Intranasal Ketamine for Procedural Sedation

Phase 3

• Conditions: Bone Fractures; Dislocations
• Interventions: Drug: IN ketamine; Drug: IV ketamine; Drug: IV saline 0.9%; Drug: IN saline 0.9%

• Registration Number: NCT02828566
• Lead Sponsor: Lawson Health Research Institute

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

Basic Information
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Recruitment & Eligibility
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Study & Design

Study Timeline

• Study First Submitted: 2016-06-30
• Study First Submitted QC: 2016-07-07
• Study First Posted: 2016-07-11
• Status Verified: 2017-03
• Last Update Submitted: 2017-08-25
• Last Update Posted: 2017-08-29
• Study Start: 2017-10
• Primary Completion: 2019-01
• Study Completion: 2019-02

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 470

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)

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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)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
IN ketamine and IV saline	IN ketamine	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
IN ketamine and IV saline	IV saline 0.9%	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
IV ketamine and IN saline	IV ketamine	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
IV ketamine and IN saline	IN saline 0.9%	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

Primary Outcome Measures

Name	Time	Method
Adequacy of sedation	Duration of fracture reduction	Proportion with DOCS score -2 to +2 for duration of fracture reduction

Secondary Outcome Measures

Name	Time	Method
Caregiver satisfaction	Within 2 hours of intervention	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
Depth of sedation	Duration of fracture reduction	Score using Pediatric Sedation State Scale
Onset of adequate sedation	Within 1 hour following intervention	Time interval from first IN sprays to first DOCS score between -2 and +2 in minutes
Duration of sedation	Within 2 hours following intervention	Duration of time between the first DOCS score -2 to +2 to last DOCS score between -2 and +2 post-fracture reduction
Participant satisfaction	Within 2 hours of intervention	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.
Physician satisfaction	Within 2 hours of intervention	Obtained immediately prior to discharge using a Visual Analog Scale
Proportion of time participant adequately sedated during fracture reduction	Within 2 hours following intervention	Proportion of time DOCS score is -2 to +2 during fracture reduction.
Adverse events	Within 2 hours following intervention	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.
Length of stay due to PSA	Within 3 hours of intervention	Time interval from the first pair of IN sprays to discharge
Duration of procedure	Within 3 hours of intervention	Time of the first pair of IN sprays to the end of cast or splint application
Pain	Within 2 hours of intervention	Pain scores will be recorded using the FPS-R on arrival and when the child is awake and drinking
Nurse satisfaction	Within 2 hours of intervention	Obtained immediately prior to discharge using a Visual Analog Scale
Requirement for additional sedative medication	Within 2 hours of intervention	Number of doses and type of adjunctive sedative medication required; Deemed inadequate if additional sedative medication given (for IN ketamine group only)
Analgesic medication	Within 2 hours of intervention	Number of doses and type of analgesic medication required
Emergence delirium	20 to 80 minutes post-IV intervention	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
Nasal irritation	Within 2 hours following intervention	Measured using the Faces Pain Scale - Revised when awake and drinking
Successful sedation	Within 2 hours following intervention	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
Adjunctive IV therapy	Within 2 hours following intervention	Other reasons for IV insertion (analgesia, anxiolysis, fluids, etc.)
Number of IN sprays received / Intended number of sprays	Within 2 hours following intervention	Number of IN sprays received / Intended number of sprays
Number of IV attempts	Within 2 hours following intervention	Number of IV attempts and time to IV insertion Number of IV attempts
Time to IV insertion	Within 2 hours following intervention	Time from first breakage of skin to establishment of successful flow with a flush