Intranasal Dexmedetomidine Plus Ketamine for Procedural Sedation

Fracture Clinical Trial

— Ketodex  

Official title:

Intranasal Dexmedetomidine Plus Ketamine for Procedural Sedation in Children: an Adaptive Randomized Controlled Non-inferiority Multicenter Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04195256
• Other study ID #: 091819
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: March 11, 2020
• Est. completion date: December 2024

Study information

• Verified date: February 2023
• Source: Lawson Health Research Institute
• Contact: Naveen Poonai, MD
• Phone: 5196858500
• Email: naveen.poonai[@]lhsc.on.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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?

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 4 Years to 17 Years

Eligibility

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 4-17 years

2. Weighing up to and including 60 kg

3. Painful procedure including one of the following:

• Forearm fracture

• Metacarpal or phalangeal fracture

• Dislocation of a shoulder or elbow

• Type II supracondylar fracture

4. Closed reduction expected to not require more than one dose of IV sedative sedation medication (as determined by the procedure physician and not including cast or splint application).

5. Both nares are fully patent.

6. Fracture is minimally or not shortened

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

Related Conditions & MeSH terms

• Dislocation
• Fracture

Intervention

Drug:
• IN Ketodex (D4K2)
Dexmedetomidine (Pfizer, Kirkland, Quebec), single-dose, 4 mcg/kg (0.04 mL/kg) of 100 mcg/mL solution, maximum of 200 mcg (2 mL) THEN Ketamine (Sandoz, Mississauga, Ontario), single dose, 2 mg/kg (0.04 mL/kg) of 50 mg/mL solution, maximum of 200 mg (4 mL) (D4K2), both delivered intranasally using a mucosal atomizer device (MAD) and divided to both nares AND 0.9% normal saline 0.03 mL/kg delivered intravenously to a maximum of 2 mL
• IN Ketodex (D3K3)
Dexmedetomidine (Pfizer, Kirkland, Quebec), single-dose, 3 mcg/kg (0.03 mL/kg) of 100 mcg/mL solution, maximum of 200 mcg (2 mL) THEN Ketamine (Sandoz, Mississauga, Ontario), single dose, 3 mg/kg (0.06 mL/kg) of 50 mg/mL solution, maximum of 300 mg (6 mL) (D3K3), both delivered intranasally using a mucosal atomizer device (MAD) and divided to both nares AND 0.9% normal saline 0.03 mL/kg delivered intravenously to a maximum of 2 mL
• IN Ketodex (D2K4)
Dexmedetomidine (Pfizer, Kirkland, Quebec), single-dose, 2 mcg/kg (0.02 mL/kg) of 100 mcg/mL solution, maximum of 200 mcg (2 mL) THEN Ketamine (Sandoz, Mississauga, Ontario), single dose, 4 mg/kg (0.08 mL/kg) of 50 mg/mL solution, maximum of 400 mg (8 mL) (D2K4), both delivered intranasally using a mucosal atomizer device (MAD) and divided to both nares AND 0.9% normal saline 0.03 mL/kg delivered intravenously to a maximum of 2 mL
• IV Ketamine
Ketamine, single dose, 1.5 mg/kg (0.03 mL/kg) of 50 mg/mL solution delivered intravenously, to a maximum of 100 mg (2 mL) AND two aliquots of 0.9% normal saline in 3 possible combinations: (i) 0.04 mL/kg (max 2 mL) then 0.04 mL/kg (max 4 mL) (placebo D4K2), (ii) 0.03 mL/kg (max 2 mL) then 0.06 mL/kg (max 6 mL) (placebo D3K3), (iii) 0.02 mL/kg (max 2 mL) then 0.08 mL/kg (max 8 mL) (placebo D2K4), delivered intranasally using a MAD and divided to both nares

Locations

Country	Name	City	State
Canada	Stollery Children's Hospital	Edmonton	Alberta
Canada	McMaster Children's Hospital	Hamilton	Ontario
Canada	London Health Sciences Centre	London	Ontario
Canada	Children's Hospital of Eastern Ontario	Ottawa	Ontario
Canada	BC Children's Hospital	Vancouver	British Columbia
Canada	Winnipeg Children's Hospital	Winnipeg	Ontario

Sponsors (1)

Lead Sponsor	Collaborator
Naveen Poonai

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Length of stay due to procedural sedation	Defined as the time interval from the first pair of IN sprays/IV dose to discharge, reflective of the time difference associated with different routes of administration.	Through study completion in the ED (4 hours)
Other	Duration of procedure	Defined as time of the first pair of IN sprays to the end of cast or splint application (closed reduction) in minutes	Through study completion in the ED (4 hours)
Other	Caregiver, participant, bedside nurse or respiratory therapist, and physician satisfaction	Satisfaction will be measured using a visual analog scale (VAS) when the participant is deemed ready for discharge. The following questions will be posed: How satisfied were you with your child's sedation? (Caregiver if at bedside), How happy were you with your sleep? (Participant), or How satisfied were you with the level of sedation in your patient? (Sedating physician & nurse/respiratory therapist as per who is at bedside).	Through study completion in the ED (4 hours)
Other	Nasal irritation	Discomfort associated with nasal sprays will be assessed by the research nurse using the Faces Pain Scale -Revised (FPS-R) when the participant is deemed ready for discharge. The FPS-R is a self-report measure scored as either 0,2,4,6,8,10, with increasing numbers indicating greater pain.	Through study completion in the ED (4 hours)
Other	Volume of IN intervention received / Volume of IN intervention intended	Volume of IN intervention received / Volume of IN intervention intended	Through study completion in the ED (4 hours)
Other	Adjunctive IV therapy and medications	The number of participants requiring an IV for therapy unrelated to sedation (eg. analgesics, antibiotics, antiemetics, fluids) will be recorded.	Through study completion in the ED (4 hours)
Other	Pre-sedation Pain	Will be recorded by the research nurse from the participant using the Faces Pain Scale - Revised (FPS-R) immediately prior to the first pair of intranasal sprays	Through study completion in the ED (4 hours)
Other	Patient Preference	The following question will be posed to the child: "If you were to be put to sleep again for an injury, what would you prefer, an intravenous needle or nasal sprays (choose one)?"	Through study completion in the ED (4 hours)
Other	Exploratory subgroup analyses	A planned subgroup analyses to determine whether the between group difference in adequacy of sedation is dependent on (i) pain score prior to sedation.	Through study completion in the ED (4 hours)
Primary	Adequate sedation	Adequate is defined as fulfillment of all three of the following criteria: (i) A Pediatric Sedation State Scale (PSSS) score of 2 or 3 for the duration of the procedure (defined for closed reduction as the interval of time from the first application of traction or manipulation of the injured limb for the purpose of anatomical realignment to the last application of a realigning force). The PSSS is scored from 0 to 5 in discrete integer values every 15 seconds. A score of 4 or 5 indicates under-sedation and a score of 0 or 1 indicates over sedation.; (ii) No additional medication is given during the procedure for the purpose of sedation.; (iii) The patient did not actively resist, cry, or require physical restraint for completion of the closed reduction.	Through study completion in the ED (4 hours)
Secondary	Length of stay	Defined as the time recorded in the medical record between triage and discharge.	Through study completion in the ED (4 hours)
Secondary	Time to wakening	This will be defined as the duration of time between the first pair of IN sprays and the first PSSS score of > 3 post-closed reduction.	Through study completion in the ED (4 hours)
Secondary	Adverse effects	Adverse effects as defined by Health Canada reporting standards	Through study completion in the ED and up to 72 hours post-discharge