Conditions: Subarachnoid Hemorrhage Stroke
Keywords: Acetaminophen interleukin-6 interleukin-1 thromboxane A2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3
Healthy volunteers: no

Brief summary:
This study compares the bioavailability of IV and PO acetaminophen in both blood and the cerebrospinal fluid (CSF) of patients following subarachnoid hemorrhage. The study will also compare the temperature and levels of inflammatory cytokines in both blood and CSF of patients treated with IV and PO acetaminophen.

Detailed description:
In individuals diagnosed with subarachnoid hemorrhage (SAH), fevers have been shown to have detrimental micro and macroscopic effects on the brain that can ultimately cause secondary brain injury. The anti-pyretic effects of oral acetaminophen have been studied in critically ill patients but no study has been able to compare these effects to the IV form of acetaminophen also known as OFIRMEV. The investigators wish to explore the notion that IV acetaminophen will be more effective than enteral acetaminophen in reducing the incidence of non-infectious fevers in critically ill patients. In addition, the investigators propose to study the levels of inflammatory cytokines after administration of IV or enteral acetaminophen, as well as, determine the incidence of vasospasm in SAH patients treated with IV acetaminophen. Currently, external ventricular drain (EVD) placement is the "standard of care" in patients who present with SAH and altered mental status/coma. The presence of an EVD allows for continuous sampling and removal of cerebral spinal fluid (CSF) as necessary to alleviate dangerous elevations in intracranial pressure. This clinical scenario allows for a unique, continuous outlet to access the CSF, without placing patients at risk, and without further invasive procedures (i.e. repeated spinal taps). These samples of CSF can be assayed for levels of acetaminophen, as well as inflammatory markers of fever which include interleukin-1 (IL-1), interleukin-6 (IL-6), and thromboxane-2 (TXA-2), in patients selected to be given enteral or IV acetaminophen.

Arms:
arm 1: Patients in this group will receive IV acetaminophen and an oral placebo. The IV formulation will be given using the FDA approved OFIRMEV which comes in a single glass bottle at a concentration of 1000mg/100ml (10mg/ml) containing a total of 1 gram of acetaminophen. arm 2: Patients in this group will receive oral acetaminophen and a saline solution placebo through their IV. The enteral formulation will be in the standard tablet form of 500mg per pill. Patients will receive two pills, or 1 gram of acetaminophen.

Interventions: intervention 1: IV acetaminophen intervention 2: Oral acetaminophen intervention 3: Oral placebo intervention 4: IV placebo
Intervention descriptions: intervention 1: Patients in this group will receive IV acetaminophen and an oral placebo every 6 hours for a 14 day period. Blood and CSF samples will be collected from patients throughout the 14 day period. intervention 2: Patients in this group will receive oral acetaminophen and an IV saline solution placebo every 6 hours for a 14 day period. Blood and CSF samples will be collected from patients throughout the 14 day period. intervention 3: Patients who receive IV acetaminophen will also receive an oral placebo with their IV treatments (every 6 hours for a 14 day period). intervention 4: Patients who receive oral acetaminophen will also receive a saline solution placebo at the same time that they receive the oral acetaminophen treatment (every 6 hours for 14 days).

Protocol document:
Prot_SAP_000.pdf: 
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HRP-592 - Protocol for
Human Subject Research
with Use of Test Article(s)
Protocol Title:
Comparisons of Clinical, Pharmacological and Molecular Effects of Intravenous and Oral 
Acetaminophen in Adults with Sub-Arachnoid Hemorrhage
Principal Investigator:
Name: Sprague W Hazard III
Department: Anesthesiology
Telephone: x311253
E-mail Address: shazard@hmc.psu.edu
Version Date:
February 12, 2018Clinicaltrials.gov Registration #:
NCT02549716
Table of Contents
1.0
Objectives
2.0
Background
3.0
Inclusion and Exclusion Criteria
4.0
Recruitment Methods
5.0
Consent Process and Documentation
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
7.0
Study Design and Procedures
8.0
Data and Specimen Banking For Future Undetermined Research
9.0
Statistical Plan
10.0
Confidentiality, Privacy and Data Management
11.0
Data and Safety Monitoring Plan
12.0
Risks
13.0
Potential Benefits to Subjects and Others
14.0
Sharing Results with Subjects
15.0
Economic Burden to Subjects
16.0
Number of Subjects
17.0
Resources Available
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18.0
Other Approvals
19.0
Subject Stipend (Compensation) and/or Travel Reimbursements
20.0
Multi-Site Research
21.0
Adverse Event Reporting
22.0
Study Monitoring, Auditing and Inspecting
23.0
References
24.0
Appendix
1.0
Objectives
1.1
Study Objectives
In individuals diagnosed with subarachnoid hemorrhage (SAH), fevers have been 
shown to have detrimental micro and macroscopic effects on the brain that can 
ultimately cause secondary brain injury. The anti-pyretic effects of oral acetaminophen 
have been studied in critically ill patients but no study has been able to compare these 
effects to the IV form of acetaminophen also known as OFIRMEV. We wish to explore 
the notion that IV acetaminophen will be more effective than enteral acetaminophen in 
reducing the incidence of non-infectious fevers in critically ill patients. In addition, we 
propose to study the levels of inflammatory cytokines after administration of IV or 
enteral acetaminophen, as well as, determine the incidence of vasospasm in SAH 
patients treated with IV acetaminophen. Currently, external ventricular drain (EVD) 
placement is the “standard of care” in patients who present with SAH and altered mental 
status/coma.  The presence of an EVD allows for continuous sampling and removal of 
cerebral spinal fluid (CSF) as necessary to alleviate dangerous elevations in intracranial 
pressure.  This clinical scenario allows for a unique, continuous outlet to access the 
CSF, without placing patients at risk, and without further invasive procedures (i.e. 
repeated spinal taps). These samples of CSF can be assayed for levels of 
acetaminophen, as well as inflammatory markers of fever which include interleukin-
1beta (IL-1β), interleukin-6 (IL-6), and thromboxane A-2 (TXA-2), in patients selected to 
be given enteral or IV acetaminophen.  
1.2
Primary Study Endpoints
Our primary objective is to determine and compare the bioavailability of 
acetaminophen given in the enteral and IV formulation. The primary endpoint will be to 
quantify the amount of acetaminophen in the CSF, in patients with SAH, at eleven time 
points (0, 5, 15, 30, 45, 60, 90, 120, 180, 240, 360 minutes) beginning directly after 
administration of either IV or enteral acetaminophen. This will be done by sampling the 
CSF attained from the EVD (External-Ventricular Drain). Additionally, we will measure 
the levels of acetaminophen in the blood at these time points. Acetaminophen levels will 
be continuously monitored in both the blood and CSF with samples collected every 24 
hours following first drug administration for 14 days. Patients will also have steady state 
levels of acetaminophen monitored by taking blood and CSF samples every 35 hours (1 
hour before 6th loading dose). 
1.3
Secondary Study Endpoints
In addition to acetaminophen, we will measure the levels of IL-1 beta, IL-6, and 
TXA-2 in the CSF which will be obtained at five time points: 0, 60,120, 240, 360 minutes 
after administration of either IV or enteral acetaminophen. IL-1β, IL-6, and TXA-2 levels 
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will be continuously monitored in both the blood and CSF with samples collected every 
24 hours following first drug administration for 14 days. We will also obtain temperature 
readings at these time points making note of the number of febrile events (temperature 
greater than 38.3 as defined by the Society of Critical Care Medicine) as well as the 
median and mean temperature for each group) Following the first set of eleven 
samples, patients will have their temperature and inflammatory cytokines monitored with 
blood and CSF samples every 24 hours following the time of first drug administration. 
Age and sex of patients will also be analyzed to determine if they play a significant role 
in the level of inflammatory cytokines.
Additionally, we will measure the incidence of vasospasm in patients with SAH 
who receive IV acetaminophen starting on post-bleed day 0 and continuing for 14 
consecutive days (typical vasospasm window). Clinical vasospasm will be defined as 
the presence of new focal neurological deficits (motor or speech deficits) that developed 
after SAH, a decrease in the Glasgow Coma Score (GCS) of 2 or more points for >6hrs, 
a new cerebral infarction unrelated to post-treatment (coiling or clipping) complications, 
re-bleed, progressive hydrocephalus, electrolyte or metabolic disturbance, or infection. 
The incidence of clinical vasospasm will be identified in the patients EMR after the 14 
day period. 
2.0
Background 
2.1
Scientific Background and Gaps
Fever occurs in almost three quarters of acute brain injury patients admitted to 
the Neuro Surgical Intensive care Unit (1). A recent meta-analysis, which included over 
14,000 patients, demonstrated that the presence of fever was associated with worse 
outcomes (2). Fever is known to cause elevations in intracranial pressure and disruption 
of blood–brain barrier in the injured brain, as well as releasing excitatory amino acids 
and free radicals, which can lead to ischemic depolarization.  All of these micro and 
macroscopic effects contribute to secondary brain injury (3-5). SAH accounts for only 
5% of all strokes, however, it is responsible for 25% of all stroke-related mortality (6). Of 
the patients who survive the initial bleed and subsequent surgical/endovascular 
procedures, up to one-third develop delayed cerebral ischemia (7). The mechanism of 
delayed cerebral ischemia still remains unclear; however, vasospasm and inflammation 
are currently the most common targets for novel therapeutic interventions (8,9). 
Presently, only oral nimodipine has been proven (in one large randomized control trial) 
to improve outcomes in patients with subarachnoid hemorrhage through an unknown 
mechanism.  Numerous subsequent clinical trials targeting vasospasm have been 
universally disappointing (10). 
The release of modulators of inflammation is a key process in cerebral ischemia 
and is likely driven by the cytokine interleukin-1 (11). Interleukin-1 up-regulates the 
expression of interleukin-6, causing local inflammation. Clinical studies have 
demonstrated elevated interleukin-6 levels in the CSF of patients after SAH.  Studies 
have also shown a correlation between higher concentrations of CSF interleukin-6 and 
worse clinical outcomes (11,12).  There is a proposed link between fever and 
vasospasm; in 2001, a study demonstrated that SAH patients who were febrile during 
admission were more likely to experience vasospasm and a poor outcome (13). 
Paracetamol has been available in Europe in an IV formulation since 2002. Studies 
have shown that it penetrates rapidly into the cerebrospinal fluid of children and can be 
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detected in as little as 5 minutes (with the highest CSF concentration detected 57 
minutes after administration) (14) (15). Currently, the only study to compare plasma and 
CSF pharmacokinetics of intravenous, oral, or rectal formulations of acetaminophen 
consisted of just 6 healthy male volunteers (17). There have been no studies comparing 
the antipyretic effects of IV and enteral acetaminophen in critically ill adults (16).
2.2
Previous Data
Not applicable. No previous studies have been performed comparing the 
antipyretic effects of IV and enteral acetaminophen in critically ill adults.
2.3
Study Rationale
Previous studies have demonstrated that the presence of fever in critically ill 
patients is associated with worse outcomes and secondary brain injury. Controlling 
fever with the anti-pyretic effects of oral acetaminophen (given either via a feeding tube 
or if swallowing evaluation has been passed, given by mouth) is the standard of care in 
patients with SAH.  To date there have been no studies that have compared the oral 
and IV formulations in decreasing the duration of fever. This could potentially lead to 
overall better outcomes for the patient. Additionally, the IV formulation may have an 
effect on preventing vasospasms compared to the oral form.  
3.0
Inclusion and Exclusion Criteria
3.1
Inclusion Criteria
1. Adults: aged18-100y, inclusive.
2. Diagnosis of subarachnoid hemorrhage. CT, CTA, lumbar puncture, or MRI can 
confirm this diagnosis.
3. Placement of an external ventricular drain.
4. Cleared by standard of care dysphagia screen and/or speech therapy for ability to 
swallow. Subjects may also be enrolled with an NG/J tube if they fail the dysphagia 
screening.
3.2
Exclusion Criteria
1. Anyone under the age of 18 or over the age of 100.
2. Contraindication to acetaminophen such as a known hypersensitivity, hepatic 
impairment {this will be defined using liver function tests (LFT’s) ALT, Alkaline 
phosphatase, and Total Bilirubin: specifically, transaminase (ALT) greater than twice 
the normal range} or known/documented severe active liver disease.
3. Known Glucose-6-phosphate dehydrogenase deficiency (G6PD) 
4. Severe renal impairment (creatinine clearance ≤ 30 mL/min).
3.3
Early Withdrawal of Subjects
3.3.1 Criteria for removal from study
1. Removal of EVD
2. Serious adverse reactions to acetaminophen including hepatic injury, serious 
skin reactions, hypersensitivity, and anaphylaxis.
3. Intolerable side effects of acetaminophen including severe nausea, vomiting, 
headache, and insomnia.
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4. Patients can be withdrawn from the study if ALT, ALK Phosphatase, or T. 
Bilirubin rise to a level of three times the upper limit of normal or at any point 
that the treating physician believes that the study protocol unnecessarily 
places the patient at risk for adverse outcomes.
3.3.2 Follow-up for withdrawn subjects
If the LFTs meet stopping criteria, drug product will be discontinued and LFT monitoring 
will continue three days and 7 days post initial onset.  If LFT’s do not decrease to an 
acceptable level, the PI will continue to monitor past 7 days until labs have reached 
normal values.
4.0
Recruitment Methods
4.1
Identification of subjects
Potential participants of the study will be identified in the neurosurgical intensive 
care unit by an intensivist or staff physician or resident. The physician will notify a study 
coordinator 
4.2
Recruitment process
An initial screen of their medical record will be performed via a pre-enrollment 
screening document that will include the study’s inclusion criteria. Once patients are 
identified, the patient will be approached in the hospital and the study will be explained 
in detail to them or their legally authorized representative. If legally authorized 
representative (LAR) is required and they are not in the hospital, a member of the 
research team will telephone the LAR and explain the study in detail to them.
4.3
Recruitment materials
Not applicable
4.4
Eligibility/screening of subjects
Patients’ medical records will be reviewed to determine their eligibility. A 
screening document will be used to assess the eligibility of each potential subject. This 
document will include the inclusion criteria for this study which can be answered via the 
EMR.
5.0
Consent Process and Documentation 
5.1
Consent Process. 
5.1.1 Obtaining Informed Consent
5.1.1.1
Timing and Location of Consent
After identifying potential study subjects, informed consent 
will only be obtained by  a Research Team Members who are IRB-
approved members of the study team as per IRB policies and 
procedures. The IRB approved study team member will obtain 
consent, either from the patient directly (If patient is cognitively 
aware and able to give consent) or through the legal authorized 
representative (LAR) if the patient is unable to give consent. 
Indications that a patient may not give consent include sedation 
and or altered mental status. In such cases, the LAR will be 
responsible for consenting to the study. Acquiring consent will be 
done in a quiet and private setting such as the patient’s room or 
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nearby office. If LAR is not in the hospital, a member of the 
research team will telephone them and ask if they can fax or email 
the consent to them for review. Once the LAR has received the 
consent, the research team member will go over the form with them 
by phone. The team member will ensure that a witness who is not a 
research team member is present while the team member conducts 
the consent process with the LAR. If the LAR agrees to allow the 
patient to be enrolled into the research, the LAR will be instructed 
to sign at the appropriate signature area in the consent form. The 
team member and the witness will then sign the phone consent 
form (see:STUDY00002767 Phone Consent Script). The team 
member will ask the LAR to send the original, signed consent form 
back to the team member. Once received, the team member will 
send a copy of the signed consent form and phone consent form 
with signatures to the LAR for their records. LAR will be advised 
that participation in the study may begin when the signed forms are 
received. Subject participation may begin before receiving the 
original documents if the LAR is able to send the signed consent 
form to investigators electronically. However, the LAR still must 
mail the original consent form to the investigators.
5.1.1.2
Coercion or Undue Influence during Consent
It will be explained that research participation is voluntary. 
Their decision to participate or not participate will not affect their 
level of care.
5.1.2 Waiver or alteration of the informed consent requirement
We are requesting a partial waiver to review the patient’s medical record 
to determine their eligibility.
5.2
Consent Documentation
5.2.1 Written Documentation of Consent
Written informed consent for the procedure and participation in the study 
will be obtained. If consent is obtained by phone, the phone script with signatures 
will be kept with the signed consent form. An original will be given to the patient 
or their LAR for their records and another original will be kept by the research 
team. A copy will be uploaded to their medical record.
5.2.2 Waiver of Documentation of Consent
Not applicable
5.3
Consent – Other Considerations 
5.3.1 Non-English Speaking Subjects
The current IRB approved short consent form and summary (same as the 
English consent form used for long form of consent documentation) will be 
obtained.
We will verify that we are using the most current IRB-approved version of the 
study specific short consent form and summary and that the short consent form 
is in a language understandable to the subject/representative.
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Copies will be given to the subject/representative. Whenever possible we will 
provide the short consent form and summary to the subject/representative in 
advance of the consent discussion.
The services of an interpreter fluent in both English and the language understood 
by the subject/representative will be obtained. Should subject/representative 
insist upon the use of a friend or family member to provide them with interpreting 
service, staff shall retain a healthcare interpreter to participate in the exchange to 
ensure that it represents accurate communication of information between 
hospital staff and patients (PC-22HAM).
The services of an impartial witness who is fluent in both English and the 
language spoken by the subject/representative will be obtained to be present 
during the entire consent discussion to attest that the information in the short 
consent form, summary, and any other information provided was accurately 
explained to, and apparently understood by, the subject/representative, and that 
consent was freely given. The witness and the interpreter may be the same 
person. 
The witness may be a family member or friend. The witness will not be a person 
involved in the design, conduct, or reporting of the research study.
The interpreter will translate the summary (not the short consent form) to the 
subject/representative.
Through the interpreter we will explain the details in such a way that the 
subject/representative understands what it would be like to take part in the 
research study. When necessary, we will provide a different or simpler 
explanation to make the information understandable.
We will have the subject/representative read the short consent form or have the 
interpreter read the short consent form to the subject/representative.
5.3.2 Cognitively Impaired Adults
5.3.2.1
Capability of Providing Consent
The physician will decide if the subject is capable of providing 
consent. If the patient is deemed incapacitated by the ICU team, we 
will obtain consent from his/her guardian or legal authorized 
representative prior to study participation.
5.3.2.2
Adults Unable To Consent
   If the subject is unable to provide written consent, authorization 
will be obtained by the patient’s legally authorized representative. 
Should patient become able to provide consent, we will then obtain 
written consent from them as well. 
5.3.2.3
Assent
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If subject is unable to provide written consent, we will try and obtain 
assent from the subject. Assent will be documented on the consent 
form that is uploaded to the medical record.
5.3.3 Subjects who are not yet adults (infants, children, teenagers) 
Not applicable
6.0
HIPAA Research Authorization and/or Waiver or Alteration of 
Authorization
6.1
Authorization and/or Waiver or Alteration of Authorization for the Uses and Disclosures 
of PHI
Check all that apply:
Authorization will be obtained and documented as part of the consent process.
Partial waiver is requested for recruitment purposes only (Check this box if patients’ 
medical records will be accessed to determine eligibility before consent/authorization 
has been obtained)
Full waiver is requested for entire research study (e.g., medical record review studies) 
Alteration is requested to waive requirement for written documentation of authorization
6.2
Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
6.2.1
Access, use or disclosure of PHI representing no more than a minimal risk to the 
privacy of the individual
6.2.1.1 Plan to protect PHI from improper use or disclosure
Information is included in Section 10 of this protocol.
6.2.1.2 Plan to destroy identifiers or a justification for retaining identifiers 
Identifiers will be destroyed once the study is completed.
6.2.2
Explanation for why the research could not practicably be conducted without 
access to and use of PHI
The PHI is necessary to access the patient’s medical records.
6.2.3
Explanation for why the research could not practicably be conducted without the 
waiver or alteration of authorization
The information required for screening is only available in the medical record.
6.3
Waiver or alteration of authorization statements of agreement
Protected health information obtained as part of this research will not be reused or 
disclosed to any other person or entity, except as required by law, for authorized 
oversight of the research study, or for other permitted uses and disclosures according to 
federal regulations.
The research team will collect only information essential to the study and in accord with 
the ‘Minimum Necessary’ standard (information reasonably necessary to accomplish the 
objectives of the research) per federal regulations. 
Access to the information will be limited, to the greatest extent possible, within the 
research team. 
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All disclosures or releases of identifiable information granted under this waiver will be 
accounted for and documented. 
7.0
Study Design and Procedures
7.1
Study Design 
This is a randomized double-blind controlled trial.  Adults will be randomized to either 
the enteral or IV acetaminophen group.   
7.2
Study Procedures
7.2.1  Day 1 – Consent and Randomization  

Following consent and screening LFT’s (exclusion criteria for 
transaminase, ALT, and T. Bilirubin is listed above), eligible subjects will 
be randomized to either an enteral or IV acetaminophen group.
7.2.2 Day 1 – Day 14 

Patients will receive two drugs; one enteral drug and one IV drug. The 
pharmacist will randomize which drug contains acetaminophen and which 
contains a placebo (based on the patient’s randomization code). Patients 
in the enteral group will receive acetaminophen orally (or per nasogastric 
tube if necessary), and a saline solution through their IV. Patients in the IV 
group will receive acetaminophen through their IV and an oral placebo (or 
per nasogastric tube if necessary).  

Study drugs:  patients weighing greater than 50 kg will receive either 1 
gram of acetaminophen IV or enteral (as determined by their 
randomization), this will be administered by the bedside nurse. The IV 
formulation (OFIRMEV) will be administered via an infusion pump over 15 
minutes as prescribed by the manufacturer. In patients that weigh less 
than 50kg a dose of 15mg/kg every 6 hours will be utilized for both the IV 
and enteral formulations. The nurse will be blinded to which drug contains 
acetaminophen.

Following the first administration of either formulation, a 2ml sample of 
CSF will be attained from the EVD. The EVD has an initial chamber that is 
at the level of the trachea which allows for sampling without directly 
opening the CSF container itself and potentially introducing a source of 
infection. This chamber is easy to empty between each time point which 
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ensures that the next sample won’t be contaminated with the previous 
sample of CSF. These samples will be obtained by either a 
neurointensivist attending/fellow or neurosurgery resident. A blood sample 
will also be obtained using the in place arterial line following drug 
administration.

Blood samples (approx. 2ml) will be obtained at the same times in which we 
sample the CSF. If the arterial line has been removed, subsequent blood 
draws will be done through a vein in the arm. If a line is absent for a 
prolonged period of time, the research team will correlate blood sample 
collection with standard of care routine blood draws between 6-8 am every 
morning in hopes of minimizing discomfort to the patient.

Sampling of CSF and blood will be done at eleven time points, including: 
0, 5, 15, 30, 45, 60, 90, 120, 180, 240, and 360 minutes after first 
administration of the drug.

Measurements of external body temperature will be done at each time 
point as well. 

Blood and CSF samples once collected will be transported on ice to the 
Anesthesia Clinical Research laboratory.  Whole blood specimens will 
then be centrifuged for 15 minutes at 1500 RCF.  The supernatant will 
then be aspirated and placed into 1.5ml eppendorf tubes where they will 
be labeled, cataloged and placed into -70 degree centigrade storage. CSF 
samples will also be centrifuged and aliquoted (500µl quantities) into 1.5ml 
eppendorf tubes; labeled and cataloged, and placed into -70 degree C. 
storage. The levels of acetaminophen, IL-1 beta, IL-6, and TXA-2 will be 
assayed and quantified for each sample. 

Following the first administration of the drug, patients will continue to 
receive treatment with an active drug and a placebo every 6 hours through 
day 14. After the first sequence of measurements (11 CSF and 11 blood 
samples), patients will have their blood and CSF tested once every 24 
hours through day 14,  starting from the time of the first drug treatment. 
Timing of the daily blood samples may vary a few hours if the patient 
doesn’t have an arterial line and requires a venous puncture, in order to 
collectively get blood samples needed for the day.  Daily blood and CSF 
sampling will allow for analysis of long-term changes in inflammatory 
cytokine levels. Temperature will also be taken at this time.

Patients will also have their acetaminophen levels tested at 35 hours (1 
hour before 6th loading dose) in separate samples taken from both blood 
and CSF. This will be used to determine the steady state level of 
acetaminophen If for any reason (e.g. an emergency or unexpected 
situation), the flood sample at the 35th hour couldn’t be obtained, it will be 
collected at the earliest stable period and will be noted.

Liver function tests, ALT, ALK Phosphatase, and T. Bilirubin will be 
monitored (upon enrollment in the study) and every three days for the 
duration of the study.  The hold/call order for these labs will be written on a 
paper pharmacy order sheet and/or electronic order page (if available). 
The paper order sheet will be kept in the patient’s bedside chart.

Upon enrollment, the medical record will be checked daily, for clinical 
and/or research LFT lab results (including weekends), from day 1 through 
day 14, or until patient is removed from the study.  The PI or a study team 
physician will be responsible to check Cerner Labs in Powerchart daily 
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and if LFTs were drawn, determine if they meet criteria to hold the drug.   
Clinical LFT’s -drawn on any day and safety labs obtained every third day 
will be documented per protocol.  The physician will determine if any 
elevations in ALT, Alk Phos or T. Bili are clinically insignificant or 
significant based on the reported lab values. ICU nursing HOLD/Call 
orders are in place with the paper study drug order sheet and/or electronic 
order to make sure study drug is not given if LFTS are elevated 3X upper 
limit of normal.  Nursing staff will notify research physician if subject meets 
study drug HOLD/Call order criteria.  Lab values will be printed as Lab 
Safety documents and placed in the Study Binder located in C2813.  This 
will serve as documentation that laboratory values were assessed in a 
timely manner for to ensure subject safety.  If LFTs are determined to be 
clinically significant but are below stopping criteria, the labs will be 
followed daily, and the PI will assess if any changes are needed for drug 
administration or dosing. If the LFTs meet stopping criteria, drug product 
will be discontinued and LFT monitoring will continue three days and 7 
days post initial onset.  If LFT’s do not decrease to an acceptable level, 
the PI will continue to monitor past 7 days until labs have reached normal 
values.  All LFT monitoring will be printed off from Powerchart to 
document continued review and assessment of LFT values.

Incidence of vasospasm will be reviewed in the patients EMR chart 
starting on post-bleed day 0 and continuing for 14 consecutive days 
(typical vasospasm window). Patients who meet the clinical definition of 
vasospasm defined in section 1.3 will be recorded. 
7.3
Duration of Participation
Each individual enrolled in the study will be given either enteral or IV 
acetaminophen and a corresponding placebo every six hours for a total of 14 days. The 
primary study end point of quantifying the amount of acetaminophen in the CSF until 
steady state is reached requires obtaining CSF from the EVD for a duration of six hours. 
The secondary end point of quantifying the number of vasospasms will occur with chart 
review after the individual has been hospitalized for 14 days.  
7.4
Test Article(s) (Study Drug(s) and/or Study Device(s))
7.4.1 Description
The study will be performed using acetaminophen in both the enteral and 
IV form. The enteral formulation will be acetaminophen oral suspension at a 
concentration of 160mg/5mL.  . In cases where the patient is unable to swallow, 
the oral suspension will be given through the nasogastric tube. The IV 
formulation will be the FDA approved OFIRMEV which comes in a single glass 
bottle at a concentration of 1000mg/100ml (10mg/ml) containing a total of 1 gram 
of acetaminophen.
The pharmacy will provide the appropriate placeboes for this study.  
Placebo for the IV formulation will be 0.9%NaCl.  Placebo for enteral/oral doses 
will be an oral suspension consisting of Ora-Plus (suspending vehicle), Ora-
Sweet (sugar-free flavored syrup vehicle), and flavored syrup (syrup vehicle for 
oral solution).  
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7.4.2 Treatment Regimen
The total dose of acetaminophen regardless of route of administration will 
be 1 gram every 6 hours in subjects weighing greater than or equal to 50kg or  
15mg/kg every 6 hours in subjects weighing less than 50 kg.  Treatment should 
begin within 24-48 hrs subject meeting the inclusion criteria. At the time of active 
drug administration, a corresponding placebo dose (IV saline or placebo oral 
suspension) will be administered. Medications will be given for a total of 14 days 
as to encompass the typical window for vasospasm.  If for any reason a dose 
needs to be skipped (eg. Emergency situation (alteration in consciousness, CPR, 
need for intubation, and surgical intervention)), it can be given as a coupled 
treatment in each alternative scenario.
7.4.3 Method for Assigning Subject to Treatment Groups
The department of Public health Sciences will supply the Investigational 
pharmacy with the randomization table assigning patients into the enteral or IV 
acetaminophen treatment group. 
7.4.4 Subject Compliance Monitoring
 Not Applicable as study drug will be administered by study personnel.
7.4.5 Blinding of the Test Article
Pharmacy will assign patients to either an IV or an enteral form of 
acetaminophen based on the patient’s randomization code. Pharmacy will 
provide the study team with the blinded test articles. Patients in the enteral group 
will receive acetaminophen orally, and a saline solution through their IV. Patients 
in the IV group will receive acetaminophen through their IV and an oral placebo 
suspension. Nursing staff, who will administer the drugs, will not be aware of 
which form of drug (IV or PO) contains acetaminophen. Data that identifies a 
patient’s group will not be released until after the entire study is completed.
7.4.6 Receiving, Storage, Dispensing and Return 
As this is a randomized, blinded study we will be obtaining the medications from 
the investigational pharmacy. The pharmacy will prepare and store the drugs as per 
package insert until the time that patient specific doses are drawn up. Once drawn up 
the IV medications may be stored for up to 6 hours at room temperature.
8.0
Data and Specimen Banking For Future Undetermined Research
Not applicable
9.0
Statistical Plan 
9.1
Sample size determination
A parallel design will be used to make comparisons between two 
treatment groups: oral acetaminophen or IV acetaminophen.  The primary outcome 
variable will be the maximum concentration of acetaminophen in plasma (Cmax).  
Subjects will be randomized to treatment groups in blocks to attempt to maintain 
balance in the sample size between the groups.
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From a previous study, we found a pooled standard deviation for the 
difference between oral and IV acetaminophen in Cmax to be 4.864.  The basic method 
at the core of ANCOVA that we can use to determine the total sample size needed for 
each group is a Two-sample t-test.  Given these parameters, a sample size of 25 
subjects for each group for a total sample size of 50 subjects will provide 80% power to 
detect a difference of at least 4.0 µg/mL (an effect size of 0.822) between treatment 
groups using a two-sided Two-sample t-test and Type I error rate of 0.05.
 
9.2
Statistical methods
To make comparisons between the treatment groups, an Analysis of 
covariance (ANCOVA) model will be used (Neter J, Kutner MH, Nachtsheim CJ, 
Wasserman W. Applied Linear Statistical Models. The McGraw-Hill Companies, Inc., 
1996.)  The ANCOVA model is an extension of the Analysis of variance and the Two-
sample t-test that allows us to adjust for potentially confounding covariates if deemed 
necessary such as age or sex.  Diagnostics will be assessed to determine the fit of the 
model and the adherence to modeling assumptions, and, if necessary, transformations 
of the outcome variable will be used to meet modeling assumptions.  The effect size will 
be quantified using the difference in means between the groups with their associated 
95% confidence intervals.  Post-hoc hypothesis tests will be corrected as needed for 
multiple testing using appropriate techniques such as Bonferroni’s method or Tukey’s 
procedure.
10.0 Confidentiality, Privacy and Data Management 
See Research Data Plan Review Form
11.0 Data and Safety Monitoring Plan
11.1
Periodic evaluation of data
The PI and research coordinator will review cumulative adverse events, early 
termination of study participation, and accrual every six months and report any issues 
requiring modification of the study or alteration of the risk: benefit ratio to the IRB 
immediately.  A summary of adverse events, study progress and protocol modifications 
will be included for IRB review in the continuing review.
11.2
Data that are reviewed 
The data to be reviewed will be:

Safety data

Untoward events

Efficacy data
11.3
Method of collection of safety information
Safety information will be collected by the research staff as described in Section 7.2.
11.4
Frequency of data collection
Samples of CSF and blood will be collected for analysis at time points 0, 5, 15, 30, 45, 
60, 90, 120, 180, 240, 360 minutes after administration of either IV or enteral 
acetaminophen. Starting from the point of first drug administration, additional data will 
be collected from both CSF and blood every 24 hours to determine changes in 
temperature, IL-1, IL-6, TXA-2, and acetaminophen. Samples will also be collected 
every 35 hours (one hour prior to the 6th loading dose) to determine acetaminophen 
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concentration. Additionally, data will be collected to determine confirmed instances of 
vasospasm throughout the 14 day study period. This data will be obtained from the 
patient’s chart.
11.5
Individual’s reviewing the data
Oversight for the conduct of the study will be provided by the PI and the research 
coordinator will monitor the data. They will ensure that all eligibility criteria and consent 
requirements are met prior to a subject’s participation in the study and that the 
procedures and adverse event reporting occur according to the IRB approved protocol.
11.6 Frequency of review of cumulative data
The PI and research coordinator will review cumulative adverse events, early 
termination of study participation, and accrual every six months and report any issues 
requiring modification of the study or alteration of the risk: benefit ratio to the IRB 
immediately.  A summary of adverse events, study progress and protocol modifications 
will be included for IRB review in the continuing review.
11.7 Statistical tests
Not applicable
11.8 Suspension of research
Not applicable
12.0 Risks
The possible risks for this study include:
Oral Solution: 
Dermatologic: Skin rash
Endocrine & metabolic: Decreased serum bicarbonate, decreased serum calcium, 
decreased serum sodium, hyperchloremia, hyperuricemia, increased serum glucose
Genitourinary: Nephrotoxicity (with chronic overdose)
Hematologic & oncologic: Anemia, leukopenia, neutropenia, pancytopenia
Hepatic: Increased serum alkaline phosphatase, increased serum bilirubin
Hypersensitivity: Hypersensitivity reaction (rare)
Renal: Hyperammonemia, renal disease (analgesic)
IV Solution:
>10%: Gastrointestinal: Nausea (adults 34%; children ≥5%), vomiting (adults 15%; 
children ≥5%)
1% to 10%: Cardiovascular: Hypertension, hypotension, peripheral edema, tachycardia
Central nervous system: Headache (adults 10%; children ≥1%), insomnia (adults 7%; 
children ≥1%), agitation (children ≥5%), anxiety, fatigue, trismus
Dermatologic: Pruritus (children ≥5%), skin rash
Endocrine & metabolic: Hypervolemia, hypoalbuminemia, hypokalemia, 
hypomagnesemia, hypophosphatemia
Gastrointestinal: Constipation (children ≥5%), abdominal pain, diarrhea
Genitourinary: Oliguria (children ≥1%)
Hematologic & oncologic: Anemia
Hepatic: Increased serum transaminases
Local: Infusion site reaction (pain)
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Neuromuscular & skeletal: Limb pain, muscle spasm
Ophthalmic: Periorbital edema
Respiratory: Atelectasis (children ≥5%), abnormal breath sounds, dyspnea, hypoxia, 
pleural effusion, pulmonary edema, stridor, wheezing
Miscellaneous: Fever (children ≥1%)

Both IV and Oral formulations: <1%, postmarketing, and/or case reports: 
Anaphylaxis, hepatic injury (dose-related), hypersensitivity reaction, severe 
dermatological reaction (acute generalized exanthematous pustulosis, Stevens-
Johnson syndrome, toxic epidermal necrolysis)

Treatment of Suspected overdose:  If an acetaminophen overdose is suspected, we 
will obtain a serum acetaminophen assay as soon as possible followed by liver 
function studies initially and repeat at 24-hour intervals. We will administer the 
antidote N-acetylcysteine (NAC) as early as possible. 

Patients who have their arterial line removed prior to the conclusion of the study may 
have their blood drawn from a vein. Risks include a slight pinch or pinprick when the 
sterile needle enters the skin. The risks also include mild discomfort and/or a black 
and blue mark at the site of puncture. Less common risks include a small blood clot, 
infection or bleeding at the puncture site, and on rare occasions fainting during the 
procedure

The risk of randomization. The route of the acetaminophen will be assigned 
randomly; there is a 50/50 chance of how the drug will be administered. Either the IV 
or oral form of acetaminophen may carry a greater risk of side effects.

Risk of loss of confidentiality if your medical information or your identity is obtained 
by someone other than the investigators, but precautions will be taken to prevent 
this from happening.
. 
13.0 Potential Benefits to Subjects and Others
13.1
Potential Benefits to Subjects
Previous studies have demonstrated that the presence of fever is associated with 
worse outcomes, secondary injury to the brain, and prolonged hospitalizations. If the 
antipyretic effects of IV acetaminophen are greater than those from oral administration, 
the duration of fever could potentially be lessened leading to better overall outcomes for 
the patient. Additionally, this route of administration may have an effect on preventing 
vasospasms compared to the oral form.  
13.2
Potential Benefits to Others
If the study concludes that the IV formulation has a higher bioavailability, 
decreased duration of fever, decreased incidence of vasospasm, and/or produces a 
better overall patient outcomes, this formulation could potentially become the standard 
of care compared to the enteral formulation. 
14.0 Sharing Results with Subjects
We will not be sharing the results with subjects.
15.0 Economic Burden to Subjects
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15.1
Costs 
There are no additional costs to the subjects to participate in this study. We are 
obtaining funding from sponsor to provide study drugs.
15.2
Compensation for research-related injury
It is the policy of the institution to provide neither financial compensation nor free 
medical treatment for research-related injury. In the event of injury resulting from this 
research, medical treatment is available but will be provided at the usual charge. Costs 
for the treatment of research-related injuries will be charged to subjects or their 
insurance carriers. 
16.0 Number of Subjects
We plan to accumulate a total of 50 patients with 25 to be assigned to the enteral 
formulation and another 25 to be assigned to the IV formulation.
17.0 Resources Available
17.1
Facilities and locations
The research will be conducted at the Hershey Medical Center.
17.2
Feasibility of recruiting the required number of subjects
A preliminary search in the EMR for “subarachnoid hemorrhage” yielded 350 patients.  
A majority of subarachnoid hemorrhage is caused by trauma and not aneurysm rupture 
however. Looking back at the NSICU census for patients admitted for aneurysmal 
subarachnoid hemorrhage over the past 1year yielded as few as 0 and as many as 9 
patients per month. Obviously not all of these patients will meet inclusion criteria; 
however, it seems feasible that 50 patients could be enrolled in as little as one year as 
more ‘telestroke” centers join Penn State Hershey Medical Center.   
17.3
PI Time devoted to conducting the research
Currently I am employed as a 0.9 FTE in the department of Anesthesia leaving one 
academic day per week that I devote to research.  In addition I spend one week per 
month as the intensivist in the NSICU.  
17.4
Availability of medical or psychological resources
Not applicable
17.5
Process for informing Study Team
Meetings will be held periodically as needed to ensure all research team members are 
informed about the protocol and their duties. Team emails will also be used to keep 
team members updated.
18.0 Other Approvals
Registered with clinicaltrials.gov
Bio-safety 
Departmental review
Sponsor approval
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19.0 Subject Stipend (Compensation) and/or Travel Reimbursements
Not applicable
20.0 Multi-Site Research
Not applicable
21.0 Adverse Event Reporting
21.1
Adverse Event Definitions
For drug studies, incorporate the following definitions into the below 
responses, as written:
Adverse event
Any untoward medical occurrence associated with the use of the drug in 
humans, whether or not considered drug related
Adverse reaction
Any adverse event caused by a drug
Suspected 
adverse reaction
Any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event.  Suspected adverse reaction implies a lesser degree 
of certainty about causality than “adverse reaction”.

Reasonable possibility.  For the purpose of IND safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.
Serious adverse 
event or Serious 
suspected 
adverse reaction
Serious adverse event or Serious suspected adverse reaction: An adverse 
event or suspected adverse reaction that in the view of either the investigator or 
sponsor, it results in any of the following outcomes: Death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions, or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. 
Life-threatening 
adverse event or 
life-threatening 
suspected 
adverse reaction
An adverse event or suspected adverse reaction is considered “life-threatening” 
if, in the view of either the Investigator (i.e., the study site principal investigator) 
or Sponsor, its occurrence places the patient or research subject at immediate 
risk of death.  It does not include an adverse event or suspected adverse 
reaction that had it occurred in a more severe form, might have caused death.
Unexpected 
adverse event or 
Unexpected 
suspected 
adverse reaction.  
An adverse event or suspected adverse reaction is considered “unexpected” if it 
is not listed in the investigator brochure, general investigational plan, clinical 
protocol, or elsewhere in the current IND application; or is not listed at the 
specificity or severity that has been previously observed and/or specified.
For device studies, incorporate the following definitions into the below 
responses, as written:
Unanticipated 
adverse device 
effect
Any serious adverse effect on health or safety or any life-threatening problem or 
death caused by, or associated with, a device, if that effect, problem, or death 
was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or IDE application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects.
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21.2
Recording of Adverse Events
All adverse events (serious or non-serious) and abnormal test findings observed 
or reported to study team believed to be associated with the study drug(s) or device(s) 
will be followed until the event (or its sequelae) or the abnormal test finding resolves or 
stabilizes at a level acceptable to the investigator.
An abnormal test finding will be classified as an adverse event if one or more of 
the following criteria are met:

The test finding is accompanied by clinical symptoms

The test finding necessitates additional diagnostic evaluation(s) or 
medical/surgical intervention; including significant additional concomitant drug 
treatment or other therapy
Note: Simply repeating a test finding, in the absence of any of the other listed 
criteria, does not constitute an adverse event.  

The test finding leads to a change in study drug dosing or discontinuation of 
subject participation in the clinical research study

The test finding is considered an adverse event by the investigator.
21.3
Causality and Severity Assessments
The investigator will promptly review documented adverse events and abnormal 
test findings to determine 1) if the abnormal test finding should be classified as an 
adverse event; 2) if there is a reasonable possibility that the adverse event was caused 
by the study drug(s) or device(s); and 3) if the adverse event meets the criteria for a 
serious adverse event.
If the investigator’s final determination of causality is “unknown and of 
questionable relationship to the study drug(s) or device(s)”, the adverse event will be 
classified as associated with the use of the study drug(s) or device(s) for reporting 
purposes.  If the investigator’s final determination of causality is “unknown but not 
related to the study drug(s) or device(s)”, this determination and the rationale for the 
determination will be documented in the respective subject’s case history.
21.4
Reporting of Adverse Reactions and Unanticipated Problems to the FDA  
Not applicable
21.5
Reporting Adverse Reactions and Unanticipated Problems to the Responsible IRB
In accordance with applicable policies of The Pennsylvania State University 
Institutional Review Board (IRB), the investigator will report, to the IRB, any observed or 
reported harm (adverse event) experienced by a subject or other individual, which in the 
opinion of the investigator is determined to be (1) unexpected; and (2) probably related 
to the research procedures. Harms (adverse events) will be submitted to the IRB in 
accordance with the IRB policies and procedures.
21.6
Unblinding Procedures
The Investigational Pharmacist will provide pertinent information to attending physician 
should unblinding become necessary.
21.7
Stopping Rules
Patients can be withdrawn from the study if LFT’s, ALT, ALK phosphatase, or T. 
Bilirubin rise to a level of three times the upper limit of normalor at any point that the 
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treating physician believes that the study protocol unnecessarily places the patient at 
risk for adverse outcomes.   
22.0 Study Monitoring, Auditing and Inspecting
22.1
Study Monitoring Plan
22.1.1Quality Assurance and Quality Control
This is a low risk therapeutic study with agents with a known safety profile.
The PI will ensure that this study is conducted, and that the data are generated, 
documented (recorded), and reported, in compliance with this protocol, with 
institutional and IRB policies, with Good Clinical Practice guidelines and any 
other applicable regulatory requirements. 
22.1.2Safety Monitoring
The Principal Investigator will confirm that all adverse events (AE) are 
correctly entered into the AE case report forms by the coordinator; be available to 
answer any questions that the coordinators may have concerning AEs; and will 
notify the IRB, FDA, sponsor and/or DSMB of all applicable AEs as appropriate. 
All assessments of AEs will be made by a licensed medical professional who is 
an investigator on the research. 
The research coordinator will complete the appropriate report form and 
logs; assist the PI to prepare reports and notify the IRB, FDA, and/or DSMB of all 
Unanticipated Problems/SAE’s.
23.0 References
1.
Hocker SE, Tian L, Li G, Steckelberg JM, Mandrekar JN, Rabinstein AA. Indicators of central 
fever in the neurologic intensive care unit. JAMA Neurol 2013;70:1499-504.
2.
Greer DM, Funk SE, Reaven NL, Ouzounelli M, Uman GC. Impact of fever on outcome in 
patients with stroke and neurologic injury: a comprehensive meta-analysis. Stroke 
2008;39:3029-35.
3.
Rossi S, Zanier ER, Mauri I, Columbo A, Stocchetti N. Brain temperature, body core 
temperature, and intracranial pressure in acute cerebral damage. J Neurol Neurosurg 
Psychiatry 2001;71:448-54.
4.
Dietrich WD, Bramlett HM. Hyperthermia and central nervous system injury. Prog Brain Res 
2007;162:201-17.
5.
Picetti E, De Angelis A, Villani F, Antonini MV, Rossi I, Servadei F, Caspani ML. Intravenous 
paracetamol for fever control in acute brain injury patients: cerebral and hemodynamic effects. 
Acta Neurochir (Wien) 2014;156:1953-9.
6.
van Gijn J, Kerr RS, Rinkel GJ. Subarachnoid haemorrhage. Lancet 2007;369:306-18.
7.
Dorsch NW, King MT. A review of cerebral vasospasm in aneurysmal subarachnoid 
haemorrhage Part I: Incidence and effects. J Clin Neurosci 1994;1:19-26.
8.
Crowley RW, Medel R, Kassell NF, Dumont AS. New insights into the causes and therapy of 
cerebral vasospasm following subarachnoid hemorrhage. Drug Discov Today 2008;13:254-60.
9.
Lehmann E, Sagher O. Novel treatments for cerebral vasospasm following aneurysmal 
subarachnoid hemorrhage. Acta Neurochir Suppl 2008;105:225-8.
10.
Pickard JD, Murray GD, Illingworth R, Shaw MD, Teasdale GM, Foy PM, Humphrey PR, Lang 
DA, Nelson R, Richards P, et al. Effect of oral nimodipine on cerebral infarction and outcome 
after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ 1989;298:636-42.
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11.
Fassbender K, Hodapp B, Rossol S, Bertsch T, Schmeck J, Schutt S, Fritzinger M, Horn P, 
Vajkoczy P, Kreisel S, Brunner J, Schmiedek P, Hennerici M. Inflammatory cytokines in 
subarachnoid haemorrhage: association with abnormal blood flow velocities in basal cerebral 
arteries. J Neurol Neurosurg Psychiatry 2001;70:534-7.
12.
Singh N, Hopkins SJ, Hulme S, Galea JP, Hoadley M, Vail A, Hutchinson PJ, Grainger S, 
Rothwell NJ, King AT, Tyrrell PJ. The effect of intravenous interleukin-1 receptor antagonist on 
inflammatory mediators in cerebrospinal fluid after subarachnoid haemorrhage: a phase II 
randomised controlled trial. J Neuroinflammation 2014;11:1.
13.
Oliveira-Filho J, Ezzeddine MA, Segal AZ, Buonanno FS, Chang Y, Ogilvy CS, Rordorf G, 
Schwamm LH, Koroshetz WJ, McDonald CT. Fever in subarachnoid hemorrhage: relationship 
to vasospasm and outcome. Neurology 2001;56:1299-304.
14.
Kumpulainen E, Kokki H, Halonen T, Heikkinen M, Savolainen J, Laisalmi M. Paracetamol 
(acetaminophen) penetrates readily into the cerebrospinal fluid of children after intravenous 
administration. Pediatrics 2007;119:766-71.
15.
Suffredini AF, Hochstein HD, McMahon FG. Dose-related inflammatory effects of intravenous 
endotoxin in humans: evaluation of a new clinical lot of Escherichia coli O:113 endotoxin. J 
Infect Dis 1999;179:1278-82.
16.
Kett DH, Breitmeyer JB, Ang R, Royal MA. A randomized study of the efficacy and safety of 
intravenous acetaminophen vs. intravenous placebo for the treatment of fever. Clin Pharmacol 
Ther 2011;90:32-9.
17.
Singla NK, Parulan C, Samson R, Hutchinson J, Bushnell R, Beja EG, Ang R, Royal MA. 
Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration of 
intravenous, oral, or rectal acetaminophen. Pain Pract 2012;12:523-32.
24.0 Appendix
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