Inhalation anesthetic agents: Clinical effects and uses

INTRODUCTION — This topic will review the anesthetic and other clinical effects of inhalation anesthetics including the potent volatile agents (sevoflurane, desflurane, isoflurane [and in some countries, halothane]) and one gas (nitrous oxide [N₂O]), as well as their use to induce and maintain general anesthesia. Properties of the inhalation anesthetics and techniques for their delivery via an anesthesia machine are discussed separately. (See "Inhalation anesthetic agents: Properties and delivery" and "Anesthesia machines: Prevention, diagnosis, and management of malfunctions".)

Clinical uses of intravenous agents to induce and maintain general anesthesia are reviewed in separate topics. (See "General anesthesia: Intravenous induction agents" and "Maintenance of general anesthesia: Overview", section on 'Total intravenous anesthesia'.)

CLINICAL EFFECTS — Inhalation anesthetics produce sedation on a spectrum up to and including general anesthesia as well as other clinical effects. Pharmacodynamic parameters for each agent describe these effects (ie, what the drug does to the body).

Sedation and anesthesia

Continuum of effect: sedation to general anesthesia — Inhalation anesthetic agents demonstrate a dose-response effect, with progressively higher doses providing progressively deeper levels of sedation and anesthesia. General anesthesia is a reversible state that includes:

●Hypnosis (ie, loss of consciousness)

●Amnesia (ie, lack of recall)

●Analgesia (ie, pain relief)

●Akinesia (ie, immobility)

●Autonomic and somatic block

Inhalation agents are complete general anesthetic agents, in that they provide all of these components at clinically relevant concentrations.

MAC and MAC-awake values for inhalation agents — The minimum alveolar concentration (MAC) and MAC-awake values are measures of inhalation anesthetic potency.

●MAC value – The MAC value is the concentration of an inhalation agent in the alveoli required to prevent movement in response to a noxious stimulus in 50 percent of subjects after allowing sufficient time for uptake and redistribution of the inhalation agent to reach a steady state (table 1) [1]. In human studies, the tested noxious stimulus is typically a skin incision. Thus, MAC is the effective dose (ED)₅₀ for absence of movement in response to surgical pain.

MAC values differ for each inhalation anesthetic agent (table 2). Only nitrous oxide (N₂O) gas has a MAC value >100 (105 percent at standard pressure and temperature). Thus, N₂O has extremely low potency, and MAC cannot be achieved when N₂O is delivered under standard conditions.

●MAC-awake value – The MAC-awake (also termed MAC-aware) value is the concentration of an inhalation agent in the alveoli at which 50 percent of patients will not respond to a verbal or non-noxious tactile stimulus. Thus, MAC-awake is the ED₅₀ for response to voice or light touch and is thought to approximate the ED₅₀ required for perceptive awareness and anesthetic recall. For each inhalation agent, MAC-awake values are approximately 40 percent of the standard MAC value required to tolerate surgical stimuli without movement.

Influence of drug-drug interactions — The anesthetic effects of the different inhalation agents are additive. For example, if N₂O is administered at 0.5 MAC (approximately 50 percent N₂O concentration) together with isoflurane administered at 0.5 MAC (approximately 0.6 percent isoflurane concentration), then the additive anesthetic effects should be approximately 1.0 MAC.

MAC for any inhalation anesthetic is decreased by concurrent administration of any intravenous (IV) anesthetic, sedative, and/or analgesic agent (eg, sedative-hypnotics, benzodiazepines, opioids, lidocaine) [2].

When anesthetic drugs from different classes are combined, the effects are typically synergistic rather than merely additive [3]. Synergy is particularly common when drugs acting primarily on gamma-aminobutyric acid_A (GABA_A) receptors (eg, volatile inhalation agents, propofol, etomidate, benzodiazepines) are combined with drugs acting on other receptor types (eg, opioids).

MAC is decreased by acute alcohol use due to its sedative effects, or chronic use of amphetamines or alpha2 agonists, which may deplete central nervous system (CNS) catecholamine levels (table 3). Conversely, MAC is increased by chronic alcohol use (likely due to enhanced hepatic metabolism) and by recent use of either amphetamines, cocaine, or ephedrine since these agents may acutely increase CNS catecholamine levels that enhance focused consciousness (table 3).

Influence of patient-related factors — MAC values are also influenced by patient age and coexisting conditions (table 3) [4]. Awareness of such effects is important to avoid inadequate anesthesia or, conversely, anesthetic overdose.

●Age – In general, MAC decreases incrementally with age, as shown in figures for isoflurane (figure 1), sevoflurane (figure 2), and desflurane (figure 3). MAC is reduced at the extremes of age (eg, premature infants or patients >60 years old), although effects vary by agent. For more soluble agents such as halothane (figure 4) and isoflurane (figure 5), MAC is reduced at birth, particularly in premature infants, rising until around age six months before beginning to decrease with further aging. For newer less soluble agents such as sevoflurane (figure 6) and desflurane (figure 4), and for N₂O (figure 4), decreases in MAC have not been demonstrated in young infants.

●Other factors – Typically, MAC is markedly reduced in patients with certain acute conditions including severe anemia with hemoglobin <5 g/dL, hypothermia, hypercarbia, hypoxia, metabolic acidosis, shock, or acute electrolyte abnormalities (table 3).

Also, pregnancy decreases MAC, as does clinical hypothyroidism. In one study, the MAC-awake value for sevoflurane in patients with end-stage renal disease (ESRD) was lower than that in patients without renal disease (0.59 percent, 95% CI 0.50-0.66 percent versus 0.71 percent, 95% CI 0.63-0.80 percent) [5]. This may be due to altered brain sensitivity to anesthetic agents in ESRD.

Conversely, hyperthermia, hyperthyroidism, anxiety, and other conditions associated with psychomotor activation increase MAC (table 3).

Monitoring anesthetic effect — Continuous monitoring of the end-tidal anesthetic concentration (ETAC) of the inhaled anesthetic agent is typically used to titrate the inhalation anesthetic. An ETAC concentration close to the MAC value for the selected inhalation agent is typically targeted, in order to maintain adequate anesthetic depth and avoid intraoperative awareness. In addition, raw or processed electroencephalography or other neuromonitoring techniques may be employed to aid in managing dosing in older adults and other patients at risk for excessive anesthetic depth, thereby avoiding doses that are either excessive or inadequate for an individual patient (table 4) [6]. (See "Accidental awareness during general anesthesia", section on 'Monitoring' and "Anesthesia for the older adult", section on 'Anesthetic depth: General considerations'.)

Other clinical effects

Skeletal and smooth muscle relaxation — All potent volatile inhalation anesthetics induce dose-dependent relaxation of both skeletal and smooth muscle by inhibiting nicotinic acetylcholine receptors.

●Skeletal muscle relaxation – The volatile inhalation agents potentiate and reduce the required dose of a neuromuscular blocking agent (NMBA). The degree of potentiation of NMBA effect depends upon the concentration of inhalation anesthetic administered, the duration of exposure, and the specific agent. The degree to which each inhalation agent potentiates NMBA effects (from highest to lowest) is (see "Clinical use of neuromuscular blocking agents in anesthesia", section on 'Drug interactions'):

The degree of skeletal muscle relaxation induced by administration of an inhalation agent alone may be insufficient for procedures requiring profound muscle relaxation. Also, the degree of skeletal muscle relaxation may be insufficient to prevent patient movement in response to all noxious surgical stimuli during light or moderate anesthetic depth. Thus, monitoring of the degree of neuromuscular blockade is recommended to achieve adequate skeletal muscle relaxation when desired, particularly when using pharmacologic neuromuscular blocking agents, as well to ensure complete reversal when relaxation is no longer needed. (See "Monitoring neuromuscular blockade".)

●Smooth muscle relaxation – All volatile inhalation agents also induce smooth muscle relaxation, which may be beneficial in certain situations. For example, uterine relaxation may be induced with administration of an inhalation anesthetic agent to facilitate extraction of retained products of conception. Other clinical effects resulting from smooth muscle relaxation may be detrimental. For example, gastrointestinal smooth muscle relaxation contributes to postoperative nausea, emesis, and ileus, while vesicoureteral smooth muscle relaxation contributes to postoperative urinary retention.

Respiratory effects

●Airway reflexes – Inhalation of volatile anesthetic agents can produce airway irritation and may precipitate coughing, laryngospasm, or bronchospasm during induction of anesthesia, particularly with the more pungent agents (desflurane and isoflurane). This is more likely in patients who smoke or have reactive airway disease (eg, asthma, chronic obstructive pulmonary disease [COPD], cystic fibrosis, α₁-antitrypsin deficiency, chronic lung disease of prematurity, or bronchopulmonary dysplasia [BPD]). The likelihood of airway complications, such as laryngospasm and bronchospasm, due to inhalation agent pungency is (from most to least likely):

In particular, high concentrations (≥1.5 MAC) of desflurane are likely to cause airway irritation [7,8].

During Stage II, excitement and hyperstimulation exaggerate responses to laryngeal or pharyngeal stimuli (see 'Agitation and excitability' below). These responses increase risk for laryngospasm or emesis. As transition to Stage III and deeper levels of anesthesia occurs, laryngeal and pharyngeal airway reflexes are abolished, which facilitates laryngoscopy and intubation. However, risk for aspiration is present until the airway has been secured. Hence, an inhalation anesthetic induction technique is typically avoided in patients with pre-existing risk factors for aspiration.

●Bronchial effects – At higher concentrations, he potent volatile inhalation anesthetic agents are bronchodilators, decrease airway responsiveness, and attenuate bronchospasm. The bronchodilatory properties of the inhalation agents result from beta₂ receptor stimulation, which results in an increase in intracellular cyclic adenosine monophosphate, causing relaxation of bronchial smooth muscle [9]. In fact, volatile anesthetic agents may be used for treatment of severe status asthmaticus. Sevoflurane has the most pronounced bronchodilatory properties of the available inhalation anesthetics. Halothane was historically the agent of choice to prevent or treat bronchoconstriction, but it is no longer available in the United States. Although desflurane directly relaxes airway smooth muscle at lower concentrations, higher concentrations (>1.5 MAC) may increase airway resistance, particularly in patients who currently smoke [8,10-12]. (See "Anesthesia for adult patients with asthma", section on 'Anesthetic agents' and "Anesthesia for patients with chronic obstructive pulmonary disease", section on 'Maintenance of anesthesia'.)

N₂O gas is not an airway irritant, but it is also not a bronchodilator, and has little effect on airway smooth muscle [9].

●Ventilation – During induction and maintenance with inhalation anesthetic agents, spontaneous ventilation is relatively preserved in Stage I, chaotic and unpredictable in Stage II, tachypneic with reduced tidal volume in Stage III, and abolished in Stage IV (figure 7). During Stages III and IV, dose-dependent respiratory depressant effects of the inhalation agents progressively shift the respiratory carbon dioxide (CO₂) response curve to the right (blunting ventilatory response to hypercapnia), blunt the hypoxic ventilatory drive, and reverse hypoxic pulmonary vasoconstriction (promoting perfusion of poorly ventilated lung, thereby increasing ventilation/perfusion ratio [V/Q] mismatch, which may result in hypoxia).

Interventions to assist or control ventilation typically become necessary, depending on the stage of anesthetic depth and the patient's clinical status.

Cardiovascular effects

●Potent volatile inhalation agents – The potent volatile anesthetics all induce myocardial depression with dose-dependent reductions in blood pressure (BP) and cardiac output, although the mechanisms for decline in BP and the degree of myocardial depression differ among agents (table 5 and table 6) [2]. These effects may be beneficial in certain situations. For example, as anesthetic depth is increased with a volatile agent during induction, sympathetic stress responses are beneficially blunted in anticipation of noxious stimuli caused by laryngoscopy and endotracheal intubation.

Isoflurane, sevoflurane, and desflurane have primary vasodilatory properties, thereby reducing systemic vascular resistance (SVR) with relatively little initial effect on cardiac inotropy. Isoflurane and desflurane tend to produce progressive tachycardia at progressively higher concentrations, and tachycardia may be seen with sevoflurane at concentrations >1.0 MAC. In particular, desflurane may induce tachycardia and hypertension due to its sympathomimetic properties, particularly with high or abruptly increased concentrations.

Halothane preserves SVR but is a negative inotrope. In progressively higher doses, halothane also has negative chronotropic properties and may induce bradycardia or asystole, particularly in infants and young children who have relatively greater parasympathetic tone compared with adults. Also, halothane sensitizes the myocardium to catecholamines more readily than all other inhalation agents, and is thus associated with a higher incidence of ventricular and other dysrhythmias.

Although vascular, inotropic, and chronotropic effects of the potent volatile inhalation agents differ, at high concentrations that induce Stage IV anesthetic depth (significantly above 1.0 MAC) each of these agents eventually induces cardiovascular collapse due to progressive vasodilation, bradycardia, and negative inotropy. This is one manifestation of anesthetic overdose (ie, anesthetic depth that is "too deep") (see 'Continuum of effect: sedation to general anesthesia' above).

●Nitrous oxide – N₂O induces few hemodynamic changes in most patients (table 6), in part because delivery of concentrations higher than approximately 0.75 MAC is not possible at standard temperature and pressure. However, N₂O may cause mild myocardial depression and sympathetic nervous system stimulation, with mild increases in pulmonary vascular resistance (table 5).

Effects on cerebral physiology — Effects of inhalation and other anesthetic agents on cerebral physiology are summarized in the table (table 7).

●Potent volatile inhalation agents – The potent, halogenated inhalation anesthetics (sevoflurane, desflurane, isoflurane, halothane) are all dose-dependent cerebral vasodilators. While they reduce cerebral metabolic rate (CMR), they can blunt cerebral autoregulation by uncoupling cerebral blood flow (CBF) and metabolism, thereby increasing CBF and intracranial pressure (ICP). At MAC values <1 MAC, the net effect is a modest decrease in CBF and responsiveness to CO₂ is generally maintained. However, CBF increases more significantly at concentrations >1 MAC. (See "Anesthesia for craniotomy in adults", section on 'Potent inhalation agents'.)

●Nitrous oxide – N₂O can increase CBF, CMR, and ICP, with generally preserved CO₂ responsiveness. N₂O-induced changes in cerebral physiology are affected by ventilation and the administration of other anesthetic agents. (See "Anesthesia for craniotomy in adults", section on 'Potent inhalation agents'.)

Agitation and excitability — During inhalation induction of general anesthesia, a continuum of effect occurs as progressively higher doses of inhalation anesthetics are administered. Patients initially pass through Stage I, lasting from the onset of sedation until initial loss of consciousness (table 8) [13,14]. Patients then pass through Stage II, characterized by delirium, excitability, and an exaggerated response to stimuli. This stage is likely to be more overt during administration of inhalation anesthetic agents rather than IV agents. Various ocular, laryngeal, and musculoskeletal responses are manifestations of Stage II (figure 7). During Stage II, patients are particularly prone to laryngospasm, emesis, and aspiration of gastric contents. Management of these risks during Stage II involves maintenance of adequate ventilation, avoidance of unnecessary stimulation, and either rapid deepening of anesthesia to reach Stage III (surgical anesthesia), or termination of anesthetic administration if appropriate (eg, awakening the patient after an unsuccessful endotracheal intubation attempt in order to perform an alternative technique such as awake flexible bronchoscopic intubation).

Agitation may also occur during emergence from general anesthesia as the patient transitions from a deeper Stage III anesthetic state through a transient phase with risk of laryngospasm and agitation (Stage II), before becoming aware and responsive to commands (Stage I) (table 8). (See "Emergence from general anesthesia", section on 'Airway or respiratory problems' and "Emergence from general anesthesia", section on 'Severe agitation'.)

Postoperative nausea and vomiting — All inhalation agents are associated with increased risk for postoperative nausea and vomiting (PONV) compared with IV anesthetic agents [15,16]. N₂O is associated with a modestly higher incidence of PONV compared with other inhalation anesthetics, although this may be mitigated if standard antiemetic prophylactic measures are employed [17,18]. Prolonged administration may induce nausea and emesis based on mechanical factors since N₂O diffuses into bowel gas with resultant visceral distension [19]. (See "Postoperative nausea and vomiting", section on 'Anesthetic factors'.)

Reactions with carbon dioxide absorbents — Carbon dioxide (CO₂) absorbents are used in the circle breathing system of an anesthesia machine to prevent hypercapnia caused by rebreathing of exhaled CO₂. These absorbents contain strong bases (eg, calcium hydroxide, sodium hydroxide [NaOH], potassium hydroxide [KOH], barium hydroxide, lithium hydroxide), which react with CO₂ to form a carbonate. CO₂ absorbents also react with potent volatile anesthetic agents passing through them, particularly if the absorbent becomes desiccated. For this reason, the color of the pH indicator of the CO₂ absorbents is checked as part of the pre-use machine checkout to verify that the absorbent is not exhausted [20]. (See "Anesthesia machines: Prevention, diagnosis, and management of malfunctions", section on 'Carbon dioxide absorbent exhaustion or toxicity'.)

Reactions between volatile anesthetic agents and CO₂ absorbents that may result in adverse effects include:

●Formation of carbon monoxide – CO₂ absorbents containing NaOH or KOH can induce production of carbon monoxide upon exposure to halogenated volatile inhalation agents, with potential risk of carbon monoxide toxicity and significant carboxyhemoglobinemia. Absorbents containing lithium hydroxide or barium hydroxide are not associated with carbon monoxide production although these CO₂ absorbents are more expensive. Desiccation of the absorbent, high absorbent temperature, high concentration of inhaled agent, or low fresh gas flow all increase risk of carbon monoxide production.

Reactions of inhaled anesthetics with CO₂ absorbents to induce carbon monoxide production (from most to least likely) may occur with:

●Formation of compound A – Sevoflurane interacts with the strong bases (NaOH, KOH) in some CO₂ absorbents to produce compound A (fluoromethyl-2,2-difluoro-1-[trifluoromethyl] vinyl ether). Compound A is nephrotoxic in rats. No study has demonstrated clinically significant nephrotoxicity in humans even after prolonged administration of sevoflurane with low fresh gas flow rates, despite significant compound A production. Nevertheless, the US Food and Drug Administration (FDA) recommends use of sevoflurane with fresh gas flow rates ≥1 L/min for exposure less than one hour and ≥2 L/min for exposures more than one hour. Federal agencies in other countries have not made such recommendations, nor have professional societies.

Neurotoxic effects in developing brain — Possible neurotoxic effects of inhalation agents on the developing brain are discussed separately. (See "Neurotoxic effects of anesthetics on the developing brain".)

Teratogenic effects — Historically, there was significant concern regarding increased risk for pregnancy loss and association with congenital malformations in the offspring of pregnant women chronically exposed to low levels of inhalation agents (eg, operating room nurses, surgeons, anesthesiologists). Data are conflicting and the precise extent of risk, if any, is unclear [21]. However, these concerns resulted in requirements for fastidious scavenging and appropriate venting of inhalation agents. This is an American Society of Anesthesiologists (ASA) recommendation [20], as well as an Occupational Health and Safety Administration (OHSA) guideline [22].

Malignant hyperthermia (volatile inhalation agents) — All potent volatile inhalation anesthetic agents may induce malignant hyperthermia in susceptible individuals. (See "Malignant hyperthermia: Diagnosis and management of acute crisis", section on 'MH triggers'.)

CLINICAL USES

Induction of general anesthesia

Inhalation induction (sevoflurane, halothane, nitrous oxide) — Primary inhalation induction is employed in the following situations:

●Pediatric patients – Induction with an inhalation agent is usually preferred in infants and young children because of their fear of needles and response to the pain of a needle stick [23]. (See "General anesthesia in neonates and children: Agents and techniques", section on 'Inhalation induction'.)

●Adult patients – Inhalation induction may be preferred in an adult if spontaneous breathing during induction is desired (eg, when intravenous [IV] access cannot be obtained, or in patients with tracheal stenosis or an intraoral, pharyngeal, or mediastinal mass causing compression of the airway). (See "Anesthesia for patients with an anterior mediastinal mass", section on 'Airway management during induction'.)

In general, adult patient satisfaction is lower after primary inhalation induction compared with IV induction, due to the unpleasant odor of the gas [24] and a higher incidence of postoperative nausea and vomiting (PONV) [24-26]. However, development of nonpungent, nonirritant volatile anesthetics with rapid onset, particularly sevoflurane, has made inhalation induction of anesthesia via facemask a more pleasant and viable option (compared with older inhalation agents, particularly halothane) [25].

Inhalation induction of anesthesia requires a high concentration of a volatile anesthetic agent (see "Inhalation anesthetic agents: Properties and delivery", section on 'Concentration effect'). Generally, the inspired concentration of a volatile anesthetic agent (eg, sevoflurane) is increased incrementally over 30 to 60 seconds during inhalation induction in order to avoid unpleasant pungency, airway irritation, and laryngospasm or bronchospasm, which is more likely when high concentrations are rapidly introduced (see 'Respiratory effects' above). Desflurane should not be used to induce anesthesia via facemask because it is the most pungent of the volatile anesthetics and has the highest incidence of airway irritation (coughing, salivation, breath-holding, laryngospasm) and bronchospasm, particularly at high concentrations (≥1.5 minimum alveolar concentration [MAC]) [7,27]. (See 'Disadvantages and adverse effects' below.)

Overpressurization of the anesthetic concentration or coadministration of nitrous oxide (N₂O) speeds inhalation induction. (See "Inhalation anesthetic agents: Properties and delivery", section on 'Overpressurization' and "Inhalation anesthetic agents: Properties and delivery", section on 'Second gas effect'.)

Since the time required to induce anesthesia with an inhalation technique is longer (usually requiring several minutes of ventilation), this technique is not suitable for rapid sequence induction and intubation (RSII). (See "Rapid sequence induction and intubation (RSII) for anesthesia".)

Use as a supplement (all inhalation agents) — Any of the inhalation agents may be employed as a component of anesthetic induction, rather than as the primary induction agent. With this technique, initial loss of consciousness is achieved by administration of one or more IV agents (see "General anesthesia: Intravenous induction agents"). Subsequently, an inhalation agent is administered to deepen anesthesia so that airway reflexes and sympathetic stress responses will be beneficially blunted during laryngoscopy (see 'Respiratory effects' above and 'Cardiovascular effects' above). The potent volatile agents also induce a dose-dependent decrease in skeletal muscle tone, which improves conditions for insertion of an endotracheal tube (ETT) or a supraglottic airway (SGA). (See 'Skeletal and smooth muscle relaxation' above.)

Maintenance of general anesthesia (all inhalation agents)

●Maintenance – All available volatile inhalation anesthetic agents (sevoflurane, desflurane, isoflurane, and in some countries halothane) may be used for complete maintenance of general anesthesia. Dosing of an inhalation agent to maintain general anesthesia is determined by its potency, reported as the MAC value (table 2) [4]. (See 'MAC and MAC-awake values for inhalation agents' above.)

MAC is decreased by concurrent administration of N₂O or IV anesthetic agents such as sedative-hypnotics or opioids during maintenance of general anesthesia (see 'Influence of drug-drug interactions' above and 'Influence of patient-related factors' above). Often, a volatile anesthetic agent is administered with or without N₂O gas as a supplemental agent to maintain general anesthesia. Multiple medications are utilized in such balanced techniques in order to provide a combination of hypnosis, amnesia, and analgesia, and may be supplemented with a neuromuscular blocking agent (NMBA) if necessary to achieve complete immobility. (See "Maintenance of general anesthesia: Overview", section on 'Selection of maintenance techniques'.)

●Emergence – As the surgical procedure nears completion, optimal timing for discontinuation of an inhalation agent must be planned to prepare for an emergence from general anesthesia that is neither too early nor overly delayed. Timing for discontinuation depends on the selected agent(s), doses employed, and duration of administration. Details are discussed in separate topics. (See "Emergence from general anesthesia", section on 'Inhalation agents' and "Inhalation anesthetic agents: Properties and delivery", section on 'Clearance'.)

Procedural sedation (nitrous oxide) — N₂O may be used during procedural sedation, most commonly in dental offices and other settings outside the operating room (see "Office-based anesthesia", section on 'Selection of anesthetic agents'). N₂O is also used as a self-administered agent for management of pain during labor and delivery. (See "Pharmacologic management of pain during labor and delivery", section on 'Nitrous oxide'.)

In these settings, specific advantages of the inhalation agent N₂O include its availability, ease of delivery, and relative safety with usual preservation of airway patency, spontaneous ventilation, and cardiovascular function, compared with use of various IV agents (eg, sedative-hypnotics, anxiolytics, opioids, and other anesthetic adjuvant agents) (see 'Advantages' below). Disadvantages include inability to deliver concentrations greater than approximately 75 percent MAC at standard clinical temperature and pressure. (See 'MAC and MAC-awake values for inhalation agents' above and 'Disadvantages and adverse effects' below.)

In remote settings, lack of scavenging and appropriate venting is a potential disadvantage. Also, anesthesia care teams may not be available to manage complications or provide a deeper level of anesthesia if necessary.

SPECIFIC INHALATION ANESTHETIC AGENTS — There are properties shared by all volatile inhalation anesthetic agents (see 'Clinical effects' above). However, specific advantages, disadvantages, and adverse effects differ among the available potent volatile agents as noted below.

Sevoflurane — Sevoflurane is supplied as a colorless bottled liquid that readily evaporates at standard temperature and pressure. It is delivered via a vaporizer mounted on the anesthesia machine. Its properties are noted in the table (table 6).

Advantages

●Sweet-smelling, low pungency. Thus, sevoflurane is useful for inhalation induction.

●Low blood:gas partition coefficient, with consequent rapid uptake and induction of general anesthesia as well as rapid clearance and emergence. (See "Inhalation anesthetic agents: Properties and delivery", section on 'Blood:gas partition coefficient'.)

●Moderately high potency with a moderately low minimum alveolar concentration (MAC). (See 'MAC and MAC-awake values for inhalation agents' above.)

●Lack of significant negative chronotropic or negative inotropic effects at concentrations near MAC, modest vasodilatory properties.

●Little effect on cerebral autoregulation across a range of concentrations [28]. (See 'Effects on cerebral physiology' above.)

Disadvantages and adverse effects

●High cost, particularly with use during longer procedures. Compared with other potent volatile anesthetic agents, expense is higher because slightly higher fresh gas flows are employed (typically 1 to 2 L/minute of oxygen and/or air) to avoid formation of compound A. (See 'Reactions with carbon dioxide absorbents' above.)

●Theoretical risk of compound A-associated nephropathy. However, compound A is not generated by newer carbon dioxide absorbents. (See 'Reactions with carbon dioxide absorbents' above.)

Typical uses — Overall, sevoflurane is the most commonly used potent volatile inhaled agent in industrialized countries.

●Induction – Sevoflurane is the most frequently used inhaled agent for induction of anesthesia (because of its minimal odor, lack of pungency, and potent bronchodilatory characteristics [23-27,29,30]. Sevoflurane has many characteristics of the ideal induction agent, including relatively rapid onset due to its low tissue and blood solubility. The time to loss of consciousness may be as little as 60 seconds if a high concentration of sevoflurane (eg, 4 to 8 percent) is delivered via a facemask [23,31,32].

●Maintenance – Sevoflurane is also frequently selected for maintenance of anesthesia because more rapid changes in anesthetic depth are possible during painful interventions compared with more soluble agents such as isoflurane, and more rapid recovery occurs during emergence after a short procedure. However, for procedures lasting longer than approximately two hours, emergence times are similar after administration of sevoflurane or isoflurane because of their nearly identical fat solubilities, which allow similar accumulation in tissues during prolonged administration. This is in contrast to desflurane, which is markedly less soluble in fat, accumulates less in tissues even after prolonged administration, and is associated with more rapid emergence in most settings [33]. (See 'Advantages' below.)

Desflurane — Desflurane is supplied as a colorless bottled liquid that does not readily evaporate at standard temperature and pressure. Desflurane is delivered by an electric heated vaporizer mounted on the anesthesia machine. Its properties are noted in the table (table 6).

Advantages

●Very low blood:gas partition coefficient, with consequent very rapid uptake and induction of general anesthesia, as well as very rapid clearance and emergence. (See "Inhalation anesthetic agents: Properties and delivery", section on 'Blood:gas partition coefficient'.)

●Very low oil:gas partition coefficient with consequent minimal uptake into adipose tissue. Due to its absence of accumulation in tissues because of its low solubility in oil, desflurane is particularly advantageous for patients with obesity or sleep apnea [34-36]. (See "Inhalation anesthetic agents: Properties and delivery", section on 'Oil:gas partition coefficient/potency'.)

●Undergoes the least metabolism of all potent volatile agents. (See "Inhalation anesthetic agents: Properties and delivery", section on 'Metabolism'.)

●Compared with sevoflurane, an advantage for desflurane is safety during use with low fresh gas flows in the breathing circuit. (See 'Sevoflurane' above.).

Disadvantages and adverse effects

●Very high pungency. Desflurane is the most pungent of the volatile anesthetics.

●Marked airway irritation (eg, coughing, salivation, breath-holding, laryngospasm), particularly with administration at concentrations ≥1.5 MAC, due to high pungency. (See 'Respiratory effects' above.)

●A high incidence of coughing during emergence compared with sevoflurane [7,27,35,36]. (See "Emergence from general anesthesia", section on 'Airway or respiratory problems'.)

●For these reasons, desflurane is not suitable for inhalation induction of anesthesia (see 'Inhalation induction (sevoflurane, halothane, nitrous oxide)' above) [7,27]. Also, desflurane is not ideal for patients who smoke or have reactive airway disease (eg, asthma, chronic obstructive pulmonary disease [COPD], cystic fibrosis, α₁-antitrypsin deficiency, chronic lung disease of prematurity, or bronchopulmonary dysplasia [BPD]). Although desflurane at lower concentrations (<1.5 MAC) has been used during maintenance of anesthesia for patients at risk for bronchospasm, higher concentrations may increase airway resistance [8,10-12]. (See "Anesthesia for adult patients with asthma", section on 'Maintenance of anesthesia' and "Anesthesia for patients with chronic obstructive pulmonary disease", section on 'Maintenance of anesthesia'.)

●Tachycardia and hypertension due to sympathomimetic properties, particularly with administration of high or abruptly increased inspired concentrations [37]. With continued administration, hypertension tends to resolve at steady state, although tachycardia may persist. These properties also limit use of desflurane as a primary agent for induction of general anesthesia, since any inhalation agent must be rapidly increased to produce a high enough concentration to induce unconsciousness in a previously awake patient.

●Since tachycardia may persist, desflurane is not ideal for patients with significant ischemic heart disease, hypertrophic obstructive cardiomyopathy, aortic or mitral stenosis, or other patients for whom tachycardia is undesirable. If desflurane is used during maintenance of anesthesia for such patients, high concentrations and rapid increases in concentration are avoided. (See "Anesthesia for noncardiac surgery in patients with ischemic heart disease", section on 'Prevention of ischemia'.)

●Very high cost, particularly during long procedures.

●Need for a specialized electric heated vaporizer.

●Low potency with high MAC.

Typical uses — Desflurane is frequently selected for maintenance of anesthesia, particularly during short procedures, because very rapid changes in anesthetic depth are possible during painful interventions, and very rapid recovery occurs during emergence. Due to ease of titration, rapidity of recovery, and minimal residual effects, desflurane is particularly advantageous for older patients and those with obesity or sleep apnea [35,36].

Isoflurane — Isoflurane is supplied as a colorless bottled liquid that readily evaporates at standard temperature and pressure. It is delivered via a vaporizer mounted on the anesthesia machine. Its properties are noted in the table (table 6).

Advantages

●High potency with low MAC.

●Very low cost, particularly with use during long procedures.

●Little effect on cerebral autoregulation at concentrations <1 MAC [38,39].

Disadvantages and adverse effects

●High pungency, which limits its utility as a primary agent for inhalation induction of anesthesia.

●Moderately high blood:gas partition coefficient, with consequent slow uptake and induction of general anesthesia, compared with sevoflurane or desflurane. This further limits use of isoflurane during induction (except as a supplemental agent). (See 'Use as a supplement (all inhalation agents)' above.)

●High solubility in fat, associated with prolonged emergence particularly after prolonged procedures because of accumulation in tissues. This property limits its use in procedures of prolonged duration.

●Positive chronotropy with associated tachycardia that may be clinically significant when tachycardia is undesirable (eg, ischemic heart disease). (See "Anesthesia for noncardiac surgery in patients with ischemic heart disease", section on 'Prevention of ischemia'.)

●Mild negative inotropy, vasodilatory properties.

Typical uses

●Maintenance – Isoflurane is frequently selected for maintenance of anesthesia, particularly if the anticipated duration of the procedure is long, because it is inexpensive, widely available, and the most potent of the volatile anesthetics. Its unpleasant pungency limits its utility as a primary inhalation agent during induction, although it may be employed as a supplemental agent after administration of IV induction agents in order to deepen and maintain anesthesia.

As with sevoflurane, isoflurane has high solubility in fat and is associated with prolonged emergence particularly after prolonged procedures because of accumulation in tissues. Thus, timing for discontinuation of isoflurane must be carefully planned as the surgical procedure is nearing completion. (See "Emergence from general anesthesia", section on 'Discontinue anesthetic agents'.)

Halothane — Halothane is supplied as a bottled liquid that readily evaporates at standard temperature and pressure. It is delivered via a vaporizer mounted on the anesthesia machine. Properties of halothane are noted in the table (table 6).

Stability of halothane is maintained with the addition of 0.01 percent thymol, which may accumulate in the vaporizer to eventually impart a yellow color to the remaining liquid. Development of such discoloration indicates that the halothane vaporizer should be drained and cleaned.

Advantages

●Sweet-smelling gas with only moderate pungency. Thus, halothane is often used for inhalation induction in resource-challenged countries where it remains available.

●Low cost.

●Very high potency with very low MAC.

Disadvantages and adverse effects

●Very high solubility in blood, tissue, and oil, with consequent very slow uptake and induction of general anesthesia, as well as very slow clearance and emergence. (See "Inhalation anesthetic agents: Properties and delivery", section on 'Blood:gas partition coefficient' and "Inhalation anesthetic agents: Properties and delivery", section on 'Brain:blood partition coefficient' and "Inhalation anesthetic agents: Properties and delivery", section on 'Oil:gas partition coefficient/potency'.)

●Negative inotropy and significant negative chronotropy, even if administered at relatively low concentrations. At high concentrations, halothane may induce severe bradycardia or asystole.

●High incidence of ventricular and other dysrhythmias due to sensitization of the myocardium to catecholamines.

●Undergoes greater hepatic metabolism than all other inhalation agents, with associated risks for both cytotoxic and autoimmune hepatotoxicity and halothane hepatitis [40-42]:

•Halothane hepatotoxicity – Hepatotoxicity can occur with or without prior halothane exposure. Postoperative elevation in serum aminotransferases has been observed in 20 to 30 percent of patients receiving halothane [43]. Most patients are asymptomatic, although a subset develops symptoms of mild clinical hepatitis characterized by nausea, lethargy, and fever. The aminotransferases remain elevated for one to two weeks following exposure and resolve without treatment [44]. This reaction is generally considered a non-immune phenomenon, and recovery is the rule.

•Halothane hepatitis – A rarer and more unpredictable occurrence is an acute severe hepatitis "halothane hepatitis," with potential development of hepatic necrosis and acute liver failure that is often fatal. The incidence is 1 in 6000 to 1 in 15,000 following a single exposure to the anesthetic, and increases to approximately 1 in 1000 following multiple exposures, particularly if they occur within 28 days of prior exposure [45]. Other risk factors for severe hepatotoxicity may include short intervals between exposures, female sex (2:1), age greater than 40 years (80 percent of cases), obesity, underlying liver dysfunction, and a genetic predisposition to hepatitis [46-48].

Symptoms generally develop approximately two days to three weeks after exposure. Approximately 75 percent of patients present with a fever and may complain of anorexia, nausea, myalgias, arthralgias, and rash [49]. Eosinophilia occurs in approximately 40 percent of cases, suggesting that toxicity is immunoallergic [50]. Tender hepatomegaly and jaundice are common. Some patients present with acute liver failure, markedly elevated serum aminotransferases and prothrombin time, and possibly hepatic encephalopathy.

Halothane-associated hepatitis is rare in children, occurring in between 1 in 82,000 and 1 in 200,000 [51,52]. The reason for the lower incidence of halothane-associated hepatitis observed in children is unclear [53].

Typical uses — Halothane is no longer commercially available in North America, Europe, and many other countries due to its adverse effects (particularly the possibility of halothane hepatitis), and the development of newer inhalation agents that have replaced it, in particular sevoflurane. However, due to its low cost, halothane is still used for both induction and maintenance of general anesthesia in resource-challenged countries, particularly in children.

Nitrous oxide — Nitrous oxide (N₂O) is supplied as a pressurized gas in equilibrium with its liquid phase that is delivered via a flow meter on the anesthesia machine. (See "Anesthesia machines: Prevention, diagnosis, and management of malfunctions", section on 'Compressed gas flowmeter malfunction'.)

Advantages

●Slightly sweet-smelling gas, with no pungency and no potential for airway irritation. Thus, N₂O is useful for inhalation induction.

●Very low blood:gas partition coefficient, with consequent very rapid rate of rise of its alveolar concentration and onset of anesthetic effect. Changes in anesthetic depth during maintenance are also very rapid. Furthermore, addition of N₂O near the end of surgery may speed recovery from anesthesia, particularly if a volatile agent with a high blood:gas partition coefficient is being administered (eg, isoflurane, halothane). In one study, addition of N₂O during the last 30 minutes of an isoflurane-based anesthetic reduced the time to extubation by approximately two minutes (2.0 minutes, 95% CI 0.6-3.4), as well as reducing time to eye opening, following commands, and being oriented [54]. Presumably, faster recovery occurred because the anesthesia provider could reduce the administered concentration of isoflurane, as well as taking advantage of the "second-gas" effect of N₂O, as noted in the next bullet. (See "Inhalation anesthetic agents: Properties and delivery", section on 'Blood:gas partition coefficient' and 'Disadvantages and adverse effects' below.)

●Increases speed of anesthetic onset and offset when coadministered with any potent volatile inhalation agent, compared with administration of the potent agent alone. This is due to a phenomenon termed the "second gas" effect. Notably, second gas effects with N₂O are more pronounced with more soluble volatile anesthetics (eg, isoflurane, halothane). (See "Inhalation anesthetic agents: Properties and delivery", section on 'Second gas effect'.)

●Analgesic and anxiolytic properties, which typically decrease requirements for the primary inhalation agent and/or for IV anesthetic agents. (See 'Influence of drug-drug interactions' above.)

●Reduced likelihood of postoperative opioid-induced hyperalgesia and potentially reduced incidence of chronic postsurgical pain [55,56]. Results of the Enhanced Neuro Imaging Genetics through Meta-Analysis (ENIGMA) multicenter study of N₂O as a component of balanced general anesthesia suggested a decreased incidence of chronic pain in patients receiving N₂O [15].

●Negligible hemodynamic effects.

●Undergoes no significant biotransformation.

●Low cost.

Disadvantages and adverse effects

●Very low potency and consequent inability to deliver concentrations greater than approximately 0.75 MAC at standard clinical temperature and pressure. (See "Inhalation anesthetic agents: Properties and delivery", section on 'Oil:gas partition coefficient/potency'.)

●Association with a modestly higher incidence of postoperative nausea and vomiting (PONV) compared with other inhalation anesthetic agents, although this may be mitigated if antiemetic prophylactic measures are employed [17,18]. Diffusion into bowel gas with associated visceral distension may increase risk of PONV, particularly after prolonged use. However, not all studies have noted increased risk of PONV with short-term administration of N₂O, even if no prophylactic antiemetic agents were administered [54]. (See "Postoperative nausea and vomiting", section on 'Anesthetic factors'.)

●Diffuses into any gas-filled cavity. Thus, administration is avoided in patients with possible pre-existing bowel distention, increased middle ear pressure, pneumothorax, pneumoperitoneum, pneumocephalus, intraocular gas, or venous air embolism [2,17,18]. Further gaseous distension of such spaces has potentially significant adverse consequences (eg, nausea with emesis, tension pneumothorax, increased intracranial pressure (ICP), vision loss, expansion of entrapped intravascular air).

●Possible increased incidence of postoperative atelectasis in patients with pre-existing poor pulmonary function. In one systematic review, patients undergoing N₂O-based techniques had an increased incidence of atelectasis (odds ratio [OR] 1.57, 95% CI 1.18-2.10), but there were no effects on mortality, pneumonia, or other adverse postoperative outcomes [17]. Thus, the clinical relevance of this finding is unclear.

●Potential for transient diffusion hypoxia with discontinuation of N₂O at low inspired oxygen concentrations. Upon discontinuation, bulk transfer of N₂O gas into the alveolus displaces oxygen and decreases alveolar oxygen concentration, potentially inducing desaturation. Such diffusion hypoxia may be prevented by delivery of high inspired oxygen concentration for several minutes before and after discontinuing N₂O. (See "Inhalation anesthetic agents: Properties and delivery", section on 'Second gas effect'.)

●Potential for fire hazard. Although not itself flammable, N₂O supports combustion, and a potential fire hazard exists (particularly in combination with bowel gas). (See "Fire safety in the operating room", section on 'Nitrous oxide'.)

●Mild myocardial depression and sympathetic nervous system stimulation, with mildly increased pulmonary vascular resistance (table 5). Although N₂O is typically avoided in patients with severe cardiomyopathy and pulmonary hypertension, it has not been associated with increased risk of cardiac complications after noncardiac surgery [15,17,57,58].

●N₂O should be avoided in patients with disorders of B12, folate, or methionine synthesis or metabolism.

N₂O inactivates vitamin B₁₂. In patients who have pre-existing vitamin B₁₂ deficiency, this may result in neurotoxicity with sensory neuropathy, myelopathy, and encephalopathy. Recovery may be slow and incomplete even after treatment with vitamin B₁₂.

Vitamin B₁₂ is an essential cofactor for methylenetetrahydrofolate reductase (MTHFR; ie, methionine synthetase), an enzyme critical in both folate (vitamin B₉) and homocysteine/methionine pathways. N₂O-induced oxidation of vitamin B₁₂ inhibits methionine synthetase activity [2], thereby impairing synthesis of both tetrahydrofolate and methionine. Reduced tetrahydrofolate synthesis impairs purine and thymidine synthesis and may cause immunosuppression [59]. Reduced methionine synthesis and associated increased levels of homocysteine also theoretically increase risk for thrombosis and may lead to endothelial dysfunction [60].

●Some potential for abuse because of its analgesic, anxiolytic, and euphoric properties.

●Association with teratogenic effects in animal models, although this has not been demonstrated in humans. However, adequacy of scavenging should be ensured during use near potentially pregnant health care workers in operating rooms or other settings [61,62]. (See 'Teratogenic effects' above.)

Typical uses

●Induction – N₂O gas is commonly used as an adjuvant agent during inhalation induction of general anesthesia. Due to its very low solubility in blood, the rate of rise of its alveolar concentration occurs very rapidly during inhalation induction. Since N₂O has low potency it is rarely used as the sole anesthetic agent (MAC value is 104 percent); however, it is commonly coadministered with a potent volatile inhalation agent because its "second gas" effect hastens the onset of anesthesia and increases in anesthetic depth [17]. (See "Inhalation anesthetic agents: Properties and delivery", section on 'Second gas effect'.)

●Maintenance – N₂O gas is also commonly used during maintenance of general anesthesia as an adjuvant to a volatile anesthetic and/or IV anesthetic agents because it is widely available and inexpensive [63]. Administration of N₂O increases anesthetic depth, resulting in decreased dosing of other anesthetic agents. However, N₂O cannot be used as a sole agent to maintain anesthesia because of its low potency (MAC value is 104 percent) [17].

●Procedural sedation – N₂O may be used during procedural sedation or as a self-administered agent for management of pain during labor and delivery.

N₂O use is avoided in patients with pre-existing bowel distention, increased middle ear pressure, pneumothorax, pneumoperitoneum, pneumocephalus, intraocular gas, or venous air embolism [2,17,18]. Also, N₂O is typically avoided in patients with cardiomyopathy and pulmonary hypertension because it causes mild myocardial depression and sympathetic nervous system stimulation with increases in pulmonary vascular resistance. Furthermore, N₂O use is generally avoided in patients with vitamin B₁₂ deficiency or those with other MTHFR deficiencies.

SUMMARY AND RECOMMENDATIONS

●Dose-dependent clinical effects

•Sedation and anesthesia – The primary clinical effect of inhalation anesthetic agents is dose-dependent sedation progressing to complete general anesthesia with hypnosis, amnesia, analgesia, akinesia, and autonomic and somatic block (table 8 and table 9). (See 'Continuum of effect: sedation to general anesthesia' above.)

The minimum alveolar concentration (MAC) value is the concentration of an inhalation agent in the alveoli required to prevent movement in response to a noxious stimulus in 50 percent of subjects (figure 2 and figure 3 and figure 1), while the MAC-awake (also termed MAC-aware) value is the concentration of an inhalation agent in the alveoli at which 50 percent of patients will not respond to a verbal or non-noxious tactile stimulus (table 1). MAC values differ for each inhalation agent, and are measures of anesthetic potency (table 2). (See 'MAC and MAC-awake values for inhalation agents' above.)

•Respiratory effects – Respiratory depression and suppression of airway reflexes. (See 'Respiratory effects' above.)

•Cardiovascular effects – Myocardial depression with decreased blood pressure (table 5). (See 'Cardiovascular effects' above.)

•Cerebral effects – Decreased cerebral metabolic rate with increased cerebral blood flow (table 7). (See 'Effects on cerebral physiology' above.)

•Effects on muscle tone – Decreased skeletal and smooth muscle tone, as well as bronchial and uterine relaxation. (See 'Skeletal and smooth muscle relaxation' above.)

●Other clinical effects

•Agitation and excitability – Transient delirium and exaggerated responses to stimuli during Stage II as anesthesia is being induced (Stage II (table 8 and figure 7)), with increased risk of laryngospasm, emesis, and aspiration of gastric contents. (See 'Agitation and excitability' above.)

•Postoperative nausea and vomiting – Increased risk compared with intravenous alternatives. (See 'Postoperative nausea and vomiting' above.)

•Neurotoxic and teratogenic effects – All have possible neurotoxic and teratogenic effects. Malignant hyperthermia can be induced in susceptible individuals. (See 'Neurotoxic effects in developing brain' above and 'Teratogenic effects' above.)

•Malignant hyperthermia – All potent volatile inhalation anesthetic agents may induce malignant hyperthermia in susceptible individuals. (See 'Malignant hyperthermia (volatile inhalation agents)' above.)

●Clinical uses

•General anesthesia – Inhalation agents may be used as primary agents to induce general anesthesia (sevoflurane or halothane with or without nitrous oxide [N₂O]), or as supplemental agents to induce and/or maintain anesthesia (all inhalation agents). (See 'Induction of general anesthesia' above and 'Maintenance of general anesthesia (all inhalation agents)' above.)

•Procedural sedation – N₂O is occasionally used during procedural sedation or as a self-administered agent for management of pain during labor and delivery. (See 'Procedural sedation (nitrous oxide)' above.)

●Advantages and disadvantages – The potent volatile agents differ in their specific advantages, disadvantages, and adverse effects, as described above (table 6) (see 'Specific inhalation anesthetic agents' above):

•Sevoflurane (See 'Sevoflurane' above.)

•Desflurane (See 'Desflurane' above.)

•Isoflurane (See 'Isoflurane' above.)

•Halothane (See 'Halothane' above.)

•Nitrous oxide (See 'Nitrous oxide' above.)