What is the maximum dose for intranasal (IN) precedex in pediatric patients? Specifically, is there data for a maximum dose when IN precedex is used preoperatively?

Comment by InpharmD Researcher

Available evidence does not establish an absolute maximum intranasal dexmedetomidine dose for pediatric preoperative premedication. A 2022 evidence-based dosing review recommends 1 to 2 mcg/kg once before anesthetic induction in patients aged 6 months to 18 years but specifies a maximum total dose of 200 mcg only for procedural sedation. Two meta-analyses of pediatric preoperative premedication identified 2 mcg/kg as the highest intranasal dose studied but did not establish a maximum recommended dose. Higher doses, including 4 mcg/kg and institutional maximum total doses of 100 to 200 mcg, have been reported in pediatric procedural-sedation studies; however, these studies did not evaluate preoperative premedication.
Background

According to a 2022 evidence-based dosing review from the Dutch Pediatric Formulary, intranasal (IN) dexmedetomidine 1 to 2 mcg/kg as a single dose before induction of anesthesia is recommended for premedication in pediatric patients aged 6 months to 18 years. The recommendation was developed from a risk-benefit assessment of available pediatric efficacy, safety, and pharmacokinetic evidence. For procedural sedation, experts recommend a higher IN dose of 2 to 3 mcg/kg/dose, which may be repeated if necessary, with a maximum total dose of 200 mcg. Notably, although the review establishes a 200-mcg maximum total dose for procedural sedation, it does not specify an absolute maximum dose for IN dexmedetomidine when used as preoperative premedication. [1]

A 2017 systematic review and meta-analysis evaluated the efficacy and safety of intranasal dexmedetomidine for preoperative premedication in 1,190 pediatric patients across 13 randomized controlled trials. The included studies administered intranasal dexmedetomidine at doses ranging from 0.5 to 2 mcg/kg, generally 30 to 75 minutes before anesthetic induction or surgery. The highest evaluated dose was 2 mcg/kg, which was administered in two trials to a total of 80 children: 30 children undergoing cataract surgery received the dose 45 minutes before induction, and 50 children undergoing reconstructive surgery received it 30 to 40 minutes before induction. Compared with other premedication regimens, intranasal dexmedetomidine produced a higher rate of satisfactory sedation at parental separation (risk ratio [RR] 1.45; 95% confidence interval [CI] 1.19 to 1.76; p= 0.0002), but no significant difference in satisfactory sedation at mask induction (RR 1.25; 95% CI 0.98 to 1.59; p= 0.08). Intranasal dexmedetomidine also reduced the requirement for rescue analgesics (RR 0.58; 95% CI 0.40 to 0.83; p= 0.003), postoperative nausea and vomiting (RR 0.63; 95% CI 0.40 to 0.99; p= 0.04), and nasal irritation compared with intranasal midazolam (RR 0.05; 95% CI 0.01 to 0.36; p= 0.003). Although dexmedetomidine decreased systolic blood pressure by a weighted mean of 6.7 mm Hg and heart rate by 6.8 beats/min, no patients in the included trials required treatment for hypotension or bradycardia. The authors rated the overall quality of evidence as low to moderate because of inconsistency and imprecision. Importantly, the review identified 2 mcg/kg as the highest dose studied in the included trials but did not establish this as a recommended maximum dose or specify an absolute maximum total dose for pediatric preoperative use. [2]

A 2015 meta-analysis evaluated nonintravenous dexmedetomidine versus midazolam as preanesthetic medication in 1,033 children across 13 randomized controlled trials. Nine trials administered dexmedetomidine intranasally, with doses ranging from 0.5 to 2 mcg/kg; 2 mcg/kg was the highest intranasal dose evaluated, administered 30 to 40 minutes before anesthesia induction in children undergoing elective reconstructive surgery. Across all administration routes, dexmedetomidine doses ranged from 0.5 to 4 mcg/kg, although the 2.5-, 3-, and 4-mcg/kg doses were administered orally rather than intranasally. Compared with midazolam, dexmedetomidine increased satisfactory sedation at parental separation (74% vs 50%; RR 1.30; 95% CI 1.05 to 1.62; p= 0.02), reduced postoperative agitation (10% vs 40%; RR 0.31; 95% CI 0.13 to 0.73; p= 0.008), and reduced the need for postoperative rescue analgesics (20% vs 39%; RR 0.52; 95% CI 0.39 to 0.70; p<0.001); satisfactory sedation at anesthesia induction did not differ significantly. No differences were identified in hypotension, bradycardia, nausea and vomiting, laryngospasm, or shivering. Although this meta-analysis documents pediatric preoperative intranasal dosing up to 2 mcg/kg, it did not evaluate doses above 2 mcg/kg by the intranasal route or establish a maximum recommended intranasal dose. [3]

Background References: [1] Freriksen JJM, van der Zanden TM, Holsappel IGA, Molenbuur B, de Wildt SN. Best evidence-based dosing recommendations for dexmedetomidine for premedication and procedural sedation in pediatrics: outcome of a risk-benefit analysis by the Dutch Pediatric Formulary. Pediatr Drugs. 2022;24(3):247-257. doi:10.1007/s40272-022-00498-y.
[2] Jun JH, Kim KN, Kim JY, Song SM. The effects of intranasal dexmedetomidine premedication in children: a systematic review and meta-analysis. Can J Anaesth. 2017;64(9):947-961. doi:10.1007/s12630-017-0917-x.
[3] Pasin L, Febres D, Testa V, et al. Dexmedetomidine vs midazolam as preanesthetic medication in children: a meta-analysis of randomized controlled trials. Paediatr Anaesth. 2015;25(5):468-476. doi:10.1111/pan.12587.
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the maximum dose for intranasal (IN) precedex in pediatric patients? Specifically, is there data for a maximum dose when IN precedex is used preoperatively?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-2 for your response.

Optimal Dose of Intranasal Dexmedetomidine for Laceration Repair in Children: A Phase II Dose-Ranging Study
Design

Phase II, single-arm, dose-ranging study using the Bayesian Continual Reassessment Method

N= 55
Objective

To determine the optimal sedative dose of intranasal dexmedetomidine for children undergoing laceration repair
Study Groups

1 mcg/kg (n= 3)

2 mcg/kg (n= 9)

3 mcg/kg (n= 21)

4 mcg/kg (n= 22)
Inclusion Criteria

Children aged 0 to 10 years with a single laceration (<5 cm) requiring single-layer closure, who received topical anesthetic
Exclusion Criteria

Lacerations requiring debridement, planned intravenous procedural sedation, or regional anesthesia; concomitant fractures, dislocations, nailbed injuries; occlusion of at least 1 nare; hypersensitivity to dexmedetomidine; bradycardia or hypotension below the fifth percentile for age; renal insufficiency; uncorrected mineralocorticoid deficiency; cyanotic congenital heart disease or cardiac conduction disorder; weight more than 50 kg
Methods

Children were nonrandomly assigned to a single dose of intranasal dexmedetomidine 1, 2, 3, or 4 mcg/kg according to the Bayesian Continual Reassessment Method. Pharmacy-prepared kits contained dexmedetomidine 100 mcg/mL, with a maximum available dose of 200 mcg. The dose was administered using a mucosal atomizer, with ≤0.5 mL delivered per nare and a maximum of 2 pairs of sprays; pairs were separated by ≥60 seconds. Topical lidocaine 4%–epinephrine 0.1%–tetracaine 0.5% gel was placed immediately before dexmedetomidine administration, and laceration preparation was initiated 30–40 minutes after the final sprays. Procedures were video-recorded, and blinded assessors evaluated sedation and distress. The dose-escalation method defined the optimal dose as the dose having a probability of adequate sedation closest to 80%. Safety was reviewed after every 3 children before dose escalation. Efficacy outcomes were analyzed per protocol.
Duration

February 2, 2020 to March 26, 2022
Outcome Measures

Primary: Proportion with adequate sedation (Pediatric Sedation State Scale score of 2 or 3 for ≥90% of the time)

Secondary: Observational Scale of Behavior Distress–Revised scores, postprocedure length of stay, adverse events
Baseline Characteristics  

1 mcg/kg (n= 3)

 2 mcg/kg (n= 9) 3 mcg/kg (n= 21) 4 mcg/kg (n= 21)
Median age, years (IQR)

9 (5, 10)

 3 (2, 6) 3 (2, 4.5) 5 (3, 6)
Male

2 (67%)

 5 (56%) 14 (67%) 13 (62%)
Median length of laceration, cm (IQR)

2.5 (1, 3)

 3 (2, 4) 2 (1, 2) 2 (1, 2)
Median number of sutures (IQR)

4 (1, 5)

 5 (4, 6) 3 (2, 4) 3 (2, 3)
Results

Adequate sedation occurred in 1 of 3 (33%), 2 of 9 (22%), 13 of 21 (62%), and 12 of 21 (57%) children receiving intranasal dexmedetomidine 1, 2, 3, and 4 mcg/kg, respectively.

The corresponding posterior mean probabilities of adequate sedation were 0.38 (95% equitailed credible interval [CrI], 0.04–0.82), 0.25 (95% credible interval [CrI] 0.05–0.54), 0.61 (95% CrI 0.41–0.80), and 0.57 (95% CrI 0.36–0.76).

Median Observational Scale of Behavioral Distress–Revised (OSBD-R) scores during suturing were 2.7, 0, 0.6, and 0, respectively, while median postprocedure lengths of stay were 67, 76, 89, and 113 minutes, respectively.

One child in the 4-mcg/kg group experienced oxygen saturation below 90% for 30 seconds, which resolved with head repositioning; no other adverse events were reported.
Adverse Events

There was 1 adverse event, a decrease in oxygen saturation at 4 mcg/kg, which resolved with head repositioning.
Study Author Conclusions

Overlapping equitailed credible intervals suggested that intranasal dexmedetomidine doses of 3 or 4 mcg/kg produced similar sedative efficacy for laceration repair in children suggesting that either could be considered optimal. Although sedation efficacy may be less than what would be expected of intravenous agents, such as ketamine, intranasal dexmedetomidine, offers the advantage of avoiding painful needle-related procedures.
Critique

This prospective dose-ranging study directly compared intranasal dexmedetomidine doses through 4 mcg/kg and used blinded video-based outcome assessment; however, it evaluated emergency department laceration repair rather than preoperative premedication, and only 54 children contributed efficacy data. The highest studied dose was 4 mcg/kg, with study kits capped at 200 mcg, but the authors explicitly stated that safety above 4 mcg/kg had not been established; therefore, the study does not establish a universally recommended maximum dose for pediatric preoperative use.
Table 1 References:
[4] Poonai N, Sabhaney V, Ali S, et al. Optimal Dose of Intranasal Dexmedetomidine for Laceration Repair in Children: A Phase II Dose-Ranging Study. Ann Emerg Med. 2023;82(2):179-190. doi:10.1016/j.annemergmed.2023.01.023

Clinical Outcomes Associated With Intranasal Dexmedetomidine Sedation in Children
Design

Multicenter prospective observational study

N= 578
Objective To describe the quality of sedation and additional clinically-meaningful outcomes associated with different intranasal dexmedetomidine-based regimens in children undergoing nonpainful procedures
Study Groups

2–2.9 mcg/kg (n= 100)

3–3.9 mcg/kg (n= 318)

≥4 mcg/kg (n= 160)
Inclusion Criteria Children aged 2 months to 17 years undergoing MRI, ABR, ECHO, EEG, or CT scan
Exclusion Criteria Known allergy to dexmedetomidine, abnormal renal or hepatic function, concurrent use of digoxin or b-blockers, cardiac conduction abnormality or heart block
Methods Children received intranasal dexmedetomidine with or without adjunct sedatives (oral or intranasal midazolam). The dose and use of adjuncts were at the clinician's discretion. Outcomes were assessed using the Pediatric Sedation State Scale and other metrics. Monitoring included continuous pulse oximetry and blood pressure, with variations in cardiorespiratory monitoring across sites.
Duration September 2018 to January 2020
Outcome Measures

Primary: Quality of sedation (Pediatric Sedation State Scale)

Secondary: Procedure completion, time-based outcomes (time to onset, duration, recovery), adverse events and interventions
Baseline Characteristics   All patients (n= 578) 2–2.9 mcg/kg (n= 100) 3–3.9 mcg/kg (n= 318) ≥4 mcg/kg (n= 160)
Sex - Female 217 (37.5%) 51 (51%) 110 (34.6%) 56 (35%)
Sex - Male 361 (62.5%) 49 (49%) 208 (65.4%) 104 (65%)
Age, 0–2 mo 3 (0.5%) 1 (1%) 0 2 (1.3%)
Age, 3–11 mo 66 (11.4%) 9 (9%) 43 (13.5%) 14 (8.8%)
Age, 1–2.9 y 281 (48.6%) 58 (58%) 151 (47.5%) 72 (45%)
Age, 3–7.9 y 203 (35.1%) 24 (24%) 115 (36.2%) 64 (40%)
Age, 8–12.9 y 14 (2.4%) 3 (3%) 6 (1.9%) 5 (3.1%)
Age, ≥13 years 11 (2%) 5 (5%) 3 (0.9%) 3 (1.9%)
Results   All doses and regimens (n= 578)* 2–2.9 mcg/kg (n= 100)** 3–3.9 mcg/kg (n= 318)** ≥4 mcg/kg (n= 160)**
Acceptable Sedation State 469 (81.1%) 30 (78.9%) 195 (89%) 76 (80.9%)
Procedure Completed 528 (91.3%) 36 (94.7%) 216 (98.6%) 83 (88.3%)
Oversedation 10 (1.8%) 1 (2.7%) 3 (1.4%) 0
Undersedation 44 (8.1%) 2 (5.4%) 15 (6.8%) 14 (14.9%)

*Total all doses and regimens

**IN DEX dose (no adjunct sedative)
Adverse Events Bradycardia (1.9%), hypotension (0.7%), snoring or partial airway obstruction (1%), oxygen desaturation (0.9%), apnea (0.2%), complete airway obstruction (0.2%), agitation (1.3%), vomiting (0.2%).
Study Author Conclusions Intranasal dexmedetomidine-based regimens can achieve acceptable sedation states and high rates of procedure completion in children undergoing sedation for nonpainful procedures with a low incidence of adverse events requiring serious airway, breathing, or cardiovascular interventions.
Critique The study's strengths include its multicenter design and large sample size, which enhance the generalizability of the findings. However, the observational nature limits the ability to establish causality, and the convenience sampling for ECHO procedures may introduce bias. Additionally, the study did not enroll sufficient numbers in all subgroups for robust comparisons.



Table 2 References:
[5] Tsze DS, Rogers AP, Baier NM, et al. Clinical Outcomes Associated With Intranasal Dexmedetomidine Sedation in Children. Hosp Pediatr. 2023;13(3):223-243. doi:10.1542/hpeds.2022-007007