An equivalence study comparing IN BRIEF • Improves knowledge of the efficacy of RESEARCH low-dose sevoflurane and oxygen as an nitrous oxide and oxygen with inhalation sedation agent. • Provides evidence for a viable alternative to nitrous oxide and oxygen. • Opens the way for further research into low-dose sevoflurane and oxygen higher, sub-MAC, use of sevoflurane and as inhalation sedation agents in oxygen. dentistry for adults M. Allen*1 and S. Thompson2 Objective The aim of this study was to examine whether sevoflurane in oxygen was equivalent to near equipotent concentrations of nitrous oxide in oxygen when used as an inhalation sedation agent in terms of patient and user acceptability. Method Forty anxious dental patients referred to the sedation suite at Cardiff University School of Dentistry received either nitrous oxide to a maximum concentration of 40% or sevoflurane to a maximum concentration of 0.3% for a routine maxillary plastic restoration with articaine infiltration local analgesia. The inhalation sedation agent to be administered was chosen by a random number allocator. Measurements of blood pressure, oxygen saturation, heart rate, respiratory rate and bispectral index were recorded every 5 minutes. At the end of the treatment episode the patient, the operator and an observer who was unaware of the agent used, recorded their impressions about the episode by completing questionnaires. Results In the doses used in this study, sevoflurane was found to be as effective as an inhalation sedation agent as the standard dose of nitrous oxide used in normal inhalation sedation in the treatment of adult anxious dental patients. Conclusion Sevoflurane in low concentrations is equivalent in effect to near equipotent concentrations of nitrous oxide. This would suggest that further research, perhaps with slightly higher concentrations of sevoflurane, is needed. If sevoflurane was shown to be acceptable at slightly higher concentrations, there is scope to explore the development of equipment specifically designed to deliver sevoflurane as an inhalation sedation agent in future. INTRODUCTION treatment should carry a margin of safety with oxygen to produce the ozone depleting Inhalation sedation is a conscious sedation wide enough to render loss of consciousness compound nitric oxide.18 It is good clinical technique used to manage anxiety that unlikely’.1–3 At present the inhalation governance to prevent unnecessary exposure an individual dental patient can feel sedation agent of choice is nitrous oxide. 1–3 of staff to nitrous oxide. In the UK, limits of about dental treatment. During inhalation During inhalation sedation, nitrous oxide is exposure to staff form part of the Control of sedation a gaseous sedative is mixed with incrementally introduced to the individual Substances Hazardous to Health Regulations oxygen to provide relief of that anxiety. patient’s response to produce a feeling of (COSHH) in particular the Occupational The commonest inhalational sedative agent relaxation and anxiolysis.4 exposure standards (OES) introduced in used in the UK is nitrous oxide. Conscious The success in managing dental anxiety January 1996.19 Exposure of staff can be sedation in the UK is defined as; ‘a technique using nitrous oxide inhalation sedation has decreased by: efficient scavenging, suitable in which the use of a drug or drugs produces been confirmed by many clinical studies.5–8 nosepieces, good technique to reduce mouth a state of depression of the central nervous These studies examined the success of breathing and using well-ventilated rooms. system enabling treatment to be carried out, inhalation sedation in the management The increased appreciation of the difficulties but during which verbal contact with the of paediatric dental cases. Successful associated with using nitrous oxide has led patient is maintained throughout the period completion of treatment was found to occur to the examination of alternative inhalation of sedation. The drugs and techniques used in around 84% of cases. sedation agents (Table 1). The agents that to provide conscious sedation for dental The use of nitrous oxide, however, is not have been examined are: without local and global environmental • Isoflurane20–22 effects. Chronic exposure of medical and • Xenon23,24 1 2 Lecturer in Sedation and Special Care Dentistry, Reader 25–27 in Sedation and Special Care Dentistry, School of Den‑ dental staff to nitrous oxide can lead to • Sevoflurane, both in isolation tistry, College of Biomedical and Life Sciences, Cardiff adverse effects.9,10 These adverse effects can and with other drugs.28–30 University, Heath Park, Cardiff, CF14 4XY be haematological,11,12 neurological,13 hepato- *Correspondence to: Mick Allen 9 14 15 Email: [email protected] renal, reproductive and ophthalmological. From these studies it might be assumed Nitrous oxide is also a drug of misuse by that any of the above agents might be Online article number E18 dental professionals16 and in wider society. a suitable alternative to nitrous oxide. Refereed Paper - accepted 20 May 2014 31 DOI: 10.1038/sj.bdj.2014.998 Globally nitrous oxide is a ‘greenhouse However, isoflurane is too irritant and ©British Dental Journal 2014; 217: E18 gas’17 and in the atmosphere can combine pungent for patients to tolerate; xenon is BRITISH DENTAL JOURNAL VOLUME xxx NO. x MON xx 2014 1 © 2014 Macmillan Publishers Limited. All rights reserved. RESEARCH 23 extremely expensive and must be used via Table 1 A comparison of the ideal inhalation sedation agent with nitrous oxide and sevoflurane a rebreathing circuit; and sevoflurane, while expensive, lacks equipment dedicated for its Agent Ideal Sevoflurane Nitrous oxide use an inhalation sedation agent. Anxiolysis Yes Yes Yes OBJECTIVE Ease of titration Yes Yes Yes Clinical trials are used to test the effectiveness of either a new drug, a new formulation of an Induction Smooth and rapid Smooth and rapid Smooth and rapid existing drug or a new means of delivering Recovery Rapid Rapid Rapid a drug. Trials can be designed to establish if the effect on a particular outcome measure, Cardio/respiratory stability Yes Yes Yes perhaps a reduction in the level of cholesterol, Pungent and irritant to airway No No No is superior to the effect of a placebo. This Yes with prolonged or is referred to as a ‘placebo controlled trial’. Toxicity No No chronic exposure However, it might be considered unethical to test a new drug against a placebo if Metabolism 0% 3% Less than 1% an effective treatment for the particular Blood gas solubility Low 0.69 0.47 outcome measure already exists. In a ‘superiority trial’ a new drug might be tested Ease of altering depth of sedation Rapid Rapid Rapid to see if it performs better than the existing Environmental pollutant No No Yes therapy. In such trials a ‘null hypothesis’, that there is no difference between the drugs, is tested using an appropriate statistical test. and hypnotic effect on the patient and service practitioner to the sedation suite The trial attempts to demonstrate that the working conditions for an operator at Cardiff University School of Dentistry. hypothesis can be rejected, by showing a experienced in treating patients under The management strategies utilised in the statistically significant difference. Failure to inhalation sedation. This was recorded sedation suite include the use of behavioural demonstrate a difference does not mean that via sedation scores and behavioural management techniques, hypnosis, inhalation the drugs are equivalent. Researchers may characteristics scores sedation using nitrous oxide and oxygen, hope to demonstrate equivalence between a • Physiological measurement of blood intravenous sedation using midazolam, new drug and the standard therapy. The new pressure, oxygen saturation, pulse, oral sedation and intranasal sedation using drug may be cheaper or provide a second respiratory rate and bispectral index at midazolam. Intravenous sedation using line treatment if, or when, the first line 5 minute intervals. propofol administered by a consultant treatment has proved ineffective or poorly anaesthetist is used in a separate area as part tolerated. It is not possible to demonstrate On statistical advice from colleagues at of an MSc module in conscious sedation. exact equivalence between two drugs but the the Department of Anaesthetics, Intensive Patients referred to the sedation suite vary aim of an equivalence trial is to demonstrate Care and Pain Medicine, the 95% confidence widely in their medical status. For safety and that any differences in a particular outcome interval was calculated for the difference in ethical reasons only patients who met the lie within an accepted range known as scores between the two groups of patients American Society of Anaesthesiologists (ASA) the equivalence margin. It is crucial that (one group receiving sevoflurane and the rating I were included in the study. Exclusion equivalence trials follow exact methods to second group nitrous oxide). The primary criteria were: prevent false results being produced.32 outcome measure was the response to the Unwillingness to participate in the study In this equivalence trial, the aim was to question ‘Did you find this form of sedation • ASA II or greater explore if sevoflurane could be considered effective?’, recorded on a 100 mm visual • Patients taking psychoactive medication equivalent to nitrous oxide as an inhalation analogue scale. Assuming that a difference • Pregnancy sedation agent for dental treatment in adults of less than 10 mm between the groups • Intellectual impairment that may have in terms of patient and user acceptability. was unimportant, further calculations with prevented the patient understanding the a sample size of 20 patients in each group aim of the study and therefore not being MAIN OUTCOME MEASURES provided a confidence interval of ‑6.4 to able to give informed consent The outcome measures used to demonstrate 6.4 mm for no difference, much less than • Inability to arrange an escorting adult equivalence were: the acceptable 10 mm. • Participating in other studies • Effectiveness of the sedative and • Anatomical anomalies such a nasal anxiolytic effect for patients.