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Summary A major question often asked about sevoflurane is why, if it meets all the needs of the practitioner, was it not introduced earlier? After all, the drug has been around since 1975. Most of the reasons sevoflurane has been somewhat of a ‘late bloomer’ have been due to hesitations on the part of the drug manufacturers. This has been discussed in a recent editorial ( Brown and Frink, 1992 ). The authors feel that sevoflurane is a useful drug which may have certain advantages over currently available halogenated anaesthetics. Some of the advantages of sevoflurane are listed. 1. Cardiovascular. There is reason to believe that in clinical practice sevoflurane may cause less cardiovascular depression than other drugs. These clinical impressions are subtle, but seem inevitable after clinical familiarity with the drug is obtained. It does not appear to produce tachycardia in humans. Certainly, sevoflurane is less arrhythmogenic than other inhalation anaesthetics in use. The anaesthetic is very ‘user friendly’. 2. Induction and awakening time are remarkably short and smooth. 3. Paediatric inhalation induction is unparalleled with other anaesthetics, including halothane. Certainly sevoflurane may be a ‘niche’ drug for such use, to answer a question poised in the introduction of this chapter. 4. The potential toxicity for interaction of sevoflurane and CO 2 absorbents is probably more theoretical than real. This is an area, however, where more investigation, both clinical and laboratory, is needed. In summary, sevoflurane at the present time seems to offer many advantages over currently available drugs. Its place in practice will be determined by experience in clinical practice.

Study Objectives: To evaluate the decomposition of sevoflurane in soda lime during prolonged sevof lurane anesthesia in humans. To evaluate for evidence of renal or hepatotoxicity as a result of exposure to these sevoflurane degradation compounds. Design: Prospective evaluation in healthy volunteers. Setting: Clinical research unit and postanesthesia care unit of a university hospital. Patients: Six healthy male volunteers. Interventions: Subjects were anesthetized with sevoflurane 1 to 1.2 minimum alveolar concentration for greater than 9 hours with a semiclosed circuit anesthetic technique (5-liter total flow) with fresh soda lime as the absorbent. Measurements and Main Results: Laboratory tests of renal and hepatic function were performed before anesthesia and 1 and 5 days after anesthesia. During sevoflurane anesthesia, inhalation and exhalation circuit limb gas samples were obtained for degradation compound analysis. Only one degradation product, fluoromethyl-2,2-difluoro-l-(trifluoromethyl) vinyl ether (compound A), was detected. Inhalation concentration was maximal (7.6 ± 1.0 ppm) at 2 hours and did not increase further after this time point. There were no differences in preanesthesia and postanesthesia tests of hepatic and renal function. Conclusions: Levels of the degradation compound (compound A) produced in semiclosed circuit sevoflurane anesthesia with soda lime are well below potential toxic levels and thus appear safe. When sevoflurane is administered under these conditions for prolonged anesthesia, concentrations of compound A do not continue to increase throughout anesthesia.

The biotransformation and plasma inorganic fluoride ion production of sevoflurane (the new volatile anesthetic) during and after surgical anesthesia was studied in 50 ASA I or II surgical patients. Twenty-five additional patients served as controls by receiving isoflurane. Sevoflurane or isoflurane was administered with a semiclosed (total gas flow, 2 L/min O2) circle absorption system for durations of 1.0 to greater than 7.0 minimal alveolar concentration (MAC) hours for surgical anesthesia (sevoflurane MAC, 2.05%; isoflurane MAC, 1.15%). Preoperative and postoperative blood urea nitrogen and creatinine concentrations were determined. Blood samples were obtained during and after anesthesia in both groups for determining anesthetic blood concentration analysis and plasma fluoride level. Plasma fluoride concentrations did not significantly increase during isoflurane anesthesia. Sevoflurane biotransformation produced a mean peak plasma inorganic fluoride concentration of 29.3 +/- 1.8 mumol/L, 2 h after anesthesia, which decreased to 18 mumol/L concentration by 8 h after anesthesia. The peak plasma inorganic fluoride ion concentration correlated with duration of sevoflurane anesthetic exposure. Five patients given sevoflurane had peak levels transiently exceeding 50 mumol/L, and one of these had a history of ingesting drugs potentially producing hepatic enzyme induction. No increases in postoperative levels of creatinine, blood urea nitrogen, direct bilirubin, or hepatic transaminase and no changes in serum electrolyte level occurred in either anesthetic group. Indirect bilirubin concentration increased significantly after sevoflurane anesthesia, but the increase was not of clinical significance (from 0.30 +/- 0.03 to 0.38 +/- 0.06 mg/dL). Indirect bilirubin concentrations did not increase after isoflurane anesthesia; the concentrations reached 0.31 +/- 0.04 mg/dL and did not differ significantly from those found with sevoflurane.(ABSTRACT TRUNCATED AT 250 WORDS)

Verapamil clearance is reduced during halothane administration. This study evaluated relative contributions of reduced hepatic flow rate and hepatic metabolizing enzyme inhibition by halothane as a cause of reduced verapamil clearance. An isolated perfused rat liver model was utilized in which flow rate could be fixed during halothane administration. Perfusions were performed on five to six livers under each of the following conditions: (a) control--40 mL/min flow rate with no anesthetic exposure; (b) 1.5% halothane--40 mL/min; (c) 2.25% halothane--40 mL/min; (d) reduced flow--20 mL/min with no anesthetic exposure; and (e) reduced flow with 1.5% halothane--20 mL/min. Halothane caused dose-dependent decreases in both total hepatic and intrinsic clearance rates (P less than 0.05). With no anesthetic exposure, a flow reduction of 50% (20 mL/min) also gave a large reduction (P less than 0.05) in hepatic clearance of verapamil compared with the control condition (40 mL/min). The addition of 1.5% halothane to the reduced flow condition was not associated with further reduction in hepatic clearance rate. Results of this study suggest that although both reduced hepatic perfusion and hepatic enzymatic inhibition by halothane administration are associated with decreased verapamil clearance, a greater proportion of this decrease appears to be due to reductions in hepatic flow. The present results may apply to other drugs used in anesthesia that have high hepatic extraction ratios; thus, clearance of these drugs may be more dependent on hepatic blood flow than on hepatic enzyme activity.

Chronic pain may occur in the ilioinguinal nerve distribution spontaneously or following herniorrhaphy or other surgery. Primary ilioinguinal neuropathy may also cause abdominal muscle motor weakness resulting in direct hernia. We describe 12 patients with ilioinguinal nerve disorders and discuss therapeutic alternatives and results of treatment.

Three cases of postoperative malignant hyperthermia (MH) episodes, after what was considered to be a "safe" anaesthetic, are described. In each case the temperature rose in a delayed fashion after an uneventful anaesthetic. Treatment included intravenous dantrolene, surface cooling and ventilation with 100 per cent oxygen. Stress in the postoperative period may have been the triggering factor responsible for these reactions. Patients should be monitored well into the postoperative period as MH episodes may occur long after surgery is completed. If stress represents a significant triggering mechanism then no anaesthetic technique can be considered entirely safe.

Since CF3CH2Cl and CF2CHCl are probably the products of reactive intermediates formed during the reductive metabolism of halothane (CF3CHClBr), factors affecting their in vitro and in vivo formation were investigated. In vitro studies with rat hepatic microsomes showed that CF3CH2Cl and CF2CHCl are produced by cytochrome P-450 mediated reductive pathways which were inhibited by the presence of CO. Under conditions of exposure known to promote halothane hepatotoxicity in phenobarbital treated rats (1 per cent halothane, 14 per cent oxygen), the hepatic and blood concentrations of the volatile metabolites were enhanced. Central venous levels of the volatile metabolites were much higher than he concentration in peripheral vessels. The CF3CH2Cl/CF2CHCl ratio in blood was approximately three, whereas the ratio in vitro was almost unity. Liver levels of the two volatile metabolites greatly exceeded the blood levels, but interestingly they were present in equivalent concentrations. The differences in the ratio of CF3CH2Cl to CF2CHCl may be explained by the fact that CF2CHCl is further degraded under oxidative conditions, whereas CF3CH2Cl appears relatively stable. Measurement of these metabolic products in patients undergoing halothane anesthesia may permit rapid detection of an unusually high level of halothane biotransformation along its hepatotoxic pathway.

Hepatic necrosis was induced in rats by a single exposure to 1 per cent halothane in oxygen following pretreatment with a single dose of Aroclor 1254, a polychlorinated biphenyl. The hepatic lesion was centrilobular and multifocal, and morphologically similar to that reported to occur in man. In-vitro incubation with 14C-halothane indicated an enhanced covalent binding of halothane metabolites to hepatic microsomal macromolecules, particularly lipids, following Aroclor 1254 pretreatment. Lipoperoxidation of microsomal unsaturated fatty acids was not observed with these animals.

Hepatic microsomal lipoperoxidation in vivo is stimulated by anesthetic concentrations of halothane (Fluothane) and chloroform in phenobarbital-pretreated rats. Diethyl ether and fluroxene (Fluoromar) do not share this property in the rat. Studies in vitro show no enhancement of lipoperoxidation, but in this circumstance metabolism of the anesthetics is minimal. It is speculated that enhancement of metabolism of halothane and chloroform by phenobarbital induction is capable of fostering a peroxidative breakdown of hepatic microsomal polyenoic lipid esters.

Halothane depresses the metabolism of amobarbital, hexobarbital, pentobarbital, and aminopyrine (type I substrates) by rat hepatic microsomal enzymes. This inhibition is dose-dependent, reversible, noncompetilive, and independent of the lipid solubilities of the substrates. In contrast, the metaboli

Circulating catecholamines have been proposed as trophic agents for the heart. Denervation of the adrenal medullae, the major source of plasma epinephrine, totally blocked left ventricular hypertrophy after aortic coarctation in the dog. The level of epinephrine after adrenal medullary cholinergic denervation dropped to a mean of 10 pg/ml within 48 hours compared to 317 pg/ml in coarcted dogs with intact adrenal innervation, and 116 pg/ml in sham-coarcted controls. Decreased epinephrine levels were concomitant with a decrease in the heart weight to body weight ratios. These data implicate epinephrine as the specific hormone regulating cardiac hypertrophy.

To the Editor:— Mouth-to-mouth resuscitation is the preferred method of assisting ventilation in the emergency situation and is being taught to many lay groups such as lifeguards and firemen. However, there are complications attendant with the use of the technique, particularly by the less experienced. Complications include partial or total airway obstruction resulting in air being vented via the esophagus into the stomach when the operator exhales forcibly, and active or passive regurgitation of the victim's stomach contents into the upper airway. Since the report of Sellick, 1 many anesthesiologists have used posterior displacement of the cricoid cartilage to prevent active or passive regurgitation during the induction of anesthesia prior to insertion of an endotracheal tube in the patient with a full stomach. The cricoid cartilage is signet-ring shaped with the large flat plate just anterior to the esophagus. By applying posterior pressure to the skin over the anterior surface

Reports in the literature have suggested possible impairment of immunocompetence in operating theater personnel. In a group of 18 physician anesthesiologists the following were determined: hemoglobin concentration; white blood cell count; numbers of T, B, and natural killer (NK) lymphocytes; number of T-active cells; and numbers of T-helper/inducer (Th) and T-suppressor/cytotoxic (Ts) cells; and the Th/Ts ratio. Function of T lymphocytes was evaluated using the local xenogeneic graft-versus-host reaction and spontaneous suppressor or helper activity of T cells. The same parameters were determined in a group of 18 age- and sex-matched healthy controls. It was found that no matter what their age or how long they have been engaged in anesthetic practice, anesthetists show no immunosuppression as evidenced by these parameters.

A rat model of cnflurane-associated hepatotoxicity was compared with the halothane-hypoxia (HH) model (adult male rats, phenobarbital induction, 1% halothane, 14% O2, for 2 hr). The enflurane-hypoxia heating (EHH) model involved exposing phenobarbital-pretreated male adult rats to 1.5–1.8% enflurane at 10% O2 for 2 hr with external heating to help maintain body temperature. Exposure to either anesthetic without temperature support led to a decrease in body temperature of 7–9°C, while heating the animals during anesthesia resulted in only a 0.5–2°C decrease. Reducing the oxygen tension to 10% O2 combined with heating the animals during exposure produced significant decreases in the oxidative metabolism of both halothane and enflurane as compared to exposures of 14% O2. The same conditions also caused a significant increase in the reductive metabolism of halothane, indicating that a severe hepatic hypoxia or anoxia occurs during anesthesia at 10% O2 with external heating. The time course of lesion development in the HH model paralleled results obtained with an oral dose of CCl4: gradual progression of necrosis up to 24 hr. EHH resulted in a classic hypoxic/anoxic injury with elevated serum glutamate pyruvate transaminase values and a watery vacuolization of centrilobular hepatocytes immediately after exposure. The HH model required phenobarbital pretreatment of the rats for expression of hepatic injury; EHH did not. Heating of the animals during anesthesia exposure was necessary for enflurane-induced hepatotoxicity but had little effect on the HH model. Exposure to 5% O2 without anesthetic mimicked EHH in both requirements for and type of hepatic injury. Thus the HH model appears to act via a bioactiva- tion/chemotoxic mechanism, whereas models of anesthetic- induced hepatotoxicity that require very low oxygen tensions and heating of the animals during exposure result from a severe hypoxia/anoxia of the liver.

PHYSICIANS commonly are faced with cervical and lumbar pain problems from antecedent trauma, muscular tension, or postural abnormalities. The common denominator of these conditions is skeletal muscle and ligamentous strain. Pain originating from lesions in these structures, regardless of anatomic localization, has been termed "primary myofascial syndrome." Paramount to the diagnosis of myofascial syndrome is the absence of demonstrable neurologic or orthopedic deficits. In fact, this constellation of pain problems frequently mimics conditions such as herniated cervical and lumbar disks, facet syndromes, fractured transverse processes, thoracic outflow syndrome, and spondylolisthesis. Obviously, therapy for these latter diagnoses is different from that for primary myofascial syndrome, and attention should be given to ruling out such surgically correctable lesions by evaluation of past history, adequate physical examination, and appropriate laboratory and roentgenographic studies. More than 500 cases of primary myofascial syndrome have been diagnosed and treated in the past six years at the

The effectiveness of cyclobenzaprine hydrochloride, a new tricyclic skeletal muscle relaxant, was shown in patients with long-term intractable pain of cervical and lumbar origin aggravated by skeletal muscle spasm and tenderness. The investigation was double-blind and randomized, comparing cyclobenzaprine hydrochloride (10 mg three times a day) with diazepam (5 mg three times a day) and with placebo. After two weeks of treatment, the 16 patients in the cyclobenzaprine group showed an overall improvement in pain variables as did the 16 patients in the diazepam group. No serious adverse reactions to cyclobenzaprine were observed in the study. However, dry mouth due to cyclobenzaprine's anticholinergic action and mild degrees of drowsiness were encountered more often than with diazepam or placebo. (JAMA240:1151-1152, 1978)

A recently reported animal model of halothane-associated hepatotoxicity in males of a colored strain of guinea pig was further characterized as to possible sex and strain specificity in outbred albino Amana, inbred albino Hartley, inbred colored strain 2, and inbred colored strain 13 guinea pigs. Exposure to 1 % halothane for 4 hr in 21 % O2 proved to be hepatotoxic in both sexes. Forty-eight hours after halothane exposure fatty vacuolization of hepatocytes was present in all animals. Histologically identifiable hepatic necrosis occurred in 60% of the guinea pigs exposed, along with concomitant increases in SGPT. Approximately one half of these responding animals had extensive centrilobular necrosis, which was still present 96 hr after halothane exposure. Females of the inbred strain 2 and males and females of strain 13 were the most susceptible to halothane-induced hepatic necrosis whereas the inbred Hartley strain was almost totally refractory to necrosis. Outbred Amana and male inbred strain 2 animals exhibited an intermediate hepatotoxic response. Comparison of the halothane-associated hepatic lesion with that induced by anoxidischemic mechanisms, (exposure to low (8%) oxygen during 1.7% enflurane anesthesia) showed obvious differences in the morphology of the hepatic necrosis and the apparent time course of lesion development. This guinea pig model of halothane-associated hepatotoxicity appears to be superior to previous animal models in that no pretreatment of the guinea pigs is required, both sexes are affected, and the resulting hepatic lesion is more persistent.

In a previous report, the incidence of tourniquet pain was found to be 25% with bupivacaine and 60% with tetracaine (P less than 0.05) spinal anesthesia. On the other hand, tetracaine is more potent than bupivacaine in abolishing the single-compound action potential in vitro in isolated nerves. These conflicting observations may be reconciled if bupivacaine produced greater frequency-dependent conduction blockade of nerve action potentials. This hypothesis was tested in C fibers of isolated, desheathed rabbit vagus nerves. The nerves were supramaximally stimulated at frequencies of 9 or 15 Hz. After a control period, the nerves were exposed to bupivacaine (0.2 mM) or tetracaine (0.02 mM) for 30 minutes. The local anesthetics were then washed out by continuous constant-rate perfusion. The decline and recovery of the first and last action potential amplitudes of the train were measured. Bupivacaine and tetracaine produced similar depression of the first action potential of the 9-Hz and 15-Hz trains. However, bupivacaine caused a delayed recovery of the last action potential of the 15-Hz train but not of the 9-Hz train. These results show that bupivacaine produces greater frequency-dependent conduction blockade of C fibers than does tetracaine. These findings offer a possible explanation as to why spinal anesthesia with bupivacaine results in a lower incidence of tourniquet pain than tetracaine.

THE inhalation anesthetic fluroxene (Fluoromar, 2,2,2,-tri-fluoro-ethyl vinyl ether), has just been considered hepatotoxic.1 Recently, a patient taking phenobarbital and diphenylhydantoin died of massive hepatic necrosis after fluroxene anesthesia – conditions suggestive of an acquired enhanced sensitivity to the anesthetic.2 Case Report An obese 69-year-old woman with grand-mal epilepsy since the age of 15 that had been effectively controlled with diphenylhydantoin (Dilantin), 300 mg per day, and phenobarbital, 120 mg per day, had also received phenylbutazone (Butazolidin) for osteoarthritis. At 65 years of age a gastric ulcer was treated conservatively. Four months before admission ulcer symptoms recurred, 1 week before she . . .

Excerpt Since January 1964 the diagnosis of pheochromocytoma has been established in 20 patients on the basis of urinary catecholamine studies performed in this laboratory. Six were members of 2 se...