IN Midazolam vs IN Dexmedetomidine vs IN Ketamine During Minimal Procedures in Pediatric ED

Anxiety Clinical Trial

Official title:

Randomized Controlled Trial of Intranasal (IN) Midazolam vs IN Dexmedetomidine vs IN Ketamine Evaluating Length of Stay After Medication Administration and Anxiolysis During Minimal Procedures in Pediatric Population in Pediatric Emergency Department (ED)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05934669
• Other study ID #: 15872
• Status: Recruiting
• Phase: Phase 4
• Start date: November 14, 2023
• Est. completion date: June 2024

Study information

• Verified date: March 2024
• Source: University of Oklahoma
• Contact: Gavely Toor, DO
• Phone: 405-271-2429
• Email: gavely-toor[@]ouhsc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Pain in young children has been universally under-recognized due to their inability to describe or localize pain. Improvements in pharmacological interventions are necessary to optimize patient and family experience and allow for successful and efficient procedure completion. This is the first study that will compare three intranasal medications (Intranasal Midazolam, Dexmedetomidine, and Ketamine) to evaluate the length of stay after medication administration along with patient and provider satisfaction. The objective of this study is to demonstrate superior intranasal anxiolysis for pediatric laceration repairs with the shortest emergency department stay and highest patient and provider satisfaction. Based on previous studies and medication pharmacokinetics, we hypothesize that Intranasal Ketamine will have the shortest Emergency Department (ED) stay followed by Midazolam and then Dexmedetomidine with the longest stay; however, Dexmedetomidine will have the highest patient and provider satisfaction followed by Ketamine and then Midazolam.

Description:

Children commonly present to ED with injuries requiring procedures that can be painful or require a child to be absolutely still. Pain in young children has been universally under-recognized due to their inability to describe or localize pain. Multiple surveys of parents and families have showed that ED satisfaction is highly dependent on the degree of pain a patient experiences and the efforts made to alleviate the pain. Therefore, improvements in pharmacological interventions are necessary to optimize patient and family experience and allow for successful and efficient procedure completion.

Intranasal Midazolam is widely used for minimal procedural anxiolysis in pediatric population. Intranasal medication delivery has the highest parent and provider satisfaction with the advantage of avoiding painful needle stick and faster absorption compared to oral or intramuscular medication. Midazolam is a gamma-aminobutyric acid (GABA) receptor agonist that can provide anxiolysis and amnesia but no analgesia. Intranasal Midazolam has a rapid onset of 5-10 minutes with peak at 30 minutes. There have been limited studies evaluating the length of stay or time to discharge after medication administration with an average length of stay of about 30 minutes. It has been shown to be safe and effective in children for minor procedures; however, intranasal Midazolam is notoriously noxious and irritating to nasal mucosa and requires larger volumes for intranasal dosing. Main side effects include respiratory depression and hypotension. It is also known to cause paradoxical reaction with hyperactivity, agitation, and restlessness especially in developmentally delayed or children with Autism or behavioral concerns. Therefore, several new studies have evaluated other newer intranasal medications for minor procedures including intranasal Dexmedetomidine and intranasal Ketamine.

Dexmedetomidine is an alpha 2 agonist that mirrors sleep in children and can provide anxiolysis and minimal analgesia. Intranasal dosages that have provided adequate minimal sedation is 2-4mcg/kg (max dosage 100-200mcg) with wide range of onset 10-45 mins with average 30 minutes and peak at 90 minutes. Unlike Midazolam, it preserves airway reflexes without clinically significant hemodynamic instability in children. Studies have also shown that it is well tolerated by children and preferred in children with Autism and behavioral concerns.

Ketamine is an N-methyl-D-aspartate (NMDA) antagonist that provides both anxiolysis and analgesia. It is widely used in ED settings for intravenous procedural sedation; however, intranasal route provides non-invasive method of medication administration. Gutherie et al conducted a study demonstrating intranasal Ketamine providing safe and successful anxiolysis and analgesia in pediatric patients in an ED setting. Intranasal dosage of 3-5mg/kg (max dosage 100-200mg) provides optimal onset of action within 10 minutes with peak at 15-20 minutes and duration of 45-60 minutes. It has few significant side effects including the rare laryngospasm and recovery agitation, however, it preserves airway reflexes and favorable in hemodynamic instability.

Previous Studies:

Limited studies have demonstrated anxiolysis with patient and provider satisfaction or time to discharge after medication administration comparing intranasal Midazolam to intranasal Dexmedetomidine or intranasal Ketamine in a pediatric emergency medicine setting. Neville et al conducted a study comparing intranasal Dexmedetomidine and intranasal Midazolam prior to laceration repair in a pediatric emergency department and concluded that patients who received Dexmedetomidine had less anxiety at the time of positioning for the procedure. Several other studies have demonstrated similar outcomes with better patient and provider satisfaction in pre-operative settings, imaging, and dental settings. Surendar et al is the only study that compared all three intranasal medications. The study included uncooperative pediatric patients in a dental setting. Although overall differences were not statistically significant, the onset of sedation was rapid among Intranasal Ketamine and Midazolam groups but overall success was highest in Dexmedetomidine group.

Objective/Aims/Hypothesis:

This is the first study that will compare all three intranasal medications to evaluate the length of stay after medication administration along with patient and provider satisfaction. The objective of this study is to demonstrate superior intranasal anxiolysis for pediatric laceration repairs with the shortest emergency department stay and highest patient and provider satisfaction. The primary outcome will measure the time to discharge after medication administration. Other measurements with include patient's anxiety using previously validated scale Modified Yale Preoperative Anxiety Scale (mYPAS) and physician and parent satisfaction using 5 point Likert scale. Based on previous studies and medication pharmacokinetics, we hypothesize that Ketamine will have the shortest ED stay followed by Midazolam and then Dexmedetomidine with the longest stay; however, Dexmedetomidine will have the highest patient and provider satisfaction followed by Ketamine and then Midazolam.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 90
• Est. completion date: June 2024
• Est. primary completion date: May 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 1 Year to 5 Years

Eligibility

Inclusion Criteria:

• Age 1-5 years old

• Presents to the ED for suture repair for lacerations less than or equal to 5cm in length

• Parent(s)/Caregiver(s) speak English

Exclusion Criteria:

• Younger than 12 months of age or older than 5 years old

• Suture repair needed for lacerations are greater than 5cm in length

• Known allergy or adverse effect to Midazolam, Dexmedetomidine, Ketamine, or any other sedatives

• Any abnormal vital signs for age, especially heart rate and blood pressure

• History of Cardiac, respiratory, renal, or liver disease

• Known electrolyte abnormalities

• Any ocular trauma, nasal injury, nasal deformity, significant nasal congestion, abnormalities in the nasal or oral mucosa, facial deformity, or facial injury

• Home medications include beta blockers or any other blood pressure lowering agents Classified ASA III and above

• Known or anticipated difficult airway

• Abnormal neurological exam

• Parent(s)/Caregiver(s) do not speak English

Related Conditions & MeSH terms

• Anxiety
• Laceration of Skin
• Lacerations

Intervention

Drug:
• Intranasal Midazolam
Using a computer-generated randomization schedule by the research pharmacist, all 90 subjects will be divided into 3 even groups to receive either medication A (intranasal Midazolam), B (intranasal Dexmedetomidine), or C (intranasal Ketamine). Based on the randomization schedule, the pharmacist will dispense medication A, B, or C to the chronological number provided in the order. The total amount of the medication will be based on the patient's charted weight. Small volumes of less than 1ml per nostril are preferred for reliable absorption; therefore, the medication will be dispensed in a 1ml syringe and the barrel of the syringe will be covered by the pharmacist. All the syringes sent from the pharmacy will appear the same, regardless of the volume of the medication.
• Intranasal Dexmedetomidine
See above
• Intranasal Ketamine
See above

Locations

Country	Name	City	State
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma

Sponsors (1)

Lead Sponsor	Collaborator
University of Oklahoma

Country where clinical trial is conducted

United States, 

References & Publications (16)

Azizkhani R, Heydari F, Ghazavi M, Riahinezhad M, Habibzadeh M, Bigdeli A, Golshani K, Majidinejad S, Mohammadbeigi A. Comparing Sedative Effect of Dexmedetomidine versus Midazolam for Sedation of Children While Undergoing Computerized Tomography Imaging. J Pediatr Neurosci. 2020 Jul-Sep;15(3):245-251. doi: 10.4103/jpn.JPN_107_19. Epub 2020 Nov 6. — View Citation

Carlone G, Trombetta A, Amoroso S, Poropat F, Barbi E, Cozzi G. Intramuscular Dexmedetomidine, a Feasible Option for Children With Autism Spectrum Disorders Needing Urgent Procedural Sedation. Pediatr Emerg Care. 2019 Jun;35(6):e116-e117. doi: 10.1097/PEC.0000000000001776. No abstract available. — View Citation

Cravero JP, Askins N, Sriswasdi P, Tsze DS, Zurakowski D, Sinnott S. Validation of the Pediatric Sedation State Scale. Pediatrics. 2017 May;139(5):e20162897. doi: 10.1542/peds.2016-2897. — View Citation

Everitt IJ, Barnett P. Comparison of two benzodiazepines used for sedation of children undergoing suturing of a laceration in an emergency department. Pediatr Emerg Care. 2002 Apr;18(2):72-4. doi: 10.1097/00006565-200204000-00002. — View Citation

Guthrie AM, Baum RA, Carter C, Dugan A, Jones L, Tackett T, Bailey AM. Use of Intranasal Ketamine in Pediatric Patients in the Emergency Department. Pediatr Emerg Care. 2021 Dec 1;37(12):e1001-e1007. doi: 10.1097/PEC.0000000000001863. — View Citation

Gyanesh P, Haldar R, Srivastava D, Agrawal PM, Tiwari AK, Singh PK. Comparison between intranasal dexmedetomidine and intranasal ketamine as premedication for procedural sedation in children undergoing MRI: a double-blind, randomized, placebo-controlled trial. J Anesth. 2014 Feb;28(1):12-8. doi: 10.1007/s00540-013-1657-x. Epub 2013 Jun 26. — View Citation

Iirola T, Vilo S, Manner T, Aantaa R, Lahtinen M, Scheinin M, Olkkola KT. Bioavailability of dexmedetomidine after intranasal administration. Eur J Clin Pharmacol. 2011 Aug;67(8):825-31. doi: 10.1007/s00228-011-1002-y. Epub 2011 Feb 12. — View Citation

Kain ZN, Mayes LC, Cicchetti DV, Bagnall AL, Finley JD, Hofstadter MB. The Yale Preoperative Anxiety Scale: how does it compare with a "gold standard"? Anesth Analg. 1997 Oct;85(4):783-8. doi: 10.1097/00000539-199710000-00012. — View Citation

Lewis J, Bailey CR. Intranasal dexmedetomidine for sedation in children; a review. J Perioper Pract. 2020 Jun;30(6):170-175. doi: 10.1177/1750458919854885. Epub 2019 Jun 27. — View Citation

Marra P, Di Stadio A, Colacurcio V, Scarpa A, La Mantia I, Salzano FA, De Luca P. Sedation with Intranasal Dexmedetomidine in the Pediatric Population for Auditory Brainstem Response Testing: Review of the Existing Literature. Healthcare (Basel). 2022 Feb 1;10(2):287. doi: 10.3390/healthcare10020287. — View Citation

Neville DN, Hayes KR, Ivan Y, McDowell ER, Pitetti RD. Double-blind Randomized Controlled Trial of Intranasal Dexmedetomidine Versus Intranasal Midazolam as Anxiolysis Prior to Pediatric Laceration Repair in the Emergency Department. Acad Emerg Med. 2016 Aug;23(8):910-7. doi: 10.1111/acem.12998. — View Citation

Shaw KN, Bachur RG, editors. Fleisher & Ludwig's Textbook of Pediatric Emergency Medicine. 8th Edition. Philadelphia: Wolters Kluwer, e129, 2021

Surendar MN, Pandey RK, Saksena AK, Kumar R, Chandra G. A comparative evaluation of intranasal dexmedetomidine, midazolam and ketamine for their sedative and analgesic properties: a triple blind randomized study. J Clin Pediatr Dent. 2014 Spring;38(3):255-61. doi: 10.17796/jcpd.38.3.l828585807482966. — View Citation

Tug A, Hanci A, Turk HS, Aybey F, Isil CT, Sayin P, Oba S. Comparison of Two Different Intranasal Doses of Dexmedetomidine in Children for Magnetic Resonance Imaging Sedation. Paediatr Drugs. 2015 Dec;17(6):479-85. doi: 10.1007/s40272-015-0145-1. — View Citation

Yuen VM, Hui TW, Irwin MG, Yao TJ, Wong GL, Yuen MK. Optimal timing for the administration of intranasal dexmedetomidine for premedication in children. Anaesthesia. 2010 Sep;65(9):922-9. doi: 10.1111/j.1365-2044.2010.06453.x. — View Citation

Zempsky WT, Cravero JP; American Academy of Pediatrics Committee on Pediatric Emergency Medicine and Section on Anesthesiology and Pain Medicine. Relief of pain and anxiety in pediatric patients in emergency medical systems. Pediatrics. 2004 Nov;114(5):1348-56. doi: 10.1542/peds.2004-1752. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The primary outcome will measure the time to discharge after intranasal medication administration	The nurse will document the time the medication is administered and the time of discharge once the patient meets AAP criteria of discharge. AAP discharge criteria includes cardiovascular function and airway potency satisfactory; arousable and protective reflexes are intact; able to talk appropriately for age; able to sit up appropriately for age; and state of hydration is adequate	Day 1
Secondary	The secondary outcome will measure patient's anxiety using the previously validated scale mYPAS and physician and parent satisfaction using a 5-point Likert scale	Once the pharmacy dispenses the medication, the nurse will fill out an 18-point scale survey (Modified Yale Preoperative Anxiety Scale [mYPAS]) to assess the patient's anxiety level. At the end of the procedure, both the physician and the parent will answer a question using a 5-point Likert scale and the nurse will fill out the same mYPAS survey utilized prior to medication administration. The mYAS scale evaluates four domains including activity, vocalizations, emotional expressivity, and state of apparent arousal. The scoring is combined into a total anxiety score between 23.3 and 100 with a patient scoring less than or equal to 30 being categorized as not anxious. The scores on 5-point Likert scale are categorized into very satisfied, satisfied, no difference, unsatisfied, very unsatisfied for 5, 4, 3, 2, and 1, respectively.	Day 1