chapter 8 · chapter 8 anxiolysis for oral surgery and other dental procedures dr. fred quarnstrom...

Chapter 8

Anxiolysis for Oral Surgery andOther Dental ProceduresDr. Fred Quarnstrom

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IntroductionThis chapter discusses the need for sedation,the risks of various modalities of sedation,techniques to minimize the risks, and twosafe techniques to control fear and apprehen-sion in the dental office. The biggest risk ofsedation is respiratory depression. Mech-anisms of respiratory control will be re-viewed, and various forms of monitoring willbe discussed along with respiratory condi-tions that complicate sedations. Nitrousoxide/oxygen sedation are covered, as are oralsedatives—with emphasis on benzodi-azepines and specifically the use of triazolam(Halcion) for conscious sedation to controlfear and apprehensive.

Oral surgery is somewhat traumatic for allpatients. Because of this, many oral surgeonswill suggest deep intravenous (IV) sedation/general anesthesia for even simple surgeryprocedures. Most of the in-office surgery pro-cedures can be done with local anesthesia;however, many patients prefer some form ofsedation for their surgery. The surgery is eas-ier and faster for the surgeon if the patient iscomfortable. The use of nitrous oxide/oxygen

sedation with and without oral triazolam arediscussed. With these two drugs, almost allsurgery procedures can be completed on evenquite fearful patients without the need for themore hazardous general anesthesia.

A second issue is the dental patient who isa dental phobic. A USA Today article quotedAmerican Dental Association (ADA) figuresdetailing that 12 million Americans are den-tal phobics. Another source estimated that12 to 24 million suffer dental anxiety.1 Cop-ing with the difficult-to-manage fearful pa-tient has long plagued the profession, andone of the major challenges of dentistry isapprehension control. Fear and pain controlare closely related. Fear of future treatment isoften the result of lack of pain control in pastappointments. Pain control is most oftenachieved with local anesthesia. According toWeinstein,2 patients report the incidence offailure of the local anesthetic injection to beas high as 26.4 percent. It is suggested thatfear has a high correlation with those whohave anesthetic-related problems.3

About half the U.S. population avoidsyearly dental care. Between 6 and 14 percent

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of patients avoid any treatment whatsoeverbecause of fear. This phenomenon is notunique to the United States. Others haveshown similar problems in Sweden andJapan.4–6

Government regulations that dictate whocan and cannot be hospitalized (Medicare,Medicaid) and the threat of litigation havecaused many dentists to avoid providingdental treatment on all but the most cooper-ative and easily managed patients. Somedentists refuse to see those patients unable toreceive dental care in the usual manner.7

In the late 1990s and early 2000s thegreatest barrier to using sedation has becomedental politics. The target is primarily oralsedation and those practitioners who providethis service. The American Dental Associ-ation’s committee H proposed guidelinesthat were passed by the ADA House ofDelegates in 2004, severely limiting the useof oral sedatives. Many states’ licensing bod-ies have started adopting these guidelines.The American Association of Oral andMaxillofacial Surgeons has encouraged statelicensing boards to limit the use of oral seda-tion. In one letter sent to state boards, theysuggested that the use of oral sedationshould have the same certification requiredof IV sedation.

In this chapter, considerable space is spentreferring to the patient who is unconscious,asleep, dozing, and napping—and explainingwhy I am not comfortable with such a pa-tient. On the other hand, the patient who isorally sedated but awake and will respond toverbal directions is a safe patient. So long asthis patient remains conscious, the operatorcan relax and enjoy performing dentistry.With a proper preoperative evaluation, care-ful use of the right drug and calculation ofits dose, a dentist should never have a patientlose consciousness; that is, “go to sleep.”Should this occur, all else should cease untilthe patient is again verbally responsive orawake. Some states have regulations dictatingdentist training and equipment for treating

patients receiving general anesthesia, andrightfully so. It is a little late to start buyingequipment and getting training when a pa-tient is unconscious. General dentists admin-istering oral conscious sedation need trainingand special equipment.

As we discuss triazolam, it will becomeobvious that the chance of problems arisingwith this drug, when it is used properly, isvery slight. But even if complications shouldoccur, with the availability of a selective re-versal agent, flumazenil (Romazicon), we re-verse the effect that is going beyond the lev-els we wanted. As you will see later,flumazenil is reported to rapidly reverse thesedation of benzodiazepine drugs, much asnaloxone (Narcan) does the opiate drugs.

Various forms of oral sedation have beenused by dentists to help apprehensive pa-tients. Patient comfort can be achieved bythe practitioner who uses oral sedation,and/or nitrous oxide to allay patient’s anxietyand apprehension. Anxiolysis (a relief of anx-iety) also decreases the likelihood of stress-induced medical emergencies. The difficultyof using oral agents is the time it takes to getan effect. Since these drugs must be swal-lowed and absorbed via the small intestine itoften takes over an hour to get the drugs intothe circulation and see the maximum effect.

What Are the Levels of Sedation?Sedation needs to be matched to the level ofapprehension along with the physical andmental stimulation the patient will have toendure while their dentistry is being pro-vided. Apprehension control is a continuumof the levels of sedation—from no sedationthrough general anesthesia. A patient withminimal apprehension and a short simpleprocedure will need less help than a severelyphobic patient who will be undergoing apainful, lengthy, noisy, stressful procedure.The levels have been named anxiolysis, mod-erate sedation/analgesia, deep sedation, andgeneral anesthesia.

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Anxiolysis is a drug-induced state duringwhich the patient responds normally to ver-bal commands. Their cognitive functionsand coordination may be impaired, but ven-tilatory and cardiovascular functions are nor-mal. This level could be compared to a glassor two of wine. These patients are exposed tolittle, if any, risk. Anxiolysis may be protec-tive for patients with mild to moderate med-ical conditions that can worsen due to thestress of dentistry. This level of sedation isachieved with light oral sedation and/or ni-trous oxide/oxygen sedation.

Moderate sedation/analgesia is a bitdeeper; the patient will respond to verbalcommands, but you might have to add lighttactile stimulation to get a response. Theyare able to maintain their airway, and spon-taneous ventilation is adequate. Their cardio-vascular system is normal. This level of seda-tion is most often achieved with an oralsedative, but light IV sedation could alsoachieve these levels.

Deep sedation/analgesia takes a patientto a level where they respond only after re-peated or painful stimulation. They may not

be able to maintain their airway and mayneed an assist to maintain adequate ventila-tion. This level requires advanced trainingfor the practitioner, as protective reflexes arenow obtunded or absent. Cardiovascularfunction is maintained.

General anesthesia is a complete loss ofconsciousness. Often patients will need helpto maintain their airway, and their respira-tory function may need assistance. They will have lost the protective swallowing, gag,and laryngeal reflexes. General anesthesia canbe achieved by the inhalation of potentanesthetics, with IV drugs, with oral drugs if high enough doses are given, or acombination of these. It is imperative if thislevel is achieved that the practitioner iscapable of monitoring the patient’s vitalsigns, maintaining the airway, assistingrespiration if necessary, and handling all the various life-threatening emergencies that can occur. Children are much more dif-ficult because they are less forgiving of alter-ations from normal. Their respiratory physi-ology has a narrower margin of safety (seeFigure 8.1).

A N X I O LY S I S F O R O R A L S U R G E R Y A N D O T H E R D E N TA L P R O C E D U R E S 223

Figure 8-1. This chapter will discuss only area 1 of the spectrum of anesthesia. Areas 2 and 3 requireadvanced training and come with greater risk to the patient.


How Safe Is Sedation?Dentists with proper training can performoral sedation safely and effectively. Mostdental therapy can be accomplished on pho-bic patients using local anesthesia and seda-tion. Therefore, adequate use of local anes-thesia must be considered as the first step ofnot only pain control but also anxiety con-trol. Many central nervous system (CNS)depressants can alter the level of conscious-ness. Most of these can produce a hypnoticstate if given in higher doses, but only a se-lect few can actually produce a completestate of general anesthesia.

The potential for complications is notlimited to the general anesthetic state. It mayaccompany any degree of drug-inducedCNS depression. Respiratory and cardiovas-cular depression are the most feared compli-cations. Respiratory depression represents theprincipal negative variable introduced withconscious sedation and, left unrecognizedand untreated, is the cause of most seriouscomplications.

Further complicating the question, “ToSedate or Not To Sedate?” is the fact thatnearly all dentistry is elective. It is very rareto face the situation in which a life will belost if treatment is not initiated. A nerve maydie; a tooth may be lost; all the teeth may belost; but the patient will still be alive and rea-sonably healthy. It is very difficult to accept adental procedure where there is even a slightrisk of death. This is not to say that there isnot a very slight risk with even the most sim-ple procedures. Even administration of localanesthesia has resulted in death. But, what-ever we do, safety protocol is of the utmostimportance (see Figure 8.2).

Sedation and deep sedation/general anes-thesia has a remarkable safety record; how-ever, there have been studies showing thatthe deeper the sedation, particularly whenadministered to medically compromised pa-tients such as the very young and the elderly,the greater the risk. Dionne reported thatoverall mortality in the United States associ-ated with general anesthesia, based on self-

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Figure 8-2. The relative risks of various forms of sedation anesthesia. Because of the high levels ofoxygen, nitrous oxide is protective for almost all patients. Anxiolysis with oral sedation of a benzodi-azepine drug is nearly as safe. With help from Dr. Mark Donaldson B.Sc., Pharm.D.


report of oral surgeons, has ranged from1:740,000 to 1:349,000; however, self-reporting is usually given little credence be-cause not all cases are acknowledged. A morecredible study came out of records from theUnited Kingdom, where the overall mortal-ity risk was 1:248,000 for general anesthesiaand 1:1,000,000 for conscious sedation.Only very low risk could be determined forlocal anesthesia.8

The risk of sedation and anesthesia can bedramatically decreased with modern moni-toring devices and the use of persons trainedin monitoring and administrating anesthesia.It has been shown that the risk of anesthesiais dramatically reduced when a separate prac-titioner trained in general anesthesia admin-isters and controls the sedation/anesthesia. Inthe case of two-operator administered anes-thesia, the risk went from 1:248,000 to1:598,000.9 This is particularly true whentreating patients with underlying medicalproblems.

Patient AmbulationA problem that was unique to dentistry butis now affecting our medical colleagues whouse day surgery is the need for rapid ambula-tion. We need to get our patients back to astate that allows them to leave the office in atimely manner. Their reflexes need to besuch that they can walk unassisted after ashort period of time, even though this au-thor insists that another adult take their armfor additional support. It may be wise to usea wheelchair to transport the patient fromthe dental chair to their auto. They shouldnot drive, undertake any task that might behazardous, be placed in a position of respon-sibility (for example, taking care of children),or make important decisions. Even climbingstairs should be avoided. They need to be ac-companied and supervised by a responsibleadult for the rest of the day, during whichtime their activities should be very limited.Operating the remote control of a television

is about as complex a cognitive activity asthey should attempt. It should be stressed tothe patient that although they might feelnormal, their reflexes could still be de-pressed. They need to take the remainder ofthe day off.

It should be mentioned that some of thebenzodiazepine drugs are initially bound toplasma proteins. This binding tends to re-verse about six hours after administration.This phenomenon is known as a “secondpeak effect.”10 When using most benzodi-azepines, it is necessary to inform our pa-tients that they will experience an increase insedation about 5–8 hours after leaving theoffice. Interestingly, even after this time,blood concentrations of active drug havebeen reported to be close to 50 percent ofwhat they were during sedation. For this rea-son, it is imperative that they not undertakeany activity requiring cognitive or coordina-tion skills the rest of the day. Because of thelong half-life of diazepam (Valium), somepractitioners have felt there was reason forsome concern even the next day.

Drug Selection Our choice of drugs is guided by considera-tion of elimination half-lives and side effects.When we examine sedative systems, we finda continuum of effects from slightly notice-able changes through more profound seda-tion to general anesthesia, eventually leadingto death, if enough drug is administered.“General anesthesia is less safe than con-scious sedation, which is less safe than localanesthesia.”11

It is our goal to choose a sedation systemwith a very wide difference between desiredeffect and death in a very broad range of pa-tients. It is ideal if the effects of the drugscan be reversed at will if our system seems tobe getting out of control.

It is also our goal to create a state of tran-quility that will allow the patient to comfort-ably undergo the needed procedure. If we



can alleviate apprehension without changingany of the patient’s other parameters, wehave achieved success. In fact, we alwayscause some change in our patients’ physiol-ogy; however, with modern drugs thesechanges are much less hazardous than whatwas accepted a few years ago.

Routes of Drug AdministrationIn attempting to create a state of tranquility,we must get a certain concentration of agentto the appropriate location in the centralnervous system. When considering routes,we should consider patient comfort, time toachieve effect, control of the effect, ease ofadministration, the skill needed for adminis-tration of the drug, necessary equipment foradministration, and monitoring of the pa-tient. Unfortunately, we must also considermedical-legal questions of insurance and reg-ulation by governmental organizations.

In general, the faster the drug reaches theCNS and has an effect, the better the controlwe have over the sedation. By titrating for ef-fect, we can give just that amount of drugthat is necessary to control apprehension.Both intravenous and inhalation agents canbe readily controlled in this manner. Otherroutes of administration require administer-ing an appropriate dose and waiting up to anhour to see the desired effect. These routesrequire very specific dosages, usually associ-ated with body size. They require conserva-tive dosages, as hypersensitivity to a medica-tion will not be obvious until it is much toolate to adjust the dosage. It is imperative thata drug with a very wide range of safety beused when these slower routes of uptake areutilized. Ideally, we will have reversal agentsthat can deactivate the drug in the case ofoverdose when using these routes.

We, in dentistry, have used and continueto use a variety of agents and combinationsof agents. Multiple agents often complicatethe treatment, as each has side effects thatcan be additive. They all are CNS depres-

sants and some have unwanted depressingeffects on respiratory and the cardiovascularsystems. The combination of all these effectscan lead to problems that are hard to predictand even more difficult to control and treat.However, if only one agent is used, the sideeffects are often more predictable and moretreatable.

It is easier and safer to use a single agent,as we then only have one set of side effects.This assumes a single agent will provide theneeded result at a concentration where fewside effects are present. When Dionnelooked at drug mixtures used by 264 den-tists, he found 82 distinct combinations.12

He said, “The scientific basis for the use ofsuch a diverse group of agents and combina-tions is unclear.”13

INHALATION SEDATION

The inhalation route of administration offersa major advantage when we consider anoverdose. By removing the source of thedrug (having the patient breathe room air or100 percent oxygen), the patient will excretemost inhalation agents via the lungs, thus re-versing the overdose.

ORAL SEDATION

Several factors come to light when we con-sider oral sedatives. The time from ingestionto sedation becomes very important. For anyeffect to take place, the drug must be ab-sorbed into the bloodstream and delivered tothe site of action, usually thought to be inthe central nervous system, in sufficientquantities to be effective. Some drugs can be absorbed sublingually; others must beswallowed and absorbed from the small in-testine. Depending on the time necessary for absorption, it might be necessary to havethe patient take the drug at home beforecoming to the office. This author prefers toadminister the drug in the office becausethen you know how much was taken, when

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it was taken, and by whom it was taken. You don’t have to worry about the patienttrying to drive to the appointment as thedrug starts to take effect, and should there be a reaction to the drug, the patient is in the office where aid can be administered.

One downside is that because it will take45 minutes to one hour to get the desiredsedation, it is time-consuming to titrate oralter the dose if a patient is not adequatelysedated.

INTRAVENOUS SEDATION

With the regulations that are now in place inmany states, it is nearly impossible for theaverage general dentist to use intravenous se-dation. Many states require a 60-hour coursewith 20 patient sedations in addition to anytraining that was received in dental school.Intravenous sedation has several advantages,however. When giving a drug IV, one slowlytitrates the amount to the level of sedationdesired. For most drugs, these effects beganto diminish in a short period of time—first,due to redistribution to other tissues in thebody (primarily fat stores), and then moreslowly as the drug is metabolized into inac-tive forms or eliminated in the urine or feces.

Although this should be the safest routeof administration, it is possible to go fromconscious to deep general anesthesia in amatter of seconds. Although this should be avery safe technique, this is where we are see-ing deaths.

Drug OptionsHistorically, many drugs and routes of ad-ministration have been used to control ap-prehension in dental offices. As stated earlier,insurance companies, state regulatory bodies,and other entities have all but eliminatedintravenous sedation from the armamentar-ium of general dentists. If we look into other methods of sedation, however, we

will see that all is not lost for the phobicpatient.

NITROUS OXIDE

Nitrous oxide is possibly the safest of all seda-tives. It is estimated that close to 40 percentof dentists are equipped to administer nitrousoxide. It has been used in dentistry for morethan 150 years. Trace nitrous oxide releasedinto the air of the dental office, and its effecton the dental staff, however, must be consid-ered. It is recommended that there be post-operative oxygenation for not only nitrousoxide but also other sedatives. If one is look-ing for a very safe anxiolytic drug from whichthe patient recovers quickly and with whichthe patient is able to drive to and from theoffice, nitrous oxide is the only choice.

ALCOHOL

Alcohol has been used by some patients foryears to help with their dental treatments. Itis not unusual for a patient to self-medicatewith a bit of liquid reinforcement beforecoming to an appointment. It is importantwhen considering the use of sedatives forapprehension control that patients bewarned against using any other substancethat is a central nervous systemdepressant. The combination of benzodi-azepines and alcohol has lead to very seriousrespiratory depression and death.

CHLORAL HYDRATE

This drug has been a favorite, particularly forchildren. Evidence is emerging, however, thatindicates it may not be as safe as we believed.Chloral hydrate’s sedative action comes fromits metabolite, trichloroethanol. The peak ac-tivity occurs in the plasma within 20 to 60minutes after oral administration. Its half-lifeis 4–12 hours. It acts primarily on the CNSand has little effect on the respiratory andcardiovascular systems of healthy patients.



In higher doses, chloral hydrate becomesa cardiac irritant. There have been several re-ported cases of overdose leading to hypoten-sion. In one report of two patients, whenthis hypotension was treated with cate-cholamines or agents that released cate-cholamines, both patients experienced car-diac arrest; one survived, the other did not.Any other CNS depressant will enhance thesedation-depression of chloral hydrate, in-cluding nitrous oxide and narcotics.14

Deaths have occurred in combination withlocal anesthetics when used with small chil-dren. It is thought that often this is due tousing a toxic dose of local anesthesia: fourcartridges—one for each quadrant to betreated. Even two cartridges of local anesthe-sia can be a toxic dose for small children.

BARBITURATES

Barbiturates were the standard antianxietyagent for both medical and dental patientsfor many years. Barbiturates make a patientdrowsy, and sleepy patients tend to be lessapprehensive. In larger doses, barbiturateshave the potential to render patients asleep.It is in this way that the short- and ultra-short-acting barbiturates were used as induc-tion agents for general anesthesia and forvery brief general anesthetics.

The ratio of the dose necessary for sleepand the dose that will end in death—thetherapeutic index—is usually stated to be afactor of two, as compared to diazepam,with a ratio of 20.15 Unfortunately, barbitu-rate drugs in higher doses tend to be potentcardiac and respiratory depressants. Becauseof their addictive nature, they are not admin-istered for long-term anxiety control.16

BENZODIAZEPINES

Benzodiazepine (BZD) drugs come in manyvarieties. They differ in the rapidity that theytake effect, the time it takes for them to wearoff, time to peak blood levels, and half-lives.

While the names are different they are moresimilar than different in their effect (beyonduptake and deactivation times). Dentistryhas several BZDs that are ideal for use withapprehensive patients, and the effect can betailored to the time necessary to perform theprocedures being contemplated. One, triazo-lam, is well suited to dentistry. Triazolamcame to market as a sleep aid and has be-come very popular and controversial.Triazolam will be discussed in detail.

THE TWO MOST USEFUL SEDATIVE

DRUGS FOR THE GENERAL DENTIST

Nitrous oxide has an interesting history.Originally it was used as an attraction atpublic science shows. It was at such a pro-gram that a dentist, Horris Wells, saw a par-ticipant in a nitrous frolic receive a seriousinjury causing a dramatic wound . . . withno pain. He took this knowledge to his of-fice and began offering painless dentistryusing nitrous oxide as a general anesthetic.

Its history as a general anesthetic hasbrought dentistry some criticism. Nitrousoxide is a weak anesthetic agent. At one at-mosphere of pressure, 80 percent nitrousoxide is usually considered to be the mini-mum concentration that will achieve generalanesthesia. Even at this concentration, it isnot possible to render some patients uncon-scious. If we go to a higher concentration,we begin to encroach on the 21 percent oxy-gen found in the atmosphere and expose ourpatients to hypoxia.

The standard of the past was to watch thepatient’s color. When they began to show ablue tinge of cyanosis, the procedure wasstarted. (I like to state, tongue in cheek, thatdentists hoped the pain of the extractionwould restart the heart.) Anesthetics werevery short. One tooth in the forceps, one inthe air and one hitting the bucket, simulta-neously, was the goal. Actually, many generalanesthetics were done by this technique withan amazing safety record, which may be

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more testimony to a patient’s desire to livethan to the safety of the procedure. Today,this hypoxic anesthesia technique would beseverely criticized, as it should be.

Because nitrous oxide is absorbed and re-moved from the blood stream via the lungsessentially unchanged, nitrous oxide is a verysafe sedative. But its major disadvantage—itsrelative weakness—is also its major advan-tage. Although sedation with nitrous oxide isnot adequate for our severely phobic patientsbecause it is such a weak anesthetic agent,there is little risk of sedation rendering thepatient unconscious—that is, in a state ofgeneral anesthesia. However, it is not impos-sible. I have had two patients in 40 yearswho were under general anesthesia with verymodest concentrations (less than 40 percent)nitrous oxide. Neither had taken any otherdrugs. If the patient is not responding evenat low concentrations this might be theproblem. The mask should be removed andthe patient allowed to breathe room air orjust oxygen.

Our primary concern in anesthesia is theloss of swallowing and laryngeal reflexes thatcan lead to regurgitation of stomach con-tents and aspiration of the low-pH stomachcontents into the lungs. So long as a 50 per-cent concentration of nitrous oxide is not ex-ceeded, there is little chance of general anes-thesia or other complications.

The complications that may arise are notserious ones. Occasional vomiting may beseen, but since our patients are always con-scious, this is not serious, as protective laryn-geal reflexes are present. The patient isdefinitely uncomfortable, and vomiting cer-tainly can be messy, but it is usually not life-threatening.

Patients will occasionally hallucinate withnitrous. Again, this can be uncomfortable forthem. Treatment consists of removing thesource of nitrous oxide and reassuring thepatient, typically by telling them they are allright and will return to normal in a fewminutes. It is helpful to repeatedly assure

the patient until the hallucination is over.Use their first name and remind them theyare in the dental office—that they shouldrelax and will be back to normal in a fewminutes.

Another potential problem deserves men-tion—that of sexual aberrations. A certainnumber of female patients will experiencesexual feelings while on nitrous oxide.17 Thiscan happen at relatively low concentrations.Some patients describe the sensation of asexual orgasm. It is not all that easy to iden-tify when this is taking place. However, if itlooks like a duck, walks like a duck, andquacks like a duck, the chances are we areobserving a duck. This may, in fact, be theultimate distraction to dental treatment.Fortunately, it is very rare. For this reason itis important that a male dentist, hygienist, orassistant always be accompanied by a femaledental assistant when treating female patientswith nitrous oxide. This phenomenon hasnever been documented in male patients.

A potentially more serious problem canarise if we treat chronic obstructive pul-monary disease (COPD) patients with ni-trous oxide. Should a patient be overdosedwith nitrous oxide, it is a simple matter toremove the source of the gas, and providedthe patient is breathing, they will eliminatethe excessive concentration of nitrous oxide.If they are not breathing, we should be readyand able to assist their respiration. Thiswould be a very unusual complication andprobably would suggest the patient hadother sedatives or was given excessive nitrousoxide (greater than 80 percent). It should bestressed that nitrous oxide is a very safe seda-tive for almost all patients, provided equip-ment has been properly installed and main-tained.

Nitrous Usage

It is estimated that about 50 percent of den-tists have the equipment to administer thismix and that more than 424,000 dental per-



sonnel are exposed to the trace amounts ofgas as a result of its administration.18

Many dental and dental hygiene schoolsnow take a very cautious attitude toward theuse of nitrous oxide. This has come aboutbecause of the publication of a number ofpapers concerned with the effect of wastegases on office personnel, particularly thosewho are pregnant.

The first indication that anesthetic gasesmight be a problem for humans was a reportin 1967 by Vaisman, who studied Russianfemale anesthesiologists and reported that 18of 31 pregnancies ended in spontaneousabortion.19 Studies have shown similar prob-lems in U.S. operating rooms.20 It was clearthe operating room had the potential to be ahazardous place to work, but it was not clearwhich chemicals were the causative agents.

Animal Studies

Potent anesthetic agents have been shown tohave teratogenic effects in animal studies.Because nitrous oxide was part of manyanesthetic administrations, it needed to beevaluated. Many studies showed problemsfor animals exposed to high levels of nitrousoxide.21–31 It was shown that nitrous oxidedecreases vitamin B12, which can impairDNA synthesis.32 These studies hint that ifthe levels are kept low enough the problemscan be lessened.

Retroactive Human Studies

The dental office was an ideal study site asthere were two types of offices, those thatused nitrous oxide and those that did not.Cowen did two such studies in conjunctionwith the American Dental Association.These studies suggested there is a problemwith higher levels of exposure for pregnantstaff.33, 34 Although there may be someproblems with these retrospective studies,35

they did point to a concern for females whowere pregnant and working in dental offices

where nitrous oxide was used. The studiesdid not suggest at which level exposure be-came a problem.

Occupational Hygiene Agencies

There are three governmental bodies associ-ated with setting appropriate levels of expo-sure to chemicals: OSHA, NIOSH, andACGIH.36 The NIOSH publication, Alert,suggests the recommended exposure limit(REL) of 25 parts per million (ppm) on atime-weighted average (TWA) of 25-ppm.These levels were recommended after review-ing two studies by Bruce.37, 38

The Problem Studies

The TWA level of 25-ppm came from twostudies done by Bruce, Bach, and Arbit. Inthe first study, a difference was shown whensubjects were exposed to 50-ppm nitrousoxide with 1-ppm halothane but not to 500-ppm nitrous oxide, except for a digit spantest.39 The second study showed a slight ef-fect to subjects exposed to 500-ppm nitrousoxide for four hours.40 Note that Bruce re-canted this study as flawed in two letters—one in 1983 the other in 1991. He stated,

“Several years later, we learned thatmost of the subjects we studied were aunique population that used no moodaltering substances and as such, mighthave been abnormally sensitive to depres-sant drugs such as nitrous oxide andhalothane. There is no longer any need to refer to our conclusions as ‘controver-sial.’ They were wrong, derived from datasubject to inadvertent sampling bias andnot applicable to the general population.The NIOSH standards should berevised”.41,42

Many papers have been published in thedental literature that mention the motor skilleffect, which was not shown for just nitrous

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oxide in either study. These two studies andthe publications of NIOSH that arose fromthese studies have been referenced in somany dental journals they have become fact,ignoring the two retraction letters. After apaper is published, it is very nearly impossi-ble to retract the paper.

What Is a Safe Level of Exposure?

What studies have been done with humansthat suggest appropriate exposure levels?Ahlborg showed Swedish midwives exposedto nitrous oxide and shift work had no diffi-culty getting pregnant unless they used ni-trous oxide 30 or more times a month to as-sist with deliveries.43 In another study ofmidwives, he showed no increase in sponta-neous abortions with exposure to nitrousoxide, but he saw an increase with nightshifts, high work loads, and no nitrous.44

Sweeney performed a study on 20 practic-ing dentists. The exposures ranged from 50 ppm to more than 5,000 ppm on a time-weighted average. The only depressionseen was in three dentists with exposure ofmore than 1,800 ppm. To set levels thatwould ensure safety, Sweeney suggested we should not exceed 450 ppm on an 8-hour.45, 46

Rowland looked at the ability of femaledental assistants to become pregnant (fe-cundability). He showed no problems ifscavenging was used.47 These two studiesstrongly suggest that if we use scavengingand keep levels below 450 ppm, the dentaloffice staff is at no risk.

What Levels of Exposure Can BeAchieved?

Early studies showed that the Brown mask, amask within a mask with suction, couldachieve levels of 50 ppm under ideal settings.OSHA reviewed these data and suggestedthat since this was achievable, it should beour goal. Donaldson has shown that many

scavenging devices being used in practicingdental offices can achieve levels in the 40 to60 ppm range.48

How Can Levels Be Controlled?

It is clear that offices should have one of theavailable scavenging systems on each nitrousoxide/oxygen unit. Today’s scavenging sys-tems are predominantly systems with suctionplaced on the mask over the pop-off valve.Some systems attempt to suck up additionalair that is around the mask, and they may re-move traces of nitrous oxide that the patientexhaled through their mouth or that leakedfrom around the mask.

Every nitrous machine must have a scav-enging system with adequate suction. Thereshould be a reasonable exchange of air in ourdental offices. Outside air should be broughtinto the office by our heating and coolingsystems. It is suggested that the minimumair exchange is five changes per hour, al-though is it recognized that 15 to 20 changesper hour is better. Hoses and connectorsshould be checked for leaks. Masks shouldbe selected that fit the patient, and the pa-tient should be discouraged from speakingwhile receiving nitrous oxide sedation. If allthese suggestions are followed, it is possibleto stay in the 50-ppm range49—well belowthe 450-ppm exposure level suggested byseveral authors.

OXYGENATION AFTER NITROUS OXIDE

OXYGEN

Oxygen is the one drug that should be avail-able in all dental offices. Oxygen can be usedwith little regard for side effects or otherproblems and should be available in everyoffice as part of the emergency protocol.There are exceptions to this generality andtimes when it should not be used. For exam-ple, oxygen should be used cautiously forCOPD patients (severe emphysema). If aCOPD patient’s disease has progressed to its



final stages, his or her breathing may be onan oxygen drive—not the primary carbondioxide drive. Giving high levels of oxygento one of these patients could cause him orher to go into respiratory arrest. These pa-tients are normally quite easy to identify be-cause of their obvious respiratory difficulty.

Oxygen is routinely administered aftergeneral anesthesia when nitrous oxide wasused in order to avoid diffusion hypoxia.This phenomenon was first described byFink to explain a transient hypoxia afteranesthesia in conjunction with nitrousoxide.50 Nitrous oxide would diffuse out ofthe blood and fill the alveoli of the lungs andthe rest of the respiratory tree. Nitrous oxidecrosses from the blood to the alveoli of thelung much more quickly than either oxygenor nitrogen, and thus, nitrous oxide wouldtend to fill the dead space in the lungs. Onthe first inspiration of room air, the patientwould have a mixture of nitrous oxide fromthe dead space (150cc of 100 percent nitrousoxide) and 350cc of room air. In theory, thiswould result in hypoxia that could be aproblem for a sick patient, a patient with acompromised respiratory system, or a patientwith respiratory depression due to the anes-thesia drugs. In the case of general anesthe-sia, this could be a serious issue.

What is the harm in using some oxygen?Nothing, unless the two gas lines have beenswitched. In such a case, although the ma-chine reads 100 percent oxygen, it is in real-ity delivering 100 percent nitrous oxide.There are many ways this can happen. Onecase occurred in a surgery practice using gen-eral anesthesia and resulted in the death of ayoung, healthy, adult patient.

You can use a pulse oximeter to investi-gate the need for oxygen after nitrous oxide/oxygen administration. One study failed toshow any drop in oxygen saturation if themask was simply removed at the end of theappointment where nitrous oxide had beenused.51 The study has now been repeated byothers with the same results.52, 53

An overriding reason for leaving a patienton oxygen, however, is to scavenge the gasthe patient is exhaling. With our presentknowledge of the risks of trace contaminantsof nitrous oxide, we believe we should leaveour patients on 100-percent oxygen for fiveminutes to ensure that the nitrous oxygenthey exhale is removed from the atmospherewe breathe. However, if a patient ever be-comes unresponsive while on 100-percentoxygen, remove the mask. It may be that thegases have been switched.

Respiratory Effects of DrugsUsed for SedationSedation can be performed safely and effec-tively by dentists with proper training.Respiratory depression is the principal con-cern when sedation is administered. If we aregoing to get into trouble, the most likelycause will be due to respiratory depression orrespiratory inadequacy due to airway ob-struction.

In all cases of dental sedation, patientsshould remain awake. If the patient tends tofall asleep, they should be awakened. Generalanesthesia has been described as greatamounts of boredom occasionally dispersedwith moments of stark terror. Unless you arewell equipped, well trained, and certified,you do not want patients to be unconscious.It is not possible to tell napping, dozing, orsleep from general anesthesia without tryingto wake the person. If the patient awakes,keep them awake. If they do not awaken,you are not doing conscious sedation. Thepatient is under general anesthesia. If thepatient is not awake, you need to reverse thesedation.

With some drugs, our concern may bethat we have depressed the respiration to thepoint that an adequate exchange of gas is nottaking place. The presence of an open airwayshould be established, evaluation of the levelof respiration assessed, and vital signs shouldbe taken. It should be noted that several

232 C H A P T E R 8


studies have shown that watching the chestand/or reservoir bag move is not adequate toensure an adequate minute volume. Skincolor has been relied on in the past as a wayof ensuring adequate tissue profusion. Thearterial oxygen level can be dangerously low,however, before we see the blue tinge ofcyanosis. Cyanosis is no longer considered tobe an adequate monitor of arterial oxygenlevels. A pulse oximeter and/or capnographare invaluable in assessing the adequacy ofventilation (see Figures 8.3 and 8.4).

Physiologic Basis of VentilationTo properly appreciate the importance ofmonitoring respiration along with reviewingthe respiratory advantages of benzodiazepinedrugs, we need to review a topic we all stud-ied in dental school but most likely have notthought about since then—respiratory physi-ology. This is not intended to be a complete

discussion. Yet, it will review a minimal levelof knowledge that we should have whenusing sedative drugs.

Our breathing is controlled by severalmechanisms. When we consciously take abreath, we have conscious control. Normally,though, our breathing rate and depth arestimulated by carbon dioxide (CO2), a by-product of our metabolism. CO2 alters thehydrogen ion concentration, or the pH ofour blood. This pH change is the primarystimulus to breathing (see Figure 8.5).Breathing is also stimulated, to a lesser ex-tent, by low concentrations of oxygen. Manydrugs affect the CO2 drive, but nitrous oxidedepresses the secondary drive because of alower oxygen level (see Figure 8.6).

The solution to the aforementioned prob-lems lies in several areas. We should usedrugs that minimally depress respiration.Avoid combinations of different drugs thataffect several things at once. Monitor the


Figure 8-3. Early dental anesthesia with nitrous oxide was monitored by the patient’s color. Pink wasawake. Slight cyanosis was time to do the extractions. Deep cyanosis was time to give oxygen.


234

Figure 8-4. A pulse oximeter shines light through tissue, usually a finger. Receptors read the levels ofeach light. This information is analyzed, and the percentage of oxygen saturation is displayed on themonitor.

Figure 8-5. Food is oxidized in our bodies and becomes CO2 and water. The CO2 is absorbed in thewater of the plasma to become carbonic acid. Carbonic acid disassociates into hydrogen ions and bi-carbonate ions. The negative log of the hydrogen ion concentration is known as pH. The hydrogen ionis the prime stimulus to respiration. In the COPD patient, bicarbonate ions are absorbed by the kidneys,forcing the hydrogen ions back to carbonic acid. In this way, the stimulation of the hydrogen ion isblunted, forcing them to breathe on oxygen drive. The oxygen drive is depressed by nitrous oxide. Highlevels of O2 can do the same.


patient to ensure that adequate arterial oxy-gen levels are maintained and that CO2 lev-els do not increase. Hypoventilation is char-acterized by a reduction in arterial oxygentension and an elevation of CO2 tension.With the advent of pulse oximetry, it is nowpossible to easily monitor oxygen saturationof hemoglobin.

Pulse oximetry shows the oxygen satura-tion of hemoglobin. In addition, most ma-chines also display pulse rate. Knowing thesaturation of hemoglobin, one can approxi-mate the arterial oxygen tension, assuming anormal pH of the blood. Although 90 per-cent saturation provides reasonable assuranceof adequate arterial oxygen tension, 95

percent is preferred. Although oximetry isnot equivalent to capnography, it is valuablein alerting the dentist that ventilation isdepressed.54

The importance of monitoring a patient’srespiration cannot be overemphasized. If apatient is awake and responding to verbalcommands, we can assume the patient issafe. If the patient is unconscious (asleep?),we must have more concern. Several studiesof medical and dental anesthesia have showninadequate ventilation to be the most com-mon cause of death or brain damage. Aspractitioners, we must be prepared to moni-tor and assist respiration should it becomenecessary.


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Figure 8-6. Stimulus to the inspiratory area of the respiratory center stimulates the diaphram to con-tract. This increases the volume of the chest cavity, drawing air into the lungs as they expand. Stretchreceptors send an inhibitory signal to the respiratory center. The diaphragm relaxes, and the elasticfibers of the lungs cause them to collapse, forcing the air out. The mechanism can be stimulated byhigh hydrogen ion concentrations, low pH, high CO2 concentrations, or low O2 levels.


THE RESERVOIR BAG

In the 1960s, watching the reservoir bag wasused on several popular television programsas a means of determining when it was timeto discontinue surgery and give condolencesto the next of kin. We have now all beentaught via television to read electrocardio-graphs (ECGs) and to recognize flat line.Some feel the movement of the bag can beused to monitor respiration. There have been several studies that show one shouldnot depend on movement of the bag as anaccurate indication of the adequacy of respi-ratory exchange. It will indicate respiratoryrate.

PULSE OXIMETER

The advent of an affordable pulse oximeterhas made our lives much easier and patients’lives more secure. By passing two differentfrequencies of light through various tissues,reading the absorption of the two frequen-cies, and evaluating these differences, a pulseoximeter can determine the percentage ofoxygen saturation of the arterial blood withgreat accuracy. In addition to O2 saturation,most equipment also shows pulse rate, andsome shows a pletysmograph of the pulsewave. The use of such monitoring has madegeneral anesthesia much safer and, conse-quently, has decreased the frequency of tragicoutcomes.

However, there is at least one possiblecaveat to their use: If a patient is given sup-plemental oxygen, his or her hemoglobinsaturation will approach 100 percent. In pa-tients with severe respiratory complications,oxygen saturation could be normal eventhough exchange rates were inadequate tocleanse the blood of CO2. This could lead to high CO2 levels and result in low pH of the blood. This potential problem can be circumvented by limiting sedation topatients with no significant respiratoryproblems.

CAPNOGRAPHY

Capnography is very sensitive to respiratorydepression or apnea. This equipment meas-ures the CO2 of a patient’s expired gas. Itthen gives a reading of the concentration ofCO2 in these gases. This information can beinvaluable when monitoring patients withrespiratory problems or those undergoinggeneral anesthesia, but it is not necessary forthe sedated patient.

BENZODIAZEPINES

It was established that barbiturates, mepro-bamate, and alcohol all affect the chlorinechannel in brain neurons. They hyperpolar-ize the neuron, increasing its threshold fordepolarization. Benzodiazepines act at a dif-ferent but closely related site. Alcohol, barbi-turates, and meprobamate all act at the samesite, and all put animals to sleep with onlymodestly higher doses than are required forsedation.

It was shown that all these drugs interactwith the neurotransmitter gamma aminobutyric acid (GABA). When GABA bindswith a receptor site on the neurons, it slowsthe neuron’s rate of firing. It serves to modu-late the nervous system.

Specific benzodiazepine receptors exist inthe brain. If either GABA or a benzodi-azepine is present, the other’s binding abilityis enhanced. Thus, the effects of the benzo-diazepines are explained by the increasedactivity of GABA.55 56

The receptor sites are concentrated inparts of the brain that regulate emotional be-havior. The advantage to benzodiazepines istheir ability to relieve anxiety. They producesome drowsiness and, unfortunately, aresomewhat addicting. Tolerance developswith continued use, and withdrawal occurswhen the drug is stopped. However, the ex-tent of tolerance and withdrawal are lessthan what is seen with barbiturates.

Historically, we have used barbiturates

236 C H A P T E R 8


and narcotics, both of which have significanteffects on respiration and circulation. Themost clear-cut advantage of the single-agent,benzodiazepine sedation is the fact that over-doses are rarely lethal. In the case of barbitu-rates, the lethal dose is only a few timesgreater than the dose necessary to cause sleep(see Figure 8.7).

To deactivate most oral sedatives, we mustwait for the drug to be excreted or metabo-lized. In the case of diazepam it is metabo-lized in liver to another sedative, oxazepam(Serax), which is available as a long-termsedative on its own. Triazolam, along withmidazolam (Versed), have the shortest half-life of the benzodiazepine drugs; both are inthe one- to two-hour range. Midazolam isnormally considered to be an intravenousdrug, although it is being used orally and asa nasal spray. It is available in Europe as atablet. Unfortunately, it has been shown to

have a noticeable respiratory depressant ef-fect in higher doses.

THE ADVANTAGES OF ORAL TRIAZOLAM

SEDATION

Oral sedation with triazolam is simple toadminister, and because of the nature of the drug, it is convenient and safe to use.Triazolam is readily available from any phar-macy. Reports of adverse drug reactions arerare and tend to be relatively mild. A majorplus for all oral sedatives is that it is not nec-essary to administer an injection or start anintravenous line. (The last thing most pho-bic patients need is a needle puncture beforethey are sedated.) Getting an IV started in aphobic patient can be the most difficult partof a dental appointment. Patients readilyaccept oral sedation.

Triazolam is a drug that has been around


Figure 8-7. Most central nervous system (CNS) drugs if given in large enough quantities will result indeath, usually from respiratory depression. When given as a single agent, benzodiazepines can be givenin very large doses without causing death. They have a wide margin of safety.


for some time but has been used primarily asa sleep aid. In this context, it has receivedbad press because of side effects that haveshown up in patients who used it over an ex-tended period of time. In the early 1990s, itis the most commonly prescribed sleepingpill used in the United States; 7.2 millionprescriptions were written annually.57 Itshould be emphasized that triazolam is notapproved by the FDA as a sedative for dentalpurposes.58–60 This is an “off-label” use.

Triazolam comes close to being an idealdrug for dental sedation.61 It has the advan-tage of being absorbed rapidly, achievingpeak blood levels in 1.3 hours. Its half-life istwo to three hours. In addition, it may be upto eight times more effective as a hypnoticthan diazepam. Yet, triazolam has very littleeffect on the circulatory or respiratory sys-tems. Several studies have shown no changesin blood pressure, pulse, or percentage ofoxygen saturation, and only a slight changein respiratory rate. The high incidence ofanterograde amnesia on conscious patientsfurther endears it to the dental practitioner.Patients do not have to be asleep for theirdental treatments if they can be relaxedenough for us to do the required proceduresand not have any memory of the proce-dure.62–65

Triazolam’s relative lack of respiratory andcardiovascular sedation is important forsafety. Safety is dependant on the ratio of theL/D 50 dose (that dose usually fatal to 50percent of study animals) to the E/D 50dose (concentration that provides sedation to50 percent of study animals).

It would be ideal if this ratio were con-stant for humans. If this ratio held for hu-mans, it would take a tablet about the size ofa bowling ball to have fatal consequences.Unfortunately, this is not true. The greaterthe difference between the E/D 50 and L/D50, the safer the drug. Several patients havecommitted suicide with triazolam. Frompostmortem blood samples, it was estimatedthat one person ingested 26 0.25-mg tablets.

Another individual was found dead in a hottub. It was estimated she had taken 10tablets. So it is possible to overdose and die,but the amounts necessary are well beyondwhat is necessary for dental sedation.66

Ambien (zolpidem) has been used bysome dentists to replace triazolam. Ambien isan agonist of the GABA-benzodiazepineomega-1 receptor site. It has a similar half-life to triazolam, but is a nonbenzodiazepinehypnotic of the imidazopyridine class. Someclaim it has a little faster absorption than tri-azolam; however, the manufacturer reportsmaximum blood levels occurred at 59 and121 minutes for 5- and 10-mg doses. It has ahalf-life of 1.4–4.5 hours

Yagiela suggested lorazepam (Ativan)would be an alternative to multiple doses oftriazolam.67 Lorazepam has a 10–20-hourhalf-life and a slower uptake. He suggested itshould be taken two hours prior to startingtreatment. Five hours later, less than half ofthe drug has been deactivated. Ten to 20hours later half the effect is still present. Beconcerned about the patient driving the day after treatment. It makes more sense touse a drug with a shorter half-life and give asupplemental dose after one to two half-lives have passed. In this way, recoveryshould be faster. Lorazepam makes sense ifyou will give only one dose of a sedativedrug, and you need sedation for four ormore hours.

Pharmacology of TriazolamThe unique properties of triazolam are at-tributed to its chemical configuration. Thenitrogen atom prevents it from being water-soluble. Midazolam has a carbon in this po-sition and, thus, is water soluble and suitablefor IV administration.

One chlorine atom is responsible for po-tency. Without this chlorine, the drug isone-fifth as potent. Larger alkyl substitutionsalso decrease potency. The second chlorine isnecessary for benzodiazepine action. Bromo

238 C H A P T E R 8


and nitro substitution are only weakly anxi-olytic. The nitro version is also anticonvul-sant, as illustrated by clonazepam. The tria-zolo ring and attached methyl group areresponsible for the rapid oxidation by theliver enzymes, resulting in a short elimina-tion half-life and conversion to metabolitesthat are rapidly excreted. The methyl groupalso makes a drug more potent.68, 69

ABSORPTION

Triazolam reaches a rapid peak within 1.3hours.70 It works faster in the elderly and inyoung women.71 It also works more rapidlyin daytime than at night, due to a longerpredose fasting period. It is as much as twotimes quicker after a 12-hour fast.72 Onestudy reported that 85 percent of the drug isabsorbed into the bloodstream. The studyalso found that it is absorbed 28 percentmore quickly if given sublingually, wheresome of it is absorbed but most of it isswallowed.73

DISTRIBUTION

The distribution of triazolam shows no dif-ference in obese and normal patients. It is 89percent bound to plasma and 49 percentbound to serum proteins and crosses readilyinto the central nervous system because ofhigh lipid solubility. It also crosses the placen-tal barrier and has been found in milk of rats.

METABOLISM AND ELIMINATION

Triazolam is oxidized in the first passthrough the liver and the lining of the gut bythe cytochrome P450-mono-oxygenase sys-tem. The P450 system is made up of manyenzymes. Triazolam is metabolized by the3A4 enzyme. Tagamet, cimetidine, erythro-mycin, isoniazid, possibly some oral contra-ceptives, some anti-HIV drugs, delavirdine(DLV), efavirenz (EFV), and grapefruit de-press the cytochrome P450-mediated oxi-

datative system, thus reducing the first-passliver clearance by decreased metabolism andreduction in hepatic blood flow.74 The ab-sence of an enzyme in some people can beidiosyncratic or associated with certain pa-tient subsets. Southeast Asians may have less3A4 enzyme (see Figure 8.8).

Triazolam has no active metabolites. Asmentioned, its half-life is approximately twoto three hours but is slower at night. Thehalf-life is longer in the elderly because oflower liver oxidizing capacity. There is nochange with kidney dialysis, but the half-lifeis slower with cirrhosis. Ninety-one percentis eliminated in urine and 9 percent in feceswithin 72 hours.75 76

CENTRAL NERVOUS SYSTEM EFFECT

All the benzodiazepines have clinically usefulantianxiety, sedative-hypnotic, anticonvul-sant, and skeletal muscle relaxant properties.They all depress the CNS to some degree,tending to be more antianxiety oriented ascompared with barbiturates and othersedative-hypnotics. They depress the limbicsystem and areas of the brain associated with emotion and behavior, particularly the hippocampus and the amygdaloid nu-cleus. The major effects are attributed to an interaction with the GABA receptor com-plex.

CARDIOVASCULAR SYSTEM EFFECT

In normal therapeutic doses, the benzodi-azepines cause few alterations in cardiacoutput or blood pressure when administeredintravenously to healthy persons. Slightlygreater than normal doses cause slight de-creases in blood pressure, cardiac output, and stroke volume in normal subjects andpatients with cardiac disease, but thesechanges are not usually clinically significant.Triazolam did not affect cardiovasculardynamics in doses four to eight times greaterthan normal.77



RESPIRATORY SYSTEM EFFECT

Most benzodiazepines are mild respiratorydepressants. Given alone to a healthy patientthey have little effect; however, they can po-tentate other CNS depressants. Midazolamis one that can cause respiratory depressionand apnea. Triazolam did not depress respi-ratory response to CO2 in doses four toeight times normal.

REPRODUCTION

In rats, slightly reduced fertility occurred,but the drug did not affect their postnataldevelopment.

RECOVERY

One method of measuring recovery, a visualcoordination study (following a randomly

moving dot with their finger), had patientsback to normal in five hours after ingesting0.25mg and in 11.5 hours after ingesting0.5mg benzodiazepins. Reported side effectsinclude 8 percent sleepiness; 4 percentheadache; and dizziness, neuritis, and drymouth.

TRIAZOLAM PHARMACOLOGY

Before practitioners use any medication, theyshould be knowledgeable of its pharmacology.Likewise, every practitioner, but particularlythose using sedatives, should be able to initi-ate resuscitation (including cardiopulmonaryresuscitation) and ventilation. The equipmentnecessary to provide these emergency treat-ments must, of course, be available.

There are a few absolute contraindicationsto the use of triazolam. Patients who areknown to be hypersensitive to triazolam or

240 C H A P T E R 8

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Figure 8-8. Benzodiazepine drugs are absorbed through the intestinal wall, where metabolic break-down is initiated by the cytochrome P450 metabolic enzymes. They travel to the liver via the portal cir-culation. When in the liver, further metabolism occurs prior to entering the systemic circulation. When inthe systemic circulation the drugs can affect the target organ, the brain.


other benzodiazepine drugs should avoid itsuse. Myasthenia gravis patients should notbe treated, as triazolam has a muscle relax-ation effect. Glaucoma patients should avoidall benzodiazepines, as these drugs raise in-traocular pressure by increasing the outflowresistance to aqueous humor.78 (This canoften be reversed by pilocarpine.) All thebenzodiazepine drugs are teratogenic andshould not be given to pregnant women. Astriazolam has been shown to pass throughthe mammary glands of mice into the milk,it should not be given to lactating mothers.As it is a CNS depressant, it should be givencautiously to anyone on other CNS depres-sants or drugs that suppress the P450 meta-bolic system.79

Relative Contraindications

There are no detailed studies of triazolam’suse as a sedative with pediatric and geriatricpopulations, and practitioners should be cau-tious when giving triazolam to these groups.Some clinicians teach not to use it with pa-tients under 18 or over 65 years of age.There have been reports of suicide attemptsby psychiatric patients. Suicidal tendencieswere unmasked, creating this paradoxical be-havior.80 Several European countries haveoutlawed triazolam. One report showed anincidence of psychotic episodes after triazo-lam. However, the study was done in a psy-chiatric hospital, where many patients havepsychotic tendencies. The final relative con-traindication is the fact that triazolam hasnot been approved by the FDA for dentalsedation or the sedation of children.

Adverse Effects

Adverse effects have been reported in lessthan 4 percent of patients. Most adverse ef-fects were with doses greater than 0.5mg orwhen combined with other CNS depres-sants. As with all sedatives, patients cannotdrive, operate machinery, or undertake any

activity that could be hazardous. This in-cludes such activities as walking unaided,climbing stairs, and so on. They should notundertake positions of responsibility or careof children and should not make importantdecisions (legal, monetary, and so on) for therest of the day. They should not have alcoholor other sedatives for 24 hours.81

The office should have an effective, effi-cient emergency protocol. This should in-clude a person to be continuously in theroom with the patient from the time of ad-ministration of the drug until the patient isjudged able to leave the office. The patientshould not be allowed to sleep at any time.Oxygen saturation should be continuouslymonitored and recorded starting before ad-ministration of the drug. Vital signs shouldbe taken at regular intervals such as every 15minutes or even more often if there is anyindication of over-sedation.

Management of adverse reactions shouldbe planned before the drug is used andshould be reviewed on a periodic basis. Itshould be noted that most adverse effectswould be prevented by complete history tak-ing, physical examination, and appropriateadjustment of drug dosage. Recognition of anemergency situation must be followed by ini-tiation of a stabilization routine. This essen-tially entails the A-airway, B-breathing, andC-circulation of basic cardiac life support.Opening and maintaining a patient’s airway isof paramount importance, as is monitoringvital signs. Calling the Emergency MedicalService by dialing 911 should follow if anydoubt exists as to how to proceed.

USE IN THE GENERAL DENTAL OFFICE

Over 15 years, this author has used triazolammore than 400 times. The patients come tothe office one hour before we want to starttheir dental procedure. They are monitoredby recording blood pressure, pulse rate, andpulse oximetry. The drug dose is determinedby the patient’s weight and purposely kept



conservative—less than might be necessary.We usually administer a supplemental dosesublingually if at the 30-minute mark we seeno signs of sedation.

My patient population has ranged from 7to 83 years of age and from 60 to 320 lbs.103

All patients were ASA 1 or 2 with no historyof recent illness. All adult patients were den-tal phobics who requested IV sedation orgeneral anesthesia for their procedures. Thechildren had previous attempts at treatmentwith conventional methods, including ni-trous oxide, which were unsuccessful.

Cardiovascular and respiratory parametersmeasured and recorded included blood pres-sure (systolic and diastolic), heart rate, andoxygen saturation. With uncooperative chil-dren, only heart rate and oxygen saturationcould be measured. Cardiovascular parame-ters were recorded every 15 minutes. Duringthe procedure, oxygen saturation was contin-uously monitored with a pulse oximeter.

After recording initial baseline data, oraltriazolam was dispensed. Many authors havereported on the appropriate dosage for sleepenhancement. Suggested dosages range from0.125mg to 0.5mg.82, 83, 84, 85, 86, 87

After a discussion and completion of aninformed consent document and recordingof preoperative vital signs, a dose of triazo-lam is administered. An assistant stays in theoperatory with the patient for the next hour,taking vital signs, blood pressure, pulse, andrespiration every 15 minutes with instruc-tions to alert me if there is any change. Theassistant is instructed to talk with the patientto ensure that they remain awake. I check tosee whether there is any sign of sedation at30 minutes. If there is no sedation evident,we will administer one-half the original dose.If even slight sedation is noted at that time,we normally will have adequate sedation forthe procedure. (Many patients will be disap-pointed at the end of the 40 minutes by therelative lack of sedation. They are assuredthat this is normal, and they will be ade-quately sedated by the time we start.)

As mentioned, we decide to administerone-half the initial dose after 30 minutes ifthere is no evidence of sedation.Supplemental dosages were necessary forabout 10 percent of patients. We used thefollowing protocol to determine the dosages.Dose in mg = 0.25 mg + 0.125 mg for every70-pound weight increment over 40pounds.88

Patients reported a decrease in apprehen-sion that was greatest the first 30 minutes,with the second largest drop between 30 and60 minutes. About 50 percent had moderateto complete forgetfulness of the appoint-ment, and most did not remember the ridehome. There were no significant changes in blood pressure, pulse rate, or oxygensaturation.

It should be emphasized that no patientsslept, snoozed, snored, or napped. All wereawake and responded to verbal commandswithout painful stimulation. We have had noadverse effects on any of my patients. Wedid have three who were not sedated ade-quately to treat.

Protocol in Our Office

It should be stressed, and I will repeat again,that we do not want a patient who is asleep.If a patient sleeps, they are oversedated andshould be kept awake by verbal commands,or if this does not work, the drug should bereversed. We do not worry whether the pa-tient is disappointed by their level of seda-tion because the amnesia that is common tothis technique will allow them to forgetmost, if not all, of the appointment. Itshould be emphasized with children thatthey might still cry during the appointment.If they are controlled enough to allow den-tistry to be safely done, they are adequatelyrelaxed. Crying, although distracting to thepractitioner, is an indication of adequateventilation. I would suggest not using anyform of sedation on children under 7 yearsof age, unless you are trained in pediatric

242 C H A P T E R 8


anesthesiology and are equipped and trainedto handle general anesthesia and all the com-plications of anesthesia.

The Procedure

At a pre-appointment interview, the medicalhistory is reviewed to determine that thereare no contraindications to triazolam, theprocedures, or from possible risks. Benefitsand options are discussed with the patientor, in the case of children, with their parents.

Patient Selection

01. The patient is over 7 years of age and 70lbs of weight.

02. The patient is ASA 1 or 2. I suggest nottreating any person who has any medicalproblem, however slight.

03. Have a signed consent form. 04. Start with a dose of triazolam appropri-

ate for the patient’s size.a. 70 to 110 lbs gets 0.25 mgb. 110 to 180 lbs gets 0.375 mgc. 180 to 240 lbs get 0.5 mgd. 240 plus get 0.625 mg (see Figures

8.9 and 8.10)

05. If after 30 minutes you see absolutely noeffect and if the patient tells you they donot feel any different, give half the origi-nal dose sublingually. If they show evena very slight effect, no second dose isnecessary (see Figure 8.11).

06. Two hours later you can give half thetotal dose if you have another hour togo and the patient is much less sedatedthan they were at 60 minutes. You aregiving a dose equal to the amount thathas been metabolized.

07. If you need a little more sedation towardthe end of a case, augment with nitrousoxide.

08. Only use one oral drug, triazolam. Havethe reversal agent and be prepared to in-ject it into the floor of the mouth if thepatient does not respond to verbal com-mand without any tactical stimulation.A pinch will arouse the patient until youcan inject the reversal agent. Reverse thesedation as they are starting to getdeeper, not after they are under generalanesthesia.

09. We are not talking SLEEP, DOZE,SNORE, or NAP. We are talking awakewith anxiolysis.


Figure 8-9. Dosage calculation: Dose in mg = 0.25mg + 0.125mg for every 70 lb weight increase over40 lbs. This equals 0.5 mg for a 180-pound man. If no sedation is observed at 30 minutes, a seconddose is administered that is half the original dose. For long cases additional doses may be necessary asthe drug is metabolized.


244

Figure 8-10. Weight vs. dose of triazolam. This was an early graph of our use of triazolam in 110patients. It was from these data that I developed a dosing scheme relating to the patient’s weight.

Figure 8-11. Titration of triazolam: Long cases may require a second dose that equals the amount ofdrug that has been metabolized. Based on information from the following two references: (1) Friedman,H. et al. 1886. Population study of triazolam pharmacokinetics. Br J Clin Pharm. 22(6):639–42. (2) Derry,C.L. et al. 1995. Pharmacokinetics and pharmacodynamics of triazolam after two intermittent doses inobese and normal-weight men. J Clin Psychopharmacol. 15(3):197–205.

2879_Koerner_Chap 08 4/17/06 1:31 PM 4

10. Never leave the patient alone in theroom.

11. Never leave a male dentist, hygienist, orassistant alone with a female patient.

12. Monitor BP, pulse, and oxygen satura-tion continuously after you give the ini-tial dose.

13. If the patient needs to use the restroom,they must be accompanied by a same-sex staff person.

14. The patient must be with a responsibleadult the rest of the day. a. They are to have no alcohol or other

sedatives for 24 hours before the ap-pointment.

b. There should be no chance that theyare pregnant.

c. They should have none of the othercontraindications.

d. They cannot drive, operate machin-ery, or undertake any activity thatcould be hazardous. This includessuch things as walking unaided,climbing stairs, and so on.

e. They should not undertake positionsof responsibility, such as care of chil-dren, and should not make impor-tant decisions—legal, monetary, andso on, for the rest of the day.89, 90, 91

It is stressed that we are not attemptingnor is it our intent to have the patient sleep,although they might experience amnesia forsome or all of the appointment. I havefound that about 75 percent of patients haveamnesia from the time we start the proce-dure (60 minutes after administering triazo-lam). The amnesia lasts for 2–3 hours. Allpatients have had some amnesia or forgetful-ness of the appointment.

When the appointment is complete, wekeep the patient in the dental chair untilthey are able to walk out with someoneholding their arm. The dentist is the one todetermine whether they are able to safelyleave the office. You are looking for a notice-able decrease in sedation. Postoperative in-

structions, the same as were given to the pa-tient in the pre-appointment, are reviewedwith the adult who is going to take the pa-tient home and watch over them the rest ofthe day. I assess and record the patient’s levelof sedation prior to his or her leaving the of-fice. In addition, my home phone is given tothis accompanying adult, who is encouragedto call if they have any questions or prob-lems. Finally, an assistant accompanies thepatient out to the car, supporting the patientso there is no chance of a fall. The patient isseated in the passenger seat, and the seat beltis buckled.

It should be noted that a second appoint-ment will normally be easier than the first. Ithas never been necessary to use a higher doseat the second appointment if the dose on thefirst appointment was adequate. Also, as thisis a class IV drug, it is necessary to keep care-ful accounting records of its use.

Status of TriazolamUPJOHN

The Upjohn company distributes triazolamin the United States. They make no claimsof its usefulness as a dental sedative, nor hasit been tested for use with children. TheUpjohn company made it very clear to mein a letter that the use of this drug for dentalsedation and with children is investigationalin nature and not supported or encouragedby the company. The patent has run out fortriazolam. Consequently, there is littlechance that it will ever be certified for dentalsedation.

FDA

The FDA does not recognize triazolam’s usefor either dental or pediatric sedation. Apractitioner must recognize that should therebe a problem, the lack of FDA approvalwould create problems from a medical-legalstandpoint. Lack of FDA approval does not,



however, prevent our using the drug forsedation.

RECORDKEEPING REQUIREMENTS

The Drug Enforcement Administration, adivision of the U.S. Department of Justice,has a booklet that is available from any DEAoffice, entitled, Physician’s Manual, AnInformational Outline of the ControlledSubstances Act of 1970. This manual spellsout the requirements of recordkeeping, stor-age, inventory, security, and so on requiredfor prescribing and dispensing a controlledsubstance. Triazolam is a schedule IV sub-stance.

To administer, prescribe, or dispense anycontrolled substance, a physician (dentist)must be registered with the DEA. The DEArequires that “The registration must be re-newed every three years and the certificate ofregistration must be maintained at the regis-tered location.”

“It is necessary for dentists to keep recordsof drugs purchased, distributed and dis-pensed. Having this closed system, a con-trolled substance can be traced from the timeit is manufactured, to the time it is dis-pensed to the ultimate user.”

“All controlled substance records must befiled in a readily retrievable location from allother business documents, retained for twoyears, and made available for inspection bythe DEA. Controlled substance recordsmaintained as part of the patient file will re-quire that this file be made available for in-spection by the DEA.”

“A physician (dentist) who dispenses con-trolled substances is required to keep arecord of each transaction.”

Inventory requirements“A physician (dentist) who dispenses or

regularly engages in administering controlledsubstances is required to keep records andmust take an inventory every two years of allstocks of the substances on hand.”

Security“A physician (dentist) must keep these

drugs in a securely locked, substantially con-structed cabinet or safe.”

In my office, the triazolam is kept lockedin a keyed locker, which is permanently at-tached to an office wall. Inventory sheets arekept in a book with patient record forms.This sheet shows date and patient name, age,and weight and has space for comments.The inventory total is changed with eachdrug administration so as to provide a run-ning total of the drug inventory. When re-stocking the drug supply, a copy of theprescription is attached to the inventorysheet.

PATIENT RECORDS

Patient records are kept for all treatments.These records would be the same for anysedative agent except when nitrous oxide isused with no other sedative drugs. Theserecords include the consent form, post-sedation evaluation, and a sedation recordthat includes blood pressure records, pulserates, and pulse oximeter readings. Thesevalues are taken and recorded preoperativelyand at 15-minute increments from the drug administration until the case is com-pleted. The patient’s medical status (ASArating) is recorded along with age, sex,weight, amounts of drug administered,name, date, and whether this is the firstadministration of this sedative.

Sedation records are necessary for severalreasons. First, they establish a baseline andwould be one of the first indicators of apotential problem. If any of the measuredparameters start to change, we should im-mediately be alerted and start corrective ac-tion. Second, the stress of an emergencymakes time sequencing difficult for thepractitioner. It becomes all but impossible torecall vital signs and the times they wererecorded. Complete records can provideclues about the case and possible solutions

246 C H A P T E R 8


to our problem as it progresses. (At whatpoint did we lose verbal contact? How longhas the patient been at this level? Did thechange come on rapidly or have vital signsbeen slowly changing for some time?) Lastly, in the event of legal action, completeand accurate records are a must for one’sdefense.

Flumazenil (Romazicon) ReversalAgentIt would be a great advantage to have a med-ication that would reverse the effects of anydrug we use. This is particularly true of anydrug that requires excretion or metabolismto be deactivated. When using drugs intra-venously, small test doses can be given andaugmented as necessary to achieve the de-sired effect. These test doses go directly tothe CNS and show their effect. They arethen redistributed to the rest of the tissues ofthe body, effectively diluting the effect in thecase of an overdose or sensitivity to an agent.Titration with oral drugs is very slow. Ittakes considerable time before it is obviousthat we have a problem. Redistribution andsaturation into the body have already takenplace and are of little aid. In the case of over-dose, there is little we can do except treat thesymptoms of the overdose and support respi-ration and circulation. For this reason, a re-versal agent for oral drugs is very desirable.The reversal agent for benzodiazepines isflumazenil.

HISTORY

In 1974, Haefely hypothesized and showedthat benzodiazepines act by increasing the ef-fectiveness of the most important inhibitoryneurotransmitter, GABA. Later, several com-pounds were produced that had a greateraffinity for this site than diazepam. One ofthese, flumazenil, was selected as an antago-nist for clinical trials.92

PHARMACOLOGY

Flumazenil was shown to prevent benzodi-azepine sedation if given before the benzodi-azepine and to reverse the effect if given dur-ing or after the sedative drug. To reversesedation or general anesthesia of benzodi-azepine drugs, flumazenil is administered in-travenously in titrated doses from 0.2-to-1.0mg doses. In the case of overdose, 2.0 to 3.0mg may be necessary.93

TOXICITY AND SAFETY

“Flumazenil has a high therapeutic indexand a wide margin of safety.” It showed min-imal effect on patients with ischemic heartdisease. No withdrawal symptoms were seenwhen it was given to patients who had beenon diazepam or triazolam for up to 14 days.Some symptoms were seen in patients whohad been on lorazepam. It should not begiven to patients with severe head injuriesand unstable intracranial pressures.94 Whengiven to patients with panic disorder, 2mg of flumazenil intravenously precipitatedpanic attacks. It had no effect on healthypatients.95

Use with Children

Jones administered flumazenil to 40 healthychildren aged 3–12 years of age after theyhad received midazolam for the induction ofanesthesia. The drug was given along with aplacebo, and the efficacy of antagonism wasassessed. Those receiving the active drugawoke approximately four times faster. Therewere no cases of resedation and minimalchanges in the cardio-respiratory variables.96

Use with Adults

The half-life of flumazenil at 54 minutes (.7 to 1.3 hr) is less than triazolam, midazo-lam, and diazepam, so you may see some re-bound of effect (see “Resedation” section



later in this chapter). Sedation was gonewithin 2 to 5 minutes. I have seen the rever-sal drug used sublingually in the floor of themouth. The pain of this injection noticeablyaroused the patient. Their sedation was obvi-ously lessened within two minutes; however,maximum reversal took 10 minutes for IVadministration and 20 minutes for sublin-gual. In both cases, most of the effect oc-curred in the first five minutes.

Contraindications

Flumazenil is contraindicated in patientswith a known hypersensitivity to flumazenilor to benzodiazepines, in patients who havebeen given a benzodiazepine for control of apotentially life-threatening condition (forexample, control of intracranial pressure orstatus epilepticus), and in patients who are

showing signs of serious cyclic antidepressantoverdose.97

RESEDATION

Because of the relatively short half-life offlumazenil, 54 minutes, it is possible that itsreversal effect could disappear before thesedative effect of triazolam, with its half-lifeof one to two hours (see Figure 8.12). Mida-zolam has a similar half-life (one to twohours), and several studies have failed toshow significant resedation if appropriatedoses of midazolam had been used.98–100

Resedation has been shown with diaze-pam,101 which has a much longer half-life(20–50 hours), and with larger doses of mi-dazolam.102 Until studies have been reportedshowing no resedation with triazolam, a pa-tient who requires flumazenil should be ob-

248 C H A P T E R 8

noiclaH fo lasreveR lonezamulF noiclaH fo lasreveR lonezamulF

evitca.cnocevitca.cnoc

emit emit 11 22 33 44 55

lonezamulf lonezamulf

noiclahtuohtiwlasrever

noiclahtuohtiwlasrever

linezamulF

malozairT malozairTlinezamulF linezamulF linezamulF fo lasreveR fo lasreveR malozairT malozairT

level laciteroehTsa malozairt fo tnega lasrever

dezilobatem si .

linezamulF

malozairTtuohtiw.lasrever

Figure 8-12. The figure shows the reversal with Flumazenil. At time 1 the triazolam is completely re-versed. At time 2 one hour later, half the Flumazenil has been metabolized, and part of the effect of thetriazolam has rebounded. This effect increases through hour 3.


served for several hours after reversal to bepositive resedation does not occur. There is arisk that with reversal the patients may feelnormal and attempt activities they are notcapable of safely performing.

With the introduction of this reversalagent, we are able to use triazolam with thecomfort of knowing that we can reverse itssedation should we achieve an overdose. Ofcourse, this in no way should cause us to useexcessive doses of triazolam, nor does it re-lieve us of the responsibility of monitoring apatient’s physical status and responding ac-cordingly in the case of cardiovascular or res-piratory depression.

Politics of SedationOral conscious sedation has become a con-troversial subject for dentistry. The AmericanDental Association, specialty groups, andsome state boards have attempted to severelylimit the use of this very necessary and im-portant technique.

In general, benzodiazepine drugs, andspecifically triazolam, are very safe when usedconservatively. Triazolam has become a drugof choice in dentistry because of its rapid up-take, short half-life, and amnesia. Oral seda-tion has come a long way toward addressingthe unmet needs of phobic patients.

The ADA’s guidelines state that titrationor “giving a second dose of an oral sedative”is unpredictable and can lead to deeper levels of sedation. These guidelines limit the doseof an oral sedative to the maximum recom-mended dose (MRD). MRD is a FDA term.In the case of triazolam, it refers to the doseused as a sleep-aid for a patient who may behome alone and has nothing to do with den-tal sedation. The MRD for triazolam is 0.50mg.

When you face a sedation/anesthesiaemergency, you need all the skill and train-ing you have acquired, previous experiencehandling such emergencies, and a little luck.This is an area where dental patients can and

do die. Conservative dosing of triazolam fororal conscious sedation will never expose thepractitioner to these moments of terror orthe patient to theses risks. Always rememberDO NO HARM! Death is forever.

Case ReportsIt can be helpful to clinicians to have exam-ples of situations in which a medication wasactually used with a patient. Following aretwo care reports using triazolam in clinicalsettings.

PATIENT NO. 1

A seven-year-old was sedated for dental treat-ment by a pediatric dentist. The patient leftthe office able to walk holding the hand ofher mother. She went home and tended tosleep if left alone. The dentist’s home phoneline was out of order that evening. Aftertrying to reach the dentist, her mother be-came concerned and called a local emer-gency room, who told her to watch the pa-tient and that triazolam was not approvedfor use with children. The mother thencalled poison control and was again told thattriazolam should not be used with children.The dentist relieved the mother’s concernswhen she reached him in the office the nextday.

PATIENT NO. 2

A 40-year-old black male about 6�1� tall and230 pounds had an uneventful sedation. Atthe close of the case, when he was judged tobe ready to leave, his wife, a rather petitewoman of 5�6�, was brought in and givenpostoperative instructions. At this time shementioned they would be taking publictransportation, a bus, home. Because I wasconcerned about her being able to help thepatient on and off the bus, we kept him anextra hour to ensure that his wife would nothave any problem getting him home. We did



not insist that the patient be transported byauto. The patient arrived home safely.

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chapter 8 · chapter 8 anxiolysis for oral surgery and other dental procedures dr. fred quarnstrom...

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