Scientific Abstracts

Human renal function following methoxy- The antagonism of anesthesia by flurane anesthesia naloxone R.B. Merkle, F.D. McDonald, J. Waldman, J.D. Hasbrouck G.D. Maynwrd, J. Petiti, P.J. Fleming, and Anesth Analg (Cleveland) 50(6):954 Nov.- W.J. Murray Dec., 1971 JAMA 218(6):841 Nov. 8, 1971 The use of morphine as an has some advantages with hypoxic, acidotic, and , both hypotensive patients undergoing intracar- fluorinated hydrocarbons, have become diac surgery, in that it produces little car- popular , but the effect of meth- diovascular depression and may- actually oxyflurane on renal function has recently augment ventricular action in the failing been the object of much concern. The 1960 heart. A major disadvantage is that somno- report of Artusio et al., introducing meth- lence and respiratory depression due to the oxyflurane with its results in 100 patients, dosage required for anesthesia may last 8 did not cover renal effects, though Artusio to 16 hours. Levallorphan and nalorphine, and other workers later described patients the most commonly used antagonists to with elevated urinary output and BUN morphine, frequently produce CNS excita- following exposure to this agent. tion and other undesirable side effects in In this study, 49 patients requiring 50 the doses required to counteract morphine retinal detachment repairs were selected anesthesia. Naloxone, the N-allyl deriva- alternately to receive methoxyflurane or tive of oxymorphone, is virtually free of halothane. This surgical procedure was such side effects. Its efficacy in antagoniz- chosen to exclude effects of hypotension, ing morphine anesthesia was tested in 25 blood loss, and trauma to the kidneys. The patients undergoing surgery for valvular two groups of patients were well matched heart disease. A 19-lead EEG record was in age, weight, and duration of anesthesia. obtained in addition to the usual monitors The group receiving methoxyflurane ex- before and after the administration of nar- hibited increased serum creatinine and cotic and during its reversal with naloxone. lowered urine osmolality on each post-op- Each patient's degree of narcosis was as- erative day, while the halothane patients sessed by examination and questioning, did not. A greater decline in urine osmolal- and objectively by respiratory and EEG ity for older patients, reported by other measurements. Repeated 5 mcg/kg doses workers, was noted in the methoxyflurane of naloxone were given at intervals; a total group but not in the halothane group. The dose of 10 mcg/kg was effective in re- data indicate that renal function changes versing respiratory depression in all pa- are identifiable in a group of patients re- tients. The mean duration of action was ceiving methoxyflurane, but the relation of about three hours, so the narcotic effect these changes to the progressive renal in- tended to outlast the naloxone; patients sufficiency that has been reported for spe- breathing spontaneously were observed cific patients is unclear. Additional surgical carefully and given additional doses as nec- stress, prolonged hypotension, or dehydra- essary. Naloxone has a wide margin of safe- tion may cause the abnormalities described ty and no narcotic effects; its potential may here to progress to the more severe syn- also make morphine anesthesia more at- drome. tractive for other types of surgery. SEPTEMBER-OCTOBER, 1972 129 Apparent anaphylactic reaction to propanidid man phenomena of sensitization. A case is H.L. Thornton reported of primary necrosis of the liver, Anaesthesia 26(4) :490 Oct. 1971 associated with extensive renal oxalosis, fol- Propanidid, an ultra-short-acting intra- lowing a single exposure to methoxyflurane. venous anesthetic, has been used in thou- A 67-year-old patient undergoing surgery sands of patients over the past six to seven for bladder carcinoma with methoxyflurane years without evidence of serious reaction; anesthesia had an uneventful recovery for however, a 34-year-old female undergoing the first two postoperative days, but on the orthopedic manipulation of the sacro-iliac third day became stuporous and developed received propanidid twice with about two fever, jaundice, and seizures. Steroids were weeks intervening, and on the second ex- begun on the sixth day, but the patient posure displayed an anaphylactic reaction. died on the seventh. Autopsy revealed ex- The first administration was uneventful. tensive liver necrosis with evidence of Following recovery from the second expo- biliary stasis; the kidneys showed hydropic sure, the patient began to retch, suffered a degeneration of the tubular epithelium and transient fall in blood pressure, and then amino acid crystals in the tubules, re- complained of dyspnea and chest pain. The flecting the damage to the liver parenchy- blood pressure recovered when the pa- ma. tient's head was lowered; oxygen was ad- The time of onset and the fact that this ministered, and the dyspnea subsided. The was the patient's first exposure to this type patient then complained of severe abdom- of anesthetic eliminates acquired hypersen- inal and pelvic pain but recovered enough sitivity as the explanation of the reaction; to return home after about four hours; she infective processes and other hepatotoxic reported facial edema and erythema of the drugs are ruled out for similar reasons. trunk lasting several hours more. The chain Fewer than ten cases of primary hepato- of symptoms strongly suggest a drug- toxicity due to methoxyflurane have been induced anaphylaxis, especially in view of reported previously. In this case and a few the identical but uneventful previous ad- others, liver damage preceded renal failure. ministration. A search of English literature The true incidence of hepatorenal damage revealed five other cases of reactions to caused by methoxyflurane remains to be propanidid, one fatal, all of which were established. marked by hypotension and erthymatous skin reactions. Though such dangerous re- Thiopental anaphylaxis: A case and a sponses to propanidid are rare, their pos- method sibility argues that this agent should not for diagnosis be used except in the presence of all neces- G.S. Fox, R.D. Wilkinson, and F.I. Rabow sary facilities for resuscitation. Anesthesiology 35(6) :655 Dec., 1971 Seven cases of anaphylactic shock due to thiopental have been reported to date, in- dicating that such reactions are extremely Hepatorenal failure with renal oxalosis after rare; they may sometimes go undiagnosed. methoxyflurane anesthesia A case is reported of thiopental anaphylaxis J.W. Mostert, U. Kim, and M.W. Woodruff confirmed by the basophil degranulation New York J. Med 71(22):2676 Nov. 15, test. 1971 A 40-year-old woman, admitted for cor- The renal toxicity of methoxyflurane has rection of bilateral hallux valgus, had a his- received more attention than its tendency tory of a rash following , and to damage the liver. With repeated expo- coryza from perfumed cosmetics, but had sure to halothane, a related anesthetic, liver no seasonal allergies; she had received necrosis is usually explained on the basis thiopental in 1957, 1958, and 1967 without of acquired sensitivity, and patients similar- untoward reaction. In the present instance, ly sensitive to methoxyflurane have been anesthesia was induced with sodium thio- reported. Like other fluorocarbons, how- pental, and recovery was uneventful. The ever, these compounds can cause liver patient returned 14 days later for below- damage without the characteristic Shwartz- knee casts. Anesthesia was induced with 130 ANESTHESIA PROGRESS thiopental again, and salivation and cyano- The time course of EDVST response to sis were noted after a few minutes; blood differed significantly, however, pressure and brachial and radial pulse were from the reaction to lidocaine. Lidocaine absent. Lanatoside and phenylephrine precipitated a more rapid rise followed were given, then epinephrine and hydo- by a gradual decline, while diazepam cortisone when skin reddening and facial reached a gradual plateau. edema appeared. The patient responded, The EDVST reaction to 2 mg/kg of and was discharged in good condition after lidocaine was significantly greater after 0.5 four days. mg/kg than after 1.0 mg/kg of diazepam. Diagnosis was difficult, since the patient And the EDVST reaction to 2 mg/kg lido- had tolerated thiopental in the past. Apart caine was greater than to 1 mg/kg. from the three historical exposures, the last Because diazepam has little harmful ef- had been two weeks previously, and a two- fect hemodynamically, has an inherent anti- week incubation period is optimal for ex- arrhythmic action, and increases the anti- pression of a primary sensitivity to drugs. arrhythmic effect of lidocaine, it suggests Not only the multiplicity but the timing of that this is a useful drug in daily anesthesia. previous exposures can be important in such sensitivity. Confirmation of thiopental hypersensitivity has been difficult, but the indirect basophil degranulation test partial- What's Wrong with Our Operating Rooms? ly duplicates anaphylaxis in vitro. Applied Harold Laufman to blood samples from this patient the test Amer I Surg 122(9) :332-43 Sept. 1971. revealed marked degranulation with thiop- Surgical suites constructed over more ental, slight with penicillin G and secobar- than 20 years ago, which have not been bital, and no response to other drugs tested. renovated, are easy to discern. They often consist of poor space usage, a disorderly or badly designed traffic pattern, ineffec- tive materials-handling system, and unsatis- The Effect of Diazepam on the Antiarrhythmic factory electrical wiring system or a poorly Response to Lidocaine. designed ventilation system. Newly built Ronald W. Dunbar, Robert B. Boettner, surgical rooms often contain worse offenses John V. Haley, Vivian E. Hall, and Dean which are harder to determine, due to the H. Morrow. bright new atmosphere and the abundance Anesthes and Analges 50(4): 685-92 July- of awesome equipment. There may even be Aug, 1971. more instruments and equipment (thus Thirty-two open-chest dogs, weighing more money expended) than necessary. about 12 kg. each, underwent Some defects may also exist which are anesthesia. Doses administered were 30-40 found in the older suites, as well. mg/kg. This experiment was carried out to It is suggested that surgeons, nurses, and ascertain the antiarrhytmic effects of diaze- anesthesiologists advocate and recommend pam and lidocaine with and without pre- functional environmental designs, as they vious diazepam therapy. The drugs were should be aware of the needs. administered intravenously, diazepam at Rather than considering the surgical the dosage of 0.5 or 1.0 mg/kg, and lido- area as an architectural plan, it should be caine at the dosage of 1 or 2 mg/kg. seen as a series of related systems. These Increases in the end-disatolic-ventricu- systems are based on sets of activities and lar-stimulation-threshold (EDVST) in re- essential hardware required for attaining lation to control saline injections were used particular operative aims. The 4 major sys- to measure the effects of diazepam, lido- tems would be: 1) surgical support systems caine, and diazepam-lidocaine interaction. (the environment), 2) traffic and com- Each diazepam dosage significantly elevat- merce (the activities), 3) communication ed the EDVST. Lidocaine also did so, and information (the record), and 4) ad- when administered with or without the ministration (the management). These de- previous therapy with either diazepam partments should be able to function to- dosage. gether like a well-oiled machine. SEPTEMBER-OCrOBER, 1972 131 Problems are analyzed briefly and some Epilepsy or anesthesia with suggestions are made for the following: sur- W. D. Winters gical suite design, operating room shape and Anesthesiology 36(4) :309 April, 1972 size, surgical suite traffic patterns, air han- dling, air movement, physiologic monitor- Anesthetics do not all induce CNS de- ing in the operating room (EEG, EEC, ar- pression; the erroneous notion that they do terial blood pressure, etc.), surface mate- derives from experience with . rials, and operating room electrical require- The four stages of anesthesia are excitation ments, radiofrequency, illumination, and (I), delirium (II), surgical anesthesia equipment. (III), and medullary paralysis (IV), and ether anesthesia usually is referred to stage III. Stage II induced by ether or nitrous Nonspecific Stimulation of Drug Metabolizing oxide is a state of hallucinosis and catalep- Enzymes by Inhalation Anesthetic Agents. sia accompanied by epileptoid 2.5 cps hy- persynchronous EEG activity and in- Harry W. Linde, and M. Lawrence Berman creased activity of reticular-formation neu- Anesthesia and Analgesia 50(4) :656-67 rones. , however, is not cap- July-Aug. 1971. able of inducing stages III and IV at one Male Sprague-Dawley rats, weighing 40- atmosphere, thus ether anesthesia occurs 60 grams, originally, were studied. Some during CNS depression and nitrous oxide were subjected to anesthetic agents which anesthesia occurs during cataleptoid exci- flowed into a closed area between 5 and tation. Two types of anesthetic agents are 10 L/minute, while other rats were exposed distinguished by this difference in effect: to the same flow rate of air. diethyl ether, halothane, and ultrashort- The study on pre-treatment influence acting produce stage III an- with anesthetic agents was conducted to esthesia with CNS depression; the second determine duration of hexobarbitol hyp- type includes nitrous oxide, , nosis and enzyme activity in rat-liver ho- ketamine, gamma-hydroxybutyrate, and mogenates. others that produce stage II anesthesia with A decrease in hexobarbitol sleeping time cataleptoid CNS excitation. Ketamine and was observed when the rates were ex- nitrous oxide produce stage II only, while posed to subanesthetic concentrations of phencyclidine and gamma-hydroxybuty- diethyl ether, isopropyl ether, , rate, in higher doeses, will produce gen- , and . These gases in- eralized convulsions. Ketamine, a deriva- creased their power to metabolize hexo- tive- of phencyclidine, differs mainly in hav- barbitol. However, nitrous oxide and cy- ing a shorter duration of catalepsy and clopropane caused no decrease in hexo- less potency for inducing grand mal type barbitol sleeping time. seizures, but it nonetheless produces excita- Homogenates of liver from rats sub- tory activity in the thalamus and limbic mitted to 7 hours of 1.6%o diethyl ether or system, and the emergence experience is 0.4%c halothane metabolized hexobarbitol, hallucinatory and often distressing. and hydroxylated aniline more rapidly than The significance of these findings is did the control rats' liver homogenates. two-fold: first, the distinction between excit- Pretreatment with ether but not halothane, ant and depressant anesthetics should be however, increased the demethylase per- clearly understood since the epileptiform formance of liver homogenates. A reduc- EEG may be misinterpreted, and since tion in hexobarbitol sleeping time was ob- ketamine would be dangerous if mistakenly served after a minimum of only 3 hours used in emergency treatment of a convulsive inhalation of ether, and the decrease after patient. The second point is that this cata- halothane exposure lasted for 3 days fol- leptoid limbic excitation is also the mech- lowing intake. anism of action of LSD and mescaline, and Thus, inspiration of some anesthetics can phencyclidine is in fact becoming a popular increase rats' metabolization of drugs. If street drug under the name "pep" or "angel applied to humans, it may influence drug dust." The effect of such drugs on the devel- therapy in the postoperative term. oping young nervous system has not been 132 ANESTHESIA PROGRESS evaluated, but there is some evidence that The intravenous toxicity and clearance of rats given ketamine daily for several weeks bupivacaine in man develop spontaneous epileptiform EEG pat- L. E. Mather, G. 1. Long, and J. Thomas terns. This should be kept in mind when it is necessary to anesthetize a young pa- Clin Pharmacol Ther 12(6) :935 Nov.-Dec., tient repeatedly over a long period, as in 1971 treatment of extensive burns. Bupivacaine, a relatively new long-acting anesthetic related to mepivacaine and lido- caine was tested for toxicity in three nor- Some effects of local anesthetic agents on mal young male volunteers. Arterial plasma skeletal muscle. concentrations of the drug achieved in this Peter W. Benoit and W. Duane Belt study were nearly twice the levels reported Exp Neurol 34(2) :264-79 Feb. 1972. previously in conscious subjects, and ven- The gracilis anticus and posticus muscles ous plasma concentrations were in the of albino rats were exposed to a number range previously reported to cause con- of common local anesthetic agents. In gen- vulsions in dogs, but no significant evidence eral, clinically used concentrations of most of toxicity was noted. Subjective signs of agents appeared to be specifically destruc- toxicity-primarily dizziness and a sense of tive of skeletal muscle. Results also suggest pressure in the ears-were mild and fleet- that higher concentrations are more gen- ing, and no significant changes in blood erally histotoxic. The sequence of muscle pressure, EKG records, or heart rate were changes after one drug (2% lidocaine solu- observed. Blood samples were taken every tion) was followed over an extensive time 20 minutes for eight hours following injec- period. Muscle regeneration from single my- tion of the drug: assay of plasma levels oblasts was rapid and complete by 2 showed an initial rapid decline, due in part weeks. Preferential destruction of red- or to binding to plasma -proteins, followed by white-type muscle fibers was observed af- a decline with a half-life of about 2.5 ter many of the agents. The drug effects hours. From 4 to 10% of the drug was ex- are discussed relative to the characteristics creted unchanged in the urine. Over 90%/ of mature and immature muscle fibers and of bupivacaine is bound to plasma pro- the physical properties and biological activ- teins in humans, which probably explains ities of the local anesthetics. its lower toxicity in man than in dogs. Lidocaine and mepivacaine are reported to have clearance rates about the same as Danger of hypoxia during propanidid anes- bupivacaine, but their shorter duration of thesia. action requires larger doses or prolonged G. Hempelmann, W. Hartmann, H. Reichelt administration for an equivalent period of and W. Hempelmann. anesthesia. Bupivacaine may be useful for Anaesthesist 21(2) :40-4, 1972. procedures, e.g., in obstetrics, where ac- Continuous oxygen-tension monitoring cumulation of drugs is undesirable. has been performed in 12 patients with ar- teriosclerosis of the femoral arteries during Effect of bilateral carotid-body- resection on propanidid anaesthesia for arteriograms. ventilatory control at rest and during ex- The initial period of hyperventilation led ercise in man to a pO2 increase of 21 Torr; during the period of hypoventilation of apnea an aver- R. Lugliani, B. J. Whipp, C. Seard, and K. age decrease of 10 Torr below the initial Wasserman- value occurred. Five of 12 patients dropped New Eng J Med 285(20): 1105 Nov. 11, 1971 down to a pO2 minimum below 55 Torr. The role of the carotid bodies in control A second or third propanidid anesthesia of ventilation was examined in seven asth- within a short time led to a prolonged re- matics who had had both carotid bodies re- covery time and hypoxaemia. Therefore it moved. Ten normal and five asthmatic sub- is suggested that propanidid anaesthesia jects with intact carotid bodies served as be given only with assisted ventilation and controls. All subjects were exercised on a simultaneous administration of oxygen. cycle ergometer while breathing air, 12% SEPTEMBER-OCrOBER, 1972 133 oxygen in , 25%o oxygen in nitro- precede the jaundice; and 4) hepatic dam- gen, and 5% carbon dioxide-21%o oxygen age has occurred in apparently healthy pa- in nitrogen. Minute ventilation was meas- tients exposed only to the anesthetic and ured and arterial blood was monitored for the usual premedications. However, the in- pH, carbon dioxide tension, bicarbonate, cidence of this syndrome is very low, and and oxygen tension. The subjects were also neither incidence nor severity are dose-re- tested for baroreceptor function by the lated; time of onset is variable, sometimes Valsalva maneuver and carotid-sinus mas- many days; the lesions are not reproduc- sage. ible in animals, and do not resemble the The carotid body-resected subjects were damage caused by carbon tetrachloride not responsive to hypoxia, and their ven- and other directly hepatotoxic agents; and tilatory response to carbon dioxide was re- the lesions often simulate those caused by duced to about 70% of that of the controls, viral infections. suggesting that the carotid bodies mediate about 30% of the total ventilatory response to inhaled carbon dioxide. The absence of Cerebral blood flow and metabolism: Effects carotid bodies did not affect the ventilatory of anesthetic drugs and techniques response of subjects to exercise. A. L. Smith and H. Wollman Anesthesiology 36(4) :378 April, 1972 Toxicity of halogenated anesthetics, hypnotics This review article, drawing on nearly and sedatives 200 references, covers in detail the effect of many anesthetics, adjuvants, and tech- J. Adriani niques such as hypothermia on cerebral I Amer Assn Nurse Anesth 40(2) :95 April, blood flow (CBF) and cerebral metabolic 1972 rate (CMR). Measurement methods are The term "halogenated" has come to im- described, and accepted normal values for ply toxicity, for many persons, especially in these and other parameters are listed. The reference to anesthetics, hypnotics, and authors review the effects on CBF of carbon sedatives. The toxicity of such compounds, dioxide tension and oxygen tension, and however, is not directly related to the fact discuss some abnormal responses to CO2: that they are halogenated. The halogen- the "luxury perfusion syndrome" due to ated form of a compound may be either loss of autoregulation around cerebral in- more or less toxic than its unhalogenated farctions often occurs, but hypercarbia may form, and its pharmacologic potency may dilate artioles in normal areas, resulting in be either greater or less without reference a net decrease of perfusion in ischemic to its toxicity. areas. A reverse effect, or "inverse steal," In general, the volatile halogenated hy- is postulated to occur in hypocarbia. drocarbons and ethers are most likely to The effects of a number of inhalation display toxicity: cardiotoxicity, hepatotox- anesthetics on CBF and its response to CO2, icity, nephrotoxicity, and neurotoxicity may CMR, and intracranial pressure are re- occur, though the last two are less common. viewed; only one agent, , is The hepatotoxicity ascribed to halothane reported to influence cerebral metabolic has recently caused concern among many pathways: this drug is said to increase cere- anesthetists, but it has not yet been def- bral lactate production, but whether it pro- initely proven to be a true clinical entity. duces cerebral hypoxia has not been deter- Facts that suggest that halothane causes the mined. Th-e, significance of changes in in- hepatitis that sometimes follows its use are tracranial pressure in patients with space- that 1) halothane belongs to the group of occupying lesions is discussed. compounds that have a propensity to cause Intravenous anesthetics such as barbitu- hepatotoxicity; 2) about 10 percent of this rates, narcotics and neuroleptics, and keta- agent is metabolized in the body, and the mine are discussed. Thiopental has marked metabolite could be toxic or could trigger a effects on cerebral hemodynamics, while dormant or subelinical hepatitis; 3) sensi- narcotics in premedication doses have little tivity phenomena such as fever and rashes or no effect; ketamine, studied in dogs with 134 ANESTHESL4 PROGRESS basal nitrous oxide anesthesia, produces anesthetics, including three fully fluorin- a transient drop in both CBF and CMR, ated compounds, are investigated using indicating a need for caution in using this loss of the righting reflex in mice as an drug in patients with cerebrovascular dis- endpoint. The olive oil solubilities and hy- ease. Vasoactive drugs and some other drugs drate dissociation pressures were deter- such as chlorpromazine, ethanol, d-Tubo- mined for the three compounds for which curarine, and some steroids are also re- these measures were not already available; viewed. Hypothermia and deliberate altera- ED50 data from other studies were com- tions of blood pressure are reviewed, and pared to the findings of this study. problems of anesthesia for cartoid-artery The dose response curves found in this surgery are discussed. and other studies are remarkably well de- fined, indicating little individual variation in dose required within several species. Physiochemical approaches to the mode of This homogeneity of response within spe- action of general anesthetics cies suggests a close genetic control of the K. W. Miller, W. D. M. Paton, E. B. Smith structures mediating the anesthesia. The and R. A. Smith correlation of ED50 with olive oil-gas parti- tion coefficients is exact within the experi- Anesthesiology 36(4):339 April, 1972 mental uncertainty, while correlation of The mechanism of action of general an- ED50 with hydrate dissociation pressures is esthetics has not yet been defined in de- only approximate; moreover, many com- tail. Because the classic approach involves mon anesthetics do not appear to form a correlation of anesthetic potency with phys- pure hydrate. While the lipid-solubility ical properties relating to intermolecular theories are supported, it is not possible forces, study of anesthetics such as the fully to distinguish on the basis of these data fluorinated compounds, with anomalous between the Overton-Meyer theory, which properties of solubility, etc., has been fruit- postulates that the mole-fraction concen- ful in allowing discrimination between var- tration at a lipid site governs anesthesia, ious models of anesthetic action. In general, and the Mullins theory, which postulates the lipid-solubility theories rather than the volume-fraction concentration as the crit- aqueous-site theories of Pauling and S. L. ical factor; the two theories imply slight dif- Miller have been supported by such stud- ferences in the nature of the lipid site. ies, but before closer definition of a hydro- Measurement of the solubility parameter phobic site is possible, large amounts of ac- of anesthetics in solvents of graded solvent curate and consistently defined data on an- powers is suggested as an approach to more esthetic potencies are needed. In this work precise definition of the site of anesthetic the potencies (ED50) of seven gaseous action.

SEPTEMBER-OCrOBER, 1972 135