Interaction of Sevoflurane Propofol and Remifentanil in Anesthesia for Laparoscopic Surgery

Study Overview
=================
Brief Summary
-----------------
Recently a new model for the interaction of sevoflurane propofol and remifentanil was developed. The potency of any combination of the three drugs is defined as probability that a subject tolerates laryngoscopy without movement response. The model allows to compare the potency of intravenous and inhalation anesthetics. If the model is valid also for other stimuli than laryngoscopy and for other responses (e.g. blood pressure or heart rate increase upon stimulation). If the model is valid equipotent concentrations of sevoflurane and propofol the same remifentanil concentration would be sufficient to suppress hemodynamic response to a given stimulus. This will be investigated it the study.

Detailed Description
-----------------
Background In general anesthesia propofol or volatile anesthetic are usually combined with opioids and the synergy between hypnotics and opioids is used to reduce the dose of each component in order to minimize side effects and to allow a rapid recovery. Current pharmacodynamic interaction models allow to estimate the potency of combinations of propofol and opioids, volatile anesthetics and opioids or propofol and sevoflurane respectively. In these interaction models the potency of the drug combinations is expressed as probability that motor response to laryngoscopy is suppressed (= tolerance of laryngoscopy, PTOL). The potency of the hypnotic drugs is represented by the concentration preventing motor response to laryngoscopy in 50% of the population (Ce50 hypnotic). Conversely potency of the opioids is represented as concentration reducing the Ce50 of the hypnotics by 50%. The data of the three previous studies on propofol-remifentanil, propofol-sevoflurane and sevoflurane-remifentanil interaction were pooled and reanalyzed. The result was a triple interaction model of sevoflurane, propofol and remifentanil where sevoflurane and propofol were additive and either propofol or sevoflurane were synergistic with remifentanil. In contrast to the previous studies the response surface of the propofol-remifentanil and sevoflurane-remifentanil derived from the pooled re-analysis had a similar shape, which is reflected by a common C50 remifentanil and a common slope parameter. This means that remifentanil is equally synergistic to propofol and sevoflurane. The next step is to validate this interaction model with other stimuli than laryngoscopy and with other responses to stimulation that movement. In clinical practice not motor response but hemodynamic response (heart rate and arterial blood pressure increase) upon surgical stimulation is used to titrate anesthetics and opioids. In laparoscopic surgery after a small skin incision, carbon dioxide is inflated into the abdominal cavity to maintain an intraabdominal pressure of 14 mmHg. Recently the sevoflurane concentration preventing a heart rate or blood pressure increase greater than 20% upon installation of pneumoperitoneum (MAC BAR pneumoperitoneum) has been determined: The MAC BAR pneumoperitoneum (95% CI) of sevoflurane was 4.6 (4.3-4.9) without opioids and 2.4 (2.2-2.6) and 1.7 (1.4-2.1) vol% with an effect site remifentanil concentration of 1 and 2 ng ml-1.These values all correspond to 90% probability to tolerate laryngoscopy (PTOL) according to our triple interaction model (Hannivoort, BJA 2016), which indirectly supports our model. The main purpose of this randomized controlled study is to validate our sevoflurane-propofol-remifentanil interaction model using skin incision and carbon dioxide insufflation (pneumoperitoneum) as stimulus and blood pressure and heart rate response as endpoint. Objective To determine the C50 remifentanil preventing a 20% increase of heart rate or mean arterial pressure upon installation of pneumoperitoneum at equipotent concentrations of sevoflurane or propofol To determine the C50 of sevoflurane and propofol preventing a 20% increase of heart rate or mean arterial pressure upon installation of pneumoperitoneum at a standardized concentration of remifentanil To determine the C50 of propofol or sevoflurane preventing a 20% increase of heart rate or mean arterial pressure upon installation of pneumoperitoneum at standardized concentrations of remifentanil plus sevoflurane or propofol respectively. Methods Patients will be randomly assigned to six groups with different propofol sevoflurane and remifentanil target concentrations for skin incision: Two groups with be given propofol-remifentanil, sevoflurane-remifentanil and sevoflurane-propofol-remifentanil respectively. The up-and-down method will be applied to determine the C50ies. During surgery primarily remifentanil and secondarily sevoflurane or propofol are titrated to maintain mean arterial pressure and bispectral index within predefined limits.

Official Title
-----------------
Validation of the Interaction Model of the Anesthetic Potency of Sevoflurane, Propofol and Remifentanil

Conditions
-----------------
Drug Interactions, Anesthesia, Conduction

Intervention / Treatment
-----------------
* Drug: Propofol and Remifentanil
* Drug: Propofol and Remifentanil
* Drug: Sevoflurane and Remifentanil
* Drug: Sevoflurane and Remifentanil
* Drug: SPR 1
* Drug: SPR2


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: ASA physical status 1 or 2 Written informed consent Exclusion Criteria Cardiovascular disease Pulmonary disease Liver disease CNS disease Alcohol or drug abuse Chronic intake of CNS active drugs Body mass index > 35 Diabetes mellitus Hypersensitivity or allergy to one of the study drugs

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: PR1<br>(Arm closed in May 2022) Propofol-Remifentanil: Prop high, Remi low. Changing Remi (up-and-down) | Drug: Propofol and Remifentanil<br>* High propofol and low remifentanil, changing remifentanil (up-and-down method)<br>|
| Active Comparator: PR2<br>(Arm closed in May 2022) Propofol-Remifentanil: Prop low, Remi high. Changing Prop (up-and-down) | Drug: Propofol and Remifentanil<br>* Low propofol and high remifentanil, changing propofol (up-and-down method)<br>|
| Active Comparator: SR1<br>(Arm closed in May 2022) Sevoflurane-Remifentanil: Sevo high, Remi low. Changing Remi (up-and-down) | Drug: Sevoflurane and Remifentanil<br>* High sevoflurane and low remifentanil, changing remifentanil (up-and-down method)<br>|
| Active Comparator: SR2<br>(Arm closed in May 2022) Sevoflurane-Remifentanil: Sevo low, Remi high. Changing Sevo (up-and-down) | Drug: Sevoflurane and Remifentanil<br>* Low sevoflurane and high remifentanil, changing sevoflurane up-and-down method)<br>|
| Active Comparator: SPR1<br>(Arm closed in October 2023) Sevoflurane-Propofol-Remifentanil: Sevo plus Remi intermediate, Remi intermediate; changing Propofol. | Drug: SPR 1<br>* Triple combination with intermediate propofol and sevoflurane and intermediate remifentanil. SPR 1: Changing Propofol for skin incision.<br>|
| Active Comparator: SPR2<br>(Arm closed in October 2023) Sevoflurane-Propofol-Remifentanil: Sevo plus Remi intermediate, Remi intermediate; changing Sevoflurane. | Drug: SPR2<br>* Triple combination with intermediate propofol and sevoflurane and intermediate remifentanil. Changing Sevoflurane for skin incision.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 20% heart rate or mean arterial pressure increase upon installation of pneumoperitoneum |  | 5 Minutes upon establishment of intraabdominal working pressure (12 mmHg) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean (SD) Bloodpressure during surgery |  | Values recorded on computer HD every 10 sec during anesthesia, expected to be on average ca. 60 - 240 minutes | 
| Mean (SD) Bispectral Index during surgery |  | Values recorded on computer HD every 10 sec. during anesthesia, expected to be on average ca. 60 - 240 minutes | 
| Mean (SD) Remifentanil concentration during surgery |  | During surgery, expected to be on average ca. 60 - 240 minutes | 
| Postoperative quality of recovery score |  | During hospital stay, expected to be on average ca. 3-5 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Anesthetics, Inhalation, Anesthetics, Intravenous, Analgesics, Opioid