Sevoflurane
1995; Lippincott Williams & Wilkins; Volume: 81; Issue: Supplement Linguagem: Inglês
10.1097/00000539-199512001-00001
ISSN1526-7598
Autores Tópico(s)Medical History and Innovations
ResumoSeveral years ago, Dr. E. J. Frink and I wrote an editorial in the Canadian Anesthetists' Society Journal entitled "Whatever Happened to Sevoflurane?" [1]. The answer to this obvious rhetorical question is that a great deal has happened lately with sevoflurane. This supplement issue of Anesthesia & Analgesia corroborates this activity. Sevoflurane was first synthesized in the late 1960s and began its history as an orphan drug in every respect except for official nomenclature. Wallin, Napoli, and Regan were pharmacologists at Baxter-Travenol laboratories in Morton Grove, IL, who were interested in anesthetics. Regan was the primary investigator concerned with synthesis and testing of new halogenated inhaled anesthetics. He developed a series of fluorinated isopropyl ethers, the most promising of which was given the generic name sevoflurane [2]. During a few Phase I trials, the senior investigator, Dr. D. A. Holaday, commented that the characteristics of sevoflurane as an anesthetic were excellent [3]. However, because Baxter-Travenol did not have a primary interest in inhaled anesthetics, there was little enthusiasm for sevoflurane, or any other anesthetic, at the top ranks of the company. In addition, sevoflurane possessed two "non-ideal" characteristics that were difficult to put to rest: metabolism that released fluoride ion and base instability, which rendered it chemically active in the presence of soda lime. Neither isoflurane nor desflurane, inhaled anesthetics being developed simultaneously, demonstrated these characteristics. Thus, the investment of large sums of money to develop sevoflurane to compete against the less reactive drugs did not seem to be worthwhile. Consequently, after only a few clinical trials, no further development of sevoflurane was undertaken. In 1988, the Japanese firm Maruishi Pharmaceuticals (Osaka) expressed interest in sevoflurane and began bench and clinical research. Clinical trials showed the drug to be safe, rapid, and what can be best described as "user friendly" [4]. These results led to clinical approval of the anesthetic in Japan in 1990. At present, sevoflurane is the most popular halogenated inhalation anesthetic in Japan with an excellent safety record. Sevoflurane has now been administered to more than 2,000,000 patients in Japan. Besselar of New Jersey (under contract with Maruishi) initiated American studies with sevoflurane in 1990. A comparison with isoflurane demonstrated that sevoflurane produced faster wake-up and at least comparable cardiovascular effects compared with isoflurane [5]. This study cleared the way for more extensive clinical trials in the United States, South America, and Europe. Abbott Laboratories of Chicago licensed sevoflurane from Maruishi in 1992 and assumed responsibility for the drug in all countries except Japan and China. Experience with sevoflurane in clinical practice in Japan, and during clinical trials in the United States and Europe, has shown it to have several attributes that make it a useful alternative to currently available anesthetics. In addition, the early concerns regarding fluoride and compound A toxicity have proven to be largely unfounded. These features of and concerns about sevoflurane are introduced briefly in this article and are discussed in more detail in subsequent articles in this supplement. Features of Sevoflurane As with isoflurane, halothane, and enflurane, the physical characteristics of sevoflurane permit the use of conventional vaporizers. This is due to its high boiling point and low vapor pressure. Another desirable characteristic of sevoflurane is faster induction and awakening compared with all other anesthetics except desflurane. Awakening time is approximately half that of isoflurane for comparable surgical procedures [5]. Earlier recovery with sevoflurane permits rapid patient assessment and improved potential for discharge from the operating room and postanesthesia care unit. As demonstrated by a cost analysis model developed by Duke University, the comparable maintenance drug cost was similar for isoflurane, desflurane, and sevoflurane for surgeries lasting up to 1 h. In this cost analysis, it was noted that total anesthetic drug cost continues to be a very small component in the total overall surgical costs. Several factors may be responsible for comparable cost between isoflurane, desflurane, and sevoflurane. Although the minimum alveolar anesthetic concentrations for both sevoflurane and desflurane are greater than that for isoflurane (i.e., lower potency), the low solubility of new anesthetics reduces anesthetic consumption such that cost does not increase to the degree one might assume based on potency alone. For example, the rate at which the ratio of delivered anesthetic concentration and the alveolar concentration approach a value of 1.0 is four-fold more rapid with sevoflurane than with isoflurane for a given fresh gas flow rate of 2 L/min. This property of sevoflurane provides greater anesthetic control and also reduces its required rate of consumption. To attempt to achieve greater rapidity and control with isoflurane, the anesthesiologist must increase fresh gas flow and/or greatly increase the delivered concentration, both of which increase anesthetic use and cost. In addition to the drug cost per se, savings in the cost of anesthesia related to more rapid awakening may occur with sevoflurane. This is an undocumented area, but potential exists for reduction in both operating room and postanesthesia care unit costs. A unique feature of sevoflurane is the acceptability for an inhaled induction of anesthesia and lack of respiratory irritation. In volunteers, sevoflurane has been shown to result in less respiratory irritation than halothane, enflurane, or isoflurane [6]. This attribute is borne out by the ease of an inhaled induction of anesthesia noted in pediatric patients [7]. The low solubility of sevoflurane permits rapid alterations in alveolar concentration during maintenance of anesthesia, thus permitting improved control of the depth of anesthesia. This rapid alteration ability potentially reduces total anesthetic used when compared with inhaled drugs having higher solubilities. In addition, sevoflurane seems to be relatively benign to the cardiovascular system both in animals and humans [8,9]. Cardiac rhythm in the presence of exogenously administered epinephrine remains very stable. Fluoride Ion and Base Stability Concerns regarding possible nephrotoxicity from fluoride ion formation during biotransformation and toxicity from degradation in the presence of alkaline carbon dioxide absorbents were primary reasons for the slow development of sevoflurane outside Japan. Both these trepidations are more theoretical than real, as addressed in this supplement issue. For example, a long-held theory of clinical anesthesia is the concept that plasma fluoride ion levels of greater than 50 micro Meter lead to subclinical nephrotoxicity, and that levels greater than 90 micro Meter lead to clinically apparent highoutput renal failure [10]. Studies in both volunteers and patients have shown plasma fluoride levels exceeding 50 micro Meter in 7% of those who received sevoflurane anesthesia, but no evidence of impaired renal toxicity has been observed [11]. However, enflurane anesthesia can produce evidence of impaired renal concentrating ability with fluoride levels of <40 micro Meter. This apparent paradox has been resolved by new evidence demonstrating that methoxyflurane (and possibly enflurane) is defluorinated extensively in the kidney by cytochromes P450-2A6 and P450-3A. Sevoflurane is not a substrate for, and is not metabolized by, renal enzymes. Thus, intrarenally generated fluoride, rather than hepatically generated fluoride (causing higher plasma levels), may be the mechanism responsible for the high-output failure seen after anesthesia with anesthetics such as methoxyflurane [12]. This concept is given further credence by the finding that enflurane anesthesia produced evidence of renal concentrating deficiency in 2 of 7 volunteers, whereas no deficit was seen under identical conditions with sevoflurane [13]. Of interest is the observation that plasma fluoride concentrations were lower in the volunteers given enflurane anesthesia that in those given sevoflurane anesthesia. The other issue regarding sevoflurane is its base instability. Sevoflurane can be degraded in carbon dioxide absorbents to fluoromethyl-2,2-difluoro-1-(trifluoromethyl) vinyl ether, known as compound A. This substance can produce renal toxicity in rats at concentrations between 50 and 100 ppm [14,15]. During prolonged anesthesia with sevoflurane at low flow rates (< 700 mL/min) in humans, compound A concentrations were maximal at 7.6 +/- 1.0 ppm using soda lime as the carbon dioxide absorbent. No renal abnormalities were observed [16]. Thus, sevoflurane degradation product concentrations with soda lime during prolonged anesthesia were well below the toxic levels seen in the rat. In another study, low-flow anesthesia (total flow 500-700 mL/min) demonstrated compound A levels no higher that 16 ppm using soda lime. Again, no evidence of renal (or hepatic) toxicity was observed in these patients [17]. Certainly no evidence of consistent renal toxicity has been apparent in the 2,000,000 patients anesthetized with sevoflurane in Japan. Interestingly, halothane is also base-unstable. In the presence of soda lime, halothane is broken down to the vinyl compound difluoromonochloroethylene. This substance is more toxic in animals than is compound A. Yet decades of clinical use of halothane, including use in low-flow and closed systems, have not demonstrated nephrotoxic activity. In summary, sevoflurane is an inhaled anesthetic with multiple uses, and certainly a very practical pediatric anesthetic. Although the future of sevoflurane appears bright, only years of clinical use will determine its eventual use in the production of safe anesthesia. Conflict of Interest Statement The printing of this supplement has been funded by Abbott Laboratories as part of their educational program for new products. None of the authors have received a grant for writing the manuscripts. Some of the authors attended a round Table discussionon sevoflurane for which they received an honorarium. In addition, in recognition of the efforts of Dr. Burnell Brown on behalf of the specialty of anesthesia, including the development of sevoflurane, the Abbott Laboratories Foundation has awarded a $50,000 matching grant to the anesthesia department of the University of Arizona for 5 years. It is hoped that the University will be able to raise a similar amount to match this contribution.
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