Ketamine procedural analgosedation before and after introducing nitrous oxide 70 % in a paediatric emergency department

AIMS OF THE STUDY: The spectrum of agents available for procedural analgosedation (PAS) in paediatric emergency departments (EDs) has increased over the last few decades, yet the pharmacological agents most used in our ED are ketamine and nitrous oxide (N2O). The aim of this study was to assess which patient characteristics in an ambulatory setting were associated with physicians selecting N2O 70% or ketamine as the sedating agent in our paediatric ED, after N2O 70% was introduced.


Introduction
Procedural analgosedations (PAS) in paediatric emergency departments (EDs) are challenging.On the one hand, appropriate pain control is of paramount importance to avoid psychological trauma for a child and on the other, several other factors must also be considered: the child's character-istics, the planned procedure, and the ED's resources (manpower, bed space) [1][2][3][4].Although the spectrum of agents available for PAS has increased over the last two decades, our ED mainly uses two pharmacologic agents, ketamine and nitrous oxide (N 2 O) [5][6][7][8][9][10][11][12][13].
Ketamine, a nonbarbiturate anaesthetic with an onset within seconds when applied intravenously, is a noncompetitive N-methyl-D-aspartate (NMDA) and glutamate receptor antagonist with sedative, analgesic, and amnestic properties.It is mainly used for short-term procedures that do not require skeletal muscle relaxation.Ketamine is metabolised via the hepatic system, with a half-life of approximately 45 minutes [7,8].Since the 1990s, it has become one of the most often used sedatives in paediatric EDs because it allows spontaneous respiration due to the maintenance of laryngeal and pharyngeal reflexes and is also associated with respiratory and cardiovascular stimulation [2].Potential serious side effects of ketamine are, amongst others, apnoea and laryngospasms, as well as cardiac and respiratory arrest.Therefore, both close monitoring and highly trained personnel who can manage these complications are essential.In our ED, this PAS is performed exclusively by anaesthesiologists [5,9].Nitrous oxide (N 2 O), a colourless, tasteless and odourless gas with sedative, analgesic, anxiolytic and amnestic effects, has been used in dental-care settings for decades, but was introduced into paediatric EDs only in the 1990s, mainly for minor, painful procedures like placing an intravenous line or suturing a laceration in anxious children [5,9,[11][12][13].For procedures with a high pain score, the analgesic power of N 2 O 50% combined with 50% oxygen is insufficient, so N 2 O 70% was introduced into our ED a decade ago.N 2 O 70% is an almost ideal agent for PAS in children because it is sufficient for most short, painful procedures, and neither an intravenous line nor fasting is required.Furthermore, its onset is rapid and recovery takes only three to five minutes once the gas is withdrawn [13].Adverse events are mainly nausea, vertigo and vomiting.Hence, a trained ED consultant performs these PAS without an anaesthesiologist in our ED [13].
Ketamine and N 2 O 70% are routinely used for sedation in paediatric EDs.However, studies have focused mainly on adverse events and sedation practices [14][15][16].Our local policy, with anaesthesiologists performing ketamine sedations, may not be representative of most paediatric ED practices but, to the best of our knowledge, we are the first to analyse the changes of PAS practice caused by the implementation of N 2 O 70% in a paediatric ED.
The aim of this study was to assess which patient characteristics were associated with physicians selecting N 2 O 70% or ketamine as the sedating agent in our paediatric ED after the introduction of N 2 O 70%.

Patient population
Patients aged 0 to 16 years who received PAS in the ED of the University Children's Hospital Zurich in 2007 (before N 2 O 70% implementation) and in 2016 (after N 2 O 70% implementation) were included in this retrospective, single-centre cohort study.The local ethics board approved this study.

Data collection
Data was collected by querying our outpatient ED database for N 2 O and ketamine.The clinical records of all patients included were reviewed and the following data were collected: demographics (age and gender), indication for PAS, choice of N 2 O or ketamine, whether ketamine had to be chosen because of the insufficiency of N 2 O sedation, adverse events of N 2 O PAS, and who performed the procedure (ED physician or other specialist).
Procedural analgosedation N 2 O was applied through a facemask covering the patient's nose and mouth with a demand valve system, using the Ventyo machine (LINDE Gas GmbH, 4651 Stadl-Paura, Austria).No fasting period or intravenous line was necessary, parents were allowed to be present during PAS, and discharge was possible immediately following the procedure.
In contrast, ketamine PAS required the child to fast and receive an intravenous line.An anaesthesiologist performed the ketamine PAS and monitored the patient during and after the procedure until discharge.The parents were sent out of the room as soon as the child was analgosedated, and then the intervention was performed by either an ED physician or, in potentially more severe cases, a paediatric surgeon.

Statistics
Categorical data were described as frequencies, while continuous variables were described as means with standard deviation (SD).Statistical analyses were performed with IBM® SPSS® statistics version 24.

Results
A total of 1168 children were treated with PAS during the study period and were included in this study, of which 59.8% (699/1,168) were boys.Overall, 53.7% of children received N 2 O 70% and 46.3% ketamine, most frequently for orthopaedic interventions (29.9%), wound suturing (25.9%), burn debridement (15%) and removal of foreign bodies (13.3%) as detailed in table 1.
The overall mean age was 6.3 (± 4.0) years; in the ketamine subgroup, the mean age was 4.6 (± 4.0) years, while in the N 2 O subgroup it was 7.8 (± 3.4) years.Figure 1 3).The rate of N 2 O for the reduction of upper extremity fractures increased from 0% to 90.8% (table 3).Suturing showed a less significant decrease in ketamine PAS; N 2 O PAS increased from 0% to 61.1%, mainly in older children (mean age ± SD: with ketamine PAS, 3.3 ± 3.3 years compared to N 2 O PAS, 6.6 ± 2.9 years) (table 4).Age and the affected localisations were decisive factors as to which PAS was chosen for suturing, as detailed in table 4. Similarly, a shift from ketamine PAS toward N 2 O PAS occurred in burn debridement, but significant differences in mean age and amount of injured skin appeared between the two PAS groups.Children who received N 2 O had a mean age of 5.8 (± 3.2) years compared the PAS in these children were, amongst others, burn debridement (6.5%; 4/62), removal of foreign bodies (4.9%; 3/61), and reduction of upper extremity fractures (1.4%; 3/ 218).
The cost of treatment of a displaced upper-arm fracture with ketamine PAS were approximately twice as high as for N 2 O 70% PAS (CHF 990 compared to CHF 470).Cost analysis showed that the main factor for the higher costs for ketamine PAS was the requirement of more medical personnel compared to N 2 O PAS.

Discussion
This retrospective study analysed the change in PAS for children before and after introducing N 2 O 70% in an ambulatory ED setting, with a shift from ketamine PAS to N 2 O PAS, especially in children older than three years and most significantly for the reduction of displaced upper extremity fractures.
Choosing the best PAS for children in a paediatric ED depends on factors affecting the child, the planned procedure, the ED physician's experience, and the ED's and the institution's resources.First, N 2 O PAS requires a cooperative child breathing strongly enough to open a demand valve system.In our study, this meant that N 2 O PAS was only chosen for 28.5% of children three years and younger.An alternative to a demand valve system is a system with continuous flow, which might lower the possible age limit, but which brings with it the danger of increasing the concentration of N 2 O in the room air above the legally set minimum alveolar concentration (MAC) values for N 2 O [17].Second, N 2 O 70% is ideal for short, painful procedures and therefore it is mainly chosen for reduction of displaced fractures, small burn debridement, abscess incision and removal of foreign bodies, whereas ketamine is more suitable for longer and more painful procedures.It is noteworthy that in 2016, N 2 O 70% PAS was chosen for fracture treatment in over 90% of cases of displaced forearm fractures.Ketamine PAS was chosen when a primary osteosynthesis was indicated, the child was too young for a demand valve system, or was uncooperative about accepting a facemask.A less apparent shift from ketamine to N 2 O 70% occurred in patients with lacerations.Ketamine PAS was administered in 80.6% of lip suturing cases in 2016, because it had been determined that local anaesthesia and anxiolytics were insufficient for this delicate repair.The vermilion border must be precisely repaired, even though lip lacerations are usually slight.However, these lacerations mostly occurred in children too young for N 2 O PAS (2016 data: mean age 2.7 ± SD 2.6), which implies that age was the actual decisive factor for ketamine PAS.Similar results were found for burn debridement in 2016, where ketamine PAS was chosen for the younger children (mean age 2.1 years) and those with larger affected body surface areas (mean 3.2% ± SD 2.4).The third factor concerned the ED physician.An ED physician's experience with PAS as well as the planned procedure probably also influence the decision whether to choose N 2 O or ketamine.This choice is determined by weighing benefits and risks in the context of the child's needs [18].Fourth, the overall picture must be taken into consideration.In our ED, the following factors are considered: ED resources, crowding and the availability of the anaesthesiology team, which performs ketamine PAS.
The fifth factor in choosing the best PAS concerns the institution's resources.A socioeconomic analysis tends towards N 2 O PAS because less medication and fewer medical personnel are required, and there is a faster discharge and a lower risk of complication.In contrast, for ketamine PAS, children must be fasting and have an intravenous line placed.Anaesthesiologists are needed to perform the anaesthesia in our ED, and a place in the recovery ward must be organised.As a consequence, costs for ketamine PAS are approximately twice as high as for N 2 O PAS.
Based on our data, we conclude that alternatives to N 2 O are needed for children younger than three years and for procedures that require longer lasting effects of analgesia in order to improve efficacy and efficiency.For these cases, nasal application of ketamine might be an effective alternative to the intravenous route.Another alternative would be introducing newer pharmacologic agents like dexmedetomidine, which we are planning to include in our ED [19].
This study confirmed that N 2 O 70% PAS is safe in that no serious adverse events occurred.A change from N 2 O PAS to ketamine was documented in 1.8% of all children receiving N 2 O, either because N 2 O PAS was insufficient or because adverse events occurred.

Limitations
Several factors limit the interpretation and generalisation of these results.First, this was a retrospective and singlecentre study.Second, patients and families were not asked by default about the pros and cons of the chosen PAS.Other potential limitations include the lack of data as to why a certain PAS was chosen and whether adverse events during ketamine PAS occurred.
Our local ED setting, which depended on the availability of the anaesthesiology team for ketamine PAS, differs from most ED settings.

Conclusions
The rate of ketamine PAS use shifted to N 2 O PAS, especially in children older than three years and in the patient group with displaced upper extremity fractures.However, in children younger than three years and for interventions like wound suturing and debridement, ketamine PAS was chosen most frequently.
illustrates the variability of the PAS chosen in different age groups in 2016.The use of N 2 O in the age group up to three years was low (28.5%;63/221), in contrast to the other age groups (4-16 years) where it was chosen in 86.7% (561/647) of cases.An increase in PAS with N 2 O and a corresponding decrease in ketamine use was observed from 2007 to 2016 (table 2).The most apparent shifts from ketamine to N 2 O over the study period occurred in the patient group with displaced upper extremity fractures and in patients with lacerations (table

Table 1 :
Characteristics of patients who received nitrous oxide 70% (N 2 O 70%) or ketamine a mean age of 2.1 (± 2.3) years for children who received ketamine.Children who received N 2 O had a mean affected body surface area of 1.6% (± 1.2), while children who received ketamine had a mean affected body surface area of 3.2% (± 2.4).Adverse events, mostly nausea, vertigo and vomiting during and after N 2 O PAS, occurred at a rate of 40%, although no serious adverse events occurred during N 2 O PAS and the satisfaction rate among children and parents was over 95%.The N 2 O PAS regime needed to be changed to ketamine in 1.8% (11/627) of all children who received N 2 O, either because N 2 O PAS was insufficient or because adverse events occurred.These children were mostly boys (81.8%) with a mean age of 7.8 ± 4.5 years.Indications for Figure 1: Procedural analgosedation in different age groups in 2016.Ketamine-ED: Intervention was performed by an ED physician; Ketamine-OR: Intervention was performed in the operation room by a paediatric surgeon (potentially more severe cases).Swiss Medical Weekly • PDF of the online version • www.smw.chPublishedunder the copyright license "Attribution -Non-Commercial -No Derivatives 4.0".No commercial reuse without permission.See http://emh.ch/en/services/permissions.html.to

Table 2 :
Age * Intervention was performed by a paediatric surgeon (potentially more severe cases)

Table 3 :
Procedural analgosedation for reduction of upper extremity fractures and wound suturing in 2007 and 2016 * nitrous oxide 70%; ** emergency department; *** operation room: intervention was performed by a paediatric surgeon (potentially more severe cases)