
Rinkel
GJE
,
Anderson
CS
:
Blood pressure management after intracerebral and subarachnoid hemorrhage: The knowns and known unknowns.
Stroke
2022
;
53
:
1065
73
30.
Bath
PM
,
Woodhouse
LJ
,
Krishnan
K
et al
.:
Prehospital transdermal glyceryl trinitrate for ultra-acute intracerebral hemorrhage: Data from the RIGHT-2 trial.
Stroke
2019
;
50
:
3064
71
31.
Panzer
O
,
Moitra
V
,
Sladen
RN
:
Pharmacology of sedative-analgesic agents: Dexmedetomidine, remifentanil, ketamine, volatile anesthetics, and the role of peripheral mu antagonists.
Crit Care Clin
2009
;
25
:
451
69 vii
32.
Glass
PS
,
Hardman
D
,
Kamiyama
Y
et al
.:
Preliminary pharmacokinetics and pharmacodynamics of an ultra-short-acting opioid: Remifentanil (GI87084B).
Anesth Analg
1993
;
77
:
1031
40
33.
Devlin
JW
,
Skrobik
Y
,
Gélinas
C
et al
.:
Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU.
Crit Care Med
2018
;
46
:
e825
73
34.
Tipps
LB
,
Coplin
WM
,
Murry
KR
,
Rhoney
DH
:
Safety and feasibility of continuous infusion of remifentanil in the neurosurgical intensive care unit.
Neurosurgery
2000
;
46
:
596
601; discussion 601
35.
Fodale
V
,
Schifilliti
D
,
Praticò
C
,
Santamaria
LB
:
Remifentanil and the brain.
Acta Anaesthesiol Scand
2008
;
52
:
319
26
36.
Oddo
M
,
Crippa
IA
,
Mehta
S
et al
.:
Optimizing sedation in patients with acute brain injury.
Crit Care
2016
;
20
:
128
37.
Albertin
A
,
Casati
A
,
Federica
L
et al
.:
The effect-site concentration of remifentanil blunting cardiovascular responses to tracheal intubation and skin incision during Bispectral Index-guided propofol anesthesia.
Anesth Analg
2005
;
101
:
125
30, table of contents
38.
Baraka
A
,
Siddik
S
,
Alameddine
M
:
Remifentanil for modulation of hemodynamics in a patient undergoing laparoscopic resection of pheochromocytoma.
Middle East J Anaesthesiol
2004
;
17
:
585
92
39.
Jung
JW
,
Park
JK
,
Jeon
SY
et al
.:
Dexmedetomidine and remifentanil in the perioperative management of an adolescent undergoing resection of pheochromocytoma -A case report.
Korean J Anesthesiol
2012
;
63
:
555
8
40.
Ren
C
,
Gao
J
,
Xu
GJ
et al
.:
The nimodipine-sparing effect of perioperative dexmedetomidine infusion during aneurysmal subarachnoid hemorrhage: A prospective, randomized, controlled trial.
Front Pharmacol
2019
;
10
:
858
41.
Manning
L
,
Hirakawa
Y
,
Arima
H
et al
.;
INTERACT2 investigators
:
Blood pressure variability and outcome after acute intracerebral haemorrhage: A post-hoc analysis of INTERACT2, a randomised controlled trial.
Lancet Neurol
2014
;
13
:
364
73
42.
Lattanzi
S
,
Cagnetti
C
,
Provinciali
L
,
Silvestrini
M
:
Blood pressure variability and clinical outcome in patients with acute intracerebral hemorrhage.
J Stroke Cerebrovasc Dis
2015
;
24
:
1493
9
43.
Chung
PW
,
Kim
JT
,
Sanossian
N
et al
.;
FAST-MAG Investigators and Coordinators
:
Association between hyperacute stage blood pressure variability and outcome in patients with spontaneous intracerebral hemorrhage.
Stroke
2018
;
49
:
348
54
44.
Rass
V
,
Ianosi
BA
,
Lindner
A
et al
.:
Hemodynamic response during endotracheal suctioning predicts awakening and functional outcome in subarachnoid hemorrhage patients.
Crit Care
2020
;
24
:
432
45.
Mutolo
D
:
Brainstem mechanisms underlying the cough reflex and its regulation.
Respir Physiol Neurobiol
2017
;
243
:
60
76
46.
Mazzone
SB
,
Undem
BJ
:
Vagal afferent innervation of the airways in health and disease.
Physiol Rev
2016
;
96
:
975
1024
47.
Shehabi
Y
,
Bellomo
R
,
Reade
MC
et al
.;
Sedation Practice in Intensive Care Evaluation Study Investigators
:
Early goal-directed sedation versus standard sedation in mechanically ventilated critically ill patients: A pilot study*.
Crit Care Med
2013
;
41
:
1983
91
48.
Treggiari
MM
,
Romand
JA
,
Yanez
ND
et al
.:
Randomized trial of light versus deep sedation on mental health after critical illness.
Crit Care Med
2009
;
37
:
2527
34
49.
Vincent
JL
,
Shehabi
Y
,
Walsh
TS
et al
.:
Comfort and patient-centred care without excessive sedation: The eCASH concept.
Intensive Care Med
2016
;
42
:
962
71
50.
Anderson
CS
,
Huang
Y
,
Wang
JG
et al
.;
INTERACT Investigators
:
Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): A randomised pilot trial.
Lancet Neurol
2008
;
7
:
391
9
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