GENERAL ANESTHETICS: a COMPARATIVE REVIEW of PHARMACODYNAMICS Stephen B

BRIEF REVIEW: GENERAL ANESTHETICS: A COMPARATIVE REVIEW OF PHARMACODYNAMICS Stephen B. Milam, D.D.S. Baylor College of Dentistry Dallas, Texas SUMMARY General anesthetics, in addition to eliminating the perception of stimuli, produce profound physiologic effects in other systems including the cardiovascular and respiratory systems. A thorough knowl- edge of the pharmacodynamics and pharmacokinetics of each agent as well as an understanding of the patient's physiologic reserve will allow the anesthetist to reasonably predict the response to a given drug. The ability to forecast patient responses imparts control over an anesthetic technique which con- tributes to the overall safety of the procedure. This paper reviews pharmacodynamics of general anesthetic agents commonly used in dentistry. Introduction general anesthesia was simply defined as a loss of According to the statistics compiled by the all sensations produced by a drug-induced depres- National Institutes of Health, 20% of all general anes- sion of the CNS. However, studies of physiologic thetics administered in the U.S. are administered for function clearly indicate that the physical liabilities dental procedures.' Though conscious-sedation associated with general anesthesia begin with loss techniques are becoming increasingly popular as an of consciousness which is clinically defined as an alternative to general anesthesia, the fact remains inability to respond rationally to command. The that these techniques have limited applicability and reported goals of general anesthesia include the pro- cannot be substituted for general anesthesia in cer- duction of unconsciousness, inhibition of autonomic tain situations. Children, mentally handicapped, responses to noxious stimuli, production of amnesia, medically compromised or excessively anxious den- relaxation of skeletal muscles and rapid recovery to a tal patients and patients requiring major surgical pro- mentally alert state. To achieve these goals, toxic cedures frequently require general anesthesia for doses of potent drugs which can produce significant dental procedures. physiologic insult are administered to patients. The main objective of general anesthesia is the ablation of pain perception. An ideal general anes- Effects on CNS thetic would simply "put the patient to sleep" and Although the exact mechanism of action is still would be void of any unwanted side effects such as unknown, agents capable of producing general loss of protective reflexes, and respiratory and/or anesthesia are believed to act at hydrophobic sites in cardiovascular depression. However, the ideal gen- nerve membranes. A strong correlation exists eral anesthetic does not yet exist and general anes- between anesthetic potency, which is defined in thesia is not sleep. Significant changes in terms of minimum alveolar concentration (MAC) for cardiovascular, respiratory, renal, hepatic and endo- inhalation general anesthetics and ED50 for paren- crine function often accompany the general anes- teral general anesthetics, and lipid solubility (i.e. oil/ thetic state. Therefore, the safety of any general gas or oil/water partition coefficient). In fact, virtually anesthetic technique rests with the ability of the any lipid soluble agent can produce general anesthe- anesthetist to recognize and control these concur- sia. Even air administered at 23.6 atmospheres can rent changes in physiologic function. produce an anesthetic effect.2 Of the inhalation anesthetics commonly employed Definition for use in dentistry, halothane is the most potent with General anesthesia is the culmination of a contin- a MAC value of 0.76% followed by isoflurane uum of physiologic responses to reversible, drug- (1.15%), enflurane (1.68%), and nitrous-oxide induced CNS depression which is heralded by the (101-105%). The most common parenteral agents production of unconsciousness. In the recent past, used for induction and/or for maintanance of general anesthesia in dentistry rank in potency from midazolam and etomidate (most potent) to thiopental and Methohexital and Accepted for publication April 27, 1984. thiamylal (least potent). Address reprint requests to: Dr. Stephen Milam, Department of ketamine, agents of intermediate potency, are Pharmacology, Baylor College of Dentistry, 3302 Gaston Avenue, approximately one-third to one-fifth as potent as Dallas, Texas 75246. midazolam and etomidate (see Table 1). 116 ANESTHESIA PROGRESS Table 1. Relative potencies of commonly used 45- general anesthetics A

Drug Relative Potencies 0._c 30- 28 Inhalation MAC (%) 26 N20 1 101-105 E 44 Enflurane 62.5 1.68 FI Isoflurane 91 1.15 15- Halothane 138 0.76 Parenteral Induction Dose L44.9d.d.a* J.44d.d.iCj'.AL------i&6-dd.. S (mg/Kg) Thiopental Ketamine Midazolam Ketamine Thiopental 1 4.0 (4 mg* kg'-1) (1.5 mg- kg'1) (0.3mg kg'1) (0.15 mg. kg'1) Thiamylal 1.1 3.5 Midazolam Ketamine 2.5 1.0-1.5 (0.75 mg * kg-1) 2.6 1.5 Methohexital Fig. 1 Recovery time from anesthesia. Etomidate 15 0.3 Data from White, PF, Anesthesiology 1982;57:279-284. Midazolam 15-20 0.3 Amnesia The term amnesia refers to a complete inability to Recovery recall events during a period when the subject was The most common side-effect produced by a gen- considered to be sufficiently awake to be aware of eral anesthetic is prolonged drowsiness. If post- their happening. Significant anterograde amnesia operative somnolence is excessive, patient dis- (i.e. memory loss following drug administration) can charge will be significantly delayed. Recovery from be produced by all general anesthetic agents at general anesthesia is dependent upon a number of subanesthetic doses." Little is known about this factors including duration of anesthesia, physico, effect; however, studies indicate that the hippocam- chemical properties of the anesthetic agent (i.e. solu- pus, important in memory trace consolidation, is bility and protein binding), and the rate of metabolism depressed by anesthetic agents.'2 and/or excretion. In addition, certain disease states The alveolar concentration of an inhalation anes- and drug interactions can influence the duration of thetic agent at which amensia occurs is approxi- anesthetic action. For example, diazepam can mately 0.2 MAC. Therefore, patients not paralyzed increase the sleeping time of patients anesthetized with depolarizing or non-depolarizing muscle relax- with ketamine by as much as 40%.67 This effect is ants will usually respond to a noxious stimulus with presumed to reflect inhibition of the hepatic metabo- gross movement before they have recall when anes- lism of ketamine by the benzodiazepine.8 thetized with inhalation agents. Since narcotics do The duration of anesthesia and the solubility of the not produce amnesia, balanced anesthesia tech- anesthetic in blood are the major determinants of the niques usually rely on neuroleptic and/or duration of anesthetic effect for the inhalation psychosedative agents for amnestic effects. agents. Isoflurane, with the lowest blood/gas partition coefficient of the commonly used potent inhalation agents, theoretically should be eliminated more Seizure Activity and Emergence rapidly than enflurane or halothane and allow for a Phenomena more rapid recovery. However, recovery times for In addition to producing CNS depression and gen- enflurane, halothane, and isoflurane are not eral anesthesia, some anesthetic agents may excite significantly different. Patients anesthetized with certain areas of the brain. Ketamine, a compound isoflurane for less than one hour open their eyes on structurally related to phencyclidine and cyclohexa- command an average 7.3 minutes after discontinua- mine, excites regions of the thalamus and limbic sys- tion of anesthesia.3 Recovery time is increased 65% tem'3 resulting in epileptiform patterns. However, in patients anesthetized for two to three hours; how- there is no evidence that this seizure activity can pre- ever, a longer exposure does not appear to prolong cipitate generalized convulsions. In fact, Reder et al. recovery any further.3-5 have demonstrated anticonvulsant properties of Compared to ketamine and thiopental, midazolam ketamine.'4 has the slowest onset and the longest duration of Psychic emergence reactions are frequently action (see Fig. 1). Onset and recovery time for observed following ketamine anesthesia. thiopental, ketamine, and a midazolam-ketamine "Flashback" experiences have been reported sev- combination do not differ significantly after intrave- eral weeks after ketamine administration in adults nous administration.9 Methohexital and etomidate and children.'5'6 These psychomimetic effects vary are similar in onset and duration of effect and do not in incidence from 5 per cent to 72 per cent'0'7 and differ significantly from thiopental. occur more frequently in females; when large doses

MAY/JUNE 117 are administered rapidly; in adults; and/or when activity.33 Though there is no indication that patients ketamine is administered to patients with personality with a history of seizure disorders are more disorders.'18 Certain premedicants are known to susceptable to this effect, it would be prudent to affect the incidence of psychic disturbances avoid enflurane in these patients. Isoflurane, an following ketamine. Atropine and droperidol have optical isomer of enflurane, does not produce seizure been shown to increase the frequency of unpleasant activity.33 dreams19-22; while bartiturates,23 inhalation general Shivering is commonly observed in the recovery anesthetics,24 and benzodiazepines62526 have been phase of general anesthesia.34 Shivering can be reported to reduce the incidence of the psychic extremely detrimental since it is associated with a actions of ketamine (see Table 2). Since atropine 200-300% increase in metabolic 02 demand. It is increases the incidence of dreaming after ketamine now recognized that one component of shivering is administration, glycopyrolate (Robinul), a quaternary neurologic and is not related to changes in body tem- anticholinergic which does not cross the blood-brain perature. This component may represent an acute barrier, is recommended to prevent secretions stimu- withdrawal phenomena which has been observed in lated by ketamine. animals35 and can be controlled with intravenous methylphenidate or meperidine but not fentanyl.36 Fentanyl in doses as low as 200 ug has been Table 2. Benzodiazepines which attenuate psychic reported to precipitate grand mal seizures,37 an actions of ketamine effect which may be related to its lack of efficacy in Administration reducing post-anesthetic shivering. Drug Dosage Route Lorazepam 0.02-0.05 mg/Kg PO, i.v. Cardiovascular Effects Diazepam 0.15-0.30 mg/Kg PO, i.v. All general anesthetics cause direct dose-related Midazolam 0.10-0.30 mg/Kg i.m., i.v. depression of the myocardium. However, this may Flunitrazepam 0.03 mg/kg not be evident clinically since the cardiovascular signs of anesthesia are the result of a balance Spontaneous tremor (i.e. myoclonus) may occur between this direct effect (i.e. depression) and after intravenous injection of methohexital.27 The increased sympathetic activity,38 produced by phys- exact cause of this excitatory effect is unknown; how- ical stimulation, some general anesthestics, and ever, since epileptogenic foci are preserved during other adjunctive agents commonly used during gen- methohexital anesthesia it is recommended that eral anesthesia (i.e. pancuronium). Halothane and methohexital not be used in patients with a history of enflurane depress the sympathoadrenal system seizure disorders. reducing catecholamine production and are Myoclonus is frequently (i.e. 32%) observed after therefore more commonly associated with clinical the administration of etomidate, a recently released signs of cardiovascular depression (i.e. hypotension, ultra short-action non-narcotic, non-barbiturate bradycardia) than are agents such as ketamine induction agent. Chemically, etomidate is unrelated which produces adrenergic stimulation. to any currently available hypnotic agent but is Of the inhalation general anesthetic agents, pharmacodynamically similar to thiopental. Myoclo- enflurane produces the greatest cardiovascular nus usually occurs with the onset of sleep and during depression. The cardiovascular effects of 1.6 MAC recovery and is felt to be the result of disinhibition of enflurane are equivalent to 2.0 MAC halothane. In the cortex. Myoclonus produced by etomidate is not fact, there is a narrow margin of safety between con- associated with epileptiform discharges on EEG.28 centrations of enflurane required for surgical anes- Boralessa and Holdcroft compared methohexital 1.5 thesia and concentrations associated with danger- mg/Kg to etomidate 0.3 mg/Kg for induction of dental ous cardiovascular depression. For this reason, anesthesia and found the incidence of involuntary enflurane is usually supplemented with N20 and/or muscle movements to be comparable.' However, narcotics. Isoflurane does not produce significant Yelavich and Holmes were forced to discontinue a cardiac depression below 1.5 MAC. The margin of study evaluating etomidate for outpatient cystoscopy safety is greater with isoflurane than with enflurane because of an unacceptable incidence of side effects or halothane.8 Although evidence that N20 when including a 50% incidence of skeletal movements used as the sole agent produces direct negative and a 25% incidence of emergence psychoses.30 inotropic and chronotropic effects, it is also known to Involuntary movements produced by etomidate may produce mild oc-adrenergic stimulation.39 be attenuated by pretreatment with droperidol and/or The net effect of N20 on the cardiovascular sys- fentanyl.3' tem is insignificant. At doses approaching 1.5 MAC, enflurane pro- Barbiturates are direct myocardial depressants duces hypersynchrony and spike activity on EEG.32 and vasodilators. Arterial hypotension is a frequently In the presence of hypocarbia (i.e. hyperventilation) encountered phenomenon associated with barbit- auditory stimuli can precipitate generalized seizure urate anesthesia and depends upon a number of 118 ANESTHESIA PROGRESS factors including the total dose administered, the rate nomena, does not affect cardiovascular stimulation of administration, and the physical status of the by ketamine.54 patient. A maximum fall in blood pressure usually Thiopental Ketamine Midazolam Ketamine/ occurs within seconds of administration and may Midazolam persist even after the return of consciousness.404° Allen et al.41 observed pronounced cardiovascular depression in dental patients given thiopental supplemented with N20/O2 for general anesthesia which continued long into the post-operative period (i.e. 45 minutes). Furthermore, phenothiazine and/or narcotic premedicants may potentiate a hypotensive : response to barbiturates.40 These effects may produce devastating results in patients with coronary artery disease, congestive heart failure, or valvular defects. A major advantage of etomidate is that it produces a minimal effect on the cardiovascular system. Etomidate causes a slight transient decrease in peripheral vascular resistance with a mild reflexive Fig. 2 Changes in mean arterial pressure associated with induc- increase in heart rate (approximatey 10/min for 1 tion of general anesthesia. min.). Coronary perfusion pressure and myocardial Data from White, PF, Anesthes!ology 1982;57:279-284. oxygen demand are unaffected, making etomidate a suitable induction agent for patients with cardiovascular disease.4243 Arrhythmogenicity Like etomidate, the benzodiazepines (diazepam There is a high incidence (17%) of cardiac and midazolam) exert minimal cardiovascular dysrhythmias associated with general anesthesia for effects. Increased coronary blood flow, increased dentistry.55 Etiologic factors associated with an myocardial function, reduced myocardial oxygen increased incidence of cardiac dysrhythmias during consumption, and stable systemic blood pressure general anesthesia include: a prior history of heart have been observed in patients with cardiovascular disease, endotracheal intubation, surgical stimula- impairments following diazepam administration.4446 tion, inadequate ventilation, hemodynamic changes, Likewise, White'° found remarkable cardiovascular electrolyte disturbances, and myocardial sensitiza- stability in healthy patients given midazolam (see tion to catecholamines by anesthetic agents (see Fig. 2). An induction dose of midazolam (i.e. 0.3 Fig. 3). mg/Kg) did not affect mean arterial pressure (MAP). However, in a recent study comparing the cardiovascular effects on midazolam with thiopental Hypoventilation Heart disease Visceral stimulation in ASA III patients, midazolam produced a significant fall in MAP (15.7%). This effect was maximum CardiacCar dysrhythmiasrhythmias approximately ten minutes after the administration of midazolam.47 A similar effect has been observed in / 1 \~~~~ patients with chornic renal failure.48 Furthermore, Electrolyte Hemodynamic changes Anesthetic agents changes in cardiovascular function induced by either disturbances midazolam or thiopental are not significantly Fig. 3 Factors associated with an increased incidence of cardiac different.47 Therefore, with respect to effects on dysrhythmias during general anesthesia. cardiovascular function, midazolam does not appear to offer a significant advantange over thiopental. Patients with significant heart disease are natu- Ketamine is a direct myocardial depressant49.50; rally more prone to develop dysrhythmias under gen- however, ketamine does produce sympathomimetic eral anesthesia than are healthy individuals. The effects in some patients primarily by direct stimula- incidence of dysrhythmias associated with general tion of the CNS18, making it the induction agent of anesthesia in this group can be as high as 35%.56 choice in acutely traumatized patients suspected of Furthermore, Williams and Stone57 have observed a being hypovolemic. However, unexpected drops in higher incidence of ventricular dysrhythmias in blood pressure have been observed when ketamine patients with heart disease anesthetized with was used as an induction agent in critically ill or halothane (20%) compared to enflurane (7%). acutely traumatized patients.51 Furthermore, Under light general anesthesia, surgical and tra- premedication with diazepam,52 thiopental,53 and/or cheal stimulation from endotracheal intubation can midazolam18 significantly attenuate ketamine- produce significant cardiac dysrhythmias. Concur- induced cardiovascular stimulation. Lorazepam, the rent use of local anesthesia can reduce the incidence most effective agent in reducing emergence phe- of dysrhythmias associated with excessive surgical

MAY/JUNE 119 stimulation and may have the secondary benefit of Ketamine may sensitize the myocardium to controlling pain in the recovery phase of general catecholamines, however, clinical reports are anesthesia. conflicting and this issue remains controversial.18 Hypoventilation may precipitate significant cardiac Myocardial sensitization has not been described for dysrhythmias. Although hypercarbia in an awake other parenteral anesthetic agents. state is rarely associated with cardiac dysrhythmias, under general anesthesia arterial carbon dioxide tensions as low as 60 mmHg can produce dysrhythmias. This is especially true when anesthe- 1:x sia is produced by halogenated hydrocarbons (i.e. 1( 0. halothane).58 Therefore, the ventilatory status of the S o.c patient must be continuously assessed during gen- .QC ! eral anesthesia and should be supported with positive pressure if hypoventilation is suspected. I4 Hemodynamic changes which increase ventricu- 0 lar wall tension or myocardial perfusion may precipi- E tate ischemic changes in the myocardium leading to dysrhythmias. In addition, variations in electrolyte 0 composition may alter the automaticity in myocardial Halothane Halothane Isoflurane Enflurane cells and precipitate dysrhythmias. Hypokalemia and Lidocaine hypocalcemia enhance automaticity and increase Fig. 4 Arrhythmogenic dose (ED50) of epinephrine administered the likelihood of multifocal ectopic activity. submucosally. Hyperkalemia, hyponatremia, and hypercalcemia Data from Johnston, RR, et al. Anesth and Analg (Cleve) reduce excitability and conduction velocity setting 1976;55:709. the stage for re-entry mechanisms which can initiate dysrhythmias. A preoperative assessment of electro- Respiratory Effects lyte balance is indicated when the medical history Depression of central regulatory mechanisms, and physical examination indicate the potential for alterations in chemoreceptor and pulmonary stretch electrolyte imbalance (i.e. diuretic therapy, excessive receptor sensitivities, changes in mechanical proper- vomiting and/or diarrhea). Furthermore, agents with ties of the lung and chest wall, changes in blood pH, minimal cardiovascular effects such as diazepam or and catecholamine release are factors which deter- etomidate should be employed for induction of gen- mine the respiratory effects of general anesthetics. eral anesthesia in patients with significant All general agents depress alveolar ventilation cardiovascular disease to avoid hemodynamic with the possible exception of nitrous oxide.7' The changes conducive to cardiac dysrhythmias. ventilatory response to hypoxia appears to be more Some general anesthetics sensitize the myocar- sensitive to the depressant effects of inhaled anes- dium to the direct myocardial effects of sympatho- thetics than is the carbon dioxide-driven component mimetics including epinephrine,59 levonordefrin,60 of respiration.72'73 For example, the ventilatory dopamine,6' phenylephrine,62 and metaraminol.63 In response to hypoxia is significantly depressed in addition, bretylium,6 guanethidine,65, cocaine66, humans at 0.1 MAC isoflurane and is terminated aminophylline,67 pancuronium,& and atropine69 have completely at 1 MAC isoflurane; however, a also been observed to provoke cardiac dysrhythmias ventilatory response to carbon dioxide can be during general anesthesia (i.e. halothane). Children observed up to 2 MAC isoflurane.574 appear to be less sensitive to epinephrine- Parenteral general anesthetics may also produce associated dysrhythmias than adults.70 Myocardial respiratory depression and hypoxemia. Significant sensitization is a major concern in dentistry because reductions in transcutaneous 02 tension (Tc PO2), of the potential interaction involving vasoconstrictors which is strongly correlated with arterial 02 tension: commonly employed with local anesthetic solutions (r = 0.98), have been observed within 2 to 3 minutes and gingival retraction cord. of induction with barbiturates.75 Hypoventilation and Of the commonly used inhalation anesthetics, changes in ventilation-perfusion relationships con- halothane produces the lowest arrhythmogenic tribute to hypoxemia that may accompany onset of threshold for epinephrine. Enflurane has a minimal unconsciousness produced by anesthetics. Supple- effect on myocardial sensitivity to sympatho- mental oxygen will increase PaO2 but hypoventil- mimetics (see Fig. 4) while isoflurane has an inter- ation can only be corrected with proper airway man- mediate effect. The recommended maximum dose of agement and positive pressure ventilation. epinephrine for a patient anesthetized with Enflurane is the most potent respiratory depress- halothane is 0.1 mg in 10 minutes or 0.3 mg in 60 ant of the inhaled general anesthetics followed by minutes. For levonordefrin, the maximum dose is 0.3 isoflurane and halothane. Enflurane and isoflurane mg in 10 minutes or 0.9 mg in 60 minutes.69 produce significant dose-dependent depression

120 ANESTHESIA PROGRESS resulting in increased PaCO2 (see Fig. 5). Although Apnea produced by midazolam (15 mg) is less com- surgical stimulation will increase ventilation in mon (50% vs. 92%) and of shorter duration (22 sec. patients breathing enflurane or isoflurane, PaCO2 vs. 45 sec.) than apnea produced by thiopental (270 may not be affected since CO2 production also mg).79 However, respiratory depression in patients increases in response to surgical stress. with chronic obstructive lung disease is more pro- Furthermore, assisted ventilation cannot lower nounced and protracted after midazolam than after PaCO2 more than 3.4 mmHg since the minimum thiopental.80 Therefore, benzodiazepines should be PaCO2 which initiates ventilation (apneic threshold) administered cautiously to patients with pulmonary is approximately 3.4 mmHg lower than the PaCO2 disease. produced by spontaneous ventilation.576 Therefore, Though significant reductions to PaCO2 and controlled ventilation is required to achieve apnea have been observed following ketamine normocapnia in patients anesthetized with administration, the effect is transient and is largely isoflurane and enflurane. dependent upon the rate of administration.81 Despite early claims that protective pharyngeal and laryngeal reflexes remain intact with ketamine,82 aspiration 80- W Enflurane has been reported.83 Therefore, as with other anes- 76 thetic techniques, protection of the airway by D Isoflurane frequent suctioning, oropharyngeal partitioning, 70- and/or endotracheal intubation is essential. 65 Etomidate may produce apnea which, like

A 61 60- midazolam, is short lived and less common (42%) E than after thiopental or methohexital.84 However, the E incidence of cough, hiccough, and o' laryngospasm 50- 50 associated with etomidate administrations is compa- Q.a rable to that which occurs with methohexital. 40- 39 Considerations for patients with bronchospastic disease

V6 - 1------Halothane produces bronchodilation in con- L- id.4d.444AL-----i -- - dd. L.. Awake 1 MAC 1.5 MAC stricted airways and has been considered the anesthetic of choice in patients with bronchospastic dis- Fig. 5 Ventilatory depression by enflurane and isoflurane in spon- ease (i.e. asthma). However, cardiac dysrythmias taneously breathing volunteers. have been observed in asthmatic patients treated Data from Calverley, RK, Smith, NT, Jones, CW, et al. Anesth Analg 1978;57:610-618 and Fourcade, HE, Ste- with bronchodilators such as aminophylline when vens, WC, Larson, CP, et al. Anesthesiology halothane was administered.85 Since enflurane is as 1971;35:26-31. effective as halothane in producing bronchodil- - atation and does not sensitize the heart to Combining potent inhaled anesthetics with nitrous catecholamines like halothane, many anesthetists oxide has the advantage of substituting part of the prefer it for use in asthmatic patients receiving dose of a volatile agent with nitrous oxide which has sympathomimetics. minimum respiratory effects. In addition, nitrous Isoflurane (1.5 MAC) has also been observed to oxide significantly reduces the ratio of dead space to prevent allergic bronchoconstriction.86 However, tidal volume (VD/VT) and increases CO2 excretion Rahder et al.87 have despribed a modest increase in at a rate not expected from changes in ventilation total airway resistance following exposure to lower alone.77 concentrations of isoflurane. This effect may be Barbiturates depress CNS respiratory centers and related to the pungency of isoflurane which causes produce changes in pulmonary dynamics which mild airway irritation. Therefore, there may be a results in acute changes in both PaO2 and PaCO2. greater potential risk of inducing bronchospasm with Unlike inhalation anesthetics, barbiturates affect isoflurane than with enflurane or halothane in ventilatory response to CO2 more than the response patients with bronchospastic disease. to hypoxia.78 In fact, hypoxemia may play a more pre- In vitro studies with ketamine have demonstrated dominant role in respiration during barbiturate anes- muscle relaxation and antispasmogenic effects.m thesia. Supplemental oxygen, by increasing arterial Hirshman and Downes89 found ketamine to be as 02, may reduce this drive and further increase effective as enflurane or halothane in preventing PaCO2. Therefore, the proper response to respira- experimentally induced bronchospasm in dogs. tory depression produced by barbiturates should Therefore, despite early observations of broncho- include the establishment of a patent airway and pos- spasm following ketamine administration to patients itive pressure ventilation. with reactive airways,99 ketamine appears to be a The benzodiazepines depress respiration. good parenteral anesthetic agent for use in patients Diazepam and midazolam can produce apnea.78.79 with bronchospastic disease. Etomidate and the MAY/JUNE 121 benzodiazepines are preferred over the barbiturates 23. Liang HS, Liang HG. Minimizing emergency phenomena: in asthmatic patients since these agents do not liber- Subdissociative dosage of ketamine in balanced surgical ate histamine. anesthesia. Anesth Analg (Cleve) 1975;54:312-16. 24. Gidwai AV, Stanley TH, Graves CL, et al. The effects of ketamine on cardiovascular dysamics during halothane and enflurane anesthesia. Anesth Analg (Cleve) 1975;54:588-92. REFERENCES 25. Dundee JW, Lilburn JK. Ketamine-lorazepam: attenuation of 1. U.S. Department of Health, Education, and Welfare: Oral dis- the psychic sequelae of ketamine by lorazepam. Anaesthesia ease. Target for the 70's: five-year plan of the National Insti- 1977;37:312-14. tutes of Dental Research for Optimum Development of the 26. Barclay A, Houlton PC, Downing JW. Total intravenous anes- Nation's Dental Research effort. National Institutes of Health, thesia - a technique using flanitrazepam, ketamine, muscle Bethesda, Md., 1970. relaxants, and controlled ventilation of the lung. Anaesthesia 2. Winter PM, Bruce DL, Bach MJ, et al. The anesthetic effect of 1980;35:287-90. air at atmospheric pressure. Anesthesiology 1975;42:658-61. 27. Dundee JA. Some effects of premedication on the induction 3. Eger El, II. Isoflurane (Forane): A compendium and reference. characteristics of intravenous anaesthetics. Anaesthesia Madison, Wisconsin, Ohio Medical Products, 1981. 1965;20:299. 4. Cromwell TH, Eger, El, ll, Stevens WC, et al. Forane uptake, 28. Meinck HM, Mohlenhof L, Kettler D. Neurophysiologic effects excretion, and blood solubility in man. Anesthesiology of etomidate, a new short-acting hypnotic. Electroencephalo- 1975;35:401 -08. gram Clin Neurophysiol 1980;50:515-22. 5. Eger El, II. Isoflurane: a review. Anesthesiology 29. Boralessa H, Holdcroft A: Methohexitone or etomidate for 1981 ;55:559-76. induction of dental anaesthesia. Can Anaesth Soc J 6. Kothary SP, Zsigmond EK: A double-blind study of the 1980;27:578-83. effective antihallucinatory doses of diazepam prior to 30. Yelavich PM, Holmes CM. Etomidate: a foreshortened clinical ketamine anesthesia. J. Clin Pharmacol Ther 1977;21 :108-109. trial. Anaesth Intensive Care 1980;8:479-483. 7. Lo JN, Cumming JF: Interaction between sedative 31. Helmers JH, Adam AA, Giezen J. Pain and myoclonus during premedicants and ketamine in man and in isolated perfused induction with etomidate. A double-blind, controlled evalua- rat livers. Anesthesiology 1965;43:307-12. tion of the influence of droperidol and fentanyl. Acta 8. Zsigmond EK, Domino EF: Ketamine-clinical pharmacology, Anaesthesiol BeIg 1981;32:141-47. pharmacokinetics, and current clinical uses. Anesth Rev 32. Michenfelder JD, Cucchiaria RF: Canine cerebral oxygen 1980;7:13-33. consumption during enflurane anesthesia and its modifi- 9. White PF. Comparative evaluation of intravenous agents for cation during induced seizures. Anesthesiology 1974;40:575. rapid sequence induction - thiopental, ketamine, and 33. Joas TC, Stevens WC, Eger, El, II. Electroencephalographic midazolam. Anesthesiology 1982;47:279-84. seizure activity in dogs during anesthesia. Br J Anaesth 10. White PF. Use of continuous infusion versus intermittent 1971;43:739. bolus administration of fentanyl or ketamine during outpatient 34. Dripps RD, Eckenoff JE, Vandam LD, eds. Introduction to anesthesia. Anesthesiology 1983;59:294-300. anesthesia: the principles of safe practice. W.B. Saunders 11. Kendig JJ. Axon and synapse in relation to anaesthesia. In: Co., Philadelphia, 1982, 412-413. Gray TC, Nunn JF, Utting JE, eds. General Anaesthisa. 35. Smith RA, Winter PM, Smith M, et al. Convulsions in mice Butterworths, London, 1980, 99-116. after anesthesia. Anesthesiology 1979;50:501-04. 12. Richards CD, White AE. The actions of volatile anaesthetics 36. Roy RC, Pauca AL, Savage RT, et al. Meperidine, not fentanyl on synaptic transmission in the dentate gyrus. J. Physiol, or morphine stops postanesthetic shivering. Anesthesiology Lond. 1975; 252:241-257. 1983;59:A349. 13. Domino EF, Chodaff P, Corssen G. Pharmacologic effects of 37. Safevat AM, Daniel D. Grand mal seizure after fentanyl Cl-581, a new dissociative anesthetic in man. Clin Pharmacol administration. Anesthesiology 1983;59:78. Ther 1965; 6:279-91. 38. Hickey RF, Eger EIl,l. Circulatory pharmacology of inhaled 14. Reder BS, Trapp LD, Troutman KC. Ketamine suppression of anesthetics in Anesthesia, RD Miller, ed, Churchill chemically induced convulsions in the two-day-old white leg- Livingstone, New York, 1981, 331-348. horn cockerel. Anesth Analg (Cleve) 1980;59:406-09. 39. Eisale JH, Smith NT. Cardiovascular effects of 40 percent 15. Fine J, Finestone SC. Sensory disturbances following nitrous oxide in man. Anesth Analg 1972;51:956-961. ketamine anesthesia - recurrent hallucinations. Anesth 40. Dundee JW, Wynant GM. Intravenous anesthesia. Edinburgh, Analg (Cleve) 1973;52:428-30. Churchill-Livingstone, 1974, 23-63. 16. Perel A. Davidson JT. Recurrent hallucinations following 41. Allen GD, Kennedy WF, Tolas AG, et al. Comparative ketamine. anaesthesia 1976;31 :1081-1083. cardiovascular effects of general anesthesia for outpatient 17. Odantun SA, Gool RY. Clinical trial of ketamine (C0-581) Can oral surgery. J. Oral Surgery 1968;26:784-89. Anaesth Soc J 1970;14:411-16. 42. Prakash 0, Dhasmana KM, Vardouw PD, et al. Cardio- 18. White PF, Way WL, Trevor AJ. Ketamine - its pharmacology vascular effects of etomidate with emphasis on regional and therapeutic uses. Anesthesiology 1982;56:119-36. myocardial blood flow and performance. Br J Anaesth 19. Bovill JG, Dundee JW, Coppel L, et al. Current status of 1981;53:591-99. ketamine anesthesia. Lancet 1971;1:1285-88. 43. Meyer BH, Hugo JM. Etomidate as anaesthetic induction 20. Morgan M, Loh L, Singer L. Ketamine as the sole anesthetic agent in open-heart surgery. S Afr Med J 1980;58:759-61. agent for minor surgical procedures. Anaesthesia 44. Dundee JW, Wynant GM. Intravenous anesthesia. 1971;26:158-65. Edinburgh, Churchill Livingstone, 1974, 249-273. 21. Erbguth PH, Reiman B, Klein RL. The influence of 45. Abel RM, Staroscik RN, Reis RL. The effects of diazepam chlorpromazine, diazepam, and droperidol on emergence (Valium) on left ventricular function and systemic vascular from ketamine. Anesth Analg (Cleve) 1972;51:693-700. resistance. J Pharmacol Exp Ther 1970;173:364. 22. Figallo EM, Cosali H, McKenzie R, et al. Ketamine as the sole 46. Ikran H, Rubin AP, Jewkes RF. Effect of diazepam on anesthetic agent for laparoscopic sterilization. Br J Anaesth myocardial blood flow of patients with and without coronary 1977; 49:1159-1165. artery disease. Br Heart J 1973;35:626.

122 ANESTHESIA PROGRESS 47. Lebowitz PW, Cote ME, Daniels AL, et al. Cardiovascular tachycardia in relation to alveolar halothane, dose of effects of midazolam and thiopentane for induction of anaes- pancuronium and prior atropine. Anesthesiology thesia in ill surgical patients. Can Anaesth Soc J 1975;42:352-55. 1983;30:19-23. 69. Thurlow AC. Cardiac dysrhythmias in outpatient dental anes- 48. Vinik HR, Reves JG, Greenblatt DJ, et al. The pharmacokine- thesia in children. Anaesthesia 1972;27:429. tics of midazolam in chronic renal failure patients. Anesthesi- 70. Karl HW, Swerdlow DB, Lee KW, et al. Epinephrine-halothane ology 1983;59:390-94. interactions in children, Anaesthesia 1972;27:429. 49. Traber DL, Wilson RD, Priano LL. Differentiation of the 71. Winter PM, Hornbein T, Smith G, et al. Hyperbaric nitrous cardiovascular effects of CI-581. Anaesth Analg (Cleve) oxide anesthesia in man: Determination of anesthetic potency 1972;51 :247-250. (MAC) and cardiorespiratory effects. Abstracts of Scientific 50. Schwartz DA, Horwitz LD. Effects of ketamine on left Papers, annual meeting of the American Society of ventricular performance. J Pharmacol Exp Ther 1975;194:410-14. Anesthesiologists, 1972,103-104. 51. Waxman K, Shoemaker WC, Uppmann M. Cardiovascular 72. Knill RL, Belb AW. Ventilatory responses to hypoxia and effects of anesthetic induction with ketamine. Anesth Analg hypercapnia during halothane sedation and anesthesia in (Cleve) 1980;59:355-58. man. Anesthesiology 1978;49:244-51. 52. Zsigmond EK, Kothary SP, Martinez OA, et al. Diazepam for 73. Knill RL, Mannimen PH, Clement JL. Ventilation and prevention of the rise in plasma catecholamine caused by chemoreflexes during enflurane sedation and anaesthesia in ketamine. Clin Pharmacol Ther 1974;15:223-224. man. Can Anaesth Soc J 1979;26:353-60. 53. Dobson MB. Anaesthesia with ketamine and thiopentane for 74. Fourcade HE, Stevens WC, Larson CP, et al. The ventilatory short surgical procedures. Anaesthesia 1978;33:268-70. effects of Forane, a new inhaled anesthetic. Anesthesiology 54. Lilburn JK, Moore J, Dundee JW. Attempts to attenuate the 1971;35:26-31. cardiostimulatory effects of ketamine. Anaesthesia 75. Beech AD, Lytle JL. Continuous transcutaneous oxygen ten- 1978;32:449-505. sion monitoring during ultralight anesthesia for oral surgery. J 55. Thomas WJE, Kyriakou KP, Thurlow AC. Cardiac arrhythmia Oral Maxillofac Surg 1982;40:559-565. during outpatient dental anaesthesia: a comparison of 76. Hickey RF, Fourcade HE, Eger El, ll, et al. The effects of ether, controlled ventilation with and without halothane. Brit J halothane, and Forane on apneic thresholds in man. Anesthe- Anaesth 1978;50:1243-1245. siology 1971;35:32-37. 56. Vanik PE, Davis HS. Cardiac arrhythmias during halothane 77. Lam AM, Clement JL, Chung DC, et al. Respiratory effects of anesthesia. Anesth Analg (Cleve) 1968;47:299-307. nitrous oxide during enflurane anesthesia in humans. Anes- 57. Williams HD, Stone L. Cardiac arrhythmias during coronary thesiology 1982; 56:298-303. artery operations with halothane or enflurane anesthesia. 78. Bruce DL. Functional toxicity of anesthesia. Green and Anesthesiology 1970;50:551-53. Strattan, New York, 1980, pp 35-53. 58. Black GW, Linde HW, Dripps RD, et al. Circulatory changes 79. Sarnquist FH, Mathers WD, Brock-Utne, et al. A bioassay of a accompanying respiratory acidosis during halothane anes- water-soluble benzodiazepine against sodium thiopental. thesia in man. Br J Anaesth 1959;31 :238-46. Anesthesiology 1980;53:149-153. 59. Johnston RR, Eger El, II, Wilson C. A comparative interaction B0. Gross JB, Smith TC. Ventilation after midazolam and of epinephrine, with enflurane, isoflurane, and halothane in thiopental in subjects with COPD. Anesthesiology man. Anesth Analg (Cleve) 1976;55:709-712. 1981 ;55:A384. 60. Buhrow-JA, Bastron RD: A comparative study of vasocon- 81. Zsigmond EK, Matsuki A, Kothary SP, et al. Arterial strictors and determination of their safe dose under halothane hypoxemia caused by intravenous ketamine. Anesth Analg anesthesia. J Oral Surg 1981;39:934-37. (Cleve) 1976;55:311-14. 61. Zahed B, Miletich DJ, Svankovitch Ad, et al. Arrhythmic doses 82. Lanning CF, Harmel MH. Ketamine anesthesia. Annu Rev of epinephrine and dopamine during halothane, enflurane, Med 1975; 26:137-41. methoxyflurane, and fluorxene anesthesia in goats. Anesth 83. Penrose BH. Aspiration pneumonitis following ketamine Analg (Cleve) 1977;56:207-210. induction for a general anesthetic. Anesth Analg (Cleve) 62. Lochning RW; Czorny VP. Halothane induced hypotension 1972;51 :41. and the effect of vasopressors. Can Anaesth Soc J 84. Nimmo WS, Miller M. Pharmacology of etomidate in New 1960;7:304-09. Pharmacologic Vistas in Anesthesia. Ed. by Brown BR, F.A. 63. Tucker WK, Rockstun AD, Munson ES. Comparison of Davis, Philadelphia, 1983, pp. 83-95. arrhythmic doses of adrenaline, metaraminol, epinephrine 85. Stirt JA, Sullivan SF. Aminophylline. Anesth Analg (Cleve) and phenylephrine during isoflurane and halothane anaes- 1981;60:587-602. thesia in dogs. Brit J Anaesth 1974;46:392-96. 86. Hirshman CA, Bergman NA. Halothane and enflurane protect 64. Condouris GA, Ortez J, Lyness W. Cardiac arrhythmias pro- against bronchospasm in asthma dog model. Anesth Analg duced by bretylium in cats anesthetized with halothane. Eur J (Cleve) 1978;57:629-633. Pharm 1979;55:94-97. 87. Rahder K, Mallow JE, Fibuch EE, et al. Effects of isoflurane 65. Condouris GA, Kopia GA. Cardiac arrhythmias induced by anesthesia and muscle paralysis on respiratory mechanics in guanethidine in cats anaesthetized with halothene. Eur J normal man. Anesthesiology 1974;41:477-485. Pharm 1 980;68:257-65. 88. Wanna HT, Bergis SD. Procaine, lidocaine, and ketamine 66. Kochntop DE, Liao JC, Van Bergen FH. Effects on inhibit histamine-induced contracture of guinea pig tracheal pharmacologic alterations of adrenergic mechanisms by muscle in vitro. Anesth Analg (Cleve) 1978;57:25-27. cocaine, tropolone, aminophylline, and ketamine on epinephrine-induced arrhythmias during halothane-nitrous 89. Hirshmann CA, Downs H, Farbood A, et al. Ketamine block of oxide anesthesia. bronchospasm in experimental canine asthma. Br J Anaesth Anesthesiology 1977;46:83-93. 1979;51 :713-718. 67. Stirt JA, Berger JM, Roe SD, et al. Halothane-induced cardiac arrhythmias following administration of aminophylline in 90. Corssen G, Guitierrez J, Reves JG, et al. Ketamine in the experimental animals. Anesth anesthetic management of asthmatic patient. Anesth Analg Analg (Cleve) 1981;60:517-20. (Cleve) 1972;51:588-596. 68. Miller Rd, Eger El, II, Stevens WE. Pancuronium-induced

MAY/JUNE 123