J Oral Maxillofac

Surg

49:1050-1054,199i

Rectal Ke’tamine and Midazo Premedica tion in Pediatric P. VAN DER BIJL, BSc (HONS) (PHARM), BCHD, PHD,” J.A. ROELOFSE, MMED (ANAESTH), PHD,~- AND I.A. STANDER, BSc (HANS) Rectally administered midazolam (0.30 mg/kg) and ketamine (5 mg/kg) were compared for preanesthetic medication in children undergoing dental extractions. Sixty patients between the ages 2 and 9 years were randomly allocated to three groups in this double-blind study. In one group of patients who received ketamine rectally, intravenous midazolam (0.05 mg/ kg) also was administered immediately after induction of anesthesia. The results from this trial show that 30 minutes after rectal administration of the two drugs, good anxiolysis, sedation, and cooperation were obtained in most patients. Although midazolam appeared to be marginally more efficacious than ketamine in the majority of assessments made and seemed to have less adverse effects, no statistically significant differences could be shown. Ketamine showed a slight decrease and midamolam a slight increase in average blood pressures after premeditation. These blood pressure differences were, however, considered to be of little clinical importance.

Although previous studies have shown rectally administered midazolam to be an excellent form of premeditation, l-5 ketamine is an attractive alternative. This drug is well tolerated and absorbed by the rectal mucosa6-9 and has unique sedative, amnestic, anesthetic, and analgesic properties.‘O~l’ Undesirable dose-dependent properties,‘2 particularly the psychic disturbances, can be attenuated by administering a benzodiazepine in conjunction with ketamine.“,” We wished to compare rectally administered midazolam and ketamine as premeditations in a double-blind randomized trial in children who required Received from the Faculty of Dentistry, University of Stellenbosch and Institute for Biostatistics, Medical Research Council, Tygerberg, South Africa. * Associate Professor, Department of Oral Medicine and Periodontics. t Senior Lecturer, Department of Maxillofacial and Oral Surgery. $ Biometrician, Institute for Biostatistics, Medical Research Council. Address correspondence and reprint requests to Dr van der Bijl: Department of Oral Medicine and Periodontics, Faculty of Dentistry, University of Stelienbosch, Private Bag Xl, Tygerberg 7505, South Africa.

dental extractions under general anesthesia. Vital signs and variables such as oxygen saturation Ievels, 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 evalnated during this study. Material and Methods

Sixty ASA I children of both sexes, aged betwee_n 2 and 9 years (Table 1) who required dental extractions under general anesthesia participated in this study. Children with myasthenia gravis, those known to be hypersensitive to benzodiazepines car ketamine, 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 before their children were included in the study. None of the parents refused to allow their children to participate after the use of the drug as well as the study events were explained to them. DRUGS AND PRO@EDUIPE

0 1991 American

Association

of Oral and Maxillofacial

Sur-

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

geons 0278-2391/91/4910-0004$3.00/O

1050

VAN DER BHJL, RQELOFSE,

AND STANDER

Table 4m Gharacteristies of the Three Trial Gmups Parameter

Group A

Group B

Group C

n Age (yr) Weight (kg) Height (m) Sex M F

26) 4.49 (1.64) 15.45 (4.01) 0.99 (0.12)

20 4.85 (1.42) 15.40 (3.14) 1.02(0.12)

20 4.55 (1 S9) 16.45 (2.86) 1.01 (0.09)

11 9

10 10

10 10

Values are mean (SD).

tion. Group A received midazolam 0.30 mglkg rectally and groups B and C received ketamine 5 mg/kg rectally 30 minutes before administration of general anesthesia. Midazolam 0.05 mg/kg was also administered intravenousEy (IV) to all children in group C immediately after induction of anesthesia. The children received rm preceding cleansing enemas. Suitably diluted parentera midazolam (15 mg/3 mL Dormicum, Roche Products, Hsando, South Africa) and ketamine (100 mg/mL Ketalar, Parke-Davis, Tokai, South Africa) solutions were administered through a IO-mk syringe connected to a gellubricated 3 J-mm outside-diameter pediatric feeding tube inserted 3 lo 4 cm into the rectum. The tube was shown to the children to convince them that it was pliable and would not cause pain. Subsequent flushing of the system with approximately 2 mL of air drawn into the same syringe ensured complete rectal deposition of the drug. The buttocks were tightly apposed for a few mirmtes to avoid ioss of the drugs. A standard anesthetic technique was used: Patients were induced and maintained with 1% to 2% halothane and 60% nitrous oxide in oxygen while breathi+g spontaneously. After induction, a 21gauge butterfly needle was inserted in a vein on the dorsum of the band and connected by an infusion set to a bag containing 29 mL of 5% dextrose in 0.2% sopium cMoride. A slow rate of this infusion was maintained during anesthesia. Nasotracheal intubation was performed after IV administration of 0.02 m&kg a&opine, followed by 1 mg./kg suxamethonium. For each patient, the electrocardiogram (FCC+) tgacing, arterial oxygen saturation, and vital signs were monitored confinuously during anesthesia. After recovery, patients were discharged and thejr parents were instructed to administer simple analgesics for pain as needed in the postoperative period. ASSESSMENTS On arrival of the patients in the anesthetic induction room, a previously calibrated Dinamap 845XT adult/pediatric vital signs monitor (Critikon,

Tampa, FL) and an Ohmeda Biox 3700 pulse oximeter (Bioximetry Technology, Boulder, CO) were connected to each patient. Pulse rate, systolic, diastolic, and mean arterial pressure (MAP) readorats from the Dinamap, as we11 as respiratory rates and oxygen saturation, were all recorded before rectal administration of premeditations and again 30 mitiutes 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; or 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 after admini&-ation sf midazolam or ketamine, an independent observer noted anxiety and sedation levels, as we14 as any adverse reactions experienced by patients. Anxiety levels were recorded on a scale ranging from I to 3 that corresponded to whether the child was very anxious and weeping, anxious but not weeping, calm, indifferent, not anxious, or prepared for the procedure. The level of sedation was,judged on a scale from I to 6 according to whether the patient was awake, agitated, and weeping; awake, alert, aaad normal; awake but quiet, sedated; somnolent, drowsy; sleeping, but easy to wake; or sleepitig, but difficult to wake. Adverse reactions were grouped according to wbether the child was agitatedlexcitedi disinhibited, restless/irritated, disorientated/ confused, emotibnilllcrying, subject to visu?l distenrbances/nystagmus, haillucinated, salivated, or with muscle rigidity/uncoordinakion. Other ‘adverse events were noted separately. In the operatiaig room, a Diascope 2 ECG monitor (S & W Medico Teknik A/S, Albertslund, Denmark) was &ached to the patient. At commencement of induction of anesthesia, the anestbet@ judged acceptance of the inhalation mask as good, moderate, or poor. The’ time taken from administrafion of premedication until awakening in the recovery room after the genera! anesthetic was also recorded for each child.

Before data obtained from this study were analyzed statistically, they were checked for incowsistencies, recording errors and/or extreme outliers. All data recorded for grdups B and C, ie, the ketamine group, before and during induction of general anesthesia were combined. Analysis of variance and the x2 test for independence were used for statistical analysis of the data. Where the expected cell

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frequencies became too small, Fisher’s exact test was used. A significance level of 5 was used for al% statistical tests and comparisons. Results Table 1 shows the characteristics of the three trial groups used in this study. Patients in each group were similar with respect to age, weight, height, and sex. Blood pressures and heart and respiratory rates, as well as blood oxygen saturation levels for patients before (BP) and 30 minutes after (BP) premedication, are shown in Table 2. No significant differences were noted in blood pressures, heart and respiratory rates, and oxygen saturation levels before drug administration between the two groups of patients. The children who had received ketamine (groups B and C) showed a slight increase in systolic blood pressure levels (mean, 1.4 mm Hg), whereas those in the group who had received midazolam showed a larger decrease (mean, - 7.8 mm Hg) between the BP and AP stages of the trial. The difference between the changes that occurred for the two drug groups was statistically significant (I’ = .02). The diastolic blood pressures followed a similar BP:AP pattern. The patients who had received ketamine showed an increase (mean, 4.3 mm Hg), and the midazolam group showed a decrease (mean, 9.0 mm Hg) in average diastolic blood pressure. The difference between changes in diastolic blood pressure for the groups was statistically sigTable 2. Blood Pressure, Heart Rate, Respiratory Rate, and Blood Oxygen Saturation for Patients Before and 30 Minutes After Premeditation Group A

Parameter Systolic pressure (mm Hg) BP AP Diastolic pressure (mm Hg) BP AP Heart rate (beatsimin) BP AP Respiratory rate (breaths/min) BP AP Oxygen saturation (%) BP AP

(n = 20)

Group B/C (n = 40)

109.4 (12.03) 101.6 (6.64)

114.0 (16.13) 115.4 (11.86)

66.7 (13.05) 57.7 (9.80)

67.2 (12.97) 71.5 (10.79)

101.0 (17.18) 97.2 (10.48)

102.2 (20.65) 105.6 (17.83)

29.4 (3.13) 29.7 (2.70)

29.5 (3.00) 29.8 (4.25)

97.6 (1.80) 97.1 (1.39)

97.8 (1.38) 97.4 (1.92)

Values are mean (SD). Abbreviations: AP, 30 minutes after premeditation; fore premeditation.

BP, be-

KETAMBNE AND MIDAZOLAM

IN PEDIATRIC

DENTISTRY

nificant (P = .0006). No significant differences were noted between changes in oxygen saturation levels or in heart and respiratory rates for the two groups ~ The different acceptance levels of the rectal premedication and of the anesthetic mask 30 minutes later are shown in Pig 1. No significant differences existed between groups with regard to rectal acceptance of midazolam or ketamine-, and no signs of pain or defecation were observed in any of the patients. Overall, 81.6% of the patients had good acceptance of both the rectal administration procedure and of the anesthetic mask. The midazdam group tended to have higher mask acceptance than did patients who had received ketamine (95% and 75%, respectively), but n4) statisticahy significant differences between the two groups could be shown. Because anxiety was measured on an ordinal scale from 1 to 3, we could determine the degree of improvement in the anxiety levels of each patient between the BP and AP stages of the trial. Generally, anxiety levels improved in both groups of patients. Only three patients became more anxious than they were before premeditation; ie, in the ketamine group two patients and in the midazohun group 1 patient changed from anxiety Bevel 2 to level 1. Ten patients, (nine received ketamine, and one received midazolam) showed ncs change in anxiety levels. Proportional improvement between these two group’s BP and AP stages was 90% for the midazolam and 70% for the ketamine groups, respectively, but statistically significant differences could not be demonstrated. Sedation levels were also rated on an ordinal scale from 1 to 4, and changes in these levels for each patient between the BP and AP stages of the trial could be determined. Qf a11patients, 95% were at level 2, ie, awake, alert, and normal before premedication. Only three patients (5%) were at level I, ie, awake, agitated, at this stage of the trial. The

Group

A

Groups B and

FIGURE 1. Acceptance levels (%) of rectal premeditation and the anesthetic mask (M) 30 minutes after premeditation. Good; q, moderate; n , poor.

C

(P) a,

VAN DER BIJt,

ROELOFSE,

AND STANDER

level of sedation 30 minutes after premeditation of three patients in the ketamine group did not change. Three patients from the ketamine group and 1 patient from the midazolam group, respectively, became less sedated and changed from level 2 to level 1 30 minutes after premeditation. Proportional improvement in sedation level between the BP and BP stages was 95% for the midazolam and 85% for the ketamine groups, respectively, but statistically significant differences between the groups could not be shown. Hn most patients, sedation levels improved from level 2 to level 3 or 4. Twenty-six patients (43%) experienced adverse reactions at various times preoperatively after receiving the premeditation. Twenty of them belonged to the k&amine group, and six belonged to the midazolam group (Table 3). No association could be shown between the preoperative adverse reactions and, the type of drug administered. One patient who had received ketamine only (ie, group B) experienced hallucinations postoperatively. The times taken to awaken after the general anesthetic, measured from the time at which the premedication was given, are shown in Fig 2. Patients in group C, who had received rectal ketamine as well as IV midazolam immediately after induction, took sligh~Iy Banger to awaken than those who had received either midazolam or k&amine. These differences, h&eves, were not statistically significant. Rectal administration of drugs for premeditation is relatively noninvasive and has been shown to be particularly useful in pediatric patients.‘3-‘5 Rectally administered midazolam is well absorbed, causes no mucoslal irritation, and has been shown to be efficacious as a premedicant in young children before administration of general anesthesia,ld5 but previous studies have shown this drug to be associated with a relatively high prevalence of disinhibitory reactions. G These reactions, which appear to be idiosyncratic except that &ey appear more fre‘M&S 3. 1QdveaSe.Reactions Observed No. of Individuals Adverse Reaction Agitatiornlexcitemeratidisinhibition Restlessness/irritation Disorientation/confusion EmotionaE/crying Visual disturbancelnystagmus Hallucinations Salivation Muscle rigidityiuncoordination

GroupA W20Patients) 1 2 3 2

GroupB/C (20/40 Patients)

3 1 1 4 11 5 7 3

Group A

Group B

Group C

FIGURE 2. Time taken to awaken from rectal administration of midazolam or ketamine (means and SD).

quently in patients who previously exhibited poor impulse control, may also be dose-reiated.55’6 The phencyclidine derivative 3 keeamiame, has well-characterized sedative, amnestic, anesthetic, and analgesic properties and has been widely used in children.‘7‘19 The drug is well absorbed through the rectum, probably owing to its amine character (pMa = 7.5), and is devoid of local irritant effects.6-” However, ketamine can caose cardiovascular-stimulating, neuromuscular, and psychic side effects.LQ*‘1These undesirable side effects can be greatly reduced by using low dosages i;8fthe drug in conjunction with a benzodiazepine. The sedation, followed by analgesia of reasonable dysation, which occurs even at low dosages, promptcajdus to compare ketamine with midaiolam as a rkctai premedicant. In addition, we decided 2~ administer IV midazolam, which was recently reccamr&nded for this purpose,1* immediately after induction to ,20 patients who had received rectal ketainink, We wished to determine whether postoperative psychic effects of ketamine, if any, would be affected. In terms of their ability ,to attenuate psychic &starbances, the benzodiaae$ines appear to be +.~u;CBlyeffective whether adininistered at the be&m@ or at the complietioo of the general anesthetic. The ketarnine groups of patienti showed a slight increase and those who received, midazolam showed a slight decrease in syst~lid land diastolic blood presdures after premedicktiasn. Altlmugh

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RECTAL

these blood pressure changes were statistically significant, they probably have little clinical importance. These minimal effects of both drugs on blood pressure support their safety when administered rectally in children in the doses used in this study, a finding which concurs with the previous studies on rectal midazolam.4>5 However, somewhat higher blood pressures would be expected with ketamine, which is known for its central nervous systemmediated cardiovascular stimulation.” However, ketamine also has a direct myocardial-depressant effect that is generally not appreciated because of the sympathomimetic stimulation which occurs,2o probably as a result of high doses. The relatively low doses of the drug used in the present study may therefore explain the lesser degree of cardiovascular stimulation observed. Acceptance of rectal drug administration by both groups of patients was good (Fig 1). No patient experienced pain on rectal injection, and none had an urge to defecate or actually defecated. No late complaints of rectal irritation were received. This linding is in agreement with the good tissue compatibility of both drugs reported previously.‘-’ Adequate preparation of the children as well as the small volumes of fluid and air injected into the rectum also played a role in acceptance of the technique. Although 20 of 26 patients who experienced adverse reactions had received ketamine, no significant association between the reactions and drug type could be shown. However, patients in groups B/C generally experienced more nystagmus, hallucinations, and salivation than did patients in group A (Table 3). These adverse effects have often been associated with ketamine. lo>11 That the times taken to awaken after the general anesthetic did not differ significantly for patients in groups A, B, and C is definitely related to the short plasma half-lives of the drugs used in this study. In this respect, IV administration of a drug such as midazolam immediately after induction would be preferred to use of a benzodiazepine with a long plasma half-life, eg, diazepam. When low doses of rectal ketamine are used, as in this study, administering a benzodiazepine to attenuate postoperative psychic side effects is probably unnecessary. The present study has shown that both rectal midazolam (0.30 mg/kg) and ketamine (5 mg/kg) are adequate for premeditation when administered 30 minutes before induction of anesthesia. Although midazolam appeared to have marginal advantages over ketamine as far as mask acceptance, anxiety and sedation improvement, and adverse reactions experienced, the differences were not statistically significant. The well-known analgesic effect of ketamine, which is important in the perioperative and

RETAMINE

AND MIDAZQLAM

IN PEDIATRIC

DENTISTRY

postoperative periods, at least partially cotmters its marginal disadvantages as compared with midazolam. Acknowledgment The authors wish to thank nursing sisters CA. Olivier and A.M. Fourie for assistance in premeditating amd observing the

patients.

References 1. Saint-Maurice C, Meistelman MD, Rey E, et al: The pharmacokinetics of rectal midazolam for premeditation in children. Anesthesiology 65:536, 1986 2. Saint-Maurice E, Esteve C, Holzes .I, et al: Premeditation par le midazolam intrarectal. Recherche de la dose efficace en anesthesie pediatrique (Premeditation with rectal midazolam. Effective dose in paediatric anaesthesia). Ann Fr Anesth Reanim 3:181, 1984 3. Czomy-Rtitten M, Biittner W, Finke W: Rektale gabe von Midazolam als Adjuvans zur Pramedikation von Kleinkindem (Rectal dose of midazolam as an adiuvant for the premeditation of infants). Anaesthesist 35:197, 1986 4. Kretz FJ. Lieal M. Heinemever G. et al: Die rektale Narkoseeinleitung bei’Kleinkindkm mit Diazepam und Midazolam (Rectal pm-anaesthetic medication in young children with diazepam and midazolam). Anasth Intensivmed 26:343, 1985 5. Roelofse JA, Van der Bijl P, Stegmann DH, et al: Preanesthetic medication with rectal midazolam in children undergoing dental extractions. J Qral Maxillofac Surg 48:791, 1990 6. Saint-Maurice C, Laguenie G, Couturier 63, et ak Rectal ketamine in paediatric anaesthesia. Br J Anaesth 51:573, 1979 7. Idvall I, Holasek J, Stenberg P: Rectal ketamine for induction of anaesthesia in children. Anaesthesia 38:60. 1983 8. Jantzen J-P, Erdmann K, Hilley DM, et al: Vergleichende Untersuchung von Analgesie und PlasmaspiegeIn nach rektaler, intramuskularer und intravenoser Gabe von Ketamin. Anaesthesist 34:359, 1985 9. Jantzen J-P, Tzanova I, Klein AM, et al: Rektale Narkoseeinleitung-eine vergleichende Untersuchung mit Methohexital und Ketamm. Anasth Intensivmed 28:56, 1987 10. White PF. Wav WL. Trevor AJ: Ketamine-its nharmacology and therapeutic uses. Anesthesiology 56:119, 1982 11. White PF: Ketamine update: its clinical uses in anesthesia. Semin Anesth 7:113, 1988 12. Grant IS, Nimmo WS, Clements JA: Pbarmacokinetics and analgesic effects of IM and oral ketamine. Br J Anaesth 53:805, 1981 13. Benson D, Saame A: Rectal pentothal in paediatric anaesthesia. Acta Anaesthesiol Stand 4:51, 1960 14. Haagensen RE: Rectal premeditation in children: comptison of diazepam with a mixture of morphine, scopolamine and diazepam. Anaesthesia 40:956, 1985 15. Julia JM. Rochette A. Ricard C. et al: Comuaraison du midazolam et du flunitrazepam’en premeditation par voie rectale chez le nourrisson (Comparative study of rectal premeditation with midazolam and flumtrazepam in infants). Ann Fr Anesth Reanim 3:185, 1984 16. Van der Bijl P, Roelofse JA: Disinhibitory reactions to benzodiazepines. J Oral Maxillofac Surg 49:519, 1991 17. Wyant GM: Intramuscular ketalar ((X-581) in paediatric anaesthesia. Can Anaest Sot J 18:72, 1971 18. Page P, Morgan M, Loh L: Ketamine anaesthesia in paediattic procedures. Acta Anaesthesiol Stand 16155, 1972 19. Elliot E, Hanid TK, Arthur LJH, et al: Ketamine anaesthesia for medical procedures in children. Arch Dis Child 51:1167, 1979 20. Roberts RJ: Drug Therapy in Infants-Pharmacologic Principles and Clinical Experience, Philadelphia, Saunders, 307, 1984

Rectal ketamine and midazolam for premedication in pediatric dentistry.

Rectally administered midazolam (0.30 mg/kg) and ketamine (5 mg/kg) were compared for preanesthetic medication in children undergoing dental extractio...
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