PharmacodynamicsNCT03813875
Modeling and Application of Triple Drug Response Surface Models
An observational study of Pharmacodynamics and Drug Interactions, run by Taipei Veterans General Hospital, Taiwan at 1 site in Taiwan.
Trial summary
Demand for anesthesiologists outside the operating rooms is increasing. Surgeons, radiologists, endoscopists and other interventionists are performing procedures with greater complexity, sometimes accompanied by greater pain and therefore require some sedation. Read more about this study
- Who is it for?
- Ages 20 to 85 years
- Conditions the study is for
- Pharmacodynamics, Drug Interactions
- What is being tested?
- Fentanyl, Bispectral index (BIS) and analgesia nociception index (ANI) and alfentanil
- Type of treatment
- Injection or infusion
- How many people
- 100 participants
- Where
- 1 siteTaiwan
- Study dates
- 12 Jun 2019to 25 May 2022
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 to 85 years
- All sexes
- Adult, Older adult
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.
Who may be able to join
- 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.
Who cannot join
- TEE arm:
- hearing impairment
- neurologic or behavioral disorders
- habitual sedative use
- alcoholism
- allergy to midazolam, alfentanil or propofol
Show all 18Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Triple Drug Response Surface Modeling for Patients Receiving Airway Managements
Demand for anesthesiologists outside the operating rooms is increasing. Surgeons, radiologists, endoscopists and other interventionists are performing procedures with greater complexity, sometimes accompanied by greater pain and therefore require some sedation. This growing need place a pivotal role on careful handling the delivered drugs. Specifically, the investigators wish to know how different classes of drugs interact in order for us to titrate the effects more precisely. Early studies used isobolograms and concentration effect curves as their tools but these methods are limited and incapable of making continuous bedside monitoring. Researchers integrated these methodologies mathematically and developed response surface models. It's becoming a very convenient tool to assess drug interactions. Drug interactions are visualized with a three dimensional graph, or a surface. Users will only need the calculated drug concentrations and a predicted loss of response probability will be given after a model is built. The process of model construction is complex and time demanding process. Our team has successfully built a dual-drug model for midazolam and alfentanil and several works have been published in renowned anesthesia journals. Dual-drug models are simple but their use is very limited. The investigators often use more than two drugs during practice and a three-drug model will be a great leap to monitor clinical pharmacodynamics. The investigators will collect vital signs, anesthestic depth (BIS=bispectral index, analgesia nociception index (ANI)), drug dosing (propofol, midazolam and alfentanil), and the MOAA/S (modified observer's assessment/alertness score) scores in patient who are receive routine general anesthesia under laryngeal mask or sedation for TEE (transesophageal echocardiography) examinations. Patient's consent will be obtained prior to enrollment. These recordings will be pooled into computer program for model construction. A novel model in the field of anesthesia was chosen and modified. As pioneers in this field in Taiwan, the investigators plan to perform a series of analysis using a novel model the investigators have built to look into detail on how drugs interact with each other. A safety boundary to avoid excessive respiratory depression can be drawn by the model. The main goal is to provide sedation that gives precision, patient comfort, rapid return of consciousness and safety based on the triple-drug response surface model.
Read the 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.
- Conditions
- Pharmacodynamics, Drug Interactions
- Being tested
- Fentanyl, Bispectral index (BIS) and analgesia nociception index (ANI), alfentanil, Propofol, sevoflurane
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
FentanylDrug
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.
Bispectral index (BIS) and analgesia nociception index (ANI)Other
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.
alfentanilDrug
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.
PropofolDrug
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.
sevofluraneDrug
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.
midazolamDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Other: Bispectral index (BIS) and analgesia nociception index (ANI); Drug: alfentanil; Drug: Propofol; Drug: midazolam | |
| 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. Receives: Drug: Fentanyl; Other: Bispectral index (BIS) and analgesia nociception index (ANI); Drug: Propofol; Drug: sevoflurane |
What is being measured
The primary outcome is the main question the study is designed to answer.
Modified Observer's Assessment Alertness Scale(MOAA/S) score and changes between specified timepoints.
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.
Measured: 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 outcomes (2)
BIS (bispectral index) value and changes between specified timepoints.
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.
Measured: 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.
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.
Measured: ANI will recorded continuously during the total anesthesia time (from induction to emergence).Reference time: TEE 15 minutes, LMA 2 hours..
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jan 2019
- Study start12 Jun 2019
- Primary completion1 May 2022
- Study completion25 May 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for PharmacodynamicsStudies of the same condition, open and under way.
- More trials run by Taipei Veterans General Hospital, TaiwanThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 100 participants (actual)
Sponsor and investigators
- Lead sponsor
- Taipei Veterans General Hospital, Taiwan
- Sponsor type
- Other government
- Responsible party
- Sponsor
- Investigators
- Jing Yang Liou, MD, Principal investigator, Taipei Veterans General Hospital; National Yang-Ming University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03813875
- Sponsor's protocol ID
- 2017-12-024BC
- Status last verified
- Jul 2022
- First submitted
- 29 Oct 2018
- Last updated
- 20 Jul 2022
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- Yes
- Individual data sharing
- No
Publications
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.
PubMed 29793588Liou 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.
PubMed 27192475LaPierre 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.
PubMed 22728781Ting 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.
PubMed 24557102Liou 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.
PubMed 26831450[40 years of scientific-research work in medicine]. Patol Fiziol Eksp Ter. 1969 May-Jun;13(3):91-4. No abstract available. Russian.
PubMed 4907643Chernik 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.
PubMed 2286697Wang HY, Hou YY, Ting CK, Liou JY. Prospective response surface modeling of analgesia nociception index using propofol, fentanyl and sevoflurane synergism for laryngeal mask airway placement. J Formos Med Assoc. 2026 Apr 23:S0929-6646(26)00421-3. doi: 10.1016/j.jfma.2026.04.083. Online ahead of print.
PubMed 42031608
Study at a glance
From the registry record, last updated by the sponsor on 20 Jul 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Triple Drug Response Surface Modeling for Patients Receiving Airway Managements
- ClinicalTrials.gov ID
- NCT03813875
- Acronym / sponsor ID
- 2017-12-024BC
- Conditions
- Pharmacodynamics, Drug Interactions
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 100 participants (actual)
- Lead sponsor
- Taipei Veterans General Hospital, TaiwanOther government
- Study start
- 12 Jun 2019 (actual)
- Primary completion
- 1 May 2022 (actual)
- Study completion
- 25 May 2022 (actual)
- First posted
- 23 Jan 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Demand for anesthesiologists outside the operating rooms is increasing. Surgeons, radiologists, endoscopists and other interventionists are performing procedures with greater complexity, sometimes accompanied by greater pain and therefore require some sedation. This growing need place a pivotal role on careful handling the delivered drugs. Specifically, the investigators wish to know how different classes of drugs interact in order for us to titrate the effects more precisely. Early studies used isobolograms and concentration effect curves as their tools but these methods are limited and incapable of making continuous bedside monitoring. Researchers integrated these methodologies mathematically and developed response surface models. It's becoming a very convenient tool to assess drug interactions. Drug interactions are visualized with a three dimensional graph, or a surface. Users will only need the calculated drug concentrations and a predicted loss of response probability will be given after a model is built. The process of model construction is complex and time demanding process. Our team has successfully built a dual-drug model for midazolam and alfentanil and several works have been published in renowned anesthesia journals. Dual-drug models are simple but their use is very limited. The investigators often use more than two drugs during practice and a three-drug model will be a great leap to monitor clinical pharmacodynamics. The investigators will collect vital signs, anesthestic depth (BIS=bispectral index, analgesia nociception index (ANI)), drug dosing (propofol, midazolam and alfentanil), and the MOAA/S (modified observer's assessment/alertness score) scores in patient who are receive routine general anesthesia under laryngeal mask or sedation for TEE (transesophageal echocardiography) examinations. Patient's consent will be obtained prior to enrollment. These recordings will be pooled into computer program for model construction. A novel model in the field of anesthesia was chosen and modified. As pioneers in this field in Taiwan, the investigators plan to perform a series of analysis using a novel model the investigators have built to look into detail on how drugs interact with each other. A safety boundary to avoid excessive respiratory depression can be drawn by the model. The main goal is to provide sedation that gives precision, patient comfort, rapid return of consciousness and safety based on the triple-drug response surface model.
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 design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| TEE (transesophageal echocardiography) | – | Other: Bispectral index (BIS) and analgesia nociception index (ANI), Drug: alfentanil, Drug: Propofol, Drug: midazolamThis 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. |
| LMA (laryngeal mask airway) | – | Drug: Fentanyl, Other: Bispectral index (BIS) and analgesia nociception index (ANI), Drug: Propofol, Drug: sevofluraneThis 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. |
Who may qualify
- Ages
- 20 to 85 years
- Sex
- All
- Age groups
- Adult, Older adult
- 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.
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (18 listed)
- hearing impairment
- neurologic or behavioral disorders
- habitual sedative use
- alcoholism
- allergy to midazolam, alfentanil or propofol
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| FentanylThe 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. | Drug | LMA (laryngeal mask airway) |
| Bispectral index (BIS) and analgesia nociception index (ANI)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. | Other | LMA (laryngeal mask airway), TEE (transesophageal echocardiography) |
| alfentanilThe 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. | Drug | TEE (transesophageal echocardiography) |
| PropofolThe 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. | Drug | LMA (laryngeal mask airway), TEE (transesophageal echocardiography) |
| sevofluraneThe 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. | Drug | LMA (laryngeal mask airway) |
| midazolamThe 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. | Drug | TEE (transesophageal echocardiography) |
Primary outcome
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.
2 secondary outcomes
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..
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..
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Jul 2022.
- Background: PubMed 29793588Liou 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.
- Background: PubMed 27192475Liou 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.
- Background: PubMed 22728781LaPierre 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.
- Background: PubMed 24557102Ting 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.
- Background: PubMed 26831450Liou 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.
- Background: PubMed 4907643[40 years of scientific-research work in medicine]. Patol Fiziol Eksp Ter. 1969 May-Jun;13(3):91-4. No abstract available. Russian.
- Background: PubMed 2286697Chernik 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.
- Derived from this study: PubMed 42031608Wang HY, Hou YY, Ting CK, Liou JY. Prospective response surface modeling of analgesia nociception index using propofol, fentanyl and sevoflurane synergism for laryngeal mask airway placement. J Formos Med Assoc. 2026 Apr 23:S0929-6646(26)00421-3. doi: 10.1016/j.jfma.2026.04.083. Online ahead of print.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jing Yang Liou, MD principal investigator
Taipei Veterans General Hospital; National Yang-Ming University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Pharmacodynamics and Drug Interactions, run by Taipei Veterans General Hospital, Taiwan at 1 site in Taiwan.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Jul 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Taiwan. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03813875, which also lists 8 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Jul 2022.