The Application and Validation of Triple Drug Response Surface Models on Density Spectral Array in Clinical Anesthesia

Precision anesthesia is the current trend. The benefits including faster recovery, earlier return to normal activity, increased patient satisfaction and shorter length of stay. In order to avoid unnecessarily deep or too light anesthesia, processed electroencephalogram (EEG) monitors are applied for accurate assessment of the depth of anesthesia (DoA). Bispectral index (BIS) and PSI monitor are among the most widely used. Recently, density spectral array (DSA) has been developed to facilitate the interpretation of EEG signals. Real-time DSA EEG monitoring helps in detecting even subtle changes in the depth of anesthesia and provides more comprehensive information then simple digits.

An emerging field of pharmacodynamics in anesthesia is the response surface models. They describe the interaction of different anesthetics during sedation or anesthesia. Our research team has developed the first comprehensive two-drug response surface models for midazolam and alfentanil during gastrointestinal procedural sedations. However, adequate anesthesia is often achieved with multiple drugs. Two-drug models thus have limited applications. We aim to extend the models into three-drug interactions where it can be used for a broader range of clinical scenarios.

The main goal of the study is to establish and validate the three-drug response surface model by collecting and analyzing EEG parameters (BIS or PSI values, DSA, SEF95 (95% spectral edge frequency) and MF (Median frequency) ) from 60 patients undergoing general anesthesia for thoracic surgeries. We aim to establish the models that help anesthesiologist to achieve rapid emergence, appropriate analgesia, adequate DoA, and patient safety. The secondary aim is to apply this model to provide a guideline for drug dosage adjustment and improve the quality of anesthesia.

This is an observational study of the routine clinical practice of anesthesia and surgery with no specific additional interventions required. Types of surgery (non-intubated video-assisted thoracoscopic surgery or video-assisted thoracoscopic surgery) are discussed and decided totally by patients and surgeons.

Data acquisition (Non-intubated video-assisted thoracoscopic surgery, NI-VATS)

1. After screening for eligible patients, protocol and study details will be thoroughly explained to them.
2. Each patient received standard anesthetic care of our institute. Strict fasting protocols were followed. A 22 or 20-gauge intravenous catheter was secured for drug administration.

   Monitors are comprised of ECG (electrocardiography), oxygenation saturation (SpO2) ,NIBP (non-invasive blood pressure)and arterial blood pressure (ABP). ECG, SpO2 and ABP were monitored continuously and NIBP were measured every 60 minutes. Supplemental oxygen was given via high flow nasal cannula, and SpO2 (oxygenation saturation) maintained above 90%. Induction and maintenance of anesthesia is achieved by intravenous propofol, dexmedetomidine and alfentanil. Dosage are according to anesthesiologist's preference. Anesthetic depth was monitored with BIS or PSI monitor.
3. BIS or PSI monitor is continuously recorded throughout the surgery to collect EEG parameters such as BIS or PSI values, DSA, SEF95 (95% spectral edge frequency) and MF (Median frequency). MOAA/S score would be recorded at induction and emergence phase.
4. At the end of the procedure, the patient was observed until return of consciousness (MOAA/S \> 5). Collected data 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 (Video-assisted thoracoscopic surgery, VATS)

1. After screening for eligible patients, protocol and study details will be thoroughly explained to them.
2. Each patient received standard anesthetic care of our institute. Strict fasting protocols were followed. A 22 or 20-gauge intravenous catheter was secured for drug administration. Monitors are comprised of ECG (electrocardiography), oxygenation saturation (SpO2) ,NIBP (non-invasive blood pressure)and arterial blood pressure (ABP). ECG, SpO2 and ABP were monitored continuously and NIBP were measured every 60 minutes. Induction and maintenance of anesthesia is achieved by intravenous propofol, dexmedetomidine, alfentanil and neuromuscular blocking agents. Dosage are according to anesthesiologist's preference. Anesthetic depth was monitored with BIS or PSI.
3. After double lumen endotracheal tube placement, FiO2: 100 % and fresh gas flow at 1\~6 L/m was set. BIS or PSI monitor is continuously recorded throughout the surgery to collect EEG parameters such as BIS or PSI values, DSA, SEF95 (95% spectral edge frequency) and MF (Median frequency). MOAA/S score would be recorded at induction and emergence phase
4. At the end of the procedure, endotracheal tube was removed if the patient was breathing smoothly. The patient was observed until return of consciousness (MOAA/S \> 5). Collected data 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 or PSI 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 Non-intubated VATS or VATS surgery depending on study arm.
* American Society of Anesthesiologists (ASA) physical status I to III.

Exclusion Criteria:

* hearing impairment
* neurologic or behavioral disorders
* habitual sedative use
* alcoholism
* allergy to dexmedetomidine, alfentanil or propofol
* resting room air SpO2 \< 90%.
* History of upper airway tumors