Quick viewing(Text Mode)

A Review of Its Use for Conscious Sedation of Children

A Review of Its Use for Conscious Sedation of Children

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 in pediatric dentistry. serum concentration peaks in less than i hr. The metabolic The drug has been used as a preanesthetic 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 . 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. ’selimination half-life of 24-57 hr. 6 An association between the plasma 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 Amnesiceffects receptors. It has anxiolytic, sedative, , 12 , muscle-relaxant, and anterograde amne- Initial studies on adults have indicated that midazolam sic effects. Its chemicalstructure is different fromclassic produces a profound anterograde . For example, 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 , 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 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 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 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 , sedation, or general were delayed in discharge from the hospital; however, 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 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 offered effective sedation and amnesia during bone rain prior to treatment. marrow aspirations and lumbar punctures. 17 IV midazo-

238 Pediatric Dentistry: July/August1993 - Volume15, Number4 lam (0.1-0.15 mg/kg) now has replaced diazepam as the combativeness, and involuntary movements.43 No long- first choice sedative agent for invasive endoscopic proce- term adverse effect has been reported. dures. 19 Intranasal midazolam(0.17 mg/kg) together with The relative safety of midazolamand lack of adverse IM allowed placement of a central venous cath- effects maybe attributed to the drug’s selective rather than eter in a critically burned child.38 It appears that midazo- generalized CNSdepressant action. The sedative effect of lam maybe used effectively in pediatric patients for short, midazolamis related to its occupation of the benzodiaz- slightly painful and invasive procedures. For extremely epine receptor-enhancing GABAaction. This effect of painful treatment, an analgesic drug supplement may be midazolam can be reversed by IV administration of required. Midazolam has been used together with opi- 17,3s 3°, (MaziconWM--RocheLaboratories of Hoffman oids and ketamine 39 but no study has reported its use LaRoche,Nutley, NJ),~,4s and reversal of sedation occurs in conjunction with . within a few minutes23 Due to midazolam’sshort half-life recurrence of sedation following reversal is not likely to Adverse reactions occur. Routine use of flumazenil is not recommendedand The benzodiazepine group of drugs is one of the safest should be reserved for emergencies only. Although the presently in use. Midazolamis virtually free of any side use of flumazenil has been reported in , pediatric effects. The major risk associated with high doses of dosage recommendations have not been made. midazolam17 is and associated hypoxemia. Respiratory depression has been reported in adults, 4° how- Discussion ever, there have been few reports of depression in chil- Midazolam offers many advantages when compared dren. One reason for the numerousearly reports of with diazepam (Table 2). It is more water soluble and, in adults was the initial dose guidelines that underesti- thus, whengiven intravenously, it is less irritating and mated the relative potency of midazolam, which is now causes fewer adverse local vascular reactions and pain. Its believed to be three- to four-times more potent than diaz- distribution and elimination half-lives are muchshorter epam--not twice as was originally thought.19 than with diazepam. The metabolites of diazepam are Respiratory depression developed in one patient who pharmacologically active while those of midazolam are received IV midazolam and meperidine, however, it was not. These features facilitate the use of midazolamin a not determined whether the complications were due to dental setting where the patient is expected to be dis- the meperidine, the midazolam, or a combination of the charged and sent home immediately after the sedation- two drugs.21 Another case involved in a assisted procedure. The use of sedation in a pediatric pa- toddler41 who had received IV midazolarn and . tient is always an interim method of managementallowing This complication appeared to be due to the excessive treatment to take place. Eventually the child is expected-- dose of fentanyl. through various managementtechniques--to "graduate" It is advisable to monitor children receiving midazolam and receive further dental treatment without sedation. for early signs of hypoventilation or apnea. Respiratory The pediatric patient who vividly remembersdental pro- depression appears to be dose related, 6,17 and dosage regi- cedures like restraints (Papoose Board®--OlympicMedi- mens should be strictly followed. Someauthors advise cal Group, Seattle, WA),administration of local anesthe- against routine use of concomitant administration of an sia, and complicated restorative treatment may become opiate-like analgesic, whichcould both intensify respira- traumatized and be reluctant to return for further treat- tory depression19, 2~ and increase the likelihood of an ad- ments. The level of amnesia achieved by a sedative agent verse cardiopulmonary event. However, others use the is therefore of utmost importance. It has been shownthat combination without complicationY,38 In a study examin- midazolam produces anterograde amnesia more reliably ing loss of consciousness in children, only one of 41 chil- and2 for a longer duration than diazepam2 dren receiving 0.4-5.0 mg/kg rectal midazolamlost con- The or preschool child presents additional chal- scionsness (4.5 mg/kg).27Decreasedoxygen saturation and lenges to the pediatric dentist as administering a sedative depressed respiration were resolved with verbal stimula- tion, release of airway obstruction, and / or supply of posi- Table2. Clinical advantagesof midazolam tive pressure ventilation with oxygen. Whengiven in seda- tive doses without any additional medications, no clinically Water soluble significant respiratory depression has been reported. Rapid onset Aninteresting report described tmconsciousness asso- Short acting ciated with the use of oral midazolam(0.5 mg/kg) with Anticonvulsant, (400 mg) given for antibiotic prophylaxis before adenoidectomy.42 The altered pharmacokinetics of Anterograde amnesia midazolammay have resulted from reduced hepatic clear- Clinically inactive metabolites ance of midazolam by the erythromycin, an enzyme-in- Relatively high marginof safety hibiting drug. Therefore, care should be exercised when Reversal agent available using midazolamtogether with erythromycin. Other less Maybe administered intranasally commonadverse effects include: agitation, hyperactivity, Pediatric Dentistry: July/August 1993 - Volume15, Number4 239 agent is frequently difficult. Althoughthe IV route is the centrations within the brain when administered nasally most effective, it is not the preferred route in pediatric than intravenously. Clhticians using this technique should patients. Children generally injections, and the ad- proceed as cautiously as if the drug were being given ministration of an IV drug may be as traumatic to the intravenously. apprehensive and anxious child as the dental treatment Another relative disadvantage of the nasal administra- itseff. Hence,there has been a search for effective alternate tion is its dependence on the nasal mucousmembrane for routes. drug absorption, thereby permitting the commoncold to Oral administration of midazolam has many disadvan- be a contraindication for its use. Other possible adverse tages. Midazolamhas a disagreeable taste that is difficult effects to the nasal mucosa caused by long-term use of to mask.= Children may refuse to swallow and may ex- midazolamor its vehicle remain to be determined. pectorate part of the drug. The clinician then is uncertain The majority of the studies with children deal with howmuch medication actually was ingested by the child. induction into anesthesia or other examinations Oral agents tend to have a slow and variable onset and (echocardiographic, ophthalmologic). These procedures depth of sedation. They may cause and have a are relatively painless, noninvasive, of relatively short relatively prolongedeffect. In addition, oral midazolamis duration, and require only limited patient cooperation. In absorbed via the gastrointestinal tract and passes through contrast, dental treatment often consists of a long proce- the portal circulation decreasingbioavallabillty of the drug. dure involving administration of local and com- IV doses given orally are ineffective, and triple the IV dose plicated restorative techniques necessitating total patient is required,s, 9,15 cooperation. The short duration of midazolamsedation is The rectal route has been studied as an alternative to also of concern. For its incorporation into pediatric den- the parenteral and oral routes. This route was preferred tistry, a longer period of sedation is usually required and since it was believed to be reliable, rapid, and virtually perhaps more than one dose will be necessary. Alterna- painless, but conflicting clinical results were found with tively, a single dose maybeadequate when supplemented this method.27, ~ Rectal absorption was found to be poor with nitrous oxide. and irregular s and is the least reliable of all the routes All of the studies reviewed indicate the relative safety studied. Furthermore, rectal administration maybe un- of midazolamin children regardless of its administration comfortable and embarrassing for the child. Incidence of route. Whengiven in sedative doses, clinically important rectal pain, itching, and intraoperative defecation have respiratory depression does not occur. However,as with been reported. Although rectal administration has been all sedative agents, children must be observed carefully popular in Europe, it has not found favor in Great Britain and dosage regimens strictly followed whenever or the United States and is not recommendedfor use in the midazolamis used. In the unlikely occurrence of respira- pediatric dental setting. tory depression, a reversal agent, flumazenil, is available Preliminary studies suggest that intranasal midazolam and is effective. is an effective anxiolytic and sedative in infants and pre- Future research should include study of the effects of school children. 3°-37 The rapid onset of relatively high intranasal midazolamtogether with nitrous oxide for se- plasma concentrations obtained after intranasal adminis- dation of children. In addition, the effectiveness and safety tration of midazolamoffers significant advantages com- of multiple doses of intranasal midazolamfor prolonged pared with the orally or rectally administered drug.34 The sedative effect should be investigated. drug is particularly useful in the dental setting, allowing Summary administration to occur just 10 min prior to treatment. Administrationis simple andrelativelypainless. Although Midazolamis a short-acting, water-soluble benzodiaz- intranasal administration maybe objectionable, less pa- epine. It has anxiolytic, sedative, hypnotic, anticonvulsant, tient cooperation is required than with oral administra- muscle-relaxant, and anterograde amnesic effects. The drug tion in which the child must swallow the medication. has been used as a preanesthetic sedative in adults, and Nasal midazolam is absorbed from an area rich in blood more recently in children. This paper reviewed the phar- supply, avoiding the disadvantage of passing through the macokinetics of midazolamand its routes of administra- portal circulation, thus increasing the bioavailabflity of the tion in children. Intranasal administration was found to drug. It seems that nasal midazolam has all the advan- have manyadvantages including rapid onset of sedation, tages of IV administration without the disadvantages of ease of administration, and safety. The use of intranasal pain and fear associated with intravenous injections. midazolam together with nitrous oxide/oxygen for con- However,additional careful study is needed before con- scious sedation of children during dental treatment should cluding that nasal midazolamis the ideal sedative agent be investigated. for use by pediatric dentists. The exact mechanismsof Dr. Kupietzky is a postdoctoral student and Dr. Houpt is professor intranasal absorption of drugs is unknown.It is specu- and chairman, Department of Pediatric Dentistry,UMDNJ--New Jer- lated that these drugs maybe absorbed into the brain and sey Dental School, Newark. cerebrospinal4~ fluid directly through the cribriform plate, 1. Walser A, Benjamin LE Sr, Flynn T, Mason C, Schwartz R, Fryer and some drugs may achieve proportionately higher con- RI: Quinazolines and 1, 4-benzodiazepines. 84. Synthesis and

240 Pediatric Dentistry: July/August1993 - Volume15, Number4 reactions of imidazo (1,5 -a) (1,4)-benzodiazepines. J Org anxiety of preschool children during laceration repair. Ann Emerg 43:936-44, 1978. Med19:1006-9, 1990. 2. Gerecke M: Chemical structure and properties of midazolam 25. Silver TC: Evaluation of oral midazolam sedation for pediatric compared with other benzodiazepines. Br J Clin Pharmacol dental patients. Pediatr Dent abst. 14:413, 1992. 16(Suppl 1):11S-16S, 1983. 26. WynnRL: General principles of drug action. In Clinical Pharma- 3. Heizmann P, Eckert M, Ziegler WH: Pharmacokinetics and cology in Dental Practice, 4th Ed. SV Holroyd, RL Wynn, B of midazolamin man. Br J Clin Pharmaco116(Suppl Requa-Clark, EDS. St. Louis: CVMosby Co, 1988, pp 12. 1):43S-49S, 1983. 27. Spear RM, Yaster M, Berkowitz ID, Maxwell LG, Bender KS, 4. Greenblatt DJ, Abernethy DR, Locniskar A, Harmatz JS, Limjuco Naclerio R, Manolio TA, Nichols DG: Preinduction of anesthesia RA, Shader RI: Effect of age, gender, and obesity on midazolam in children with rectally administered midazolam. Anesthesiol- kinetics. 61:27-35, 1984. ogy 74:670-74, 1991. 5. AllonenH, Ziegler G, Klotz U: Midazolamkinetics. Clin Pharmacol 28. Roelofse JA, Van der Bijl P, Stegmann DH, Hartshorne JE: Ther 30:653-61, 1981. Preanesthetic medication with rectal midazolam in children un- 6. Reves JG, Fragen RJ, Vinik HR, Greenblatt DJ: Midazolam: Phar- dergoing dental extractions. J Oral Maxillofac Surg48:791-96,1990. macology and uses. Anesthesiology 62:310-24, 1985. 29. Wilton NCT, Leigh J, Rosen DR, Pandit UA: Preanesthetic seda- 7. Persson P, Nilsson A, Hartvig P, TamsenA: Pharmacokinetics of tion of preschool children using intranasal midazolam. Anesthe- midazolamin total IV anaesthesia. Br J Anaesth 59:548-56, 1987. siology 69:972-75, 1988. 8. Payne K, Mattheyse FJ, Liebenberg D, Dawes T: Pharmacokinet- 30. Saint-Maurice C, Landais A, Delleur MM,Esteve C, MacGeeK, ics of midazolam in paediatric patients. Eur J Clin Pharmacol Murat I: The use of midazolam in diagnostic and short surgical 37:267-72, 1989. procedures in children. Acta Anaesthesiol Scand Supp192:39-41, 9. Tolia V, Brennan S, Aravind MK, Kauffman RE: Pharmacokinetic 1990. and pharmacodynamic study of midazolam in children during 31. Rose E, Simon D, Haberer JP: Premedication with intranasal esophagogastroduodenoscopy. J Pediatr 119:467-71, 1991. midazolam in pediatric anesthesia. Ann Fr Anesth Reanim 9:326- 10. Kanto J, Allonen H: Pharmacokinetics and the sedative effect of 30, 1990 (French). midazolam. Int J Clin Pharmacol Ther Toxicol 21:46~63, 1983. 32. Latson LA, Cheatham JP, Gumbiner CH, Kugler JD, Danford DA, 11. Crevoisier C, Ziegler WH,Eckert M, Heizmann P: Relationship Hofschire PJ, Honts J: Midazolam nose drops for outpatient between plasma concentration and effect of midazolamafter oral echocardiography sedation in infants. AmHeart J 121:209-10, and intravenous administration. Br J Clin Pharmacol 16:(Suppl 1991. 1)51S-61S, 1983. 33. de Santos P, Chabas E, Valero R, Nalda MA:Comparison of 12. Ochs MW,Tucker MR, White Jr RP: A comparison of amnesia in intramuscular and intranasal premedication with midazolam in outpatients sedated with midazolam or diazepam alone or in children. Rev Esp Anestesiol Reanim 38:12-15, 1991 (Spanish). combination with fentanyl during oral surgery. J AmDent Assoc 34. Walbergh EJ, Wills RJ, Eckhert J: Plasma concentrations of 113:894-97, 1986. midazolamin children following intranasal administration. An- 13. Pearson RC, McCloy RF, Morris P, Bardhan KD: Midazolam and esthesiology 74:233-35, 1991. flumazenil in gastroenterology. Acta Anaesthesiol Scand Suppl 35. Gobeaux D, Sardnal F, Cohn H, Lequoy O: Intranasal midazolam 92:214, 1990. in pediatric ophthalmology. Cah Anesthesiol 39:34--6, 1991 14. Church JA, Pollock JSS, Still DM, Parbrook GD: Comparison of (French). two techniques for sedation in dental surgery. Anaesthesia 46:780- 36. Bunz R, Gossler M: Intranasal premedication of young children 83, 1991. using midazolam (Dormicum): Clinical experience. Anasthesiol 15. Feld LH, Negus JB, White PF: Oral midazolam preanesthetic Intensivmed Notfallmed Schmerzther 26:76-8, 1991 (German). medication in pediatric outpatients. Anesthesiology 73:831-34, 37. Karl HW, Keifer AT, Rosenberger JL, Larach MG, Ruffle JM: 1990. Comparisonof the safety and efficacy of intranasal midazolamor 16. Payne KA, Coetzee AR, Mattheyse FJ: Midazolam and amnesia in sufentanil for preinduction of anesthesia in pediatric patients. pediatric premedication. Acta Anaesthiol Belg 42:101-5, 1991. Anesthesiology 76:209-15, 1992. 17. Sievers TD, Yee JD, Foley ME, Blanding PJ, Berde CB: Midazolam 38. Rice TL, Kyff JV: Intranasal administration of midazolam to a for conscious sedation during pediatric oncology procedures: severely burned child. Burns 16:307-8, 1990. safety and recovery parameters. Pediatrics 88:1172-79, 1991. 39. Van der Bijl P, Roelofse JA, Stander IA: Rectal ketamine and 18. Tolia V, Fleming SL, Kauffman RE: Randomized, double-blind midazolam for premedication in pediatric dentistry. J Oral trial of midazolam and diazepam for endoscopic sedation in Maxillofac Surg 49:1050-54, 1991. children. Dev Pharmacol Ther 14:141-47, 1990. 40. Lewis JH, Benjamin SB: Safety of midazolam and diazepam for 19. McCloyRF, Pearson RC: Which agent and how to deliver it? A conscious sedation. [Letter] J Clin Gastroentero112:716-17, 1990. review of benzodiazepine sedation and its reversalin endoscopy. 41. Yaster M, Nichols DG, Deshpande JK, Wetzel RC: Midazolam- Scand J Gastroenterol Suppl 179:7-11, 1990. fentanyl intravenous sedation in children: Case report of respira- 20. Bergman SA, Wynn RL, Roth-Schechter BF, Requa-Clark B, tory arrest. Pediatrics 86:463-66, 1990. Holroyd SV: The benzodiazepines, sedative-, and cen- 42. Hiller A, Olkkola KT, Isohanni P, Saarnivaara L: Unconscious- tral muscle relaxants. In Clinical Pharmacologyin Dental Prac- ness associated with midazolam and erythromycin. Br J Anaesth tice, 4th Ed. SV Holroyd, RL Wynn, B Requa-Clark, EDS. St. 65:826-28, 1990. Louis: CVMosby Co, 1988, pp 82-90. 43. Versed. In Physicians Desk Reference, Montvale, NewJersey: 21. Diament MJ, Stanley P: The use of midazolam for sedation of Medical Economics. Data, 1992, pp 1924-26. infants and children. AmJ Roentgeno1150:377-78, 1988. 44. Davies CA, Sealey CM, Lawson JIM, Grant IS: Reversal of 22. Anderson BJ, Exarchos H, Lee K, BrownTCK: Oral premedication midazolam sedation with flumazenil following conservative den- in children: A comparison of hydrate, diazepam, tistry. J Dent 18:113-18, 1990. , midazolam and placebo for day surgery. Anaesth 45. Collins S, Carter JA: Resedation after administration of Intensive Care 18:185-93, 1990. midazolamto an infant andits reversal by flumazenil. Anaesthesia 23. Peterson MD:Making oral midazolam palatable for children. 46:471-72, 1991. [Letter] Anesthesiology 73:1053, 1990. 46. Hussain AA: Mechanismof nasal absorption of drugs. Prog Clin 24. Hermes HM, Wagner V, Bonadio WA, Glaeser PW, Losek JD, Biol Res 292:261-72, 1989. Walsh-Kelly CM, Smith DS: The effect of oral midazolam on

Pediatric Dentistry: July/August1993 - Volume15, Number4 241

Top View