Pediatrics

Intranasal ketamine for procedural sedation in children: An open-label multicenter clinical trial

a b s t r a c t

Introduction: There are limited options for pain and distress management in children undergoing minor proce- dures, without the burden of an intravenous line insertion. Prior to this study, we conducted a dose-escalation study and identified 6 mg/kg as a potentially optimal initial dose of Intranasal ketamine.

Objective: To assess the efficacy and safety of intranasal ketamine at a dose of 6 mg/kg for procedural sedation to

repair lacerations with sutures in children in the emergency department.

Methods: We conducted a single-arm, open-label multicenter clinical trial for intranasal ketamine for laceration repair with sutures in children aged 1 to 12 years. A convenience sample of 30 patients received 6 mg/kg of in- tranasal ketamine for their procedural sedation. The primary outcome was the proportion (95% CI) of patients who achieved an effective procedural sedation.

Results: We recruited 30 patients from April 2018 to December 2019 in two pediatric emergency departments in Canada. Lacerations repaired were mostly facial in 21(70%) patients and longer than 2 cm in 20 (67%) patients. Sedation was effective in 18/30 (60% [95% CI 45, 80]) children and was suboptimal in 5 (17%) patients but pro- cedure was completed in them with minimal difficulties. Sedation was poor in the remaining 7 (23%) patients, with 3 (10%) of them required additional Sedative agents. No serious adverse events were reported.

Conclusions: Using a single dose of 6 mg/kg of intranasal Ketamine for laceration repair led to successful sedation in 60% of patients according to our a priori definition. An additional 17% of patients were considered suboptimal, but their procedure was still completed with minimal difficulty.

Clinical trial registration: ClinicalTrials.gov (NCT03053947).

(C) 2023 Published by Elsevier Inc.

  1. Introduction

Pain and distress management is an important component of the care of injured children undergoing minor surgical procedures, such as those with a laceration requiring sutures [1]. It is also a key component for patient and family satisfaction [2]. For some children, nonpharmacological strategies as well as Topical anesthetic can be

Abbreviations: ED, Emergency department; IV, intravenous; INMAD, Intranasal mucosal atomization device; BRT, Behaviour/Response to Treatment rating scale; RSS, Ramsay Sedation Scale; FLACC, Face Legs Activity Cry Consolability; FPS-R, Faces Pain Scale Revised; OSBD-R, Observation Scale of Behavioral Distress- Revised; UMSS, University of Michigan sedation scale; IQR, interquartile ranges.

* Corresponding author at: CHU Sainte Justine, Department of Pediatric Emergency Medicine, 3175 Chemin de la Cote-Sainte-Catherine, Montreal, QC H3T 1C5, Canada.

E-mail address: [email protected] (S. Rached-d’Astous).

sufficient to treat pain and distress related to their laceration repair in the emergency department (ED). However, for younger or particularly distressed children, sedation is often required to facilitate the procedure [3]. In an effort to avoid additional pain and distress caused by intrave- nous (IV) insertion in children which frequently requires several at- tempts [4,5], the intranasal route of medication administration gained popularity in recent years. It is painless for the patient, is simple and rapid to administer by the healthcare provider and requires minimal training and expertise [6,7]. Safe and effective procedural sedation using the intranasal route can significantly improve the care of children in the ED. Intranasal ketamine may be an ideal single agent, as it is also the most commonly used IV procedural sedation medication in children in the ED, [8] with the least associated serious adverse events [9].

In 2017, the evidence for the use of intranasal ketamine in children has been summarized in a systematic review [10] with a Dose range

https://doi.org/10.1016/j.ajem.2023.01.046 0735-6757/(C) 2023 Published by Elsevier Inc.

studied between 3 and 9 mg/kg. In most included studies intranasal ke- tamine was used for Dental procedures, at doses of 5-6 mg/kg, with se- dation reported to be effective between 67% and 94% of the time, without serious adverse events [11-13]. In 2019, Guthrie et al. published a retrospective study of ED patients who received repeated dose of in- tranasal ketamine for up to 2 to 6.5 mg/kg for varioUS procedures [14]. They concluded that intranasal ketamine was effective and safe, but that further studies are needed to determine optimal dosing [14]. Prior to this study, we conducted a dose-escalation clinical trial [15] of intranasal ketamine for a dose ranging from a 3 to 9 mg/kg in children undergoing laceration repair in the ED. We identified 6 mg/kg as the optimal dose from the escalation procedure. The objective of the present study was to assess the efficacy and safety of a 6 mg/kg dose of intrana- sal ketamine for procedural sedation in children aged 1 to 12 years undergoing repair laceration with sutures in the ED.

  1. Methods
    1. Study setting and protocol

We conducted a Phase 2 multicenter, single-arm, open-label inter- ventional clinical trial in two tertiary care pediatric EDs in Canada with 80,000 and 74,000 visits annually. A convenience sample of 30 pa- tients during research nurses hours (8:00 to 20:00 weekdays) received a dose of 6 mg/kg using an intranasal mucosal atomization device (INMAD) to achieve effective procedural sedation for their laceration re- pair with sutures, in addition to Standard care including topical (LET gel: topical Lidocaine 4%, Epinephrine 0.05%, Tetracaine 0.5%) and local an- esthetics (lidocaine or xylocaine), as per the decision of the attending physician. The decision to administer additional sedative agents, if it was felt that intranasal ketamine did not achieve adequate sedation, was at the discretion of the treating physician. The INMAD and the keta- mine were used off label, as this route of ketamine administration in children is not approved on the drug label. The study was approved by Health Canada, and by both institutional review boards, and was regis- tered on ClinicalTrials.gov (NCT03053947) before patient recruitment. Written, informed consent was obtained from the parent or legal guard- ian and a patient assent was also signed, when appropriate. No blinding was done in the context of the study. An independent data and safety monitoring board committee was responsible for overseeing the safe conduct of the trial.

    1. Study population

We included children 1 to 12 years of age with weight between 10 and 30 kg who were brought to the ED with a laceration and requirED procedural sedation for the repair with sutures at the discretion of the treating emergency physician. The 30-kg weight limit (i.e., total of 180 mg ketamine) was determined a priori to limit the total volume of intranasal ketamine to be administered. Exclusion criteria included previous administration of IV, intranasal or oral analgesics other than acetaminophen and/or ibuprofen in the past 24 h, allergy or previous adverse reaction to ketamine, known glaucoma, schizophrenia or psy- chotic event, cognitive impairment, American Society of Anesthesiolo- gist (ASA) physical status class III and higher, known or suspected cardiac disease, Uncontrolled hypertension, kidney disease, pregnancy, active respiratory symptoms and patients who presented to the ED with airway instability, multiple trauma, head injury with loss of con- sciousness or altered mental status, suspicion of Intracranial bleeding or eye rupture, significant nasal trauma, aberrant airways anatomy or active epistaxis.

    1. Intervention

The Ketamine dose (ketamine hydrochloride 50 mg/mL, Sandoz Canada Inc.) was equally divided in two and was administered in the

two nostrils using an INMAD (Wolfe-Tory Medical Inc., Salt Lake City, Utah). A maximum of 1 mL (50 mg) per nostril was delivered at a time. If >2 mL (i.e., >1 mL per nostril) was required as the total keta- mine dose, the volume to be administered was divided in two doses and delivered two minutes apart between the administrations. The re- search nurse assured continuous monitoring with pulse oximetry, blood pressure measurement every 5 min and capnography. The start of procedure was allowed when the patient reached a sedation level of two or more using the Ramsay Sedation Scale (RSS), or after 10 min, whichever occurred first as assessed by the research nurse.

    1. Baseline characteristics

Recorded data included age, weight, sex, past medical history, lacer- ation size, localization and cleanliness, oral analgesics use prior to the procedure, fasting status at the time of medication administration, and the number of sutures done.

    1. Primary outcome

The primary outcome was the proportion (95%CI) of patients with an effective procedural sedation. The goal of the sedation was to reduce distress and safely facilitate the completion of the procedure. We used the suggested definition from the consensus-based recommendations from the Pediatric emergency research Canada and the Pediatric Emer- gency Care Applied Research Network, the Quebec guidelines [16]. It was designed for standardizing terminology in procedural sedation in children, using four criteria (Fig. 1). To assess the first criterion “The cre- ation of conditions necessary to safely facilitate the completion of a pro- cedure through attenuation of pain, anxiety and movement with amnesia or decreased awareness”, no specific measure of patient dis- tress or sedation level was endorsed. We chose to use the Behaviour/Re- sponse to Treatment rating scale (BRT) to evaluate the ease of procedure completion, Supplementary Table 1, combined with the RSS

[17] to assess the depth of sedation. The RSS is a widely used sedation scale and has been validated for the pediatric population including in the ED [17] but only reflect the sedation level and not the conditions to safely facilitate the completion of the procedure. Although not a val- idated scale, we decided to use the BRT scale as it is simple and describes patient disposition relating to completion of a procedure which is not reflected by other validated observational scales developed to assess pain and distress scale such as the Face Legs Activity Cry Consolability (FLACC) and the Observation Scale of Behavioral Distress Revised (OSBDR). The BRT scale has also been previously used in other intrana- sal ketamine studies [12,18]. For criteria C, the definition of a serious ad- verse events was an event that stopped the procedure, led to permanent complication, unplanned admission or prolonged observation in emer- gency department.

The primary outcome was assessed by one of two trained research nurses at each site for all criteria, except for the BRT evaluation that was a consensus between the treating physician and the trained re- search nurse was used. If no consensus was reached, the worst score would have been recorded, but this did not happen.

See Fig. 1 for a detailed definition of primary outcome.

    1. Secondary outcome

Secondary outcome measures included the evaluation of pain and distress. This was performed by the research nurse performing continu- ous evaluation of the patient before, during and after the procedures using age-appropriate scales at pre-specified times. We used the Face Legs Activity Cry Consolability (FLACC) scale for pain evaluation, the Faces Pain Scale Revised (FPS-R) for patient reported pain if patients were 4 years and older and the Observation Scale of Behavioral Distress Revised (OSBDR) for distress evaluation. Moreover, in addition to the RSS, the University of Michigan sedation scale (UMSS) was used for

Fig. 1. Detailed definition for effective procedural sedation primary outcome definition from the consensus-based recommendations from the Pediatric Emergency Research Canada and the Pediatric Emergency Care Applied Research Network, the Quebec guideline.

sedation evaluation, as a comparison. The detailed timeline of scales used is available in the Supplementary Fig. 1.

Other secondary outcomes included time to recovery from medica- tion administration (defined as time to return to a UMSS score of zero), side effects at administration as reported by patients or parents, and other adverse events not requiring an intervention. Also, the satis- faction of providers, parents, and patients aged 6 years and older, was evaluated after the procedure using a conventional 5-point Likert scale. A telephone follow-up call was done the next day to assess post-discharge adverse events.

    1. Data analysis

Baseline characteristics were summarized using percentages of cat- egorical or binary data. Medians with interquartile ranges (IQR) for non-normal continuous data describe the study population. The propor- tion of missing data was reported, when present, for all outcomes. The primary outcome, the proportion (two-sided 95%CI) of patients with an effective procedural sedation, was calculated using the Wald test. Analyses were conducted in Stata/SE 16.1.

No hypothesis testing was done given it is a single arm, open-label drug trial with no comparative treatment group. Also, the small number of patients prevents us from doing formal comparison with hypothesis testing between patients with successful and unsuccessful sedation.

  1. Results
    1. Study participants

From April 2018 through December 2019, a total of 30 children were enrolled in the two pediatric EDs and all received 6 mg/kg of in- tranasal ketamine for their laceration repair with sutures. The indi- vidual baseline characteristics of patients are reported in Table 1. Twenty-two (73%) children were male with a median age of 3.2 years (IQR, 1.9, 4.7) and weight of 15.5 kg (IQR, 12.9, 17.7). None of the patients had significant past Medical issues; 27 were classified as ASA physical status I, and three as ASA physical status II, with known asthma. Twenty-five (83%) lacerations were described as clean, and 21 (70%) involved the face. Twenty (67%) lacerations were longer than 2 cm. Eventually, laceration repair required sutures in all but one patient. For the latter, a change in the initial plan from suture to glue instead was done after the patient received the intra- nasal ketamine.

The median total volume of intranasal ketamine administered was

1.8 (IQR 1.5, 2.1) mL. >2 mL of ketamine was required in 8/30 (27%) pa- tients. The median time from ketamine administration to the beginning of the procedure was 18 (IQR, 13-25) minutes and median procedure time in patient who received only intranasal ketamine was 11 (IQR, 9-19) minutes.

Table 1

Demographic and baseline characteristics of study population.

Table 2

Effective procedural sedation outcome and criterions to fulfill the definition.

Intranasal ketamine 6 mg/kg (n = 30)

Intranasal ketamine 6 mg/kg (n = 30)

Age (yrs)

Effective procedural sedation, n (%,95%CI)

median (IQR)

3.2 (1.9, 4.7)

Yes

18 (60 [45,85])

range

1.2-10.7

Behaviour/Response to Treatment rating scale, n

Age group, n (%)

(%)

1-2 yrs

8 (27)

5 – Excellent

11 (37)

2-3 yrs

6 (20)

4 – Good

7 (23)

3-4 yrs

6 (20)

3 – Fair

5 (17)

> 4 yrs

10 (33)

2 – Poor

4 (13)

Male gender, n (%)

22 (73)

1 – Prohibitive

2 (7)

ASA physical status, n (%)

Maximal Ramsay score, n (%)

1

27 (90)

1- Anxious and agitated or restless or both

5 (17)

2

3 (10)

2- Cooperative, oriented, and tranquil

19 (63)

Liquid fasting, n (%)

29

3- Respond to commands only

3 (11)

< 2 h

9 (31)

4- Brisk response to a light glabellar tap or loud

2 (7)

2-4 h

6 (21)

auditory stimulus

4-8 h

12 (41)

Unpleasant recall of sedation, n (%)?

6

>8 h

2 (7)

Yes

0 (0)

Solid fasting, n (%)

No

6 (100)

< 2 h

8 (27) Physical restriction, n (%)

2-4 h

14 (47)

Movement redirection

10 (33)

4-8 h

7 (23)

Light restriction

4 (13)

>8 h

1 (3)

Important restriction

7 (23)

Laceration, n (%)

Serious adverse event, n (%)

size

Yes

0 (0)

<2 cm

11 (37)

No

30 (100)

2-5 cm 17 (57)

>5 cm 2 (7)

Region

Head and neck 22 (73)

Lower limb 5 (17)

Upper limb 3 (10)

local anesthesia, n (%)

Topical 15 (50)

Injected 19 (63)

Sutures, n (%)

0

1 (3)

1-3

15 (50)

4-6

8 (27)

7-10

6 (20)

    1. Primary outcome

Procedural sedation using 6 mg/kg of intranasal ketamine was ef- fective in 18 (60%; 95% CI, 42% to 78%) patients. In 5 (17%) patients, the sedation was suboptimal, but enabled procedure completion with minimal difficulties. Sedation was poor in the remaining 7 (23%) patients from whom 3 (10%) required additional sedative agents (one patient received additional Intranasal fentanyl and mid- azolam, while the other two were administered intravenous keta- mine). Effective procedural sedation outcome and definition criteria are reported in Table 2.

    1. Secondary outcomes

A sedative effect was seen in most of patients with maximum UMSS score reached during the procedure of 1 (minimally sedated: tired/ sleepy, appropriate response to verbal conversation, and/or sound) in 15 (50%) patients, of 2 (moderately sedated: somnolent/sleeping, easily aroused with light tactile stimulation or a simple verbal command) in 6 (20%) patients and of 3 (deeply sedated: deep sleep, aroused only with significant physical stimulation) in 3 (10%) patients. The remaining 6 (20%) patients stayed at a UMSS of 0 (awake and alert). Fig. 2 summa- rizes the FLACC, OSBDR, UMSS, and RSS distributions across time.

During procedure, two (7%) patients experienced a desaturation with one of them who required an intervention; oxygen supplementa- tion and head repositioning. After the procedure two (7%) patients vomited. Other adverse events and side effect at the intranasal ketamine administration are reported in Table 3. Nystagmus was observed in 22

* 6 patients aged 6 years old or older were able to answer the question.

(73%) patients; of them 15 (68%) had an effective sedation. The median time to return to baseline status with a UMSS score of zero was 49 (IQR, 61-76) minutes.

Individual parent and Physician satisfaction evaluations with a 5-point Likert scale are reported in Fig. 3. A total of 21/28 (75%) of phy- sicians would reuse intranasal ketamine at the same dose and 20/30 (67%) strongly agreed or agreed that the sedation was effective. Among parents, 25/28 (89%) strongly agreed or agreed that they were satisfied with the sedation. Of the four patients aged 6 years old and above, two strongly agreed, one agreed that they liked how their lacer- ation was repaired and one did not answer. At the 24 h phone follow-up call, no patient had to seek medical attention since discharge and 25/29 (86%) of parents would prefer similar procedural sedation for their child, if needed in the future. Vomiting after discharge was reported in 5 (17%) patients leading to a total of 6 (20%) who vomited either in the ED or within 24 h post discharge. Other adverse events at 24 h after discharge are reported in Table 3.

  1. Discussion

The results of this study suggest that a single dose of 6 mg/kg of in- tranasal ketamine using a 50 mg/mL solution administered via an INMAD can effectively facilitate the completion of a laceration repair using sutures in 60% of children, according to the Quebec guidelines from the Pediatric Emergency Research Canada and the Pediatric Emer- gency Care Applied Research Network consensus-based recommenda- tions definitions. The sedation was suboptimal, but permitted the completion of the procedure with minimal difficulties in another 17%, but was inadequate in 23% and required the additional sedative agents in 10% of patients. Parental and physician satisfaction with intranasal ketamine was high, and most parents would support this sedation for their child if needed again.

Comparing our findings to the available literature on intranasal keta- mine, the proportion of effective sedation in our cohort appears to be on the lower range. Most studies on intranasal ketamine for procedural se- dation were randomized control trials for brief dental procedures with 76 to 94% adequate sedations at doses of 5 to 6 mg/kg [11-13,19]. How- ever, the delivery system for the ketamine administration and the

Image of Fig. 2

Fig. 2. Charts of sedation scores, pain evaluation scores and distress evaluation score over time for patients (n = 30).

concentration used was not detailed in most of those studies, increasing the risk of heterogeneity of the intervention. Also, there was significant heterogeneity in the measurements of effectiveness of sedation [10]. Furthermore, the type of dental procedures was not specified in the studies. A tooth extraction and a laceration repair with several sutures potentially have different durations, different requirements in terms of target level of procedural sedation or cooperation, that may further limit the comparison.

Table 3

Side effect at administration and adverse events.

Intranasal ketamine 6 mg/kg (n = 30)

Side effects at administration, n (%)

Cough 1 (3)

Bad taste 2 (7)

Nasal burning 2 (7)

Sneezing 1 (3)

Discomfort 2 (7)

Adverse events during the procedure, n (%)

Desaturation 2 (7)

Adverse events after the procedure, n (%)

Vomiting 2 (7)

Nausea 1 (3)

Dizziness 1 (3)

Adverse events after hospital discharge at the 24 h phone call, n (%)

Nausea 3 (10)

Vomiting 5 (17)

Regurgitation 1 (3)

Dizziness 2 (7)

Headache 1 (3)

Imbalance 2 (7)

Only three studies assessed intranasal ketamine for laceration repair. Cristoforo and al. used different terminology and outcomes than in our study, but they conclusions seems to align with our results as their 5 mg/kg dose was appropriate in 80% of patients for anxiolysis [20]. Tsze and al. favored 9 mg/kg to 3 and 6 mg/kg dose, but the level of sedation required to considered an adequately sedated (ramsay score of 4,5 or 6) was higher, representing deeper sedation level than in our study [21]. The study by Guthrie et al. was the only study which investigated intranasal ketamine redosing. It is a retrospective study of pediatric ED patients, aged 6 months to 18 years, who underwent various procedures using intranasal ketamine. Patients received an initial dose of 2 to 5 mg/kg with three optional additional doses of 0.5 mg/kg. The study re- ported an overall treatment failure rate, i.e., progression to procedural sedation with IV medications of only 7.7%. This rate of progression to procedural sedation is comparable to our 10% of patients who needed additional sedative agents, despite methodological differences.

To our knowledge, this study was one of the first studies to refer to the consensus-based recommendations for standardizing terminology in procedural sedation from Pediatric Emergency Research Canada and the Pediatric Emergency Care Applied Research Network, the Quebec guidelines, for the efficacy of sedation. We found that the scales we used to assess their definition of the first criterion (BRT for the ease of procedure completion and RSS for the depth of sedation) applied well to our population and provided good representation of how effective the procedural sedation went. However, as the BRT was not validated, we wonder if classifying the four patients whose BRT of 3 (Crying with minimal disruption to treatment. Treatment completed with min- imal difficulties.) and fulfilled all other criteria (no unpleasant recall of sedation if obtainable, no serious adverse event and no active resistance of physical restrain was needed) as ineffective was too strict. This poten- tial misclassification bias may have underestimated the efficacy of the

Image of Fig. 3

Fig. 3. Parent and physician satisfaction evaluation using a 5-point likert scale.

intranasal ketamine in our study. As this study is a convenience sample single arm trial, the results are exploratory, and conclusions may not be generalizable to the ED population.

The administration of intranasal ketamine has some limitations. There is no labeled or widely accepted weight- or age-based recom- mended volume to account for the change in nasal mucosa surface with growth. Generally, smaller volumes of around 0.2 to 0.3 mL are considered optimal when medications are administered using an INMAD, as volumes higher than 1 mL per nostril are less reliably absorbed due to limited surface area for absorption [7]. We used the 50 mg/mL concentration for generalizability, as the concentration 100 mg/mL is not marketed in Canada. To deliver a 6 mg/kg dose with the 50 mg/mL concentration, we administerED volumes close to 1 mL per nostril. It is possible that the intranasal absorption was limited by vol- ume and that some of the ketamine was swallowed and was absorbed through the gastrointestinal tract with slower peak of action [22].

  1. Conclusion

A single dose of 6 mg/kg of intranasal ketamine using an INMAD safely facilitated the completion of laceration repair in 60% of pediatric patients according to our a priori definition. An additional 17% of pa- tients were considered suboptimal, but their procedure was still com- pleted with minimal difficulty. Although the efficacy is somewhat limited, it is a safe option that can be a valuable alternative, especially

when looking at the current intranasal options for procedural sedation. It circumvents the burden of an IV-line placement, which may require several attempts and thus be unproportionally painful and anxiety- provoking compared to the procedure itself. Larger study to validate our finding as well as generalization of this route of administration in children undergoing other brief or minor surgical and diagnostic proce- dures calls for future research.

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajem.2023.01.046.

Funding sources

The study received financial support from Sainte-Justines Youth Challenge for Traumatology by the CHU Sainte-Justine Foundation.

Data sharing statement

Deidentified individual participant data (including data dictionaries) will be made available, in addition to study protocols, and the informed consent form. The data will be made available upon publication to re- searchers who provide a methodologically sound proposal for individ- ual participant data meta-analysis for proposal submitted up to 5 years following publication. Proposals should be submitted to soha. [email protected]

Authors contribution

Soha Rached-dAstous, Benoit Bailey and Evelyne D.Trottier have contributed to the study concept and design, acquisition of the data, analysis and interpretation of the data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, and acquisition of funding.

Yaron Finkelstein had contributed to the acquisition of the data, interpretation of the data and critical revision of the manuscript for important intellectual content, and acquisition of funding.

Christopher Marquis, Denis Lebel, Marie-Pier Desjardins has contrib- uted to the study concept and design, critical revision of the manuscript for important intellectual content.

All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

CRediT authorship contribution statement

Soha Rached-dAstous: Writing – review & editing, Writing – origi- nal draft, Validation, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization. Yaron Finkelstein: Writing – review & editing, Methodology, Investigation, Funding acqui- sition. Benoit Bailey: Writing – review & editing, Supervision, Method- ology, Investigation, Funding acquisition, Conceptualization. Christopher Marquis: Writing – review & editing, Resources, Method- ology, Investigation, Conceptualization. Denis Lebel: Writing – review & editing, Resources, Project administration, Funding acquisition, Con- ceptualization. Marie-Pier Desjardins: Writing – review & editing, Methodology, Funding acquisition. Evelyne D. Trottier: Writing – review & editing, Validation, Supervision, Project administration, Methodology, Investigation, Funding acquisition.

Declaration of Competing Interest

The authors have no conflicts of interest relevant to this article to disclose.

References

  1. Trottier ED, Dore-Bergeron MJ, Chauvin-Kimoff L, Baerg K, Ali S. Managing pain and distress in children undergoing brief Diagnostic and therapeutic procedures. Paediatr Child Health. 2019;24(8):509-35. https://doi.org/10.1093/pch/pxz026.
  2. Magaret ND, Clark TA, Warden CR, Magnusson AR, Hedges JR. Patient satisfaction in the emergency department – a survey of pediatric patients and their parents. Acad Emerg Med. 2002;9(12):1379-88. http://www.ncbi.nlm.nih.gov/pubmed/12460 841.
  3. Kumar K, Ali S, Sabhaney V, Trottier E, Drendel A, Bhatt M, et al. Anxiolysis for lacer- ation repair in children: a survey of pediatric emergency providers in Canada. CJEM. 2022;24(1):75-83. https://doi.org/10.1007/s43678-021-00210-y.
  4. Rauch D, Dowd D, Eldridge D, Mace S, Schears G, Yen K. Peripheral difficult venous access in children. Clin Pediatr (Phila). 2009;48(9):895-901. https://doi.org/10. 1177/0009922809335737.
  5. Lininger RA. Pediatric peripheral i.v. insertion success rates. Pediatr Nurs. 2003;29

(5):351-4. https://www.ncbi.nlm.nih.gov/pubmed/14651305.

  1. Fein JA, Zempsky WT, Cravero JP, Committee on Pediatric Emergency M, Section on A, Pain M, et al. Relief of pain and anxiety in pediatric patients in emergency medical systems. Pediatrics. 2012;130(5):e1391-405. https://doi.org/10.1542/peds.2012- 2536.
  2. Wolfe TR, Braude DA. Intranasal medication delivery for children: a brief review and update. Pediatrics. 2010;126(3):532-7. https://doi.org/10.1542/peds.2010-0616.
  3. Green SM, Roback MG, Kennedy RM, Krauss B. Clinical practice guideline for emer- gency department ketamine dissociative sedation: 2011 update. Ann Emerg Med. 2011;57(5):449-61. https://doi.org/10.1016/j.annemergmed.2010.11.030.
  4. Bhatt M, Johnson DW, Chan J, Taljaard M, Barrowman N, Farion KJ, et al. Risk factors for adverse events in emergency department procedural sedation for children. JAMA Pediatr. 2017;171(10):957-64. https://doi.org/10.1001/jamapediatrics.2017.2135.
  5. Poonai N, Canton K, Ali S, Hendrikx S, Shah A, Miller M, et al. Intranasal ketamine for Procedural sedation and analgesia in children: a systematic review. PLoS One. 2017; 12(3):e0173253. https://doi.org/10.1371/journal.pone.0173253.
  6. Bahetwar SK, Pandey RK, Saksena AK, Chandra G. A comparative evaluation of intra- nasal midazolam, ketamine and their combination for sedation of young uncooper- ative pediatric dental patients: a triple blind randomized crossover trial. J Clin Pediatr Dent. 2011;35(4):415-20. https://www.ncbi.nlm.nih.gov/pubmed/2204 6702.
  7. Pandey RK, Bahetwar SK, Saksena AK, Chandra G. A comparative evaluation of drops versus atomized administration of intranasal ketamine for the procedural sedation of young uncooperative pediatric dental patients: a prospective crossover trial. J Clin Pediatr Dent. 2011;36(1):79-84. http://www.ncbi.nlm.nih.gov/pubmed/22 900449.
  8. Surendar MN, Pandey RK, Saksena AK, Kumar R, Chandra G. A comparative evalua- tion of intranasal dexmedetomidine, midazolam and ketamine for their sedative and analgesic properties: a triple blind randomized study. J Clin Pediatr Dent. 2014;38(3):255-61. http://www.ncbi.nlm.nih.gov/pubmed/25095322.
  9. Guthrie AM, Baum RA, Carter C, Dugan A, Jones L, Tackett T, et al. Use of intranasal ketamine in pediatric patients in the emergency department. Pediatr Emerg Care. 2019. https://doi.org/10.1097/PEC.0000000000001863.
  10. Rached-d’Astous S, Bailey B, Marquis C, Lebel D, Desjardins MP, Trottier ED. Lacera- tion repair using intranasal ketamine: a phase 2 dose escalation clinical trial. CJEM. 2021. https://doi.org/10.1007/s43678-021-00235-3.
  11. Bhatt M, Kennedy RM, Osmond MH, Krauss B, McAllister JD, Ansermino JM, et al. Consensus-based recommendations for standardizing terminology and reporting adverse events for emergency department procedural sedation and analgesia in children. Ann Emerg Med. 2009;53(4):426-35. e4. https://doi.org/10.1016/j. annemergmed.2008.09.030.
  12. Lozano-Diaz D, Valdivielso Serna A, Garrido Palomo R, Arias-Arias A, Tarraga Lopez PJ, Martinez Gutierrez A. Validation of the Ramsay scale for invasive procedures under deep sedation in pediatrics. Paediatr Anaesth. 2021;31(10):1097-104. https://doi.org/10.1111/pan.14248.
  13. Singh C, Pandey RK, Saksena AK, Chandra G. A comparative evaluation of analgo- sedative effects of oral dexmedetomidine and ketamine: a triple-blind, randomized study. Paediatr Anaesth. 2014;24(12):1252-9. https://doi.org/10.1111/pan.12493.
  14. Abrams R, Morrison JE, Villasenor A, Hencmann D, Da Fonseca M, Mueller W. Safety and effectiveness of Intranasal administration of sedative medications (ketamine, midazolam, or sufentanil) for urgent brief pediatric dental procedures. Anesth Prog. 1993;40(3):63-6. https://www.ncbi.nlm.nih.gov/pubmed/7645790.
  15. Cristoforo T, Gonzalez D, Bender M, Uy G, Papa L, Ben Khallouq BA, et al. A pilot study testing intranasal ketamine for the treatment of procedural anxiety in children un- dergoing laceration repair. J Child Adolesc Trauma. 2022;15(2):479-86. https:// doi.org/10.1007/s40653-021-00402-9.
  16. Tsze DS, Steele DW, Machan JT, Akhlaghi F, Linakis JG. Intranasal ketamine for pro- cedural sedation in pediatric laceration repair: a preliminary report. Pediatr Emerg Care. 2012;28(8):767-70. https://doi.org/10.1097/PEC.0b013e3182624935.
  17. Malinovsky JM, Servin F, Cozian A, Lepage JY, Pinaud M. Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth. 1996;77(2):203-7. http://www.ncbi.nlm.nih.gov/pubmed/8881626.