Anesthesia; Adverse Effect
Conditions
Brief summary
To demonstrate that intraoperative NOL-guided titration of fentanyl improves initial recovery characteristics.
Detailed description
Previous work has shown that NOL (Nociception Level) accurately quantifies nociception during general anesthesia.6 Presumably, titrating opioids to NOL will therefore provide individual guidance so that patients will be given about the right amount. Patient given the right amount will presumably awaken quickly when anesthesia is done, and have good initial pain control in the PACU (Post-Anesthesia Care Unit). To the extent that NOL titration facilitates optimal opioid dosing, patients are likely to have better PACU experiences - which would be an important outcome that clinicians and regulators are likely to take seriously.
Interventions
Clinical judgement will be according to their standard practice and may include interpretation of blood pressure, heart rate, diaphoresis, tearing, and pupil size. Boluses of fentanyl 1 µg/kg actual body weight (ABW), up to a maximum dose of 100 µg per bolus, can be given per clinical judgement.
DEVICEPMD-200 Nol-guided opioid administration
PMD-200 Nociception level (NOL) values exceeding 25 for more than 30 seconds will typically be treated with boluses of fentanyl 1µg/kg ABW, up to a maximum of 100 µg per boluses, 5-minute intervals. Towards the end of the surgery (approximately 30-45 minutes before end of surgery, based on clinical judgment), the boluses of fentanyl will be reduced to 0.5 µg/kg ABW, up to a maximum of 50 µg per boluses, 5 minutes intervals. The target of a PMD-200 NOL score below 25 will be maintained until surgery ends
Sponsors
The Cleveland Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Adults having major non-cardiac surgery expected to last ≥2 hours * American Society of Anesthesiologists physical status 1-3 * Age 21-85 years old * Planned endotracheal intubation
Exclusion criteria
* Planned neuraxial or regional block * Clinician preference for an opioid other than, or in addition to, fentanyl * Non-sinus heart * Neurologic condition that, in the opinion of the investigators, may preclude accurate assessment of postoperative pain and nausea * Lack of English language fluency * Routine user of psychoactive drugs other than opioids * Contraindication to sevoflurane, fentanyl, morphine, or ondansetron. * Intracranial surgery. * BMI \> 40
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pain Scores at 10-minute Intervals for the Initial Hour of Recovery | At 10-minute intervals during the first 60 minutes after extubation. | Pain scores are measured using a Verbal Response Scale (VRS) every 10 minutes in the initial hour of recovery. VRS is a scale from 0 to 10 where 0 signifies no pain and 10 signifies the worst pain ever experienced. |
| Pain Scores at 10-minute Intervals for the Initial 30 Minutes of Recovery | At 10-minute intervals during the first 30 minutes after extubation. | Pain scores are measured using a Verbal Response Scale (VRS) at 10-minute intervals for the initial 30 minutes of recovery. VRS is a scale from 0 to 10 where 0 signifies no pain and 10 signifies the worst pain ever experienced. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Measurements With Pain Score Less Than 5 (vs ≥5) for Initial Hour of Recovery | At 10-minute intervals during the first 60 minutes after extubation. | Binary repeated-measures outcome of pain score will be defined as a pain score less than 5 (vs ≥5). Pain scores will be measured using a Verbal Response Scale (VRS) at 10-minute intervals for the initial hour of recovery. VRS is a scale from 0 to 10 where 0 signifies no pain and 10 signifies the worst pain ever experienced. |
| Number of Measurements With Pain Score Less Than 5 (vs ≥5) for the Initial 30 Minutes of Recovery | At 10-minute intervals during the first 30 minutes after extubation. | Binary repeated-measures outcome will be defined as a pain score less than 5 (vs ≥5). Pain scores will be measured using a Verbal Response Scale (VRS) at 10-minute intervals for the 30 minutes of recovery. VRS is a scale from 0 to 10 where 0 signifies no pain and 10 signifies the worst pain ever experienced. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Ramsay Scores During the First 60 Minutes | At 10-minute intervals during the first 60 minutes after extubation. | Ramsay scores will be measured using Ramsay Sedation Scale every 10 minutes in the initial hour of recovery. Ramsay Sedation Scale: 1 = Patient is anxious and agitated or restless, or both; 2 = Patient is co-operative, oriented, and tranquil; 3 = Patient responds to commands only; 4 = Patient exhibits brisk response to light glabellar tap or loud auditory stimulus; 5 = Patient exhibits a sluggish response to light glabellar tap or loud auditory stimulus; 6 = Patient exhibits no response. Frequencies for each score were reported. |
| Treatment Effect on the Time to Emergence From Anesthesia. | From discontinuation of sevoflurane anesthesia to extubation intraoperatively, assessed up to the timepoint of leaving operation room. | Time to emergence from anesthesia is defined as minutes from discontinuation of sevoflurane anesthesia to extubation |
| Number of Analgesic Rescue Boluses | During the first 60 minutes after extubation. | Number of analgesic rescue boluses in the first 60 minutes after extubation. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PMD-200 NOL Group Clinicians will titrate fentanyl to keep PMD-200 NOL under 25 - always using good clinical judgement for individual patients
PMD-200 Nol-guided opioid administration: PMD-200 NOL values exceeding 25 for more than 30 seconds will typically be treated with boluses of fentanyl 1µg/kg ABW, up to a maximum of 100 µg per boluses, 5-minute intervals. Towards the end of the surgery (approximately 30-45 minutes before end of surgery, based on clinical judgment), the boluses of fentanyl will be reduced to 0.5 µg/kg ABW, up to a maximum of 50 µg per boluses, 5 minutes intervals. The target of a PMD-200 NOL score below 25 will be maintained until surgery ends | 35 |
| Control Group Clinicians will be blinded to PMD-200 NOL monitoring and use clinical judgement to determine how much fentanyl should be given, and when.
Routine opioid management: Clinical judgement will be according to their standard practice and may include interpretation of blood pressure, heart rate, diaphoresis, tearing, and pupil size. Boluses of fentanyl 1 µg/kg actual body weight (ABW), up to a maximum dose of 100 µg per bolus, can be given per clinical judgement. | 37 |
| Total | 72 |
Baseline characteristics
| Characteristic | PMD-200 NOL Group | Control Group | Total |
|---|---|---|---|
| Age, Continuous | 58 years STANDARD_DEVIATION 16 | 54 years STANDARD_DEVIATION 15 | 56 years STANDARD_DEVIATION 16 |
| ASA (American Society of Anesthesiologist) physical status I (healthy) | 0 Participants | 1 Participants | 1 Participants |
| ASA (American Society of Anesthesiologist) physical status III (severe systemic disease) | 25 Participants | 28 Participants | 53 Participants |
| ASA (American Society of Anesthesiologist) physical status II (mild systemic disease) | 10 Participants | 8 Participants | 18 Participants |
| BMI | 27 kg/m2 STANDARD_DEVIATION 5 | 28 kg/m2 STANDARD_DEVIATION 6 | 28 kg/m2 STANDARD_DEVIATION 6 |
| Height | 171 cm STANDARD_DEVIATION 11 | 171 cm STANDARD_DEVIATION 10 | 171 cm STANDARD_DEVIATION 10 |
| Preoperative antihypertension medication use | 9 Participants | 15 Participants | 24 Participants |
| Preoperative opioid use | 3 Participants | 3 Participants | 6 Participants |
| Procedure type Laparoscopy | 14 Participants | 22 Participants | 36 Participants |
| Procedure type Open | 21 Participants | 15 Participants | 36 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 4 Participants | 8 Participants |
| Race/Ethnicity, Customized White | 31 Participants | 33 Participants | 64 Participants |
| Sex: Female, Male Female | 16 Participants | 19 Participants | 35 Participants |
| Sex: Female, Male Male | 19 Participants | 18 Participants | 37 Participants |
| Surgery type Colorectal | 34 Participants | 25 Participants | 59 Participants |
| Surgery type Hernia | 1 Participants | 0 Participants | 1 Participants |
| Surgery type Other | 0 Participants | 2 Participants | 2 Participants |
| Weight | 78 kg STANDARD_DEVIATION 19 | 82 kg STANDARD_DEVIATION 23 | 80 kg STANDARD_DEVIATION 21 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 35 | 0 / 37 |
| other Total, other adverse events | 0 / 35 | 0 / 37 |
| serious Total, serious adverse events | 0 / 35 | 0 / 37 |
Outcome results
Primary
Pain Scores at 10-minute Intervals for the Initial 30 Minutes of Recovery
Pain scores are measured using a Verbal Response Scale (VRS) at 10-minute intervals for the initial 30 minutes of recovery. VRS is a scale from 0 to 10 where 0 signifies no pain and 10 signifies the worst pain ever experienced.
Time frame: At 10-minute intervals during the first 30 minutes after extubation.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| PMD-200 NOL Group | Pain Scores at 10-minute Intervals for the Initial 30 Minutes of Recovery | Time point 2 | 1.0 score on a scale |
| PMD-200 NOL Group | Pain Scores at 10-minute Intervals for the Initial 30 Minutes of Recovery | Time point 3 | 2.5 score on a scale |
| PMD-200 NOL Group | Pain Scores at 10-minute Intervals for the Initial 30 Minutes of Recovery | Time point 1 | 0 score on a scale |
| Control Group | Pain Scores at 10-minute Intervals for the Initial 30 Minutes of Recovery | Time point 2 | 5.0 score on a scale |
| Control Group | Pain Scores at 10-minute Intervals for the Initial 30 Minutes of Recovery | Time point 3 | 5.0 score on a scale |
| Control Group | Pain Scores at 10-minute Intervals for the Initial 30 Minutes of Recovery | Time point 1 | 0 score on a scale |
p-value: 0.22899% CI: [-2.66, 0.99]Mixed Models Analysis
Primary
Pain Scores at 10-minute Intervals for the Initial Hour of Recovery
Pain scores are measured using a Verbal Response Scale (VRS) every 10 minutes in the initial hour of recovery. VRS is a scale from 0 to 10 where 0 signifies no pain and 10 signifies the worst pain ever experienced.
Time frame: At 10-minute intervals during the first 60 minutes after extubation.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| PMD-200 NOL Group | Pain Scores at 10-minute Intervals for the Initial Hour of Recovery | Time point 1 | 0 score on a scale |
| PMD-200 NOL Group | Pain Scores at 10-minute Intervals for the Initial Hour of Recovery | Time point 3 | 2.5 score on a scale |
| PMD-200 NOL Group | Pain Scores at 10-minute Intervals for the Initial Hour of Recovery | Time point 4 | 5.0 score on a scale |
| PMD-200 NOL Group | Pain Scores at 10-minute Intervals for the Initial Hour of Recovery | Time point 2 | 1.0 score on a scale |
| PMD-200 NOL Group | Pain Scores at 10-minute Intervals for the Initial Hour of Recovery | Time point 5 | 4.5 score on a scale |
| PMD-200 NOL Group | Pain Scores at 10-minute Intervals for the Initial Hour of Recovery | Time point 6 | 4.5 score on a scale |
| Control Group | Pain Scores at 10-minute Intervals for the Initial Hour of Recovery | Time point 5 | 3.0 score on a scale |
| Control Group | Pain Scores at 10-minute Intervals for the Initial Hour of Recovery | Time point 1 | 0 score on a scale |
| Control Group | Pain Scores at 10-minute Intervals for the Initial Hour of Recovery | Time point 2 | 5.0 score on a scale |
| Control Group | Pain Scores at 10-minute Intervals for the Initial Hour of Recovery | Time point 3 | 5.0 score on a scale |
| Control Group | Pain Scores at 10-minute Intervals for the Initial Hour of Recovery | Time point 6 | 3.0 score on a scale |
| Control Group | Pain Scores at 10-minute Intervals for the Initial Hour of Recovery | Time point 4 | 4.0 score on a scale |
p-value: 0.89599% CI: [-1.43, 1.58]Mixed Models Analysis
Secondary
Number of Measurements With Pain Score Less Than 5 (vs ≥5) for Initial Hour of Recovery
Binary repeated-measures outcome of pain score will be defined as a pain score less than 5 (vs ≥5). Pain scores will be measured using a Verbal Response Scale (VRS) at 10-minute intervals for the initial hour of recovery. VRS is a scale from 0 to 10 where 0 signifies no pain and 10 signifies the worst pain ever experienced.
Time frame: At 10-minute intervals during the first 60 minutes after extubation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PMD-200 NOL Group | Number of Measurements With Pain Score Less Than 5 (vs ≥5) for Initial Hour of Recovery | 112 measurements |
| Control Group | Number of Measurements With Pain Score Less Than 5 (vs ≥5) for Initial Hour of Recovery | 130 measurements |
p-value: 0.56595% CI: [0.4, 1.65]generalized linear mixed effects model
Secondary
Number of Measurements With Pain Score Less Than 5 (vs ≥5) for the Initial 30 Minutes of Recovery
Binary repeated-measures outcome will be defined as a pain score less than 5 (vs ≥5). Pain scores will be measured using a Verbal Response Scale (VRS) at 10-minute intervals for the 30 minutes of recovery. VRS is a scale from 0 to 10 where 0 signifies no pain and 10 signifies the worst pain ever experienced.
Time frame: At 10-minute intervals during the first 30 minutes after extubation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PMD-200 NOL Group | Number of Measurements With Pain Score Less Than 5 (vs ≥5) for the Initial 30 Minutes of Recovery | 63 measurements |
| Control Group | Number of Measurements With Pain Score Less Than 5 (vs ≥5) for the Initial 30 Minutes of Recovery | 61 measurements |
p-value: 0.37995% CI: [0.62, 3.54]Generalized linear mixed effects model
Other Pre-specified
Number of Analgesic Rescue Boluses
Number of analgesic rescue boluses in the first 60 minutes after extubation.
Time frame: During the first 60 minutes after extubation.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PMD-200 NOL Group | Number of Analgesic Rescue Boluses | 1 Number of boluses |
| Control Group | Number of Analgesic Rescue Boluses | 2 Number of boluses |
p-value: 0.03995% CI: [0.3, 0.97]Wilcoxon (Mann-Whitney)
Other Pre-specified
Ramsay Scores During the First 60 Minutes
Ramsay scores will be measured using Ramsay Sedation Scale every 10 minutes in the initial hour of recovery. Ramsay Sedation Scale: 1 = Patient is anxious and agitated or restless, or both; 2 = Patient is co-operative, oriented, and tranquil; 3 = Patient responds to commands only; 4 = Patient exhibits brisk response to light glabellar tap or loud auditory stimulus; 5 = Patient exhibits a sluggish response to light glabellar tap or loud auditory stimulus; 6 = Patient exhibits no response. Frequencies for each score were reported.
Time frame: At 10-minute intervals during the first 60 minutes after extubation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PMD-200 NOL Group | Ramsay Scores During the First 60 Minutes | 1 (Patient is anxious and agitated or restless) | 0 Measurements |
| PMD-200 NOL Group | Ramsay Scores During the First 60 Minutes | 3 (Patient responds to commands only) | 106 Measurements |
| PMD-200 NOL Group | Ramsay Scores During the First 60 Minutes | 2 (Patient is co- operative, oriented, and tranquil) | 92 Measurements |
| PMD-200 NOL Group | Ramsay Scores During the First 60 Minutes | 4 (Patient exhibits brisk response to light glabellar tap or loud auditory stimulus) | 5 Measurements |
| Control Group | Ramsay Scores During the First 60 Minutes | 4 (Patient exhibits brisk response to light glabellar tap or loud auditory stimulus) | 3 Measurements |
| Control Group | Ramsay Scores During the First 60 Minutes | 2 (Patient is co- operative, oriented, and tranquil) | 85 Measurements |
| Control Group | Ramsay Scores During the First 60 Minutes | 3 (Patient responds to commands only) | 132 Measurements |
| Control Group | Ramsay Scores During the First 60 Minutes | 1 (Patient is anxious and agitated or restless) | 1 Measurements |
p-value: 0.16995% CI: [0.35, 1.82]proportional odds model
Other Pre-specified
Treatment Effect on the Time to Emergence From Anesthesia.
Time to emergence from anesthesia is defined as minutes from discontinuation of sevoflurane anesthesia to extubation
Time frame: From discontinuation of sevoflurane anesthesia to extubation intraoperatively, assessed up to the timepoint of leaving operation room.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PMD-200 NOL Group | Treatment Effect on the Time to Emergence From Anesthesia. | 18 minutes |
| Control Group | Treatment Effect on the Time to Emergence From Anesthesia. | 20 minutes |
p-value: 0.96795% CI: [0.63, 1.63]Cox proportional hazards regression