Clinical trial NCT03813875: Modeling and Application of Triple Drug Response Surface Models
Official title: Triple Drug Response Surface Modeling for Patients Receiving Airway Managements
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Pharmacodynamics
Drug Interactions
Lead sponsor: Taipei Veterans General Hospital, Taiwan
Sponsor class: OTHER_GOV
First posted: 2019-01-23
Enrollment: 100
Sex: ALL
Minimum age (years): 20
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

Detailed description: This is an observational study of the routine clinical practice with no specific additional interventions required.

Data acquisition (TEE patients)

1. After screening for eligible patients, protocol and study details will be thoroughly explained to them.
2. 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.
3. 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.
4. 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)

1. After screening for eligible patients, protocol and study details will be thoroughly explained to them.
2. 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.
3. 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.
4. 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)

1. 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).
2. MOAA/S, BIS and ANI (analgesia nociception index) models would be constructed.
3. 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Modified Observer's Assessment Alertness Scale(MOAA/S) score and changes between specified timepoints.
timeFrame: 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:
measure: BIS (bispectral index) value and changes between specified timepoints.
timeFrame: BIS will recorded continuously during the total anesthesia time (from induction to emergence). Reference time: TEE 15 minutes, LMA 2 hours..
measure: ANI (Analgesia nociception index) and changes between specified timepoints.
timeFrame: ANI will recorded continuously during the total anesthesia time (from induction to emergence).Reference time: TEE 15 minutes, LMA 2 hours..
Other outcomes:
Locations:
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
Study officials:
affiliation: Taipei Veterans General Hospital; National Yang-Ming University
name: Jing Yang Liou, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: [40 years of scientific-research work in medicine]. Patol Fiziol Eksp Ter. 1969 May-Jun;13(3):91-4. No abstract available. Russian.
citation: 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.