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ISOFLURANE - a NEW GENERAL ANESTHETIC for the 1980S* ELIZABETH A

ISOFLURANE - a NEW GENERAL ANESTHETIC for the 1980S* ELIZABETH A

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ISOFLURANE - A NEW GENERAL FOR THE 1980s* ELIZABETH A. M. FROST, M.D. Professor of Anesthesiology Albert Einstein College of Medicine of Yeshiva University Bronx, New York

ISOFLURANE (Forane compound 469), synthesized in 1965 by Terrell, was developed after its isomer, , another halogenated anesthet- ic agent.

PHYSICOCHEMICAL PROPERTIES The molecular weight of isoflurane is the same as that of enflurane (184.5) and slightly less than (197.4). The (48.50C) is closer to that of halothane (50.20C) than of enflurane (56.50C). The at 220C, which is the critical factor in determining precentage administered through the vaporizer, is 261.9 mm. Hg, which approximates that of halothane (265.5 mm. Hg). Isoflurane and enflurane maintain stability in the presence of soda lime and ultravio- let light and do not require additional preservatives. Halothane, on the other hand, must be stored in dark bottles and decomposes on contact with soda lime. The minimal flammable concentration in 70% N20/30% 02 is 7% with isoflurane as compared with enflurane (5.8%) and halothane (4.8%).1 The minimum alveolar concentration of isoflurane, at which 50% of patients do not move on skin incision, decreases with age and the addition of . Under age 30, the minimum alveolar concentration for isoflurane in 100% 02 is 1.28% and with 70% N20 it falls to 0.56%.2 Percentages for patients over 55 are 1.05% and 0.37%. Thus isoflurane falls between enflurane and halothane (which is greatest) in potency. Animal studies have indicated no change in minimum alveolar concentra- tion with duration of anesthesia3 although concentration does decrease by 5.3% with each 1°C fall in temperature.4 In pregnant sheep, minimum

* Presented at a meeting of the Section on Anesthesiology of the New York Academy of Medicine January 6, 1982. Address for reprint requests: Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, N.Y. 10461

Vol. 58, No.9, December 1982 804 E. A. M. FROST alveolar concentration is decreased by 40%,5 which may indicate that administration of "ordinary" concentrations of isoflurane to parturients may produce more rapidly and to a deeper level. ingestion increases the minimum alveolar concentration of isoflurane by about 25%, which makes alcoholic patients more difficult to anesthetize. Drugs which stimulate central neurotransmitters (e.g., ephedrine and ) also increase this,7 which may explain the apparent greater potency of isoflurane over enflurane despite the similarity of their lipid . Enflurane has a central nervous system stimulant effect not possessed by isoflurane, which may antagonize its anesthetic action.

UPTAKE AND DISTRIBUTION Isoflurane has a low blood and tissue solubility, second only to that of nitrous oxide. Thus induction is rapid, although the pungent smell may induce breath holding. The alveolar (or arterial) partial pressure reaches 50% of inspired concentration in 4 to 8 minutes and 60% in 15 minutes.' Fifty percent equilibration of isoflurane with brain, liver, and heart is reached in 5 to 15 minutes, with muscle in two hours and with fat in seven hours.8 The low solubility of isoflurane allows flexibility in altering anesthetic depth as clinical requirements change. Recovery from isoflurane is rapid. The average interval from discontinuation of anesthesia to opening of the eyes is about 91/2 minutes and to answering questions is 12'/2 minutes (Isoflurane New Drug Application, p. 54). Comparable figures for halo- thane are 11½/2 and 15 minutes. An increase in duration of anesthesia from one to three hours significantly prolongs the time for recovery but time increases beyond three hours do not further delay awakening. (Isoflurane New Drug Application, pp. 626-27).

METABOLISM Isoflurane is more stable than other volatile in that it does not break down on exposure to soda lime or ultraviolet light. It requires no preservative and has a shelf life of at least five years.' In vivo metabolism of isoflurane is extremely low. Only 0.17% of isoflurane taken up by the body has been recovered as metabolites. This figure compares to 2 to 4% for enflurane, 20% for halothane, and 50% for . Isoflurane also causes an extremely small increase in serum inorganic fluoride (1/10 of that seen with enflurane)9 and urinary organic fluoride'0 (from day

Bull. N.Y. Acad. Med. ISOFLURANE 805 ISOFLURANE three to ten, about 1/6 to 1/10 of that observed after halothane). Pretreatment of animals with such drugs as and pheny- toin, which induce the enzymes responsible for metabolism of isoflurane, have failed to demonstrate significant increase in microsomal defluorinase activity, further attesting to the in vivo stability of the agent." The absence of biodegradation is a desirable characteristic because toxicity such as liver and kidney injury, mutogenicity, carcinogenicity, and terato- genicity may result from the process or products of metabolism.

EFFECTS ON ORGAN SYSTEMS Isoflurane has several effects on bodily functions, some of which are predictable and others which are unique to the drug. Respiratory system. Isoflurane depresses respiration in a dose-related fashion to a slightly greater extent than occurs with halothane but consid- erably less than that seen during enflurane anesthesia.'2 However, addition of N20 (70%) or (0.15 mg./kg.), which may be used to replace isoflurane, significantly decrease the ventilatory depression seen with isoflurane alone.'3"4 All inhaled agents depress the ventilatory response to imposed increases in Paco2, which implies that the drive to overcome resistance to respiration is impaired and thus the danger of hypoxia occuring is enhanced. Apnea occurs at concentrations above 2 minimum alveolar concentration. The ventilatory response to decreased Pa02 is also depressed by halogenated anesthetic agents. This depression is evi- dent at 0.1% minimum alveolar concentration and no ventilatory response is seen at 1. 1%.' Thiopental also depresses the response to hypoxia but to a lesser extent. Ventilatory depression is accompanied by both general metabolic de- pression and decreased functional requirements.' Whole body consumption is reduced from 250 ml./min. to 150 ml./min. at 2% mini- mum alveolar concentration. Relatively, the greatest decrease in oxygen consumption occurs in the myocardium.'7 Respiratory depression is offset by assisting ventilation and by surgical stimulation, which increases venti- lation by 40% at clinical levels of anesthesia.'4 The effects of isoflurane on pulmonary mechanics are similar to those of other general anesthetics. Functional residual capacity and lung compli- ance decrease slightly at 1% but not at 2%. Chest wall compliance does not change. Pulmonary resistance increases to about 140% of the awake value. This increase has also been reported with other general anesthet-

Vol. 58, No. 9, December 1982 806 E. A. M. FROST ics.18 Thus, isoflurane is as suitable as other agents for anesthetizing patients with chronic obstructive pulmonary disease. Postoperative respiratory complications with isoflurane are few. In a large study, 3.4% developed postoperative atelectasis, 0.6% were diag- nosed as having some degree of pneumonic infiltration, and aspiration or pneumothorax occurred in 1.3%. Complications were related to age, duration of anesthesia, pre-existing disease, and surgical site. (Isoflurane New Drug Application, p. 3018). Cardiovascular system. Isoflurane concentrations which provide surgi- cal anesthesia cause little or no depression of myocardial function, cardiac output, or tissue perfusion.16 No change was seen in the acceleration imparted to the body by the ejection of blood from the heart (ballistocar- diogram wave) with up to 1.9% minimum alveolar concentration isoflur- ane as compared to at least a 50% decrease from the awake state observed with both halothane and enflurane.16 A further indication of the minimal myocardial depression caused by isoflurane is the absence of an increase in right atrial pressure up to 1.4% and only a slight increase at 1.9%. 6 All other inhalation agents increase right atrial pressure, indicating greater depression of myocardial function. The cardiac anesthetic index, which is the ratio of the anesthetic concentration in the heart at minimum alveolar concentration, is significantly longer for isoflurane than for other haloge- nated anesthetics. However, circulatory depression becomes progressively more evident at concentrations above 2.5%.19 Although stroke volume is decreased by about 20% at 2% minimum alveolar concentration, cardiac output is kept constant by a small compen- satory increase in heart rate.16 Isoflurane may also have mild beta recep- tor-stimulating properties which may also support myocardial function.16 Despite the maintenance of cardiac output and myocardial function, arterial blood pressure decreases in a dose-related fashion due to decrease in total peripheral resistance.'6 Increased peripheral flow to all tissues, especially muscle, increases, which again may be due to a peripheral beta sympathetic effect on blood vessels caused by interference with the c- AMP system.20 Minimal changes in base excess from the awake state suggest that there is overall adequacy of tissue perfusion during isoflurane anesthesia. 16 Administration of 1 to 2% minimum alveolar concentration does not significantly change pulmonary arterial blood pressure, wedge pressure, or vascular resistance. Stability of the pulmonary circulation is maintained

Bull. N.Y. Acad. Med. ISOFLURANE 807 ISOFLURANE

during both spontaneous and controlled ventilation. The only exception appears to be in the effect of isoflurane on the pulmonary vasoconstrictive response to hypoxia.22 Unlike halothane, both isoflurane and nitrous oxide diminish this vasoconstrictive response, i.e., PaO2 is lower during isoflur- ane administration if there is a coexistent hypoxic lung segment. If there is no respiratory disease, there is no evidence of a decrease in PaO2 during spontaneous respiration. An important difference between isoflurane and halothane is the greater stability of myocardial rhythm after exogenous administration of epineph- rine which is seen with the former agent. Whereas during halothane anesthesia 2.1 pug./kg. epinephrine produces ventricular extrasystoles, under isoflurane this dose is increased to 6.7 ,ig./kg.23 Deepening anes- thesia and increasing Paco2 further increases the dose of epinephrine that causes for both agents.2:3 The relative stability of heart rhythm is also seen when other vasoactive drugs such as metaraminol phenyleph- rine or ouabain are injected.24 The mechanism for the difference in effect between halothane and isoflurane has been attributed to the effect of the agents on impulse transit through the heart. Whereas halothane slows the conduction of impulses through the cardiac conduction system and de- presses conduction within the atrioventricular node which tends to facili- tate the re-entry of sinus impulses, isoflurane does not.25 A similar stability of the circulatory system is also seen in older patients (> 60 years).21 Profound hypothermia (< 20°C) can be tolerated without the development of ventricular extrasystoles in dogs.26 Animal experi- ments suggest a greater protective effect with isoflurane during progres- sive blood loss, perhaps due to decreased sympathetic response producing lower serum catecholamine and lactate levels and higher pH, base excess, and mixed venous P02.27 Clinical observations suggest that isoflurane has no adverse effect in combination with the usual premedications and can also be given safely in the presence of therapeutic levels of beta-adrenergic blockade.28 No clini- cally significant changes in serum electrolytes occur, but blood glucose levels rise by about 60 mg./dl. after one hour.29 Plasma levels of growth and thyroid hormone also increase. Cortisol is higher, an effect seen more after surgical incision than during isoflurane alone. A slight increase in the Bohr shift has been described, which means that if pH is decreased in the presence of isoflurane, oxygen dissociates more readily from hemoglobin.30 Postoperative circulatory complications are very low following isoflur-

Vol. 58, No. 9, December 1982 80880 E..AA. M.M FROSTRS ane anesthesia (4%). An identical incidence was seen after halothane but the patients in this latter group were younger, healthier preoperatively, and underwent a shorter anesthetic exposure (Isoflurane New Drug Applica- tion, p. 515). Specific indications for the use of isoflurane might include patients with coronary artery disease or congestive cardiac failure when the decrease in myocardial oxygen requirement induced by isoflurane and the stability of right and left atrial pressures and cardiac rhythm are advantageous. However, the tachycardia and decrease in peripheral resistance induced may be hazardous to the patient with aortic stenosis. Neuromuscular effects. Not only can isoflurane produce sufficient relaxation for most surgical procedures, it is at least twice as effective as halothane in enhancing the effect of muscle relaxants.31 Using d-tubocur- arine, the dose of relaxant required to produce a 50% decrease in twitch height (i.e., the ED50) during 1.25% minimum alveolar concentration isoflurane was found to be 1.7 mg./m2; the comparison dose at 1.25% halothane was 5.6 mg./m2.32 The ability of a muscle to sustain contraction in response to tetanic stimulation is also decreased in a dose-related fashion.33 The enhancement of relaxant effect reduces possible complications induced by such relexants as histamine release, , tachycardia, increased myocardial consumption, and postoperative respiratory depres- sion. Speculation that isoflurane would be useful for patients with myas- thenia gravis has yet to be tested. Similarly, as metabolism and elimina- tion of muscle relaxants requires adequate hepatic and renal function, isoflurane may be the agent of choice in patients with compromise of these systems. Central nervous system effects. At subanesthetic concentrations of isoflurane, electroencephalographic frequency increases from 8 to 12 Hz (alpha) to greater than 15 Hz. Voltage is also increased. As the isoflurane concentration reaches minimum alveolar concentration, maximum elec- troencephalographic amplitude increases to an average of 140-150 micro- volts. A lower frequency develops. Further deepening of anesthesia sup- presses the low amplitude waves with 12-14 Hz frequency. appears at 1.5% minimum alveolar concentration, and an isoelectric line develops at 2% .31 In contradistinction to the isomer enflur- ane, isoflurane does not cause seizure activity in man. Epileptic patterns cannot be evoked by increasing depth, lowering Pac02 or by auditory or visual stimuli.34 The ability to produce electroencephalographic silence at

Bull. N.Y. Acad. Med. ISOFLURANE 809 surgical concentrations suggests a cerebral protective effect of isoflurane which has been confirmed in animal studies.'3 As might be expected, isoflurane causes a transient central nervous system depression immediately after anesthesia but there appear to be no long-term effects.36 No retrograde amnesia occurs even after a six-hour anesthetic procedure,7 although there may be memory impairment for acoustically or visually presented items for up to two hours. Isoflurane causes significantly less adverse general symptoms such as nausea or weakness than are reported after exposure to halothane.38 Cerebral blood flow and intracranial pressure do not increase from awake levels at 0.6-1.1% but double at 1.6% minimum alveolar concen- tration.39 These increases may be prevented by hyperventilation.40 Thus, at levels that produce neurosurgical anesthesia there appear to be no significant changes in intracranial dynamics. We also found that at up to 1.5%,vascular response to CO2 and autoregulation are well maintained. However, after creation of a small cryogenic lesion in dogs, higher increases in intracranial pressure and edema are associated with isoflurane and the other halogenated anesthetics than with .4' Hepatic effects. In healthy volunteers isoflurane and enflurane do not alter. bromsulphalein retention, although halothane significantly impairs this aspect of liver function for up to seven days after administration.42 Other indices of hepatic integrity, such as serum LDH and SGOT, are also maintained intact but do increase slightly with .3' Periopera- tive factors such as preexisting liver disease, shock, congestive heart failure, upper abdominal surgery, or viral infection may all alter hepatic function and, theoretically, response to anesthetic administration. Howev- er, patient studies support the safety of isoflurane with regard to liver function. Bromsulphalein levels may increase slightly on the second postoperative day but quickly return to normal.42 Postoperative enzyme values do not correlate with duration of anesthesia and have been shown to relate inversely to the level found before anesthesia. Repeated adminis- tration of isoflurane has also failed to produce hepatic dysfunction (Iso- flurane New Drug Application, p. 86). Animal studies have shown that hypoxia in the presence of isoflurane does not increase liver injury43 and that prolonged exposure to subanes- thetic concentrations produces neither degenerative hepatic lesions nor a failure to thrive.44 Liver methionine synthetase activity, important for the synthesis of DNA and red blood cell formation, is decreased by N20 but remains intact in the presence of isoflurane.45

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Renal action. As do all anesthetics, isoflurane decreases renal blood flow, glomerular filtration rate, and urinary flow.46 Serum potassium levels increase about 25% although other electrolytes are unchanged.42 The minimal metabolism and rapid elimination of isoflurane suggest little impairment of renal function which has been confirmed by volunteer, patient, and animal studies.1 Rat experiments have indicated that metabo- lism of isoflurane (i.e., no increase in serum liver enzyme) is not altered even during renal failure.47 Obstetrics. Isoflurane causes a dose-related depression of uterine muscle contractions which is about 50% at 1.5% minimum alveolar concentra- tion. Although isoflurane analgesia probably does not increase blood loss at term delivery, anesthesia increases hemorrhage during therapeutic abor- tion.49 Experiments in ewes have shown that at 1 to 1.5% minimum alveolar concentration, uterine blood flow, fetal base excess, and fetal oxygenation all remain at awake levels despite a dose-related decrease in maternal systemic arterial blood pressure and cardiac output. At 2%, all the variables decrease.5 In a study comparing analgetic concentrations of isoflurane with 40% N20, no differences were detected in indices of fetal well being. However, isoflurane analgesia developed more slowly during the first 10 minutes.5O The additional oxygen which is delivered with isoflurane may be advanta- geous in some situations. Genetic and immune studies. Mutagenicity and carcinogenicity of chemicals may be due to alteration in DNA or chromosomal proteins. The limited metabolism of isoflurane minimizes the potential for interaction with DNA, and the low solubility and rapid elimination lessen the time of exposure of the immune system. The Ames test for mutagenicity measures the conversion of bacteria from histidine-dependent to histidine-independent organisms which occur when the bacteria are exposed to a suspected mutagen. It is a widely accepted test which identifies 90% of carcinogenic compounds and gives false positive results in only 10 to 15% of cases. Using this test, no mutagenic potential for isoflurane or its metabolites have been identified.5' Similarly, results from the sister chromatid exchange test (another test of mutagenicity) showed no evidence of adverse action with isoflurane.52 Teratogenicity studies in animals with prolonged isoflurane exposure during gestation have shown no differences in fetal viability or congenital anomalies over controls.' A pilot study had suggested that mice exposed to isoflurane for ex-

Bull. N.Y. Acad. Med. ISOFLURANE 811 tended periods had a higher incidence of liver tumors.53 A subsequent, better controlled study eliminating all contaminants did not confirm this finding.54 Effects of isoflurane in immune defences are undetermined, although liquid isoflurane is bactericidal55 and, at 0.2% minimum alveolar concentration, replication of measles virus in vitro is inhibited by 50%.

CONCLUSION Isoflurane is a nonflammable, stable halogenated anesthetic agent. It has low blood and tissue solubility and permits rapid induction and recovery. Metabolism is minimal. Cardiovascular stability is well main- tained and muscle relaxation is good. Organ toxicity is absent or extreme- ly low. Its few disadvantages include the pungent smell, respiratory depression, increased uterine relaxation, and decreased cerebrovascular resistance. The cost, although higher than that of enflurane and halothane, remains a relatively small part of the entire anesthetic experience.

REFERE NCES 1. Eger, E. I., II: Isoflurane A Compendi- thetic requirement (MAC). Anesthesi- um and Reference. Ohio Medical Prod- ology 29:1153-58, 1968. ucts, 1981. 8. Holaday, D. A., Fiserova-Bergerova, 2. Stevens, W. C., Dolan, W. M., Gib- V., Latto, I. P., et al.: Resistance of bons, R. T., et al.: Minimum alveolar isoflurane to biotransformation in man. concentrations (MAC) of isoflurane Anesthesiology 43:325-32, 1975. with and without nitrous oxide in pa- 9. Dobkin, A. B., Kin, D., Choi, J. K., tients of various ages. Anesthesiology and Levy, A. A.: Blood serum fluoride 42:197-200, 1975. levels with enflurane (Ethrane) and iso- 3. Koblin, D. D., Eger, E. I., II, Johnson, flurane (Forane) anaesthesia during and B.H., et al.: Are convulsant also following major abdominal surgery. anesthetics? Anesthesiology 53:S47, Can. Anaesth. Soc. J. 20:494-98, 1973. 1980. 10. Mazze, R. I., Cousins, M. J., and Barr, 4. Vitez, T. S., White, P. F., Eger, E. I., G. A.: Renal effects and metabolism of II: Effects of hypothermia on halothane isoflurane in man. Anesthesiology MAC and isoflurane MAC in the rat. 40:536-42, 1974. Anesthesiology 41:80-81, 1974. 11. Caughey, G. H., Rice, S. A., Kosek, J. 5. Palahniuk, R. J., Shnider, S. M., and C., and Mazze, R. I.: Effect of pheny- Eger, E. I., II: decreases the toin (DPH) treatment on methoxyflur- requirement for inhaled anesthetic ane metabolism in rats. J. Pharmacol. agents. Anesthesiology 41:82-83, 1974. Exp. Ther. 2/0:180-85, 1979. 6. Johnstone, R. E., Kulp, R. A., and 12. Calverley, R. K., Smith, N. T., Prys- Smith, T. C.: Effects of acute and Roberts, C., et al.: Cardiovascular ef- chronic ethanol administration on iso- fects of enflurane anesthesia during con- flurane requirement in mice. Anesth. trolled ventilation in man. Anesth. Analg. 54:277-81, 1975. Analg. 57:619-28, 1978. 7. Miller, R. D., Way, W. L., and Eger, 13. Eger, E. I., II, Dolan, W. M., Stevens, E. I., II: The effects of alpha-methyl- W. C., et al.: Surgical stimulation an- dopa, reserpine, guanethidine, and tagonizes the respiratory depression iproniazid on minimum alveolar anes- produced by Forane. Anesthesiology

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36:544-49, 1972. Munson, E. S.: Comparison of arrhyth- 14. France, C. J., Plumer, M. H., Eger, E. mic doses of adrenaline, metaraminal, I., II, and Wahrenbrock, E. A.: Ventila- ephedrine and phenylephrine during iso- tory effects of isoflurane (Forane) or ha- flurane anaesthesia in dogs. Br. J. An- lothane when combined with morphine, aesth. 46:392-96, 1974. nitrous oxide and surgery. Br. J. An- 25. Blitt, C. D., Raessler, K.L., Wight- aesth. 46:117-20, 1974. man, M. A., et al.: Atrioventricular 15. Fourcade, H. E., Stevens, W. C., Lar- conduction in dogs during anesthesia son, C. P., et al.: The ventilatory effects with isoflurane. Anesthesiology 50:210- of Forane, a new inhaled anesthetic. An- 12, 1979. esthesiology 35:26-31, 1971. 26. Sato, S., Vanini, V., Sands, M. P., et 16. Stevens, W. C., Cromwell, T. H., Hal- al.: The use of Forane anesthesia for sey, M. J., et al.: The cardiovascular surface-induced deep hypothermia. effects of a new inhalation anesthetic, Ann. Thorac. Surg. 20:299-307, 1975. Forane, in human volunteers at constant 27. Theye, R. A., Perry, L. P., and Bri- arterial carbon dioxide tension. Anesthe- zica, S. M.: Influence of anesthetic siology 35:8-16, 1971. agent on response to hemorrhagic 17. Theye, R. A. and Michenfelder, J. D.: hypotension. Anesthesiology 40:32-40, Whole-body and organ V02 changes 1974. with enflurane, isoflurane, and haloth- 28. Philbin, D. M. and Lowenstein, E.: ane. Br. J. Anaesth. 47:813-16, 1975. Hemodynamic consequences of the 18. Rehder, K., Mallow, J. E., Fibuch, E. combination of isoflurane anesthesia (1 E., et al.: Effects of isoflurane anesthe- MAC) and beta-adrenergic blockade in sia and muscle paralysis on respiratory the dog. Anesthesiology 42 :567-73, mechanics in normal man. Anesthesiol- 1975. ogy 41:477-85, 1974. 29. Oyama, T., Latto, P., and Holaday, D. 19. Wolfson, B., Hetrick, W. D., Lake, C. A.: Effect of isoflurane anaesthesia and L., and Siker, E. S.:. Anesthetic indices surgery on carbohydrate metabolism and - further data. Anesthesiology 48:187- plasma cortisol levels in man. Can. An- 90, 1978. aesth. Soc. J. 22:696-702, 1975. 20. Sprague, D. H., Yang, J. C., and Ngai, 30. Waltemath, C. L.: The effect of Forane S. H.: Effects of isoflurane and haloth- on hemoglobin function in vitro. Anes- ane on contractility and the cyclic 3', 5'- thesiology 37:454-56, 1972. adenosine monophosphate system in the 31. Homi, J., Konchigeri, H. N., Ecken- rat aorta. Anesthesiology 40:162-67, hoff, J. E., and Linde, H. W.: A new 1974. anesthetic agent - Foraneg. Preliminary 21. Tarnow, J., Bruckner, J. B., Eberlein, observations in man. Anesth. Analg. H. J., et al.: Haemodynamics and myo- 51:439-47, 1972. cardial oxygen consumption during iso- 32. Miller, R. D., Way, W. L., and Dolan, flurane (Forane) anaesthesia in geriatric W. M.: Comparative neuromuscular ef- patients. Br. J. Anaesth 48:669-75, fect of pancuronium, gallamine and suc- 1976. cinylcholine during Forane and halo- 22. Mathers, J., Benumof, F. J., and Wah- thane anesthesia in man. Anesthesiology renbrock, E. A.: General anesthetics 35:509-14, 1971. and regional hypoxic pulmonary vaso- 33. Miller, R. D., Eger, E. I., II, and Way, constriction. Anesthesiology 46:111-14, W. L.: Comparative neuromuscular ef- 1977. fects of Forane and halothane alone and 23. Joas, T. A. and Stevens, W. C.: Com- in combination with d-tubocurarine in parison of the arrhythmic doses of epin- man. Anesthesiology 35:38-42, 1971. ephrine during Forane, halothane and 34. Eger, E. I., II, Stevens, W. C., and anesthesia in dogs. Anesthesi- Cromwell, T. H.: The electroenceph- ology 35:48-53, 1971. alogram in man anesthetized with For- 24. Tucker, W. K., Rackstein, A. D., and ane. Anesthesiology 35:504-08, 1971.

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35. Newberg, L. A. and Michenfelder, J. E., et al.: Inactivitation of methionine J. D.: Cerebral Protection by isoflurane synthetase (MS) by nitrous oxide. Anes- during hypoxemia or ischemia. Anesthe- thesiology 53:S49, 1980. siology, In press. 46. Mazze, R. I., Cousins, M. J., and Barr, 36. Adam, N.: Effects of general anesthesia G. A.: Renal effects and metabolism of on memory functions in man. J. Comp. isoflurane in man. Anesthesiology Physiol. Psychol. 83:294-305, 1973. 40:536-40, 1974. 37. Bahlman, S. H., Eger, E. I., II, and 47. Rice, S. A., Sievenpiper, T. S., and Cromwell, T. H.: Anesthetics and am- Mazze, R. I.: In vitro anesthetic defluor- nesia. Anesthesiology 36:191, 1972. ination and in vivo liver function in Fi- 38. Davison, L. A., Steinhelber, J. C., scher 344 rats with chronic renal failure. Eger, E.I., II, et al.: Psychological ef- Anesthesiology 53:S253, 1980. fects of halothane and isoflurane anes- 48. Munson, E. S., and Embro, W. J.: En- thesia. Anesthesiology 43:313-24, flurane, isoflurane and halothane and 1975. isolated human uterine muscle. Anesthe- 39. Murphy, F. L., Jr., Kennel, E. M., siology 46:11-14, 1977. Johnston, R. E., et al.: The effects of 49. Dolan, W. M., Eger, E. I., II, and enflurane, isoflurane and haiothane on Margolis, A. J.: Forane increases bleed- cerebral blood flow and metabolism in ing in therapeutic suction abortion. An- man. Annual Meeting Amer. Soc. esthesiology 36:96-97, 1972. Anes., 1974, pp. 61-2. 50. Hicks, J. S., Shnider, S. M., and Co- 40. Adams, R. W., Cucchiara, R. F., Gron- hen, H.: Isoflurane (Forane) analgesia in vert, G. A., et al.: Isoflurane and cer- obstetrics. Annual Meeting Amer. Soc. brospinal fluid pressure in neurosurgical Anes., 1975, pp. 99-100. patients. Anesthesiology 54:97-99, 51. Waskell, L.: A study of the mutageni- 1981. city of anesthetics and their metabolites. 41. Smith, A. L. and Marque, J. J.: Anes- Mutat. Res. 57:141-53, 1978. thetics and cerebral edema. Anesthesi- 52. White, A. E., Takehisa, S., Eger, E. I., ology 45:64-72, 1976. II, et al.: Sister chromatid exchanges 42. Stevens, W. C., Eger, E. I., II, Joas, T. induced by inhaled anesthetics. Anesthe- A., et al.: Comparative toxicity of iso- siology 50:426-40, 1979. flurane, halothane, fluroxene and diethyl 53. Corbett, T. H.: Cancer and congenital ether in human volunteers. Can. An- anomalies associated with anesthetics. aesth. Soc. J. 20:357-68, 1973. Ann. N. Y. Acad. Sci. 271:58-66, 1976. 43. Harper, M. H., Johnson, B. H., Col- 54. Eger, E. I., II, White, A. E., Brown, C. lins, P., and Eger, E. I., II: Hepatic L., et al.: A test of the carcinogenicity injury following halothane, enflurane of enflurane, isoflurane, halothane, me- and isoflurane anesthesia in rats. Anes- thoxyflurane, and nitrous oxide in mice. thesiology 53:S242, 1980. Anesth. Analg. 57:678-94, 1978. 44. Stevens, W. C., Eger, E. I., II, White, 55. Johnson, B. H. and Eger, E. I., II: A., et al.: Comparative toxicities of en- Bactericidal effects of anesthetics. An- flurane, fluroxene and nitrous oxide at esth. Analg. 58:136-38, 1979. subanaesthetic concentrations in labora- 56. Knight, P. R., Nahrwold, M. L., Co- tory animals. Can. Anaesth. Soc. J. hen, P. J., and Gayner, J. A.: Alteration 24:479-89, 1977. of virus growth by halogenated anesthe- 45. Koblin, D. D., Watson, J. E., Deady, tics. Anesthesiology 51:S253, 1979.

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