Volatile Inhalation Agents
Currently, four volatile inhalation agents are available for use in the United States: desflurane, sevoflurane, isoflurane, and enflurane, with the latter being less commonly used in clinical practice than the other three. The volatile inhalation agents are unique in that they can produce all components of the anesthetic state, to varying degrees (e.g., minimal, if any, analgesia). Immobility to surgical stimuli and amnesia is postulated to be the predominant effect produced by these agents. Unlike IV anesthetic agents, these drugs are administered into the lungs via an anesthesia machine, and as a result, it is easy to increase or decrease drug levels in the body. The anesthetist can estimate, with the use of technology, the anesthetic partial pressure at the site of action (brain); this helps the anesthetist maintain an optimal depth of anesthesia.34
Although the volatile inhalation agents could, theoretically, be used to produce general anesthesia by themselves, it is much more common to use a combination of drugs intended to take advantage of smaller doses of each drug while avoiding the disadvantages of high doses of individual agents. This practice is referred to as balanced anesthesia. For example, midazolam is used routinely to produce sedation, anxiolysis, and amnesia, whereas the administration of a barbiturate (e.g., thiopental) or other IV anesthetic agent (e.g., propofol), followed by administration of a neuromuscular blocking agent (e.g., succinylcholine), can induce rapid loss of consciousness and muscle relaxation to facilitate endotracheal intubation. Volatile inhalation agents provide maintenance of general anesthesia, along with reflex suppression (e.g., lowering BP and heart rate) and some muscle relaxation. Opioids (e.g., fentanyl) also can induce reflex suppression, thereby lowering total anesthetic requirements. Subsequent doses of a nondepolarizing neuromuscular blocking drug might be necessary to provide adequate relaxation for surgery.
Uses
The volatile inhalation agents are primarily used in clinical practice to maintain general anesthesia. Sevoflurane also can be used to induce general anesthesia via a face mask because of its low pungency. Desflurane and sevoflurane, because of their low blood solubility, are ideally suited for maintenance of general anesthesia in ambulatory surgery patients and for inpatients when rapid wake-up is desired (e.g., neurosurgery procedures).
Site/Mechanism of Action
The goal of inhalation anesthesia is to develop and maintain a satisfactory (anesthetizing) partial pressure of anesthetic in the brain, which is the site of anesthetic action.34 Although the mechanism of action of the volatile inhalation agents is not fully understood, these agents are believed to disrupt neuronal transmission in discrete areas throughout the CNS by either blocking excitatory, or enhancing inhibitory, transmission through synapses. Ion channels (especially GABA receptors) are likely targets of volatile inhalation anesthetic agent action.25
Anesthesia Machine and Circuit
A basic understanding of the anesthesia machine and circuit is helpful to understanding many of the concepts associated with the administration of volatile inhalation agents. Three parts of the anesthesia machine are critically important for the administration of volatile inhalation anesthetics. The flow meters regulate the amount of nitrous oxide (an anesthetic gas), air, and oxygen delivered to the patient. The vaporizers regulate the concentration of volatile inhalation agent administered to the patient, whereas the carbon dioxide absorber, which contains either soda lime or Baralyme, removes carbon dioxide from exhaled air. The first step in the administration of a volatile inhalation agent to a patient is to begin the flow of background gases. Flow is measured in liters per minute. A mixture of nitrous oxide and oxygen is commonly used. This gas mixture flows to one of the vaporizers, where a portion of it enters the vaporizer and “picks up” the anesthetic vapor of the volatile inhalation agent. The concentration of volatile inhalation agent delivered by the vaporizer is proportional to the amount of gas mixture passing through it, which is regulated by adjusting the vaporizer's concentration dial. The gas and anesthetic vapor mixture exits the vaporizer and continues through the anesthetic circuit, where it is ultimately delivered to the patient via an endotracheal tube or face mask. The exhaled air from the patient, which contains the volatile inhalation agent and carbon dioxide, is returned to the circuit. If a semiclosed circle breathing system is being used, rebreathing of the exhaled volatile agent can occur if the fresh gas flow rate is low enough (e.g., ≤2 L/minute).35
Potency
Potency of the volatile inhalation agents is compared in terms of minimum alveolar concentration (MAC). MAC is the alveolar concentration of anesthetic at one atmosphere that prevents movement in 50% of subjects in response to a painful stimulus (e.g., surgical skin incision).34 The lower an agent's MAC, the greater is the anesthetic potency. A value of 1.3 MAC is required to produce immobility in 95% of patients, whereas 1.5 MAC is required to block the adrenergic response to noxious stimuli.34 Furthermore, the inhalation agents are additive in their effects on MAC; the addition of a second agent reduces the required concentration of the first agent. For example, when desflurane, isoflurane, and sevoflurane are administered with 60% to 70% nitrous oxide, their MAC values decrease from 6%, 1.15%, and 1.71% to 2.38%, 0.56%, and 0.66%, respectively.34 Of the volatile inhalation agents routinely used, isoflurane has the lowest MAC and desflurane the highest (Table 9-6).34
Chemical Stability
Desflurane and isoflurane are very stable compounds and are not broken down by the moist soda lime or Baralyme contained in the carbon dioxide absorber of the anesthesia machine. Sevoflurane degrades in the presence of carbon dioxide absorbent to multiple by-products, with compound A being most important. In rats, compound A has caused nephrotoxicity,36 but no clinically significant changes in serum creatinine and blood urea nitrogen (BUN) have been demonstrated in human studies.37,38,39 The administration of sevoflurane at low flow rates is one of the major factors that increases compound A concentration. The U.S. Food and Drug Administration (FDA) requires that the sevoflurane package insert contain a warning that sevoflurane exposure should not exceed 2 MAC hours at flow rates of 1 to <2 L/minute, and flow rates <1 L/minute are not recommended. Nevertheless, even when low fresh gas flows are used for long periods of time and exposure to compound A was high, the levels of compound A are much less than what is believed to be a toxic level.40
Unlike sevoflurane, desflurane, isoflurane, and enflurane can react with dry carbon dioxide absorbent to produce carbon monoxide.41 The water content of the absorbent is the major factor leading to the production of carbon monoxide.42 When these agents pass through dry absorbent, carbon monoxide is produced. This situation is most commonly encountered on a Monday morning in an anesthesia machine that has been idle during the weekend and has had a continuous flow of fresh gas through the absorbent. Carbon monoxide production can be prevented by ensuring that only fully hydrated absorbent is used.
The newer alkali hydroxide-free carbon dioxide absorbents containing calcium hydroxide (vs. sodium or potassium hydroxide) make the chemical stability of volatile inhalation agents in the absorbent not a clinical concern. In an in vitro study of one of these absorbents (Amsorb), compound A levels were no higher than those found in sevoflurane itself when it was passed through this absorbent at a low flow rate (1 L/minute). Likewise, carbon monoxide production was negligible when desflurane, isoflurane, or enflurane passed through an anhydrous form of this absorbent.43
Pharmacokinetics
A series of anesthetic partial pressure gradients beginning at the anesthesia machine serve to drive the volatile inhalation agent across barriers to the brain. These gradients are as follows: anesthesia machine > delivered > inspired > alveolar > arterial > brain. The alveolar partial pressure provides an indirect measurement of the anesthetic partial pressure in the brain because the alveolar, arterial, and brain partial pressures rapidly equilibrate.34
Factors that influence the uptake and distribution of a volatile inhalation agent include the inspired concentration of the agent, alveolar ventilation, solubility of the agent in the blood (blood/gas partition coefficient), blood flow through the lungs, distribution of blood to individual organs (levels rise most rapidly in highly perfused organs—brain, kidney, heart, liver), solubility of the agent in tissue (tissue/blood partition coefficient), and mass of tissue.34 If all other factors are equal,
agents with low solubilities will equilibrate quickly and, as a result, have a faster wash-in (onset). Solubility is also a factor in the elimination of volatile inhalation agents, in addition to metabolism and extent of tissue equilibration. Low-solubility agents are more rapidly washed out (eliminated) because more of the agent is removed from the blood in one passage through the lungs.34 As can be seen in Table 9-6, desflurane has the lowest solubility of any of the volatile inhalation agents, with sevoflurane's solubility being lower than isoflurane's for blood and muscle. As a result of their low solubility, quicker responses to intraoperative concentration changes are seen with desflurane and sevoflurane as well as a faster emergence and awakening from anesthesia and a more rapid return to normal motor function and judgment when compared with isoflurane.44-46
As seen in Table 9-6, the metabolism of the volatile inhalation agents varies (e.g., desflurane is metabolized least). An important point is that metabolism does not alter the rate of induction or maintenance of anesthesia because the amount of anesthetic administered to the patient greatly exceeds its uptake.34 Metabolism of sevoflurane has resulted in peak inorganic fluoride levels >100 µmol/L.38 Historically, a fluoride level of 50 µmol/L has been used as a cut-off for potential nephrotoxicity based on reports of methoxyflurane-associated nephrotoxicity at levels >50 µmol/L.47 Despite this, sevoflurane has not been demonstrated to produce nephrotoxicity. Potential reasons for this include the fact that sevoflurane's low blood gas solubility may limit the degree of its metabolism once the anesthetic is discontinued and that sevoflurane, unlike methoxyflurane, undergoes minimal renal defluorination.48 In clinical studies examining the preanesthetic and postanesthetic serum creatinine and BUN values in patients receiving sevoflurane anesthesia, clinically significant renal damage in patients with normal renal function has not been reported, nor has renal function worsened in patients with stable renal insufficiency or in those undergoing hemodialysis.49,50,51
Pharmacologic Properties
All volatile inhalation agents depress ventilation (with an elevation of PaCO2) and dilate constricted bronchial musculature in a dose-dependent manner. As mentioned previously, sevoflurane can be used for mask induction of general anesthesia because it is not as pungent as desflurane, isoflurane, or enflurane. Administration of a pungent agent by mask for induction can cause coughing, breath-holding, laryngospasm, and salivation in the patient. All volatile inhalation agents depress myocardial contractility and decrease arterial BP in a dose-dependent manner. Isoflurane can increase heart rate, so cardiac output is usually maintained. Sevoflurane produces little increase in heart rate, so cardiac output may not be as well maintained as with isoflurane. Although enflurane can increase heart rate, cardiac output is usually decreased. Desflurane can produce sympathetic nervous system activation, resulting in a transient increase in BP and heart rate, when concentrations are rapidly increased.52 The sympathetic nervous system activation may be due to stimulation of medullary centers via receptors in the upper airway and lungs.53 Enflurane can sensitize the myocardium to the arrhythmogenic effects of epinephrine. The volatile inhalation agents decrease cerebral metabolic rate and produce cerebral vasodilation, resulting in increased cerebral blood flow and volume. Enflurane can cause epileptiform activity that can result in clinical tonic-clonic seizures. All volatile inhalation agents produce muscle relaxation and potentiate the actions of the neuromuscular blocking agents. The volatile inhalation agents relax uterine smooth muscle, which can contribute to perinatal blood loss. All volatile inhalation agents have been implicated as triggers of malignant hyperthermia (MH) and are contraindicated in MH-susceptible patients. Finally, all volatile inhalation agents are associated with postoperative nausea, vomiting, and shivering.34,47
Drug Interactions
Opioids, benzodiazepines, α-2 agonists, and neuromuscular blocking agents potentiate the effects of the volatile inhalation agents. Thus, their administration permits use of lower dosages of the volatile inhalents, thereby reducing their potential for adverse effects.
Economic Considerations
The following items must be considered when examining the costs associated with the administration of volatile inhalation agents from an institutional perspective: cost of the volatile inhalation agent (including waste), cost of the equipment necessary to administer the volatile inhalation agent, cost of adjuvants used to treat adverse effects of the volatile agent, and time spent in the OR and PACU.
The cost of a volatile agent depends on (a) the cost per milliliter of the liquid anesthetic, (b) the amount of vapor generated per milliliter, (c) the amount of volatile agent that must be delivered from the anesthesia machine to sustain the desired alveolar concentration, and (d) the flow rate of the background gases.54 Items a and b are, for the most part, constant, with price increases or decreases occurring periodically. Because desflurane and sevoflurane are less soluble in blood and tissue than isoflurane, lower amounts of these agents will need to be delivered to the alveoli to attain the desired anesthetic depth.54 The flow rate of background gases is a major determinant of the cost; as flow rate increases, the amount of anesthetic consumed per time increases.55 The following formula is frequently used to calculate the cost of volatile inhalation agent used:
where P is vaporizer concentration (%), F is fresh gas flow (L/minute), T is time (minute), M is molecular weight of the agent, C is the cost of the agent ($/mL), and d is the density of the agent.56 The use of low flow rates can result in substantial reductions in the volatile anesthetic drug cost per case. An important point to keep in mind when comparing only the cost of the volatile inhalation agents themselves (e.g., excluding any benefits in terms of cost reduction that may be realized by a quicker discharge from the recovery room) is that the low-solubility volatile agents have to be administered at low flow rates to prevent their cost from being substantially higher than that of the more traditional agents (e.g., isoflurane) when administered at rates of 2 to 3 L/minute.
The cost of purchasing new vaporizers and upgrading or replacing agent analyzers that are used to administer and monitor volatile inhalation agents, respectively, can be significant. These costs become a concern when a new product is introduced onto the market.
Medications used to treat adverse effects associated with the volatile inhalation agents include β-blockers, opioids, benzodiazepines, vasopressors, and antiemetic agents. Antiemetic agents are routinely used to prevent and/or treat the PONV seen with the volatile inhalation agents. Intraoperative use of volatile inhalation agents is a leading cause of early (within the first 2 hours following surgery) postoperative vomiting.57 Although the administration of an antiemetic agent adds costs,58 it is significantly less than the cost of an unanticipated admission to the hospital secondary to PONV.
The use of low-solubility volatile inhalation agents can significantly reduce the overall net cost of the surgical procedure by reducing the time patients spend in the OR and PACU. This concept is discussed at the end of this chapter.
Desflurane Use for Maintenance of General Anesthesia
Sympathetic Nervous System Activation
8. C.K., a 26-year-old man, ASA-I, is scheduled to undergo a laparoscopic hernia repair on an outpatient basis. During his preoperative evaluation on the morning of surgery, his BP was 115/75 mmHg, and his heart rate was 70 beats/minute. The surgery is expected to last <2 hours, so a propofol induction is planned followed by maintenance of general anesthesia with desflurane without nitrous oxide. After induction of anesthesia, the desflurane concentration on the vaporizer was rapidly increased to 8%. Within 1 minute of the concentration increase, C.K.'s BP increased to 148/110 mmHg, and his heart rate increased to 112 beats/minute. What could be causing C.K.'s increased BP and heart rate, and how could it have been prevented?
Desflurane can produce sympathetic nervous system activation with a resultant increase in BP and heart rate under certain circumstances. One of these is the rapid increase of desflurane concentration to 1.1 MAC as seen with C.K.59 This hemodynamic response can be attenuated by the IV administration of fentanyl approximately 5 minutes before the increase in desflurane concentration.60 Fentanyl is a good choice because it effectively blunts the increase in heart rate and BP, while having minimal cardiovascular depressant and postoperative sedative effects. Alternatively, nitrous oxide can be administered with desflurane, thereby allowing the desflurane concentration to be maintained at <1 MAC (6%).
Emergence Agitation in Children
9. P.F., a 3-year-old child, ASA-I, is undergoing a tonsillectomy. General anesthesia will be induced and maintained with sevoflurane and nitrous oxide. His surgery was uneventful, with a duration of 30 minutes. He was awakened from anesthesia and transferred to the postanesthesia care unit to recover. Shortly after he arrived, P.F. became extremely restless and began crying. The nurse and his mom were unable to console him. Could this reaction be attributed to sevoflurane, and, if so, can it be prevented?
Emergence agitation following the administration of the short-acting inhaled anesthetics, desflurane and sevoflurane, is fairly common, with a reported incidence as high as 80%.61 Emergence agitation is more common in young children, and its cause is not clear. Children become restless, cry, and exhibit involuntary physical activity that can result in self-injury. Caring for a child experiencing emergence agitation is difficult and very upsetting to the caregiver and the parents of the child. Premedication with oral midazolam62 and administering analgesics to minimize postoperative pain63 may reduce the incidence. A small dose of dexmedetomidine (0.3 mcg/kg IV), an α-2 agonist with sedative and analgesic properties, after induction of anesthesia reduces the incidence of emergence agitation, without prolonging recovery in children undergoing sevoflurane anesthesia.64 Although desflurane cannot be used to induce general anesthesia, switching to desflurane for maintenance of anesthesia following sevoflurane induction effectively reduces the severity of emergence agitation when it occurs.65
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