Hrev_master Abstract In recent years, the nasal route has increasingly been viewed as an alternative option for the delivery of analgesia, especially when the traditional ways are complicated or time-intensive. However, little is known about the value of this intervention in acute pain management in pediatric emergency medicine. This evidence-based analysis review aims to assess the current evidence regarding the use, safety, and effectiveness of intranasal analgesics in acutely painful conditions encountered in Pediatric Emergency Departments (PEDs). A systemic electronic searching of Cochrane library, PubMed, and EMBASE databases from the beginning of each database until October 2018 was conducted using a maximally sensitive search- ing strategy. Only randomized controlled trials (RCTs) or quasi- randomized controlled trials that evaluated the use of intranasal analgesia for acute pain in children in the Emergency Department and published between January 1990 and October 2018 were included. The methodological quality of the trials was assessed using the Grading of Recommendations Assessment, Development, and Evaluation criteria. Risks of bias within each included study were evaluated according to the Cochrane Risk of Bias Tool for RCTs. This review was reported following the Preferred Reporting Items for Systematic Reviews and Meta- Analyses statement. Seven RCTs and one quasi-randomized study met the inclusion criteria. Five studies compared an intranasal analgesic and an alter- native intervention, two compared intranasal fentanyl against ket- amine, and one compared two different concentrations of intranasal fentanyl. All included trials reported reductions in pain scores, especially within the first 10 to 30 minutes post-interven- tion; however, pain reduction was maintained to 60 minutes in only one study. No evidence of significant adverse events was associat- ed with the administration of any intranasal analgesic in any of the included studies. This review identified eight articles that discussed the intranasal analgesia as a possible route of analgesia in the PED. While no paper was entirely perfect, the findings support the idea that intranasal analgesia may be an effective analgesic for the treat- ment of children (3-18 years) with acute moderate to severe pain, and its administration appears to cause minimal adverse effects. Introduction Acute pain is one of the significant symptoms and pervasive source of suffering for children presenting to the Pediatric Emergency Departments (PEDs).1,2 The prevalence of acute pain in children who present to the PED had been reported as presenting complain in 41% of children who transported by emergency ambu- lance to four tertiary referral hospitals in a recent study in Ireland.3 Of 334 children older than four years who studied in another pilot study, 48% had severe pain.1 Acute pain in Emergency Department (ED) can be a result of several medical conditions (trauma, injuries, burn, or painful dis- eases) as well as simple venipuncture and surgical interventions.4 Murphy et al. found that 2071 out of 2635 (78%) of acute pain episodes resulted from traumatic injuries, while non-traumatic conditions reported in 20% of cases.3 It has been recognized that sever unrelieved pain has long-term consequences on a child’s behavior such as increased anxiety, decreased pain tolerance, and fear of future medical visits.5-8 The literature also indicates that children may suffer posttraumatic stress disorder symptoms after painful and stressful procedures in the PED.9 Furthermore, the lack of appropriate and effective anal- gesia in the ED had associated with higher admission rates, more extended hospitalization, and higher cost to patients and organiza- tions.10 Therefore, adequate pain control had recommended in sev- eral clinical practice guidelines in pediatric emergency medi- cine.11,12 Although several advances have been made in improving pedi- atric pain management,13 timely management of acute pain in chil- dren continues to be suboptimal in both prehospital and PED.14-16 Emergency Care Journal 2019; volume 15:8320 Correspondence: Nabil Abdulrahman Aleysae, Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia. Tel. 0126677777, ext. 63516. E-mail: nal-esaei@kfshrc.edu.sa Acknowledgments: the author acknowledges the support of his tutor Dr. Thomas Beattie, University of Edinburgh, for organizing and supervis- ing the course of the project and the article, as well as his encourage- ment in carrying out this college work. Key words: Intranasal; Analgesia; Acute pain; Pediatric emergency medicine. Conflict of interest: the author declares no potential conflict of interest. Funding: none. Received for publication: 31 May 2019. Revision received: 6 July 2019. Accepted for publication: 17 September 2019. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright: the Author(s), 2019 Licensee PAGEPress, Italy Emergency Care Journal 2019; 15:8320 doi:10.4081/ecj.2019.8320 [Emergency Care Journal 2019; 15:8320] [page 97] Is the nasal route a viable option for relieving acute pain in pediatric emergency medicine? A literature review Nabil Abdulrahman Aleysae Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia Non -co mmerc ial us e o nly [page 98] [Emergency Care Journal 2019; 15:8320] The difficulty of assessing pain in young children, the unfamiliar- ity of medical staff with new products and techniques, fear of adverse medication effects, staffing limitations, and time con- straints17,18 are the significant barriers to adequate pain manage- ment in PEDs. Additionally, some healthcare providers still have been believing that neonates and infants feel less pain than adults, making their pain management ineffectively.19 Optimal pain management in children requires both non-phar- macological interventions and adequate administration of pain medications. Different distraction techniques, oral sucrose admin- istration to the neonates, cutaneous stimulation, elevation and immobilization of a fractured limb, and applying protective dress- ings to burns have shown to have a beneficial effect during differ- ent procedures in the PED, especially in younger age groups.20-22 The administration of systemic analgesia is warranted whenever non-pharmacological approaches are insufficient, or not achieved the needed pain relief lonely. The main aim of systemic analgesic administration is the establishment of useful pain relieving at the first attempt through using an appropriate drug, dose, and route without causing more pain.23 Nonsteroidal anti-inflammatory drugs and opioids remain the most commonly used drugs for con- trolling moderate to severe pain in PEDs.24 Multiple options for delivering systemic analgesia have prac- ticed in pediatric medicine, including oral, rectal, topical, subcuta- neous, mucosal, parenteral, and inhalation. Despite having many advantages, these traditional routes are not always appropriate or feasible, particularly in PED and prehospital settings. Therefore, the availability of an alternative way, thereby providing analgesia rapidly and safely is an attractive route. The nasal cavity is an eas- ily accessible vascular bed that has many features making it a love- ly route for analgesic administration. Six arterial branches serve the nasal cavity, which makes it a much-vascularized surface.25 Its venous return drains to the internal jugular vein which in turn flows into the right heart chambers,26,27 enables the intranasal absorbed drug to avoid the gastrointestinal degradation and hepatic first-pass metabolism, resulting in a rapid onset of action similar to those being by intravenous (IV) administration and better than sub- cutaneous (SC), intramuscular (IM), and rectal one.28,29 Moreover, the nasal cavity is lined by a mucous membrane that covered by numerous microvilli and its subepithelial cells are bound by a fen- estrated epithelium, features converting it to a large and suitable area for fast and reliable drug absorption which minimize the lag time associated with oral drug delivery.26,30 Furthermore, unlike parenteral drug therapy, nasal drug administration is a simple, painless, non-invasive, self-used, and convenient method.31 This review aims to assess the current evidence regarding the use, safety, and effectiveness of intranasal (IN) analgesia in the treatment of the children who presented with acute moderate to severe pain to the PEDs. Methods of research Design This literature review was conducted to identify and evaluate all randomized controlled trials (RCTs) and quasi-randomized tri- als (QRTs) that assessed the analgesic efficacy of one or more IN analgesic(s) in children who presented with acute moderate to severe pain. The retrieved studies were not sufficiently homoge- neous to design systemic review and meta-analysis, so, only qual- itative analysis was conducted. This review was reported following the Preferred Reporting Items for Systematic Reviews and Meta- Analyses statement.32 Inclusion and exclusion criteria All RCTs and QRTs that compared one (or more) IN analgesic agent(s) against a placebo, other IN analgesic, or against alterna- tive analgesic intervention for relieving of acute pain of children in PED or prehospital setting, were included. Only articles published in English, conducted in humans, and published between January 1990 and October 2018 were selected. Conference abstracts, case reports, narrative reviews, editorials, comments, dissertations, ani- mal studies, unpublished or unavailable in English, studies not contained sufficient details regarding the primary outcomes; and those evaluated the efficacy of IN analgesia in a setting outside the PED were excluded. The inclusion and exclusion criteria are sum- marized in Table 1. Search strategy A systemic electronic searching of the Cochrane library, PubMed, and EMBASE databases from the beginning of each database until October 2018 was conducted using a maximally sensitive strategy to identify all relevant literature. Search strate- gies for each database were shown in Appendix 1. The search strat- egy was adapted for each database as required, using Boolean operators and wildcards to account for variations across databases. Several keywords including intranasal analgesics, nasal, intra- nasal, analgesia, acute pain, pain, procedural, young child, chil- Review Table 1. Inclusion and exclusion criteria. Item Inclusion criteria Exclusion criteria Comments Time span 01 Jan 1990 - 31 October 2018 Before Jan 1990; after October 2018 - Age limits Aged 1-18 years <1 year; over 18 years One study has a mixed population (children and adults) was excluded Language English Other languages When the full report had not available in English it had been excluded Type of study RCTs and quasi-randomized trials Case reports, retrospective, cohort, Only studies conducted in humans case-control, and narrative review were included Type of publication Full report Conference abstracts, editorials, - comments, dissertations, and unpublished studies Setting Trials conducted in EDs and/or Studies conducted in setting Studies conducted in mixed ED prehospital settings outside the EDs (pediatric and adults) were included RCTs, randomized controlled trials; EDs, emergency departments. Non -co mmerc ial us e o nly [Emergency Care Journal 2019; 15:8320] [page 99] dren, pediatric, emergency department, and pre-hospital setting were used independently as well as in various combinations. Moreover, nasal or intranasal term matching with specific medica- tion including fentanyl, sufentanil, alfentanil, remifentanil, keta- mine, dexmedetomidine, diamorphine, butorphanol as well as buprenorphine were used too. After that, hand-searching of the ref- erence lists of relevant articles was done to identify other potential references and grey literature. Population Children less than 18 years old who presented with an acute pain severity caused by either bone fractures, burns, wounds, emergency medical procedures, or medical illness; who received at least one dose of intranasal analgesia in the PED. This review excluded patients who used IN analgesia for the treatment of post- operative pain in operation rooms, the pain of dental procedures in dental clinics, or as a pretreatment before endoscopies. Patients who received IN analgesics in a setting outside the ED or for indi- cations other than analgesia were also excluded. Outcome measures The primary outcome is to determine if the intranasal delivery of analgesia is as effective as other routes of drug delivery in pro- viding analgesia in the PED through comparison to the reduction in pain as measured by a recognized pain score. The minimum clinically significant differences (MCSD) in pain score, which selected by the authors and considered as the cutoff value for establishing the therapeutic importance of the results, were deemed to be significant when they had achieved. The secondary outcomes were to determine the rate of failure with IN drug delivery as determined by the rate of rescue medica- tion and to compare rates of adverse events with IN drug delivery. Data management, collection, and analysis Once collected, the obtained articles were exported to Mendeley Desktop bibliographic software for storage. After removal of duplicates, each title and abstract of the remaining stud- ies were assessed for relevance. The full copies of all relevant stud- ies were screened and evaluated for selection according to the inclusion criteria. Principles of the Grading of Recommendation, Assessment, Development, and Evaluation system were used to assess the methodological quality of each trial.33 Risks of bias within each included study were evaluated according to the Cochrane Risk of Bias Tool for RCTs.34 The following criteria were taken into consideration: random sequence generation; allo- cation concealment; blinding of personnel, participants and out- come assessment; incomplete outcome data; selective reporting; and other bias. The relevant data were extracted from the selected studies using a pre-specified data extraction form (Appendix 2) which recorded many specified items like the methodological character of the study, participant’s characteristics, inclusion and exclusion criteria, main features of intervention and comparison agents, and relevant outcomes. The descriptive data were tabulated within tables, and after that, the consistent findings brought togeth- er as a narrative review. Results Results of the search The primary search of electronic databases and other sources yielded a total of 363 publications. After the removal of duplicates and screening of the titles and abstracts of all remaining studies, 27 full papers were retrieved for possible inclusion. When the full texts had been examined, 19 articles were excluded, and only eight randomized trials met the inclusion criteria. Figure 1 summarizes the study selection process. This review was performed based on those eight articles.35-42 Included studies were published between 1999 and 2018, and were conducted in Australia (n=4), United State (n=2), and the United Kingdom (n=2). All included studies contained two com- parison arms. Three IN analgesics were evaluated in these clinical trials: fentanyl (INF), diamorphine (IND), and ketamine (INK). Borland (2007),35 Kendal,37 Younge,40 Fenster,41 and Wilson42 com- pared IN analgesics vs alternative interventions, while Graudins38 and Reynolds39 compared INF against INK, and Borland (2011)36 compared two different concentrations of INF. Table 2 showed the main methodology characteristics of included studies. A typically included study asked verbal children to score their pain intensity immediately before the administration of the study drug and then at multiple time points after the intervention. Every subject was shown age-appropriate pain scale and asked to rank his pain by pointing to the face that he feels is most consistent with his current pain level, and verbalizing the number that corresponds to their pain on the numeric rating scale. Pain intensity at each subse- quent follow-up point was compared with the baseline reading to measure the amount of pain reduction. Six studies described the reduction in pain intensity over time as the primary outcome measure while remaining39,40 as a second- ary outcome. With the exception of Fenster et al.,41 all the investi- gators ask the patients, their parents, and/or attending physician/nurse to measured pain intensity at 0-time (baseline) and compared it to several follow-up measurements (e.g., at 5, 10, 15, 20, 30, or 60 minutes) post IN drug administration. Instead, Fenster et al. assigned an Observational Scale of Behavioral Distress–revised (OSBD-R) score to each of the following prede- termined phases of abscess incision and drainage: i) pre-analgesic Review Figure 1. Study selection process. Flow chart of retrieved, exclud- ed and analyzed trials. PED, Pediatric Emergency Department. Non -co mmerc ial us e o nly [page 100] [Emergency Care Journal 2019; 15:8320] Review Ta bl e 2. M et ho do lo gy c ha ra ct er is ti cs o f in cl ud ed s tu di es . St ud y ID /D es ig n/ Se tt in g I nt er ve nt io n S am pl e si ze a nd s am pl in g P op ul at io n G ra de o f e vi de nc e Bo rla nd e t a l., 2 00 7:3 5 Ac tiv e IN F (1 .4 m cg /k g) p lu s 1 m L IV s al in e as p la ce bo n = 67 ; C hi ld re n ag ed 7 -1 5 ye ar s wi th c lin ic al ly de fo rm ed H ig h Do ub le -b lin d RC T in a s in gl e v s Ac tiv e IV M ( 0.1 m g/ kg ) p lu s 1 m L IN s al in e as p la ce bo C on ve ni en t s am pl e c lo se d lo ng -b on e fr ac tu re s. te rt ia ry P ED , A us tr al ia Bo rla nd e t a l., 2 01 1:3 6 Tw o do se s of S IN F (5 0u g/ m L) a t 1 .5 ug /k g vs 2 d os es n = 18 9; C hi ld re n ag ed 3 -1 5 ye ar s wh o pr es en te d to th e ED H ig h Do ub le -b lin de d RC T in a s in gl e o f H IN F (3 00 u g/ m L) a t 1 .5 ug /k g C on ve ni en t s am pl e w ith c lin ic al ly de fo rm ed c lo se d lo ng b on e fr ac tu re s. te rt ia ry h os pi ta l, Au st ra lia Ke nd al l e t a l., 2 00 1:3 7 IN D Sp ra y a t d os e of 0 .1m g/ kg vs IM M a t d os e of 0 .2m g/ kg n= 41 3; C hi ld re n ag ed 3 -1 6 ye ar s wh o pr es en te d wi th Hi gh O pe n- la be l R CT in e ig ht E Ds , Co nv en ie nt s am pl e cl os ed lo ng b on e fr ac tu re s of li m bs . Un ite d Ki ng do m Gr au di ns e t a l., 2 01 5:3 8 I NK a t a d os e of 1 m g/ kg vs IN F at a d os e of 1 .5 ug /k g n= 80 ; C hi ld re n ag ed 3 -1 3 ye ar s an d we ig hi ng le ss th an H ig h Do ub le -b lin d RC T in 2 E Ds , No n- co ns ec ut ive 50 k g, wi th is ol at ed li m b in ju ry . Au st ra lia co nv en ie nt s am pl e Re yn ol ds e t a l., 2 01 7:3 9 IN K at a d os e of 1 m g/ kg vs IN F at a d os e of 1 .5 ug /k g n = 87 ; C hi ld re n ag es 4 -1 7 ye ar s (n = 87 ) wi th a s us pe ct ed Hi gh Do ub le -b lin d RC T, C on ve ni en t s am pl e si ng le e xt re m ity fr ac tu re . Un ite d St at es Yo un ge et a l., 1 99 9:4 0 S in gl e do se IN F at 1 u g/ kg vs IM M ( 0.2 m g/ kg ) n = 47 ; C hi ld re n ag ed 3 -1 0 ye ar s wh o pr es en te d wi th M od er at e A pr os pe ct ive , r an do m ize d, C on se cu tiv e sa m pl in g a cl in ic al fr ac tu re o f t he u pp er o r l ow er li m bs . op en -la be l, pi lo t s tu dy at s in gl e ED , A us tr al ia Fe ns te r e t a l., 2 01 8:4 1 IN F (2 g/ kg ) vs IV M ( 0.1 m g/ kg ) n= 20 ; E ng lis h an d Sp an is h- sp ea ki ng c hi ld re n ag ed 4 -1 8 ye ar s L ow Si ng le -b lin d, R CT in C on ve ni en t s am pl e w ho p re se nt ed w ith a c ut an eo us a bs ce ss re qu ire d a si ng le u rb an P ED , in ci si on a nd d ra in ag e in P ED Un ite d St at es W ils on e t a l., 1 99 7:4 2 IN D at d os e of 0 .1 m g/ kg vs IM M a t d os e of 0 .2 m g/ kg n = 58 ; C hi ld re n ag e 3- 16 ye ar s pr es en tin g to E D wi th li m b fr ac tu re . V er y l ow Q ua si -R CT in s in gl e ED , C on se cu tiv e sa m pl e Un ite d Ki ng do m RC T, Ra nd om ize d Co nt ro lle d Tr ia l; PE D, P ed ia tr ic E m er ge nc y D ep ar tm en t; ED , E m er ge nc y D ep ar tm en t; IN F, In tr an as al F en ta ny l; IV , I nt ra ve no us ; I VM , I nt ra ve no us M or ph in e; IN , I nt ra na sa l; SI NF , S ta nd ar d In tr an as al F en ta ny l; HI NF , H ig h Co nc en tr at io n In tr an as al F en ta ny l; IN D, In tr an as al Di am or ph in e; IM M , I nt ra m us cu la r M or ph in e; IN K, In tr an as al K et am in e. Non -co mmerc ial us e o nly [Emergency Care Journal 2019; 15:8320] [page 101] administration; ii) 10 minutes after analgesic administration but pre-procedural; iii) lidocaine infiltration; iv) skin incision; v) abscess drainage; and vi) 10 minutes after procedure completion. All trials assessed pain intensity by single or combined validated scales. Seven studies reported results as the difference between the median/mean pain scores of both groups at each time point, while one study compared and reported the cumulative percentages of patients’ pain scores over time according to Wong-Baker Faces (WBF) pain scale.37 The participant’s tolerance to the drug admin- istration was reported in four studies,35,37,40,41 and the occurrence of adverse events and assessment of the failure rate of IN analgesia after administration was documented in all included trials. This outcome was reported as a number or percentage of the patient who needs rescue analgesia during the emergency room stay. Patients’ characteristics The patient population in the included trials was heteroge- neous. Sample sizes were varied widely, ranging from 20 to 413 patients. Each of the eight selected studies evaluated IN analgesia in pediatric patients (aged between 3 to 18 years) who had present- ed with moderate to severe acute pain to the EDs. All trials inves- tigated pain in suspected limb fractures except Fenster who studied pain of cutaneous abscess incision and drainage. All the trials reported comparable baseline characteristics and presenting pain between control and intervention arms. Exclusion criteria found to be similar for all included studies (e.g., no consent, head injury or trauma impairing judgment, known allergy to opiates, blocked/traumatized nose, parenteral or IN opioid analgesic use before arrival, participants requiring immediate IV access, and inability to perform pain scoring). Risk of bias in included studies The included trials had various methodological methods (Table 2). Four trials conducted as double-blind, two as open-labeled, one as single labeled, and one as a quasi-RCT. Judgments about each bias item for every study were summarized in Figures 2 and 3. Effects of interventions A summary of the main findings of the included trials is pre- sented in Table 3. Reduction in pain score All included trials reported significant reductions in pain scores especially within the first 10 to 30 minutes post-interven- tion, however, pain reduction was maintained to 60 minutes in only one study for both intervention agents, IN fentanyl (INF) and IN ketamine (INK).38 Borland et al. (2011)36 found an equivalent effect in reducing pain when two doses of standard INF (50 ugs/mL) were compared with 2 doses of highly concentrated (300 ugs/mL) at dose of 1.5 ug/kg, with the trend to increased oral additional agents in the more diluted solution. Each intervention demonstrated a statistical- ly and clinically significant decrease in pain scores (median reduc- tion for both groups 40 mm, P=0.000) over the study time (at 10, 20- and 30-minutes) post initial dose. Some studies comparing INF to parenteral morphine (IV or IM) and reported that INF was an effective alternative to the use of morphine in the management of pain in children who had limb fractures or procedure pain. Both Younge40 and Fenster41 is favor- ing INF against morphine. Younge reported a significant reduction in pain scores at 10 min after INF administration. The median WBF pain score was 1 in the INF group vs 2 in IM morphine (P=0.014), while no significant difference observed in other time points. Despite this analgesic effect of INF, which lasted for 30 min period, the analgesia was not perfect, as only 11% of children were pain-free at 10 min and 22% at 30 min. Likewise, Fenster reported that INF was superior to IV morphine for the procedural analgesia as a whole as well as for the lidocaine infiltration and abscess drainage phases while it was non-inferior during abscess incision and 10 minutes post procedure phases. The total mean OSBD-R was 5.48 in INF vs 19.9 for IVM (mean difference: -13.4, 1-tailed 97.5% CI: −24.24 to −2.67). In contrast, in his high-qual- ity, randomized, and double-blind trial, Borland (2007)35 found no statistically significant differences in Visual Analogue Scale (VAS) Review Figure 2. Risk of bias: review authors’ judgments about each risk of bias item presented as percentages across all included studies. Figure 3. Risk of bias summary: review authors’ judgments about each risk of bias item for each included study. Non -co mmerc ial us e o nly [page 102] [Emergency Care Journal 2019; 15:8320] Review Ta bl e 3. S um m ar y of t he m ai n fi nd in gs o f th e in cl ud ed t ri al s. St ud y ID Pr im ar y ou tc om e Se co nd ar y ou tc om e C om m en ts C on cl us io n M ea su re m en t F in di ng s A r eq ui re m en t f or A n oc cu rr en ce o f re sc ue a na lg es ia a dv er se e ve nt s Bo rla nd et al ., 2 00 7:35 Re du cti on in pa in int en sit y N o s tat ist ica lly si gn ifi ca nt Tw o p ati en ts in th e I VM N o s er iou s a dv er se ev en ts. M CS D de fin ed as a ch an ge IN F p ro vid ed an (IN F v sI VM ) us ing VA S s co re at 0, 5, 10 , 2 0 d iff er en ce s a t e ac h t im e p oin ts. gr ou p r eq uir ed re sc ue No si gn ifi ca nt di ffe re nc e i n p ain sc or e o f 1 3 m ms . an alg es ic ef fe ct a nd 30 m inu te s T he co mb ine d V AS sc or e s ho we d an alg es ia sim ila r t o I VM a s tat ist ica lly si gn ifi ca nt re du cti on at all in te rva ls po st an alg es ia ex ce pt at 30 m in Bo rla nd et al. , 2 01 1:36 Re du cti on in pa in int en sit y N o s tat ist ica lly si gn ifi ca nt di ffe re nc e R es cu e a na lge sia w as gi ve n S ide -e ffe cts w er e m ini ma l. A di ffe re nc e g re ate r t ha n Th e e ffi ca cy of tw o (S IN F v sH IN F) u sin g V AS sc or e a t 0 , 1 0, 20 - at an y t im e p oin ts. in 35 % of pa tie nt s. N o s ign ifi ca nt di ffe re nc e ± 10 m ms in VA S b ein g c lin ica lly c on ce nt ra tio ns of IN F a nd 30 -m inu te s E ac h a ge nt de mo ns tra te d a st ati sti ca lly sig nif ica nt wa s e qu iva len t an d c lin ica lly si gn ifi ca nt de cr ea se in pa in sc or es ov er th e s tu dy ti me Ke nd all et al .,2 00 1:37 Cu mu lat ive pe rc en tag es of pa in P ain sc or es im pr ov ed ov er ti me in bo th N o d iff er en ce be tw ee n N o s er iou s a dv er se ev en ts. L ar ge sa mp le siz e I ND is a sa fe an d e ffe cti ve (IN D vs IM M) s co re s ( WB F s ca le) at g ro up s a nd w er e l ow er in th e I ND gr ou p th e g ro up s F re qu en cie s o f a ll a dv er se ev en ts in ac ut e p ain re lie vin g 0 , 5 , 1 0, 20 , a nd 30 m inu te s a t 5 , 1 0, an d 2 0, bu t n ot af te r 3 0 m inu te s w er e s im ila r Gr au din s e t a l., 20 15 :38 M ed ian pa in re du cti on S im ila r p ain re du cti on s a t a ll p oin ts A dd iti on al an alg es ia wa s g ive n Th e d iff er en ce ra te w as si gn ifi ca nt M CS D de fin ed as a de cr ea se IN K is an ef fe cti ve (IN K vs IN F) (F PS -R or VA S) at 30 m inu te s Re du cti on s e xc ee de d 2 0 m m in 82 % fo r 14 % of IN K gr ou p be tw ee n g ro up s w ith hi gh er in pa in sc or e o f 2 0 m ms an alg es ic fo r a cu te fo r I NK an d 7 9% fo r I NF vs 32 % of IN F in IN K gr ou p s ev er e p ain Re yn old s e t a l., 20 17 :39 M ea n d iff er en ce in pa in re du cti on N o s ign ifi ca nt di ffe re nc e a t 1 6% of pa rti cip an ts ne ed No se rio us ef fe cts . T he di ffe re nc e i n p ain sc or e B ot h I NK an d I NF ar e e ffe cti ve (IN K vs IN F) ( FP S- R or VA S) at 20 m inu te s an y t im e p oin ts. r es cu e a na lge sia in IN K T he cu mu lat ive nu mb er o f 2 0 m ms ha ve ch os en as M CS D; a na lge sic s f or ac ut e p ain No di ffe re nc e i n t he pr op or tio n gr ou p vs 18 % in IN F of si de ef fe cts w as 2. 2 t im es Sm all sa mp le siz e of pa tie nt s a ch iev ing a cli nic all y h igh er in th e I NK gr ou p. sig nif ica nt re du cti on in pa in at 20 m inu te s Yo un ge et al ., 1 99 9:40 Co mp ar ed to th e m ed ian I NF ac hie ve d l ow er pa in sc or es th an IM M O ne ch ild (4 .1% ) r ec eiv ing IN F N o s er iou s a dv er se ef fe cts . M CS D no t d ef ine d; IN F p ro vid es si mi lar an alg es ic (IN F v s I MM ) pa in sc or es (W BF sc ale ) at 10 m in. N o s ign ifi ca nt di ffe re nc e r eq uir ed re sc ue an alg es ia No si gn ifi ca nt di ffe re nc e. Sm all sa mp le siz e e ffe cts to IM M wit h b ett er tol era nc e a t 0 , 5 , 1 0, 20 an d 3 0 m in at ot he r p oin ts B et te r t ole ra nc e f or IN F Fe ns te r e t a l., 20 18 :41 Me an di ffe re nc es in pa in sc or e D iff er en ce be tw ee n t ot al sc or es Fo ur pa tie nt s ( 40 %) re ce ivi ng N o s ign ifi ca nt di ffe re nc e. 1 .8 ch an ge in O SB D- R sc or es IN F i s s up er ior to IV M (IN Fv sI VM ) b et we en th e 2 gr ou ps at 6 tim es (p ro ce du re as a wh ole ) w as − IV M ha d t re atm en t f ail ur es co ns ide re d a s M CS D. fo r r ed uc ing pr oc ed ur al pa in p oin ts us ing O SB D- R sc ale 1 3.4 5 f av or ing IN F S ma ll s am ple si ze No St ati sti ca l d iff er en ce at ab sc es s i nc isi on , an d p os t-p ro ce du ra l p ha se s. Wi lso n e t a l., 19 97 :42 C om pa re d s um me d o f Th e I ND gr ou p s ho we d a la rg er O ne in ea ch gr ou p r eq uir ed N o s ign ifi ca nt ad ve rs e I mp ro pe r r an do mi za tio n. IN D se em s t o b e a n e ffe cti ve (IN D vs IM M) m ed ian re du cti on in pa in sc or e c ha ng e i n t he su mm ed m ed ian s r es cu e a na lge sia e ffe cts w er e n ot ed . M CS D no t d ef ine d a na lge sic in ac ut e p ain ( WB F a nd VA S) at 5, 10 , 2 0, 30 o f t he pa in sc or es bu t n ot si gn ifi ca nt m inu te s IN F, In tr an as al F en ta ny l; IV M , I nt ra ve no us M or ph in e; S IN F, St an da rd In tr an as al F en ta ny l; HI NF , H ig h Co nc en tr at io n In tr an as al F en ta ny l; IN D, In tr an as al D ia m or ph in e; IM M , I nt ra m us cu la r M or ph in e; IN K, In tr an as al K et am in e; V AS , V is ua l A na lo gu e Sc al e; W BF -R , W on g- Ba ke r F ac es -R ev is ed ; F PS -R , Fa ce s Pa in S ca le -R ev is ed ; O SB D- R, O bs er va tio na l S ca le o f B eh av io ra l D is tr es s- Re vis ed ; M CS D, M in im um C lin ic al ly Si gn ifi ca nt D iff er en ce . Non -co mmerc ial us e o nly [Emergency Care Journal 2019; 15:8320] [page 103] scores between the two treatment arms for each time point. However, when the VAS scores were combined (to form an overall score for each time point), he found statistically significant reduc- tions at 5 minutes post analgesia of 20 mm (P=0.000), at 10 min- utes of 4 mm (P=0.012), and at 20 minutes of 8 mm (P=0.000) but no further significant reductions beyond this time point. Two trials studied IN diamorphine (IND) at a dose of 0.1 mg/kg against IM morphine at a dose of 0.2 mg/kg and favored IND. Kendall37 reported that the onset of pain relief was faster in the diamorphine spray group than in the morphine group and found statistically significant lower pain scores in the spray group at 5, 10, and 20 minutes after treatment but not after 30 minutes. Similarly, Wilson42 reported that the IND group showed a broader change in the summed medians of the pain scores than the IM mor- phine group (9 vs 8) at 30 minutes, though this was not statistically significant. When compared head to head, IN ketamine and fentanyl have been found to have similar pain reduction in children with moder- ate to severe pain from limb injury in 2 trials. Graudins et al.38 found similar pain reductions between groups at all points (i.e., 0, 15, 30, and 60 minutes after intervention). At the primary endpoint of 30 minutes, he had found clinically significant reductions in VAS ratings with approximately 80% of subjects in both groups exceeding the defined MCSD of 20 mm. Further, both treatments provided a considerable analgesic effect to 60 minutes post admin- istration. Similarly, Reynolds et al.39 demonstrated no difference in efficacy between the two drugs either at 20 min or at other time points. However, thirty (77%) subjects in the ketamine group and 35 (80%) in the fentanyl group achieved a clinically significant reduction in pain at 20 minutes (risk difference=-3% [95% CI =- 20% to 15%]; P=0.77) but no difference in the magnitude of change in pain score over time between the two treatment groups. A requirement for rescue analgesia All included trials reported the use of rescue analgesia in a pro- portion of 0 to 35.4% of patients who received IN analgesia. Data on the specific rescue agent and protocol used were reported in only five studies35-38,42 and were not specified in most studies regarding the used doses. The majority of studies offered rescue analgesia from 20 min onwards after the intervention. Only Reynolds’s trial presented data on the amount of rescue analgesia consumed by the patients. Borland (2011)36 was the only one who described a statistically significant difference in the number of patients who required res- cue analgesia. In this trail, rescue IV morphine was given to 67 of 189 patients (42 patients [41.1%] received SINF, vs 25 [27.4%] received HINF). The SINF group had significantly (P=0.028) more additional analgesia than HINF. Fenster found that the number of patients requiring rescue analgesia in the IN group was lower as compared to its comparator groups (0 vs 4). However, the sample size of this study was tiny. In contrast, Graudins and Reynolds con- cluded that patients who received IN Fentanyl required more res- cue analgesia than those received IN ketamine but with no statisti- cally significant difference. The rate of rescue analgesia was 32% in INF vs 14% in INK in Graudins’s trial. Fifteen patients in Reynolds study required additional opioid rescue analgesia during the ED stay; seven patients in the ketamine group (16%) and eight patients in the fentanyl group (18%; risk difference=-2% [95% CI=-18% to 14%]). No differences or data reported in the remain- ing studies. An occurrence of adverse events with intranasal drug delivery Based on patients or parental perceptions, tolerance of IN anal- gesic was found to be significantly better than tolerance of intra- muscularly administered morphine in three trials.37,40,42 All includ- ed trials reported a minimum or no side effects for IN analgesia. No one study reported any serious adverse events (e.g., opiate tox- icity) or death. The most common reported side effects were bad taste, drowsi- ness, nausea, vomiting, and itching nose. The frequencies of adverse events were similar between IN analgesia and alternative intervention groups. For example, 24% of patients who received IND spray in the Kendall trial had some adverse events compared to 19% of patients who received IM morphine. Although 84 seri- ous adverse events were reported in this study, all were mild except for one in the spray group that was considered severe (abdominal pain and vomiting). However, two studies reported significantly higher incidences of adverse events when compared IN interven- tions to each other. All patients (100%) of IN ketamine group vs 61% of the IN Fentanyl group in Reynolds trial and 78% vs 40% in Graudins’s trial were found to have some adverse events. Discussion This literature review located and assessed eight published articles (7 RCTs and one QRC) that evaluated the safety and effi- cacy of IN analgesic for acute pain in children in PEDs. Summary of evidence Based on the findings of this review, three IN analgesics found to be safe, have equivalent or superior analgesic effects, and better tolerance than parenteral morphine in children who presented to PED with limb fracture or cutaneous abscess required incision and drainage. Besides, this review found that the associated adverse effects were infrequently reported and, when present, were minor and transient and did not need any intervention. No evidence of significant adverse events (e.g., opiate toxicity, anaphylaxis) or death was associated with the administration of any IN analgesia in any of the included studies. The current evidence seems to show that IN fentanyl, diamor- phine, and ketamine have an accepted efficacy for the treatment of moderate to severe traumatic and procedural pain in the PED. Similar results were also reported in a Cochrane review in 2014.28 Based on three trails, Murphy et al.28 concluded that INF might be an effective analgesic in painful conditions. Likewise, another sys- temic review by Poonai43 supports the result of this review regard- ing the effectiveness of IN ketamine. He concluded that IN keta- mine administration is well tolerated and without serious adverse effects during procedural sedation and analgesia in children. The majority of trials enrolled children aged three years or more with clinically deformed closed long bone fractures. No data in included studies investigate the use of any one of retrieved nasal analgesics in children less than three years. It is important to note that all studies demonstrated equivalence in pain scores reduction at all intervals during the ED stay; howev- er, significant pain relief was not last beyond 10 min,40 20 min,35 and 30 minutes.36,37,42 Though, pain rating reduction was main- tained to 60 minutes in two studies.38,39 Additionally, it is thought that slower absorption of intranasal medications in comparison to IV administration, would most likely make their efficacy slower than IV analgesics, especially 5 minutes post analgesia. However, the results of Borland (2007)35 and Fenster41 studies showed no sta- tistically significant difference in median pain score between the two agents at any of the studies time points, including 5 minutes. Therefore, intranasal analgesia may decrease the time to pain relief Review Non -co mmerc ial us e o nly [page 104] [Emergency Care Journal 2019; 15:8320] and the time to analgesia administration. As the studies comparing IN ketamine and fentanyl analgesia are sparse and limited, existence of 2 high-quality pieces of evi- dence in this review regarding head to head comparisons of IN ket- amine vs IN fentanyl, make us confident to conclude that there is a no significant difference in pain reduction when the various forms of IN analgesia would compare for control of acute pain in PED. However, adverse effects seem to be more frequent with ketamine. As mentioned above, the frequencies of adverse events were limited, and when they occurred were all relatively mild. Based on this finding, we could conclude that the IN analgesia has an accept- able safety profile. However, the majority of included studies have small sample sizes, make this conclusion unconfident. Therefore, a large, multicenter study in children would be required to determine the exact rate of their side effects. Besides, safety studies have not been conducted to look at long-term effects on the nasal mucosa. Due to incomplete data regarding the specific rescue agent used were not specified in most studies, various time points at which rescue was offered, and a lack of enough data on the amount of rescue analgesia consumed by patients, it was unable to evaluate the potential impact rescue analgesia had on the reported outcomes of this review. Even though the majority of studies offered rescue analgesia either at 20 min or 30 min after administration of the intervention drug, this finding suggested that physicians should expect that patients who receive IN analgesia may require to receive rescue analgesia after 30 minutes due to the short duration of action. Further, as two trials35,41 reported that the percentage of patients requiring rescue analgesia in the INF groups was signifi- cantly lower than their comparator groups, it should be noted that those trial used either higher dose (2ug/kg) or concentration (300 mg/mL) of fentanyl. Admittedly, among presented studies, it does not exist a stan- dard dosage per Kg (minimum effective dosage of which would be the suggested one to obtain the best result with less adverse events) in children. Furthermore, also at higher dosages IN therapy remains safe with lower side effects. Quality of included evidence The overall quality of the included evidence ranged from very low to high. Some limitations were noted in the design and imple- mentation of all included studies. Despite Kendall’s trial37 down- graded by (-1) as has a high risk of detection and performance bias, the significance levels for tests of difference in outcomes between groups were upgraded to high quality. Younge’s study40 was limit- ed in design by the open nature of the trial and did not meet all the criteria for a good quality study, suggesting a likely potential source of bias. The comparative efficacy of the two drugs in Reynolds’ study39 was an exploratory measure as the study was not powered to detect a difference in this outcome. Borland (2007)35 used a convenience sample for enrolments that were dependent on the identification of suitable participants at triage. No record was kept of potential participants who were not enrolled so that no con- clusion can be drawn about potential selection bias. Enrolment in Borland (2011)36 was not compulsory but was actively encouraged by study investigators. Not all patients were able to be screened for inclusion in the study, and this might affect external validity. However, based on reported similarities between cohorts of includ- ed and non-included patients, this potential source of selection bias was minimized. Despite prior specific criteria for inclusion, there was potential selection bias based on the need for opiate analgesia. Fenster’s study has a high risk of detection bias, as the treating physician was not blinded to the study drug, and it has significant imprecision due to few participants were enrolled in each arm. Finally, Wilson describes a non-random component in the sequence generation process, the patients were randomized accord- ing to their hospital number, without blinding of participants or outcome assessors, made it at very high risk for selection, perform- ance, and detection bias. Neither indirectness of evidence nor unexplained heterogeneity or inconsistency of results were identi- fied in any included study. The overall risk of publication bias was thought to be low in all included studies. Limitations This literature review has certain limitations. Only trials that were written in the English language were included. To obtain the highest possible internal trial validity, only double-blinded RCTs or quasi-RCT were chosen, this could potentially result in a high trial exclusion rate and might be a limitation of this review. However, in the inclusion of trials with no adequate blinding, the risks of false-negative and false positive results are difficult to assess and could potentially result in an inaccurate conclusion. Further, the majority of the included studies were either open- label, single-blinded, had a small sample size, or conducted in a single center. Another limitation was in the quality of the studies and the use of a single reviewer to grade them. Five of the studies were high quality while remaining studies were either moderate,40 low,41 or very low-quality42 evidence. Furthermore, the authors were not contacted regarding some missed trial information. Due to significant heterogeneity in the methodology and outcomes assessment of the included studies, hence only a narrative synthe- sis of the results was reported. Studies evaluate pain scores applied up to 30 minutes from drug administration and not later. In this way, the antalgic effect of the drug can only be evaluated in the initial acute phase of the pain but not in the following one: comparison, for example, with mor- phine, is applicable only for initial 30 minutes when fentanyl has the fastest action but for the prolonged half-life of morphine its IV or IM action after 30 minutes is probably higher than IN drugs. Therefore, also, evaluation time has to be considered as a limita- tion of the study to the real evaluation of the antalgic effects of drugs. I believe that the findings of this review are valid and widely applicable. However, all included trials were conducted in devel- oped countries. Therefore, the findings may not be generalizable to all PED pediatric patients in all countries. Conclusions This review identified eight articles that discussed the IN anal- gesia as a possible route of analgesia in the PED. While no paper was entirely perfect, the findings support that IN analgesia may be an effective analgesic for the treatment of the children (3-18 years) with acute moderate to severe pain, and its administration appears to cause minimal adverse effects. References 1. Johnston C, Gagnon P, Fullerton M, et al. One-week survey of pain intensity on admission to and discharge from the emer- gency department: a pilot study. J Emerg Med 1998;16:377-82. 2. Friedland L, Pancioli A, Duncan K. Pediatric emergency department analgesic practice. Pediatr Emerg Care 1997;13:103-6. Review Non -co mmerc ial us e o nly [Emergency Care Journal 2019; 15:8320] [page 105] 3. Murphy A, McCoy S, O’Reilly K, et al. A prevalence and man- agement study of acute pain in children attending emergency departments by ambulance. Prehosp Emerg Care 2016;20:52- 8. 4. McGrath P, Walco G, Turk D, et al. Core outcome domains and measures for pediatric acute and chronic/recurrent pain clinical trials: PedIMMPACT recommendations. J Pain 2008;9:771- 83. 5. Hennes H, Kim M, Pirrallo R. Prehospital pain management: a comparison of providers’ perceptions and practices. Prehosp Emerg Care 2005;9:32-9. 6. Pate J, Blount R, Cohen L, Smith A. Childhood medical expe- rience and temperament as predictors of adult functioning in medical situations. Child Health Care 1996;25:281-98. 7. Anand KJ. Pain, plasticity, and premature birth: A prescription for permanent suffering? Nat Med 2000;6:971-3. 8. Kennedy R, Luhmann J, Zempsky W. Clinical implications of unmanaged needle-insertion pain and distress in children. Pediatrics 2008;122:S130-3. 9. Kassam-Adams N. Introduction to the special issue: posttrau- matic stress related to pediatric illness and injury. J Pediatr Psychol 2006;31:337-42. 10. Rupp T, Delaney K. Inadequate analgesia in emergency medi- cine. Ann Emerg Med 2004;43:494-503. 11. Schug S, Palmer G, Scott D, et al. Working Group of the Australian and New Zealand College of Anesthetists and Faculty of Pain Medicine. The pediatric patient. In: Schug SA, Palmer GM, Scott DA, et al., eds. Acute pain management: sci- entific evidence. 4th ed. Melbourne: ANZCA & FPM. pp 409- 514. 12. Fein J, Zempsky W, Cravero J. Relief of pain and anxiety in pediatric patients in emergency medical systems. Pediatrics 2012;130:e1391-405. 13. Baker DW. Joint Commission Statement on Pain Management: The Joint Commission. Oakbrook Terrrace, IL: The Joint Commission; 2012. Available from: https://www.jointcommis- sion.org/joint_commission_statement_on_pain_management/ Accessed: September 28, 2018. 14. Selbst S, Henretig F. The treatment of pain in the emergency department. Pediatr Clin North Am 1989;36:965-78. 15. Probst B, Lyons E, Leonard D. Factors affecting emergency department assessment and management of pain in children. Pediatr Emerg Care 2005;21:298-305. 16. Elder K, Rice S, Dean C, Piper C. Addressing the differences by race in analgesia use among pediatric patients attending emergency departments. J Pediatr 2014;165:434-6. 17. Czarnecki M, Simon K, Thompson J, et al. Barriers to pediatric pain management: a nursing perspective. Pain Manag Nurs 2011;12:154-62. 18. Alexander J, Manno M. Underuse of analgesia in very young pediatric patients with isolated painful injuries. Ann Emerg Med 2003;41:617-22. 19. WHO. WHO Normative Guidelines on Pain Management. Report of a Delphi study to determine the need for guidelines and to identify the number and topics of guidelines that should be developed by WHO. Report prepared by Prof Neeta Kumar. Geneva, Switzerland: World Health Organization; 2007. 20. Pancekauskaitė G, Jankauskaitė L. Paediatric pain medicine: pain differences, recognition, and coping acute procedural pain in the pediatric emergency room. Medicina (Kaunas) 2018;54:94. 21. Oakley E, Barnett P, Babl FE. Backslap versus no back slab for immobilization of undisplaced supracondylar fractures: a ran- domized trial. Pediatr Emerg Care 2009;25:452-6. 22. Mills E, Craig S, Oakley E. Busted! Management of pediatric upper limb fractures: not all that it’s cracked up to be. Emerg Med Australas 2014;26:384-91. 23. College of Emergency Medicine Clinical Effectiveness Committee. Management of pain in children (Rev July 2013). London: The Royal College of Emergency Medicine; 2013. Available from: https://www.rcem.ac.uk/docs/RCEM% 20Guidance/RCEM%20Pain%20in%20Children%20- %20Best%20Practice%20Guidance%20(REV%20Jul%20201 7).pdf Accessed: September 29, 2018. 24. Krauss B, Calligaris L, Green S, Barbi E. Current concepts in the management of pain in children in the emergency depart- ment. Lancet 2016;387:83-92. 25. Gizurarson S. Anatomical and histological factors affecting intranasal drug and vaccine delivery. Curr Drug Delivery 2012;9:566-82. 26. Cauna N, Hinderer K. Fine structure of blood vessels of the human respiratory mucosa. Ann Otol Rhinol Laryngol 1969;78:865. 27. Williams P, Warwick R, eds. Gray’s anatomy. 36th ed. Edinburgh: Churchill Livingstone; 1980. 28. Murphy A, O’Sullivan R, Wakai A, et al. Intranasal fentanyl for the management of acute pain in children. Cochrane Database Syst Rev 2014;10:CD009942. 29. Walbergh E, Wills R, Eckliert J. Plasma concentrations of midazolam in children following intranasal administration. Anesthesiology 1991;74:233. 30. Sarkar MA. Drug metabolism in the nasal mucosa. Pharm Res 1992;9:1-9. 31. Marttin E, Nicolaas G, Schipper J, et al. Nasal mucociliary clearance as a factor in nasal drug delivery. Adv Drug Del Rev 1997;29:13-38. 32. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA state- ment. Ann Intern Med 2009;151:264-9. 33. Guyatt G, Oxman A, Vist G, et al. GRADE: an emerging con- sensus on rating quality of evidence and strength of recom- mendations (Grading of Recommendations Assessment, Development and Evaluation). BMJ 2008;26:924-6. 34. Higgins J, Green S, eds. Cochrane handbook for systematic reviews of interventions version 5.1 [updated March 2011]. The Cochrane Collaboration; 2011. Available from: http://handbook.cochrane.org 35. Borland M, Jacobs I, King B, O’Brien D. A randomized con- trolled trial comparing intranasal fentanyl to intravenous mor- phine for managing acute pain in children in the emergency department. Ann Emerg Med 2007;49:335-40. 36. Borland M, Milsom S, Esson A. Equivalency of two concen- trations of fentanyl administered by the intranasal route for acute analgesia in children in a paediatric emergency depart- ment: a randomized controlled trial. Emerg Med Australas 2011;23:202-8. 37. Kendall J, Barnaby R, Victoria S. A multicenter randomized controlled trial of nasal diamorphine for analgesia in children and teenagers with clinical fractures. BMJ 2001;322:26. 38. Graudins A, Meek R, Egerton-Warburton D, et al. The PICH- FORK (Pain in Children Fentanyl or Ketamine) trial: a ran- domized controlled trial comparing intranasal ketamine and fentanyl for the relief of moderate to severe pain in children with limb injuries. Ann Emerg Med 2015;65:248-54. 39. Reynolds S, Bryant K, Studnek J, et al. Randomized controlled feasibility trial of intranasal ketamine compared to intranasal Review Non -co mmerc ial us e o nly [page 106] [Emergency Care Journal 2019; 15:8320] fentanyl for analgesia in children with suspected extremity fractures. Acad Emerg Med 2017;24:1430-40. 40. Younge P, Nicol M, Kendall J, et al. A prospective randomized pilot comparison of intranasal fentanyl and intramuscular mor- phine for analgesia in children presenting to the emergency department with clinical fractures. Emerg Med 1999;11:90-4. 41. Fenster D, Dayan P, Babineau J, et al. Randomized trial of intranasal fentanyl versus intravenous morphine for abscess incision and drainage. Pediatr Emerg Care 2018;34:607-12. 42. Wilson J, Kendall J, Cornelius P. Intranasal diamorphine for paediatric analgesia: assessment of safety and efficacy. J Accid Emerg Med 1997;14:70-2. 43. Poonai N, Canton K, Ali S, et al. Intranasal ketamine for pro- cedural sedation and analgesia in children: A systematic review. PLoS One 2017;12:e0173253. Review Non -co mmerc ial us e o nly