Brain Infarct
Conditions
Keywords
brian infarction, thrombolysis, haemodilution, normal saline
Brief summary
This study aims to explore the safety and efficacy of 0.9% normal saline （NS） infusion on stroke after intravenous thrombolysis (IVT), we decided to conduct this multi-centre randomized controlled trial for the first time. This trial will provide an innovative strategy to facilitate functional independence after stroke administered with IVT. This is a multi-center, randomized controlled two arm (1:1 ratio) clinical trial. The enrolled participators will be divided into the NS group and the control group randomly after confirming as acute ischemic stroke (AIS). In the NS group, the patient will undergo NS 2000ml intravenous infusion immediately after IVT, with the speed of 200ml/h. In the control group, the patient will receive an NS 200-400ml after IVT. The primary efficacy is disability at days 90, as scored by means of the modified Rankin scale (mRS), dichotomized as a favorable outcome (a score of 0-2), or an unfavorable outcome (a score of 3 to 6). The secondary outcomes mainly comprise neurological deficits, disability, imaging and laboratory tests at each follow-up time. The safety outcomes include the cerebral edema at 24-hour post-IVT detected by cranial CT, the 24-hour fluctuation of blood pressure and the cardiac function detected by ultrasonic cardiogram within 3 days after IVT.
Interventions
DRUG0.9% NaCl 2000ml
The patient will undergo NS 2000ml intravenous infusion immediately after IVT. Subsequent therapy is based on Chinese guidelines for diagnosis and treatment of acute ischemic stroke 2018. All of the subjects should be treated in the hospital at least 7 days according to the guidelines for early management of stroke.
DRUG0.9% NaCl 200-400ml
The patients receive an NS 200-400ml after IVT. Subsequent therapy is based on Chinese guidelines for diagnosis and treatment of acute ischemic stroke 2018. All of the subjects should be treated in the hospital at least 7 days according to the guidelines for early management of stroke.
Sponsors
Affliated Hospital of Jiujiang University
Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine
Tianjin Medical University General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. AIS; 2. Age 18-80 years; 3. Prestroke mRS≤1; 4. NIHSS score 0-25; 5. Onset-to-needle time≤4.5 h; 6. Sign the informed consent.
Exclusion criteria
(1) Massive infarction, characterized by infarction area larger than 1/3 of the effected middle cerebral artery territory and/or the cerebellum territory presented in admitted computed tomography (CT) or MRI; (2) Intention to undergo endovascular treatment; (3) History of heart failure or pre-IVT BNP≥500pg/ml or having presentations or signs indicating heart failure; (4) Haemorrhage during IVT, including ICH, severe digestive haemorrhage and severe respiratory haemorrhage; (5) Allergy to thrombolysis drugs; (6) Intolerant to thrombolysis due to any reasons and had to terminate thrombolysis; (7) Arterial puncture at a non-compressible site within previous 7 days, major surgery within previous 14 days, sever trauma, gastrointestinal or urinary tract bleeding within previous 21 days; (8) Cerebral infarction or myocardial infarction within previous 3 months, previous intracranial haemorrhage (ICH) including parenchymal haemorrhage, intraventricular haemorrhage, subarachnoid haemorrhage, subdural/external haematoma, etc; (9) Severe brain trauma, intracranial or intraspinal surgery within previous 3 months or known malignant intracranial neoplasm, giant intracranial aneurysm or arteriovenous malformation; (10) Persistent systolic blood pressure≥180mmHg or diastolic blood pressure≥100mmHg; (11) Admitted blood glucose\<2.8mmol/L or \>22.22mmol/L; (12) Defect in coagulation, for example, current use of oral warfarin with an international normalised ratio\>1.7, or prothrombin time\>15s, or heparins during the last 48 hours, or use of direct thrombin inhibitors or direct factor Xa inhibitors during the last 48 hours or with an elevated activated partial thromboplastin time; (13) Known defect of platelet or clotting function, platelet count\<100×109/L; (14) Stroke mimics, such as seizure and hysteria; (15) Brain haemorrhage identified by CT or MRI; (16) Any terminal illness such that patients would not be expected to survive\>1 year; (17) Pregnant women or nursing mother; (18) Poor compliance, or inability to adhere to the trial protocol or follow-up; (19) Participating in other clinical trials within previous 3 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With 90-day Favorable Outcome | 90 days | Disability on day 90, as scored by means of the modified Rankin scale (mRS), dichotomized as a favorable outcome (a score of 0 to 2), or an unfavorable outcome (a score of 3 to 6). Scores on mRS range from 0 (no symptoms at all) to 6 (death), with higher values reflecting more severe disability or death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| NIHSS Scores on Day 7 | 7 days | The National Institutes of Health Stroke Scale (NIHSS), a 15-item scale that measures the level of neurologic impairment. Total scores on the NIHSS range from 0 to 42, with higher values reflecting more severe cerebral infarcts (\<5, mild impairment; ≥25, very severe neurologic impairment). |
| mRS on Day 7 | 7 days | Scores on the modified Rankin scale(mRS) range from 0 (no symptoms at all) to 6 (death), with higher values reflecting more severe disability or death. |
| mRS on Day 30 | 30 days | Scores on the modified Rankin scale(mRS) range from 0 (no symptoms at all) to 6 (death), with higher values reflecting more severe disability or death. |
| Number of Participants With Barthel Index 60-100 on Day 30 | 30 days | The 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. |
| Number of Participants With Barthel Index 60-100 on Day 90 | 90 days | The 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. |
| Number of Pariticipants With Early Neurological Deterioration (END, △NIHSS≥2) | 24 hours | Early neurological deterioration (END) indicates an increase of ≥2 in the NIHSS score within 24 hours after IVT, and the deterioration is not caused by intracranial hemorrhage that is confirmed by cranial CT. The National Institutes of Health Stroke Scale (NIHSS), a 15-item scale that measures the level of neurologic impairment. Total scores on the NIHSS range from 0 to 42, with higher values reflecting more severe cerebral infarcts. |
| Number of Participants With Early Neurological Deterioration (END, △NIHSS≥4) | 24 hours | Early neurological deterioration (END) indicates an increase of ≥4 in the NIHSS score within 24 hours after IVT, and the deterioration is not caused by intracranial hemorrhage that is confirmed by cranial CT. The National Institutes of Health Stroke Scale (NIHSS), a 15-item scale that measures the level of neurologic impairment. Total scores on the NIHSS range from 0 to 42, with higher values reflecting more severe cerebral infarcts. |
| Imaging Infarction Volume at 24 Hours | 24 hours | Cranial computed tomography (CT) scans are performed before IVT and 24 hours after randomization. The infarction area is confirmed using CT maps and the infarction volume is calculated by 3D-Slicer (Version4.6.2, https://www.slicer.org/). |
| Blood Pressure at 24 Hours | 24 hours | Blood pressure, including systolic blood pressure (SBP) and diastolic blood pressure (DBP), is monitored at 24 hours after randomization. |
| NIHSS Scores at 24 Hours | 24 hours | The National Institutes of Health Stroke Scale (NIHSS), a 15-item scale that measures the level of neurologic impairment. Total scores on the NIHSS range from 0 to 42, with higher values reflecting more severe cerebral infarcts (\<5, mild impairment; ≥25, very severe neurologic impairment). |
| Death Rate | 90 days | Death rate within 90 days after randomization. |
| Number of Paricipants With Intracaranial Hemorrhage | 7 days | Intracaranial hemorrhage confirmed by cranial CT within 7 days after randomization. |
| Number of Participants With Symptomatic Intracranial Hemorrhage | 7 days | Symptomatic intracranial hemorrhage indicates NIHSS deterioration≥2 scores in combination with intracranial hemorrhage on CT scan without other causes for the deterioration within 7 days after randomization. |
| Neutrophil-to-lymphocyte Ratio (NLR) | 24-48 hours | Peripheral blood inflammatory indices, neutrophil-to-lymphocyte ratio (NLR),24-48 hours after randomization. |
| Platelet-to-lymphocyte (PLR) | 24-48 hours | Peripheral blood inflammatory indices, platelet-to-lymphocyte (PLR) at 24-48 hours after randomization. |
| SII | 24-48 hours | Peripheral blood inflammatory indices, (platelet✖neurophil)/lymphocyte (SII) at 24-48 hours after randomization. |
| S100-β | 24-48 hours | Laboratory examinations, peripehral S100-β at 24-48 hours after randomization. |
| Myeloperoxidase (MPO) | 24-48 hours | Laboratory examinations, peripheral myeloperoxidase (MPO) at 24-48 hours after randomization. |
| Brain Derived Neurotrophic Factor (BDNF) | 24-48 hours | Laboratory examinations, brain derived neurotrophic factor (BDNF)at 24-48 hours after randomization. |
| Ejection Fraction | 72 hours | Ejection fraction was assessed by ultrasonic cardiogram within 72 hours after randomization. |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| NS Group The patient will undergo NS 2000ml intravenous infusion immediately after IVT. | 121 |
| Control Group The patient will the patients receive an NS 200-400ml after IVT. | 120 |
| Total | 241 |
Baseline characteristics
| Characteristic | Control Group | Total | NS Group |
|---|---|---|---|
| Age, Continuous | 66 years | 67 years | 67.0 years |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment China | 120 participants | 241 participants | 121 participants |
| Sex: Female, Male Female | 38 Participants | 73 Participants | 35 Participants |
| Sex: Female, Male Male | 82 Participants | 168 Participants | 86 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 121 | 5 / 120 |
| other Total, other adverse events | 0 / 121 | 0 / 120 |
| serious Total, serious adverse events | 0 / 121 | 0 / 120 |
Outcome results
Primary
Number of Participants With 90-day Favorable Outcome
Disability on day 90, as scored by means of the modified Rankin scale (mRS), dichotomized as a favorable outcome (a score of 0 to 2), or an unfavorable outcome (a score of 3 to 6). Scores on mRS range from 0 (no symptoms at all) to 6 (death), with higher values reflecting more severe disability or death.
Time frame: 90 days
Population: One patient in each group was lost to follow-up at 90 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NS Group | Number of Participants With 90-day Favorable Outcome | 106 Participants |
| Control Group | Number of Participants With 90-day Favorable Outcome | 93 Participants |
Secondary
Blood Pressure at 24 Hours
Blood pressure, including systolic blood pressure (SBP) and diastolic blood pressure (DBP), is monitored at 24 hours after randomization.
Time frame: 24 hours
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| NS Group | Blood Pressure at 24 Hours | systolic pressure | 142 mmHg |
| NS Group | Blood Pressure at 24 Hours | diastolic pressure | 79 mmHg |
| Control Group | Blood Pressure at 24 Hours | systolic pressure | 135 mmHg |
| Control Group | Blood Pressure at 24 Hours | diastolic pressure | 77 mmHg |
Secondary
Brain Derived Neurotrophic Factor (BDNF)
Laboratory examinations, brain derived neurotrophic factor (BDNF)at 24-48 hours after randomization.
Time frame: 24-48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NS Group | Brain Derived Neurotrophic Factor (BDNF) | 1019.59 pg/ml | Standard Deviation 810.89 |
| Control Group | Brain Derived Neurotrophic Factor (BDNF) | 999.6 pg/ml | Standard Deviation 817.42 |
Secondary
Death Rate
Death rate within 90 days after randomization.
Time frame: 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NS Group | Death Rate | 2 Participants |
| Control Group | Death Rate | 5 Participants |
Secondary
Ejection Fraction
Ejection fraction was assessed by ultrasonic cardiogram within 72 hours after randomization.
Time frame: 72 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NS Group | Ejection Fraction | 63 percentage |
| Control Group | Ejection Fraction | 63 percentage |
Secondary
Imaging Infarction Volume at 24 Hours
Cranial computed tomography (CT) scans are performed before IVT and 24 hours after randomization. The infarction area is confirmed using CT maps and the infarction volume is calculated by 3D-Slicer (Version4.6.2, https://www.slicer.org/).
Time frame: 24 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NS Group | Imaging Infarction Volume at 24 Hours | 0.21 ml |
| Control Group | Imaging Infarction Volume at 24 Hours | 0.31 ml |
Secondary
mRS on Day 30
Scores on the modified Rankin scale(mRS) range from 0 (no symptoms at all) to 6 (death), with higher values reflecting more severe disability or death.
Time frame: 30 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NS Group | mRS on Day 30 | 1 score on a scale |
| Control Group | mRS on Day 30 | 1 score on a scale |
Secondary
mRS on Day 7
Scores on the modified Rankin scale(mRS) range from 0 (no symptoms at all) to 6 (death), with higher values reflecting more severe disability or death.
Time frame: 7 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NS Group | mRS on Day 7 | 1 score on scale |
| Control Group | mRS on Day 7 | 1 score on scale |
Secondary
Myeloperoxidase (MPO)
Laboratory examinations, peripheral myeloperoxidase (MPO) at 24-48 hours after randomization.
Time frame: 24-48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NS Group | Myeloperoxidase (MPO) | 52746.41 pg/ml | Standard Deviation 35023.82 |
| Control Group | Myeloperoxidase (MPO) | 53902.99 pg/ml | Standard Deviation 47152.39 |
Secondary
Neutrophil-to-lymphocyte Ratio (NLR)
Peripheral blood inflammatory indices, neutrophil-to-lymphocyte ratio (NLR),24-48 hours after randomization.
Time frame: 24-48 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NS Group | Neutrophil-to-lymphocyte Ratio (NLR) | 2.75 ratio |
| Control Group | Neutrophil-to-lymphocyte Ratio (NLR) | 2.63 ratio |
Secondary
NIHSS Scores at 24 Hours
The National Institutes of Health Stroke Scale (NIHSS), a 15-item scale that measures the level of neurologic impairment. Total scores on the NIHSS range from 0 to 42, with higher values reflecting more severe cerebral infarcts (\<5, mild impairment; ≥25, very severe neurologic impairment).
Time frame: 24 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NS Group | NIHSS Scores at 24 Hours | 2 score on a scale |
| Control Group | NIHSS Scores at 24 Hours | 2 score on a scale |
Secondary
NIHSS Scores on Day 7
The National Institutes of Health Stroke Scale (NIHSS), a 15-item scale that measures the level of neurologic impairment. Total scores on the NIHSS range from 0 to 42, with higher values reflecting more severe cerebral infarcts (\<5, mild impairment; ≥25, very severe neurologic impairment).
Time frame: 7 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NS Group | NIHSS Scores on Day 7 | 1 score on scale |
| Control Group | NIHSS Scores on Day 7 | 1 score on scale |
Secondary
Number of Paricipants With Intracaranial Hemorrhage
Intracaranial hemorrhage confirmed by cranial CT within 7 days after randomization.
Time frame: 7 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NS Group | Number of Paricipants With Intracaranial Hemorrhage | 7 Participants |
| Control Group | Number of Paricipants With Intracaranial Hemorrhage | 3 Participants |
Secondary
Number of Pariticipants With Early Neurological Deterioration (END, △NIHSS≥2)
Early neurological deterioration (END) indicates an increase of ≥2 in the NIHSS score within 24 hours after IVT, and the deterioration is not caused by intracranial hemorrhage that is confirmed by cranial CT. The National Institutes of Health Stroke Scale (NIHSS), a 15-item scale that measures the level of neurologic impairment. Total scores on the NIHSS range from 0 to 42, with higher values reflecting more severe cerebral infarcts.
Time frame: 24 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NS Group | Number of Pariticipants With Early Neurological Deterioration (END, △NIHSS≥2) | 10 Participants |
| Control Group | Number of Pariticipants With Early Neurological Deterioration (END, △NIHSS≥2) | 25 Participants |
Secondary
Number of Participants With Barthel Index 60-100 on Day 30
The 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: 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NS Group | Number of Participants With Barthel Index 60-100 on Day 30 | 108 Participants |
| Control Group | Number of Participants With Barthel Index 60-100 on Day 30 | 104 Participants |
Secondary
Number of Participants With Barthel Index 60-100 on Day 90
The 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 (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NS Group | Number of Participants With Barthel Index 60-100 on Day 90 | 111 Participants |
| Control Group | Number of Participants With Barthel Index 60-100 on Day 90 | 105 Participants |
Secondary
Number of Participants With Early Neurological Deterioration (END, △NIHSS≥4)
Early neurological deterioration (END) indicates an increase of ≥4 in the NIHSS score within 24 hours after IVT, and the deterioration is not caused by intracranial hemorrhage that is confirmed by cranial CT. The National Institutes of Health Stroke Scale (NIHSS), a 15-item scale that measures the level of neurologic impairment. Total scores on the NIHSS range from 0 to 42, with higher values reflecting more severe cerebral infarcts.
Time frame: 24 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NS Group | Number of Participants With Early Neurological Deterioration (END, △NIHSS≥4) | 8 Participants |
| Control Group | Number of Participants With Early Neurological Deterioration (END, △NIHSS≥4) | 19 Participants |
Secondary
Number of Participants With Symptomatic Intracranial Hemorrhage
Symptomatic intracranial hemorrhage indicates NIHSS deterioration≥2 scores in combination with intracranial hemorrhage on CT scan without other causes for the deterioration within 7 days after randomization.
Time frame: 7 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NS Group | Number of Participants With Symptomatic Intracranial Hemorrhage | 2 Participants |
| Control Group | Number of Participants With Symptomatic Intracranial Hemorrhage | 0 Participants |
Secondary
Platelet-to-lymphocyte (PLR)
Peripheral blood inflammatory indices, platelet-to-lymphocyte (PLR) at 24-48 hours after randomization.
Time frame: 24-48 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NS Group | Platelet-to-lymphocyte (PLR) | 135.70 ratio |
| Control Group | Platelet-to-lymphocyte (PLR) | 128.11 ratio |
Secondary
S100-β
Laboratory examinations, peripehral S100-β at 24-48 hours after randomization.
Time frame: 24-48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NS Group | S100-β | 2.17 ng/ml | Standard Deviation 5.82 |
| Control Group | S100-β | 1.22 ng/ml | Standard Deviation 2.19 |
Secondary
SII
Peripheral blood inflammatory indices, (platelet✖neurophil)/lymphocyte (SII) at 24-48 hours after randomization.
Time frame: 24-48 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NS Group | SII | 527.05 ratio |
| Control Group | SII | 531.51 ratio |