|Year : 2015 | Volume
| Issue : 1 | Page : 56-63
A comparative study between midazolam, promethazine, and chloral hydrate as oral premedication in pediatric patients
Osama A El Hay, Mostafa A Abo El Enin, Mohamad H Hamada, Abdallah M Ahmed
Department of Anaesthesia and Intensive Care, Al Azhar University, Cairo, Egypt
|Date of Submission||15-Sep-2014|
|Date of Acceptance||01-Dec-2014|
|Date of Web Publication||25-Mar-2015|
Mostafa A Abo El Enin
Assisstant Professor of Anesthesia and Intensive Care, 37 El Taef Street from Sudan Street Mohandesen, Giza
Source of Support: None, Conflict of Interest: None
Ensuring adequate preoperative sedation and anxiolysis is essential, especially in pediatric surgery. Various drugs and routes of administration have been evaluated to determine the optimal method of sedation.
The aim of the study was to compare the clinical effects of orally administered midazolam, promethazine, and chloral hydrate as premedication in pediatric patients.
Patients and methods
Ninety children of both sexes, of ASA grade I-II, aged 3-6 years, scheduled to undergo pediatric surgery were allocated randomly into three groups of 30 patients each. Group M (midazolam) patients were premedicated with a dose of 0.5 mg/kg of injectable midazolam mixed in sugar-free apple juice. Group P (promethazine) patients were premedicated with 1 mg/kg of the commercially available syrup. Group CH (chloral hydrate) patients were premedicated with 50 mg/kg of the commercially available syrup. In the presence of their parents, oral sedative premedication in the form of syrup was given 45 min before induction of general anesthesia. On arrival at the operating room, the sedation score, the easy separation score, and behavior at the time of venipuncture were assessed. At the end of the operation, recovery was assessed using the 'Vancouver sedative recovery scale for children'. The incidence of adverse effects was recorded and amnesia was assessed after 24 h.
Sedation and ease of separation scores were higher in the M group than in the P and CH groups. As regards behavior at the time of venipuncture the proportion of children with no reaction was higher in the M group than in the P group; no cases were recorded in the CH group. The recovery time from anesthesia was shorter in group M (15.3 ± 5.2 min), longer in group CH (24.2 ± 3.7 min), and midway in group P (20.8 ± 3.5 min) (P < 0.001). Anterograde amnesia was more pronounced in group M in comparison with groups P and CH (P < 0.001).
Oral midazolam at a dose of 0.5 mg/kg of body weight is a suitable premedication for children. It may be preferred over promethazine and chloral hydrate because of its better sedative effect, good easy separation score, good behavior scores of children at the time of venipuncture, and better recovery from anesthesia with postoperative amnesia.
Keywords: chloral hydrate, midazolam, promethazine
|How to cite this article:|
El Hay OA, Abo El Enin MA, Hamada MH, Ahmed AM. A comparative study between midazolam, promethazine, and chloral hydrate as oral premedication in pediatric patients. Ain-Shams J Anaesthesiol 2015;8:56-63
|How to cite this URL:|
El Hay OA, Abo El Enin MA, Hamada MH, Ahmed AM. A comparative study between midazolam, promethazine, and chloral hydrate as oral premedication in pediatric patients. Ain-Shams J Anaesthesiol [serial online] 2015 [cited 2021 May 9];8:56-63. Available from: http://www.asja.eg.net/text.asp?2015/8/1/56/153939
| Introduction|| |
The perioperative period is often an extremely traumatic time for the young child undergoing surgery. Up to 65% of all children undergoing anesthesia and surgery develop intense anxiety and fear in the preoperative holding area and during induction of anesthesia  . Preoperative anxiety stimulates the sympathetic, parasympathetic, and endocrine system, leading to an increase in heart rate, blood pressure, and cardiac excitability. Maladaptive behavioral responses, such as general anxiety, night-time crying, enuresis, and separation anxiety, occur in up to 44% of children 2 weeks after surgery and about 20% of these children continue to demonstrate negative behaviors up to 6 months after surgery  . Children who are not premedicated object frequently to inhalational induction of anesthesia and often consider the use of needles as one of the most worrisome aspects of hospital stay  . Children aged 2-6 years are especially vulnerable to this problem as their understanding is limited. Therefore, these children should be premedicated to allow smooth induction, reduce anxiety, and prevent postoperative psychological and behavioral changes  . To reduce the incidence of preoperative anxiety in children, a number of pharmacological (e.g. sedatives) and nonpharmacological (e.g. parental presence, behavioral preparation programs, music, acupuncture, etc.) approaches have been successfully adopted. Midazolam has been the pharmacological agent of choice for preoperative anxiety in day-case surgery because of its rapid onset and short half-life. Midazolam is an effective agent in alleviating anxiety in children  . It is a benzodiazepine that can be administered parenterally, intranasally, sublingually, rectally, or orally to produce anxiolytic hypnosis and sedation and anterograde amnesia , . In pediatric surgery, promethazine has been used as a sedative drug for premedication with antihistaminic, antiemetic, anticholinergic, and antimotion sickness properties , . Promethazine blocks postsynaptic dopaminergic receptors in the brain and has a strong a-adrenergic inhibitory effect  . Consequently, it has strong sedative and hypnotic effects. Chloral hydrate, which is a sedative-hypnotic drug administered orally, is one of the most widely used sedatives in children undergoing MRI  and dental procedures  . It has no analgesic properties; therefore, it should not be used to treat pain or during painful procedures unless combined with an analgesic agent such as an opioid  . This study was conducted to compare the efficacy of oral premedication with midazolam, promethazine, and chloral hydrate as premedication in children.
| Patients and methods|| |
After obtaining the local ethics committee's approval, we obtained written informed consent from the children's parents. We studied 90 male and female children, of ASA physical status I-II, aged 3-6 years, who were scheduled to undergo pediatric surgery in El-Hussein University Hospital. The exclusion criteria included a history of chronic illness, gastrointestinal tract disorders or malformation, known reactions to the drugs used, seizure disorder, and an active or recent upper respiratory tract infection. Children were kept off solid food for 6 h and of clear fluids for 2 h. By using the sealed envelope technique (random permuted blocks) the patients were allocated randomly into three groups of 30 patients each. Group M (midazolam) patients were premedicated with a dose of 0.5 mg/kg  of injectable midazolam (Dormicum; Roche; USA; ampoule containing 15 mg/3 ml mixed in sugar-free apple juice limiting the total volume mixed with a double volume of apple juice). Group P (promethazine) patients were premedicated with a dose of 1 mg/kg  of commercially available syrup (Phenergan; Aventis; France; 5 mg/5 ml). Group CH (chloral hydrate) patients were premedicated with a dose of 50 mg/kg  of commercially available syrup (Chloral; Nile; Egypt; 500 mg/5 ml). In the preoperative holding area and in the presence of the child's parent, oral premedication in the form of syrup was given 45 min before induction of general anesthesia. Children who refused to take the whole dose were excluded from the study. On arrival at the operating room (OR), a three-point sedation score was used to assess sedation at the time of administration of the premedication (baseline) and reassessed again 45 min after its administration. The scores were excellent (fully co-operative, unafraid, or asleep), good (mild to moderate fear and/or crying, which ceases and the child becomes co-operative with reassurance), or poor (un-co-operative, crying, inconsolable). Ease of separation score  was used to assess the children's responses when taken away from the parents at the time of administration of the premedication (baseline) and reassessed again after 45 min of its administration. They were graded as excellent (unafraid, co-operative, or asleep), good (slight fear and/or crying, quietens down with reassurance), fair (moderate fear and crying, does not quieten down with reassurance), or poor (crying, need for restraint) at baseline and after 45 min. Behavior at the time of venipuncture scale  was used to evaluate the behavior of the child at the time of puncture for inserting an intravenous line in the OR (1, fight without success; 2, fight with success; 3, minor resistance; 4, no reaction). Routine monitors were connected before induction of anesthesia (for evaluating heart rate, noninvasive arterial blood pressure, and peripheral oxygen saturation). Anesthesia was induced with propofol at 2 mg/kg intravenous, fentanyl at 1 µg/kg, and inhalational 2% sevoflurane in oxygen. Endotracheal intubation was carried out after administration of atracurium at 0.5 mg/kg. Anesthesia was maintained with 1% sevoflurane in oxygen with controlled ventilation. During surgery, the children received lactated Ringer's solution at 6 m/kg/h, whereas in the postoperative period 5% dextrose in 0.45% NaCl was infused at 6 ml/kg/h. We defined an intraoperative reduction of MAP or heart rate by more than 30% of baseline values as hypotension or bradycardia, respectively; as necessary, these were treated with fluid bolus, ephedrine, or atropine. Residual neuromuscular block was antagonized with atropine sulfate at 0.02 mg/kg and neostigmine at 0.05 mg/kg. After extubation, the patients were admitted to the postanesthetic care unit for at least 2 h until complete recovery. Heart rate was monitored, as well as SpO 2 and mean arterial blood pressure (MAP). The recovery time was recorded from discontinuation of anesthesia until the baseline score was regained and evaluated using the 'Vancouver sedative recovery scale for children'  . The scores were recorded before giving sedation preoperatively and then reassessed every 5 min postoperatively until the baseline score was regained. The discharge time was recorded from discontinuation of anesthesia until achievement of a score of 10-12 of 'the Short-Stay Surgery Discharge Score'  , which was evaluated postoperatively every 30 min until discharge.
Anterograde amnesia was assessed after 24 h by means of a telephone call to the parents; the conversation included questions pertaining to recall of the events that took place after the administration of sedation. The quality of anterograde amnesia was rated as 'yes' or 'no'  . The incidence of adverse effects such as nausea, vomiting, laryngospasm in the preinduction area, postoperative agitation, and preoperative hiccough was recorded.
The sample size was calculated using the Medcalt (USA) program, version 3.2. The minimum sample size was 25 in each group and the present study included 30 in each group, with type I error (α) 0.05 and type II error (β) 0.01 by power of test 90%. We fed the data into a computer and analyzed it using SPSS software package (version 20.0; IBM, USA). Qualitative data were described using numbers and percentages, and quantitative data using mean and SD for normally distributed data. Using the χ2 -test, we tested and made comparisons of categorical variables between the different groups. When more than 20% of the cells had an expected count less than 5, a correction for χ2 by using Fisher's exact test or Monte Carlo correction was made. The distributions of quantitative variables for normality were tested using the Kolmogorov-Smirnov test, the Shapiro-Wilk test, and the D'Agstino test. Histograms and QQ plots for vision were also used. Parametric tests were applied for normally distributed data: the F-test (ANOVA) was used to analyze for comparisons between the studied groups; in addition, we used the post-hoc test (Scheffe, which was assessed using adjusted Bonferroni and ANOVA with repeated measures to make comparisons between different periods). Nonparametric tests were used for abnormally distributed data: the Kruskal-Wallis test was used to make comparisons between groups and the Mann-Whitney test to conduct a pairwise comparison. Also, the Wilcoxon signed-rank test was applied to make comparisons between the two stages. Significance of test results was quoted as two-tailed probabilities. The significance of the obtained results was judged at the 5% level. P value of 0.05 or less was considered significant and P value of 0.01 or less was considered highly significant.
| Results|| |
This study was conducted on 90 children of both sexes undergoing pediatric surgery, as shown in [Table 1]. The three groups (M, P, and CH) were comparable with respect to patient number, age, sex, body weight, duration of surgery, and procedures.
|Table 1 Comparison between the studied groups according to demographic surgical data|
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Before administration of sedation, there was no statistically significant difference in sedation scores between the groups. However, sedation scores differed significantly at 45 min after drug administration between the groups. At this time, midazolam administration resulted in higher scores compared with promethazine and chloral hydrate administration (P < 0.001). Also there was a statistically significant difference with higher scores in group P than in group CH (P = 0.043), as shown in [Table 2].
|Table 2: Comparison between the studied groups according to sedation score|
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Ease of separation scores
Before administration of sedation, there was no statistically significant difference in ease of separation scores between the groups. However, the time of separation from the parent was significantly different between the three groups (45 min after drug administration) (P < 0.001). At this time, midazolam administration resulted in better scores compared with promethazine, which was highly statistically significant (P = 0.004), and chloral hydrate administration, which was very highly statistically significant (P < 0.001). There were statistically significantly better scores in group P than in group CH (P = 0.041), as shown in [Table 3].
|Table 3: Comparison between the studied groups according to ease of separation score|
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Behavior at the time of venipuncture scale
There was a statistically significant difference between the three groups at 45 min after drug administration (P < 0.001). At this time, midazolam administration resulted in better behavior compared with promethazine and chloral hydrate administration. There were statistically significantly better scores in group P than in group CH (P < 0.001). There was no statistically significant difference between group M and group P (P = 0.309), as shown in [Table 4].
|Table 4 Comparison between the studied groups according to behavior at the time of venipuncture scale|
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Recovery and discharge times
There was a statistically significant difference between the three groups with respect to recovery (P < 0.001). There was a statistically significant difference between group M and group P (P < 0.001) as well as between group M and group CH (P < 0.001) and between group P and group CH (P 0≤ 0.05). There was no significant difference in discharge times to home between the groups (P = 0.215), as shown in [Table 5].
|Table 5 Comparison between the studied groups according to recovery and discharge times (min)|
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Anterograde amnesia was more pronounced in group M in comparison with groups P and CH. The variation in achievement of amnesia between both groups M and P and groups M and CH was very highly significant (P < 0.001). There was no statistically significant difference between group P and group CH (P ≥ 0.05), as shown in [Table 6].
|Table 6 Comparison between the studied groups according to achievement of amnesia|
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The incidence of adverse effects was significantly different between the three studied groups (P = 0.004). The incidence of postoperative nausea, vomiting, and agitation was higher in the CH group (30.0%) compared with the M group (13.3, 20.0%) and P group (6.7, 10.0%). Also hiccough was noticed in three (10.0%) patients in the M group only, and only one (3.3%) case of desaturation occurred, again in the M group, as shown in [Table 7].
|Table 7: Comparison between the studied groups according to incidence of adverse effects|
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| Discussion|| |
The oral route is usually the most preferred for pediatric patients for achieving conscious sedation through combinations of drugs  . Thus, in this study, all drugs were given orally as the sole agent. The optimal time interval between premedication and separation from parents should provide maximum sedation and anxiolysis at the time of separation from parents or guardians and at venous cannulation for induction of anesthesia.
The results of the present study showed that midazolam administration resulted in better scores compared with promethazine and chloral hydrate administration, which was in accordance with the results of Derakhshanfar et al.  , who compared preschool children who received oral midazolam syrup at 0.5 mg/kg with another group that received oral promethazine syrup at 1 mg/kg. They found that midazolam had a significantly shorter onset of sedation. Nausea and vomiting was the only complication that was more significant in the M group. Jalbout et al.  compared midazolam with promethazine as premedication and found that only 55.6% of patients who received promethazine had a reduced state of anxiety, which increased to 83.3% for those receiving midazolam. Thus, it was declared to be a better anxiolytic than promethazine.
Also, the results of the present study were similar to those of Shoroghi et al.  , who compared the effect of oral midazolam at 0.5 and 1 mg/kg with placebo in children undergoing skin laser treatment. They received injected midazolam mixed with equal volume of orange juice and were assessed for sedative scores on a four-point sedation scale, on mask acceptance, on behavioral scales, and for postoperative events. The median sedation score for 0.5 mg/kg of midazolam was 2 (1.7-3.0) and for that for 1 mg/kg was 3 (2.0-3.0); the median separation score was 3 (good: separated without crying) (range 2.0-3.0) for both doses. The score for acceptance of face mask was also 3 (2.0-3.0) for both doses but ease of intravenous cannulation was 1.5 (1.0-2.0) for 0.5 mg/kg midazolam and 3.0 (2.0-3.0) for 1 mg/kg midazolam. As regards behavior at the time of venous puncture the results of the present study showed that midazolam administration resulted in better behavior compared with promethazine and chloral hydrate, and this was in accordance with the results of Kumar et al.  , who found satisfactory behavior at venipuncture (minor resistance or no reaction) in 70% of children aged 3-10 years who were premedicated with oral midazolam at 0.5 mg/kg. Also a placebo-controlled study by Liacouras et al.  to evaluate the effect of oral midazolam as premedication before intravenous conscious sedation found a significant difference in the midazolam group with respect to the level of sedation for intravenous placement, preprocedural sedation, ease of intravenous insertion, ease of separation from parents, and ease of the nursing personnel's ability to monitor the patient during the procedure. In contrast to this study's results, Mortazavi et al.  found that patients who received 0.25 mg/kg of the prepared oral midazolam showed significantly better behavior during treatment compared with the placebo control group. In comparison with the placebo group, reduced movement and crying was observed in the M group. They found that, in the M group, none of the children slept during treatment but remained relaxed or sleepy; this might have been attributed to the low dose of midazolam that was used; however, the present study used 0.5 mg/kg. As regards easy separation score, the results of the present study showed that midazolam administration resulted in better scores compared with promethazine and chloral hydrate (P < 0.001) and there were statistically significant differences with better score in group P than in group CH (P = 0.041). This is in accordance with the study by Naziri et al.  , who compared the effect of midazolam at 0.3 mg/kg with promethazine at 1 mg/kg oral on reducing anxiety in children presenting for elective surgery 30 min before entering the operating room when they were being separated from their parents before anesthesia. This study showed that child separation from parents was easier in the M group compared with the P group (P = 0.019). Consequently, before general anesthesia, the use of oral midazolam is preferred to oral promethazine for children (under 5 years) being separated from their parents. Also the results of the present study are in accordance with those of Singh et al.  , who evaluated the safety and efficacy of orally administered midazolam in children as a sedative agent and compared it with triclofos (oral triclofos derivative of chloral hydrate) and promethazine in children presenting for short dental procedures. They concluded that oral midazolam produced the best levels of conscious sedation in these patients compared with promethazine and chloral hydrate. Similarly, Hamid et al.  compared the effectiveness of oral midazolam and chloral hydrate on anxiety and sedation at various stages of the preoperative period in congenital heart surgery patients and found that chloral hydrate provided comparable anxiolysis but superior sedation and mask acceptance scores. Higher doses of chloral hydrate (50 mg/kg) were required to keep these patients calm and peaceful at the time of mask application for inhalation induction.
In contrast to the results of the present study, Parameswari et al.  compared the efficacy of oral midazolam at 0.5 mg/kg and oral triclofos at 75 mg/kg as premedication for children aged 1-10 years undergoing elective surgery. They concluded that children who received oral triclofos as premedication were sedated better and were asleep, whereas children who received oral midazolam as premedication were awake but calm and showed better acceptance of the face mask. This may be attributed to the use of a higher dose of 75 mg triclofos compared with the present study (50 mg/kg chloral hydrate). In this study, recovery was most rapid for group M and slowest for group CH, which is in accordance with the results of the study by Singh et al.  showing a more rapid recovery from sedation in children premedicated with midazolam in comparison with the P group. As regards discharge time, the results of the present study showed that there was no statistically significant difference in discharge times to home between the studied groups, which was in accordance with the results of McMillan et al.  , who found that mean times to hospital discharge were similar in both the midazolam-treated group and the placebo group. Also, they demonstrated that children who received midazolam were suitable for discharge to their home ~1 h after arrival in the postoperative anesthesia care unit (PACU); this was similar to the usual time to discharge home after surgery. Also, another study by Horgesheimer et al.  evaluated the effect of oral premedication with midazolam on recovery times of children undergoing dental restorations under general anesthesia. They concluded that preoperative administration of oral midazolam did not delay discharge of children receiving general anesthesia. The total postoperative times, which included recovery time and discharge time for the midazolam and control groups, were almost identical: 148.2 and 141.1 min, respectively.
In this study, we assessed anterograde amnesia after 24 h by means of telephone recall of the parents. It was more pronounced in group M compared with groups P and CH. This result was in accordance with those of Bulach et al.  , which found that intravenous midazolam up to a dose of 10 mg did not produce any reliably significant degree of clinically relevant retrograde amnesia and that intravenous midazolam produced immediate-onset anterograde amnesia at doses of 5 and 10 mg in adult patients. This might be useful in preventing explicit recall of perioperative events. The extent of sedation, as measured by bispectral index (BIS), was correlated with anterograde amnesia as measured by event recall. It should also be recognized that midazolam administration during anesthesia might be influenced by the amnesic effects of propofol or other coadministered hypnotic drugs  . Also, the study by Kain et al. showed that midazolam administered orally produced significant anterograde amnesia when given as early as 10 min before a surgical procedure. Their study aimed to establish the minimum time necessary for effective anterograde amnesia to develop in children after administration of oral midazolam. Further, they found that recognition memory was impaired as early as 10 min after oral administration of midazolam, and recall was impaired as early as 13 min after oral administration of midazolam.
In this study, we observed the adverse effects of the drugs used for premedication and recorded the results preoperatively, intraoperatively, and postoperatively. We did not detect any severe adverse events among children. Except for one patient in the M group who suffered from desaturation (SpO 2 <92%) and was managed early, other adverse events like nausea, vomiting, and agitation were more in group CH than in the other groups.
| Conclusion|| |
This study results showed that oral midazolam at a dose of 0.5 mg/kg of body weight is a safe and suitable premedication for children. It may be preferred over promethazine and chloral hydrate because of the better sedative effect, good easy separation score, good behavior score at the time of venipuncture, and better recovery from anesthesia with postoperative amnesia.
| Acknowledgements|| |
The authors thank all doctors of the Anesthesia Department in El-Hussein University Hospital.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]