Scientific Article the Influence of Midazolam and Nitrous Oxide On

Scientific Article

The influence of midazolamand nitrous oxide on respiratory depressionin laboratory rats

R.J. Henry, DDS, MS J. Vaikuntam, DDSD.J. Jones, PhD

Abstract unique anxiolytic, sedative, hypnotic, anticonvulsant, muscle1- relaxant, and anterograde amnesic properties. Midazolamin combination with nitrous oxide (N20) 3 Pharmacologically, midazolamacts at benzodiazepine is a commonlyused sedative approachfor pediatric dental patients. Respiratory morbidity and mortality have been receptors, resulting in increased glycine and GABA inhibitory activity within the cerebral cortex, hypo- reported with midazolam administration, particularly thalamus, cerebellum, midbrain, hippocampus, as well whenused in combinationwith other drugs in the absence 4, of supplementaloxygen. Thus, the purposeof this inves- as in the spinal cord. 5 Asignificant analgesic effect, tigation wasto determinethe effect of midazolamalone and through a GABA-ionopheremediated action, also has been reported.6, 7 in combinationwith N20on respiration in laboratory rats Midazolamhas twice the affinity for benzodiazepine by measuringarterial blood gas levels. Sixty-four Sprague- receptors and up to four times the hypnotic potency of DawleyTM rats, weighing 250-320g, were assigned to one of eight groups (eight per group). Groupswere allocated diazepam.1.5, 8 Its unique pH-dependent molecular based upon the dosageof midazolamadministered (0, 1.0, structure accounts for manyof midazolam’s desirable properties. In the parenteral preparation, midazolam 2.0 or 4.0 mg/kg i.p.) and exposure to N20/O (50%/50%) 2 has a pHof 3.5 and is a water soluble nonirritating so- or roomair. Arterial blood was obtained from a femoral lution that allows multiple administration approaches. artery catheter and pH, 02, CO2 (mm Hg), and oxygen saturation (%) were determined. Samples were analyzed At physiologic pH, midazolamis highly lipophilic. This form greatly facilitates transport across the blood-brain using a System 1306 pH/Blood Gas Analyzer. Baseline z ~, arterial blood gasses wereobtained for each animaland at barrier and accounts for the rapid onset of action, 8 Because of these properties, midazolam is becoming 15-min intervals following midazolam administration throughout the 45-min experiment. Following midazolam increasingly more popular as a pharmacologic aid in administration, animals were placed into a sealed cham- the behavioral managementof selected pediatric den- tal1,3, patients.9 ber through which flowed either N20 or roomair. Group As with all sedative/hypnotic agents, midazolam comparisonsdemonstrated that: 1) arterial CO2 levels increased in midazolam-exposedanimals breathing roomair, has a respiratory depressant potential. The respiratory influence is variable and thought to be dose related. but not in those exposedto N20(P < 0.05), and 2) as Studies have demonstrated that hypnotic dosages of pected, N20/O2-exposedanimals showed an increase in midazolamare required to produce depressant effects arterial 02 and a %saturation that was not observed in roomair groups (P < 0.01). This investigation demon- such as hypoventilation, decreased tidal volume, and reduced.5, ventilatory response to elevated arterial CO2 strated that coadministration of N20/O2 to midazolam- 8, 10. 11 These effects are more pronounced when exposed animals did not result in hypercarbia, an early indicator of respiratory depression. (Pediatr Dent 18:281- midazolam is administered in combination with narcotics such as meperidineor fentanyl.1°’ 11 In 1989, the 86, 1996) Department of Health and HumanServices reported idazolam (Versed ®, Roche Laboratories, epidemiologic data on midazolam-related adverse re- 12 Nutley, NJ) is a relatively new benzodiaz- actions. At the time of that report, more than 1,600 S . epine approved by the Food and Drug Ad- incidents, ranging from hiccups to death, had been re- ministration in 1986. Although not approved for pedi- ported. Apnea(defined as no spontaneous respiration atric patients, midazolamhas becomeanesthesiology’s for at least 15 sec) and hypoxia (desaturation less than most frequently used preoperative sedative for chil- 90%for at least 10 sec) occurred in 12%of the incidents dren. Its popularity is due to its water solubility and and 86 patients died. Features commonto the more ex-

PediatricDentistry- 18:4, 1996 AmericanAcademy of PediatricDentistry 281 treme adverse reactions included: treatment in an out- midazolam(0, 1.0, 2.0 or 4.0 mg/kg) and whether ani- patient clinic setting, drug administration by person- mals were exposed to N20/O2 or room air. Rats were nel with limited anesthesia training, improper patient housed in a standard laboratory animal facility with monitoring, lack of supplemental oxygen administra- free access to food and drinking water prior to and tion, and the simultaneous administration of either during the study. 1°, meperidineor fentanyl. 12 Femoralartery cannulation The original Guidelines for the Elective Use of Con- scious Sedation, Deep Sedation, and General Anesthe- Rats were anesthetized by inhalation of methoxyflu- sia in Pediatric Patients were published largely as a rane. The animals underwentsterile surgical cannulation result of outpatient sedation deaths involving pediat- of the left femoral artery under a binocular microscope 13-15 (Sterio Star, AmericanOptical, Los Angeles, CA)using ric dental patients. Continuedreports of sedation- 3°,3~ related adverse reactions, both in medicine and den- surgical procedurepreviously reported. A heparinized tistry, are disturbing and prompted the American polyethylene cannula was inserted into the femoral artery Academyof Pediatrics (AAP) Committee on Drugs with the pulse confirmed by use of a polygraph (Model modifyits guidelines2°-12, ~5,16 Other factors contribut- 7: Grass Instrument Co, Quincy, MA).The tubing was su- ing to the AAPupdate relate to the variety in special- tured to the femoral artery and then tunneled subcuta- ties involved as well as the diverse clinical settings, neously to exit from a sterile incision on the back of the numeroussedation protocols, and variation in anesthe- animal’s neck. This prevented chewing and allowed easy sia training of the different specialists. 1~ TheAAP’s goal access for collection of arterial blood and blood pressure was to develop a uniform standard of care regardless measurement. Surgical incisions were stapled and the of the practice location or specialist involved. It is not animal was allowed to recover for 24 hr. surprising that certain subspecialties do not embrace Drugsadministration all aspects of such a broad reaching document. Of particular concernfor pediatric dentistry is nitrous oxide’s Midazolam and N20 were used in this study. (N20) deep sedation designation when administered Midazolamwas diluted with normal saline to a con- conjunction with narcotics, sedatives, or other CNS centration of 2.5 mg/mland administered intraperitoo depressants. 17 Conscious sedation with agents such as neally (iop.) at a dose of either 1.0-, 2.0- or 4.0-mg/kg, chloral hydrate, meperidine, and midazolamgenerally depending on group assignment. Two groups of animals received no midazolam and served as controls. employ the simultaneous coadministration of N20 in Previous information was utilized to establish the 1.0, oxygen2~-23 Although N20 is a CNSdepressant and is 2.0 or 4.0 mg/kg dosages selected for this investiga- knownto act at opiate receptors, its respiratory depres- tion.B2, 33 Midazolamwas administered and each animal sant action or potentiation of respiratory effects of other TM agents is considered to be minimal.2~-27The potential for was placed into a sealed Plexiglas container and ex- N20coadministration to alter consciousness to a state posed to either N20or roomair. Gases were delivered to the container via a length of polyethylene tubing at of deep sedation is largely unestablished and likely dependent on numerous variables. Objective information a total flow rate of 6 L/min using a standard 2N20/O in this area is lacking and was the impetus for this in- anesthesia machine (Matrix Medical Inc, Orchard Park, vestigation. NY). Half of the animals were exposed to 50%N20 (3 Our aim was to determine the effect of midazolam L/min N20 and 3 L/rain oxygen) and the other half were exposed to room air. Exhausted gas was vented and N20 on respiration in laboratory rats. Arterial cannulation and measurement of blood pressure, blood from the Plexiglas cage to a nearby fumehood via a gases, and pH are methods of prospectively evaluat- second length of polyethylene tubing. ing respiratory and cardiovascular influences of seda- Bloodgas and bloodpressure analysis tive combinations. Hypoventilation has been associated The study protocol called for baseline blood pres- with hypoxemia, hypercarbia, and acidosis in labora- sure and arterial blood sampling prior to and every 15 tory animals and has been studied previously via arte- 28, min (up to 45 min) following i.p. administration rial blood gases. 29 This investigation’s intention was midazolam. Arterial blood samples (0.2 cc) were col- to evaluate the cardiovascular and respiratory depres- lected in a heparinized syringe and analyzed immedi- sant effects of N20 and midazolam, alone and in com- ately using a blood gas analyzer (System 1306 pH, In- bination, in laboratory rats using hypercarbia as an in- strumentation Laboratory, Lexington, MA). Arterial dicator of deep sedation. blood pressure was measured continuously by use of Experimental design and methods a polygraph and recorded just prior to the sampling of arterial blood. Animals Sixty-four male Sprague-Dawleyrats weighing 250- Statistical analysisof data 320g (mean 290g) were utilized in this experiment. Baseline arterial pH, PO2, PCO2 (mm Hg), oxygen Animals were allocated to one of eight groups, eight saturation (%), and blood pressure were obtained for animals per group, based upon the combination of each animal. Data were expressed as changes from

282American Academy of PediatricDentistry PediatricDentistry - 18:4,1996 TABLE1. COMPARISONOF GROUP MEAN CHANGE (_+SD) IN artEriaL PCO., LEVELS (MM Hg) ovERTHE EXPERIMENTAL PERIOD

Room Air Nitrous oxide (50%) Midazolam Midazolam MidazoIam Midazolam Midazolam Midazolam Midazolam Midazolam 0 mg/kg 1 mg/kg 2 mg/kg 4 mg/kg 0 mg/kg 1 mg/kg 2 mg/kg 4 mg/kg

Baseline 31.0 + 1.6 32.6 + 4.3 30.7 + 4.0 31.2 + 1.4 32.7 + 1.8 32.8 + 3.1 31.4 + 5.0 32.1 + 3.4 (ram Hg)

15 rain 1.3 + 1.3’ 1.9 + 0.7* 4.4 + 2.7** 5.3 + 1.7’* 0.8 + 0.8 * 0.3 + 5.9 -0.8 + 4.1§ 0.3 + 3.8§ (changefrom baseline)

30min 1.4+1.4" 1.7+2.7 4.1+5.4 4.4+ 3.1’; 1.5+1.1’ 0.8+3.2 0.2+4.5 0.4±4.6 (change frombaseline)

45~nin 1.6±1.6 ° 2.9±4.4 3.1±3.8 ° 4.2±1.5’~ 1.7±1.2’ 3.2±5.4 2.6±3.3 3.0±3.7° (change~ombase~e)

¯ Signifiessignificant difference in the groupmean change from pre-exposure baseline levels, P < 0.05. 4 Signifies significant differencein the groupmean change from pre-exposure baseline levels, P<0.01. :1:Signifiessignificant differencefrom control group animals not receivingmidazolam at correspondingtime interval, P < 0.05. § Signifies significant differencein meanchange from baselinebetween N20 androom air exposedanimals at corresponding midazolamdosage and time interval, P<0.01.

baseline for each animal over time. The respiratory and cardiovascular influence of midazolam and N20 were ¯ Room Air I "1" analyzed for significant changes from the mean 5 baseline value within each group over time as well as between groups. Data analysis indicated that informa- ~ tion at the 15-min time interval was of greatest inter- est. Therefore, group analysis was accomplished by comparing the population means (arterial pH, PO2, PCO2 [mm Hg], oxygen saturation [%] and blood pressure) from baseline by use of paired t-test and two 1 sample t-test. Wedetermined: 1) significant differences between pre-exposure baseline values and exposure 0 values within each group, 2) dose response differences

within N20 and room air exposed groups, and 3) dif- -1 ferences between N20- and room air-exposed animals at various concentrations of midazolam. Significance -2 was established at P < 0.05. -3 Dose(m~/k~) Results * Significantdifference from control group animals not receiving Table 1 shows mean baseline PCO2 values and in- midazolamat correspondingtime interval (P < 0.05). tra- and intergroup changes following i.p. midazolam ff Significant differencein meanchange from baselinebetween administration in rats exposed to the various experi- N20-and room air-exposed animals at corresponding mental conditions. Arterial CO2 initially increased from midazolamdosage and time interval (P < 0.01). pre-exposure baseline levels in all animals breathing Figure. Comparisonof meanchange (±SEM) from room air (paired t-test, P < 0.01). Dose response differ- baselinePCO 2 levels (mmHg)15 rain after i.p. injection ences with 2- and 4-mg/kg groups breathing room air of midazolam. were significant. Similar animals exposed to N20 did not demonstrate increased PCO2 levels. In fact, PCO2 The Figure demonstrates both the dose response re- levels in N20-exposed animals pretreated with 2 or 4 lationship of midazolam on PCO2 levels in animals mg/kg of midazolam were significantly lower than breathing room air and the intergroup differences from corresponding animals exposed to room air (two- N20-exposed animals. Higher concentrations of sample t-test, P < 0.01). These differences became non- midazolam, 2 and 4 mg/kg, resulted in significantly significant over time. elevated arterial CO2 levels compared with control ani-

PediatricDentistry - 18:4, 1996 AmericanAcademy of Pediatric Dentistry 283 TABLE2. COMPARISONOFGROUP MEAN (+SD) ARTERIALBLOOD GAS DATA (MM Hg AND % SATURATION FIFTEENMINUTES AFTER I.P. INJECTIONOFMIDAZOLAM

RoomAir Nitrous Oxide (50%) Midazolaln Midazolam Midazolam Midazolam Midazolam Midazolam Midazolam Midazolam 0 ~ng/kg 1 mg/kg 2 mg/kg 4 mg/kg 0 mg/kg 1 mg/kg 2 mg/kg 4 mg/kg ~ ~ 2PO 94.3 + 5.6 87.2 + 5.7 96.0 + 8.1 91.9 + 4.8" 172.2 + 9.2 188.4 + 32.3 196.6 + 23.5~ 198.1+21.6~ %Saturation 97.9 + 1.4 97.2 + 1.1 97.2 + 0.8 97.4 + 0.8 99.2 + 0.5 ~ 99.6 + 1.4 ~ 99.5 + 1.0~ 99.7 + 0.9~

¯ Signifiessignificant difference in the groupmean change from pre-exposure baseline levels, P < 0.05. *Signifiessignificant difference from mean pre-exposure baseline levels, P < 0.01. :l: Signifiessignificant difference between N20 androom air exposedanimals at correspondingmidazolam dosages, P< 0.05. mals not receiving midazolam(P < 0.05). N20-exposed deep sedation designation that N~Ocoadministration animals did not demonstrate increased PCO2 levels. In- constitutes, restricts use without consideration of po- tergroup differences were evident amongthe 2- and 4- tential dose reduction benefits that N20 allows when mg/kg groups (P < 0.01). used in multidrug protocols. Guidelines mayalso pre- Apnea and hypoxemia have been shown to occur clude the possible beneficial influences of enriched early after midazolamadministration. Table 2 demon- oxygen received during N20 administration should B, strates early changes in oxygenation, mean PO2, and % practitioners abandonthis approach. 3s, 36 Theobjective saturation in rats exposed to the various experimental of this investigation was to further the understanding conditions 15 min after i.p. midazolamadministration. of respiratory influences of a commonsedative combi- Other than the 4-mg/kg group, arterial 02 levels and nation in laboratory rats. % saturation in animals exposed to room air did not A review of respiratory physiology indicates that change significantly from baseline values. The lower respiration is regulated by two basic mechanisms:the PO2 levels in that group became nonsignificant over central involuntary control and the backup for invol- time. NRO-exposedanimals showed highly significant untary respiration. The central involuntary control is increases in arterial 02 and %saturation when com- influenced by arterial PCOalevels, which, whensuffi- pared with baseline (paired t-test, P < 0.01) and to cor- ciently elevated (hypercarbia), initiate spontaneous responding room air exposed groups (two-sample t- respiration. The backup for involuntary respiration are test, P < 0.01). chemoreceptors located in the carotid and aortic bod- Examination of arterial pH and hemodynamicdata ies that are sensitive to hypoxiaand trigger respiration ~6 (blood pressure and heart rate) found no significant when PO2 levels fall below 80mmHg. Agents that differences in any parameter from pre-exposure depress the central nervous system decrease the venti- baseline over time or between any of the eight groups latory response to arterial PCO~levels and/or suppress studied. the apneic threshold so that greater arterial PCO~levels would be required to stimulate spontaneous respi- Discussion ration. 1~ Depressant medications also mayinfluence the The 1992 revision of the AAPguidelines for manage- hypoxic drive so that significantly lower levels of PO~ ment17 of pediatric patients during and after sedation would be required to activate respiratory backup stemmedfrom continuing reports of life-threatening mechanisms. complications involving respiratory morbidity and The depressant effects of agents such as the opioids, mortality during outpatient sedation of pediatric pa- benzodiazepines, and N20 are dose related and reduce tients.10,12,15,16, 3~ Commonalitiesof morbidincidents in- both CO2 sensitivity and the respiratory drive. For ex- cluded: multiple drug protocols, outpatient clinic en- ample, opioids produce a reduction of the ventilatory vironment, anesthesia administration by untrained response to elevated arterial CO2,an increase of the personnel, inadequate monitoring, and lack of supple- apneic threshold, and also suppression of the hypoxic mental oxygen administration. The intent of the guide- drive. 26 Benzodiazepines alter respiration through line change was to ensure patient safety by establish- hypoventilation, decreased tidal volume, and reduced ing minimal standards for patient assessment, dietary responsiveness to PCO2 -- but without alteration of the restrictions, and electronic monitoring, irrespective of apneic threshold. TM 37 The influence of N20 on respira- the clinical setting. 15, ~ The child’s responsiveness and tion is limited. It producesa decreased tidal volumethat ability to maintain protective reflexes (as opposed to is offset by a correspondingincrease in the respiratory the drug protocol, drug combination, or administration rate. N20 has little effect on the ventilatory response to route) are fundamental in distinguishing the conscious CO~but does depress the ventilatory response to hy- state from deep sedation. Under current guidelines, the poxemia.2S-27,3s Although N20’s ability to potentiate

284 AmericanAcademy of PediatricDentistry PediatricDentistry- 18:4, 1996 respiratory depressant effects of other sedative agents Readers should be cautious in the interpretation and is unestablished, some data suggest that its combined clinical application of these animal data. The average administration1° may adversely influence respiration. changes reported here do not reflect individual varia- Midazolam/narcotic combinations in sufficient dos- tion displayed by hyper-responders. This was evident ages are known to produce significant respiratory de- in our investigation where sedated animals, breathing pression. Although analgesia produced by N20 is com- N20 or room air, demonstrated PCO2 increases of up parable to opioids, the respiratory depressant to 22% and 32%respectively. The clinical significance properties of N20 are not fully established. This animal of individual potential for development of this degree investigation evaluated respiratory and cardiovascular of hypercarbia is obvious and is why our results are not influences of midazolam both alone and in combina- directly related to conscious sedation practices. More- tion with N20. Our results show that blood pressure over, the possibility exists that the supplemental oxy- and heart rate effects were not significant and confirm gen the animals received during N~O administration previous reports stating that midazolam and N20 have might have masked hypoventilation and respiratory limited cardiovascular influences, s, 39 This animal inves- depression.26,35 This would be of particular concern for tigation demonstrated that the coadministration of N20 pediatric patients where pulse oximetry is the sole and midazolam did not result in hypercarbia. method of physiologic monitoring. So, until further Midazolam-treated animals breathing room air did information involving human subjects is available, one however retain CO2, an early sign of respiratory depres- should adhere strictly to AAPDguidelines and moni- sion. Some beneficial influence apparently was pro- tor patients cautiously for signs and symptomsof res- vided the animals receiving N20, either from the en- piratory depression. riched oxygen administration or the N20 itself. In a pilot investigation, we attempted to ascertain Conclusions the influence of N20 on PCO2 levels by studying ani- 1. Arterial PCO2 levels increased in midazolam- mals pretreated with 4 mg/kg of midazolam and ex- exposed animals breathing room air, but not in posed to 50% nitrogen (N2) mixed with 50% At t he 2. those exposed to N20/O 2. The hypercarbia de- 15-min time period, arterial CO2 levels in the 2-N2/O tected was significant and was an early indica- exposed animals (37.7 + 1.8 mmHg)were not signifi- tor of respiratory depression. cantly different from corresponding animals exposed 2. Arterial PO2 levels increased by approximately to room air (36.5 + 1.7 mmHg). Thus we theorize that 100% in midazolam-exposed animals breathing N20, not the supplemental 02, somehow prevented N20/O2, but no significant change was observed hypercarbia. Determination of the mechanism for this in animals exposed to room air. The effect was beyond the scope of our investigation. How- coadministration of N20 to sedated animals did ever, N20’s sympathomimetic action of the reticular not result in hypoxemia, regardless of the activating system25,4° may stimulate involuntary respi- midazolam dose received -- in fact oxygen saturation and explain the CO2 stability that was not appar- ration increased significantly. ent with either room air or nitrogen-exposed animals. 3. Blood pressure, heart rate, and arterial pH val- N20’s later parasympathetic activation also may ex- ues were not significantly different among plain why mild hypercarbia was evident over time. groups or over time. The safety benefits of enriched oxygen administra- Dr. Henryis associate professor and postdoctoral programdirec- tion after conscious sedation or general anesthesia have tor, departmentof pediatric dentistry and Dr. Jones is professor, been reported. 35, 36, 41, 42 Earlier incidents of midazolam- departmentof anesthesiology, University of TexasHealth Science related morbidity and mortality have been associated Center at San Antonio.At the time of the research, Dr. Vaikuntam with1°, a lack of supplemental oxygen administration. was a postdoctoralfellow, departmentof pediatric dentistry, Uni- 12 Thus, the increased arterial PO~levels observed dur- versity of TexasHealth Science Center at San Antonioand is now assistant professor, departmentof pediatric dentistry, University ing supplemental oxygen administration would seem of MinnesotaSchool of Dentistry. desirable during pediatric sedation. The possibility of Reprint requests to: Dr. RobertJ. Henry,Department of Pediatric similar benefits from supplemental oxygen received Dentistry, The University of TexasHealth Science Center at San during N20 administration has not been established. Antonio, 7703 Floyd Curl Dr., San Antonio, TX78284-7888. However, reports suggest that N20 does not cause hy- 1. KupietzkyA, HouptMI: Midazolam:a review of its use for poxia and that the high oxygen content received dur- conscioussedation of children. Pediatr Dent 15:237-41,1993. 2. Wright SW, ChudnofskyCR, Dronen SC, Kothari R, Birrer ing N20/O administration may, in fact, reduce the like- 2 41, P, Blanton DM,Bruner A: Comparison of midazolam and lihood of hypoxemia. 43~5 This animal investigation diazepamfor conscious sedation in the emergencydepart- confirms that possibility. Arterial PO2 levels in rats ex- ment. AnnEmerg Med22:201-5, 1993. posed to N20 increased from 90 to approximately 180 3. Hartgraves PM, Primosch RE: An evaluation of oral and mmHg.Although the increased arterial oxygen tension nasal midazolamfor pediatric dental sedation. ASDCJ Dent Child 61:175-81, 1994. is not surprising, the N20/midazolam-exposed animals 4. Richter JJ: Current theories about the mechanismsof ben- did not demonstrate hypercarbia or hypoxemia -- re- zodiazepines and neuroleptic drugs. Anesthesio154:66-72, gardless of the midazolam dose. 1981.

PediatricDentistry - 18:4, 1996 AmericanAcademy of Pediatric Dentistry 285 5. Reves JG, Fragen RJ, Vinik HR, Greenblatt DJ: Midazolam: 25. Eger EI: Nitrous Oxide/N20. NewYork: Elsevier, 1985, pp pharmacology and uses. Anesthesiol 62:310-24, 1985. 109-21, 157-72. 6. Rattan AK, Tejwani GA: Sodium ions modulate differen- 26. Becker DE: The respiratory effects of drugs used for con- tially the effect of benzodiazepine agonist of rat spinal mu-, scious sedation and general anesthesia. I AmDent Assoc delta-, and kappa-opioid receptors. Pharmacol 48:30-40, 119:153-56, 1989. 1994. 27. MalamedSF: Sedation, a guide to patient management, 3rd 7. Schwieger IM, Jorge-Costa M, Pizzolato GP, Forster A, Ed. St. Louis: CVMosby Co, 1994, pp 198-221. Morel DR: Intrathecal midazolam reduces isoflurane MAC 28. Achike FI, Dai S: Cardiovascular responses to nifedipine in and increases the apnoeic threshold in rats. Can J Anaes~h anaesthetized rats with abnormal blood gas/pH levels. Clin 41:144-48, 1994. Exp Pharmacol Physiol 18:223-30, 1991. 8. Wright SW, Chudnofsky CR, Dronen SC, Wright MB, 29. Whelan G, Flecknell PA: The use of etorphine/ Borron SW: Midazo|am use in the emergency department. methotrimeprazine and midazolam as an anaesthetic tech- Am J Emerg Med 8:97-100, 1990. nique in laboratory rats and mice. Lab Anim28:70-77,1994. 9. Fuks AB, Kaufman E, RamD, Hovav S, Shapira J: Assess- 30. Raff H, Fagin KD: Measurement of hormones and blood ment of two doses of intranasal midazolam for sedation of gases during hypoxia in conscious cannulated rats. J Appl young pediatric dental patients. Pediatr Dent 16:301-5,1994. Physiol 56:1426-30, 1984. 10. Bailey PL, Pace NL, Ashburn MA, Moll JWB, East KA, 3l. Maskrey M, Evans SE, Mesch U, Anderson NA, Sherry JH: Stanley TH: Frequent hypoxemia and apnea after sedation Phrenicotomy in the rat: acute changes in blood gases, pH, with midazolam and fentanyl. Anesthesio173:826-30,1990. and body temperature. Respir Physiol 90:47-54, 1992. 11. Yaster M, Nichols DG, Deshpande JK, Wetzel RC: 32. Aarons L, MandemaJ, Danhof J: A population analysis of Midazolam-fentanyl intravenous sedation in children case the pharmacokinetics and pharmacodynamics of report of respiratory arrest. Pediatrics 86:463-67, 1990. midazolam in the rat. J Pharmacokinet Biopharm 19:485-96, 12. Department of Health and HumanServices, Office of Epi- 1991. demiology and Biostatistics, Center for Drug Evaluation and 33. Rich G, Roos C, Anderson S, Daugherty M, Uncles D: Di- Research, Data Retrieval Unit HFD-737, June 27, 1989. rect effects of intravenous anesthetics on pulmonary vascu- 13. AAPD:Guidelines for the elective use of conscious sedation, lar resistance in the isolated rat lung. Anesth Analg 79:961- deep sedation, and general anesthesia in pediatric patients. 66, 1994. Pediatr Dent 7:334-7, 1985. 34. Litman RS: Recent trends in the management of pain dur- 14. Goodson MJ, Moore PA: Life-threatening reactions after ing medical procedures in children. Pediatr Arm24:158-63, pedodontic sedation: an assessment of narcotic, local anes- 1995. thetic, and antiemetic drug interaction. J AmDent Assoc 35. Croswell R, Dilley D, Lucas W, Varm W: A comparison of 107:239-45, 1983. conventional versus electronic monitoring of sedated pedi- 15. Cote CJ: Sedation protocols-why so many variations? Pedi- atric dental patients. Pediatr Dent 17:332-39, 1995. atrics 94:281-83, 1994. 36. Papageorge MB, Hunter MJ, Norris LH, Rosenberg MB: 16. Krippaehne J, Montgomery M: Morbidity and mortality Supplemental oxygen after outpatient oral and maxillofa- from pharmacosedation and general anesthesia in the den- cial surgery. Anesth Prog 39:24-7, 1992. tal office. J Oral Maxillofac Surg 50:691-99, 1992. [Discus- 37. Forster A, Morel D, BachmannM, Gemperle M: Respiratory sion 698-9] depressant effects of different doses on midazolam and lack 17. American Academy of Pediatrics Committee on Drugs: of reversal with naloxone-a double blind randomized study. Guidelines for monitoring and management of pediatric Anesth Analg 62:920-24, 1983. patients during and after sedation for diagnostic and thera- 38. Yacoub O, Doel D, Kryger MH, Anthonisen NR: Depression peutic procedures. Pediatrics 89:1110-15, 1992. of hypoxic ventilatory response by nitrous oxide. 18. Giovanniti JA: Nitrous oxide and oral premedication. Anesthesio145:385-89, 1976. Anesth Prog 31:56-63, 1984. 39. Giovanniti JA: Midazolam: review of a versatile agent for 19. Currie W, Biery K, Campbell R, Mourino A: Narcotic seda- use in dentistry. Anesth Prog 34:164-70, 1987. tion: an evaluation of cardiopulmonary parameters and be- 40. Stoelling R.K: Pharmacology and Physiology in Anesthetic havior modification in pediatric dental patients. J Pedod 12: Practice. Philadelphia: JB Lippincott, 1987, pp 82-83. 230-49, 1988. 41. Anderson J, Vann WF, Jr.: Respiratory monitoring during 20. McKee KC, Nazif MM,Jackson DL, Barnhart DC, Close J, pediatric sedation: pulse o×imetry and capnography. Moore PA: Dose responsive characteristics of meperidine Pediatr Dent 10:94-101, 1988. sedation in preschool children. Pediatr Dent 12:222-27,1990. 42. Hardeman J, Sabol S, Goldwasser M: Incidence of hypox- 21. Poorman TL, Farrington FH, Mourino AP: Comparison of emia in the postanesthetic recovery room in patients hav- a chloral hydrate/hyctroxyzine combination with and with- ing undergone intravenous sedation for outpatient oral sur- out meperidine in the sedation of pediatric dental patients. gery. J Oral Maxilofac Surg 48:942-44, 1990. Pediatr Dent 12:288-91, 1990. 43. Whitehead G, Durr D, Adair S, Proskin H: Monitoring se- 22. Houpt MhProject USAPthe use of sedative agents in pedi- dated pediatric dental Patients. ASDCJ Dent Child 55:329- atric dentistry: 1991 update. Pediatr Dent 15:36-40, 1993. 33, 1988. 23, Sams DR, Russell CM: Physiologic response and adverse re- 44. Hasty MF, Vann WF Jr, Dilley DC, Anderson J: Conscious actions in pediatric dental patients sedated with promethaz- sedation of pediatric dental patients: an investigation of ine and chloral hydrate or meperidine. Pediatr Dent 15:422- chloral hydrate, hydroxyzine pamoate, and meperidine vs. 24, 1993. chloral hydrate and hydroxyzine pamoate. Pediatr Dent 24. Duncan GH, Moore P: Nitrous oxide and the dental patient: 13:10-9, 1991. a review of adverse reactions. J AmDent Assoc 108:213-19, 45, Verwest TM, Primosch RE, Courts FJ: Variables influencing 1984. hemoglobin oxygen desaturation in children during routine restorative dentistry. Pediatr Dent 15:25-9, 1993.

286 American Academyof Pediatric Dentistry Pediatric Dentistry - 18:4, 1996