Comparison the Oral Premedication of Midazolam, Dexmedetomidine, and Melatonin for Children's Sedation and Ease of Separation from Parents before Anesthesia.

BACKGROUND: Children's fear of surgery and preoperative separation from parents can contribute to anxiety and distress in children undergoing surgery. The study addressed the comparable efficacy of oral premedication of midazolam, dexmedetomidine, and melatonin to alleviate preoperative anxiety and easing the children's separation from parents.
MATERIALS AND METHODS: A double-blinded trial enrolled three equal-sized groups of children (n = 153, aged 2-10 years) undergoing elective surgery who received oral midazolam, melatonin, and dexmedetomidine 30 min before induction. The observation sedation score, and ease of separation, acceptance of drug both preceding and following premedication administration were assessed and recorded every 5min till anesthesia induction.
RESULTS: A significant difference was observed in the mean scores of sedation before premedication and after separation from parents, as well as in the degree of the separation when comparing between the midazolam and melatonin groups and the dexmedetomidine and melatonin groups (P < 0.001). The scores were significantly lower in the melatonin group than the other two groups, whereas no significant difference was found in those between the midazolam and dexmedetomidine groups, as well as in the acceptance of anesthesia induction between the midazolam and melatonin groups (P = 0.250). The differences were significant between the midazolam and dexmedetomidine groups (P = 0.002) and melatonin and dexmedetomidine groups (P < 0.001) and anesthesia induction was effective in the dexmedetomidine group than that in the other two groups.
CONCLUSION: Dexmedetomidine is more effective in acceptance of anesthesia induction. Furthermore, the midazolam and dexmedetomidine groups indicated better ease of separation and sedation scores than melatonin. Copyright:

INTRODUCTION

The preoperative period is expected to be a stressful time for the majority of people undergoing surgery, especially for children,[1] Among them, about 60%–75% experience preoperative fear or anxiety.[123] Preoperative anxiety is an unpleasant state of anxiety, which is secondary to the patient’s concern about hospitalization or is deemed as an outcome of being separated from their parents––the surgical settings with which children are unfamiliar, or reaction to dealing with strangers.[34] The anxiety is depicted as a mental state shown in numerous ways, for instance, among the children who are surgery candidates, and it can emerge as irritability and odd behaviors at the time of separation from parents, or difficulty of acceptance of anesthesia mask or that of separation from parents.[56] Untreated anxiety is related to difficult induction, increased postoperative pain, need for more pain relief, emergence of agitation. In addition, some postoperative psychological effects and behavioral problems such as sleep disorders, bed-wetting, appetite changes, and separation anxiety might be creating that some which can persist postoperatively for months.[36,7]

Hence, measures to alleviate their anxiety are needed to improve parent management of postoperative period for children.[28] Sedative premedication; presence of parents at anesthesia induction and behavioral intervention are methods to be used for sedate and alleviate children’s preoperative anxiety before anesthesia induction.[8] Premedication to manage anxiety is more time-consuming and effective as compared to non-pharmacological treatments, such as the presence of parents during induction or preoperative behavioral preparation programs.[9] The sedative premedication aims at alleviating preoperative anxiety, easing children’s separation from parents, minimizing emotional trauma, as well as helping to accept masks and facilitating anesthesia induction.[110] This study aimed at comparing oral midazolam, dexmedetomidine, and melatonin as premedication so that a suitable drug can be developed for sedating children and easing separation from parents to prepare children for surgery.

MATERIALS AND METHODS

The study was under the supervision of Faculty Research deputy after permission from the University’s Ethics Committee, registered under IRCT20141209020258N77 at the Iranian Registry of Clinical Trials (IRCT). The double-blind clinical trial was conducted on 153 children aged 2–10 years admitted at Arak’s educational and therapeutic hospitals, Iran, during 2018 where the sample size is calculated for each 51-people group by using the statistical formula by power 80%, type one error 5%, and results of recent studies.

The written informed consent was obtained from parents of children participating in this study, after providing full details. Then, 153 children aged 2–10 years for elective surgery were enrolled and then randomized to three groups by random allocation method. The inclusion criteria of the study were children between 2 and 10 years old, signing the informed consent by their parents and diagnosed that need for selective surgery. The exclusion criteria of the study were any fracture surgery, history of allergies, or contraindications for dexmedetomidine, midazolam, and melatonin, liver, kidney, and cardiovascular disorders, long-term use of anticonvulsants, sleep disturbances, speech or communication problems, and gastrointestinal disorders. A balanced block randomization scheme was established for all subjects in three groups while being kept NPO for 8h. Children and their parents were unaware of the type of drug used. Moreover, the intern who was responsible for completing the questionnaires and recording scores of sedation and ease of separation was unaware of patient grouping, as well as the type of oral solution, while completing merely questionnaires based on the numbers assigned in the operating room by an anesthesiologist in charge of the project.

A total of 153 eligible children with considering the inclusion and exclusion criteria were randomly allocated into three 51-people groups who were first monitored 30 min before anesthesia induction while measuring vital signs including blood pressure (BP), heart rate (HR), and peripheral capillary oxygen saturation (SpO2). Groups I–III received oral 0.5 mg/kg midazolam (Caspian Tamin Pharmaceutical, Tehran, Iran), 0.2 mg/kg melatonin (Schiff Nutrition Group, Salt Lake City, USA), and 2.5 mg/kg dexmedetomidine (Hospira, Illinois, USA), respectively. All the mentioned vital signs were recorded every 5min until induction anesthesia, and then the children were transferred to the operating room and anesthetized with anesthetic gas. Observation sedation score was assessed before the administration and then at the time of being separated. Moreover, the ease of separation score and acceptance of drug in which observation sedation score is evaluated and measured.

Sedation status and vital parameters are recorded at intervals of 5min where, by observing the status, the sedation scores are labeled as 1–5, that is, agitated, alert, calm, drowsy, and asleep from which 1–2 and 3–5 are considered inappropriate and appropriate, respectively. The score for ease of separation from parents is one that is recorded as excellent, good, fair, or poor when the child is separated from the parent (20–30 min after administration) by 1: unafraid, cooperative; 2: slight fear or crying, quiet with assurance (acceptable or satisfactory); 3: moderate fear or crying not quiet with assurance); and 4: crying, need for restraint (unsatisfactory or difficult separation). Medication acceptance scores were recorded as 1: poor (no acceptance); 2: moderate (acceptance with difficulty); and 3: good (acceptance without complaint).[11]

The aforementioned points were determined by an anesthesiologist who was unaware of the type of drug administered and then recorded in the questionnaires. Furthermore, other patient data, including demographic data, hemodynamic status (SpO2, pulse rate, mean blood pressure [MBP]) before and after administration, and then every 5min until anesthesia induction, were collected and recorded in questionnaires. Finally, the three study groups were compared regarding to the variables.

STATISTICAL ANALYSIS

The project data were extracted from the questionnaires and entered to Statistical Package for the Social Sciences software, version 20.0. (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY). For analysis of ease of separation, we labeled excellent and good separation as appropriate and fair and poor as inappropriate. Data were analyzed by analysis of variance (ANOVA) to compare three groups regarding to age and hemodynamic parameters in each time after operation. Chi-squared test was used to compare three groups according to ease of separation and medication acceptance level. Moreover, ANOVA for repeated measurements was used to compare the trend of hemodynamic parameters in different time after operation. Then the results were ultimately expressed in tables and charts.

RESULTS

A total of 153 children (aged 2–10 years; 82 boys, 71 girls) who were candidate for elective surgery and the mean age and weight of patients was 5.90 ± 2.22 years and 21.35 ± 5.89kg, respectively. Table 1 shows the baseline measurements and based on statistical tests, age (P = 0.950), weight (P = 0.955), and gender (P = 0.221) of subjects were not statistically significantly different among the three groups. The appropriate satisfactory observational sedation score after administration of premedication was observed in 78.4% (n = 40), 31.3% (n = 16), and 88.2% (n = 45) of patients in the midazolam, melatonin, and dexmedetomidine groups, respectively, and no any significant differences were found between the midazolam and dexmedetomidine groups (P = 0.30). Although a significant difference was found between the midazolam and melatonin groups and the dexmedetomidine and melatonin groups (P < 0.001), the sedation score was significantly lower in the melatonin group than the other two groups.

Table 1

Comparison of the demographic characteristics of three study groups at the baseline

Demographic characteristics		Group I (MID)	Group II (MEL)	Group III (DEX)	P value
Age		5.92 ± 2.11	5.82 ± 2.34	5.96 ± 2.24	0.950
Weight		21.33 ± 5.59	21.54 ± 6.17	21.19 ± 6.00	0.955
Gender					0.201
Boy		32 (62.7)	27(52.9)	23(45.1)
Girl		19(37.3)	24(47.1)	28(54.9)

Furthermore, as depicted in Chart 1, 35 (68.6%), 11 (21.6%), and 39 (76.5%) patients in the midazolam, melatonin, and dexmedetomidine groups, respectively, had a better and easier separation (scores 1–2) in terms of ease of separation from parents, whereas 16 (31.4%), 40 (78.4%), and 12 (23.5%) patients in the groups, respectively, had an inappropriate and more difficult separation. Chi-squared test showed a significant difference among three groups regarding the ease of separation (P < 0.001). As seen in Chart 1, the rate of ease separation from parents was same statistically between the midazolam and dexmedetomidine groups (P = 0.37) and was similar in them. However, a significant difference was, however, observed between the melatonin and midazolam groups, as well as between melatonin and dexmedetomidine groups (P < 0.001). However, the score for ease of separation was less in the melatonin group than the other two groups [Chart 1].

Chart 1

Frequency and ease of separation from parents among the groups

Weak anesthetic induction in acceptance of anesthesia induction observed in 11 patients (21.6%), 17 (33.3%), and 7 (13.7%) of subjects in the midazolam, melatonin, and dexmedetomidine groups, respectively, and 29 (56.9%), 28 (54.9%), and 16 (41.3%) of patients of the above groups, respectively, showed moderate induction, whereas good anesthetic induction was observed in 11 (21.6%), 6 (11.8%), and 28 (43.1%) patients in the groups, respectively. On the basis of chi-squared test, a significant difference was observed among three groups regarding the acceptance of anesthesia induction (P = 0.003). Future analysis showed that no significant difference was found between the midazolam and melatonin groups (P = 0.25), whereas a significant difference was found between the dexmedetomidine and midazolam groups (P = 0.002), as well as the dexmedetomidine and melatonin groups (P < 0.001). The acceptance of anesthesia induction in dexmedetomidine groups was significantly better than the other groups [Chart 2].

Chart 2

Comparison of acceptance of anesthesia induction among the groups

MBP was significant among three groups at 10-20 minutes’ post administration (P < 0.05). Based on our results, the mean of MBP was less in the DEX group than MID and MEL groups. Moreover, no significant difference was found between midazolam and melatonin (p > 0.05). Although a significant difference was observed between the dexmedetomidine and melatonin groups 20 min after administration, and MBP was less in the dexmedetomidine group than that in the melatonin group, no significant difference was found in other times [Table 2]. A significant difference was seen in the NHR, when compared, between the groups the 10 and 20 min after premedication administration (P < 0.05). Although the rate was lower in the dexmedetomidine group than those in the other two groups, no significant difference was found between midazolam and melatonin at that time. Furthermore, a significant difference was found between the melatonin and midazolam vs. melatonin and dexmedetomidine groups at 25 and 30 min after administration of medication (P < 0.001). MHR was higher in the melatonin group, but with no significant difference between the dexmedetomidine and midazolam groups [Table 3]. Although the midazolam group had lower SpO2, no significant difference was found among the groups at any time (P > 0.05) [Table 4].

Table 2

Comparison of MBP before and after premedication administration in the studied groups

MBP at different time of administration	Group I (MID)		Group II (MEL)		Group III (DEX)		P value
	Mean	SD	Mean	SD	Mean	SD
Before administration	77.87	5.69	78.16	4.46	78.14	5.59	0.955
5min post-admin	77.71	5.55	78.06	4.40	78.03	5.60	0.930
10 min post-admin	77.15	5.38	77.96	4.46	73.01	5.42	<0.001
15min post-admin	75.71	5.76	77.15	4.53	72.57	5.27	<0.001
20 min post-admin	74.66	5.24	75.39	5.69	72.18	5.54	0.010
25min post-admin	73.54	5.26	72.92	4.96	71.70	5.61	0.236
30 min post-admin	72.84	5.27	72.47	5.01	71.32	5.49	0.320

Table 3

Comparison of MHR before and after premedication administration in the studied groups

MHR at different time of administration	Group I (MID)		Group II (MEL)		Group III (DEX)		P value
	Mean	SD	Mean	SD	Mean	SD
Before administration	102.51	11.63	105.35	12.38	102.76	8.62	0.356
5min post-admin	101.07	9.13	104.66	12.57	100.07	8.28	0.060
10 min post-admin	99.47	8.63	102.07	11.40	93.25	10.18	<0.001
15min post-admin	96.74	7.47	98.70	10.80	92.27	8.56	0.002
20 min post-admin	91.29	7.61	95.13	8.58	86.31	8.08	<0.001
25min post-admin	80.37	7.37	93.01	8.54	81.09	6.18	<0.001
30 min post-admin	77.74	6.79	92.01	8.50	77.17	6.192	<0.001

Table 4

Comparison of SaO2 before and after premedication administration in the studied groups

SaO2 at different time of administration	Group I (MID)		Group II (MEL)		Group III (DEX)		P value
	Mean	SD	Mean	SD	Mean	SD
Before administration	95.78	2.01	95.90	2.07	95.84	2.02	0.958
5min post-admin	95.65	1.96	95.86	2.02	95.83	1.99	0.826
10 min post-admin	95.61	1.92	95.82	2.02	95.68	1.96	0.894
15min post-admin	94.07	2.23	94.62	2.44	94.19	2.23	0.451
20 min post-admin	93.43	1.88	94.00	2.29	93.60	2.05	0.373
25min post-admin	92.43	1.87	93.07	2.27	92.61	1.98	0.273
30 min post-admin	91.70	1.78	92.27	2.09	91.82	1.93	0.299

DISCUSSION

The sedative premedication aims to alleviate preoperative anxiety to ease children’s separation from parents, to minimize emotional trauma, as well as to help to accept mask and to facilitate anesthesia induction.[110] In this study, the preoperative administration of dexmedetomidine and midazolam as premedication was observed to have the equal and appropriate sedation, so that the children were more easily separated from their parents, whereas children receiving melatonin had significantly lower sedation and ease of separation from parents and quality of anesthesia induction was superior in children receiving dexmedetomidine than those receiving the other two drugs.

Midazolam, a water-soluble benzodiazepine, remains the most commonly used tranquilizing or sedative premedication for children, covering many benefits, counting rapid onset of action, effective relief, anterograde amnesia, and alleviating postoperative anxiety, and vomiting. Nonetheless, unwanted effects such as restlessness, hiccups, and paradoxical hyperactive reactions associated with the midazolam make it less than an ideal sedative drug.[12] Dexmedetomidine is a highly potent and selective α-2 adrenoceptor agonist, with both sedative and analgesic effects,[10] which provides sedation, known as “cooperative” or “arousable” which differs that from GABA drugs.[1] Its sedation is like real sleep, with a site of action located in the locus coeruleus, and unlike conventional gabaminergic sedative medications, such as midazolam with that site in the cerebral cortex.[10]

Melatonin (N-acetyl-5-methoxytryptamine) is an endogenously produced indoleamine secreted by the pineal gland[13] whose hormone, that is, melatonin, has several key physiological functions, including the regulation of the circadian rhythms, the regulation of the reproductive axis, the antioxidant activity, as well as anti-inflammatory and anti-seizure effects, as suggested by numerous evidence.[1314] The first and most important use of exogenous melatonin is the management of sleep disorders and jet lag, whereas information on the reduction of anxiety status is inconsistent.[13] Midazolam is currently the most commonly used drug for alleviating preoperative child anxiety[6] and can be administered orally, intravenously, muscularly, rectally, and intranasally, but oral and intrauterine methods are preferred to sedation for children.[11] The evidence does, moreover, show that dexmedetomidine provides satisfactory sedation at separation from parents and accepting respiratory masks, whereas reducing the need for more pain relief and the incidence of postoperative agitation,[15] whereas melatonin has no known serious side effect[16] and its antianxiety effects occur after the activation of GABAergic system. The latter has been successfully used in treating anxiety associated with sleep disorders in children.[13] and can, thus, be an appropriate preoperative premedication and can act as a substitute for benzodiazepines.[17] Our study results are consistent with one from many previous studies, despite the different results from previous studies comparing the sedation effects of these drugs.

Kain et al.[18] compared the effect of oral melatonin and midazolam in alleviating preoperative anxiety and observed that preoperative melatonin administration is not effective in alleviating anxiety, as compared to midazolam. Faghihian et al.[19]’s clinical trial randomly divided 132 children who were general anesthesia candidates for dental treatment into three groups receiving midazolam, melatonin, and normal saline as premedication, assessing and recording sedation scores before general anesthesia, easy venipuncture, the need for pain relief, and recovery time. Their result suggested that midazolam was preferable to melatonin as a premedication because of more sedation, easier venipuncture, less need for pain relief, and better recovery in children under general anesthesia for dental treatment, compared to melatonin, whereas our study showed better sedation score, ease of separation from parents, and admission of anesthesia with midazolam than melatonin. Sun et al.[12] compared the effect of premedication of dexmedetomidine vs. midazolam for children in 11 clinical trials, concluding that the dexmedetomidine premedication is better and preferred than midazolam in terms of satisfactory aesthetic after the separation from parents and acceptance of mask.

Sheta et al.[10] examined the sedation status and acceptance of mask in the two groups (intranasal dexmedetomidine compared with intranasal midazolam premedication) in a double-blind trial on 72 children aged 3–6 years. They indicated that intranasal dexmedetomidine is an effective and safe alternative to premedication in children, and that provides better sedation than intranasal midazolam. Furthermore, dexmedetomidine is reported to be more effective in alleviating anxiety when separating from parents, in reducing postoperative restlessness and in providing effective postoperative analgesia, as compared to midazolam, based on Pasin et al.’s[1] systematic review on 13 clinical trials. This study did, though, show better acceptance of anesthesia induction in the dexmedetomidine group than the midazolam group; the ease of separation from parents and children sedation was the same in the dexmedetomidine and midazolam groups.

Peng et al.’s[2] review study explored the role of dexmedetomidine premedication for children by including 13 trial involving 1190 pediatric patients and comparing dexmedetomidine vs. midazolam and ketamine or placebo. Their results showed that dexmedetomidine is better than midazolam due to increasing preoperative sedation and alleviating postoperative pain. Another study by Yuen et al.[20] compared the 0.5 mg/kg midazolam in acetaminophen syrup with intramuscular dexmedetomidine of 0.5 or 1 mg/kg in acetaminophen syrup in 96 children undergoing for elective surgery. The results showed that intranasal dexmedetomidine produces more sedation as compared oral midazolam, whereas no significant difference was seen in sedation score between our dexmedetomidine and midazolam groups.

Jannu et al.[21] conducted a trial study on 60 children aged 1–7 years undergoing elective surgery and compared the 0.75 mg/kg midazolam and 4 mg/kg dexmedetomidine, 40 min before anesthesia induction. They showed similar preoperative sedation in both groups, despite better recovery profiles in children receiving dexmedetomidine vs. midazolam. The study result was consistent with ours, whereas sedation was similar in both the dexmedetomidine and midazolam groups. Moreover, Peng et al.’s[2] study reported a significant reduction in HR for the dexmedetomidine vs. midazolam groups, whereas no difference was found in BP and SpO2 between them. Although Sun et al.[12] review on several studies reported that dexmedetomidine had a significant reduction in MBP and HR as compared with midazolam. Based on our results, no significant difference was found in SpO2 among our groups, but more HR reduction was observed in the dexmedetomidine group than midazolam and melatonin in 10–20 min after administration. Moreover, higher reduction in MBP was obtained in dexmedetomidine group at 10 and 15 min.

CONCLUSION

This study results indicated that dexmedetomidine is more effective than midazolam and melatonin in accepting anesthesia induction and that the ease of separation from parents and sedation scores is better in the midazolam and dexmedetomidine groups than the melatonin group. However, no significant difference was found between the midazolam and dexmedetomidine groups.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.