Modeling and Application of Triple Drug Response Surface Models

NCT03813875 | Completed FDA Drug FDA Device

• 1 other identifier: 2017-12-024BC
• Study Type: observational
• Target: 100
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Pharmacodynamics; Drug Interactions

Outcome Measures

Primary Outcomes (1)

• 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.

  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.

  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.

  ANI will recorded continuously during the total anesthesia time (from induction to emergence).Reference time: TEE 15 minutes, LMA 2 hours..

Study Arms (2)

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.

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.

Drug: Fentanyl; Other: Bispectral index (BIS) and analgesia nociception index (ANI); Drug: Propofol; Drug: sevoflurane

Interventions

Fentanyl DRUG

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.

LMA (laryngeal mask airway)

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.

LMA (laryngeal mask airway); TEE (transesophageal echocardiography)

alfentanil DRUG

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.

TEE (transesophageal echocardiography)

Propofol DRUG

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.

LMA (laryngeal mask airway); TEE (transesophageal echocardiography)

sevoflurane DRUG

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.

LMA (laryngeal mask airway)

midazolam DRUG

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.

TEE (transesophageal echocardiography)

Eligibility Criteria

• Age: 20 Years - 85 Years
• Sex: all
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

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.

You may qualify if:

• 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.

You may not qualify if:

• 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%

Sponsors & Collaborators

• Taipei Veterans General Hospital, Taiwan: lead

Study Sites (1)

Taipei Veterans General Hospital

Taipei, 11217, Taiwan

Location

Related Publications (7)

• 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.

  PMID: 29793588 BACKGROUND

• 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.

  PMID: 27192475 BACKGROUND

• 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.

  PMID: 22728781 BACKGROUND

• 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.

  PMID: 24557102 BACKGROUND

• 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.

  PMID: 26831450 BACKGROUND

• [40 years of scientific-research work in medicine]. Patol Fiziol Eksp Ter. 1969 May-Jun;13(3):91-4. No abstract available. Russian.

  PMID: 4907643 BACKGROUND

• 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.

  PMID: 2286697 BACKGROUND

MeSH Terms

Interventions

Fentanyl; Alfentanil; Propofol; Sevoflurane; Midazolam

Intervention Hierarchy (Ancestors)

Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Methyl Ethers; Ethers; Hydrocarbons, Fluorinated; Hydrocarbons, Halogenated; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Jing Yang Liou, MD

  Taipei Veterans General Hospital; National Yang-Ming University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 29, 2018
• First Posted: January 23, 2019
• Study Start: June 12, 2019
• Primary Completion: May 1, 2022
• Study Completion: May 25, 2022
• Last Updated: July 20, 2022

Record last verified: 2022-07

Data Sharing

• IPD Sharing: Will not share

Locations

TW (1)