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Clinical Overview of Current Inhaled Anesthetics: Isoflurane, Desflurane, Sevoflurane, Xenon, Nitrous Oxide

Isoflurane is a halogenated methyl ethyl ether that is a clear, nonflammable liquid at room temperature and has a high degree of pungency. It is the most potent of the volatile anesthetics in clinical use, has great physical stability, and undergoes essentially no deterioration during storage for up to 5 years or on exposure to sunlight. It has become the “gold standard” anesthetic since its introduction in the 1970s. There was a brief period of controversy concerning the use of isoflurane in patients with coronary disease because of the possibility for coronary “steal” arising from the potent effects of isoflurane on coronary vasodilation. In clinical use, however, this has been, at most, a rare occurrence.

Desflurane is a fluorinated methyl ethyl ether that differs from isoflurane by just one atom: a fluorine atom is substituted for a chlorine atom on the α-ethyl component of isoflurane. The process of complete fluorination of the ether molecule has several effects. It decreases blood and tissue solubility (the blood:gas solubility of desflurane equals that of nitrous oxide), and it results in a loss of potency (the MAC of desflurane is 5 times higher than isoflurane). Moreover, fluorination of the methyl ether molecule results in a high vapor pressure owing to decreased intermolecular attraction. Thus, a new vaporizer technology was developed to deliver a regulated concentration of desflurane as a gas. It is a heated, pressurized vaporizer requiring electrical power and more frequent servicing. One of the advantages of desflurane is the near-absent metabolism to serum trifluoroacetate. This makes immune-mediated hepatitis a rare occurrence. Desflurane is the most pungent of the volatile anesthetics, and if administered via the face mask results in coughing, salivation, breath holding, and laryngospasm. In extremely dry CO2 absorbers, desflurane (and to a lesser extent isoflurane, enflurane, and sevoflurane) degrades to form carbon monoxide. Desflurane has the lowest blood:gas solubility of the potent volatile anesthetics; moreover, its fat solubility is roughly half of that of the other volatile anesthetics. Thus, desflurane requires less downward titration in long surgical procedures to achieve a rapid emergence by virtue of decreased tissue saturation. Desflurane has been associated with tachycardia, hypertension, and, in select cases, myocardial ischemia when used in high concentrations or rapidly increasing the inspired concentration (without using opioid adjuvants to prevent such a response).

Sevoflurane is a sweet-smelling, completely fluorinated methyl isopropyl ether. Its vapor pressure is roughly one-fourth that of desflurane and it can be used in a conventional vaporizer. The blood:gas solubility of sevoflurane is second only to desflurane in terms of potent volatile anesthetics. Sevoflurane is approximately half as potent as isoflurane, and some of the preservation of potency, despite fluorination, is because of the bulky propyl side chain on the ether molecule. Sevoflurane has minimal odor, no pungency, and is a potent bronchodilator. These attributes make sevoflurane an excellent candidate for administration via the face mask on induction of anesthesia in both children and adults. Sevoflurane is half as potent a coronary vasodilator as isoflurane, but is 10 to 20 times more vulnerable to metabolism than isoflurane. The metabolism of sevoflurane results in inorganic fluoride; the increase in plasma fluoride after sevoflurane administration has not been associated with renal-concentrating defects. Unlike other potent volatile anesthetics, sevoflurane is not metabolized to trifluoroacetate; rather, it is metabolized to an acyl halide (hexafluoroisopropanol). This does not stimulate formation of antibodies.
Sevoflurane can form carbon monoxide during exposure to dry CO2 absorbents, and an exothermic reaction in dry absorbent has resulted in canister fires. New generic versions of sevoflurane have the potential to break down to hydrogen fluoride when exposed to metal compounds because of their lack of adequate water in the formulation. Sevoflurane also breaks down in the presence of the carbon dioxide absorber to form a vinyl halide called compound A. Compound A has been shown to be a dose-dependent nephrotoxin in rats, but has not been associated with renal injury in human volunteers or patients, with or without renal impairment, even when fresh gas flows are 1 L/min or less.

Xenon is an inert gas. Difficult to obtain, and hence extremely expensive, it has received considerable interest in the last few years because it has many characteristics approaching those of an “ideal” inhaled anesthetic, although it can trigger malignant hyperthermia. Its blood:gas partition coefficient is 0.14, and unlike the other potent volatile anesthetics (except methoxyflurane), xenon provides some degree of analgesia. The MAC of xenon in humans is 71%, which might prove to be a limitation. It is nonexplosive, nonpungent, and odorless, and thus can be inhaled with ease. In addition, it does not produce significant myocardial depression. Because of its scarcity and high cost, new anesthetic systems need to be developed to provide for recycling of xenon. If this proves to be too difficult from either a technical or patient safety standpoint, it may be necessary to use it in a very low, or closed, fresh gas flow system to reduce wastage.

Nitrous Oxide
Nitrous oxide is a sweet-smelling, nonflammable gas of low potency (MAC = 104%) and is relatively insoluble in blood. It is most commonly administered as an anesthetic adjuvant in combination with opioids or volatile anesthetics during the conduct of general anesthesia. Although not flammable, nitrous oxide will support combustion. Unlike the potent volatile anesthetics in clinical use, nitrous oxide does not produce significant skeletal muscle relaxation, but it does have documented analgesic effects. Despite a long track record of use, controversy has surrounded nitrous oxide in four areas: its role in postoperative nausea and vomiting, its potential toxic effects on cell function via inactivation of vitamin B12, its adverse effects related to absorption and expansion into air-filled structures and bubbles, and lastly, its effect on embryonic development. The one concern that seems most valid and most clinically relevant is the ability of nitrous oxide to expand air-filled spaces because of its greater solubility in blood compared to nitrogen. Several closed gas spaces, such as the bowel and middle ear, exist in the body and other spaces may occur as a result of disease or surgery, such as a pneumothorax. Because nitrogen in air-filled spaces cannot be removed readily via the bloodstream, nitrous oxide delivered to a patient diffuses from the blood into these closed gas spaces quite easily. Movement of nitrous oxide into these spaces continues until the partial pressure equals that of the blood and alveoli. Compliant spaces will continue to expand until sufficient pressure is generated to oppose further nitrous oxide flow into the space. The higher the inspired concentration of nitrous oxide, the higher the partial pressure required for equilibration.
Seventy-five percent nitrous oxide can expand a pneumo-thorax to double or triple its size in 10 and 30 minutes, respectively. Air-filled cuffs of pulmonary artery catheters and endotracheal tubes also expand with the use of nitrous oxide, possibly causing tissue damage via increased pressure in the pulmonary artery or trachea, respectively. In a rabbit model, the volume of an air embolus resulting in cardiovascular compromise is less during coadministration of nitrous oxide. Accumulation of nitrous oxide in the middle ear can diminish hearing postoperatively and is relatively contraindicated for tympanoplasty because the increased pressure can dislodge a tympanic graft.

Barash's Clinical Anesthesia 6th Edition (Lippincott Williams & Wilkins) 2009

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