10: Volatile Anesthetics

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CHAPTER 10 Volatile Anesthetics

Michelle Dianne Herren, MD

1 What are the properties of an ideal anesthetic gas?

An ideal anesthetic gas would be predictable in onset and emergence; provide muscle relaxation, cardiostability, and bronchodilation; not trigger malignant hyperthermia or other significant side effects (such as nausea and vomiting); be inflammable; undergo no transformation within the body; and allow easy estimation of concentration at the site of action.

2 What are the chemical structures of the more common anesthetic gases? Why do we no longer use the older ones?

Isoflurane, desflurane, and sevoflurane are the most commonly used volatile anesthetics. As the accompanying molecular structures demonstrate, they are substituted halogenated ethers, except halothane, a halogenated substituted alkane. Many older anesthetic agents had unfortunate properties and side effects such as flammability (cyclopropane and fluroxene), slow induction (methoxyflurane), hepatotoxicity (chloroform and fluroxene), nephrotoxicity (methoxyflurane), and the theoretic risk of seizures (enflurane) (Figure 10-1).

Figure 10-1 Molecular structures of contemporary gaseous anesthetics.

3 How are the potencies of anesthetic gases compared?

The potency of anesthetic gases is compared using minimal alveolar concentration (MAC), which is the concentration at one atmosphere that abolishes motor response to a painful stimulus (i.e., surgical incision) in 50% of patients. Of note, 1.3 MAC is required to abolish this response in 99% of patients. Other definitions of MAC include the MAC-BAR, which is the concentration required to block autonomic reflexes to nociceptive stimuli (1.7 to 2 MAC), and the MAC-awake, the concentration required to block appropriate voluntary reflexes and measure perceptive awareness (0.3 to 0.5 MAC). MAC appears to be consistent across species lines. The measurement of MAC assumes that alveolar concentration directly reflects the partial pressure of the anesthetic at its site of action and equilibration between the sites.

4 What factors may influence MAC?

The highest MACs are found in infants at 6 to 12 months of age and decrease with both increasing age and prematurity. For every Celsius degree drop in body temperature, MAC decreases approximately 2% to 5%. Hyponatremia, opioids, barbiturates, α₂-blockers, calcium channel blockers, acute alcohol intoxication, and pregnancy decrease MAC. Hyperthermia, chronic alcoholism, and central nervous system (CNS) stimulants (cocaine) increase MAC. Factors that do not affect MAC include hypocarbia, hypercarbia, gender, thyroid function, and hyperkalemia. MAC is additive. For example, nitrous oxide potentiates the effects of volatile anesthetics.

5 Define partition coefficient. Which partition coefficients are important?

A partition coefficient describes the distribution of a given agent at equilibrium between two substances at the same temperature, pressure, and volume. Thus the blood-to-gas coefficient describes the distribution of anesthetic between blood and gas at the same partial pressure. A higher blood-to-gas coefficient correlates with a greater concentration of anesthetic in blood (i.e., a higher solubility). Therefore a greater amount of anesthetic is taken into the blood, which acts as a reservoir for the agent, reducing the alveolar concentration and thus slowing the rate of induction. Equilibration is relatively quick between alveolar and brain anesthetic partial pressure. Thus alveolar concentration ultimately is the principal factor in determining onset of action.

Other important partition coefficients include brain to blood, fat to blood, liver to blood, and muscle to blood. Except for fat to blood, these coefficients are close to 1 (equally distributed). Fat has partition coefficients for different volatile agents of 30 to 60 (i.e., anesthetics continue to be taken into fat for quite some time after equilibration with other tissues) (Table 10-1).

TABLE 10-1 Physical Properties of Contemporary Anesthetic Gases

6 Review the evolution in hypothesis as to how volatile anesthetics work

At the turn of the century Meyer and Overton independently observed that an increasing oil-to-gas partition coefficient correlated with anesthetic potency. The Meyer-Overton lipid solubility theory dominated for nearly half a century before it was modified.

Franks and Lieb found that an amphophilic solvent (octanol) correlated better with potency than lipophilicity and concluded that the anesthetic site must contain both polar and nonpolar sites.

Modifications of Meyer and Overton’s membrane expansion theories include the excessive volume theory, in which anesthesia is created when a polar cell membrane components and amphophilic anesthetics synergistically create a larger cell volume than the sum of the two volumes together.

In the critical volume hypothesis, anesthesia results when the cell volume at the anesthetic site reaches a critical size. These theories rely on the effects of membrane expansion on and at ion channels.

The previous theories oversimplify the mechanism of anesthetic action and have been abandoned for the following reasons: volatile anesthetics lead to only mild perturbations in lipids, and the same changes can be reproduced by changes in temperature without leading to behavioral changes; also, variations in size, rigidity, and location of the anesthetic in the lipid bilayer are similar to those in compounds that do not have anesthetic activity, which implies that specific receptors are involved.

Newer accepted theories propose distinct molecular targets and anatomic sites of action rather than nonspecific actions on cell volume or wall. Volatile anesthetics are thought to enhance inhibitory receptors, including γ-aminobutyric acid (GABA) type A and glycine receptors.

There is also evidence supporting an inhibitory effect on excitatory channels such as neuronal nicotinic and glutamate receptors.

Most likely the actions of immobilization and amnesia are caused by separate mechanisms at different anatomic sites. At the spinal cord level anesthetics lead to suppression of nociceptive motor responses and are responsible for immobilization of skeletal muscle. Supraspinal effects on the brain are responsible for amnesia and hypnosis. The thalamus and midbrain reticular formation are more depressed than other regions of the brain.

8 What is the second gas effect? Explain diffusion hypoxia

In theory this phenomenon should speed the onset of anesthetic induction. Because nitrous oxide is insoluble in blood, its rapid absorption from alveoli results in an abrupt rise in the alveolar concentration of the accompanying volatile anesthetic. However, even at high concentrations (70%) of nitrous oxide, this effect accounts for only a small increase in concentration of volatile anesthetic. Recent studies have had conflicting results as to whether this phenomenon is valid. When nitrous oxide is discontinued abruptly, its rapid diffusion from the blood to the alveolus decreases the oxygen tension in the lung, leading to a brief period of decreased oxygen concentration known as diffusion hypoxia. Administering 100% oxygen at the end of a case can mitigate this.

KEY POINTS: Volatile Anesthetics

1. Speed of onset of volatile anesthetics is increased by increasing the delivered concentration of anesthetic, increasing the fresh gas flow, increasing alveolar ventilation, and using nonlipid-soluble anesthetics.

2. Volatile anesthetics lead to a decrease in tidal volume and an increase in respiratory rate, resulting in a rapid, shallow breathing pattern.

3. MAC is decreased by old age or prematurity, hyponatremia, hypothermia, opioids, barbiturates, α_2-blockers, calcium channel blockers, acute alcohol intoxication, and pregnancy.

4. MAC is increased by hyperthermia, chronic alcoholism, and CNS stimulants (e.g., cocaine).

5. The physiologic response to hypoxia and hypercarbia is blunted by volatile anesthetics in a dose-dependent fashion.

6. Because of its insolubility in blood and rapid egress into air-filled spaces, nitrous oxide should not be used in the setting of pneumothorax, bowel obstruction, or pneumocephalus or during middle ear surgery.

7. Degradation of desflurane and sevoflurane by desiccated absorbents may lead to CO production and poisoning.

8. Nitrous oxide toxicity is a rare but real threat in abusers, patients with vitamin B₁₂ deficiencies, and possibly unborn fetuses because of impaired methionine synthesis and results in neurologic sequelae.

9 Should nitrous oxide be administered to patients with pneumothorax? Are there other conditions in which nitrous oxide should be avoided?

Although nitrous oxide has a low blood-to-gas partition coefficient, it is 20 times more soluble than nitrogen (which comprises 79% of atmospheric gases). Thus nitrous oxide can diffuse 20 times faster into closed spaces than it can be removed, resulting in expansion of pneumothorax, bowel gas, or air embolism or in an increase in pressure within noncompliant cavities such as the cranium or middle ear (Figure 10-2).

Figure 10-2 Increase in intrapleural gas volume on administration of nitrous oxide (open squares, circles, and triangles) as opposed to change in volume on administration of oxygen, plus halothane (filled triangles and circles).

(Redrawn from Eger EI II, Saidman LJ: Hazards of nitrous oxide anesthesia in bowel obstruction and pneumothorax. Anesthesiology 26:61?68, 1965.)

10 Describe the ventilatory effects of the volatile anesthetics

Delivery of anesthetic gases results in dose-dependent depression of ventilation mediated directly through medullary centers and indirectly through effects on intercostal muscle function. Minute volume decreases secondary to reductions in tidal volume, although rate appears generally to increase in a dose-dependent fashion. Ventilatory drive in response to hypoxia can be easily abolished at one MAC and attenuated at lower concentrations. The ventilatory response to hypercarbia is also attenuated by increasing the delivered anesthetic concentration.

11 What effects do volatile anesthetics have on hypoxic pulmonary vasoconstriction, airway caliber, and mucociliary function?

Hypoxic pulmonary vasoconstriction (HPV) is a locally mediated response of the pulmonary vasculature to decreased alveolar oxygen tension and serves to match ventilation to perfusion. Inhalational agents decrease this response.

All volatile anesthetics appear to decrease airway resistance by a direct relaxing effect on bronchial smooth muscle and by decreasing the bronchoconstricting effect of hypocapnia. The bronchoconstricting effects of histamine release also appear to be decreased when an inhalational anesthetic is administered.

Mucociliary clearance appears to be diminished by volatile anesthetics, principally through interference with ciliary beat frequency. The effects of dry inhaled gases, positive-pressure ventilation, and high inspired oxygen content also contribute to ciliary impairment.

12 What effects do volatile anesthetics have on circulation?

See Table 10-2.

TABLE 10-2 Circulatory Effects of Contemporary Anesthetic Gases

13 Which anesthetic agent is most associated with cardiac dysrhythmias?

Halothane has been shown to increase the sensitivity of the myocardium to epinephrine, resulting in premature ventricular contractions and tachydysrhythmias. The mechanism may be related to the prolongation of conduction through the His-Purkinje system, which facilitates the reentrant phenomenon and β₁-adrenergic receptor stimulation within the heart. Compared with adults, children undergoing halothane anesthesia appear to be relatively resistant to this sensitizing effect, although halothane has been shown to have a cholinergic, vagally induced bradycardic effect in children.

14 Discuss the biotransformation of volatile anesthetics and the toxicity of metabolic products

For the most part oxidative metabolism occurs within the liver via the cytochrome P-450 system and to a lesser extent within the kidneys, lungs, and gastrointestinal tract. Desflurane and isoflurane are metabolized less than 1%, whereas halothane is metabolized more than 20% by the liver. Under hypoxic conditions halothane may undergo reductive metabolism, producing metabolites that may cause hepatic necrosis. Halothane hepatitis is secondary to an autoimmune hypersensitivity reaction.

Fluoride is another potentially toxic product of anesthetic metabolism. Fluoride-associated renal dysfunction has been linked to the use of methoxyflurane and greatly contributed to the withdrawal of methoxyflurane from the market. The fluoride produced by sevoflurane has not been implicated in renal dysfunction, perhaps because sevoflurane is not as lipid soluble as methoxyflurane and the time of exposure (fluoride burden) is much less.

Soda lime can also degrade sevoflurane. One of the metabolic by-products is a vinyl ether known as Compound A. Compound A has been shown to be nephrotoxic to rats, but no organ dysfunction in association with clinical use in humans has been noted. Compound A may accumulate during longer cases, low-flow anesthesia, and dry absorbent and with high sevoflurane concentrations.

15 Review the effects of CO₂ absorbants on volatile anesthetic by-products

Desflurane, much more than any other volatile anesthetic, has been associated with the production of carbon monoxide (CO). There are a number of key conditions. The volatile compound must contain a difluoromethoxy group (desflurane, enflurane, and isoflurane). This group interacts with the strongly alkaline and desiccated CO₂ absorbent. A base-catalyzed proton abstraction forms a carbanion that can either be reprotonated by water to regenerate the original anesthetic or form CO when the absorbent is dry. Because of the greater opportunity to dry the absorbent out, the incidence of CO exposure is highest, the first case of the day, when machines have not been used for some time, or when fresh gas flow has been left on for a protracted period of time. The prior conditions are often found to be most significant on Monday morning if the machine has not been used during the weekend. Absorbants should be changed routinely despite lack of apparent color change, and moisture levels monitored.

Potassium hydroxide (KOH)–containing absorbents are the stronger alkalis and result in greater CO production. From greatest to least, KOH-containing absorbents are Baralyme (4.6%) > classic soda lime (2.6%) > new soda lime (0%) > calcium hydroxide lime (Amsorb) (0%). Choice of volatile anesthetic also determines the amount of CO produced, and at equiMAC concentrations desflurane > enflurane > isoflurane. Sevoflurane, once thought to be innocent, has recently been implicated as well when exposed to dry absorbant (especially KOH-containing). This leads to CO production and a rapid increase in absorbant temperature, generation of formic acid leading to severe airway irritation, and a lower effective circuit concentration of delivered sevoflurane compared to that of vaporizer dial concentration.

16 Which anesthetic agent has been shown to be teratogenic in animals? Is nitrous oxide toxic to humans?

Nitrous oxide administered to pregnant rats in concentrations greater than 50% for over 24 hours has been shown to increase skeletal abnormalities. The mechanism is probably related to the inhibition of methionine synthesis, which is necessary for synthesis; the mechanism may also be secondary to the physiologic effects of impaired uterine blood flow by nitrous oxide. Although ethically this is not possible to study in humans, it may be prudent to limit the use of nitrous oxide in pregnant women.

Several surveys have attempted to quantify the relative risk of operating room personal exposure to nonscavenged anesthetic gases. Pregnant women were found to have a 30% increased risk of spontaneous abortion and a 20% increased risk for congenital abnormalities. However, in these investigations responder bias and failure to control for other exposure hazards may account for some of these findings.

Nitrous oxide can be toxic to humans because of its abilty to prevent cobalamin (vitamin B₁₂) to act as a coenzyme for methionine synthase. Generally toxic effects are seen in persons abusing nitrous oxide for long periods of time (e.g., myelinopathies, spinal cord degeneration, altered mental status, paresthesias, ataxia, weakness, spasticity). Other patients may be disposed to toxicity during routine nitrous-based anesthetics, including pernicious anemia and Vitamin B12 deficiency. Patients having surgery where 70% nitrous oxide was used for over 2 hours have been shown to have more postoperative complications, including atelectasis, fever, pneumonia, and wound infections. It seems prudent then to limit the use of nitrous oxide in longer procedures.

SUGGESTED READINGS

1. Campagna J.A., Miller K.E., Forman S.A. Mechanisms of actions of inhaled anesthetics. N Engl J Med. 2003;348:2110-2124.

2. Coppens M.J., Versichelen L.F.M., Rolly G., et al. The mechanism of carbon monoxide production by inhalational agents. Anaesthesia. 2006;61:462-468.

3. Eger E.I.II, Saidman L.J. Hazards of nitrous oxide anesthesia in bowel obstruction and pneumothorax. Anesthesiology. 1965;26:61-68.

4. Myles P.S., Leslie K., Chan M.T.V., et al. Avoidance of nitrous oxide for patients undergoing major surgery. Anesthesiology. 2007;107:221-231.

5. Sanders R.D., Weimann J., Maze M. Biologic effects of nitrous oxide. Anesthesiology. 2008;109:707-722.

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