Evaluation of the Compensatory Reserve Index and Psychosocial Factors in Pediatric Autonomic Dysfunction
Conditions: Postural Orthostatic Tachycardia Syndrome
Sponsor: University of Colorado, Denver

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                     COMIRB 
Protocol 
 
 
PROTOCOL #: 18-2618 
 
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD 
CAMPUS BOX F-490    TELEPHONE:  303-724-1055 Fax:  303-724-0990 
 
 
 
Project Title:   
Evaluation of the Compensatory Reserve Index and Psychosocial 
Factors in Pediatric Autonomic Dysfunction 
 
Principal Investigator:   
Dr. Clio Pitula 
 
 
Co-Investigators: 
Dr. David Kaplan 
                               Dr. Steven Moulton 
 
 
     Dr. Niti Shahi 
     Gabrielle Shirek 
     Noelle Whitney 
     Dr. Rachel Workman 
     Adam Goldsmith 
     Dr. Ryan Phillips 
     Dr. David Leopold 
     Jamie Shoop MA 
 
 
 
     Alex Schwartz 
 
Version Date:  
September 29, 2019 
 
I. Hypotheses and Specific Aims:   
 
Specific Aims:  
1) Evaluate the Compensatory Reserve Index (CRI) (i.e., decrement in CRI from supine to standing 
position) in youth (12 to 21 years old) with Postural Orthostatic Tachycardia Syndrome (POTS; a 
type of autonomic dysfunction) compared to youth without POTS.  
2) Assess associations between CRI values, hypermobility, and parent- and youth-reported 
symptoms of POTS and associated functional impairment, to determine the utility of CRI in indexing 
the severity of Autonomic Dysfunction/POTS. 
3) Examine psychosocial factors measured by parent and youth report (i.e., symptoms of anxiety 
and depression, sleep quality, social connectedness, friendship, family functioning, parent 
behaviors, and parent mental health) in a representative sample of youth with POTS compared to 
youth without POTS. 
 
Hypotheses: 
1) Participants with POTS will have a greater change (decrease) in CRI from baseline following 
positional changes (i.e., supine to standing) than participants without POTS. 
2) Greater change in CRI and/or lower minimal CRI value will be associated with greater severity of 
symptoms, as measured by increased frequency of parent- and youth-reported symptoms and 
greater degree of functional impairment.   
3) Participants with POTS will show more psychosocial difficulties than participants without POTS, 
indexed by scores on parent- and youth-report measures of anxiety, depression, sleep quality, 
social connectedness, friendship, family functioning, parent behaviors, and parent mental health. 
 

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II. Background and Significance:  
Pediatric Autonomic Dysfunction. Autonomic dysfunction (or dysautonomia) describes several 
medical conditions linked to the autonomic nervous system. One of these is Postural Orthostatic 
Tachycardia Syndrome (POTS). In pediatric populations, symptoms of autonomic dysfunction 
include an increase in heart rate when standing up (tachycardia), dizziness, nausea, vomiting, 
fatigue, headaches, abdominal discomfort, and sleep disturbances (9,10). POTS is specifically 
characterized by orthostatic intolerance and a forty beats per minute (bpm) increase in heart rate 
upon standing. The etiology of POTS is poorly understood, and there is limited literature on the 
management of POTS in pediatric populations. In the U.S., POTS is estimated to affect 1-3 million 
people (8, 11). Research to date indicates that individuals diagnosed with POTS are predominately 
female (87.7%) and Caucasian (85.1 to 94%) (8, 11). According to one source in the U.S., the 
mean age at presentation is 15.6 years old (11). 
 
Initial presentation of POTS often occurs following prolonged recovery from a viral illness 
or physical injury (9, 10). POTS has been associated with significant functional disability and 
psychological distress, oftentimes persisting after the inciting illness resolves. Many physicians 
currently use a tilt table test and traditional vital signs measurement (e.g., blood pressure) to assess 
the presence of POTS. However, the tilt table test has notable limitations. For example, tilt table 
tests and orthostatic vital signs have been shown to lead to different heart rate responses with a 
standing position, specifically a higher increase in heart rate in the tilt table group (66). In this study 
by Plash et al. (66), the changes in heart rate in tilt tests and orthostatic vital signs were compared 
in subjects with autonomic dysfunction and healthy controls; ultimately, orthostatic vital sign 
measurement (over 10 minutes) was found to be superior to a 10-minute tilt table test in accurately 
identifying patients with autonomic dysfunction. There was also a higher rate of false positive results 
in the tilt table group (66). Thus, it is very important to develop more effective and efficient tools to 
screen for and assess POTS illness severity, and it is essential to improve our understanding of 
psychosocial factors associated with POTS, as these may serve as risk and/or protective factors in 
individuals with POTS. 
 
Compensatory Reserve Index. One of the most difficult tasks in clinical medicine is the 
assessment of decreasing volume status (4). This evaluation is usually made by physical 
examination and a review of the patient’s traditional vital signs: heart rate (HR), blood pressure 
(BP), respiratory rate, and oxygen saturation. These vital signs are, however, notoriously unreliable 
(18, 19). As computing power and computational methods improve, it is now evident that current 
monitoring technology is allowing physiological information to pass by unseen and unharnessed. 
Many pathological states have been characterized by analysis of simple, continuous physiologic 
waveforms, and previous studies have demonstrated that photoplethysmogram (PPG) waveforms 
obtained with a pulse oximeter sensor significantly change with volume loss (20-24). In a series of 
previous experiments, Dr. Steve Moulton (co-investigator on this protocol) and his colleagues used 
advanced feature extraction and machine-learning methods to extract information from PPG 
waveforms generated in a model of human blood loss, resulting in an algorithm called the 
Compensatory Reserve Index (CRI) (e.g., 31).  
 
The ability of the CRI algorithm to accurately distinguish individuals with varying tolerances 
to reduced central blood volume can be attributed to a unique function of the algorithm, which 
analyzes and compares the entirety of each waveform in a window of time to trend subtle features 
that correspond with varying degrees of central volume loss. This analytical advantage is based on 
the relationship described by the arterial waveform (ejection wave) and peripheral vascular 
resistance (reflected wave). As such, all mechanisms associated with compensation for central 
volume loss are represented in each waveform. Thus, subtle changes in waveform features, which 
are detected by the CRI algorithm, allow it to differentiate individual patients (i.e. those with high or 
low tolerance to central volume loss) within the first thirty beats of monitoring and every beat 
thereafter (29-31).  The CRI algorithm estimates the following quantity: 
CRI = 1- [BLV/BLVHDD] 

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Where BLV is the current blood loss volume of the patient and BLVHDD is the blood loss 
volume at which the patient will experience hemodynamic decompensation (SBP < 80 mm Hg) (31). 
CRI ranges from ‘1’ to ‘0’ and corresponds to the body’s ability to compensate for acute intravascular 
volume loss (Figure 1 below).  A CRI of ‘1’ equates to supine normovolemia, while a CRI of ‘0’ 
equates to being volume depleted and unable to compensate (cardiovascular collapse, SBP < 80 
mm Hg).  CRI values between ‘1’ and ‘0’ indicate the proportion of reserve remaining before 
hemodynamic decompensation—much like the fuel gauge of a car indicates the amount of fuel 
remaining in the tank.  When a patient loses intravascular volume due to bleeding or dehydration, 
the “tank” empties and CRI goes down.  With appropriate fluid resuscitation, the “tank” refills and CRI 
goes up. The CRI can also be affected by autonomic vascular tone.  Dr. Moulton and his colleagues 
have subsequently shown that changes in CRI can be used to detect low volume blood loss with 
greater sensitivity and specificity than traditional vital signs (62,63).   
 
CRI can also detect vascular changes associated with postural orthostatic tachycardia 
syndrome.  Stewart et al. (64) described a patient with POTS whose traditional vital signs and CRI 
values were measured during positional changes. “The CRI was measured during a stand-to-supine 
demonstration conducted on a 16-year-old girl, who had developed postural orthostatic tachycardia 
syndrome (POTS) 6 years earlier. Figure [1] shows her continuously recorded HR (upper panel) and 
CRI values (lower panel). She demonstrated a typical tachycardic response (average HR, 120-125 
bpm) when she was asked to quietly stand; her average CRI was 0.17. At 3 minutes, the subject was 
instructed to assume a supine posture. Within 30 seconds, the subject became clinically “normal,” 
with a HR of 60 bpm and CRI >0.8. After 2.5 minutes in the supine posture, the subject stood up, 
resulting in immediate tachycardia and a drop in her CRI to nearly 0.2” (64, p. 9-10).” 
 
Figure 1.  Heart rate (top) and compensatory reserve (bottom) measured during a 5-minute 
orthostatic test in a patient with postural orthostatic tachycardia syndrome (copied from 64). 
 
Compared to traditional vital signs, CRI may be less influenced by anxiety than heart rate 
and may be more useful than heart rate in trending values over time. Because of the strong 
association between anxiety and POTS, we hypothesize that CRI may be a more accurate measure 
for diagnosing POTS than just relying on changes in heart rate. Moreover, CRI could greatly improve 
our ability to guide treatment among youth with POTS, by providing a continuous, non-invasive, 
physiologic parameter that is specific, sensitive, and instantaneous. Other than the one case report 
cited above, there are no prior studies that use CRI to evaluate POTS patients and assess if there 
is an association between CRI values and reported mood and functional status of the patient.  Li et 
al. (5) utilized the FinometerPro to evaluate the hemodynamic status (with noninvasive blood 

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pressure monitoring) of patients with POTS, but did not have a comparison control population or an 
association with common symptoms. Clearly, further research is needed to determine the utility of 
CRI in: 1) refining the diagnostic criteria for POTS; 2) stratifying pediatric POTS patients by 
autonomic instability, 3) evaluating the effectiveness of various interventions; and 4) determining 
prognosis among youth with POTS. 
 
Many factors can influence the validity of CRI, including vasoactive medications and 
conditions such as dehydration (67). This study will be executed in an outpatient setting, where 
there is minimal risk of the effect of vasoactive medications. In the POTS patient population, 
dehydration is common, with a decreased blood volume in up to 70% of patients (68, 72). While 
dehydration can trigger POTS symptoms, the specific etiology for the high rate of dehydration in 
POTS patients is poorly understood. Dehydration can also exacerbate present POTS symptoms. 
As a result, POTS patients are recommended to drink 2-3 L of fluids daily and supplement their salt 
intake for a goal of 10-12 g/day (72). Dehydration leads to decreased central blood volume and has 
been shown to be associated with lower CRI values in a prior study by Gagnon et al. (67). Urine 
specific gravity, the measure of the weight of the particles in urine, has been widely used in human 
studies via refractometers for assessment of fluid status (70). To better evaluate the CRI changes 
attributed to POTS, the hydration status of study subjects will be evaluated with urine specific 
gravity, and subjects with elevated urine specific gravity will be asked to drink an electrolyte-rich 
solution to improve their hydration status. Then, the CRI values and vital signs will be measured 
again in order to more accurately assess POTS patients (while they are hydrated). 
 
Psychosocial Correlates. There is some evidence that patients with POTS are more likely to 
experience psychiatric problems, including depression, anxiety, and pain catastrophizing (8). These 
patients are sometimes misdiagnosed with a psychiatric disorder prior to an official POTS diagnosis 
(8). However, because studies showing a link between anxiety, depression, and pain catastrophizing 
in POTS have been limited by small sample sizes (e.g., n = 33 in 14) and the absence of an 
appropriate comparison group (e.g., 14; 15), the associations between psychiatric symptoms, 
functioning, and the severity of POTS are poorly understood (14, 15). Co-morbid conditions such as 
hypermobility may also affect the severity of POTS’ symptoms. Patients with hypermobility appear 
to have more associated psychological issues, especially anxiety, than non-hypermobile POTS 
patients, even though their orthostatic measurements appear similar. In a study by Miglis et al., POTS 
patients with hypermobility were more likely to have outpatient visits and chronic pain symptoms 
(65). Further research is necessary to evaluate the differences in psychologic functioning between 
autonomic dysfunction patients with and without hypermobility 
 
Additionally, sleep disorders are frequently reported in the literature on pediatric POTS, 
although sleep studies in adults have not shown a consistent link (7).  Importantly, social-interaction 
factors, including social connectedness and parent-child relationships, appear to impact and be 
influenced by POTS symptoms; for instance, many youth with POTS express feeling socially 
isolated. Parents often describe difficulty in knowing “how much to push” their children to re-engage 
with activities, and parents express feeling stressed themselves (e.g., based on authors’ clinical 
experiences). Research with pediatric chronic pain patients suggests that parental behaviors (e.g., 
accommodating, minimizing, and empathic support) and family functioning (e.g., family 
communication, problem solving, and satisfaction) are associated with children’s functioning and 
pain-related disability (16, 17). Parental behaviors and family functioning are likely to play a 
significant role in understanding the risk for functional impairment in other chronic pediatric 
conditions, namely in POTS (17). However, research has not yet explored these variables among 
pediatric patients with POTS. Taken together, further research is very much needed to better 
understand to what extent psychiatric symptoms, sleep, and social interaction factors are 
associated with POTS. Thus, the third aim of the present study is to examine these psychosocial 
factors in a representative group of pediatric patients with POTS compared to healthy control 
subjects, in order to broaden our understanding of factors associated with POTS.  
 
 
III. Preliminary Studies/Progress Report:    

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Preliminary Studies. In preparation for the current study, preliminary data have been gathered on 
12 POTS patients from the CHCO Adolescent Medicine Clinic. Vital signs and CRI values were first 
measured in a supine position every minute for a total of 5 minutes (Phase 1). Then, the patients 
were asked to assume a standing position for the same measurements for 10 minutes (Phase 2). 
The remainder of measurements were taken when the patient resumed a supine position for 5 
minutes (Phase 3). These patients were found to have an increased heart rate in a standing position, 
as expected, in addition to a significant drop in CRI ≥ 0.5 from their baseline supine values. Means 
and standard deviations for these pilot data are shown in Table 1 below; note, the method of 
calculating the changes in HR and CRI was based on that used in Singer et al. (2012), i.e., to 
compare the value 30 seconds before tilt (most closely approximated by our minute 5 of Phase 1) 
with the value 5 minutes into the tilt (our minute 5 of Phase 2). These preliminary results support the 
potential usefulness of a continuous, real-time measure of compensatory reserve as a sensitive and 
specific assessment of orthostatic instability. Further research is necessary to expand the size of 
the study group with POTS and establish a control group for comparison for vital signs and CRI 
values. 
 
Table 1. Pilot Data on Heart Rate and CRI in 12 Adolescent Patients with POTS 
 
 
Heart Rate (beats per 
minute) 
M (standard deviation) 
Compensatory Reserve Index 
M (standard deviation) 
Supine (minute 5 Phase 1) 
75.4 (15.7) 
0.77 (0.17) 
Standing (minute 5 of Phase 2) 
105.6 (20.5) 
0.27 (0.15) 
Absolute change with standing 
30.2 (12.9) 
0.50 (0.17) 
CRI = Compensatory Reserve Index; Phase 1 refers to first supine period, and Phase 2 refers to 
standing period. 
 
Our pilot participants’ heart rate increment with standing is relatively consistent with the 
average increment reported in the literature in adolescents with POTS (i.e., Singer et al., 2012, 
reported a mean of 32 bpm and standard deviation of 14 in their sample of 654 adolescent patients). 
This increment has been found to be significantly larger among POTS patients than healthy 
adolescents tested with the same procedure (e.g., mean of 27 bpm and standard deviation of 13 
reported by Singer et al., 2012 in their sample of 106 normal control subjects). There are no known 
data on how CRI changes in response to postural changes in healthy adolescents, and thus this will 
be an important contribution of the present study.  
 
Moreover, preliminary data on psychosocial factors associated with POTS have been 
obtained in a previous study by Dr. Pitula (with her colleague, Dr. Jessica Malmberg). By examining 
more than 20 adolescents with POTS as part of an intervention study, Dr. Pitula has observed that 
psychological factors including symptoms of anxiety and depression, social connectedness, and 
parental behaviors appear to be involved in predicting functional impairment resulting from POTS 
symptoms. Moreover, these factors seem to play an important role in predicting engagement in 
interventions.  
 
Research Personnel. Members of the research team have extensive clinical and research 
experience in the fields of adolescent medicine and psychology generally as well as specific 
expertise in child and adolescent autonomic dysfunction and CRI calculation and measurement. 
Moreover, they have access to adolescents (12-21 years old) with autonomic dysfunction/POTS 
through their own practices in Adolescent Medicine as well as professional relationships with 
physicians in several specialty departments where patients with POTS tend to present, including 
cardiology, neurology, genetics, psychiatry, and gastroenterology. 

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Principal Investigator (PI): Clio Pitula PhD is a Licensed Psychologist and an Assistant Professor 
in the Departments of Pediatrics and Psychiatry at the University of Colorado School of Medicine 
(UCSOM). In her work to date, she has helped to develop and facilitate a psychological group 
intervention program for adolescents (13 to 18 years) with autonomic dysfunction at CHCO, as part 
of a research study on which she was the co-investigator. She is currently involved in a multi-
disciplinary clinic within Adolescent Medicine aiming to provide assessment and brief intervention to 
youth with autonomic dysfunction and POTS, as well as chronic fatigue. Dr. Pitula has published 
multiple research studies pertaining to the functional adaptation of youth who are at-risk for mental 
health problems, and as such has demonstrated her high level of competence in the development, 
completion, analysis, and dissemination of scientific research. 
Co-investigators:  
Steven Moulton MD: Dr. Steven Moulton is a tenured Professor of Surgery at the University of 
Colorado School of Medicine and Director of Pediatric Trauma and Burn Programs at Children’s 
Hospital Colorado. His research spans the fields of trauma and burn care, resuscitation, and 
hemodynamic monitoring. He co-founded Flashback technologies with Jane Mulligan and Greg 
Grudic, and together they developed the first, FDA cleared medical monitor (the CipherOx CRI M1) 
for continuous, beat-to-beat non-invasive assessment of acute blood loss.  He is actively involved 
in research in trauma and pediatric surgery and has authored (and co-authored) more than 70 peer-
reviewed articles and 15 book chapters. 
David Kaplan MD: Dr. David Kaplan is a tenured Professor of Pediatrics at the University of 
Colorado School of Medicine, Head of Adolescent Medicine, and Chief Medical Information Officer 
at Children’s Hospital Colorado. Throughout his career, he has concentrated on improving access 
to health services for adolescents by developing programs that impact the major morbidity and 
mortality among adolescents and young adults. His clinical practice is focused on seeing 
adolescents with combined medical and emotional problems, particularly patients with chronic 
fatigue, POTS, depression, and anxiety. 
Niti Shahi MD (Primary contact): Dr. Niti Shahi is a general surgery resident from the University 
of Massachusetts and a current pediatric surgery research fellow at Children’s Hospital Colorado 
(2018-2020) with a focus in trauma and burn with an interest in clinical outcomes research and 
machine learning with CRI. She is working on developing multiple clinical research studies including 
prospective and retrospective studies. She has experience in study design and data collection, 
leading to the publication of multiple manuscripts. 
 
Gabrielle Shirek BA: Gabrielle is a pediatric surgery research coordinator in Dr. Moulton’s Lab. 
She is working on multiple projects in trauma in burn and will play a key role in enrollment of study 
patients. 
 
Ryan Phillips MD: Dr. Ryan Phillips is a General Surgery Resident who spending two years as a 
Pediatric Surgery Research Fellow at Children’s Hospital Colorado. His research focuses on 
numerous aspects of pediatric trauma, burns, and fetal diagnosis and treatment. He is leading 
numerous multi-center trials where Children’s Colorado is the primary study site.  
David Leopold MD: Dr. David Leopold is a current Pediatric Surgery research fellow (2016-
present) who has led multiple studies in the implementation of the CRI device in different patient 
populations. He has extensive familiarity with the machine learning based Compensatory Reserve 
Index and has conducted multiple prospective and retrospective investigational studies using this 
technology to predict hemodynamic instability and clinical outcomes.  
Jamie Shoop MA: Jamie Shoop is a pre-doctoral psychology intern at Children’s Hospital Colorado. 
Her research primarily explores social influences on risk and resilience during adolescence. Having 

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worked on multiple research projects, she has experience with data collection and analysis and has 
published multiple peer-reviewed manuscripts.  
 
Alexandra Schwartz BA: Alexandra Schwartz is a Master of Public Health in Applied Biostatistics 
student at the Colorado School of Public Health. Her research experience has focused on 
adolescent depression and anxiety. She has worked on multiple research projects, she has 
experience with study design, data collection and analysis.   
 
Other study personnel include: Rachel Workman MD, Noelle Whitney, Adam Goldsmith 
 
IV. Research Methods 
 
A. Description of Population to be Enrolled: 
 
This study aims to enroll pediatric participants and their parent/legal guardian(s). 
 
Inclusion criteria: 
Adolescent participants must be aged 12 to 21 years (inclusive). Each participant must have at one 
parent/legal guardian who can provide informed consent for the adolescent and participate in the 
study by completing study questionnaires. Adolescents will be recruited into one of two groups: 
POTS participants and healthy controls. In order to recruit two groups of similar participants who 
differ 
primarily 
on 
whether 
they 
have 
POTS, 
healthy 
controls 
will 
be 
loosely matched to POTS participants on the basis of age, gender and race/ethnicity (i.e., Caucasian, 
Black or African-American, Hispanic/Latino, and other). Thus, as part of recruitment and scheduling, 
participants will be called for pre-screening for demographic information (i.e., age, gender, and 
race/ethnicity), and we will attempt to loosely approximate the demographics of POTS patients (e.g., 
aiming for gender and race proportions within 5-10% of POTS patients, aiming for mean age within 
1-2 years). Moreover, as the majority of study measures are only validated for use in English, only 
English-speaking patients will be included in this study. 
 
As discussed in the data analysis plan below, we aim to have 105 completed adolescent participants 
per group, i.e., 210 adolescents, plus one parent per adolescent, resulting in a total number of 
participating individuals of 420. As described in the application form, we will aim to recruit up to 250 
adolescents to allow for drop-out during the study visit.  
 
POTS Participants. Participants must have been diagnosed by a healthcare provider with POTS. 
Healthy Controls: Participants do not have a diagnosis of any form of autonomic dysfunction. 
“POTS” participants that do not meet physiologic criteria: There may be some subjects with an 
existing diagnosis of POTS who do not meet the physiologic criteria, i.e., an increase of heart rate 
greater than 40 bpm with standing. These participants will be included in the POTS group consistent 
with an intent to treat model. However, exploratory analyses will consider how this difference may 
impact study findings (e.g., primary analyses conducted with and without these participants’ data; 
comparison of these participants to the remaining POTS participants and healthy controls).  
 
Exclusion criteria: 
Adolescents will be excluded from the study if they are outside the age range of 12-21 years old, or 
are wards of the state, incarcerated, decisionally impaired (i.e., have difficulty understanding the 
protocol during the consent process, and/or research team member is unsure of individual’s ability 
to correctly identify whether the research study would need to stop or not), object at any time to 
participating in the study, have a pacemaker, are taking beta blocker medications, or were 
hospitalized in the past month for serious medical conditions affecting their cardiopulmonary system 
(note, this does not include recent hospitalizations for trauma or burns). Adolescents will also be 
excluded if their parent/legal guardian(s) are unwilling to participate in the study and/or do not have 
legal custody of the adolescent participant. Lastly, adolescents who do not speak English will be 
excluded from the study as majority of the study measures are only validated in English. 

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B. Outcome Measures: 
 
For adolescent participants: 
 
1. Demographic information (from pre-screening phone call and intake form): Gender, race, 
ethnicity, Date of screening. Parents will also be asked about their household income and 
highest education level. 
2. Measurement of CRI values and changes in CRI will be conducted with a supine position for 
5 minutes, followed by a standing position for 10 minutes, and then a return to supine position 
for 5 minutes (see below for rationale). The time on the device (and device number) will be 
recorded prior to CRI value collection in addition to the actual time from a room clock or 
wristwatch. The time of CRI measurement (and thus the entire study visit) will be standardized 
to afternoon.  
3. Measurement of Orthostatic Vital Signs: Traditional orthostatic vital signs will be measured 
concurrently with CRI values. In POTS patients, after a supine position, heart rate is expected to 
increase >40 bpm (beats per minute) within 10 minutes of an upright position (78,79). We plan 
to conduct measurements with an initial supine position for 5 minutes, standing position for 10 
minutes, and then a supine position for 5 minutes for both measures. Height and weight will be 
obtained by research staff. 
4. Urine specific gravity will be measured and reported for each patient via the use of a 
refractometer.  
5. Hypermobility: The Beighton Score is a validated measure used to evaluate hypermobility in 
children on a scale of 0-9 for different joints using 3 score bands (32).  
6. History intake form: A brief history will be conducted by research staff (jointly with 
the adolescent participant and his/her parent). The following measures will be 
obtained: 
a) Onset of symptoms (month and year) 
b) Diagnosis of POTS (month and year) 
c) List of medications and dosages 
d) Current treatment regimen: We will ask parents and subjects about their current 
treatment regimen for POTS including medications, salt supplementation, and current 
therapy (e.g., physical therapy, psychiatry, psychology). 
e) Other medical diagnoses. 
7. Survey utilization: 
1. List of physical symptoms: Patients will be asked about the frequency of physical 
symptoms on a scale of 0-3 (Not at all-0, Several days-1, More than half the days-2, 
Nearly every day-3) for the following symptoms: Fatigue, dizziness/syncope, weakness, 
headaches, 
chest 
pain, 
heart 
racing/palpitations, 
sweating, 
shortness 
of 
breath/diaphoresis, abdominal (tummy) pain, nausea, vomiting, menses (periods) pain, 
cry easily, altered temperature sensation/heat intolerance, discoloration of extremities, 
peripheral edema/venous pooling, numbness, brain fog, diarrhea, constipation, blurred 
vision, muscle pain, joint pain, exercise intolerance/shortness of breath with activity, 
insomnia/trouble sleeping, joint hypermobility, sensitivity to light/photophobia, early 
satiety, and other (11, 33). Each symptom endorsed will be multiplied by its frequency 
(i.e., 0, 1, 2, or 3) to result in a total score representing the sum of weighted items. 
2. Anxiety/Stress frequency: This scale asks patients to rate their perception of the 
frequency of anxiety and stress experienced from environmental influences on a scale 
of 0-3 (Not at all-0, Several days-1, More than half the days-2, Nearly every day-3).  
3. Sleep survey: Insomnia subscale and one sleep quality item drawn from Children’s 
Report of Sleep Patterns, total 7 items, Meltzer et al. and consistent with the Pittsburgh 
Sleep Quality index described by Buysse (34, 35). 
4. Revised Child Anxiety and Depression Scale (RCADS and RCADS-P): The RCADS 
is a well-established survey tool used to assess symptoms of anxiety and depression, 
and this tool has been validated in cross-cultural samples with over 88,000 children (36). 

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There is also evidence that this measure retains its validity when used in adult samples 
(i.e., 18 plus) (76). 
5. Functional disability inventory (FDI): The Functional disability inventory, established 
by Walker and Greene, is a valid measure of perceived activity limitations in children 
and adults (39). Participants will be asked to complete a 15-question survey to evaluate 
the difficulty of daily tasks with a scale of impossible (4), a lot of trouble (3), some trouble 
(2), a little trouble (1), and no trouble (0) (39). This measure will be adapted very slightly 
to reflect the ubiquity of electronic media for today’s adolescents, i.e., question 11 will 
be modified from “Watching TV” to “Watching TV and other screens.” This measure 
yields an overall summed score.   
6. Social Connectedness Scale: The Social Connectedness Scale, developed by Lee, 
assesses the responder’s perceptions of social connectedness (i.e., the perception of 
interpersonal closeness with the social world) through 15 self-report items (please refer 
to Lee, Dean, & Jung, 2008, for 15-item version compared with 20 item version) (40, 
41). Note, for adolescents in college, we will administer the Campus Connectedness 
Scale, which is an adaptation of the SCS by the same authors. 
7. Friendship: The “Close Friend Support/Regard” subscale of the Social Support Scale 
for Children and Adolescents (42, 43) will be used to assess the adolescent’s perception 
that he/she has a close friend who he/she can tell problems to, who truly understands 
him/her, who he/she can complain to about things that bother them, who he/she can 
spend time with, and who really listens to what he/she says. This subscale comprises 6 
items rated on a Likert scale from “really true for me” and “sort of true for me” for the 
positive phrasing of the item (e.g., “Some teenagers have a close friend who really 
understands them”) to “sort of true for me” and “really true for me” for the negative 
phrasing of the item (e.g., “Other teenagers don’t have a close friend who really 
understands them.”). Given that some participants will be above 18 years, we will modify 
the wording to “some people”.  
8. Frequency of friendship contact: Participants will be asked to indicate, over the past 
month, on how many occasions they have spent time with a close friend outside of 
school (i.e., free entry). 
9. Family Assessment Device General Functioning scale (GFS): The Family 
Assessment GFS is a twelve-point scale that evaluates the “overall health or pathology 
in family functioning” via analysis of six dimensions of family functioning: problem 
solving, communication, roles, affective responsiveness, affective involvement, and 
behavior control (44-46). This scale has been validated with established psychometrics 
in multiple prior studies with comparison to other self-reported family measurements 
(44, 47). 
10. Sexual 
maturity 
Rating 
(Tanner 
stage): 
This 
questionnaire 
with 
image 
demonstrations of the different Tanner stages will ask patients to self-report their 
appropriate Tanner stages (55, 56). The Tanner Sexual Maturity Rating has been widely 
utilized for evaluation of growth and development and endorsed by the Bright Futures 
AAP guidelines (74). Self-assessment of Tanner stages has been validated in the 
adolescent population (75). In female patients, the scale will document the Tanner 
stages in respect to of breasts and pubic hair. In male patients, the scale will document 
the presence of a pubic hair. Subjects will be asked to complete a survey with images 
representing their own pubertal development (56).  
 
For the parent/legal guardian(s): 
1. Functional disability inventory (FDI): The Functional disability inventory, established 
by Walker and Greene, is a valid measure of perceived activity limitations in children 
and adults (39). Parents will be asked to complete a 15-question survey to evaluate the 
difficulty of daily tasks with a scale of impossible, a lot of trouble, some trouble, a little 
trouble, and no trouble (39). This measure will be adapted very slightly to reflect the 
ubiquity of electronic media for today’s adolescents, i.e., question 11 will be modified 
from “Watching TV” to “Watching TV and other screens.” 

10 COMIRB 18-2618 Pitula 
 
 
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2. Revised Child Anxiety and Depression Scale – Parent Version (RCADS-P): The 
Revised Child Anxiety and Depression Scales-Parent Version (RCADS-P) is a 47-
question survey created for parents to assess parents’ perception of symptoms of 
anxiety and depression in their children. (37, 38). 
3. Family Assessment Device General Functioning scale (GFS): The Family 
Assessment GFS is a twelve-point scale that evaluates the “overall health or pathology 
in family functioning” via analysis of six dimensions of family functioning: problem 
solving, communication, roles, affective responsiveness, affective involvement, and 
behavior control (44-46). This scale has been validated with established psychometrics 
in multiple prior studies with comparison to other self-reported family measurements 
(44, 47). A score greater than 2 for each question was determined as the cut-off for a 
healthy response (47). These instruments will be framed in light of living with their child 
with POTS symptoms, to reduce the likelihood that parents will feel blamed due to being 
asked these questions, i.e., “There are many ways in which caring for a young person 
with chronic illness can affect people’s lives. Below are some statements that may or 
may not apply to you.” 
4. Parent Behavior Adult Responses to Children’s Symptoms (ARCS): The ARCS is 
a 29-point scale with a goal of assessment of parent responses to their children’s 
symptoms (i.e. protectiveness, minimization, encouragement, and monitoring). Existing 
research suggests that parental response style is associated with functional impairment 
and mental health in chronic pain populations (16). Less is known about the role that 
parental response style plays in understanding physical and emotional functional in 
pediatric POTS patients, despite calls from researchers to explore this issue (48). The 
psychometrics of the ARCS has been studied in regard to the specific factors: protect, 
minimize, and encourage and monitor (49). 
5. Parent Mental Health (PHQ-9, GAD-7): Parents of children with chronic medical 
conditions tend to experience higher levels of anxious and depressive symptoms (50). 
The chronic pain literature suggests that parent mental health and child functioning are 
closely linked, such that parents who are functioning better tend to have children who 
are functioning better, as well (51). Additional research from the chronic pain literature 
suggests that parent mental health may directly impact parental response to children’s 
symptoms (52). The Parent Mental Health scales, Parent Health Questionnaire 9 item 
scale (PHQ-9) and Generalized Anxiety Disorder 7 item scale (GAD-7), are short self-
reported questionnaires that are widely used with established psychometrics in the 
parent population (53, 54).  
 
C. Study Design and Research Methods 
A control group of 100 participants and a group of 100 participants with POTS will be recruited for 
the study. The subjects and their parents will participate in one research clinic visit for the study. 
 
Recruitment of POTS participants: 
Participants with POTS 12 to ≤21 years old will be recruited from clinics in Children’s Hospital 
Colorado including those in the departments of Adolescent Medicine, Neurology, Gastroenterology, 
Cardiology, and Genetics. To determine the pediatric POTS population, a search of medical records 
by ICD codes in EPIC for POTS using the Snomed grouper for Postural orthostatic tachycardia 
syndrome (Concept ID C1299624, includes ICD 10 code I49.8 and ICD 9 code 337.9) will be 
conducted. Research team members will first identify potential subjects through their clinics with 
whom they have a treatment relationship (e.g., Dr, Kaplan’s Adolescent Medicine clinic). A letter 
briefly describing the study will be sent to these patients (and/or their parents) to inform them about 
the study and provide them with the research team’s contact information. For patients who do not 
have a treatment relationship with research team members, we will provide the patient’s provider 
with this letter template; they will also be provided with a HIPAA-A form to allow us to contact families 
they see in their clinics, and/or they can give interested families our research team’s contact 
information. Additional advertisement for the study will be provided through posters placed in CHCO 

11 COMIRB 18-2618 Pitula 
 
 
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clinics; emails will be sent to providers identified as working with these patients, and an 
advertisement will be placed on the University of Colorado Clinical Trials website. Subjects will be 
financially compensated $50.00 for participating in the study, and they will be provided with a letter 
from the study team and a certificate acknowledging their contributions to the research study. Once 
study patients have been recruited for the study, the patient and their parent(s) will be called to set 
up a research appointment to complete the evaluation of their CRI and psychosocial assessments. 
If more than one parent comes to the clinic appointment, they will both be offered the opportunity to 
complete the surveys. These surveys will be built into REDcap and completed by parents and their 
child on an iPad. 
 
Recruitment of Healthy Controls: 
Healthy pediatric subjects 12 to ≤21 years old will be recruited under the clinical relationship they 
have with research team members (e.g., Dr, Kaplan’s Adolescent Medicine clinic). We will also use 
poster advertisements, UC Clinical Trials website, and email local pediatricians in private practice in 
the Denver/Aurora area to recruit control patients, which will likely be a better demographic match 
for the POTS patients. We will request the patient's providers fill out a HIPAA-A form and ask that 
the provider give the families our contact information as well. Financial compensation of $50.00 will 
be offered for involvement in the study, and participants will be provided with a letter from the study 
team and a certificate acknowledging their contributions to the research study. Once study patients 
have been recruited for the study, the patient and their parent(s) will be called to set up a research 
appointment for evaluation of their CRI and psychologic assessments. If more than one parent comes 
to the clinic appointment, they will both be offered the opportunity to complete the surveys. These 
surveys will be built into REDcap and emailed to  parent(s) and their child for remote completion. 
 
Consent process: 
If agreeable to participation, potential subjects and their parent/legal guardian(s) will go through the 
consent process. A COMIRB approved consent form or assent form will be used as appropriate 
based on the potential subject’s age.  A signed and dated copy of the consent form will be provided 
to all subjects via email. Consent/assent will be obtained by a meeting with the potential subject (and 
their parent(s) if the potential subject is a child) and a member of the research team over the phone 
using an eConsent form available through RedCap. The link to the consent form will be sent to 
potential participants for review before and during the phone meeting. The research team member 
will be trained on this specific protocol, trained through required Research and HIPAA CITI courses, 
trained on the research consent process, and supervised by the PI or their delegate, and will be listed 
and approved on the COMIRB personnel form. Given the clinical relationships that some 
investigators will have with the potential subjects, to minimize the possibility of coercion or undue 
influence, medical providers involved in the patient’s treatment will not be consenting potential 
subjects. Other research personnel not involved in the patient’s treatment will do the consent process 
with the potential subjects and will make it clear that this is for research, that their participation is 
voluntary, and that they will receive the same medical care regardless of if they participate in the 
research study.  The consent process will happen in a quiet and private setting over the phone with 
the use of an eConsent accessible via RedCap. Potential subjects will be given time to read the form, 
ask questions, and have time to consider whether or not to be involved in this study. The research 
personnel obtaining consent will ask questions to verify that the potential subject has understood the 
consent or assent form. The research personnel will also follow a checklist to make sure that all 
required parts of the consent process have happened appropriately. If blind, illiterate, or those with 
similar reading limitations desire to participate in the study, the entire consent form will be read to 
the potential subjects and a member of the clinical staff or a member of the Adolescent Medicine 
Clinic staff (who are not on the research team) will serve as a witness.  
 
Parents of participants 18 or older will be allowed to complete the surveys remotely. A postcard 
consent will be used for this process, and the participant will be consented in person in the clinic. 
 
Study clinic appointment: 

12 COMIRB 18-2618 Pitula 
 
 
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The participant and accompanying parent(s) will be met by a member of the research team after 
arriving to the research space. The informed consent/assent process will then be completed by 
member of the research team. The participant will then be met by a nursing staff member or co-
investigator for urine specific gravity and measurement of CRI and other vitals (approx. 30 mins). In 
the literature, there are varying numerical cutoffs for normal hydration ranging from 1.006 to 1.029, 
and most of these studies have been conducted in adults (84). However, one of the most widely 
accepted values for normal hydration from urine specific gravity was established by the American 
College of Sports Medicine; they released a statement with the determination of a urine specific 
gravity <1.020 “is indicative of being euhydrated (83, 84),” (note, euhydrated refers to normal 
hydration). Thus, if urine specific gravity is too high (>1.020) as measured via spectrometer, the 
participant will be asked to drink 1-2 8 oz bottles of  electrolyte-rich solution (i.e., Gatorade) and 
return for CRI and other vitals measurement after approximately 1-2 hours. In the meantime, patients 
will be asked to complete the surveys while waiting for rehydration. After they complete the surveys, 
the urine specific gravity will be re-checked, and if it is <1.020, then CRI measurements will be 
checked. To maximize likelihood that participants will be sufficiently hydrated, they will be 
encouraged to drink fluids prior to the appointment start (i.e., when confirming the appointment by 
phone and when arriving to the research facility). All research staff will be trained on collecting and 
measuring urine specific gravity with a refractometer with samples with different specific gravity 
values. The hand-held refractometer is an optical instrument manufactured by Kibeland that will be 
utilized by all the research staff. It uses a few drops of solution for measurement of the specific 
gravity, and it has automatic temperature compensation. 
After these measures are complete (or while waiting for hydration), a research team member 
will instruct the participant to complete surveys on electronic tablet and will administer some interview 
items. The parent will also be instructed to complete his/her surveys and interview items during this 
time. Once surveys, interview items, and vitals are complete, the participant and parent(s) will be 
paid by a member of the research team and excused. 
 
CRI measurement during study clinic appointment: 
A FDA cleared and/or investigational CipherOx CRI M1 devices will be used for CRI data collection.  
The devices are equivalent and run the same exact software package; the only difference is that the 
FDA cleared devices are new and manufactured by an ISO compliant manufacturer (Evergreen 
Technologies). These devices use a standard pulse oximetry sensor, which will be attached to the 
CRI device and the participant’s right or left index finger. The participant will lie down on an 
examination table for 5 minutes, then will stand for 10 minutes, then return to the supine position for 
5 minutes (all while the pulse oximeter is obtaining continuous CRI readings).  
 
 
 
V. 
Description, Risks and Justification of Procedures and Data Collection Tools: 
 
Risks to the subject are minimal.  Non-invasive physiological waveform data will be collected 
using non-invasive sensors. The research for this study does not involve specialized procedures or 
changes to the standard of care for patients enrolled in this study; therefore, there are minimal risks 
to patients who will be enrolled in this study. Flashback Technologies’ FDA cleared CipherOx CRI 
M1 devices will be used for data collection, however, CRI will not be displayed or available to the 
clinicians during the data collection process. 
 
Risks to the subject associated with continuous, non-invasive blood pressure measurements from 
finger cuffs are minimal and include: 
● 
slight discomfort from the cuffs inflating around a finger 
● 
water blisters may occur under the cuffs (this is rare—it has only happened to one subject 
to our knowledge) 
● 
during measurement, some coloring of the fingertip may occur; the coloring will disappear 
within a few minutes after removing the cuff 
 

13 COMIRB 18-2618 Pitula 
 
 
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Risks to the subject associated with pulse oximetry are minimal and include:  
● 
Slight discomfort from applying the finger sensor to the subject’s finger  
● 
Temporary pressure marks on the finger resulting from application of the sensor 
  
The risk of syncope is no greater than in routine clinical visits or getting out of bed after sleeping at 
night.  If the patient feels dizzy, we will have them resume a supine position until the dizziness 
resolves. 
 
All devices and equipment used for monitoring and collecting data must pass the appropriate hospital 
Biomedical Engineering electrical safety testing. There are very minimal risks associated with filling 
out questionnaires (which will be directly uploaded to REDcap) in the outpatient clinic, and this study 
does not affect patient care. The study is voluntary. There is a potential risk of patient information 
being accidentally seen by someone who is not on the research protocol. The risk is minimal, and 
usually not serious. All protected information that is accessed and obtained as part of this protocol 
will be kept on a Children’s Hospital Colorado encrypted computer and server.  Computer and server 
access at Children’s is protected with a password. The computers are kept in a badge access only 
area of the hospital (the administrative pavilion). Furthermore, protected health information will be 
kept separate from other research information. Once data analysis is complete, all data related to 
individual protected health information will be destroyed.   
 
Participants and their parents might feel uncomfortable or upset when completing study 
measures and answering personal questions about themselves and their children. This risk is 
minimal. Risk will be mitigated by providing explanation during informed consent that participants 
have the right to refrain from completing study measures, and to skip questions that are difficult 
and/or make them uncomfortable. Participants will also be informed that their participation is 
voluntary so that they can withdraw from the study at any time, and that their participation/withdrawal 
from the study does not influence their current and/or future ability to access therapeutic services. A 
licensed psychologist (Dr. Pitula) will also be available to debrief families over the phone if needed. 
    
VI. 
Data Safety Monitoring Plan: Data will be managed in a secure and HIPAA-compliant 
manner. The data that is collected by Flashback Technologies’ pulse oximeters is 
collected in a de-identified fashion and stored on a drive internal to the device itself. 
These devices will be kept in locked rooms or locked carts within areas of the campus 
buildings that require badges to enter. Identifiable data will be kept on computers that 
are password protected and can only be accessed by members of the research team. 
These computers are also kept in areas of campus buildings which require badges to 
enter. De-identification of data will occur after the waveform data is collated with 
pertinent medical record data. The paper informed consent forms and CRI data 
collection sheets will be stored in the locked filing cabinets at the desk of a member of 
the research team (which is also inside an area of campus buildings which require 
badges to enter).  The surveys will be directly conducted in REDCap. The CRI data (from 
data collection sheets) will be manually transcribed into REDCap as well. The CRI data 
from the device (uploaded to the computer) will also be uploaded into REDCap.  
 
If the surveys uncover suicidality in the subjects (adolescents and/or parents), this will 
be addressed by the psychologist, who will conduct a risk assessment, and a report will 
be made if necessary (e.g., calling 911 or accompanying the participant to the 
emergency department). 
 
 
VII. 
Potential Scientific Problems:   
The physiological responses of our populations of interest may be different from those on which the 
CRI algorithm was built.  While we have no reason to believe otherwise, there is no way to be certain 
if the CRI algorithm will be effective in tracking the primary outcomes measures of our study.  Since 

14 COMIRB 18-2618 Pitula 
 
 
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this is a survey study, there is a risk of recall bias. Given the length of the survey, there is a risk of 
survey fatigue for subjects and incomplete completion of the survey and missing information.  
 
IX.   Data Analysis Plan:   
 
All data will be stored and managed in REDCap. Subjects (both children and parents) will be asked 
to complete the surveys on an iPad in clinic. Data analysis plan is outlined for each study aim below. 
 
Aim #1: To examine group differences in CRI, the primary outcome variable will be the absolute 
change in CRI from supine (i.e., supine minute 5) to standing (i.e., standing minute 5). Use of this 
primary outcome variable is modeled after the primary outcome variable used by Singer et al., 2012 
(i.e., HR increment from baseline at 5 minutes post-tilt); note, secondary outcome variables used by 
Singer and colleagues included values at baseline and 1, 5, and 10 minutes post-tilt, as well as 
change from baseline at 1 minute and 10 minutes post-tilt. Linear regression analysis will be used to 
assess the influence of age and BMI on variables. The chi-squared test will be used to assess for 
the influence of sex and Tanner stage. Because previous research suggests that these data may be 
non-parametric, Mann-Whitney Wilcoxon testing will be used to assess for differences in variables 
between patients and controls. Significance will be set at the 5% level.  
 
As this is the primary study aim, power analysis was conducted to assess sample size needed to 
adequately fulfill this aim. Power analysis was conducted using the program G*Power (57) to 
determine the sample size needed to detect a true difference in CRI decrement between patient and 
control groups given likely effect size (i.e., 0.36, based on group means for heart rate increment 
reported by Singer et al., 2012) employing the traditional statistical analysis criteria of 5% alpha error 
probability and 80% power (58). Given these parameters, power analysis indicated that a sample 
size of 103 participants per group would be necessary to detect a true difference in CRI decrement 
between groups. As a result, we aim to have 105 participants per group in order to be adequately 
powered to detect a group difference in our primary outcome variable. 
 
Aim #2: To assess associations between CRI values, symptoms of POTS, and functional impairment, 
regression analyses will be used. Thus, in hierarchical linear regression, two separate regression 
analyses would be conducted with POTS symptom score (i.e., continuous variable representing the 
sum of weighted items) and functional impairment score (i.e., sum of FDI total score for parent and 
child report) as outcomes. In each analysis, covariates (e.g., age, sex) would be entered in the first 
step and CRI value (i.e., two sets of analyses using a) CRI decrement from supine to standing, as 
defined above, and b) lowest CRI value attained when standing) entered in the second step. 
Analyses would be corrected for multiple comparisons using Boneferroni correction. Exploratory 
analyses will also consider how comorbid hypermobility influences the associations between CRI 
values and severity and impact of POTS (e.g., by comparing youth with POTS and hypermobility to 
youth with POTS without hypermobility).  
 
Aim #3: To examine differences in psychosocial factors between POTS and control groups, separate 
scores will be used for each psychosocial variable, i.e., symptoms of anxiety and depression 
(RCADS total anxiety T score, RCADS depression subscale T score, separate scores for parent and 
child report), sleep quality (mean of 7 items), social connectedness (mean score on SCS), friendship 
(mean score on Close Friend Support subscale), family functioning (mean score on GFS, separate 
scores for parent and child report), parent behavior (mean score on ARCS), and parent mental health 
(sum of GAD-7 and PHQ-9 sum scores), resulting in 11 separate continuous outcome variables. 
First, individual outcomes will be assessed first using independent paired sample t-tests with group 
as the between factor. Psychosocial variables showing no independent relationships to the groups 
will be discarded, and those showing a group difference will be entered into a Multiple Analysis of 
Variance (MANOVA). Group (i.e., POTS versus control) will be the between factor, and age, sex, 
and/or Tanner stage can be used as covariates if they are shown to be associated with the outcome 
variables in preliminary analyses.  
 

15 COMIRB 18-2618 Pitula 
 
 
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X.  Summarize Knowledge to be gained:   
Measurement of CRI in children with POTS and the association with somatic and psychological 
symptoms is expected to help us better understand how to assess the severity of their disease and 
will likely inform more effective interventions for these patients. 
 
XI. Budget: In attached spreadsheet 
 
 
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