Duncan A. Holaday

Clinical Characteristics and Biotransformation of Sevoflurane in Healthy Human Volunteers

Sevoflurane was submitted to phase-1 studies in man following extensive testing in animal species without evidence of toxicity. Sevoflurane, 2–3 per cent inspired during maintenance, was administered with oxygen to produce one hour of anesthesia in six healthy adult male volunteers. Respiratory and cardiovascular functions, the electroencephalogram, arterial blood gases, blood sevoflurane, inorganic fluoride and total, nonvolatile fluorine concentrations, and inspired and mixed expired sevoflurane concentrations were measured during exposure. Concentrations of expired sevoflurane, blood and urinary fluoride, and total nonvolatile fluorine metabolites were also measured after anesthesia. During exposure spontaneous respiratory frequency increased 28 per cent, respiratory minute volume changed insignificantly, and Paco2s averaged 50 torr. Pao2s remained near 400 torr. Arterial systolic blood pressure declined an average of 17 per cent. Pulse rate changed insignificantly. After an hour of exposure arterial blood serum inorganic fluoride concentrations averaged 22 μM and plasma nonvolatile organic fluorine concentrations averaged 9.1 mg/l, or 61.3 μM. Uptakes of sevoflurane averaged 94 (±63 SD) mmol. Following exposure 37 (±12) mmol of unaltered sevoflurane were estimated to be excreted in exhaled air and 0.90 mmol of inorganic fluoride and 163 mg, or 1.43 (±0.26) mmol of organic fluorine were excreted in the urine. Recoveries in exhaled air and urine averaged 51.5 (±2.4) per cent of uptake. There was no significant drug-exposure-related change in the chest radiogram, electrocardiogram, electroencephalogram, urinalysis results, complete blood count, prothrombin time, serum electrolytes, transaminases, or hepatic and renal functions during four weeks following exposure compared with preexposure values. Sevoflurane produced anesthesia of excellent quality; it appears to undergo limited biotransformation and to have little or no systemic toxicity.

Resistance of Isoflurane to Biotransformation in Man

Pulmonary and renal excretion of isoflurane and its metabolites was studied in nine surgical patients following administration of known quantities of isoflurane. Uptake and pulmonary washout were predictable by a mathematical model for inert vapors. The agreement between predicted and experimental data supports the view that isoflurane is subject to little or no biotransformation. The average recovery in exhaled air was 95 per cent, SE 7 per cent. The postoperative increase of urinary exeretion of fluoride and organic fluorine accounted for less than 0.2 per cent of fluorine administered as isoflurane. This small extent of biotransformation is probably biologically insignificant, but only after extensive clinical experience can the hazard of delayed toxic response be conclusively evaluated.

The Biotransformation of Ēthrane in Man

The biotransformation of Ēthrane was studied in seven healthy female patients by measuring urinary fluorine excretion. The total amount of Ēthrane recovered was 85.1 per cent of the amount absorbed; 82.7 ± 18.8 per cent was recovered as unchanged Ēthrane in exhaled air and 2.4 per cent as nonvolatile fluorinated metabolites in urine. Of the urinary fluorine, 0.5 per cent was excreted in inorganic form and 1.9 per cent in organic form. Following anesthesia, urinary excretion rates of fluoride in reached a maximum in seven hours. Maximum excretion of organic fluorine metabolites was reached on the second day. Urinary excretion then assumed a simple exponential decay, with half-times of 1.53 days for inorganic fluoride and 3.69 days for or-ganic fluorine. The excretion of unaltered Ēthrane in exhaled air assumed a three-term exponential decay, with half-times of 17.8 minutes, 3.2 hours, and 36.2 hours.

The Metabolic Degradation of Methoxyflurane in Man

The metabolism and excretion of methoxyflurane were studied in 12 human subjects, five of whom were exposed to methoxyflurane labeled with 14C in the methoxy position. Biodegradation of methoxyflurane began immediately after the onset of exposure and continued for nine to 12 days, after which storage depots of intact drug approached depletion. Identified products of bio-transformation were CO2, fluoride ion, dichloroacetic acid, and methoxyfluoroacetic acid. Twentynine and 35 per cent of the absorbed methoxyflurane, respectively, were estimated to be exhaled unaltered by two subjects. Seven to 21 per cent underwent cleavage of the ether linkage, producing CO2, fluoride ion and dichloroacetic acid. A larger fraction, 40 per cent in one subject, was dechlorinated and oxidized to methoxydifluoroacetic acid, which was excreted promptly by the kidney.

Asphyxial Death The Roles of Acute Anoxia, Hypercarbia and Acidosis

&NA; Respiratory and circulatory responses to acute, severe hypoxia, hypoxia combined with moderate hypercarbia, and severe hypercarbia were measured in 22 dogs under conditions of apnea and spontaneous breathing. Survival times before circulatory collapse and physiological death indicated that depletion of oxygen stores progresses ten times more rapidly than accumulation of lethal quantities of hydrogen ion. Consequently, the responses to acute asphyxia differed little from those to breathing an oxygen‐free atmosphere. Depletion of oxygen arrested respiratory drive before causing cardiac arrest in systole. During CO2 retention, acidosis progressively paralyzed the myocardium; respiratory drive persisted until the circulation failed. Arterial Po2 at the time of death was 5 to 10 mm. of mercury during anoxia with and without moderate CO2 retention. Death occurred during extreme CO2 retention over a narrow range of pH of arterial blood, from 6.50 to 6.45, whereas Paco2 varied from 149 to 400 mm. of mercury, suggesting that acidosis causes death, rather than hypercarbia. Hypoxia and acidosis became additive in producing circulatory collapse at a Pao2 below 25 mm. of mercury and at a pHa below 6.80. The rate of depletion of oxygen or accumulation of hydrogen ion did not alter the lethal values of either.

Uptake and clearance of inhalation anesthetics in man.

The uptake, distribution, and clearance of inhaled vapors is governed by rules of partial pressure equilibration in a multicompartmental system. Since halogenated anesthetic agents are not soluble in water, biotransformation is their only clearance pathway during anesthesia. When apparent steady state is reached, the rate of overall metabolism can be determined from the pulmonary uptake rate. As a result of metabolism, pulmonary uptake increases but the concentration of inhaled vapor in blood and tissues decreases, and only a fraction of uptake is exhaled following anesthesia. Uptake and pulmonary clearance of five halogenated anesthetic agents were studied in 45 surgical patients. The susceptibility to biotransformation increases in the following order: isoflurane, enflurane, halothane, fluroxene, methoxyflurane.

Uptake, Distribution, and Excretion of Fluorocarbon FX-80 (Perfluorobutyl Perfluorotetrahydrofuran) during Liquid Breathing in the Dog

The uptake, distribution, and excretion of FX-80, a water-insoluble mixture of isomers of perfluorobutyl perfluorotetrahydrofuran, were studied in 17 dogs subjected to liquid breathing with oxygenated FX-80. The absence of excess fluoride ion in urine suggests that FX-80 is not metabolized, nor is it excreted in urine unchanged. Its distribution in the body depends on the lipid content of tissues. The uptake and desaturation curves are multiple exponential functions, the rate constants of which can be predicted from the ratios of lipid contents of blood and tissues and the fractions of cardiac output supplying the tissue compartments. During liquid breathing the concentration of FX-80 in arterial blood averages 0.43 mg/100 ml. Calculations indicate that at saturation a 13.8-kg dog would absorb 1.25 g of FX-80. Of this amount, 71 per cent would be deposited in adipose tissues and bone marrow, 25 per cent in muscles and skin, and 4 per cent in parenchymatous tissues. Desaturation is delayed because deposits of liquid FX-80 are sequestered in the lungs following liquid breathing.

Metabolism of Methoxyflurane in Man

Excretion of methoxyflurane was studied in 12 patients receiving anesthesia in a closed rebreathing circuit at a constant alveolar concentration of approximately 0.24 per cent. The mean methoxyflurane uptake was 1S g (range 7.6–31 g) during a mean time of anesthesia administration of 2 hours. 1S minutes (range 55–309 minutes). An average of 19 per cent of the uptake was recovered unchanged in the exhaled air after anesthesia. Urinary excretion of organic fluorine, fluoride, and oxalic acid was equivalent to 29, 7.7 and 7.1 per cent of methoxyflurane uptake. respectively. Approximately a third of the uptake remained unrecovered. It is postulated that a portion of the unrecovered drug became permanently bourn to tissues and hence its exeretion was delayed beyond the period of the study.

Biotransformation of Fluroxene in Man

Biotransformation and excretion of fluroxene were studied in nine patients following administration of known quantities. An average of 58 per cent was exhaled unaltered following anesthesia. Ten per cent of the fluorine administered as fluroxene was recovered in urine, mainly as trifluoroacetic acid. In contrast to other species, which excrete trifluoroethanol primarily, in man free and conjugated trifluoroethanol accounted for only 0.6 per cent of the administered dose. Fluoride ion excretion in urine did not exceed normal rates of excretion. The fate of 32 per cent of administered fluroxene remains unknown.

Effect of isoflurane anaesthesia and surgery on carbohydrate metabolism and plasma cortisol levels in man

SummaryThe present study was undertaken to investigate in nine male surgical patients the effects of isoflurane anaesthesia alone on the carbohydrate metabolism by determining plasma growth hormone (GH), insulin, blood glucose, and cortisol, and to compare them with the effects of anaesthesia associated with surgical operations. Determination of plasma GH, insulin, cortisol, and blood glucose were made simultaneously before induction of isoflurane anaesthesia, after maintenance of anaesthesia for 15 minutes and 30 minutes and during and after conclusion of the operation.Plasma GH concentrations showed a significant elevation during isoflurane anaesthesia, and maintained a similar high level one hour after the start of the operation. An insignificant elevation in plasma insulin level and significant increases in blood glucose were noted during anaesthesia and operation. Plasma cortisol levels increased insignificantly during anaesthesia, but increased markedly during operation. Our observations would suggest that the increased blood level of GH and elevated blood cortisol play a part in the increase of blood glucose during isoflurane anaesthesia and surgical operations in man.RésuméCe travail avait pour objet l’étude des effets de l’lsoflurane seul sur le métabolisme des hydrates de carbone et de les comparer à ceux causés par l’addition du traumatisme chirurgical; à cette find, on a déterminé chez neuf sujets, le taux de l’lnsuline, de la Glycémie et du Cortisol. Des échantillons ont été prélevés avant l’induction de l’anesthésie à l’lsoflurane, 15 et 30 minutes après l’induction, avant l’incision, durant et après l’intervention.On a observé une élévation significative au niveau de l’Hormone de Croissance durant l’anesthésie, élévation qui s’est maintenue une heure après le début de l’intervention. On a également noté au cours de l’anesthésie et de l’intervention une augmentation non significative de I’Insulinémie et une augmentation significative de la Glycémie.Le Cortisol plasmatique pour sa part s’est élevé de façon non significative durant l’anesthésie, et de façon significative durant le temps chirurgical.Nos observations suggèrent que 1’élévation du taux de l’Hormone de Croissance et du Cortisol joue un rôle dans 1’élévation de la Glycémie observée au cours de l’ahesthésie à l’lsoflurane chez 1’homme.