Physiological Effects of Nitrous Oxide on Anaesthesia

Study Overview
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Brief Summary
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Nitrous oxide is the oldest anaesthetic agent still in routine use today. Despite huge changes in the pharmacology of volatile anaesthetic agents and intravenous anaesthetics, the unique properties of nitrous oxide have maintained its place in modern practice, where it is used in combination with other, more powerful inhaled agents, such as sevoflurane. It has useful analgesic properties, unlike the other agents used today, and its inclusion reduces the concentration of other agents required to maintain an adequate depth of anaesthesia for surgery. In particular, its low solubility in body tissues gives it a unique pharmacokinetic profile, with rapid washin and washout from the body. It has been shown to have a similar effect on the speed of uptake of accompanying agents like sevoflurane (the second gas effect), which have much slower pharmacokinetics. A recent study by us suggested that this promotes faster and smoother onset of anaesthesia, as measured using the standard monitor of depth of anaesthesia (the BIS monitor). This finding requires confirmation prospectively in a larger group of patients. The investigators further hypothesise that a similar effect also exists on washout of sevoflurane at the end of the procedure, promoting quicker recovery (emergence) from anaesthesia. This has never been previously demonstrated. This information will help better define the place of nitrous oxide in achieving optimal outcomes in modern anaesthetic practice. The investigators propose to conduct a simple study to measure the effects of nitrous oxide washin and washout on exhaled concentrations of accompanying sevoflurane during both induction of anaesthesia and emergence, and identify any accompanying effect on the rate of change in depth of anaesthesia using BIS. The investigators hypothesise that the rate of fall of exhaled sevoflurane concentration at the end of anaesthesia will be more rapid in the group of patients breathing a gas mixture containing nitrous oxide, and that the rate of fall of BIS on induction and the rate of rise of BIS on emergence will be faster in the nitrous oxide group.

Detailed Description
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Nitrous oxide is the oldest anaesthetic agent still in routine use today. Despite huge changes in the pharmacology of volatile anaesthetic agents and intravenous anaesthetics, the unique properties of nitrous oxide have maintained its place in modern practice, where it is used in combination with other, more powerful inhaled agents, such as sevoflurane. It has useful analgesic properties, unlike the other agents used today, and its inclusion reduces the concentration of other agents required to maintain an adequate depth of anaesthesia for surgery. In particular, its low solubility in body tissues gives it a unique pharmacokinetic profile, with rapid washin and washout from the body. It has been shown to have a similar effect on the speed of uptake of accompanying agents like sevoflurane (the second gas effect), which have much slower pharmacokinetics. A recent study by us suggested that this promotes faster and smoother onset of anaesthesia, as measured using the standard monitor of depth of anaesthesia (the BIS monitor). This finding requires confirmation prospectively in a larger group of patients. We further hypothesise that a similar effect also exists on washout of sevoflurane at the end of the procedure, promoting quicker recovery (emergence) from anaesthesia. This has never been previously demonstrated. This information will help better define the place of nitrous oxide in achieving optimal outcomes in modern anaesthetic practice. We propose to conduct a simple study to measure the effects of nitrous oxide washin and washout on exhaled concentrations of accompanying sevoflurane during both induction of anaesthesia and emergence, and identify any accompanying effect on the rate of change in depth of anaesthesia using BIS. Consenting adult participants will be recruited who are undergoing general anaesthesia for elective surgery anticipated to take a minimum of 1 hour and where an arterial line is considered appropriate for monitoring of blood pressure. As, in normal practice, the decision whether to include of nitrous oxide in the anaesthetic mixture is largely discretionary on the part of the anaesthetist, and therefore allocation to either arm of the protocol is consistent with routine practice, it is intended that the patients will be approached for consent on admission to hospital for their surgery. Standard patient monitoring will be used including BIS and a 2 mL sample of blood will be taken to assess blood gas content lung function and optimise lung ventilation. Following induction of anaesthesia, participants will receive an inhaled gas mixture containing standard concentrations of sevoflurane. They will be randomised to a treatment group where a standard concentration of nitrous oxide is included in this mixture, or a control group where nitrous oxide is not included. Monitoring and recording of exhaled gas concentrations will be made by continuous sampling of gas from the breathing circuit and computer storage. We hypothesise that the rate of fall of exhaled sevoflurane concentration at the end of anaesthesia will be more rapid in the group of patients breathing a gas mixture containing nitrous oxide, and that the rate of fall of BIS on induction and the rate of rise of BIS on emergence will be faster in the nitrous oxide group.

Official Title
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Nitrous Oxide and Inhalational Agent Pharmacokinetics During Anaesthetic Induction and Emergence

Conditions
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Anesthesia

Intervention / Treatment
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* Drug: sevoflurane on air/O2
* Drug: sevoflurane in N2O/O2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients undergoing elective general or orthopaedic surgery under relaxant general anaesthesia anticipated to take >1 hour Exclusion Criteria: Age under 18 years Morbid obesity BMI > 35 Severe or moderately severe lung disease (FEV1 < 1.0L, FEV1/FVC < 50%) Past history of severe post-operative nausea and vomiting Pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Air/Oxygen<br>Sevoflurane with Air/Oxygen Mix | Drug: sevoflurane on air/O2<br>* sevoflurane on air/O2<br>|
| Experimental: sevoflurane in N2O/O2<br> | Drug: sevoflurane in N2O/O2<br>* sevoflurane in N2O/O2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pa t/Pa0 Sevo (Arterial Partial Pressure of Sevoflurane), t=Time(Minutes) | Rate of fall in the arterial partial pressure of sevoflurane relative to baseline at 2 minutes (Pa 2/Pa0 Sevo), 5 minutes (Pa 5/Pa0 Sevo, and 30 minutes (Pa 30/Pa0 Sevo) | Baseline, 2 minutes, 5 minutes, and 30 minutes after emergence | 
| PA t/PA0 Sevo (End Tidal Partial Pressure of Sevoflurane), t=Time (Minutes) | Rate of fall in the end-tidal partial pressure of sevoflurane relative to baseline at 2 minutes (PA2/PA0 sevo) and 5 minutes (PA5/PA0 sevo) | Baseline, 2 minutes, and 5 minutes after emergence | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Eye Opening | The time to eye opening to command after cessation of inhalational anaesthetic administration | 20 Minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nitrous Oxide, washin, washout, second gas effect, sevoflurane, induction, emergence