Sleep-Disordered Breathing and CPAP After Adenotonsillectomy in Children
Phase: NA
Conditions: Sleep Apnea, Obstructive, Sleep Apnea Syndromes, Child Behavior Disorders, Attention Deficit Disorder With Hyperactivity, Disorders of Excessive Somnolence
Sponsor: University of Michigan

 
 
 
 
 
 
 
TITLE:  Sleep-Disordered Breathing and CPAP after Adenotonsillectomy in Children 
 
 
 
 
 
 
PI:  Ronald D. Chervin, M.D., M.S. 
Professor, Department of Neurology 
University of Michigan Health System  
C728 Med Inn Building, SPC 5845 
Phone: 734-647-9064 
Fax:  734-647-9065 
Pager:  0770 
Email:  chervin@umich.edu 
 
 
 
 
IRBMED#: HUM00041319  
 
 
 
 
IRB approval:     10/16/2018 
 
 
 
Clinicaltrials.gov number: NCT01554527 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
2.2  SPECIFIC AIMS:  Sleep-Disordered Breathing and CPAP after Adenotonsillectomy in Children     
 
Obstructive sleep-disordered breathing (SDB) affects at least 2-3% of children and may have substantial 
adverse impact on behavior and cognition.  Adenotonsillectomy (AT), the second most common surgical 
procedure in children, is now performed more often for suspected SDB than for any other indication.  However, 
recent studies among an increasingly obese population now show something alarming: many if not most 
children still have SDB after AT, and many still suffer from residual neurobehavioral morbidity.  Furthermore, 
the investigators’ ongoing, 12-year, NIH-funded research has shown that standard preoperative 
polysomnographic measures of SDB do not consistently predict post-AT improvement in behavior and 
cognition.  This may arise in part because many children after AT still have SDB, and because linear 
relationships between standard SDB measures and neurobehavioral morbidity may not exist.  Even at subtle 
levels, SDB may promote significant neurobehavioral morbidity.  Some have suggested that polysomnography 
may be more important after AT than before AT.  However, in practice few children receive polysomnography 
before AT, and even fewer after AT, when continuous positive airway pressure (CPAP) could still provide 
definitive relief from SDB.  Preliminary data from our group suggest that CPAP after AT is well-tolerated by 
most children and may provide significant benefit.  However, virtually no published evidence exists to address 
critical clinical questions:  which children benefit most from CPAP after AT; what role can clinical symptoms or 
polysomnography play in that determination; and what neurobehavioral gains are achieved by CPAP after AT? 
 
 
The investigators therefore propose a highly practical, clinical study with two main goals: (1) to assess the 
extent that behavior, cognition, and sleepiness in children can improve with CPAP after AT, and (2) to 
identify which patients stand to gain most from post-operative assessment and treatment.  This 
research will use reversible SDB-related neurobehavioral morbidity as the criteria by which to judge the utility 
of clinical symptoms and polysomnography in identification of candidates for CPAP after AT.  Neurobehavioral 
outcomes will be assessed with instruments shown to be sensitive to SDB in the past.  Clinical sleep 
symptoms will be assessed by use of a pediatric SDB questionnaire developed and validated by the 
investigators and now used around the world.  Standard polysomnography will be supplemented by innovative 
approaches shown by the investigators to help identify subtle pediatric SDB.  Subjects will be 5-12 years old 
and have had AT in recent months for suspected SDB.  To enroll a reasonable distribution of children with and 
without obvious SDB symptoms after AT, the sample will be enriched selectively if necessary.  All analyses will 
be adjusted for body mass index z-scores.  These novel investigations will come at a critical juncture and could 
well transform clinical care for an exceedingly common and consequential childhood condition. 
 
Aim 1:  Complete parental sleep questionnaires, sleep laboratory-based nocturnal polysomnograms, Multiple 
Sleep Latency Tests of daytime sleepiness, parental behavioral ratings, and neuropsychological tests for 
n=120 children 4 months after AT for clinically suspected or laboratory-confirmed SDB. 
H1a:  After AT, an SDB symptom scale will help identify children who have residual SDB on polysomnography. 
H1b:  After AT, residual problems with behavior, cognition, and sleepiness will show associations with 
persistent SDB as identified by the SDB scale or polysomnography. 
Impact:   Results will show that after AT, a symptom-based questionnaire can help identify children likely to 
have residual SDB, which in turn is a risk factor for persistent neurobehavioral morbidity.  Clinicians and 
families will have, for the first time, data that can guide evaluation after an exceedingly common surgery. 
  
Aim 2:  Randomize Aim 1 subjects to receive 6 months of standard clinical care (control group, n=40) vs. 
CPAP titration (CPAP group, n=80), home use of CPAP, and monitored adherence; and then re-assess all 
subjects with all baseline sleep and neurobehavioral tests. 
H2a:  Among CPAP subjects who have adhered to the therapy, residual questionnaire or polysomnographic 
evidence of SDB from 4 months post-AT, as compared to no residual SDB, will predict greater improvement 10 
months post-AT in hyperactive behavior, attention deficit, and sleepiness. 
H2b:  Among all CPAP subjects (n=80), neurobehavioral outcomes will improve more, from baseline to follow-
up, among subjects who adhere successfully to CPAP than among those who do not. 
H2c:  Among all subjects (n=120), neurobehavioral outcomes will improve more among CPAP subjects than 
control subjects in an intent-to-treat analysis. 

 
Impact:  Results will demonstrate the clinical utility of an SDB questionnaire and polysomnography after AT; 
implicate post-AT residual SDB as a potential cause of persistent neurobehavioral problems; and suggest that 
successful treatment of post-AT SDB provides tangible clinical benefits. 
 
 
2.3  RESEARCH STRATEGY 
 
A.  SIGNIFICANCE 
 
A1.  Pediatric sleep-disordered breathing (SDB) is common and consequential, especially for behavior and 
cognition.  A growing volume of literature suggests that obstructive sleep apnea affects 2-3% of children.1  The 
condition involves repeated upper airway narrowing or closure, which stops breathing, interrupts sleep, causes 
gas exchange abnormalities, and has profound effects on many different organs and systems.  A milder form 
of SDB, in which a narrowed upper airway causes increased effort to breathe rather than discrete apneas or 
hypopneas,2,3 was recently added to the definition of sleep apnea by the American Academy of Sleep 
Medicine,4 and may affect many more of the estimated 10% of children who have habitual snoring.  Sleep-
disordered breathing represents a serious public health challenge as most affected children probably remain 
undiagnosed.5  Consequences can have substantial impact on many aspects of health, among which 
neurobehavioral development may be the most sensitive.6  Some of the earliest reports on children with SDB 
noted that many presented with inattention, hyperactivity, aggressive behavior, or a history of diagnosed and 
treated Attention Deficit / Hyperactivity Disorder (ADHD).7,8  Subsequent sizable surveys, by the investigators 
as well as several other groups, generally showed consistent associations between symptoms of childhood 
SDB and the same constellation of neurobehavioral problems.9-13  Brain, prefrontal cortex, and hippocampal 
mechanisms implicated as possible causes of neurobehavioral morbidity in SDB involve vulnerability to sleep 
fragmentation,14,15 intermittent hypoxia,16 oxidative stress,17 inflammation,18 neuronal injury,19 and apoptosis.20 
 
A2.  Adenotonsillectomy (AT) improves, but may not eliminate SDB and its neurobehavioral morbidity.  Once 
identified, pediatric SDB is most often treated by AT.  This is one of the two most common surgeries performed 
in children.21  A survey of North American otolaryngologists, performed by the investigators, showed that 
suspected SDB rivaled recurrent pharyngitis as the most common indication for ATs performed during a one-
year period in approximately 24,000 children.22  Moreover, early data suggested that AT was curative in 
approximately 80% of cases.23  Other studies also suggested that substantial neurobehavioral improvements 
could be achieved in operated children.2,7,24,25  However, recent data are more concerning.  Sizeable series 
now show that 50% or more of children who undergo AT have some degree of residual SDB after the 
procedure.26-28  The same studies strongly suggest that the reason may well be the obesity epidemic.  Among 
69 children, the odds ratio for persistent SDB in obese vs. non-obese subjects was about 4, even after 
adjustment for initial apnea severity.29  Moreover, data from the investigators now confirm that not all 
neurobehavioral morbidity resolves after surgery.  In a study of 78 children aged 5 – 12 years, 22 children had 
ADHD by DSM-IV criteria prior to surgery, and 11 qualified for this diagnosis one year after surgery.30  Children 
whose ADHD did not resolve were those who still had evidence -- subtle but statistically significant and 
consequential -- of residual SDB after surgery.31  Among all operated children, parent behavioral rating scales, 
cognitive performance, and psychiatric interviews no longer revealed statistically significant differences with 
controls, but might have done so in a larger sample as postoperative scores recovered less than half the pre-
operative discrepancy between operated children and controls.24,30  The fact that many children still have some 
morbidity after AT for SDB highlights the potential importance of identifying and treating any residual SDB. 
 
A3.  Debate exists on how to identify clinically significant SDB in children.  Residual SDB detected after AT is 
usually not severe, as measured by polysomnography.24,26  However, residual SDB even at low levels could 
have profound consequences for cognition and behavior, at least as suggested by studies of SDB severity and 
neurobehavioral problems prior to SDB treatment.32  Several studies have now confirmed that neurobehavioral 
problems arise even at the lowest polysomnographic levels of SDB severity.13,15,33  Comparisons of healthy 
controls to ADHD-diagnosed children not selected for any sleep problems show that the latter are more likely 
to have SDB, when definitions include the most subtle levels,34,35 but not so consistently when children with the 
most mild SDB are excluded.36,37  Several large studies have failed to confirm linear dose-response 
relationships between SDB, as measured on polysomnography, and neurobehavioral outcomes as rated by 
parents.13,38-41  The investigators recently reported that children with SDB symptoms, but no sleep apnea on 

 
polysomnography, in comparison to symptomatic children with positive sleep studies, have if anything more 
rather than less cognitive deficit and hyperactive behavior on objective testing and parental rating scales.42 
 
These observations raise critical questions for clinical practice.  Much debate in past years has centered on 
sleep specialists’ contention that polysomnography should be routine prior to AT, vs. the opinion and practice 
of otolaryngologists, who rarely obtain a polysomnogram prior to AT for suspected SDB.22  Instead, common 
practice among otolaryngologists, as supported by otolaryngology textbooks, is to base a decision to operate 
on information that can be gleaned from a history and physical.  Some support for this approach was provided 
when a commonly used pediatric symptom-based SDB scale (developed and validated by the investigators,43 
see appendix) was tested against polysomnography as a predictor for neurobehavioral outcomes among 
children undergoing AT.44  Questionnaire results, in comparison to several polysomnographic measures, 
predicted hyperactivity and daytime sleepiness, and their improvement after surgery, at least as well.   
 
The 2002 recommendations from the American Academy of Pediatrics note that advice to obtain objective 
confirmation of SDB prior to surgery is predicated on the assumption that primary snoring, without clear sleep 
disruption or gas exchange abnormalities, is unlikely to cause symptoms.6  Data since that time raise serious 
questions about this assumption.  Children with SDB symptoms, with or without frank sleep apnea on standard 
polysomnographic measures, appear to benefit from AT.24,45  However, AT (like uvulopalatopharyngoplasty in 
adults) may in some cases reduce or hide symptoms without eliminating SDB, and pediatric sleep specialists 
have now begun to wonder whether polysomnography may be even more important after AT than before the 
procedure.  Testing in a sleep laboratory is routinely recommended after surgery for SDB in adults.46  In 
contrast, polysomnography is rarely performed for children after AT, unless prominent symptoms persist, other 
risk factors remain, or the preoperative SDB was particularly severe.47  The near total absence of data to 
indicate what levels of postoperative polysomnographic SDB findings merit further treatment has complicated 
not only clinical decisions, but research as well.  For example, in a recent study of children after AT, residual 
SDB was defined – in the absence of data linking postoperative polysomnographic results to clinical outcomes 
– as an apnea / hypopnea index (AHI) > 3, even though the same study used the more generally 
recommended4 AHI > 1 to help define treatable SDB before surgery.27 
 
A4.  Pediatric SDB can be treated effectively and safely by CPAP.  For adults with SDB, continuous positive 
airway pressure (CPAP) is the mainstay of treatment and in the investigators’ experience works well for 
approximately 80% of patients.  Although some studies of adherence report success rates at this level, others 
that have used electronic monitoring have shown that as few as half of adult patients treated with CPAP use 
the machine for at least 4 hours on at least 5 nights per week.48  Although far from ideal, a 50% adherence rate 
is no worse than that observed among adults with chronic conditions such as hypertension, and no worse than 
the average medication adherence found among children.49 
 
Two 1995 reports of sizeable samples found that CPAP is highly effective in controlling childhood SDB, and is 
well tolerated in more than 80% of patients.50,51  A smaller, randomized trial to compare CPAP with bilevel 
positive airway pressure (BPAP) found that one third of 29 participants aged 2 – 16 years dropped out by 6 
months; CPAP and BPAP showed no difference in adherence or effectiveness; and mean nightly use recorded 
electronically was adequate on average (5.3 ± 2.5 hours per night) in subjects who finished the protocol.52  
Parental reports of adherence exceeded electronically recorded adherence, just as subjective CPAP use 
among adults exceeds electronically monitored use.48  In a retrospective study of 46 children aged 7 – 19 
years, all treated with PAP after AT, the intervention again controlled SDB well (in all subjects); 70% of 
subjects used PAP for more than 4 hours on 5 or more nights per week; parents overall estimated adherence 
well, though they overestimated machine use for those children documented to use it 4 hours or less per night; 
and adherence did not vary significantly by age, gender, BMI, or race.53  In another retrospective study, 65 of 
79 children aged 6 months to 18 years successfully used PAP, with a mean daily use of 4.7 hours.54  The 
commitment and investment of the parents is particularly important.  Initial trials of low pressure settings or 
behavioral intervention may be necessary in some cases.55,56  Behavioral therapy can include positive 
reinforcement, differential positive reinforcement, counterconditioning, and graduated exposure.55  These 
improved adherence in 75% of 20 non-compliant children in one study; parents usually considered the 
treatment successful and most reported improvements in children’s mood, alertness, and learning.55 
 
These trials of PAP in children also show that the therapy is safe.  Mid-face hypoplasia, a reported but 

 
probably uncommon complication of long-term PAP in young children,57 did not occur in a trial of PAP for 6 
months in 2 – 16 year-old children.52  Other side effects are minor, and can include initial difficulty with masks, 
nasal congestion or drying, or skin irritation, one or more of which were reported in 11 of 46 subjects in one 
study.53  In another study, side effects were minor, affected “a small percentage of children,” were “easily 
addressed,” and did not diminish adherence.54 
 
Existing studies of PAP in children also have several limitations.  All but one of the above were retrospective, 
and each included age ranges spanning a total of 12 to 19 years, during which SDB, its effects, and its 
treatment could vary significantly.  Most studies either did not specify whether participants had had AT, or did 
specify that the majority of subjects were those with complicating medical disorders, such as Down syndrome 
or other clear reasons for developmental delay.  Most of the studies discussed above included children with an 
AHI of 5 or more apneic events per hour of sleep, or did not specify the criteria used, which means that mild 
cases with an AHI between 1 and 5, in addition to those without clear SDB on standard polysomnographic 
measures, were most likely excluded.  This is important because recent data now show that children with the 
mildest SDB findings on polysomnography, like adults, may still have prominent neurobehavioral morbidity.24,58  
None of the above studies included any objective measures of sleepiness or cognition, and none used 
validated parental rating scales to assess behavior.  Finally, none explored post-AT residual symptoms, 
validated pediatric SDB questionnaires, or polysomnography as predictors of benefit from PAP. 
 
Alternatives to CPAP, such as anti-inflammatory agents or orthodontic treatments, also show promise for post-
AT residual SDB.59  However, these approaches are not extensively studied and are likely to be effective for 
only the mildest cases of residual SDB.  Compliance cannot be monitored as effectively as can adherence to 
CPAP with electronic usage meters.  Perhaps most importantly for the research now proposed, in fully 
adherent subjects, essentially complete resolution of underlying residual SDB cannot be assumed for any 
treatment other than PAP.  Therefore, PAP provides the best opportunity to study what clinical benefit children 
stand to gain through elimination of residual SDB, by any means, after AT. 
 
A5.  Whether CPAP for residual SDB after AT improves neurobehavioral outcomes remains virtually 
unexplored.  Despite the availability of reports that document success with CPAP in children, with regard to 
adherence and amelioration of SDB, few have reported whether the CPAP improves SDB-related morbidity.  In 
particular, virtually no data are available to examine whether CPAP further improves neurobehavioral 
outcomes after AT.  Among 29 subjects aged 2 - 16 years in one prospective PAP trial, intervention was not 
associated with improved daytime behavior (according to parents), school performance, growth, or blood 
pressure, but was associated with improved parental assessments of sleepiness.52  In a retrospective study of 
46 children aged 7 – 19 years, parent-reported sleepiness and school problems did improve with PAP, and 
hyperactive behavior nearly showed significant improvement (p=0.053).53  A recent abstract did document 
improvement in several different cognitive and behavioral spheres when CPAP was administered to 21 
children aged 6 – 16 years with SDB, but did not specify how many of these children had already undergone 
AT.60  Adherence to PAP correlated with improvements in parent-rated hyperactive behavior and subjective 
sleepiness.  Neither of the above studies explored what pre-CPAP measures may predict neurobehavioral 
response to CPAP.  In an era when obesity rates continue to rise unchecked; AT is increasingly performed for 
suspected SDB rather than pharyngitis; residual SDB may affect more than half of operated children; and 
unexplained hyperactivity is a hugely common and vexing problem for many families, data on the potential for 
neurobehavioral improvement when any SDB persists after AT would seem particularly critical. 
 
A6.  How candidates for CPAP after AT should be identified remains unexplored.  While optimal strategies to 
identify childhood SDB that requires AT are still studied and debated, indications for additional treatment after 
AT have received virtually no attention.  Among unoperated children, SDB is often defined in the setting of 
appropriate symptoms by an AHI that is at least somewhere between 1 and 5 events per hour of sleep.  A 
population-based study of children in Arizona compared polysomnographic results to outcomes and suggested 
a cutoff of 2-3.61  The current American Academy of Sleep Medicine definition,4 at one event per hour of sleep, 
is likely to be a sensitive criterion for use in clinical practice.  However, a threshold that is effective prior to AT 
may not provide an optimal cutoff after surgery.  This is especially true given the inability of most studies to 
show a linear relationship between the AHI and the neurobehavioral morbidity likely to be most sensitive, 
compared to other forms of morbidity, to mild SDB.  Although well conducted studies have now suggested that 
large numbers of children, after AT, have residual SDB, the use of preoperative SDB criteria postoperatively 

 
may not have identified most effectively those individuals who stand to gain from further treatment. 
 
A7.  Summary of Significance.  Findings from the proposed research will have critical impact on basic clinical 
practice questions that arise so frequently after an exceedingly common childhood procedure.  Clinicians and 
families will have unique data from which they can begin to make judgments about the meaning of residual 
clinical symptoms after AT; the potential role for a validated SDB symptom questionnaire; the indications for 
post-operative polysomnography; how to select good candidates for CPAP after AT; and what neurobehavioral 
benefits to expect from CPAP.  The most widely used pediatric SDB questionnaire and standard pediatric 
polysomnographic measures will provide the main explanatory variables for the study, but new and highly 
sensitive laboratory methods developed by the investigators also will be applied in a paradigm that could 
motivate refinement in current approaches to evaluation of children in sleep laboratories.  Beyond clinical 
practice questions, results will also advance our understanding that post-AT, residual SDB may still be 
responsible for persistent neurobehavioral problems, and that definitive treatment of residual SDB could 
ameliorate behavior, cognitive impairment, and sleepiness that families and patients find highly undesirable.  
These data could identify key variables, determine effect sizes, and provide invaluable ground work to justify a 
multicenter randomized clinical trial to prove that neurobehavioral morbidity results from post-AT residual SDB, 
and to establish clear evidence-based recommendations for evaluation and treatment of SDB in this setting. 
 
B.  INNOVATION 
 
The morbidity of postoperative, residual SDB, and outcomes of its treatment in children have scarcely been 
studied.  The post-AT predictive value of clinical, questionnaire, and objective polysomnographic measures 
have not been assessed.  The proposed research will therefore address several critical clinical questions for 
the first time.  It will be performed by highly experienced investigators, in a setting proven to be most 
productive, using state-of-the-art polysomnography and widely accepted, standard measures that the PI 
helped to investigate and develop.62,63  However, the proposed research also will capitalize on the 
investigators’ leading efforts, during the past decade, to improve the clinical utility of pediatric 
polysomnography through innovative electronic analyses of polysomnographic data normally scored only by 
human eye.  As described below, the investigators will apply 1) computer algorithms that link increased 
respiratory effort, outside apneas and hypopneas, to subtle EEG changes that may represent inspiratory 
microarousals; 2) automated quantification of esophageal pressure monitoring results; and 3) analysis of sleep 
dynamics that focus on durations of specific sleep stage bouts rather than more crude but traditional totals of 
minutes spent in each sleep stage.  Each of these approaches holds promise, as explained below, for 
increasing the sensitivity and value of polysomnography in discrimination of clinically meaningful childhood 
SDB from normal and less consequential results.  In short, therefore, the innovation of the proposed research 
rests on two sources:  the protocol will begin to ask common, clinically relevant questions that have not been 
addressed before, and will complement standard assessment approaches with highly sensitive, new 
techniques that the investigators have invented, developed, validated, or investigated for several years. 
 
C.  APPROACH 
 
C1.  Overview.  We propose a single-center, randomized and controlled but not blinded clinical trial to assess 
what variables predict further response to CPAP after AT (Figure 1).  Potential inclusion of any child, 
regardless of post-operative polysomnographic results at 4 months, will allow the full spectrum of 
polysomnographic results to be tested as predictors of neurobehavioral response to CPAP.  Standard cut-offs 
used to define clinically significant SDB remain untested in the post-AT setting, but will be applied first to test 
hypotheses 1a, 1b, and 2a.  Other cut-offs and continuous measures that have been proposed by our group 
and others also will be tested in key exploratory analyses that could prove highly informative.  The protocol will 
allow for example assessment of the possibility that clinical symptoms as detected on a questionnaire, but too 
insensitive to register on polysomnography, still deserve treatment.44,45  Every child who participates in this 
protocol will stand a chance to benefit.  Two-thirds will receive CPAP; no standard care will be denied; and at 
the end of the study, summaries of sleep and neurobehavioral findings will be made available to all families, 
along with guidance on how to obtain follow-up clinical care for any remaining concerns. 
 
C2.  Subjects.  Recruitment will be directed by co-investigator Susan Garetz, MD, a University of Michigan 
pediatric otolaryngologist, with the assistance of 4 additional otolaryngologists in the Division of Pediatric 

 
Otolaryngology, and 4 at St. Joseph Mercy Hospital in Ann Arbor.  Both groups of surgeons have energetically 
supported recruitment for the PI’s sleep research on children undergoing AT for the past 10 years.  Surgeons 
or clinic office personnel will ask each parent or guardian of a child scheduled to undergo full AT for suspected  
SDB whether he or she would be willing to hear about the research.  If so, a brief signed consent will be faxed 
to the investigators, who will initiate discussion by phone and then invite the family to the sleep laboratory to  
 
 
discuss the study in more detail. Occasionally parents may request referral to the study during phone contacts 
with the surgeon’s office which will then fax the referral form to the study team.  Children may also be referred 
into the program by sleep physicians, other providers, or their staff at UMHS and SJMHS sleep disorders 
centers and surgeons or their staff at Allegiance Health System.   In some cases, interested parents may 
contact the study team directly for information about participation.  To increase awareness of the study 
opportunity and encourage study participation, a copy of the IRB-approved study brochure and a reference to 
the study will be included with the UM Pediatric Otolaryngology follow-up letter which is sent to patients after 
adenotonsillectomy. Brochures are also available in all of the pediatric otolaryngology and sleep disorders 
clinics.  Brochures may be mailed to families interested in research whose children are being referred into 
pediatric otolaryngology for possible adenotonsillectomy.  At UMHS identification and recruitment of potentially 
eligible children will be assisted by MiChart Recruitment Alerts. 
 
If the parent and eligible child are still interested, the parent will sign a full, written informed consent, the child 
will assent verbally, and any child over the age of 8 or able to comprehend the basic nature of the study will 
sign written assent.  Families will also provide basic medical history and background information through a 
systematic interview and by granting access to medical records. Eligibility will be determined as soon as 
possible during the above process.  Inclusion criteria, to be specified more completely in an operations manual, 
will include: 
 
1) Age !5.00 and "12.99 years at study visit 2, consistent with the investigators’ past work.  Children younger 
than 5 years cannot be assessed with the same cognitive tests useful at older ages.  Children older than 12, 
past puberty, may in their teenage years develop symptoms, signs, and neurobehavioral outcomes of SDB that 
resemble those of adults more than younger children.64  Existing comparisons of age vs. more complicated 
Tanner staging, as peri-pubertal covariates of sleep outcomes, generally do not justify use of Tanner stages.65 
2) Parental ability to speak and read English, for example on behavioral rating scales. 
3) Absence of known or anticipated neurological, psychiatric, medical, or social factors likely to invalidate 
assessments, make adherence with CPAP highly unlikely, confound ability to demonstrate improvement with 
CPAP, or make local follow-up after AT or CPAP use unfeasible.  Psychiatric conditions may be provoked or 
exacerbated by SDB, and those most commonly implicated – Attention Deficit/Hyperactivity Disorder, Conduct 
Disorder, and Oppositional Defiant Disorder – will not be exclusions.  However, more pervasive conditions 
such as severe autism will be excluded. 
4) Absence of chronic stimulant, hypnotic, or strongly sedating medication, unless families and their 
pediatricians are comfortable with 2-week drug holidays before the evaluations at 4 and 10 months after AT.  
Other chronic medications, in children without anticipated dose changes, will not be exclusions.  
 
After careful consideration, neither specific SDB symptoms, laboratory evidence, nor neurobehavioral 
Subject enrolls prior to 
adenotonsillectomy for sleep-
disordered breathing.  Family 
provides baseline medical history, 
demographic information, 
Pediatric Sleep Questionnaire, 
and main behavior rating scales.  
Child undergoes short introduction 
to individualized cognitive testing. 
Randomization to: 
 
CPAP Group (n=80) 
Titration study; initiate home 
CPAP use; monitor adherence 
 
OR 
 
Control Group (n=40) 
Standard care, with no CPAP or 
other intervention unless 
specifically sought by family 
Assessment 10 months after 
adenotonsillectomy: 
Questionnaires 
Polysomnogram 
Multiple Sleep Latency Test 
Behavior Rating Scales Cognitive 
Testing 
Transition to clinical care 
resources for initiation or 
continuation of CPAP at home if 
clinically indicated and desired 
Assessment 4 months after 
adenotonsillectomy: 
Questionnaires 
Polysomnogram 
Multiple Sleep Latency Test 
Behavior Rating Scales Cognitive 
Testing 
Figure 1 

 
comorbidity will be required initially to participate in this research.  This will (1) allow participation by subjects 
with a wide range of SDB symptoms and neurobehavioral comorbidities; (2) facilitate detection of associations 
between these measures; and (3) avoid dependence on unsubstantiated assumptions as to what particular 
symptom, laboratory finding, or neurobehavioral deficit is necessary for improvement to occur on CPAP.  The 
investigators realize that in practice, self-selection may enrich the sample with children whose families do have 
post-AT concerns about SDB symptoms.  To avoid the possibility that such participants may be too infrequent, 
the investigators will assess the proportion of children with positive SDB questionnaire scores (> 0.33 43) after 
each group of 10 subjects has had AT.  If this proportion falls below 50%, the investigators will enrich the 
sample, for example by requiring every other (i.e., every 2nd) participant to have a high SDB score, at both the 
initial pre-AT screen and re-assessment 4 months later, before randomization.  For this purpose, the SDB 
score will be as useful, if not more useful, than polysomnography would be.15,44  The proposed research is not 
epidemiologic, and validity will not suffer from selection bias or artificial enrichment of the sample. 
 
Note that Addendum #1 provides for enrollment of subjects after adenotonsillectomy at or prior to study visit 2. 
This allows increased opportunity for interested families who are not able to schedule the pre-operative visit or 
who are referred to the study after their surgery to participate in this research.  More information on this 
additional study arm Is provided in the addendum and the MOP.   
 
C3.  Procedures.  Each participant will undergo a baseline, pre-randomization evaluation of sleep and 
neurobehavioral variables at 4 months after AT, as several months are required to ensure complete healing.  
Most of the neurobehavioral benefit achieved after AT for SDB accrues in the first 3 months (unpublished data 
from the investigators).  After baseline assessments, all subjects will be randomized to CPAP or non-CPAP 
(standard care) groups.  Group assignments will be made using a randomization algorithm, possibly with 
automatic adjustment that prospectively ensures balance between groups for SDB status, residual post-
operative SDB symptoms, gender, age and/or BMI.  Non-CPAP families will be contacted by the program 
manager for 6 months at intervals designed to replicate the frequency and nature of investigator contacts in the 
CPAP group.  Discussion will focus on recuperation after AT, general health, and any suggestion of serious 
adverse effects that would warrant discontinuation of study participation and referral for clinical evaluation.  
These end-points would include recommendations by a child’s pediatrician or otolaryngologist to pursue this 
option; development of a new, serious cardiopulmonary condition that makes prompt assessment and 
treatment for any residual SDB imperative; or emergence of serious academic or developmental concerns in 
the setting of obvious, persistent symptoms of SDB.  Each questionable case will be brought by the program 
manager to the PI (section 6.5) for a decision and possible notification of the DSMB per the Data and Safety 
Management Plan guidelines. 
 
Subjects randomized to the CPAP group will have prompt PAP titration in the sleep laboratory, and then use 
PAP (CPAP or BPAP) at home at the prescribed setting.  Subjects will be fitted for masks in the sleep 
laboratory, with additional adjustments later, as necessary, by a respiratory therapist at MedEQUIP, the DME 
provider.  Whenever possible, prior to their CPAP titration study or DME setup appointment, subjects will be 
issued a PAP mask for use at home while awake.  This mask may not be identical to the mask that the child is 
fitted with at the setup appointment, but it will be sufficiently similar to allow the child to become familiar with 
the look and feel of a PAP mask. The parent or guardian will be instructed to have the child wear the mask for 
increasing intervals while awake to allow the child to acclimate to wearing a mask. The goal is to prepare the 
child for their upcoming CPAP titration study and PAP treatment.  The child will be asked to practice wearing 
the mask several times daily until the setup appointment at which time the child will be fitted with a mask and 
issued their PAP machine and supplies.   
 
Documentation of patient education on the use and potential safety concerns regarding PAP mask use without 
PAP for the acclimation process will be completed by the technologist issuing the mask or study staff.  A copy 
of the patient education form and a summary of the acclimation protocol is provided in the Manual of 
Operations.   
 
Adherence will be followed and fostered by Susan Armstrong, RN, who has extensive experience in CPAP 
desensitization for children in the Pediatric Sleep Clinic.  Children and families with difficult adherence issues 
will be able to consult with Dawn Dore-Stites, PhD, a psychologist and faculty member of the multidisciplinary 
Pediatric Sleep and Behavior Clinic who is experienced with behavioral therapy to promote adherence.  These 

 
efforts to promote adherence will match or exceed those that have, in clinical practice here, produced a CPAP 
adherence rate of 67% (see section C9.7).  Thresholds for referral are not well established in the literature, but 
possible examples might include: 
 
 
a) Inability to tolerate CPAP during the CPAP titration trial; 
 
b) Success during the CPAP titration trial but inability to use the mask/machine at home for more than 4 
 
    hours on the majority of nights over a 3 week period; 
 
c) Failure to sustain use of CPAP after a period of success; or, 
 
d) Failure to reinitiate CPAP therapy after a period off-treatment due to an upper respiratory illness or    
 
    other interfering event. 
 
The number and frequency of visits will depend on: (1) the child’s current threshold; and (2) how the child and 
family advance through each step of the desensitization protocol.  The decision to hold on a particular step of 
the desensitization program will be based on whether the homework was completed and/or whether the child’s 
current level of anxiety or opposition is elevated.  A recommendation to discontinue CPAP treatment may be 
made if the child or family has not progressed to another step in 2-4 weeks (depending on the number of visits 
during that time).  Discontinuation of PAP treatment may occur after case consultation with other members of 
the study team to insure that all strategies have been considered.  Additional effort to improve adherence is not 
desirable because this would not resemble practice available at most other clinical centers.  In addition, varying 
levels of adherence will be necessary to test hypothesis 2b. 
 
Approximately ten months after AT (six months after randomization), sleep studies (on steady PAP for the 
CPAP subjects, without PAP for controls) and neurobehavioral assessments will all be repeated.  The sleep 
study is required to precede a valid Multiple Sleep Latency Test;66 will allow confirmation in CPAP subjects that 
any SDB is well controlled; and will allow reassessment for residual SDB in the control group.  The 6-month 
interval is selected to ensure adequate time for PAP habituation, neurobehavioral response to consistent use 
of PAP, and acceptably low risk of test-retest learning effects on cognitive measures.  The outcome measures 
have been used by the investigators in two NIH-funded R01s (HD038461 and HL080941) over the past 10 
years and all derive from well-validated, widely accepted instruments.  The explanatory polysomnographic 
measures are all consistent with American Academy of Sleep Medicine 2007 standards.63  Esophageal 
pressure monitoring, with which this laboratory has extensive clinical, research, and published experience,24,67-
70 will be used to provide a gold-standard assessment of respiratory effort.  In addition, at least 3 highly 
innovative, most promising, and particularly sensitive computerized measures, all pioneered previously in 
children by the investigators, will be available to complement standard analyses.  These include respiratory 
cycle-related EEG changes (RCREC) thought to reflect subtle but numerous and consequential inspiratory 
microarousals;71-75 an analysis of sleep dynamics, which focus on continuity of sleep and specific sleep stage 
bouts rather than traditional totals of time spent in each stage;76-79 and quantitative analysis of esophageal 
pressure swings during each respiratory cycle through the night.75,80  Based on the investigators’ preliminary 
data (see below and section C9.5), these automated measures may well improve the ability of pediatric 
polysomnography to distinguish children with and without clinically significant SDB and potential to benefit from 
CPAP. 
 
One week prior to each sleep study, an investigator will call the family to confirm the appointment, verify 
absence of unexpected illness, and encourage completion of a one-week sleep log.  Nocturnal sleep studies 
will be performed by registered, child-experienced sleep technologists in the 10-bed Michael S. Aldrich Sleep 
Disorders Laboratory, where 4 spacious rooms specifically designed to accommodate young children, and 
parents in a separate bed, are available also for research use.  Weight and height will be measured at the 
laboratory.  The next day, a Multiple Sleep Latency Test will be administered.  Between naps, a trained 
technician will administer neuropsychological tests.  All children will be tested after a night in the same 
environment, equivalent opportunities for good sleep, and measured total sleep times.  During each child’s 
testing, a parent will complete behavioral rating scales, the Pediatric Sleep Questionnaire (described 
above),43,44 and a standard measure of socioeconomic status.81  After the sleep studies at 4 months post-AT, 
submission of electronic adherence data (CPAP group) or other follow-up information (control group) at 7 
months, and final assessments at 10 months, each child will receive a $30 gift certificate.  After evaluations at 
4 months and 10 months post-AT, each parent will receive $250 for their time spent on this research. Parents 
will also be compensated for timely, monthly follow-up contacts ($5 for each contact completed within 5 

 
business days of the target follow-up call date), which are important in assessing possible safety concerns on 
study.   
 
C4.  Polysomnography.  Sleep studies will include six EEG channels (F3-A2, F4-A1, C3-A2, C4-A1, O1-A2, 
O2-A1 of the 10-20 international electrode placement system), 2 electro-oculogram channels (right and left 
outer canthi), chin and bilateral anterior tibialis surface EMG, 2 EKG leads, nasal and oral airflow 
(thermocouples), nasal pressure through pediatric sensor cannulae, esophageal pressure (using a pediatric 
esophageal balloon), thoracic and abdominal excursion (inductance plethysmography), and finger oximetry 
with pulse waveform.  Esophageal pressure has been monitored by the investigators for clinical and research 
purposes for 15 years;67 demonstrated to affect children’s sleep negligibly;67,68 successfully performed on the 
majority of the investigators’ pediatric research subjects in the past;68 and now listed among preferred 
measures for children63 although many laboratories still have not adopted it.  All recordings will be made on 
digital equipment (Compumedics, Inc.) with which the investigators have extensive laboratory-wide clinical and 
research experience since 2003.  End-tidal or transcutaneous CO2 will be monitored per the new (2012) AASM 
(American Academy of Sleep Medicine) guidelines for pediatric polysomnography.  Both a research program 
manager and a physician will be on call by page during the studies. 
  
Multiple Sleep Latency Tests will follow standard procedures.66  As children have longer sleep latencies than 
adults, opportunities to fall asleep will be lengthened from the adult standard of 20 minutes to 30 minutes.34,85  
Five nap attempts will be scheduled 2 hours apart, usually at about 8:00, 10:00, 12:00, 2:00, and 4:00 pm.  
Parents will remain just outside the testing room.  Urine drug screens will not be used because in 450 such 
tests for research here since 1999, none have turned up results that were both unexpected and meaningful. 
 
An unmasked, board-certified sleep specialist will interpret each sleep study, not to provide study variables but 
rather to inform families and their physicians.  Study results generally will not be communicated until after the 
participant has finished the entire protocol, when sleep and psychological test results are fully scored.  
However, an investigator will promptly communicate any finding that could have medically urgent significance 
for the patient, such as an unsuspected arrhythmia, paroxysmal EEG spikes, or severe residual SDB. 
 
Nocturnal polysomnograms and Multiple Sleep Latency Tests will be scored by a single chief technologist (J. 
Fetterolf, RPSGT, REEGT) masked to subject identity.  This technologist has meticulously scored about 1,000 
pediatric sleep research studies in the past 10 years.  Borderline polysomnographic features will be arbitrated 
between the technician and the PI.  Scoring will be performed in batches: pre- and post-PAP studies of 5 
subjects will be randomly ordered and presented for scoring.  This procedure, used for two past R01s, assures 
that any subtle changes in scoring tendencies over time do not confound pre- vs. post-PAP comparisons.   
Scoring for sleep stages, respiratory events, periodic leg movements, and arousals will follow standard criteria 
for children.63  Double-scoring of arousals and respiratory events, in 20% of the records, will be performed to 
generate a Kappa statistic for intra-rater reliability.  Inter-rater reliability will also be determined by having 
another experienced polysomnographic technologist score these same records. 
 
For Multiple Sleep Latency Tests, the sleep latency of each nap will be scored as the time between lights out 
and the first epoch of stage 1 sleep.66  The mean sleep latency across naps is the most well-validated and 
commonly used objective measure of daytime sleepiness in both adults and children.86,87  Childhood sleepiness 
as a continuous variable for research purposes can be detected in SDB patients as young as 3 years old by 
questionnaires43 and by Multiple Sleep Latency Tests.85 
 
Respiratory cycle-related EEG changes (RCREC) will be computed as previously described.71,74  Briefly, a 
central EEG lead and airflow from a thermocouple signal are analyzed.  Signals from computer-detected 
regions of apnea or hypopnea (generally a small minority of the total recording time) are excluded.  Remaining 
respiratory cycle airflow signals are smoothed and divided into quarters (early expiration, late expiration, early 
inspiration, and late inspiration); EEG spectral power within pre-determined frequency ranges of interest are 
computed by digital filtering; and the mean power for each quarter-cycle, relative to power over the entire 
respiratory cycle, is computed.  Results for each quarter-cycle segment are averaged over thousands of 
respiratory cycles (generally several hours of recording) and the maximal difference between mean relative 
segment powers is defined, for any given subject and within the targeted EEG frequency band, as the RCREC 
value.  The investigators have shown that RCREC are greater in children with SDB than those without SDB;72 

 
RCREC improve after adenotonsillectomy;72 they correlate with subjective and objective measures of 
sleepiness in children and adults;72-74 this association persists after accounting for objective measures of SDB 
severity;73,74 RCREC correlates with esophageal pressure swings but is far from completely explained by 
them;75 and RCREC may well reflect subtle but numerous cortical microarousals in response to labored non-
apneic breathing that pervades much of the night for patients with SDB.73  In the research now proposed, 
sigma range (12-15 Hz) RCREC will be the main focus, as RCREC within this range have proved most 
sensitive to sleepiness in both adults and children.73,74 
 
Esophageal pressure swings for all respiratory cycles, after exclusion of irregular breaths and artifacts, will be 
computed automatically using an algorithm developed by the investigators and previously shown to match well 
with much more time-consuming visual analyses.75,80  Sleep dynamics analyses will involve computation of the 
mean lengths of contiguous sleep and specific sleep stage bouts.  The investigators have previously shown 
that these data may characterize sleep fragmentation more sensitively, in children with SDB,76 adults with 
fibromyalgia,77 or adults with asthma,88 than do arousals or standard analyses of sleep stages as total minutes, 
percentages of total sleep time, or sleep efficiency. 
 
C5.  Neurobehavioral Assessments.  Standardized, well-validated tests will be used to assess outcomes widely 
recognized as some of the most important and sensitive in childhood SDB.  As noted above, many studies of 
SDB morbidity have found associations with inattentive, hyperactive, and aggressive behavior, and with 
cognitive problems such as attention deficit.15  Behavioral and cognitive measures, confirmed to be useful in 
our previous studies of childhood SDB42 and in related work by our group and others,15 will provide outcomes 
for this study.  Validated parental rating scales for inattention, hyperactivity, general behavioral issues, and 
quality of life will best assess the primary complaints parents often communicate and clinicians seek to 
address.  Other outcomes will include neuropsychological measures of short-term attention, visuospatial 
problem solving, executive functioning, and memory.  These measures are important for assessment of 
cognitive changes in treated and untreated patients with sleep disorders,15 as well as attention deficit and other 
medical disorders,89,90 and many are available in multiple, equated forms to reduce practice effects.91-95  
General intelligence and academic achievement will be briefly assessed, because in some reports they are 
sensitive to SDB34 and because they should be taken into account when other specific outcomes are analyzed. 
Although the investigators have in previous research on AT included psychiatric evaluations, these are now 
omitted because AT effectively reduces the rates of DSM-IV diagnoses to a level that would be difficult to study 
without an enormous postoperative sample.  In contrast, continuous measures provided postoperatively by 
parental behavior rating scales, cognitive assessments, and Multiple Sleep Latency Tests do not reach levels 
identical to those of controls and should be more sensitive to benefits from CPAP after AT. 
 
Behavioral Assessments:  Standardized rating scales to be completed by a child’s parent or guardian will 
include the Conners’ Parent Rating Scales (CPRS-R:L)96 and the Child Behavior Checklist (CBCL),97 with the 
primary study outcome measure, Behavioral Index, being constructed from the sum of the T-scores from the 
Conners’ ADHD Index and CBCL Attention Deficit/Hyperactivity Problems.  Parents also will complete the 
CPRS-R:L and CBCL at the pre-operative meeting after signing the consent materials with their child.  
Although not representing a primary outcome point for this study, this assessment will serve to familiarize 
parents with the process of observational reporting on their child; provide important information or grouping 
variables for secondary analyses; and help to confirm that CPAP and control groups have equivalent behavior 
at baseline.  Because of the importance consistently reported for the measurement of executive functioning in 
children with SDB,15  the Behavior Rating Inventory of Executive Functioning (BRIEF)98 also will be completed.  
Finally, quality of life will be measured from both the Peds-QL parent and child forms.99  The CPRS-R:L, CBCL, 
and BRIEF are available in teacher forms that will allow secondary, corroborative assessment in both a home 
and school environment, and help address any evident42 parental bias.  Through experience in our laboratory 
and work with the multicenter Childhood Adenotonsillectomy (CHAT) trial, for which our center directs quality 
assurance and monitoring of behavioral and cognitive assessments, we have developed techniques to sustain 
strong return rates for teacher ratings.  
 
Any or all survey instruments used in this study may be administered as paper forms or electronic versions, 
which may be delivered by email or via a web-based software system such as Qualtrics, or as a combination of 
paper and pencil and electronic formats, depending on the form type and the reporter (child, parent or teacher).   
Any instrument for survey over the internet will be or is being developed through the auspices of the computer 

 
support group in Psychiatry and MCIT to be sure it is HIPPA compliant, as are current measures employed in 
Psychiatry for their patient metrics.   
 
 
Cognitive Assessments.  Tests will be administered by an experienced, neuropsychologist-supervised 
psychometrist who is well trained to maintain children’s motivation and monitor the need for rest breaks or 
changes in conditions.  Each child also will receive a brief introduction to face-to-face testing using CogState 
(described below) during the time just following consent signing.  As many children will not have had the 
experience of being tested before, this introduction will reduce apprehension and familiarize each child with the 
types of materials to be tested.  The total testing time for post-AT sessions will be approximately 2 hours, 
spread between nap studies.  This is less time than routine clinical evaluations (usually 4-8 hours).  All specific 
test sessions will occur at the same time of day, without variance between subjects or test and retest visits. 
 
The Attention/Executive Functions domain score of the NEPSY-II100 and the computerized continuous 
performance test, Integrated Variables of Attention,101 will comprehensively cover short term and sustained 
attention, vigilance, impulsivity, and executive ability.  Overall intelligence and academic achievement will be 
assessed briefly using the two Stanford-Binet, 5th Edition (SB5) “routing tests”, Matrices and Vocabulary102 and 
selected Woodcock Johnson-III91 subtests (Letter Word Identification, Reading Fluency, Calculation, and 
Applied Problems).  The Selective Reminding Test is sensitive to children’s memory,95 specifically verbal 
encoding and retrieval.  Speed and control of fine motor ability will be measured with the Purdue Pegboard.103  
Finally, the brief computerized CogState battery will provide valid indices of processing speed, working 
memory, executive functioning, and memory in a combined measure that remains stable over time, 
incorporates simple response requirements and self-contained training modules, and has proven inherently 
interesting and motivating, and sensitive to subtle cognitive change in children.94  This test also includes the 
Groton Maze Test,92 a brief, computerized measure of psychomotor speed and visuospatial problem solving. 
 
As newer versions of these or other equivalent neurobehavioral tests are released, they may be substituted for 
currently available versions, as deemed necessary by the PI and CoInvestigators on the project to meet the 
project aims.  For example, an equivalent battery of neurobehavioral and quality of life measures has been 
developed as part of a NIH Toolbox for the Assessment of Neurological and Behavioral Function and is 
expected to become available in the near future.  Because the NIH toolbox battery spans ages 3-85 and is 
designed to minimize subject burden, components of this battery may be substituted, whenever appropriate, on 
this study.   
  
C6.  Intervention.  All CPAP group participants will have a CPAP titration study shortly after the initial post-AT 
polysomnogram.  During this additional night in the sleep laboratory, pediatric core technologists will fit each 
child with an appropriate mask, monitor sleep and breathing as above, and remotely increase administered 
pressures until SDB resolves.  Each record will be scored as above, but by any available registered pediatric 
sleep technologist (not waiting for batching) so that an investigator (Dr. Hoban) can promptly review the study 
and determine an ideal pressure setting to prescribe.  An experienced respiratory therapist at MedEQUIP will 
then meet with the family, issue them a CPAP machine and mask at no cost to the family, educate them about 
CPAP use, and serve as a contact should any mechanical problems arise.   
 
Approximately every 30 days (or more often as necessary) over the next 6 months, the DME provider or study 
team staff will review compliance data that is remotely downloaded via modems on the PAP machines.  
Alternatively, data downloads may also be done onsite from the SD memory cards in the PAP machines.  
Adherence and therapeutic data will be stored in a secure office of Encore Anywhere, a HIPAA compliant, 
web-based patient compliance management system provided by Philips Respironics, the manufacturer of the 
PAP machines used on this protocol.  Restricted access to Encore Anywhere “offices” is provided by Philips 
Respironics, and the offices are password protected.  The study data files will be maintained in a separate 
office from the UMHS clinical patient compliance database in Encore Anywhere.  This will restrict casual 
access to the research data by other UM providers or staff.  Linkable identifiers will be used in the place of 
subject names to help maintain privacy for research participants.      
 
Detailed plans to promote adherence, to be elaborated in the operations manual, will include phone calls 
approximately weekly for the first 3 weeks to detect any problems early; a meeting with the study nurse or 

 
other investigators at 3 months; additional meetings or phone interviews every 4-6 weeks; further intervention 
of Susan Armstrong, RN (research assistant and experienced pediatric sleep clinic nurse) as needed; and 
referral to Dawn Dore-Stites, PhD (co-investigator and psychologist in Pediatric Sleep and Behavior Clinic) 
when adherence is problematic.  All no-CPAP group participants will receive a series of contacts from an 
investigator, to control for this potential confound (see Introduction), including an interval visit with the study 
nurse or other investigators between study visits 2 and 4, whenever possible; assistance with referral at the 
end of the study for any desired or indicated clinical follow-up; and research-funded PAP equipment if a child 
without insurance coverage requires treatment.  A brief 7-items survey will be administered to children and 
parents (both arms of the study) at the interval (~3month followup) clinic visit with study staff and again at the 
endpoint visit to elicit additional information on their experience or health status during their participation.    
Copies of the survey are available in the Manual of Procedures. 
 
C7. Outcome Measures:   
This section defines the outcome measures to be gathered for this trial, classified into primary, secondary and 
exploratory. Other measures referred to anywhere within the protocol are to be considered baseline, 
exploratory for cross-analyses or safety related, as appropriate. Study visit 2 (SV2) represents the initial 
polysomnogram approximately 4 months following AT and study visit 4 (SV4) represents the final 
polysomnogram approximately 6 months later (equivalent to approximately 10 months after AT).  
 
(a) Primary Outcome Measure: 
1. Neurobehavioral change (hypothesis 2c CPAP vs controls intent to treat) 
Change in behavioral index following 6 months of CPAP vs. no CPAP use by children after AT 
 
(b) Secondary Outcome Measures: 
1. Neurocognitive change after AT (hypothesis 2c CPAP vs controls intent to treat) 
Change in NIH Toolbox Total Composite Score Age Adjusted following 6 months of CPAP vs. no CPAP 
use by children after AT  
2. Change in subjective sleepiness after AT (hypothesis 2c CPAP vs controls intent to treat) 
Change in Epworth Sleepiness Scale score following 6 months of CPAP vs. no CPAP use by children after 
AT  
3. Change in objective sleepiness after AT (hypothesis 2c CPAP vs controls intent to treat) 
Change in MSLT following 6 months of CPAP vs. no CPAP use by children after AT 
4. Change in quality of life (hypothesis 2c CPAP vs controls intent to treat) 
Change in PedsQL following 6 months of CPAP vs. no CPAP use by children after AT  
5. For CPAP subjects, neurobehavioral outcomes will improve more from baseline to follow up among those 
who have adhered to CPAP than those who are non-adherent (hypothesis 2b) 
 Change in behavioral index from SV2 to SV4 in adherent vs non-adherent CPAP users 
6. For CPAP subjects, neurobehavioral outcomes will improve more from baseline to follow up among those 
who have adhered to CPAP than those who are non-adherent (hypothesis 2b) 
 Change in NIH Toolbox Total Composite Score Age Adjusted from SV2 to SV4 in adherent vs non-adhere 
7. For CPAP subjects, neurobehavioral outcomes will improve more from baseline to follow up among those 
who have adhered to CPAP than those who are non-adherent (hypothesis 2b) 
 Change in ESS from SV2 to SV4 in adherent vs non-adherent CPAP users 
8. For CPAP subjects, neurobehavioral outcomes will improve more from baseline to follow up among those 
who have adhered to CPAP than those who are non-adherent (hypothesis 2b) 
 Change in MSLT from SV2 to SV4 in adherent vs non-adherent CPAP users 
9. For CPAP subjects, neurobehavioral outcomes will improve more from baseline to follow up among those 
who have adhered to CPAP than those who are non-adherent (hypothesis 2b) 
 Change in PedsQL from SV2 to SV4 in adherent vs non-adherent CPAP users 
10. Among adherent CPAP users residual SRBD score at SV2 will predict greater improvement at SV4 for 
behavior (hypothesis 2a) 
Change in behavioral index from SV2 to SV4 in CPAP adherent subjects will be associated with SRBD score 
at SV2 
11. Among adherent CPAP users residual SRBD score at SV2 will predict greater improvement at SV4 for 
cognition (hypothesis 2a) 
Change in NIH Toolbox Total Composite Score Age Adjusted from SV2 to SV4 in CPAP adherent subjects 

 
will be associated with SRBD score at SV2 
12. Among adherent CPAP users residual SRDB score at SV2 will predict greater improvement at SV4 for 
subjective sleepiness (hypothesis 2a) 
Change in ESS from SV2 to SV4 in CPAP adherent subjects will be associated with SRBD score at SV2 
13. Among adherent CPAP users residual SRDB score at SV2 will predict greater improvement at SV4 for 
objective sleepiness (hypothesis 2a) 
Change in MSLT from SV2 to SV4 in CPAP adherent subjects will be associated with SRBD score at SV2 
14. Among adherent CPAP users residual SRDB score at SV2 will predict greater improvement at SV4 for 
quality of life (hypothesis 2a 
Change in PedsQL from SV2 to SV4 in CPAP adherent subjects will be associated with SRBD score at SV2 
15. Among adherent CPAP users AHI at SV2 will predict greater improvement at SV4 for behavior (hypothesis 
2a) 
 Change in behavioral index from SV2 to SV4 in CPAP adherent subjects will be associated with AHI at SV2 
16. Among adherent CPAP users AHI at SV2 will predict greater improvement at SV4 for cognition (hypothesis 
2a) 
Change in NIH Toolbox Total Composite Score Age Adjusted from SV2 to SV4 in CPAP adherent subjects 
will be associated with AHI at SV2 
17. Among adherent CPAP users AHI at SV2 will predict greater improvement at SV4 for subjective sleepiness 
(hypothesis 2a) 
Change in ESS from SV2 to SV4 in CPAP adherent subjects will be associated with AHI at SV2 
18. Among adherent CPAP users AHI at SV2 will predict greater improvement at SV4 for sleepiness 
(hypothesis 2a) 
Change in MSLT from SV2 to SV4 in CPAP adherent subjects will be associated with AHI at SV2 
19. Among adherent CPAP users AHI at SV2 will predict greater improvement at SV4 for quality of life 
(hypothesis 2a) 
Change in PedsQL from SV2 to SV4 in CPAP adherent subjects will be associated with AHI at SV2 
 
(c) Exploratory Outcome Measures; 
Measures of academic achievement, fluid cognition, and REREC are all considered exploratory. 
 
C8.  Analyses.  For Hypothesis 1a, post-AT SDB as an outcome variable will be defined as a respiratory 
disturbance index (RDI) ≥ 1 obstructive or mixed apnea, hypopnea, or respiratory effort-related arousal per 
hour of sleep.63  The 22-item SDB scale score (on a continuous scale from 0.0 to 1.0 43) will provide the main 
explanatory variable.  Logistic regression models will be assessed for sensitivity to potential covariates or 
confounds, including age, gender, race, body mass index z-score, and socioeconomic status.  Secondary 
analyses will focus on RDI as a continuous outcome; validated snoring, sleepiness, and behavior subscales 
within the SDB scale; habitual snoring as a single, previously informative9,104 question-item; and most 
importantly SDB data generated by innovative algorithms, as described above, exploratory analyses for 
RCREC, esophageal pressures, and sleep dynamics.  For Hypothesis 1b, multiple linear regression models 
will be constructed to assess cross-sectional associations between each neurobehavioral morbidity (the 
Behavioral Index being the primary outcome) and the SDB questionnaire score or RDI as the main explanatory 
variable.  Models of the SDB questionnaire will use a slightly shortened, 16-item version (as previously 9,105) to 
exclude behavioral questions that would correlate with outcome measures for artificial reasons.  Covariates as 
above will be taken into account.  Secondary analyses will 1) assess the impact of SDB scores or RDI on other 
behavioral and cognitive measures; 2) take IQ and achievement into account within the main models; and 3) 
test the 3 newer, computed SDB measures in place of RDI.  To assess Hypothesis 2a, the investigators will 
define adequate adherence as at least 4 hours of electronically recorded CPAP use per night, on average over 
the most recent 3 months on treatment.  A series of multiple linear regression models will be used, with post-
PAP improvement in neurobehavioral variables as outcomes.  The pre-CPAP SDB questionnaire scores or 
RDI will serve as the main explanatory variables.  Secondary analyses will use the 3 SDB measures generated 
by computer algorithms as the explanatory variables.  To assess Hypothesis 2b, the same outcomes will be 
regressed on CPAP adherent vs. non-adherent categorization, as well as (secondarily) a continuous measure 
of adherence as defined by mean hours of nightly use during the last 3 months of the trial.  As with Hypotheses 
1a and 1b, models for 2a and 2b also will be assessed after adjustment for similar potential covariates or 
confounds.  To assess Hypothesis 2c, intent-to-treat analyses will use models that regress each primary 
neurobehavioral outcome on initial CPAP vs. control group assignment, after adjustment for BMI z-scores, age, 

 
gender, race, and socioeconomic status.  Exploratory models will in addition consider RDI (or computer 
algorithm proxy measures) and PSQ scores at 4 or 10 months post-AT, to assess whether residual SDB on 
these measures may explain differences in neurobehavioral outcomes.  Exploratory analyses will also compare 
outcomes between CPAP-adherent subjects and controls, to assess (by contrast to the primary intent-to-treat 
analysis) what benefit may be lost by poor adherence, cross-overs, or drop outs.   
 
In addition to standard SAS and Excel databases, REDCap (Research Electronic Data Capture) may be used 
for database development and data capture and management on this study as well as in tracking study activity.  
REDCap is a web-based electronic data capture system available under contract to the University of 
Michigan.  Developed by Vanderbilt University, with collaboration from a consortium of institutional partners, 
REDCap provides a secure, web-based application designed to support data capture for research 
studies.  REDCap is endorsed by the Michigan Institute for Clinical and Health Research (MICHR) and is part 
of larger data collection initiatives under the CTSA grant.  REDCap was developed specifically around HIPAA-
Security guidelines and has been disseminated for use locally at other institutions.  By mid-2011, REDCap was 
being used by more than 200 academic/nonprofit consortium partners on six continents supporting more than 
20,000 research end-users (www.project-redcap.org). 
 
At the University of Michigan, the application is restricted to users on the UMHS Internal Network requiring a 
secure connection to communicate with U-M services i.e. VPN.  The database is stored on a server separate 
from the application.  Servers are maintained and supported by the Medical School Information Services 
(MSIS). REDCap Application support and services are provided by the Michigan Institute for Clinical and 
Health Research (MICHR). 
    
C9.  Sample Size.  Plans are based on extensive preliminary data from the investigators on effects of AT for 
childhood SDB, and on the only quantitative preliminary data published, in 2009, for the neurobehavioral 
effects of CPAP in children with obstructive sleep apnea.60  Data from our group (section C9.3) show that the 
proportion of children, among those who undergo AT here for SDB, who have residual SDB 6 months later is 
about 50% or more, depending on criteria used to define SDB.  Children with mildest SDB can have robust 
improvement in behavior, as measured with particular relevance for the current application on the Conners’ 
ADHD Index.  This improvement, by 0.5 standard deviations, is at least as strong as the that observed in more 
severe apneics.24,30,42  Yet, more than 0.5 standard deviations still separate Connors’ scores in post-AT SDB 
patients from those in controls.24  The CPAP intervention we propose is a gold-standard widely believed to 
completely remedy any residual airway obstruction in adherent subjects.  The CPAP may well, therefore, prove 
to be a more definitive treatment than AT in final elimination of even mild SDB.  In a study of 21 children aged 
6 to 16 years, with SDB of any severity and unselected for neurobehavioral problems, 3 months of CPAP was 
associated with robust improvement in inattention and hyperactivity on the Conners’ scale (p<.001 despite the 
limited sample) and in subjective sleepiness (Epworth, p<.001).60  Adherence with PAP correlated with 
improvement in the Conners’ measure (r=.48, p=.03) and the Epworth (r=.58, p=.006).  These results emerged 
despite use of PAP by the subjects on only 56% of all nights on average.  Our preliminary data (C9.7) suggest 
that we can expect about 67% our subjects to show adequate adherence. 
 
Given these observations, we anticipate conservatively that a sample of 80 CPAP subjects who complete the 
protocol will contain about 40 with SDB (RDI>1); that 53 will be adherent with PAP; and that most subjects with 
RDI>1 along with some subjects who have RDI<1 (but perhaps SDB symptoms) will benefit from PAP.  For 
hypothesis 1a, to test for a correlation between SDB questionnaire scores and polysomnographically-defined 
SDB, we will have 80% power to detect a clinically meaningful Spearman correlation rho ≥ 0.25 with α=.05.  
Similarly, for hypothesis 1b, which focuses on an association between residual neurobehavioral problems and 
either SDB questionnaire scores or RDI, we will be able to detect a rho ≥ 0.25.  For hypothesis 2a, with about 
27 post-AT, CPAP-adherent subjects who have RDI>1 and 26 who have RDI<1, we will have 82% power to 
reject the null hypothesis (that the mean 6-month change scores in the Behavioral Index for the two groups are 
equal) if the effect size is ≥ 0.8.  The likelihood of this result is based on observations in our previous studies 
with the Conners’ ADHD Index, which is a main component of the Behavioral Index now proposed.  Based on 
improvement we have measured in the past after AT for children with mildest levels of SDB, for the current 
hypothesis 2b, in which we will compare about 53 treated (adherent) to 27 non-treated (non-adherent) residual 
apneics, we should have power of 0.78 to detect an effect size ≥ 0.65.  This effect size is substantially smaller 
than that implied by the correlations above among 21 children60 and by our own preliminary data below.  For 

 
hypothesis 2c, comparison of 80 CPAP-treated subjects to 40 controls should provide 80% power to detect a 
Behavioral Index difference between groups (effect size) ≥ 0.55.  The 120 subjects will be recruited from the 
2,475 children aged 5-12 years anticipated to have AT at the two otolaryngology practices during 3 years and 4 
months of study enrollment.  In each of two previous R01 studies here that followed children for 12 or 6 months 
after AT, attrition was only 5% with careful attention to each family from an experienced project manager.  The 
study now proposed will conservatively anticipate 10% attrition, and target enrollment of 132 subjects. 
 
C10.  Preliminary Studies. 
C10.1  The investigators are experienced and well prepared to conduct the proposed research.  The 
investigators have held continuous funding from the NIH since 1997 to study childhood SDB, its assessment 
by subjective and objective means, and its neurobehavioral outcomes.  Findings of this highly multidisciplinary 
group helped to call attention to the association between SDB and inattention, hyperactive behavior, and 
aggression in children.9,104,105  In one of the first long-term prospective studies of snoring, they showed that it 
predicts incident hyperactivity 4 years later.106  They demonstrated that although daytime sleepiness may not 
be obvious in children with SDB, it can often be detected by history or questionnaire, or by objective testing.74  
They have studied treatment of SDB, by AT, for 11 years.  They have examined in detail the psychiatric and 
neuropsychological outcomes of treatment for pediatric SDB.30,42  They have advanced the ability to monitor 
outcome-relevant, objective features of subtle pediatric SDB.72,74,75  In particular, they are experienced with 
esophageal pressure monitoring to assess respiratory effort optimally, and have shown that the procedure 
does not substantially disrupt children's sleep.67,68  They have developed new approaches to assess subtle 
effects of childhood SDB on the brain.  For example, they were the first to characterize respiratory cycle-
related EEG changes (RCREC),71,72 as well as sleep stage dynamics in children.76 
 
C10.2.  The pediatric SDB questionnaire to be used in this study was developed and validated by the 
investigators, and shown to be useful in many research studies.  The 22-item SDB component of the Pediatric 
Sleep Questionnaire asks about chronic snoring, snorting, observed apneas, other breathing difficulties, 
ancillary symptoms, and behavioral signs (see appendix), each of which individually predicts childhood SDB as 
confirmed by polysomnography.43  The scale can be licensed online from the University of Michigan by any 
investigator at no cost.  When tested against polysomnographically-defined pediatric SDB, the SDB scale 
showed a sensitivity of 0.81, specificity of 0.87, and overall classification accuracy of 85%, with good internal 
consistency and test-retest reliability.43  In a subsequent study of 78 children who underwent AT for clinical 
purposes, and 27 controls, the SDB scale identified subjects with polysomnographically-confirmed SDB both 
before and one year after AT.44  The SDB scale predicted current hyperactive behavior, sleepiness (mean 
sleep latency), and their responses to AT at least as well as sleep studies did.  However, these important 
findings require confirmation, as the original aims of the research did not include these analyses.  Furthermore, 
no data were collected on response to PAP.  Nonetheless, the SDB scale is now used in many studies at the 
University of Michigan, elsewhere in the U.S.,107-109 and around the world,110-112 where it has been translated (at 
minimum) into Spanish, German, Chinese, and Turkish, with Korean and Portuguese versions in progress. 
 
C10.3.  Pediatric SDB often fails to resolve completely after AT.  Obstructive sleep apnea in children is defined 
in part by an RDI > 1.4,63  In the investigators’ recently completed, longitudinal cohort of 135 children who had 
AT for clinical indications, 89 (66%) had an RDI > 1 six months after AT.  Using a slightly more conservative 
cut-off to define abnormality,113 based on statistical analyses of sizeable samples, 63 (47%) of the 135 subjects 
still had an RDI ≥ 1.5 after AT.  However, the number of children after AT who might benefit from additional 
treatment for SDB remains unknown, and could be higher, lower, or more complicated than the numbers 
identified by the above RDI thresholds.  Studies have not assessed what polysomnographic criteria are most 
informative, as judged by response to further treatment.113  Potential for meaningful treatment response, rather 
than a somewhat arbitrary polysomnographic number, can best determine what clinical care should be offered. 
  
C10.4.  Many children have residual neurobehavioral morbidity after AT.  Previous data from the investigators 
have demonstrated clear improvement in objective measures of attention, parental ratings of hyperactive 
behavior, and both subjective and objective measures of daytime sleepiness one year after AT.24,30  The 
magnitude of these improvements has approached one half of a standard deviation and is clearly meaningful 
clinically.  However, many children are not cured, and a minority actually worsen.  The investigators have 
hypothesized that brain injury earlier in childhood may only manifest later in a developmental trajectory.106  
Another distinct possibility, however, is that low levels of residual SDB after surgery continue to provoke 

 
neurobehavioral morbidity.  Patients with symptoms of SDB but minimal or no evidence of frank sleep apnea 
on standard polysomnography, in comparison to those with clearly positive studies, have sometimes been 
found by the investigators and others to have equivalent70 or even worse42,58,114 neurobehavioral morbidity. 
 
C10.5.  Subtle SDB measures on polysomnography may identify children who stand to benefit from PAP after 
AT.  Standard polysomnographic measures have not always correlated well with neurobehavioral morbidity 
widely attributed to SDB.32  The investigators are highly experienced with rigorous pediatric scoring protocols 
necessary to produce accurate standard SDB measures, as well as more subtle, experimental ones.  The PI 
assisted on the American Academy of Sleep Medicine committee that reviewed pediatric scoring standards 
and developed the Academy's 2007 Scoring Manual.62,63  The investigators are funded by the NIH (HL080941) 
to further develop esophageal pressure and RCREC methods that improve identification of outcome-relevant 
pediatric SDB.  They have already published preliminary data to suggest that esophageal pressures, in 
contrast to standard sleep study measures, can distinguish post-AT children with and without residual ADHD.31  
The investigators also have shown that RCREC predict sleepiness as well or better than other objective 
polysomnographic measures, and continue to do so even after the standard apnea / hypopnea index is taken 
into account.72,73  The RCREC are derived from a patented computer algorithm (see appendix), invented by the 
PI and co-investigator Joseph Burns, PhD, at Michigan Technological University.  Quantified RCREC reflect 
the degree to which EEG spectral power in specified frequencies varies in synchrony with non-apneic 
respiratory cycles during sleep.  Published data from the investigators suggest that RCREC reflect subtle but 
numerous microarousals that are invisible to the human eye,73 magnified by increased respiratory effort in 
SDB,75 and ameliorated by treatment for SDB.72  Finally, the investigators have also been the first to 
demonstrate that analysis of sleep dynamics can distinguish children with SDB from normal controls more 
effectively than do standard polysomnographic measures.76  The mean lengths of contiguous, specific sleep 
stage bouts, and especially non-REM stage 2 sleep, are computed from staging files generated by manual 
scoring.  These measures show considerable promise to improve the utility of pediatric polysomnograms. 
 
C10.6  The investigators have extensive experience in CPAP titration and home CPAP use for children.   The 
University of Michigan Sleep Disorders Center is among the largest in the U.S. and is one of only 4 now 
recognized by the American Academy of Sleep Medicine as a Comprehensive Academic Sleep Program of 
Distinction.  About 4,500 patient visits and 5,500 nocturnal sleep studies are performed annually in 19 modern, 
well-equipped sleep laboratory beds at two accredited Ann Arbor sites.  The Pediatric Sleep Medicine 
Program, directed by investigator Timothy Hoban, MD, is widely recognized as one of the most active and well-
developed.  Together with a pediatric pulmonary sleep specialist, a child psychologist, a behavioral / 
developmental pediatrician, and a dedicated registered nurse, the program evaluates about 450 new children 
each year for SDB.  A sizeable pediatric otolaryngology group evaluates many more children for SDB, and 
performs about 350 ATs each year in 5-12 year-old children, the large majority for obstructed breathing and 
especially SDB.  As in most of the U.S., virtually none of these children receive follow-up polysomnograms.  
Only those with clearly persistent post-operative SDB symptoms, or occasional children with particularly severe 
SDB pre-operatively, receive post-operative polysomnograms as part of their clinical care.  Those who do have 
residual SDB are managed through the Pediatric Sleep Clinic, which regularly follows about 120 such children 
aged 5-12 years on CPAP.  Clinic staff, and especially co-investigator Dawn Dore-Stites, PhD, have extensive 
experience with strategies to optimize CPAP adherence, as these faculty serve as referral resources for a 
large medical system when it comes to difficult adherence challenges. 
 
C10.7  Children treated by the investigators with CPAP for residual SDB after surgery usually adhere to 
treatment and experience clinically significant benefit.  An IRB-approved, retrospective chart review was 
performed for 64 children aged 3-12 years who had received a recent AT, been treated with CPAP thereafter 
for clinical indications, and then had at least one clinic follow-up within the U-M Pediatric Sleep Program.  
Among these subjects, 24 (56%) of the boys and 15 (71%) of the girls were obese (with BMI z-scores of at 
least 1.84 or 1.76, respectively).  Among the 43 children (67%) who had been adherent with CPAP for at least 
3 months, with adherence defined as ≥ 4 hours of use per night on average, 35 (81%) experienced some 
significant neurobehavioral improvement as reported by parents to their children’s clinicians.  Among the 8 
children with less, but some regular CPAP use, 4 (50%) were reported to have such benefit.  In contrast, 
among the 13 children who were non-adherent, only 10 (23%) had such benefit (p<0.0001 for the difference 
between children with and without good adherence).  Where improvement or lack thereof in specific 
neurobehavioral benefits had been documented, benefits likely to have arisen because of CPAP included 

 
improvement in sleepiness (86% of adherent subjects, vs. 25% of the non-adherent) and school performance 
(43% vs. 14%).  Adherent children experienced improved mood (78%), attention (58%), and daytime behavior 
overall (50%), with reduced aggressive behavior (40%), hyperactive behavior (20%), and snoring (92%).  
These preliminary data are important because they show that CPAP as administered by the investigative team, 
after AT, is 1) well tolerated by the majority of children (43 of 64); 2) associated with significant clinical 
improvement beyond that provided by surgery; and 3) likely to cause the improvement, as non-adherent 
children, a natural if imperfect control group, did not as often experience the same benefits.  Furthermore, this 
clinical sample in the State of Michigan shows high rates of obesity, an important risk factor that makes 
residual SDB after AT most likely.26  With one of the highest obesity rates in the U.S. 
(http://www.cdc.gov/obesity/data/trends.html), Michigan is an ideal setting for the proposed research. 
 
 

 
 
6.  Protection of Human Subjects 
 
6.1  Risks to Human Subjects 
 
6.1.a  Human Subjects Involvement, Characteristics, and Design:  Enrolled human subjects will number 
132 and range in age from 5.00 through 12.99 years old at enrollment.  Their parents or guardians will likely be 
young or middle-aged adults.  Children will have sleep, behavioral, and cognitive assessments and two-thirds 
will use continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BPAP) for 6 months.  
The protocol will require several visits to the medical center, and either a) 3 nights and 2 days (total) spent in 
the sleep laboratory as an outpatient over a 6-month period for the CPAP group, or b) 2 nights and 2 days for 
the control group.  Parents will be interviewed and asked to fill out child sleep and behavior questionnaires.  
The gender, racial, and ethnic composition of the subject population for all specific aims will resemble a cross-
section of the local and surrounding, Southeast Michigan population, as reflected by data from previous NIH-
funded pediatric sleep research here and from state-wide figures (see Targeted/Planned Enrollment table).  
The age range for this study is chosen because 1) the focus is on childhood sleep-disordered breathing (SDB), 
which is likely to have different etiologies, symptoms, and consequences in adults, 2) children younger than 5 
years-old would require different cognitive assessments that would be difficult to synthesize with those of older 
subjects, 3) children younger than 5 years often take daytime naps, and Multiple Sleep Latency Testing would 
have less clear validity, 4) teenagers gradually develop adult rather than childhood features of sleep-
disordered breathing (SDB), and 5) the frequency of adenotonsillectomy (AT) is greatly reduced in children 
older than the group to be studied.  The health status of the subjects involved in this research will generally be 
good.  At the time of enrollment, subjects will be scheduled to undergo AT on an elective basis within several 
weeks, based on their otolaryngologists’ clinical determination (with or without objective confirmation) that 
significant SDB is present.  Some subjects may also have a history of recurrent or chronic infections as 
another reason to have AT.  Most will be otherwise healthy, as medical and psychiatric conditions that would 
significantly limit the ability to test the proposed hypotheses will be exclusion criteria. 
 
Specific inclusion criteria will include: 
 
1) Age ≥5.00 and ≤12.99 years at study visit 2, for reasons explained above. 
2) Parental ability to speak and read English, for example on behavioral rating scales, which are important 
measures for this study. 
3) Absence of known or anticipated neurological, psychiatric, medical, or social factors likely to invalidate 
assessments, make adherence with PAP highly unlikely, confound ability to demonstrate improvement with 
PAP, or make local follow-up at 6 months unfeasible.  Some psychiatric conditions may be provoked or 
exacerbated by SDB, and those most commonly implicated – Attention Deficit/Hyperactivity Disorder, Conduct 
Disorder, and Oppositional Defiant Disorder – will not be exclusions.  However, more pervasive conditions 
such as severe autism will be excluded. 
4) Absence of chronic stimulant, hypnotic, or strongly sedating medication, unless families and their 
pediatricians are comfortable with 2-week drug holidays before the evaluations at 4 and 10 months after AT.  
Other chronic medications, in children without anticipated dose changes, will not be exclusions.  
 
After careful consideration, neither specific SDB symptoms, laboratory evidence, nor neurobehavioral 
comorbidity will be required initially to participate in this research.  This will (1) allow participation by subjects 
with a wide range of SDB symptoms and neurobehavioral comorbidities; (2) facilitate detection of associations 
between these measures; and (3) avoid dependence on unsubstantiated assumptions as to what particular 
symptom, laboratory finding, or neurobehavioral deficit is necessary for improvement to occur on PAP.  The 
investigators realize that in practice, some self-selection may enrich the sample with children whose families 
do have post-AT concerns about SDB symptoms.  To avoid the possibility that such participants may be too 
infrequent, the investigators will assess the proportion of children with positive SDB questionnaire scores (> 
0.33 43) after each group of 10 subjects has had AT.  If this proportion falls below 50%, the investigators will 
enrich the sample, for example, by requiring every other (i.e., every 2nd) participant to have a high SDB score, 
at both the initial pre-AT screen and re-assessment 4 months later, before randomization.  The proposed 
research is not epidemiologic, and validity will not suffer from selection bias or artificial enrichment of the 
sample.  The research does test for associations that will depend on wide ranges of requisite variables, but 

 
also on sufficient numbers of post-AT children with residual SDB and comorbidities that may improve with 
PAP.  The current inclusion criteria and contingency plan are likely to permit the most effective tests of the 
proposed hypotheses. 
 
Recruitment will occur at practices of 9 otolaryngologists who together are estimated to perform 90% of all 
childhood ATs in Washtenaw County.  The investigators have worked with these surgeon groups and their staff 
for 10 years to recruit pediatric subjects successfully, achieving targeted goals for two other NIH-funded R01 
projects.  Co-investigator Susan Garetz, MD, a pediatric otolaryngologist and board-certified sleep specialist, 
will lead recruitment efforts.  In the research now proposed, the investigators will establish contact with families 
and enroll those interested just prior to AT.  Most commonly the clinical decision to perform an AT is based on 
symptoms of obstructed breathing at night, such as loud snoring, restless sleep, snorting with arousals, and 
perceived consequences.  Previous surveys by the investigators have shown that these 9 otolaryngology 
practices rarely obtain polysomnography prior to scheduling AT for a clinical diagnosis of SDB.  This practice 
closely resembles those of North American otolaryngologists more broadly, who obtain polysomnography in 
less than 10% of cases prior to AT for SDB.22 
 
Contact will be made with subjects before AT (as opposed to 4 months later) for two reasons.  First, the 
investigators would like to minimize decisions not to participate simply because good improvement in 
symptoms are seen after AT.  Although every family will have the right to withdraw at any time from the 
research, the investigators believe that even children who improve after AT may well improve further with 
definitive treatment for any residual SDB.  Second, the visit just before AT will allow the investigators to 
administer simple but important questionnaires that will assess SDB symptoms and neurobehavioral morbidity 
at baseline, before any major intervention in most cases.  This could provide important opportunities to explore 
selection bias at study entry; adjust statistical models for SDB or neurobehavioral problem severity at entry; 
compare gains from AT to those from subsequent PAP; and perhaps gain insight into what symptoms prior to 
AT may predict ultimate need for post-surgical PAP that provides additional benefit.  Further, this visit will 
include a very brief cognitive assessment that will give young children experience with a one-on-one testing 
experience to reduce subsequent novelty and improve reliability.  However, an addendum to this protocol also 
allows enrollment after the child’s adenotonsillectomy (at or before study visit 2) for families who are not able to 
to schedule a preoperative study visit due to time constraints at the time of the initial referral, or because they 
were referred only after the surgery.  This will allow more opportunities for participation of eligible children who 
would otherwise have enrolled preoperatively.  
 
. 
 
Adherence to CPAP or BPAP is also central to the proposed research.  The investigators do not wish to set up 
an adherence-promoting system that would be completely unrealistic in clinical practice, for fear that research 
results would not be generalizable.  Furthermore, hypothesis 2b seeks to compare adherent and non-adherent 
subjects.  However, the protocol does have several features that will facilitate adherence and help to ensure 
that about 2/3 of participants are in fact adherent to PAP.  These features include involvement of an equipment 
provider (respiratory therapist at MedEquip) who is particularly experienced with PAP for children; regular 
follow-up by phone and in person with Sue Armstrong, RN (Pediatric Sleep Clinic Nurse) and the study 
coordinator; and intervention whenever necessary by Dawn Dore-Stites, PhD, a child psychologist and faculty 
member of the Pediatric Sleep and Behavior Clinic who specializes in desensitization and other behavioral 
approaches needed to help children and parents adapt to successful use of PAP at home.  Approaches that 
are similar if not quite so thorough (e.g., with weekly contact initially) are routine in our pediatric sleep clinic, as 
at other leading academic programs, and have resulted in a 67% adherence rate in our preliminary data.   
 
Despite their special vulnerability as research subjects, children are involved in this protocol for compelling 
reasons.  Childhood SDB is a distinct entity from the adult form in many respects, and only study of the 
appropriate age group will improve understanding and treatment of childhood SDB.  Large tonsils most often 
play an important role in children whereas they rarely do in adults.  Adenotonsillectomy for SDB is performed 
much more commonly in children than adults.  Vulnerability to effects of SDB during childhood, in comparison 
to adulthood, is complicated by rapid development in intellectual, emotional, and physical spheres that could 
have lifelong impact.  Neurobehavioral consequences of SDB arise in both children and adults, but whereas 
inattention and hyperactivity are often main complaints for families of affected children, adults much more often 

 
focus on daytime sleepiness.  Extensive data from adults are already being generated with regard to CPAP, 
optimal candidates for CPAP, and benefits of CPAP, including neurobehavioral benefits (e.g., see 5 U01 
HL068060), whereas neurobehavioral effects of CPAP in children remain largely unexplored. 
 
The proposed protocol adheres to the ethical principles outlined by the National Commission for the Protection 
of Human Subjects of Biomedical and Behavioral Research.115  Respect for persons is maintained, as the adult 
parent or guardian with full capacity will provide written informed consent, a child over age 8 or able to 
understand the study will provide written assent, and a younger child will give verbal assent.  The principle of 
beneficence is respected as for each participant the potential for personal benefit from this study will outweigh 
the small risks involved.  This study will not subject any child to tests or treatments that stand no chance to 
benefit him or her personally.  This follows from decisions made about the randomized control arm (see 
Introduction), which will involve only standard care and periodic contacts from investigators.  No child will be 
deprived of needed medical care.  Agreement to participate in this research will not prevent any family from 
withdrawing at any time.  Although control subjects will receive no intervention beyond frequent contacts with 
investigators or the program manager, the investigators anticipate based on their previous research that few 
will leave the protocol to seek clinical care.  Those contacts also will be used to ensure that any highly unlikely 
but conceivable situations in which absence of CPAP could pose an urgent medical threat will be detected 
early so that the subject can be removed from the study.  Lastly, the principle of justice is respected because 
the population to be studied will be exactly that which stands to gain most from the results of the study. 
 
For the CPAP group, the dose, frequency, and administration of PAP after AT will follow standard clinical care 
approaches.  Use of the PAP machine will be encouraged for every night and whenever sleep occurs during 
the day.  The pressure setting will be determined in a sleep laboratory during a standard CPAP (or BPAP, 
when necessary) titration study.  Titrations will start at 4 cm of water pressure, a minimal amount necessary to 
counter-act the effects of breathing through the mask and tubing, and provide a slight splinting effect for the 
upper airway.  Sleep technologists experienced with children, in a control room adjacent to the sleep laboratory 
bedroom, will increase pressure settings in small increments until they see no residual evidence of SDB.  If 
CPAP settings become too high, CPAP is not tolerated even at lower settings, CPAP is not effective, or 
hypoventilation persists, BPAP may be tried and titrated in a similar manner.  After scoring by technologists, 
Timothy Hoban, MD (director of the Pediatric Sleep Medicine Program and board certified in sleep medicine) 
will review the entire recording and determine an optimal pressure setting.  Requests for this setting, and 
equipment that proved effective in the sleep laboratory, will then be sent to MedEquip, where an experienced 
respiratory therapist will distribute the equipment to families and educate them on how to use it. 
 
The proposed clinical research will occur at one site (University of Michigan Health System).  Another site, 
Michigan Tech Research Institute (an Ann Arbor unit of Michigan Technological University) will perform signal 
analysis on de-identified recordings.  Otolaryngologists at the University of Michigan and St. Joseph Mercy 
Hospital, also in Ann Arbor, will assist with identification of subjects and families willing to hear more about the 
protocol, and will forward contact information to the investigators on a FAX form.  This form, in use for the past 
11 years, contains minimal information about the scheduled surgery, and a brief signed parental consent for 
investigators to call back to discuss the study.  No identifiable data will be sent from the investigators to St. 
Joseph Mercy Hospital, except in the rare instance in which urgent health information has been uncovered in 
the course of the research.  The protocol then calls for prompt notification of the subject’s otolaryngologist, with 
permission of the parents.  This IRB-approved system has worked well in practice for many years. 
 
6.1.b  Sources of Materials:  Research material will be obtained from questionnaires, interviews, parental 
behavior rating scales, neuropsychological tests, nocturnal polysomnography, and daytime Multiple Sleep 
Latency Tests.  All of these data will be obtained specifically for research purposes.  Access to medical records 
will be requested from the University of Michigan Medical IRB, mainly for any demographic data, medication 
lists, or other information that might be missing from study-specific forms, and not for collection of any of the 
main variables under study.  Each of the investigators will have access to individually identifiable private 
information about human subjects.  Individuals not on the investigative team will not have access to this 
information.  Written data will be stored in locked cabinets, in locked offices, separate from keys that identify 
subject names.  Electronic data will be stored on password-protected, regularly-backed-up server files and on 
DVDs or external hard drives kept securely. 
 

 
6.1.c  Potential Risks:  Only minimal risks are associated with the interviews, behavioral ratings, and 
neuropsychological tests to be administered to children or their parents.  Neuropsychological testing will be 
brief, about 2 hours in total, but could induce some fatigue.  Children who have difficulty with the tests could 
experience some level of anxiety.  Results of testing could in some cases engender parental concern.  
Similarly, risks associated with sleep tests are relatively small.  In preparation for polysomnography, 
particularly for the first time, placement of the esophageal catheter down the nose and throat can create 
transient discomfort or anxiety for some children.  Vomiting, persistent coughing, or nose bleeding occur rarely.  
Other risks of the sleep studies include the stress of an unfamiliar environment, stranger anxieties, separation 
anxieties (e.g., during daytime nap studies), a night of sleep that may not be as restful as that obtained at 
home, and cutaneous allergic reaction or irritation that can occur at the site of electrode or tape placement.  
Finally, as in any research, risks exist for breach of confidentiality and loss of data.  Overall, the benefit to the 
child of sleep study results, neurobehavioral assessment, and what is almost always a fun, positive, and 
memorable experience is likely to outweigh potential harm.  Almost all children and families (95%) who have 
completed similar testing protocols at baseline in the past have been glad to repeat them again one year later. 
 
The protocol also calls for 2/3 of the subjects to use CPAP or BPAP nightly for 6 months.  This requires 
commitment on the part of each child and parent.  However, the treatment is not onerous, and in clinical 
settings CPAP has been used for many years in children of all ages.47  The treatment is considered safe and 
effective in children47, however, PAP devices, most masks, and equipment are not yet FDA-approved for use in 
children.   In adults with sleep apnea, use of CPAP improves quality of life to an extent that substantially 
outweighs any detriment arising from having to use the equipment.116  Randomized controlled CPAP trials now 
commonly use sham CPAP or no CPAP as a control, even in vulnerable or gravely ill populations such as 
patients with amyotrophic lateral sclerosis, heart failure, epilepsy, or stroke.117,118  The research now proposed 
will include a “No  CPAP” comparison group.  However, children who are identified as having excessively 
severe OSA at study visit 2, to the point that the investigators do not have equipoise with randomizing them to 
PAP or no PAP groups, will be withdrawn from the study and referred to clinical care before randomization. 
Surgical and orthodontic alternatives to PAP, after AT in children, are neither well-studied nor widely available.  
Although non-steroidal anti-inflammatory or steroid medications may be of some use in children with the most 
mild sleep-disordered breathing,119 these agents are not universally effective, may fail particularly in more 
severe cases of residual sleep apnea, and can carry their own risks.  The large majority of children who have 
AT at the University of Michigan or St. Joseph/Mercy Hospital receive no SDB-specific testing or treatment 
after their surgical procedure, so the control subjects will not lack intervention they would otherwise receive.  
Like all subjects outside this research protocol, they will have the option to pursue any evaluation or 
intervention they would like outside the research protocol. 
 
Specific risks from using PAP include mask discomfort or irritation of the face.  Nasal congestion or mouth 
dryness can arise from mouth leaks when a nasal mask is used.  Embarrassment at having to use PAP, 
especially if observed by peers, could be another risk, especially for older children.  These risks are not 
generally considered serious, though they need to be addressed to optimize PAP adherence.  Rare but more 
serious consequences can conceivably include infection or changes in pigmentation at a persistently irritated 
site on the face (e.g., the bridge of the nose) or limitation of mid-facial growth during the period when the mask 
is used. Mid-facial growth retardation57 in particular is highly unlikely in the proposed protocol, which requires 
use of the mask for only 6 months.52 There have also been rare reports of a pneumothorax associated with 
PAP use, aspiration of vomit from a PAP mask by a severely developmentally delayed, disabled child, and 
death of a disabled child who became entangled in the PAP tubing.   
 
6.2  Adequacy of Protection Against Risks 
 
6.2.a  Recruitment and Informed Consent:  Potential subjects and their parents or guardians will first hear 
about the study from their pediatric otolaryngologists and associated office staff, at the time that the surgery is 
scheduled.  A parent or guardian willing to hear more about the study will sign a brief consent, and on the 
same one-page form provide (in conjunction with the otolaryngologist) simple information about contact 
numbers, date of surgery, reason for surgery, symptoms of SDB, and likelihood of SDB.  The form will be faxed 
to the investigators. Alternatively, parents of potentially eligible subjects may learn about the study from the 
study brochure provided to patients or the ClinicalTrials.gov posting.  They may then request contact by a 
member of the study team.   An investigator will call the parents to explain that: 

 
 
• We are conducting a study on sleep disorders, behavior, and thinking in children who have AT for SDB; 
• We believe a good number of children with SDB may be affected in these areas;  
• Participation in the research will require either 2 or 3 separate overnight stays in the Sleep Laboratory; 
• Some compensation to both parent and child will be provided for their time and effort; 
• Some children (2/3) will be randomly assigned to use PAP at home nightly for 6 months, starting 4 
months after AT; other children (1/3) will use no PAP during the same period;  
• All data collected will be kept confidential; 
• All participants are free to withdraw from the study at any time; 
• Summary test results will be provided upon request within several months after final testing, when scored 
neuropsychology and sleep results from initial and follow-up sessions are ready; 
• If preliminary review of test results suggests that something may need urgent medical attention, these 
findings will be communicated promptly to the family and treating surgeon.   
 
During this initial phone call, data also will be gathered to ensure that the subject meets inclusion and 
exclusion criteria.  Potential participants and their families will be invited to the Sleep Disorders Center to 
further review the above points, hear about the research protocol in more depth, tour the sleep rooms, see the 
equipment used during sleep studies, and see sample PAP equipment.  At this time, a study team member  will 
obtain signed permission / consent from a parent or guardian and assent from the child.  Children older than 8 
years or able to understand the nature of the research will be asked to sign assent; other children will be asked 
for verbal assent.  One copy of the documents will be placed in the subject’s medical record, one given to the 
parent, and one kept on file by Dr. Ruzicka. 
 
6.2.b  Protection Against Risk:  Fatigue and anxiety during cognitive testing will be minimized by a 
neuropsychology technician who has extensive experience with children and will give breaks from testing as 
needed.  If results of behavioral or cognitive assessments engender parental concern, the child and parents 
will be invited back to a meeting with a child psychologist co-investigator, who will discuss the findings in an 
appropriate manner and review options for further evaluation or treatment outside the research protocol.  Prior 
to study enrollment, tours of the sleep laboratory will give subjects and families a preview of that environment 
and equipment used there, reduce any possible fears or anxieties, and give them a good understanding of 
study requirements in relation to family, school, and job commitments.  Technicians experienced with children 
and anxieties of this age group will conduct sleep studies.  Children will be offered a topical anesthetic prior to 
insertion of the esophageal pressure catheter.  However, children who do not tolerate placement of the 
esophageal catheter (anticipated based on this group’s past work to constitute a minority of these volunteer 
subjects68) or other equipment will not be required to use them.  Parents will stay with children during overnight 
testing to reduce separation anxiety.  Spacious pediatric sleep rooms are designed to include a separate bed 
for the parent.  We will instruct subjects who obtain poor sleep in the laboratory to avoid operating dangerous 
toys, bicycles, and machinery until adequate sleep is recovered.  We will also ask parents to supervise such 
children at home until restorative sleep is obtained.  During sleep studies, a physician investigator will always 
be on call for any unexpected emergencies.  Studies will be performed at the Sleep Disorders Center in the 10-
bed Michael S. Aldrich Sleep Disorders Laboratory, where a 24-hour technical staff including pediatric and 
research technologist pods is well prepared to meet the needs of children and families who participate in 
research.  If a cutaneous reaction to electrode placement occurs, technicians will remove the electrode and 
reapply it at another site with a different type of adhesive.  Mild skin irritation will be treated with topical creams 
as needed.  Moderate reactions at multiple sites, or any severe reaction, will warrant study termination.  
Finally, every effort will be made to ensure, as in the investigators’ past NIH-funded pediatric sleep protocols, 
that this research experience is fun, positive, and rewarding for each subject and family. 
 
Problems with PAP use will be preempted in part by thorough education of parents, and children, about the 
purpose, potential benefits, and importance of nightly adherence.  Participating families will be well educated 
about potential problems, and what to do about them, even before starting PAP.  The PI has some of the 
earliest published experience with strategies to optimize CPAP adherence,120 and the investigators are 
thoroughly familiar with application of this therapy to children.  Best efforts will be made first in the sleep lab, 
just prior to the CPAP titration study, and again at the visit to the durable medical equipment company, to make 
sure each child is optimally fitted for a CPAP interface (generally a nasal mask, though sometimes a face mask 
or nasal pillows).  This will minimize risk for discomfort or irritation. 

 
 
After PAP is initiated, contact initially with investigators will occur weekly (at least by phone) and will provide 
multiple opportunities to detect poor fit before this could lead to serious irritation, wound, or infection.  Mask 
discomfort will be addressed as soon as it is apparent by re-adjustment of headgear straps, or trials of different 
mask models.  Nasal congestion or mouth dryness, depending on the apparent cause, will be ameliorated by 
reducing any mouth leak (e.g., by using a chinstrap); use of a full face mask; nasal saline irrigation; or 
improved use of heated humidification.  Use of PAP on every night will be encouraged: parents and children 
will be educated about its importance, what can happen if PAP is not used, and also the fact that an occasional 
night off PAP could have some consequence – but not enough to make an occasional exception (e.g., for a 
“sleep over” at a friend’s house) impossible.  The concern that long-term use of a PAP mask could diminish 
growth of the mid-face will be broached, but presented as most unlikely to occur within a 6-month protocol. 
 
Some children in this protocol will use PAP without having enough underlying, residual SDB to benefit from the 
intervention.  During the treatment trial, neither investigators nor families will know who these children are.  
Although symptoms may be readily apparent, sleep study results will not be available until after study 
participation is complete, for several reasons.  One is that sleep studies are to be scored in batches -- with 
several subjects’ pre-PAP and post-PAP studies all in the same de-identified batch -- to avoid any influence of 
scoring drift over time.  A second reason is that at present, knowledge about how post-AT care should be 
guided by sleep study results remains quite limited.  The research now proposed, in fact, aims in large part to 
address this void.   
 
Fortunately, subjects without residual SDB after AT, as compared to subjects with SDB, have no known 
additional risks to use of PAP.  When the PAP titration studies are performed, children without SDB will have 
normal breathing, technologists will have no reason to test more than the lowest CPAP settings, and the 
reviewing physician (co-investigator Timothy Hoban, MD) can be expected to assign the lowest settings for use 
at home.  In other studies of adults, even CPAP at fixed pressure settings for all research subjects, whether 
healthy or ill, has been safe whether SDB is present or absent.121-123 
 
Families whose children have been randomized to the control group will be contacted by the program manager 
during the 6-month trial at intervals designed to replicate the frequency of investigator contacts in the CPAP 
group.  Discussion will focus on recuperation after AT, general health, and also any suggestion of serious 
adverse effects that would warrant discontinuation of study participation and referral for clinical evaluation.  
These end-points would include recommendation by a child’s pediatrician or otolaryngologist to pursue this 
option; development of a new, serious cardiopulmonary condition that makes prompt assessment and 
treatment for any residual SDB imperative; or emergence of serious academic or developmental concerns in 
the setting of obvious, persistent symptoms of SDB.  Each questionable case will be brought by the program 
manager to the PI and, depending on the nature of the event as outlined in the Data and Safety Management 
Plan, the DSMB(section 6.5 below) for a decision. 
 
All information collected in the course of this protocol will be treated confidentially.  Written authorization will be 
obtained from a parent or guardian prior to release of any study results, except in the rare case of emergent 
findings that require immediate attention of a child’s clinician.  Applicable IRB, privacy office, and contract 
office approvals will be obtained prior to transfer of data outside the research team.  Printed data will be stored 
in locked cabinets within a locked private office of the program manager.  Data will be linkable to subject 
names only by a key kept separately from the data files.  Computer data will be password-protected, 
accessible only by study personnel, and backed-up to prevent accidental loss.  Published reports will not 
include names or make individual participants readily identifiable in other ways.  These precautions are highly 
likely to maintain confidentiality effectively. 
 
Any unforeseen urgent medical problems that arise during testing will be handled or triaged by the physician 
investigator on call and the technologists at the Aldrich Sleep Laboratory.  This fully accredited facility studies 
about 5 children every night of the week for clinical or research purposes.  Standard protocols are known by 
the technologists and readily available for emergencies such as fire, threatening arrhythmia, or seizure.  Data 
and safety monitoring for this non-randomized clinical trial will proceed as outlined below. 
 
6.3  Potential Benefits of the Proposed Research to Human Subjects and Others 

 
 
Each subject has a significant chance of substantive benefit, at comparatively low risk and expense.  Each 
child will benefit by 1) free testing for residual, post-AT SDB; 2) family knowledge, if desired, of any residual 
SDB after the clinical trial is completed, to facilitate decisions about ongoing care thereafter; 3) identification of 
potentially treatable behavioral or cognitive problems that may not have been suspected or diagnosed in the 
past; 4) participation in research that past subjects and families have often found to be an enjoyable, 
educational, and rewarding experience; 5) development of positive attitudes toward clinical research and ability 
to serve as community liaisons who can raise awareness of SDB among other families and children at risk.  In 
addition, families whose child has been randomized to the CPAP group may benefit from the free, gold-
standard treatment for any possible residual SDB, with careful expert attention to PAP adherence for the 
duration of the trial.  After families have completed the protocol, those from CPAP and control groups will be 
assisted with referrals for any sleep, behavioral, or mental health care that they would like to pursue.  Children 
whose families and pediatricians would like them to remain on PAP will be able to keep the PAP equipment at 
no cost, which could be an important opportunity in some instances.  The CPAP machines that will not 
continue to be used by CPAP group subjects will be returned to the investigators.  These units will be made 
available to any control families who, with assistance from their child’s physician, wish to use CPAP for clinical 
purposes after completion of the research protocol.   
 
Potential benefits to other children of the data to be obtained in this study are significant.  The long-term risks 
to sleep, health, cognition, and behavior of unrecognized and incompletely treated SDB after AT could be 
substantial.  Diagnosis and treatment of residual SDB after AT – now believed to occur in half or more of 
operated children – could have significant impact on social, intellectual, monetary, and health-related spheres 
not only during childhood but into adulthood as well.  Risks to the subject from this protocol are not more than 
“minor over minimal,” as described above.  Therefore, the risk:benefit ratio for children who participate in this 
study and parents who assist them is excellent. 
 
6.4  Importance of the Knowledge to be Gained 
 
For society, the potential benefits are sizable.  Sleep-disordered breathing has high prevalence among children 
(at least 2-3%) and is most commonly treated by AT.  However, current data, perhaps in part because of 
increased childhood obesity, suggest that many children still have some residual SDB after the procedure is 
performed.  This research will begin to clarify which methods best identify appropriate candidates for additional 
SDB treatment after AT, and what benefits can be expected from PAP in this setting.  This research will 
provide some of the first data directly relevant to common clinical decisions – who to evaluate and who to treat 
further after AT – that at present must be made based largely on published pre-operative data that may not 
pertain.  The potential impact of knowledge from this study will therefore be substantial, both in terms of 
improved health outcomes and reduced societal and healthcare costs for children with incompletely treated 
SDB.  Risks of this research arise from testing procedures (neurobehavioral and sleep) that are commonly 
performed in children and generally rated as “minor over minimal risk” at most.  Risks also arise from treatment 
with PAP, but this is not a systemic medication, remains non-invasive, and has overall an extremely favorable 
side-effect profile and safety record in children as in adults.  Finally, risks may arise from randomization of 
some children to receive no PAP.  However, in standard care the vast majority of children who have AT are 
offered no follow-up testing or treatment.  In this protocol, all children will receive follow-up testing, and 
treatment will still be available outside the research protocol to any subject whose family decides to seek 
treatment as part of their standard clinical care.  Therefore, risks for this study seem highly reasonable in 
relation to knowledge to be gained.  No test article is to be used in this research. 
 
 
6.5  Data and Safety Monitoring Plan 
 
The goal of the data and safety monitoring plan (DSMP) will be to protect patient safety and ensure the 
integrity and validity of the data.  We will achieve this with a protocol designed to monitor and report adverse 
events specifically related to the protocol evaluations and PAP treatment, monitor study progress, assess 
appropriateness of continuing or stopping the trial, ensure protocol compliance and data accuracy, and prevent 
biased interpretation of data or conflict of interest.  We will register this trial in a clinical trial registry that meets 

 
NIH approval.  We will elaborate and modify this DSMP as necessary in working with the NIH to formulate 
acceptable approaches. 
 
The original protocol was submitted to NIH and approved for funding with a medical monitor to oversee 
participant safety and data integrity.  But, more recent discussions with the NIH program officer have led to the 
suggestion that this project may be better served by a data and safety monitoring board.  Plans for a DSMB 
have not been elaborated in detail: 
 
Data and safety monitoring for this randomized, controlled, single-site clinical trial comparing CPAP treatment 
to no CPAP treatment after adenotonsillectomy will be accomplished in part by a Data and Safety Monitoring 
Board (DSMB).  The board will be composed of individuals with expertise relevant to this study, its participants, 
or the evaluations and interventions that are planned.  The DSMB board members will be external to the 
investigators, external to the University of Michigan, and otherwise uninvolved in this research.  The DSMB will 
be assembled and guided with assistance from the relevant Program Officer at the NIH.  The DSMB will 
convene, at least annually, and generally by phone, to review and make recommendations regarding 
recruitment and retention, adverse events, any treatment safety concerns, and data quality or integrity.  The 
Principal Investigator will review, grade, and report any adverse events, ORIOs, or unanticipated problems, 
with the assistance of the Program Manager, to the IRBMED, the DSMB, and the NIH program officer as 
required by the approved study-specific DSMP.  
 
Adverse Events 
 
The Principal Investigator will review and assess adverse events for nature, seriousness, severity, frequency, 
expectedness, and relatedness to the study interventions.  Information on adverse events or other significant 
reportable occurrences on this protocol will be reported to the Data Safety Monitoring Board.  The DSMB will 
be responsible for (1) periodic review and evaluation of participant safety, recruitment and retention, and study 
conduct, and for (2) recommendations for continuation, modification, or termination of this clinical trial.  The 
DSMB will be notified of project-related, medical or psychological conditions, or adverse events that may 
require intervention.  Protections against risks in the proposed research will include those detailed above 
(section 6.2.b).  No new intervention, device, or drug is to be studied in this protocol, and risks are likely to be 
considered by the IRB as “minor over minimal,” as in the past for other pediatric sleep research studies at the 
University of Michigan.  The PAP equipment used in the treatment arm of this clinical trial is commercially 
available (by prescription) and commonly used for adults and children with SDB, though PAP is not specifically 
FDA-approved for use in children.   
 
Adverse consequences related to sleep studies, cognitive testing, PAP treatment, or lack of PAP will be 
communicated by the Principal Investigator to the IRB and the DSMB, either individually or in aggregate 
reports, depending on the nature, frequency, severity, and seriousness of the event.  The investigators will 
follow an approved study-specific IRB reporting plan for expected and unexpected adverse events, serious 
adverse events, and unanticipated problems.  The PI, IRB, and the DSMB will be responsible for monitoring 
the safety of the study.  The PI will characterize the nature and grade of the adverse event.  Non-serious 
expected adverse events that may be reasonably anticipated to arise as a result of study procedures will be 
described in the consent form, recorded in practice, and reported to the IRB annually as part of the progress 
report.  SAEs and UaPs related to the study will be reported within 7 days to the IRB, DSMB, and NHLBI 
program officer per the study-specific reporting plan (see the Data and Safety Management Plan) .  The PI or 
designee will notify the DSMB chair and NHLBI program officer about the occurrence of a SAE related to the 
study or any death regardless of attribution within 24-48 hours of the PI being notified of the occurrence.   Non-
serious, expected adverse events that occur with greater than anticipated frequency or severity will be reported 
to the IRB; consent forms will be modified as necessary; and subjects already enrolled will be advised 
accordingly.  Unexpected, nonserious adverse events that are moderate to severe and related to the protocol 
will be reported to the IRB and DSMB within 14 days and to the NHLBI program officer within 30 day if the 
events are unanticipated problems.  An expected but serious adverse event that is related to study 
interventions will trigger notification of the IRB, DSMB, and NIH program officer within 7 days of the event, or  
within 7 days of the date that the study team is notified of the event.  Nonserious unanticipated problems or 
device effects will be reported to the IRB, DSMB and program officer within 14 days of study team awareness 
of the safety issue.  Intercurrent events and adverse events that are nonserious and expected or not related to 

 
the study interventions (for example, common childhood illnesses, peri- or post-operative events or sequelae) 
will not be reported with the exception of a subject death which will be reported in expedited manner regardless 
of attribution.  Participating families will receive written directions and encouragement to contact an appropriate 
physician or nurse at any time, 24 hours per day, 7 days per week, about any medical concern or adverse 
event related to the research study.  In addition, frequent phone and face-to-face contacts, as described in 
section C6 of the research strategy, will be maintained with each family during the clinical trial. 
 
An adverse event log will be maintained by the Program Manager.  The Program Manager will meet weekly 
with the PI to review study progress, any protocol deviations, and resolution of adverse events.  The project 
and consent forms will be reviewed at least once each year by the IRB.  The investigators will prepare a full 
report annually for the DSMB to summarize adverse events, responses of the investigators, and any changes 
to the protocol or consent and regulatory documentation. 
 
Data Monitoring 
 
The annual report from the investigators to the DSMB will include summaries of enrollment, subject 
withdrawals, and numbers of subjects who have completed the protocol.  Any problems with data collection, 
quality, analysis, management, loss, or confidentiality will be described, along with any consequent protocol 
changes and options still available to remedy the concerns.  Interim data analysis, to assess appropriateness 
of trial completion, is not anticipated.  This early stage clinical trial involves extensive study, among 120 
participants, of many variables to be examined in this setting for the first time.  Completion of the trial will 
provide key initial insight into a range of variables that warrant assessment even if other variables prove 
informative with fewer than 120 subjects.  Risks of PAP are small, potential benefits are large, and harm to 
participants from completion of the trial with the full sample size is not anticipated. 
 
DSMB Reports 
 
The DSMB will complete annual reports indicating: a) approval that the study retains acceptable safety and 
data validity; b) approval contingent on specified modification to existing protocols; or c) disapproval for 
continuation based on safety concerns that cannot adequately be addressed, or threats to validity of the data 
sufficient to warrant closure of the study. 
 
If the PI disagrees with recommendations to modify or terminate the study, the DSMB Chair, IRB, and NIH will 
be notified in writing about the disagreement and the reasons for it.  The PI, DSMB Chair, and designated NIH 
official will be responsible for reaching a mutually acceptable decision regarding the recommendations. 
 
6.6  ClinicalTrials.gov 
 
This application includes an applicable clinical trial that requires registration in ClinicalTrials.gov.  The PI, 
unless informed otherwise by the NIH, will be responsible for registering the trial before it begins. 

 
7.  Inclusion of Women and Minorities 
 
The proposed study population – children with SDB – is composed of approximately equal numbers of boys 
and girls, perhaps with a slight preponderance of boys.1  The sex/gender distribution within the proposed 
research sample should reflect this broader population distribution.  Boys and girls will be recruited for this 
study irrespective of gender.  Some evidence suggests that the association between SDB and daytime 
behavioral problems may be more prominent in boys than in girls,9 but not to an extent that would warrant 
exclusion of girls from the research.  Children will be enrolled in year 1 through the beginning of year 4 of this 
project.  Another NIH-funded protocol by the investigators, focused on sleep apnea in children undergoing AT 
between 2005 and 2009, enrolled only slightly more boys than girls within a sample of n = 140.  Therefore, no 
outreach plans are anticipated to be necessary to recruit either gender in the research now proposed.  The 
sample composition should resemble that shown in the Targeted/Planned Enrollment table, extrapolated from 
data on (1) children undergoing AT at this institution from 2006-2009, (2) children (n > 1000) referred to the 
PI’s previous NIH-funded research protocols by the same two Ann Arbor otolaryngology groups that will 
identify potential subjects for the research now proposed, and (3) State of Michigan 2008-2009 health services. 
 
Similarly, SDB affects children of all races and ethnicities.  Some studies suggest excess frequency of SDB 
among African American children,124 but no studies suggest race or ethnicity-based differences in effects of 
SDB on cognition, behavior, or daytime sleepiness, the neurobehavioral outcome variables for this protocol.  
No data or plausible physiology suggest differential response of SDB to PAP among different races or 
ethnicities.  Therefore, recruitment for the proposed research will proceed without plans to select or exclude 
any given race or ethnicity. 
 
In the Targeted/Planned Enrollment table, some races or ethnicities are not highly represented because the 
overall sample size for subjects who complete the protocol is only n = 120; the geographical location of the 
study encompasses only limited numbers for some of these minority groups; and otolaryngology practices 
where subjects will be identified already account for an estimated 90% of all adenotonsillectomies (defining 
eligibility for the study) in a large geographic area (Washtenaw County, population 347,000).  

 
9.  Inclusion of Children  
 
The proposed study will enroll only children, who must be between 5.00 and 12.99 years old at study entry.  
These ages represent a period at which several of the outcomes central to this study, such as inattention, 
hyperactivity, and disruptive behavior, are particularly prominent problems.  Optimal cognitive functioning, 
behavior, and alertness are critical to rapid learning and normal development.  In children less than 5 years 
old, assessment of cognitive function would require different instruments (and generate different data) than 
those that can be used starting at age 5.  Hyperactivity could be more difficult to distinguish from normal 
behavior.  In addition, performance of the Multiple Sleep Latency Test to assess daytime sleepiness becomes 
increasingly difficult in children under 5 years, many of whom still take regular daytime naps.  Above age 12, 
AT is increasingly rare, and morbidity due to SDB is more likely to show an adult pattern with overt daytime 
sleepiness but little or no hyperactivity.64 
  
The investigative team has considerable experience working with children between 5.00 and 12.99 years old.  
Most of the investigative team involved with the proposed research also worked together on 1, 2, or 3 
previously funded NIH awards that focused on SDB in children within the same age range.  This includes Dr. 
Giordani, a neuropsychologist particularly experienced in pediatric research; Dr. Garetz, a faculty member of 
the Division of Pediatric Otolaryngology; Dr. Hoban, who directs the Pediatric Sleep Program; Dr. Ruzicka, a 
program manager who has coordinated or managed NIH-funded pediatric SDB research for 11 years; Mr. 
Guire, a statistician who has assisted with pediatric sleep research for more than 10 years; and Ms. Fetterolf, 
an experienced polysomnographic technologist.  The sleep studies will be performed in the Michael S. Aldrich 
Sleep Disorders Laboratory, a 10-bed, fully accredited facility where pediatric and research pods of interested, 
committed technologists will be available to assist subjects and families who participate in the proposed 
research.  This facility is ideal for children’s sleep research protocols.  Rooms are large enough to 
accommodate comfortably a parent who spends the night with the child.  Sufficient numbers of children are 
included in this study to provide a meaningful analysis, as explained in section C8 of the Research Strategy. 

 
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