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Anesth Prog 38:154-171 1991

Adult Sedation: Oral, Rectal, IM, IVJoseph A. Giovannitti, DMD,* and Larry D. Trapp, DDS, MSt

*Division of Pain and Anxiety Control, Baylor College of Dentistry, Dallas, Texas; andtSection of Hospital Dentistry, UCLA, Los Angeles, California, and

Department of Dental Anesthesiology, Loma Linda University,Loma Linda, California.

onscious sedation is a pharmacologically inducedstate of relaxation in which the patient remains

conscious and cooperative throughout dental treatment.Apprehension, fear, and anxiety are either eliminated orreduced to the point where a previously objectionableprocedure, such as dentistry, becomes acceptable. Theprotective reflexes remain intact, cardiorespiratory pa-rameters are stable, and the pain threshold may be ele-vated.

Selection of the appropriate technique is based uponthe patient's level of apprehension and should be individ-ualized according to the sedative effect required, the needfor amnesia, the need for an elevated pain threshold, andthe duration of the dental procedure. Sedative medica-tions may be administered singly or in combination, de-pending on the individual patient and procedural require-ments. Single sedatives are useful in managing mild tomoderate apprehension levels. Benzodiazepines withspecific anxiolytic properties, such as diazepam or mida-zolam, are the most widely used drugs for this technique.Not all patients however, will respond to a single drugdue to the many factors contributing to pharmacologicvariability. Multiple-drug techniques may result in lessvariability in patient response; but with greater potentialfor drug-induced side-effects and drug interactions.Whenever conscious sedation is being considered for

use in a particular patient, the benefits of the sedationmust be weighed against its inherent risks and the risksassociated with the body's physiologic response to stress.Catecholamine release during stress may lead to syn-cope, agitation, excitement, tachycardia, hypertension,and cardiac dysrhythmias. These physiologic and behav-ioral changes are at best undesirable, and at worst majorcauses of medical emergencies. Dionne, and others1have shown that benzodiazepines attenuate this stressresponse during oral surgery, thus validating the use ofsedation in dentistry. The safety of conscious sedation isexemplary. Ceravolo et a12 published an 11-year casestudy of 10,000 patients receiving IV sedation in whichthere were no major complications. Coplans estimates

Address correspondence to Dr. Larry D. Trapp, 25616 NarbonneAvenue, #204, Lomita, CA 90717-2536.

© 1991 by the American Dental Society of Anesthesiology

the mortality rate for parenteral sedation to be approxi-mately 1 in a million.3 Thus, with its proven benefit ofstress reduction and its relative safety, intravenous con-scious sedation has a wide variety of uses.

Aside from the obvious use in fearful or apprehensivepatients, sedation may be indicated in medically compro-mised patients, children, gaggers, patients with a historyof problems with local anesthesia, and in those requiringsurgical or other prolonged dental procedures. An impor-tant side benefit of conscious sedation is that it enablesthe dentist to perform a maximum amount of work in aminimum amount of time.

BALANCING EFFICACY AND SAFETY

When drugs are administered to patients to produce con-scious sedation, the observed effects are the culminationof a series of altered physiologic functions. In a truesense, we produce pathophysiologic changes when weadminister these agents, some of which are desirable, andsome of which are undesirable. Factors which determinehow a drug or drug combination will affect the variousfunctions of the human body include: the pre-existingmedical condition of the patient, the nature and durationof the present illness, drug interactions, age, nutritionalstatus, environmental factors, and genetically determinedfactors that may render patients more susceptible or re-sistant to the effects of a particular drug. In order to maxi-mize the desirable effects produced by these agents andminimize the undesirable effects, a clinician must accu-rately assess the patient's preanesthetic condition, bethoroughly familiar with the pharmacodynamics of thedrugs employed, and be properly trained to continuouslymonitor the effects produced by these agents. In addition,the clinician should be properly trained to correct anysignificant pathophysiologic changes produced by the ad-ministration of these drugs. The office team should beexperienced and well-trained, and there should be suffi-cient backup resources in the event of an emergency.Without these basic precautions, inadvertent but signifi-cant changes in physiologic function may lead to injury oreven death.

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Adult Sedation: Oral, Rectal, IM, IV 155

Care should be taken to avoid the pitfalls that may leadto an adverse outcome. Without a doubt, the most com-mon cause of anesthetic misadventures is an inadequatepreoperative evaluation. This in turn may lead to clinicalfailure due to improper technique selection, overdosage,or drug interaction. Exposing a medically compromisedpatient to the risks of deep sedation or general anesthesiawhen conscious sedation will suffice places the patient atunnecessary risk. Conversely, using conscious sedationwhen general anesthesia is indicated may lead the practi-tioner to extend the technique beyond the limits of safepractice. This invariably leads to overdosage, airway ob-struction, and cardiorespiratory depression. Inadequateor improper monitoring also contributes directly to anes-thetic morbidity and mortality. The mere presence of anelectronic monitor does not guarantee the patient'ssafety. Certain knowledge is required for proper interpre-tation, and during conscious sedation no monitor shouldbe a substitute for verbally and visually ascertaining thepatient's level of consciousness, comfort, and coopera-tion.

ORAL PREMEDICATION

Oral premedication is generally given first considerationin the management of the mildly apprehensive patient.Because of its ease of administration, convenience, andavailability, oral premedication is a popular choice forconscious sedation. The predoctoral dental curriculumoffers the training necessary to master this technique, andthus its use is widespread. The availability of a liquid doseform makes oral premedication highly applicable to thepediatric dental patient. It is also a useful modality inpatients who are unwilling to accept alternate routes ofdrug administration. Patients with mask-induced claustro-phobia or those with an irrational fear of needles may findthe oral route less objectionable.The primary objective of oral premedication is to re-

duce anxiety while maintaining consciousness, comfort,and cooperation. This objective is usually met in themildly apprehensive patient. For the management of themoderately apprehensive patient, oral premedication canbe effective when combined with either intramuscular orinhalational agents. However, it is not very effective inextremely apprehensive patients unless intravenous tech-niques are also used.

Results with oral premedicants are not always predicta-ble since patients may not always follow the prescribedinstructions. Also, there is much variability in patient re-sponse to oral medication. A full stomach will delay theabsorption of oral medication, and thus prolong the onsetor produce less than desirable blood levels. Anxiety willdelay gastric emptying and produce similar results. The

Table 1. Summary of Advantages and Disadvantages ofOral Premedications

AdvantagesSimple and convenient to use.

- Drugs readily available by prescription.Drug reactions are generally less severe.Oral route less objectionable than parenteral.Requires only minimal training.Duration of action may extend into posttreatment

period.

Disadvantages- Patient noncompliance.-Dosages are largely empirical.- Titration to clinical endpoint impossible.-Erratic absorption makes response unpredictable.-Level of sedation cannot be altered.-Not useful in extremely apprehensive patients.-Duration of action may extend into posttreatment

period.

dosages used for premedication are largely empirical andare usually based upon body weight. Unfortunately, thisalso contributes to a variable response. The advantagesand disadvantages of oral premedication are summarizedin Table 1.

Pharmacological Factors InfluencingClinical Efficacy.

Drug Absorption. The overall efficacy of oral pre-medication is dependent upon the rate and completenessof absorption from the gastrointestinal tract. Lipid-solubledrugs are more rapidly absorbed than nonlipid-solubledrugs, and therefore have a more rapid rate of onset. Therate of absorption is also heavily influenced by the pH ofthe gastric tissues. The absorption of most oral medica-tions occurs in the small intestine, where there is muchmore mucosal surface area as compared to the stomach.Therefore, in order to expedite absorption the drug mustpass through the stomach and into the small intestine asrapidly as possible. The presence of food in the stomachsignificantly delays gastric emptying time, and retardsdrug absorption. Similarly, increased levels of anxietyalso delay gastric emptying. This may be one of the rea-sons why the efficacy of oral premedication decreases asanxiety increases.

Other factors that influence the systemic absorption oforal medication are the dose form of the drug and inacti-vation of the drug by the liver. The efficient absorption ofone dose form over another has to do with the bioavaila-bility of the drug. In other words, only a portion of thedose administered is available to exert its pharmacologi-cal effects. Two different formulations of the same drug

Anesth Prog 38:154-171 1991

Anesth Prog 38:154-171 1991

Table 2. Drug Absorption Characteristics Influencing theClinical Efficacy of Oral Sedation

1. Lipid solubility2. pH of gastric tissues3. Gastric emptying time

a. presence of food in stomachb. anxiety

4. Mucosal surface area5. Dosage form6. Hepatic metabolism ("first pass" effect)7. Bioavailability

dose that has been determined to be effective. The re-maining population may require more or less than thestandard dose, and about 2.5% will either be very resist-ant or very sensitive to the drug effect. It is no wonder,then, that there is so much variability in the doses re-quired to produce a satisfactory clinical result. Thus, tech-niques that allow for incremental dose titration to a clini-cal endpoint are much more preferable than fixed-dosetechniques. The limitation of oral premedication becomesobvious.

do not necessarily have the same biological or therapeu-tic equivalencies. Differences in the disintegration anddissolution and differences in the size of the dissolvedparticles affect their absorption from the GI tract. Liquiddose forms are generally absorbed more rapidly thantablet or capsule forms of the same drug.

Systemic absorption of oral medication is further hin-dered by hepatic metabolism. Unlike parenteral drug ad-ministration, oral drugs are absorbed from the small intes-tine and transported to the liver via the portal circulation.The drug is subjected to enzymatic degradation before itever has a chance to reach the active site ("first pass"effect). A summary of drug absorption characteristics in-fluencing clinical efficacy is found in Table 2.

Patient Variability. In an ideal situation, 100% ofthe population would respond in like manner to a stan-dard dose of any given drug. However, as discussed pre-

viously, there are numerous factors that can influence theultimate patient response. Additionally, even if these fac-tors remained constant, people are going to respond dif-ferently to set doses of medication. Patient variability isillustrated by the typical dose-response curve shown inFigure 1.Assuming a normal distribution of drug sensitivity, ap-

proximately 68% of patients will respond within plus or

minus one standard deviation from the mean to a drug

Figure 1. Typical dose-response curve.

.11 11%

-3 -2a-la pu la 2a 3a

Therapeutic Suggestions for Oral Sedation

One of the most significant problems associated with oralpremedication is patient noncompliance. This can makethe difference between a successful and unsuccessfuldental experience, and may also have medicolegal impli-cations. Since anxiety itself causes noncompliance, it isbest to give the patient both verbal and written instruc-tions concerning the oral premedication procedures.These should include not only the type and nature of themedication, but also how much and what time the drugshould be taken. A copy of the written instructions shouldbecome a part of the patient's permanent record. In orderto attain the optimum effect from oral premedication, oneshould prescribe a dose of medication at bedtime thenight before the dental appointment. The same drug thatwill be used for treatment should be prescribed for thispurpose if possible. The dose to be administered prior todental treatment should be given well in advance of theneed. This may be 1 or 2 hours in advance dependingupon the medication used. The patient should avoidheavy meals prior to the premedication in order to pre-vent delays in gastric uptake. Finally, the patient musthave a responsible adult to transport him to and from theoffice. The dentist should prescribe or dispense only theamount of drug that the patient is to take in order to avoidmisunderstandings or medication errors. Ideally, the pre-medicant should be administered to the patient by thedentist in the dental office. This will prevent noncompli-ance and allow for close supervision as the medicationtakes effect. These suggestions are summarized inTable 3.

Table 3. Therapeutic Suggestions for Oral Sedation

Verbal and written instructions should be givenBedtime dose encouragedAdminister well in advance of needAvoid heavy meals prior to premedicationPatient must be accompanied by a responsible adultPrescribe or dispense only the amount of drug requiredDoctor-administered dose recommendedRecovery and assistance may be required

156 Giovannitti and Trapp


Drugs for Oral Sedation

Benzodiazepines. The benzodiazepines have distinctadvantages over other oral premedicants. They are themajor drug group with specific anxiolytic properties. If thedesired level of sedation is not achieved initially, higherdoses may be safely administered at subsequent appoint-ments due to the high therapeutic index of the benzo-diazepines. In contrast, higher doses of other agents, suchas the opioids or barbiturates, will increase the likelihoodof adverse reaction because their therapeutic index islower.

In addition to their anxiolytic effects, benzodiazepinesalso have anticonvulsant, sedative, and amnestic proper-ties. Specific benzodiazepine receptors have been iso-lated in the brain and spinal cord. Their location parallelsthat of the major inhibitory neurotransmitter in the brain,gamma-aminobutyric acid (GABA), and the major inhibi-tory neurotransmitter in the spinal cord, glycine. The re-ceptor sites are predominantly found in neuronal surfacemembranes and are distributed widely throughout thecentral nervous system. Benzodiazepines intensify thephysiologic inhibitory effects of GABA by interfering withGABA reuptake.45The termination of clinical activity of the benzodiaze-

pines is determined by the rate of redistribution from theCNS to a peripheral compartment along a concentrationgradient. The rate of distribution is reversible and rapidfor benzodiazepines since it is dependent upon the lipidsolubility of the drug. The elimination phase is irreversibleand slow since it is governed by the rate of biotransforma-tion of the drug. For example, the elimination half-life fordiazepam is from 20 to 70 hours. In addition, diazepamhas active metabolites which produce prolonged sedativeeffects. The combination of active metabolites and thelong elimination half-life accounts for the residual "hang-over" effects seen clinically following diazepam adminis-tration. In comparison, the elimination half-life for triazo-lam is 1.5-5.5 hours, which is the shortest for anybenzodiazepine. There are also no active metabolites oftriazolam. This results in few, if any, residual effects withtriazolam.The benzodiazepines may produce paradoxical excite-

ment. Prolonged sedation may be seen in patients takingcimetidine. Caution in dosing should be exercised in theelderly patient, since they may be highly sensitive to theeffects of the drug. Elderly patients may have a decreasein the number of benzodiazepine receptors, impaired to-tal metabolic clearance, and a diminished plasma vol-ume, protein binding capacity, and CNS function. There-fore, drug potency will be enhanced and the doserequirements will be reduced. Benzodiazepines are con-traindicated in patients with acute narrow angle glau-coma.

Diazepam is the benzodiazepine prototype and is prob-ably the most widely prescribed oral premedicant. It pro-duces reliable sedation and anxiety reduction in mostadult and child patients. Its major disadvantage is its pro-longed residual effects. The pediatric dose ranges from0.15-0.3 mg/kg.

Triazolam (Halcion) is a rapid-onset, short-durationbenzodiazepine which produces excellent sedation, andoften induces sleep as well as a degree of amnesia. It isvery useful for pretreatment night-time dosing. Its manyadvantages make it a drug of choice for adult premedica-tion. Lorazepam is a long-acting benzodiazepine whichmay produce amnesia following oral dosing. It should beadministered 2 hours prior to dental treatment for optimaleffect. It is useful for longer dental appointments (3-4hours), but at the expense of prolonged recovery. Otherbenzodiazepines used for oral sedation include alprazo-lam (Xanax) and oxazepam (Serax). The duration ofalprazolam results in prolonged residual sedativeeffects while oxazepam's slow onset limits its clinicalutility.

Although midazolam is not available for oral adminis-tration in the United States, it is rapidly absorbed from theGI tract following oral administration. The oral dose ofmidazolam must be approximately twice the parenteraldose since first-pass hepatic metabolism may remove asmuch as 50-60% of the drug. Its rapid onset and shortduration are advantages for its use orally. In one study,an oral dose of 15 mg of midazolam produced acceptablesedation lasting for 45 min in healthy adults undergoingthird molar surgery.6 An interesting side-effect was theproduction of partial to complete amnesia in 75% of thesubjects. It also appears to have value as an oral premedi-cant in pediatric patients.

Barbiturates. The degree of CNS depression seenwith barbiturates is dose-dependent. They may be usedto produce both sedation and sleep. However, barbitu-rates are not specific anxiolytic agents, and although apatient may appear adequately sedated following an oraldose, anxiety may not be relieved. Paradoxical excite-ment secondary to barbiturate administration is not un-common, and there may be a decrease in the patient'spain threshold, which may contribute to an already exist-ing patient management problem. Barbiturates may alsoproduce respiratory and cardiovascular system depres-sion and the potential hazards that accompany them.Barbiturates are contraindicated in patients with acuteintermittent porphyria and in patients with suicidal ten-dencies.

Secobarbital (Seconal) and pentobarbital (Nembutal)are usually given in doses of 50 to 100 mg for oral seda-tion. The pediatric dose for either agent is 2 mg/kg.

Anesth Prog 38:154-171 1991

Anesth Prog 38:154-171 1991

Table 4. Summary of Benzodiazepines Used for Oral Sedation (After Greenblatt et al7)

Elimination rate ActiveDrug Onset (half-life) metabolites Adult dose

Diazepam rapid slow (20-70 h) oxazepam 5-15 mgtemazepamdesmethyldiazepam

Triazolam intermediate very rapid (1.5-5 h) none 0.25-0.5 mgLorazepam intermediate intermediate (10-20 h) none 1-4 mgAlprazolam intermediate intermediate (12-15 h) hydoxyalprazolam 0.25-0.5 mgOxazepam slow rapid (5-12 h) none 10-15 mg

Histamine-Blocking Agents with Sedative Prop-erties. Histamine-blocking agents all produce mild CNSdepression and have anticholinergic and antiemetic prop-erties. The mild CNS depression seen with these drugsmakes them suitable agents for combination with otherdrugs, such as opioids, for oral premedication. Their anti-cholinergic properties may diminish salivary flow and im-prove visualization of the operative site. Their antiemeticeffects are useful if combinations with opioids are em-

ployed.Antihistamines may produce orthostatic hypotension.

Paradoxical excitement and agitation may occur as a con-

sequence of the anticholinergic effects (central anticholin-ergic syndrome). When used alone, the sedative-hypnotic effect of the antihistamines is highly variable. Asa result they are often given (in reduced doses) in combi-nation with other agents.

Promethazine (Phenergan) is rarely used alone as an

oral premedicant, but rather in combination with meperi-dine. The usual adult dose is 25-50 mg, reduced to12.5-25 mg for pediatric use.

Hydroxyzine (Vistaril, Atarax) is also rarely used aloneas an oral premedicant, usually being given in combina-tion with meperidine or a barbiturate. Adult doses rangefrom 50-100 mg; the pediatric dose is 0.6 mg/kg.

Diphenhydramine (Benadryl) may be useful for pre-medication of an atopic or asthmatic individual. It is alsouseful for premedication of patients with an "allergic"history to local anesthetics. The dose range for adults is25-50 mg; the pediatric dose is 12.5-25 mg.

Opioids. The opioids have the desirable pharmaco-logic effects of analgesia and sedation, which make themuseful for oral premedication. However, opioids are

poorly active orally, and thus vary greatly in their sedativeactivity from patient to patient. They may also producerespiratory and cardiovascular system depression whichcan result in airway obstruction, hypoventilation, and hy-potension. When opioids are administered alone and in

the absence of pain, they may produce dysphoria insteadof the desired sedation or tranquilization.

Opioids may produce GI disturbances such as nauseaand vomiting and constipation. Other adverse effects in-clude dysphoria and confusion, orthostatic hypotension,and urinary retention. Opioids are relatively contraindi-cated in patients with restrictive or obstructive lung dis-eases.

Meperidine is the opioid most frequently used orally,primarily for pediatric sedation. It is rarely used alone, butrather in combination with promethazine or hydroxyzine.In the authors' experience, a so-called "successful" pre-medication with meperidine often involves an obtundedchild with a compromised airway. It has been reportedthat most pediatric anesthetic morbidity and mortality isassociated with opioid premedication. The usual adultdose of meperidine is 50-75 mg; the pediatric dose is 1mg/kg.

Alternative Drugs and Routes of Administra-tion. Scopolamine has been proved effective when ad-ministered transdermally for the control of motion sick-ness. It has also been demonstrated to be effective as apreoperative sedative, antiemetic, and antisialogogue viathis route.8 A prepackaged disk containing scopolamine(Transderm-Scop) is applied to the posterior auricularskin on the night before the appointment. Scopolamine isslowly released, and the sedative effects should be evi-dent at the time of the appointment. The antiemetic ef-fects persist up to 72 hours when the disk is worn contin-uously.A recent development in premedication techniques has

been the use of the intranasal route of administration.Midazolam, fentanyl, and sufentanil have been adminis-tered this way to both adult and pediatric patients. It hasbeen shown to be rapid in onset, safe, and highly effec-tive. A fentanyl-coated lollipop has also been used withsome success in pediatric patients. Further investigation isjustified in this area, as intranasal premedication could be



a useful alternative to the oral route in a wide variety ofsituations.9

Atropine and glycopyrrolate as oral premedicants maybe used primarily as drying agents for improved operatorvisibility. Although atropine crosses the blood/brain bar-rier and may produce sedation, it should not be consid-ered as a primary agent in this regard.

Atropine, and especially scopolamine, may producedisorientation, confusion, and agitation (central anticho-linergic syndrome), and may cause urinary retention. At-ropine and scopolamine are contraindicated in patientswith glaucoma.

RECTAL SEDATION

Rectal administration of medicines for the purpose ofachieving local effects have been used since ancienttimes.10 The potential value of this approach has beendifficult to fully realize because of inconsistent bioavaila-bility and hence decreased effectiveness of the supposi-tory dosage form. 11-13 The continued interest in the rectalroute of administration stems from the difficulty of initiat-ing surgery on an uncooperative patient and from theincreasing frequency of surgery performed in the officewhere sophisticated anesthesia skills may not be availablebut safe methods of patient management are still needed.Rectal administration of sedative-hypnotics in the infantand child has been the subject of many studies.14-7However, the use and efficacy of rectally administeredsedative-hypnotics in adults has been infrequently inves-tigated.The usual candidate for rectal sedation is either a child

from 1 to 7 years of age or an emotionally handicappedolder child or adult. Less frequently, one encounters thepatient who is unable to swallow a tablet and also has aneedle phobia. Individuals with a severe physical handi-cap such as cerebral palsy may also be a candidate forrectal sedation. Rectal sedation for adults in the UnitedStates, however, is usually only indicated for patientsneeding sedation who are unable to be optimally sedatedby the oral, inhalation, or parenteral routes.With the clinical introduction of the benzodiazepines,

research and clinical interest was redirected from the useof rectal suppositories to the rectal administration of solu-tions.14 Subsequently, many studies have investigatedthe pharmacokinetics of rectally administered solutions ofmethohexital or diazepam in children.15-8 A few studieshave focused on the pharmacokinetics of rectally admin-istered diazepam in adults.19-22

Rectal Physiology

The rectum, about 10-15 cm long and 15-35 cm in cir-cumference, is empty and flat most of the time. The main

blood supply is from the inferior rectal arteries whichbranch from the pudendal arteries and the middle rectalarteries. Three veins drain the rectum: the superior, themiddle, and the inferior rectal veins. The superior rectalvein drains the upper or proximal portion of the rectum.The size of this portion varies among individuals. Thesuperior rectal vein drains into the inferior mesentericvein and subsequently into the portal vein. The middleand inferior rectal veins drain into the internal pudendalvein and subsequently into the internal ileac vein. Theinternal ileac vein then drains into the internal venacava. 10-11The blood flow pattern from the rectum is important

because the portion of the rectally administered sedativethat is absorbed into the middle and inferior rectal veinsdoes not pass through the liver before entering the sys-temic circulation. This portion of the absorbed sedativedoes not undergo so-called "first-pass" clearance or elim-ination. That fraction of the sedative absorbed and car-ried through the superior rectal vein would pass throughthe portal circulation. It would therefore be partiallycleared by the liver before entry into the systemic circula-tion like orally administered sedatives. For those agentslike meperidine that undergo a large first-pass clearance,the physiology of the rectum may allow a higher serumconcentration of a rectally administered sedative thanthat for an equivalent oral dose. One factor that reducespredictability is that there are extensive anastomoses be-tween the inferior, middle, and superior rectal veins, andsome variability in directional flow has been reported."

Dosage Form

The most widely employed dosage form is the rectal sup-pository. In recent years, evidence has accumulated thata suppository dosage form results in a delayed and muchmore variable systemic absorption when compared torectally administered solutions. For example, infants andadults that receive diazepam suppositories experiencepeak serum levels of diazepam an hour or more afterrectal administration while peak plasma levels after a rec-tal solution occur approximately 20 min following admin-istration.18,22 The factors affecting absorption of supposi-tories include particle size, surface properties, drug solu-bility, as well as any fluid content of the rectum."1 Anadditional disadvantage is the relatively fixed dosage for-mat of suppositories.As a result of the slow and variable absorption patterns,

research has been redirected to the rectal administrationof solutions and their pharmacokinetics. Recent clinicalevaluations in adults of the pharmacokinetics of rectallyadministered diazepam in solution compared to intrave-nous diazepam showed similar peak serum levels. Thepeak serum level for the rectal diazepam occurred only

Anesth Prog 38:154-171 1991

Anesth Prog 38:154-171 1991

15 min after that for intravenous diazepam. 19-22 Thisrapid systemic uptake following rectal administration ofsedative solutions results in quicker onset and less vari-ability than the use of sedative suppositories. An addi-tional advantage to solutions is the ability to adjust thedose rather than administering a fixed dose with a sup-pository. These advantages suggest that rectal solutionshold great promise for a variety of therapeutic endeavorsin infants and children; use of rectal solutions in adults isless certain.

Patient Acceptance

In some parts of the world, the rectal administration ofmedicines for systemic absorption is not widely utilized oraccepted. For example, in the United States, the rectaladministration of sedative agents is enjoying resurgenceamong anesthesiologists who treat young children. How-ever, this increase in usage has not extended to the adultpopulation.An important application of rectal sedation in adults

can nevertheless be identified in the management of thephysically or emotionally handicapped adult. This patientpopulation includes those individuals with cerebral palsy,autism, moderate to severe retardation, some patientswith Down's Syndrome, some patients with Alzheimer'sdisease, and other disorders where voluntary patient co-

operation cannot be expected. These patients may beinstitutionalized. Where rectal temperatures are routinelytaken, rectal sedatives can be administered and sedationachieved without special cooperation or even the pa-tient's knowledge. This approach minimizes patient dis-ruption, greatly facilitates treatment, and increases patientand staff safety.

Therapeutic Recommendationsfor Rectal Sedation.

Deep Sedation with Thiopental. The requireddepth and duration of sedation for dental treatment willdepend on the extent of patient anxiety and the proce-dures to be performed, respectively. Based on consider-ations previously discussed, it is assumed that the patientis an uncooperative, unpredictable, emotionally labileadult and that deep sedation is the therapeutic objective.When a short dental treatment time (eg, 15 min) is

anticipated, the optimal approach to the uncooperativeadult patient is rectal sedation with thiopental in solution.This sedative is commercially available in a prefilled sy-ringe designed for rectal administration (Figure 2). Thesyringe comes with flared applicator tips, and the desireddose can be set by turning a threaded nut located on thesyringe plunger. An effective dose for deep sedation is 44

Figure 2. Prefilled syringe for rectal administration of thiopental.



mg/kg or approximately 10 times the intravenous dosefor general anesthesia.

After a flared applicator tip has been adapted to thesyringe barrel, the tip is coated with a water-soluble lubri-cant. The patient is placed in a nonthreatening area andpositioned on his left side (if the administrator is right-handed) with the uppermost leg flexed. The individualadministering the sedative stands behind the patientwhere access is better and the patient cannot see thesyringe. The tip is then inserted into the rectum, the con-tents injected, and the tip withdrawn. The patient willgenerally become deeply sedated and fall asleep within10 min.

Encountering the dentist and his professional para-phernalia usually makes sedation of the uncooperativepatient more difficult. Elevation of patient anxiety can beminimized if the patient has a responsible attendant orfamily member who routinely takes rectal temperatures.The attendant or family member can and should adminis-ter the thiopental after the dose has been set, and the tipadapted to the syringe. If the dentist prepares the syringeand explains the procedure to the attendant or familymember while out of view of the patient, then the dentistcan remain out of sight until the patient is sleeping. Thepatient can be told they are going to have a temperaturetaken. This allows for a much smoother and less trau-matic induction of sedation. Once adequate sedation hasbeen achieved, an intravenous infusion should bestarted, local anesthetic given, and the treatment begun.If after starting it is decided that the treatment cannot becompleted in approximately 15 min, then other sedativeagents should be given intravenously before the patientbecomes awake enough to remove the intravenous infu-sion line. If it has been determined before starting that thetreatment time will be longer than approximately 15 min,sedation can be planned as a multidrug approach withthe only goal for rectal thiopental being access to anintravenous infusion. Sufficient anesthesia training tomanage deep sedation is a prerequisite for a dentist utiliz-ing rectal sedation with thiopental.

Conscious Sedation with Diazepam. Rectal diaze-pam has not been widely studied or utilized in the UnitedStates in adults or children. However, in other countries,sedation with rectal diazepam in solution has been re-ported to be well accepted and effective for normal adultsundergoing outpatient oral surgery when compared tointravenous sedation with the same agent.20 The meanrectal dose per kilogram of diazepam is approximatelytwice that for intravenous administration. Patients se-dated rectally achieve lower peak serum levels (71%),higher mean peak desired effects, and have a 50% longerrecovery time than those sedated intravenously.20 It is ofnote that both routes of administration in this study re-

sulted in a similar incidence of amnesia. Both approachesprovided an equal duration of effect as judged by thepatient for surgery averaging 33 min. Thus, rectally ad-ministered diazepam may indeed represent a practical,longer-acting alternative to barbiturates.20 One study hasreported a small percentage of patients receiving rectaldiazepam experienced rectal pain after administration ofthe agent.21 Based on its pharmacology, toxicity, andpharmacokinetics, diazepam is very promising as a rec-tally administered sedative. The lack of an available for-mulation for rectal use in the United States makes it im-practical to make therapeutic recommendations fordiazepam at this time.

Suppositories. The use of suppositories is timetested. However, the lack of widespread use of this routeof sedation rests in part with the variable bioavailability,consequent variable absorption, and thus lack of depend-able clinical effectiveness. The substantial delay to peakeffect has reduced its usefulness even more. If, however,a suppository is to be used, a dose must be selectedbased on a recommended dose per kilogram bodyweight. If the commercially available product contains toolarge a dose of sedative, the suppository can be sectioned(eg, cut in half) to obtain the desired dose. The supposi-tory is inserted without additional lubrication in order toavoid delays in absorption. A responsible patient, familymember, or attendant can do this at home.

ComplicationsThe most common complication of rectal sedation is theinitiation of a bowel movement and passing part or all ofthe suppository or drug solution. The incidence of thiscomplication is relatively low, but no data are available toprovide hard numbers. It would appear to be in the 5% to10% range.The most worrisome complication is overdose from the

sedatives and the unintended induction of general anes-thesia with the potential for airway obstruction by thetongue. This complication is not serious if the dentist iswell-trained in anesthesia and is monitoring closely oncethe patient shows signs of deep sedation. Oxygen vianasal cannula and monitoring with a pulse oximeter arerecommended once the patient has achieved deep seda-tion. A thorough medical history will prevent the adminis-tration of thiopental to a patient with a diagnosis ofporphyria.

Erosion of the rectal or anal mucosa is infrequentlyencountered. This can occur when the uncooperative pa-tient tightens the anal sphincter during insertion or with-drawal of the syringe tip.

Anesth Prog 38:154-171 1991

Anesth Prog 38:154-171 1991

INTRAMUSCULAR SEDATION

The use of intramuscular injections can be traced back tothe middle of the last century when the first hypodermicneedle and syringe were developed. Opium was injectedalong the course of nerves to achieve pain relief. Seda-tion was a side-effect, the primary purpose being analge-sia. In spite of a century of use, relatively little researchhas been published on the clinical efficacy of intramuscu-lar sedation or, indeed, on the use of intramuscular injec-tions as a route of drug administration.

Intramuscular (IM) sedation is a form of parenteral se-dation, ie, sedation requiring a needle for administration.Thus, parenteral drug administration encompasses thesubcutaneous, submucosal, intramuscular, and intrave-nous routes of administration.The objective of IM sedation is the attainment of an

optimal level of patient sedation as quickly as possiblewithout complication and without the establishment of anintravenous infusion. Intramuscular sedation does nothave a major role in sedation for dental treatment. Mostpractitioners select the intravenous route because of theability to titrate medications or they select the oral routedue to ease of use and lack of pain on administration. Ifthe dentist is unable to establish an intravenous line andthe patient cannot take sedatives by mouth, IM sedationmay then be indicated. Sedation of the mild to moder-ately retarded, uncooperative dental patient is anotherexample of a possible indication for IM sedation.

Volume of Injection

The volume to be injected usually depends on severalfactors, including patient weight and the concentration ofthe sedative in the commercially available product. If thevolume for injection is less than 4 mL, the deltoid may beused (Figure 3). If the volume of injection is in the 4-8 mL

Figure 3. Intramuscular injection site: shoulder (deltoid).

4.,- · ', ,Deltoid

1 -; e-;

,_-Gluteus max

- Sciatic nerve

.tflvI17Figure 4. Intramuscular injection site: buttocks (gluteus maxi-mus).

range, the gluteal, ventrogluteal, or vastus lateralis sitesshould be utilized (Figures 4 and 5). If the volume ofinjection is in the 8-15 mL range, then the vastus lateralissite is mandatory. These volume guidelines apply only tothe adult patient.The injection volume that the muscle can tolerate is

directly proportional to the muscle size. These guidelinesare based on empirical evidence that limiting maximuminjected volumes based on total muscle mass minimizesmuscle distortion and dissection, thereby reducing painboth during and after injection.23,24 There is, however,some indirect scientific support for the belief that post-injection pain is proportional to injected volume. Serumlevels of a muscle enzyme called creatine phosphokinase(CPK) have been measured following IM injections andconfirm that muscle damage is proportional to the vol-ume of injection.25,26 This enzyme is released after muscleinjury. The larger the injury, the higher the serum CPKlevels that are observed. It is reasonable to believe that

Figure 5. Intramuscular injection sites: buttocks (gluteus max-imus) and thigh (vastus lateralis).

Gluteus medius

ephalic vein


,(

it"


postinjection soreness is proportional to extent of muscledamage, which is in turn proportional to injected volume.However, rigid guidelines about limiting injection volumecannot be drawn, as serum CPK levels are also directlyproportional to the concentration of the injected solu-tion.26 When sedating the dental patient, intramuscularlyinjected volumes greater than 3 mL are rarely necessary.

Any of the traditional sites will therefore suffice.

Selection of an Intramuscular Site

Any muscle will suffice for an IM injection. However,there are considerations which have resulted in recom-

mendations that IM injections be routinely made into oneof only four anatomic sites.24 These sites are the glutealarea (ie, the upper outer quadrant of each buttock), theventrogluteal area (ie, lateral hip), the vastus lateralis (ie,antero-lateral thigh), and the deltoid area (ie, shoulder).Clinical and anatomic descriptions of these areas are

available.24,27 Factors which led to the use of only foursites include: 1) minimal numbers of larger nerve path-ways, which reduces the chance for iatrogenic nerve

damage, 2) minimal numbers of larger blood vesselswhich reduce the risk of intraarterial or intravenous injec-tions, and 3) adequate size of the muscle to accommo-

date the volume of injected solution and thereby mini-mize pain during and after injection. In medicine, thegluteal area has historically been the preferred single sitefor IM injections in adults.23 Specifically, the upper, outerquadrant of each buttocks is recommended because ofthe lack of large blood vessels and nerves in this area ofthe muscle. The ventrogluteal area is preferred for bed-ridden patients.23 Ambulatory patients often receive IMinjections in the deltoid muscle.

Studies of muscle group blood flow utilizing the wash-out of radioactive materials have demonstrated signifi-cantly different perfusion rates (mL blood/100 gm tissue/min) for the four traditional sites for IM injections.25 Theperfusion of the deltoid was determined to be 20% higherthan that for the gluteal area, with the vastus lateralissomewhere in between. This is important, because otherstudies of the pharmacokinetics of IM injections haveidentified perfusion of the injection site as the rate-limitingstep in the absorption of medicines given intramuscu-larly.23 When taken together, these observations indicatethat onset of sedation is primarily a function of injectionsite selection. The deltoid muscle thus becomes the pre-

ferred side for IM sedative administration in order to mini-mize the waiting time before surgery can begin.

It is not customary to have a dental patient disrobe foroffice treatment. Because of this tradition, accessibility atthe injection site without disrobing is another factor thatshould be considered when selecting an IM injection site.The deltoid's accessibility is optimal.

After considering factors such as injection volume,muscle blood flow, onset of sedation, and accessibility, adistinct preference exists for the deltoid muscle for IMinjection of sedatives for dental treatment.

Therapeutic Suggestions forIntramuscular Sedation

IM Injection Technique. The skin over the prefer-red injection site should be cleansed with an antisepticsolution such as isopropyl or rubbing alcohol. A mass ofthe muscle, for example the lateral aspect of the deltoid,is held with the nondominant hand, allowing the indexfinger to draw the skin tight by pulling it to the side. Theneedle is inserted perpendicular to the skin in a thrustingmanner to a depth of approximately one inch into themuscle. If extraordinary amounts of adipose tissue arepresent, a proportionately greater depth from the skinmust be used. The syringe is aspirated to assure extravas-cular needle location, and the contents injected at a mod-est, smooth rate similar to that for dental injections in theperioral areas. The total time for injection will of coursebe directly related to the volume injected. Injecting toorapidly causes unnecessary pain. The needle is thenquickly removed, and the injected area massaged with adry gauze for a few seconds in order to spread the in-jected solution and thereby improve absorption.24The armamentarium for IM injections consists of a ster-

ile syringe, a sterile needle, the sedative to be injected, anantiseptic on an applicator pad, and a dry gauze pad. Inan effort to assure sterility, dental and medical practition-ers in the United States have discontinued use of reusablesyringes and needles for IM and intravenous drug admin-istration. All needles and syringes are now disposable,and this has become the standard of care.The dentist must be certain of the compatibility of two

sedatives before drawing both up into the same syringe.The bioavailability of one or both may be dramaticallyreduced in some cases as a result of mixing two drugstogether.An effort should be made to relax the muscle into

which the sedatives will be injected. It is generally be-lieved that an injection into a contracted muscle is morepainful than if the muscle is relaxed.28 Patient apprehen-sion frequently makes relaxation a challenge.

Agents for IM Sedation. Agents useful for sedationof the dental patient may be selected from the sedative-hypnotic, opioid, phenothiazine, and antihistamine cate-gories of pharmacologic agents. Probably the most com-monly used IM sedative in medicine has been acombination of an opioid and a phenothiazine or antihis-tamine. This probably represents the optimal IM sedation

Anesth Prog 38:154-171 1991

Anesth Prog 38:154-171 1991

approach for dental patients as well. Specifically, thecombination of meperidine (Demerol) and promethazine(Phenergan) or hydroxyzine (Vistaril) seems well-suitedfor dental treatment. However, practically any combina-tion of agents from these categories can be found in clini-cal use. Single agent IM sedation is rarely seen in medi-cine or dentistry.The benzodiazepines are not commonly administered

as an IM sedative. This appears surprising as diazepam(Valium) has widespread clinical use as an oral and intra-venous sedative. Numerous reports suggest that diaze-pam absorption after IM administration is slower than thatseen after oral administration. One study demonstratedthat peak serum levels of diazepam occur 60 min afteroral absorption and 90 min after IM administration in theleg.22 Diazepam is also associated with considerable painduring and after IM injection.29 With the oral route equalor more effective and less painful, the IM administrationof the benzodiazepines has not been widely utilized andcannot be recommended. It may be that the newer, wa-ter-soluble midazolam will meet with more widespreadclinical use an as IM sedative.Dose selection for any particular adult patient will vary

with the health status, age, and procedure to be per-formed. With the exception of extractions, most dentalprocedures in which local anesthesia is employed are notsignificantly stimulating and should not be a consider-ation in setting dose. After 60 years of age, dose must beprogressively decreased. This is especially true for thebenzodiazepines.The optimal drug combination for IM sedation is me-

peridine (Demerol) 75 mg and promethazine(Phenergan) 50 mg drawn into the same syringe andgiven as one injection in the deltoid muscle (1.0 mg/kgand 0.7 mg/kg, respectively). This should be effective forthe average 20 to 50 year old healthy, anxious 70-kgdental patient needing 1 hour of dental treatment. If thesedation is clearly inadequate 45 min after injection, ni-trous oxide and oxygen can be added. If the patient isadequately sedated to fall asleep, 3 L/min oxygen shouldbe given by nasal cannula. Again, advanced age, poorhealth, or lack of anxiety usually requires a reduction insedative dose. Onset occurs in about 20 min, reaches auseful therapeutic sedation level in about 45 min andlasts an hour. A useful side-effect of this combination isthe drying of oral secretions.

ComplicationsComplications of IM injections that relate to techniqueinclude (1) pain or numbness due to nerve injury, (2)painful inflammatory induration (sterile abscess) in sub-cutaneous tissues, sometimes accompanied by ulcerationof the overlying skin, (3) infection from the use of non-

sterile needles, syringes, or contaminated sedatives, and(4) unintentional intravascular administration of seda-tives.

Nerve injury is highly unlikely in the deltoid muscle, butis reported in as many as 8% of patients when the glutealsite is injected.2 Clinically, the patient reports tingling ornumbness going down the leg to the foot. It is usually ofshort duration, but rarely can last months or years. Thisclinical picture results from injury to the large sciaticnerve, which exits the pelvis into the inner lower quad-rant of each buttocks.Some medications are quite irritating to surrounding

tissues and are better tolerated as an IM injection ratherthan a subcutaneous injection. This improved tolerancemay be due to the greater perfusion of muscle and thefaster absorption of the irritating sedative. Promethazineand hydroxyzine are examples of irritating sedatives. Ifthe depth of injection is inadequate or some of the drugtracks back to the subcutaneous tissues, an inflammatoryresponse results, and an area of induration can be pal-pated. This phenomenon is frequently referred to as thedevelopment of a sterile abscess. Occasionally, the skinover the induration will undergo necrosis, and an ulcerwill also form.

The need for sterile needles and syringes has resultedin the development and widespread use in the UnitedStates of disposable needles and syringes for intramuscu-lar injections. The only exception to this is the use of aheat-sterilizable metal syringe apparatus used with dis-posable needles and glass cartridges similar to that usedto administer local anesthetics in dental practices. Use ofdisposables for IM injections has rendered infection com-plications quite rare.

Inadvertent intravascular administration is very un-usual if the appropriate IM injection technique is followedand the syringe is aspirated before drug administration.Unintentional intravenous administration of sedativeshould be treated as a potential overdose. Intra-arterialadministration can cause loss of limb, depending on thesedative. If the patient is complaining of pain in the limbdistal to the injection site and the dentist believes intra-arterial injection was a possibility, the patient should behospitalized immediately. Aspiration of the syringe beforeinjection will make this complication highly unlikely.

INTRAVENOUS SEDATION

The intravenous administration of drugs for the reductionof patient anxiety represents the last phase in which con-sciousness is maintained in the continuum from con-scious to unconscious pharmacologic techniques. Therapid distribution of drugs when administered by the in-



travenous route overcomes many of the shortcomings ofother routes of administration but also introduces greaterpotential for adverse effects due to overdosage, too rapidadministration of an otherwise appropriate dose, oroversedation due to additive effects of drugs given inseries. IV premedication became very popular as an alter-native to less effective forms of sedation and as a safermodality than general anesthesia. Unfortunately, it wasbelatedly recognized that this greater efficacy was oftenaccompanied by incidences of serious morbidity and thatthe use of deeper levels of sedation without proper moni-toring carries many of the same risks of general anesthe-sia. Public and professional concern over the risks of IVadministration has led to legislative restrictions to the use

of this route of administration and the development of a

distinction between conscious sedation and deep seda-tion. This chapter will be limited to discussion of IV pre-

medication with anxiolytic drugs and adjunctive agents inwhich consciousness is maintained, protective reflexesare intact, and the patient is capable of responding toverbal instructions and inquiries.

Technical considerations in the use of the intravenousroute of administration, such as venipuncture, are be-yond the scope of this paper and are readily availablefrom other sources. Other important considerations forthe use of the intravenous route discussed elsewhere in-clude monitoring, emergencies, and medicolegal aspectsof sedation. While legislative and educational guidelinesdistinguish between conscious sedation and deep seda-tion, a clinician administering drugs intravenously cannotbe lulled into complacency by nomenclature and must beprepared to manage a patient who becomes less respon-

sive or unconscious. It has been proposed that a maindeterminant of patient safety during sedative techniques

is the choice of the drug, dose, and route of administra-tion, not necessarily the clinical prowess of the adminis-trator.3031 Thus, the choice to use IV sedation in clinicalpractice requires judicious selection of drugs, administra-tion at the recommended rate, limiting the dose to themaximum recommended by the manufacturer, only em-ploying drug combinations when greater efficacy can bedemonstrated in comparison to a full therapeutic dose ofa single agent, and decreasing the dose of the individualagents when a combination is used. The remainder of thissection will focus on aspects of the pharmacology ofdrugs unique to their use for IV premedication in dentaloutpatients and on therapeutic recommendations for theuse of single agents and combinations.

Drugs Used for IV Sedation

Opioid Analgesics. Opioid analgesics exert their ef-fects primarily through interaction with four major typesof receptors found in the central nervous system and inthe spinal cord (Table 5). The mu and kappa receptorsare associated with analgesia, delta receptors are thoughtto be associated with alterations in affective behavior, andsigma receptors are involved in the dysphoria and psy-chotomimetic effects associated with some opioids.32Opioid analgesics are classified according to their rela-tionship with the various receptors. The first group,opioid agonists, are drugs which bind to mu, kappa, anddelta receptors. The second group, opioid agonist-antag-onists, are agonists at some receptors and antagonists atothers.Morphine is the prototype opioid analgesic against

which all other drugs in this class are compared. Drugs in

Table 5. Opioid Analgesics and Opioid Receptors

Receptor

Drug mu kappa delta sigma

AgonistsMorphine + + +Meperidine + + +Fentanyl + +

Agonist-AntagonistsNalbuphine - + +Butorphanol + +

AntagonistsNaloxone

Key: + + = strong agonism+ = agonism- = antagonism

Anesth Prog 38:154-171 1991

Anesth Prog 38:154-171 1991

this class seem to have preferential affinity for mu recep-tors, but they are active to varying degrees at the otherreceptor sites as well.

Opioid agonists exert their primary action on the cen-tral nervous system and the bowel.33 In the central ner-vous system they produce analgesia without the loss ofconsciousness, drowsiness, and alterations in mood. Mor-phine raises both the patient's pain threshold and paintolerance. During intravenous conscious-sedation, the in-creased pain threshold, mood elevation, and indifferenceare valuable commodities to be exploited. Most opioidagonists also produce constriction of the pupil through anexcitatory action on the Edinger-Westphal nucleus of theoculomotor nerve. Miosis is pathognomonic of opioid ag-onists, and no tolerance develops to this effect.

Opioid agonists also produce undesirable effects, suchas respiratory depression, nausea, and vomiting. Mor-phine is a primary and continuous respiratory depressantwhich affects both respiratory rate and tidal volume. Mor-phine decreases the responsiveness of the medullary re-spiratory centers to increasing concentrations of carbondioxide. The usual ventilatory response to increased car-bon dioxide tension is to increase ventilation and returnthe carbon dioxide levels to normal. The stimulus tobreath is obtunded in a dose-related fashion with mor-phine as carbon dioxide levels rise. If the respiratory de-pression is significant, patients may be forced to rely ontheir hypoxic ventilatory drive; that is, they breath only inresponse to low arterial oxygen concentrations. The ven-tilatory status must be monitored closely and positivepressure ventilation instituted if necessary.Nausea and vomiting are at best annoying, and at

worst debilitating, side effects of opioid agonists. Al-though all drugs in this class have the potential for emeticeffects, morphine is most commonly implicated. This oc-curs primarily through direct stimulation of the chemore-ceptor trigger zone in the medulla. This dopaminergiceffect can sometimes be countered by dopaminergic-blocking drugs such as phenothiazines. There also ap-pears to be a vestibular component to the nausea andvomiting seen with opioids, in that rapid positionalchanges may induce emesis.

Opioid agonists are cardiovascularly stable drugs thatproduce no major effect on blood pressure, heart rate, orheart rhythm in the recumbent patient.33 Peripheral vaso-dilation does occur, however, as a result of histaminerelease. Thus, when patients are returned to an uprightposition, postural hypotension and syncope may occur.Morphine and meperidine promote the most histaminerelease and are the most likely candidates for posturalhypotension. The cerebral circulation is affected indirectlyin the presence of respiratory depression. If carbon diox-ide levels rise, the cerebral blood vessels dilate, and intra-cranial pressure increases.

Opioid agonists also have effects on the gastrointestinaltract and other smooth muscle. In the GI system, motilityis decreased and smooth muscle tone is increased in thestomach and first part of the duodenum. This causes amajor delay in gastric emptying and contributes toopioid-induced constipation. Similar increases in smoothmuscle tone occur in the small and large intestines. Biliarytract pressure increases, often with spasm at the sphincterof Oddi. Opioid agonists also increase smooth muscletone in the ureter and bladder, which results in urinaryretention. The volume of urine may also be affected sincethe secretion of antidiuretic hormone is stimulated. Con-stipation, urinary retention, and biliary spasm are side-effects to be considered when opioid agonists are usedfor sedation. In susceptible individuals, these side-effectscan override any potential benefit from the drug andshould be avoided at all costs. The prudent course ofaction would be to eliminate them entirely or use a drugin the agonist-antagonist group which is not associatedwith these effects. The histamine-releasing opioid ago-nists, morphine and meperidine, may exacerbate or in-duce an acute asthmatic attack. They also may producepruritus, sweating, urticaria, and flushing of the face,neck, and upper thorax.The above pharmacologic properties of opioid agonists

apply specifically to morphine and generally to meperi-dine (Demerol) and fentanyl (Sublimaze), two useful ago-nists for intravenous conscious sedation. Meperidine wasfirst studied as an atropine-like agent,33 but it was discov-ered to have analgesic activity similar to morphine. Me-peridine is a weaker agent than morphine; 80-100 mg ofmeperidine is equivalent to 10 mg morphine. It interactsmore strongly with the kappa opioid receptor, and itsduration of action is less than morphine. Propertiesunique to meperidine are its profound antisialogue effectand tachycardia following intravenous administration. Ametabolite of meperidine, normeperidine, is associatedwith toxic effects, such as tremors, muscle twitching, andconvulsions. High doses of meperidine may thereforecause an excitatory sequence of events. Meperidine iscontraindicated in patients taking MAO inhibitors due inpart to an alteration in the rate of metabolic transforma-tion. Inhibition of MAO causes an accumulation of nor-meperidine which can lead to delirium, hallucinations,seizures, hyperpyrexia, or respiratory depression.

Fentanyl is an extremely potent analgesic which is 80-100 times as potent as morphine.33 It acts primarily at themu receptor, and it produces the most profound respira-tory depression of the drugs discussed in this class. How-ever, its short duration of action makes it useful as asedative agent for shorter dental procedures. Fentanylproduces little if any euphoria or mood alteration. It iseasy to overdose patients with fentanyl if this fact is notappreciated. Inexperienced clinicians, expecting to see



mood elevation with fentanyl, will readminister the druguntil severe respiratory depression occurs. Fentanyl doesnot produce histamine release and may be used in asth-matic patients, providing that respiratory depression isavoided. Fentanyl has been associated with chest-wallrigidity, or stiff-chest syndrome.34,35 This occurs throughthe enhancement of dopaminergic transmission. Al-though all opioid agonists can do this, fentanyl seems

more prone to this effect. Chest-wall rigidity is usuallyassociated with the rapid administration of high doses,but it has been reported with as little as 25 ,g of fen-tanyl.35 This effect can be antagonized by naloxone.There are two opioid agonist-antagonists which are

useful for intravenous conscious sedation, nalbuphine(Nubain) and butorphanol (Stadol). Nalbuphine is a

competitive antagonist at the mu receptor, but it has par-tial agonist properties at the kappa and sigma receptors(Table 1). Nalbuphine is equipotent with morphine, butin contrast to the dose-dependent respiratory depressionseen with morphine, there is a ceiling or plateau effect tothe respiratory depression of nalbuphine. Nalbuphineproduces no histamine release, minimal biliary constric-tion, and is cardiovascularly stable.36

Butorphanol has little effect on the mu receptor, but itacts as a partial agonist at the kappa and sigma receptors(Table 1). It is a much more potent drug in that 2 mg ofbutorphanol is equivalent to 10 mg of nalbuphine or

morphine. While respiratory depression can occur, it alsoexhibits a ceiling effect. Butorphanol does not cause his-tamine release or biliary constriction, but unlikenalbuphine, it increases pulmonary arterial pressure andthe cardiac index.37 The increased work of the heart maypreclude its use in patients with significant cardiac dis-ease.

Any drug that stimulates sigma receptors has the po-

tential for psychotomimetic effects. These are describedas uncontrollable or strange thoughts, anxiety, night-mares, and hallucinations. These are not common intherapeutic dose ranges, but their incidence may increasewith increasing dosages. Both nalbuphine and bu-torphanol may produce these effects, but it is unlikely inthe doses used for conscious sedation. Agonist-antagonistdrugs are contraindicated in opioid-dependent patientsdue to the possibility of precipitating a withdrawal syn-

drome.

Precautionsfor Use. Opioid analgesics are contrain-dicated in cases of closed-head injury where intracranialpressure may be elevated. The carbon dioxide retentionthat may occur with opioids could further increase intra-cranial pressure and produce disastrous results. Thesedrugs should also be used with caution in patients withsevere restrictive or obstructive pulmonary diseases. Fur-ther increasing carbon dioxide levels in patients with

chronically elevated arterial carbon dioxide could effec-tively knock out the respiratory drive. Caution should beused with asthmatic patients as well. Opioids that releasehistamine, such as morphine and meperidine, could pre-cipitate an acute asthmatic episode during treatment.Therefore, opioids are relatively contraindicated in thepresence of respiratory disease.Drug interactions between opioid analgesics and other

drugs may be cause for concern. The central nervoussystem, cardiovascular, and respiratory depression asso-ciated with opioids can be potentiated by benzodiaze-pines, phenothiazines, tricyclic antidepressants, and MAOinhibitors. Dosages should be appropriately reduced inthese instances. The combination of meperidine with anMAO inhibitor is potentially life-threatening and is to beavoided.

Benzodiazepines. Although benzodiazepines usedfor IV sedation have a high margin of safety, their clinicaleffects are highly variable. They must be carefully titratedto clinical effect rather than administered as a bolus injec-tion. Midazolam (Versed) has twice the affinity for thebenzodiazepine receptor as diazepam (Valium).38 Thisaccounts in part for the higher potency and greater am-nestic and anticonvulsant effects of midazolam.39 Bothdiazepam and midazolam produce respiratory depressionin a dose-related manner by decreasing the ventilatoryresponse to carbon dioxide. This respiratory depression ismarkedly worsened when midazolam is used in patientswith chronic obstructive lung disease.40,41 In contrast,when diazepam and midazolam are slowly titrated intra-venously to a fixed clinical endpoint, no clinically signifi-cant ventilatory changes occur.4243Diazepam and midazolam have little effect on hemody-

namic stability. Glisson et al44 found that midazolam sup-pressed plasma elevations of epinephrine and nore-pinephrine during induction of general anesthesia. Thisindicates that midazolam, like diazepam, may be of valuein attenuating catecholamine surges during stress.The pharmacokinetic profile of the benzodiazepines

conforms to a classic two-compartment model; that is,distribution from a central compartment to a peripheralcompartment along a concentration gradient, and thenelimination. The distribution phase is reversible and rapidfor benzodiazepines. The elimination phase is irreversibleand slow since it is governed by the rate of biotransforma-tion of the drug. Termination of activity for the benzo-diazepines is caused by a combination of redistributioninto the tissues and metabolic biotransformation.The extreme lipid solubility of midazolam produces a

very rapid onset. The distribution half-life for midazolamis 6-15 min. The short duration of action of midazolam isattributed to its very high rate of metabolic clearance andrapid rate of elimination. The elimination half-life for mi-

Anesth Prog 38:154-171 1991

Anesth Prog 38:154-171 1991

dazolam is 1-4 hours, which is faster than that of otherbenzodiazepines. In addition, the metabolites of midazo-lam are mostly inactive.45Diazepam has a slower rate of distribution than most

benzodiazepines (half-life = 30-66 min), and thereforehas a somewhat slower (twice) onset than midazolam.The elimination half-life for diazepam is 24-57 hours,which is at least 10 times slower than for midazolam.Diazepam also has two active metabolites, desmethy-ldiazepam (elimination half-life = 41-139 hours) andoxazepam, which both produce sedative effects.45 Termi-nation of clinical activity for diazepam occurs primarilythrough redistribution. However, the combination of ac-tive metabolites and the long elimination half-life ac-counts for the residual "hangover" effects seen clinicallyfollowing diazepam administration.A number of factors influence the pharmacokinetic

profile of the benzodiazepines. For example, the elimina-tion half-life for diazepam and midazolam is prolonged inthe elderly patient due to an impairment in the total meta-bolic clearance rate.46 The number of benzodiazepinereceptors may also be decreased. Therefore, the doserequirement for diazepam and midazolam is lower in theelderly patient.The extremely obese patient also presents as a man-

agement problem, because the elimination half-life ofboth diazepam and midazolam increases along with thevolume of distribution. However, higher than usual dos-ages may be required to counteract the rapid redistribu-tion of the drugs into fatty tissues. Thus, in the obesepatient, higher drug doses may be necessary to producethe desired effect, and the recovery period may likewisebe more prolonged.A decrease in plasma proteins, especially serum al-

bumin, as is often seen in renal failure, results in an altera-tion in protein binding capacity. Since the benzodiaze-pines are highly protein bound, renal failure couldincrease the free fractions of midazolam and of diazepamand its metabolites. This could result in more profoundand prolonged effects. Therefore, the dose of diazepamand midazolam should be reduced in patients withchronic renal failure.47

Therapeutic Suggestions for Sedation with Ben-zodiazepines. Diazepam and midazolam have beenused extensively as primary agents, and in conjunctionwith opioids, for intravenous sedation. The properties ofdiazepam and midazolam are compared in Table 6.Diazepam is not water soluble, and is therefore dissolvedin a vehicle containing 40% propylene glycol. This vehi-cle has been implicated in a significant incidence of painduring intravenous injection and venous irritation. Thelong elimination half-lives of its two active metabolitestend to prolong recovery by producing residual sedation

Table 6. Midazolam Versus Diazepam

Property Midazolam Diazepam

Water solubility Yes NoPain on injection No YesVenous irritation < 1% 5-30%Distribution half-life 6-15 min 30-66 minElimination half-life 1-4 hr 24-57 hrMetabolites Inactive Active

and "hangover" effects. Despite these negatives, diaze-pam has been the mainstay for years as the principle drugfor intravenous conscious sedation in dentistry. Its safetyrecord has been remarkable, and it is decidedly less ex-pensive than midazolam.Compared with diazepam, midazolam has some signifi-

cant advantages. Because it is water soluble, there is littleor no pain during intravenous injection, and the inci-dence of venous irritation is virtually nonexistent. Mida-zolam has a more rapid onset and produces more pro-found sedation and better amnesia than diazepam.Although patients who receive midazolam may be slightlymore somnolent at the end of a procedure, and the re-turn to "street fitness" may be slightly longer,48 the shortelimination half-life and the lack of active metabolitesmake overall recovery from midazolam sedation ex-tremely rapid when compared with diazepam. With allelse being equal, the water solubility and short elimina-tion half-life of midazolam make it the superior drug forintravenous conscious sedation for outpatient proce-dures.The recommended dose range for intravenous con-

scious sedation with diazepam and midazolam is 0.15-0.3 mg/kg and 0.05-0.075 mg/kg, respectively. How-ever, a more appropriate method of sedation withdiazepam and midazolam is slow titration of the drug untila predetermined clinical endpoint is reached. Cardiores-piratory depression should be absent when this titrationmethod is used. Should readministration become neces-sary, 25% of the initial dose of either drug will generallyreturn the patient to the baseline level of sedation.

Precautionsfor Use. The incidence of adverse reac-tions with the benzodiazepines is low. Nausea and vomit-ing, coughing, and hiccoughs have occasionally beennoted. Respiratory depression with prolonged somno-lence may also occur infrequently with midazolam. Theseeffects have been rapidly and effectively reversed withphysostigmine administration and with the specific ben-zodiazepine antagonist, flumazenil.49,50

Caution should also be observed in the managementof elderly patients with the benzodiazepines. In general,dosages should be reduced by at least 25%, and there is a



less frequent need for readministration. Cardiac output isdiminished in the elderly patient, and the onset of seda-tion is delayed after the intravenous administration ofthese drugs. Reduced plasma volume, protein binding,and central nervous system function act to increase thepotency of the drugs. Reduced metabolic rate, hepaticand renal clearance, and a higher percentage of body fattend to slow metabolism and elimination and allow fordrug accumulation. This increases the duration of action

of the benzodiazepines, and prolongs the interval be-tween readministration.The benzodiazepines must never be used for intrave-

nous sedation without individualization of dosage. Priorto IV administration of any dose, oxygen and resuscita-tive equipment for the maintenance of a patent airwayand support of ventilation should be readily available.Patients should be continuously monitored for early signsof hypoventilation or apnea. Neither diazepam nor mida-zolam should be administered by rapid or single bolusintravenous injection. This mode of administration hasresulted in serious cardiorespiratory events, predomi-nately in older, chronically ill patients and especially ifother cardiorespiratory depressant agents are being takenconcomitantly. Midazolam especially has been associatedwith respiratory depression, apnea, and respiratory and/or cardiac arrest in this age group, sometimes resulting indeath. These events have almost always been a conse-

quence of improper midazolam administration as well as

violations of the tenets of diligent anesthesia care.

Adverse reactions such as agitation, involuntary move-ment, hyperactivity, and combativeness have been re-

ported with the benzodiazepines. These reactions may bedue to inadequate or excessive doses or improper admin-istration. However, consideration should be given to thepossibility of cerebral hypoxia or true paradoxical reac-

tion.The water solubility and rapid clearance of midazolam

make it a clear choice over diazepam for intravenousconscious sedation. Additionally, midazolam produces a

more profound and prolonged amnestic effect thandiazepam. This effect does not necessarily correlate withthe clinical sedation level. Thus, patients are more likelyto experience amnesia without having to be heavily se-

dated. This should serve to enhance the experience ofboth the patient and the clinician.

Antiemetics. The antiemetics are structurally similarto antipsychotic agents but which happen to have anti-emetic effects. They consist of two drug groups, thephenothiazines and the butyrophenones, both of whichhave similar pharmacologic properties.51 Promethazine(Phenergan) and prochlorperazine (Compazine) are

phenothiazine derivatives, and droperidol (Inapsine) is abutyrophenone.

Additional pharmacological properties of these drugsinclude ganglionic and alpha-adrenergic blocking effects,anticholinergic activity, anti-dopaminergic effects, andantihistaminic properties. They also potentiate the effectsof other central nervous system depressants. Postural hy-potension is common when rapidly changing positionfrom supine to upright. Because of the variety of actions,drug interactions are also common with the antiemetics.In combination with epinephrine, the alpha-blockingproperties of the phenothiazines could allow the beta ef-fects of epinephrine to predominate. This could result in aprecipitous drop in blood pressure.The anticholinergic effects of the antiemetics can lead

to problems either alone or in combination with otheranticholinergic drugs such as tricyclic antidepressants, an-tihistamines, and atropine. A central anticholinergic syn-drome characterized by anxiety, agitation, disorientation,restlessness, delirium, or stupor may occur. While rarelylife-threatening, it can be extremely disruptive and is tobe avoided.

Other potentially disheartening side effects of the anti-emetics are extrapyramidal reactions. These are medi-ated through the dopaminergic blocking effects of thedrugs. It is ironic that the same mechanism that producesthe desirable effect of emesis control also produces theundesirable effects of extrapyramidal reactions. These arecharacterized by parkinsonian-like tremors at rest, akathi-sia (compelling need to be in constant motion), dystonia(facial grimacing and torticollis), and tardive dyskinesia(sucking and smacking of the lips, lateral jaw movements,darting of the tongue).

It should be obvious that due to the potential variety ofadverse effects, antiemetic drugs are to be used only asan adjunct to intravenous sedation. The routine prophy-lactic use of antiemetic agents is not necessary since theincidence of nausea and vomiting associated with con-scious sedation is rare. The risks of routine administrationfar outweigh the perceived benefits, thus relegating thesedrugs to the role of adjuncts in susceptible individuals.

Antisialogogues. The role of antisialogogues in an-esthetic practice probably evolved from the early days ofether anesthesia when excessive airway secretionscaused significant management problems. Atropine andscopolamine where used to produce a dry field, reducethe incidence of laryngospasm, and improve visualizationof the airway. These drugs are parasympatholytic or va-golytic agents. Among other things, they reduce salivaryflow, increase the heart rate, and cross the blood/brainbarrier to produce sedation. Scopolamine producesmuch more sedation than atropine, and is still used as asedative agent in some techniques. However, it can pro-duce the central anticholinergic syndrome, and therefore

Anesth Prog 38:154-171 1991

170 Giovannitti and Trapp Anesth Prog 38:154-171 1991

Table 7. Comparative Summary of Intravenous Agents

Drug Dose Onset Duration

Diazepam 0.15-0.3 mg/kg* 0.5-1 min 45 minMidazolam 0.05-0.075 mg/kg* 1-2 min 30-60 minMorphine 0.05-0.1 mg/kg 5-10 min 2-4 hrMeperidine 0.3-0.6 mg/kg 2-4 min 30-45 minFentanyl 0.001-0.002 mg/kg 30 sec 30-60 minNalbuphine 0.05-0.1 mg/kg 2-3 min 2-4 hrButorphanol 0.007-0.014 mg/kg 2-3 min 2-4 hrPromethazine 12.5-25 mg 2-3 hrProchlorperazine 5-10 mg 2-3 hrDroperidol 0.625-1.25 mg 3-6 hrAtropine 0.2-0.4 mg 1 min 1-2 hrGlycopyrrolate 0.1-0.2 mg 1-2 min 2-3 hr

*Usual dose range for conscious sedation, however, these drugs must be titrated to a clinical endpoint onan individual basis.

has no real value in dental sedation. Atropine may alsoproduce the syndrome, but the incidence is less.

Glycopyrrolate (Robinul) is a quaternary amine whichcannot cross the blood/brain barrier. Therefore, it doesnot produce sedation or the central anticholinergic syn-drome. Additionally, it is a more prolonged drying agentthan atropine, and its cardiac acceleratory effects are less.Because of this, glycopyrrolate should be the antisialogo-gue of choice.As with the antiemetics, the antisialogogues are only

adjuncts to the sedative technique. Sedation with a ben-zodiazepine alone or in combination with an opioid willproduce sufficient drying in the vast majority of cases.The routine administration of an antisialogogue is notwarranted because of the potential for producing tachy-cardia or central nervous system side effects. If salivationis a problem even after sedation has been administered,glycopyrrolate is the drug of choice. Atropine should berelegated to the emergency drug kit for the treatment ofbradycardia associated with hypotension.A comparative summary of useful drugs for intrave-

nous conscious sedation is provided in Table 7.

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