Is premedication with midazolam more effective by the sublingual than the oral route?

BACKGROUND: In this study, we compared the sedative effects of sublingual midazolam solution with the oral tablet as premedication. Sixty pediatric patients of ASA physical status I and II were randomly selected to receive either 0.5 mg/kg of tablet or 0.5 mg/kg of sublingual solution of midazolam as premedication, about 45 min before elective surgery.
MATERIALS AND METHODS: There were 30 patients in each group. In Group I, the patients received premedication in the form of oral midazolam tablet 0.5 mg/kg. In Group II, the patients received midazolam solution 0.5 mg/kg. The degree of sedation and ease of separation was assessed according to the Niall C. Wilton scale and the procedure of Davis Peter, respectively. The time for complete drug dissolution was noted in both the groups. Then, the patients were interviewed regarding their acceptance of taste.
RESULTS: The sedation scores in the sublingual group were higher than in the oral group at 30 and 45 min after drug administration (P=0.0134 and P=0.0157). 66.6% of the patients in the sublingual group found it satisfactory as compared to 53.3% in the case of group receiving tablet.
CONCLUSION: Thus, from the present study, it is concluded that premedication with midazolam is more effective by the sublingual than the oral route in children.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Some form of medication is necessary to calm the patient and lessen the anxiety related to surgery and anesthesia. Role of anesthesiologists for premedication before induction of anesthesia is of vital importance. There is almost universal agreement on the need for some premedication, which forms an integral part of anesthetic management. However, surprisingly, despite the supreme importance of the subject, there are few established facts regarding facing anxious and apprehensive patients before anesthesia.

Premedication is more important in case of children because of the fear of painful and unpleasant procedures, separation from parents, and unwillingness to breathe through anesthesia face mask which may produce stormy anesthetic induction in unpremedicated patients.[113] Because of this preanesthetic anxiety, sedation should be an integral part of pediatric anesthetic practice. Premedication in children can pave the way to achieve a smooth anesthetic and postoperative course. It is also an important adjunct to alleviate the stress and fear of surgery as well as to ease the child–parent separation and promote a smooth induction of anesthesia.[2]

The present position of premedication and preoperative sedation in children is one of the most confusing and unsatisfactory aspects of pediatric anesthesia. Although most anesthetists agree that sedation is indicated, no two agree on what or how much should be given, or by what route it should be administered. Almost all the drugs currently available for preanesthetic medication of children either are administered as injection or as a pill or by nasal or rectal administration.[3] Any of these methods could be difficult or traumatic for 1–7 year old children. In addition, many of the currently used drugs like narcotics and benzodiazepines also cause respiratory depression and none provides a uniform balance of sedation, amnesia along with adequate safety. In various studies comparing midazolam, a newer fused ring benzodiazepine, with other drugs like diazepam, ketamine, morphine, fentanyl, sufentanyl, promethazine and pethidine, it was found to be very effective, short acting, safe, and also was found to have profound amnesic properties, hemodynamic stability, and lesser respiratory depression.[4-6] As children dislike injections, other routes of premedication such as oral, rectal, intranasal and sublingual were found to be effective.[7]

MATERIALS AND METHODS

After getting approval from the institutional ethical committee, the present study was carried out in randomly selected patients of both sexes and of ASA physical status of I and II from the routine lists. They were divided into two groups of 30 patients each.

There were no significant differences between the two groups regarding age, weight, sex ratio and surgical procedures and duration of anesthesia. All the patients were seen a day before surgery and screened for past history of convulsion, meningitis, congenital anomalies, upper respiratory tract infection (URTI), lower respiratory tract infection (LRTI) fever, hemoglobin level less than 9%, drug allergy, etc. Routine investigations like hemoglobin, urine and blood sugar, blood urea, serum creatinine estimation and X-ray of chest were done to find if they were within normal limits. On the day of surgery, they were assessed for pulse rate, respiratory rate, SPO2, temperature, and a short history of any recent development of URTI and sore throat. The patients were instructed to roll their tongue and touch their upper teeth with the tongue. The premedication containing solution was administered from a 2-ml plastic dispovan. They were instructed not to spit or swallow the solution. Compliance with instruction was noted. The groupings were as follows.

Group I: Patients received premedication in the form of oral midazolam tablet 0.5 mg/kg

Group II: Patients received midazolam solution 0.5 mg/kg

Resuscitative equipment was immediately available at the bedside. Dose and time were noted in each of the cases. After administration of the drug to the patients, the response to drug administration was noted. It was noted whether the patient accepted the medication willfully, showed resistance or required assurance for administration. If the child accepted the premedication willfully, did not cry or cried for less than 1 min, did not spit the drug within 20 seconds, the response was called satisfactory. The patients were observed at an interval of 1, 2, 6, 10 and 15 min and the following observations were made. Vital parameters like pulse rate, respiratory rate, SPO2, level of sedation (sedation score by Niall C. Wilton),[8] onset of sedation, response to child-parent separation, venipuncture and ease of induction were assessed and graded according to the 4-point separation and induction score [Tables 1 and 2].

Table 1

Sedation score

Table 2

Separation and induction score

Special observation was done during separation from parents (10 min) or attempting venipuncture (15 min) and on applying the mask (20 min), in addition to the above-mentioned parameters, using separation score.[9]

All the patients were induced with Thiopentone sodium 5 mg/kg and endotracheal intubation was done with appropriate sized portex tube facilitated by Inj. succinylcholine 1.5 mg/kg IV, after preoxygenation for 3 min. Pulse, blood pressure, SPO2 at and after 1, 3, 5, 10, 20, 30, 45, and 60 min of induction and duration of surgery and anesthesia were noted. All the patients were reversed with Inj. Neostigmine 50 mcg/kg and Inj. Glycopyrrolate 8 mcg/kg. Pulse, respiratory rate, SPO2, and sedation score were noted at the time and various intervals after extubation. Time of awakening, presence of crying at extubation and postoperative complications like lethargy, excessive sedation, hypoxemia, nausea, and vomiting were also noted.

Statistical analysis

All the qualitative data were analyzed using the Chi-square test and Students’ unpaired t-test. The results were expressed as Mean±SD. P value <0.05 was taken as statistically significant and P value <0.001 was taken as highly significant, and the accepted power of study was 0.8.

RESULTS

Demographic data like age, sex, and weight were comparable in both the groups [Table 3].

Table 3

Demographic data

All the results for the changes in mean arterial pressure, pulse rate and oxygen saturation were comparable in the two groups. They did not change significantly at any time after premedication, induction or in the postoperative period in either group [Tables 4–6 and Figure 1].

Table 4

Comprehensive changes in mean pulse rate per minute in both the groups

Table 6

Oxygen saturation by pulse oximetry in both the groups

Figure 1

Changes observed in cardiovascular and respiratory system in both the groups

From the statistical analysis, it is evident that the difference in mean separation and induction score and sedation score between the two groups at separation were not significant (P>0.05), but it was significant at venipuncture (P<0.001) and induction (P<0.05). The sublingual group was having higher sedation score both at 30 and 45 min (P=0.0134 and 0.0157, respectively). The separation and induction score of 2 or less was considered to be acceptable during the time of separation, venipuncture and induction, which was lower in sublingual than in oral group but statistically nonsignificant.

It is evident that the difference in mean sedation score at separation from their parents and prior to induction of anesthesia between the two groups with regards to the basal presedation score was not statistically significant up to 30 min after premedication. As the peak action of the midazolam tablet in oral and sublingual forms was at 45 and 30 min, respectively, the difference between the mean sedation score was statistically significant at 30 and 45 min after premedication [Tables 7–8 and Figure 2].

Table 7

Sedation score at various intervals

Table 8

Mean emotional score during separation, venipuncture and induction

Figure 2

Mean sedation score changes in both the groups

No statistically significant difference was found when the postoperative complications between the two groups were compared [Table 9].

Table 9

Incidence of postoperative complications in patients of both the groups

DISCUSSION

Oral route of administration has not only advantages, but also disadvantages like longer duration of onset of action, significant first pass metabolism leading to larger dose requirement, unpredictable absorption and bioavailability, unpredictable effects and inter-individual variability.[710] Sublingual route has an advantage of mucosal absorption directly into the systemic circulation with no first pass hepatic metabolism due to the rich blood supply of oral mucosa, is easy to administer, has rapid action, reliable predictable effect and the drug is not destroyed by the gastrointestinal enzymes.[1112]

Midazolam, a water-soluble, short acting benzodiazepine, has been found to be an effective premedicant in children. which can be administered by various routes like intramuscular, oral, rectal, intranasal and sublingual.[1314]

Premedication with midazolam has shown to be more effective than parental presence or placebo in reducing anxiety and improving compliance at induction of anesthesia. The beneficial effects of midazolam include sedation, anxiolysis, and reduction of postoperative vomiting. A recent evidence-based clinical update has shown that oral midazolam 0.5 mg/kg is effective in reducing both separation and induction anxiety in children, with minimal effect on recovery time.[13]

However, the acceptability of oral midazolam by pediatric patients is only 70%. Other undesirable effects including restlessness, paradoxical reaction, and negative postoperative behavioral changes have made it less than an ideal premedication. Although amnesia is considered an advantage by some authorities, others have also regarded it as a possible disadvantage.[1516]

In the present study of 60 cases, a comparison was made between the sublingual and oral routes of midazolam as premedication in children. Each group was studied for the presedation behavior, onset of sedation, sedation and emotional score and cardiovascular changes. We studied the presedation behavior of all patients, to have a baseline trend of behavior, among pediatric surgical patients, using a 5-point sedation scale. The two groups were comparable to each other in the presedation scale of the patients. There was no significant difference in the trend of behavior of the pediatric surgical patients. The difference in mean sedation score between the two groups with regards to the basal presedation score was not statistically significant up to 10 min after premedication, but it was significant at 30 min (P value 0.0134) and 45 min (P value 0.0157) after medication. In the oral group, the sedation score was higher at 45 min, but at 30 min the sublingual group showed higher score; but when the child had to go through maximum stress at induction, both were comparable. Similar observations were made by Naqash et al.[3] and Karl et al.[10] in their respective studies. Naqash et al.[3] found that a sedation score of >3 was achieved in both the intranasal and sublingual groups within 10 min of drug administration, and also that the incidence was higher (80%) in the sublingual group.

Karl et al.[10] noted that at the point of maximum anxiolysis, i.e. at 20 min after administration, midazolam by sublingual route had produced significant decrease in apparent anxiety in majority of the patients.

An emotional score of 2 or less was considered to be acceptable during the time of separation, venipuncture and induction, which was earlier in the sublingual group.

Naqash et al.[3] found the child–parent separation to be satisfactory in 93.4% of the children receiving sublingual midazolam and a satisfactory response to venipuncture in 90% of the patients in both the groups receiving midazolam by intranasal and sublingual routes.

Pandit et al.[8] found satisfactory child–parent separation in 95% of the patients premedicated with sublingual midazolam compared to 59% patients in the placebo group. Karl et al.[10] found child–parent separation to be satisfactory in 85% children receiving sublingual midazolam and satisfactory response to induction in 81% of the patients. Niall Wilton[8] et al. found 60% of patients receiving normal saline as premedication to be agitated during induction, as compared to only 3% of those receiving midazolam.

Hemodynamic variables did not change significantly (P<0.05) at any time after premedication, induction or in the postoperative period. The results are comparable to other studies. Naqash et al.,[3] Karl et al.,[10] and Wilton et al.[7] found no significant changes in mean arterial pressures and adequate oxygen saturation (SPO2>95%) in their respective studies.

In studies of the sedative medications, it is necessary to evaluate whether the drug causes any excessive sedation, respiratory depression, cardiovascular instability or any other serious adverse effects such as nausea, vomiting, laryngospasm, oxygen desaturation or any other observed variable. The postoperative complications like lethargy, excessive sedation, respiratory depression, nausea, vomiting, tongue fall, and need for airway support were also not significant between the oral and sublingual groups.

CONCLUSION

From the present study, as it was found that the desirable level of sedation and separation was achieved earlier in case of sublingual midazolam, it can be concluded that premedication with midazolam is more effective by the sublingual than by the oral route.

Table 5

Comprehensive changes in mean arterial blood pressure (mm Hg) in both the groups