2879_Koerner_Chap 08 4/17/06 1:30 PM Page 221

Chapter 8

Anxiolysis for Oral Surgery and Other Dental Procedures Dr. Fred Quarnstrom

Introduction sedation with and without oral triazolam are This chapter discusses the need for sedation, discussed. With these two drugs, almost all the risks of various modalities of sedation, surgery procedures can be completed on even techniques to minimize the risks, and two quite fearful patients without the need for the safe techniques to control fear and apprehen- more hazardous general anesthesia. sion in the dental office. The biggest risk of A second issue is the dental patient who is sedation is respiratory depression. Mech- a dental phobic. A USA Today article quoted anisms of respiratory control will be re- American Dental Association (ADA) figures viewed, and various forms of monitoring will detailing that 12 million Americans are den- be discussed along with respiratory condi- tal phobics. Another source estimated that tions that complicate sedations. Nitrous 12 to 24 million suffer dental anxiety.1 Cop- oxide/oxygen sedation are covered, as are oral ing with the difficult-to-manage fearful pa- sedatives—with emphasis on benzodi- tient has long plagued the profession, and azepines and specifically the use of triazolam one of the major challenges of dentistry is (Halcion) for conscious sedation to control apprehension control. Fear and pain control fear and apprehensive. are closely related. Fear of future treatment is Oral surgery is somewhat traumatic for all often the result of lack of pain control in past patients. Because of this, many oral surgeons appointments. Pain control is most often will suggest deep intravenous (IV) sedation/ achieved with local anesthesia. According to general anesthesia for even simple surgery Weinstein,2 patients report the incidence of procedures. Most of the in-office surgery pro- failure of the local anesthetic injection to be cedures can be done with local anesthesia; as high as 26.4 percent. It is suggested that however, many patients prefer some form of fear has a high correlation with those who sedation for their surgery. The surgery is eas- have anesthetic-related problems.3 ier and faster for the surgeon if the patient is About half the U.S. population avoids comfortable. The use of nitrous oxide/oxygen yearly dental care. Between 6 and 14 percent

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of patients avoid any treatment whatsoever patients receiving general anesthesia, and because of fear. This phenomenon is not rightfully so. It is a little late to start buying unique to the United States. Others have equipment and getting training when a pa- shown similar problems in Sweden and tient is unconscious. General dentists admin- Japan.4–6 istering oral conscious sedation need training Government regulations that dictate who and special equipment. can and cannot be hospitalized (Medicare, As we discuss triazolam, it will become Medicaid) and the threat of litigation have obvious that the chance of problems arising caused many dentists to avoid providing with this drug, when it is used properly, is dental treatment on all but the most cooper- very slight. But even if complications should ative and easily managed patients. Some occur, with the availability of a selective re- dentists refuse to see those patients unable to versal agent, flumazenil (Romazicon), we re- receive dental care in the usual manner.7 verse the effect that is going beyond the lev- In the late 1990s and early 2000s the els we wanted. As you will see later, greatest barrier to using sedation has become flumazenil is reported to rapidly reverse the dental politics. The target is primarily oral sedation of benzodiazepine drugs, much as sedation and those practitioners who provide naloxone (Narcan) does the opiate drugs. this service. The American Dental Associ- Various forms of oral sedation have been ation’s committee H proposed guidelines used by dentists to help apprehensive pa- that were passed by the ADA House of tients. Patient comfort can be achieved by Delegates in 2004, severely limiting the use the practitioner who uses oral sedation, of oral sedatives. Many states’ licensing bod- and/or nitrous oxide to allay patient’s anxiety ies have started adopting these guidelines. and apprehension. Anxiolysis (a relief of anx- The American Association of Oral and iety) also decreases the likelihood of stress- Maxillofacial Surgeons has encouraged state induced medical emergencies. The difficulty licensing boards to limit the use of oral seda- of using oral agents is the time it takes to get tion. In one letter sent to state boards, they an effect. Since these drugs must be swal- suggested that the use of oral sedation lowed and absorbed via the small intestine it should have the same certification required often takes over an hour to get the drugs into of IV sedation. the circulation and see the maximum effect. In this chapter, considerable space is spent referring to the patient who is unconscious, asleep, dozing, and napping—and explaining What Are the Levels of Sedation? why I am not comfortable with such a pa- Sedation needs to be matched to the level of tient. On the other hand, the patient who is apprehension along with the physical and orally sedated but awake and will respond to mental stimulation the patient will have to verbal directions is a safe patient. So long as endure while their dentistry is being pro- this patient remains conscious, the operator vided. Apprehension control is a continuum can relax and enjoy performing dentistry. of the levels of sedation—from no sedation With a proper preoperative evaluation, care- through general anesthesia. A patient with ful use of the right drug and calculation of minimal apprehension and a short simple its dose, a dentist should never have a patient procedure will need less help than a severely lose consciousness; that is, “go to sleep.” phobic patient who will be undergoing a Should this occur, all else should cease until painful, lengthy, noisy, stressful procedure. the patient is again verbally responsive or The levels have been named anxiolysis, mod- awake. Some states have regulations dictating erate sedation/analgesia, deep sedation, and dentist training and equipment for treating general anesthesia. 2879_Koerner_Chap 08 4/17/06 1:30 PM Page 223

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Anxiolysis is a drug-induced state during be able to maintain their airway and may which the patient responds normally to ver- need an assist to maintain adequate ventila- bal commands. Their cognitive functions tion. This level requires advanced training and coordination may be impaired, but ven- for the practitioner, as protective reflexes are tilatory and cardiovascular functions are nor- now obtunded or absent. Cardiovascular mal. This level could be compared to a glass function is maintained. or two of wine. These patients are exposed to General anesthesia is a complete loss of little, if any, risk. Anxiolysis may be protec- consciousness. Often patients will need help tive for patients with mild to moderate med- to maintain their airway, and their respira- ical conditions that can worsen due to the tory function may need assistance. They stress of dentistry. This level of sedation is will have lost the protective swallowing, gag, achieved with light oral sedation and/or ni- and laryngeal reflexes. General anesthesia can trous oxide/oxygen sedation. be achieved by the inhalation of potent Moderate sedation/analgesia is a bit anesthetics, with IV drugs, with oral deeper; the patient will respond to verbal drugs if high enough doses are given, or a commands, but you might have to add light combination of these. It is imperative if this tactile stimulation to get a response. They level is achieved that the practitioner is are able to maintain their airway, and spon- capable of monitoring the patient’s vital taneous ventilation is adequate. Their cardio- signs, maintaining the airway, assisting vascular system is normal. This level of seda- respiration if necessary, and handling all tion is most often achieved with an oral the various life-threatening emergencies sedative, but light IV sedation could also that can occur. Children are much more dif- achieve these levels. ficult because they are less forgiving of alter- Deep sedation/analgesia takes a patient ations from normal. Their respiratory physi- to a level where they respond only after re- ology has a narrower margin of safety (see peated or painful stimulation. They may not Figure 8.1).

Figure 8-1. This chapter will discuss only area 1 of the spectrum of anesthesia. Areas 2 and 3 require advanced training and come with greater risk to the patient. 2879_Koerner_Chap 08 4/17/06 1:30 PM Page 224

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How Safe Is Sedation? Further complicating the question, “To Dentists with proper training can perform Sedate or Not To Sedate?” is the fact that oral sedation safely and effectively. Most nearly all dentistry is elective. It is very rare dental therapy can be accomplished on pho- to face the situation in which a life will be bic patients using local anesthesia and seda- lost if treatment is not initiated. A nerve may tion. Therefore, adequate use of local anes- die; a tooth may be lost; all the teeth may be thesia must be considered as the first step of lost; but the patient will still be alive and rea- not only pain control but also anxiety con- sonably healthy. It is very difficult to accept a trol. Many central nervous system (CNS) dental procedure where there is even a slight depressants can alter the level of conscious- risk of death. This is not to say that there is ness. Most of these can produce a hypnotic not a very slight risk with even the most sim- state if given in higher doses, but only a se- ple procedures. Even administration of local lect few can actually produce a complete anesthesia has resulted in death. But, what- state of general anesthesia. ever we do, safety protocol is of the utmost The potential for complications is not importance (see Figure 8.2). limited to the general anesthetic state. It may Sedation and deep sedation/general anes- accompany any degree of drug-induced thesia has a remarkable safety record; how- CNS depression. Respiratory and cardiovas- ever, there have been studies showing that cular depression are the most feared compli- the deeper the sedation, particularly when cations. Respiratory depression represents the administered to medically compromised pa- principal negative variable introduced with tients such as the very young and the elderly, conscious sedation and, left unrecognized the greater the risk. Dionne reported that and untreated, is the cause of most serious overall mortality in the United States associ- complications. ated with general anesthesia, based on self-

Figure 8-2. The relative risks of various forms of sedation anesthesia. Because of the high levels of oxygen, 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. 2879_Koerner_Chap 08 4/17/06 1:30 PM Page 225

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report of oral surgeons, has ranged from is about as complex a cognitive activity as 1:740,000 to 1:349,000; however, self- they should attempt. It should be stressed to reporting is usually given little credence be- the patient that although they might feel cause not all cases are acknowledged. A more normal, their reflexes could still be de- credible study came out of records from the pressed. They need to take the remainder of United Kingdom, where the overall mortal- the day off. ity risk was 1:248,000 for general anesthesia It should be mentioned that some of the and 1:1,000,000 for conscious sedation. benzodiazepine drugs are initially bound to Only very low risk could be determined for plasma proteins. This binding tends to re- local anesthesia.8 verse about six hours after administration. The risk of sedation and anesthesia can be This phenomenon is known as a “second dramatically decreased with modern moni- peak effect.”10 When using most benzodi- toring devices and the use of persons trained azepines, it is necessary to inform our pa- in monitoring and administrating anesthesia. tients that they will experience an increase in It has been shown that the risk of anesthesia sedation about 5–8 hours after leaving the is dramatically reduced when a separate prac- office. Interestingly, even after this time, titioner trained in general anesthesia admin- blood concentrations of active drug have isters and controls the sedation/anesthesia. In been reported to be close to 50 percent of the case of two-operator administered anes- what they were during sedation. For this rea- thesia, the risk went from 1:248,000 to son, it is imperative that they not undertake 1:598,000.9 This is particularly true when any activity requiring cognitive or coordina- treating patients with underlying medical tion skills the rest of the day. Because of the problems. long half-life of diazepam (Valium), some practitioners have felt there was reason for some concern even the next day. Patient Ambulation A problem that was unique to dentistry but is now affecting our medical colleagues who Drug Selection use day surgery is the need for rapid ambula- Our choice of drugs is guided by considera- tion. We need to get our patients back to a tion of elimination half-lives and side effects. state that allows them to leave the office in a When we examine sedative systems, we find timely manner. Their reflexes need to be a continuum of effects from slightly notice- such that they can walk unassisted after a able changes through more profound seda- short period of time, even though this au- tion to general anesthesia, eventually leading thor insists that another adult take their arm to death, if enough drug is administered. for additional support. It may be wise to use “General anesthesia is less safe than con- a wheelchair to transport the patient from scious sedation, which is less safe than local the dental chair to their auto. They should anesthesia.”11 not drive, undertake any task that might be It is our goal to choose a sedation system hazardous, be placed in a position of respon- with a very wide difference between desired sibility (for example, taking care of children), effect and death in a very broad range of pa- or make important decisions. Even climbing tients. It is ideal if the effects of the drugs stairs should be avoided. They need to be ac- can be reversed at will if our system seems to companied and supervised by a responsible be getting out of control. adult for the rest of the day, during which It is also our goal to create a state of tran- time their activities should be very limited. quility that will allow the patient to comfort- Operating the remote control of a television ably undergo the needed procedure. If we 2879_Koerner_Chap 08 4/17/06 1:30 PM Page 226

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can alleviate apprehension without changing sants and some have unwanted depressing any of the patient’s other parameters, we effects on respiratory and the cardiovascular have achieved success. In fact, we always systems. The combination of all these effects cause some change in our patients’ physiol- can lead to problems that are hard to predict ogy; however, with modern drugs these and even more difficult to control and treat. changes are much less hazardous than what However, if only one agent is used, the side was accepted a few years ago. effects are often more predictable and more treatable. It is easier and safer to use a single agent, Routes of Drug Administration as we then only have one set of side effects. In attempting to create a state of tranquility, This assumes a single agent will provide the we must get a certain concentration of agent needed result at a concentration where few to the appropriate location in the central side effects are present. When Dionne nervous system. When considering routes, looked at drug mixtures used by 264 den- we should consider patient comfort, time to tists, he found 82 distinct combinations.12 achieve effect, control of the effect, ease of He said, “The scientific basis for the use of administration, the skill needed for adminis- such a diverse group of agents and combina- tration of the drug, necessary equipment for tions is unclear.”13 administration, and monitoring of the pa- tient. Unfortunately, we must also consider INHALATION SEDATION medical-legal questions of insurance and reg- ulation by governmental organizations. The inhalation route of administration offers In general, the faster the drug reaches the a major advantage when we consider an CNS and has an effect, the better the control overdose. By removing the source of the we have over the sedation. By titrating for ef- drug (having the patient breathe room air or fect, we can give just that amount of drug 100 percent oxygen), the patient will excrete that is necessary to control apprehension. most inhalation agents via the lungs, thus re- Both intravenous and inhalation agents can versing the overdose. be readily controlled in this manner. Other routes of administration require administer- ORAL SEDATION ing an appropriate dose and waiting up to an hour to see the desired effect. These routes Several factors come to light when we con- require very specific dosages, usually associ- sider oral sedatives. The time from ingestion ated with body size. They require conserva- to sedation becomes very important. For any tive dosages, as hypersensitivity to a medica- effect to take place, the drug must be ab- tion will not be obvious until it is much too sorbed into the bloodstream and delivered to late to adjust the dosage. It is imperative that the site of action, usually thought to be in a drug with a very wide range of safety be the central nervous system, in sufficient used when these slower routes of uptake are quantities to be effective. Some drugs can utilized. Ideally, we will have reversal agents be absorbed sublingually; others must be that can deactivate the drug in the case of swallowed and absorbed from the small in- overdose when using these routes. testine. Depending on the time necessary We, in dentistry, have used and continue for absorption, it might be necessary to have to use a variety of agents and combinations the patient take the drug at home before of agents. Multiple agents often complicate coming to the office. This author prefers to the treatment, as each has side effects that administer the drug in the office because can be additive. They all are CNS depres- then you know how much was taken, when 2879_Koerner_Chap 08 4/17/06 1:30 PM Page 227

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it was taken, and by whom it was taken. will see that all is not lost for the phobic You don’t have to worry about the patient patient. trying to drive to the appointment as the drug starts to take effect, and should there NITROUS OXIDE be a reaction to the drug, the patient is in the office where aid can be administered. Nitrous oxide is possibly the safest of all seda- One downside is that because it will take tives. It is estimated that close to 40 percent 45 minutes to one hour to get the desired of dentists are equipped to administer nitrous sedation, it is time-consuming to titrate or oxide. It has been used in dentistry for more alter the dose if a patient is not adequately than 150 years. Trace nitrous oxide released sedated. into the air of the dental office, and its effect on the dental staff, however, must be consid- INTRAVENOUS SEDATION ered. It is recommended that there be post- operative oxygenation for not only nitrous With the regulations that are now in place in oxide but also other sedatives. If one is look- many states, it is nearly impossible for the ing for a very safe anxiolytic drug from which average general dentist to use intravenous se- the patient recovers quickly and with which dation. Many states require a 60-hour course the patient is able to drive to and from the with 20 patient sedations in addition to any office, nitrous oxide is the only choice. training that was received in dental school. Intravenous sedation has several advantages, ALCOHOL however. When giving a drug IV, one slowly titrates the amount to the level of sedation Alcohol has been used by some patients for desired. For most drugs, these effects began years to help with their dental treatments. It to diminish in a short period of time—first, is not unusual for a patient to self-medicate due to redistribution to other tissues in the with a bit of liquid reinforcement before body (primarily fat stores), and then more coming to an appointment. It is important slowly as the drug is metabolized into inac- when considering the use of sedatives for tive forms or eliminated in the urine or apprehension control that patients be feces. warned against using any other substance Although this should be the safest route that is a central nervous system of administration, it is possible to go from depressant. The combination of benzodi- conscious to deep general anesthesia in a azepines and alcohol has lead to very serious matter of seconds. Although this should be a respiratory depression and death. very safe technique, this is where we are see- ing deaths. CHLORAL HYDRATE

This drug has been a favorite, particularly for Drug Options children. Evidence is emerging, however, that Historically, many drugs and routes of ad- indicates it may not be as safe as we believed. ministration have been used to control ap- Chloral hydrate’s sedative action comes from prehension in dental offices. As stated earlier, its metabolite, trichloroethanol. The peak ac- insurance companies, state regulatory bodies, tivity occurs in the plasma within 20 to 60 and other entities have all but eliminated minutes after oral administration. Its half-life intravenous sedation from the armamentar- is 4–12 hours. It acts primarily on the CNS ium of general dentists. If we look into and has little effect on the respiratory and other methods of sedation, however, we cardiovascular systems of healthy patients. 2879_Koerner_Chap 08 4/17/06 1:30 PM Page 228

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In higher doses, chloral hydrate becomes While the names are different they are more a cardiac irritant. There have been several re- similar than different in their effect (beyond ported cases of overdose leading to hypoten- uptake and deactivation times). Dentistry sion. In one report of two patients, when has several BZDs that are ideal for use with this hypotension was treated with cate- apprehensive patients, and the effect can be cholamines or agents that released cate- tailored to the time necessary to perform the cholamines, both patients experienced car- procedures being contemplated. One, triazo- diac arrest; one survived, the other did not. lam, is well suited to dentistry. Triazolam Any other CNS depressant will enhance the came to market as a sleep aid and has be- sedation-depression of chloral hydrate, in- come very popular and controversial. cluding nitrous oxide and narcotics.14 Triazolam will be discussed in detail. Deaths have occurred in combination with local anesthetics when used with small chil- THE TWO MOST USEFUL SEDATIVE dren. It is thought that often this is due to DRUGS FOR THE GENERAL DENTIST using a toxic dose of local anesthesia: four cartridges—one for each quadrant to be Nitrous oxide has an interesting history. treated. Even two cartridges of local anesthe- Originally it was used as an attraction at sia can be a toxic dose for small children. public science shows. It was at such a pro- gram that a dentist, Horris Wells, saw a par- BARBITURATES ticipant in a nitrous frolic receive a serious injury causing a dramatic wound . . . with Barbiturates were the standard antianxiety no pain. He took this knowledge to his of- agent for both medical and dental patients fice and began offering painless dentistry for many years. Barbiturates make a patient using nitrous oxide as a general anesthetic. drowsy, and sleepy patients tend to be less Its history as a general anesthetic has apprehensive. In larger doses, barbiturates brought dentistry some criticism. Nitrous have the potential to render patients asleep. oxide is a weak anesthetic agent. At one at- It is in this way that the short- and ultra- mosphere of pressure, 80 percent nitrous short-acting barbiturates were used as induc- oxide is usually considered to be the mini- tion agents for general anesthesia and for mum concentration that will achieve general very brief general anesthetics. anesthesia. Even at this concentration, it is The ratio of the dose necessary for sleep not possible to render some patients uncon- and the dose that will end in death—the scious. If we go to a higher concentration, therapeutic index—is usually stated to be a we begin to encroach on the 21 percent oxy- factor of two, as compared to diazepam, gen found in the atmosphere and expose our with a ratio of 20.15 Unfortunately, barbitu- patients to hypoxia. rate drugs in higher doses tend to be potent The standard of the past was to watch the cardiac and respiratory depressants. Because patient’s color. When they began to show a of their addictive nature, they are not admin- blue tinge of cyanosis, the procedure was istered for long-term anxiety control.16 started. (I like to state, tongue in cheek, that dentists hoped the pain of the extraction BENZODIAZEPINES would restart the heart.) Anesthetics were very short. One tooth in the forceps, one in Benzodiazepine (BZD) drugs come in many the air and one hitting the bucket, simulta- varieties. They differ in the rapidity that they neously, was the goal. Actually, many general take effect, the time it takes for them to wear anesthetics were done by this technique with off, time to peak blood levels, and half-lives. an amazing safety record, which may be 2879_Koerner_Chap 08 4/17/06 1:30 PM Page 229

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more testimony to a patient’s desire to live the patient until the hallucination is over. than to the safety of the procedure. Today, Use their first name and remind them they this hypoxic anesthesia technique would be are in the dental office—that they should severely criticized, as it should be. relax and will be back to normal in a few Because nitrous oxide is absorbed and re- minutes. moved from the blood stream via the lungs Another potential problem deserves men- essentially unchanged, nitrous oxide is a very tion—that of sexual aberrations. A certain safe sedative. But its major disadvantage—its number of female patients will experience relative weakness—is also its major advan- sexual feelings while on nitrous oxide.17 This tage. Although sedation with nitrous oxide is can happen at relatively low concentrations. not adequate for our severely phobic patients Some patients describe the sensation of a because it is such a weak anesthetic agent, sexual orgasm. It is not all that easy to iden- there is little risk of sedation rendering the tify when this is taking place. However, if it patient unconscious—that is, in a state of looks like a duck, walks like a duck, and general anesthesia. However, it is not impos- quacks like a duck, the chances are we are sible. I have had two patients in 40 years observing a duck. This may, in fact, be the who were under general anesthesia with very ultimate distraction to dental treatment. modest concentrations (less than 40 percent) Fortunately, it is very rare. For this reason it nitrous oxide. Neither had taken any other is important that a male dentist, hygienist, or drugs. If the patient is not responding even assistant always be accompanied by a female at low concentrations this might be the dental assistant when treating female patients problem. The mask should be removed and with nitrous oxide. This phenomenon has the patient allowed to breathe room air or never been documented in male patients. just oxygen. A potentially more serious problem can Our primary concern in anesthesia is the arise if we treat chronic obstructive pul- loss of swallowing and laryngeal reflexes that monary disease (COPD) patients with ni- can lead to regurgitation of stomach con- trous oxide. Should a patient be overdosed tents and aspiration of the low-pH stomach with nitrous oxide, it is a simple matter to contents into the lungs. So long as a 50 per- remove the source of the gas, and provided cent concentration of nitrous oxide is not ex- the patient is breathing, they will eliminate ceeded, there is little chance of general anes- the excessive concentration of nitrous oxide. thesia or other complications. If they are not breathing, we should be ready The complications that may arise are not and able to assist their respiration. This serious ones. Occasional vomiting may be would be a very unusual complication and seen, but since our patients are always con- probably would suggest the patient had scious, this is not serious, as protective laryn- other sedatives or was given excessive nitrous geal reflexes are present. The patient is oxide (greater than 80 percent). It should be definitely uncomfortable, and vomiting cer- stressed that nitrous oxide is a very safe seda- tainly can be messy, but it is usually not life- tive for almost all patients, provided equip- threatening. ment has been properly installed and main- Patients will occasionally hallucinate with tained. nitrous. Again, this can be uncomfortable for them. Treatment consists of removing the Nitrous Usage source of nitrous oxide and reassuring the patient, typically by telling them they are all It is estimated that about 50 percent of den- right and will return to normal in a few tists have the equipment to administer this minutes. It is helpful to repeatedly assure mix and that more than 424,000 dental per- 2879_Koerner_Chap 08 4/17/06 1:30 PM Page 230

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sonnel are exposed to the trace amounts of where nitrous oxide was used. The studies gas as a result of its administration.18 did not suggest at which level exposure be- Many dental and dental hygiene schools came a problem. now take a very cautious attitude toward the use of nitrous oxide. This has come about Occupational Hygiene Agencies because of the publication of a number of papers concerned with the effect of waste There are three governmental bodies associ- gases on office personnel, particularly those ated with setting appropriate levels of expo- who are pregnant. sure to chemicals: OSHA, NIOSH, and The first indication that anesthetic gases ACGIH.36 The NIOSH publication, Alert, might be a problem for humans was a report suggests the recommended exposure limit in 1967 by Vaisman, who studied Russian (REL) of 25 parts per million (ppm) on a female anesthesiologists and reported that 18 time-weighted average (TWA) of 25-ppm. of 31 pregnancies ended in spontaneous These levels were recommended after review- abortion.19 Studies have shown similar prob- ing two studies by Bruce.37, 38 lems in U.S. operating rooms.20 It was clear the operating room had the potential to be a The Problem Studies hazardous place to work, but it was not clear which chemicals were the causative agents. The TWA level of 25-ppm came from two studies done by Bruce, Bach, and Arbit. In Animal Studies the first study, a difference was shown when subjects were exposed to 50-ppm nitrous Potent anesthetic agents have been shown to oxide with 1-ppm halothane but not to 500- have teratogenic effects in animal studies. ppm nitrous oxide, except for a digit span Because nitrous oxide was part of many test.39 The second study showed a slight ef- anesthetic administrations, it needed to be fect to subjects exposed to 500-ppm nitrous evaluated. Many studies showed problems oxide for four hours.40 Note that Bruce re- for animals exposed to high levels of nitrous canted this study as flawed in two letters— oxide.21–31 It was shown that nitrous oxide one in 1983 the other in 1991. He stated, decreases vitamin B12, which can impair DNA synthesis.32 These studies hint that if “Several years later, we learned that the levels are kept low enough the problems most of the subjects we studied were a can be lessened. unique population that used no mood altering substances and as such, might Retroactive Human Studies have been abnormally sensitive to depres- sant drugs such as nitrous oxide and The dental office was an ideal study site as halothane. There is no longer any need there were two types of offices, those that to refer to our conclusions as ‘controver- used nitrous oxide and those that did not. sial.’ They were wrong, derived from data Cowen did two such studies in conjunction subject to inadvertent sampling bias and with the American Dental Association. not applicable to the general population. These studies suggested there is a problem The NIOSH standards should be with higher levels of exposure for pregnant revised”.41,42 staff.33, 34 Although there may be some problems with these retrospective studies,35 Many papers have been published in the they did point to a concern for females who dental literature that mention the motor skill were pregnant and working in dental offices effect, which was not shown for just nitrous 2879_Koerner_Chap 08 4/17/06 1:30 PM Page 231

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oxide in either study. These two studies and scavenging devices being used in practicing the publications of NIOSH that arose from dental offices can achieve levels in the 40 to these studies have been referenced in so 60 ppm range.48 many dental journals they have become fact, ignoring the two retraction letters. After a How Can Levels Be Controlled? paper is published, it is very nearly impossi- ble to retract the paper. It is clear that offices should have one of the available scavenging systems on each nitrous What Is a Safe Level of Exposure? oxide/oxygen unit. Today’s scavenging sys- tems are predominantly systems with suction What studies have been done with humans placed on the mask over the pop-off valve. that suggest appropriate exposure levels? Some systems attempt to suck up additional Ahlborg showed Swedish midwives exposed air that is around the mask, and they may re- to nitrous oxide and shift work had no diffi- move traces of nitrous oxide that the patient culty getting pregnant unless they used ni- exhaled through their mouth or that leaked trous oxide 30 or more times a month to as- from around the mask. sist with deliveries.43 In another study of Every nitrous machine must have a scav- midwives, he showed no increase in sponta- enging system with adequate suction. There neous abortions with exposure to nitrous should be a reasonable exchange of air in our oxide, but he saw an increase with night dental offices. Outside air should be brought shifts, high work loads, and no nitrous.44 into the office by our heating and cooling Sweeney performed a study on 20 practic- systems. It is suggested that the minimum ing dentists. The exposures ranged from air exchange is five changes per hour, al- 50 ppm to more than 5,000 ppm on a though is it recognized that 15 to 20 changes time-weighted average. The only depression per hour is better. Hoses and connectors seen was in three dentists with exposure of should be checked for leaks. Masks should more than 1,800 ppm. To set levels that be selected that fit the patient, and the pa- would ensure safety, Sweeney suggested tient should be discouraged from speaking we should not exceed 450 ppm on an while receiving nitrous oxide sedation. If all 8-hour.45, 46 these suggestions are followed, it is possible Rowland looked at the ability of female to stay in the 50-ppm range49—well below dental assistants to become pregnant (fe- the 450-ppm exposure level suggested by cundability). He showed no problems if several authors. scavenging was used.47 These two studies strongly suggest that if we use scavenging OXYGENATION AFTER NITROUS OXIDE and keep levels below 450 ppm, the dental OXYGEN office staff is at no risk. Oxygen is the one drug that should be avail- What Levels of Exposure Can Be able in all dental offices. Oxygen can be used Achieved? with little regard for side effects or other problems and should be available in every Early studies showed that the Brown mask, a office as part of the emergency protocol. mask within a mask with suction, could There are exceptions to this generality and achieve levels of 50 ppm under ideal settings. times when it should not be used. For exam- OSHA reviewed these data and suggested ple, oxygen should be used cautiously for that since this was achievable, it should be COPD patients (severe emphysema). If a our goal. Donaldson has shown that many COPD patient’s disease has progressed to its 2879_Koerner_Chap 08 4/17/06 1:30 PM Page 232

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final stages, his or her breathing may be on An overriding reason for leaving a patient an oxygen drive—not the primary carbon on oxygen, however, is to scavenge the gas dioxide drive. Giving high levels of oxygen the patient is exhaling. With our present to one of these patients could cause him or knowledge of the risks of trace contaminants her to go into respiratory arrest. These pa- of nitrous oxide, we believe we should leave tients are normally quite easy to identify be- our patients on 100-percent oxygen for five cause of their obvious respiratory difficulty. minutes to ensure that the nitrous oxygen Oxygen is routinely administered after they exhale is removed from the atmosphere general anesthesia when nitrous oxide was we breathe. However, if a patient ever be- used in order to avoid diffusion hypoxia. comes unresponsive while on 100-percent This phenomenon was first described by oxygen, remove the mask. It may be that the Fink to explain a transient hypoxia after gases have been switched. anesthesia in conjunction with nitrous oxide.50 Nitrous oxide would diffuse out of Respiratory Effects of Drugs the blood and fill the alveoli of the lungs and the rest of the respiratory tree. Nitrous oxide Used for Sedation crosses from the blood to the alveoli of the Sedation can be performed safely and effec- lung much more quickly than either oxygen tively by dentists with proper training. or nitrogen, and thus, nitrous oxide would Respiratory depression is the principal con- tend to fill the dead space in the lungs. On cern when sedation is administered. If we are the first inspiration of room air, the patient going to get into trouble, the most likely would have a mixture of nitrous oxide from cause will be due to respiratory depression or the dead space (150cc of 100 percent nitrous respiratory inadequacy due to airway ob- oxide) and 350cc of room air. In theory, this struction. would result in hypoxia that could be a In all cases of dental sedation, patients problem for a sick patient, a patient with a should remain awake. If the patient tends to compromised respiratory system, or a patient fall asleep, they should be awakened. General with respiratory depression due to the anes- anesthesia has been described as great thesia drugs. In the case of general anesthe- amounts of boredom occasionally dispersed sia, this could be a serious issue. with moments of stark terror. Unless you are What is the harm in using some oxygen? well equipped, well trained, and certified, Nothing, unless the two gas lines have been you do not want patients to be unconscious. switched. In such a case, although the ma- It is not possible to tell napping, dozing, or chine reads 100 percent oxygen, it is in real- sleep from general anesthesia without trying ity delivering 100 percent nitrous oxide. to wake the person. If the patient awakes, There are many ways this can happen. One keep them awake. If they do not awaken, case occurred in a surgery practice using gen- you are not doing conscious sedation. The eral anesthesia and resulted in the death of a patient is under general anesthesia. If the young, healthy, adult patient. patient is not awake, you need to reverse the You can use a pulse oximeter to investi- sedation. gate the need for oxygen after nitrous oxide/ With some drugs, our concern may be oxygen administration. One study failed to that we have depressed the respiration to the show any drop in oxygen saturation if the point that an adequate exchange of gas is not mask was simply removed at the end of the taking place. The presence of an open airway appointment where nitrous oxide had been should be established, evaluation of the level used.51 The study has now been repeated by of respiration assessed, and vital signs should others with the same results.52, 53 be taken. It should be noted that several 2879_Koerner_Chap 08 4/17/06 1:30 PM Page 233

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studies have shown that watching the chest discussion. Yet, it will review a minimal level and/or reservoir bag move is not adequate to of knowledge that we should have when ensure an adequate minute volume. Skin using sedative drugs. color has been relied on in the past as a way Our breathing is controlled by several of ensuring adequate tissue profusion. The mechanisms. When we consciously take a arterial oxygen level can be dangerously low, breath, we have conscious control. Normally, however, before we see the blue tinge of though, our breathing rate and depth are cyanosis. Cyanosis is no longer considered to stimulated by carbon dioxide (CO2), a by- be an adequate monitor of arterial oxygen product of our metabolism. CO2 alters the levels. A pulse oximeter and/or capnograph hydrogen ion concentration, or the pH of are invaluable in assessing the adequacy of our blood. This pH change is the primary ventilation (see Figures 8.3 and 8.4). stimulus to breathing (see Figure 8.5). Breathing is also stimulated, to a lesser ex- tent, by low concentrations of oxygen. Many Physiologic Basis of Ventilation drugs affect the CO2 drive, but nitrous oxide To properly appreciate the importance of depresses the secondary drive because of a monitoring respiration along with reviewing lower oxygen level (see Figure 8.6). the respiratory advantages of benzodiazepine The solution to the aforementioned prob- drugs, we need to review a topic we all stud- lems lies in several areas. We should use ied in dental school but most likely have not drugs that minimally depress respiration. thought about since then—respiratory physi- Avoid combinations of different drugs that ology. This is not intended to be a complete affect several things at once. Monitor the

Figure 8-3. Early dental anesthesia with nitrous oxide was monitored by the patient’s color. Pink was awake. Slight cyanosis was time to do the extractions. Deep cyanosis was time to give oxygen. 2879_Koerner_Chap 08 4/17/06 1:30 PM Page 234

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

Figure 8-5. Food is oxidized in our bodies and becomes CO2 and water. The CO2 is absorbed in the water 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 ion is 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 is blunted, forcing them to breathe on oxygen drive. The oxygen drive is depressed by nitrous oxide. High

levels of O2 can do the same.

234 2879_Koerner_Chap 08 4/17/06 1:30 PM Page 235

ANXIOLYSIS FOR ORAL SURGERY AND OTHER DENTAL PROCEDURES 235

lortnoc yrotaripseR yrotaripseR lortnoc lortnoc 3 voluntary, yrotaripser irritant receptors retnec

H+ OCH 3 - H CO ni sp ri ota ry 3 2 3 COO + H aera 2OC 2 + H 2O 1 ac or dit dob y O2 < 06 RROT citroa b ydo yretra naivalcbus yretra

nommoc 2 oc rotid a r et ry hcterts recept ro s 4

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. Stretch receptors send an inhibitory signal to the respiratory center. The diaphragm relaxes, and the elastic fibers of the lungs cause them to collapse, forcing the air out. The mechanism can be stimulated by

high hydrogen ion concentrations, low pH, high CO2 concentrations, or low O2 levels.

patient to ensure that adequate arterial oxy- percent is preferred. Although oximetry is gen levels are maintained and that CO2 lev- not equivalent to capnography, it is valuable els do not increase. Hypoventilation is char- in alerting the dentist that ventilation is acterized by a reduction in arterial oxygen depressed.54 tension and an elevation of CO2 tension. The importance of monitoring a patient’s With the advent of pulse oximetry, it is now respiration cannot be overemphasized. If a possible to easily monitor oxygen saturation patient is awake and responding to verbal of hemoglobin. commands, we can assume the patient is Pulse oximetry shows the oxygen satura- safe. If the patient is unconscious (asleep?), tion of hemoglobin. In addition, most ma- we must have more concern. Several studies chines also display pulse rate. Knowing the of medical and dental anesthesia have shown saturation of hemoglobin, one can approxi- inadequate ventilation to be the most com- mate the arterial oxygen tension, assuming a mon cause of death or brain damage. As normal pH of the blood. Although 90 per- practitioners, we must be prepared to moni- cent saturation provides reasonable assurance tor and assist respiration should it become of adequate arterial oxygen tension, 95 necessary. 2879_Koerner_Chap 08 4/17/06 1:30 PM Page 236

236 CHAPTER 8

THE RESERVOIR BAG CAPNOGRAPHY

In the 1960s, watching the reservoir bag was Capnography is very sensitive to respiratory used on several popular television programs depression or apnea. This equipment meas- as a means of determining when it was time ures the CO2 of a patient’s expired gas. It to discontinue surgery and give condolences then gives a reading of the concentration of to the next of kin. We have now all been CO2 in these gases. This information can be taught via television to read electrocardio- invaluable when monitoring patients with graphs (ECGs) and to recognize flat line. respiratory problems or those undergoing Some feel the movement of the bag can be general anesthesia, but it is not necessary for used to monitor respiration. There have the sedated patient. been several studies that show one should not depend on movement of the bag as an BENZODIAZEPINES accurate indication of the adequacy of respi- ratory exchange. It will indicate respiratory It was established that barbiturates, mepro- rate. bamate, and alcohol all affect the chlorine channel in brain neurons. They hyperpolar- PULSE OXIMETER ize the neuron, increasing its threshold for depolarization. Benzodiazepines act at a dif- The advent of an affordable pulse oximeter ferent but closely related site. Alcohol, barbi- has made our lives much easier and patients’ turates, and meprobamate all act at the same lives more secure. By passing two different site, and all put animals to sleep with only frequencies of light through various tissues, modestly higher doses than are required for reading the absorption of the two frequen- sedation. cies, and evaluating these differences, a pulse It was shown that all these drugs interact oximeter can determine the percentage of with the neurotransmitter gamma amino oxygen saturation of the arterial blood with butyric acid (GABA). When GABA binds great accuracy. In addition to O2 saturation, with a receptor site on the neurons, it slows most equipment also shows pulse rate, and the neuron’s rate of firing. It serves to modu- some shows a pletysmograph of the pulse late the nervous system. wave. The use of such monitoring has made Specific benzodiazepine receptors exist in general anesthesia much safer and, conse- the brain. If either GABA or a benzodi- quently, has decreased the frequency of tragic azepine is present, the other’s binding ability outcomes. is enhanced. Thus, the effects of the benzo- However, there is at least one possible diazepines are explained by the increased caveat to their use: If a patient is given sup- activity of GABA.55 56 plemental oxygen, his or her hemoglobin The receptor sites are concentrated in saturation will approach 100 percent. In pa- parts of the brain that regulate emotional be- tients with severe respiratory complications, havior. The advantage to benzodiazepines is oxygen saturation could be normal even their ability to relieve anxiety. They produce though exchange rates were inadequate to some drowsiness and, unfortunately, are cleanse the blood of CO2. This could lead somewhat addicting. Tolerance develops to high CO2 levels and result in low pH with continued use, and withdrawal occurs of the blood. This potential problem can when the drug is stopped. However, the ex- be circumvented by limiting sedation to tent of tolerance and withdrawal are less patients with no significant respiratory than what is seen with barbiturates. problems. Historically, we have used barbiturates 2879_Koerner_Chap 08 4/17/06 1:30 PM Page 237

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

and narcotics, both of which have significant have a noticeable respiratory depressant ef- effects on respiration and circulation. The fect in higher doses. most clear-cut advantage of the single-agent, benzodiazepine sedation is the fact that over- THE ADVANTAGES OF ORAL TRIAZOLAM doses are rarely lethal. In the case of barbitu- SEDATION rates, the lethal dose is only a few times greater than the dose necessary to cause sleep Oral sedation with triazolam is simple to (see Figure 8.7). administer, and because of the nature of To deactivate most oral sedatives, we must the drug, it is convenient and safe to use. wait for the drug to be excreted or metabo- Triazolam is readily available from any phar- lized. In the case of diazepam it is metabo- macy. Reports of adverse drug reactions are lized in liver to another sedative, oxazepam rare and tend to be relatively mild. A major (Serax), which is available as a long-term plus for all oral sedatives is that it is not nec- sedative on its own. Triazolam, along with essary to administer an injection or start an midazolam (Versed), have the shortest half- intravenous line. (The last thing most pho- life of the benzodiazepine drugs; both are in bic patients need is a needle puncture before the one- to two-hour range. Midazolam is they are sedated.) Getting an IV started in a normally considered to be an intravenous phobic patient can be the most difficult part drug, although it is being used orally and as of a dental appointment. Patients readily a nasal spray. It is available in Europe as a accept oral sedation. tablet. Unfortunately, it has been shown to Triazolam is a drug that has been around 2879_Koerner_Chap 08 4/17/06 1:30 PM Page 238

238 CHAPTER 8

for some time but has been used primarily as Another individual was found dead in a hot a sleep aid. In this context, it has received tub. It was estimated she had taken 10 bad press because of side effects that have tablets. So it is possible to overdose and die, shown up in patients who used it over an ex- but the amounts necessary are well beyond tended period of time. In the early 1990s, it what is necessary for dental sedation.66 is the most commonly prescribed sleeping Ambien (zolpidem) has been used by pill used in the United States; 7.2 million some dentists to replace triazolam. Ambien is prescriptions were written annually.57 It an agonist of the GABA-benzodiazepine should be emphasized that triazolam is not omega-1 receptor site. It has a similar half- approved by the FDA as a sedative for dental life to triazolam, but is a nonbenzodiazepine purposes.58–60 This is an “off-label” use. hypnotic of the imidazopyridine class. Some Triazolam comes close to being an ideal claim it has a little faster absorption than tri- drug for dental sedation.61 It has the advan- azolam; however, the manufacturer reports tage of being absorbed rapidly, achieving maximum blood levels occurred at 59 and peak blood levels in 1.3 hours. Its half-life is 121 minutes for 5- and 10-mg doses. It has a two to three hours. In addition, it may be up half-life of 1.4–4.5 hours to eight times more effective as a hypnotic Yagiela suggested lorazepam (Ativan) than diazepam. Yet, triazolam has very little would be an alternative to multiple doses of effect on the circulatory or respiratory sys- triazolam.67 Lorazepam has a 10–20-hour tems. Several studies have shown no changes half-life and a slower uptake. He suggested it in blood pressure, pulse, or percentage of should be taken two hours prior to starting oxygen saturation, and only a slight change treatment. Five hours later, less than half of in respiratory rate. The high incidence of the drug has been deactivated. Ten to 20 anterograde amnesia on conscious patients hours later half the effect is still present. Be further endears it to the dental practitioner. concerned about the patient driving the Patients do not have to be asleep for their day after treatment. It makes more sense to dental treatments if they can be relaxed use a drug with a shorter half-life and give a enough for us to do the required procedures supplemental dose after one to two half- and not have any memory of the proce- lives have passed. In this way, recovery dure.62–65 should be faster. Lorazepam makes sense if Triazolam’s relative lack of respiratory and you will give only one dose of a sedative cardiovascular sedation is important for drug, and you need sedation for four or safety. Safety is dependant on the ratio of the more hours. L/D 50 dose (that dose usually fatal to 50 percent of study animals) to the E/D 50 dose (concentration that provides sedation to Pharmacology of Triazolam 50 percent of study animals). The unique properties of triazolam are at- It would be ideal if this ratio were con- tributed to its chemical configuration. The stant for humans. If this ratio held for hu- nitrogen atom prevents it from being water- mans, it would take a tablet about the size of soluble. Midazolam has a carbon in this po- a bowling ball to have fatal consequences. sition and, thus, is water soluble and suitable Unfortunately, this is not true. The greater for IV administration. the difference between the E/D 50 and L/D One chlorine atom is responsible for po- 50, the safer the drug. Several patients have tency. Without this chlorine, the drug is committed suicide with triazolam. From one-fifth as potent. Larger alkyl substitutions postmortem blood samples, it was estimated also decrease potency. The second chlorine is that one person ingested 26 0.25-mg tablets. necessary for benzodiazepine action. Bromo 2879_Koerner_Chap 08 4/17/06 1:30 PM Page 239

ANXIOLYSIS FOR ORAL SURGERY AND OTHER DENTAL PROCEDURES 239

and nitro substitution are only weakly anxi- datative system, thus reducing the first-pass olytic. The nitro version is also anticonvul- liver clearance by decreased metabolism and sant, as illustrated by clonazepam. The tria- reduction in hepatic blood flow.74 The ab- zolo ring and attached methyl group are sence of an enzyme in some people can be responsible for the rapid oxidation by the idiosyncratic or associated with certain pa- liver enzymes, resulting in a short elimina- tient subsets. Southeast Asians may have less tion half-life and conversion to metabolites 3A4 enzyme (see Figure 8.8). that are rapidly excreted. The methyl group Triazolam has no active metabolites. As also makes a drug more potent.68, 69 mentioned, its half-life is approximately two to three hours but is slower at night. The ABSORPTION half-life is longer in the elderly because of lower liver oxidizing capacity. There is no Triazolam reaches a rapid peak within 1.3 change with kidney dialysis, but the half-life hours.70 It works faster in the elderly and in is slower with cirrhosis. Ninety-one percent young women.71 It also works more rapidly is eliminated in urine and 9 percent in feces in daytime than at night, due to a longer within 72 hours.75 76 predose fasting period. It is as much as two times quicker after a 12-hour fast.72 One CENTRAL NERVOUS SYSTEM EFFECT study reported that 85 percent of the drug is absorbed into the bloodstream. The study All the benzodiazepines have clinically useful also found that it is absorbed 28 percent antianxiety, sedative-hypnotic, anticonvul- more quickly if given sublingually, where sant, and skeletal muscle relaxant properties. some of it is absorbed but most of it is They all depress the CNS to some degree, swallowed.73 tending to be more antianxiety oriented as compared with barbiturates and other DISTRIBUTION sedative-hypnotics. They depress the limbic system and areas of the brain associated The distribution of triazolam shows no dif- with emotion and behavior, particularly ference in obese and normal patients. It is 89 the hippocampus and the amygdaloid nu- percent bound to plasma and 49 percent cleus. The major effects are attributed to bound to serum proteins and crosses readily an interaction with the GABA receptor com- into the central nervous system because of plex. high lipid solubility. It also crosses the placen- tal barrier and has been found in milk of rats. CARDIOVASCULAR SYSTEM EFFECT

METABOLISM AND ELIMINATION In normal therapeutic doses, the benzodi- azepines cause few alterations in cardiac Triazolam is oxidized in the first pass output or blood pressure when administered through the liver and the lining of the gut by intravenously to healthy persons. Slightly the cytochrome P450-mono-oxygenase sys- greater than normal doses cause slight de- tem. The P450 system is made up of many creases in blood pressure, cardiac output, enzymes. Triazolam is metabolized by the and stroke volume in normal subjects and 3A4 enzyme. Tagamet, cimetidine, erythro- patients with cardiac disease, but these mycin, isoniazid, possibly some oral contra- changes are not usually clinically significant. ceptives, some anti-HIV drugs, delavirdine Triazolam did not affect cardiovascular (DLV), efavirenz (EFV), and grapefruit de- dynamics in doses four to eight times greater press the cytochrome P450-mediated oxi- than normal.77 2879_Koerner_Chap 08 4/17/06 1:30 PM Page 240

240 CHAPTER 8 ytilibaliavaoiB esoD larO esoD VI esoD fo noitcarF fo aT tegr nagrO gurd degnahcnu gurd gnihcaer cimetsys eht cimetsys cimetsyS italucric on retfa noitalucriC yb noitartsinimda yb Portal Circulation .etuor yna .etuor

Inoitalahn emorhcotyC esoD ni msilobatem 054P msilobatem ni gninil tug dna revil dna tug gninil 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 in the systemic circulation the drugs can affect the target organ, the brain.

RESPIRATORY SYSTEM EFFECT moving dot with their finger), had patients back to normal in five hours after ingesting Most benzodiazepines are mild respiratory 0.25mg and in 11.5 hours after ingesting depressants. Given alone to a healthy patient 0.5mg benzodiazepins. Reported side effects they have little effect; however, they can po- include 8 percent sleepiness; 4 percent tentate other CNS depressants. Midazolam headache; and dizziness, neuritis, and dry is one that can cause respiratory depression mouth. and apnea. Triazolam did not depress respi- ratory response to CO2 in doses four to TRIAZOLAM PHARMACOLOGY eight times normal. Before practitioners use any medication, they REPRODUCTION should be knowledgeable of its pharmacology. Likewise, every practitioner, but particularly In rats, slightly reduced fertility occurred, those using sedatives, should be able to initi- but the drug did not affect their postnatal ate resuscitation (including cardiopulmonary development. resuscitation) and ventilation. The equipment necessary to provide these emergency treat- RECOVERY ments must, of course, be available. There are a few absolute contraindications One method of measuring recovery, a visual to the use of triazolam. Patients who are coordination study (following a randomly known to be hypersensitive to triazolam or 2879_Koerner_Chap 08 4/17/06 1:30 PM Page 241

ANXIOLYSIS FOR ORAL SURGERY AND OTHER DENTAL PROCEDURES 241

other benzodiazepine drugs should avoid its activity that could be hazardous. This in- use. Myasthenia gravis patients should not cludes such activities as walking unaided, be treated, as triazolam has a muscle relax- climbing stairs, and so on. They should not ation effect. Glaucoma patients should avoid undertake positions of responsibility or care all benzodiazepines, as these drugs raise in- of children and should not make important traocular pressure by increasing the outflow decisions (legal, monetary, and so on) for the resistance to aqueous humor.78 (This can rest of the day. They should not have alcohol often be reversed by pilocarpine.) All the or other sedatives for 24 hours.81 benzodiazepine drugs are teratogenic and The office should have an effective, effi- should not be given to pregnant women. As cient emergency protocol. This should in- triazolam has been shown to pass through clude a person to be continuously in the the mammary glands of mice into the milk, room with the patient from the time of ad- it should not be given to lactating mothers. ministration of the drug until the patient is As it is a CNS depressant, it should be given judged able to leave the office. The patient cautiously to anyone on other CNS depres- should not be allowed to sleep at any time. sants or drugs that suppress the P450 meta- Oxygen saturation should be continuously bolic system.79 monitored and recorded starting before ad- ministration of the drug. Vital signs should Relative Contraindications be taken at regular intervals such as every 15 minutes or even more often if there is any There are no detailed studies of triazolam’s indication of over-sedation. use as a sedative with pediatric and geriatric Management of adverse reactions should populations, and practitioners should be cau- be planned before the drug is used and tious when giving triazolam to these groups. should be reviewed on a periodic basis. It Some clinicians teach not to use it with pa- should be noted that most adverse effects tients under 18 or over 65 years of age. would be prevented by complete history tak- There have been reports of suicide attempts ing, physical examination, and appropriate by psychiatric patients. Suicidal tendencies adjustment of drug dosage. Recognition of an were unmasked, creating this paradoxical be- emergency situation must be followed by ini- havior.80 Several European countries have tiation of a stabilization routine. This essen- outlawed triazolam. One report showed an tially entails the A-airway, B-breathing, and incidence of psychotic episodes after triazo- C-circulation of basic cardiac life support. lam. However, the study was done in a psy- Opening and maintaining a patient’s airway is chiatric hospital, where many patients have of paramount importance, as is monitoring psychotic tendencies. The final relative con- vital signs. Calling the Emergency Medical traindication is the fact that triazolam has Service by dialing 911 should follow if any not been approved by the FDA for dental doubt exists as to how to proceed. sedation or the sedation of children. USE IN THE GENERAL DENTAL OFFICE Adverse Effects Over 15 years, this author has used triazolam Adverse effects have been reported in less more than 400 times. The patients come to than 4 percent of patients. Most adverse ef- the office one hour before we want to start fects were with doses greater than 0.5mg or their dental procedure. They are monitored when combined with other CNS depres- by recording blood pressure, pulse rate, and sants. As with all sedatives, patients cannot pulse oximetry. The drug dose is determined drive, operate machinery, or undertake any by the patient’s weight and purposely kept 2879_Koerner_Chap 08 4/17/06 1:30 PM Page 242

242 CHAPTER 8

conservative—less than might be necessary. As mentioned, we decide to administer We usually administer a supplemental dose one-half the initial dose after 30 minutes if sublingually if at the 30-minute mark we see there is no evidence of sedation. no signs of sedation. Supplemental dosages were necessary for My patient population has ranged from 7 about 10 percent of patients. We used the to 83 years of age and from 60 to 320 lbs.103 following protocol to determine the dosages. All patients were ASA 1 or 2 with no history Dose in mg = 0.25 mg + 0.125 mg for every of recent illness. All adult patients were den- 70-pound weight increment over 40 tal phobics who requested IV sedation or pounds.88 general anesthesia for their procedures. The Patients reported a decrease in apprehen- children had previous attempts at treatment sion that was greatest the first 30 minutes, with conventional methods, including ni- with the second largest drop between 30 and trous oxide, which were unsuccessful. 60 minutes. About 50 percent had moderate Cardiovascular and respiratory parameters to complete forgetfulness of the appoint- measured and recorded included blood pres- ment, and most did not remember the ride sure (systolic and diastolic), heart rate, and home. There were no significant changes oxygen saturation. With uncooperative chil- in blood pressure, pulse rate, or oxygen dren, only heart rate and oxygen saturation saturation. could be measured. Cardiovascular parame- It should be emphasized that no patients ters were recorded every 15 minutes. During slept, snoozed, snored, or napped. All were the procedure, oxygen saturation was contin- awake and responded to verbal commands uously monitored with a pulse oximeter. without painful stimulation. We have had no After recording initial baseline data, oral adverse effects on any of my patients. We triazolam was dispensed. Many authors have did have three who were not sedated ade- reported on the appropriate dosage for sleep quately to treat. enhancement. Suggested dosages range from 0.125mg to 0.5mg.82, 83, 84, 85, 86, 87 Protocol in Our Office After a discussion and completion of an informed consent document and recording It should be stressed, and I will repeat again, of preoperative vital signs, a dose of triazo- that we do not want a patient who is asleep. lam is administered. An assistant stays in the If a patient sleeps, they are oversedated and operatory with the patient for the next hour, should be kept awake by verbal commands, taking vital signs, blood pressure, pulse, and or if this does not work, the drug should be respiration every 15 minutes with instruc- reversed. We do not worry whether the pa- tions to alert me if there is any change. The tient is disappointed by their level of seda- assistant is instructed to talk with the patient tion because the amnesia that is common to to ensure that they remain awake. I check to this technique will allow them to forget see whether there is any sign of sedation at most, if not all, of the appointment. It 30 minutes. If there is no sedation evident, should be emphasized with children that we will administer one-half the original dose. they might still cry during the appointment. If even slight sedation is noted at that time, If they are controlled enough to allow den- we normally will have adequate sedation for tistry to be safely done, they are adequately the procedure. (Many patients will be disap- relaxed. Crying, although distracting to the pointed at the end of the 40 minutes by the practitioner, is an indication of adequate relative lack of sedation. They are assured ventilation. I would suggest not using any that this is normal, and they will be ade- form of sedation on children under 7 years quately sedated by the time we start.) of age, unless you are trained in pediatric 2879_Koerner_Chap 08 4/17/06 1:31 PM Page 243

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anesthesiology and are equipped and trained 05. If after 30 minutes you see absolutely no to handle general anesthesia and all the com- effect and if the patient tells you they do plications of anesthesia. not feel any different, give half the origi- nal dose sublingually. If they show even The Procedure a very slight effect, no second dose is necessary (see Figure 8.11). At a pre-appointment interview, the medical 06. Two hours later you can give half the history is reviewed to determine that there total dose if you have another hour to are no contraindications to triazolam, the go and the patient is much less sedated procedures, or from possible risks. Benefits than they were at 60 minutes. You are and options are discussed with the patient giving a dose equal to the amount that or, in the case of children, with their parents. has been metabolized. 07. If you need a little more sedation toward Patient Selection the end of a case, augment with nitrous oxide. 01. The patient is over 7 years of age and 70 08. Only use one oral drug, triazolam. Have lbs of weight. the reversal agent and be prepared to in- 02. The patient is ASA 1 or 2. I suggest not ject it into the floor of the mouth if the treating any person who has any medical patient does not respond to verbal com- problem, however slight. mand without any tactical stimulation. 03. Have a signed consent form. A pinch will arouse the patient until you 04. Start with a dose of triazolam appropri- can inject the reversal agent. Reverse the ate for the patient’s size. sedation as they are starting to get a. 70 to 110 lbs gets 0.25 mg deeper, not after they are under general b. 110 to 180 lbs gets 0.375 mg anesthesia. c. 180 to 240 lbs get 0.5 mg 09. We are not talking SLEEP, DOZE, d. 240 plus get 0.625 mg (see Figures SNORE, or NAP. We are talking awake 8.9 and 8.10) with anxiolysis.

Figure 8-9. Dosage calculation: Dose in mg = 0.25mg + 0.125mg for every 70 lb weight increase over 40 lbs. This equals 0.5 mg for a 180-pound man. If no sedation is observed at 30 minutes, a second dose is administered that is half the original dose. For long cases additional doses may be necessary as the drug is metabolized. 2879_Koerner_Chap 08 4/17/06 1:31 PM Page 244

Figure 8-10. Weight vs. dose of triazolam. This was an early graph of our use of triazolam in 110 patients. 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 of drug 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 in obese and normal-weight men. J Clin Psychopharmacol. 15(3):197–205.

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10. Never leave the patient alone in the structions, the same as were given to the pa- room. tient in the pre-appointment, are reviewed 11. Never leave a male dentist, hygienist, or with the adult who is going to take the pa- assistant alone with a female patient. tient home and watch over them the rest of 12. Monitor BP, pulse, and oxygen satura- the day. I assess and record the patient’s level tion continuously after you give the ini- of sedation prior to his or her leaving the of- tial dose. fice. In addition, my home phone is given to 13. If the patient needs to use the restroom, this accompanying adult, who is encouraged they must be accompanied by a same- to call if they have any questions or prob- sex staff person. lems. Finally, an assistant accompanies the 14. The patient must be with a responsible patient out to the car, supporting the patient adult the rest of the day. so there is no chance of a fall. The patient is a. They are to have no alcohol or other seated in the passenger seat, and the seat belt sedatives for 24 hours before the ap- is buckled. pointment. It should be noted that a second appoint- b. There should be no chance that they ment will normally be easier than the first. It are pregnant. has never been necessary to use a higher dose c. They should have none of the other at the second appointment if the dose on the contraindications. first appointment was adequate. Also, as this d. They cannot drive, operate machin- is a class IV drug, it is necessary to keep care- ery, or undertake any activity that ful accounting records of its use. could be hazardous. This includes such things as walking unaided, climbing stairs, and so on. Status of Triazolam e. They should not undertake positions UPJOHN of responsibility, such as care of chil- dren, and should not make impor- The Upjohn company distributes triazolam tant decisions—legal, monetary, and in the United States. They make no claims so on, for the rest of the day.89, 90, 91 of its usefulness as a dental sedative, nor has it been tested for use with children. The It is stressed that we are not attempting Upjohn company made it very clear to me nor is it our intent to have the patient sleep, in a letter that the use of this drug for dental although they might experience amnesia for sedation and with children is investigational some or all of the appointment. I have in nature and not supported or encouraged found that about 75 percent of patients have by the company. The patent has run out for amnesia from the time we start the proce- triazolam. Consequently, there is little dure (60 minutes after administering triazo- chance that it will ever be certified for dental lam). The amnesia lasts for 2–3 hours. All sedation. patients have had some amnesia or forgetful- ness of the appointment. FDA When the appointment is complete, we keep the patient in the dental chair until The FDA does not recognize triazolam’s use they are able to walk out with someone for either dental or pediatric sedation. A holding their arm. The dentist is the one to practitioner must recognize that should there determine whether they are able to safely be a problem, the lack of FDA approval leave the office. You are looking for a notice- would create problems from a medical-legal able decrease in sedation. Postoperative in- standpoint. Lack of FDA approval does not, 2879_Koerner_Chap 08 4/17/06 1:31 PM Page 246

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however, prevent our using the drug for Security sedation. “A physician (dentist) must keep these drugs in a securely locked, substantially con- RECORDKEEPING REQUIREMENTS structed cabinet or safe.” In my office, the triazolam is kept locked The Drug Enforcement Administration, a in a keyed locker, which is permanently at- division of the U.S. Department of Justice, tached to an office wall. Inventory sheets are has a booklet that is available from any DEA kept in a book with patient record forms. office, entitled, Physician’s Manual, An This sheet shows date and patient name, age, Informational Outline of the Controlled and weight and has space for comments. Substances Act of 1970. This manual spells The inventory total is changed with each out the requirements of recordkeeping, stor- drug administration so as to provide a run- age, inventory, security, and so on required ning total of the drug inventory. When re- for prescribing and dispensing a controlled stocking the drug supply, a copy of the substance. Triazolam is a schedule IV sub- prescription is attached to the inventory stance. sheet. To administer, prescribe, or dispense any controlled substance, a physician (dentist) PATIENT RECORDS must be registered with the DEA. The DEA requires that “The registration must be re- Patient records are kept for all treatments. newed every three years and the certificate of These records would be the same for any registration must be maintained at the regis- sedative agent except when nitrous oxide is tered location.” used with no other sedative drugs. These “It is necessary for dentists to keep records records include the consent form, post- of drugs purchased, distributed and dis- sedation evaluation, and a sedation record pensed. Having this closed system, a con- that includes blood pressure records, pulse trolled substance can be traced from the time rates, and pulse oximeter readings. These it is manufactured, to the time it is dis- values are taken and recorded preoperatively pensed to the ultimate user.” and at 15-minute increments from the “All controlled substance records must be drug administration until the case is com- filed in a readily retrievable location from all pleted. The patient’s medical status (ASA other business documents, retained for two rating) is recorded along with age, sex, years, and made available for inspection by weight, amounts of drug administered, the DEA. Controlled substance records name, date, and whether this is the first maintained as part of the patient file will re- administration of this sedative. quire that this file be made available for in- Sedation records are necessary for several spection by the DEA.” reasons. First, they establish a baseline and “A physician (dentist) who dispenses con- would be one of the first indicators of a trolled substances is required to keep a potential problem. If any of the measured record of each transaction.” parameters start to change, we should im- mediately be alerted and start corrective ac- Inventory requirements tion. Second, the stress of an emergency “A physician (dentist) who dispenses or makes time sequencing difficult for the regularly engages in administering controlled practitioner. It becomes all but impossible to substances is required to keep records and recall vital signs and the times they were must take an inventory every two years of all recorded. Complete records can provide stocks of the substances on hand.” clues about the case and possible solutions 2879_Koerner_Chap 08 4/17/06 1:31 PM Page 247

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to our problem as it progresses. (At what PHARMACOLOGY point did we lose verbal contact? How long has the patient been at this level? Did the Flumazenil was shown to prevent benzodi- change come on rapidly or have vital signs azepine sedation if given before the benzodi- been slowly changing for some time?) azepine and to reverse the effect if given dur- Lastly, in the event of legal action, complete ing or after the sedative drug. To reverse and accurate records are a must for one’s sedation or general anesthesia of benzodi- defense. azepine drugs, flumazenil is administered in- travenously in titrated doses from 0.2-to-1.0 mg doses. In the case of overdose, 2.0 to 3.0 Flumazenil (Romazicon) Reversal mg may be necessary.93 Agent TOXICITY AND SAFETY It would be a great advantage to have a med- ication that would reverse the effects of any “Flumazenil has a high therapeutic index drug we use. This is particularly true of any and a wide margin of safety.” It showed min- drug that requires excretion or metabolism imal effect on patients with ischemic heart to be deactivated. When using drugs intra- disease. No withdrawal symptoms were seen venously, small test doses can be given and when it was given to patients who had been augmented as necessary to achieve the de- on diazepam or triazolam for up to 14 days. sired effect. These test doses go directly to Some symptoms were seen in patients who the CNS and show their effect. They are had been on lorazepam. It should not be then redistributed to the rest of the tissues of given to patients with severe head injuries the body, effectively diluting the effect in the and unstable intracranial pressures.94 When case of an overdose or sensitivity to an agent. given to patients with panic disorder, 2mg Titration with oral drugs is very slow. It of flumazenil intravenously precipitated takes considerable time before it is obvious panic attacks. It had no effect on healthy that we have a problem. Redistribution and patients.95 saturation into the body have already taken place and are of little aid. In the case of over- Use with Children dose, there is little we can do except treat the symptoms of the overdose and support respi- Jones administered flumazenil to 40 healthy ration and circulation. For this reason, a re- children aged 3–12 years of age after they versal agent for oral drugs is very desirable. had received midazolam for the induction of The reversal agent for benzodiazepines is anesthesia. The drug was given along with a flumazenil. placebo, and the efficacy of antagonism was assessed. Those receiving the active drug HISTORY awoke approximately four times faster. There were no cases of resedation and minimal In 1974, Haefely hypothesized and showed changes in the cardio-respiratory variables.96 that benzodiazepines act by increasing the ef- fectiveness of the most important inhibitory Use with Adults neurotransmitter, GABA. Later, several com- pounds were produced that had a greater The half-life of flumazenil at 54 minutes affinity for this site than diazepam. One of (.7 to 1.3 hr) is less than triazolam, midazo- these, flumazenil, was selected as an antago- lam, and diazepam, so you may see some re- nist for clinical trials.92 bound of effect (see “Resedation” section 2879_Koerner_Chap 08 4/17/06 1:31 PM Page 248

248 CHAPTER 8

later in this chapter). Sedation was gone showing signs of serious cyclic antidepressant within 2 to 5 minutes. I have seen the rever- overdose.97 sal drug used sublingually in the floor of the mouth. The pain of this injection noticeably RESEDATION aroused the patient. Their sedation was obvi- ously lessened within two minutes; however, Because of the relatively short half-life of maximum reversal took 10 minutes for IV flumazenil, 54 minutes, it is possible that its administration and 20 minutes for sublin- reversal effect could disappear before the gual. In both cases, most of the effect oc- sedative effect of triazolam, with its half-life curred in the first five minutes. of one to two hours (see Figure 8.12). Mida- zolam has a similar half-life (one to two Contraindications hours), and several studies have failed to show significant resedation if appropriate Flumazenil is contraindicated in patients doses of midazolam had been used.98–100 with a known hypersensitivity to flumazenil Resedation has been shown with diaze- or to benzodiazepines, in patients who have pam,101 which has a much longer half-life been given a benzodiazepine for control of a (20–50 hours), and with larger doses of mi- potentially life-threatening condition (for dazolam.102 Until studies have been reported example, control of intracranial pressure or showing no resedation with triazolam, a pa- status epilepticus), and in patients who are tient who requires flumazenil should be ob-

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emit emit 11 22 33 44 55 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 the triazolam has rebounded. This effect increases through hour 3. 2879_Koerner_Chap 08 4/17/06 1:31 PM Page 249

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served for several hours after reversal to be do die. Conservative dosing of triazolam for positive resedation does not occur. There is a oral conscious sedation will never expose the risk that with reversal the patients may feel practitioner to these moments of terror or normal and attempt activities they are not the patient to theses risks. Always remember capable of safely performing. DO NO HARM! Death is forever. With the introduction of this reversal agent, we are able to use triazolam with the comfort of knowing that we can reverse its Case Reports sedation should we achieve an overdose. Of It can be helpful to clinicians to have exam- course, this in no way should cause us to use ples of situations in which a medication was excessive doses of triazolam, nor does it re- actually used with a patient. Following are lieve us of the responsibility of monitoring a two care reports using triazolam in clinical patient’s physical status and responding ac- settings. cordingly in the case of cardiovascular or res- piratory depression. PATIENT NO. 1

A seven-year-old was sedated for dental treat- Politics of Sedation ment by a pediatric dentist. The patient left Oral conscious sedation has become a con- the office able to walk holding the hand of troversial subject for dentistry. The American her mother. She went home and tended to Dental Association, specialty groups, and sleep if left alone. The dentist’s home phone some state boards have attempted to severely line was out of order that evening. After limit the use of this very necessary and im- trying to reach the dentist, her mother be- portant technique. came concerned and called a local emer- In general, benzodiazepine drugs, and gency room, who told her to watch the pa- specifically triazolam, are very safe when used tient and that triazolam was not approved conservatively. Triazolam has become a drug for use with children. The mother then of choice in dentistry because of its rapid up- called poison control and was again told that take, short half-life, and amnesia. Oral seda- triazolam should not be used with children. tion has come a long way toward addressing The dentist relieved the mother’s concerns the unmet needs of phobic patients. when she reached him in the office the next The ADA’s guidelines state that titration day. or “giving a second dose of an oral sedative” is unpredictable and can lead to deeper levels PATIENT NO. 2 of sedation. These guidelines limit the dose of an oral sedative to the maximum recom- A 40-year-old black male about 6Ј1Љ tall and mended dose (MRD). MRD is a FDA term. 230 pounds had an uneventful sedation. At In the case of triazolam, it refers to the dose the close of the case, when he was judged to used as a sleep-aid for a patient who may be be ready to leave, his wife, a rather petite home alone and has nothing to do with den- woman of 5Ј6Љ, was brought in and given tal sedation. The MRD for triazolam is 0.50 postoperative instructions. At this time she mg. mentioned they would be taking public When you face a sedation/anesthesia transportation, a bus, home. Because I was emergency, you need all the skill and train- concerned about her being able to help the ing you have acquired, previous experience patient on and off the bus, we kept him an handling such emergencies, and a little luck. extra hour to ensure that his wife would not This is an area where dental patients can and have any problem getting him home. We did 2879_Koerner_Chap 08 4/17/06 1:31 PM Page 250

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