a b s t r a c t

Background: Nitrous oxide (N₂O) has a rapidly analgesic effect, but evidence regarding its role in managing pain in adults in the emergency department (ED) is conflicting. The purpose of this meta-analysis is to investigate the Analgesic efficacy and safety of N₂O in adults in ED.

Methods: We systematically searched PubMed, the Cochrane Library, Embase, Web of science, China National Knowledge Infrastrusture (CNKI) and Wanfang Database up to August 10th, 2021. Randomized controlled trials were included if they compared N₂O/O₂ to placebo or other analgesic methods for management of pain in adults in ED or prehospital. The primary outcome was the analgesic efficacy of N₂O. Secondary outcomes included adverse events, satisfaction of patients and the duration of procedure.

Results: 14 RCTs with 1751 patients were included. Pooled analysis suggested that N₂O had better analgesia than placebo in the pain score (WMD = -3.00, 95% CI = -3.99 to -2.02, P < 0.00001, I² = 91%) and the number of patients with pain relief (OR = 6.18, 95% CI = 3.22 to 11.85, P < 0.00001, I² = 0%), while there were no significant difference in the pain score (WMD = 0.93, 95% CI = -1.09 to 2.95, P = 0.37, I² = 97%) or the number of patients with pain relief (OR = 0.07, 95% CI = 0.00 to 3.47, P = 0.18, I² = 86%) between the N₂O group and the other analgesic method group. Although N₂O did not increase nausea (OR = 1.52, 95% CI = 0.44 to 5.21, P = 0.50, I² = 54%) or satisfaction of patients (OR = 1.06, 95% CI = 0.16 to 7.18, P = 0.96, I² = 81%), it was associated with

higher tendency of vomiting (OR = 6.50, 95% CI = 2.07 to 20.42, P = 0.001, I² = 29%) and dizziness (OR = 4.54,

95% CI = 2.27 to 9.09, P < 0.0001, I² = 26%), and shorter procedure time (WMD = -5.73 min, 95% CI =

-10.14 min to -1.32 min, P = 0.01, I² = 98%).

Conclusions: The present meta-analysis suggested that N₂O could provide better analgesia than placebo and similar analgesia to other methods with more vomiting and dizziness in adults in ED.

(C) 2022

1. Introduction

* Correspondence to: F. Wang, Department of Anesthesiology, the 960th hospital of PLA, Jinan 250031, China.

?? Correspondence to: L. Tang, Department of Stomatology, the 960th hospital of PLA, Jinan 250031, China.

E-mail addresses: [email protected] (F. Wang), [email protected] (L. Tang).

¹ These authors were equal contributors to the article.

Pain is common in the emergency department (ED) with the inci- dence up to 60%-80%, which is often inadequately treated [1-3]. Pain can cause patients’ tension and anxiety, which has a series of negative effects and is associated with extended length of hospital stay, poor re- habilitation of patients and low level of satisfaction [4-6]. Although the opioids can provide very effective analgesia, concern about the side ef- fects, drug-related abuse and interference in the assessment of patients’ vital signs may lead to physician hesitate to use them [1,7]. A recent re- port suggested that use of Prescription opioids in ED in the United States

https://doi.org/10.1016/j.ajem.2022.03.028

0735-6757/(C) 2022

showed a downward trend. Due to strict drug control, it may make the insufficient analgesia worse [8]. Therefore, it is necessary to find an al- ternative technology to treat pain in ED.

Nitrous oxide (N₂O) is a self-controlled inhalation analgesic that no need for an endovenoUS procedure. It is usually stored in steel cylinders in the form of 50% N₂O and 50% oxygen (O₂) premix (Entonox) [2,3]. It provides analgesia, anxiolysis and hypnosis without serious side effects. N₂O has been shown to be effective for pain in various procedures, e.g., labor, dental treatment and gastrointestinal endoscopy [9-12]. Due to the minimum blood solubility, no bound to proteins and the fastest action, N₂O can rapidly onset and quickly eliminate by lung after discontinuation [3]. It does not mask the signs and symptoms that may be necessary for disease diagnosis [13-15]. These properties suggest that N₂O may be an option for analgesia for the ED patients.

The characteristics of N₂O can benefit children with fear and anxiety for pain, and more and more evidence supports its use in the management of pain in children in ED, such as in venipuncture, lacera- tion repair, fracture reduction, and other minor surgery [16,17]. Al- though there are few such problems in adults, a simple and safe analgesic technology is still needed due to the lack of adequate monitor- ing, sufficient analgesic knowledge and practice of clinicians in ED [18]. The available literature of the efficacy of N₂O for pain in adults in ED is conflicting [19] and no meta-analysis has been conducted on the topic. Therefore, we aimed to perform a meta-analysis in adults in ED to ob- tain the precise estimates of: (1) the analgesic efficacy of N₂O;

(2) adverse effects attributable to N₂O; (3) satisfaction of patients and duration of the procedure.

1. Methods
   1. Search strategy

The protocol for this review was registered with the International Prospective Register of Systematic Review (PROSPERO) with the regis- tration number 270963. The review protocol can be accessed at https://www.crd.york.ac.uk/PROSPERO/.

A literature search was carried out to identify the studies comparing N₂O/O₂ to placebo or other analgesic methods for management of pain in adults in ED. The search strategy followed the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions [20]. We searched electronic databases PubMed, the Cochrane Library, Embase, Web of Science, China National Knowledge Infrastrusture (CNKI) and Wanfang Database up to August 10th, 2021. The following search strategy was used: (nitrous oxide) or (N₂O) (Entonox) and (prehospital) or (emergency setting) or (emergency department) or (emergency) and (pain) or (analgesia) or (sedation).

The reference lists of the included publications were checked in order to identify relevant articles not found in the original search.

• 1. Inclusion and exclusion criteria

Randomized controlled trials were included if they compared N₂O/O₂ to placebo or other analgesic methods for management of pain in adults in ED or prehospital. Children (younger than 18 years old) and the studies that were not conducted in ED or prehospital were not in- cluded in this review.

• 1. Data extraction

For eligible trials, the following data were extracted by two indepen- dent authors using Excel 2010: study author, year of publication, sample size, patient age, patient diagnosis, the ratio of N₂O/O₂, the analgesic method in the control group, pain score and adverse events.

The primary outcome was the pain score measured by visual ana- logue scale (VAS) or Numeric rating scale (NRS), and the number of pa- tients with pain relief. The two pain scales were strongly correlated at all

time periods. Therefore, VAS and NRS can be interchangeably applied for acute Pain measurement in adult patients [21]. If the pain score was reported on a 0-100 mm Visual analogue scale, the date was trans- formed to a 0-10 cm scale. When the pain scores at different time points were all available in the trial, the last data before N₂O withdrawal was selected.

The secondary outcomes included adverse events (nausea, vomiting and dizziness), satisfaction of patients and duration of the procedure. Duration of the procedure refers to the time from the beginning of the implementation of Analgesia management to the end of the operation.

• 1. Statistical analysis

For dichotomous data, odds ratio (OR) with 95% confidence interval (CI) was used to describe and for continuous data, weighted mean dif- ference (WMD) with 95% CI was used. A fixed-effect model was used. The level of significance for the outcomes was set at a level of 0.05. All statistical analyses were performed with Review Manager (RevMan)

5.3 (The Cochrane Collaboration 2014). Heterogeneity was measured and expressed as I², which described the percentage of total variation across studies that was due to heterogeneity rather than chance. I² was calculated from basic results obtained from a typical meta- analysis as I² = 100%x (Q - df)/Q, where Q was the Cochrane hetero- geneity statistic. A value of I² = 0% indicated no observed heterogeneity, and larger values showed increasing heterogeneity. If the value of I² > 50%, a random-effects model was applied. Sensitivity analysis was con- ducted if the statistical or clinical heterogeneity were detected.

1. Results
   1. Search results

The systematic search identified 208 relevant articles. 9 additional studies were identified by other sources. After removing 191 abstracts that did not meet the inclusion criteria, the remaining 26 full-text arti- cles were thoroughly reviewed. The two authors examined the articles and they were able to agree on which articles to be included. Finally, 14 RCTs involving 1751 patients were included in the meta-analysis (Fig. 1) [22-35]. The reason for exclusion of every identified study was reported in S1 Appendix. The characteristics of the included studies were illustrated in Table 1.

• 1. Quality assessment

Two authors independently performed the critical appraisal of in- cluded trials using the Cochrane Collaboration’s tool for assessing risk of bias [20]. The risk of sequence generation, allocation concealment, blinding of participants, blinding of outcome assessment, incomplete outcome data, selective outcome reporting and other potential sources of deviation were shown in Fig. 2. Seven of the fourteen RCTs [23- 26,28,29,35] had a high risk of bias, with the main reasons being lack of random sequence generation, allocation concealment or blinding of patients, participants and outcome assessments.

• 1. Comparisons

In the included trials, mixture of N₂O and O₂ was compared with O₂ [22,30-32,34] medical air [27], fentanyl plus O₂ [26,33] morphine [29,35] lidocaine [23], midazolam plus fentanyl [25,28] and haematoma block [24]. One study [34] used a mixture of 65% N₂O/O₂ and the others [22-33,35] used a mixture of 50% N₂O/O₂. Pain was classified as traumatic in eight studies (dislocation or fracture of joint, soft tissue injuries, traffic injuries, blunt or Sharp trauma, falls and burn) [23-27,31,32,34] and nontraumatic in six studies (acute renal colic, myocardial infarction and peripheral intravenous cannulation) [22,28-30,33,35].

Fig. 1.. Flowchart of study selection. ED, emergency department.

• 1. Primary outcome

The pain score was reported in eleven trials [22,23,25,26,28-34] In patients receiving N₂O, the pain score was lower in nine trials [22,26,28-34]and higher in the other two [23,24]. Pooled analysis suggested that patients in the N₂O group had a significantly lower pain score than patients in the placebo group (WMD = -3.00, 95% CI =

-3.99 to -2.02, P < 0.00001, I² = 91%) (Fig. 3) [22,30-34] while there

was no significant difference (WMD = 0.93, 95% CI = -1.09 to 2.95, P = 0.37, I² = 97%) (Fig. 4) between the N₂O group and the other analgesic method group [23,24,26,28,29].

Among trials comparing N₂O with the other analgesic methods, sensitivity analyses were conducted due to the high heterogeneity. Two studies [26,28] compared N₂O with fentanyl and pooled analysis indicated that the pain score of the nitrous oxide group was significantly lower than that of the fentanyl group (WMD = -1.45, 95% CI = -2.48 to -0.41, P = 0.006, I² = 77%). In studies comparing N₂O with intravenous regional anesthesia [23] or haematoma block

[24] in Distal radius fractures, the pain score was significantly higher in patients inhaling N₂O (WMD = 4.00, 95% CI = 3.15 to 4.86, P < 0.00001, I² = 0%).

Four trials [24,27,33,35] reported the number of patients with pain relief defined as a decrease in pain score of at least 2. Pooled analysis in- dicated that the analgesic effect of N₂O was better than placebo (OR = 6.18, 95% CI = 3.22 to 11.85, P < 0.00001, I² = 0%) (Fig. 5) and similar to

the other analgesic methods (OR = 0.07, 95% CI = 0.00 to 3.47, P = 0.18, I² = 86%) (Fig. 6).

• 1. Secondary outcomes

Nausea was reported in five trials and there was not a significant dif- ference in nausea (OR = 1.52, 95% CI = 0.44 to 5.21, P = 0.50, I² = 54%) (S2 Appendix) [27,30-32,34] Three RCTs reported the outcome of vomiting and pooled analysis showed that patients receiving N₂O showed a higher tendency for vomiting (OR = 6.50, 95% CI = 2.07 to 20.42, P = 0.001, I² = 29%) [30,32,35] (Fig. 7). Four trials reported the outcome of dizziness and patients receiving N₂O were associated with more dizziness (OR = 4.54, 95% CI = 2.27 to 9.09, P < 0.0001, I² =

26%) [26,30,32,34] (Fig. 8).

Satisfaction of patients was reported in three trials [24,30,31] There was not a significant difference in patients’ satisfaction (OR = 1.06, 95% CI = 0.16 to 7.18, P = 0.96, I² = 81%) (S3 Appendix). Duration of the

Table 1

Study characteristics and outcomes of included studies

Author	Patients	Age(years)	Experimental group	Control group	Outcomes
Gerhardt et al. (2001) [22]	10 adult patients (each person received twice	18-50	n = 10, 50:50 N2O/O2 inhalation	n = 10, O2 inhalation	Pain and feeling of anxiety
	operations)
Goh et al.	67 adult patients with	The experimental	n = 35, 50% N2O/O2	n = 32, intravenous injection of 2 mg/kg 1%	Procedure time, pain
(2002) [23]	closed distal redius	group: 62 +- 16.5;	inhalation for 3 min	lidocaine, diluted with normal saline to 20	perception, patient
	fractures	The control group:	or more if necessary	mL, additional dose 3 mg/kg as needed	acceptance, failed
		61.5 +- 16			manipulation, complications
Man et al. (2010) [24]	67 adult patients with fracture of the distal	The experimental group: 67.55 +- 11.75;	n = 33, 50% N2O/O2 inhalation	n = 34, haematoma block	Pain perception, procedure time, patient acceptance and
	radius	The control group:			complications
		64.53 +- 10.71
Mahshidfar	120 patients with	The experimental	n = 60, 50% N2O/O2	n = 60, intravenous injection of midazolam	Change in pain score,
et al. (2011)	recurrent anterior	group: 28.4 +- 11;	inhalation	and fentanly	satisfaction, duration of
[25]	Shoulder dislocation	The control group:			procedures and recovery,
		31.8 +- 0.3			adverse events
Kariman et al. (2011) [26]	100 patients with isolated long bone fracture or	15-85	n = 50, 50% N2O/O2 inhalation	n = 50, 2 mg/kg fentanyl by slow intravenous injection with no total dose limit while	Pain score, adverse events, vital signs
Ducasse et al.	main Joint dislocation 60 adult patients with	The experimental	n = 30, 50% N2O/O2	receiving O2 inhalation at 6 L/min n = 30, medical air (MA) at 9 L/min	The percentage of patients
(2013) [27]	acute moderate pain (NRS	group: 37 (26-66);	inhalation at 9 L/min		with pain relief, adverse
	score between 4 and 6 out	The control group: 29			events, time to analgesia,
	of 10) caused by trauma	(23-50)			satisfaction of patients and
					investigator
Masoumi et al.	40 adult patients	The experimental	n = 20, 50% N2O/O2	n = 20, 30-s intravenous injection of	Pain score, duration of
(2015) [28]	requiring synchronized	group: 52 +- 10.2;	inhalation	midazolam (0.15 mg/kg) and fentanyl	sedation, time to Full recovery
	cardioversion	The control group:		(1.5 ug/kg)	consciousness, need of
		55.4 +- 15.6			additional doses
Kariman et al.	100 adult patients with	The experimental	n = 50, 50% N2O/O2	n = 50, morphine sulfate injection	Pain score, need of additional
(2015) [29]	renal colic	group: 34.7 +- 8.3;	inhalation for 30 min	(0.1 mg/kg) with 100 mg diclofenac	doses, adverse events,
		The control group:	via mask and 100 mg	suppository	duration of hospitalization
		32.1 +- 8.3	diclofenac suppository
Aguilar Mulet et al. (2016)	146 adult patients with renal colic	The experimental group: 43.6 +- 14.1;	n = 70, 50% N2O/O2 inhalation	n = 77, O2 inhalation	Change in pain score, satisfaction, adverse events
[30]		The control group:
		41.7 +- 13.7
Jebali et al. (2017) [31]	100 patients requiring skin suture	The experimental group: 26 +- 9.5;	n = 50, 50% N2O/O2 inhalation for 5 min	n = 50, O2 inhalation	Pain score, adverse events, satisfaction of both patients
		The control group:			and physicians
		23.7 +- 8.4
Tao et al. (2017) [32]	106 patients with trauma and VAS > 5 were	16-65	n = 53, 50% N2O/O2 inhalation	n = 53, O2 inhalation	Pain score, vital signs, adverse events, respiratory
	enrolled				depression, hypoxemia
Ahmadi et al. (2018) [33]	120 adult patients with renal colic	The experimental group: 33.2 +- 10.3;	n = 60, 50% N2O/O2 inhalation and 50 ug	n = 60, O2 inhalation +50 ug fentanyl	Pain score, duration of hospitalization
		The control group:	fentanyl
		33.0 +- 10.5
Gao et al.	60 adult patients with	The experimental	n = 30, conventional	n = 30, conventional pain treatment plus	Change in the pain, vital signs,
(2019) [34]	moderate to severe acute pain caused by trauma	group: 45 (31-48); The control group: 46 (36-59)	pain treatment plus 65% N2O/O2 inhalation	100% O2 inhalation	the incidence of adverse events, satisfaction of both patients and physicians
Charpentier et al. (2020)	644 adult patients	The experimental group: 61.9 +- 13.7;	n = 315, N2O/O2 inhalation with	n = 329, morphine was titrated every 5 min assessed on a numeric rating scale: a 2 mg	Proportion of patients achieving pain relief, adverse
[35]		The control group:	intravenous	bolus (or 1 mg, for body weight < 60 kg) was	events
		62.1 +- 13.0	acetaminophen 1 g	given for the score 4-5; and a 3 mg bolus
				(or 2 mg, for body weight < 60 kg) for the
				score >= 6

procedure was reported in three trials comparing N₂O with other analgesic methods [23-25] and it was shorter in patients receiving N₂O (WMD = -5.73 min, 95% CI = -10.14 min to -1.32 min, P = 0.01, I² = 98%) (S4 Appendix).

1. Discussion

To our knowledge, this was the first meta-analysis to characterize the effect of N₂O in the management of pain in adults in ED. Our meta-analysis combined the results of fourteen RCTs comparing N₂O to placebo, morphine, lidocaine, midazolam plus fentanyl and haematoma block and suggested that N₂O could provide better analgesia than placebo and similar analgesia to other methods with more vomiting and dizziness in adults in ED.

The minimum alveolar concentration of N₂O was 104%, and N₂O was not bound to protein and had low solubility, so that it could enter and exit through the lungs and the patients would not lose consciousness while getting the lowest efficacy anesthesia [3,13-15] Different from opioids, N₂O had no negative effect on respiration and remained the intact of airway reflexes [16]. Studies showed that N₂O, as an NMDA an- tagonist, might be able to inhibit opioid-induced postoperative hyperal- gesia and reduce consumption of opioids [36]. These characteristics suggested that N₂O was better suited for patients who were not suitable for opioids or needed rapid analgesia. In previous studies, N₂O could be operated by trained non-physicians [14], which had certain benefits for patients with insufficient analgesia caused by doctors’ heavy workload in ED. In addition, the anti-anxiety effect of N₂O was beneficial for ED patients.

Fig. 2. Risk of Bias assessment.

The present study provided evidence that N₂O was not significantly different from other analgesic methods in the reduction of pain score or the number of patients with pain relief, suggesting that N₂O could provide adequate analgesia for adults in ED. Sensitivity analysis indicated that N₂O had a significant advantage in reducing the pain score compared with fentanyl. Hamid et al. [29] found that N₂O could provide faster, safer and more effective analgesia than morphine sulfate for acute renal colic. Kambiz et al. [28] suggested that the Muscle relaxation properties of N₂O may make it a greater analgesic effect in synchronized cardioversion than midazolam plus fentanyl. However, in two RCTs [23,24] for patients with upper arm fractures, N₂O was less effective than intravenous regional anesthesia or haematoma block. In the KH et al.’s study [24], the pain score in the N₂O group increased to more than 7 during fracture reduction, indicating that the patient still experienced severe pain. PL Goh et al.

[23] found that although the pain score was higher in the N₂O group

than that in the intravenous local anesthesia group, the type and severity of the fracture might have an impact on the result. Therefore, N₂O can still be regarded as an effective substitute when intravenous local anesthesia is not suitable or contraindicated in ED. Considering N₂O provides both analgesia and sedation, the effectiveness of N₂O versus ketamine, propofol or other sedation options should be evaluated in rigorously designed and adequately powered RCTs in ED in the future.

Although N₂O can be used continuously or as-required [37], in practice it was often used intermittently for fear of side effects. Our meta-analysis suggested that N₂O increased the incidence of vomiting and dizziness. Previous reviews had shown that the most common adverse reaction of N₂O was nausea and vomiting [15]. The potential mechanism of postoperative nausea and vomiting (PONV) was that N₂O was easy to cause bowel extension and might act on dopamine and Opioid receptors in the brain [15]. A large study investigating addition of N₂O to general anesthesia showed that the risk of severe PONV could be reduced by antiemetic prophylaxis [38]. A meta-analysis showed that the exposure of N₂O within one hour had no clinically significant effect on the increased risk of PONV [39]. Therefore, it cannot be considered that N₂O is not suitable for short-term analgesia in ED. Other adverse events re- corded in the included studies included delirium like stat, headache, slimly reduced consciousness, thirst and xerostomia, which usually disappeared after discontinuation rapidly.

Three studies [23-25] comparing N₂O with other analgesic methods investigated duration of the procedure. Pooled results suggested that N₂O significantly shortened the procedure time by 5.73 min (95% CI =

-10.14 min to -1.32 min, P = 0.01). A study investigating the mean

time of recovering consciousness suggested that the Recovery time of N₂O was significantly shortened [28]. Mraovic et al. found that the addition of N₂O to isoflurane anesthesia can reduce the time of recovery [40]. This property has a positive effect on the patients leaving hospital as soon as possible, reducing costs and improving patients’ satisfaction.

Fig. 3. Forest plot for the pain score between the nitrous oxide group and the placebo group.

Fig. 4. Forest plot for the pain score between the nitrous oxide group and the other analgesic method group.

Fig. 5. Forest plot for the number of patients with pain relief between the nitrous oxide group and the placebo group.

Fig. 6. Forest plot for the number of patients with pain relief between the nitrous oxide group and the other analgesic method group.

Fig. 7. Forest plot for vomiting.

Fig. 8. Forest plot for dizziness.

1. Limitations

Seven [23-26,28,29,35] of the fourteen studies included in this meta- analysis had high bias in quality evaluation. The largest risk of bias was the blind setting of patients, doctors and data collectors, which indi- cated that the experimental design of future research should be more perfect. In addition, there were three studies [26,30,31] included the pa- tients with minors over 15 years old. However, we believed that adoles- cents over the age of 15 had good communication skills and the ability to express pain and pain relief, and the cognitive ability of all patients was complete. Furthermore, the outcomes were characterized by a high level of heterogeneity. The ratio of nitrous oxide and oxygen, the Analgesic drug in the control group, cause of pain and population characteristics in the included studies were all the reasons for the heterogeneity.

1. Conclusions

The present meta-analysis suggested that N₂O could provide better analgesia than placebo and similar analgesia to other methods with more vomiting and dizziness in adults in ED. The adverse events were mild and disappeared soon after discontinuation. Therefore, N₂O could be an option for analgesia in adults in ED.

Funding

This study was supported by clinical medical science and technology innovation project of Jinan (Grant number: 202019018; 202019025).

Credit author statement

XYH, ZLJ and YJQ: literature search, data collection, data analysis, and manuscript writing.

WZY: data collection, manuscript writing and critical revision. DZG: Data interpretation, manuscript writing and critical revision. XC: manuscript writing and critical revision.

LYX: manuscript writing and critical revision.

WF and TF: Study design, data analysis, data interpretation, manuscript writing and critical revision.

CRediT authorship contribution statement

Yihui Xing: Writing - original draft, Formal analysis, Data curation. Lingjun Zhou: Writing - original draft, Formal analysis, Data curation. Jianqiang Yu: Writing - original draft, Formal analysis, Data curation. Ziyang Wang: Writing - review & editing, Data curation. Zhiguo Ding: Writing - review & editing, Data curation. Chen Xie: Writing - review & editing, Data curation. Yuxiang Li: Writing - review & editing, Data curation. Fei Wang: Writing - review & editing, Writing - original draft, Supervision, Project administration, Funding acquisition, Data curation. Lu Tang: Writing - review & editing, Writing - original draft, Supervision, Project administration, Methodology, Funding acquisi- tion, Formal analysis, Data curation.

Declaration of Competing Interest

None.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajem.2022.03.028.

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