J Oral Maxillotac

Surg

46:791-796.1990

Preanesthetic Medication With Rectal Midazolam in Children Undergoing Dental Extractions J.A. ROELOFSE, MMED(Anaesth), PHD,* P. VAN DER BIJL, BSC(Hons)(Pharmacol), BCHD, PHD,t D.H. STEGMANN,BCHD,* AND J.E. HARTSHORNE, BCHD, MCHDS Three different dosages (0.25, 0.35, and 0.45 mg/kg) of rectally administered midazolam were compared with each other and with placebo for preanesthetic medication in children undergoing dental extractions. Eighty patients between the ages of 2 and 10 years were randomly allocated into four groups in this double-blind study. The results from this trial show that 30 minutes after rectal administration of all doses of midazolam, good anxiolysis, sedation, and cooperation were obtained in most patients. A high prevalence (23%) of disinhibition reactions was observed, particularly in the 0.45 mg/kg group. For this reason, 0.25 or 0.35 mg/kg appears to be the dose of choice when rectal midazolam is used for premedication in children.

levels, acceptability of rectal administration, levels of sedation and anxiety, adverse reactions, acceptance of the anesthetic mask, and time taken to awaken after the general anesthetic were all evaluated during this study.

Because children generally fear injections, rectal administration of premeditation, a relatively painless procedure, has become popular. A variety of agents including barbiturates, narcotics, anticholinergics, and benzodiazepines have all been administered via this route.le3 More recently the rectal administration of midazolam, with its short plasmaelimination half-life of 1.5 to 2.5 hours in adults and children as well as its absence of clinically significant active metabolites, 4*5has been studied as a rectal premedicant in children.6-9 In the present study different doses of rectally administered midazolam were compared with each other and placebo in a double-blind randomized trial in children who required dental extractions. Vital signs and variables such as oxygen saturation

Materials and Methods PATIENTS

Eighty ASA I children of both sexes, between the ages 2 and 10 years (Table 1) requiring dental extractions under general anesthesia participated in this study. Children suffering from myasthenia gravis, those known to be hypersensitive to benzodiazepines, or patients being treated with psychotropic drugs were excluded from the trial. The study was approved by the local ethics committee and written informed consent was obtained from all parents prior to inclusion of their children in the study. None of the parents refused to allow their children to participate after they had been assessed and the drug and study events explained to them.

Received from the Faculty of Dentistry, University of Stellenbosch, Tygerberg, South Africa. * Deuartment of Maxillofacial and Oral Suraerv. t Department of Oral Medicine and Periodontics. $ Department of Community Dentistry. Address corresoondence and reprint reouests to Dr van der Bijl: Department of Oral Medicine-and Periodontics, Faculty of Dentistry, University of Stellenbosch, Private Bag Xl, 7505 Tygerberg, South Africa. 0 1990 geons

American

Association

of Oral

and Maxillofacial

DRUGS AND PROCEDURE

Sur-

The children were allocated to four groups, each consisting of 20 patients by formal random selec-

0278-2391/90/4808-0004$3.00/O

791

RECTAL

792 Table 1.

No. Age (yr) Weight (kg) Height (m) Sex M F

MIDAZOLAM

PREMEDICATION

IN CHILDREN

Characteristics of the Four Trial Groups Group A (0.25 m&g Midazolam)

Group B (0.35 mg/kg Midazolam)

Group C (0.45 mgikg Midazolam)

Group D (Placebo)

20 6.0 f 1.54 19.0 f 3.18 1.11 f 0.09

20 5.4 2 1.79 17.1 f 2.94 1.04 * 0.11

20 5.6 f 1.70 18.3 * 4.08 1.06 f 0.12

20 4.5 + 1.47 15.7 f 4.29 0.99 f 0.15

14 6

12 8

12 8

11 9

Values expressed as mean (2SD).

tion. Groups A, B, and C received midazolam 0.25, 0.35, and 0.45 mg/kg, respectively, while group D was given placebo (sodium chloride BP 0.9% mass/ vol). Suitably diluted parenteral midazolam (15 mg/ 3 mL Dormicum, Roche Products, Isando, South Africa) and placebo solutions were administered by means of a lo-mL syringe connected to a 3.5-mm outside-diameter pediatric feeding tube inserted 3 to 4 cm into the rectum. Subsequent flushing of the system with approximately 2 mL of air, drawn into the same syringe, ensured complete rectal deposition of the drug and placebo. All premeditation and placebo solutions were administered 30 minutes before induction of anesthesia. A standard anesthetic technique was used, patients being induced and maintained with 1% to 2% halothane and 60% nitrous oxide in oxygen, while breathing spontaneously. After induction, a no. 21 butterfly needle was inserted in a vein on the dorsum of the hand and connected by way of an infusion set to a bag containing 200 mL of sodium chloride BP 0.9% (mass/vol). A slow rate of this infusion was maintained during anesthesia. Nasotracheal intubation was performed after intravenous administration of 0.02 mg/kg atropine, followed by 1 mg/kg suxamethonium. For each patient the electrocardiogram (ECG) tracing, arterial oxygen saturation, and vital signs were monitored continuously during anesthesia. After recovery, simple analgesics were given for pain as needed in the postoperative period and patients were discharged. ASSESSMENTS

On arrival in the operating room a previously calibrated Dinamap adult/pediatric vital signs monitor (Critikon Inc, Tampa, FL), an Ohmeda Biox III pulse oximeter (Bioximetry Technology Inc, Boulder, CO), and an ECG monitor (Simonsen & Weel, Copenhagen, Denmark) with a memory twinscope facility were connected to each patient. Pulse rate, systolic, diastolic, and mean arterial pressure (MAP) readouts from the Dinamap, as well as respiratory rates and oxygen saturation were all

recorded prior to rectal administration of midazolam or placebo and again 30 minutes thereafter, ie, immediately before induction of anesthesia. Acceptance of the rectal administration procedure was classified according to whether it was good, with no defense reactions; moderate, but with defense reactions and weeping; poor, with refusal and weeping. Immediately after injection of the drug into the rectum, the investigator observed whether the child showed any signs of pain and noted this as either “yes” or “no.” During the 30 minutes following administration of midazolam or placebo an independent observer noted anxiety and sedation levels, as well as any adverse reactions experienced by patients. Anxiety levels were recorded according to whether the child was very anxious, weeping; anxious, not weeping; calm, indifferent, and not anxious; or prepared for the procedure. The level of sedation was judged according to whether the patient was awake, agitated, weeping; awake, alert, and normal; awake but quiet, sedated; somnolent, drowsy; sleeping, but easy to wake; sleeping, but difficult to wake. Adverse reactions were grouped according to whether the child was agitated/excited; restless/ irritated; uncooperative; disorientated/confused; emotional/crying; subject to visual disturbances. Other adverse events were noted separately. At commencement of induction of anesthesia, the anesthetist judged acceptance of the inhalation mask as being good, moderate, or poor. The time taken from administration of midazolam or placebo until awakening in the recovery room after the general anesthetic was also recorded for each child. STATISTICAL

METHODS

The one-way analysis of variance (ANOVA) and x2 test for independence were used for statistical analysis of the data using the Statgraphics program. lo A 5% significance level was used in all comparisons.

ROELOFSE

ET AL

Results Characteristics of the four trial groups used in this study are given in Table 1, which shows that the patients receiving any of the doses of midazolam or the placebo were similar with respect to age, weight, height, and sex. No ECG changes were observed in any of the patients during the study. Table 2 shows the blood pressures and heart and respiratory rates, as well as blood oxygen saturation, for patients before and 30 minutes after premedication. Only the oxygen saturation levels for groups B and C differed significantly from those of the placebo groups 30 minutes after premeditation (P < .05). The different acceptance levels of the rectal premedication and of the anesthetic mask 30 minutes later are shown in Fig 1. No significant differences could be shown between groups as far as rectal acceptance of midazolam or placebo were concerned, and no signs of pain were observed in any of the patients. Of the children who participated in this study, 71.3% showed good acceptance of the rectal administration procedure. Acceptability of this procedure was moderate in 22.5% and poor in only 6.3% of the participants. Mask acceptance was judged to be good in 48.8%, moderate in 33.8%, and poor in 17.5% of all the patients. Of the 16 participants who poorly accepted the anesthetic mask, 13 belonged to group D. Mask acceptability was significantly (P < .OOOl) associated with the use of midazolam. A significant (P < .OOOl)association between the reduction of anxiety and use of midazolam also could be shown (Fig 2). In group A, no children were very anxious and weeping, and only 5% and

lo%, respectively, were observed in groups B and C. However, 60% in group D were very anxious and weeping. Sedation in those participants who had received midazolam was excellent (Fig 3). In groups A, B, and C drowsiness or sleepiness was observed in 90%, 85%, and 85% respectively. In group D. 90% of children were alert and 10% were agitated. A significant association (P < .OOOl)between level of sedation and midazolam use was found. The prevalence of adverse reactions was strongly associated with the increasing dose of midazolam (Table 3). No adverse effects were observed in groups A and D. No other adverse events other than those listed in Table 3 were observed or reported in any of the patients. A statistically significant (P < .05) difference was found in the time it took to awaken after general anesthesia in the different groups (Fig 4). In addition, a definite relationship between dose of midazolam and time taken to awaken was observed. Discussion Although some anesthesiologists consider rectal preanesthetic medication in pediatric anesthesia to be messy and unpleasant, it is a relatively painless procedure and, hence, acceptable to small children. Provided that the absorption from the rectal mucosa is reliable, this route of administration should result in an appropriately sedated and more cooperative patient, the latter facilitating a much smoother induction of anesthesia. Several benzodiazepines, including midazolam, have been administered rectally as premedicaments prior to general anesthesia. l-3 Midazolam is well ab-

Table 2. Blood Pressures, Heart Rates, Respiratory Rates, and Blood Oxygen Saturation for Patients Before and 30 Minutes After Premeditation Group A: Mean (95% CI) Systolic pressure (mm Hg) BP 116.3 AP 103.2 Diastolic pressure (mm Hg) BP 71.2 AP 61.8 Heart rate (beats/min) BP 95.1 AP 93.5 Respiratory rate (breaths/min) BP AP Oxygen saturation (%) BP AP Abbreviations:

(109.15-123.45) (97.35-109.04)

Group B: Mean (95% CI)

Group C: Mean (95% CI)

Group D: Mean (95% CI)

P Value

112.6 (105.50-119.80) 106.5 (100.70-112.39)

116.0 (108.85-123.15) 108.1 (102.25-113.94)

113.9 (106.80-121.10) 105.7 (99.85-111.54)

NS NS

(64.86-77.54) (56.27-67.43)

69.6 (63.26-75.94) 63.4 (57.87-69.03)

70.3 (63.96-76.64) 64.7 (59.12-70.28)

67.1 (60.81-73.49) 64.7 (59.17-70.33)

NS NS

(87.33-102.87) (85.88-102.22)

103.9 (96.13-111.67) 100.0 (92.38-107.72)

96.5 (88.73-104.27) 99.0 (91.38-106.72)

101.7 (93.93-109.47) 99.2 (91.53-106.87)

NS NS

29.7 (28.20-31.19) 27.3 (26.34-28.36)

28.8 (27.30-30.29) 27.8 (26.79-28.81)

29.4 (27.90-30.89) 27.3 (26.29-28.31)

29.4 (27.90-30.89) 29.1 (28.09-30.11)

NS NS

98.6 (98.24-99.06) 98.2 (97.82-98.67)

98.5 (98.14-98.96) 97.6 (97.17-98.02)

98.6 (98.19-99.01) 97.7 (97.32-98.17)

98.5 (98.14-98.96) 98.4 (97.97-98.82)

NS S

CI, confidence interval; BP, before premeditation;

AP, 30 minutes after premeditation.

794

RECTAL MIDAZOLAM PREMEDICATION

IOC

P E

I

GOOD

0

MODERATE

IN CHILDREN

POOR

8C

F

2

b

z 2

FIGURE 1. Percentage of patients showing different acceptance levels of the rectal premeditation (P) and, 30 minutes thereafter, of the anesthetic mask (M).

6a

40

3 x

2c

L

Group

A

Group S

Group C

sorbed by the rectal route, as has been shown by several clinical and pharmacokinetic studies.6-9 However, widely varying clinically useful dosages ranging from 0.3 mg/kg to 0.82 mg/kg of midazolam, sometimes in combination with other drugs, have been reported. In addition, a high incidence (10% to 20%) of adverse reactions following the use of 0.5 mg/kg of rectally administered midazolam was found in one particular study.’ Therefore, it was decided to further evaluate effective premeditation dosage ranges and possible adverse effects in the present study. From our previous experience,” as well as from other studies in adults,12*13 there seems little doubt as to the cardiovascular depressant action of intravenous midazolam in doses of 0.1 mglkg when compared with placebo. With rectal midazolam as used in the present study, no significant differences were found between any of the midazolam and placebo groups as far as blood pressure, heart rates, and respiratory rates were concerned (Table 2). The absence of significant cardiovascular depressant effects observed in this study, and the very low incidence of some of these effects observed in a previous study,’ is indicative of the relative safety with

Group 0

respect to the cardiovascular system of rectal midazolam in children in doses below 0.5 mg/kg. It is clear from the results obtained in the present study that rectal midazolam lowers blood oxygen saturation 30 minutes after administration to levels below those of the placebo group (Table 2). Although not recorded in this study, these oxygenlowering effects are probably of short duration.” However, care must be taken not to intensify these effects by the concomittant administration of opiate-like analgesics. Children must be observed carefully and dosage regimens strictly adhered to whenever midazolam is used for preanesthetic medication. The rectal route of drug administration was wellaccepted by the majority of children participating in this study (Fig 1). None of the patients experienced pain on rectal injection, developed an urge to defecate, or actually defecated. This is in contrast to the results obtained in a previous study in which small numbers of patients experienced these undesirable effects.’ The small volumes of fluid and air injected in this study may at least partially explain these differences. That children were appropriately sedated and, therefore, more cooperative 30 minutes

100 VERY

?

ANXIOUS.

ANXIOUS,

WEEPING

NOT WEEPING

CALM,

INDIFFERENT.

PREPARED

NOT

ANXIOUS

FOR PROCEDURE

80

c 5 a 60 k

FIGURE 2. Percentage of patients showing different levels of anxiety in each group.

W

s: 5 !?

40

20 %

Group

A

Group B

Group C

Group D

ROELOFSE

795

ET AL

2 n k FIGURE 3. Percentage of patients showing different levels of sedation in each group.

r

60

: 2

4c

E 0 k n

20

GroupA

following rectal administration of midazolam, is shown by the high percentage of patients who readily accepted the anesthetic mask (Fig 1). Although maximum plasma levels of midazolam probably no longer existed at this point, the generally good induction conditions found in groups A, B, and C compared with those of group D were similar to those found in a previous study.’ The present study showed significant associations between the levels of anxiolysis and sedation for those children who had received midazolam rectally (Figs 2 and 3). In general, these patients were more calm, sedated, and drowsy than those in the placebo group. This relief of anxiety and sedation is commensurate with the pharmacological properties of the benzodiazepine group as a whole.“-14 The high prevalence of adverse reactions (23%) in those patients who had received rectal midazolam is notable (Table 3), but concurs with that found in a previous study.’ These reactions, which may be termed deviational, disinhibitory, or paradoxical, have been described before for midazolam and other benzodiazepines. 15,i6 It has been suggested that reactions of this nature are more likely to occur with those benzodiazepines that are rapidly excreted and have no persistent active metabolites.17 The time taken from rectal administration of midazolam or placebo for patients in each group to

Group

B

Group

C

Group

D

awaken after the general anesthetic is shown in Fig 4. Average times taken to awaken in groups A and B were only slightly higher than for placebo group D. However, it is evident that patients in group C took significantly longer to wake up than those in the other groups. Increasing average times taken to awaken of those groups of patients who had received midazolam suggests longer waking up times associated with increasing doses of midazolam. The present study has shown that rectal midazolam 0.25, 0.35, or 0.45 mg/kg in children is an excellent preanesthetic medication. Administered 30 minutes before the induction of anesthesia, it produces sufficient anxiolysis and sedation but still enables the patient to cooperate. However, the high prevalence of disinhibition reactions observed in this study, particularly in the 0.45 mg/kg group,

__-- __--

Table 3. Adverse Reactions Observed in Groups B and C Adverse Reaction Observed Agitation/excitement Restlessness/irritation Uncooperativeness Disorientation/confusion Emotional/crying Visual disturbances

No. of Individuals GroupB (n 4 2 1 -

= 4)

Group C (n = 10)

4 8 2 5 3 2

FIGURE 4. Time taken from rectal administration of midazolam or placebo, for patients in each group to awaken after the general anesthetic. (Mean times and 95% confidence intervals are given for each group.)

796

RECTAL MIDAZOLAM PREMEDICATION

would appear to make 0.25 or 0.35 mglkg the doses of choice whenever this drug is to be used rectally in children as a preanesthetic medication.

8. Czomy-Riltten M, Biittner W, Finke W: Rektale gabe von Midazolam als Adjuvans zur Pramedikaton von Kleinkindem (Rectal dose of midazolam as an adjuvant for the premeditation of infants). Anaesthesist 35: 197, 1986 9. Kretz FJ, Liegl M, Heinemeyer G, et al: Die rektale Narkoseeinleitung bei Kleinkindem mit Diazepam und Midazolam (Rectal pre-anaesthetic medication in young children with diazepam and midazolam). Antisth Intensivmed 26:343, 1985 10. STSC Inc: Statgraphics-Statistical graphics system, Version 2.6. Rockville, MD, 1986 11. Van der Bijl P, Roelofse JA, Joubert JJ de V, et al: Intravenous midazolam in oral surgery. Int J Oral Maxillofac Surg 16:325, 1987 12. McGimpsey JG, Kawar P, Gamble JA, et al: Midazolam in dentistry. Br Dent J 155:47, 1983 13. Dundee JW, Halliday NJ, Harper K, et al: Midazolam: A review of its pharmacological properties and therapeutic use. Drugs 28519, 1984 14. Van der Bijl P, Roelofse JA, Joubert JJ de V: Comparison of sublingual lorazepam with intra-muscular diazepam as sedatives during oral surgery. J Oral Maxillofac Surg 46:559, 1988 15. Hall RCW, Zisook S: Paradoxical reactions to benzodiazepines. Br J Clin Pharmacol 11995, 1981 16. Lobo BL, Miwa LJ: Midazolam disinhibition reaction. Drug Intel1 Clin Pharm 22:725, 1988 17. Jerram T: Hypnotics and sedatives, in Dukes MNG (ed): Meyler’s Side Effects of Drugs (ed 11). New York, NY, Elsevier, 1988, p 93-104

References 1. Benson D, Saame A: Rectal pentothal in paediatric anaesthesia. Acta Anaesth Stand 451, 1960 2. Haagensen RE: Rectal premeditation in children: Comparison of diazepam with a mixture of morphine, scopolamine and diazepam. Anaesthesia 40:956, 1985 3. Julia JM, Rochette A, Ricard C, et al: Comparaison du midazolam et du flunitrazepam en prtmtdication par voie rectale chez le nourrisson (Comparative study of rectal premeditation with midazolam and flunitrazepam in infants). Ann Fr Anesth Reanim 3:185, 1984 _ 4. Allonen H. Ziealer G. Klotz H: Midazolam kinetics. Clin Pharmadol Tier 30:653, 1981 5. Greenblatt DJ, Locniscar A, Ochs HR, et al: Automated gas chromatography for studies of midazolam pharmacokinetits. Anesthesiology 55:176, 1981 6. Saint-Maurice C, Meistelman MD, Rey E, et al: The pharmacokinetics of rectal midazolam for premeditation in children. Anesthesiology 65:536, 1986 7. Saint-Maurice C, Esteve C, Holzer J, et al: Premeditation par le midazolam intrarectal. Recherche de la dose efticace en anesthtsie pediatrique (Premeditation with rectal midazolam. Effective dose in paediatric anaesthesia). Ann Fr Anesth Reanim 3: 181, 1984

IN CHILDREN

Preanesthetic medication with rectal midazolam in children undergoing dental extractions.

Three different dosages (0.25, 0.35, and 0.45 mg/kg) of rectally administered midazolam were compared with each other and with placebo for preanesthet...
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