Supplemental Table 1. PRODIGY Trial Sites. Region Trial Site United States University of Colorado Hospital Emory University Hospital Brigham and Women’s Hospital Beaumont Hospital Buffalo General Medical Center MetroHealth Medical Center Cleveland Clinic The Ohio State University Wexner Medical Center Providence Regional Medical Center Europe Hôpital Foch (France) University Hospital Bonn (Germany) Maastricht University Medical Center (Netherlands) Hospital Clinico Universitario de Valencia (Spain) Asia Okayama University Hospital (Japan) Jikei University School of Medicine Hospital (Japan) National University Hospital (Singapore)
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Supplemental Table 1. PRODIGY Trial Sites. Region Trial ...
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Supplemental Table 1. PRODIGY Trial Sites.
Region Trial Site
United
States
University of Colorado Hospital
Emory University Hospital
Brigham and Women’s Hospital
Beaumont Hospital
Buffalo General Medical Center
MetroHealth Medical Center
Cleveland Clinic
The Ohio State University Wexner Medical
Center
Providence Regional Medical Center
Europe
Hôpital Foch (France)
University Hospital Bonn (Germany)
Maastricht University Medical Center
(Netherlands)
Hospital Clinico Universitario de Valencia
(Spain)
Asia
Okayama University Hospital (Japan)
Jikei University School of Medicine Hospital
(Japan)
National University Hospital (Singapore)
Supplemental Table 2. Detailed PRODIGY Trial Inclusion and Exclusion Criteria.
Inclusion Criteriaa Exclusion Criteria
Patient was age ≥18, 20, or 21 years in
United States/Europe, Japan, and Singapore,
respectively
Patient whose hospital stay was expected to be
≤24 h
Patient was able to give informed consent Patient received intrathecal opioids
Receiving parenteral opioid therapy for
post-surgical or non-surgical pain on
hospital general care floor
Post-surgical patient with American Society of
Anesthesiologist (ASA) physical status V or
higher
Patient with status of Do Not Resuscitate
(DNR)
Patient receiving hospice or end of life therapy
Patient was ventilated or intubated
Patient was unwilling or unable to comply with
trial procedures
Patient was a member of a vulnerable
population (per ISO 14155)
Patient participating in another potentially
confounding drug or device clinical trial aPatients on oxygen and/or positive airway pressure were eligible for enrollment
Supplemental Table 3. Definitions of Clinical Episodes and Events.
Term Definition
Respiratory Depression
Any of the following: respiratory rate ≤5 bpm
for ≥3 minutes; SpO2 ≤85% for ≥3 minutes;
ETCO2 ≤15 or ≥60 mmHg for ≥3 minutes;
apnea episode lasting >30 seconds; or any
respiratory opioid-related adverse drug event
Opioid-related adverse drug event Any untoward medical occurrence,
2 Surgical Patient, Intravenous and Epidural Opioid
Routea
Excluded: Other reasonse
aPredictor described in the literature as a risk factor for respiratory depression1-6 bGeography and Effective length of monitoring quartiles were included as random effects. cCovariables with very low prevalence (<0.5%) were excluded from the multivariable model. dFrom the correlation analysis some covariables correlated with other covariables were excluded
using statistical (correlation significant cut off >0.25) and clinical judgement. ASA score was
excluded but several factors contributing to ASA score, such as BMI, CHF, and sleep disorders,
were used in model derivation. Neck circumference was strongly correlated with BMI which is a
standard clinical parameter. Thus, neck circumference was excluded. Pneumonia was excluded
because it was strongly correlated with COPD, which is a reported risk factor for respiratory
depression. eMedical patients were enrolled only in United States; opioid route and doses may be used in
future ad hoc analysis
Abbreviations: ASA = American Society of Anesthesiologists; BMI = body mass index; CHF =
aThe multivariable logistic regression models used stepwise selection with entry 0.25, stay criteria 0.15, and respiratory depression as the dependent variable.
Supplemental Table 7. Adverse Events in the Modified Full Analysis Set (N=1,335).
Adverse Event Total Patients
(N = 1335) Number of Adverse Event NE (NP, Y%) 367 (313,
23.4%) Cardiac disorders 8 (8, 0.6%) Congenital, familial and genetic disorders 1 (1, 0.1%) Ear and labyrinth disorders 2 (2, 0.1%) Gastrointestinal disorders 26 (25, 1.9%) General disorders 166 (163,
12.2%) Hepatobiliary disorders 2 (2, 0.1%) Infections and infestations 48 (45, 3.4%) Injury, poisoning, and procedural complications
22 (21, 1.6%)
Investigations 6 (6, 0.4%) Metabolism and nutrition disorders 3 (3, 0.2%) Musculoskeletal and connective tissue disorders
4 (4, 0.3%)
Neoplasms benign, malignant and unspecified (incl. cysts and polyps)
3 (3, 0.2%)
Nervous system disorders 9 (9, 0.7%) Product issues 4 (4, 0.3%) Psychiatric disorders 2 (2, 0.1%) Renal and urinary disorders 4 (4, 0.3%) Respiratory, thoracic, and mediastinal disorders
47 (44, 3.3%)
Skin and subcutaneous tissue disorders 5 (4, 0.3%) Surgical and medical procedures 2 (2, 0.1%) Vascular disorders 3 (3, 0.2%)
Adverse event: Any untoward medical occurrence, unintended disease or injury, or untoward clinical sign, observed by standard of care patient monitoring. All adverse events were recorded independent of their relationship to opioids or respiratory depression. Abbreviations: NE= Number of events; NP = Number of patients
Supplemental Table 8. Opioid-related Adverse Events, Detection by Continuous Monitoring, and PRODIGY Scores for Patients with Opioid-related Adverse Events. Twenty-two opioid-related adverse events occurred during the trial period, of which eleven occurred outside of continuous capnography and pulse oximetry monitoring. Adverse events occurring outside of continuous monitoring were excluded from model derivation.
aFour adverse events (2 hypoxia, 1 respiratory failure, 1 discomfort) took place before capnography and pulse oximetry monitoring commenced bSeven adverse events (4 hypoxia, 2 respiratory failure, 1 abdominal pain) took place after capnography and pulse oximetry monitoring ended cFour patients each had 2 opioid-related adverse events; PRODIGY score was determined once per patient. One opioid-related adverse drug event (hypoxia) occurred during continuous monitoring but was not detected.
Supplemental Table 9. Adverse Event Incidence and Action Taken for Patients With and Without ≥1 Respiratory Depression Episode (Full Analysis Set = 1,495).
aHospitalization defined as prolongation of initial hospital stay or re-hospitalization during ≤30 day follow-up bCumulative exposure time is the sum of the individual exposure time per patient.
Endpoint Any Adverse Event Adverse Event with Any Action
Supplemental Table 10. Healthcare Resource Utilization, Including Hospital Length of Stay and ≤30 Day Readmission of Patients with and without Respiratory Depression.
Patient Characteristic
Patients with ≥ 1 Respiratory
Depression Episode
Patients without Respiratory Depression
Significance (p value)
Mean Length of Stay (N Days, SD) [N Patients]
10.5 (10.8) [614]
7.7 (7.8) [721] <0.0001
Percent patients with ≤30 day readmission (N/Pts)
4.1% (23/556)
4.0% (24/597) 0.92
Primary Diagnosis at Readmission
Patients (N, %) with
≥ 1 Respiratory Depression
Episode (N = 23)
Patients (N, %) without
Respiratory Depression
(N = 24)
Blood and lymphatic system disorders 0 (0%) 1 (4.17%)
Gastrointestinal disorders 5 (21.74%) 4 (16.67%) General disorders 2 (8.7%) 1 (4.17%) Infections and infestations 5 (21.74%) 5 (20.83%) Injury, poisoning and procedural complications 1 (4.35%) 2 (8.33%)