REVIEW ARTICLE Midazolam:a review of its use for conscioussedation of children Ari Kupietzky, DMD,MSc Milton I. Houpt, DDS,PhD Introduction Muchinterest has been focused on the use of midazo- tration method,s IM and rectal routes peak at 15 and 30 lam (Versed~Roche Laboratories of Hoffman LaRoche, min after administration, respectively, while the oral route Nutley, NJ) for conscious sedation in pediatric dentistry. serum concentration peaks in less than i hr. The metabolic The drug has been used as a preanesthetic sedative in turnover of midazolamin children is more rapid than in adults and more recently in children. However, studies adults due to children’s more active fiver metabolism. The are lacking concerning its use in pediatric dentistry. The elimination haft-life is approximately45-60 minSin a child purpose of this paper is to review the pharmacokineticsof as compared with 2-6 hr in an adult. 4, 5 Midazolamis midazolamin children and its routes of administration eliminated significantly faster when compared with including intravenous, oral rectal, and nasal routes. diazepam’selimination half-life of 24-57 hr. 6 An association between the plasma midazolam con- Pharmacology centration and the level of clinical sedation has been estab- Pharmacologicstructure fished in adults1°, 11 and in children. 9 Maximumlevel of Midazolam HCLfirst was synthesized by Fryer and sedation in children corresponds to a mean peak Walserin 1976.1It is a short-acting, water soluble benzodi- midazolamplasma concentration of 229/zg / L. Thereafter, azepine®- drug that acts similarly to diazepam (Vafium a decline in the sedation level parallels the decrease in Roche Laboratories of HoffmanLaRoche, Nutley, NJ) on plasma midazolam concentration. GABA-(y-amino butyric acid) associated benzodiazepine Amnesiceffects receptors. It has anxiolytic, sedative, hypnotic, 12 anticonvulsant, muscle-relaxant, and anterograde amne- Initial studies on adults have indicated that midazolam sic effects. Its chemicalstructure is different fromclassic produces a profound anterograde amnesia. For example, benzodiazepines such as diazepam, and this is respon- more than 75%of patients were amnesic following the sible for its unique characteristics of rapid absorption and passage of an endoscope23 Amnesia also was demon- rapid metabolism. 2 Unlike diazepam, midazolam may be strated in patients treated during dental surgery for more 14 prepared as a water soluble salt that facilitates intrave- than 4 hr. Although diazepam also has been shown to nous (IV) and intramuscular (IM) administration cause anterograde amnesia, it has significant individual minimal if any, local irritation. Onceadministered, mi- variance. Midazolam produces anterograde amnesia in adults more reliably and for a longer duration than does dazolam becomeshighly lipophilic. The high lipid solu- 2 bility enhances rapid absorption and penetration into the diazepam or fentanyU CNS.Because of its chemical structure, the drug is oxi- Oral midazolam, at a dose of 0.5-0.75 mg/kg~produces dized by the liver muchmore rapidly than other benzodi- amnesia in children undergoing surgical procedures.15 The azepines2 and, consequently, has a short duration of ac- degree of amnesia is not dependent on the route of admin- tion. istration, as there was no significant difference whenthe amnesic effect of oral (0.45 mg / kg) was comparedwith Kinetics and metabolism midazolam (0.2 mg/kg) in children.16Midazolam was The pharmacokinetics of midazolamin adults has been found to provide partial or completeamnesia in 90%of chil- studied,~-7 however,the available data in children are lim- dren undergoing bone marrowaspirations or lumbar punc- ited.S, 9 After midazolamis absorbed from its administra- tures. 17 Significantly fewer children undergoing tion site, it is transported to its action site by the blood gastroendoscopy recall pain or discomfort with midazo- plasma. In the plasma, midazolamis bound extensively to lam compared with diazepam at both I and 24 hr follow- plasma proteins and only the unbound drug is pharmaco- ing the procedure. Morepatients receiving midazolamin- logically active. The drug is metabolized to alpha-hy- dicated preference for the same sedation for future droxy-midazolam and immediately is conjugated by glu- procedttres2s curonic acid to form a pharmacologically inactive end product that is eliminated in the urine. Twoother metabo- Routes of administration lites3 are excreted in insignificant amounts. |v and |M routes Peak serum concentrations of midazolam are reached The use of midazolamin adults via the parenteral routes at different times in children depending on the adminis- is well documented and is marketed by the manufacturer Pediatric Dentistry: July/August1993 - Volume15, Number4 237 exclusively for 1V and IM use in adults. When given The rectal route parenterally, 19 midazolam is preferred to diazepam. Whereas oral administration requires patient coopera- Diazepam’sabsorption after IM injection is slow and er- tion, the rectal route does not. Children could be told that ratic2°wher andeas it is often associated with severe pain, their temperature is being taken and frequently they will midazolamis well-absorbed and is less painful via the IM cooperate for the procedure. Most drugs, however, are route. Whenadministered intravenously, diazepam may not26 as well-absorbedrectally as from the upper intestine. cause phlebitis and local pain, whereas midazolamdoes Rectal midazolam has been studied as a preanesthetic not, due to its increased water solubility. The recom- medication for children27, 2s and the optimal sedative dose mended dose for IV administration of midazolam is be- was determined to be 1.0 mg/kg.27 Children receiving tween 0.05-0.1 mg/kg, depending on the nature of the variable doses of rectal midazolam as high as 5 mg/kg procedure (whether premedication, sedation, or general were delayed in discharge from the hospital; however, anesthesia induction) and whether other drugs are being only one of the 41 patients lost consciousness. used9,18,21(Table 1). The nasal route Table1. Commonpediatric doses The first study of intranasal administration of Route Dose mg/kg midazolamin children was conducted by Wilton in 198829 and other studies have been performedsince.3°-g7A dose of Intravenous 0.05 - 0.1 0.2 mg/kg-0.3 mg/kg (5 mg/ml, IV solution) in a 1-ml Oral 0.3- 0.75 syringe was given. If patients did not show significant Rectal 0.4- 1.0 sedation in 5 to 10 min, a repeat dose was administered. Nasal 0.2- 0.3" Higher doses necessitated a larger volume of the drug, resulting in more coughing, sneezing and expulsion of ¯ Repeatdose after 10 min if needed. part of the drug. To avoid this problem, administration of the3R drug was performed in two steps instead of one. Althoughthe IV route is the mosteffective s, 9, is, 19,21it is Children sedated with intranasal midazolam are passive not preferred for children. Parenteral administration is a and moderately drowsy but usually do not fall completely major cause of anxiety, discomfort, and trauma in chil- asleep. The average time to peak plasma concentrations dren and the trend in pediatrics is to avoid injections and maximaleffect is 10 min31, 32, 36 and recovery time is whenever possible. Consequently, other routes including approximately 30 min, with the degree of the sedative the oral, rectal, and nasal routes have been used. effect33 similar to that obtained with IM administration. The oral route Noincidence of significant respiratory depression, emesis, or oversedation has been reported and all vital signs in- Midazolamcurrently is available in the United States cluding oxygen saturation remain stable during sedation. only as an IV solution. It has been used as an oral agent but Intranasal midazolammay be used in combination with it has a distinct bad taste that is not easily disguised in other drugs in diagnostic and short surgical procedures in apple juice or other clear or carbonated liquids. Various children. One technique involved 0.2 mg/kg intranasal homemadepreparations to mask the bad taste have been midazolam followed by 9.0 mg/kg ketamine adminis- reported.S, 15, z2 Oneuseful methoduses a 2-quart package tered rectally. ~° Cardiovascular stability was found to be of grape flavored Kool-Aid® (Kraft General Foods, Inc., excellent and no respiratory depression was evidenced. White Plains, NY) with Nutrasweet® (Nutrasweet, Skokie, The mean recovery time was 40 min in this noninvasive ~3 IL) mixed in only 2 cups of water. The concentrated method of deep sedation. midazolarn (5 ml/mg) at 0.5 mg/kg then is mixed with Intranasal midazolamhas also been used in doses higher 10 ml of the concentrated grape drink and refrigerated. than 0.3 mg/kg for children undergoing ophthalmologi- This formulation takes the bitterness out of the parenteral cal examination.3s No local or general adverse reactions preparation. were observed. Midazolam is not FDA approved for Numerousstudies of oral midazolam in children have intranasal administrations; however, the available litera- given conflicting results2s,16,2~,24 A single oral dose of 0.2 ture supports its use in that fashion. mg/kgwas found to be effective during laceration repair in the emergency room.24 However, most studies indi- Studies of its use in conscious sedation cated that a higher oral dose is needed,s,15,16, 2s Only15-30% Although midazolam has not been recommended for of an orally administered dose reaches the systemic circu- children by the manufacturer, the drug has been used lation in its nonmetabolizedform due to an extensive first- effectively for brief invasive procedures in children. A 0.2- pass hepatic effect, s Thus, the oral dose should be approxi- mg/kg oral dose was successful in children younger than mately double or triple the IV dose to achieve similar 6 years old during laceration repair. 34 Wmidazolam (maxi- clinical effects. Oral doses ranging between0.3-0.75 rag/ mumdose 0.15 mg/kg) alone or in conjunction with an kg commonlyare recommended8, is, 2~ to be given 20-30 opioid offered effective sedation and amnesia during bone rain prior to treatment.