- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03813875
Modeling and Application of Triple Drug Response Surface Models
Triple Drug Response Surface Modeling for Patients Receiving Airway Managements
Study Overview
Status
Conditions
Detailed Description
This is an observational study of the routine clinical practice with no specific additional interventions required.
Data acquisition (TEE patients)
- After screening for eligible patients, protocol and study details will be thoroughly explained to them.
- Strict fasting protocols were followed. A 22-gauge intravenous catheter was secured for drug administration. Each patient received standard anesthetic care monitors comprised of ECG (electrocardiography), oxygenation saturation (SpO2) and NIBP (non-invasive blood pressure). ECG and SpO2 (oxygenation saturation) were monitored continuously and NIBP were measured every 5 minutes. Supplemental oxygen (3~5 L/m) was given via nasal cannula, and SpO2 (oxygenation saturation) maintained above 90%. Intravenous bolus midazolam, alfentanil and propofol were given according to the anesthesiologist's preferences. Reference dosage range for midazolam is 0~5mg, alfentanil 0~1000mcg and propofol 0~60mg. Anesthetic depth was monitored with BIS and analgesia nociception index (ANI). BIS and ANI (analgesia nociception index) were for monitoring purposes only.
- Instrumentation began after loss of response as evaluated by the anesthesiologist with the modified observer's assessment/alertness scale (MOAA/S). Intolerable desaturation was managed with mask ventilation or insertion of a nasal airway. An MOAA/S score lesser than 2 was considered loss of response (LOR) and fit for instrumentation. MOAA/S score would be recorded at induction, instrumentation, and emergence phase. Recordings will be added if patient had a MOAA/S score greater than 2. ANI (analgesia nociception index) and forehead BIS monitors will be used as an adjunct to assess anesthetic depth. Additional drug boluses were given if the patient expresses pain or excessive movements observed.
- At the end of the procedure, the patient was observed until return of consciousness (MOAA/S > 5). The patients will be randomly divided into a model training group and a validation group after data acquisition by computer randomization using computer clock as seed.
Data acquisition (Laryngeal mask patients)
- After screening for eligible patients, protocol and study details will be thoroughly explained to them.
- Strict fasting protocols were followed. A 22 or 20-gauge intravenous catheter was secured for drug administration. Each patient received standard anesthetic care monitors comprised of electrocardiography (ECG), SpO2 (oxygen saturation) and non-invasive blood pressure (NIBP). ECG and SpO2 (oxygen saturation) were monitored continuously and NIBP were measured every 5 minutes. Intravenous fentanyl and propofol were given according to the anesthesiologist's preferences. Reference dosage range for fentanyl 0~150mcg and propofol 0~200mg. Anesthetic depth was monitored with BIS and ANI (analgesia nociception index). BIS and ANI were for monitoring purposes only.
- Instrumentation began after loss of response as evaluated by the anesthesiologist with the MOAA/S score. A MOAA/S score lesser than 2 was considered LOR (loss of response) and fit for instrumentation. After LMA placement, sevoflurane was started at 2~3% with a fresh gas flow at 1~6 L/m. The end-tidal sevoflurane concentration would be maintained above 0.7 minimal alveolar concentration to avoid awareness. MOAA/S score would be recorded at induction, instrumentation, during skin incision/closure and emergence phase. Recordings would be added if patient had a MOAA/S score greater than 2. ANI (analgesia nociception index) and forehead BIS monitors would be used as an adjunct to assess anesthetic depth. Additional drug boluses were given if the patient expresses pain or excessive movements observed.
- At the end of the procedure, LMA was removed if the patient was breathing smoothly. The patient was observed until return of consciousness (MOAA/S > 5). The patients will be randomly divided into a model training group and a validation group after data acquisition by computer randomization using computer clock as seed.
Model building, assessment and validation (both groups)
- Collected data were fed to a pharmacokinetic simulation software (TIVA trainer Version 9.1) to calculate second-by-second plasma and effect-site drug concentration changes for all three drugs. The training patient group is used for model training. The bootstrap technique is used with 2000 iterations. Model fit was optimized using -2 Log likelihood (-2LL).
- MOAA/S, BIS and ANI (analgesia nociception index) models would be constructed.
- The results are validated with the validation patient data to confirm its clinical utility. Receiver operating characteristics (ROC) curve analysis is used to assess the quality of model prediction. ROC and area under the curve (AUC) will be compared between the training and validation group.
Study Type
Enrollment (Actual)
Contacts and Locations
Study Locations
-
-
-
Taipei, Taiwan, 11217
- Taipei Veterans General Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Sampling Method
Study Population
TEE (transesophageal echocardiography) population: patients were sent to TEE examination based on cardiologist's expertise. Patients who are willing to receive sedation are candidates for enrollment and will be screened for eligibility.
LMA (laryngeal mask airway) population: The investigators plan to enroll patients who will receive breast surgery under LMA as requested by general surgeons. These patients will be screened for eligibility.
Description
Inclusion Criteria:
- Patients aged between 20 and 85
- Scheduled for transesophageal echocardiography (TEE) examination or surgery under laryngeal mask airway (LMA) depending on study arm.
- American Society of Anesthesiologists (ASA) physical status I to III.
Exclusion Criteria:
TEE arm:
- hearing impairment
- neurologic or behavioral disorders
- habitual sedative use
- alcoholism
- allergy to midazolam, alfentanil or propofol
- resting room air SpO2 < 90%.
- History of upper airway tumors
LMA arm
- hearing impairment
- neurologic or behavioral disorders
- habitual sedative use
- alcoholism
- allergy to sevoflurane, fentanyl or propofol, resting room air
- SpO2 < 90%
- poor dentition
- non-fitting LMA
- LMA insertion attempt greater than 2.
Study Plan
How is the study designed?
Design Details
- Observational Models: Cohort
- Time Perspectives: Prospective
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
---|---|
TEE (transesophageal echocardiography)
This is a purely observational study of the routine anesthestic practice involving the simultaneous use of three drugs. TEE group: the routine sedation medication for the procedure include midazolam (approximately 1~5mg per patient), alfentanil (200~1000mcg per patient) and propofol (small boluses of 10~20mg on demand, total dose usually below 100mg per patient depending on the overall examination timespan) all in intravenous boluses. Patients are monitored with standard monitors (electrocardiography, Non-invasive blood pressure, and pulse oximetry), bispectral index (BIS) and analgesia nociception index (ANI). Patients are observed in the recovery unit with designate nursing staff until full conscious recovery before discharge. |
After giving routine anesthetic medications, the investigators assess the depth of anesthesia based on bispectral index (BIS) and modified observer's assessment/alertness scale (MOAA/S).
BIS is maintained between 40 - 60 and MOAA/S less than 2. The vital signs, BIS, analgesia nociception index (ANI) are recorded automatically and continuously through computerized software.
ANI is used to observational purposes only and do not guide anesthetic management in our protocol.
Upon conclusion of the surgery or examination, the patient is observed until return of consciousness (MOAA/S = 5) before sending them to the recovery unit.
The investigators assess the depth of anesthesia based on bispectral index (BIS) and modified observer's assessment/alertness scale (MOAA/S) after routine drug regimen is given.
BIS is maintained between 40 and 60 and MOAA/S less than 2. The drug doses are given as a part of routine anesthesia practice and is identical regardless of study participation.
Typical alfentanil ranged from 0~1000mcg according to patient condition.
The timing and doses are recorded for backend analysis.
At the conclusion of the examination, the patient is observed in the examination room until return of consciousness before sending them to the recovery unit.
The investigators assess the depth of anesthesia based on bispectral index (BIS) and modified observer's assessment/alertness scale (MOAA/S) after routine drug regimen is given.
BIS is maintained between 40 and 60 and MOAA/S less than 2. The drug doses are given as a part of routine anesthesia practice and is identical regardless of study participation.
Typical propofol ranged from 0~200mg according to patient condition.
The timing and doses are recorded for backend analysis.
At the conclusion of the surgery or examination, the patient is observed in the surgery or examination room until return of consciousness before sending them to the recovery unit.
The investigators assess the depth of anesthesia based on bispectral index (BIS) and modified observer's assessment/alertness scale (MOAA/S) after routine drug regimen is given.
BIS is maintained between 40 and 60 and MOAA/S less than 2. The drug doses are given as a part of routine anesthesia practice and is identical regardless of study participation.
Typical midazolam ranged from 0~5mg in boluses according to patient condition.
The timing and doses are recorded for backend analysis.
At the conclusion of the examination, the patient is observed in the examination room until return of consciousness before sending them to the recovery unit.
|
LMA (laryngeal mask airway)
This is a purely observational study of the routine anesthestic practice involving the simultaneous use of three drugs. LMA group: routine induction medications include propofol (50~200mg per patient), fentanyl (50~150mcg per patient) and sevoflurane (machine setting at 1.5% to 3% according to clinical needs). Patients are monitored with standard monitors (electrocardiography, Non-invasive blood pressure, and pulse oximetry), bispectral index (BIS) and analgesia nociception index (ANI). Patients are observed in the recovery unit with designate nursing staff until full conscious recovery before discharge. |
After giving routine anesthetic medications, the investigators assess the depth of anesthesia based on bispectral index (BIS) and modified observer's assessment/alertness scale (MOAA/S).
BIS is maintained between 40 - 60 and MOAA/S less than 2. The vital signs, BIS, analgesia nociception index (ANI) are recorded automatically and continuously through computerized software.
ANI is used to observational purposes only and do not guide anesthetic management in our protocol.
Upon conclusion of the surgery or examination, the patient is observed until return of consciousness (MOAA/S = 5) before sending them to the recovery unit.
The investigators assess the depth of anesthesia based on bispectral index (BIS) and modified observer's assessment/alertness scale (MOAA/S) after routine drug regimen is given.
BIS is maintained between 40 and 60 and MOAA/S less than 2. The drug doses are given as a part of routine anesthesia practice and is identical regardless of study participation.
Typical propofol ranged from 0~200mg according to patient condition.
The timing and doses are recorded for backend analysis.
At the conclusion of the surgery or examination, the patient is observed in the surgery or examination room until return of consciousness before sending them to the recovery unit.
The investigators assess the depth of anesthesia based on bispectral index (BIS) and modified observer's assessment/alertness scale (MOAA/S) after routine drug regimen is given.
BIS is maintained between 40 and 60 and MOAA/S less than 1.
The drug doses are given as a part of routine anesthesia practice and is identical regardless of study participation.
Typical fentanyl ranged from 0~200mcg according to patient condition.
The timing and doses are recorded for backend analysis.
At the conclusion of the surgery, the patient is observed in the operation room until return of consciousness before sending them to the recovery unit.
The investigators assess the depth of anesthesia based on bispectral index (BIS) and modified observer's assessment/alertness scale (MOAA/S) after routine triple drug regimen is given.
BIS is maintained between 40 and 60 and MOAA/S less than 1.
The drug doses are given as a part of routine anesthesia practice and is identical regardless of study participation.
Typical sevoflurane concentration ranged from 0~3% according to patient condition.
The timing and concentrations data are acquired for backend analysis.
At the conclusion of the surgery, the patient is observed in the surgery room until return of consciousness before sending them to the recovery unit.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Modified Observer's Assessment Alertness Scale(MOAA/S) score and changes between specified timepoints.
Time Frame: Specific events during the surgical or examination procedure (LMA insertion, TEE insertion, skin incision, skin closure, emergence, and patient movements).Reference time: TEE 15 minutes, LMA 2 hours.
|
Our study records these parameters on an observational basis. Anesthetic management remains identical regardless of patient participation or not. Lack of patient movement during TEE(transesophageal echocardiography) or LMA (laryngeal mask airway) insertion is considered Modified Observer's Assessment Alertness Scale score(MOAA/S) < 1. Return of consciousness is defined by a score of MOAA/S greater than 4. MOAA/S is a unitless score between 0 and 5 and is applicable in different anesthesia settings such as sedation for gastrointestinal endoscopy or awake craniotomies. Different procedures do not give different MOAA/S units. The score is a part of anesthetic depth evaluation and the recordings are aggregated to perform fit in a mathematic model. |
Specific events during the surgical or examination procedure (LMA insertion, TEE insertion, skin incision, skin closure, emergence, and patient movements).Reference time: TEE 15 minutes, LMA 2 hours.
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
BIS (bispectral index) value and changes between specified timepoints.
Time Frame: BIS will recorded continuously during the total anesthesia time (from induction to emergence). Reference time: TEE 15 minutes, LMA 2 hours..
|
Our study records these parameters on an observational basis.
Anesthetic management remains identical regardless of patient participation or not.
BIS values are recorded throughout the surgery or TEE examination to correlate with clinical observations.
The recorded BIS reading is uniform and contains only a unitless number ranging from 0 to 100.
Different procedures do not give different units.
The value is a part of anesthetic depth evaluation and the recordings are aggregated to perform fit in a mathematic model.
|
BIS will recorded continuously during the total anesthesia time (from induction to emergence). Reference time: TEE 15 minutes, LMA 2 hours..
|
ANI (Analgesia nociception index) and changes between specified timepoints.
Time Frame: ANI will recorded continuously during the total anesthesia time (from induction to emergence).Reference time: TEE 15 minutes, LMA 2 hours..
|
Our study records these parameters on an observational basis.
Anesthetic management remains identical regardless of patient participation or not.
ANI values are recorded throughout the surgery or TEE examination to correlate with clinical observations.
The recorded ANI reading is uniform and contains only a unitless number ranging from 0 to 100.
Different procedures do not give different units.
The index is a part of anesthetic depth evaluation and the recordings are aggregated to perform fit in a mathematic model.
|
ANI will recorded continuously during the total anesthesia time (from induction to emergence).Reference time: TEE 15 minutes, LMA 2 hours..
|
Collaborators and Investigators
Investigators
- Principal Investigator: Jing Yang Liou, MD, Taipei Veterans General Hospital; National Yang-Ming University
Publications and helpful links
General Publications
- Chernik DA, Gillings D, Laine H, Hendler J, Silver JM, Davidson AB, Schwam EM, Siegel JL. Validity and reliability of the Observer's Assessment of Alertness/Sedation Scale: study with intravenous midazolam. J Clin Psychopharmacol. 1990 Aug;10(4):244-51.
- Liou JY, Ting CK, Teng WN, Mandell MS, Tsou MY. Adaptation of non-linear mixed amount with zero amount response surface model for analysis of concentration-dependent synergism and safety with midazolam, alfentanil, and propofol sedation. Br J Anaesth. 2018 Jun;120(6):1209-1218. doi: 10.1016/j.bja.2018.01.041. Epub 2018 Apr 17.
- Liou JY, Ting CK, Mandell MS, Chang KY, Teng WN, Huang YY, Tsou MY. Predicting the Best Fit: A Comparison of Response Surface Models for Midazolam and Alfentanil Sedation in Procedures With Varying Stimulation. Anesth Analg. 2016 Aug;123(2):299-308. doi: 10.1213/ANE.0000000000001299.
- LaPierre CD, Johnson KB, Randall BR, Egan TD. A simulation study of common propofol and propofol-opioid dosing regimens for upper endoscopy: implications on the time course of recovery. Anesthesiology. 2012 Aug;117(2):252-62. doi: 10.1097/ALN.0b013e31825fb1b2.
- Ting CK, Johnson KB, Teng WN, Synoid ND, Lapierre C, Yu L, Westenskow DR. Response surface model predictions of wake-up time during scoliosis surgery. Anesth Analg. 2014 Mar;118(3):546-53. doi: 10.1213/ANE.0000000000000094.
- Liou JY, Ting CK, Huang YY, Tsou MY. Previously published midazolam-alfentanil response surface model cannot predict patient response well in gastrointestinal endoscopy sedation. J Chin Med Assoc. 2016 Mar;79(3):146-51. doi: 10.1016/j.jcma.2015.11.002. Epub 2016 Jan 28.
- [40 years of scientific-research work in medicine]. Patol Fiziol Eksp Ter. 1969 May-Jun;13(3):91-4. No abstract available. Russian.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Physiological Effects of Drugs
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Central Nervous System Depressants
- Peripheral Nervous System Agents
- Analgesics
- Sensory System Agents
- Anesthetics, Intravenous
- Anesthetics, General
- Anesthetics
- Platelet Aggregation Inhibitors
- Analgesics, Opioid
- Narcotics
- Tranquilizing Agents
- Psychotropic Drugs
- Hypnotics and Sedatives
- Adjuvants, Anesthesia
- Anti-Anxiety Agents
- GABA Modulators
- GABA Agents
- Anesthetics, Inhalation
- Fentanyl
- Midazolam
- Propofol
- Sevoflurane
- Alfentanil
Other Study ID Numbers
- 2017-12-024BC
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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