The current place of nitrous oxide in clinical practice

Introduction Nitrous oxide (N2O) has been used for years as an essential part of general anaesthesia. During the past few decades, however, its use in general anaesthesia has steadily declined. Parallel to this evolution, we witness a growing interest in the use of N2O by nonanaesthesiologists, mainly as a sedative and adjuvant for pain therapy during procedural interventions.1–4 In line with this paradigm shift, heated debates, frequently blurred by strong emotional viewpoints, are questioning the current place of N2O during anaesthesia and during procedural sedation.5 In an attempt to search for up-to-date answers to these issues, the European Society of Anaesthesiology (ESA) convened a number of clinical experts to debate specifically on the following questions. What is the place of N2O in today's perioperative anaesthesia management? What is the place of N2O in procedural analgesia and sedation? Is administration of N2O associated with a health risk for patients and/or providers? Members of the task force consisted of the chairs of the ESA Scientific Committee and Research Committee, and the chairs of the scientific subcommittees on Pharmacology, Paediatrics, and Monitoring, Ultrasound and Equipment. In addition, Western and Eastern European key opinion leaders on the use and place of N2O in adult and paediatric anaesthesia were asked to join the task force. The present consensus statement is the result of an intensive debate based on the available literature and the expert opinion of the task force members. What is the place of N2O in today's perioperative anaesthesia management? Members of the task force agreed that, despite its continuously decreasing use in perioperative care, there are no arguments to state that the use of N2O should be abandoned. This statement was primarily motivated by the known basic physicochemical properties of N2O. In clinical practice, these properties translate into potential benefits at anaesthesia induction, maintenance and emergence. Indeed, faster and smoother induction with improved oxygenation has been reported in the presence of N2O.6–8 During maintenance, N2O is always combined with other drugs, and the addition of N2O dose-dependently allows the concentrations of the other drugs to be decreased, which, in turn, may result in faster recovery at the end of the procedure.9–11 The specific place of N2O in the context of anaesthesia induction in children was discussed. The use of N2O is still very common in today's clinical care and has been generally considered to induce anxiolysis, thereby facilitating mask acceptance as well as peripheral venous line insertion.12–14 Nevertheless, members of the Task Force agreed that these goals can also be achieved with adequate child preparation, conversational hypnosis, parental presence and/or pharmacological premedication. Although perioperative use of N2O may increase the incidence of postoperative nausea and vomiting (PONV),15–19 it is, however, important to state that in patients with a low risk for PONV, this nondesirable side effect can easily be controlled with antiemetic prophylaxis.20 Moreover, the exposure time to N2O seems to be an important factor, with no clinically significant effect of this drug on the incidence of PONV when the duration of exposure is less than 1 h.21 What is the place of N2O in procedural analgesia and sedation? Members of the task force agreed that there is a place for N2O in procedural analgesia and sedation in both adult and paediatric populations. The safety profile based on existing clinical data suggests that N2O administered as the sole sedation/analgesic agent can safely be provided by nonanaesthesiologists who are appropriately trained in the administration modalities of the drug. The members of the task force agreed that thorough basic life support training should be mandatory for anyone providing sedation using N2O or any other sedative drug. An extensive amount of clinical evidence indicates that N2O can be used safely for procedural pain management (in the emergency room, in the normal ward or in a prehospital situation), for the management of labour pain,20–25 and for anxiolysis and sedation in dentistry.26 N2O continues to be the mainstay for paediatric procedural sedation in a large variety of clinical settings. Administration of N2O appears to be well tolerated in this setting and no major problems have been reported.27 However, although currently available work suggests that N2O can be an effective agent to provide sedation in procedures resulting in minor to moderate pain, it is definitely insufficient as a sole agent in more painful procedures.27 Given the variety of procedures performed in paediatric patients, future research needs to define the most appropriate procedure-related effective use of N2O. Is administration of N2O associated with a health risk for patients and/or for providers? Members of the task force agreed that, despite theoretical concerns and laboratory data, there is no evidence indicating that the use of N2O in a clinically relevant setting would increase health risk in patients or providers exposed to this drug. The contraindications to the use of N2O are few: the presence of closed gas containing cavities (e.g. pneumothorax) or abnormalities of the metabolism of vitamin B12 (e.g. vegetarianism, some rare metabolic disorders).13,28 However, whether a 5 to 10-min long single administration of 50% N2O is deleterious in these specific cases is currently unknown. The issue of repeated anaesthesia or sedation with N2O is poorly studied. Cases of chronic N2O abuse have shown that both polyneuropathy and megaloblastic anaemia can occur and some groups therefore recommend not to use N2O more than twice a week.29 With the ubiquitous availability of scavenging systems in the modern operating room, the health concern for medical staff has decreased dramatically. Properly operating scavenging systems reduce N2O concentrations by more than 70%, thereby efficiently keeping ambient N2O levels well below official limits.30–32 The National Institute for Occupational Safety and Health (NIOSH) recommends an exposure limit to N2O of 25 parts per million (ppm) as a time-weighted average (TWA) during the period of anaesthetic administration.33 The primary intention of this exposure limit was to prevent the possible decreases in mental performance, audiovisual acuity and manual dexterity during exposure to N2O. The limits of exposure were then established by different health authorities and were expressed in ppm as 8-h TWA (maximum allowed exposure during 8 h), although in the setting of procedural sedation by nonanaesthesiologists, peak value limits would probably be more appropriate (e.g. in Germany, 200 ppm during 15 min for a maximum of four times per day). Interestingly, the limit for N2O TWA varies greatly from country to country: for France 25 ppm, for the USA, Italy and Belgium 50 ppm, and for Germany, Sweden and the UK 100 ppm.34 However, these limits do not take into account the variability in the exposure throughout the different phases of anaesthesia, which may depend greatly on the breathing system used for induction, the fresh gas flow rate, ventilation rate of the operating room and on the use of a scavenging system.35 The potential teratogenic effect of N2O observed in experimental models cannot be extrapolated to humans.29,36,37 There is a lack of evidence for an association between N2O and reproductive toxicity.29,38 The incidence of health hazards and abortion was not shown to be higher in women exposed to, or spouses of men exposed to N2O than those who were not so exposed. Moreover, the incidence of congenital malformations was not higher among women who received N2O for anaesthesia during the first trimester of pregnancy39 nor during anaesthesia management for cervical cerclage, nor for surgery in the first two trimesters of pregnancy.40 Conclusion Members of the task force agreed that there is currently no clinically relevant evidence for the withdrawal of N2O from the armamentarium of anaesthesia practice or procedural sedation. In procedural sedation, the use of N2O should be limited to procedures resulting in minor to moderate pain intensity. Finally, there is no evidence indicating that the use of N2O in a modern clinically relevant setting increases health risk in patients or providers exposed to this drug. Members of the ESA task force (in alphabetical order) Wolfgang Buhre, Department of Anaesthesia and Pain Treatment, Department of Intensive Care, Maastricht University Medical Centre MUMC, Maastricht, The Netherlands. Vladimir Cerny, Department of Anaesthesiology, Perioperative Medicine and Intensive Care, Masarik Hospital, Usti nad Labem, Czech Republic. Stefan De Hert, Department of Anaesthesiology, Ghent University Hospital, Ghent, Belgium. Nicola Disma, Department of Paediatric Anaesthesia, Istituto Giannina Gaslini, Genoa, Italy. Walid Habre, Department of Anaesthesiology, Geneva University Hospitals, Geneva, Switzerland. Jan Hendrickx, Department of Anaesthesiology, Onze Lieve Vrouw Hospital, Aalst, Belgium. Markus W. Hollmann, Department of Anaesthesiology, Academic Medical Center, Amsterdam, Netherlands. Jan Jakobsson, Institution for Clinical Science, Karolinska Institute, Stockholm, Sweden. Radmilo Jankovic, Department of Anaesthesiology and Intensive Care, University of Nis, Nis, Serbia. Mikhail Kirov, Department of Anaesthesiology and Intensive Care Medicine, Northern State Medical University, Arkhangelsk, Russian Federation. Dusica Simic, Department of Anaesthesiology, University Children's Hospital, Medical Faculty, University of Belgrade, Serbia. Francis Veyckemans, Department of Anaesthesiology, Cliniques universitaires St Luc, UCL, Brussels, Belgium. Sergey Vorotyntsev, Department of Anaesthesiology and Intensive Care, Zaporozhye State Medical University, Ukraine. Laszlo Vutskits, Department of Anaesthesiology, Geneva University Hospitals, Geneva, Switzerland. Jörg Weimann, Department of Anaesthesiology and Intensive Care Medicine, Sankt Gertrauden Hospital, Berlin, Germany. Magdalena Wujtewicz, Department of Ophthalmology, Medical University of Gdansk, Gdansk, Poland. Marzena Zielinska, Department of Anaesthesiology and Intensive Care, Wroclaw Medical University, Wroclaw, Poland. Acknowledgements relating to this article Assistance with the study: none. Financial support and sponsorship: ESA received an educational grant from Air Liquide (France) to convene the task force. There was no interference by industry in the choice of the experts or the content of the consensus statement. Conflicts of interest: JH has received meeting organisational support from Air Liquide; JW has received funding for lectures from Linde Healthcare; JJ has received consultation fees from Linde Healthcare. Comment from the editor: FV, SDH and WH are associate editors of the European Journal of Anaesthesiology.