A
comparison of oral dexmedetomodine and oral midazolam as premedicants in
children.

Abstract

Background
and Aims: Midazolam has been the most popular oral
premedicant in children despite its side effects. Dexmedetomidine with its
favourable clinical profile is a suitable alternative, but with limited
research. The aim of this study was to compare the effectiveness of
dexmedetomidine and midazolam as oral premedicants in children.

Material
and Methods: 80 children of American
Society of Anesthesiologist physical status ? scheduled for elective herniotomy
were included in this prospective randomized double blind study. Patients were
randomly assigned to receive either dexmedetomidine 4 µ/kg (Group A, n=40) or
midazolam 0.5 mg/kg (Group B, n=40) orally 40 min prior to induction.
Pre-operative sedation, response to parental separation and venepuncture,
emergence agitation, recovery nurse satisfaction and side effects were compared
between the two groups. Quantitative
data was compared using unpaired Student’s t-test and categorical variables with Chi-square test.

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Results:
Pre-operative sedation, response to parental separation and venepuncture were
similar between the two groups. Group A had a significantly lower incidence and
severity of emergence agitation (P= 0.000). Recovery nurse satisfaction was
significantly higher in Group A (P= 0.002). However, incidence of hypotension
and bradycardia was found to be more in Group A (P= 0.04).

Conclusion: Premedication with oral dexmedetomidine
is as effective as oral midazolam in providing sedation and anxiolysis in
children. Dexmedetomidine in addition reduces the incidence and severity of
emergence agitation.

 Keywords:
Dexmedetomidine, midazolam, pediatric,
oral premedication.

 

Introduction

Apprehensive, crying and
uncooperative children are not rare sights in operation theatre. Incidence of preoperative
anxiety is about 60 – 70% in pediatric
population.1 This is associated with increased risk of
negative effects such as difficult induction, postoperative agitation and
increased postoperative pain.2 Delayed psychological and
behavioural changes like night time crying, enuresis, separation anxiety,
decreased eating and temper tantrums can also result from excessive
perioperative anxiety.2 Sedative premedication is an effective
method to allay anxiety and provide a calm and cooperative child.3
Being atraumatic, oral premedication is easily accepted by children. Midazolam,
a benzodiazepine is one of the commonest sedative premedication prescribed.4
Though midazolam has a strong record of safety and efficacy, it has no
analgesic effect. Several untoward effects like restlessness, paradoxical
reaction, respiratory depression and negative post-operative behaviour has been
described with midazolam.2,5 So search for a better alternative is
always in vogue.

         Dexmedetomidine
is a highly specific ?2 agonist with sedative, analgesic and anxiolytic properties
and minimal respiratory depression.2,6,7 Use of dexmedetomidine in
paediatric anaesthesia is increasing because of its favourable safety profile.
However there is limited literature regarding its use as oral premedicant in
children though preliminary studies have shown promising results.2,8 We hypothesised
that dexmedetomidine is a suitable alternative to midazolam as oral
premedication in children.

This prospective randomized double blind study was
conducted to compare the efficacy of dexmedetomidine and midazolam as oral premedicants
in children undergoing herniotomy. Effects of premedication were assessed with
regard to preoperative sedation, response to parenteral separation, response to
venepuncture and incidence and severity of postoperative emergence agitation.
Secondary outcomes studied include hemodynamic stability and incidence of
adverse effects of drugs.

     

Materials and Methods

           After approval from Institutional Ethics Committee and written informed
consent from a parent, this prospective randomized double blind study was
conducted in 80 children of either sex, aged 1-6 years belonging to the
American Society of Anesthesiologist physical status ?, posted for herniotomy
under general anesthesia. Patients with known allergy to study drugs, mental
retardation or neurobehavioral problems were excluded from the study. In
a previous study, 21.9% patients in midazolam group
and 75% in dexmedetomidine group had satisfactory sedation scores at
separation.9 Targeting the same
difference, with 95% confidence level and 80% power, minimum sample size was
calculated as 17 in each group. We included forty patients in each group in our
study. Children were randomized using computer generated random numbers to two groups
of 40 each to receive: Group A: Oral dexmedetomidine 4 µg/kg and Group B: Oral
midazolam 0.5 mg/kg respectively; 40 min prior to induction.

Before giving the premedication, heart
rate (HR), systolic blood pressure (SBP) and oxygen saturation (SpO2)
were recorded. The emotional status of the children were assessed and graded
using a 4 point scale (Grade 1- Calm, Sleepy; Grade 2- Apprehensive; Grade 3-
Crying; Grade 4-Thrashing).

An injectable
preservative free preparation of the study drugs mixed in 5ml of honey was
administered by a nurse not involved in the observation or anesthetic care, in
the preoperative holding area in presence of a parent. All children who refused
to take the premedication or spat it out or vomited were excluded from the
study protocol. The patient/parent, observer and the attending anesthesiologist
were blinded to the study drug given.

The level of sedation was
assessed 30 minutes after premedication using a 5 point grading system (Grade
1- Awake and anxious; Grade 2- Awake, not anxious;     Grade 3 – Eyes closed, responds to speech;
Grade 4           – eyes closed, responds
to shaking; Grade 5 – Unresponsive). Grades 1 and 2 were grouped as poor sedation and grades 3 and 4 were considered as good sedation.

Children were separated
from the parent 40 min after premedication and the behaviour of the child on
separation from parents was assessed and graded using the parental separation
anxiety scale (PSAS). Grade 1- Easy separation, Grade 2- Whimpers, but is
easily reassured, not clinging, Grade 3 – Cries and cannot be easily reassured,
but not clinging, Grade 4 – Crying and clinging to parents. A PSAS score of 1
and 2 were considered as acceptable separation from parents and grades 3 and 4 were taken as not acceptable.

The child was taken inside the operating
room and response to venepuncture was graded using 4 point IV (intravenous)
acceptability score.  Grade 1- asleep,
not responsive to painful stimulus and IV cannulation, Grade – 2 calm, awake,
but not crying, no withdrawal to painful stimulation or IV cannulation, Grade –
3 withdrawal to painful stimulus, but allows for IV cannulation, Grade- 4 crying
and uncooperative, not able to start IV line. Grade1 and grade 2 was considered
as ideal and grade 3 acceptable condition
for venepuncture. Grade 4 was taken as not acceptable.

            After establishing standard
monitoring, IV induction was done with thiopentone sodium and maintained on
spontaneous ventilation through face mask with 66% nitrous oxide in oxygen and
titrated concentration of isoflurane. All patients received fentanyl 1 µg/kg
followed by caudal epidural block with 1 ml/kg 0.25% bupivacaine. Throughout
the procedure and in the recovery, HR, SBP and SpO2 were monitored. Side
effects of the drugs like nausea, vomiting, respiratory depression, bradycardia
and hypotension were looked for. Bradycardia
is defined by HR < 80 bpm in 1-3 years and < 70 bpm in 4-6 years and hypotension by SBP < 70 mmHg in 1-3 years and < 80 mmHg in 4-6 years. In the post anesthesia care unit (PACU), occurrence and severity of emergence agitation was measured using the Pediatric Anesthesia Emergence Delirium Scale (PAEDS) at the time when child was fully awake or at the pinnacle of the agitation.10 A score greater than 10 was taken as presence of EA (emergence agitation).  Satisfaction of the recovery nurse who is blinded to the study groups was recorded using a five point scale ((1 = very dissatisfied, 2 = somewhat dissatisfied, 3 = neutral, 4 = somewhat satisfied, 5 = very satisfied) before the patient was discharged to the post-operative ward.   Statistical Analysis: The numerical data were compared using the unpaired Student's t-test and reported as mean ± standard deviation (SD). The categorical variables were compared by the Chi-square test and reported as median with interquartile range (IQR) and also numbers and percentages. A P value of 0.05 or less was set for assessing the statistical significance. Analysis was done by using the PASW statistics for Windows, Version18 (Chicago. SPSS Inc, IBM Corp. 2010).                                                                                                                                                                                                                                                                                                                                                     Results Eighty children scheduled for inguinal herniotomy were enrolled in the study and assigned to Group A (n = 40) and Group B (n = 40). There were no statistically significant difference among the groups with respect to demographic characteristics and the duration of surgery Table 2. All patients included in the study were ASA class ?. The emotional status assessed prior to premedication was comparable in both groups (P = 0.514) Table 2.  The sedation score after 30 min of premedication, the parental separation anxiety score and IV acceptability score were comparable between the two groups Table 3. Four patients in group A developed bradycardia and hypotension, but none in group B had these side effects (P = 0.04). Emergence agitation was significantly less in Group A than Group B (P = 0.000), Figure 3. Higher Nurse Satisfaction Scores were seen in Group A (P = 0.002), Figure 4.   Discussion Children aged 1-5 years are at maximum risk of experiencing severe preoperative anxiety and has highest incidence of EA.10,11 This not only causes suffering in children, but negatively affects their recovery and necessitate utilization of additional resources too. The rational use of premedication makes the patient's surgical experience better, safer and more pleasant without increasing the cost of health care.3,10 Midazolam is considered as the gold standard in premedication by many. It is an effective sedative, anxiolytic with a fast onset of action and provides anterograde amnesia. But many authors consider it suboptimal for premedication in children. They advocate use of ?2 agonists with additional analgesic effect in children.2 ?2 agonists produce sedation that is similar to normal sleep and do not affect memory. Our study involved 80 children in the age group 1-6 years with high risk of preoperative anxiety. The two groups had comparable demographic profile in addition to similar base line emotional status and duration of surgery. Dexmedetomidine was used in a dose of 4 µ/kg to circumvent poor bioavailability after oral administration as recommended by Zub et al. and Mountain et al.8,11 This also explains the delay in onset of action of dexmedetomidine necessitating it to be administered at least 40min prior to induction as evident from previous studies. Parenteral preparation of dexmedetomidine is colourless, odourless and tasteless unlike midazolam which is bitter to taste.  However, none of our children spat out the drug mixed in honey. In our study, sedation score at 30min was similar in both groups. 45% of children in dexmedetomidine group and 57.5% in midazolam group were very well sedated at 30 min. This is contrary to findings of Kumari and colleagues who found faster onset and higher mean sedation scores at 30, 45 and 60 min with oral midazolam.12 Jannu et al. also confirmed early onset of sedation and faster achievement of peak sedative effect in midazolam group compared with oral dexmedetomidine.13  Though we did not study the onset of sedation, both drugs were found to be equally effective in producing sedation at 30 min. No patient in either group became unarousable. We found satisfactory sedation with both drugs as early as 30 min, though long onset time was one of the disadvantages quoted in many studies against dexmedetomidine.12,13 Awake IV placement, parental separation and induction are the time points of maximum anxiety in children during preoperative period. We observed no significant difference in the parental separation anxiety score at 40 min between the two groups akin to Jannu et al.13 Acceptable parental separation was found in 92.5% and 95% of children belonging to dexmedetomidine and midazolam groups respectively (P=0.644). In contrast to our findings, Kumari and coworkers found oral midazolam to be superior to dexmedetomidine in providing easy separation from parents.12 Mountain et al. however could not find any significant difference with regard to acceptable behaviour at parent separation or mask acceptance in children receiving these two premedicants 30 min prior to induction.11  Children in both the study groups had similar IV acceptability scores; 17.5% children in dexmedetomidine group and 20% in midazolam group resisted venepuncture. Zub and colleagues reported easy IV cannulation in children with neurobehavioral disorders premedicated with oral dexmedetomidine in whom previous attempts at sedation had failed.8 Prabhu and Mehandale observed three times better mask acceptance and induction environment in the dexmedetomidine group unlike findings of Kumari et al.12,15 Emergence agitation is a common problem encountered in pediatric anesthesia (20-30%).10,11,14 Anxious children have a higher incidence of EA.3 An agitated child disrupts the controlled environment of PACU. It not only inflicts harm to the patient, but also puts strain on health care personals and increases resource utilization. Post-operative pain is an important aggravating and confounding factor for EA. We ensured good pain relief with fentanyl and caudal epidural block. PAEDS score was used to identify and assess severity of EA. PAEDS score was significantly lower in the dexmedetomidine group (P = 0.000). Prabhu and Mehandale reported a reduction in the incidence and severity of EA with oral dexmedetomidine premedication compared to oral midazolam; similar to Jannu et al.13,15 Mountain et al. however could not demonstrate any advantage of dexmedetomidine over midazolam.11 Zhu et al. undertook meta-analysis involving 20 RCTs of dexmedetomidine on EA and found that use of dexmedetomidine reduced the occurrence of EA when compared to placebo regardless of route of administration or surgical procedure, but prolonged discharge from recovery. They did not find significant difference in the incidence of EA between patients receiving dexmedetomidine, fentanyl or midazolam, but cautioned against that interpretation as only few studies were included.16 Recovery nurse satisfaction was found to be better in dexmedetomidine group (P=0.002). In our study, incidence of bradycardia and hypotension was significantly more in dexmedetomidine group; possibly an exaggeration of its physiological effects, but was amenable to treatment. Prabhu and Mehandale observed consistently lower HR in dexmedetomidine group which required treatment with atropine in few patients.15 They also reported lower MAP which was not clinically significant in patients receiving oral dexmedetomidine.  However Kumari et al. and Mountain et al. noticed no significant hemodynamic side effects with dexmedetomidine.11,12 None of the patients in the study had episodes of desaturation, reinforcing the safety of both drugs. Limitations of the study - Oral preparation of midazolam and dexmedetomidine were not available, so IV preparations of drugs were used. Time of onset and peak sedation was not studied. Parental satisfaction was not included in the study protocol. Further research is necessary to establish the proper dose and timing of premedication with oral dexmedetomidine. Effect on long term outcomes are yet to be studied. Summary: This randomized double blind study confirms the safety and efficacy of oral dexmedetomidine as premedication in children. In a dose of 4 µ/kg it provides sedation and anxiolysis similar to 0.5 mg/kg midazolam. We found a lower incidence and severity of emergence agitation in children receiving dexmedetomidine. Bradycardia and hypotension was observed more in the dexmedetomidine group. Our study projects dexmedetomidine as a better alternative to midazolam in providing a pleasant perioperative experience.  Conclusion Oral dexmedetomidine is as effective as oral midazolam in providing sedation and anxiolysis in pediatric age group. In addition dexmedetomidine reduced the occurrence and severity of emergence agitation making recovery more pleasant.  

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