Wearable Device for Prevention of Opioid-Induced Hypoxemia
Conditions: Non-cardiac Surgery
Sponsor: The Cleveland Clinic

 
 
Wearable Device for Prevention of Opioid-
Induced Hypoxemia 
Version 24, 3/18/21 
 
Kai Li, Daniel I. Sessler, and colleagues 
 
 
  
Anesthesiology Institute 
Department of Outcomes Research and Department of General Anesthesiology 
 
Cleveland Clinic 
Main Campus 
9500 Euclid Ave — P77 
Cleveland, OH   44195 
Tel: 216 870-2620 
email: ds@or.org  
 
 
 
 
 

Version 24, 3/18/21 
 
 
2 
Amendments: 
Protocol date changed from September 16, 2020 – November 10, 2020 Version 21: 
Page 4 updates in Primary Efficacy Outcomes  
 
Protocol date changed from May 26, 2020 Version 18 - to September 16, 2020 
Version 19: 
Page 7 of 14 in the Subject Selection (Added) 
We will also enroll up to 25 pre-pilot patients which will allow us to better understand 
and “de-bug” the system and therefore maximize effective data acquisition for the trial 
itself. 
 
Page 12 of 14 at the end (Added) 
There is a small degree of discomfort associated with wearing the Oxalert device, and 
we ask patients to bring the device back to the Clinic or mail it back to us in pre-paid 
envelopes. As an incentive to wear the Oxalert, we propose to pay patients $3/hour of 
use, up to $500 which will fully cover the pre-hospital and post-hospital days, along with 
up to five days of hospitalization.  
 
Protocol changed March 18, 2021, version 24: Full statistical analysis plan. 
 
 

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Specific Aims 
We propose a pilot randomized trial of the Oxalert EPO (Enhanced Pulse 
Oximeter) in surgical patients who are at high risk of opioid-induced respiratory 
compromise. Primarily, we will determine the feasibility of a full randomized control trial 
to assess the extent to which the Oxalert EPO reduces postoperative hypoxemia. The 
anticipated primary hypothesis for the full future trial is that Oxalert EPO alerts will reduce 
the time-weighted average of SpO2 below a threshold of 90%. 
Aim 1 
 
We will evaluate the feasibility of a fully randomized validation trial for the Oxalert 
EPO. All patients will wear the Oxalert for 24 hours preoperatively in the monitoring only 
mode (no alerts), throughout hospitalization up to six days, and for 24 post-discharge 
hours. Randomization will be to Oxalert in monitor-only mode or to its normal mode which 
provides progressive audible and tactile alerts for hypoxemia. Randomized assignment 
will start after surgery and continue through up to six days of hospitalization and 
after discharge.   
Feasibility will be defined by: 1) a single-center enrollment rate of at least two 
patients per week at the Cleveland Clinic Main Campus; 2) the extent to which the system 
is tolerated, defined as the fraction of time during the initial six post-operative in-hospital 
days that patients wear the device; and, 3) the frequency of hypoxemic episodes detected 
by the Oxalert EPO that generate an alert in the hospital.   
Aim 2  
We will evaluate efficacy outcomes that might be included in a future definitive trial. 
While under-powered in this pilot, the results will guide a realistic sample-size estimate 
for the future trial. 

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Primary efficacy outcomes                  
1. Time-weighted average SpO2 below a threshold of 90% during hospitalization up 
to 6 days.  
2. Number and duration of in-hospital postoperative desaturation events (saturation 
<90%) lasting at least 2 min. 
3. Number and duration of hypoxemic episodes (saturation <90%) during the initial 
24 post-discharge hours lasting at least 2 min.  
4. Time-weighted average SpO2 < 90% during the preoperative baseline 
assessment, time-weighted average SpO2 < 90% during the post-discharge 
assessment, and the difference between them.  
Secondary outcomes 
1. Patient evaluation of device comfort/tolerability, including discomfort from the 
alerts.  
2. Nursing evaluation of device convenience and function.  
   
 

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Background 
There are over 70 million surgeries performed annually in USA. Postoperative pain 
is a ubiquitous problem among the US population. Up to 70% of surgery patients have 
moderate to severe pain, especially within the first 72 hours1,2.  Opioid analgesics are the 
most effective analgesics, especially for management of the moderate to severe 
postoperative pain. On the other hand, sleep apnea is common, largely because obesity 
is common3. Both increase sensitivity to opioids and presumably increase the risk of 
postoperative insufficiency5.  
Some opioid-induced complications are common, but not especially serious, 
including nausea, vomiting, ileus, confusion, and dizziness6. Of importance, opioids also 
decrease the respiratory rate and alveolar ventilation, resulting in hypercarbia, respiratory 
acidosis, and hypoxemia6. Hypoxemia (low hemoglobin saturation) from opioid-induced 
respiratory depression is usually not clinically apparent, compromise wound healing, 
cause brain dysfunction, promote myocardial ischemia, and even progress to death7-9. All 
these outcomes are considered important measures of hospital quality and safety10,11.   
Postoperative respiratory compromise is common as well as respiratory arrests12. 
Standard post-operative monitoring is based on a “spot-check” model, in which vital signs, 
including oxygen saturation, are determined and recorded every 4-6 h13,14.  From Sun et 
al 15, we know that 37% of postoperative patients have contiguous SpO2 <90% lasting at 
least an hour. 21% of the patients experienced ≥ 10 min/h with SpO2 <90%. Disturbingly, 
nurses monitor at 4-hour intervals missed 90% of all serious desaturation episodes15. 
Even if increasing the frequency of nursing assessments were practical, it would be 
unlikely to detect all respiratory insufficiency events. 
According to Stone16, the incidence of nocturnal hypoxemia is 50% with patient-
controlled analgesia. Since patients undergoing surgical procedures are being 
discharged earlier and earlier17, it is likely that many continue to experience hypoxemic 
episodes at home, especially during sleep.    

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FDA-cleared continuous saturation monitoring systems for in-hospital use are 
currently commercially available18-20. They are battery powered, untethered, and can 
directly be connected to electronic record systems. However, monitoring alone may not 
prevent ventilator complications if clinicians do not recognize desaturation quickly and 
intervene appropriately. An alternative is a device that both detects hypoxemia, and alerts 
patients to the problem. Arousal is often sufficient to awaken patients’ robust voluntary 
control of breathing, reverse hypoxemia and respiratory arrest. Consistent with this 
theory, it is fairly easy to give patients sufficient opioid to decrease or stop normal 
ventilation, but preserve voluntary breathing in response to command. Even when audible 
commands fail, patients will often breathe in response to tactile stimulation.  
One such device is the Apnea Prevention Device (APD)21, which is a prototype 
that has a continuous monitor, alarm headphone, and tactile nerve stimulation. However, 
the system tethers patients and is thus impractical even in hospitals, much less at home. 
An alternative is the Oxalert EPO which is a small (92 X 53 X 21 mm), battery-powered, 
and wrist-worn apnea prevention device. The system continuously monitors SpO2 and 
generates audible voice prompts when the saturation is <90% for at 2 min. The audible 
prompts will then continue until saturation increases to ≥90%. When saturation remains 
low for an additional 1 min, a mild electrical shock will provide tactile stimulation, with 
intensity increasing four times every 20 seconds to an intense, but safe maximum. 
Compared to existing proven alternatives, the “point-of-care” Oxalert EPO 
provides a more tolerable, effective, promptly diagnosis of opioid-induced hypoxemia. 
Then the Oxalert EPO automatically evokes arousals to terminate respiratory depression 
and prevent arrest from relatively opioid overdose. It might make opioids safer both in 
hospital and home setting. 
Methods 
The trial will be conducted with IRB approval and a written informed consent will 
be obtained from adults scheduled for non-cardiac surgery with general anesthesia.  All 

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patients will be enrolled at the Cleveland Clinic Main Campus. The trial will be registered 
at ClinicalTrials.gov before the first patient is enrolled.   
Subject selection 
We will enrich the study population to enhance the number of desaturation events 
by enrolling patients who are at increased risk for respiratory insufficiency. Specifically, 
we will focus on patients scheduled for laparoscopic or open major abdominal or pelvic 
surgery whose analgesia is primarily opioid-based. We will further restrict enrollment to 
obese patients (body mass index ≥25 kg/m2) who are likely to have respiratory 
compromise. Sample size for the proposed pilot trial will be 40 valid patients.  We will also 
enroll up to 25 pre-pilot patients which will allow us to better understand and “de-bug” the 
system and therefore maximize effective data acquisition for the trial itself.  Both men and 
women will be recruited, and we will encourage under-represented minorities to 
participate.  
Inclusion criteria 
1) Adults having major laparoscopic and open abdominal or pelvic surgeries; 
2) Body Mass Index ≥25 kg/m2 
3) American Society of Anesthesiologists physical status 1-3; 
4) Age 18-85 years old; 
5) Able to understand and consent to the trial and fully participate; 
6) Anticipated primary opioid analgesia after surgery; 
7) Expected duration of hospitalization at least 24 hours after surgery; 
8) Consenting at least a day before anticipated surgery. 
Exclusion criteria 
1) Epidural analgesia (field and fascial plane blocks permitted); 
2) Pre-operative SpO2 <95%; 
3) No wrist available for the study; 
4) Severe hearing loss; 
5) Lack of English language fluency; 

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6) Serious hearing deficit (unable to understand normal speech in a quite 
environment); 
7) Serious peripheral neuropathy (unable to feel pin prick at wrist). 
Protocol 
At least a day before surgery, patients will be approached and consented in the 
pre-anesthetic consult and evaluation (PACE) clinic. Vital signs will be measured, per 
routine, including SpO2. The protocol will be explained, and interested patients will be 
given a brief demonstration of the Oxalert, including audible prompts and the sensation 
produced by the electrical stimulator.  
Participating patients will be given an Oxalert to take home with them. The device 
will be set to a record-only mode, with no alerts will be generated. Patients will be asked 
to wear the device for at least 24 hours. The device will thereafter be turned off in time, 
brought to the hospital on the day of surgery or sent back to the investigators in a pre-
paid mailer. Only those who wish to continue will remain in the study.   
Enrolled patients will receive routine nursing care, standard physiologic 
monitoring, and analgesic administration. Supplemental oxygen will be administered 
according to nurse discretion.  Participation in the study will not alter the types or amounts 
of analgesics provided which will follow clinical routine. The PACU and ward nurses 
caring for study patients will be introduced to the protocol and the device. Vital sign and 
other monitoring will be exactly per clinical routine, usually at 4-hour intervals, but more 
often as clinically indicated.  
On the day of surgery, enrolled patients will be randomized 1:1 without 
stratification. Randomization will be based on computer-generated codes using random-
sized blocks. Investigators will receive individual assignments from a web-based system 
that will be interrogated in the recovery unit after surgery. Allocation will thus be concealed 
until the last practical moment. Randomization will be to monitor-only (no alerts) or Oxalert 
in normal mode which includes progressive audible and tactile stimulation in response to 
saturation <90% lasting more than 2 min.  

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An Oxalert EPO will be strapped to each patient’s wrist, and standard 
electrocardiogram surface electrodes will be placed on the dorsum of the hand and 
connected to the nerve stimulator. The Oxalert devices will be programmed per 
randomization (monitoring and alerts versus monitoring without alerts) and data collection 
will be set to “on.” Data collection will continue throughout hospitalization, up to 6 
postoperative days. As necessary, de-identified data will be down-loaded onto a secure 
Cleveland Clinic computer and transferred to Redcap. The memory card of the Oxalert 
EPO will then be refreshed. 
Patients will be monitored for an additional ≈24 hours after discharge. Monitoring 
after discharge will be done according to the assigned group for each patient. The study 
will be blinded to the extent practical. Devices with active and deactivated alerts will look 
identical. Patients who receive alerts will know that they have active systems, but those 
who have yet to receive an alert will not know if their system is deactivated or if an alert 
simply was not necessary.  
The high saturation alarm will be disabled. Alarms for heart rate will be set to the 
minimum (≈30 beats/min) and maximum (≈120 beats/min) since heart rate is not an 
outcome of interest. For purposes of the proposed trial, the threshold will be a saturation 
<90% continuously maintained for 2 min. When these criteria are met, the Oxalert EPO 
will trigger continuous audible prompts (“Please take a breath and check the finger 
sensor”) will begin. Tactile stimulation will begin 1 min later at a low level, and ramp up 4 
times at 20-second intervals, to a safe but uncomfortable maximum intensity. The brief 
290-micro-second pulses are delivered 2/second (120 Hz) through electrode pads on the 
dorsum of the wrist. Both audible prompts and stimuli of up to 35 milli-amperes will 
continue until SpO2 rises above 90% whereupon the device will reset and audible and 
tactile prompts cease. Patients can discontinue alerts by pressing a button at any time. 
Measurements 
Demographic and morphometric characteristics will be recorded at PACE clinic, 
including sex, age, race, height and weight. Vital signs will be recorded, including baseline 
of SpO2.  

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Oxalert EPO comfort and tolerability will be evaluated by phone shortly after 
patients complete their home monitoring. Patients will also be reminded to turn off the 
machine, bring or send the machine back. 
Anesthetic and procedural details will be recorded electronically as usual. 
Intraoperative and postoperative opioid use will be calculated in equivalent amount.    
Monitoring with Oxalert EPO will begin in the postanesthesia care unit and 
continue until the patient is discharged from the hospital (from surgery day until up to 
postoperative day 6). During hospital stay, the equipment status checking and data 
download will be completed once a day. The Oxalert EPO will be continued to be used 
for 24 hours after discharge according to the subject’s assigned group after randomization. 
Therefore, the configuration of either active alerts or blinded monitoring without alerts will 
be performed throughout hospital stay as well as discharge. 
 Patients’ evaluation of device comfort and tolerability will be queried at discharge 
day. During hospitalization, one nursing staff responsible for the enrolled subject will be 
given inform sheet, voluntary to participate in an anonymous questionnaire to evaluate 
the convenience of the device near the end of a nursing shift. 
Patients will be called on the second discharged day to ask about 24-h opioid 
consumption and evaluate adverse events. Patients will also be reminded to send back 
the Oxalert EPO using a prepaid mail.  De-identified data from the Oxalert EPO will be 
downloaded to a trial computer, and from there to a secure REDCap trial database.  
Data Analysis 
SpO2 trends will be recorded and averaged in 1-minute increments for analysis. 
SpO2 values <60% will be discarded as artifact (only 0.09% of all values). 
The demographic and morphometric characteristics of patients in the blinded and 
un-blinded groups will be tabulated and absolute standardized differences will be 
computed. POD1-POD6 or discharge, whichever first. Summarize after removing gaps.  
The frequency and duration of desaturation events (SpO2< 90%) will be compared using 

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two-tailed t-tests if normally distributed, or Wilcoxon tests if not, with P<0.05 
being considered statistically significant. Patient’s tolerance and nursing experience 
will be compared qualitatively. 

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Detailed Statistical Analysis Plan (outline. 
The demographic and morphometric characteristics of patients will be tabulated and 
absolute standardized differences will be computed. 
We will also report the number of patients in each group who dropped out of the trial, 
and the reason (s).    [technical failure / one patient dropped out after 5 minutes.  
Remove this one from all analyses, but report as a technical failure.]  
Primary efficacy outcomes  
1. Time-weighted average SpO2 below a threshold of 90% during hospitalization up to 6
days, 
and 
separately 
for 
the 
24-hour
post-discharge 
period. 
     -- mirror histograms of TWA < 90% ; histograms by group, 
◼Mean (SD) and median (Q1, Q3), min, max, percent zero for TWA, by group;
◼Compare groups using WRS test and median difference (CI)
◼Repeat all of above for AUC < 90% * minutes.
2. Number and duration of in-hospital postoperative desaturation events (saturation
<90%) lasting at least 2 min.  Same for initial 24 post-discharge period.
  -- summary stats on number per patient (0, 1, 2, 3, etc); include sum per group. 
  -- use WRS to compare groups on number per patient; median diff (CI). 
3. Difference between preoperative baseline and post-discharge 24 hour time-weighted
average SpO2 < 90%.
        --- descriptive summaries on change from baseline to post d/c (post minus pre) 
Time-weighted average SpO2 < 90% during the preoperative baseline assessment, time-
weighted average SpO2 < 90% during the post-discharge assessment, and the difference 
between them (post minus pre). 
.        --  Between groups: compare groups on difference between post-discharge 24 hours 
  and preoperative TWA < 90% using Wilcoxon rank sum test and median 
      difference 
(CI). 
 -- Within group: assess whether significant change from baseline to post-d/c 
 24 hrs  --- Wilcoxon signed rank test.  Could be paired t-test if differences 
  look normal. 

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Secondary outcomes 
3. Patient evaluation of device comfort/tolerability, including discomfort from the
alerts.
     --- summary stats and WRS test.     5 levels. 
4. Nursing evaluation of device convenience and function – WRS test.
    --  summary stats.     5 levels. 
Feasibility will be defined by: 
1) a single-center enrollment rate of at least two patients per week at the Cleveland
Clinic Main Campus;
-Summarize enrollment: total N enrolled over what time period, and average N/week.
2) the extent to which the system is tolerated, defined as the fraction of time during the
initial six post-operative in-hospital days that patients wear the device; and,
3) Percent of time successful records were made, defined as the percent of time in
each period that usable SpO2 monitoring data was retrieved and usable– independent
of whether the device was being worn or not.
Record separately for the three periods:   the pre-hospital 24 hours;  the initial six post-
surgical hospital days; and the post-discharge 24 hours.  
     -- summarize time that patient should have been able to records data, time of 
   successful recording  and percent of total time there were successful recordings. 
     -- compare groups on percent of total time there were successful recordings using 
  WRS test. 
4) Estimate  the frequency of hypoxemic episodes detected by the Oxalert EPO that
generate an alert in the hospital. Since device does not record if alerts were given, we
use the collected SpO2 data to summarize for each group the frequency of desaturation
events lasting 1, 2, 3, 4 …. ≥10 minutes numerically and using histograms. 
Human Subjects Protection 
The study will be approved by the IRB at the Cleveland Clinic. Written informed 
consent will be obtained. Patients will be free to exit the trial at any time. They will also 

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be given the option to have the frequency of awakenings decreased, if poorly tolerated, 
by lowering the SpO2 thresholds used to trigger those awakenings. The trial will be 
registered at ClinicalTrials.gov. 
All routine nursing assessments and clinical treatments (including supplemental 
oxygen if necessary) will continue as usual. Therefore, nothing about the proposed study 
will in any way increase patient risk except for the Oxalert itself which is powered by a 
rechargable 3.7-volt battery. Patients will thus be untethered and free to move around. 
The device consists of essentially a commercial pulse oximeter connected to a circuit 
resembling a nerve stimulator of the type that is used routinely during anesthesia. Please 
see the Electrical Engineering Analysis provided with this application.  
The Oxalert EPO is not yet cleared by the Food and Drug Administration; we 
therefore request a non-significant-risk (NSR) device exemption. A Data Development 
Plan has been submitted to and discussed with the FDA/CDRH Anesthesia Division. In 
support of the NSR exemption, the Anesthesia Division of the FDA has agreed to consider 
a De Novo or PMA submission without the results of a full clinical outcome trial being 
completed before pre-marketing approval because of its great potential benefit to 
patients.  At this point they are not requiring an Investigational Device Exception (IDE). 
The proposed pilot trial is designed to provide information that will help the investigators, 
and the FDA optimally design a trial that might support FDA clearance. We provide three 
documents related to electrical safety, including two independent engineering analyses.  
At the Cleveland Clinic Main Campus, 21% of patients have postoperative 
saturations below 90% for at least 10 minutes; 8% of patients have postoperative 
saturation below 90% for at least 20 minutes; and 8% of patients have saturations below 
85% for more than 5 minutes. Post-operative desaturation is thus common and 
prolonged. Routine vital signs, usually at 4-hour intervals miss 90% of serious 
desaturation episodes.15 The only aspect of our protocol that is non-standard is an extra 
saturation monitoring with Oxalert EPO, and the associated audible and tactile stimuli. 
Standard vital signs monitoring will continue to be used per current routine care. 

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Participation in the proposed trial is thus likely to benefit patients, at least in the alert 
group, whereas those assigned to monitoring only will be no worse off.   
There is a small degree of discomfort associated with wearing the Oxalert device, 
and we ask patients to bring the device back to the Clinic or mail it back to us in pre-paid 
envelopes. As an incentive to wear the Oxalert, we propose to pay patients $3/hour of 
use, up to $500 which will fully cover the pre-hospital and post-hospital days, along with 
up to five days of hospitalization.  
Change Log 
Protocol version 21 dated 11/10/2020 is based on pilot patients. It is the protocol that will 
be used for formally randomized patients. Any subsequent changes will be detailed 
below.  

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