Clonidine Versus Midazolam Premedication and Postoperative Negative Behavioral Changes in Younger Children: A Randomized Controlled Trial

Abstract

BACKGROUND: Postoperative negative behavioral changes (NBCs) are common among children, but risk for this is thought to be reduced with premedication. Midazolam has for many years been a standard premedication for children. More recently, the alpha-2 adrenergic agonist clonidine has also become popular as a preanesthetic sedative. We hypothesized that clonidine was superior to midazolam for limiting new NBCs in children as assessed using the Post Hospital Behavior Questionnaire (PHBQ). METHODS: This was a prospective, randomized, controlled, blinded study, including 115 participants aged 24 to 95 months and their parents. The participants underwent ear, nose, or throat outpatient surgery and were randomly allocated to premedication with oral midazolam 0.5 mg/kg or oral clonidine 4 µg/kg. Participants were anesthetized by protocol. At home, later, parents were asked to complete the PHBQ assessment instrument for postoperative NBCs for the participants 1 week, 1 month, and 6 months after the surgery. A secondary outcome, preinduction anxiety, was assessed using modified Yale Preoperative Anxiety Scale (mYPAS). RESULTS: The primary outcome, more than 3 NBCs in an individual case at 1 week, showed no difference in proportions between treatment in the clonidine group compared to the midazolam group, (12/59 or 20% vs 7/56 or 13%, respectively, odds ratio 1.39, 95% confidence interval [CI], 0.75-2.58; P = .32). A secondary result showed a higher preinduction anxiety level in the clonidine compared to the midazolam group (mYPAS >30, 43/59 or 71% vs 12/56 or 21%, respectively; P < .001). CONCLUSIONS: These results did not show a clinical or statistically significant difference, with respect to the primary outcome of behavior changes at 1 week, between the cohorts that received midazolam versus clonidine as a premedication. (Anesth Analg 2022;135:307-15) KEY POINTS• Question: Is clonidine more beneficial as a premedication than midazolam for small children, in terms of postoperative negative behavioral changes? • Findings: Clonidine was not better than midazolam for this outcome as assessed at 1 postoperative week, though midazolam may be more effective in limiting preinduction anxiety. • Meaning: While neither of these premedications prevents postoperative negative behavioral changes in younger children, they may have differential effects at different times in the perioperative process.

Preoperative anxiety level is not associated with postoperative negative behavioral changes in premedicated children

“…13,14 The details concerning this outcome have been presented earlier. 10 day at home, rescue morphine directly postoperatively, and adverse events including new symptoms for prolonged nausea/vomiting within the first week. Instruments used for pain scoring were Face Legs Activity Cry Consolability (FLACC) 15,16 and Faces Pain Scale-Revised (FPS-R).…”

“…The PHBQ outcome definition used here is explained in some depth in the original trial publication. 10 Premedication can be useful for calming an anxious child and to get a smooth anesthesia induction, but this may not affect the development of meaningful postoperative NBCs. Exactly what causes post-NBCs can be multifactorial and differ from child to child.…”

“…[7][8][9] These results bring into question whether levels of preanesthesia anxiety in children are associated with or could predict postoperative negative outcomes. In this secondary analysis of results from a recently published premedication trial in children, 10 we aimed to assess the relationship between preinduction anxiety level in premedicated children and development of postoperative NBC, regardless of premedication type. The null hypothesis is that there is no relationship between preanesthetic anxiety scores and postoperative NBC.…”

A new view on old problems in paediatric anaesthesia: premedication, postoperative agitation and dosing

“…Midazolam is primarily an anxiolytic drug [7 ▪▪ ,8 ▪▪ ] and, at least in children, the sedative properties are moderate at best. In a dose-finding study with the oral cyclodextrin-based preparation ozalin, no additional sedation could be achieved with doses of more than 0.25 mg/kg [9].…”

“…Dexmedetomidine is considered to be a suitable [12 ▪ ] or even superior agent [13] for premedication compared with midazolam; this judgement was mainly based on the observation of more peaceful recovery and improved postoperative analgesia. However, recently two articles comparing midazolam with clonidine [7 ▪▪ ] and midazolam with clonidine and dexmedetomidine [8 ▪▪ ] showed that α 2 -agonists cause marked sedation, but virtually no anxiolysis. Anxiolysis (what we usually want) and sedation (what we can easily see) are not the same entities.…”