Volatile Anesthetic Toxicity

Evan D. Kharasch, MD, PhD

Professor, Anesthesiology and Medicinal Chemistry (adjunct) University of Washington, Seattle, WA USA

Since the eras of methoxyflurane nephrotoxicity and halothane hepatitis, anesthesiologists have been concerned about the potential for organ toxicity. This analysis will review the most current and controversial data on sevoflurane and desflurane toxicities.

Halothane hepatitis is initiated by halothane metabolism and binding to liver proteins forming antigens which may stimulate the formation of antibodies, Upon reexposure to halothane (or enflurane, isoflurane or desflurane), these antibodies mediate massive hepatic necrosis. Because the extent of desflurane metabolism is small, the risk of such hepatic necrosis is small; only one case has been published, Sevoflurane metabolism does not result in the formation of these liver antigens, Immune-based hepatitis from sevoflurane, after worldwide administration of approximately 15 million anesthetics, has not been reported. Thus "halothane hepatitis" is not a problem after sevoflurane,

The potential for renal toxicity was a concern during sevoflurane development, based on the 1960's experience with methoxyflurane. This drug caused dilute polyuric renal failure, related to methoxyflurane metabolism. The "fluoride hypothesis" was that the methoxyflurane metabolite inorganic fluoride was the ultimate renal toxin, because methoxyflurane nephrotoxicity was observed at peak fluoride > 50 /^M. This hypothesis was later generalized to all anesthetics, and the 50 ^M fluoride toxic threshold evolved (albeit without supporting data). Anesthetics are scrutinized for the potential to cause 50 μM fluoride. and supposedly, renal toxicity. Sevoflurane is less metabolized than methoxyflurane (2.5% vs 75%), Peak fluoride Of 10-20 μM. after 1-2 MAC-hr and 20-40 ^M after 2-7 MAC-hr sevoflurane is typical in normal adults, However fluoride >50μμ occurred in approximately 7% of patients in preapproval and 15% in published Studies. Fluoride >90-100 μM after sevoflurane has been reported. Despite fluoride commonly >50μM, almost every investigation has found no evidence of fluoride-related nephrotoxicity in patients with normal renal function, those at risk for postoperative renal dysfunction, and those with preexisting renal insufficiency. Renal effects have been assessed by the "gold standards" of BUN and creatinine, other conventional measures such as creatinine clearance, urine and/or serum osmolality, specific gravity, and urinary concentrating ability, and also by experimental so-called "sensitive markers" such as proteinuria, glucosuria and excretion of various proteins released after tubular cell injury (N-acetyl-B-glucosaminidasc (NAG), gluiathione-.S-transferase (GST), alanine aminopeptidase (AAF). In the first year of clinical use (~4 million anesthetics) the incidence of sevoflurane-related renal adverse experiences was no different than that with desflurane in a comparable period of use. Presently the worldwide clinical experience with sevoflurane is approximately 15 million anesthetics. Clinically significant fiuoride-relatcd sevoflurane nephrotoxicity has not become apparent,

Another concern, not initially anticipated, was the effect of sevoflurane degradation products. Sevoflurane decomposes in CO; absorbents to "compound A", a haloalkene difluorovinyl ether which is nephrotoxic in rats, causing proximal tubular necrosis with elevated serum BUN and creatinine, glueosuria, proteinuria, and enzymuria (NAG and GST), The threshold in rats is 50 or 100-114 ppm compound A for 3 hr. In anesthesia machines, higher compound A concentrations occur with Baralyme vs soda lime, lower fresh gas flows, higher CO; absorbent temperature (which occurs with lower gas flows), greater sevoflurane concentrations and increased CO; production. Compound A during low-flow sevoflurane averages 8-24 and 20-32 ppm with soda lime and Baralyme, respectively. Sevoflurane MAC-hr is the best predictor of compound A exposure. Renal effects of compound A have been examined in humans, specifically during low-flow or closed-circuit anesthesia. Renal effects in human volunteers are controversial, One investigation described profound postanesthesia albuminuria, glucosuria, and increased GST excretion after 8 hr of 3,0% 2 L/roin sevoflurane, interpreted as significant glomerular, proximal tubular and distal tubular injury. In contrast, two other investigations, which duplicated the identical sevoflurane protocol, found no significant differences in these same measures. In contrast, in surgical patients, several studies have shown no significant changes in renal function, assessed by serum BUN and creatinine, and urine excretion of protein, glucose, NAG, GST, and AAP. There was also no correlation between compound A exposure and the biomarkers of renal injury. All investigations in surgical patients to date show that low-flow sevoflurane (with compound A formation) has renal effects that are no different from those of low-flow isoflurane or high-flow sevoflurane. Low-flow sevoflurane was recently considered as safe as low-flow isoflurane.

NEW DEVELOPMENTS IN CARBON DIOXIDE ABSORBENTS

JM Murray and JPH Fee

Belfast

In 1756, Joseph Black, a Scot. showed that what we now call carbonates contained a 'fixed air' (carbon dioxide) which was fundamentally different in its properties from atmospheric air. Unlike it, it turned lime water milky and it would not support combustion. Some thirty years later, the founder of modem chemistry, Antoine Lavoisier, in his Traite elementaire de chemie of 1789 reported experiments in guinea-pigs in which he claimed that respiration was the same in any concentration of oxygen provided carbon dioxide was removed.

In the 1850s John Snow wrote the following about ether:

'It follows as a necessary consequence of this mode of excretion of vapour, that if its exhalation by the breath could anyway be stopped, its narcotic effects ought to be much prolonged'.

Snow proceeded to demonstrate this point on himself using a primitive closed-circuit apparatus which included an absorber for carbon dioxide.

'A solution of caustic potash was employed for the purpose of absorbing the carbonic acid gas generated by respiration as the air passed to and fro over a large extent of its surface… '.

Thirty years later, Paul Bert, Professor of Physiology at the Sorbonne, described his experimental methods for assessing the toxic and lethal effects of chloroform. These were to place an animal in a closed vessel already filled with chloroform and potash and sufficiently large to obviate asphyxia. He wrote:

' The use of potash to absorb carbon dioxide must be absolutely rejected... at least in experiments with chloroform, which it rapidly breaks down'.

Since 1914, when Dr D E Jackson first applied the carbon dioxide absorption principle of rebreathing to inhalational anaesthesia, various absorbent materials have been produced in order to optimise the removal of carbon dioxide absorption from anaesthetic gas mixtures. Soda lime (sodium and calcium hydroxide) and baralyme (barium and calcium hydroxide) are chemical absorbents which have been used in clinical anaesthesia for almost 80 years. During this time many changes have been made to prevent excessive heating and to minimise crumbling and the formation of dust. The percentage of sodium hydroxide in soda lime has been reduced to 5%. The

dust. The percentage of sodium hydroxide in soda lime has been reduced to 5%. The remainder of the material comprises calcium hydroxide with a moisture content which varies between 2-18%.

The soda lime method is an efficient way of removing carbon dioxide from closed and semi-closed anaesthetic systems. However, it is far from ideal; strong bases such as sodium and potassium hydroxide promote the dehalogenation and alkaline hydrolysis of many inhaled anaesthetics [1]. A historical example was the formation of dichloroacetylene when trichloroethylene (Trilene) was used in the presence of soda lime. The re-inhalational of dichloroacetylene from the absorber resulted in cranial nerve palsies in some individuals before the problem was recognised. Although trichloroethvlene is no longer manufactured for use as an inhalational anaesthetic.

 

Possible alternatives

There are many methods of removing carbon dioxide from expired air. Some are impractical at present but rapid advances are being made in the fields of aviation, space and underwater medicine and those methods currently regarded as far-fetched may ultimately become a reality. The ideal carbon dioxide 'scrubber' should;

a) remove CO₂ efficiently (6-10 litres ofCO₂/100g)

b) remove only CO₂

c) be non-degradable in the presence of inhaled anaesthetics

d) be in a suitable form for use in anaesthetic circuits (granular, dustless, non-toxic)

e) provide heat, moisture and be bacteriostatic

1) Zeolite molecular sieves

Carbon dioxide adsorption by synthetic zeolites is an alternative method which we have recently evaluated. Naturally occurring zeolites have been used in industry and medicine for many years, e.g. in petroleum refining, for water purification and as oxygen concentrators. Molecular sieves are crystalline metal aluminosilicates having a three-dimensional interconnecting network of silica and alumina tetrahedra. Natural water ofhydration is removed from this network by heating to produce uniform cavities which selectively adsorb molecules of a specific size. The cavities are 2-8 A wide and are presented in either powder or bead form. Two of the commonest synthetic zeolites (4A, 5A and 13X) have pore diameters of between 4.0 A and 7.44 A. Carbon dioxide is a polar molecule with a diameter of less than 4.2 A. It is retained in 4A, 5A and 13X sieves by Van der WaaPs forces rather than chemical bonding, allowing the process to be reversed by changes in temperature and pressure.

 

A number of studies will be described regarding the removal of carbon dioxide and the interaction of 4A, 5A and 13X molecular sieves with nitrous oxide and current inhaled anaesthetics. Data will also be presented regarding the degradation of sevoflurane when soda lime or molecular sieves were used for the removal ofC0₂.

2) A non-regenerative (chemical) method

Chemical methods of carbon dioxide are effective, inexpensive and allow for excellent heat and moisture preservation during anaesthesia. However, the presence of strong alkalis (NaOH and/or KOH) results in a material which is caustic and chemically reactive with regard to certain inhaled anaesthetics. As stated, the degradation products produced (compound A, carbon monoxide) raise doubts about the safe administration of these drugs in low-flow or closed system anaesthesia.

A number of recent in vitro and in vivo studies have examined the potential toxicity of compound A when sevoflurane was administered during low-flow anaesthesia with soda lime [8-11]. These studies report peak concentrations of compound A ranging from 8-60 ppm. This wide variation may be due several factors. Firstly, there is a chemical reaction between sevoflurane and the strong bases present in modern soda lime. This reaction is not quantitatively precise as different types of soda lime produce different amounts of compound A [8]. The material used in UK practice differs in its composition to that used in North America and Japan. The greater part of soda lime comprises Ca(OH)2 (94%). But, in addition to calcium hydroxide, the United States Pharmacopoeia specifies either NaOH, or KOH, or both. whereas the British Pharmacopoeia specifies either NaOH or KOH, but not both.

 

Both NaOH and KOH are included as activators and it is their salts which are responsible for the degradation ofsevoflurane to compound A and for the formation of formates from isoflurane, enflurane and desflurane. These chemical reactions are directly related to alkalinity, rather than to a specific formulation [5-7].

A new chemical method of carbon dioxide absorption will be described.

 

References

1. Mono M. Fuji; K, Mukai S, Kodama G. Decomposition ofhalothane by soda lime and the metabolites ofhalothane in expired gases. Exerpta Medica / International Congress Series 1976; 387: 214-5.

2. Mono M, Fujii K, Satoh N, Imai M, Kawakami U, Mizuno T, Kawai Y, Ogasawara Y, Tamura T, Negishi A, Kumagi Y, Kawai T. Reaction of sevoflurane and its degradation products with soda lime. Toxicity of the by-products. Anesthesiology 1992; 77:1155-67.

3. Morita S, Latta W, Hambro K, Snider MT. Accumulation of methane, acetone and nitrogen in the inspired gas during closed circuit anesthesia. Anesthesia and Analgesia 1985; 64: 343-7.

4. Rolly G, Versichelen LF, Mortier E. Methane accumulation during closed-circuit anesthesia. Anesthesia and Analgesia 9194; 79: 545-7.

5. Lentz R. Carbon monoxide poisoning during anesthesia poses puzzles. Anesthesia Safety Foundation Newsletter 1994; 9: 13-14.

6. Moon R, Meyer A, Scott D, Fox E, Millington D, Norwood D. Intraoperative carbon monoxide toxicity. Anesthesiology; 73: A1049.

7. Moon R, Ingram C, Brunner E, Meyer A. Spontaneous generation of carbon monoxide within anesthetic circuits. Anesthesiology 1991; 75: A873.

 

8. Frink EJ, Malan TP, Morgan SE, Brown EA, Malcomson M, Brown BR.

Quantification of the degradation products ofsevoflurane in two CO₂ absorbents

during low-flow anesthesia in surgical patients. Anesthesiology 1992; 77:1064-9.

9. Bito H, Ikeda K. Closed-circuit anesthesia with sevoflurane in humans. Effects on renal and hepatic function and concentrations of breakdown products with soda lime in the circuit. Anesthesiology 1994; 80: 71-6.

10. Gonsowski C T, Laster M J, Eger E I, Ferrell L D, Kerschmann R L. Toxicity of compound A in rats. Effect of a 3-hour administration. Anesthesiology 1994, 80:556-65.

11. Gonsowski C T, Laster M J, Ferrell L D, Kerschmann RL. Toxicity of compound A in rats. Effect of increasing duration of administration. Anesthesiology 1994;80:566-73.

Reducing the flows - saving the pounds

David Bawden, The Audit Commission

The cost of drugs is rising in most trusts as newer and more expensive drugs are introduced. Although the cost of anaesthetic drugs is a small part of the total cost of an operation, any savings, however small, through more efficient use of them are worthwhile. Cotter et al showed that use of low flow techniques can result in savings of over 50% in the cost of anaesthetic agents and that these are achievable by all anaesthetists, not just enthusiasts for the technique (ref).

The Audit Commission has studied anaesthetic and pain relief services over the last 18 months. Starting in November 1997, every hospital in England and Wales will have an audit of their services based on the Audit Commission's work. Part of the audit will look at the capability for low flow anaesthesia, ie whether the equipment exists, and will calculate potential savings if investment is made in equipment and/or if existing equipment is used more efficiently. The calculations are firmly based on what is achievable by all anaesthetists and use fresh gas flow rates of 2 litres a minute as the benchmark.

Findings from 45 trusts in the Audit Commission's study showed that 14 had all their theatres where general anaesthetics are regularly given equipped with low flow circuitry including agent monitors. We estimate that total annual savings of £850,000 are possible in the other 31 trusts if they fully equip their theatres for low flow anaesthesia.

Further savings are possible in trusts which already have the capability for low flow anaesthesia. At three trusts surveyed so far where all the theatres have low flow circuitry, expenditure on agents can be reduced by between 14 and x per cent through more efficient use of the equipment by anaesthetists.

The presentation will describe the Audit Commission's findings and the survey auditors will carry out to assess the potential for savings.

The report of the Audit Commission's study will be published in December 1997 Each trust will receive it own report which will comment on its services and, if appropriate, include recommendations for improvements, after its local audit has been completed.

Reference:

Cotter et al. Low -flow anaesthesia. Practice, cost implications and acceptability. Anaesthesia. 1991, vol 46, pp 1009 - 1012