Depth of Hypnosis and Postoperative Nausea and Vomiting During Xenon Anaesthesia (XABP)

1) The Effect of Xenon and Sevoflurane on Hypnosis Monitors. 2) Prevention of Postoperative Nausea and Vomiting. 3) Rescue Treatment of Established Postoperative Nausea and Vomiting. Sevoflurane.

The purpose of this study is ad 1) to measure the depth of hypnosis as assessed by BIS and cAAI during an average general anesthesia with xenon or sevoflurane and to establish a reliable monitoring system for measuring and documenting the actual depth of hypnosis for the volatile anesthetics investigated. Ad 2) the question is to be answered whether 4 mg dexamethasone i.v. is an effective prophylactic treatment against postoperative nausea and vomiting in case of xenon or sevoflurane anesthesia. Ad 3) it serves to gain evidence about the (non-)effectiveness and kinetics of ondansetron as antiemetic remedy after xenon or sevoflurane anesthesia.

Study Overview

• Status: Completed
• Conditions: Postoperative Nausea; Postoperative Vomiting; Depth of Anaesthesia; Anaesthetics Gases, Xenon; Anaesthetics Volatile, Sevoflurane
• Intervention / Treatment: Drug: Xenon; Drug: Sevoflurane; Drug: Dexamethasone; Drug: NaCl; Drug: Ondansetron

Detailed Description

1. Patients included into the trial will randomly be allocated to either 0.8-1.1 minimum alveolar concentration (MAC) xenon in 30 % oxygen or 0.8-1.1 MAC sevoflurane (age adapted)/30 % oxygen. The MAC is defined and will therefore be applied according to the investigated subject's age. Premedication will be performed with midazolam 7.5 mg orally 45 min before induction (standard dose and application form for adults as clinical practice of our department). Anesthesia will be induced in both groups with propofol 2 mg/kg i.v. and remifentanil 0.5 mcg/kg/min by infusion over 60 s. For tracheal intubation non-depolarizing neuromuscular blocking agents can be used (rocuronium 0.6 mg/kg). Both groups will receive remifentanil at a base rate of 0.2 mcg/kg/min. Xenon or sevoflurane can be titrated in the range from 0.8-1.1 MAC according to clinical needs based on the patient's hemodynamic, autonomic and somatic signs. Twenty minutes before the estimated cessation of all surgical procedures 0.05 mg kg-1 piritramide for post anesthetic pain management will be administered intravenously, as well as a short infusion of metamizole 15 mg kg-1.

   Depth of anesthesia (hypnosis) will be monitored with spontaneous EEG (BIS VISTA, Aspect Medical Systems, Newton, MA) and the mid latency auditory evoked potentials including a monitoring variable indicating the patients hypnotic state calculated from the MLAEP and the electroencephalogram, the composite A-Line ARX Index (cAAI) with the AEP Monitor/2 (Danmeter A/S, Odense, Denmark). Dosing will be conducted according to the current clinical standard without the monitoring, thus the anesthesia provider will be blinded towards both measurements.

2. After induction of anesthesia patients will be randomized to a second factor, i.e. 4 mg dexamethasone or placebo for the prevention of PONV. To avoid potential imbalances, this will be achieved using a factorial design. The application of dexamethasone or placebo will be blinded to the investigator assessing postoperative nausea and vomiting.
3. Patients who experience significant nausea will be randomized to receive either 4 mg ondansetron or placebo and the course of nausea will be assessed for > 32 min. Again, the application of ondansetron or placebo will be blinded to the investigator assessing postoperative nausea and vomiting. If the symptoms of postoperative nausea and vomiting persist for more than 32 min after treatment additional rescue treatment will be offered. Of note, all patients are able to receive further rescue treatment at any time point of the study on demand.

• Study Type: Interventional
• Enrollment (Anticipated): 220
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Aachen, Germany, D-52074
    • RWTH Aachen University; Department of Anesthesiology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• patients ≥ 18 < 75 years
• ASA physical status I-II
• planned duration of anesthesia ≥ 60 minutes
• Apfel score ≥ 2-3
• elective (laparoscopic) surgery (abdominal, gynecological)
• women: with a highly effective contraception, defined as methods with a pearl index < 1 (i.e. hormonal contraceptives, IUD)

Exclusion Criteria:

• history of hypersensitivity to any used drugs or additive components used for preparation and stabilization of the named drugs in this trial
• history or reasonable suspicion of malignant hyperthermia and/or degenerative neuromuscular disease, in the subject observed or blood relatives
• history of liver function disorders, leucocytosis and unclear fever after usage of halogenated anesthetics.
• any indisposition that may be aggravated by the use of the drugs investigated:
• liver and/or kidney function disorders
• severe acute or chronic infectious disease (i.e. viral, bacterial, fungal)
• elevated intracranial pressure
• history of gastrointestinal ulcer(s) or inflammatory bowel disease
• severe metabolic disorders
• hematoporphyria
• glaucoma
• hearing disorders
• any disease including air-filled closed cavities, such as pneumothorax, ileus
• pregnancy and lactation period
• subjects under the age of 18 years
• ambulatory surgery
• any disease that is associated with the requirement of a high oxygen yield and/or
• risk of high oxygen consumption:
• severe lung and/or airway disease
• coronary heart disease and/or seriously impaired cardiac function
• severe psychiatric disorder

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 4	Drug: NaCl; Intravenous use; single shot
Placebo Comparator: 6	Drug: NaCl; Intravenous use; single shot
Experimental: 1; The effect of xenon as an anaesthetic on the depth of hypnosis.	Drug: Xenon; Inhalational gas; maximum dose allowed: 70 % Xenon; the duration of the treatment will be defined through anesthesia-time.; Other Names: LENOXe
Active Comparator: 2; The effect of sevoflurane as an anesthetic on the depth of hypnosis	Drug: Sevoflurane; Inhalation gas; age adapted MAC-values; the duration of the treatment will be defined through anesthesia-time; Other Names: Sevorane
Experimental: 3; Dexamethasone as prevention of postoperative nausea and vomiting after xenon or sevoflurane anesthesia	Drug: Dexamethasone; Intravenous use, 4 mg, single shot; Other Names: Fortecortin Inject
Experimental: 5; Ondansetron, to determine the onset-time of ondansetron when used as rescue medication for postoperative nausea and vomiting	Drug: Ondansetron; Intravenous use; 4 mg; single shot; Other Names: Zofran

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The average depths of hypnosis as assessed by the BIS and the cAAI between skin incision and start of closure.	During anaesthesia
Postoperative nausea as assessed by a verbal rating scale (VRS) ranging between 0 and 10.	After anesthesia at 5, 10, 15, 30, 45, 60, and 90 min. At 2, 6 and 24 h after anesthesia the maximum nausea will be rated for the 30-120 min, 2-6 h, and 6-24 h interval.
Reduction of VRS nausea immediately at 2, 5, 7.5, 10, 15, 20 and 30 min after rescue treatment administration.	Maximum nausea will be rated at 2, 6 and 24 hours after treatment for the 30-120 min, 2-6 h and 6-24 h interval.

Secondary Outcome Measures

Outcome Measure	Time Frame
Heart rate and blood pressure	During anesthesia
Observer´s assessment of alertness and sedation scales	Recovery from anesthesia
Sensitivity and specificity characteristics for both the BIS and the cAAI.	During anesthesia
Awareness after anesthesia assessed by the Brice questionnaire at 2 and 24 hours after anesthesia.	24 hours after anaesthesia
Occurrence of postoperative vomiting and the respective time-points will be recorded. Postoperative vomiting is defined as vomiting or retching.	24 hours postoperative
Usage of rescue medication, time and dosage	24 hours postoperative
Time to discharge from post anesthetic care unit (Aldrete Score ≥ 9 equals the hypothetic discharge time from post anesthetic care unit)	Time in the post anesthetic care unit

Collaborators and Investigators

• Sponsor: RWTH Aachen University
• Collaborators: Air Liquide Santé International
• Investigators: Study Chair: Rolf Rossaint, MD, RWTH University Aachen; Department of Anesthesiology

Publications and helpful links

General Publications

• Fahlenkamp AV, Stoppe C, Cremer J, Biener IA, Peters D, Leuchter R, Eisert A, Apfel CC, Rossaint R, Coburn M. Nausea and Vomiting following Balanced Xenon Anesthesia Compared to Sevoflurane: A Post-Hoc Explorative Analysis of a Randomized Controlled Trial. PLoS One. 2016 Apr 25;11(4):e0153807. doi: 10.1371/journal.pone.0153807. eCollection 2016.

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (Actual): April 1, 2011
• Study Completion (Actual): April 1, 2011

Study Registration Dates

• First Submitted: November 18, 2008
• First Submitted That Met QC Criteria: November 18, 2008
• First Posted (Estimate): November 19, 2008

Study Record Updates

• Last Update Posted (Estimate): May 17, 2011
• Last Update Submitted That Met QC Criteria: May 16, 2011
• Last Verified: May 1, 2011

More Information

Terms related to this study

• Keywords: Xenon; Sevoflurane; Postoperative Nausea and vomiting; Depth of anaesthesia
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Signs and Symptoms, Digestive; Nausea; Vomiting; Postoperative Nausea and Vomiting; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Anesthetics, General; Anesthetics; Anti-Inflammatory Agents; Platelet Aggregation Inhibitors; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dermatologic Agents; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Serotonin Antagonists; Anti-Anxiety Agents; Anesthetics, Inhalation; Antipruritics; Dexamethasone; Dexamethasone acetate; Sevoflurane; Ondansetron
• Other Study ID Numbers: ALS-8-08-A-401; EudraCT-number:; 2008-004132-20; Protocol version:; Version V3; Date: 20.10.2008