Interaction of Sevoflurane Propofol and Remifentanil in Anesthesia for Laparoscopic Surgery

Condition(s) targeted: Drug Interactions; Anesthesia, Conduction

Intervention: Propofol and Remifentanil (Drug); Propofol and Remifentanil (Drug); Sevoflurane and Remifentanil (Drug); Sevoflurane and Remifentanil (Drug); SPR 1 (Drug); SPR2 (Drug)

Phase: Phase 4

Status: Not yet recruiting

Sponsored by: University Hospital Inselspital, Berne

Official(s) and/or principal investigator(s):
Martin Luginbühl, PD Dr. med., Study Chair, Affiliation: Spitalnetzbern. Institut für Anästhesiologie Tiefenau-Ziegler

Overall contact:
Martin Luginbühl, PD Dr. med, Phone: +41 31 308 84 44, Email: martin.luginbuehl@dkf.unibe.ch

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.

Official title: Validation of the Interaction Model of the Anesthetic Potency of Sevoflurane, Propofol and Remifentanil

Study design: Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Outcomes Assessor), Primary Purpose: Supportive Care

Primary outcome: 20% heart rate or mean arterial pressure increase upon installation of pneumoperitoneum

Secondary outcome:

Mean (SD) Bloodpressure during surgery

Mean (SD) Bispectral Index during surgery

Mean (SD) Remifentanil concentration during surgery

Postoperative quality of recovery score

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 (Hannivort L et al., submitted 2014), 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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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

Martin Luginbühl, PD Dr. med, Phone: +41 31 308 84 44, Email: martin.luginbuehl@dkf.unibe.ch

Department of Anesthesiology and Pain Therapy, Bern University Hospital, Bern 3010, Switzerland; Not yet recruiting
Martin Luginbühl, PD Dr. med, Phone: +41 31 308 84 44, Email: martin.luginbuehl@spitalnetzbern.ch
Loreen Erass, CNRA, Phone: +41 31 632 39 65, Email: loreen.erass@insel.ch
Loreen Erass, CRNA, Sub-Investigator

Related publications:

Schumacher PM, Dossche J, Mortier EP, Luginbuehl M, Bouillon TW, Struys MM. Response surface modeling of the interaction between propofol and sevoflurane. Anesthesiology. 2009 Oct;111(4):790-804. doi: 10.1097/ALN.0b013e3181b799ef.

Heyse B, Proost JH, Schumacher PM, Bouillon TW, Vereecke HE, Eleveld DJ, Luginbühl M, Struys MM. Sevoflurane remifentanil interaction: comparison of different response surface models. Anesthesiology. 2012 Feb;116(2):311-23. doi: 10.1097/ALN.0b013e318242a2ec.

Luginbühl M, Schumacher PM, Vuilleumier P, Vereecke H, Heyse B, Bouillon TW, Struys MM. Noxious stimulation response index: a novel anesthetic state index based on hypnotic-opioid interaction. Anesthesiology. 2010 Apr;112(4):872-80. doi: 10.1097/ALN.0b013e3181d40368.

Bouillon TW, Bruhn J, Radulescu L, Andresen C, Shafer TJ, Cohane C, Shafer SL. Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis, tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy. Anesthesiology. 2004 Jun;100(6):1353-72.

Starting date: July 2015
Last updated: May 27, 2015