Percutaneous Neurostimulation for Treatment of Paroxysmal Sympathetic Hyperactivity in Children With Acute Severe Brain Injury
Phase: NA
Conditions: Paroxysmal Sympathetic Hyperactivity
Sponsor: Medical College of Wisconsin

 
 
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Version date of this document (initial or revision):  5/6/2024 
Study Title: Percutaneous neurostimulation for treatment of paroxysmal sympathetic hyperactivity in children 
with acute severe brain injury 
Principal Investigator:  Binod Balakrishnan M.D.  
Sponsor (if not sponsored, indicate that study is investigator-initiated): Investigator initiated 
Section 1 Regulatory Criterion for Approval: Risks are Minimized   
Risks to subjects are minimized: (i) by using procedures that are consistent with sound research design 
and that do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using procedures 
already being performed on the subjects for diagnostic or treatment purposes. 
 Risks must be identified and classified as risks that would only be present if the subject participates in the 
research versus those risks that would happen as part of routine care or regardless of the subject’s 
participation. 
 ONLY evaluate the research risks and consider how to minimize those risks: 
o 
Is the question important scientifically/scholarly to answer? 
o 
Is the study designed so the question can be answered? 
o 
Can less risky procedures answer the question? 
o 
Can fewer procedures answer the question? 
o 
Are the procedures needed at all? 
o 
Can additional procedures reduce risk? 
o 
Can different eligibility criteria reduce risk? 
o 
Are investigators and key personnel adequately qualified relative to the activities being performed and 
are the activities within each individual’s scope of practice? 
o 
Are procedures that will answer the scientific question being done anyway? If so, can the data from 
these procedures be used to reduce the likelihood or magnitude of harm? 

 
 
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CW Protocol Summary Page 2 of 27 
Study Design 
A. Has this proposal undergone separate formal review to determine appropriateness of study design (i.e. 
formal Scientific Review Committee)? 
☐No 
If NO, the IRB is responsible for determining that scientific design is appropriate 
☒Yes If YES, describe the entity and outcome of the review (provide minutes or supporting documents in the 
submission package, if available): Critical Care Research Operations Committee 
B. Purpose of the study: 
       Evaluate the feasibility of using a percutaneous electrical nerve field stimulator (PENFS) for treatment of 
paroxysmal sympathetic hyperactivity (PSH) in children 2-17 years of age with acute severe brain injury (ASBI). 
C. Hypothesis/specific aims: 
 Aim 1: Demonstrate the feasibility of use of PENFS to treat PSH, and tolerability of the device. 
Hypothesis: The PENFS device will be well tolerated, defined as < 10% early termination from the study. We 
will recruit 20 patients with ASBI and PSH who will receive PENFS therapy. 
Aim 2a: Evaluate the feasibility of capturing pediatric PSH symptoms using the CFS scoring tool. 
Hypothesis: It is feasible to monitor the severity of PSH using a CFS scoring tool (Table 1a,1b). The scoring 
tool will be adapted for the appropriate age range of the patient (Table 2). We aim for at least 80% scoring (≥ 
8/10 scheduled scoring per protocol while the device is worn). 
Aim 2b: Evaluate the effectiveness of the PENFS device in reducing PSH symptoms using change in CFS 
score. 
Hypothesis: A decrease in CFS severity score with use of PENFS will be associated with a lower number 
and/or doses of maintenance and rescue medications for control of PSH symptoms.    
Aim 3a: Evaluate the change in autonomic balance with use of PENFS device 
Hypothesis: Heart Rate Variability (HRV) and pupillometry parameters that correspond to sympathetic and 
parasympathetic activity will be different after PENFS device placement compared to before, reflecting an 
increase in parasympathetic tone. All patients will be on routine continuous EKG monitoring in the PICU 
during the study period of interest. Similarly, pupillometry is routinely performed in patients with ASBI in the 
PICU. 
Aim3b: Evaluate feasibility of measuring PENFS effectiveness in treating PSH by a decrease in medication 
use. 
Hypothesis: It would be feasible to use the maintenance and rescue medication dosing and frequency as a 
marker of severity of PSH. PENFS device use will result in lesser number and/or doses of maintenance and 
rescue medications for control of PSH symptoms. We will compare the pilot sample to a historical cohort to 
allow power analysis and sample size calculation for a future larger efficacy trial, recognizing that this pilot 
study is not powered for efficacy. 
 
D. Background, significance, and rationale (including description of preliminary studies and any results): 
Paroxysmal sympathetic hyperactivity – incidence, pathophysiology, diagnosis, treatment, 
prognosis and implications for treatment  
Paroxysmal sympathetic hyperactivity is frequently seen in survivors of acute severe brain injury (ASBI). It is 
most commonly associated with severe traumatic brain injury (sTBI) with a reported incidence of 10-20% 
among survivors of sTBI (1-4,6-9). Survivors of anoxic brain injury have a higher incidence of PSH 
(approximately 30%) (5). The pathophysiology of PSH is incompletely understood. Current consensus is that 
it the result of disconnection between with neuroinhibitory higher centers in the diencephalon and the 

 
 
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CW Protocol Summary Page 3 of 27 
excitatory pathways in the brainstem and spinal cord (10). PSH is characterized by a constellation of 
symptoms such as tachycardia, tachypnea, hypertension, hyperthermia, rigidity, tremors, sweating, and 
pupillary dilation as a result of sympathetic hyperactivity due to the brain injury (1,5,7,8). Research on PSH 
has been hampered by lack of a uniform definition and use of various terms such as neurostorming, 
dysautonomia. Consensus diagnostic criteria and a scoring algorithm (CFS) were developed in 2014 (1) 
(Table 1a,1b). PSH increases the risk for secondary brain injury and is associated with worse functional 
outcomes, longer hospitalization and higher healthcare costs (2,3,7,11). Appropriate treatment of PSH is 
important for patient comfort and to prevent secondary brain damage (12,13). Currently, PSH is treated 
using a combination of multiple neurotropic medications (narcotics, benzodiazepines, sympatholytics, 
gabapentin, muscle relaxants etc.) that can result in complications due to their side effects such as 
excessive sedation, respiratory depression, drug dependence, and constipation. Some of these medications 
necessitate longer ICU stays due to their CNS depressant effects thus potentially increasing healthcare 
costs (3). There has been very little research into novel ways of treating PSH other than the use of various 
neurotropic medications (14,15). 
 
Measurement of autonomic function – HRV and Pupillometry Autonomic function can be evaluated 
clinically and is most commonly measured using heart rate variability (HRV) (16).  Established standards for 
measurement of HRV are available (17). HRV has been studied in various disease states in the intensive 
care environment such as post-acute MI, sepsis, multi-organ dysfunction, brain injury, and brain death 
(18,19). HRV is decreased or lost in severe disease and has been shown to be associated with increased 
mortality in the ICU (18,19). Higher sympathetic activity in severe disease states is associated with 
decreased HRV (18). HRV was shown to be significantly different between children and adults with ASBI 
and controls (20,21). Similarly, pupillary reactivity is also under autonomic control. Recently, pupillometry 
has also been used to measure autonomic activity. A pupillometer quantitatively measures pupil size (size, 
minimum size with light stimulus, % change in pupil size) and reactivity (constriction velocity, max 
constriction velocity, latency, dilation velocity) that can be compared to established norms and trended over 
time (22,23). These parameters have been shown to reflect  
 
Table 1a Clinical Feature Scale (CFS) – used for scoring1 
 
 
 
 
 
 
 
 
 
Table 2 PSH scoring modified for pediatric population34 

 
 
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CW Protocol Summary Page 4 of 27 
 
sympathetic (dilation velocity) and parasympathetic system (% change in pupil size, latency, constriction 
velocity) activity and sympatho-parasympathetic balance (baseline pupil size) (24). PSH, as the name 
implies, is associated with uncontrolled paroxysms of sympathetic activity that results in pupillary dilation 
among other symptoms. It is conceivable that an increase in parasympathetic activity would alter these 
parameters that could be compared using the patient as his/her own control 
 
PENFS device – description, mechanism of action, and applications The PENFS (auricular 
neurostimulator) device is a novel, non-pharmacological therapy that has 
been effectively used for various conditions such as functional abdominal 
pain, chronic pain, and narcotic withdrawal (25-27). Recent data from CW 
also demonstrates efficacy in a pilot study for children with cyclic vomiting 
syndrome, with improvement in episode severity and frequency lasting an 
average 5 months (unpublished data). Cyclic vomiting syndrome (CVS) is a 
disorder of autonomic imbalance manifested by severe sympathetic 
hyperactivity. Symptoms of nausea/vomiting, pallor, diaphoresis, and 
tachycardia are similar to PSH. Many of the symptoms of narcotic 
withdrawal are also very similar to those of PSH including tachycardia, 
tachypnea, hypertension, fever, tremors, sweating (28). Clonidine, an 
alpha-2 agonist with sympatholytic properties is commonly used as an 
adjunct in the treatment of narcotic withdrawal syndrome (29). Clonidine is 
also one of the first-line medications used for treatment of PSH (12,13). Thus, it 
is plausible that PENFS could be effective in treatment of PSH.  
 
The PENFS device is applied over the external ear (Fig.1) and is continuously worn for 120 hours at a time. 
The electrical current stimulates the auricular branch of the vagus nerve (ABVN) and auricular branches of 
cranial nerves V, VII and IX. The nerves project to the various parts of the brain, including the brainstem 
nucleus tractus solitarius. fMRI scans in healthy human volunteers have shown significant activation of the 
central vagal projections by stimulating ABVN (30). Sympathoinhibition has been shown to be one of the 
primary mechanisms of actions of the device in the various conditions for which it is used (31-33). The study 
by Mahadi et al., showed that electrical stimulation of the tragus in rats resulted in central sympathoinhibition 
by up to 36% within 5 minutes of stimulation (31). This central sympathoinhibition by the PENFS device 
could improve the symptoms of PSH. 
 
Figure 1. PENFS device 

 
 
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One of the advantages of PENFS in the treatment of PSH is that it is continuously active while it is worn thus 
providing symptomatic treatment throughout that period. This could help prevent or ameliorate the 
paroxysmal symptoms classically seen in PSH and thus reduce the need for rescue medications. The device 
also has been shown to have a relatively rapid onset of action. A recent study showed that the onset of 
action was rapid with 63% reduction in narcotic withdrawal score within 20 minutes of activation of the device 
and 85% reduction within 60 minutes (26). Thus, PENFS could offer a non-pharmacological tool for 
managing PSH, helping to decrease the need for maintenance and rescue medications and thus limiting the 
side effects of some of these medications. Decreased need for neurosedative medications could further 
decrease the length of ICU stay for these patients thus decreasing healthcare costs. The device is also well-
tolerated without any serious adverse effects (25).  
 
Innovation:  
The treatment of PSH has been limited to various combinations of neurotropic medications. We explore the 
novel use of an auricular neurostimulator (PENFS) device for PSH treatment. We hypothesize that the 
PENFS device, by stimulating the parasympathetic AVBN will inhibit the sympathetic hyperactivity due to 
PSH. If this approach proves to be efficacious, it will help to decrease the need for neurotropic medications 
thus decreasing some of the serious adverse effects of these medications (drug dependence, acute 
cardiorespiratory compromise due to neurodepressant effects, constipation and feeding intolerance due to 
bowel dysmotility). The PENFS device is worn continuously for 120 hours thus providing continuous 
treatment of PSH symptoms which would potentially decrease the need for rescue medications. Limiting the 
need for neurodepressant medications would reduce the need for close monitoring in the ICU resulting in 
decreased healthcare costs. The use of objective measures of autonomic function - HRV and pupillometry – 
is also a novel way of evaluating response to treatment using the PENFS device. Further, the application of 
the CFS score in pediatrics will potentially provide a simple, instantaneous mode of tracking symptoms 
severity and response to treatment. 
 
E. Design and methods (including experimental design, technical details and laboratory methodology): 
Design & Methods  
In this prospective unblinded pilot study we will enroll eligible patients until 20 parent/child dyads complete 
the study. It is expected many of the consented patients will not meet the eligibility criteria of CFS score > 6 
(moderate severity of PSH. Those children will be considered Screen Failures and their parents/LAR told 
they are ineligible to continue in the study. Children admitted to the PICU at CW aged 2-17 years with ASBI 
and symptoms of PSH with a CFS score > 6 (moderate severity of PSH) will be eligible for inclusion. 
Exclusion criteria include age < 2 years (small ears thus less surface area to apply the leads), ear deformity 
or severe dermatitis of ear lobes, intractable seizures, heart block, patients with other implantable devices 
(cardiac pacemaker, vagal nerve stimulator, etc.) or known pregnancy. 
 
Study treatment 
Patients with ASBI are routinely co-managed by the ICU Neurology team who have extensive experience 
diagnosing and treating PSH. Potentially eligible patients will be identified by the ICU Neurologists (Co-I). 
Once enrolled, the PENFS device will be placed over the external ear and will remain continuously active for 
120 hours. CFS scores will be calculated before and after initiation of PENFS as per study protocol.  
 
Medication detail during study treatment: 
No additional maintenance medications (propranolol, bromocriptine, dantrolene, gabapentin, baclofen) will 
be allowed to be initiated for the first 12 hours after initiation of PENFS. Patients could continue to receive 
rescue medications (morphine, benzodiazepines such as lorazepam, midazolam, diazepam, clonidine) 
during this period for break through symptoms or remain on maintenance medications that were already in 

 
 
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CW Protocol Summary Page 6 of 27 
place that would normally be used to treat PSH. Additional maintenance medications could be instituted 
beyond the initial 12-hour period if PSH symptoms are not adequately controlled. Initiation of maintenance 
medications before placement of PENFS will not be a contraindication to enrollment, but once enrolled, no 
new maintenance medications would be allowed for the initial 12 hours after device placement.  
 
  
 
Methods: Parent(s)/legal guardians, 18 years or older, will be approached for informed consent if their child 
has ASBI and is exhibiting clinical signs and symptoms of PSH. Once consented, the CFS scoring tool 
(Table 1a,) will be used to evaluate patients felt to be exhibiting symptoms of PSH to identify eligible ASBI 
patients. Patients with CFS score > 6 will be eligible for enrollment in the study. 
 Families of patients who do not meet the CFS score criteria > 6 will be told their child did not meet scoring 
criteria of study and will be considered consented but not enrolled in study.  
Study Enrollment is defined as meeting CFS criteria of > 6 after consent. If CFS scores are already being 
collected for subject prior to subject consent as a standard of care, we can use already available CFS scores 
from medical record.   The PENFS device will be placed over the external ear by study investigator or one of  
trained nurses (RNs) from the Pediatric Translational Research Unit (P-TRU) within 24 hours of meeting 
CFS > 6 score criteria..  
There are 380-400 PICU admissions/year that are seen by ICU Neurology. Using a conservative estimate of 
8-10% incidence of PSH, we expect to have 35-40 patients with PSH. At a conservative 60% enrollment 
rate, we expect to be able to successfully enroll 20 patients in this pilot study. Previous studies using the 
device has shown it to be well-tolerated with minimal side effects (25,26). In a large, randomized sham-
controlled trial Kovacic et al showed a very low rate of discontinuation of the device due to side effects. We 
hypothesize that the dropout rate will be ≤ 10%. Tolerability of the device will be assessed by subjective 
assessments of device tolerance by the bedside nurse, the CFS score (increasing score after device 
placement would suggest worsening PSH symptoms) and skin integrity (bedside nurses will perform routine 
skin evaluation and care while the device is in place.). To evaluate safety, we will monitor for serious 
adverse effects such as cardiac dysrhythmia (EKG monitoring), and new-onset seizures.  
 
 
 
        
 
 
Methods: The CFS (Table 1a) will be used to score the severity of PSH using the pediatric adaptation for the 
appropriate age range (Table 2 – diastolic blood pressure will not be used for scoring)34. CFS scoring will be 
performed by the bedside nurse who will be trained in using the scoring tool. PSH severity for the 12-hour 
period prior to placement of the device will be calculated retrospectively based on the features of CFS. After 
placement of the device, patients will be scored prospectively every 12 hours while the device is worn. The 
device will be discontinued after 120 hours of wear (usual duration of wear of a device). Scoring will be 
continued every 12 hours until 120 hours of device placement and then for another 72 hours(total of 192 
hours for complete study duration). Every CFS score will be based on the severity of PSH symptoms in the 
preceding 12 hours.  
 
Methods: We will analyze the within-patient change in the modified CFS score with use of the device (before 
and after device placement and trend in score over time). No maintenance medications will be allowed 
Aim 1: Identify and enroll 20 pediatric patients with ASBI and PSH. 
Aim 2a: Evaluate feasibility of scoring PSH symptoms using the PSH scoring tool 
Aim 2b: Evaluate the effectiveness of the device in reducing PSH symptoms using the change 
in CFS score 

 
 
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during the initial 12 hours of use of the device; however, rescue medications will be allowed during this 
period. Maintenance medications would be allowed after 12 hours of device use. We will also compare the 
trend in scores while using the device to the trend once the device is discontinued after 120 hours of use as 
we will be following the trend in the CFS scores every 12 hours for an additional 72 hours after removal of 
the device. This will be impactful as the patient will be his/her own control. However, we recognize that this 
could be confounded by the initiation of maintenance medications. 
 
        
 
 
Methods: We will use two separate validated modalities to evaluate the autonomic activity/balance in 
response to use of the device – HRV and Pupillometry. HRV denotes the beat-to-beat variability in the R-R 
interval on the EKG. Cardiac pacemaker automaticity is continuously altered and regulated by the autonomic 
nervous system (ANS). The parasympathetic system regulates HR on a beat-to-beat basis whereas the 
sympathetic system has slower onset but longer duration of action (16-18). Decreased HRV parameters has 
been shown to be associated with increased 30-day mortality in critically ill patients (19). Children with PSH 
were shown to have significant differences in HRV parameters compared to controls (20). We will calculate 
time-domain (mean heart rate, standard deviation of all average R-R intervals (SDNN), root mean square of 
the successive differences (RMSSD), physical stress index (PSI), approximate entropy (ApEn); successive 
R-R interval difference (SRD)) and frequency-domain indices (total power (TP), high frequency (HF), low 
frequency (LF), normalized HF, normalized LF, and LF/HF ratio) and compare the 12-hour period before and 
after placement of the PENFS device. Three separate 5-minute segments of continuous EKG tracings at rest 
(lying in bed) and body temperature 36-37.5C will be identified for both periods for comparison. Similarly, we 
will compare the pupillometry parameters along with direction of change before and after device placement.  
Methods: The maintenance medications and the number of doses and type of rescue medications 
administered will be collected for every 24 hours (0-24h, 25-48h, 49-72h, 73-96h, 97-120h, 121-144h, 145- 
168h, 169- 192h) for the enrolled patients. These will be compared to a historical cohort of PSH patients. 
The historical cohort will consist of PSH patients (2-17 years old) identified using the ICU Neurology 
administrative dataset from January 2018 – August 2021. This dataset will be used to identify ASBI patients 
who likely developed PSH. Eligible patients with PSH will be identified and relevant data collected by 
individual chart review. During this period all the PSH patients were followed by ICU Neurology thus 
ensuring a uniform approach to their treatment. We have also developed a practice guideline for treatment of 
PSH that will ensure uniform treatment of these patients during the study period. Similar to Aim 2a, we will 
examine the need for additional maintenance medications or change in frequency of rescue medications with 
discontinuation of the device. We hypothesize that, with discontinuation of the device, the patients may 
experience worse PSH symptoms as demonstrated by increasing CFS score and need for additional 
maintenance and/or rescue medications. 
 
Data collection & Management 
Screening & Consent: 
We will screen all ASBI patients who appear to have symptoms of PSH during their PICU stay. If they meet 
study eligibility, we will approach the parents/LAR for informed consent. The PI will verify the status of who 
has been appointed the subject’s guardian or LAR. Due to the nature of ASBI, we assume all children will be 
incapable of assenting to this study.  Once the parent(s) / LAR have consented for their child to participate in 
the study, the CFS scores will be calculated to confirm study eligiblity. The families will be told that their child 
does not qualify for the study if they do not meet the CFS scoringcriteria. We expect 20 parent/child dyads to 
Aim 3b: Evaluate feasibility of measuring PENFS effectiveness in treating PSH by a decrease 
in medication use 
Aim 3a: Evaluate the change in autonomic balance with use of PENFS device 

 
 
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complete the study. If the patient does meet CFS scoring criteria for study enrollment, we will collect the CFS 
score for a 12-hour period before placement of the device followed by every 12 hours while the device is in 
place and for an additional 72 hours after removal of the device.   
Data collection & Management: We will collect demographics, cause of ASBI, imaging findings, sedative, 
pain and other neurotropic medications, and maintenance and rescue medications for PSH including their 
number and doses for every 24-hour period from placement of the device. We will also collect all the HRV 
and pupillometry parameters for the 12-hour period before and after placement of the device. For the 
historical cohort, we will collect demographics, cause of ASBI, imaging findings, maintenance and rescue 
medications used in each 24 hour period for the first 120 hours and then additional 72 hours from the time of 
meeting CFS score > 6 criteria. . The REDCap database for this study will be developed and managed by 
Quantitative Health Sciences on MCW-secure servers  
 
 
 
 
 
 
 
 
Table 3: Data collection plan 
 
-24 to 
-12 h 
-12 
to 0h 
Device 
place
ment 
0 h 
 
6h 
12h 
24h 
24-
48h 
48-
72h 
72-
96h 
96-
120h 
120-
144h 
144-
168h 
168-
192h 
Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
CFS score 
 
x 
x 
 
 
x 
X 12 
hour
ly 
x 12 
hrly 
x 12 
hrly 
x 12 
hrly 
x 12 
hrly 
x 12 
hrly 
x 12 
hrly 
x 12 
hrly 
Pupillometry 
 
x 
x 
 
x 
x 
 
 
 
 
 
 
 
 
HRV using EKG 
 
x 
x 
 
x 
x 
 
 
 
 
 
 
 
 
Maintenance 
meds1 
 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Rescue Meds2 
 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
X 
Adverse Events  
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
X 
1 No additional new Maintenance Medications are allowed for the first 12 hours after device placement. Patients may remain on Maintenance Medications they are already taking. Additional 
Maintenance Medication are allowed after the first 12 hours of device placement.   
2 Patients may continue Rescue Medications during the first 12 hours of device placement.  
Data analysis & interpretation (Overview) 
Missing data: In general, the assumption of missing at random (MAR) will be assumed. Under this 
assumption, we will impute or use mixed models. A sensitivity analysis, using clinical and biological expertise 
will be included. Exploratory data analysis will include exploration of distributions and relationships of the 
variables, using summaries, such as correlation, plots such as Loess smooth plots, and Classification and 
Regression Trees (CART). To satisfy parametric assumptions, transformation of variables will be used or 
non-parametric tests when necessary. Continuous data:  we will use mixed models to describe changes over 
time, the variance covariance matrix will be chosen to be parsimonious but to fit the data and will likely be an 
autocorrelation matrix. Design justification: Although it would be better as a pilot to randomize patients to a 
sham and active PENFS, the numbers would be so small (and heterogeneous) that the study would have 
limited information. The next step would be to evaluate the acceptability of randomization in this group of 
patients.  

 
 
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Hypothesis 1: The number approached and consented will be tracked. Reactions/ adverse events will be 
summarized and reasons for early termination, if any, evaluated.  
Hypothesis 2a, 2b: The scoring tool will be adapted for the appropriate age range of the patient (Table 2). 
We aim for at least 80% scoring (≥ 8/10 scheduled scoring per protocol while the device is worn). The 
association of the score and the number of doses of maintenance and rescue medications will be 
summarized with a spearman correlation and exact 95% Confidence intervals (CI).  
Hypothesis 3a: HRV and Pupillometry measures will be tracked over time with any loss of data recorded with 
reasons. Wilcoxon Rank Sum test will be used to compare the mean ±SD for the parameters for the 12-hour 
periods before and after device placement. 
Hypothesis 3b: The number of doses of maintenance and rescue medications for control of PSH symptoms 
will be compared to historic data using a t-test or non-parametric Mann Whitney. Further a classification tree 
will be used to evaluate the effect of demographics, clinical history and use of PENFS. 
 

 
 
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F. Research procedures such as lab draws (including volume of samples), ECG, imaging, clinical procedures, 
genetic testing, surveys (may attach activity table if available): 
 
Describe what will happen to the subject solely for the purpose of this research study: 
1) Placement of PENFS device on the external ear of the enrolled patient by study investigator or one of trained 
P-TRU nurses (RNs) that will remain in place for 120 hours. 
2) CFS scoring per protocol by the bedside nurse 
3) Evaluation of heart rate variability using EKG data obtained from the bedside monitor during the 12 hour period 
before and after placement of PENFS device. 
4)  The bedside RN, TRU RN, or physician will remove the device and dispose of properly in a sharps 
container.  The devices are easily removed by removing the tape and adhesives. 
5) Parental survey of their perceptions about the use of the device at the end of the study. 
Describe what is happening per protocol but is considered part of routine care (would happen even if the 
individual did not participate): 
1) Pupillometry 
2) Medical management of PSH 
 
Clinical Trial 
A. Is this study a Clinical Trial/Clinical Investigation?  
Clinical Trial means a research study in which one or more human subjects are prospectively assigned to one or 
more interventions (which may include placebo or other control) to evaluate the effects of the interventions on 
biomedical or behavioral health-related outcomes. [45 CFR 46.102(b)] 
Clinical Investigation means any experiment that involves a test article and one or more human subjects, and that 
either must meet the requirements for prior submission to the Food and Drug Administration under section 505(i) or 
520(g) of the act, or need not meet the requirements for prior submission to the Food and Drug Administration 
under these sections of the act, but the results of which are intended to be later submitted to, or held for inspection 
by, the Food and Drug Administration as part of an application for a research or marketing permit. The term does 
not include experiments that must meet the provisions of part 58, regarding nonclinical laboratory studies. The 
terms research, clinical research, clinical study, study, and clinical investigation are deemed to be synonymous for 
purposes of this part. [21 CFR 56.102(c)]. Note: this also include biospecimens. 
☐No  If NO, skip questions B-H ☒ Yes If YES, answer the following questions B-H: 
B. What phase of clinical trial best describes this research? 
☐Phase I   ☐ Phase I/II   ☐ Phase II   ☐ Phase II/III   ☐ Phase III   ☒ Phase IV    
☒Feasibility   ☐ Pivotal (Feasibility vs Pivotal device studies) 
C. Is this trial “first-in-human” (in clinical trials, the first Phase-1 study in which a test product is administered 
to human beings)? 
☒No   ☐ Yes 
If YES, the protocol must contain an adequate description of the pre-clinical research and/or other relevant data that 
supports the performance of the study. 

 
 
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D. Is this trial the first in a population (e.g., children)? 
☒No   ☐Yes 
If YES, the protocol must contain an adequate description of the pre-clinical research and/or other relevant data 
that supports the performance of the study in the new population. 
E. Does this trial evaluate one or more FDA-regulated products?   
Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/P’s) may be classified as drugs, devices, 
and/or biologics.  Information on the classification of HCT/P’s is available on this FDA website.   
The 21st Century Cures Act excludes certain medical and decision support software from the definition of medical 
device meaning that such software is not subject to FDA regulations.  Information regarding these exclusions is 
available on FDA’s website for digital health.  If uncertain whether a product under investigation is a medical device, 
contact the CW HRPP office. 
☐No   ☒ Yes  If YES, indicate the following: 
Product Type(s): Percutaneous electrical nerve field stimulator 
Product Name(s): IB Stim  
If YES, also include in the submission package IRB – Supplement Form – Drugs and Biologics for studies of 
drugs and biologics and/or IRB – Supplement Form – Devices for medical device studies. These forms are 
found in IRBNet under Forms and Templates.  
F. Will this trial enroll pregnant women or minors/women who are of child-bearing potential? 
☒ No  ☐ Yes  
If YES, the protocol and consent must contain an adequate description of any known or anticipatable risks to 
pregnant women and fetuses and any measures to mitigate those risks. Birth control requirements, if applicable, 
must also be described. CW template pregnancy test language regarding disclosure of results must be included in 
parental permission/assent documents. 
G. Does the sponsor intend to collect data on “pregnant partners” (sexual partners of clinical trial subjects 
who become pregnant while the subject is receiving investigational agents)?   
☒No   ☐Yes 
If YES, review Children’s Wisconsin IRB Position Statement Pregnant Subjects and Pregnant Partners found in 
IRBNet under Forms and Templates and on the HRPP web pages. 

 
 
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H. Is this trial registered in ClinicalTrials.gov? 
Contact MCW CTSI if there are questions about what needs to be registered or visit their website for registration 
instructions. 
☐N/A, registration is not required for this trial (confirm with CTSI if uncertain)  
☐No, but trial will be registered prior to enrolling any subjects 
☒Yes, ClinicalTrials.gov #: NCT05343988 
For FDA-regulated and NIH funded clinical trials that are or will be registered in ClinicalTrials.gov, the 
following statement must be included verbatim in the consent/parental permission forms: 
FDA: "A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This
Web site will not include information that can identify you. At most, the Web site will include a summary of the results. 
You can search this Web site at any time." 
NIH: "A description of this clinical trial will be available on http://www.ClinicalTrials.gov. This Web site will not include 
information that can identify you. At most, the Web site will include a summary of the results. You can search this Web
site at any time." 
Risks 
A. Describe potential research-related risks and discomforts (consider physical, psychological, legal, 
social/economic/financial, loss of confidentiality, group harms); describe the probability, magnitude, and 
duration of the potential risks; do not address risks that would be present if the individual did not 
participate: 
Local discomfort/pain, skin irritation. Theoretical risks include cardiac dysrhythmia and new-onset seizures neither 
of which have been reported in previous studies. In a randomized sham-controlled trial of the use of the device for 
115 children with functional abdominal pain, only 1 patient among 60 with active device discontinued treatment due 
to discomfort, whereas 6 patients in the sham-group discontinued the device one being adhesive allergy. Patients 
will be monitored (including EKG monitoring at least in the initial 48 hours of the device) as inpatient during the time 
the device is in place. Other studies35,36 have also reported minimal to no side-effects using the device for other 
indications.  
Other risks include  remote possibility of loss of confidentiality if there is any breach of study data.  
B. Describe steps taken to minimize risks: 
       Patient comfort will be monitored to assess tolerability, skin will be monitored for contact dermatitis. EKG/Heart rate 
monitoring for dysrhythmia and monitoring for new onset clinical seizures. To minimize the remote possibility of a 
breach in confidentiality, patient data including PHI will be assigned a study ID and stored in a password-protected 
Excel file on MCW’s secured drive: and be only accessible to limited members of the study team. Only coded data with 
a Study ID will be entered into the password-protected REDCap database.  
Section 2 Regulatory Criterion for Approval: Benefits 
Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the 
importance of the knowledge that may reasonably be expected to result. In evaluating risks and benefits, 
the IRB should consider only those risks and benefits that may result from the research (as distinguished 
from risks and benefits of therapies subjects would receive even if not participating in the research). 
 If there is no benefit and no knowledge to be gained, there is no justification to expose subjects to risk. 
 

 
 
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A. Describe the potential benefits to science and/or society which may accrue as a result of this research: 
If found to be effective in treatment of PSH, the PENFS device will offer a non-medication modality for treatment of 
PSH thus helping to decrease the need for neurosedative medications and decreasing the adverse effects of the 
medications.  
The natural history of PSH is that the symptoms are worse initially requiring multiple medications to ameliorate the 
symptoms. Over time, the PSH symptoms decrease allowing weaning of some of the medications. Thus, the 
PENFS device might offer significant benefit in the initial period helping to limit the number of medications needed 
to control the symptoms of PSH. 
B. Are there any benefits which may accrue to the individual subjects in this research (compensation is not 
considered a benefit)?  
☐No   ☒ Yes   
If YES, describe: Improvement in PSH symptoms and reduction in need for medications to treat PSH could 
potentially decrease the adverse effects associated with use of these medications. 
Section 3 Regulatory Criterion for Approval: Equitable Selection 
Selection of subjects is equitable. In making this assessment the IRB should take into account the 
purposes of the research and the setting in which the research will be conducted. The IRB should be 
particularly cognizant of the special problems of research that involves a category of subjects who are 
vulnerable to coercion or undue influence, such as children, prisoners, individuals with impaired decision-
making capacity, or economically or educationally disadvantaged persons. 
 No population is unfairly targeted 
 No population is unfairly excluded 
 Burdens are distributed fairly 
 Benefits are distributed fairly 
 

 
 
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The research population includes the following: 
Check all that apply: 
Normal adults/health volunteers 
☒ 
Inpatient population 
☒ 
Outpatient population 
☐ 
CW or MCW Employees/Staff 
☐ 
Students of (describe) Click here to enter text. 
☐ 
Residents/Fellows 
☐ 
Prisoners 
☐ 
Children 
☒ 
Pregnant Women, Fetuses, Neonates (of uncertain viability or nonviable), after delivery, 
placenta, dead fetus, or fetal material 
☐ 
Adults with Impaired Decision-Making Capacity (enrolled by legally authorized 
representative) 
☐ 
Individuals with limited English proficiency (specify anticipated primary language): Click 
here to enter text. 
☐ 
Economically disadvantaged persons 
☐ 
Educationally disadvantaged persons 
☐ 
Other (describe): Click here to enter text. 
☐ 
A. Total number of human research subjects proposed: 
Locally: 20 parent/child dyads who complete the study  /  Study-wide (if applicable): N/A 
Describe what are these numbers are based on: There are 380-400 PICU admissions/year that are seen 
by ICU Neurology. Using a conservative estimate of 8-10% incidence of PSH, we expect to have 35-40 
patients with PSH. At a conservative 60% enrollment rate, we expect to be able to successfully enroll 20 
patients in this pilot study who complete the study and 20parents/legal guardians to take the parental 
questionnaire.  
B. How do you plan to identify subjects for recruitment or records for inclusion in the study? 
All of the eligible patients (those with acute severe brain injury) would already have had an ICU 
Neurology consult. If they exhibit symptoms of PSH per Neurology and Critical Care teams routine 
assessment, a member of treatment team will evaluate their interest to hear about a research study. If 
they agree to hear about a research study, one of research team members will approach the family for 
consent..  
For the historical controls, the Neurology ICU Billing administrative dataset will be used to collect the 
MRNs of patients who meet the broad criteria of TBI.  
C. Eligibility Criteria (inclusion/exclusion criteria): 
Inclusion criteria: 

 
 
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1) Children admitted to the PICU aged 2-17 years  
2)  Acute severe brain injury (ASBI) and symptoms of PSH- defined as  CFS score > 6 (moderate severity 
of PSH)  
 
Exclusion criteria: 
1) age < 2 years (small ears thus less surface area to apply the leads) 
2) ear deformity 
3) severe dermatitis of ear lobes 
4) intractable seizures 
5) heart block 
6) other implantable devices (cardiac pacemaker, vagal nerve stimulator, etc.) 
7) known pregnancy 
8) Parent or LAR under the age of 18.  
 
D. Who will be responsible for determining whether potential subjects satisfy eligibility criteria and how will 
they do so? 
Note: if the analysis of health information is necessary to determine eligibility, a medically-qualified person must be 
involved in the determination. 
Eligibility will be determined by either the Principal Investigator or Sub-Investigator. A checklist of the 
Inclusion/Exclusion criteria will be followed to determine eligibility.  
E. Will recruitment materials be used?  
☒No   ☐ Yes 
If YES, describe how and where materials will be posted/distributed: Click here to enter text.  
Documents containing exact language to be used must be included in submission package for review and approval 
by the IRB. Review Guidance – Recruitment for Human Subject Research (found in IRBNet under Forms and 
Templates) for more information and instructions for logo use.  
Section 4 Regulatory Criterion for Approval: Informed Consent Process 
Informed consent will be sought from each prospective subject or the subject's legally authorized 
representative, in accordance with, and to the extent required by, §46.116./50.20. 
 Circumstances of the consent process will provide the subject sufficient opportunity to consider whether to 
participate (this is an ongoing process and should be confirmed at the time of each interaction) 
 Circumstances of the consent process will minimize the possibility of coercion or undue influence 
 Information will be given in an understandable language 
 Special issues that could present undue influence and need additional consideration: advertisements, payment 
for participation 
Description of Process to Obtain Consent  
Information regarding parental permission and assent is captured in Section 8: Vulnerable Populations. 

 
 
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A. WHO: List appropriately trained personnel by role rather than individual name (i.e., Investigators, Study 
Coordinators, etc.) who have been delegated authority by the PI to conduct the consent process, and 
indicate whether those individuals have an existing treating relationship with the potential subject: 
Members of study team including research coordinators will  conduct the consent process. None of these 
will have an existing relationship with the potential subject. 
B. WHEN: Describe when subjects are being informed of the research opportunity and how much time they 
are given to consider whether to participate: 
The local research team will screen all admitted PICU patients to determine the eligibility for study. Once eligibility is 
confirmed, the study team will reach out to attending physician and clinical team to obtain their permission to 
approach the subject and family. If the clinical team is ok for the subject to participate in the study, someone who 
has a treating relationship with the subject will make the initial contact, introducing the research study and study 
team to the subject and their family. It is expected that ample time will be provided to   subject’s family so they can 
think about participation and receive answers to any questions they may have.  
Parent as Participant: After the main study consent is signed, parent(s)/guardians will be given the “CHW Minimal 
Risk template” to read and discuss. All of their questions regarding this consent, which pertains to completing a brief 
questionnaire about their perceptions of their child’s involvement in this device study will be answered. It is 
expected this consent process will take approximately 15 minutes. 
After the consents are signed, the CFS assessment will be made to ascertain study eligibility. If the child does not 
meet eligibility criteria based on their CFS scores, the family will be told their child is not eligible for the study as 
they did not meet study defined CFS scoring criteria. Study Enrollment is defined as meeting CFS criteria of > 
6 after consent. If CFS scores are already being collected for subject prior to subject consent as a 
standard of care, we can use already available CFS scores from medical record.  The PENFS device will 
be placed over the external ear by study investigator or one of trained nurses (RNs) from the Pediatric 
Translational Research Unit (P-TRU) within 24 hours of meeting CFS > 6 score criteria   
C. WHERE and HOW: Describe the physical location of the consent discussion and how it will be conducted: 
Someone who has a treating relationship with the potential subject will make initial contact with the patient, obtain 
permission for the study team to approach, study team will then approach the patient and family for consent 
discussion in private setting in PICU. 
D. SPECIAL CONSIDERATIONS: Describe any subject compensation (reimbursement for expenses; 
compensation for time and effort): 
No subject compensation is offered in this study. 
E. If you are requesting to waive consent for some or all subjects, provide rationale:  
We are requesting a full waiver of assent for this study as we do not anticipate any of the subjects will be able to 
assent because of their severe brain injury. These patients will either have reduced consciousness or will 
cognitively not be able to understand what they are consenting/assenting to.  
Include IRB – Request form for Alteration or Waiver of Assent, Consent, Parental Permission (found in 
IRBNet under Forms and Templates) in the submission package. 

 
 
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Section 5 Regulatory Criterion for Approval: Documentation of Informed Consent 
Informed consent will be appropriately documented or appropriately waived in accordance with 
§46.117/50.27. 
 
A. Describe the plan for documentation of consent and process that is specific to the protocol and consistent 
with local requirements: 
If you are requesting to waive documentation of consent/assent/parental permission, include IRB – Request form 
for Alteration or Waiver of Assent, Consent, Parental Permission (found in IRBNet under Forms and 
Templates) in the submission package. 
The study team anticipates an adequate number of qualifying patients to be available within the PICU. These 
patients will be identified during their PICU stay and approached if they meet the study inclusion criteria and do not 
meet any of the exclusion criteria. The research coordinator or other members of research team will approach the 
family for consent after receiving permission from the clinical team. If the principal investigator is part of the potential 
subject’s care team he/she will not approach the family and one of the sub-investigators or research coordinators 
will participate in the consent conversation instead. Someone who has a treating relationship with the potential 
subjects will make the initial contact with the patient, obtaining permission for the study team to approach, and a 
member of study team will then approach the patient and family for research study participation. The research team 
will meet with the patient and their parent(s)/ legal guardian to discuss the study and obtain consent.  A copy of the 
consent signed by the parent(s)/ legal guardian will be uploaded into the patient’s medical record. A signed copy of 
the consent will be given to the patient’s parent(s) or legal guardian. 
Parent as Participant: The original consent and documentation will not be scanned into the child’s medical record, 
but  will be secured in the subject’s study file in a locked cabinet along with other study documents. The 
parent(s)/guardian will be given a signed copy of the Minimal Risk template.  
 
 
Section 6 Regulatory Criterion for Approval: Safety Monitoring 
When appropriate, the research plan makes adequate provision for monitoring the data collected to 
ensure the safety of subjects. 
Considerations applicable to research that is deemed greater than minimal risk include: 
 Who reviews safety data? 
 What data are reviewed (safety and efficacy)? 
 When/how often are data reviewed? 
 
A. Is a Data Safety Monitoring Board (DSMB)/Data Monitoring Committee (DMC) in Place? 
☒No   ☐ Yes   ☐ N/A (study is not greater than minimal risk) 
If YES, describe its members and how often they meet (you may include any DSMB/DMC charters in the 
submission package; once the study has been opened locally any DSMB/DMC reports should be submitted for 
review as reportable new information): 
 

 
 
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B. If there is no formal DSMB/DMC, describe the monitoring plan or indicate that the study involves no more 
than minimal risk (if the IRB disagrees and determines the study to be greater than minimal risk, the study 
will be deferred until an appropriate monitoring plan has been developed): 
Members from the division of critical care (MD, APP) will meet every 2 months to review data on device safety. Any 
serious adverse event deemed related to study will be notified immediately for adjudication. 
C. Have stopping rules been established for the study (to evaluate whether the objectives have been met, or 
that the objectives cannot be met, or that the accumulated data indicates that the risks exceed the benefits 
of the study)?  
☐No   ☒ Yes   ☐ N/A (study is not greater than minimal risk) 
 
If YES, describe the stopping rules:                                                                                                                           
Any symptomatic cardiac dysrhythmia or new-onset seizure deemed to be as a result of the device use.                      
5 consecutive patients showing device intolerance i.e worse comfort scores, worse CFS score,  
D. Describe procedures to be employed in analyzing data (including a power analysis): 
This is a pilot feasibility study of use of the device. A convenience sample of 20 patients was chosen. 
Section 7 Regulatory Criterion for Approval: Privacy and Confidentiality 
When appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the 
confidentiality of data. 
 Privacy refers to persons and their interest in controlling access to themselves 
 Confidentiality refers to agreements with the subject about how data are to be handled 
 
A. Provisions for the protection of privacy of subjects (having control over the extent, timing, and 
circumstances of sharing oneself [physically, behaviorally, or intellectually] with others): 
Every effort will be maintained to protect the privacy of subjects. Potential patients and their families will be 
approached in a private room in the PICU to discuss the study. If they agree, the consent process will also 
take place in this private room without interference from others. In addition, during the consenting process 
the subject of privacy surrounding the subject’s data will be discussed.   
Individuals will not be identified in scientific presentation of findings or in publications. The subject will have 
right to withdraw from study anytime by writing to study PI and any further data collection will be stopped 
beyond that point.  
B. Provisions to maintain the confidentiality of data (the treatment of information that an individual has 
disclosed in a relationship of trust and with the expectation that it will not be divulged to others in ways 
that are inconsistent with the understanding of the original disclosure, without permission): 
Every effort will be made to protect the confidentiality of patient’s data. Their coded data, including a Study 
ID, will be entered into a password protected REDCap database for study analysis. A separate password 
protected Excel file will exist as a key to the coded data. It will contain the Study ID number along with some 
PHI such as MRNs. The MRN in this file is the PHI which serves as the key to the code. Both password 
protected files will be stored on the secured MCW secured servers and are only accessible by the study 
team.  

 
 
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All research team members will be trained regarding human subject research and the confidentiality of data 
using the institution’s standard, web-based CITI training modules and will possess appropriate CITI 
certification. 
C. If paper records are being maintained, indicate where paper documents will be kept and how secured (This 
includes hard copies of signed consent forms, as well as any other documents containing subject PHI): 
Any hard copy data forms will be assigned the appropriate Study ID. The data will be entered into the 
REDCap study database. The hard copies will be stored in a locked cabinet accessible only to the study 
team. A copy of the signed consent with HIPPA authorization will be maintained in patient’s medical records 
at Children’s Wisconsin. 
D. Describe whether data will be shared outside MCW/CW, with whom (include outside collaborators and their 
institutions), and how (anonymous, identifiable, coded, de-identified [review OHRP guidance if uncertain]): 
If an investigator leaves MCW/CW during the study and the PI intends for the individual to continue to work 
on the study as a collaborator, this section must be updated and submitted as amendment package for IRB 
review. The CW HRPP will need to consider whether the investigator is conducting human subject 
research, whether data are appropriately protected, and whether a reliance agreement will need to be 
executed with the investigator’s new institution. 
The only people allowed to handle subject’s health information are those on the research team at 
CHW/MCW and those who check on research activities to make sure the hospital rules are followed. 
 
E. Will a Certificate of Confidentiality (CoC) be obtained for this research or is one already in place? 
Certificates of Confidentiality are issued automatically when: 
 Research is conducted or supported by NIH and falls within the scope of the NIH policy.   
 Research is conducted or supported by the CDC and involves the collection of identifiable, sensitive 
information. 
 Research is funded by the FDA in whole or in part and involves the collection or use of identifiable, 
sensitive information as defined in 42 U.S.C. 241(d). 
If you need help in making the determination, contact the HRPP office at 414.337.7133. 
☒ No   ☐Yes   ☐ N/A (study is not conducted, supported or funded by NIH/CDC/FDA) 
If YES, the required disclosure language must be included in the consent form(s) (see NIH website for suggested 
consent language). 
Data Security Provisions 
All research projects that collect electronic data must use appropriate security measures to ensure that data are 
protected from theft or loss in order to prevent breaches of confidentiality. You must indicate what encryption 
tools will be used from the options below, or indicate further below why they are not necessary. 
The IRB will not review this protocol unless you indicate the encryption tools being used to secure your research data. If 
you do not have encryption in place on your systems, contact your Information Management Systems support team to 
arrange for one of the encryptions options listed below. 
The following encryption products employ cryptographic modules that the National Institute of Standards and Technology 
has certified as meeting FIPS 140-2 requirements. Children’s Hospital and Health System endorsed the use of these 
products made to encrypt hard drives and removable media. All electronic research data must be encrypted using one or 
more of these products. 
This protocol summary/submission application must be kept current and revised via the amendment process for 
IRB approval if any security measures change during the course of the research study.  

 
 
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Indicate which encryption tools you are using to secure your research data: 
Key: HD = Hard Drive; RS = Removable Storage (USB flash drive, CD, etc.); PD = Portable Device (iPod, iPhone, PDA, etc.) 
☐ 
Credent Mobile Guardian (RS, PD) 
☐ 
McAfee Endpoint Encryption (HD, RS) 
☐ 
GuardianEdge Hard Disk and GuardianEdge 
Removable Storage Encryption (HD, RS, PD) 
☐ 
Seagate Secure Self-Encrypting Drives (HD when 
encryption option is enabled) 
☐ 
IronKey encrypted flash drives (RS) 
☒ 
Symantec Endpoint Encryption (HD, RS, PD) 
☐ 
SafeNet Protect Disk and SafeNet Protect File (HD, 
RS) 
☐ 
WinMagic SecureDoc encryption (HD) (for MCW 
owned computers) 
☐ 
Microsoft Bitlocker (HD, RS when used with 
Windows 7 and FIPS compliant algorithms are 
enabled) 
☐ 
PGP Whole Disk Encryption and PGP Portable (HD, 
RS) 
☐ 
OTHER (describe): Click here to enter text. 
NOTE: BOX is not a CW-approved tool for securing protected health information and cannot be used for research. 
 
Does not apply because: 
☐ 
Data are de-identified – no PHI collected (provide 
detailed information on data elements in the 
protocol summary/submission application) 
☐ 
Data are stored on BOTH CW and MCW secured 
shared drives 
☐ 
Data are stored on CW secured shared drives 
☐ 
Data are stored on paper only 
☒ 
Data are stored on MCW secured shared drives 
☒ 
OTHER (describe): Password protected REDCap 
Database managed by QHS 
Section 8 Regulatory Criterion for Approval: Vulnerable Populations 
When some or all of the subjects are likely to be vulnerable to coercion or undue influence, such as 
children, prisoners, individuals with impaired decision-making capacity, or economically or educationally 
disadvantaged persons, additional safeguards have been included in the study to protect the rights and 
welfare of these subjects. 
Additional steps to minimize coercion and undue influence: 
 Assessment of capacity 
 Permission of a representative 
 Assent 
 Witness to the consent process 
Subpart D—Additional Protections for Children Involved as Subjects in Research (FDA: In order to 
approve research in which some or all of the subjects are children, an IRB must determine that all 
research is in compliance with 21 CFR part 50, subpart D.) 
A. Do you intend to enroll children as subjects? 
Yes  
B. What is the age range of the children in this research? 
2-17 years 

 
 
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C. Where will the children participate? (Check all that apply): 
☒ 
CW Hospital/Facility: PICU 
☐ 
CW Outpatient Clinic/Facility: Click here to enter text. 
☐ 
Froedtert Facility:  Click here to enter text. 
☐ 
MCW lab/office: Click here to enter text. 
☐ 
Home 
☐ 
School 
If School is checked, have you obtained the necessary permission from the school district?  
☐No  ☐ Yes  (if YES, include documentation of permission in submission package) 
☐ 
Other - Specify: Click here to enter text. 
If Other is checked, have you obtained the necessary permission? 
☐No  ☐ Yes  (if YES, include documentation of permission in submission package) 
D. Are any of the children Wards (46.409) of the State or any other agency, institution, or entity? 
☒No   ☐ Yes   
If YES, contact the HRPP office prior to submission and provide protocol-specific details:  
 
E. Risk Levels For Studies Involving Children 
Check the category below that best represents the degree of risk and benefit to which the children in this 
study will be exposed.  
More than one category may be indicated such as when a protocol involves both an experimental and a control 
group. In these cases, specify which category you believe applies to which group. The IRB will consider the 
Principal Investigator’s assessment and rationale regarding the risk level for this study but it is ultimately the IRB’s 
responsibility to determine appropriate risk levels.  
☐ 
Risk Level 1 (46.404/50.51): (Research not involving greater than minimal risk.) Minimal risk means that the 
probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves 
than those ordinarily encountered in daily life or during the performance of routine physical or psychological 
examinations or tests. 
Provide protocol specific rationale (for each group): Click here to enter text. 
☒ 
Risk Level 2 (46.405/50.52): (Research involving greater than minimal risk but presenting the prospect of direct 
benefit to the individual subjects.)  More than minimal risk to children is presented by an intervention or procedure 
that holds out the prospect of direct benefit for the individual subject, or by a monitoring procedure that is likely to 
contribute to the subject's well-being. 
Provide rationale for why/how: 
(a) the risk is justified by the anticipated benefit to the subjects (for each group): PENFS device use is 
offered as a non-medication modality to these subjects for treatment of PSH symptoms. Improvement in 
PSH symptoms and reduction in need for medications to treat PSH could potentially decrease the adverse 
effects associated with use of these medications. 

 
 
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(b) the relation of the anticipated benefit to the risk is at least as favorable to the subjects as that 
presented by available alternative approaches (for each group): Reducing the need of neuro-sedative 
medications and decreasing the side effects of these medications is a benefit for these subjects in 
comparison to the discomfort of this device placement which is slight to minor. No significant side effects 
have been reported with the use of this device for other indications. 
☐ 
Risk Level 3 (46.406/50.53): (Research involving greater than minimal risk and no prospect of direct benefit to 
individual subjects, but likely to yield generalizable knowledge about the subject's disorder or condition.)  More 
than minimal risk to children is presented by an intervention or procedure that does not hold out the prospect of 
direct benefit for the individual subject, or by a monitoring procedure which is not likely to contribute to the well-
being of the subject. 
Which intervention(s) or procedure(s) present more than minimal risk without offering the prospect of 
direct benefit to individual subjects (for each group):  
Provide rationale for why/how: 
(a) the risk of the intervention(s) or procedure(s) represents a minor increase over minimal risk (for 
each group): Click here to enter text. 
(b) the intervention(s) or procedure(s) presents experiences to subjects that are reasonably 
commensurate with those inherent in their actual or expected medical, dental, psychological, social, 
or educational situations (for each group): Click here to enter text. 
(c) the intervention(s) or procedure(s) is likely to yield generalizable knowledge about the subjects' 
disorder or condition which is of vital importance for the understanding or amelioration of the 
subjects' disorder or condition (for each group): Click here to enter text. 
☐ 
Risk Level 4 (46.407/50.54): (Research not otherwise approvable which presents an opportunity to understand, 
prevent, or alleviate a serious problem affecting the health or welfare of children.) The proposed research does 
not meet the criteria of the above categories but presents an opportunity to understand, prevent, or alleviate a 
serious problem affecting the health or welfare of children. 
Provide justification for why this research of this risk level should be approved (for each group):  
Parental Permission (46.408/50.55) 
F. What permission will be obtained from the parents? 
In general, permission from both parents is required for research involving children unless one parent is deceased, 
unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care 
and custody of the child.  However, for Categories 404/51 & 405/52, the IRB may find that the permission of one 
parent is sufficient. Permission from both parents should be obtained whenever possible regardless of risk level 
determination. 
☐ Permission will be obtained from both parents where possible 
☒ Permission from only one parent is being requested 
☒ A waiver of parental permission is being requested (complete IRB – Request form for Alteration or Waiver 
of Assent, Consent, Parental Permission found in IRBNet under Forms and Templates) This is also for the 
historical controls 
☐ A waiver of DOCUMENTATION of parental permission is being requested (complete IRB – Request form for 
Alteration or Waiver of Assent, Consent, Parental Permission found in IRBNet under Forms and 
Templates) 

 
 
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G. If the research is being conducted in a group setting (e.g., a classroom), in which some children have 
permission to participation and some do not, what is the process to ensure that those children who do not 
have parental permission do not participate in the research. 
N/A 
Assent (46.408/50.55) 
Adequate provisions must be made for soliciting the assent of children when in the judgment of the IRB the children are 
capable of providing assent and for soliciting the permission of their parents or guardians.  
H. Indicate whether the children you intend to include in the research are generally capable of providing 
assent taking into account the ages, maturity and psychological state of the children proposed to be 
involved. Please be specific: 
☐ All are capable 
☒ None are capable:  Explain: The patients being studied are survivors of acute severe brain injury and would be 
unable to provide assent during the enrollment period when they have symptoms of PSH and are cognitively unable 
to provide assent.  
☐ Some are capable:  Explain: Click here to enter text. 
I. 
If children are capable of providing assent, are you planning to obtain assent from the children? 
☐Yes   ☐ No   ☒ N/A – none are capable 
If YES, describe the proposed process for obtaining assent, including who will be involved and the setting 
and circumstances under which it will be sought:   
If NO, a waiver of assent is being requested (complete IRB – Request form for Alteration or Waiver of 
Assent, Consent, Parental Permission found in IRBNet under Forms and Templates).  
We are requesting a Waiver of Assent (see uploaded form) for all children due to the child’s diminished cognitive 
functioning. Given the inclusion criteria of nature of brain injury causing subject to meet study criteria and 
associated sedation necessary as standard of care for these patients, we do not anticipate that any of subjects 
enrolled in study will be conscious enough to comprehend, process and understand the study, so we request a 
waiver of assent for all subjects who will be approached for study. 
 If child has already completed study before achieving the age of majority, we request a waiver of consent and 
HIPAA authorization for continued use of their data on reaching the age of majority. 
 
A waiver of consent/ assent is also being requested for the historical controls.  
 
J. If assent will be obtained, describe the process and select how assent will be documented. Include in the 
submission package proposed assent forms or child information sheet, if any. 
Describe the process:  
☐ All minors will sign the assent signature line on the parental permission form. Minors >12 years of age will be 
asked to sign the assent signature line on the parental permission form.  
☐ All minors will sign a separate assent form 
☐ Minors in the age range of seven to twelve years of age  will sign a separate assent form 

 
 
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☐ Verbal assent will be obtained and discussion documented in research records 
K. Describe the plan for obtaining legally effective informed consent and HIPAA Authorization at the age of 
majority [18] or describe why it is not applicable (review Guidance – Consent for Continued Participation 
When a Child Reaches Age 18 found in IRBNet under Forms and Templates): 
Age of Majority Plan: 
 
If a subject is in PICU and reaches the age of majority, we will assess already enrolled subject for their consent 
capacity during the time when device is already on the subject (active study participation phase). We do not 
anticipate the child will be conscious enough in this period and so, re-consent will be obtained from parent or legal 
guardian if subject is still in PICU. If the device has already been removed from the subject and the only study 
participation pertains to use of already collected data, we request a waiver of re-approach, consent and HIPAA 
authorization for continued use of data at the age of majority. 
 
If the subject has already left PICU and there is no active study participation, no follow up contact will be made to 
subject or family as they are lost to follow up. The only study activity ongoing is continued use of their collected 
research data and we request waiver of consent and HIPAA authorization for continued use of this data, for the 
reason subject is lost to follow up. 
 
 
Contact the CW HRPP office to obtain appropriate supplements if you intend to enroll other vulnerable 
populations such as pregnant women, fetuses and neonates, prisoners (including incarcerated 
minors), or cognitively impaired adults. 
Section 9 Potential Conflicts of Interest 
Relationships of all members of the research team: Do any research personnel or any of their family members 
(spouse or dependent children) have an incentive or interest, financial or otherwise, which may appear to affect the 
protection of the human subjects involved in this project, the scientific objectivity of the research or its integrity?  
☒No  ☐ Yes 
If YES, for each individual provide a description of each situation (including dollar values if applicable) 
as a separate document in the submission package which will be shared with the CW Conflict of 
Interest Committee. 
It is the PI’s responsibility to review applicable MCW/CW policies on conflict of interest with every study team 
member and determine whether any member has a Significant Financial Interest related to this project.  
 For MCW faculty or staff, refer to MCW's Research Financial Conflicts of Interest Policy. 
 For employees of Children’s, refer to Children’s Research Conflict of Interest Policy. 
 For subcontractors or physicians/staff who are employed outside of Children’s or MCW, contact Tom 
Twinem at 414-266-2215 for further guidance. 
 
FINANCIAL INTEREST includes any current or anticipated ownership interest or other financial relationship 
with any company or entity that sponsors, provides support, or otherwise has a financial interest in the 
conduct or outcome of this research protocol (“Financially Interested Organization”). This includes: 
 Any related party who performed any work (not directly related to the costs of conducting research) 
within the past 12 months for a Financially Interested Organization. 

 
 
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 Any related party who received compensation (not directly related to the costs of conducting research) 
within the past 12 months from a Financially Interested Organization. This includes paid/reimbursed 
travel. 
 Any related party who anticipates performing any work and/or receiving any compensation within the 
next 12 months (not directly related to the costs of conducting research) from a Financially Interested 
Organization. This includes paid/reimbursed travel. 
 Any related party that maintained a board or executive relationship related to the research, regardless 
of compensation. 
 Any related party who owns stock, stock options or other forms of ownership in a Financially 
Interested Organization. This does not include stock/stock options held in mutual, pension, or 
investment funds over which the investor has no control with regard to investment decisions. 
 Any related party who has any intellectual property related to the proposed research (e.g., named as 
an inventor in an issued patent or patent application, license fees, technology transfers, current or 
future royalties from patents and copyrights). 
 Your department/institution/organization has a financial interest in the agent under investigation or in a 
company that could benefit from the study findings, or receives significant financial support from such 
a company. 
Section 10 Bibliography 
List pertinent literature references: 
1) Baguley IJ, Perkes IE, Fernandez-Ortega JF, Rabinstein AA, Dolce G, Hendricks HT; Consensus 
Working Group. Paroxysmal sympathetic hyperactivity after acquired brain injury: consensus on 
conceptual definition, nomenclature, and diagnostic criteria. J Neurotrauma. 2014 Sep 
1;31(17):1515-20. doi: 10.1089/neu.2013.3301. Epub 2014 Jul 28. PMID: 24731076. 
2) Fernandez-Ortega, J.F., Prieto-Palomino, M.A., Munoz-Lopez, A., Lebron-Gallardo, M., Cabrera-
Ortiz, H., and Quesada-Garcia, G. (2006). Prognostic influence and computed tomography findings in 
dysautonomic crises after traumatic brain injury. J. Trauma 61, 1129–1133.  
3) Baguley, I.J., Slewa-Younan, S., Heriseanu, R.E., Nott, M.T., Mudaliar, Y., and Nayyar, V. (2007). 
The incidence of dysautonomia and its relationship with autonomic arousal following traumatic brain 
injury. Brain Inj. 21, 1175–1181. 
4) Rabinstein AA. Paroxysmal sympathetic hyperactivity in the neurological intensive care unit. Neurol 
Res. 2007 Oct;29(7):680-2. 
5) Kirk KA, Shoykhet M, Jeong JH, Tyler-Kabara EC, Henderson MJ, Bell MJ, Fink EL. Dysautonomia 
after pediatric brain injury. Dev Med Child Neurol. 2012 Aug;54(8):759-64. 
6) Fernandez-Ortega JF, Prieto-Palomino MA, Garcia-Caballero M, Galeas-Lopez JL, Quesada-Garcia 
G, Baguley IJ. Paroxysmal sympathetic hyperactivity after traumatic brain injury: clinical and 
prognostic implications. J Neurotrauma. 2012 May 1;29(7):1364-70. 
7) Baguley IJ, Nicholls JL, Felmingham KL, et al. Dysautonomia after traumatic brain injury: a forgotten 
syndrome? J Neurol Neurosurg Psychiatry 1999;67(1):39–43 
8) Blackman JA, Patrick PD, Buck ML, Rust RS Jr. Paroxysmal autonomic instability with dystonia after 
brain injury. Arch Neurol. 2004 Mar;61(3):321-8. 
9)  Krach LE, Kriel RL, Morris WF, Warhol BL, Luxenberg MG. Central autonomic   
      
dysfunction following acquired brain injury in children. Neurorehabil Neural Repair. 1997; 11:41–5. 
10) Baguley IJ, Heriseanu RE, Cameron ID, Nott MT, Slewa-Younan S. A critical review of the 
pathophysiology of dysautonomia following traumatic brain injury. Neurocrit Care. 2008; 8:293–300. 

 
 
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11) Mehta, N.M., Bechard, L.J., Leavitt, K., and Duggan, C. (2008). Severe weight loss and 
hypermetabolic paroxysmal dysautonomia following hypoxic ischemic brain injury: the role of indirect 
calorimetry in the intensive care unit. JPEN J. Parenter. Enteral Nutr. 32,281–284.  
12) Samuel S, Allison TA, Lee K, Choi HA. Pharmacologic Management of Paroxysmal Sympathetic 
Hyperactivity After Brain Injury. J Neurosci Nurs. 2016 Apr;48(2):82-9.  
13) Rabinstein AA, Benarroch EE. Treatment of paroxysmal sympathetic hyperactivity. Curr Treat 
Options Neurol. 2008 Mar;10(2):151-7. 
14) Baguley IJ, Heriseanu RE, Gurka JA, Nordenbo A, Cameron ID. Gabapentin in the management of 
dysautonomia following severe traumatic brain injury: a case series. J Neurol Neurosurg Psychiatry. 
2007;78(5):539-541.  
15) Cuny E, Richer E, Castel JP: Dysautonomia syndrome in the acute recovery phase after traumatic 
brain injury: relief with intrathecal Baclofen therapy. Brain Inj 2001,15:917–925. 
16) Draghici AE, and Taylor JA. The physiological basis and measurement of heart rate variability in 
humans. J Physiol Anthropol 2016; 35: 22. 
17) Task Force of the European Society of Cardiology and the North American Society of Pacing and 
Electrophysiology. Heart Rate Variability: Standards of Measurement, Physiological Interpretation, 
and Clinical Use. Circulation. 1996;93(5):1043-1065. 
18) Johnston BW, Barrett-Jolley R, Krige A, Welters ID. Heart rate variability: Measurement and 
emerging use in critical care medicine. J Intensive Care Soc. 2020;21(2):148-157.  
19) Bishop DG, Wise RD, Lee C, et al. Heart rate variability predicts 30-day all-cause mortality in 
intensive care units. South Afr J Anaesth Analg 2016; 22: 125–128. 
20) Kim SW, Jeon HR, Kim JY, Kim Y. Heart Rate Variability Among Children With Acquired Brain Injury. 
Ann Rehabil Med. 2017;41(6):951-960. doi:10.5535/arm.2017.41.6.951 
21) Baguley IJ, Heriseanu RE, Felmingham KL, Cameron ID. Dysautonomia and heart rate variability 
following severe traumatic brain injury. Brain Inj. 2006 Apr;20(4):437-44. 
22) Phillips SS, Mueller CM, Nogueira RG, Khalifa YM. A Systematic Review Assessing the Current 
State of Automated Pupillometry in the NeuroICU. Neurocrit Care. 2019 Aug;31(1):142-161. 
23) Larson MD, Behrends M. Portable infrared pupillometry: a review. Anesth Analg. 2015 
Jun;120(6):1242-53. 
24) Venkata Sivakumar A, Kalburgi-Narayana M, Kuppusamy M, Ramaswamy P, Bachali S. 
Computerized dynamic pupillometry as a screening tool for evaluation of autonomic activity. 
Neurophysiol Clin. 2020 Oct;50(5):321-329.  
25) Kovacic K, Hainsworth K, Sood M, Chelimsky G, Unteutsch R, Nugent M, Simpson P, Miranda A. 
Neurostimulation for abdominal pain-related functional gastrointestinal disorders in adolescents: a 
randomised, double-blind, sham-controlled trial. Lancet Gastroenterol Hepatol. 2017; 2:727-737. 
26) Miranda A, Taca A. Neuromodulation with percutaneous electrical nerve field stimulation is 
associated with reduction in signs and symptoms of opioid withdrawal: a multisite, retrospective 
assessment. Am J Drug Alcohol Abuse. 2018;44(1):56–63. 
27) FDA. FDA grants marketing authorization of the first device for use in helping to reduce the 
symptoms of opioid withdrawal [News Release]. 2017 [updated November 15, 2017. 
28) Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs. 2003 
Apr-Jun;35(2):253-9.  
29) Gowing L, Farrell M, Ali R, White JM. Alpha2-adrenergic agonists for the management of opioid 
withdrawal. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No.: CD002024.  
30) Frangos E, Ellrich J, Komisaruk BR. Non-invasive Access to the Vagus Nerve Central Projections via 
Electrical Stimulation of the External Ear: fMRI Evidence in Humans. Brain Stimul. 2015 May-
Jun;8(3):624-36.  
31) Mahadi KM, Lall VK, Deuchars SA, Deuchars J. Cardiovascular autonomic effects of transcutaneous 
auricular nerve stimulation via the tragus in the rat involve spinal cervical sensory afferent pathways. 
Brain Stimul. 2019 Sep-Oct;12(5):1151-1158.  

 
 
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32) Clancy JA, Mary DA, Witte KK, Greenwood JP, Deuchars SA, Deuchars J. Non-invasive vagus nerve 
stimulation in healthy humans reduces sympathetic nerve activity. Brain Stimul. 2014;7(6):871–877.  
33) Deuchars SA, Lall VK, Clancy J, Mahadi M, Murray A, Peers L, et al. Mechanisms underpinning 
sympathetic nervous activity and its modulation using transcutaneous vagus nerve stimulation. Exp 
Physiol. 2018;103(3):326–331.  
34) Pozzi M, Locatelli F, Galbiati S, Radice S, Clementi E, Strazzer S. Clinical scales for paroxysmal 
sympathetic hyperactivity in pediatric patients. J Neurotrauma. 2014 Nov 15;31(22):1897-8. 
35) Miranda A, Taca A. Neuromodulation with percutaneous electrical nerve field stimulation is 
associated with reduction in signs and symptoms of opioid withdrawal: a multisite, retrospective 
assessment. The American Journal of Drug and Alcohol Abuse. 2017;39:1–8. 
36) Roberts A, Sithole A, Sedghi M, Walker C, Quinn T. Minimal Adverse Effects Profile Following 
Implantation of Peri-Auricular Percutaneous Electrical Nerve Field Stimulators: A Retrospective 
Cohort Study. Medical devices: Evidence and Research. 2016;9:389-393.