Efficacy of different doses of dexmedetomidine as a rapid bolus for children: a double-blind, prospective, randomized study

Dexmedetomidine (DEX), a highly selective α₂-adrenoreceptor agonist, offers anxiolytic, sedative, and analgesic effects with negligible respiratory depression [1‐3].DEX has been approved for use in adults, but the US Food and Drug Administration has not approved the drug for children. However, DEX has been documented in pediatric patients as a premedication, a sedative in the pediatric intensive care unit, in conjunction with inhaled anesthetic agents, and as a therapeutic for the prevention and treatment of emergence agitation (EA) following general anesthesia [4‐6]. EA, particularly in children, presents a great challenge to good patient care [7, 8]. While 2-, 5-, or 10-min DEX infusions lower the occurrence of EA in pediatric patients [9, 10], it is typically not convenient to administer a bolus infusion in the clinical area of an elevated-turnover work-intensive pediatric anesthesiology unit. A quickly administered bolus injection, if deemed to be hemodynamically appropriate, would be a more opportune route of administration to avert and treat EA. Jooste EH et al. [11] had observed that rapid IV bolus administration of DEX in 12 children who underwent heart transplants was clinically well-tolerated, although its use resulted in a transient but significant increase in systemic and pulmonary blood pressure and a decrease in heart rate (HR). In addition, Hauber JA et al. [12] documented that fast IV bolus administration of 0.5 μg/kg DEX improved pediatric patients’ recuperation profile by lowering the occurrence of EA. Although a statistically significant change in hemodynamics was observed, no patient required intervention for hemodynamic changes. However, the aforementioned studies used either a small sample study or only one dose. DEX is often used to avert and treat postoperative agitation in dosages of 0.25–1 μg/kg, and many clinical institutions now commonly administer DEX as a rapid (under 5 s) IV bolus. Therefore, our study examined the efficacy of different doses of DEX as a rapid bolus for prevention and treating EA in pediatric patients.

There were 100 pediatric patients who were enrolled and randomly divided into five groups. As seen in Table 1, there were no significant demographic and surgical characteristic differences among the groups.

The incidence of EA was significantly lower in groups D₄ and D_5, and a trend of fewer was observed in group D₂ and D₃ (Table 2).

There were no significant differences in the basal HR among the five groups. In group D₁, there were no significant differences among the basal HR and every minute for 5 min thereafter, but the HR at the point of the hernial sac pull was increased significantly compared with the baseline. In group D₂, the HR was decreased at 1 min compared with the baseline, and then returned to the baseline at 2, 3, 4 and 5 min, and the points of skin cut, but the HR at the point of the hernial sac pull was increased significantly compared with the baseline. In group D₃, the HR was decreased at 1, 2,3 and 4 min compared with the baseline, and the HR returned to the baseline at 5 min, the points of skin cut and hernial sac pull. In groups D₄ and D₅, the HR was decreased at 1, 2, 3, 4 and 5 min compared with the baseline, and the HR returned to the baseline at the time point of the skin cut and hernial sac pull (Table 3).

The minimal HR of groups D₃, D₄, and D₅ were decreased significantly compared with groups D₁. And the duration time of minimal HR was significantly prolonged in group D₅ compared with group D₁. There were no significant differences in occurrence time of minimal HR among groups (Table 4).

There were no significant differences in the basal MBP among the five groups. In group D₁, there were no significant differences among the basal MBP and every minute for 5 min thereafter, but the MBP at the point of the hernial sac pull was increased significantly compared with the baseline. In group D₂, the MBP was decreased at 2, 3, 4, and 5 min compared with the baseline, and the MBP returned to the baseline at the point of skin cut and hernial sac pull. In group D₃ and D₄, the MBP was decreased at 3, 4, and 5 min compared with the baseline, and the MBP returned to the baseline at the point of skin cut and hernial sac pull. In group D₅, the MBP was decreased at 5 min and the points of the skin cut and hernial sac pull compared with the baseline (Table 5).

There were no significant differences in incidencerate of complementary medicine, adverse events, and bradycardia (we defined bradycardia as HR decrease of ≥30% during the 5-min observation period postdexmedetomidine bolus, compared to predexmedetomidine bolus baseline values). There were eight patients who had a 30% decrease from the baseline of HR, and none of the patients required treatment for bradycardia. Four patients needed propofol to treat EA, and no one needed treatment for bradycardia, pain, or other adverse events, including cough, headache, and vomiting (Table 6). All of the patients with spontaneous respiration could maintain SaO₂ ≥ 98%.There were significant differences in the recovery time between every two groups (P < 0.05) (Table 7).

Even without a pediatric label, additions to the literature on pediatric applications of DEX have risen in the last few years [4]. DEX has numerous properties that make it beneficial as a sedative and anesthetic; it has been documented to sedate in a manner that is similar to natural sleep, and it is used as an anxiolytic, analgesic, and sympatholytic [1, 2, 13]. In addition, it has an anesthetic-sparing impact with negligible respiratory depression, and it can be used to avert and treat postoperative EA [13]. The hemodynamic reactions of DEX are related to the rate of infusion and dose [5]. Although it is recommended that DEX is infused as a bolus over 10 min, the BP and HR response are still present [2, 14]. As doses of DEX get larger, hypotension and transient hypertension are greater. While there are many clinical encounters in the rapid bolus injection of DEX, there is minimal efficacy data that are accessible [11, 12, 15].

In our study, we found that 0.75 and 1.0 μg/kg DEX rapid infusion could significantly reduce the incidence of EA, while 0.25 and 0.5 μg/kg DEX had the fewer trend. Hauber JA et al. [12] had found that 0.5 μg/kg DEX rapid infusion could reducing the incidence of EA. The difference may because different subjective evaluation of the score of PAED and the smaller sample size. In addition, 0.5, 0.75 and 1.0 μg/kg DEX could reduce the surgical stress of the hernial sac pull. As the dosage increased, the recovery time was significantly prolonged, but there were no significant differences in the incidence of total adverse events. EA is a traumatic experience for children and their parents, and it can result in injury [16]. DEX has been well reported as an effective agent for EA, and the rapid bolus administration of DEX for the treatment of EA is more practical and timely than a 10-min infusion.

DEX could significantly decrease HR and MBP. The minimal HR was significantly lower after the administration of DEX in the dose of 0.5, 0.75 and 1 μg/kg, and the duration time was significantly prolonged after 1.0 μg/kg DEX infusion, but no one needed treatment. In human and animal models, DEX has a biphasic blood pressure impact: a preliminary but transitory elevation in blood pressure accompanied by a long-lasting hypotensive effect that is induced by peripheralα₂-adrenoreceptor and then central α₂-adrenoreceptor stimulation [11, 12, 17]. Therefore DEX should be administered as a loading dose during a 10-min period to diminish the dose-dependent, biphasic, hemodynamic reaction. In our study, hypertension was not seen, this could have happened since the rapid infusion of DEX eradicated the time differential between the stimulation of the peripheral and central α₂-adrenoreceptor.

The general agreement seems to be that DEX is linked to minimal respiratory depression [1, 5, 17, 18]. Our study found that the rapid injection of DEX can cause a decrease in tidal volume, but it does not affect SaO₂ without special handling. This may because deep sedation and oral/pharyngeal anatomic frequently happened in deep sleep after the administration of DEX.

In conclusion, rapid infusion of DEX at dose of 0.75, and 1.0 μg/kg DEX could prevent EA. Even though the use of DEX resulted in transient decreases in HR and MBP, the drug is well-tolerated in pediatric patients. Our study provides a new clinical application for the rapid intravenous injection of DEX for the prevention and treatment of EA.