Comparative evaluation of midazolam and clonidine as pediatric oral premedication.

BACKGROUND: Clonidine provides many desirable effects like sedation, analgesia, anxiolysis, and hemodynamic stability and these properties make it a potentially useful anesthetic premedication in the pediatric settings. The aim of this study was to compare oral midazolam (0.5 mg/kg), which is considered gold standard with oral clonidine (5 mcg/kg) as a premedication in pediatric patients.
MATERIALS AND METHODS: Sixty children classified as American Society of Anesthesiologists physical status I, aged between 2 and 12, who were scheduled to undergo an elective surgery, were enrolled for a prospective, randomized, and double blind controlled trial. They received either oral midazolam (Group M) or oral clonidine (Group C) 60 minutes before induction of anesthesia and were submitted to an evaluation of anxiety and sedation scores. We also evaluated secondary outcomes such as palatability, parental separation, effect on hemodynamic status, co-operation during venipuncture and facemask application, postoperative analgesic requirement, and recovery profile.
RESULTS: Oral midazolam had better efficacy in the preoperative period as sedative and anxiolytic (P < 0.001), allowed better cooperation during venipuncture and facemask application (P < 0.001), whereas, oral clonidine provided better palatability (P < 0.001), parental satisfaction (P < 0.001), stable perioperative hemodynamics (P < 0.001), better postoperative analgesia (P < 0.001), and night sleep pattern (P < 0.05) without any noticeable side effects (P > 0.05).
CONCLUSION: We conclude that under the conditions of this study, oral midazolam is a better medication than clonidine in children in preoperative period while clonidine is a better medication postoperatively with added advantage of palatability, hemodynamic stability, and no significant side effects.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Preoperative preparation of a child undergoing surgery is a major challenge to the anesthesiologists. Profound psychological trauma may occur due to a variety of factors like separation from parents, unaccustomed environment of the operating area, and insertion of an intravenous cannula prior to surgery, etc. which can result in negative behavioral changes in later life.[1]

Oral midazolam is the pharmacological agent of choice as pediatric premedication. However, an increased incidence of adverse postoperative behavior changes,[2] hiccups,[3] paradoxical reactions,[4] and impaired post-operative cognitive function[56] observed with midazolam has resulted into the search for other ideal agents. Clonidine, although less popular, has been shown to produce preoperative sedation and anxiolysis, has analgesic properties, provide perioperative hemodynamic stability, and decreases narcotic and volatile anesthetic requirements.[78] However, several studies on clonidine have revealed controversial results about its usefulness with some favoring its use[910] while others discouraging its usefulness.[1112]

Hence, we conducted a prospective, randomized observational trial to compare multiple characteristics of oral clonidine and oral midazolam premedication in terms of pre-anesthetic sedation, anxiolysis, palatability, parental separation, effect on hemodynamics, cooperation during venipuncture and face mask application, and postoperative analgesic requirement in children, which otherwise have not been all studied in a single study group.

MATERIALS AND METHODS

The Local Ethics Committee approved the study and written informed parental/guardian consent was obtained. Sixty children of American Society of Anesthesiology (ASA) I grade, aged 2-10 years, scheduled for herniotomy, appendectomy or urethroplasty were randomly allocated by a computer-generated list. They received either oral midazolam 0.5 mg/kg (Group M, n = 30) or oral clonidine 5 mcg/kg (Group C, n = 30) 60 min prior to anesthesia induction. A pharmacist diluted both drugs to a fixed volume of 5 ml with honey to make it palatable.

Patients aged less than 2 years or more than 10 year or with physical status ASA-II and above or undergoing emergency operations or with known sensitivity to drugs or gastrointestinal absorption disorders or patients with potential respiratory insufficiency were excluded from the study group.

The child's baseline behavior was noted during the pre-anesthetic visit as one of the following-calm, apprehensive, and crying or thrashing. Then, according to the group assigned, the child was given either oral midazolam (0.5 mg/kg) or oral clonidine (5 μg/kg) on the morning of operation. At the time of drug administration, the reaction of the child was evaluated as Drug palatability score [Table 1] with score 1, 2 as good, and 3 and 4 as poor scores. Pulse (P), systolic blood pressure (SBP), diastolic blood pressure (DBP), and respiratory rate (RR) were recorded every 10 min prior to starting drug administration till 60 min after extubation. The children were separated from their parents after 45-50 min of drug administration, and induced after 60 min of drug administration. Child's anxiety and sedation scores were evaluated before premedication, before and after separation from parents, at the time of induction, in the immediate postoperative period (at 2 hrs), and in the early postoperative period (at 4 hrs). Anxiolysis/apprehension was graded based on four point grading system: 1-no fear, 2-little/minimal expression of fear, 3-moderate/expresses fear/apprehension, and 4-excessive/vocal display of fear/apprehension. The grading of sedation was based on five point scoring system: 1-asleep/not readily arousable, 2-asleep/responds slowly to gentle stimulation, 3-drowsy/readily responds, 4-awake/calm and quiet, and 5-awake/active. In the operation theatre, intravenous cannula was placed over the dorsum of the hand of the child and the reaction of the child to venipuncture was noted as venipuncture score [Table 1]. General anesthesia was administered in a standardized manner and surgery proceeded. Mask acceptance was assessed using a 4-point scale [Table 1]. Vitals (P, SBP, DBP, and RR) were monitored throughout the surgery. Pain assessment was done using the Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) every 30 min during the first two postoperative hours and then every 2 hours up to 12 hours [Table 2]. In the present study, children with CHEOPS score more than seven received rescue paracetamol syrup 10-15 mg/kg. During the recovery period, the occurrence of any untoward effect like vomiting, shivering etc. was looked for. Parents were asked about the night sleep pattern on first postoperative day and based on its quality, night sleep was graded [Table 1]. And lastly, the parents were asked to rate their level of satisfaction with the whole perioperative experience on a scale [Table 1]. Scoring of palatability, sedation, anxiety, venipuncture, and mask acceptance was assessed by a second consultant anesthetist who was blinded to the type of premedication.

Table 1

Comparison of midazolam and clonidine (a) Drug palatability (b) Reaction at venipuncture (c) Application of face mask (d) Night sleep pattern (e) Parental satisfaction score

Table 2

CHEOPS scale

Statistical analysis

Statistical analyses were performed using Statistical Product and Service Solutions (version 15.0; SPSS, Inc, Chicago, IL, USA) software. In this study, parametric data were recorded as arithmetic mean ± standard deviation (SD). Unpaired Student's t-test was used to compare normally distributed continuous variables between the two groups. Data analysis for categorical data was performed by Fisher's exact test or Pearson’ Chi-square test to detect differences for the scores and postoperative complications. For the analysis of differences between the baseline, intubation, and after extubation hemodynamics, Students paired ‘t’ test was used. A P < 0.05 was considered statistically significant. The number of patients required in each group was determined using power analysis based on previous studies.

RESULTS

The two groups were comparable in terms of demographics (age, weight, sex, and type of surgery), baseline vital parameters (P, SBP, DBP, and RR) and baseline behavior [Table 3]. Clonidine had better acceptability than midazolam [Table 1] that was statistically significant.

Table 3

Distribution of subjects according to demographic profile and vital signs

Apprehension scores

There was no statistically significant difference between the two groups regarding apprehension scores at baseline (P = 0.94) and before separation (P = 1) [Figure 1]. However, there was a significant difference between the two groups in apprehension scores after separation from the parents (P < 0.001) and at induction (P < 0.001). In both the groups, all 30 (100%) children had a score of 1 (i.e., they had no apprehension) before separation from parent [Figure 1]. After separation and at induction, the apprehension scores in-group M were (score 1, 2) in 100% patients (significantly lower) as compared to the Group C (score 1, 2) were in 60% patients (P < 0.001).

Figure 1

Comparison of apprehension score before separation, after separation, and at induction

In Group M, apprehension scores at induction when compared to the baseline (score 1, 2) were statistically significant (P = 0.0006); while in Group C, apprehension scores at induction when compared to the baseline were non-significant (P = 0.32).

Sedation scores

Both at baseline (P = 0.9) and before separation (P = 0.98), there was no statistical difference in between the sedation scores of the two groups [Figure 2]. After parental separation, 33.33% patients in Group C were awake/active (Score 5) compared to Group M, where none of the patients were awake, which was statistically significant (P < 0.001). At induction of anesthesia, 33.33% patients in Group C and none in Group M had sedation score 5 (awake/active) while 66.67% patients in Group C and 93.33% patients in Group M had sedation score 4 (drowsy/readily responsive), respectively, which was statistically significant (P = 0.0098). Postoperatively, both in the immediate postoperative period (at 2 hrs) and early postoperative period (at 4 hrs), all 30 (100%) children in Group M had score 5 (awake/active) whereas Group C patients had score 3 (drowsy/readily responding), and score 4 (awake/calm and quiet), respectively, which was statistically significant (P < 0.001, P < 0.001).

Figure 2

Comparison of sedation score before separation, after separation, at induction, and postoperatively

Reaction at venipuncture

On intergroup comparison, there was a statistically significant (P < 0.001) number of children in Group C (76.67%) who were crying compared to Group M children, who were either just moving the limbs or had no reaction during venipuncture (66.67% combined) [Table 1].

Mask acceptance

100% patients in Group M had either excellent or good mask acceptance. No children in Group M had moderate or poor response to mask application as compared to Group C, where 10 (33.33%) patients each showed either a moderate or a poor response to application of mask. This difference was statistically highly significant (P < 0001) [Table 1].

Postoperative pain (CHEOPS score)

In Group M, the mean CHEOPS score in the immediate postoperative period and in the early postoperative period was 6.13 ± 1.69 (smallest score = 3; largest score = 9) and 7.6 ± 1.22 (smallest score = 5; largest score = 9), respectively; whereas, in Group C, the mean CHEOPS score in the immediate postoperative period and in the early postoperative period is 3.2 ± 0.96 (smallest score = 2; largest score = 6) and 4.3 ± 1.20 (smallest score = 3; largest score = 8), respectively [Table 4] which was statistically highly significant (P < 0001).

Table 4

Recovery profile and postoperative complications among the groups

Night sleep pattern

In Group C, 100% children showed night sleep pattern score 0 (mostly sleeping) in comparison to group M that showed 86.67% patient night sleep pattern score was 0. This difference wass statistically significant (P < 0.5) [Table 1].

Parental satisfaction score

In group C, parents of all the 30 (100%) children were extremely satisfied (Score 3) with the child's postoperative experience. However, in Group M, the parental satisfaction score was 2 (awake several times) in 10 (66.67%) children (P < 0.001) [Table 1].

Hemodynamics

In Group M, there was a statistically significant increase in P and a decrease in the blood pressure (BP) (SBP and DBP), and RR before induction as compared to their respective baseline values (P < 0.05), whereas, in Group C, both P and BP significantly decreased before induction as compared to their respective baseline values (P < 0.05) [Figure 3]. There was a significant increase P and BP during laryngoscopy and intubation as compared to the baseline with much higher increase in Group M as compared to Group C. Though in both the groups there was a significant increase in P and the BP at 5 min after extubation as compared to their respective baseline values but this increase was more significant in Group M as compared to Group C. The change in RR was also statistically significant in Group M (P < 0.05).

Figure 3

Comparison of vitals (pulse, systolic BP, and diastolic BP) in between midazolam and clonidine group

Recovery profile

In Group C, no children required rescue analgesics in the immediate postoperative period (within 2 hrs) and only 2 (6.67%) children required rescue analgesics in the early postoperative period (2-12 hrs) as compared to the Group M where 10 (33.33%) children required rescue analgesics in the immediate postoperative period and another 20 (66.67%) children required rescue analgesics in the early postoperative period which was statistically significant (P < 0.05) [Table 4]. Incidence of side effects in Group M was higher than Group C, which was, however, statistically insignificant.

DISCUSSION

There is a plethora of scientific articles relating to the ideal pediatric premedication and the views expressed in these lack any testimony to any superior regimen.[1314] Hence, the present study was carried out to compare the effectiveness of midazolam that is the most common pediatric premedication with clonidine that is gaining popularity in pediatric patients. The studies was conducted in children older than two years as cardiac output in neonates depends upon heart rate and clonidine is known to cause bradycardia.[15] The doses of midazolam and clonidine used in this study have been established as optimal pediatric pre-anesthetic sedation doses.[1617] We chose to induce children 60 min after drug administration as is used by previous midazolam and clonidine comparative studies[10] and to limit the time bias in between the two groups. In this study, the acceptability of oral clonidine was much better as compared to oral midazolam that had bitter taste despite mixing with honey. New commercially prepared oral midazolam formulations are more palatable[18] that were, however, not available at our institution.

Midazolam premedication resulted in a better suppression of apprehension and sedation after separation from parents and at induction in contrast to clonidine. But clonidine resulted in a good level of sedation in the immediate postoperative period (Score 3) and early postoperative period (Score 4) in comparison to midazolam that had poor sedative potential (Score 5). This was in contrast to study results of Almenrader et al.,[8] and Tazeroualti et al.,[19] where midazolam was less effective in producing sedation than clonidine. The sedative and anxiolytic effects of oral clonidine (4-5 mg/kg) have been found to produce similar degrees of sedation and anxiolysis as oral midazolam (0.1-0.5 mg/kg) in pediatric surgical patients by Lavrich et al., and Frank et al.,[2021] Midazolam has been shown to induce satisfactory sedation and anxiolysis within 20 min but clonidine has a prolonged onset time, which requires it to be administered at least 45 min before the induction.[22] Hence, midazolam provided a better level of anxiolysis and sedation preoperatively, whereas, clonidine provided a better level of anxiolysis and sedation postoperatively in our study.

Reaction at venipuncture and mask acceptance was better in midazolam group that correlates to the results of Fazi et al.[23] But are conflicting to Cao and Shi, et al.,[10] in which score of parental separation and face mask acceptance were significantly higher in clonidine group than midazolam group. In another study by Trevor et al.,[24] midazolam provided significantly superior anxiolysis at times of venipuncture and mask application but the overall degree of sedation was greater in the clonidine group children.

The mean CHEOPS score and the need for rescue analgesics were higher in the midazolam group compared to the clonidine group in our study. Hence, clonidine resulted in a much better level of analgesia compared to the midazolam group both in the immediate and early postoperative period. This was similar to the study results by Tazeroualti et al.,[19] Schmidt et al.,[25] and Bergendahl et al.,[26] where clonidine decreased the postoperative pain scores. However, conflicting results were obtained regarding analgesic activity with some studies finding a reduction in pain score or analgesic requirements, some failing to find any such differences and some increasing postoperative demand for analgesia.[232728]

In our study, parental satisfaction and night sleep pattern was much better in clonidine group in comparison to midazolam. Almenrader et al.,[8] also found oral clonidine superior to oral midazolam in children undergoing minor general surgery in terms of better acceptance of oral clonidine, a trend towards better recovery from anesthesia, and a higher degree of parental satisfaction that was similar to the results of our study but in contrast to our study clonidine had more effective preoperative sedation.

Clonidine group had a more stable hemodynamic profile both during laryngoscopy, intubation, and during extubation. Our results are in consensus with Mikawa et al.,[29] where clonidine attenuated the increases in BP and heart rate after tracheal intubation with no significant perioperative hypotension or bradycardia. However, Fazi et al., and Cao et al.,[2310] found no clinically significant episodes of bradycardia or hypotension in both the clonidine and midazolam groups.

Incidence of side effects in Group M were higher than Group C, which was, however, statistically insignificant. Although clonidine can induce hypotension and bradycardia in adults, no serious adverse effects, for example, pronounced hypotension and bradycardia, have been reported in children when using doses of clonidine of less than 10 mg/kg.[30]

Limitation of this study was that pH-based potential alterations in the absorption of drugs by addition of honey and reduced bioavailability by inhibitory effect on organic anion transporting polypeptide activities were not addressed in the study.[3132] Another limitation was the timing of the drug administration. As the timing of onset of drug action of both the drugs is different, we induced the children 60 min after the drugs were given to limit the time difference bias. Satisfactory sedation with oral clonidine can be achieved if it is administered at least 60 min prior to induction, while with midazolam it can be achieved within 30 min of administration.[10] It is possible that we would have got a better result with clonidine had we waited a bit longer before induction as clonidine was not allowed to reach its peak effect. However, this would be a very long time and would be totally impractical in an outpatient setting. Also, in case of midazolam, we might have got better result postoperatively had we induced within 30-45 min of drug administration as 60 min is too long, and for some children, the effect will be wearing off. Another limitation of this study is the use of invalidated three- or four-point scales.

Hence, sedation and anxiolysis was better in the midazolam group preoperatively, but postoperatively clonidine was more efficacious than midazolam in this regard. The superiority of clonidine over midazolam in the postoperative period was also seen in meta-analysis by Dahmani.[33] Children in the midazolam group had a better intravenous cannula and facemask acceptance but higher postoperative pain scores based on the CHEOPS scale and larger postoperative requirement of rescue analgesics. Clonidine resulted in a much more stable perioperative hemodynamic profile than midazolam. Night sleep pattern was better and the percentage of parents who were extremely satisfied with the child's perioperative experience was higher in the clonidine group. Children in the midazolam group had minimal untoward effects (non significant). We didn’t observe any noticeable side effect in the clonidine group.

In conclusion, under the conditions of this study, oral midazolam has better efficacy in the preoperative period apart for a few undesirable effects; whereas, oral clonidine provided good palatability, parental satisfaction, stable perioperative hemodynamics, better postoperative analgesia, night sleep pattern without any noticeable side effects. Hence, it can be a promising premedication in the pediatric age group.