Propofol in Obese Children
Phase: PHASE3
Conditions: Pharmacodynamics, Obesity
Sponsor: Baylor College of Medicine

Identifiers: NCT01242241
Unique Protocol ID: H-22091
Title: Propofol in Obese Children
Date: 12 June 2012

Baylor College of Medicine
Office of Research
One Baylor Plaza, 600D
Houston, Texas 77030
Phone: (713) 798-6970
Fax:
(713) 798-6990
Email: irb@bcm.edu
MEMORANDUM
TO:
OLUTOYIN OLUTOYE
TCH BASED PROGRAMS
FROM:
GABRIELHABIB,M.D.,M.S.
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
DATE:
June 20,2012
RE:
H-22091 -PROPOFOLIN OBESE CHILDREN
Your request that the above referenced protocol be closed,has been noted and filed with the protocol.
You can access any document related to this closed study via the BRAIN database at any time.
Synopsis:
This study has been completed and the findings have been written up in a
manuscript that has been accepted for publication in the journal: Anesthesia &
Analgesia
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Institutional Review Board for Baylor College of Medicine and
Affiliated Hospitals
Protocol Number:
H-22091
Status:
Closed
Initial Submit Date: 11/9/2007
Section Aa: Title & PI
A1. Main Title
PROPOFOL IN OBESE CHILDREN
A2. Principal Investigator
Name:
OLUTOYIN OLUTOYE
Phone:
832-824-5800
Id:
136354
Fax:
832-825-5801
Department:
TCH BASED PROGRAMS
Email:
oao@bcm.tmc.edu
Center:
Mail Stn:
BCM320
A3. Administrative Contact
Name:
DEBORA LYNN EAST
Phone:
832-824-5913
Id:
039330
Fax:
832-8250117
Email:
deast@bcm.tmc.edu
Mail Stn:
BCM320
A3b. Cooperative Agreement
Is this a cooperative agreement protocol?
No
Which institution is the IRB of record?
BCM: Baylor College of Medicine
Section Ab: General Information
A4. Co-Investigators
Name:
PRISCILLA GARCIA
Phone:
832-824-5809
Id:
038228
Fax:
832-824-5801
Department:
TCH BASED PROGRAMS
Email:
pg038228@bcm.tmc.edu
Center:
Mail Stn:
BCM320
Name:
IMELDA TJIA
Phone:
832-824-5802
Id:
127605
Fax:
832-825-5801
Department:
TCH BASED PROGRAMS
Email:
itjia@bcm.tmc.edu
Center:
Mail Stn:
BCM320
Name:
KATRIN CAMPBELL
Phone:
832-824-5800
Id:
139077
Fax:
Department:
TCH ANESTHESIOLOGY
Email:
katrinc@bcm.tmc.edu
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Center:
Mail Stn:
BCM320
Name:
KALYANI GOVINDAN
Phone:
832-824-5800
Id:
154505
Fax:
Department:
TCH BASED PROGRAMS
Email:
govindan@bcm.tmc.edu
Center:
Mail Stn:
BCM320
Name:
MEHERNOOR WATCHA
Phone:
832-824-5800
Id:
157663
Fax:
Department:
TCH ANESTHESIOLOGY
Email:
watcha@bcm.tmc.edu
Center:
Mail Stn:
BCM320
Name:
CHERYL GORE
Phone:
832-824-5802
Id:
672321
Fax:
832-825-5801
Department:
TCH BASED PROGRAMS
Email:
cgore@bcm.tmc.edu
Center:
Mail Stn:
SM1003
A5. Funding Source:
Baylor College of Medicine (Internal Funding Only)
A6a. Institution(s) where work will be performed:
TCH: Texas Children's Hospital
A6b. Research conducted outside of the United States:
Country:
Facility/Institution:
Contact/Investigator:
Phone Number:
If documentation of assurances has not been sent to the Office of Research, please explain:
A7. Research Category:
A8. Therapeutic Intent
Does this trial have therapeutic intent?
Not set yet
A9. ClinicalTrails.gov Registration
Section B: Exempt Request
B. Exempt From IRB Review
Not Applicable
Section C: Background Information
Obesity in children as in adults has rapidly become a public health concern. In the state of Texas, the
incidence of childhood obesity is higher than the national average at 20-23% in 4th to 8th graders, with a
more marked increase in the minority ethnic groups. The population of obese children presenting for surgery
at Texas Children's hospital reflects the state statistics with a recent study showing that 21% of children
presenting to the operating room meet the criteria for obesity. Obesity, as defined by the National Health and
Nutrition survey is a body mass index (BMI) of greater than 95th percentile. The anesthetic management of
obese children poses a variety of significant challenges. These include difficulty with placement of a breathing
tube for delivery of anesthesia gases, body positioning to avoid nerve injury and determination of the
appropriate dose of anesthetic intravenous agents. It is a common practice to administer anesthetic drugs
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based on the real body weight of children. However, obese patients have increased fat composition and
altered metabolic state that affects drug distribution and metabolism. The administration of intravenous
anesthetic drugs in doses based on the real body weight of these children could result in over dosage and
significant hemodynamic consequences particularly hypotension. Large doses of intravenous anesthetic
drugs may also result in delayed awakening from anesthesia, and an increase in the duration of hospital stay
resulting in a marked increase in health care costs. However, the administration of drugs based on the ideal
body weight may result in under-dosing of the anesthetic agents with the risk of inadequate anesthesia and
awareness. Such an event could be traumatic and result in psychological effects on the child. Studies in
adults have shown that obesity, which can be considered to be a disease state, is a modifier of
pharmacokinetics and pharmacodynamics of drugs. There is data to suggest children and adolescents do
differ from adults in the manner in which drugs and chemicals are handled but there is sparse data specifically
on the effect of obesity on the pharmacokinetics and pharmacodynamics of drugs in children. Therefore, it is
important to determine the pharmacokinetics and pharmacodynamics of anesthetic drugs in obese children
compared to normal children. Traditionally, the dose of most anesthetic agents is based on the ED 50 or
effective dose in 50% of patients, however, as anesthesiologists, ideal situations are those in which
unconsciousness is induced in majority or 95 % of patients. Anecdotally, it appears more intravenous
medicines are required in obese patients to induce unconsciousness. This study would determine what the
ED95 of propofol is in obese and non-obese children.
Section D: Purpose and Objectives
This is a study to test the hypothesis that the dose of propofol (a highly lipophilic sedative hypnotic drug )
required for induction of anesthesia will be different in obese children compared to non-obese children.
Section E: Protocol Risks/Subjects
E1. Risk Category
Category 2: Research involving greater than minimal risk, but presenting the prospect of direct benefit to the
individual subjects.
E2. Subjects
Gender:
Both
Age:
Adolescent (13-17 yrs), Child (3-12 yrs)
Ethnicity:
All Ethnicities
Primary Language:
English, Spanish
Groups to be recruited will include:
Patients
Which if any of the following vulnerable populations will be recruited as subjects?
Children
Vulnerable populations require special protections. How will you obtain informed consent, protect subject
confidentiality, and prevent undue coercion?
During the pre-operative evaluation, the study will be explained to the subject as well as parents/guardians
with emphasis on the voluntary nature of participation. Questions will be answered and consent obtained.
Assent will also be obtained in children aged 12 years and above. A Spanish translator will be available to
Spanish speakers. Subjects will be identified from the operating room schedule made available to the division
of pediatric general anesthesia for pre-operative evaluation. Subjects will be children less than 18 years of
age presenting for procedures requiring general anesthesia in which propofol use is a planned standard
management. Subjects and parents/guardians will be assured that confidentiality of records will be maintained
and that subject identifiers will be removed prior to publication of findings. Refusal to participate in the study
will not preclude subjects from receiving standard anesthetic care.
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E3. Pregnant woman/fetus
Will pregnant women and/or fetuses (as described in 45 CFR 46 Subpart B) be enrolled in the research?
No
E4. Neonates
Will neonates of uncertain viability or nonviable neonates (as described in 45 CFR 46 Subpart B) be enrolled in
the research?
No
E5. Children
Will children be enrolled in the research?
Yes
Section F: Design/Procedure
F1. Design
Select one category that most adequately describes your research:
z.z) ARCHIVED DO NOT USE - Other
Discuss the research design including but not limited to such issues as: probability of group assignment,
potential for subject to be randomized to placebo group, use of control subjects, etc.
This study will include patients who require general anesthesia with propofol for procedures at Texas
Children's Hospital. The patients will be assigned to groups based on their body mass index (BMI). All
patients meeting the inclusion criteria will be enrolled. Measurements of body weight and height, which are
part of admission vital signs, will be made at the time of patient pre-anesthetic assessment. Patients will be
assigned to groups based on their body mass index (BMI). Group A: BMI between 25th and 84th percentile
for age(non-obese or healthy weight) and Group B: BMI greater than 95th percentile for age (obese). This
study will involve two studies in one. The effective dose of propofol in 95% of non-obese children and 95% of
obese children will be determined. Pre determined sequential doses of propofol to be administered are: 1.0
mg/kg, 1.25 mg/kg, 1.5 mg/kg, 1.75 mg/kg, 2.0 mg/kg; 2.25 mg/kg; 2.5 mg/kg; 2.75 mg/kg; 3.0 mg/kg; 3.25
mg/kg; 3.5 mg/kg; 4.0 mg/kg and 4.25mg/kg. The recommended dose range for propofol is 2.5-3.5 mg/kg.
The lower doses of 1 or 1.25 mg/kg may insufficiently induce unconsciousness within the specified time but if
this occurs, additional medication will be given till a satisfactory level of unconsciousness is attained.The
doses of 4.0 and 4.25 mg/kg are beyond the recommended dose range for propofol in children however the
purpose of administering propofol is to induce unconsciousness in order for procedures to proceed and the
patients will only receive these doses if a satisfactory level of unconsciousness is not achieved with the
preceding doses within the expected period. The first patient in each study group will receive the same
initial/lowest dose of propofol from the listed doses; the response to this dose of propofol would be deemed
positive if there is loss of lash reflex within 20 seconds of administering the dose and negative if there is no
response (no loss of lash reflex within 20 seconds). The subsequent patient would receive the next
appropriate dose of propofol based on the biased coin design method of sequential dosing ( Stylianou M,
Flournoy N: Dose finding using the biased coin up-and-down design and isotonic regression. Biometrics 2002;
58:171-7). If patient #1 falls asleep with a given dose of propofol, then patient #2 is randomized to receive
either a lower dose with a probability of 0.05 OR the same dose with a probability of 0.95. If patient #1 does
not fall asleep with a given dose of propofol, then patient #2 will automatically receive the next higher dose of
propofol. In situations where the patient does not lose the lash reflex after 20 seconds, the patient would be
documented as having a negative response to the assigned dose of propofol and will be given additional
propofol till an adequate level of unconsciousness that will allow the procedure to be performed is achieved.
Inclusion Criteria:
The subject population will include patients between ages 3 -18 years of age presenting for surgery at Texas
Children's Hospital
Exclusion Criteria:
The following patients will be excluded from the study: 1.Patients classified as ASA (American Society of
Anesthesiology) Class 3 or greater. 2.Patients with documented kidney or liver disease or those presenting
for open surgery on the liver or kidney. 3.Patients who will NOT be receiving propofol for induction as part of
their anesthetic regimen. 4.Patients who are currently on anti-convulsant medication or receiving drugs with
sedative effects. 5. Patients currently being treated for attention deficit disorder. 6. Patients who are
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diagnosed with failure to thrive or those with a BMI less than 25th percentile. 7. Patients who are
hemodynamically unstable. 8. Patients with egg allergy. 9. Pateints with low levels of albumin
F2. Procedure
Once patients arrive in the holding area a pre-operative assessment will be performed by the nurse
practitioners, this includes detailed history taking and a physical examination as well as documentation of all
medications the patients are on in addition to their known drug allergies. The vital signs will be obtained which
will include the height and weight amongst others. Once the patient meets study criteria, consent will be
obtained (and assent in children aged 12 years and above) and the body mass index (BMI) will be calculated
from the body weight and height. The patients will be classified at that time into Group A (BMI between 25th
and 84th percentile) OR Group B (BMI greater than 95th percentile). An intravenous catheter will
subsequently be placed in the hand and the patients will proceed to the procedure area. On arrival there,
routine ASA monitors including EKG, pulse oximeter and blood pressure monitors will be placed and lastly, a
Bispectral index monitor (BIS monitor) will be placed on the patients¿ forehead. The Bispectral index monitor
(BIS) monitor is a monitor that gives a dimensionless empiric number, the BIS value, which correlates with the
depth of anesthesia. The BIS value, which ranges from 0 to 100, has been shown to correlate well with the
level of hypnosis in adult patients during sedation and general anesthesia. The manufacturers of the BIS
monitor have suggested that titrating anesthetics to keep the BIS value between 40 and 60 will provide the
optimal depth of anesthesia. There is some preliminary data that suggests that routine monitoring of the BIS
level may decrease the incidence of intra-operative awareness in adults considered to be at high risk for this
complication e.g. adults on cardiopulmonary bypass. There is limited data on the usefulness of this monitor in
children however it is a harmless tool and the information gathered from it (BIS value at time of loss of lash
reflex) would be examined retrospectively to see if there is correlation between this value and loss of lash
reflex. In addition, your child will be given a syringe full of water to hold tightly in their hand as they fall asleep,
the time it takes for their hand grip to weaken, causing the syringe to drop from their hands after receiving
propofol will also be noted. These end points: loss of lash reflex and time to weakening of handgrip has been
used in previous propofol studies. Obese patients with a body mass index greater than 99% will receive three
big breaths of oxygen prior to the beginning of the study in order to compensate for the desaturation that may
occur if apnea results from their study dose of propofol. Once monitors have been placed on the patient,
intravenous lidocaine 1mg/kg ( to a maximum of 60 mg) will be administered prior to the assigned dose of
propofol. This is in order to decrease the mild to moderate burning sensation experienced on administration of
propofol. The lidocaine would be immediately followed by administration of propofol through a stopcock with
0.5 cc dead space. Propofol administration would be rapidly followed by a flush of 3cc normal saline to ensure
the drug enters the circulation. Once the propofol has been flushed in the patient will be checked for loss of
lash reflex by stroking the eyelash. If blinking is observed after stroking at 20 seconds, the patient would be
deemed to have a negative response to the dose of propofol, this information will be documented and the
patient would receive additional propofol titrated to effect, to ensure an adequate level of sedation. The next
subsequent patient in this group will then receive the next higher dose of propofol according to the previously
stated dosing interval regimen. If there is loss of lash reflex at 20 seconds, the next patient would be
randomized to receive either the next lower dose or the same dose administered to the previous patient.
Section G: Sample Size/Data Analysis
G1. Sample Size
How many subjects (or specimens, or charts) will be used in this study?
Local: 85
Worldwide: 85
Please indicate why you chose the sample size proposed:
The up and down study design is characterized by non-independence of data and an unknown distribution,
which preclude the development of rules to calculate a sample size for determination of the effective dose of a
drug in a certain percentage of patients. As a result, statistical simulations have suggested that approximately
20-40 patients would provide adequate estimates of the target dose in most cases. 40 patients will be
evaluated in Group A and 40 in Group B.
G2. Data Analysis
Provide a description of your plan for data analysis. State the types of comparisons you plan (e.g. comparison of
means, comparison of proportions, regressions, analysis of variance). Which is the PRIMARY
comparison/analysis? How will the analyses proposed relate to the primary purposes of your study?
Data will be analyzed with the use of the isotonic regression estimator with confidence intervals derived by
bootstrapping to determine the ED95 of propofol in obese patients. Isotonic regression is a general technique
for estimating quantities that are assumed to be non-increasing. This method produces estimates of the
probability of toxicity (or estimates of the probability of a positive response in this case) for each dose level,
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under the assumption that the dose response function is not decreasing i.e. the higher the dose level the
higher the probability of response.
Section H: Potential Risks/Discomforts
Describe and assess any potential risks/discomforts; (physical, psychological, social, legal, or other) and assess
the likelihood and seriousness of such risks:
Propofol is a widely used sedative hypnotic agent in both children and adults. Administration of propofol may
result in a 30% decrease in the blood pressure. This is usually resolved with administration of fluids being
infused during surgery routinely. There is minimal risk to taking part in this study, as patients enrolled will be
those that would receive propofol regardless of their participation in the study. A potential risk is that your
child does not fall asleep (does not stop blinking when the eyelashes are gently touched) with his/her
assigned dose of propofol. If this happens, your child would be noted to have a negative response to the
given dose of propofol and more propofol would be given to make sure that he/she is in an adequate state of
deep sleep (anesthesia) before proceeding with their procedure. Another risk maybe that your child receives a
dose of propofol that may cause a decrease in the blood pressure. This is commonly seen when children
receive medicine to fall asleep for procedures. The blood pressure usually returns to normal within a few
minutes. If not, fluids or additional medicines are given to bring the blood pressure back to normal levels. An
additional potential discomfort to receiving propofol involves a mild burning sensation, which sometimes
occurs on injection. Precautions will be taken to decrease this discomfort by injecting lidocaine through the
intravenous catheter prior to propofol administration.
Section I: Potential Benefits
Describe potential benefit(s) to be gained by the individual subject as a result of participating in the planned
work.
There is no direct benefit to the patient for participating in this study.
Describe potential benefit(s) to society of the planned work.
This study will allow a better understanding of the response of obese children to this lipophilic, sedative
-hypnotic agent and would allow for proper dose adjustment which will in return, lead to improved care for this
increasing segment of our population.
Do anticipated benefits outweigh potential risks? Discuss the risk-to-benefit ratio.
Anticipated benefits of this study long term do outweigh the potential risks. The only potential risk to patients
is loss of confidentiality. The possible benefits to society are greater than potential risks of this study.
Therefore the risk-to-benefit ratio is favorable for this study.
Section J: Consent Procedures
J1. Waiver of Consent
Will this research require a waiver of consent and authorization?
No
Will additional pertinent information be provided to subjects after participation?
No
Explain why providing subjects additional pertinent information after participation is not appropriate.
J1a. Waiver of requirement for written documentation of Consent
Is this research subject to FDA regulations?
No
Explain how the research involves no more than minimal risk to the participants, and the specifics demonstrating
that the research does not involve procedures for which written consent is normally required outside of the
research context.
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Explain how the only record linking the participant and the research would be the consent document, and how
the principal risk would be potential harm resulting from a breach of confidentiality, and how each participant will
be asked whether he or she wants documentation linking the participant with the research and their wishes will
govern.
J2. Consent Procedures
Who will recruit subjects for this study?
PI
PI's staff
Describe how research population will be identified, recruitment procedures, any waiting period between
informing the prospective participant and obtaining consent, steps taken to minimize the possibility of coercion or
undue influence and consent procedures in detail.
Patients who require general anesthesia for their procedures will be identified from the Texas Children's
hospital operating room schedule that is made available to the pediatric anesthesia division. Voluntary patient
participation will be emphasized during recruitment of patients. Anesthetic care will have no bearing on
whether or not the patient is involved in this study. The PI or PI¿s staff will obtain standard written consent
from the parent or guardian of each patient. For the purposes of this study, consent can be obtained from only
one parent. Assent will also be obtained in children aged 12 years and above. The assent form that will be
used is attached in section S of the protocol. A Spanish translator and a short Spanish version of the consent
form will be made available for Spanish speakers; this is also attached in section S.
Are foreign language consent forms required for this protocol?
Yes
Which of the following ways will you document informed consent in languages other than English?
Short-Form consent documents
J3. Privacy and Intrusiveness
Will the research involve observation or intrusion in situations where the subjects would normally have an
expectation of privacy?
No
J4. Children
Will children be enrolled in the research?
Yes
J5. Neonates
Will non-viable neonates or neonates of uncertain viability be involved in research?
No
J6. Consent Capacity - Adults who lack capacity
Will Adult subjects who lack the capacity to give informed consent be enrolled in the research?
No
J7. Prisoners
Will Prisoners be enrolled in the research?
No
Section K: Confidentiality
Will research data include health information by which subjects can be identified?
Yes
Where will research data be kept? How will such data be secured?
The data will be kept locked in a filing cabinet with no patient identifiers in the PI's office. A separate Excel
spreadsheet linking patient information with the unique patient identifier will be kept in a password protected
computer as will the database.
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Who, besides the PI, the study staff, the IRB and the sponsor, will have access to identifiable research data?
No one else.
Will you obtain a Certificate of Confidentiality for this study?
No
Please further discuss any potential confidentiality issues related to this study.
NA
Section L: Cost/Payment
Delineate clinical procedures from research procedures. Will subject's insurance (or subject) be responsible for
research related costs? If so state for which items subject's insurance (or subject) will be responsible (surgery,
device, drugs, etc). If appropriate, discuss the availability of financial counseling.
There will be no cost to the patient related to this study.
If subjects will be paid (money, gift certificates, coupons, etc.) to participate in this research project, please note
the total dollar amount (or dollar value amount) and distribution plan (one payment, pro-rated payment, paid
upon completion, etc) of the payment.
Dollar Amount:
0
Distribution Plan:
Section M: Genetics
How would you classify your genetic study?
Discuss the potential for psychological, social, and/or physical harm subsequent to participation in this research.
Please discuss, considering the following areas: risks to privacy, confidentiality, insurability, employability,
immigration status, paternity status, educational opportunities, or social stigma.
Will subjects be offered any type of genetic education or counseling, and if so, who will provide the education or
counseling and under what conditions will it be provided? If there is the possibility that a family's pedigree will be
presented or published, please describe how you will protect family member's confidentiality?
Section N: Sample Collection
None
Section O: Drug Studies
Is this study placebo-controlled?
No
Does the research involve a drug or biologic (including radioactive drugs) that is not approved by the FDA?
No
Will the research involve a radioactive drug?
No
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Section P: Device Studies
Does this study need an IDE?
No
Regarding your device study, could potential harm to subjects be life-threatening?
No
Regarding your device study, could potential harm to subjects result in permanent impairment of a body
function?
No
Regarding your device study, could potential harm to subjects result in permanent damage to a body structure?
No
Section Q. Consent Form(s)
None
Section R: Advertisements
None
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