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

Children are known to potentially suffer negative behavioural changes (NBC) following general anaesthesia and surgical/diagnostic procedures. These may be new or a worsening of pre-existing behaviour. Premedications such as midazolam and clonidine are thought to not only help allay preoperative anxiety, but possibly reduce the incidence of NBCs. Clonidine’s longer lasting sedative effect may make it better at limiting postoperative NBCs.


Inclusion criteria: children aged 24-95 months, ASA 1&2, undergoing day case ENT surgery, including tonsillectomies.
Patients were stratified into two age groups (24-59months and 60-95 months), by sex and surgery (tonsillectomy and non-tonsillectomy groups).
Patients were then randomised to either midazolam (0.5 mg/kg PO 30 mins before start) or clonidine (4 mcg/kg PO 60 mins before start). All study personnel were blinded to medication given. A standard GA protocol was given, including analgesia appropriate for the operation.

Assessments/measurements performed:

Preoperatively: Anxiety, using a modified Yale Preoperative Anxiety Scale (mYPAS)
Recovery room: Occurrence of PONV, pain (FPS-R or FLACC scale depending on age group) including use of rescue analgesia
Home (after 24hrs at home): PONV, pain
Home (at one week, one and six months postop.): Parents answered a Post Hospital Behaviour Questionnaire (PHBQ). This was a multi-question assessment looking at a wide spectrum of behavioural changes including general anxiety, eating and sleeping disturbances, regression/aggression etc. Behaviour was compared to preoperative levels.
Primary outcome: Incidence of ≥ 4/25 Negative Behavioural Changes (NBC) at one week.
Secondary outcomes: Incidence of ≥ 4/25 NBCs at one month and six months. PONV, pain, rescue analgesia post op and preop anxiety. Analysis was done by premedication given and also by subgroups (see above).


A total of 115 children returned completed PHBQs.
Primary outcome: A majority (60) of children had no NBCs at one week. More children in the clonidine group (12/59, 20.3%) had ≥ 4NBCs compared to the midazolam group (7/56, 12.5%) but the difference was not significant (OR1.39, 95%CI 0.75-2.58, P=0.32).
Secondary outcomes: There was no significant differences between premedications for the incidence of NBCs at one or six months. Preinduction anxiety was more common in those receiving clonidine (43/59, 71%) vs. midazolam (12/56, 21%) (P=<0.001). There were no significant differences for PONV or pain scores for recovery room & first postoperative day. The use of rescue morphine in recovery was significantly more common in the midazolam group.
Regression analysis of subgroups showed an association between younger age and a higher risk of NBCs.


There was no difference in the incidence of NBCs between premedications either early or late in the postoperative period. Clonidine may be associated with less use of analgesics in the immediate postoperative period (although pain scores were similar?). Midazolam was a better preoperative anxiolytic than clonidine. It should be remembered that PHBQs rely upon parental recall which can be inaccurate with time and also influenced by other positive and negative perioperative experiences.

Take home message

I will continue to use oral midazolam as my first line anxiolytic premedication (effective, convenient and cheap) with the lack of increased postoperative NBCs compared to clonidine, being a reassuring factor.

Reviewed by Dr Henrik Hack