Clinical trial NCT04195256: Intranasal Dexmedetomidine Plus Ketamine for Procedural Sedation
Official title: Intranasal Dexmedetomidine Plus Ketamine for Procedural Sedation in Children: an Adaptive Randomized Controlled Non-inferiority Multicenter Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Fracture
Dislocation
Lead sponsor: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
Sponsor class: OTHER
First posted: 2019-12-11
Enrollment: 400
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Adaptive, multi-centre, two-arm, randomized, blinded, double-dummy, controlled, parallel group, non-inferiority, phase II/III trial
Primary purpose: TREATMENT

Brief summary: Orthopedic injuries comprise more than 10% of ED visits in children and 25 to 50% of children will sustain a fracture before age 16 years. Distal radius fractures account for 20-32% of fractures in children, making them the most common fracture type. Between 20 and 40% of extremity fractures in children require a closed reduction, often necessitating procedural sedation and analgesia (PSA). Intravenous (IV) ketamine is the most commonly used sedative agent used to perform a closed reduction. However, children rate IV insertion as the most painful hospital experience, second only to the injury itself. IV insertion can be more technically difficult in children because of smaller veins and lack of cooperation, often leading to multiple IV attempts. A combination of intranasal (IN) dexmedetomidine plus ketamine (IN Ketodex) may provide effective sedation for children undergoing a closed reduction without the distress and pain related to IV insertion. A less painful experience has been found to correlate with child satisfaction which may reduce caregiver anxiety and improve the therapeutic relationship with the health care team. This study is a multi-centre, two-arm, randomized, blinded, controlled, non-inferiority trial designed to test the hypothesis that IN Ketodex is non-inferior to intravenous (IV) ketamine with respect to depth of sedation as measured using the Pediatrics Sedation State Scale (PSSS).

Detailed description: Intranasal medications may offer a technically easier and pain-free approach to procedural sedation (PSA); one that may have widespread applicability in patients with needle-phobia, difficult IV access, resource-limited settings, or when experience placing an IV is limited. Although IN ketamine has been found to be effective for fracture pain, procedural pain, anesthetic pre-induction, and diagnostic imaging, a recent shortage of this agent in the highest concentration of 100 mg/mL has severely limited out ability to study its effectiveness and consequent clinical uptake. Our research team conducted three systematic reviews of randomized trials of IN ketamine and IN dexmedetomidine in children undergoing painful procedures. The latter review included 18 trials (n=2128) of children age 1 month to 14 years. Our review found that IN dexmedetomidine, dosed from 1-4 mcg/kg, was well tolerated and superior to conventional sedatives (midazolam and chloral hydrate) in providing adequate sedation to 525/669 (78.5%) children. A number of studies found that IN dexmedetomidine was in fact superior to IN ketamine. Surendar et al. found that IN dexmedetomidine at 1.5 mcg/kg facilitated successful sedation in 18/21 (86%) of children undergoing dental procedures and was more effective than IN ketamine 5 mg/kg. Gyanesh et al. found that the proportion of children with satisfactory IV sedation was greater with IN dexmedetomidine 1 mcg/kg compared to IN ketamine 5 mg/kg \[47/52 (90%) versus 43/52 (83%), respectively\]. Mostafa et al. found that IN dexmedetomidine 1 mcg/kg was more effective at facilitating caregiver separation than IN ketamine 5 mg/kg or IN midazolam 0.2 mg/kg \[30/32 (92%) versus 22/32 (69%) versus 28/32 (88%), respectively\]. Moreover, a combination of dexmedetomidine and ketamine appeared to be superior than either agent alone. Qiao et al. found that IN dexmedetomidine 2 mcg/kg and oral ketamine 3 mg/kg in children undergoing IV insertion was superior to both IN dexmedetomidine 2.5 mcg/kg and oral ketamine 6 mg/kg alone (80.1% versus 47.6% versus 68.3%, respectively). Bhat et al. found that a combination of IN dexmedetomidine 1 mcg/kg and IN ketamine 2 mg/kg versus IN dexmedetomidine 1 mcg/kg alone facilitated greater acceptance of face mask (67% versus 52%, respectively) and greater tolerance of caregiver separation (93% versus 89%, respectively) (38). We also found evidence that higher doses of IN dexmedetomidine were more effective. More specifically, at the higher end of the dosing range (1-4 mcg/kg), IN dexmedetomidine 3 mcg/kg was superior to IN ketamine 7 mg/kg; providing adequate sedation to 25/29 (86.3%) versus 23/29 (79.4%) of children undergoing IV insertion, respectively. A dose-finding study of IN dexmedetomidine in children \< 3 years who were post-operative from cardiac surgery and were undergoing transthoracic echocardiography found an optimal median effective dose of 3.3 mcg/kg (range 2.72-3.78 mcg/kg). Taken together, our review suggests that the most effective and tolerable intranasal agent for procedural sedation for fracture reduction is a combination of IN dexmedetomidine 4 mcg/kg and IN ketamine 2-3 mg/kg. There is ample and ongoing evidence of suboptimal management for procedural pain in children, a high frequency of orthopedic injuries requiring IV placement for PSA, and a lack of evidence to support the use of strategies that reduce the pain of IVs. However, there are no studies that have shown the effectiveness of IN ketamine for fracture reduction in children. In order to provide robust evidence supporting an alternate approach that precludes the need for an IV in children undergoing PSA, the investigators propose a study to answer the important research question: In children presenting to the ED with an orthopedic injury requiring PSA, does IN Ketodex provide as effective sedation as IV ketamine?

Eligibility criteria: INCLUSION CRITERIA

General Criteria

1. Provision of signed and dated informed consent form
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Deemed by treating physician to require procedural sedation

Specific criteria

1. Children presenting to the paediatric EDs of participating sites age 2-17 years
2. Weighing up to and including 100 kg
3. One of the following injuries:

   * Closed forearm fracture
   * Metacarpal or phalangeal fracture
   * Dislocation of a shoulder or elbow
   * Type II supracondylar fracture
4. Expected to not require more than one dose of IV sedative medication if they were not in the trial (as determined by the procedure physician and not including cast or splint application).
5. Both nares are fully patent
6. Physician plans to sedate patient

EXCLUSION CRITERIA

1. Previous hypersensitivity reaction to ketamine or dexmedetomidine including rash, difficulty breathing, hypotension, apnea, or laryngospasm;
2. Suspected globe rupture;
3. Concomitant traumatic brain injury with intracranial hemorrhage;
4. Uncontrolled hypertension;
5. Nasal bone deformity or septal deviation;
6. Poor English or French fluency in the absence of native language interpreter;
7. American Society of Anesthesiologists (ASA) class 3 or greater;
8. Previous diagnosis of schizophrenia or active psychosis as per the treating physician
9. Neuro-cognitive impairment that precludes informed consent, assent, or ability to self-report pain and satisfaction;
10. More than one fracture or dislocation requiring reduction;
11. Hemodynamic compromise as per the treating physician;
12. Glasgow coma score \< 15;
13. Previous sedation with ketamine or hematoma block within 24 hours;
14. Fracture is comminuted or associated with a dislocation;
15. Participant has undergone a hematoma block within 24 hours;
16. Obstructive sleep apnea
17. Previous enrollment in the trial;
18. Suspected pregnancy
19. Congenital heart disease or known cardiac dysrhythmia
20. Known or suspected hepatic impairment
21. Known renal insufficiency
22. Uncorrected mineralocorticoid deficiency

Primary outcomes:
measure: Adequate sedation
timeFrame: Through study completion in the ED (4 hours)
Secondary outcomes:
measure: Length of stay
timeFrame: Through study completion in the ED (4 hours)
measure: Time to wakening
timeFrame: Through study completion in the ED (4 hours)
measure: Adverse effects
timeFrame: Through study completion in the ED and up to 72 hours post-discharge
Other outcomes:
measure: Length of stay due to procedural sedation
timeFrame: Through study completion in the ED (4 hours)
measure: Duration of procedure
timeFrame: Through study completion in the ED (4 hours)
measure: Caregiver, participant, bedside nurse or respiratory therapist, and physician satisfaction
timeFrame: Through study completion in the ED (4 hours)
measure: Nasal irritation
timeFrame: Through study completion in the ED (4 hours)
measure: Volume of IN intervention received / Volume of IN intervention intended
timeFrame: Through study completion in the ED (4 hours)
measure: Adjunctive IV therapy and medications
timeFrame: Through study completion in the ED (4 hours)
measure: Pre-sedation Pain
timeFrame: Through study completion in the ED (4 hours)
measure: Patient Preference
timeFrame: Through study completion in the ED (4 hours)
measure: Exploratory subgroup analyses
timeFrame: Through study completion in the ED (4 hours)
Locations:
city: Edmonton
country: Canada
facility: Stollery Children's Hospital
state: Alberta
city: Vancouver
country: Canada
facility: BC Children's Hospital
state: British Columbia
city: Hamilton
country: Canada
facility: McMaster Children's Hospital
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: Children's Hospital of Eastern Ontario
state: Ontario
city: Winnipeg
country: Canada
facility: Winnipeg Children's Hospital
state: Ontario
Study officials:
affiliation: Western University
name: Naveen Poonai, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Heath A, Rios JD, Pullenayegum E, Pechlivanoglou P, Offringa M, Yaskina M, Watts R, Rimmer S, Klassen TP, Coriolano K, Poonai N; PERC-KIDSCAN Ketodex Study Group. The intranasal dexmedetomidine plus ketamine for procedural sedation in children, adaptive randomized controlled non-inferiority multicenter trial (Ketodex): a statistical analysis plan. Trials. 2021 Jan 6;22(1):15. doi: 10.1186/s13063-020-04946-3.