Open Access Protocol bmjpo: first published as 10.1136/bmjpo-2017-000218 on 24 January 2018. Downloaded from BMJ Protocol for a double blind, randomised Paediatrics Open placebo-controlled trial using ondansetron to reduce vomiting in children receiving intranasal fentanyl and inhaled nitrous oxide for procedural sedation in the emergency department (the FON trial) Emmanuelle Fauteux-Lamarre,1,2 Franz E Babl,1,2,3 Andrew J Davidson,3,4,5 Donna Legge,6 Katherine J Lee,2,3,5 Greta M Palmer,2,3,4 Sandy M Hopper1,2,3 To cite: Fauteux-Lamarre E, ABSTRACT INTRODUCTION Babl FE, Davidson AJ, et al. Introduction Intranasal fentanyl and nitrous oxide Inhaled nitrous oxide (N2O) is used increas- Protocol for a double blind, (N O) can be combined to create a non-parenteral randomised placebo-controlled 2 ingly as a sedative and analgesic in the paedi- procedural sedation regimen for children in the 1 2 trial using ondansetron atric emergency department (PED). N2O to reduce vomiting in paediatric emergency department. This combination of has many advantages that make it an attrac- intranasal fentanyl and N O provides effective pain relief children receiving intranasal 2 tive sedative agent: it has fast onset of action, for more painful procedures, but is associated with a fentanyl and inhaled is administered by a non-parenteral route, nitrous oxide for procedural higher incidence of vomiting than N O alone. Our aim 2 requires a short recovery period, is associ- sedation in the emergency is to assess whether ondansetron used preventatively department (the FON trial). ated with minor adverse effects and has a reduces the incidence of vomiting associated with http://bmjpaedsopen.bmj.com/ BMJ Paediatrics Open intranasal fentanyl and N O for procedural sedation documented safety profile in large paedi- 2018;2:e000218. doi:10.1136/ 2 3–8 compared with placebo. atric case series. However, N O alone does bmjpo-2017-000218 2 Methods and analysis This study is a double blind, not provide adequate analgesia for some randomised placebo-controlled superiority trial. This is common procedures in children, such as frac- 9 Received 15 October 2017 a single-centre trial of 442 children aged 3–18 years ture reduction. Revised 22 November 2017 presenting to a tertiary care Paediatric Emergency Intranasal fentanyl (INF) can be adminis- Accepted 27 December 2017 Department at the Royal Children’s Hospital (RCH), tered with minimal discomfort and delivers Melbourne, Australia, requiring procedural sedation rapid and potent analgesia in children. A recent with intranasal fentanyl and N O. After written consent, 2 meta-analysis found INF to have analgesic eligible participants are randomised to receive efficacy equal to intravenous morphine and ondansetron or placebo along with intranasal fentanyl, identified no serious adverse event following on October 2, 2021 by guest. Protected copyright. 30–60 min prior to N O administration. The primary 2 administration as a single agent.10 INF can be outcome is vomiting during or up to 1 hour after combined with N O to create a non-paren- procedural sedation. Secondary outcomes include: 2 number of vomits and retching during procedural teral regimen for children requiring proce- sedation, vomiting 1–24 hours after procedural sedation, dural sedation and analgesia (PSA). However, procedural sedation duration and associated adverse the only two prospective studies (n=131) using events, procedure abandonment, parental satisfaction INF and high-concentration N2O in combi- and the value parents place on the prevention of nation reported a 20%–30% incidence of vomiting. This trial will allow refinement of a non- vomiting.11 12 This is a much higher vomiting parenteral sedation regimen for children requiring incidence than when N2O is used alone, painful procedures. reported as 2.2%–5.7%.4 6 13 The use of INF in Ethics and dissemination This study has ethics combination with N O would be appealing if For numbered affiliations see approval at the RCH, Melbourne, protocol number 36174. 2 end of article. the incidence of vomiting was lower. However, The results from this trial will be submitted to conferences no strategies to prevent vomiting when using and published in a peer-reviewed journal. INF and N O have been reported and it is not Correspondence to Trial registration number Australian New Zealand 2 routine practice at our institution to admin- Dr Franz E Babl; franz. babl@ Clinical Trials Registry (ACTRN12616001213437). rch. org. au ister an antiemetic before its use. Fauteux-Lamarre E, et al. BMJ Paediatrics Open 2018;2:e000218. doi:10.1136/bmjpo-2017-000218 1 Open Access bmjpo: first published as 10.1136/bmjpo-2017-000218 on 24 January 2018. Downloaded from Although pulmonary aspiration has seldom been 6. Concomitant head injury with concern for concussion reported during procedural sedation in children, or intracranial injury. vomiting is a risk factor for its occurrence.14–16 Vomiting 7. Active illness associated with nausea and vomiting. during procedural sedation can also be disruptive to the 8. Planned use of additional sedatives. procedure, distressing to the patient and the family and potentially lead to procedure abandonment. Ondan- Study intervention Ondansetron setron is a potent antiemetic agent with selective 5-HT3 receptor antagonist activity. Ondansetron is commonly Ondansetron oral syrup (Zofran: Aspen Pharmacare used off-label in the PED to prevent and treat nausea Australia) is stored below 30°C in the original bottle at and vomiting related to gastroenteritis, ketamine seda- room temperature in the RCH clinical trials pharmacy. tion and concussion.17–19 In the PED, ondansetron use It is transferred into labelled oral syringes (5 and 10 mL) for dehydration from gastroenteritis is associated with by a trial pharmacist and stored in a designated secured diminished costs and greater caregiver satisfaction study box in the PED. compared with placebo and standard therapy for gastro- enteritis.20 21 In the current randomised controlled trial, Placebo we set out to assess whether preventative use of ondanse- The placebo syrup has the same appearance, taste and tron can reduce the incidence of vomiting when INF is smell to match the ondansetron oral syrup. The placebo is manufactured by the RCH clinical trials pharmacy combined with N2O for procedural sedation compared with placebo. If successful, the combination of INF and using water, strawberry flavour, sucrose and compound hydroxybenzoate solution. It is transferred into labelled N2O with ondansetron would provide a new management strategy that will add to the current standard of care for matching oral syringes (5 and 10 mL) by a trial pharma- paediatric procedural sedation. cist and stored in the same designated secured study box in the PED. Administration METHODS In the PED, there are two secured study boxes, one desig- Study design and setting nated for the 4 mg (5 mL) doses and the second box with This is a phase III, double blind, placebo-controlled supe- 8 mg (10 mL) doses. The syringe kits are stored in order riority trial of ondansetron for the prevention of vomiting of administration and protected from light. Each syringe associated with PSA using the combination of INF and kit contains a sticker with a randomisation number to N O. The target population is children aged 3–18 years attach to the participant’s case report form (CRF). 2 http://bmjpaedsopen.bmj.com/ requiring PSA for a painful procedure and presenting to Following randomisation, participants receive a single a single tertiary care PED at the Royal Children’s Hospital dose of the study drug according to their weight; patients (RCH), Melbourne, Australia. weighing 15–30 kg are administered a 4 mg dose and patients weighing >30 kg are given an 8 mg dose. In the Eligibility criteria event of vomiting or spitting out of the study drug, the dose Inclusion criteria comprise the following: is not repeated. In the rare event of persistent vomiting 1. Age 3–18 years. following PSA, treating clinicians have the discretion to 2. Weight ≥15 kg. provide a dose of ondansetron to the participant.22 3. Planned PSA with the combination of INF and N2O (potential indications include, but are not limited Study procedures on October 2, 2021 by guest. Protected copyright. to, fracture reduction, laceration repair and abscess The study procedures are summarised in figure 1. drainage). PED doctors, nurse practitioners (NPs) and research 4. Written informed consent provided by a parent or assistants (RAs) are trained to provide and explain the legal guardian. The participant may also provide parent/guardian information sheet (PGIS) to families. consent if he/she is deemed competent. Potential participants are approached after assessment Exclusion criteria comprise the following: by a clinician when the need for procedural sedation 1. Contraindication to receiving INF: opioid allergy and with INF and N2O has been established. The PGIS is acute/chronic nasal problems. provided and explained to the families of potential 2. Contraindication to receiving N2O: severe acute res- participants. When eligibility is confirmed, signed written piratory infection, current asthma exacerbation, possi- informed consent is obtained for each participant prior ble expansion of a gas-filled body cavity and increased to performing any study-specific procedures. Consent is risk of N2O-induced bone marrow suppression. voluntary and free from coercion. At the time of consent, 3. Contraindication to receiving ondansetron: known the investigator, RA or substitute (medical staff or NP) arrhythmia, use of QT-prolonging drugs or allergy to accesses the study drug supply in the PED and admin- any component of the ondansetron or placebo syrups. isters the next available syringe from the weight-appro- 4. Cardiorespiratory instability. priate box to the participant, and documents the syringe 5. Decreased level of consciousness. number on the participant’s CRF. 2 Fauteux-Lamarre E, et al.