Comments on “Sleep Mechanisms in Children: Role of Metabolism”
Panel Member: Robert M. Nelson, M.D., Ph.D.
Brief Summary of Rationale for Protocol
The investigators propose to use NMR
spectroscopy to measure certain aspects of cellular brain metabolism in four
groups of adolescent children (ages 13 – 17 years) during wakefulness, sleep
and after sleep deprivation.
Apparently, the pattern and processes of sleep differ between children,
adolescents and adults. One can then
speculate, in the absence of studies, that the underlying brain processes and
metabolic activity in children and adolescents are different from that of
adults. The study is likely to yield
generalizable knowledge about the normal physiologic processes associated with
sleep as a basis for studying abnormal sleep and sleep-related disorders. It should be pointed out that this grant
proposal was written in response to a Request for Applications from NIH that
stipulated the inclusion of adolescent subjects (SLEEP AND SLEEP DISORDERS IN
CHILDREN; Release Date: June 6, 2001;
The investigators state
(appropriately) that none of these studies have been performed before in either
children or adults. Throughout the proposal, an argument is consistently made
in favor of the research given that the metabolic measurements have not been performed previously in either
adolescents or during sleep. The
question as to whether adults should be studied before adolescents is discussed
Procedures included in the Protocol (along with a
discussion of feasibility and risks)
Resonance Imaging (4 tesla):
MRI involves three different fields:
static magnetic fields, radio-frequency (RF) fields, and gradient fields. The physical limits of human exposure during
MRI are related to the type of field, with switched gradient fields leading to
peripheral nerve stimulation, and RF fields leading to tissue heating. The limits of human exposure to static
magnetic fields are unknown. According
to the relevant chapters in Magnetic Resonance Procedures: Health Effects
and Safety (ed. F. G. Shellock, CRC Press: New York, N.Y., 2001), the use
of a 4 tesla machine has not been associated with any physical risks other than
the risks of bringing ferromagnetic materials (either internal or external to
the subject) into the MRI magnet. The
protocol discusses the screening procedures used to assure that this does not
FDA considers a 4 tesla MRI to be a non-significant risk device, assuming it
also meets several criteria. The FDA
criteria (updated October 3, 1997) for significant risk investigations
(requiring an IDE) involving MRI devices are: (1) main static magnetic field
greater than 4 tesla; (2) specific absorption rate (SAR) greater than 4 W/kg
averaged over the whole body for any period of 15 minutes; or 3.2 W/kg averaged
over the head for any period of 10 minutes; or 8 W/kg in any gram of tissue in
the head or torso, or 12 W/kg in any gram of tissue in the extremities, for any
period of 5 minutes; (3) time rate of change of gradient fields (dB/dt)
sufficient to produce severe discomfort or painful nerve stimulation; or (4)
peak unweighted sound pressure level greater than 140 dB or A-weighted r.m.s.
sound pressure level greater than 99 dBA with hearing protection in place (http://www.fda.gov/cdrh/ode/magdev.html). Recently, this reviewer was informed that
the FDA recently revised the significant risk levels of MRI scanners to be
above 8 tesla. As the FDA determined that this protocol did not require
an IDE, this reviewer assumes (in the absence of evidence to the contrary) that
the MRI scanner and techniques described in the protocol qualify as a non-significant
risk device. The investigators also state in the protocol that they will
operate the MRI scanner within these safety limits.
are other known risks that can be characterized as psychological distress,
including anxiety and claustrophobia.
There are few studies in pediatrics, and estimates range widely (from
less than 1% up to 20%) of the number of patients who experience some form of psychological
distress. The use of relaxation
techniques and MRI simulation prior to the actual MRI scan are demonstrated
effective in reducing anxiety. Those
adolescents who may suffer anxiety or claustrophobia are excluded, through a
screening process which includes a trial MRI scan. The investigators have included MRI simulation in the
protocol, however this process is not adequately described in the
protocol. For example, it is unclear is
this screening MRI scan involves acclimatization in a “mock” magnet, as needed,
or a real MRI scan. A nurse is
present at all times in the room, and the adolescent can request that the study
be stopped at any time. A physician is
present at all times in the immediate vicinity. The protocol also includes a description of screening for, and
safety procedures in response to the unlikely event of an injury from an
internal or external ferromagnetic object.
reviewer determines that the MRI scan presents no more than minimal risk,
defined as “…the probability and magnitude of harm or discomfort anticipated in
the research are not greater in and of themselves than those ordinarily
encountered in daily life or during the performance of routine physical or
psychological examinations or tests.” (45 CFR §46.102(i))
(including EEG and other Physiologic Recordings)
is performed as a screening test to exclude undiagnosed sleep disorders, and
also performed as part of the MRI scanning.
The risks of this procedure are minimal, assuming that the safety of the
procedure has been adequately tested in adults. For example, the use of wires (i.e., electrodes) for the
recording of physiologic measurements in the MRI scanner is difficult, and has
risks. The wires, if coiled, can serve
as a source of heat and possibly burn the skin. With appropriate precautions and use, these risks are minimal. In
addition, the ability to measure physiologic signals that result from
electrical (i.e., brain) activity while in the magnet needs to be
demonstrated. For this reason, the
investigators propose to study up to 5 adults to determine the feasibility and
scientific accuracy of the measurements before turning to the study of
A sample of 5 adults may be insufficient to
determine the safety and feasibility of the scientific methods. An independent data monitoring committee
(DMC) should be appointed to review the data from the adult pilot study, and
make a determination that the study is both safe and feasible before studying
adolescents. Given the financial
benefit of the grant to the institution,
this DMC should be composed of a majority of members from outside of the
With adequate safety testing in adults, as
determined by an independent DMC, this reviewer considers the risks of
polysomnography both inside and outside of the MRI scanner to be no more than
and 13C-acetate IV infusions.
is a naturally occurring, non-radioactive, stable isotope. As such, it poses no
risk above and beyond that associated with the infusion of either acetate or
glucose. The protocol involves a 90
minute 13C-acetate IV infusion, and either a 90 minute or 12 hour 13C-glucose
IV infusion. The protocol uses a
glucose clamp technique with a 20% glucose infusion, targeting serum glucose
levels at either the euglycemic (5 mM), or hyperglycemic (7 – 10 mM)
range. To minimize risks, glucose
samples are to be collected every 15 - 20 minutes, and acetate levels every 10
– 15 minutes. Although the authors
provide no data in support of the statement, they claim that the hyperglycemia
presents “no danger of hypoglycemia at the end” of the infusion. The protocol should state an appropriate
period of observation in the research facility after the glucose infusion has
ended. Also, the amount of sodium and acetate are less than that infused
during the administration of Lactated Ringers, a standard intravenous solution
for intravenous rehydration.
Nevertheless, the infusion of the solutions increases the risks of
extravasation, given the hyperosmolality of the 20% dextrose solution and the
acidity of the acetate solution.
catheters (2) will be in place anywhere from 90 minutes to 12 hours, and will
also be used for frequent blood sampling.
Local anesthesia will be used for
IV placement, although the documents reviewed are ambiguous as to whether EMLA
Cream or a lidocaine injection will be used.
The impression is that EMLA cream will be used exclusively.
Given the length of time that the catheters are in
place, and the solutions that will be infused through the catheters, this
reviewer considers these procedures to present more than minimal risk, although
the risk is no more than a minor increase over minimal risk.
History and Physical Examination, Blood Draws, and Urine
There is a discrepancy between the protocol and the
assent/permission form, with the protocol indicating that the volume of blood
will be limited to a maximum of 40 ml over 9 days, and the assent/permission
form mentioning 60 ml for each infusion study.
This discrepancy needs to be clarified. The volume of blood presents no more than
minimal risk. The blood will be used
for screening eligibility laboratory values to exclude pancreatic, hematologic,
liver or renal disease. Although HIV,
hepatitis and drug abuse are exclusions from the study, there is no mention in
the procedures about how these conditions will be ascertained. This needs to be clarified, for the
method used will impact significantly on the necessary measures to protect the
There is no mention in the protocol about what tests will
be performed on the urine. Since
pregnancy is an exclusion from having the MRI scan performed, one may presume
that a urine pregnancy test will be performed, although it is not mentioned in
either the protocol or the assent/permission form. One is left in doubt whether urine drug testing will be
performed, as drug abuse is mentioned as an exclusion but there is no mention
of any drug testing in the protocol.
Both these issues need to be clarified. With appropriate measures to protect the confidentiality of the
adolescent subjects, the history, physical examination and urine testing
present no more than minimal risk.
amount of sleep deprivation included in this study does not appear to present
more than a minimal risk. This
conclusion is supported by the lack of significant adverse events reported in
the study of 82 children and adolescents by Fallone and colleagues (Fallone G.,
Acebo C., Arnedt JT., Seifer R., Carskadon MA. Effects of acute sleep restriction
on behavior, sustained attention, and response inhibition in children. Perceptual
& Motor Skills. 93(1):213-29, 2001 Aug.). There is the remote possibility that previously undiagnosed
epilepsy may be uncovered by the sleep deprivation test. However, there is no discussion in the
assent and permission form of the risks of operating machinery and performing
other important tasks the day after the sleep deprivation procedure. For example, who is responsible for supervision
after sleep deprivation? How are the subjects getting home? This needs to be
added, and highlighted.
is also the real possibility that an adolescent will be unable to stay awake
during the MRI performed on the day after the sleep deprivation, in spite of
his or her best efforts. Procedures should be outlined that will
minimize any distress, such as an opportunity to participate again or providing
the stipend regardless of whether the adolescent did or did not stay awake.
Admission to the Clinical Research Center (CRC)
The amount of time spent in the CRC will ranging from one
day and night (24 hours), to two to three days and two night (perhaps up to 56
hours). With appropriate activities
available to the adolescent, and isolation from any patients and/or subjects
with illnesses, the length of time spent in the CRC presents no more than
Comments on Permission and Assent Process (Undue
Influence and Coercion)
of the screening process in the assent/permission form is unclear. This reviewer understands that the screening
process will include a history and physical examination, including blood and
urine testing, a screening MRI study (“mock” magnet), and polysomnography. The
order of the screening process should be as follows. Since the MRI scanning is the central aspect of the study,
the trial run though the “mock” MRI scanner to determine the adolescent’s level
of comfort should come first. There is
no reason to potentially compromise the adolescent’s confidentiality if he or
she cannot tolerate being in the MRI scanner.
The screening history, physical examination and laboratory testing
should then be performed, followed by screening polysomnography (at visit
screening process, as well as the tests that will be performed, and how the
adolescent’s confidentiality will be protected should be better described in
the assent form.
The proposed payment schedule is for the
adolescent to receive $100 and for the parent(s) to receive $350, which appears
to be the policy of the IRB at AECOM.
In this reviewer’s opinion, the distribution of financial compensation
for time and effort is backwards. The
adolescent is the one undergoing the procedures, and the presence of the parent
(who is likely sleeping as well) may actually hinder the ability of the adolescent
to withdraw from the study if the parent stands to gain financially. It is reasonable to compensate the
adolescent for the time spent in the study at the minimum wage of $5.15 an
hour. The parent should only receive reimbursement for expenses. The schedule for compensation as outlined in
the current protocol has the potential for creating undue parental pressure on
the adolescent to enroll in the study.
It should be mentioned that any advertisements and other recruitment
materials to be used were not included in the packet of materials reviewed.
The language in the assent form about
failing to “pass the screening test” should be altered. An adolescent may be sensitive to “passing
tests” and thus unduly distressed by failing to pass these initial tests.
consent form indicates that treatment for a physical injury resulting from this
research will be billed to the subject or the subject’s insurance company. This is not appropriate. Although the possibility of injury in this
study is remote, necessary treatment as a result of an injury related to this
research study should be provided by the institution free of charge. In this reviewer’s opinion, this should be
one of the “sound ethical principles” required for consideration under §46.407.
There is no discussion in the protocol of
how the confidentiality of the adolescent will be protected, especially when
the investigator may exclude an otherwise eligible adolescent for being
pregnant, HIV or hepatitis infected, or abusing drugs. For example, multiple tests should be
performed so that an exclusion cannot be traced to the results of one
test. The adolescent who is to be
excluded based on testing that should remain confidential should be “coached”
on possible reasons for not wanting to do the study.
There needs to
be a discussion of an appropriate
referral for the diagnosis of previously unrecognized sleep disorders,
along with any results obtained during the screening process (such as
pregnancy, HIV, hepatitis, and so forth).
The assent form
is inappropriately labeled a “young adult assent” rather than an “adolescent
assent.” Young adult usually refers to
the 18- 21 year old age group.
The assent form (and the protocol) has an
insufficient discussion of how the impact of the study on school performance
will be minimized.
Should these studies be performed in adults prior to
There are two general reasons why studies should
be performed in adults prior to being performed in children, whenever
possible. The first is to determine the
safety of the experimental procedures; the second is to answer the scientific
question if it is unnecessary to study children to obtain the answer. The research proposal argues (convincingly
in this reviewer’s opinion) that studying adults will not answer the scientific
questions about adolescent sleep architecture and metabolic activity. However, it remains necessary to determine
the safety and feasibility of the research procedures using adult subjects
prior to performing these procedures on adolescent subjects. This
reviewer considers the enrollment of adolescent subjects in this protocol
scientifically appropriate, provided that the safety and feasibility of the
technical procedures to be performed in this protocol are established first in
Application of the Criteria for IRB Approval
general criteria of 45 CFR 46.111.
changes in the protocol are made in accord with the italicized recommendations
(above), the risks to subjects are minimized by using procedures which are
consistent with sound research design and which do not unnecessarily expose
subjects to risk. Since the subjects
enrolled are healthy normal adolescents, it is not appropriate to use procedures
already being performed on the subjects for diagnostic or treatment purposes
(§46.111(a)(1)). If the safety and
feasibility of the procedures are established first in adult subjects, the
selection of subjects is equitable, taking into account the purposes of the
research and the setting in which the research will be conducted
(§46.111(a)(3)). The risks to subjects
are reasonable in relation to the importance of the knowledge that may
reasonably be expected to result, as there are no direct benefits to the
subjects. There may be the indirect
benefit of participating in the advancement of knowledge (§46.111(a)(2)). Nevertheless, when some or all of the
subjects are likely to be vulnerable to coercion or undue influence, such as
children, ... additional safeguards have been included in the study to protect
the rights and welfare of these subjects (§46.111(b)), requiring us to apply
the additional protections found in 45 CFR 46, Subpart D.
Assess the risk
presented by each intervention or procedure in the proposed research.
As discussed above, and after further steps are taken to
minimize risks, all of the procedures except for the 13C-glucose and
13C-acetate IV infusions present no more than minimal risk
(§46.404/50.51). The 13C-glucose
and 13C-acetate IV infusions present greater than minimal risk
(§46.405/50.52 or §46.406/50.53), and thus require us to evaluate the
possibility of direct benefit to the adolescent child. By all accounts, there is no prospect of
direct benefit (§46.406/50.53) for any of the procedures or interventions
included in the research. The 13C-glucose
and 13C-acetate IV infusions present no more than a minor increase
over minimal risk (§46.406(a)/50.53(a));
however, they do not result in any knowledge to ameliorate a disorder or
condition (§46.406(c)/50.53(c)), as the adolescents included in the research do
not have any disorder or condition.
Finally, based on the review and discussion of the protocol, this
reviewer believes that the research does present a “reasonable opportunity to
further the understanding, prevention, or alleviation of a serious problem
affecting the health or welfare of children.” (§46.407(a); 50.54(a)). This criteria does not require that the
adolescents included in the research have such a “serious problem,” only that
the knowledge that may reasonably result would further our understanding of
such a problem.
C. For all categories, consider the requirements
for parental permission and child assent (§46.408;50.55).
modification outlined above, this reviewer determines that informed consent (that
is, parental permission and adolescent assent) will be sought (and
appropriately documented) from each prospective subject and/or the subject's
legally authorized representative, in accordance with, and to the extent
required by §46.116 and §46.117. (§46.111(a)(4,5))
D. When appropriate, there are adequate
provisions for monitoring the data collected to ensure the safety of subjects.
E. When appropriate, there are adequate
provisions to protect subject privacy and to maintain data confidentiality.
With the changes outlined
above, this reviewer determines that these two criteria for IRB approval are
This reviewer finds that the research
under consideration does not satisfy the conditions of §46.404, §46.405,
or §46.406. However, after the
recommended modifications, the research “presents a reasonable opportunity to
further the understanding, prevention, or alleviation of a serious problem
affecting the health or welfare of children; (ii) …will be conducted in
accordance with sound ethical principles; and (iii) adequate provisions are
made for soliciting the assent of children and the permission of their parents
or guardians, as set forth in §46.408.”
with sound ethical principles guiding pediatric research, and assuming that the
modifications recommended above are in fact made, the use of normal adolescent
children in the proposed research is scientifically appropriate and
necessary. The adolescent subjects will
be chosen to minimize the likelihood of individual harm and maximize the
likelihood of gaining knowledge that furthers the understanding, prevention, or
alleviation of a serious problem specifically affecting the health or welfare
of other children. The risks of the
research to the adolescent subjects are balanced by the importance of the
knowledge gained. After some
modifications, the research optimizes an adolescent’s capacity to give assent,
and to understand the anticipated experience and risks of the research.