Comparison of Oral Triclofos and Oral Midazolam as Premedication in Children undergoing Elective Surgery.

BACKGROUND: Children who have experienced previous hospital admission, operation, procedures, and needle pricks are more reactive to subsequent anesthetic procedures. Many sedative agents have been used for the purpose of premedication, but few of them can be given orally, thus avoiding the pricks. Midazolam, being one such choices, can be given orally, intranasally, and parenterally but has unpredictable response. Triclofos, available as sweet syrup, is a phosphorylated derivative of chloral hydrate, has been proven to be effective within 30 min in doses of 25-75 mg/kg. Hence, this study compares triclofos hydrochloride with midazolam oral to know the efficacy of both the drugs as premedication. AIM: This study aims to assess sedation score, level of anxiety/resistance, and behavior of the child in the preoperative period. SETTINGS AND
DESIGN: After parental and institutional approval, a total of 70 children were studied based on computer-generated randomization and divided into groups M and T of 35 each.
MATERIALS AND METHODS: Group M patients received oral midazolam 0.5 mg/kg. Group T patients received commercially available triclofos syrup containing 100 mg/ml of drug in dose of 75 mg/kg. The response of children to taste of premedication was noted, whether completely ingested or not. In case of vomiting, the child was excluded from further study. STATISTICAL ANALYSIS: Numerical variables were analyzed using Student's paired t-test and other variables using Mann-Whitney U-test, Fisher exact test, and Friedman ANOVA.
RESULTS: Sedation score at 5 min interval from 0 to 30 min showed P = 0.54, 0.71, 0.65, 0.92, 0.29, 0.42, and 0.15; none were statistically significant. Anxiety score during parental separation, intravenous cannulation, and mask application were also similar in both the groups.
CONCLUSION: From data obtained, it can be concluded that parenteral formulation of either midazolam or triclofos can be safely used as premedicant in children.

INTRODUCTION

Pediatric patients constitute a specific population of patients which are different from adults due to anatomical/physiological difference and difference in their pharmacodynamics and pharmacokinetics response. Most untoward response among the pediatric age group (preschoolgoing children) is usually aggressive psychological response and reacts violently to parental separation.[1234] Hence, the anesthesiologists involved in pediatric anesthesia have to be very careful in selecting a premedicant among the long list with emphasis to preoperative sedation, transfer to operating room, and subsequent smooth induction of anesthesia. It has been studied that children who have experienced previous hospital admission, operation, procedures, and needle pricks are more reactive to subsequent anesthetic procedures.[56] It is an established fact from many previous studies that children who had difficult induction of anesthesia had more problems during emergence and authors have reported emergence delirium ranging from 2% to 6%.[78] Later in life, the pediatric population have been found to show cognitive disorders due to previous poor anesthetic management.[89] Although many sedative agents such as hyoscine, phenothiazine, clonidine, midazolam, phencyclidine derivatives, and tramadol all have been used for the purpose of premedication with a view to have calm and quiet child for smooth induction of anesthesia, few of them can be given orally and can help in avoiding the pricks. Midazolam has been a drug of choice in last two decades due to its shorter duration of action, arousable sedation, and ability to be given orally, intranasally, and parenterally but still has got unpredictable response in different patients. It has been compared with hyoscine and ketamine.[1011] Triclofos which is available in sweet syrup form and palatably acceptable by children, has been used in children as a hypnotic agent for sleep disorders in irritable children. It has also been used for conscious sedation for intravenous cannulations by pediatricians for long and also has been compared with other sedatives – premedicants in few studies. Triclofos is a phosphorylated derivative of chloral hydrate (ethanol derivative). Triclofos is converted and metabolized in liver to trichloroethanol; this acts on brain and decreases time taken to fall asleep. Its oral solution is well absorbed and proves effective within 30 min in doses of 25–75 mg/kg. Hence, this study is being carried out to compare oral triclofos hydrochloride with oral midazolam to know the efficacy of both the drugs as premedicants, emphasizing sedation and anxiety levels on parentral separation and pre-operative period.

MATERIALS AND METHODS

After obtaining parental and Institutional Ethical Committee approval and informed consent, a total of 70 children were taken into study and divided into Groups M and T, 35 each by computer-generated randomization group to receive and T group to receive triclofos

On the day of surgery, the patient was shifted to preanesthetic holding area of operation theater complex where premedication was administered by anesthetist not participating in the study

Group M patients received oral midazolam 0.5 mg/kg. The solution containing 1 mg/ml of midazolam (intravenous preparation) was mixed with sweet clear fluid (soft drink) to overcome the bitter taste of preparation to a total volume that did not exceed 15 ml

Group T patients received commercially available triclofos syrup containing 100 mg/ml of drug in dose of 75 mg/kg.

The response of children to taste of premedication was noted. If premedication was not completely ingested or vomited, the child was excluded from further study. The randomization code of excluded child was then assigned to the next child enrolled in the study.

The study was conducted among a total of 70 pediatric patients between age group 2–5 years posted for elective surgery American Society of Anesthesiologists physical status Classes I and II at IGIMS, Patna. They were divided into 2 groups of 35 each:

Group M – 0.5 mg/kg oral midazolam 30 min before taking patient to operating room

Group T – 75 mg/kg oral triclofos syrup 30 min before taking patient to operating room.

Statistical analysis

Numerical variables were analyzed using Student's paired t-test and other variables were analyzed with Mann–Whitney U-test and Fisher exact test and intragroup variables were analyzed by Friedman's ANOVA.

Aim

To Compare Oral Triclofos and Oral Midazolam as Premedication in Children undergoing Elective Surgery.

Objectives

Comparison of sedation score by Ramsay sedation scale between the two groups at 30 minute after premedication.

Comparison of anxiety score at parenteral separation.

Comparison of anxiety score at intravenous cannulation.

Comparison of anxiety score at mask application.

RESULTS

A total 70 patient were included in the study. There was no significant difference in demographic variables between the two groups, neither the pre-operative and base line sedation score were statistically significant.

DISCUSSION

Psychological preparation of children before induction of anesthesia results in better perioperative outcome. Reduction of anxiety, calm, and sedated child in preanesthesia room has better postoperative emergence. Kain et al.'s[12] primary goal of premedicating the child is to produce amnesia, anxiolysis, and prevention of stress response during preinduction period. Although a drug given parenterally is more effective, in pediatric practice, needle pricks is feared most. Some studies[156] suggest that oral midazolam is an ideal premedicant when compared with triclofos which is used as a second-line drug for insomnia in children while other drugs have failed.

In my study, Tables 1–3 depicts demographic profile of children assigned to Group M and Group T, and statistical analysis suggests no significant demographic difference between groups in terms of age, weight, and sex.

Table 1

Comparison of demographic variables

Variable (n=35)	Age	Sex		Body weight
		Male	Female
Midazolam	4.67	26	9	14.75
Triclofos	5.42	30	5	16.42
P	0.13	0.37		0.10

Table 3

Comparison of sedation score (Ramsay sedation between 2 groups at various scale time points)

Time points (min)	Groups (n=35)	Sedation score	P
0	Midazolam	1.97	0.54
	Triclofos	1.85
5	Midazolam	2.00	0.71
	Triclofos	2.02
10	Midazolam	2.20	0.65
	Triclofos	2.25
15	Midazolam	2.62	0.92
	Triclofos	2.62
20	Midazolam	2.91	0.29
	Triclofos	3.08
25	Midazolam	3.02	0.42
	Triclofos	3.14
30	Midazolam	3.08	0.15
	Triclofos	3.34

Table 2 – shows baseline sedation, i.e., before premedication is comparable. In my study, both in the Group M and Group T, majority of children were sedated to score of 3 at 20 min of administration of drugs. In a comparative study, Alderson and Lerman[1] used oral midazolam and ketamine but concluded that score of >3 was never achieved and children remained drowsy but awake. In my study, 75% children in both groups achieved sedation score of 4 at 20 min i.e., they became drowsy and asleep. In the present study, the heart rate, systolic blood pressure, and diastolic blood pressure across the group do not indicate any significant difference.

Table 2

Comparison of sedation score at 0 min (before premedication) between 2 groups

Variable (n=35)	Sedation score
Midazolam	1.97
Triclofos	1.85
P	0.54

As pricks are not acceptable mode of drug delivery, the drugs selected were given orally. Midazolam syrup was available sometimes back, but due to withdrawal from market, injectable midazolam in required doses was administered with suitable vehicle (apple juice), while triclofos is available in syrup form. As far as palatability of drugs in both groups are concerned, my study is suggestive of better acceptability of triclofos syrup than midazolam syrup while Saarnivaara et al.[13] has reported better acceptability of midazolam compared to triclofos. Another study by Jain et al.[14] reported better sedative and palatability and less gastric irritation with triclofos in children posted for sleep electroencephalogram.

In a study by Chaudhary et al.,[15] midazolam had greater percentage of excellent sedation score than triclofos whereas Shapira et al.[16] reported 95% children premedicated with midazolam and triclofos to be calm and sleepy at the time of separation from parents. My study also suggests the same as above. Results derived by Feld et al.[17] and Kumar et al.[18] concluded tearful and combative child at separation, where there was 5% combative response to parenteral separation.

My study shows sedation score of both Groups M and T. Statistical test does not show significant difference in sedation score. At different times of 5, 10, 15, 20, and 25 min at doses of 0.5 mg/kg midazolam or 75 mg/kg, triclofos produced similar sedation (Ramsay sedation score). Saarnivaara et al. have reported that 75 mg/kg and 0.5 mg/kg of midazolam produced fair anxiolysis in children of <5 years and good anxiolysis in above 5 years age group. In my study, among age group 2–5 years, the result goes with the above study but different from the Singh et al.[19] who reported better anxiolysis and sedation with midazolam compared to triclofos and promethazine premedication.

My study goes with Parameswari et al.[20] where triclofos was found to be better to midazolam.

Kazak et al.[21] used 0.25 mg/kg and parental presence compared to 0.5 mg/kg without parenteral presence, and as per University of Michigan Sedation Scale, both had similar sedation and anxiolysis during transfer to the operating room.

Geetha et al.[22] used 70 mg/kg triclofos and 0.5 mg/kg midazolam to study sedation, anxiety score, and reaction to parenteral separation and reported 86.7% patient with triclofos and 100% with midazolam were sedated at 45 min and 30 min, respectively. Anxiety score was satisfactory in triclofos and 100% in midazolam group as depicted in Tables 4–6. Parenteral separation was equally good in both the groups The findings of my study differs from the study conducted by Geetha et al.[22] as 5 mg/kg less dose of triclofos was used in their study.

Table 4

Comparison of anxiety score at parenteral separation between 2 groups

Groups (n=35)	Anxiety score
	1	2	3	4
Midazolam	26	7	2	0
Triclofos	29	4	1	1

Table 6

Comparison of anxiety score at mask application between 2 groups

Groups (n=35)	Anxiety score
	1	2	3	4
Midazolam	17	6	8	4
Triclofos	21	8	2	4

Limitation of my study was peak pricks; serum level analysis with duration could not be quantified.

CONCLUSION

It can be concluded from this study that the parenteral formulation of either midazolam or triclofos can be safely used as premedicant in children. Oral midazolam or oral triclofos does not produce any respiratory depression in children. However, oral triclofos may be considered to have better quality of anxiolysis than oral midazolam.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Table 5

Comparison of anxiety score at intravenous cannulation between 2 groups

Groups (n=35)	Anxiety score
	1	2	3	4
Midazolam	14	8	10	3
Triclofos	18	12	2	3