Clinical trial NCT02999126: Slow Stepwise Propofol TCI Induction for Titration Anesthesia Maintenance
Official title: Slow Stepwise Propofol TCI Induction for Titration Anesthesia Maintenance
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Target Controlled Infusion
Induction of Anesthesia
Bispectral Index
Keywords: Total Intravenous Anesthesia
Titration
Target Controlled Infusion
Propofol
Bispectral index
Lead sponsor: Hospital Italiano de Buenos Aires
Sponsor class: OTHER
First posted: 2016-12-21
Enrollment: 60
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief summary: The purpose of this study is to determine if a slow stepwise propofol TCI induction with Marsh model (Ke0 0.26), allows for an accurate estimation of the effect site concentration required for maintenance of the general anesthesia, with propofol and remifentanil, in adult populations older and younger than 65 years of age.

Detailed description: Introduction: Currently, propofol is the most widely used intravenous anesthetic drug that is able to provide a safe general anesthesia. Propofol can be administered by using different techniques including target controlled infusion (TCI). The ability to maintain the pharmacological conditions after achieving a predetermined clinical effect is one of the major advantages of this technique. Although the use of TCI devices has increased in common clinical practice, whether or not all patients are suitable for TCI remains unclear. Pharmacological models were created based on information from healthy volunteers which may not apply for specific clinical conditions resulting either in over- or sub-dosed when using certain drugs.

It is not only individual variability in the pharmacokinetic (PK) parameters of the anesthetic that is a clinical problem, but it is also the pharmacodynamic variability. A previous study showed up to 6 times the inter-individual difference among young volunteers in loss of consciousness (LOC) and return of consciousness (ROC). In addition, greater differences may be found in the elderly.

Inaccurate general models require the anesthetic team to manually tailor medication requirements for each individual based on the desired therapeutic effect.

The purpose of this study is to evaluate if a slow stepwise propofol TCI induction with Marsh model (Ke0 0.26), assessed by clinical and electroencephalographic parameters, allows for an accurate estimation of the effect concentration required for hypnosis titration and maintenance of the general anesthesia, in adult populations older and younger than 65 years of age.

General Objective

• To establish whether a guided slow stepwise guided propofol induction with TCI represents a good correlation between the calculated Effect-Site Concentration (Ce) for the loss of consciousness and the required Ce to maintain a bispectral index (BIS) value between 45 and 65 during anesthesia maintenance in both age populations

Specific Objectives

* To determine the BIS value achieved with every propofol infusion based on the calculated Ce for the time of loss of consciousness (TLOC)
* To compare the drug infused per time unit required for the loss of consciousness in both groups
* To compare the time and Ce required to achieve loss of consciousness in both groups
* To evaluate the impact of remifentanil during hypnosis by using the BIS index

Hypothesis

During a slow stepwise anesthetic induction with TCI using the Marsh Model 4.0, the calculated Ce for the TLOC is comparable to the Ce required for the maintenance of the hypnosis during the general anesthesia, overcoming the inter-individual variability.

Methods

Experimental study, prospective clinical trial, phase 4. Each subject will be assigned to the propofol induction modality as described in the "intervention" section.

Once consciousness has been lost and maintenance target concentration has been established, manual ventilation will be initiated. Remifentanil TCI 6 ng/ml and a neuromuscular relaxant will be administered afterwards in order to perform endotracheal intubation. An infusion of phenylephrine between 0,1 and 0,4 mcg/kg/min will be initiated in order to maintain blood pressure values within 20% of the baseline value.

Continuous monitoring of BIS will be maintained after remifentanil infusion and intubation. Three minutes after endotracheal intubation, surgery will be prepared following standard procedures. BIS, spectrogram, and hemodynamics will be registered every 15 seconds, continuously, and every 3 minutes during 10 minutes respectively.

Subsequently, propofol Ce at TLOC will be established (if any modifications were necessary after TLOC) and it will be observed for another 30 minutes.

Eligibility criteria: Inclusion Criteria:

* ASA 1 or 2.
* Age over 20 years old.
* Scheduled to undergo elective surgery of minor or medium complexity under general anesthesia.
* Regarding cognitive function: subjects will be considered with enough cognitive function if they are able to read and understand the medical history form by properly answering medical questions during the preoperative anesthesia assessment and being also able to sign the informed consent form.

Exclusion Criteria:

* Pregnancy.
* Obesity (BMI \>30).
* Patients taking benzodiazepines or other central nervous system action drugs.
* Subjects with psychiatric disorders with or without treatment.
* Allergies or any adverse reaction to propofol or any of its components (egg lecithin).

Primary outcomes:
measure: Time that BIS range remains within 45 and 65 after a stepwise TCI titration
timeFrame: A 30-minute period, starting 10 minutes after Remifentanil infusion (when propofol and remifentanil plasma-effect compartment equilibration has been reached)
Secondary outcomes:
measure: Time for loss of consciousness
timeFrame: Up to First 10 minutes, from start of propofol infusion at time 0 until loss of verbal response
measure: Effect Site Concentration required for loss of consciousness
timeFrame: Up to first 10 minutes. It will be considered the propofol effect site concentration displayed at the moment loss of consciousness is achieved.
Other outcomes:
Locations:
city: Buenos Aires
country: Argentina
facility: Hospital Italiano de Buenos Aires
Study officials:
affiliation: Hospital Italiano de Buenos Aires
name: Hernán Boveri, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Struys M, Versichelen L, Byttebier G, Mortier E, Moerman A, Rolly G. Clinical usefulness of the bispectral index for titrating propofol target effect-site concentration. Anaesthesia. 1998 Jan;53(1):4-12. doi: 10.1111/j.1365-2044.1998.00279.x.
citation: Coppens M, Van Limmen JG, Schnider T, Wyler B, Bonte S, Dewaele F, Struys MM, Vereecke HE. Study of the time course of the clinical effect of propofol compared with the time course of the predicted effect-site concentration: Performance of three pharmacokinetic-dynamic models. Br J Anaesth. 2010 Apr;104(4):452-8. doi: 10.1093/bja/aeq028. Epub 2010 Feb 26.
citation: Bienert A, Wiczling P, Grzeskowiak E, Cywinski JB, Kusza K. Potential pitfalls of propofol target controlled infusion delivery related to its pharmacokinetics and pharmacodynamics. Pharmacol Rep. 2012;64(4):782-95. doi: 10.1016/s1734-1140(12)70874-5.
citation: Iwakiri H, Nishihara N, Nagata O, Matsukawa T, Ozaki M, Sessler DI. Individual effect-site concentrations of propofol are similar at loss of consciousness and at awakening. Anesth Analg. 2005 Jan;100(1):107-110. doi: 10.1213/01.ANE.0000139358.15909.EA.
citation: Struys MM, Sahinovic M, Lichtenbelt BJ, Vereecke HE, Absalom AR. Optimizing intravenous drug administration by applying pharmacokinetic/pharmacodynamic concepts. Br J Anaesth. 2011 Jul;107(1):38-47. doi: 10.1093/bja/aer108. Epub 2011 May 30.
citation: Sepulveda PO, Cortinez LI, Recart A, Munoz HR. Predictive ability of propofol effect-site concentrations during fast and slow infusion rates. Acta Anaesthesiol Scand. 2010 Apr;54(4):447-52. doi: 10.1111/j.1399-6576.2009.02183.x. Epub 2009 Dec 14.