Role of dexmedetomidine in pediatric dental sedation

One of the simplest and popular routes for drug administration is the oral route. Its advantages include simplicity and ease of administration, affordability, risk free, and worldwide acceptance. In pediatric dental care, the ease of administration by this route makes it favorable. The rate of drug absorption via the oral mucosa is influenced by multiple factors, including the duration of its contact with the mucosa, its pKa, lipophilicity, quantity of saliva, and physiochemical characteristics at the site of action [15, 16]. At physiological pH, dexmedetomidine is present in a nonionized form and has a pKa value of 7.1. Being a highly lipophilic drug, it is easily transported into tissues [17].

Multiple studies have reported that in approximately 90 min post administration, it permeated the oral mucous, achieved a buccal bioavailability of 82%, and achieved its highest concentration [18]. However, the most widely used oral pediatric sedative, midazolam, is more lipophilic. At a pH of 4.0–4.5, the closing of its imidazole ring occurs. This high pH leads to its high lipid solubility in and fast absorption via the oral mucosa [19]. When 0.5 mg/kg midazolam is orally administered as a premedication, its mucosal absorption is likely to be reliant on its pH [6]. Some of the adverse effects associated with its 70% oral bioavailability include restlessness and postoperative respiratory depression [6].

It has been reported that the high hepatic first pass metabolism associated with oral drug administration is responsible for the low (16%) bioavailability of dexmedetomidine post oral administration, compared with 82% post buccal administration [18, 20]. As a result, the benefits of orally administered dexmedetomidine are low compared with those of midazolam [21]. Oral administration reportedly leads to few side effects such as gastric disturbances and change in taste, and shortcomings such as longer recovery time, high first pass metabolism, and slow onset of action [22].

Oral dexmedetomidine needs to be administrated at most 40 min before the induction of anesthesia, to attain the most favorable sedative effect. Previously, it has been demonstrated that with midazolam, moderate sedation is achieved about 20 min post administration [23].

Post intravenous administration, the half-life of dexmedetomidine and its terminal elimination half-life are about 6 min and 2 h, respectively. The administration of 0.2–0.7 µg/kg/h dexmedetomidine over a 24 h period leads to the linear expression of its pharmacokinetic effects.

Dexmedetomidine exerts a biphasic effect on blood pressure; as its concentration decreases, vasodilatation increases, due to its central effect. Doses of 0.25–1 µg/kg in adults and 0.5–6 µg/kg/h in children decrease blood pressure by 13–16% and 20%, respectively. Therefore, dexmedetomidine should be administered slowly as it results in unwanted blood pressure changes [5, 24].

Intranasal route is popular in pediatric sedation owing to its numerous advantages. It is void of the injections like in the intravenous and intramuscular routes, and the bitter taste associated with oral administration. Intranasal administration is easy, safe, effective, and non-invasive. In children the acquiescence to sedation via intranasal administration is higher than that of oral administration [20].

Intranasal drug delivery is also favorable in children when time is limited [25]. At most, 0.15–0.2 ml should be administered in each nostril, as volumes greater than this will be partly absorbed orally [25]. Dexmedetomidine is best absorbed after sublingual and intranasal administration, with a bioavailability of about 82% post intranasal administration.

However, midazolam has been the preferred intranasally administered premedication in children due to its ease of administration and efficiency [26]. Notwithstanding, its use is restricted by the resulting irritation and burning feeling in the nasal mucosa [20]. Yuen et al. [6] conducted a clinical trial to assess the efficacy of intranasal dexmedetomidine and oral midazolam in pediatric premedication. They reported that premedication by intranasal administration of 1 µg/kg dexmedetomidine produced moderate sedation compared to oral administration of midazolam [6]. Reportedly, the time of onset of the sedative effect after the administration of 1–1.0 µg/kg dexmedetomidine intranasally is about 45 min, with a peak onset at 1.5–2.5 h [4, 27].

A randomized double-blind controlled trial on 2–12-year-old children showed that intranasal administration of 0.5–l µg/kg dexmedetomidine produces a stronger sedative effect than oral administration of 0.5 µg/kg midazolam [27]. Additionally, intranasal dexmedetomidine administration in children results is inadequate hemodynamic effects; however, these actions are clinically irrelevant and no interference is needed [6]. Maximum reduction of systolic blood pressure (14.1%) and heart rate (16.4%) were observed after the intranasal administration of 0.5 and l µg/kg dexmedetomidine, respectively.

The nasal mucosa has an abundant blood supply, leading to quick drug absorption and onset of action. Additionally, the proximity and access to the CSF via the subarachnoid space, and the olfactory nerve and its sheath leads to speedy attainment of desired CNS levels and quicker onset of action [6]. All these make intranasal dexmedetomidine administration more tolerable and favorable in children than oral administration.

The intramuscular administration of up to 2.5 µg/kg dexmedetomidine as premedication has previously been reported [13]. Also, it was suggested that the intramuscular route permits a rapid onset of action and offers better predictability because its plasma concentration peaks within 15 min of administration [5].

In children, an ideal premedication must: 1) be available in an acceptable form; 2) have a rapid onset of action; 3) provide mild sedation along with the desired anxiolytic effect; 4) exert its effects for a desired time; 5) have no adverse effects; and 6) facilitate post-operative recovery. Midazolam, commonly used as premedication in children, has been reported to significantly ameliorate preoperative anxiety and nervousness [6].

Some studies have recommended the use of dexmedetomidine as a premedication for children, to decrease anxiety and the occurrence of delirium [21]. It is recommended that 0.33–0.67 mg/kg (i.v) or 2.5 µg/kg (i.m) should be administered 15 min before operations [13]. A meta-analysis of dexmedetomidine as a premedication reported that, compared to midazolam, it results in greater preoperative sedation and decreased postoperative pain [28]. Another meta-analysis reported the observation of a similar effect on postoperative pain, significant reduction in the doses of rescue analgesic drugs, decreased anxiety with parental separation and decreased postoperative agitation with dexmedetomidine compare with midazolam [4].

Dexmedetomidine is used for short sedation (≥24 h) of intensive care unit patients [3]. Its safety as a sedative is owed to its minimal induction of respiratory distress and high Carrico index: known as the ratio of the partial pressure of arterial oxygen and fraction of oxygen inspired [13].

The analgesic effect of dexmedetomidine results from its stimulation of central nervous system α2-adrenergic receptors. A recent systematic review of various randomized control trails on α2-adrenergic receptor agonists stated that the post-operative clinical use of dexmedetomidine was sparsely similar to that of morphine as they both decrease the intensity of pain in the 24 h postoperative period [29].

The anxiolytic effect of dexmedetomidine in premedication has been proven comparable to that of benzodiazepines. Overall, dexmedetomidine decreases the requirement of additional sedatives and post-operative delirium [3].