Anesth Prog 37:29-31 1990
Rectl Administration of Midazolam Versus Diazepam for
Preanesthetic Sedation in Children Rolf Holm-Knudsen, MD, Torben G. Clausen, MD, and Dorthe En0, RN Department of Anesthesia, Gentofte Hospital, University of Copenhagen, Denmark
Sixty childen were included in the trial. Each subject received midazolam 0.4 mg/kg body weight or diazepam 0.75 mg/kg body weight rectally in a double-blind randomized order. The degree of sedation of the children was assessed on arrival in the operating unit and during the induction of anesthesia. Adequate sedation on arrival in the operating unit and during induction of anesthesia was obtained in 84% and 67%, respectively, following administration of midazolam compared with 80% and 70% in the diazepam group. No side effects were noted. It is concluded that rectally administered midazolam 0.4 mg/kg is comparable to diazepam 0.75 mg/kg with respect to preanesthetic sedation in children.
mg/kg body weight (BW), adequate sedation for smooth induction of anesthesia was obtained in 90%-100% of the infants7 compared with 70% following rectal administration of diazepam 0.75 mg/kg.1 The aim of the present study was to compare the two drugs under equal conditions, when administered rectally for preanesthetic sedation in children. METHODS The study comprised 60 otherwise healthy children with a median age of 5.0 yr (range 1-10 yr) undergoing minor otolaryngological surgery. Severely mentally retarded children were excluded. The children were allocated at random to receive either midazolam 0.40 mg/kg BW or diazepam 0.75 mg/kg BW rectally. By dilution with isotonic saline the drugs could be administered in a dosage of 0.2 ml/kg BW in a double-blind manner. The maximum dose was 7 ml (midazolam 14 mg, diazepam 26.25 mg). The premedication was administered by a ward nurse 30 min before the expected induction of anesthesia through a rectal applicator inserted 3-4 cm. The buttocks were held together for about 2 min after the administration. The interval from premedication to the induction of anesthesia was recorded. Parents accompanied their child to the operating theater and remain there until the child was asleep. The degree of sedation of each child was scored by means of a rating scale (Table 1) at arrival in the operating theater and during the induction of anesthesia by one of the authors (D.E.), who was unaware of which drug was administered for premedication. A score of 1, 2, or 3 was considered adequate sedation. Anesthesia was induced and maintained with halothane in 02/N20. In one case, however, anesthesia was induced with thiopental according to the spontaneously expressed wish of the patient. The younger children were kept in their own bed until asleep. To obtain postoperative analgesia a small dose of lytic cocktail (0.025 ml/kg BW) was given intramuscularly intraoperatively. Each milliliter of lytic cocktail contained pethidine 28 mg, chlorpromazine 7 mg, and promethazine 7 mg.
edative premedicants are administered to children to provide smooth and peaceful induction of anesthesia. Preanesthetic medication with diazepam has been used for several years and the rectal route of administration has proved to be well accepted in children.1 After rectal administration of diazepam solution time to maximum plasma concentrations has been found to be an average of 10 min.2 The water-soluble imidazobenzodiazepine midazolam is well established as a premedicant, sedative, and anesthetic induction agent.3 Published studies on rectal administration of midazolam have demonstrated an absorption profile that very much resembles that of diazepam with respect to absorption fractions and time to maximum plasma concentrations.4,5 However, the terminal elimination half-life of midazolam is considerably shorter than that of diazepam (3 v 25 h).5,6 Following rectal administration of midazolam 0.35-0.4 Received October 24, 1989; accepted for publication January 2, 1990. Address correspondence to Rolf Holm-Knudsen, Kildeskovsvej 80, DK-2820 Gentofte, Denmark. © 1990 by the American Dental Society of Anesthesiology
ISSN 0003-3006/90/$3.50
29
Anesth Prog 37:29-31 1990
30 Midazdam Versus Diazepam in Children Table 1. Scale for Classification of Sedation 1. 2. 3. 4. 5. 6.
Number of patients 262422201816-
Asleep, anesthesia induced without reaction Drowsy or sleeping but arousable Awake, calm, cooperating Awake, resfless, apprehensive Crying or resisting Agitated
1412-
The study was approved by the National Health Authorities and by the regional Ethics Committee. In each case informed consent was obtained from the parents. Unless otherwise stated, statistical analysis was performed by means of a two-sample t-test. P s 0.05 was considered significant.
O-
---r-
1
I
I
2
3
4
5
6 Score
Figure 2. Assessment of the degree of sedation during the induction of anesthesia. Solid bars = Midazolam. Lighter bars = Diazepam.
RESULTS The groups were comparable with respect to age, sex, and bodyweight (P > 0.8). The mean interval from premedication to the induction of anaesthesia was 55 min in both groups (range 15-145 min). The scores at arrival in the operating theater and during the induction of anesthesia appear in Figures 1 and 2. Adequate sedation on arrival in the operating unit and during the induction of anesthesia was obtained in 84% and 67%, respectively, following administration of midazolam compared with 80% and 70% in the diazepam group. Statistical analysis revealed no significant differences in the scores between the two groups (P > 0.85) and no significant correlations Figure 1. Assessment of the degree of sedation on the arrival = Midazolam. Lighter bars = Diazepam.
to the operating theatre. Solid bars Number of patients 2624222018161412108642O-
1
108642-
2
3
Ir
4
5
6 Score
between the time interval from premedication to the induction of anesthesia and the scores could be demonstrated (Spearman's test for correlation). No side effects were noted.
DISCUSSION The present study demonstrates that following rectal administration, midazolam is comparable to diazepam in the dosage used with respect to preanesthetic sedation in children. The sedation was adequate for a smooth induction of anesthesia in 70% of the cases in the diazepam group, which is comparable to a previous study.' In the midazolam group adequate sedation was obtained in 67%, which is less than the 90% success rate determined by Saint-Maurice et al.7 Despite the fact that a similar dose of 0.4 mg/kg midazolam was used, their results are remarkably different from ours, which might be explained by the difference in time between administration of the sedative agent and assessment of the degree of sedation (30 min v 55 min in the present study). However, no significant correlation between the interval from premedication to the induction of anesthesia and the score was found in the present study. The relative potencies of midazolam and diazepam have been investigated, and published data indicate that midazolam is two to three times as potent as diazepam.8,9 This is in accordance with the results of the present study, which suggest that midazolam is twice as potent as diazepam when used for rectal application in children.
Anesth Prog 37:29-31 1990
Paradox reactions following administration of benzodiazepines are well known. We found none in the diazepam group but two in the midazolam group. We made no attempts to compare the degree of sedation in the two groups during recovery, as the variations in duration of the anesthesia combined with the doses of lytic cocktail given intraoperatively would drown possible differences between the groups. Nevertheless, as midazolam and diazepam administered rectally seem equally sufficient for preanesthetic sedation in children, it appears to be appropriate to choose the drug with the shortest elimination time. It is concluded that rectally administered midazolam 0.4 mg/kg is comparable to diazepam 0.75 mg/kg with respect to preanesthetic sedation in children.
REFERENCES 1. Ahn NC, Andersen GW, Thomsen A, Valentin N: Preaneaesthetic medication with rectal diazepam in children. Acta Anaesthesiol Scand 1981;25:158-160. 2. Knudsen FU: Plasma-diazepam in infants after rectal ad-
Holm-Knudsen et al. 31 ministration in solution and by suppository. Acta Paediatr Scand 1977;66:563-567. 3. Reves JG, Fragen RJ, Vinik HR, Greenblatt DJ: Midazolam: pharmacology and uses. Anesthesiology 1985;62:310324. 4. Saint-Maurice C, Meistelman C, Rey E, Esteve C, De Lauture D, Olive G: The pharmacokinetics of rectal midazolam for premedication in children. Anesthesiology 1986;65:536538. 5. Clausen TG, Wolff J, Hansen PB, Larsen F, Rasmussen SN, Dixon JS, Crevoisier C: Pharmacokinetics of midazolam and a-hydroxy-midazolam following rectal and intravenous administration. Br J Clin Pharmacol 1988;25:457-463. 6. Magnussen I, Oxlund HRW, Alsbirk KE, Arnold E: Absorption of diazepam in man following rectal and parenteral administration. Acta Pharmacol Toxicol 1979;45:87-90. 7. Saint-Maurice C, Esteve C, Holzer J, Gaudiche O, de Lauture D, Hetzel W: Bessere Akzeptanz der Mal3nahmen zur Einleitung einer Narkose nach rektaler Pramedikation mit Midazolam bei Kindern. Anaesthesist 1987;36:629-633. 8. Berggren L, Eriksson I, Mollenholt P, Wickbom G: Sedation for fibreoptic gastroscopy: a comparative study of midazolam and diazepam. Br J Anaesth 1983;55:289-296. 9. Porro GB, Baroni S, Parente F, Lazzaroni M: Midazolam versus diazepam as premedication for upper gastrointestinal endoscopy: a randomized, double-blind, crossover study. Gastrointest Endosc 1988;34:252-254.
Rectl Administration of Midazolam Versus Diazepam for
Preanesthetic Sedation in Children Rolf Holm-Knudsen, MD, Torben G. Clausen, MD, and Dorthe En0, RN Department of Anesthesia, Gentofte Hospital, University of Copenhagen, Denmark
Sixty childen were included in the trial. Each subject received midazolam 0.4 mg/kg body weight or diazepam 0.75 mg/kg body weight rectally in a double-blind randomized order. The degree of sedation of the children was assessed on arrival in the operating unit and during the induction of anesthesia. Adequate sedation on arrival in the operating unit and during induction of anesthesia was obtained in 84% and 67%, respectively, following administration of midazolam compared with 80% and 70% in the diazepam group. No side effects were noted. It is concluded that rectally administered midazolam 0.4 mg/kg is comparable to diazepam 0.75 mg/kg with respect to preanesthetic sedation in children.
mg/kg body weight (BW), adequate sedation for smooth induction of anesthesia was obtained in 90%-100% of the infants7 compared with 70% following rectal administration of diazepam 0.75 mg/kg.1 The aim of the present study was to compare the two drugs under equal conditions, when administered rectally for preanesthetic sedation in children. METHODS The study comprised 60 otherwise healthy children with a median age of 5.0 yr (range 1-10 yr) undergoing minor otolaryngological surgery. Severely mentally retarded children were excluded. The children were allocated at random to receive either midazolam 0.40 mg/kg BW or diazepam 0.75 mg/kg BW rectally. By dilution with isotonic saline the drugs could be administered in a dosage of 0.2 ml/kg BW in a double-blind manner. The maximum dose was 7 ml (midazolam 14 mg, diazepam 26.25 mg). The premedication was administered by a ward nurse 30 min before the expected induction of anesthesia through a rectal applicator inserted 3-4 cm. The buttocks were held together for about 2 min after the administration. The interval from premedication to the induction of anesthesia was recorded. Parents accompanied their child to the operating theater and remain there until the child was asleep. The degree of sedation of each child was scored by means of a rating scale (Table 1) at arrival in the operating theater and during the induction of anesthesia by one of the authors (D.E.), who was unaware of which drug was administered for premedication. A score of 1, 2, or 3 was considered adequate sedation. Anesthesia was induced and maintained with halothane in 02/N20. In one case, however, anesthesia was induced with thiopental according to the spontaneously expressed wish of the patient. The younger children were kept in their own bed until asleep. To obtain postoperative analgesia a small dose of lytic cocktail (0.025 ml/kg BW) was given intramuscularly intraoperatively. Each milliliter of lytic cocktail contained pethidine 28 mg, chlorpromazine 7 mg, and promethazine 7 mg.
edative premedicants are administered to children to provide smooth and peaceful induction of anesthesia. Preanesthetic medication with diazepam has been used for several years and the rectal route of administration has proved to be well accepted in children.1 After rectal administration of diazepam solution time to maximum plasma concentrations has been found to be an average of 10 min.2 The water-soluble imidazobenzodiazepine midazolam is well established as a premedicant, sedative, and anesthetic induction agent.3 Published studies on rectal administration of midazolam have demonstrated an absorption profile that very much resembles that of diazepam with respect to absorption fractions and time to maximum plasma concentrations.4,5 However, the terminal elimination half-life of midazolam is considerably shorter than that of diazepam (3 v 25 h).5,6 Following rectal administration of midazolam 0.35-0.4 Received October 24, 1989; accepted for publication January 2, 1990. Address correspondence to Rolf Holm-Knudsen, Kildeskovsvej 80, DK-2820 Gentofte, Denmark. © 1990 by the American Dental Society of Anesthesiology
ISSN 0003-3006/90/$3.50
29
Anesth Prog 37:29-31 1990
30 Midazdam Versus Diazepam in Children Table 1. Scale for Classification of Sedation 1. 2. 3. 4. 5. 6.
Number of patients 262422201816-
Asleep, anesthesia induced without reaction Drowsy or sleeping but arousable Awake, calm, cooperating Awake, resfless, apprehensive Crying or resisting Agitated
1412-
The study was approved by the National Health Authorities and by the regional Ethics Committee. In each case informed consent was obtained from the parents. Unless otherwise stated, statistical analysis was performed by means of a two-sample t-test. P s 0.05 was considered significant.
O-
---r-
1
I
I
2
3
4
5
6 Score
Figure 2. Assessment of the degree of sedation during the induction of anesthesia. Solid bars = Midazolam. Lighter bars = Diazepam.
RESULTS The groups were comparable with respect to age, sex, and bodyweight (P > 0.8). The mean interval from premedication to the induction of anaesthesia was 55 min in both groups (range 15-145 min). The scores at arrival in the operating theater and during the induction of anesthesia appear in Figures 1 and 2. Adequate sedation on arrival in the operating unit and during the induction of anesthesia was obtained in 84% and 67%, respectively, following administration of midazolam compared with 80% and 70% in the diazepam group. Statistical analysis revealed no significant differences in the scores between the two groups (P > 0.85) and no significant correlations Figure 1. Assessment of the degree of sedation on the arrival = Midazolam. Lighter bars = Diazepam.
to the operating theatre. Solid bars Number of patients 2624222018161412108642O-
1
108642-
2
3
Ir
4
5
6 Score
between the time interval from premedication to the induction of anesthesia and the scores could be demonstrated (Spearman's test for correlation). No side effects were noted.
DISCUSSION The present study demonstrates that following rectal administration, midazolam is comparable to diazepam in the dosage used with respect to preanesthetic sedation in children. The sedation was adequate for a smooth induction of anesthesia in 70% of the cases in the diazepam group, which is comparable to a previous study.' In the midazolam group adequate sedation was obtained in 67%, which is less than the 90% success rate determined by Saint-Maurice et al.7 Despite the fact that a similar dose of 0.4 mg/kg midazolam was used, their results are remarkably different from ours, which might be explained by the difference in time between administration of the sedative agent and assessment of the degree of sedation (30 min v 55 min in the present study). However, no significant correlation between the interval from premedication to the induction of anesthesia and the score was found in the present study. The relative potencies of midazolam and diazepam have been investigated, and published data indicate that midazolam is two to three times as potent as diazepam.8,9 This is in accordance with the results of the present study, which suggest that midazolam is twice as potent as diazepam when used for rectal application in children.
Anesth Prog 37:29-31 1990
Paradox reactions following administration of benzodiazepines are well known. We found none in the diazepam group but two in the midazolam group. We made no attempts to compare the degree of sedation in the two groups during recovery, as the variations in duration of the anesthesia combined with the doses of lytic cocktail given intraoperatively would drown possible differences between the groups. Nevertheless, as midazolam and diazepam administered rectally seem equally sufficient for preanesthetic sedation in children, it appears to be appropriate to choose the drug with the shortest elimination time. It is concluded that rectally administered midazolam 0.4 mg/kg is comparable to diazepam 0.75 mg/kg with respect to preanesthetic sedation in children.
REFERENCES 1. Ahn NC, Andersen GW, Thomsen A, Valentin N: Preaneaesthetic medication with rectal diazepam in children. Acta Anaesthesiol Scand 1981;25:158-160. 2. Knudsen FU: Plasma-diazepam in infants after rectal ad-
Holm-Knudsen et al. 31 ministration in solution and by suppository. Acta Paediatr Scand 1977;66:563-567. 3. Reves JG, Fragen RJ, Vinik HR, Greenblatt DJ: Midazolam: pharmacology and uses. Anesthesiology 1985;62:310324. 4. Saint-Maurice C, Meistelman C, Rey E, Esteve C, De Lauture D, Olive G: The pharmacokinetics of rectal midazolam for premedication in children. Anesthesiology 1986;65:536538. 5. Clausen TG, Wolff J, Hansen PB, Larsen F, Rasmussen SN, Dixon JS, Crevoisier C: Pharmacokinetics of midazolam and a-hydroxy-midazolam following rectal and intravenous administration. Br J Clin Pharmacol 1988;25:457-463. 6. Magnussen I, Oxlund HRW, Alsbirk KE, Arnold E: Absorption of diazepam in man following rectal and parenteral administration. Acta Pharmacol Toxicol 1979;45:87-90. 7. Saint-Maurice C, Esteve C, Holzer J, Gaudiche O, de Lauture D, Hetzel W: Bessere Akzeptanz der Mal3nahmen zur Einleitung einer Narkose nach rektaler Pramedikation mit Midazolam bei Kindern. Anaesthesist 1987;36:629-633. 8. Berggren L, Eriksson I, Mollenholt P, Wickbom G: Sedation for fibreoptic gastroscopy: a comparative study of midazolam and diazepam. Br J Anaesth 1983;55:289-296. 9. Porro GB, Baroni S, Parente F, Lazzaroni M: Midazolam versus diazepam as premedication for upper gastrointestinal endoscopy: a randomized, double-blind, crossover study. Gastrointest Endosc 1988;34:252-254.
