Manchester 1994

Dr M Logan

Edinburgh Royal Infirmary

With the introduction of Desflurane, the concept of low flow anaesthesia has changed. Desflurane has an optimal efficiency fresh gas flow rate of less than 11 min"' diminishing the flow rate difference between closed circle and low flow techniques. The low blood/gas partition coefficient of 0.42 for desflurane combined with its low tissue, rubber and PVC solubilities has provided us with a volatile agent that is more controllable than the older agents within low flow systems. Because, on induction, the alveolar desflurane concentration (F_ADes) rises almost as rapidly as the inspired concentration (F_iDes), the overpressuring technique that is necessary with halothane, enflurane and isoflurane is not required (figl).

At 31 min"¹ starting flow rates both the inspired (FiDes) and expired (FeDes) Desflurane concentrations rise very rapidly.

By five minutes the FeDes concentration can approach 85-90% of the vaporizer setting. With such a minimal dilution of the fresh gas concentrations there is no need to use fresh gas flow rates exceeding 31'¹. At maintenance flow rates of 11 min"¹ or more, FiDes is approximately 80-90% of the vaporizer setting in comparison with 50-50% using enflurane. This makes desflurane concentrations within the circle almost fresh gas flow independent with flows of 11 min'¹ or over. Maintenance flow rates of over 11' are therefore wasteful with virtually no clinical benefit. However, the 0-18% range of the TEC6 vaporizer (in an out-of-circuit position, of course) is more than adequate to deliver sufficient desflurane at "closed" maintenance fresh gas flow rates of 300 ml min"¹ or less. At this flow rate FiDes is usually 70-75% of the vaporizer setting. This is in contrast with a 5% enflurane vaporizer which struggles at similar flows to maintain circle concentrations at perhaps only 30% of the vaporizer setting whilst operating at the limit of its range.

300 ml min'¹ fresh gas flow rates require a very high recycled/fresh gas ratio with as a consequence slow circle responses to vaporizer changes because of the resultant large time constant of the breathing system/lung unit. Therefore, when changing concentrations at micro flows, it is usually necessary to increase the flow rate to 1 - 3 l.min^-1 for perhaps 1-3 mins to reach the desired concentration and then return to the original flow rate. With desflurane, early approximation to saturation of vessel rich compartments optimises the highly cost effective technique of "coasting" towards the end of surgery without having to adjust the fresh gas flow rate and by simply turning off the vaporizer (Fig 3). During a 60 minute case using 300 ml min'¹ maintenance flows, the tiny desflurane uptake by the patient permits "coasting" for up to 25 minutes with absolutely no volatile agent cost whatsoever. The ability to use basal fresh gas flow rates easily and to coast for long periods both reduce the cost of desflurane anaesthesia significantly.

The main objective of current sevoflurane research is to evaluate the potential for toxicity resulting from degradation by the soda-lime in circle systems and biotransformation in the body to inorganic fluoride.

The breakdown of sevoflurane in the presence of soda-lime was first described by Wallin et al in .1975'. In severe laboratory conditions, when a mixture of sevoflurane and soda-lime is heated to 120°C, five degradation products can be identified². However in clinical situations only one compound, CF₂ = C(CF₃ )OCH₂ F

(referred to as Compound A), can usually be detected. To decide whether scvoflurane can be safely delivered by a circle system, we need to know :

Three recent studies give an indication of how much Compound A is produced- The first by Frink et al studied 16 patients undergoing surgery >3 hours duration³. Anaesthesia was maintained with N₂O/O₂ and sevoflurane. The O₂ flow rate was fixed at 500 ml/min and the N₂O rate reduced from 500 ml/min to maintain the FiO₂ at 0.5 (average 273 ml/min). The mean maximum compound A measured concentration was approximately 8 ppm. (maximum 15ppm) when soda-lime was used as the absorbent and 20 ppm (maximum 61 ppm) when baralyme was used.

A study of closed-circle sevoflurane anaesthesia in 10 patients has been conducted in which liquid sevoflurane was injected into the circle, using a fresh gas flow of just 200 ml/min.⁴ The duration of anaesthesia ranged from 7 to 11 hours. The mean concentration of Compound A reached approximately 20 ppm after 1 hour and tended to decrease after 5 hours. A trace concentration of Compound B was also detected in 7 of the 10 patients.

We have completed a study of 31 patients randomised to a total fresh gas flow of either 2 1/min or 0.5 1/min. The duration of anaesthesia was approximately 2 hours and the mean peak Compound A concentrations were 19 and 17 ppm in the inspired limbs of the circle in the 0.5 and 2/lmin groups respectively.

Further laboratory studies have indicated that the most important determinants of Compound A production are the concentration of sevoflurane in the circuit and the temperature of the CO; absorbent

Sevoflurane has now been administered to over 1 million patients in Japan with no reports of hepatotoxicity or nephrotoxicity.

However the most commonly used breathing system is a semiclosed system with relatively high fresh gas flows; low-flow and closed-circuit systems are rare. At present there is no evidence of human toxicity as a result of sevoflurane degradation. None of the clinical studies mentioned above detected any clinical or biochemical evidence of toxicity. However the total number of humans exposed has been small. However, toxicity in rats has been well described. Morio et al calculated that the LC50 of Compound A was approximately 400 ppm in rats⁵. Gonowski et al, using slightly different methodology determined the LC50 in rats to be 331 ppm⁶. Moreover, histological evidence or renal injury was round in rats exposed to 50 ppm for 3 hours; evidence of cerebral and hepatic injury was detected at higher concentrations. The significance of 'his animal work in human safety has not been decided.

Approximately 3% of sevoflurane undergoes biotransformation to inorganic fluoride and hexafluoroisopropanol. Defluorination of volatile anaesthetic agents is principally catalysed by the 2E1 isoform of hepatic microsomal cytochrome P450. This enzyme is solely responsible for the biotransformation of sevoflurane, enflurane and isoflurane but defluorination of methoxyflurane is also catalysed by a number of different hepatic and renal isoforms in the liver and kidney.

The nephrotoxic effect of methoxyflurane was observed shortly after the drug was introduced into clinical practice in 1960. The syndrome of increased urine output despite dehydration and azotaemia (nephrogenic diabetes insipidus) which followed methoxyflurane anaesthesia caused a number of-deaths. A dose-response study by Cousins and Mazze in 1973 identified subclinical toxicity after 2.5 to 3 MAC hours (serum fluoride > 50 μM is now often referred to as the "nephrotoxic threshold".

μM) and overt clinical toxicity after 5 MAC hours (serum fluoride > 90 M is now often referred to as the "nephrotoxic threshold".

Enflurane is biotransformed to inorganic fluoride to a much lesser extent than methoxyflurane. It can be difficult to determine the renal effects of anaesthetic agents in surgical patients because of the confounding effects of pre-existing disease and surgical trauma. Consequently, a volunteer study was conducted to compare the effect of prolonged halothane or enflurane anaesthesia on maximum urine concentrating ability.⁸ The volunteers were exposed to approximately 9.6 MAC hours of enflurane which resulted in a mean peak fluoride concentration of 33.6 μM at 6 hours after exposure. A consistent decrease of 264 Mosmol/kg (se 34) in maximum urine concentration was recorded on post exposure day 1 but this had recovered by day 5. This study suggested that the threshold concentration for inorganic fluoride nephrotoxicity might be lower and that enflurane might pose a risk to patients with pre-existing renal disease.

The studies mentioned above provide the background for the concern that the biotransformation of sevoflurane to inorganic fluoride may be harmful. However, sevoflurane has not been associated with renal impairment although the serum inorganic fluoride concentration may exceed 50 μM. A recent study compared the effect of prolonged sevoflurane and enflurane anaesthesia on renal concentrating ability in 14 volunteers⁹. The mean peak fluoride concentrations were 47 μM in the sevoflurane group and 23 μM in the enflurane group after 9.5 MAC hours of anaesthesia. No nephrotoxic effect was detected after exposure to sevoflurane but 2 of the 7 volunteers who received enflurane had impaired renal concentrating ability (<800 osmol/kg) on day 1 post exposure.

We have repeated this study and compared renal function after 6 and 9 MAC hours of enflurane or sevoflurane exposure. Although we used slightly different methodology, no defect in renal concentrating ability could be detected in either group. Clearly, the relationship between serum fluoride concentration and renal function is not as simple as once believed.

1. Wallin RE. Regan BM, Napoli MD, Stern IJ, Sevoflurane: a new inhalational anaesthetic agent. Anesth Analg 1975; 54: 758-766

2. Hanaki C, Fujii K, Mono M, Tashinao T, Decomposition of sevoflurane by soda-lime. Hiroshima J Med Sci 1987; 36: 61-67

3. Prink EJ, Malan TP, Morgan SE, Brown EA, Malcolmson M, Brown BR, Quantification of the degradation products of sevoflurane in two CO^ absorbants during low-flow anaesthesia in surgical patients. Anesthesiology 1992; 77: 1064-1069

5. Mono M, Fujii K, Imai M, et al. Reaction of sevoflurane and its degradation products with soda-lime: Toxicity of the byproducts. Anesthesiology 1992; 77: 1155-1164

6. Gonsowski CT, Laster MJ, Eger El, et al. Toxicity of Compound A in rats: Effect of a 3 hour administration. Anesthesiology 1994; 80: 556-565

7. Cousins MJ, Mazze RI. Methoxyflurane nephrotoxicity: a study of dose response in man. JAMA 1973; 225: 1611-1616

8. Mazze RI, Calverley RK, Smith NT. Inorganic fluoride nephrotoxicity: prolonged enflurane and halothane anaesthesia in volunteers. Anesthesiology 1977; 46: 265-271

9. Frink EJ, Malan TP, Isner RJ, Brown EA, Morgan SE, Brown BR. Renal concentrating function with prolonged sevoflurane or enflurane anaesthesia in volunteers. Anesthesiology 1994; 80: 1019-1025


	Manchester 1994
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