Clinical trial NCT05993078
Conditions: Brain Infarct
Keywords: brian infarction thrombolysis haemodilution normal saline
Sponsor: Tianjin Medical University General Hospital
Start date: 2023-09-01; Completion date: 2025-01-08
Enrollment: 241 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Detailed description:

Arms: arm 1: The patient will undergo NS 2000ml intravenous infusion immediately after IVT. arm 2: The patient will the patients receive an NS 200-400ml after IVT.
Interventions: intervention 1: 0.9% NaCl 2000ml intervention 2: 0.9% NaCl 200-400ml
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol documents:
Prot_SAP_000.pdf: 
1
Protocol
Version 2.0
Normal Saline Infusion for Stroke after Intravenous Thrombolysis
A Randomized Clinical Trial
Principle Investigators
Jiayue Ding, Ming Zou


2
Table of Contents
Study Synopsis……………………………………………………………………4
Abbreviation………………………………………………………………………8
1. Background ………………………………………………………………… 10
2. Objectives ……………………………………………………………………11
2.1 Hypothesis tested…………………………………………………………11
2.2 Primary objective…………………………………………………………11
2.3 Secondary objective………………………………………………………11
3. Study Design …………………………………………………………………11
3.1 Trial plan …………………………………………………………………11
3.2 Selection criteria …………………………………………………………12
3.3 Follow-up time point………………………………………………………14
3.4 Randomization and masking ……………………………………………14
4. Trial Flow Chart………………………………………………………………15
5. Interventions …………………………………………………………………16
6. Measurement …………………………………………………………………16
6.1 Haematological examination and laboratory assessment………………16
6.2 Imaging test ………………………………………………………………16
6.3 Clinical observation ………………………………………………………17
7. Outcomes ………………………………………………………………………17
7.1 Efficacy outcomes …………………………………………………………17
7.2 Safety outcomes ……………………………………………………………18
8. Study flow diagram ……………………………………………………………18
9. Study periods……………………………………………………………………19
9.1 Screening periods……………………………………………………………19
9.2 Treatment periods……………………………………………………………19
9.3 In-hospital periods……………………………………………………………19
9.4 Follow-up periods……………………………………………………………19
10. Adverse events monitoring ……………………………………………………19


3
10.1 Adverse events (AEs) ………………………………………………………19
10.2 Serious adverse events (SAEs)………………………………………………19
10.3 Safety assessment……………………………………………………………20
10.4 Severity categorization and relationship definitions of AEs………………20
11. Statistics …………………………………………………………………………21
11.1 Sample size……………………………………………………………………21
11.2 Statistical analysis……………………………………………………………21
11.3 Analysis population …………………………………………………………22
12. Data management and monitoring………………………………………………22
12.1 Case Report Forms (CRF)……………………………………………………22
12.2 Monitoring ……………………………………………………………………23
13. References…………………………………………………………………………23
Appendix………………………………………………………………………………26


4
Study Synopsis
Title
Normal Saline Infusion for Stroke after Intravenous Thrombolysis
A Randomized Clinical Trial
Principle Centre
Tianjin Medical University General Hospital
Objective
To explore the safety and efficacy of immediate abundant normal saline
infusion after intravenous thrombolysis for patients with stroke.
Efficacy Outcomes
Primary outcome
1. Proportion of the patients with mRS 0-2 at 90 days after randomization.
Secondary outcomes
1. Proportion of the patients with early neurological deteiroration (END,
△NIHSS≥2 and △NIHSS≥4) at 24 hours after randomization.
2. Proportion of the patients with cerebrovascular events within 1 days, 7
days and 90 days after randomization.
3. Peripheral
blood
inflammatory
indices
and
laboratory
examination
(S100-β, brain derived neurotrophic factor and myeloperoxidase).
4. NIHSS scores at 7 days.
5. mRS scores at 30 days and 90 days.
6. Barthel index scores at 30 days and 90 days.
Safety Outcomes
1. Ejection fraction within 72 hours.
2. Mortality within 90 days
3. Proportion of intracranial hemorrhage (ICH) and symptomatic ICH within
7 days.
4. Infarction volume at 24 hours after randomization.
5. Blood pressure fluctuation within 24 hours.
Trial Design
NS-STAR is a prospective, multicentre, randomised, open-label, blinded
outcome reading, Phase II trial (PROBE design). Subjects included are
randomly assigned into the NS group and the control group. Follow-up is
performed at baseline, 24 hours, 7 days, 30 days and 90 days after
randomization.
The
outcome
assessors
are
blinded
to
the
allocation


5
assignment.
Trial Population
Patients with acute ischemic stroke treated by intravenous thrombolysis
Sample Size
240
Inclusion Criteria
1. Acute ischemic stroke.
2. Age 18-80 years.
3. Pre-stroke mRS≤1.
4. NIHSS score 0-25
5. Onset-to-needle time≤4.5 h.
6. Sign the informed consent.
Exclusion Criteria
1. Thrombolysis contraindication.
2. Allergy to alteplase.
3. intention to undergo emergency endovascular treatment.
4. Any terminal illness such that patients would not be expected to survive>1
year.
5. Poor compliance.
6. Participating in other clinical trials within previous 3 months.
Withdrawal Criteria
1. Acute heart failure during interventions.
2. Hypertensive crisis during interventions.
3. Edema, such as pulmonary edema, limb edema and water intoxication.
4. Other severe complications that should terminate the interventions
immediately.
5. Stroke mimics.
6. Decide to undergo emergency endovascular treatment during interventions.
7. Refuse subsequent treatment and follow-up.
Trial Cycle
All included patients are followed-up at baseline, 24 hours, 7 days, 30 days
and 90 days after randomization, respectively.
Treatment Regimens
Eligible patients are randomly (a ratio of 1:1) assigned into the NS group:
undergoing immediate 2000 mL intravenous infusion of NS after intravenous
thrombolysis at a speed of 200 mL/h, or the control group: receiving


6
200-400ml of NS after intravenous thrombolysis. A standard therapy
according to Chinese guidelines for diagnosis and treatment of acute ischemic
stroke 2023 will be performed during the whole treatment period.
Procedure
Before
intravenous
thrombolysis:
The
investigators
will
collect
demographic characteristics, medical history, blood pressure, brain imaging
(either computer tomography or magnetic resonance imaging), neurological
measurements (NIHSS score and mRS score), haematological examination
(blood routine, creatinine, urea, brain natriuretic peptide, etc.), laboratory
examination (S100-β, brain derived neurotrophic factor and myeloperoxidase)
and other pertinent information.
After intravenous thrombolysis: The informed consent will obtained and
patients will be randomly assigned into the NS group and the control group.
The
investigators
will
then
collect
blood
pressure
and
neurological
measurements (NIHSS score).
24-48
hours
after
randomization:
Brain
imaging
(either
computer
tomography or magnetic resonance imaging) will be performed at 24 hours.
The 24-hour NIHSS score will be assessed and cerebrovascular events
occurring within 24 hours will be recorded. Blood routine and laboratory
examination (S100-β, brain derived neurotrophic factor and myeloperoxidase)
will also be collected.
72 hours after randomization: Cerebrovascular imaging (either computer
tomography angiography or magnetic resonance angiography) and an
ultrasonic cardiogram will be conducted within this period.
7 days after randomization: Neurological measurements (NIHSS score and
mRS score) will be evaluated. Cerebrovascular events during this 7-day
period will also be recorded.
30 days after randomization: The mRS score and Barthel index score will be
assessed and cerebrovascular events or other adverse events will be recorded
via a telephone interview.


7
90 days after randomization: The mRS score and Barthel index score will be
again assessed and cerebrovascular events or other adverse events will be
recorded via a telephone interview.
Concomitant
Treatment
Guideline based treatment.
Statistical analysis
The primary outcome is performed in the intention-to-treat populations as well
as per-protocol populations. Sensitivity analyses are performed as well in
order to find out the influence factors. The χ2 test is used in the unadjusted
analysis. Modified Poisson regression model with robust error estimation is
used in analysis of the primary outcome and other dichotomous end points,
with adjustment for prespecified covariates. The relative risk with their 95%
confidence interval is calculated in both unadjusted and adjusted analysis.
Generalized linear models are conducted for analyse continuous end points.
The full range score on mRS is analyzed by an ordinal logistic-regression
model, and odds ratios with 95% confidence interval are calculated. No
interim analyses are performed in this study. A 2-sided P value <0.05 is
considered statistical significance. Because multiple comparisons potentially
cause type I error, findings for secondary outcome analyses should be
interpreted as exploratory. SPSS software (version 26, IBM) and R software
(version 4.1.0) are used for the statistical analyses.
Sites Number
3 centers
Collaborators
Affiliated Hospital of Jiujiang University
Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine
Duration
Enrollment about 1 year


8
Abbreviation
END, early neurological deteiroration
NIHSS, National Institutes of Health Stroke Scale
mRS, Modified Ranking Scale
BI, Barthel Index
ICH, intracranial hemorrhage
IVT, intravenous thrombolysis
AIS, acute ischemic stroke
CBF, cerebral blood flow
NS, normal saline
ESO, European Stroke Organisation
CT, computed tomography
MRI, magnetic resonance imaging
BNP, brain natriuretic peptide
MBP, myelin basic protein
GFAP, glial fibrillary acidic protein
MRA, magnetic resonance angiography
CTA, CT angiography
SBP, systolic blood pressure
DBP, diastolic blood pressure
NLR, neutrophil-to-lymphocyte ratio
PLR, platelet-to-lymphocyte
LMR, lymphocyte-to-monocyte
AEs, adverse events
SAEs, serious adverse events
RR, relative risk
GLMs, Generalized linear models
OR, odds ratio
ITT, Intention-To-Treat
PP, Per protocol


9
CRF, Case Report Forms


10
1. Background
It is well acknowledged that intravenous thrombolysis (IVT) is a safe and effective strategy for treating
acute ischemic stroke (AIS) within 4.5 h in clinical settings.[1, 2] However, only approximately 30% of
patients achieve long-term independence (modified Ranking scales 0-1).[3] A plethora of factors may
influence the effectiveness of IVT, including age, comorbid diseases, stroke subtypes, infarct size and
onset-to-needle time.[3, 4] Ultimately, all these factors can be attributed to reperfusion and the
penumbra.[5] Therefore, the further elevation of the reperfusion rate and expansion of the ischemic
penumbra after IVT are emerging challenges. A simple approach is to increase cerebral blood flow
(CBF), which can reopen occluded vessels and rescue ischemic neurons after AIS. Intravenous
administration of 0.9% normal saline (NS) is an easy-to-use strategy commonly used to expand
volume.[6, 7] The benefit of NS infusion on stroke outcomes is not a concern, but for reperfusion
therapies such as IVT, it seems to be practicable.
Investigations on volume expanders and hemodilution date back to the 1960s.[8] Since then,
accumulating evidence has indicated that volume expansion can improve the collateral circulation
status, reduce blood viscosity, and alleviate brain dysfunction.[9-12] Considering rescuing the ischemic
penumbra, the early use of hemodilution, especially within 6 h after AIS onset, is inevitable to exert its
powerful functions.[13] The no-reflow phenomenon and unexpected re-occlusion may be responsible
for poor outcomes and early neurological deterioration (END) after IVT.[14] In theory, the early use of
hemodilution after IVT can increase distal arterial perfusion and reduce the re-occlusion rate by
increasing CBF. In addition, the prevalence of dehydration accounts for approximately 48%-53% of
patients with stroke, in whom immediate fluid intake might improve their short- and long-term
prognoses, especially in people undergoing thrombolysis.[15-19] Therefore, we hypothesized that
immediate hemodilution after IVT may increase the reperfusion rate, reduce the re-occlusion rate, and
improve prognosis.
To verify our hypothesis, we administered an intravenous NS infusion immediately after IVT
termination. Generally, hemodilution-related drugs include colloids (such as hydroxyethyl and
dextroside) and crystalloid (such as NS). An appropriate solution for hemodilution should be provided
to optimize the perfusion of vital organs and avoid fluid overload. Although colloids can increase left
ventricular end-diastolic volume, stroke volume, and cardiac output, they are also associated with high
blood pressure, susceptibility to allergy, heart failure, and higher morbidity and mortality.[7] Compared


11
to colloids, crystalloids have an equivalent effect on stroke volume variability, which reflects fluid
responsiveness.[7] Therefore, these two solutions are considered to have similar effects on fluid
resuscitation, and crystalloids seem safer for patients with stroke undergoing reperfusion therapy.
Therefore, NS may be a promising therapeutic strategy for volume expansion following IVT.
2. Objectives
This novel study explores the safety and efficacy of NS infusion for patients with stroke after IVT. This
trial provides an innovative strategy for facilitating functional independence after the administration of
IVT in patients with stroke.
2.1 Hypothesis tested
The study intends to demonstrate that immediate abundant normal saline infusion after IVT is safe and
effective in improving long-term functional outcomes in AIS patients treated with IVT.
2.2 Primary objective
The proportion of favorable functional outcomes (mRS 0-2) at 90 days.
2.3 Secondary objective
1. Secondary efficacy including mRS score at 30 and 90 days, Barthel index at 30 and 90 days,
cerebrovascular events within 24 hours, 7 days and 90 days, NIHSS score at 7 days, END within 24
hours and laboratory examination at 24-48 hours.
2. Secondary safety including ejection fraction within 72 hours, death rate with any reasons within 90
days, intracranial hemorrhage and symptomatic intracranial hemorrhage within 7 days, blood pressure
fluctuation within 24 hours and infarction edema volume at 24 hours.
3. Study Design
3.1 Trial plan
This is an assessor-blinded, randomized, controlled, two-arm (1:1 ratio) clinical trial registered at
Clinicaltrials.gov (http://www.clinicaltrials.gov; unique identifier: NCT05993078) and has been
approved by the Institutional Ethics Committee.
All patients within 4.5 h from the definite onset time are screened by the criteria of IVT
recommended by European Stroke Organisation (ESO) guidelines on IVT for AIS at admission.[20] A
cranial CT scan is conducted to exclude the ICH and large brain infarctions. The participants are


12
allocated to two arms: NS and control groups. In the NS group, the patients undergo an NS 2000 mL
intravenous infusion swiftly after IVT at a speed of 200 mL/h. In the control group, the patients receive
an NS 200-400ml after IVT. All the participants are subjected to CT at 24-h after IVT; if no brain
hemorrhage occurs, antiplatelet drugs are used. In the event of brain hemorrhage, antiplatelet drugs are
not used until the hemorrhage diminishes. Subsequent therapy is based on Chinese guidelines for
diagnosis and treatment of acute ischemic stroke 2023.[21] All of the subjects should be treated in the
hospital at least 7 days according to the guidelines for early management of stroke.
3.2 Selection criteria
3.2.1 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.
3.2.2 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
magnetic resonance imaging (MRI);
(2) Intention to undergo endovascular treatment;
(3) History of heart failure or pre-IVT brain natriuretic peptide (BNP) ≥500pg/ml or having
presentations or signs indicating heart failure;
(4) Haemorrhage during IVT, including ICH, severe digestive haemorrhage and severe respiratory
haemorrhage.


13
(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 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.


14
3.2.3 Withdrawal criteria
(1) Acute heart failure during interventions.
(2) Hypertensive crisis during interventions.
(3) Edema, such as severe cerebral edema, pulmonary edema, limb edema and water intoxication.
(4) Other severe complications that should terminate the interventions immediately.
(5) Stroke mimics.
(6) Decide to undergo emergency endovascular treatment during interventions.
(7) Refuse subsequent treatment and follow-up.
3.3 Follow-up time point
All included patients are followed-up at baseline, 24 hours, 7 days, 30 days and 90 days after
randomization, respectively.
3.4 Randomization and masking
All patients are enrolled consecutively and randomized in 1:1 ratio to receive NS 2000ml or 200-400ml
using a computer-generated randomization code. Sealed envelopes containing the allocation
information (NS or control) will be labeled with sequential numbers prepared by an investigator who
does not know screening of subjects. The researchers will enroll potential patients with a sequential
number of opaque sealed envelopes, which will be opened only after obtaining informed consent. It is
ensured that investigators are masked to the treatment allocation.
This is an open label trial, so we adopt a partial blinding strategy where the clinical assessors are
blinded but the operators are not. That is, the neurological functional scores, imaging tests and
laboratory assessments are assessed by investigators blinded to the intervention and grouping. The
operators responsible for NS infusion to the patients are unblinded.


15
4. Trial Flow Chart
STUDY PROTOCOL
Enrollment
IVT ending
Interventions
Follow-up
TIMEPOINTS
-1 h
0 h
0-10 h
24 h
48 h
Day 3
Day 7
Day 30
Day 90
ENROLLMENT
Eligible Screen
X
Informed Consent
X
Allocation
X
Termination Screen
X
INTERVENTIONS
NS 2000 mL
NS 200-400 mL
ASSESSMENT
Baseline Data
X
NIHSS score
X
X
X
X
Cranial CT
X
X
Blood Indices
X
Laboratory examination
X
Ultrasonic Cardiogram
Cranial MRA/CTA
Blood pressure
mRS
X
X
X


16
Barthel index
X
X
IVT: intravenous thrombolysis; NS: 0.9% normal saline; NIHSS: Institute of Health Stroke Scale; CT: computed tomography; MRA:
magnetic resonance angiography; CTA: computed tomography angiography; mRS: modified Ranking scales.
5. Interventions
All patients within 4.5 hours from the definite onset time will be screened by the criteria of IVT
recommended by European Stroke Organisation (ESO) guidelines.[20]
During thrombolysis, the patient or his certigiers will decide whether to participate in this trial. If
they agree, an informed consent for NS-STAR trial will be signed, and allocation will proceed.
Participants will be allocated into two arms:
the NS group, undergoing immediate 2000 mL intravenous infusion of NS after IVT at a speed of
200 mL/h.
the control group, receiving 200-400ml of NS after IVT.
Subsequent therapy will follow the Chinese guidelines for the diagnosis and treatment of acute
ischemic stroke 2023.[21] All subjects will be hospitalized for at least 7 days according to the
guidelines for early stroke management.
6. Measurement
6.1 Haematological examination and laboratory assessment
Baseline blood samples are obtained before IVT administration. The blood indices comprise blood
routine, creatinine, urea, BNP, electrolyte and coagulation function. The blood routine is reassessed at
24-48 hours after randomization. Peripheral blood biomarkers that can reflect brain injury, including
S100-β, brain derived neurotrophic factor (BDNF) and myeloperoxidase (MPO) are assessed before
IVT administration and at 24-48 hours after randomization.
6.2 Imaging tests
Cranial 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 (Version 4.6.2,
https://www.slicer.org/). Magnetic resonance angiography (MRA), CT angiography (CTA), or carotid
artery ultrasound are used to evaluate cranial vessels.


17
6.3 Clinical observation
National Institutes of Health Stroke Scale (NIHSS) is commonly used to evaluate neurological deficits
in patients with AIS and includes 15 items in 11 fields of different neurological statuses. The NIHSS is
scored at admission, at the end of IVT, 24-h and 7-day after randomization during hospitalization.
END indicates an increase of ≥2 or ≥4 in the NIHSS score within 24 h after IVT, and the
deterioration is not caused by ICH, which is confirmed by cranial CT.
Modified Rankin Scale (mRS) reflects disability at follow-up time, which consists of 7 disability
levels, ranging from 0 (no symptoms) to 5 (severe disability), and 6 (death). We intend to assess the
mRS on days 7, 30, and 90 after randomization.
Barthel index (BI) is a standardized tool used to evaluate a person’s ability to perform basic
activities of daily living independently at follow-up time, and consists of 10 items, ranging from 0
(total dependence) to 100 (complete independence). We intend to assess the BI on days 30 and 90 after
randomization.
The ejection fraction is assessed by ultrasonic cardiogram within 72 hours after randomization.
Blood pressure, including systolic blood pressure (SBP) and diastolic blood pressure (DBP), is
monitored from IVT initiation every 5 min for 2 h and then continuously assessed every 30 min for 6 h
and every hour for 16 h. The 24-hour blood pressures are recorded (before IVT, after IVT, 10 hours, 12
hours and 24 hours after randomization).
7. Outcomes
7.1 Efficacy outcomes
7.1.1 Primary outcomes
Primary efficacy is independence at 90 days, as scored using the mRS, and dichotomized as a favorable
(score 0-2) or an unfavorable outcome (score 2-6), following the Cochrane analysis of thrombolysis in
stroke. The proportion of patients in each arm with favorable outcomes is compared at 90 days.
7.1.2 Secondary outcomes
(1) Proportion of patients with END (△NIHSS≥2 and △NIHSS≥4) at 24 hours after randomization.
△NIHSS indicates 24-hour NIHSS score minus post-IVT NIHSS score.
(2) Proportion of patients with cerebrovascular events within 1 day, 7 days and 90 days after
randomization. Cerebrovascular events included progressive stroke (NIHSS deterioration≥2 scores),


18
transient ischemic attack or new ischemic lesions confirmed by imaging.
(3) NIHSS scores at 7 days.
(4) Proportion of patients with mRS 0-2 at 30 days.
(5) mRS distribution at 30 days and 90 days.
(6) BI scores at 30 days and 90 days.
(7) Proportion of the patients with BI 60-100 at 30 days and 90 days.
(8)
Peripheral
blood
inflammatory
indices,
including
neutrophil-to-lymphocyte
ratio
(NLR),
platelet-to-lymphocyte (PLR), lymphocyte-to-monocyte (LMR) and (platelet×neurophil)/lymphocyte
(SII) at 24-48 hours after randomization.
(9) Laboratory examinations (S100-β, BDNF, and MPO) at 24-48 hours after randomization.
7.2 Safety outcomes
(1) The ejection fraction evaluated by ultrasonic cardiogram within 72 hours.
(2) Death rate within 90 days.
(3) Intracranial hemorrhage and symptomatic intracranial hemorrhage within 7 days.
(4) Blood pressure fluctuation within 24 hours.
(5) Infarction edema volume evaluated by cranial CT at 24 hours.
8. Study flow diagram
AIS: acute ischemic stroke; IVT: intravenous thrombolysis; NS: normal saline.


19
9. Study periods
9.1 Screening periods
Before IVT administration, enrollment screening and collection of demographic features, medical
history, onset-to-needle time, cranial CT imaging, blood pressure, neurological measurements (NIHSS
score and mRS score), haematological examinations (blood routine, creatine, urea, BNP, electrolyte,
coagulation function and laboratory biomarkers including S100-β, BDNF and MPO), and other
information are necessary.
9.2 Treatment periods
After IVT administration, patients are randomized into two groups: receiving intravenous NS 2000ml
and NS 200-400ml respectively. Therapy follows the Chinese guidelines for diagnosis and treatment of
acute ischemic stroke 2023[21]. Blood pressures are recorded at 0 hour, 10 hours, 12 hours and 24
hours after randomization. NIHSS scores are assessed immediately after IVT administration and 24
hours after randomization. Cranial CT scan is performed at 24 hours. Haematological examinations
including blood routine and laboratory biomarkers (S100-β, MBP and GFAP), and routine urine test
are conducted at 24-48 hours after randomization.
9.3 In-hospital periods
Ultrasonic cardiogram is performed at 72 hours after randomization. NIHSS score and mRS score are
assessed at 7 days after randomization.
9.4 Follow-up periods
Neurological measurements including mRS score and Barthel index are assessed via a telephone
interview at 30 and 90 days. Cerebrovascular events and death events are recorded carefully at this time.
All the adverse events should be recorded and tracked until properly resolved.
10. Adverse events monitoring
10.1 Adverse events (AEs)
All AEs information should be carefully recorded and tracked until properly resolved. AEs in this trial
include acute heart failure, hypertensive crisis, edema (such as severe cerebral edema, pulmonary
edema, limb edema and water intoxication) and other severe complications during and after
interventions that are considered to be associated with the interventions.


20
10.2 Serious adverse events (SAEs)
SAEs are any untoward medical occurrence (whether related to interventions or not) meeting any of the
following criteria: (1) fatal (AEs causes death); (2) life-threatening; (3) causing or prolonging
hospitalization; (4) disability or organ function impairment.
10.3 Safety assessment
For AEs and SAEs occurring in this study, the following factors will be evaluated for safety: (1)
severity criteria for AEs; (2) causal relationship between the event and intervention; (3) anticipation of
events.
10.4 Severity categorization and relationship definitions of AEs
10.4.1 Severity categorization
(1) Grade I, mild
A transient symptoms or the event that requires only minimal therapeutic interventions. The event does
not affect usual activities of daily living.
(2) Grade II, moderate
A significant symptoms or the event that requires additional specific therapeutic interventions. The
event affect usual activities of daily living, causing discomfort or disability but with no profound or
permanent risk of harm to the participant.
(3) Grade III, severe
A profoundly severe symptoms or the event that requires intensive therapeutic interventions. The event
profoundly affects or interrupts usual activities of daily living, causing disability and even posing
permanent risk of harm to the participant.
(4) Grade IV, life-threatening
The event leads to death at any time.
(5) Grade V, death
Death.
10.4.2 Causal relationship between the event and the intervention
(1) Definitely related
AEs occur during the intervention and/or the AEs disappear when the intervention discontinues. The
occurrence of AEs cannot be explained by factors other than the intervention. Similar AEs re-occur
when re-use of the intervention.


21
(2) Probably related
AEs occur during the intervention and/or the AEs relieve or not when the intervention discontinues.
The occurrence of AEs can or cannot be explained by factors other than the intervention. It is not sure
similar AEs re-occur when re-use of the intervention.
(3) Probably unrelated
AEs do not occur during the intervention and/or the AEs do not relieve when the intervention
discontinues. The occurrence of AEs can or cannot be explained by factors other than the intervention.
It is not sure similar AEs re-occur when re-use of the intervention.
(4) Definitely unrelated
AEs do not occur during the intervention and/or the AEs do not relieve when the intervention
discontinues. The occurrence of AEs can be explained by factors other than the intervention. Similar
AEs do not re-occur when re-use of the intervention.
(5) Unjudged
The judgment cannot be made due to incomplete information.
11. Statistics
11.1 Sample size
The sample-size is estimated according to previous trials with an expected between-group difference of
18 percentage points in favorable outcome (90-day mRS 0-2, 67.3% in the NS group and 49.3% in the
control group).[4] Based on 0.8 power to detect a significant difference (2-sided P=0.05) and to
compensate for nonadherence or dropout rate of 5%, we intend to enroll 120 patients per group
(calculated by PASS, version 15.0, https://passapp.io/).
11.2 Statistical analysis
The modified intention-to-treat analysis of efficacy outcomes and safety outcomes are performed on
the full analysis set, which is composed of all patients who receive randomization independent of
treatment and at least 1 efficacy evaluation after enrollment. The primary outcome is also performed
with sensitivity analyses, including per-protocol analysis; imputation of missing primary outcome data
under the scenarios of worst possible outcome, and best possible outcome. The χ2 test is used in the
unadjusted analysis. Modified Poisson regression model with robust error estimation is used in analysis
of the primary outcome and other dichotomous end points, with adjustment for prespecified covariates


22
(age, sex, post-IVT NIHSS scores and onset-to-needle time). The relative risk (RR) with their 95%
confidence interval (95%CI) is calculated in both unadjusted and adjusted analysis. Generalized linear
models (GLMs) are conducted for analyse continuous end points, including NIHSS scores, Barthel
scale, blood pressure, infarction volumes, ejection fraction at each follow-up time point. The full range
score on mRS is analyzed by an ordinal logistic-regression model, and odds ratio (OR) with 95%CI are
calculated. Cox regression model are used for analyzing the follow-up cerebrovascular events,
presented with cumulative probability of events in Kaplan Meier cures. No interim analyses are
performed in this study. The missing values of baseline variables in the covariate-adjusted analyses are
replaced by mean values (continous variates) or mode (dichotomous variates) only if the number of
them account for less than 10% in total.
A 2-sided P value <0.05 is considered statistical significance. Because multiple comparisons
potentially cause type I error, findings for secondary outcome analyses should be interpreted as
exploratory. SPSS software (version 26, IBM) and R software (version 4.1.0) are used for the statistical
analyses.
11.3 Analysis population
11.3.1 Intention-To-Treat (ITT)
The ITT population involves all participants in the groups to which they are originally assigned,
regardless of whether they complete the treatment or adhere to the protocol. It can reflect the real-world
effectiveness of the treatment and remain unbiased by the participants’ adherence to the treatment plan.
11.3.2 Per protocol (PP)
The PP population involves the participants who fully complete the treatment and adhere to the
protocol. It can be used to assess the efficacy of the treatment on those who followed the prescribed
procedures.
11.3.3 Safety population
The safety population included all participants who receive the protocol treatment and have at least one
time of safety evaluation.
12. Data management and monitoring
12.1 Case Report Forms (CRF)
A CRF should be completed and signed by the investigators for each participant randomized. The


23
reasons for subject withdrawing from the study must be noted on the CRF. Adverse events and its
follow-up interviewing should be recorded carefully on the CRF. All forms should be completed within
1 week after subject visit. The investigators should ensure the accuracy, completeness, legibility and
timeliness of the data submitted to the sponsor in the CRF and in all required reports.
12.2 Monitoring
Sponsor will keep close touch with each study center and will provide any study information whenever
the investigators need. Regular visits includes as follows:
(1) Confirm the adherence of the protocol and the timeliness of the data in the CRF.
(2) Verify the completeness, accuracy and legibility of the data in the CRF, including the baseline and
the follow-up measurements and neurological scores.
13. References
1.
Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, Larrue V, Lees KR,
Medeghri Z, Machnig T et al: Thrombolysis with alteplase 3 to 4.5 hours after acute
ischemic stroke. N Engl J Med 2008, 359(13):1317-1329.
2.
National Institute of Neurological D, Stroke rt PASSG: Tissue plasminogen activator for
acute ischemic stroke. N Engl J Med 1995, 333(24):1581-1587.
3.
Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, Brott T, Cohen G, Davis
S, Donnan G et al: Effect of treatment delay, age, and stroke severity on the effects of
intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of
individual patient data from randomised trials. Lancet 2014, 384(9958):1929-1935.
4.
Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, Brott T, Frankel M,
Grotta JC, Haley EC, Jr. et al: Association of outcome with early stroke treatment: pooled
analysis of ATLANTIS, ECASS, and
NINDS rt-PA stroke trials. Lancet 2004,
363(9411):768-774.
5.
Ma H, Campbell BCV, Parsons MW, Churilov L, Levi CR, Hsu C, Kleinig TJ, Wijeratne T,
Curtze S, Dewey HM et al: Thrombolysis Guided by Perfusion Imaging up to 9 Hours
after Onset of Stroke. N Engl J Med 2019, 380(19):1795-1803.
6.
Mullen MT, Parthasarathy AB, Zandieh A, Baker WB, Mesquita RC, Loomis C, Torres J,
Guo W, Favilla CG, Messe SR et al: Cerebral Blood Flow Response During Bolus Normal


24
Saline Infusion After Ischemic Stroke. J Stroke Cerebrovasc Dis 2019, 28(11):104294.
7.
Kanda H, Hirasaki Y, Iida T, Kanao M, Toyama Y, Kunisawa T, Iwasaki H: Effect of fluid
loading with normal saline and 6% hydroxyethyl starch on stroke volume variability
and left ventricular volume. Int J Gen Med 2015, 8:319-324.
8.
Gilroy J, Barnhart MI, Meyer JS: Treatment of acute stroke with dextran 40. JAMA 1969,
210(2):293-298.
9.
Shuaib A, Butcher K, Mohammad AA, Saqqur M, Liebeskind DS: Collateral blood vessels
in
acute
ischaemic
stroke:
a
potential
therapeutic
target. Lancet
Neurol
2011,
10(10):909-921.
10.
Mucke S, Grotemeyer KH, Stahlhut L, Husstedt IW, Evers S: The influence of fluid intake
on stroke recurrence--a prospective study. J Neurol Sci 2012, 315(1-2):82-85.
11.
Heros RC, Korosue K: Hemodilution for cerebral ischemia. Stroke 1989, 20(3):423-427.
12.
Chang TS, Jensen MB: Haemodilution for acute ischaemic stroke. Cochrane Database Syst
Rev 2014, 2014(8):CD000103.
13.
Aichner FT, Fazekas F, Brainin M, Polz W, Mamoli B, Zeiler K: Hypervolemic
hemodilution in acute ischemic stroke: the Multicenter Austrian Hemodilution Stroke
Trial (MAHST). Stroke 1998, 29(4):743-749.
14.
Tsivgoulis G, Katsanos AH, Sandset EC, Turc G, Nguyen TN, Bivard A, Fischer U, Khatri P:
Thrombolysis for acute ischaemic stroke: current status and future perspectives. Lancet
Neurol 2023, 22(5):418-429.
15.
Liu CH, Lin SC, Lin JR, Yang JT, Chang YJ, Chang CH, Chang TY, Huang KL, Ryu SJ, Lee
TH: Dehydration is an independent predictor of discharge outcome and admission cost
in acute ischaemic stroke. Eur J Neurol 2014, 21(9):1184-1191.
16.
Crary MA, Humphrey JL, Carnaby-Mann G, Sambandam R, Miller L, Silliman S: Dysphagia,
nutrition, and hydration in ischemic stroke patients at admission and discharge from
acute care. Dysphagia 2013, 28(1):69-76.
17.
Li SS, Yin MM, Zhou ZH, Chen HS: Dehydration is a strong predictor of long-term
prognosis of thrombolysed patients with acute ischemic stroke. Brain Behav 2017,
7(11):e00849.
18.
Lin LC, Lee JD, Hung YC, Chang CH, Yang JT: Bun/creatinine ratio-based hydration for


25
preventing stroke-in-evolution after acute ischemic stroke. Am J Emerg Med 2014,
32(7):709-712.
19.
Lin CJ, Yang JT, Huang YC, Tsai YH, Lee MH, Lee M, Hsiao CT, Hsiao KY, Lin LC:
Favorable outcome of blood urea nitrogen/creatinine-based hydration therapy 3 months
after acute ischemic stroke. Am J Emerg Med 2016, 34(12):2414-2418.
20.
Berge E, Whiteley W, Audebert H, De Marchis GM, Fonseca AC, Padiglioni C, de la Ossa
NP, Strbian D, Tsivgoulis G, Turc G: European Stroke Organisation (ESO) guidelines on
intravenous thrombolysis for acute ischaemic stroke. Eur Stroke J 2021, 6(1):I-LXII.
21.
Liu L, Li Z, Zhou H, Duan W, Huo X, Xu W, Li S, Nie X, Liu H, Liu J et al: Chinese Stroke
Association guidelines for clinical management of ischaemic cerebrovascular diseases:
executive summary and 2023 update. Stroke Vasc Neurol 2023, 8(6):e3.


26
Appendix
Appendix 1: National Institutes of Health Stroke Scale (NIHSS)
Instructions
Scale Definition
Score
1a. Level of Consciousness: The investigator must choose a
response if a full evaluation is prevented by such obstacles as
an
endotracheal
tube,
language
barrier,
orotracheal
trauma/bandages. A 3 is scored only if the patient makes no
movement (other than reflexive posturing) in response to
noxious stimulation.
0 = Alert; keenly responsive.
1
=
Not
alert;
but
arousable
by
minor
stimulation to obey, answer, or respond.
2 = Not alert; requires repeated stimulation to
attend, or is obtunded and requires strong
or painful stimulation to make movements
(not stereotyped).
3 = Responds only with reflex motor or
autonomic effects or totally unresponsive,
flaccid, and flexic.
1b. LOC Questions: The patient is asked the month and
his/her age. The answer must be correct - there is no partial
credit for being close. Aphasic and stuporous patients who do
not comprehend the questions will score 2. Patients unable to
speak because of endotracheal intubation, orotracheal trauma,
severe dysarthria from any cause, language barrier, or any
other problem not secondary to aphasia are given a 1. It is
important that only the initial answer be graded and that the
examiner not "help" the patient with verbal or non-verbal cues.
0 = Answers both questions correctly.
1 = Answers one question correctly.
2 = Answers neither question correctly.
1c. LOC Commands: The patient is asked to open and close
the eyes and then to grip and release the non-paretic hand.
Substitute another one step command if the hands cannot be
used. Credit is given if an unequivocal attempt is made but
0 = Performs both tasks correctly.
1 = Performs one task correctly.
2 = Performs neither task correctly.
_____
_


27
not completed due to weakness. If the patient does not
respond to command, the task should be demonstrated
to
him or her
(pantomime), and the result scored (i.e., follows
none,
one
or
two
commands).
Patients
with
trauma,
amputation, or other physical impediments should be given
suitable one-step commands. Only the first attempt is scored.
2. Best Gaze: Only horizontal eye movements will be tested.
Voluntary or reflexive (oculocephalic) eye movements will be
scored, but caloric testing is not done. If the patient has a
conjugate deviation of the eyes that can be overcome by
voluntary or reflexive activity, the score will be 1. If a patient
has an isolated peripheral nerve paresis (CN III, IV or VI),
score a 1. Gaze is testable in all aphasic patients. Patients with
ocular trauma, bandages,
pre-existing blindness, or other
disorder of visual acuity or fields should be tested with
reflexive movements, and a choice made by the investigator.
Establishing eye contact and then moving about the patient
from side to side will occasionally clarify the presence of a
partial gaze palsy.
0 = Normal.
1 = Partial gaze palsy; gaze is abnormal in
one or both eyes, but forced deviation or
total gaze paresis is not present.
2 = Forced deviation, or total gaze paresis not
overcome by the oculocephalic maneuver.
_____
_
3. Visual:
Visual fields (upper and lower quadrants) are
tested by confrontation, using finger counting or visual threat,
as appropriate. Patients may be encouraged, but if they look at
the side of the moving fingers appropriately, this can be scored
as normal. If there is unilateral blindness or enucleation, visual
fields in the remaining eye are scored. Score 1 only if a
clear-cut asymmetry, including quadrantanopia, is found. If
0 = No visual loss.
1 = Partial hemianopia.
2 = Complete hemianopia.
3 = Bilateral hemianopia (blind
including
cortical blindness).


28
patient is blind from any cause, score 3. Double simultaneous
stimulation is performed at this point. If there is extinction,
patient receives a 1, and the results are used to respond to item
11.
4. Facial Palsy: Ask – or use pantomime to encourage – the
patient to show teeth or raise eyebrows and close eyes. Score
symmetry of grimace in response to noxious stimuli in the
poorly responsive or non-comprehending patient. If facial
trauma/bandages, orotracheal tube, tape or other physical
barriers obscure the face, these should be removed to the
extent possible.
0 = Normal symmetrical movements.
1 = Minor paralysis (flattened nasolabial
fold, asymmetry on smiling).
2 = Partial paralysis (total or near-total
paralysis of lower face).
3 = Complete paralysis of one or both sides
(absence of facial movement in the
upper and lower face).
_____
5.
Motor
Arm: The limb is placed in the appropriate
position: extend the arms (palms down) 90 degrees (if sitting)
or 45 degrees (if supine). Drift is scored if the arm falls before
10 seconds. The aphasic patient is encouraged using urgency
in the voice and pantomime, but not noxious stimulation.
Each limb is tested in turn, beginning with the non-paretic arm.
Only in the case of amputation or joint fusion at the shoulder,
the examiner should record the score as untestable (UN), and
clearly write the explanation for this choice.
0 = No drift; limb holds 90 (or 45) degrees
for full 10 seconds.
1 = Drift; limb holds 90 (or 45) degrees, but
drifts down before full 10 seconds; does
not hit bed or other support.
2 = Some effort against gravity; limb cannot
get to or maintain (if cued) 90 (or 45)
degrees, drifts down to bed, but has
some effort against gravity.
3 = No effort against gravity; limb falls.
4 = No movement.
UN = Amputation or joint fusion, explain:
____________
5a. Left Arm
5b. Right Arm
_____


29
6. Motor Leg: The limb is placed in the appropriate position:
hold the leg at 30 degrees (always tested supine). Drift is
scored if the leg falls before 5 seconds. The aphasic patient is
encouraged using urgency in the voice and pantomime, but
not noxious stimulation. Each limb is tested in turn, beginning
with the non-paretic leg. Only in the case of amputation or
joint fusion at the hip, the examiner should record the score as
untestable (UN), and clearly write the explanation for this
choice.
0 = No drift; leg holds 30-degree position for
full 5 seconds.
1 = Drift; leg falls by the end of the 5-second
period but does not hit bed.
2 = Some effort against gravity; leg falls to
bed by 5 seconds, but has some effort
against gravity.
3 = No effort against gravity; leg falls to
bed immediately.
4 = No movement.
UN = Amputation or joint fusion, explain:
____________
6a. Left Leg
6b. Right Leg
7. Limb Ataxia: This item is aimed at finding evidence of a
unilateral cerebellar lesion. Test with eyes open. In case of
visual defect, ensure testing is done in intact visual field.
The finger-nose-finger and heel-shin tests are performed on
both sides, and ataxia is scored only if present out of
proportion to weakness. Ataxia is absent in the patient who
cannot understand or is paralyzed. Only in the case of
amputation or joint fusion, the examiner should record the
score as untestable (UN), and clearly write the explanation
for this choice. In case of blindness, test by having the
patient touch nose from extended arm position.
0 = Absent.
1 = Present in one limb.
2 = Present in two limbs.
UN = Amputation or joint fusion, explain:
____________
_____________________________


30
8. Sensory: Sensation or grimace to pinprick when tested,
or withdrawal from noxious stimulus in the obtunded or
aphasic patient. Only sensory loss attributed to stroke is
scored as abnormal and the examiner should test as many
body areas (arms [not hands], legs, trunk, face) as needed to
accurately check for hemisensory loss. A score of 2, “severe
or total sensory loss,” should only be given when a severe
or total loss of sensation can be clearly demonstrated.
Stuporous and aphasic patients will, therefore, probably
score 1 or 0. The patient with brainstem stroke who has
bilateral loss of sensation is scored 2. If the patient does not
respond and is quadriplegic, score 2. Patients in a coma
(item 1a=3) are automatically given a 2 on this item.
0 = Normal; no sensory loss.
1 = Mild-to-moderate sensory loss; patient feels
pinprick is less sharp or is dull on the affected
side; or there is a loss of superficial pain with
pinprick,
but
patient
is aware of being
touched.
2 = Severe to total sensory loss; patient is not
aware of being touched in the face, arm, and
leg.
9. Best Language:
A great deal of information about
comprehension
will
be obtained during the preceding
sections of the examination. For this scale item, the patient is
asked to describe what is happening in the attached picture,
to name the items on the attached naming sheet and to read
from the attached list of sentences. Comprehension is judged
from responses here, as well as to all of the commands in
the preceding general neurological exam. If visual loss
interferes with the tests, ask the patient to identify objects
placed in the hand, repeat, and produce speech. The
intubated patient should be asked to write. The patient in a
coma (item 1a=3) will automatically score 3 on this item.
The examiner must choose a score for the patient with stupor
0 = No aphasia; normal.
1 = Mild-to-moderate aphasia; some obvious
loss
of
fluency
or
facility
of
comprehension,
without
significant
limitation on ideas expressed or form of
expression.
Reduction
of
speech
and/or
comprehension,
however,
makes
conversation
about
provided
materials
difficult
or
impossible.
For
example,
in
conversation
about
provided
materials,
examiner can identify picture or naming card
content from patient’s response.
2 = Severe aphasia; all communication is through


31
or limited cooperation, but a score of 3 should be used only
if the patient is mute and follows no one-step commands.
fragmentary
expression;
great
need
for
inference, questioning, and guessing by the
listener. Range of information that can be
exchanged is limited; listener carries burden
of communication. Examiner cannot identify
materials provided from patient response.
3 = Mute, global aphasia; no usable speech or
auditory comprehension.
10. Dysarthria: If patient is thought to be normal, an
adequate sample of speech must be obtained by asking
patient to read or repeat words from the attached list. If the
patient has severe aphasia, the clarity of articulation of
spontaneous speech can be rated. Only if the patient is
intubated
or has
other physical barriers to producing
speech, the examiner should record the score as untestable
(UN), and clearly write an explanation for this choice. Do
not tell the patient why he or she is being tested.
0 = Normal.
1 = Mild-to-moderate dysarthria; patient
slurs at least some words and, at worst,
can be understood with some difficulty.
2 = Severe dysarthria; patient's speech is so
slurred as to be unintelligible in the absence
of or out of proportion to any dysphasia, or
is mute/anarthric.
UN = Intubated or other physical barrier,
explain:
11.
Extinction and Inattention
(formerly
Neglect):
Sufficient information to identify neglect may be obtained
during the prior testing. If the patient has a severe visual
loss preventing visual double simultaneous stimulation,
and the cutaneous stimuli are normal, the score is normal. If
the patient has aphasia but does appear to attend to both
sides, the score is normal. The presence of visual spatial
neglect or anosagnosia may also be taken as evidence of
0 = No abnormality.
1 = Visual, tactile, auditory, spatial, or
personal inattention or extinction to
bilateral simultaneous stimulation in one
of the sensory modalities.
2
=
Profound
hemi-inattention
or
extinction to more than one modality;
does not recognize own hand or orients
to only one side of space.


32
abnormality. Since the abnormality is scored only if present,
the item is never untestable.
Total NIHSS:


33
Appendix 2. Modified Ranking Scale (mRS)
Grade
Description
0
No symptoms
1
Symptoms without any incapacity (able to perform all usual activities)
2
Mild incapacity (unable to perform all usual activities but able to look after his/her
affairs alone)
3
Moderate incapacity (requires assistance but walks alone)
4
Severe incapacity (requires assistance for walking and physical body needs)
5
Severe incapacity (bedbound, incontinent, permanent surveillance required)
6
Death


34
Appendix 3. Barthel Index (BI)
Items
Criteria
Score
Bowel Control
Incontinent
Occasional incontinence or requires assistance with devices
Able to control, and can use enemas or suppositories if needed
0
5
10
Bladder Control
Incontinent
Occasional incontinence or requires assistance with devices
Able to control, and can use urine collectors if needed
0
5
10
Grooming
Needs assistance
Able to wash face, comb hair, brush teeth, and shave independently
0
5
Bathing
Depends on others
Can complete independently
0
5
Toileting
Depends on others
Needs partial help, such as with dressing/undressing or using toilet paper
Can use the toilet or bedpan independently, including dressing/undressing and flushing
or cleaning the bedpan
0
5
10
Feeding
Depends on others
Needs partial help (e.g., cutting food, stirring food)
Can use any necessary devices to eat independently within a reasonable time
0
5
10
Dressing
Depends on others
Needs help but can complete at least half of the work within a reasonable time
Can dress and undress independently (including buttoning, zipping, and putting
on/taking off braces)
0
5
10
Transfer
Completely depends on others, unable to sit
Can sit, but needs a lot of help (2 people) to transfer
Needs little help (1 person) or guidance
Can transfer independently from bed to wheelchair and back, including sitting up in bed,
braking the wheelchair, and lifting
0
5
10
15


35
Mobility
Unable to move
Can move independently in a wheelchair for 45 meters
Needs help from 1 person (physical or verbal guidance) to walk 45 meters
Can walk 45 meters on a flat surface, can use assistive devices (excluding wheeled
walkers)
0
5
10
15
Stairs
Unable to
Needs help and supervision
Can do it independently, can use assistive devices
0
5
10
Total score interpretation:

0 - 20 points: Extremely severe functional impairment, completely dependent on others for
daily life.

20 - 40 points: Great need for help in daily life.

40 - 60 points: Needs help in daily life.

Above 60 points: Basically able to take care of oneself in daily life.