Clinical trial NCT00585559
Conditions: Aneurysmal Subarachnoid Hemorrhage Cerebral Vasospasm
Keywords: Lipid Peroxidation N-Acetylcysteine Acetaminophen Vasospasm
Sponsor: Vanderbilt University Medical Center
Start date: 2007-04-01; Completion date: 2023-10-26
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
The objective of this study is to determine whether acetaminophen (APAP), N-acetylcysteine (NAC), and APAP in combination with NAC will inhibit lipid peroxidation in aneurysmal subarachnoid hemorrhage (aSAH), utilizing F2-IsoPs as biomarkers for lipid peroxidation.

Detailed description:
Aneurysmal subarachnoid hemorrhage (aSAH) is an often devastating form of stroke with high morbidity and mortality despite advances in surgical management. Approximately 30,000 patients annually suffer aSAH in the U.S. For patients who survive the initial subarachnoid hemorrhage, delayed cerebral vasospasm occurring from days 4-14 is the greatest cause of neurological disability and death. A growing body of evidence incriminates hemoprotein-catalyzed lipid peroxidation as the mediator of the vasospasm.

Hemoglobin released from lysed red cells in the subarachnoid space becomes oxidized, in which state it acts as a pseudoperoxidase and generates the protein radicals that induce lipid peroxidation. F2-isoprostanes formed by this lipid peroxidation are highly potent constrictors of cerebral arterioles. We have demonstrated a more than 5 fold mean increase in F2-isoprostanes in the cerebrospinal fluid of patients with aSAH; this increase is maximal at the time of delayed vasospasm, and the level of increase is a function of the severity of the aSAH. We hypothesize that such vasoconstrictors are major contributors to the vasospasm produced by the hemoproteins, hemoglobin and myoglobin, in diseases in which they are released from their cellular confines.

We have discovered that acetaminophen (APAP) is a potent inhibitor of hemoprotein-catalyzed lipid peroxidation with an IC50 for hemoglobin of 15 uM, which is in the range of plasma levels resulting from therapeutic doses of the drug in humans. Acetaminophen acts by reducing the ferryl-oxo radical form of the heme, and thereby prevents formation of the hemoprotein radical that initiates lipid peroxidation. To assess proof of concept in vivo, we determined the effect of acetaminophen in a rat model of rhabdomyolysis in which renal failure results from intense vasospasm. Acetaminophen blocked lipid peroxidation in this model, and prevented the renal failure with a dose that produced plasma levels in the therapeutic range for humans.

We also have demonstrated that N-acetylcysteine (NAC) will inhibit hemoprotein-catalyzed lipid peroxidation. Moreover, NAC administration increases the levels of glutathione in vivo, and glutathione is a co-substrate for the glutathione peroxidases that can reduce the levels of peroxides in the environment of the aSAH . This is important as acetaminophen is most potent in inhibiting hemoprotein-catalyzed lipid peroxidation when peroxide concentrations are low. This concerted evidence is the basis for a hypothesis that NAC will augment the efficacy of acetaminophen as an inhibitor of hemoprotein-catalyzed lipid peroxidation in aSAH.

These finding provide the rationale for a pilot study seeking proof of the concept that acetaminophen-based regimens can inhibit lipid peroxidation in patients with subarachnoid hemorrhage. Lipid peroxidation will be determined by analysis of F2-isoprostanes in cerebrospinal fluid. If such inhibition is seen, that then would provide a basis for a larger multi-center investigation to assess the effect on clinical endpoints.

This pilot study will determine whether APAP, NAC, and APAP in combination with NAC will inhibit lipid peroxidation in aneurysmal subarachnoid hemorrhage.

Arms: arm 1: Placebos for acetaminophen and N-acetylcysteine arm 2: Acetaminophen 1 gm every 6 hours and N-acetylcysteine placebo arm 3: N-acetylcysteine IV infusion at 0.5 gm hourly and acetaminophen placebo arm 4: Acetaminophen 1 gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly arm 5: Acetaminophen 1.5 gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly
Interventions: intervention 1: Placebos for acetaminophen and N-acetylcysteine intervention 2: APAP 1 gm every 6 hours and N-acetylcysteine placebo intervention 3: NAC IV infusion at 0.5 gm hourly and APAP placebo intervention 4: APAP 1 gm q6 hours, plus NAC IV infusion at 0.5 gm hourly intervention 5: APAP 1.5 gm q6 hours, plus NAC IV infusion at 0.5 gm hourly
Intervention descriptions: intervention 1: Placebos for acetaminophen and N-acetylcysteine intervention 2: Acetaminophen 1 gm every 6 hours and N-acetylcysteine placebo intervention 3: N-acetylcysteine IV infusion at 0.5 gm hourly and acetaminophen placebo intervention 4: Acetaminophen 1 gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly intervention 5: Acetaminophen 1.5 gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly

Protocol documents:
Prot_SAP_000.pdf: 
The Effect of N-Acetylcysteine on Mortality and Neurological Disability
in Patients with Aneurysmal Subarachnoid Hemorrhage
NCT # NCT00585559
October 29, 2019


 
  
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The Effect of N-Acetylcysteine on Mortality and 
Neurological Disability  
in Patients with 
Aneurysmal Subarachnoid Hemorrhage 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
  
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Introduction 
 
 
 
 
 
Principal Investigator:  
Matthew R. Fusco, MD 
 
 
 
 
 
 
 
 
 
 
The effect of N-acetylcysteine on mortality and neurological disability in 
patients with aneurysmal subarachnoid hemorrhage 
 
 
 
 
The proposed investigation is a double blinded, randomized pilot study. The study will test the ability of 
N-acetylcysteine (NAC)  to reduce mortality and neurological disability in patients with subarachnoid 
hemorrhage. 
 
 
 
 
The target population is patients with aneurysmal SAH who are at high risk for development of delayed 
vasospasm and/or hydrocephalus. Each subject will be randomized into one of three treatment groups in a 
double-blind fashion. The treatment groups include placebo, N-acetylcysteine, or N-acetylcysteine plus 
acetaminophen. 
 
This study has enrolled 89 patients to date.  An additional 30 patients will be randomized to either N-
acetylcysteine or placebo in a ratio of 2 (NAC) to 1(placebo).  
 
 


 
 
 
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Patient Eligibility Requirements 
 
Patients with aneurysmal subarachnoid hemorrhage are eligible for the study if the following criteria are 
met: 
 
Inclusion criteria 
 
∗ Ages ≥ 20 
∗ Fisher Grade III or III + IV SAH based upon admitting CT scan 
∗ Aneurysm secured by either clipping or coiling within 72 hours of SAH 
∗ Intracranial aneurysm confirmed by angiography or CTA 
∗ Presence of ventriculostomy for external ventricular drainage (EVD) prior to 
randomization 
 
Exclusion criteria 
 
∗ Consent unobtainable 
∗ Enrollment in another interventional study 
∗ Patient is pregnant or lactating 
∗ Known co-morbidities that could affect outcome of this study 
∗ Contraindication to CTA 
∗ Serum creatinine > 1.4 
∗ Documented allergy to iodinated contrast that cannot be adequately treated with 
premedication 
∗ Baseline liver disease 
∗ History of recent alcohol abuse with documented ALT or AST above normal laboratory 
values 
∗ Documented history of both malnutrition and decreased serum albumin below normal lab 
values 
∗ Documented abnormal platelet count below normal lab values 
∗ Documented abnormal PT or PTT above normal lab values 
∗ Active asthma or chronic treatment to prevent asthma in the past year-this does not include 
exercise-induced asthma 
∗ Documented allergy and/or intolerance to N-acetylcysteine 
∗ Currently taking phenytoin, carbamazepine, or phenobarbital 
∗ Currently taking isoniazid (INH, Lanzid, Nydrazid) 
∗ Severe life-threatening complications resulting from standard aneurysm treatments that 
will likely prevent completion of the study 
∗ Patient unsuitable for the study, in the opinion of the investigator(s) 
 
 
Recruitment Procedures 
 
Eligibility is assessed immediately following evaluation of the initial CT scan and cerebral angiogram or 
CT angiogram. The initial CT scan must show a Fisher Grade III or III + IV, as determined by the 
principal investigator or neurosurgical co-investigators. The criteria of Fisher grading for CT scan 
evaluation, as described in Fisher’s original publication (Fisher CM, Kistler JP, Davis JM:  Relation of 
cerebral vasospasm to subarachnoid hemorrhage visualized by CT scanning. Neurosurgery 6:1-9, 1980), 
are as follows. Measurements of the greatest longitudinal and transverse diameter of the subarachnoid 


 
 
 
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clots in fissures and cisterns are made. The thickness of vertical layers (i.e., blood in cisterns of fissures 
lying in a plane perpendicular to the plane of CT sections:  interhemispheric fissure, ambient cistern, 
insular cistern) is measured in millimeters. Classification is in four grades: 
 
 
I. 
No blood detected 
 
II. 
A diffuse deposition or thin layer with all vertical layers less than 1 mm thick 
 
III. 
Localized clots and/or vertical layers of blood greater than 1 mm in thickness 
 
IV. 
Diffuse or not subarachnoid blood, but with intracerebral or intraventricular clots 
 
Eligibility for the study is established by the principal investigator, other neurosurgical co-investigators, 
or the study coordinator in consultation with the neurosurgical investigators. A pregnancy test will be 
administered to rule-out pregnancy for all women of child-bearing potential (no history of hysterectomy 
or tubal ligation) below the age of 55. Informed consent is obtained from either the patient or from an 
appropriate surrogate. 
 
 
Randomization Procedures 
 
After eligibility is established, exclusion criteria evaluated, and informed consent obtained, all patients are 
randomized to receive either placebo or  N-acetylcysteine (NAC). Randomization takes place after the 
aneurysm has been secured by either surgical clipping or endovascular coiling and within 72 hours after 
the onset of SAH. When severe complications occur during standard treatments in the judgment of the 
principal investigator or neurosurgical co-investigators, patients do not proceed to randomization.  
 
Randomization will be performed by the Investigational Drug Serviceof the Vanderbilt University 
Medical Center, employing a computer program that generates a modified permuted block randomization 
scheme (see statistical considerations). Patients will be randomized to receive one of the following 
regimens in a double blinded investigation: 
 
 
Placebo for N-acetylcysteine (N=20) 
 
 
 
N-acetylcysteine IV infusion at 0.5 gm hourly  (N=10) 
 
 
Acetaminophen 1.5gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly (N=20) 
 
 
Placebo infusions will simulate the N-acetylcysteine infusions. Treatment will continue for 12 days or 
until hospital discharge, whichever comes first. 
 
An intent to treat paradigm will be preserved once the patients are randomized. Once randomized, 
whatever the treatment, the patient will enter that arm for purposes of data analysis. 
 
 
  
 
 
 
Assessments for Vasospasm 
This will occur on a daily basis until SAH Day 21 or discharge from hospital, whichever comes first. 
Vasospasm assessment includes standard of care procedures such as neurological exams, TCDs, CTAs, 
MRAs and angiography. On SAH Day 8 (+/- one day if day 8 is on a weekend), a CTA or MRA will be 
performed to assess for presence of vasospasm. Also as part of this study, collection of CSF for 


 
 
 
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isoprostanes measurement will occur daily. 
 
Assessments for Potential Toxicity 
This will occur every other day in which treatment is administered for 12 days  plus any additional 
hospital days up to day 21 and includes ALT and INR.  
 
CSF Collection 
 
The CSF will be collected from standard of care ventricular drain Buritrol (CSF would normally be 
discarded) by a nurse, rotating resident, fellow, or study coordinator (if appropriate) once a day until 
discharge or day 21, whichever occurs sooner, and stored in a -80 freezer.   
 
Blood Draws 
 
Blood will be drawn from IV line, when at all possible or venipuncture if necessary or incorporated into 
daily standard of care blood draws. 
 
DNA Extraction:  Blood will be drawn once for DNA extraction and storage in the VUMC DNA 
Resources Core.  
Prothrombin Time:  The prothrombin time (INR) will be measured every other day until discharge or day 
21, whichever occurs sooner. In the unlikely event that a patient’s INR were to exceed 1.4, the routinely 
administered low-dose heparin would be discontinued. An INR of 1.7 or greater would lead to 
discontinuation of the drug(s). 
 
Liver Function Test:  Liver function tests (LFTs) of the study participants will be monitored every other 
day until discharge or day 21, whichever occurs sooner. If ALT levels rise to more than 3-fold above the 
upper limit (120 IU/L) of normal, the study drug will be withheld, and the test will be repeated 
immediately. If the elevation is confirmed, the study drug will be discontinued.  
 
Testing for Hepatitis B and Hepatitis C Surface Antigen:  Upon subject enrollment, testing for Hepatitis B 
surface antigen and Hepatitis C antibody will be performed. Subjects with presence of Hepatitis B and/or C 
surface antigen will not be excluded from this study, however, presence of antigen will be documented. 
 
 
 
Computed Tomographic Angiography and Perfusion (CTA and CTP) 
 
A CTA and CTP will be performed on every patient, as part of their standard of care treatment, on SAH 
Day 8 + or – 1 day, and these images will be used to determine the presence and severity of cerebral 
vasospasm and/or brain ischemia. The CTA/CTP will not be performed if the patient’s serum creatinine is 
> 1.4. In addition, if a patient develops a delayed neurological deficit (DND) at any time between SAH 
Day 3-21, then additional CTAs/CTPs will be performed as part of the patient’s standard of care 
management to determine the presence and severity of cerebral vasospasm and/or brain ischemia at the 
time of DND. Standard of care treatments for cerebral vasospasm will proceed in the best interest of the 
patient, which could include intracranial angioplasty, intraarterial infusion of vasodilators, etc. If this 
occurs, then the worst CTA/CTP results will be used for statistical analysis for the purposes of this study. 
If no DND occurs, then the SAH Day 8 (+ or – 1 day) CTA/CTP will be used for statistical analysis for 
the purposes of this study. 
 
If a patient is too sick to be transferred to the CT scanner on SAH Day 8 (+ or – 1 day) in the opinion of 
the patient’s treating physicians, he or she will not have the scans performed. All available imaging, TCD 


 
 
 
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ultrasound, and neurological examinations used to assess vasospasm as part of standard of care will be 
collected and data recorded on the case report forms and in the database. 
 
The CTA techniques currently available allow measurement of arterial diameters under normal 
conditions, and those of vasospasm of varying severity. For this study, we will measure the diameter of 
each target arterial segment in 1 mm increments for the entire length of each segment. We will also 
measure the diameter of a reference arterial segment in 1 mm increments for the entire length of each 
reference arterial segment. The target arterial diameters will be divided by the reference arterial segments 
to provide the target arterial ratio. The average arterial diameter, average arterial ratio, the smallest arterial 
diameter (most severe vasospasm), and smallest arterial ratio will be reported for each target arterial 
segment. There are 11 target arterial segments which relate to 5 reference arterial segments as follows:  
 
I. Right extradural internal carotid artery (eRICA) Reference (measured at the right petrous/cavernous 
 
junction posterior ascending straight segment, centered around the midpoint of this ascending straight 
 
segment). This reference arterial segment is used for the following 3 target arterial segments: 
 
1.  Right intradural internal carotid artery (iRICA) (measured at the supraclinoid segment from the 
 
origin of the right ophthalmic artery to the iRICA bifurcation) 
 
2.  Right Middle Cerebral Artery M1 Segment (RMCA-M1) (Measured from the origin of the right 
 
MCA-M1 segment off the RICA bifurcation to the largest arterial branch of the M1 segment as it 
 
ascends superiorly (on the AP view) at the limen insula.  
 
3.  Right Anterior Cerebral Artery A1 Segment (RACA-A1) (measured from the origin of the right 
 
ACA-A1 segment off the RICA bifurcation to the origin of the right A2 segment at the Anterior 
 
Communicating (ACOM) complex. 
 
 
II. Left extradural internal carotid artery (eLICA) (measured at the left petrous/cavernous junction 
 
posterior ascending straight segment, centered around the midpoint of this ascending straight 
 
segment). 
 
1.  Left intradural internal carotid artery (iLICA) (measured at the supraclinoid segment from the 
 
origin of the left ophthalmic artery to the iLICA bifurcation) 
 
2.  Left Middle Cerebral Artery M1 Segment (LMCA-M1) measured from the origin of the left M1 
 
segment off the LICA bifurcation to the largest arterial branch of the M1 segment as it asends 
 
superiorly (on the AP view) at the limen insula.  
 
3.  Left Anterior Cerebral Artery A1 Segment (LACA-A1) measured from the origin of the left ACA-
 
A1 segment off the LICA bifurcation to the origin of the left A2 segment at the ACOM complex. 
 
III. Right extradural vertebral artery (eRVERT) (measured from the inferior border of the C1 vertebral 
 
body (atlas) to the superior border of the C1 vertebral body 
 
1.  Right intradural vertebral artery (iRVert) (measured from the origin of the right posterior inferior 
 
cerebellar artery (R PICA) to the vertebrobasilar junction). 
 
IV. Left extradural vertebral artery (eL Vert) (measured from the inferior border of the C1 vertebral body 
 
(atlas) to the superior border of the C1 vertebral body 
 
1.  Left intradural vertebral artery (iL Vert) (measured from the origin of the right posterior inferior 
 
cerebellar artery (R PICA) to the vertebrobasilar junction). 
 
V. The Dominant (largest) extradural vertebral artery (eDVert) (measured from the inferior border of the 
 
C1 vertebral body (atlas) to the superior border of the C1 vertebral body on whichever vertebral artery 
 
is the largest (right or left) 
 
1.  Basilar artery (measured from the vertebrobasilar junction to the basilar apex) 
 
2.  Right Posterior Cerebral Artery P1 segment (RPCA-P1) (measured from the origin of the right 


 
 
 
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PCA off the basilar apex to the branch of the right posterior communicating (PCOM) artery as the 
 
right PCA turns around the cerebral peduncle of the midbrain) 
 
3.  Left Posterior Cerebral Artery P1 segment (LPCA-P1) (measured from the origin of the left PCA 
 
off the basilar apex to the branch of the left PCOM artery as the left PCA turns around the cerebral 
 
peduncle of the midbrain) 
 
Therefore, a total of 15 arterial segments (11 target arteries and 4 reference arteries) will be measured in 1 
mm increments. The percentage stenosis for vasospasm is defined as the target arterial measurements on 
the SAH Day 8 (+ or – 1 day) CTA divided by the reference measurements on the baseline CTAs (if 
performed) or other baseline reference measurements. 
 
Ischemic Volume Determination: CT Perfusion will be used to assess the presence and severity of brain 
ischemia. The volume of brain ischemia and the severity of brain ischemia will be calculated and 
reported. The CTP data includes cerebral blood flow (CBF), cerebral blood volume (CBV), time to peak 
(TTP), and mean transit time (MTT) of each cerebral hemisphere. 
 
 
Clinical Outcome Evaluation and Follow-Up  
 
The study coordinator should maintain frequent contact with the family to maximize the probability of 
follow-up.  The outcome examiner will receive a list of patients enrolled in the study from the study 
coordinator.  Only the essential information to identify and locate the patient should be given to the 
outcome examiner so as to maintain their blinded status.   
 
Contact with families up to the follow-up exam is maintained by the study coordinator, with payment for 
transportation, if necessary. If the patient is unable to come for the followup visit, the study will be 
considered completed. 
 
The clinical outcome measures:  The Modified Rankin Scale (MRS), the Glasgow Outcome Scale (GOS), 
the Barthel Index (BI), and the NIHSS at 3 months post-SAH (+ or – 10 days). 
 
The MRS is a simple measure of functional outcome after stroke. The scale is from 0–6.  0 = no deficits or 
functional limitations, 1 = a subtle deficit but no gross disability, etc. The MRS has good inter-observer 
reliability. A structured interview will be used to improve reliability of the measure. 
 
The GOS emphasizes how major functioning has been affected, rather than emphasizing specific 
neurological deficits. The GOS uses broad divisions to categorize overall outcome: Deceased, Vegetative 
state, Severe Disability, Moderate Disability, Good Recovery. A structured interview will be used to 
improve the reproducibility of the GOS. 
 
The BI measures ability to perform normal activities of daily living (ADL) including feeding, moving, 
using the toilet independently, bathing, walking, and dressing. The BI has been shown to have excellent 
inter-rater reliability. 
 
The NIHSS is a widely used and validated tool for assessment of clinical stroke severity. The NIHSS is 
essentially a quantitative neurological examination, evaluating alertness, orientation, speech and language, 
eye movements, visual fields, facial sensation and movement, extremity strength and coordination, and 
sensation. The NIHSS score in the acute phase of stroke is a powerful predictor of final clinical outcome. 
 
Study Endpoints 
 


 
 
 
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Primary Endpoint:   
There will be two primary endpoints that will be assessed in this study: 
 
 
1.  The extent of vasospasm will be assessed by the results of the patients' worst angiographic images 
that are obtained following 48 hours post-randomization.  
The worst angiographic images includes the 
CTA performed on SAH Day 8 + or – 1 day as well as  any other CTA, catheter angiogram, or MRA 
performed as standard care for clinical reasons, such as  
for DND. 
 
2.  Neurological outcome, including death, at 3 months follow-up, assessed by NIHSS, MRS, GOS, 
and Barthel Index. 
 
Exploratory Endpoints:  This study also includes the analysis of 5 exploratory endpoints as follows:  
 
 
 
1.  The extent of brain ischemia will be assessed by the results of the patient’s worst CT 
Perfusion  (CTP) scan, performed at the same time as the above CTA. 
 
2.  Presence of any DND assessed by neurological exam. DND is defined as any change in 
 
neurological assessment that occurs between SAH Day 3 (>72 hours after SAH) and SAH Day 21 
 
which is not clearly attributable to a known intervention (e.g., surgery, ventriculostomy, medical 
 
procedures, etc.) 
 
3.  Presence of any evidence of SAH induced vasospasm as assessed daily by all clinical means 
 
available (TCDs, CTA, MRA, or catheter angiography), classified as mild, moderate, or severe. 
 
4.  Incidence of interventional treatment including intracranial balloon angioplasty for vasospasm or 
 
intra-arterial infusion of vasodilators. 
 
5.  Presence of SAH induced hydrocephalus as assessed by the following hydrocephalus grading 
 
scale: 
 
 
Grade 0=EVD weaned off on first attempt without Mental Status Decline (MSD), neuro deficit, or 
 
sustained intracranial pressure (ICP) elevation >20 mm Hg 
 
Grade 1A=EVD weaned off (after more than one trial) eventually without MSD, neuro deficit, or 
 
sustained ICP elevation > 20 mm Hg 
 
Grade 1B=Requires permanent CSF diversion 
 
Mechanisms for Blinding 
 
The only person aware of the treatment assignment during the study is the research pharmacists at 
Vanderbilt Investigational Drug Service. No one else will be present for the randomization. After the 
study has been completed the Investigational Drug Service will give the randomization assignment to the 
study coordinator for entry into the study database. If in the investigator’s judgement, medical care would 
be affected by knowledge of the treatment assignment, the treatment may be unblinded. Recording of 
complication and physiologic data is by unblinded personnel, of necessity. These personnel are, however, 
blinded to outcome data. Blinding is also done for all personnel performing clinical outcome assessment.  
      
The study database will be web-based designed by the GCRC bioinformatics division. The persons 
capable of accessing the database will be classified accordingly. The study coordinator is responsible for 
maintaining the aggregate study database, generating trial progress and safety reports. The statistician 
reviews SAE data by treatment assignment for safety monitoring purposes. 
 
Data Collection and Management 
 
Data Collection:  The investigators (neurosurgical department, neurology department, and clinical 
pharmacology division) are experienced researchers with skills in interviewing families, reviewing 


 
 
 
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medical records, and performing clinical assessment of patients.  
 
The study database is established to be accessible to all the investigators from each department, with 
variable accessible levels. The database is a custom-designed, web-based software application and will be 
used to record, store, and transmit data. The software application will be able to log on from each 
investigator’s PC with user name and password. It may contain all the data elements required to answer 
the questions raised in our hypotheses except for treatment assignment.  
 
Data entry in the database is designed to ensure data validation. The parameters are checked against data 
validation rules before they are accepted into the database. This real-time feedback greatly enhances the 
accuracy of entered data. Examples of these validation rules include:  
 
Range values: numeric, non-date fields have range values specified to minimize data entry errors. (I.e. 
typos) 
Selection lists: categorical data fields have drop-down lists of possible selections that have been 
predetermined as appropriate entries. 
Date checking: all dates entered are checked to ensure that events recorded in the database occurred 
during the time of the study.  
 
Data Management:  Data entered from each department will be stored and may be viewed by all the 
investigators depending on their classification levels. The study coordinator will be responsible for 
maintaining the aggregate database. Data encryption, user access codes, and no patient identifiers assure 
patient confidentiality. 
 
A web-based database will be able to monitor study performance, protocol compliance, safety data and to 
provide administrative reports. The statistician from the bioinformatics department may move data to an 
analytic package (R, SAS, or SPSS) for interim analysis and final analysis of the data. Protocol 
compliance and consistency of management will be monitored by the principal investigator and study 
coordinator.  
Safety and Monitoring 
 
Although hepatotoxicity is not anticipated with these regimens, levels of ALT will be determined every 
other day,  with a stopping rule for increases in ALT of more than three-fold the upper limit of normal. 
 
The prothrombin time (INR) will be measuredevery other day. In the unlikely event that a patient’s INR 
were to exceed 1.4, the routinely administered low-dose heparin would be discontinued. An INR of 1.7 or 
greater would lead to discontinuation of the drug(s). 
 
With the slow infusion of these doses of N-acetylcysteine, the possibility of the reactions previously seen 
with high dose, rapid administration of the drug should be minimized. The study would be discontinued 
for precipitation of asthma, systemic manifestations of mast cell activation, or urticaria not controlled with 
antihistamines. Should serious adverse reactions occur, they will be assessed by the Data Safety and 
Monitoring Board and reported to the IRB. 
 
Potential Risks 
 
 
Risks of N-acetylcysteine: Adverse reactions reported with rapid intravenous NAC at dose of 150 mg/kg 
in 15 minutes include bronchospasm, nausea, vomiting, stomatitis, rhinorrhea, headache, tinnitus, 
urticaria, angioedema, gastrointestinal disturbances, pruritis, tachycardia, hypotension, hypertension, 
rashes, chills, and fever. There are rare reports of anaphylactic reactions. The most common symptoms of 


 
 
 
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those experiencing anaphylactoid reactions are rash, pruritis, flushing, nausea, vomiting, angioedema, 
tachycardia, bronchospasm, hypotension, hypertension and ECG change. The intended very slow infusion 
of NAC at lower doses is expected to minimize the probability of the side effects seen with rapid 
intravenous administration. 
 
Risks of phlebotomy: Risks include mild discomfort of needle stick for blood drawing, low risk of 
bruising and infection from needle stick, and small risk of fainting. 
 
Risks of CTA/CTP scanning:  Although CTAs and CTPs are standard of care diagnostic imaging studies 
for patients with aneurysmal SAH, patients who have a contraindication to CTA scanning, including 
kidney failure, or allergy to iodinated contrast that cannot be treated with premedication, will be excluded 
from this study because of the importance of obtaining CTA/CTP data for this study. If the patient meets 
all criteria for inclusion in this study and after randomization serum creatinine exceeds 1.4, then the SAH 
Day 8 (+ or – 1 day) CTA will not be performed. Either no angiographic image will be performed or an 
MRA/MRI may be substituted if no contraindication exists. 
 
Risks of MRA/MRI scanning:  There are no known major risks with an MRA/MRI scan. Patients who 
have a contraindication to MR scanning, including a pacemaker and/or implantation of MR incompatible 
devices, will not receive an MRA/MRI scan on SAH Day 8 (+ or -1 day). 
 
Protection Against Risks 
 
We have excluded enrollment of patients with risk factors for development of serious adverse effects – 
documented allergy and/or intolerance to N-acetylcysteine, baseline liver disease, ethanol abuse, 
malnutrition, history or evidence of active asthma. Liver function tests (LFTs) of the study participants 
will be monitored every other day throughout the duration of the study. If ALT levels rise to more than 3-
fold above the upper limit of normal, the study drug will be held and the test will be repeated 
immediately. If the elevation is confirmed, the study drug will be discontinued. The prothrombin time 
(INR) will be measured every other day in the first 16 patients receiving N-acetylcysteine. A monitoring 
plan for the subsequent patients would be devised based on the data from these initial 16 patients. In the 
unlikely event that a patient’s INR were to exceed 1.4, the routinely administered low dose heparin would 
be discontinued. An INR of 1.7 or greater would lead to discontinuation of the drug(s).  
 
Data and Safety Monitoring Plan   
 
A Data Safety and Monitoring Board (DSMB) will be established. The members of the DSMB are Joseph 
Awad, M.D. (Chairman), Associate Professor of Pharmacology and Medicine; Daniel Byrne, M.S., 
Director of Biostatistics and Study Design, GCRC; Anne E. O’Duffy, M.D., Assistant Professor of 
Neurology; and Harvey Murff, M.D., M.P.H., Assistant Professor of Medicine. 
 
 
 
The responsibilities of the Board will include: 
 
1.  Review of study design prior to initiation of the investigation 
 
2.  Review of clinical data and the primary endpoint at planned intervals during the study. 
 
3.  Review of the clinical and or related data at unplanned intervals when appropriate or when  
 
     safety issues occur. 
 
4.  Provide recommendations to the PI about whether or not to continue patient enrollment in the  
 
     study. 
 
5.  Ensure that any analysis performed by or provided to the DSMB is recorded, handled, and  
 
     stored in a way that allows the PI to accurately interpret, verify, and report the data. 


 
 
 
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The DSMB will provide summary reports to the investigators. 
 
During the conduct of the trial, any serious adverse event will be reported to the DSMB and the IRB 
within10 business days after the Investigator learns of the event or problem. Board members will be 
provided with all of the available clinical data surrounding the occurrence. A serious adverse event (SAE) 
is any untoward medical occurrence that a) results in death, b) is life-threatening, c) requires prolongation 
of existing hospitalization, d) results in persistent or significant disability/incapacity. AEs will be graded 
as Mild (no limitation of usual activities), Moderate (some limitation), or Severe (inability to carry out 
usual activities) and attributed to the relationship to the study drug and/or procedures as Not related, 
Unlikely, Possible, Probable, or Definite. 
 
The investigators and study coordinators will monitor the patients, and liver function tests will be 
performed daily for the purpose of tracking adverse events (AE). The research team will be informed of 
the participants’ progress. If any change in a participant’s status is deemed to be unsafe for further 
participation in the study, for example, the liver enzymes are greater than 3 times normal, the study 
drugs/placebo will be stopped, the test results confirmed, and if confirmed, the patient will be withdawn 
from the study. Necessary treatments will be carried out based on individual condition. Any AE related or 
unrelated to the research will be discussed by the research team.  
 
 
Summary reports will be submitted to the DSMB and IRB and will contain a) The number of adverse 
events and an explanation of how each event was handled, b) The number of complaints and how each 
complaint was handled, c) The number of subject withdrawals and an explanation of why the subject 
withdrew or was withdrawn, and d) The number of protocol violations and how each was handled. 
 
Statistical Considerations 
 
Objectives and Study Design 
 
The primary objective of this placebo-controlled, double-blind, randomized trial is to assess the effects of 
N-acetylcysteine (NAC on clinical outcomes, including mortality and the power analysis and sample size 
estimation are based on the mortality data. Vasospasm and ischemia, DND, neurological outcomes, 
presence, absence, or resolution of hydrocephalus are secondary endpoints for this pilot study, but are not 
the basis for the power analysis. 
 
Power Analysis, Sample Size Estimation,  and Randomization 
All of the arms that include acetaminophen will be dropped. 
The remaining 2 arms of placebo and N-acetylcysteine will be continued. Using the data, the failure rate 
for placebo subjects is 0.2 and setting the failure rate among N-acetylcysteine subjects to 0.0001, we will 
need to study a total of 34 placebo subjects and 34 N-acetylcysteine subjects to be able to reject the null 
hypothesis that the failure rates for placebo and N-acetylcysteine subjects are equal with probability 
(power) 0.8. The Type I error probability associated with this test of this null hypothesis is 0.05. To date, 
there has been 25 placebo patients and 16 N-acetylcysteine patients enrolled. The study groups will be 
increased by 9 and 18 respectively resulting in a randomization of 1:2 (Placebo to N-acetylcysteine) 
yielding a 1:1 randomization at the end of the study. Estimating a 10% dropout rate, a total of 30 will be 
enrolled. 
 
 


 
 
 
10/29/19 
13 
 
Statistical Analysis Plan 
The Analysis of Variance (ANOVA) method and General Linear Model (GLM) with the Bonferroni 
adjustment will be applied to test mortality and mortality plus neurological deficitsamong study groups. 
Normality assumption will be checked graphically and visually (e.g. normal probability plot, stem-leaf 
plot) as well as statistically (e.g. Kolomogorov D statistic, Shapiro-Wilk statistic W). If data suggest a 
deviation from normality, then the transformations, e.g., log, will be performed to achieve normality. If 
needed, the data will be analyzed using a non-parametric test such as Kruskal-Wallis test that does not 
assume any distributional form. For secondary endpoints, such as neurological outcomes, The General 
Liner Model, Generalized Liner Model, e.g., Logistic Regression, Poisson regression will be applied to 
the single time point data. The mixed effect model and the Generalize Estimating Equation (GEE) method 
will be used to study the association among the neurological parameters among different study time 
points, the adjusted p-values as well as the adjusted 95% confidence intervals will be reported. The model 
selection will be based on Akaike’s Information Criterion (AIC) and Schwarz’s Bayesian Criterion (BIC) 
with different covariance structures, e.g., First-Order Autoregressive, Compound Symmetry etc. The 
detailed model fitting strategies are described in the Biostatistics Component of the Administration Core. 


 
 
 
10/29/19 
14 
Appendix 
 
A. 
Fisher Grading Scale 
 
 
Fisher 
Grade 
CT SAH Findings 
I 
No blood detected 
II 
A diffuse deposition or thin layer with all vertical layers less than 1 mm thick 
III 
Localized clots and/or vertical layers of blood greater than 1 mm in thickness 
IV 
Diffuse or no subarachnoid blood, but with intracerebral or intraventricular 
clots.  
 
 
B. 
Hunt and Hess Grading Scale 
 
Grade 
 
Clinical Condition 
I 
Asymptomatic or mild headache and slight nuchal rigidity 
II 
Cranial nerve palsy, nuchal rigidity, and moderate-to-severe headache 
III 
Drowsy, confused, or mild focal deficit (eg., hemiparesis, hemianesthesia) 
IV 
Stupor, moderate-to-severe hemiparesis, early decerebrate rigidity 
V 
Comatose, decerebrate rigidity, moribund appearance 
 
 
 


 
 
 
10/29/19 
15 
C. 
Glasgow Outcome Scale 
Summary Definitions 
Code 
Good Recovery 
 
Capacity to resume normal occupational and social activities. (may be minor physical or mental deficits or 
complaints) 
 
Full recovery without sign or symptoms. But for reasons (other than physical or mental deficit), subject might 
not have resumed all previous activities, in particular might not be working. 
 
The principal discriminatory factors for this category are employability and personality. 
 
A patient would fall into this category if all of the following apply: 
- 
if they are able to work at or close to the same capacity (e.g. responsibility, hours, etc.) 
- 
if they have resumed interest in their normal social and leisure activities 
- 
if they have had no personality change that is disruptive to family relationships and/or friendships 
G 
Moderate Disability 
 
Independent but disabled 
 
Independent in activities of daily living (i.e., can travel by public transport and look after self at home). 
 
Some previous activities, either at work or social life, are now no longer possible due to either physical or mental 
deficit. 
 
Despite evident post-SAH signs, subject can either resume activities at a lower level or can resume most former 
activities whether full or part-time. 
 
Some subjects can return to certain kinds of work, even to a former job if it happens not to involve a high level 
of performance. 
 
The principal discriminatory factors for this category are employability and personality.  
 
A patient would fall into this category it any of the following apply: 
- 
if they are unable to work at the same capacity (e.g. responsibility, hours, etc.) 
- 
if they have not resumed or lost interest in their normal social and leisure activities because of a mental or 
physical impairment 
- 
if they have a personality change that is disruptive to family relationships and/or friendships 
M 
Severe Disability 
 
Conscious but dependent 
 
Resumption of former life and work not possible due to many post-SAH complaints and/or deficits. 
 
Communication possible, minimally by emotional response. 
 
Patient is conscious but needs assistance of another person for some activities of daily life. 
 
Patient is conscious but almost totally dependent on another for activities of daily life. 
 
Range can be from continuous total dependency to need for assist with only one activity, such as dressing. 
 
The principal discriminatory factor for this category is dependence. 
 
A patient would fall into this category if any of the following apply: 
- 
if they cannot be left alone at home for a day if necessary 
- 
if they require a significant amount of assistance in an activity of normal living (e.g., toileting, dressing, 
feeding, bathing, etc.) 
- 
if they can not shop or keep track of money for themselves 
- 
if they can not leave their home unaccompanied and/or require someone to provide them with or arrange 
their local travel 
S 
Vegetative State 
 
Non-sentient, not obeying commands, no verbal contact, no meaningful response; may have sleep-wake rhythm. 
 
No evidence of meaningful responsiveness 
 
Breathes spontaneously; might have periods of spontaneous eye opening or follow moving objects with their 
eyes. 
 
Might show reflex response in limbs (to postural or painful stimuli) 
 
Might swallow food placed in their mouths 
 
This non-sentient state must be distinguished from other conditions of wakeful, reduce responsiveness, such as 
locked-in syndrome, akinetic mutism and total global asphasia. 
V 
Death 
D 
 
 
 


 
 
 
10/29/19 
16 
Helpful Hints on the Glasgow Outcome Scale (GOS) 
 
 Focus on how the injury/illness to the brain has affected functioning in major areas of life rather than 
on particular deficits and symptoms caused by illness/injury. 
 
 Background knowledge (any pre-SAH disabilities as well as nature and extent of brain illness/injury) 
is necessary to obtain an accurate GOS. 
 
 Consider only how current (past week) level of capability compares to pre-SAH status. 
 
 Remember to always ask why or to what extent when a patient admits to a change or an impairment in 
activity or function. 
 
 Whenever possible, seek independent verification on functional status from a family member or close 
friend of the patient. 
 
 Limitations to function and restrictions on activity due to a post-SAH seizure(s) should be considered 
a disability when determining the GOS. 
 
 Do not distinguish between changes that result from the brain injury/illness from those caused by 
disease in other parts of the body, i.e. base your rating on the current level of disability regardless of 
the cause. 
 
Rate GOS based on the worst impairment in activity or function. Indicate in your notes, the worst 
impairment(s) on which you based the GOS. 
 
 


 
 
 
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17 
Structured Interview for the Glasgow Outcome Scale (GOS) and  
Glasgow Outcome Scale - Extended (GOSE) 
 
Patient’s name: 
Date of interview: 
 
Date of Birth: 
Date of SAH: 
 
 
 
Gender: M / F 
 
Age at SAH: 
Interval post-SAH: 
 
Respondent:  
Patient alone 
Relative/friend/caregiver alone 
Patient + relative/friend/caregiver 
 
Interviewer: 
Title: 
 
 
Confirmed by: 
 
Title: 
Date: 
 
 
 
 
 
 
INSTRUCTIONS:  Cover the points listed in this worksheet during the interview, and make sure to complete the worksheet 
and comment section following the interview. Interview the patient, family members, friends and/or rehabilitation caregivers to 
obtain information. Remember to always ask WHY the patient is or is not involved in certain activities. Items should only be 
rated as ‘No’ if patients cannot perform the activity due to physical or mental deficits AS A RESULT OF THE BRAIN 
INJURY. For example, if a patient is safe to be at home alone, but is not left alone because parents/spouse are overprotective, 
they should still be rated as independent (yes) in that area. A second example, if a patient is disabled because of another 
illness/injury and that is the only reason they can not return to performing activities at work, they should still be rated as ‘Yes’, 
since the disability is not a “Brain Related Injury”. Please note to answer questions 5b, 6b, 7b, and 8b only if applicable (e.g., If 
5a is answered ‘Yes’, then a response is not required in 5b). 
 
 
CONSCIOUSNESS 
 
 
1 
Is the patient person able to obey simple commands, or say any words? 
 
Anyone who shows ability to obey even simple commands, or utter any word or communicate 
specifically in any other way is no longer considered to be in the vegetative state. Eye movements 
are not reliable evidence of meaningful responsiveness. Corroborate with nursing staff. 
Confirmation of VS requires full assessment as in Jennett et al. (1981). The Royal College of 
Physicians has published guidelines for deciding whether a patient is in a persistent vegetative 
state, and the simple approach suggested here is not intended to replace these guidelines in the 
management of the individual patient. If the patient is unable to obey commands or say words for 
some other reason, for example, because they are severely demented, then they are not in the 
vegetative state. Any words includes repetition of a simple word such as No. A person able to 
communicate using a code would no longer be in the vegetative state. 
 
1 = No (VS) 
2 = Yes 
 
 
 


 
 
 
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18 
INDEPENDENCE IN THE HOME 
 
 
2a 
Is the assistance of another person at home essential every day for some 
activities of daily living? 
 
For a ‘No’ answer they should be able to look after themselves at home for 24 hours if necessary, 
though they need not actually look after themselves. Independence includes the ability to plan for 
and carry out the following activities: getting washed, putting on clean clothes without prompting, 
preparing food for themselves, dealing with callers, and handling minor domestic crises. The 
person should be able to carry out activities without needing prompting or reminding, and should 
be capable of being left alone overnight. 
 
Dependency may be caused by physical impairment, but it is also often due to mental changes. 
People may require actual assistance with activities of daily living, they may need prompted or 
reminded to do things, or they may need someone with them to supervise them because they 
would be unsafe otherwise. In all these cases, they are dependent. However, many people receive 
assistance, but do not absolutely depend on it. This care or protection that is given by others 
should be distinguished from dependency: the person may well benefit from this help and may 
well have a real need for it, but such care does not mean that they are dependent in the sense 
required here. A difficulty may arise if - an activity was not normally carried out before the injury. 
For example, many men have little practical involvement in domestic matters and quite often will 
not usually prepare meals for themselves. In this case, it is sufficient that the person could, if the 
necessity arose, prepare food, even if this would be in a simple fashion. Examples of minor 
domestic crises: what you do if … a glass gets dropped and broken, a tap is left running, a light 
goes out, it begins to get cold, a stranger comes to the door … The person should be able to use 
the telephone to report problems or summon help. 
 
 
1 = No 
2 = Yes (SD) 
 
2b 
Do they need frequent help or someone to be around at home most of the 
time? 
 
For a ‘No’ answer they should be able to look after themselves at home for up to 8 hours during the 
day if necessary, though they need not actually look after themselves.  
 
The patient is considered to be in the lower category of severe disability if they cannot be left alone 
for 8 hours. This limit implies that a relative who is caring for them cannot work. If it is necessary 
to establish a time limit, it can be helpful to ask “what is the maximum amount of time they can be 
left alone?” 
 
1 = No 
(Upper SD) 
2 = Yes 
(Lower SD) 
2c 
Was assistance at home essential before the SAH? 
1 = No 
2 = Yes 
 
 
 
 


 
 
 
10/29/19 
19 
INDEPENDENCE OUTSIDE THE HOME 
 
 
3a 
Are they able to shop without assistance? 
 
This includes being able to plan what to buy, take care of money themselves, and behave 
appropriately in public. They need not normally shop, but must be able to do so. 
 
 
1 = No 
(Upper SD) 
2 =Yes 
 
3b 
Were they able to shop without assistance before the SAH? 
 
Independence outside the home requires ability to plan, to take care of money, and behave 
appropriately in public. It must be established if the person is actually capable of carrying out these 
activities, rather than whether they do or not. 
 
1 = No 
2 = Yes 
 
4a 
Are they able to travel locally without assistance? 
 
They may drive or use public transport to get around. Ability to use a taxi is sufficient, provided 
the person can phone for it themselves and instruct the driver. 
 
 
1 = No 
(Upper SD)  
2 = Yes 
4b 
Were they able to travel without assistance before the SAH? 
1 = No 
2 = Yes 
 
WORK 
 
 
5a Are they currently able to work to their previous capacity? 
 
If they were working before, then their current capacity for work should be at the same level. If 
they were seeking work before, then the brain injury/illness should not have adversely affected 
their chances of obtaining work or the level of work for which they are eligible. If the patient was a 
student before SAH then their capacity for study should not have been adversely affected. Work 
refers to jobs that are paid at a reasonable rate and which, in principle at least, are open to others. 
Reduced capacity for work Any of the following indicate reduced capacity for work: (a) change in 
level of skill or responsibility required; (b) change from full-time to part-time working; (c) special 
allowances made by employer (e.g., increased supervision at work); and (d) change from steady to 
casual employment (i.e., no longer able to hold steady job). Note that sometimes change in 
employment status may be unrelated to brain injury/illness, e.g., due to end of contract, retirement, 
or redundancy. Such changes do not indicate a reduced capacity for work. 
 
Students:  If the person was a student before SAH, then study can be substituted for work. Students 
should be able to return to their previous course and not have noted adverse effects on their ability 
to study. If someone has been absent from college because of brain injury/illness, then there may 
be some disruption caused by the absence itself, and this needs to be discounted when considering 
if the person has problems due to the brain injury/illness. Examples of problems which indicate 
reduced capacity for study: (a) increased difficulties in studying (e.g., needing to spend much more 
time than before); (b) unaccustomed problems with progress (e.g., failing examinations); and (c) 
revised program of study because of problems (e.g., studying for a lesser degree). 
 
1 = No 
2 = Yes 
 


 
 
 
10/29/19 
20 
 
5b 
How restricted are they? 
 
a) 
Reduced work capacity. 
b) 
Able to work only in a sheltered workshop or non-competitive job, or currently unable to 
work. 
 
Noncompetitive work includes work done voluntarily, jobs that are specifically designated for 
disabled people, and work in sheltered workshops. Normally, ability to work is indicative of inde-
pendence; however, occasionally, someone in the upper severe disability range may be working in 
a sheltered workshop. 
 
Students: (a) If the student has a reduced capacity for study but is still studying, then they are 
Upper Moderate disability; and (b) if the student is currently unable to study, then they are Lower 
Moderate disability. 
 
 
 
1 = a  
(Upper MD) 
2 = b  
(Lower MD) 
 
5c 
Were they either working or seeking employment before the SAH (answer 
‘yes’) or  were they doing neither (answer ‘no’) 
 
Work is only used as an indicator of outcome if the person was working or actively seeking work 
before the SAH, or if they were studying. 
 
 
1 = No 
2 = Yes  
 
SOCIAL & LEISURE ACTIVITIES 
 
 
6a 
Are they able to resume regular social and leisure activities outside home? 
 
They need not have resumed all their previous leisure activities, but should not be prevented by 
physical or mental impairment. If they have stopped the majority of activities because of loss of 
interest or motivation then this is also considered a disability. 
Social and leisure activities will vary depending upon the age and background of the patient. 
Representative social and leisure activities include the following: (a) participating in sport, e.g., 
football, swimming etc., (b) attending sporting events as a spectator, (c) going walking, (d) going to 
a club or pub, and (e) visiting friends. Some leisure activities are seasonal – be careful to exclude 
changes in activity that are simply due to this factor. Typical problems that may interfere with 
social and leisure activities: lack of motivation or initiative, avoidance of social involvement, 
physical problems such as loss of mobility, cognitive problems such as poor concentration, and 
problems such as poor temper control or impatience. 
 
1 = No  
2 = Yes  
 
 
6b 
What is the extent of restriction on their social and leisure activities? 
 
a) 
Participate a bit less: at least half as often as before SAH. 
b) 
Participate much less: less than half as often.  
a) 
Participate much less or unable to participate  
 
If it is necessary to question in detail, then ask the person how often they participated in social and 
leisure activities outside the home before the SAH (i.e., how many occasions per week) and how 
often they participate now. Measuring extent of participation is in terms of occasions per week 
emphasizes a quantifiable aspect of social and leisure activities. Sometimes, quality of partici-
pation is affected by the brain injury/illness; for example, the person may become a spectator in a 
sport rather than an active participant. However, changes such as this are very difficult to quantify 
and can reflect the specially demanding nature of some sports. Thus, for the sake of simplicity, it 
is the fact of participation that is rated in the interview. Experience suggests that the main effect of 
brain injury/illness on social and leisure activities tends to be withdrawal from activities that 
involve social interaction: the simple approach adopted here is sensitive to such changes. 
 
1 = a  
(Lower GR) 
2 = b  
(Upper MD) 
3 = c  
(Lower MD) 
 


 
 
 
10/29/19 
21 
 
6c 
Did they engage in regular social and leisure activities outside home before 
the SAH? 
 
Participating regularly in social and leisure activities means participating in at least one activity 
outside the home each week. 
 
1 = No 
2 = Yes 
 
FAMILY & FRIENDSHIPS 
 
 
7a 
Have there been psychological problems which have resulted in ongoing 
family disruption or disruption to friendships? 
 
The question is specifically aimed at alterations in relationships as a result of brain injury/illness. 
The presence of a reported change in personality is not of itself sufficient to warrant classifying the 
person as moderately disabled. The change must be having an adverse impact on family and 
friendships. 
 
Typical post-brain injury/illness personality changes: quick temper, irritability, anxiety, 
insensitivity to others, mood swings, depression, and unreasonable or childish behavior. 
 
 
1 = No  
2 = Yes  
 
 
 
 


 
 
 
10/29/19 
22 
 
7b 
What has been the extent of disruption or strain?  
 
a) 
Occasional - less than weekly 
b) 
Frequent – once a week or more, but tolerable. 
b) 
Frequent or constant - once a week or more 
 
 
  
l = a  
(Lower GR) 
2 = b  
(Upper MD) 
3 = c  
(Lower MD) 
The following definitions apply: (a) Occasional - Some problems since SAH, but less than once a 
week and not causing continuous strain. For example, occasional bad temper, but things blow 
over. (b) Frequent Problems at least weekly, strain on relationships, but regarded as tolerable. For 
example, temper outbursts at least once a week resulting in modification of closeness of 
relationships. (c) Constant daily problems: Breakdown or threatened breakdown of relationship 
within family or friendship; problems regarded as intolerable. If a family have become very 
withdrawn and socially isolated as a result of brain injury/illness, then this also represents constant 
disruption. 
 
 
 
7c 
Were there problems with family or friends before the SAH?  
 
If there were problems before SAH, but these have been markedly worse since SAH then answer 
‘No’ to 7c. 
 
 
 l = No 
2 = Yes 
 
 
RETURN TO NORMAL LIFE 
 
 
8a 
Are there any other current problems relating to the brain injury/illness 
which affect daily life? 
 
Other typical problems reported after brain injury/illness: headaches, dizziness, tiredness, 
sensitivity to noise or light, slowness, memory failures, and concentration problems. These 
problems are impairments; in order to cause disability, they must impinge on functioning in 
everyday life. Similar problems are reported in the general population: it is thus important to 
establish that the problems have developed since SAH. 
 
 
1 = No 
(Upper GR) 
2 = Yes 
(Lower GR) 
 
8b 
Were similar problems present before the SAH? 
 
If there were some problems before the SAH, but these have become markedly worse since SAH 
then answer ‘No’ to 8b. 
 
 
1 = No 
2 = Yes 
 


 
 
 
10/29/19 
23 
GOS Scoring: The patient’s overall rating is based on the lowest outcome category indicated on the scale. 
Refer to helpful hints and definitions for further information concerning administration and scoring. 
 
1 
Dead 
2     Vegetative State (VS) 
3 
Severe Disability (SD) 
4     Moderate Disability (MD) 
5 
Good Recovery (GR) 
 
GOSE Scoring: The patient’s overall rating is based on the lowest outcome category indicated on the 
scale. Refer to helpful hints and definitions for further information concerning administration and scoring. 
 
1 
 
Dead 
2 
Vegetative State (VS) 
3 
Lower Severe Disability (Lower SD) 
4 
Upper Severe Disability (Upper SD) 
5 
Lower Moderate Disability (Lower MD) 
6 
Upper Moderate Disability (Upper MD) 
7 
Lower Good Recovery (Lower GR) 
8 
Upper Good Recovery (Upper GR) 
 
 Lindsay Wilson, Laura Pettigrew, Graham Teasdale 1998 
VERIFICATION 
 
Has the information obtained for the GOSE been verified by a family member? 
Yes No 
 
Explain any discrepancies between the subject’s and family member’s responses:  
 
 
 
 
COMMENTS 
 
In this box, please include any pertinent details regarding the rating of the GOS or GOSE. Make sure to 
record the worst impairment(s) in activity or function on which you based your rating. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
10/29/19 
24 
 
THE  
 
 
 
 
  
 
  Patient: 
 
___________________________
BARTHEL   
 
 
 
 
  Examiner: 
___________________________ 
INDEX   
 
 
 
                 Date:                        ___________________________
Activity  
 
 
 
 
 
 
 
 
    
        
 
      Score  
FEEDING  
0 = unable  
5 = needs help cutting, spreading butter, etc., or requires modified diet  
10 = independent  
 
 
 
 
 
 
 
 
 
 
 
______  
BATHING  
0 = dependent  
5 = independent (or in shower)   
 
 
 
 
 
 
 
                       ______  
GROOMING  
0 = needs to help with personal care  
5 = independent face/hair/teeth/shaving (implements provided)    
 
 
                       ______  
DRESSING  
0 = dependent  
5 = needs help but can do about half unaided  
10 = independent (including buttons, zips, laces, etc.)   
 
 
 
 
                       ______  
BOWELS  
0 = incontinent (or needs to be given enemas)  
5 = occasional accident  
10 = continent  
 
 
 
 
 
 
  
 
 
                       ______  
BLADDER  
0 = incontinent, or catheterized and unable to manage alone  
5 = occasional accident  
10 = continent  
 
 
 
 
 
 
 
 
 
                      ______  
TOILET USE  
0 = dependent  
5 = needs some help, but can do something alone  
10 = independent (on and off, dressing, wiping)   
 
 
 
 
                       ______  
TRANSFERS (BED TO CHAIR AND BACK)  
0 = unable, no sitting balance  
5 = major help (one or two people, physical), can sit  
10 = minor help (verbal or physical)  
15 = independent  
 
 
 
 
 
 
 
 
                                  ______  
MOBILITY (ON LEVEL SURFACES)  
0 = immobile or < 50 yards  
5 = wheelchair independent, including corners, > 50 yards  
10 = walks with help of one person (verbal or physical) > 50 yards  
15 = independent (but may use any aid; for example, stick) > 50 yards   
 
 
           ______  
STAIRS  
0 = unable  
5 = needs help (verbal, physical, carrying aid)  
10 = independent  
 
 
 
 
 
 
 
 
                                  ______ 
 
 
 
 
 
 
 
 
 
 
     TOTAL (0–100): ______  
Provided by the Internet Stroke Center — www.strokecenter.org  


 
 
 
10/29/19 
25
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       
 
 
 
       
The Barthel ADL Index: Guidelines  
1. The index should be used as a record of what a patient does, not as a record of what a patient 
could do.   
2. The main aim is to establish degree of independence from any help, physical or verbal, 
however minor and for whatever reason.   
3. The need for supervision renders the patient not independent.   
4. A patient's performance should be established using the best available evidence. Asking the 
patient, friends/relatives and nurses are the usual sources, but direct observation and common 
sense are also important. However direct testing is not needed.   
5. Usually the patient's performance over the preceding 24-48 hours is important, but occasionally 
longer periods will be relevant.   
6. Middle categories imply that the patient supplies over 50 per cent of the effort.   
7.
Use of aids to be independent is allowed.
References  
Mahoney FI, Barthel D.  “Functional evaluation: the Barthel Index.” 
Maryland State Medical Journal 1965;14:56-61.  Used with permission. 
Loewen SC, Anderson BA.  “Predictors of stroke outcome using objective measurement scales.”  
Stroke. 1990;21:78-81.  
Gresham GE, Phillips TF, Labi ML.  “ADL status in stroke: relative merits of three standard indexes.”  
Arch Phys Med Rehabil. 1980;61:355-358.  
Collin C, Wade DT, Davies S, Horne V.  “The Barthel ADL Index: a reliability study.”  
Int Disability Study.1988;10:61-63.  
Copyright Information  
The Maryland State Medical Society holds the copyright for the Barthel Index.  It may be used freely for 
noncommercial purposes with the following citation:  
Mahoney FI, Barthel D.  “Functional evaluation: the Barthel Index.”
Maryland State Med Journal 1965;14:56-61.  Used with permission. 
Permission is required to modify the Barthel Index or to use it for commercial purposes.  
Provided by the Internet Stroke Center — www.strokecenter.org  


 
 
 
10/29/19 
26
MODIFIED  
 
 
 
Patient Name:      __________________________ 
RANKIN 
 
 
 
 
 
Examiner Name: __________________________ 
SCALE (MRS)  
 
 
 
Date:                     __________________________ 
 
 
Score 
 
Description                                                                                                                                  
  
0 
No symptoms at all 
 
1 
No significant disability despite symptoms; able to carry out all usual duties and activities 
 
2 
Slight disability; requiring some help, but able to walk without assistance 
 
3 
Moderate disability; requiring some help, but able to walk without assistance 
 
4 
Moderately severe disability; unable to walk without assistance and unable to attend to own 
bodily needs without assistance 
 
5 
Severe disability; bedridden, incontinent and requiring constant nursing care and attention 
 
6 
Dead 
 
 
TOTAL (0–6): _______  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Provided by 
the Internet 
Stroke Center 
— 
www.strokecenter.org  
 
 
NIHSS 
Stroke Scale 
 
 
 
 
 
 
 
                  
Patient ID: 
_________________ 
Visit Type:  
___Baseline    ___Pre-Discharge    ___30 Day   ___1 Year    ___Other 
                  
Patient #: __________________ 
References                                                                                                                                
Rankin J.  “Cerebral vascular accidents in patients over the age of 60.”
Scott Med J 1957;2:200-15  
Bonita R, Beaglehole R.  “Modification of Rankin Scale: Recovery of motor function after stroke.”  
Stroke 1988 Dec;19(12):1497-1500  
Van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. “Interobserver agreement for the assessment of 
handicap in stroke patients.”  
Stroke 
1988;19(5):604-7  


 
 
 
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Date: _________________Time: ___ ___:___ ___   [ ]am   [ ]pm  
 
 
 
               Site #: ____________________ 
Person Administering Scale _____________________________________   
  
Administer stroke scale items in the order listed.  Record performance in each category after each subscale exam.  Do not go back and 
change scores.  Follow directions provided for each exam technique.  Scores should reflect what the patient does, not what the clinician 
thinks the patient can do.  The clinician should record answers while administering the exam and work quickly. Except where indicated, 
the patient should not be coached (i.e., repeated requests to patient to make a special effort).  
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 
areflexic.  
  
  
  
  
______  
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 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.  
 0 = Performs both tasks correctly.  
  
 1 = Performs one task correctly.  
  
 2 = Performs neither task correctly.  
   
  
  
  
  
______  
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 
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.  
 0 = No visual loss.  
  
 1 = Partial hemianopia.  
  
 2 = Complete hemianopia.  
  
 3 = Bilateral hemianopia (blind including cortical blindness).  
   
  
  
  
______  


 
 
 
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28 
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    
  
  
  
  
  
  
  
  
  
  
  
______  
  
______ 
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:  ________________  
   
  
  
______  
  
  
  
  
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.  
  
  
  
  
  
______  


 
 
 
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29 
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 
or limited cooperation, but a score of 3 should be used 
only if the patient is mute and follows no one-step 
commands.  
 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 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 abnormality.  Since the abnormality is scored only if present, the item is never untestable.    
 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.  
  
  
  
______  
  
  
  
  
 Total Score 
  
  
  
  
  
  
  
  
  
 
______  
 
  
  
  
  


 
 
 
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30 
 


 
 
 
10/29/19 
31 
  
You know how.  
  
  
Down to earth.  
  
  
I got home from work.  
  
  
Near the table in the dining room.  
  
  
They heard him speak on the radio 
last night.  
  


 
 
 
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32


 
 
 
 
33
 
  
  
MAMA  
  
TIP – TOP  
  
FIFTY – FIFTY  
  
THANKS  
  
HUCKLEBERRY  
  
BASEBALL PLAYER