Published online February 29, 2008
PEDIATRICS
Vol. 121
No. 3
March 2008, pp.
e528-e532
(doi:10.1542/peds.2007-1044)
High-Concentration Nitrous Oxide for Procedural Sedation in Children: Adverse Events and Depth of Sedation
Franz E. Babl, MD, MPH,
Ed Oakley, MBBS,
Cameron Seaman, MBBS,
Peter Barnett, MBBS, MSc and
Lisa N. Sharwood, RN, BN, MPH
Emergency Department, Royal Children's Hospital, Murdoch Children's Research Institute and University of Melbourne, Melbourne, Australia
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ABSTRACT
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OBJECTIVE. Nitrous oxide is an attractive agent for procedural sedation and analgesia in the emergency department; however, there are limited safety data for high-concentration continuous-flow nitrous oxide (50%–70%) and its use in young children. We set out to characterize the depth of sedation and incidence of adverse events associated with various concentrations of nitrous oxide used in a pediatric emergency department.
METHODS. This was a prospective observational study of nitrous oxide use for procedural sedation and analgesia in a tertiary children's hospital emergency department. Nitrous oxide concentration, adverse events, and sedation depth were recorded. Adverse events were categorized as mild or serious. Sedation depth was recorded on a sedation scale from 0 to 6.
RESULTS. A total of 762 patients who were aged 1 to 17 years received nitrous oxide during the 2-year study period. A total of 548 (72%) received nitrous oxide 70%, and 101 (13%) received nitrous oxide 50%. Moderate or deep sedation with scores of 
2 occurred in 3% of patients who had received nitrous oxide 70% and no patients who had received nitrous oxide 50%. Mean sedation scores were 4.4 at nitrous oxide 70% and 4.6 at nitrous oxide 50%. Sixty-three (8.3%) patients sustained 70 mild and self-resolving adverse events, most of which were vomiting (5.7%); 2 (0.2%) patients had serious adverse events. There was no significant difference in adverse events rates between nitrous oxide 70% (8.4%) and nitrous oxide 50% (9.9%). There was no significant difference in the percentage of deep sedation when children who were 3 years of age (2.9%) were compared with older children (2.8%).
CONCLUSIONS. In this largest prospective emergency department series, high-concentration continuous-flow nitrous oxide (70%) was found to be a safe agent for procedural sedation and analgesia when embedded in a comprehensive sedation program. Nitrous oxide also seems safe in children aged 1 to 3 years.
Key Words: nitrous oxide • procedural sedation and analgesia • adverse events • emergency department
Abbreviations: N2O—nitrous oxide • ED—emergency department • PSA—procedural sedation and analgesia • O2—oxygen • IQR—interquartile range • CI—confidence interval
Nitrous oxide (N2O) is an attractive agent for pediatric procedural sedation because it provides rapid onset and offset of sedation. Most research has used N2O 50%, and there have been concerns regarding the variability of the sedation provided.1,2 Furthermore, most studies of N2O 50% have used a demand valve system, which is problematic for children who are younger than 5 years. It has been suggested that increasing the concentration of N2O to 70%, by continuous-flow mechanisms with scavenging, may overcome these problems; however, concerns regarding deeper sedation and increasing complications, in view of the propensity of N2O to cause vomiting in some children, have been raised.1,2
The primary objective of our study was to characterize the depth of sedation and incidence of adverse events associated with various concentrations of N2O that are used in a pediatric emergency department (ED). Secondary objectives included identifying associations with sedation depth, adverse events, and age.
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METHODS
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Design and Setting
We conducted a prospective observational study in the ED of a large, urban children's hospital with an annual ED census of 60000 patients. All children who were 18 years of age and presented to the ED from May 2004 to June 2006 and received N2O for procedural sedation and analgesia (PSA) were eligible for enrollment. Patients who received other sedative agents, such as midazolam, were excluded. This study was approved by the hospital institutional review board.
PSA with any agent in the ED is performed using standardized presedation assessment, monitoring during the procedure, and postsedation discharge criteria as described previously.3,4 As part of standard sedation practice, a sedation checklist, which becomes part of the medical chart, was used. For N2O sedation, minimum departmental fasting times for solids and liquids was 2 hours. Monitoring during N2O sedation included continuous oxygen (O2) saturation, heart rate, and sedation depth, with recording every 5 minutes of O2 saturation, heart rate, respiratory rate, and depth of sedation by nursing staff on the observation chart until the child had returned to the preprocedural state (within minutes). There was a dedicated trained senior nurse or physician to provide airway support and monitoring during the sedation in addition to the proceduralist. N2O was administered by inhalation of a gas mixture with O2. The administration was available in 2 forms, demand-valve-fixed N2O 50%/O2 50%, marketed as Entonox (BOC Gases, Sydney, NSW, Australia) and the continuous-flow system via the Quantiflex MDM (Matrx, Orchard Park, NY) machine, which delivers N2O 0% to 70% and includes a scavenging system to decrease environmental contamination. The continuous-flow system was installed in the procedure rooms and used wall-mounted piped N2O and O2; the demand-valve system was portable and used only rarely and only outside the procedure rooms. Device and N2O concentration used were at the discretion of the treating clinician.
The sedation checklist, which doubled as a case report form, was used to record data before, during, and after PSA with N2O. This included age, risk assessment, fasting status, procedures undertaken, highest concentration of N2O used, additional sedatives or opioids used, deepest level of sedation, and adverse events. The sedation checklist, including the recording of adverse events, was completed by the nurses and physicians who participated in the procedural sedation. All medical charts of patients who underwent sedation with N2O were also reviewed retrospectively.
Data
To measure the level of sedation, a sedation scale that was developed and validated at the Children's Hospital of Wisconsin5 was used. The scale has 7 levels of sedation ranging from 6 to 0 (6: anxious, agitated, or in pain; 5: spontaneously awake without stimulus [talking]; 4: drowsy, eyes open or closed, but easily arouses to consciousness with verbal stimulus; 3: arouses to consciousness with moderate tactile or loud verbal stimulus; 2: arouses slowly to consciousness with sustained painful stimulus; 1: arouses, but not to consciousness, with painful stimulus; 0: unresponsive to painful stimulus). Deepest level of sedation attained was recorded on the sedation checklist. Deep sedation was defined as sedation score of 0 to 2, and moderate sedation was defined as sedation score of 3.
Adverse events were defined a priori as serious or mild. Serious adverse events included O2 desaturation <95%, apnea, stridor, airway misalignment requiring repositioning, laryngospasm, bronchospasm, cardiovascular instability, pulmonary aspiration, unplanned additional tests or hospital admission, endotracheal intubation, permanent neurologic injury, and death. Inadequate sedation was not regarded as an adverse event. O2 administration, upper airway repositioning, and tactile stimulation were regarded as minor interventions. Escalation of respiratory or circulatory support beyond this was considered a major intervention.
Analysis
All data were entered into an Access software database (Microsoft, Redmond, WA). Median values are reported as median with interquartile range (IQR). We used 
2 tests for dichotomous variables and t tests for parametric variables. For all tests, values of P < .05 were considered statistically significant. The effect of various levels of N2O was analyzed by comparing N2O 50% and N2O 70%. Other concentrations were excluded from comparative analysis. Statistical calculations were performed on Stata 9.0 (Stata Corp, College Station, TX).
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RESULTS
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During the 2-year study period, we enrolled 762 patients who had received N2O for PSA in the ED. Patient demographics are listed in Table 1. Seventy-two percent of patients received N2O 70%. Nine percent received an adjunctive analgesic agent within 2 hours of the sedation. Most procedures were orthopedic (38%) and laceration repair (29%). Mean preprocedural fasting time for solids was 4.3 hours (IQR: 2.5–5.0 hours) and for liquids was 3.7 hours (IQR: 2–4.5 hours).
Sixty-three patients (8.3%; 95% confidence interval [CI]: 6.4%–10.4%) sustained 70 mild and self-resolving adverse events, mostly vomiting (5.7%), as shown in Table 2. Two (0.3%; 95% CI: 0.03%–0.9%) patients had serious adverse events; both had received N2O 70%. An 11-year-old previously healthy boy underwent PSA with N2O 70% to suture a toe laceration under lidocaine ring block. He was fasted (solids) for 5 hours. At the end of the procedure, the patient developed sustained stabbing central chest pain. His vital signs remained normal; an electrocardiogram and chest radiograph were also normal. He was administered an antacid (aluminum hydroxide, magnesium trisilicate, and magnesium hydroxide). His chest pain settled, and he was discharged from the hospital after a period of observation in the ED. A 12-year-old previously healthy boy sustained a displaced distal radius fracture. He received N2O 70% for fracture reduction under intravenous regional anesthesia (Bier's block) with 35 mL of lidocaine 0.5%. He had received morphine sulfate 2.5 mg intravenously 1 hour before the procedure and was fasted (solids) for 4 hours. During the procedure, his sedation score was 4 (drowsy, eyes open or closed, but easily arouses to consciousness with verbal stimulus). During the procedure, while receiving N2O 70%, his O2 saturation was 100%. Immediately after the procedure and N2O administration, his O2 saturation dropped to 73% with visible cyanosis. His O2 saturation returned to 100% on high-flow O2 by mask. After 10 minutes, when the O2 mask was removed, he again became cyanotic with O2 saturation at 
70%. Two additional attempts again led to visible cyanosis on removal of O2. Subsequent to this, he maintained his O2 saturation at 95% to 99% on room air. Thereafter, he vomited once. At no point was he distressed, in pain, or short of breath, and his physical examination was normal with a clear chest. He was subsequently admitted for observation and discharged without additional complaints.
No patient experienced a clinically apparent pulmonary aspiration or laryngospasm or required advanced airway support. There was no significant difference (P = .6) in adverse event rates between N2O 70% (8.4%; 95% CI: 6.2%–11.0%) and N2O 50% (9.9%; 95% CI: 4.8%–17.4%).
Table 3 shows the deepest level of sedation recorded during sedation episodes with N2O. Overall, 90.5% (95% CI: 88.0%–92.6%) of sedations for which deepest sedation score had been recorded (n = 655) were performed under mild sedation with sedation scores of 
4 (drowsy, eyes open or closed, but easily arouses to consciousness with verbal stimulus). Overall, in 2.9% of sedation episodes, patients were deeply sedated with sedation scores of 0 to 2 (2: arouses slowly to consciousness with sustained painful stimulus; 1: arouses, but not to consciousness, with painful stimulus; 0: unresponsive to painful stimulus). Comparison of patients who received a N2O /O2 mix that contained a maximum of 50% (mean sedation score: 4.6; 95% CI: 4.5–4.8) as compared with a maximum of N2O 70% (mean sedation score: 4.4; 95% CI: 4.3–4.5) showed significantly deeper sedation with N2O 70% (P = .002). An analysis of sedation episodes with sedation scores 0 to 2 indicated that there were 3.3% (95% CI: 1.9%–5.3%) of episodes of deep sedation with N2O 70% and 0% (95% CI: 0%–4.0%) with N2O 50%. A similar analysis for sedation scores of 0 to 3 indicated 10.7% (95% CI: 8.1%–13.8%) of episodes of moderate to deep sedation with N2O 70% and 3.3% (95% CI: 0.7%–9.4%) with N2O 50%, a statistically significant difference (P = .03).
A total 190 children (24.9%; 95% CI: 21.9%–28.2%) who were 3 years had received N2O of any concentration. Although this information was not collected, children who are younger than 4 years in general require administration of N2O by assisted-mask application rather than patient controlled. When comparing mean sedation depth in children who were 3 years (mean sedation score: 4.5; 95% CI: 4.3–4.6) with children who were older than 3 years (mean sedation score: 4.5; 95% CI: 4.3–4.5) and for whom sedation depth was known, younger children were found to have similar sedation depths (P = .7). An analysis of sedation episodes with sedation scores 0 to 2 indicated that there was no significant difference (P = .9) in the percentage of deep sedation when children who were 3 years of age (2.9%; 95% CI: 0.9%–6.8%) were compared with older children (2.8%; 95% CI: 1.5%–4.7%).
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DISCUSSION
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In the past decade, N2O has gained significant popularity for use in pediatric procedural sedation. A number of studies have tested it, often against other techniques, for laceration repair, fracture reduction, dental procedures, and vascular access.6–11 Most of this literature is with the use of N2O and O2 mixtures in concentrations of up to 50% via demand valve or continuous flow. More recently, interest has been shown in higher concentrations of N2O—up to 70%—given by continuous-flow mixers.12 There remains concern about the use of these higher concentrations of N2O with suggestions that deeper sedation is likely to result and that the incidence of complications is therefore likely to be higher.
This study describes experience with N2O use in >700 patients in a single pediatric ED. The majority (72%) of children were sedated with N2O 70%. The previous largest ED study of N2O 70% was a report of N2O use in 224 patients, 64 of whom received a maximum concentration of 70%.12 The largest reported series of N2O 70% was in 1018 children who underwent urethral catheterization in the radiology suite.13 Neither of these studies reported sedation depth. We found that children who were sedated with N2O 70% had overall deeper sedation (P = .002) and more had moderate or deep sedation (P = .03) than children who received N2O 50%. Mean sedation depth with N2O 70% was 0.2 sedation points lower than N2O 50% (4.4 vs 4.6); however, even at the limits of the CIs, the difference would be only 0.5 sedation points (4.3 vs 4.8). This difference is unlikely to have any clinical significance.
Adverse events were infrequent and experienced by 8% of children, with only 2 patients, both having received N2O 70%, experiencing serious adverse events. There were no airway problems encountered. The incidence and spectrum of adverse events is similar to that in other studies. There was no difference in the frequency or seriousness of adverse events between patients who were administered N2O 70% or those who were administered N2O 50%. Because of the variability of definitions used (eg, inclusion of mask intolerance), the incidence of adverse events reported here (8%) is difficult to compare with those in the other studies that used N2O 70%, ranging from 27%12 to 4%.13
The overall frequency of adverse events is higher than that cited by Cravero and Blike14 in their review of 30000 episodes of pediatric sedation/anesthesia outside the operating room. Their data did not include patients who were sedated with N2O. The incidence of adverse events found in their study was 339.6 per 10000, and our incidence was 944 per 10000. The difference is made up entirely by the increased incidence of emesis in our population (595 per 10000 compared with 47.2 per 10000). The incidence of desaturation was only 13.1 per 10000 in our population compared with 156.5 per 10000. These data support existing studies that indicated that N2O has a higher incidence of vomiting than many other procedural analgesic agents, but with current procedural sedation processes,3,4 this did not translate into an increase in airway or breathing problems.
Reviews of N2O and even proponents of its use have suggested that administration to children who are younger than 4 years should be performed with extreme caution. Luhmann et al9 reported the use of continuous-flow N2O (50%) in 2- to 6-year-olds for laceration repair, concluding it to be an effective procedural analgesic and sedative. Annequin et al15 reported using premixed N2O 50% in children for procedural sedation; 295 (24%) were younger than 6 years, and 46 (4%) were younger than 2 years. They noted more distress in the younger children but did not analyze depth of sedation or adverse events for these groups. Frampton et al12 reported the use of N2O (mostly using N2O 50%–60%) in 224 children, 113 (50.4%) of whom were younger than 5 years. Their study did not analyze adverse events in age strata. Zier et al13 described N2O 70% use in 1018 children who were aged from 11 months (median age: 4.8 years) and underwent urethral catheterization, but, again, adverse events and sedation depth were not analyzed in age strata. Gall et al16 reported the use of premixed N2O 50% in 7511 cases of procedural sedation. They found age <1 year to be the main factor affecting the incidence of adverse events (2.3% vs 0.3% for children 1 year), with no difference in adverse events in other age strata. Our ED sedation guidelines recommend the use of N2O only in children who are older than 1 year; almost one quarter of patients in this study were between 1 and 4 years of age. There was no difference in the mean sedation depth in those compared with older children (4.5 vs 4.5), and similar proportions in the groups of children who were younger than and older than 4 years experienced deep sedation (2.9% vs 2.8%; P = .9).
There are a number of limitations. Recording of adverse events depended on accurate recording of information on the sedation record or in the medical chart by staff who were involved in the procedural sedation. There were no independent observers, and staff might have felt pressured to underreport adverse events. It is possible that a number of mild transitory adverse events occurred in the ED without being recorded or occurred after discharge. Vomiting after N2O use can occur after discharge17; however, on the basis of a review of the hospital-wide adverse events reporting system, we are confident that no major adverse events and specifically no admissions related to adverse events were missed during the study period. A number of procedures under N2O during the study period were likely missed. Patients who were most likely to have been missed were those who presented with acute distress that required immediate N2O use as an analgesic (eg, to apply a backslab in a displaced fracture, for dislocations). Analysis of sedation depth was limited to patients for whom deepest sedation depth had been recorded. The age distribution and diagnoses of patients without sedation scores were similar to the group who had sedation scores available for analysis. Assignment of sedation scores, although used for a number of years in the ED and taught to all ED medical and nursing staff in a standardized sedation education program,3,4 is open to some interpretation, and the inter-rater reliability of staff-determined sedation depth was not assessed. We did not record which device was used to administer N2O, continuous-flow or demand-valve administration; however, any concentration of N2O other than N2O 50% was available only via the variable-concentration continuous-flow system. We estimate that even N2O 50% was administered only rarely via demand valve rather than continuous flow (in <5% of cases).
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CONCLUSIONS
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This is the largest reported ED study of sedation with N2O 70%. It shows that N2O 70% provides similar sedation depth to N2O 50% with no increase in adverse events. N2O seems safe for use in children who are 1 to 3 years of age. What remains to be shown is whether there is any advantage in using N2O 70% (ie, an improved ability to complete a procedure without pain and distress).
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ACKNOWLEDGMENTS
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This study was supported by grants from the Victor Smorgon Charitable Fund (Melbourne, Victoria, Australia) and the Victorian Managed Insurance Authority (Melbourne, Victoria, Australia).
We thank Sue Reid and Anna Lanigan (Child Development and Rehabilitation, Royal Children's Hospital, Melbourne, Australia) for assistance with data management.
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FOOTNOTES
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Accepted Jul 19, 2007.
Address correspondence to Franz E. Babl, MD, MPH, Emergency Department, Royal Children's Hospital, Parkville, Vic 3055, Australia. E-mail: franz.babl{at}rch.org.au
The authors have indicated they have no financial relationships relevant to this article to disclose.
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ABSTRACT
METHODS
