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Three Part Question

In [children under 18 years of age] undergoing [ketamine procedural sedation sedation] does the administration of a [prophylactic anti-emetic reduce the incidence of vomiting]?

Clinical Scenario

A 6 year old boy with an angulated forearm fracture presents to your ED. You feel he is a suitable candidate for procedural sedation. Your department’s policy for procedural sedation is IV ketamine 1-2mg/kg. You know that one of the recognised side-effects of ketamine is vomiting and you wonder whether giving prophylactic ondansetron would reduce his chance of vomiting.

Search Strategy

Pubmed, Cochrane library, MEDLINE via OVID and JAMA network searched via the world wide web.
Pubmed and Cochrane library search strategy:
(0-18 years old OR child* OR paed* OR Pediat* OR adolescent OR infant) AND (sedat*) AND (ketamine OR ketalar OR ketanest OR ketaset) AND (metoclopramide OR maxolon OR Ondansetron OR antiemetic OR “selective 5HT3 antagonists” OR zofran 0R ondemet OR ODT OR zuplenz OR setofilm OR anti-emetic OR antiemetic OR antisickness OR anti-sickness) AND (vomit OR vomiting OR emesis OR nausea OR regurgitate)

MEDLINE via OVID 1946 to April Week 1 2018 search Strategy:
(exp Child, Preschool/ or exp Pediatrics/ or exp Child/ or exp Infant/ or exp Adolescent/) AND (exp DEEP SEDATION/ or exp CONSCIOUS SEDATION/) AND (exp KETAMINE/) AND (exp METOCLOPRAMIDE/ OR exp ONDANSETRON/ OR exp ANTIEMETICS/)

Elsevier search strategy:
(child OR paediatric OR children) AND (sedation) AND (ketamine) AND (antiemetic OR metoclopramide OR ondansetron)

JAMA network search strategy:
'sedation children ketamine emesis'

Search Outcome

42 papers found of which 37 irrelevant and 1 of insufficient quality for inclusion

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Lee JS et al July 2014 Republic of Korea	237 children aged 1 to 18 years of age undergoing facial laceration repair in the Emergency Department (ED) received either IM ketamine (4mg/kg) sedation or IM ketamine (4mg/kg) plus oral ondansetron (2, 4 or 8mg depending on age)	Prospective, randomised, open, controlled study (level 2 evidence)	Vomiting in the ED	27.1% of patients in ketamine only group (n=118) and 23.5% of ketamine and ondansetron group (n= 119) vomited in ED (p=0.55)	1. Excluded children in whom a further dose of ketamine was given (considered failure of treatment) 2. Only children <6 recruited 3. Mean age of children in ketamine and ondansetron group was higher than in ketamine only group (p=0.02) 4. Oral ondansetron given at the same time as IM ketamine (which does not take into account the two drugs differing bioavailability)
			Vomiting after discharge	8.5% of patients in ketamine only group (n=118) and 8.4% of ketamine and ondansetron group (n= 119) vomited after discharge (p=1.00)
Lee JS et al September 2012 Republic of korea	338 Children between 4 months and 5 years old undergoing laceration repair in the ED randomised to receive either ketamine (4mg/kg IM) or ketamine (4mg/kg IM ) with metoclopramide (0.4mg/kg IM) or ketamine (4mg/kg IM) with atropine (0.01mg/kg IM)	Prospective, randomised, open-labelled, controlled study (Level 2 evidence)	Vomiting in the ED	Ketamine alone (n=110) 24.5%, ketamine plus atropine (n=138) 21.7%, ketamine plus metoclopramide (n=95) 21.7% (p=0.86)	1. Only children <5y included 2. Further dose of ketamine was considered failure of treatment and patient was excluded from study 3. Potentially pharmacologically suboptimal dose of metoclopramide studied 3. 1,515 pts eligible were not enrolled due to patient refusal or lack of research assistant 4. 30 further were excluded due to repeat ketamine dose or lost to follow up
			Vomiting after discharge	Ketamine alone (n=110) 9.2%, ketamine plus atropine (n=138) 12.5%, ketamine plus metoclopramide (n=95) 15.1% (p=0.44)
Langston WT et al July 2008 USA	Children between 1 and 18years old who received IV ketamine (1mg/kg) for ED procedural sedation randomised to receive IV ondansetron (0.15mg/kg max 4mg) or placebo	Prospective double-blind, randomised, placebo-controlled trial (level 2 evidence)	Vomiting in the ED	Vomiting significantly lower in Ondansetron group (4.7%, n=128) than placebo group (12.6%, n=127) (p=0.02). NNT = 13 (95% CI, 7-91) Subanalysis of children >5 years (n=95): NNT with Ondansetron = 8 (95% CI 5-34)	1. Convenience sampling used and so possible selection bias 2. Glycopyrrolate also given to all patients 3. 1118 patients eligible, 850 not enrolled, 13 withdrew or were excluded and 44 not followed up.
			Vomiting in the ED or after discharge	Vomiting significantly lower in Ondansetron group (7.8%, n=111) compared to placebo group (18.9%, n=100) (p=0.01). NNT = 9 (95% CI, 5-36) Subanalysis of children >5 years (n=85): NNT with Ondansetron = 7 (95% CI 4-30)
Bhatt M et al October 2017 Canada	6295 Children 18 years or younger receiving parenteral procedural sedation to facilitate a painful procedure in the ED	Multicentre prospective cohort study (Level 3 evidence)	Vomiting	Preprocedural antiemetics were significantly associated with decreased odds of vomiting in children receiving IV ketamine (OR, 0.5; 95% CI, 0.4-0.7, p<0.0001) Vomiting was significantly increased in children who had received a preprocedural opioid (OR 1.42; 95% CI, 1.05-1.92, p=0.02)	1. 2,897 eligible patients were not enrolled 2. 465 patients who were enrolled were not included in the final study.

Comment(s)

Vomiting is a well-known side-effect of procedural sedation using ketamine for painful procedures in the ED. Ondansetron is a widely available, regularly prescribed antiemetic in paediatric medicine. Two studies have shown a beneficial effect of ondansetron in paediatric procedural sedation with intravenous ketamine. Langston et al demonstrated that ondansetron significantly reduces emesis in children undergoing intravenous ketamine procedural sedation in children of all ages, with a NNT of 8 in children older than 5 years, although this subanalysis has a wide confidence interval. Bhatt et al (2017) have shown in a multicentre prospective cohort study that use of antiemetic significantly reduces the rate of vomiting in ketamine procedural sedation. This study also showed that the rate of emesis during ketamine procedural sedation is higher in children who have received preprocedural opioids. Two prospective randomised controlled studies showed no significant difference between intramuscular ketamine alone or ketamine with antiemetic, although both studies have significant limitations. Lee (2014) had a statistically significantly higher mean age of children in the ketamine with ondansetron group (older children are more likely to vomit whilst undergoing ketamine sedation) than in the ketamine alone group whilst Lee (2012) only included children younger than 5, an age group in whom vomiting is less common and are less likely to benefit from antiemetic.

Editor Comment

CF

Clinical Bottom Line

Ondansetron should be considered when using intravenous ketamine for procedural sedation in the ED, especially in older children or those who have received preprocedural opioids.

References

1. Lee JS, Jeon WC, Park EJ, Min YG, Kim GW, Jung YS, Choi SC Does ondansetron have an effect on intramuscular ketamine-associated vomiting in children? A prospective, randomised, open, controlled study J Paediatr Child Health 2014 Jul;50(7):557-61
2. Lee JS, Jeon WC, Park EJ, Min YG, Jung YS, Kim GW, Choi SC Adjunctive atropine versus metoclopramide: can we reduce ketamine-associated vomiting in young children? a prospective, randomized, open, controlled study Acad Emerg Med September 2012 ct;19(10):1128-33
3. Langston WT, Wathen JE, Roback MG, Bajaj L Effect of ondansetron on the incidence of vomiting associated with ketamine sedation in children: a double-blind, randomized, placebo-controlled trial Ann Emerg Med 2008 Jul;52(1):30-4
4. 4. Bhatt M, Johnson DW, Chan J, Taljaard M, Barrowman N, Farion KJ, Ali S, Beno S, Dixon A, McTimoney CM, Dubrovsky AS, Sourial N, Roback MG Sedation Safety Study Group of Pediatric Emergency Research Canada (PERC). Risk Factors for Adverse Events in Emergency Department Procedural Sedation for Children JAMA Pediatr 2017 Oct 1;171(10):957-964