Stability of inhalational anaesthestic agents
Department of Chemistry, Silesian University in Katowice
- Fig. 1. New generation anaesthetics
- Fig. 2. Chain reaction of sevoflurane (A+) degradation induced by Lewis acids [5, 9]
- Fig. 3. Degradation of anaesthetics induced by active bases (NaOH, KOH) present in CO2 absorbents containing soda or barium lime
- Table 1. Examples of Lewis acids and their origin
- Table 2. Comparison of preparations containing sevoflurane
Modern inhalational anaesthetics are liable to react with carbon dioxide absorbers and degrade under certain conditions. Sevoflurane may break down and produce toxic compounds in contact with Lewis acids or carbon dioxide absorbers. Desflurane, isoflurane and enflurane can also undergo undesirable reactions. Producers use various stabilizers, containers, and recommendations for storage times and conditions.
In this paper, the possible dangers of inappropriate use of inhalational anaesthetics, and ways to avoid production of toxic compounds are presented. The composition and degradation of inhalational anaesthetics available on Polish market, are presented. The author concludes that safe use of these agents depends strongly on storage conditions and proper use by medical personnel.
New general anaesthetics based on the structure of polyhalogenic ethers gain increasing clinical relevance. Sevoflurane, isoflurane, desflurane and enflurane  have successfully replaced the previous generation agents. Their physicochemical parameters, such as gas-blood partition coefficients, are favourable to a more rapid onset of anaesthesia and quicker recovery, lower doses and better control of the patient’s condition. On the other hand, their chemical structure determines several essential phenomena that the specialists using them should know about. Reports about instability of anaesthetics were published both in medical and chemical literature . During storage and usage the compounds in question undergo reactions leading to the formation of toxic products [2, 3]. The knowledge how to use and store these agents and how to avoid uncontrollable reactions is extremely important; particularly that several different anaesthetics are currently available. Physicians often make their choices based on incomplete information from promotional leaflets [4, 5].
The compounds discussed (fig.1) are analogues of rarely used or even historic anaesthetics: diethyl ether and halothane. Modern compounds also contain halogen atoms (fluorine, chlorine earlier present in halothane and chloroform) and the ether bond C-O-C (diethyl ether). The differences in structure include mainly higher numbers of halogen atoms or increased molecular weight. Desflurane and sevoflurane do not contain chlorine atoms, and this partly explains their lower toxicity .
From the chemical point of view, the carbon-fluorine bond, C-F in particular, is special. Its uniqueness results from the difference in electronegativity of elements, which form the bond: the fluorine (chlorine) atom, as more electronegative than the carbon atom polarizes the electron cloud of the bond, which becomes a dipole with negative charge on the fluorine atom and positive charge on the carbon atom. A similar polarization is observed in carbon-oxygen (C-O) bonds. The formation of partial charges is relevant for the reactivity. The Lewis acid and alkaline sites are formed in the molecule . Each site may be the centre of reactions leading to molecular breakdown and formation of new, undesirable or even toxic compounds. Sevoflurane is particularly sensitive, in which monofluormethyl group is susceptible to the attack of Lewis acids .
The Lewis theory on acids and bases defines an acid as any chemical individuum capable of accepting an electron pair during the covalent bond formation. Likewise, a base is a compound capable of sharing the electron pair. Thus, Lewis acids and bases should be searched for among ions or compounds of distinct bond polarization. In the Lewis theory, the terms “acid” or “base” refer to the compounds different from those known from the „school” Arrhenius theory (Table 1).
In 1996, the reports were published about sevoflurane containing toxic products of degradation. The probable cause was its contact with the Lewis acid (rust) during production . As the product was packaged into glass containers, the degradation reaction continued although there was not further contact with the primary catalyst. The resulting hydrogen fluoride attacked the glass surface increasing the access to further acid sites within the container wall. The containers with degraded sevoflurane were opaque and the content had strong, characteristic hydrogen fluoride pungent odour. The studies have demonstrated that sevoflurane is likely to have contact with Lewis acids in many places; its transformations are complex and lead to the formation of toxic products of degradation. The degradation reactions start immediately after contact, involving successive molecules (Fig. 2).
Fortunately, hydrogen fluoride and silicon tetrafluoride formed (if the reaction occurs in the glass container) are highly pungent gases of characteristic smell, which are easily identified. Hydrogen fluoride is detectable by smell already at concentrations 100-fold lower than toxic ones. The contaminated sevoflurane was first identified in such a way . The Abbott Lab. company, the only manufacturer of sevoflurane at that time, started to add water (up to 300-1000 ppm) acting as an inhibitor of degradation and changed glass containers into plastic ones (polyethylene naphthalate) . At present, sevoflurane is produced by two companies; the preparations differ in the amount of water and packaging: plastic or aluminium-lined containers (Table 2).
Sevoflurane is most highly exposed to Lewis acids in the production system, where dangerous degradation reactions may be initiated. To avoid the risk of degradation, the accurately purified product should be placed into safe containers and inhibitors of degradation should be used. It is worth pointing out that present manufacturers prepare the compound of high purity (>99.99%). The presence of water in the sevoflurane preparation results from the production process; in Sevorane/Ultane, on the other hand, higher amounts of water are added as the inhibitor of acid degradation . The presence of water in both products is extremely low, below 1%, thus the commonly used names „dry” and „wet” sevoflurane ought to be treated with great caution.
The greatest differences are in packaging of sevoflurane. The Abbott Lab. company uses containers made of dark, half-transparent plastic (polyethylene naphthalate). Baxter uses aluminium bottles lined with phenolic resin. Al2O3 is a well-known Lewis acid and is likely to cause the degradation of sevoflurane; aluminium, on the other hand, relatively readily undergoes oxidation, thus such containers could potentially contain acid. Therefore, Baxter containers have phenolic resin, which is mainly to prevent contact with the degradation catalyst; additionally, it substitutes water (Lewis base)[4, 5].
The chemical structure of sevoflurane is similar to that of diethyl ether and halohform (chloroform, fluoroform), thus it acts as an organic solvent. It may cause local weakness or damage to organic polymers, such as polyethylene naphthalate or phenolic resin [4, 12]. If control of containers into which the product is packed is improper and storage conditions inappropriate, some part of the content may evaporate as it was the case in a series of Ultane containers .
Moreover, in the process of plastic production various substances improving its functional quality are added to the polymer. Such additives may also act as potential Lewis acids and permeate the content causing degradation .
Inappropriate storage conditions, i.e. elevated temperature, exposure to sunrays, may degrade sevoflurane or cause its evaporation and diffusion through the container walls. Dark, plastic containers used by Abbott Lab. seem particularly sensitive . Low molecular weight ethers, such as sevoflurane, tend to form peroxides once exposed to sunrays . This danger is thus higher in half-transparent and easily heated containers. On the other hand, Baxter aluminium containers do not allow visual control of the content. Damaged layers of phenolic resin may result in contact between the content and Lewis acids (aluminium oxide). Therefore, the preparations should be stored under conditions specified by the manufacturer and for the shortest possible time. In cases of sevoflurane containing water, which acts as an inhibitor of degradation, the storage temperature should not be near or below 0o C as under such conditions water is a weaker Lewis base than ether [5, 15].
The problem discussed and analysed even before the introduction of new generation anaesthetics on the market is their instability in the presence of CO2 absorbents used in anaesthetic machines [16, 17, 18, 19, 20]. The first attempts to use halothane in the closed circuit with the CO2 absorbent ended with failure due to substantial amounts of toxic products of degradation formed. This phenomenon, particularly troublesome in the case of sevoflurane, is also observed in some other anaesthetics containing halogen atoms.
Enflurane, isoflurane and desflurane break down to CO whereas sevoflurane to various products (Fig. 3) [21, 22].
Irrespective of the type of anaesthetic, potentially toxic degradation products are formed in the closed anaesthesia circuit [23, 24, 25, 26]. The extent of degradation and amount of products depend mainly on temperature and moisture of the absorbent [27, 28]. Low moisture (<15%) markedly increases the capacity of the absorbent to degrade anaesthetics . Unfortunately, the majority of reactions occurring in the absorbent are exothermal; for this reason, the absorber warms up increasing the degree of degradation of the anaesthetic exposed, which additionally elevates temperature and decreases moisture (flow of warm, dry gas dries the absorber). If the technique of low flows is applied, the problem intensifies as the absorbent washed with a low gas stream heats up more easily.
The use of halothane in this method additionally complicates specific properties of the compound. At low flow of fresh gases (<1.5 L min -1), the control of concentrations of the anaesthetic, respiratory gases and other gases occurring in trace amounts is difficult. Under such conditions halothane may be easily overdosed, which leads to serious complications: myocardial ischemia, impaired circulation, acidosis or hepatonecrosis [30, 31, 32]. Increased levels of degradation products (in the case of halothane mainly: BCDFE) and metabolites may additionally affect the liver. Due to possible complications and difficulties in maintaining stable conditions of halothane anaesthesia, halothane is not recommended or even contraindicated for low flow techniques .
All current inhaled anaesthetics used improperly or with bad devices are susceptible to degradation leading to the formation of more or less toxic substances. If the major factor accelerating adverse reactions is elevated temperature of the absorber, its overheating should be limited. The literature reports describe the use of baths and thermostats, which enable to reduce the temperature of the system, thus decrease the amount of toxic compounds [29,34]. Unfortunately, low efficiency of such options does not build hope for their wider implementation.
The study results explicitly demonstrate that active sodium and potassium hydroxides are responsible for the degradation of anaesthetics [3, 17, 20].
Absorbents, which do not contain such compounds, do not cause degradation [27, 28, 35, 36, 37]. Soda or barium lime may be successfully replaced with any absorbent without hydroxides.
A relevant issue of modern inhaled anaesthetics used for general anaesthesia is proper equipment. Suitable safety and control may be provided only in a unit with trained personnel and appropriate devices. Redundant or inappropriate equipment may cause serious problems; there were cases when the use of improper vaporizers damaged the anaesthetic machines .
Great hopes were placed in long-awaited, new generation anaesthetics, mainly to improve the patient’s safety and physician’s comfort. Polyhalogenic ethers were accepted enthusiastically, taking nowadays anaesthesia by storm. Patients are more easily anaesthetized, their recovery from anaesthesia is rapid and, more importantly, new agents are rarely rejected. Sevoflurane is particularly well tolerated . Lack of chlorine atoms in the molecule decreases the susceptibility to metabolism; the anaesthetic leaves the body more quickly. Major concerns are the anaesthetic stability-related problems discussed earlier. It should be remembered that in clinical practice, the specific molecules of a chemical compound are used, thus all their properties, and not only selected pharmacological characteristics are disclosed. It took many years of multi-centre research to design polyhalogenic ethers yet the knowledge regarding them remains incomplete.
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