Normobaric Hyperoxia, Intracerebral Hemorrhage
Conditions
Keywords
Intracerebral Hemorrhage, Normobaric Hyperoxia, Perihematomal Edema
Brief summary
Perihematoma edema (PHE), as the major injury for intracranial hemorrhage (ICH) involves more than the initial tissue damage induced directly by the hematoma. How to improve hypoxia in perihematoma seems to be a promising therapeutic candidate paradigm for ICH due to its pivotal role in the pathogenesis of perihematomas. Normobaric hyperoxia (NBO), supplied by a face mask (such as oxygen storage face mask) with atmosphere pressure (1ATA = 101.325 kPa, 100% O2), has been considered a safe, convenient, and promising therapy for correcting various diseases and thus garnered great attention in recent years. The previous study identified that early NBO could attenuate blood-brain barrier damage, rescue penumbra and finally improve the prognosis of ischemic stroke in patients with delayed rt-PA treatment. Therefore, given the profound effectiveness in the ischemic penumbra, we hypothesized that NBO might yield additional benefits for the ischemic-hypoxic tissues surrounding the hematoma in patients with ICH. Although many clinical trials have shown the effectiveness and safety of NBO in treating ischemic stroke, there is currently a lack of trials focusing on using NBO to treat ICH. Accordingly, we conducted a proof-of-concept, single-center, randomized controlled trial to evaluate the safety and efficacy of NBO in treating ICH patients so as to explore an innovative adjuvant therapy for ICH.
Detailed description
Intracerebral hemorrhage (ICH) is an intractable and life-threatening stroke subtype that imposes a significant impact on people's well-being and quality of life. ICH-induced mechanical compression to the surrounding brain tissue is a major injury that increases intracranial pressure (ICP). High ICP can decrease cerebral blood flow (CBF) and influence cerebral metabolism in perihematoma and even the whole brain. Decreased aerobic metabolism and perfusion in perihematomal injury can exacerbate edema and enlarge hematoma. Moreover, secondary injury in the perihematoma, such as ischemia, oxidative stress, inflammatory response, and protease release, involves more than the initial tissue damage induced directly by the hematoma. Theoretically, low CBF and abnormal metabolism in ICH patients expose the brain tissue to the ischemic-hypoxic condition, which is similar to that in the ischemic penumbra in stroke. Therefore, the key to treating ICH is to find an approach that can rescue the perihematoma. Improving hypoxia in perihematoma seems to be a promising therapeutic candidate paradigm for ICH due to its pivotal role in the pathogenesis of perihematomas. Normobaric hyperoxia (NBO), supplied by a face mask (such as oxygen storage face mask) with atmosphere pressure (1ATA = 101.325 kPa, 100% O2), has been considered a safe, convenient, and promising therapy for correcting various diseases and thus garnered great attention in recent years. The effectiveness of NBO on ischemic stroke (IS) has been fully identified. A plethora of studies show that NBO is capable of increasing the partial pressure of oxygen (PO2), elevating the blood flow and volume, protecting the blood-brain barrier (BBB), improving oxidative metabolism, reducing free radical damage, and even relieving inflammatory response in the penumbra. Rapid amelioration of hypoxia in brain tissue can restore brain dysfunction and improve clinical prognoses. Likewise, NBO is also regarded as a promising method for treating ICH. An animal study found that NBO for a period of 6 h per day for 3 consecutive days imposed a remarkable neuroprotective effect in rat ICH, improved neurological function, reduced brain edema, downregulated HIF-1α and VEGF expression and showed a reduction in apoptotic cells in the perihematoma. Although many clinical trials have shown the effectiveness and safety of NBO in treating ischemic stroke, there is currently a lack of trials focusing on using NBO to treat ICH. Accordingly, we conducted a proof-of-concept, single-center, randomized controlled trial to evaluate the safety and efficacy of NBO in treating ICH patients so as to explore an innovative adjuvant therapy for ICH.
Interventions
DEVICEOxygen storage face masks and nasal catheter
Giving high-flow mask oxygen via oxygen storage face masks (100% O2, flow rate 8 L/min, 1 hour, four times daily, and 2 L/min via nasal catheter during intermittent periods, for 7 days) immediately at admission.
DEVICENasal catheter
Giving 2 L/min flow of 100% O2 via nasal catheter at admission for 24 hours daily for 7 days.
Sponsors
Jiujiang University Affiliated Hospital
Capital Medical University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Investigator, Outcomes Assessor)
Masking description
Investigators and clinical assessors were blinded to the allocation, whereas the operators and participants were not. Neurological functional evaluations, imaging and laboratory tests were conducted by personnel blinded to the protocol of the study.
Intervention model description
Giving high-flow mask oxygen via oxygen storage face masks (100% O2, flow rate 8 L/min, 1 hour, four times daily, and 2 L/min via nasal catheter during intermittent periods, for 7 days) or not (2 L/min via nasal catheter for 7 days) at admission.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. supratentorial hematomas confirmed by admitted cranial computed tomography (CT), with the volume ranging from 10 to 30 mL; 2. age 18-80 years; 3. National Institute of Health Stroke Scale (NIHSS) ≥ 6 and Glasgow Coma Scale (GCS) \> 8 at admission; 4. onset-to-enrollment time ≤ 24 h; 5. signed informed consent.
Exclusion criteria
1. a history of ICH, ischemic attack, brain tumor, brain trauma, and other intracranial injury or disorders; 2. pre-stroke modified ranking scales (mRS) ≥ 1; 3. life-threatening condition; 4. pre-stroke complicated with austere diseases such as cancer, heart failure, and respiratory failures; 5. severe liver and kidney disorders; 6. a history of respiratory diseases; 7. poor compliance; 8. participation in other clinical trials within the previous three months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With mRS 0-3 | 90 days | modified Rankin Scale (mRS), an ordinal global disability scale ranging from 0 (no symptoms) to 6 (death) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Glasgow Coma Scale | 3 days | Glasgow Coma Scale is a practical method for the evaluation of impairment of conscious level in response to defined stimuli, which contains three parts, including eye-opening, verbal response, and motor response (scores range from 3-15, representing deep coma to normal). |
| Barthel Index | 90 days | Barthel Index represents functional status at follow-up time, the scores of which range from 0 (complete dependence) to 100 (complete independence) measured by several items, including feeding, bathing, grooming, dressing, bowels, bladder, toilet use, transfers, and stairs. |
| mRS Distribution | 90 days | modified Rankin Scale (mRS), an ordinal global disability scale ranging from 0 (no symptoms) to 6 (death) |
| NIHSS Scores | 3 days | The NIHSS is commonly used to evaluate neurological deficits in stroke and comprises five items in 11 fields of different neurological statuses (scores range from 0-42, representing normal to severe neurological deficits). |
| Absolute Perihematomal Edema Volume | 3 days | Absolute perihematomal edema in cranial CT scan, calculated by the software from United Imaging (United Imaging Healthcare Co., Ltd., Shanghai, China). |
| Relative Perihematomal Edema Volume | 3 days | The relative perihematomal edema was calculated by dividing the absolute perihematomal edema volume by the baseline hematoma volume to obtain a dimensionless ratio. |
| Hematoma Volume | 3 days | Hematoma volume in cranial CT scan, calculated by the software from United Imaging (United Imaging Healthcare Co., Ltd., Shanghai, China). |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| NBO Group Giving high-flow mask oxygen via oxygen storage face masks (100% O2, flow rate 8 L/min, 1 hour, four times daily, and 2 L/min via nasal catheter during intermittent periods, for 7 days) immediately at admission.
Oxygen storage face masks and nasal catheter: Giving high-flow mask oxygen via oxygen storage face masks (100% O2, flow rate 8 L/min, 1 hour, four times daily, and 2 L/min via nasal catheter during intermittent periods, for 7 days) immediately at admission. | 48 |
| Control Group Giving 2 L/min flow of 100% O2 via nasal catheter at admission for 24 hours daily for 7 days.
Nasal catheter: Giving 2 L/min flow of 100% O2 via nasal catheter at admission for 24 hours daily for 7 days. | 48 |
| Total | 96 |
Baseline characteristics
| Characteristic | Total | NBO Group | Control Group |
|---|---|---|---|
| Absolute perihematoma edema volume | 24.87 mL STANDARD_DEVIATION 9.88 | 24.19 mL STANDARD_DEVIATION 9.42 | 25.55 mL STANDARD_DEVIATION 10.38 |
| Age, Continuous | 62.97 years STANDARD_DEVIATION 9.77 | 62.23 years STANDARD_DEVIATION 10 | 63.71 years STANDARD_DEVIATION 9.58 |
| Diabetes | 21 participants | 13 participants | 8 participants |
| Diastolic blood pressure at admission | 91.31 mmHg STANDARD_DEVIATION 15.34 | 92.65 mmHg STANDARD_DEVIATION 16.05 | 89.98 mmHg STANDARD_DEVIATION 14.64 |
| Drinking | 30 participants | 15 participants | 15 participants |
| GCS score | 14 scores | 14 scores | 13 scores |
| Hematoma volume | 17.18 mL STANDARD_DEVIATION 7.06 | 16.77 mL STANDARD_DEVIATION 7.18 | 17.59 mL STANDARD_DEVIATION 6.98 |
| Hyperlipidemia | 16 participants | 7 participants | 9 participants |
| Hypertension | 65 participants | 36 participants | 29 participants |
| NIHSS score | 12 scores | 10 scores | 13 scores |
| Onset-to-needle time | 6.89 hours STANDARD_DEVIATION 5.48 | 5.85 hours STANDARD_DEVIATION 4.5 | 7.91 hours STANDARD_DEVIATION 6.18 |
| Race and Ethnicity Not Collected | 0 Participants | — | — |
| Region of Enrollment China | 96 participants | 48 participants | 48 participants |
| Relative perihematoma edema volume | 1.50 ratio STANDARD_DEVIATION 0.4 | 1.53 ratio STANDARD_DEVIATION 0.49 | 1.48 ratio STANDARD_DEVIATION 0.28 |
| Sex: Female, Male Female | 31 Participants | 17 Participants | 14 Participants |
| Sex: Female, Male Male | 65 Participants | 31 Participants | 34 Participants |
| Smoking | 19 participants | 12 participants | 7 participants |
| Stroke | 19 participants | 12 participants | 7 participants |
| Systolic blood pressure at admission | 158.90 mmHg STANDARD_DEVIATION 26.2 | 159.15 mmHg STANDARD_DEVIATION 24.58 | 158.65 mmHg STANDARD_DEVIATION 27.99 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 48 | 0 / 48 |
| other Total, other adverse events | 12 / 48 | 12 / 48 |
| serious Total, serious adverse events | 0 / 48 | 0 / 48 |
Outcome results
Primary
Percentage of Patients With mRS 0-3
modified Rankin Scale (mRS), an ordinal global disability scale ranging from 0 (no symptoms) to 6 (death)
Time frame: 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NBO Group | Percentage of Patients With mRS 0-3 | 39 Participants |
| Control Group | Percentage of Patients With mRS 0-3 | 27 Participants |
Secondary
Absolute Perihematomal Edema Volume
Absolute perihematomal edema in cranial CT scan, calculated by the software from United Imaging (United Imaging Healthcare Co., Ltd., Shanghai, China).
Time frame: 14 days
Population: There were 4 patients in the NBO group and 2 patients in the control group missing imaging data at 14 days.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NBO Group | Absolute Perihematomal Edema Volume | 16.17 mL | Standard Deviation 8.36 |
| Control Group | Absolute Perihematomal Edema Volume | 20.93 mL | Standard Deviation 12.71 |
Secondary
Absolute Perihematomal Edema Volume
Absolute perihematomal edema in cranial CT scan, calculated by the software from United Imaging (United Imaging Healthcare Co., Ltd., Shanghai, China).
Time frame: 7 days
Population: There were 3 patients in the NBO group and 4 patients in the control group missing imaging data at 7 days.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NBO Group | Absolute Perihematomal Edema Volume | 28.43 mL | Standard Deviation 15.59 |
| Control Group | Absolute Perihematomal Edema Volume | 37.53 mL | Standard Deviation 14.61 |
Secondary
Absolute Perihematomal Edema Volume
Absolute perihematomal edema in cranial CT scan, calculated by the software from United Imaging (United Imaging Healthcare Co., Ltd., Shanghai, China).
Time frame: 3 days
Population: There were 2 patients missing imaging data in each group at 3 days.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NBO Group | Absolute Perihematomal Edema Volume | 30.51 mL | Standard Deviation 10.35 |
| Control Group | Absolute Perihematomal Edema Volume | 33.51 mL | Standard Deviation 11.67 |
Secondary
Barthel Index
Barthel Index represents functional status at follow-up time, the scores of which range from 0 (complete dependence) to 100 (complete independence) measured by several items, including feeding, bathing, grooming, dressing, bowels, bladder, toilet use, transfers, and stairs.
Time frame: 90 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NBO Group | Barthel Index | 80 score on scale |
| Control Group | Barthel Index | 47.5 score on scale |
Secondary
Glasgow Coma Scale
Glasgow Coma Scale is a practical method for the evaluation of impairment of conscious level in response to defined stimuli, which contains three parts, including eye-opening, verbal response, and motor response (scores range from 3-15, representing deep coma to normal).
Time frame: 7 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NBO Group | Glasgow Coma Scale | 15 score on scale |
| Control Group | Glasgow Coma Scale | 15 score on scale |
Secondary
Glasgow Coma Scale
Glasgow Coma Scale is a practical method for the evaluation of impairment of conscious level in response to defined stimuli, which contains three parts, including eye-opening, verbal response, and motor response (scores range from 3-15, representing deep coma to normal).
Time frame: 14 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NBO Group | Glasgow Coma Scale | 15 score on scale |
| Control Group | Glasgow Coma Scale | 15 score on scale |
Secondary
Glasgow Coma Scale
Glasgow Coma Scale is a practical method for the evaluation of impairment of conscious level in response to defined stimuli, which contains three parts, including eye-opening, verbal response, and motor response (scores range from 3-15, representing deep coma to normal).
Time frame: 3 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NBO Group | Glasgow Coma Scale | 15 score on scale |
| Control Group | Glasgow Coma Scale | 14 score on scale |
Secondary
Hematoma Volume
Hematoma volume in cranial CT scan, calculated by the software from United Imaging (United Imaging Healthcare Co., Ltd., Shanghai, China).
Time frame: 3 days
Population: There were 2 patients missing imaging data in each group at 3 days.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NBO Group | Hematoma Volume | 14.89 mL | Standard Deviation 6.05 |
| Control Group | Hematoma Volume | 16.8 mL | Standard Deviation 6.76 |
Secondary
Hematoma Volume
Hematoma volume in cranial CT scan, calculated by the software from United Imaging (United Imaging Healthcare Co., Ltd., Shanghai, China).
Time frame: 7 days
Population: There were 3 patients in the NBO group and 4 patients in the control group missing imaging data at 7 days.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NBO Group | Hematoma Volume | 11.14 mL | Standard Deviation 4.93 |
| Control Group | Hematoma Volume | 13.26 mL | Standard Deviation 5.32 |
Secondary
Hematoma Volume
Hematoma volume in cranial CT scan, calculated by the software from United Imaging (United Imaging Healthcare Co., Ltd., Shanghai, China).
Time frame: 14 days
Population: There were 4 patients in the NBO group and 2 patients in the control group missing imaging data at 14 days.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NBO Group | Hematoma Volume | 5.85 mL | Standard Deviation 4.02 |
| Control Group | Hematoma Volume | 6.37 mL | Standard Deviation 4.13 |
Secondary
mRS Distribution
modified Rankin Scale (mRS), an ordinal global disability scale ranging from 0 (no symptoms) to 6 (death)
Time frame: 90 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NBO Group | mRS Distribution | 2 score on scale |
| Control Group | mRS Distribution | 3 score on scale |
Secondary
NIHSS Scores
The NIHSS is commonly used to evaluate neurological deficits in stroke and comprises five items in 11 fields of different neurological statuses (scores range from 0-42, representing normal to severe neurological deficits).
Time frame: 14 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NBO Group | NIHSS Scores | 5 score on scale |
| Control Group | NIHSS Scores | 7 score on scale |
Secondary
NIHSS Scores
The NIHSS is commonly used to evaluate neurological deficits in stroke and comprises five items in 11 fields of different neurological statuses (scores range from 0-42, representing normal to severe neurological deficits).
Time frame: 7 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NBO Group | NIHSS Scores | 7 score on scale |
| Control Group | NIHSS Scores | 10 score on scale |
Secondary
NIHSS Scores
The NIHSS is commonly used to evaluate neurological deficits in stroke and comprises five items in 11 fields of different neurological statuses (scores range from 0-42, representing normal to severe neurological deficits).
Time frame: 3 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NBO Group | NIHSS Scores | 9 score on scale |
| Control Group | NIHSS Scores | 12 score on scale |
Secondary
Relative Perihematomal Edema Volume
The relative perihematomal edema was calculated by dividing the absolute perihematomal edema volume by the baseline hematoma volume to obtain a dimensionless ratio.
Time frame: 3 days
Population: There were 2 patients missing imaging data in each group at 3 days.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NBO Group | Relative Perihematomal Edema Volume | 1.99 ratio | Standard Deviation 0.58 |
| Control Group | Relative Perihematomal Edema Volume | 1.94 ratio | Standard Deviation 0.46 |
Secondary
Relative Perihematomal Edema Volume
The relative perihematomal edema was calculated by dividing the absolute perihematomal edema volume by the baseline hematoma volume to obtain a dimensionless ratio.
Time frame: 14 days
Population: There were 4 patients in the NBO group and 2 patients in the control group missing imaging data at 14 days.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NBO Group | Relative Perihematomal Edema Volume | 0.96 ratio | Standard Deviation 0.43 |
| Control Group | Relative Perihematomal Edema Volume | 1.23 ratio | Standard Deviation 0.71 |
Secondary
Relative Perihematomal Edema Volume
The relative perihematomal edema was calculated by dividing the absolute perihematomal edema volume by the baseline hematoma volume to obtain a dimensionless ratio.
Time frame: 7 days
Population: There were 3 patients in the NBO group and 4 patients in the control group missing imaging data at 7 days.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NBO Group | Relative Perihematomal Edema Volume | 1.69 ratio | Standard Deviation 0.69 |
| Control Group | Relative Perihematomal Edema Volume | 2.18 ratio | Standard Deviation 0.67 |