Intranasal Ketamine for Procedural Sedation (INK)

Intranasal Ketamine Versus Intravenous Ketamine for Procedural Sedation in Children: a Multi-centre Randomized Controlled Non-inferiority Trial

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).

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

Ketamine, single dose, 10 mg/kg (0.1 mL/kg) of 100 mg/mL solution delivered intranasally using an atomizer and divided to both nares to a maximum of 800 mg (8 mL) AND 0.9% normal saline (NS) 0.02 to 0.03 mL/kg delivered intravenously to a maximum of 2.4 mL

Ketamine, single dose, 1 to 1.5 mg/kg (0.02 to 0.03 mL/kg) of 50 mg/mL solution delivered intravenously, to a maximum of 120 mg (2.4 mL) AND 0.9% normal saline (NS) 0.1 mL/kg delivered intranasally using an atomizer and divided to both nares, to a maximum of 8 mL

Duration of time between the first DOCS score -2 to +2 to last DOCS score between -2 and +2 post-fracture reduction

The proportion of participants with adverse effects between groups will be compared. The list of adverse effects was chosen based on known adverse effects associated with ketamine and consensus-based recommendations for reporting for procedural sedation and analgesia in children.

Obtained when patient is awake and drinking using a Visual Analog Scale; Parents not wishing to remain in proximity of child for sedation may opt out

Obtained when patient is awake and drinking using a Visual Analog Scale; Satisfaction will only be assessed in children at least eight years of age as the VAS has not been validated in younger children.

Number of doses and type of adjunctive sedative medication required; Deemed inadequate if additional sedative medication given (for IN ketamine group only)

The proportion of children experiencing emergence delirium will be compared using the Paediatric Anesthesia Emergence Delirium (PAED) scale scored from the video every 5 minutes by an outcome assessor starting when fracture reduction is complete to when awake and drinking

Successful sedation - Based on the definition of Bhatt et al., this will be defined as no unpleasant patient recall of the procedure, no resistance or restraint required during the procedure, no permanent sedation-related complication or no sedation-related event requiring abandonment of the procedure. Defined as: no unpleasant patient recall of the procedure, no resistance or restraint required during the procedure, no permanent sedation-related complication or no sedation-related event requiring abandonment of the procedure. Defined as no unpleasant recall of procedure, no resistance or restraint, no permanent sedation related complication, no sedation-related event requiring abandonment of procedure

Inclusion Criteria: Age 4 -17 years Up to 80 kg Presenting the paediatric emergency department Require a closed reduction by procedural sedation and analgesia Acute (=< 48 hours) distal radius and/or ulna fracture that is angulated with or without displacement No more than 0.5 cm shortening in either the radius or ulna (not both) Exclusion Criteria: Previous hypersensitivity reaction to ketamine Globe rupture Traumatic brain injury with intracranial hemorrhage History of uncontrolled hypertension Nasal bone deformity Duration of reduction expected to be greater than 20 minutes Poor English or French fluency in the absence of a native language interpreter American Society of Anesthesiologists (ASA) class of 3 or greater Previous sedation with ketamine within 24 hours Previous diagnosis of schizophrenia or psychosis based on DSM-V criteria Pregnancy Neuro-cognitive impairment that precludes informed consent, assent, or ability to self-report pain and satisfaction Multi-limb trauma Hemodynamic compromise Glasgow coma score < 15 Fracture is comminuted Fracture is associated with a dislocation Hematoma block at index visit Unilateral or bilateral nasal obstruction (due to infectious or allergic rhinitis, nasal polyps, septal hematoma, or septal deviation)

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.