A Systematic Review of the Safety of Analgesia with 50% Nitrous Oxide: Can Lay Responders Use Analgesic Gases in the Prehospital Setting? S C Faddy, S R Garlick
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901 Emerg Med J: first published as 10.1136/emj.2004.020891 on 18 November 2005. Downloaded from PREHOSPITAL CARE A systematic review of the safety of analgesia with 50% nitrous oxide: can lay responders use analgesic gases in the prehospital setting? S C Faddy, S R Garlick ............................................................................................................................... Emerg Med J 2005;22:901–906. doi: 10.1136/emj.2004.020891 A safe and effective form of pain relief would be an variety of patients. These organisations do not provide the standard of training that allows their advantage in the prehospital treatment of patients members to administer intravenous analgesics. experiencing extreme pain. Although used by many For members of these groups to effectively treat emergency medical services, 50% nitrous oxide (an inhaled patients in extreme pain, they need to have a safe and effective alternative form of pain relief at analgesic known to have good pain relief properties) is not their disposal. Fifty per cent nitrous oxide in widely used by volunteer and semiprofessional oxygen (commercially available as a mixture in a organisations. This review aimed to determine whether single cylinder) is a patient controlled, inhaled analgesic, which has been used by many 50% nitrous oxide is safe for use by first responders who emergency medical services for many years. are not trained as emergency medical technicians. A However, it is used by only a selected few thorough search of the literature identified 12 randomised organisations employing non-medically trained personnel. Use of formal pain management such controlled trials investigating the use of 50% nitrous oxide as nitrous oxide varies widely between different (as compared with placebo or conventional analgesic organisations throughout the world. regimens) in a range of conditions. The outcomes analysed Nitrous oxide has low solubility in blood and is transported in solution without binding to for this review were: adverse events, recovery time, and protein. It diffuses rapidly across the alveolar– need for additional medication. None of the studies arterial membrane and is excreted unchanged, compared the treatments in the prehospital setting; children mainly through the lungs.1 As a result, nitrous oxide rapidly takes effect2 and is quickly rever- were well represented. Adverse effects were rare and sible on discontinuation of therapy.2–3 Hence, significant adverse outcomes such as hypotension and nitrous oxide does not mask signs and symptoms oxygen desaturation could not be attributed to nitrous that may later be necessary for definitive http://emj.bmj.com/ oxide. Compared with patients receiving conventional diagnosis of the injury or illness. The 50% oxygen content of 50% nitrous oxide:oxygen mixtures is analgesia, those receiving 50% nitrous oxide did not beneficial in ensuring adequate oxygenation and require additional medication any more frequently and has been shown to result in higher oxygen had a faster recovery from sedative effects. The low tension (PO2) compared with oxygen given through a standard oxygen therapy mask at a incidence of significant adverse events from 50% nitrous flow rate of 5 l/min.4 Clinically unimportant on September 28, 2021 by guest. Protected copyright. oxide suggests that this agent could be used safely by lay decreases in arterial oxygen saturation (SaO2) responders. have been noted in patients breathing 50% nitrous oxide in oxygen compared with 50% or ........................................................................... 79% nitrogen in oxygen under conditions of normoventilation.5 ain is a common aspect of many medical Diffusion hypoxia has been identified as a emergencies and is of major concern to potential complication of treatment with 50% Pcaregivers treating patients in the prehospi- nitrous oxide, at least theoretically.5–8 For this tal setting. The availability of pain relief is reason, some authors have advocated a period of See end of article for limited in out-of-hospital emergencies, with the oxygen therapy immediately following the cessa- authors’ affiliations use of intravenous analgesics (such as opioids) tion of nitrous oxide inhalation.9 Although ....................... largely confined to paramedics and medical theoretically a risk, several studies have failed Correspondence to: retrieval teams. Nevertheless, significant pain to demonstrate diffusion hypoxia after 50% S Faddy, Cardiac can render a patient uncooperative and can affect nitrous oxide inhalation.13710 The safety profile Catheterisation Unit, St the appropriateness, timing, and effectiveness of of any analgesic is irrelevant unless it is Vincent’s Hospital, Sydney; Victoria Street, treatments applied by primary care providers. efficacious in the relief of pain. To this end, we Darlinghurst, NSW, 2010, Many patients are treated by members of have previously presented data showing remark- Australia; sfaddy@health. volunteer or semiprofessional aid organisations able consistency in efficacy of pain relief in usyd.edu.au prior to the arrival of the emergency medical studies comparing 50% nitrous oxide with 11 Accepted for publication services (EMS). Groups such as lifeguards, placebo or conventional medication regimens. 14 December 2004 marine rescue, ski patrols, and mountain and We used previously validated pain scoring ....................... mine rescue teams provide the initial care to a systems, such as, visual analogue scales (VAS), www.emjonline.com 902 Faddy, Garlick Emerg Med J: first published as 10.1136/emj.2004.020891 on 18 November 2005. Downloaded from FACES rating scale, the Children’s Hospital of Eastern random effects model for the pooled analysis because of the Ontario Pain Scale (CHEOPS), and verbal pain scores to clinical heterogeneity in the primary studies. assess the analgesic properties of 50% nitrous oxide. Studies For each adverse effect, we have given the risk difference in a variety of patients using a range of scoring systems (RD) and 95% confidence interval (CI) from studies compar- consistently showed superiority of 50% nitrous oxide over ing nitrous oxide and placebo to allow estimation of the rate placebo, and equivalence when compared with conventional of events which may be attributed to the nitrous oxide medication regimens. treatment over and above those that would have occurred The present systematic review assessed the available because of the injury or illness. Test statistics and p values are literature to determine the safety profile of 50% nitrous those reported by each study or, where sufficient data were oxide. We carefully examined the frequency and severity of given, have been independently estimated using Prism side effects to determine whether this agent is safe enough to version 2.01 (GraphPad Software Inc, San Diego, CA). A p be used by caregivers who are not trained as emergency value less than or equal to 0.05 was considered statistically medical technicians (EMTs). significant. MATERIALS AND METHODS RESULTS Literature search Literature search One reviewer performed all of the literature searches. The From the electronic search of the Medline and EMBASE Cochrane Database of Systematic Reviews (Issue 2, 2001) was databases we identified 1585 citations that matched the searched for reviews of trials comparing nitrous oxide with search criteria. These were screened for potentially relevant placebo or other analgesic agents in the prehospital setting. studies. A total of 158 abstracts were retrieved for more No such review existed. The database was further searched detailed evaluation, of which 33 described studies that were for a review of similar trials in any setting. There were no potentially relevant to this systematic review. These studies reviews specifically involving the use of nitrous oxide in any underwent critical appraisal. Twelve studies satisfied all area of patient care. subject and methodology criteria and were subsequently The reviewer searched the Medline (1966–Oct 2001) and included in the review. EMBASE (1985—Oct 2001) databases, using an optimally sensitive search strategy, for relevant studies comparing 50% Characteristics of the studies nitrous oxide with placebo or other analgesic agents in the The characteristics of the studies included in the analysis are prehospital setting. Again, no studies in the prehospital shown in table 1; 50% nitrous oxide was compared with setting were found. Consequently, a broader search was control (placebo or conventional analgesia) in a wide variety performed to find randomised controlled trials from a wide of patient populations. Importantly, child, adolescent, and range of clinical settings. Reference lists cited in original adult patients were all well represented. Pain was experi- articles were examined for relevant studies not identified by enced from a variety of sources, many of which mimic the literature search. injuries and conditions seen in the prehospital setting. The methodological quality of included studies is described in table 2. As expected from studies with short follow up Inclusion criteria periods, collection of outcome data was complete in almost Previous studies have demonstrated increasing analgesic and all studies. psychomotor effects with increasing concentrations of nitrous oxide.12–14 In Australia, the USA, and Europe, 50% Adverse effects nitrous oxide in oxygen is the only premixed concentration Analysis of the pooled risk differences showed that none of http://emj.bmj.com/ commercially