Clinical trial NCT02828566: Intranasal Ketamine for Procedural Sedation
Official title: Intranasal Ketamine Versus Intravenous Ketamine for Procedural Sedation in Children: a Multi-centre Randomized Controlled Non-inferiority Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Bone Fractures
Dislocations
Lead sponsor: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
Sponsor class: OTHER
First posted: 2016-07-11
Enrollment: 470
Sex: ALL
Minimum age (years): 4
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will examine the effectiveness of intranasal (IN) ketamine compared to standard intravenous (IV) ketamine administration for simple reductions of orthopaedic injuries in the paediatric population. The aim is to assess if IN administration is equivalent to the current standard of care, IV. The population to be studied is children 4-17 years of age who require a simple orthopaedic reduction. Following a double dummy approach to overcome the difficulty in masking interventions, each participant will receive both IV and IN interventions, only one of which will be the real drug. Procedural sedation and analgesia (PSA) will be assessed using the Dartmouth Operative Conditions Scale (DOCS).

Detailed description: Randomization and concealment of allocation will be pharmacy-controlled using a computerized central randomization service. The treating physician, bedside nurse, research assistant, and participant will be blinded to the intervention. Eligible participants will be randomized in a 1:1 allocation ratio with a stratified block design of four or six to either (1) IN ketamine (each single dose, 10 mg/kg prepared in 0.9% NS in 3 mL syringe and atomizer, to a maximum of 8 mL) PLUS IV 0.9% NS 0.02 mL/kg or (2) IV ketamine (single dose, 1 mg/kg, to a maximum 80 mg) PLUS intranasal 0.9% NS 0.10 mL/kg divided to both nares. Due to the perceptible differences in interventional routes, each participant will receive both IV and IN interventions using this double-dummy approach. For IN dose volumes less than or equal to 0.5 mL, the entire dose will be delivered into 1 nostril and for doses greater than 0.5 mL, the dose will be divided equally between both nares. Adjunctive sedation will be given as needed in the form of IV ketamine, any dose, for participants who are adequately sedated 1 minute after IV administration at the discretion of the treating physician. Inadequate sedation in this context refers to one of the following: participant's vocalizations are consistent with pain OR participant withdraws or localizes due to pain. Eligible participants will be identified by the treating physician after viewing the radiographs and performing a clinical assessment. The physician will then inform a research assistant (RA) that the participant is eligible. The RA will then seek informed consent and explain the protocol to the family. Baseline demographic information will be obtained. Informed consent for PSA and a pre-anesthetic assessment will be performed by the treating physician in accordance with the usual standard of care. The RA will record a continuous video of the participant's entire body and monitor using an iPad starting immediately after the IV intervention until the participant is awake and able to tolerate oral fluids. DOCS scores will be obtained by two trained outcome assessors every 30 seconds for the entire duration of the video. The outcome assessors will also score the entire video for emergence delirium using the Paediatric Anesthesia Emergence Delirium (PAED) scale every 5 minutes beginning at the completion of fracture reduction until the participant is awake and drinking. Participants will receive standard monitoring of oxygen saturation, blood pressure, respiratory rate, apnea, heart rate, and rash by the attending nurse and physician every 5 minutes as per the usual standard of care. The usual standard of care also includes monitoring post-anesthetic for the presence of known idiosyncratic effects of ketamine that include vomiting, seizure, headache, emergence reaction, and hypersensitivity. The RA will obtain this information from the nursing record at discharge and based on consensus-based Canadian recommendations. Immediately prior to discharge, the RA will also record the duration of stay in the ED, parental, patient, and physician satisfaction with PSA using a 5-item Likert scale, and nasal irritation

Eligibility criteria: Inclusion Criteria:

1. Age 4 -17 years
2. Up to 80 kg
3. Presenting the paediatric emergency department
4. Require a closed reduction by procedural sedation and analgesia
5. Acute (=\< 48 hours) distal radius and/or ulna fracture that is angulated with or without displacement
6. No more than 0.5 cm shortening in either the radius or ulna (not both)

Exclusion Criteria:

1. Previous hypersensitivity reaction to ketamine
2. Globe rupture
3. Traumatic brain injury with intracranial hemorrhage
4. History of uncontrolled hypertension
5. Nasal bone deformity
6. Duration of reduction expected to be greater than 20 minutes
7. Poor English or French fluency in the absence of a native language interpreter
8. American Society of Anesthesiologists (ASA) class of 3 or greater
9. Previous sedation with ketamine within 24 hours
10. Previous diagnosis of schizophrenia or psychosis based on DSM-V criteria
11. Pregnancy
12. Neuro-cognitive impairment that precludes informed consent, assent, or ability to self-report pain and satisfaction
13. Multi-limb trauma
14. Hemodynamic compromise
15. Glasgow coma score \< 15
16. Fracture is comminuted
17. Fracture is associated with a dislocation
18. Hematoma block at index visit
19. Unilateral or bilateral nasal obstruction (due to infectious or allergic rhinitis, nasal polyps, septal hematoma, or septal deviation)

Primary outcomes:
measure: Adequacy of sedation
timeFrame: Duration of fracture reduction
Secondary outcomes:
measure: Depth of sedation
timeFrame: Duration of fracture reduction
measure: Onset of adequate sedation
timeFrame: Within 1 hour following intervention
measure: Duration of sedation
timeFrame: Within 2 hours following intervention
measure: Proportion of time participant adequately sedated during fracture reduction
timeFrame: Within 2 hours following intervention
measure: Adverse events
timeFrame: Within 2 hours following intervention
measure: Length of stay due to PSA
timeFrame: Within 3 hours of intervention
measure: Duration of procedure
timeFrame: Within 3 hours of intervention
measure: Caregiver satisfaction
timeFrame: Within 2 hours of intervention
measure: Participant satisfaction
timeFrame: Within 2 hours of intervention
measure: Physician satisfaction
timeFrame: Within 2 hours of intervention
measure: Nurse satisfaction
timeFrame: Within 2 hours of intervention
measure: Requirement for additional sedative medication
timeFrame: Within 2 hours of intervention
measure: Analgesic medication
timeFrame: Within 2 hours of intervention
measure: Pain
timeFrame: Within 2 hours of intervention
measure: Emergence delirium
timeFrame: 20 to 80 minutes post-IV intervention
measure: Nasal irritation
timeFrame: Within 2 hours following intervention
measure: Successful sedation
timeFrame: Within 2 hours following intervention
measure: Adjunctive IV therapy
timeFrame: Within 2 hours following intervention
measure: Number of IN sprays received / Intended number of sprays
timeFrame: Within 2 hours following intervention
measure: Number of IV attempts
timeFrame: Within 2 hours following intervention
measure: Time to IV insertion
timeFrame: Within 2 hours following intervention
Other outcomes:
Locations:
Study officials:
affiliation: Western University
name: Naveen Poonai, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Heath A, Offringa M, Pechlivanoglou P, Rios JD, Klassen TP, Poonai N, Pullenayegum E; KidsCAN PERC Innovative Paediatric Clinical Trials Team. Determining a Bayesian predictive power stopping rule for futility in a non-inferiority trial with binary outcomes. Contemp Clin Trials Commun. 2020 Apr 8;18:100561. doi: 10.1016/j.conctc.2020.100561. eCollection 2020 Jun.