Development of an Algorithm That Predicts Hypoventilation Due to an Opioid Overdose
Conditions: Drug Overdose, Opioid-Related Disorders
Sponsor: RTM Vital Signs, LLC

1 
 
 
Title of Project: Development of an algorithm that predicts hypoventilation due to an 
opioid overdose. 
 
Principal Investigator: 
Stephen E McNulty, DO, Department of Anesthesiology 
 
 
Co-Investigators:  
Jeffrey I Joseph, DO, Department of Anesthesiology 
 
 
 
 
Marc C Torjman, PhD, Department of Anesthesiology  
 
 
 
 
Michael Li, PhD, Health Data Science   
 
 
 
 
Jennifer Lessin, RN, Department of Anesthesiology 
 
 
 
 
 
Abstract 
 
More than 64,000 Americans died from drug overdose in 2016 and drug overdose is 
now the most common cause of death for people under 50 years old in the United 
States (1). Furthermore, the number of overdose deaths is increasing with the rise of 
abuse of powerful synthetic opioids, such as fentanyl. In May of 2017, the National 
Institutes of Health (NIH) and National Institute on Drug Abuse (NIDA) directors Drs. 
Collins and Volkow (3) outlined how research may help reduce the death toll associated 
with the current opioid epidemic; one of the current critical needs is the development of 
new overdose-reversal interventions, including wearable technologies that can detect 
an (impending) overdose from physiological signals to signal for help, or trigger a 
coupled automated injection of naloxone. Automated detection of overdose is essential 
because most opioid overdoses occur when individuals are alone and unobserved by 
family members or first responders. Opioids cause respiration to slow and become 
irregular due to mu-opioid receptor mediated suppression of respiratory related regions 
of the brainstem and spinal cord. Importantly, there are characteristic early changes in 
breathing patterns that indicate a progression towards significant hypoventilation, but 
there is currently no method to measure these patterns non-invasively without large 
hospital equipment. Recently, there has been a renewed interest in respiratory 
monitoring using tracheal sounds (2, 4, 5). Tracheal sounds originate from the vibrations 
of the tracheal wall and surrounding soft tissues caused by gas pressure fluctuations in 
the trachea. These sounds can be collected from a microphone or a piezo-electric film 
transducer placed over the trachea and have been processed to monitor respiratory rate 
and to estimate respiratory flow. We hypothesize that individual trends in tracheal 
sounds detected by a machine-learning algorithm will provide an early warning sign of 
the onset of hypoventilation as a result of opioid overdose in humans. The aim of this 
study is to develop a machine-learning algorithm that detects impending hypoventilation 
as a result of opioid overdose from tracheal sound. This algorithm could eventually be 
integrated with a miniature tracheal sound sensor and could be used to detect 
impending respiratory depression in the outpatient setting as well as in the hospital.  
 
 
 
 
IRB Approved at the 
Protocol Level 
Feb 13, 2019
20183438

2 
 
A. Specific Aims 
 
We hypothesize that advanced analysis of tracheal sound can be used to predict 
hypoventilation due to opioid overdose.  
 
The specific aim of this proof of concept study is to collect tracheal sound data in 20 
healthy subjects undergoing an incremental infusion of fentanyl to induce mild to 
moderate hypoventilation (also called permissive hypercapnia). Study subjects will 
receive supplemental oxygen to prevent hypoxemia.  The tracheal sound data will be 
refined using advanced signal processing techniques and machine learning to assess 
whether it is possible to detect and predict the onset of hypoventilation.  
 
The long-term objective of this project is to develop a real-time monitoring system based 
on tracheal sound that can be used to detect changes in minute ventilation and alarm 
before significant hypoventilation occurs due to an overdose of anesthetics and/or 
analgesics.  
 
B.  Background and Significance 
 
RTM Vital Signs, LLC is collaborating with Thomas Jefferson University to develop a 
non-invasive Tracheal Sound Sensor that continuously monitors and analyzes sounds 
from the trachea to determine upper airway patency and the adequacy of an ambulatory 
person’s respiratory rate (RR) and tidal volume (TV) to maintain a sufficient minute 
ventilation (RR X TV).  
 
Over the last decades various mathematical 
methods have been developed to estimate 
respiratory rate and respiratory flow from 
tracheal sounds (2). Airflow sounds are 
known to occur at a frequency of 200-2000 
Hz while snoring sounds occur in the  0-200 
Hz band (2). There is a near-linear 
relationship between airflow in the trachea 
and respiratory sounds - increasing flow 
increases 
the 
amplitude 
of 
sounds. 
Additionally, different transformations can be 
applied continuously on recorded tracheal 
sound to extract specific information.  
 
 
Previous studies have looked at the average 
power, envelop, spectral power, and entropy of 
sound signals. One of the most robust models to 
estimate respiratory flow from tracheal sound 
uses the entropy of tracheal sounds (a measure 
Figure 1.  Actual tracheal airflow (solid line) 
measured with a reference pneumotachometer 
and estimated airflow using a microphone over 
the sternal notch and entropy model (dashed 
line). Figure modified from Yadollahi and 
Moussavi (2). 

3 
 
of sound complexity) to determine tracheal airflow during inhalation and exhalation 
(Figure 1) (2, 4).  
 
Using these different signal processing approaches we will generate a large set of 
features that will be used for subsequent machine learning analysis. Using machine-
learning we will then train a risk-index algorithm that can recognize a significant change 
from baseline in an individual’s “normal” pattern of respiratory rate and tidal volume. 
Thus, the hypoventilation monitoring system under development will not require 
previous knowledge of an individual’s age, height, weight, model of the respiratory tract 
or external calibration. 
 
We hypothesize that the tracheal sound algorithm will be able to accurately and reliably 
track, and predict, changes in arterial carbon dioxide concentration, as a marker of 
hypoventilation. The monitoring system will alert the patient/caregiver when the 
algorithm predicts impending mild hypoventilation (PaCO2 >50 mm Hg) and alarm when 
the algorithm predicts impending moderate hypoventilation (PaCO2 > 60 mm Hg); a 
clinical situation at increased risk for hypoxemia and death.  
 
The long-term objective of this effort is to integrate a tracheal sound machine-learning 
algorithm in a miniature wearable tracheal sound sensor. This sensor can connect to a 
cell phone via Bluetooth and could be used in the outpatient setting to warn first 
responders when severe hypoventilation is predicted due to an opioid overdose. 
Similarly, the sensor could be used in the clinical setting to improve the safety of opioid 
analgesia, by alerting hospital staff if impending respiratory depression is 
detected/predicted in a patient.  
 
C.  Preliminary Studies/Progress Report   
 
The Principal Investigator, Stephen E McNulty, DO and the co-investigators Jeffrey I 
Joseph, DO and Marc C Torjman, PhD have experience conducting invasive integrative 
physiology studies in humans. Dr. Stephen McNulty is a cardiac anesthesiologist with 
35 years’ experience managing patients with fentanyl.  He will provide clinical care of 
the research subjects during the fentanyl infusion protocol. Jennifer Lessin, RN is an 
experienced research nurse coordinator who will assist with study subject recruitment 
and clinical care. Drs. Joseph and Torjman will record research data during the fentanyl 
infusion protocol. The co-investigator Dr. Michael Li is the Director of Health Data 
Science at TJU with 20 years of experience with advanced analytics, machine learning 
and their application in real-world data in healthcare.  
 
D.  Research Design and Methods 
 
A pilot human clinical study that utilizes fentanyl to induce mild and moderate 
hypoventilation will be conducted in 20 healthy adults to collect the data necessary to 
develop a diagnostic algorithm that functions as a risk-index score that continuously 
predicts the onset of mild and moderate hypoventilation using signal processing and 
machine learning methods.   

4 
 
Informed Consent/Screen- Visit # 1:   
Subjects will arrive at the Department of Anesthesiology’s research office. Jennifer 
Lessin, RN will review the informed consent document and the inclusion/exclusion 
criteria. Subjects will complete a Drug Abuse Screening Test (DAST)(6) to determine 
their risk for substance abuse (Attachment 1). They will also provide a urine sample to 
perform a drug screen toxicology analysis. For women, we will also provide urine 
pregnancy testing. Dr. Stephen McNulty will also review the informed consent 
document, answer any of the subject’s questions and obtain a signed consent form. 
Each subject will receive a copy of the consent form.  Dr. McNulty will then perform a 
detailed history and physical exam and review the subject’s vital sign data.  Ms. Lessin 
will then schedule the clinical study visit # 2.   
 
Human Clinical Study - Visit # 2: 
Study subjects will be instructed to refrain from eating after 11 pm (NPO) the day prior 
to the study and to arrive at Thomas Jefferson University Hospital around 7 am on the 
morning of study visit # 2. A urine drug screen toxicology test will be repeated on all 
study subjects. For female subjects, we will also conduct urine pregnancy testing. 
 
Subjects will be studied in a hospital clinical environment containing an anesthesia 
machine, vital sign monitors and routine emergency equipment, medications and 
supplies. All study subjects will be managed by Stephen McNulty, D.O. an experienced 
board-certified anesthesiologist with extensive experience in the respiratory effects of 
an IV infusion of fentanyl. Subjects will be continuously monitored using standard 
anesthesia vital sign monitors (ECG/upper arm cuff BP/pulse oximeter, Datex Ohmeda) 
and a BIS sedation monitor (Covidien) according to American Society of Anesthesiology 
standards. A contact microphone (BIOPAC TSD108) will be adhered to the skin over 
the trachea (above the sternal notch) with double-sided tape and a Tegaderm bandage. 
An accelerometer will be adhered to the skin close to the microphone.      
 
A catheter will be inserted into a radial artery using ultrasound guidance, lidocaine local 
anesthetic and aseptic technique to acquire samples for blood gas analysis and 
continuously monitor the arterial blood pressure (Edwards Lifesciences Truwave). A 
catheter will also be inserted into a peripheral vein using aseptic technique to facilitate 
the infusion of fentanyl. Oxygen will be continuously delivered using a soft tight-fitting 
face mask connected to an anesthesia circuit (FIO2-1.0) with a side-port for continuous 
sampling of inspired/expired gas (sampling line to BIOPAC CO2100C gas analyzer). 
Respiratory rate and airflow will be continuously measured using a commercial 
reference pneumotachometer attached to the inlet of the face mask (BIOPAC 
TSD117A). All cardiovascular, respiratory, and sound monitoring will be continuously 
recorded through a BIOPAC MP150 data acquisition system connected to a desktop 
computer. Pictures may be taken after instrumentation.   
 
Monitored study subjects will be instructed to rest comfortably in the supine position and 
refrain from talking. A standard IV dose of Ondansetron will be administered to minimize 
the risk for nausea/emesis. A standard IV dose of glycopyrrolate may be administered 
to minimize the risk for bradycardia. Vital signs and respiratory data will be recorded 

5 
 
during a 1-hour baseline period while sampling arterial blood every 15 minutes to 
measure pH, PaCO2, PaO2, HCO3, SaO2 and lactate concentrations (Epoc blood 
analysis system, Siemens, München, Germany).   
 
After an initial bolus of 1.0 mcg/kg, a stepwise continuous intravenous infusion of 
fentanyl will be started at time zero (Figure 2). The infusion will start at 1.5 mcg/kg/hr 
and will be increased by 1.5 mcg/kg every 30 minutes. The infusion will be continued for 
a maximum duration of 3 hours (final infusion rate 9.0 mcg/kg/h). In a 30-year old 70 kg 
man, the proposed stepped infusion is projected to cause a gradual increase in fentanyl 
plasma concentration up to a maximum concentration of 5.8 ng/mL (Figure 3). 
Respiratory depression typically occurs anywhere in the 2.0 – 6.0 ng/mL fentanyl 
plasma concentration range (7, 8) while loss of consciousness occurs around 34 ± 7 
ng/mL (7).   
 
Vital sign monitor data, CO2 waveform data, reference pneumotach data, and tracheal 
sound data will be continuously recorded throughout the infusion protocol. Arterial blood 
gases will be measured every 10 minutes, or immediately after the decision is made to 
stop the infusion protocol. The fentanyl infusion will be discontinued prior to the end of 
the 3 hour protocol if: (1) the PaCO2 exceeds 60 mm Hg in two consecutive blood gas 
measurements (primary end-point), (2) the subject requires positive pressure bag/mask 
assisted ventilation by the anesthesiologist, or (3) the SaO2 falls below 90% on 
supplemental oxygen (FIO2=1.0).  
 
The primary endpoint of the study will be the onset of moderate hypoventilation, defined 
as two consecutive arterial PaCO2 measurement ≥ 60 mmHg. This level of opioid 
induced hypoventilation is clinically significant because based upon the alveolar gas 
equation and the Henderson-Hasselbalch equation- breathing room air (FIO2 21%) at 
sea level (barometric pressure 760 mm Hg) (9), a PaCO2 of 60 mm Hg will decrease 
the PaO2 from 159 mm Hg to 75 mm Hg to produce an arterial partial pressure of 
oxygen (PaO2) ~75 mmHg. The respiratory acidosis will cause the hemoglobin oxygen 
dissociation curve to shift to the right and downward leading to an arterial hemoglobin 
oxygen saturation of ~88% SaO2.   
 
Respiratory and vital sign data will continue to be collected for another 2 hours after 
discontinuation of the fentanyl infusion. Arterial blood will be sampled every 15 minutes 
for pH and blood gas analysis.  The total volume of blood sampled will be approximately 
~45 ml over a 6 hour study period (25 samples x 1.5 ml/sample = 45 ml). The narcotic 
antagonist Naloxone and other emergency medications will be immediately available as 
needed to ensure safety. After the 2 hour post infusion measurements, subjects will eat 
a meal and be observed for another hour or more to confirm adequate minute 
ventilation.   
 
After completion of the experiment, study subjects will be given oral and written 
instructions similar to patients undergoing an outpatient surgical center procedure under 
general anesthesia.  Each subject will receive a phone call around 9 pm that evening 
and a phone call 5-7 days later to confirm no study related adverse events.      

6 
 
 
Summary of Subject Monitoring: 
 
1) 
Radial artery catheter to monitor and record the arterial blood pressure 
waveform. 
2) 
Heart rate & rhythm will be monitored and recorded by an electrocardiogram. 
3) 
Respiratory flow and tidal volume will be monitored and recorded using a 
pneumotach.  
4) 
End-tidal CO2 concentration and waveform will be monitored and recorded. 
5) 
Hemoglobin oxygen saturation (SaO2) will be measured and recorded.  
6) 
Skin temperature will be measured and recorded. 
7) 
Tracheal sounds will be measured and recorded using a microphone. 
8) 
Body movement will be measured and recorded using an accelerometer. 
9)  
Serial measurements of arterial blood pH, PaO2, PaCO2, bicarbonate, and 
lactate concentration. 
10) 
Serial measurement of the Bispectral Index (BIS). 
 
 
Anticipated Problems and Alternative Approaches:   
 
The anesthesiologist has the clinical experience to produce mild and moderate 
hypoventilation safely using an IV infusion of fentanyl. The research team does not 
anticipate any major difficulties in executing this protocol. The slow intravenous fentanyl 
infusion will reliably induce alveolar hypoventilation in a dose dependent manor.  A 
similar method has been safely used by research anesthesiologists in multiple clinical 
studies (4, 8, 10). The degree of sedation and hypoventilation is mild to moderate and 
the risk of hypoxemia is minimal due to the use of supplemental oxygen by face mask, 
continuous pulse oximetry, and frequent PaO2 measurements. Dr. Stephen McNulty is 
a board-certified Anesthesiologist with 35 years of expertise at TJUH managing patients 
with intravenous infusions of fentanyl and other anesthetics/medications that suppress 
minute ventilation. Dr. McNulty will closely observe and clinically manage all of the study 
subjects until they are awake, alert and stable.   
 
 
 

7 
 
Figure 2. Fentanyl Infusion Protocol.  
 
 
 
 
 
 
 
 
 
 
 

8 
 
 
Figure 3. Projected plasma concentrations of fentanyl with the proposed stepped fentanyl infusion protocol. Using the 
European Society for Intravenous Anesthesia simulator (Tivatrainer, 11) we simulated the plasma concentrations of fentanyl that 
would be achieved with the proposed stepped fentanyl infusion protocol in a 30 year old man (70 kg, 170 cm). The specific kinetic 
model for fentanyl that is used by Tivatrainer has been published previously (10). The red line depicts the projected plasma 
concentration while the green line depicts the effect site concentration (both measured on left Y-axis, time in minutes on X-axis). The 
stepwise fentanyl infusion is depicted in boxes (infusion rate of 0.05 mg/mL fentanyl on right Y-axis, time in minutes on X-axis).  
 
 
 
 
240
230
220
210
200
190
180
170
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
Concentration ng/ml
8
7
6
5
4
3
2
1
0
Inf. Rate(ml/hr) + Decr. Time
40
30
20
10
0

 
9 
 
9
E.  Statistical Methods   
 
This is a pilot study and we therefore do not have prior data to conduct a power analysis. Because 
sound and physiological data will be collected continuously, even a relatively small number of 
subjects will provide a significant data set for algorithm development. If we assume a respiratory rate 
of 12 breaths per minute then: 12 breaths per min x 60 mins per hr = 720 breaths per hr; 720 breaths 
x 6 hr study time per patient = 4,320 breaths per patient; 4,320 breaths per patient x 6 subjects = 
25,920 breaths for all 6 subjects. Previous studies on analysis of tracheal sound to track ventilation 
have used a similar n, with sometimes shorter protocols (2).  
 
The performance of the developed prediction algorithm will be evaluated by looking at the mean 
absolute error in predicted PaCO2 vs. the actual PaCO2 and by comparing predicted time to 
hypoventilation during the fentanyl ramp vs. the observed time to hypoventilation. We plan to perform 
analysis on data from an initial 6 study subjects, then study up to 20 subjects to produce a more 
robust machine learning algorithm that detects/predicts the onset of mild and moderate 
hypoventilation. 
 
F.  Gender/Minority/Pediatric Inclusion for Research 
 
Minorities will be eligible to participate in the research. Children (age < 18 years) will be excluded 
from participation. We aim to recruit robustly healthy young subjects for this initial proof of concept 
effort, because we anticipate that they will tolerate this protocol very well. We anticipate studying 
populations that are more varied if the proposed proof of concept study is successful.   
 
G.  Human Subjects 
 
Inclusion criteria will be: 
1. 
Healthy women/men between 18 and 40 years of age. 
2. 
Negative history of drug or alcohol abuse. 
3. 
Negative history of cigarette smoking in previous 6 months. 
4. 
Negative history of active cardiac, vascular, pulmonary, renal, hepatic, nervous, metabolic or 
immune disease. 
5. 
BMI < 30  
 
Exclusion criteria will be: 
1. 
Age < 18 years and > 40 years. 
2.  
Pregnant or planning to become pregnant. 
3. 
Positive history drug or alcohol abuse. 
4. 
Positive drug screen for opioids, benzodiazepines, hypnotics. 
5. 
Positive Drug Abuse Screening Test result (score of 6 or greater). 
6. 
BMI > 30  
7. 
History of sleep apnea. 
8. 
History of cigarette smoking in previous 6 months. 
9. 
History of difficult airway during anesthesia management. 
10. 
History of allergy or skin sensitivity to tape, silicone, fentanyl, chlorhexidine. 
 
Study Subject Recruitment & consent:  
Twenty healthy volunteers will be recruited from the general population around Thomas Jefferson 
University using an advertising flier (Attachment 2). Potential subjects will contact the Anesthesiology 

 
10 
 
10
research nurse coordinator Jennifer Lessin, R.N. to review the inclusion/exclusion criteria and 
schedule visit # 1 (Attachment 3, phone script). Subjects will arrive at the Department of 
Anesthesiology’s research office. Jennifer Lessin, RN will review the informed consent document and 
the inclusion/exclusion criteria. Subjects will complete a Drug Abuse Screening Test (DAST) (6) to 
determine their risk for substance abuse (Attachment 1). They will also provide a urine sample to 
perform a drug toxicology analysis. In female potential subjects, we will also perform a urine 
pregnancy test. Dr. Stephen McNulty will also review the informed consent document with subjects 
during visit #1, answer any of the subject’s questions and obtain a signed and witnessed consent 
form. Each subject will receive a copy of the consent form. Dr. McNulty will then perform a detailed 
history and physical exam and review the subject’s vital sign data.  Ms. Lessin will then schedule the 
clinical study visit # 2 in 2 to 6 weeks.   
 
General Approach to Minimize Risk:  
We plan to study only young and healthy subjects with a good airway, at very low risk for an 
anesthetic complication. Clinical trials have demonstrated the safety of managing hospitalized 
patients with mild to moderate permissive hypercapnia, as long as hypoxemia is avoided (12). 
Subjects will be studied in a hospital clinical environment containing an anesthesia machine, vital sign 
monitors and routine emergency equipment, medication and supplies. Dr. McNulty will use TJUH 
standard of care operating procedures and other well-accepted safety strategies to minimize risk. 
Supplemental oxygen will be continuously delivered via face mask to significantly minimize the risk of 
hypoxemia during fentanyl induced hypoventilation.                                                                                           
 
 
We will use estimated maximum plasma concentrations of fentanyl up to 5.8 ng/mL. Studies on the 
respiratory depressive effect of fentanyl using similar incremental concentrations of fentanyl have 
been safely conducted (8, 10). Respiratory depression typically occurs anywhere in the 1.0 – 6.0 
ng/mL (7) plasma concentration range while loss of consciousness does not occur until 34 ± 7 ng/ml 
(7). If respiratory depression needs to be reversed during the study, it can be rapidly reversed using 
one or more doses of IV naloxone. 
 
Specific Procedures and Risks: 
1. 
Radial artery catheterization: The radial artery will be catheterized using aseptic techniques 
after local anesthesia. A 5-cm 20-gauge catheter will be inserted using ultrasound guidance to 
minimize the potential need for multiple sticks, bleeding or hematoma. The anesthesiologist Dr. 
McNulty has vast experience placing catheters in a radial artery. Rare risks associated with 
radial artery catheter insertion and use are thrombus formation, hand ischemia, and infection. 
These complications are rare in healthy subjects without vascular disease who have catheters 
in place for only several hours (13). 
2. 
Insertion of intravenous catheter: The insertion of an intravenous catheter for the infusion of 
fentanyl will be performed using local anesthesia and aseptic technique. The risks of an IV-line 
may include pain at the insertion site and superficial infection as well as local bruising. These 
risks are reduced by using local anesthesia and aseptic techniques.   

 
11 
 
11
3. 
Fentanyl infusion: Fentanyl has been used in clinical anesthesiology as an opioid analgesic 
for over 50 years. Possible side effects of acute fentanyl exposure include bradycardia, 
nausea, respiratory depression, and rarely chest wall rigidity. Before the start of the fentanyl 
infusion protocol subjects will be given Ondansetron to minimize the risk of nausea. Atropine or 
Robinol may be given to prevent/treat bradycardia. Chest wall rigidity is a rare occurrence at 
the fentanyl concentrations and slow infusion we are proposing, but can be reversed quickly 
with either naloxone or a short-acting neuromuscular blocking agent.  
 
The aim of the present protocol is to induce mild to moderate respiratory depression up to the 
described endpoint of two consecutive PaCO2 measurements ≥ 60 mmHg. The fentanyl infusion will 
be stopped if: (1) the partial pressure of carbon dioxide exceeds 60 mm Hg in two consecutive blood 
gas measurements (primary end-point), (2) the subject requires positive pressure bag/mask assisted 
ventilation by the anesthesiologist, or (3) the hemoglobin oxygen saturation falls below 90% on 
supplemental oxygen (FIO2 = 1.0), (4) one blood gas of PaCO2 > 70 mmHg, and/or (5) two 
consecutive blood gas measurements with pH < 7.20. 
 
 
Potential Benefits of Proposed Research to Human Subjects & Others- Risk/Benefit Ratio: 
 
The risks of a slow intravenous infusion of fentanyl to induce hypoventilation managed by an 
experienced anesthesiologist are low. We do not anticipate any benefits of participating in this study 
to the human volunteer subjects. The benefit of developing an algorithm capable of detecting and 
preventing severe hypoventilation, hypoxemia and death due to an opioid overdose is significant.  
The clinical investigative team has a variety of systems and procedures in place to maximize subject 
safety. In the United States opioid related overdose is currently a leading cause of death in people 
aged <50 years (1). An accurate tool to alert first responders or family and friends in the case of an 
impending overdose would have significant societal impact and would potentially prevent a significant 
number of deaths by allowing for the timely administration of naloxone. In the hospital setting there is 
also a need for a continuous monitor of minute ventilation (MV = RR x TV) to improve the safety of 
opioid analgesia (5).  
 
 
H.  Data and Safety Monitoring Plan   
 
Medical Monitor: Dr. Dietrich Gravenstein will serve as medical monitor. A medical monitor is a 
physician that is independent of the research team. Dr. Gravenstein has extensive educational and 
professional experience to serve as a subject advocate. He will monitor subject enrollment and will 
discuss research progress with the Principal Investigator. He is also required to review all 
unanticipated problems involving risk to subjects or others, serious adverse events and any subject 
deaths associated with the protocol and provide an unbiased written report of the event. At a 
minimum, the medical monitor must comment on the outcomes of the event or problem and in case of 
a serious adverse event or death, comment on the relationship to participation in the study. The 
medical monitor must also indicate whether he/she concurs with the details of the report provided by 
the Principal Investigator. Reports for events determined by either the investigator or medical monitor 
to be possibly or definitely related to participation and reports of events resulting in death must be 
promptly forwarded to the Western IRB. 
 
The medical monitor will also monitor any protocol deviations and/or protocol violations.  He will 
promptly report any discrepancies or problems to the IRB.  The medical monitor also has the authority 

 
12 
 
12
to stop the research in progress, remove individual subjects from the research, and take whatever 
steps are necessary to protect the safety and well-being of the subjects until the IRB can assess the 
monitor’s report. 
 
The Principal Investigator, Dr. Stephen McNulty, will be responsible for accuracy and confidentiality of 
written and electronic participant data. Accuracy of the data will be confirmed by Dr. Stephen McNulty 
and the monitor before the study data set is locked and before the research is published in a peer 
reviewed journal.  
 
 
I. Literature Cited 
 
1. 
http://wonder.cdc.gov/mcd.html. Multiple cause of death data 2018 [ 
2. 
Yadollahi A, Moussavi ZM. Acoustical respiratory flow. A review of reliable methods for 
measuring air flow. IEEE Eng Med Biol Mag. 2007;26(1):56-61. 
3. 
Volkow ND, Collins FS. The Role of Science in Addressing the Opioid Crisis. The New 
England journal of medicine. 2017;377(4):391-4. 
4. 
Yu L, Ting CK, Hill BE, Orr JA, Brewer LM, Johnson KB, Egan TD, Westenskow DR. Using the 
entropy of tracheal sounds to detect apnea during sedation in healthy nonobese volunteers. 
Anesthesiology. 2013;118(6):1341-9. 
5. 
Ramsay MA, Usman M, Lagow E, Mendoza M, Untalan E, De Vol E. The accuracy, precision 
and reliability of measuring ventilatory rate and detecting ventilatory pause by rainbow acoustic 
monitoring and capnometry. Anesth Analg. 2013;117(1):69-75. 
6. 
Yudko E, Lozhkina O, Fouts A. A comprehensive review of the psychometric properties of the 
Drug Abuse Screening Test. J Subst Abuse Treat. 2007;32(2):189-98. 
7. 
Karch S. Pathology of Drug Abuse. NY: CRC Press; 1996. 
8. 
Mildh LH, Scheinin H, Kirvela OA. The concentration-effect relationship of the respiratory 
depressant effects of alfentanil and fentanyl. Anesth Analg. 2001;93(4):939-46. 
9. 
Curran-Everett D. A classic learning opportunity from Fenn, Rahn, and Otis (1946): the 
alveolar gas equation. Adv Physiol Educ. 2006;30(2):58-62. 
10. 
Shafer SL, Varvel JR, Aziz N, Scott JC. Pharmacokinetics of fentanyl administered by 
computer-controlled infusion pump. Anesthesiology. 1990;73(6):1091-102. 
11. 
Tivatrainer 9.1. Leiden, the Netherlands: Gutta Bv. 
12. 
Roth JV. Is permissive hypercarbia pneumoprotective? Anesthesiology. 2015;122(5):1179. 
13. 
Clermont G, Theodore AC. Arterial catherization techniques for invasive monitoring: 
UpToDate; 2017 [Available from: http://www.uptodate.com/contents/arterial-catherization-techniques-
for-invasive-monitoring. 
 
 
 
Attachment 1: Drug Abuse Screening Test 
 
Attachment 2: Recruitment poster  
 
Attachment 3: Screening script  
 
Attachment 4: CV Stephen McNulty, DO 
 
Attachment 5: Medical License Stephen McNulty, DO  

 
13 
 
13
 
 

 
14 
 
14
 
 
 
 
 

 
15 
 
15
 
TELEPHONE SCRIPT  
 
Introduction 
 
Thank you for calling to find out more about our research study or 
I am returning your call to provide more information about our research study. 
 
My name is Jennifer Lessin, and I am a research coordinator at Thomas Jefferson University. The purpose of 
our research study, ‘Development of an algorithm that predicts hypoventilation due to an opioid overdose’, is to 
look at a new method of monitoring breathing changes. Specifically, we want to determine whether it is 
possible to monitor the changes in breathing from opioid narcotics by using a small microphone that is taped to 
the outside of someone’s windpipe.  
 
The research study consists of two visits. During the first visit we will be asking people to complete a 
questionnaire to determine their risk for substance abuse. We will also collect a sample of urine to determine if 
they have recently used illegal drugs or if you are pregnant. We will then perform a detailed history and 
physical exam and review their vital signs (such as blood pressure and heart rate). If we encounter no reasons 
that prevent participating in this research study, a clinical study visit will be scheduled within four weeks from 
the initial visit.   
 
Participants will be required to refrain from eating after 11 pm the day prior to the study. On the day of the 
study, participants will arrive at Thomas Jefferson University Hospital around 7 am. We will obtain another 
urine sample from them to determine if they have recently used any illegal drugs or if you are pregnant.  
 
The clinical study will take place in a hospital clinical environment containing an anesthesia machine and 
hospital vital sign monitors. A microphone will be adhered to the skin of the neck of the participant with double-
sided tape to record the sounds of breathing. An intravenous catheter will be placed in a hand or arm vein to 
enable the administration of the opioid medication. We will also place a similar plastic catheter into an artery of 
the wrist to enable continuous measurement of blood pressure throughout the study. This artery catheter will 
also be used to frequently draw blood samples for measuring the concentration of oxygen and carbon dioxide. 
Over 3 hours we will gradually increase the intravenous infusion dosage of the opioid medication fentanyl. This 
will cause the participant’s breathing to become slower and shallower. A board-certified Anesthesiologist will 
closely monitor the stability of the participants health throughout the opioid infusion. The fentanyl infusion will 
be stopped when their breathing has become slow and shallow enough to raise the concentration of carbon 
dioxide in the blood a moderate degree. After stopping the infusion of fentanyl, we will monitor the stability of 
the participant’s health until the effects of the opioid have worn off. We expect that the entire study day # 2 will 
take around 9 hours. Participants will need to have an adult friend/family member available to take them home 
after completion of the study. Research staff will call the participant around 9 pm that evening and 5 to 7 days 
later to ask them how they are doing. 
 
Do you have any questions regarding the study? Now that you have a basic understanding of the study, do you 
think you might be interested in participating? 
 
If No: Thank you very much for calling.[end call] 
 
If caller is interested  
 
But before enrolling people in this study, we need to determine if you may be eligible to participate. I would 
now like to ask you a series of questions about your current and past health. It will take approximately 15 
minutes of your time.  
 

 
16 
 
16
There is a possibility that some of these questions may make you uncomfortable or distressed; if so, please 
let me know. You can skip questions you do not wish to answer.  
 
I will keep all the information I receive from you by phone, including your name and any other identifying 
information confidential.  
 
The purpose of these questions is to determine whether you may be eligible to participate in the study. 
Additional screening at a later time during a visit to the hospital will be necessary beyond answering these 
questions. Remember, your participation is voluntary; you do not have to complete these questions. Please 
feel free to stop me at any time if you have any questions or concerns.  
 
Do I have your permission to ask you these questions? 
 
Screening Questions 
 
What is your gender? 
 
If female, are you pregnant or planning to become pregnant? 
 
What is your age? 
 
How much do you weigh? 
 
How tall are you?  
 
Have you smoked cigarettes in the past 6 months? 
 
Have you ever had a drug abuse problem? 
 
Have you ever had an alcohol abuse problem? 
 
Do you have any type of disease?  
 
Have you ever had any type of disease? 
 
Have you ever had surgery? 
 
Do you take any medications? 
 
Do you have sleep apnea? 
 
Have you ever been told that there were difficulties with anesthesia for a surgery that you had? Or that it was 
difficult to maintain your breathing during anesthesia for surgery? 
 
Do you have a skin allergy to tape? 
 
Do you have a skin allergy to silicone? 
 
Do you have an allergy to opioid pain medications? 
 
Do you have an allergy to fentanyl? 
 
Do you have an allergy to skin disinfectants?  

 
17 
 
17
  
 
Post Response Communication 
 
If potentially eligible: 
 
Based on your answers to the questions, it appears you may eligible to participate in the research study. 
 
Would you like to schedule a time to meet with the research team to obtain more details about the research 
study and to assess whether you are definitely eligible to participate or not? 
 
In addition, would you like me to send you information to review before the meeting? 
 
Obtain the potential subject’s contact information 
 
If not eligible:  
 
Unfortunately, based on your responses, you are not eligible to participate in the research study. 
 
Study Team Contact Information 
 
Thank you for taking the time to talk with me today. If you have any questions or concerns, please feel free to 
contact me. My name is Jennifer Lessin and I can be reached at 215 955-5804 and/or 
Jennifer.Lessin@jefferson.edu.