Clinical administration of inhalation anesthetics requires a carrier gas that must include oxygen, a source of anesthetic, and a patient breathing circuit. For very small animals (e.g., laboratory rodents or small birds) this may mean nothing more than placing the animal in a closed air-filled chamber that contains a cotton pledget saturated with liquid anesthetic (e.g., isoflurane). With larger animals and/or to provide more controlled delivery of anesthetic and O₂, it is more appropriate to use a specialized delivery apparatus to improves the safety and control of anesthetic concentrations delivered to patients. The anesthetic machine includes one or more flow meters, one or more vaporizers, and a patient breathing circuit. Reviews of vaporizers and other anesthetic delivery equipment are available elsewhere (Dorsch and Dorsch, 2007; Tranquilli et al., 2007; Miller et al., 2014).

Inhalation anesthetics are either gases or vapors. N₂O exists as a gas under operating room conditions because at 1 atmosphere pressure, the boiling point of N₂O is −89°C. Consequently, N₂O for clinical use in tanks is compressed to the liquid state at about 750 psi (pounds per square inch; 750 psi/14.9 psi [1 atmosphere] = 50 atmospheres). As the N₂O gas is drawn from the tank, liquid N₂O is vaporized, and the overriding gas pressure remains constant until no further liquid remains in the tank. At that point, only N₂O gas remains, and the gas pressure decreases from this point as remaining gas is vented from the tank.

Quantities of inhalation anesthetic agent are usually characterized by one of three methods: pressure (e.g., in mmHg), concentration (in volumes), or mass (in mg or g). The form most familiar to clinicians is that of concentration (e.g., X% of agent A in relation to the whole gas mixture). Modern monitoring equipment samples inspired and expired gases and provides concentration readings for inhalation anesthetics. Precision vaporizers used to control delivery of inhalation anesthetics are calibrated in percentage of agent, and effective doses are almost always reported in percentages. Finally, the molecular weight and agent density are used in ideal gas calculations to convert from liquid to vapor volumes and mass (Hill, 1980).

Delivery of anesthetic to the alveoli – and the rate of rise of the alveolar concentration or fraction (F_A) toward the inspired concentration or fraction (F_I) – depends on the inspired anesthetic concentration itself and the magnitude of alveolar ventilation. Increasing either one of these or both increases the rate of rise of the P_A of anesthetic.

Inhalation anesthetics produce a reversible generalized CNS depression for which the degree of depression is often described as depth of anesthesia. The components of general anesthesia have traditionally been considered to include: unconsciousness, amnesia, analgesia, and immobility. Some also include in this concept, suppression of autonomic reflexes. Most recently, in attempting to better define the site(s) and mechanism(s) of action of inhalation anesthetics this list has been distilled to just two reversible qualities applying to all inhalation agents: amnesia and immobility in response to a noxious stimulus (Eger et al., 2003a; Eger and Sonner, 2006).

The inhaled agents cause immobility and amnesia, but these distinct endpoints are achieved via actions at different CNS sites. In an experimental goat model in which the cerebral circulation was isolated from the rest of the body, selective brain isoflurane administration more than doubled the anesthetic requirement for immobility compared to whole-body isoflurane administration. This demonstrated that the spinal cord, and not the brain, is principally responsible for preventing movement during surgery with inhaled anesthetics (Antognini and Schwartz, 1993). Within the spinal cord, immobility is most likely produced by depression of locomotor neuronal networks located in the ventral horn (Jinks et al., 2005).

In contrast, amnestic effects of inhaled anesthetics are produced by actions within the brain, most probably within the amygdala and hippocampus (Eger et al., 2003b). Lesions created within the amygdala of rats can block amnestic actions of sevoflurane (Alkire and Nathan, 2005). On electroencephalography, hippocampal-dependent θ-rhythm frequency slows in proportion to the amnestic effects observed with subanesthetic concentrations of isoflurane in rats (Perouansky et al., 2010). Furthermore, mutant mice lacking the gene encoding either the α₄ or β₃ subunits of GABA_A receptors are resistant to isoflurane depression of hippocampus-dependent learning and memory (Rau et al., 2009; Rau et al., 2011), and antagonism of α₅ subunit-containing GABA_A receptors restores hippocampal-dependent memory during sevoflurane administration (Zurek et al., 2012). Clearly the mechanisms of inhaled anesthetic action responsible for amnesia are different from those responsible for immobility.

At concentrations above MAC, it is presumed that inhaled anesthetics sufficiently depress cortical function to prevent animals from experiencing motivational-affective dimensions of pain (Melzack and Casey, 1967). Additionally, concentrations of modern volatile agents (halothane, enflurane, isoflurane, sevoflurane, desflurane) between 0.8 and 1.0 times MAC decrease (but do not ablate) wind-up and central sensitization and so may help prevent heightened postoperative pain sensitivity; however, higher concentrations of contemporary drugs offer no further benefit in this regard (O’Connor and Abram, 1995; Mitsuyo et al., 2006). Volatile anesthetic concentrations between 0.4 and 0.8 times MAC decrease withdrawal responses to noxious stimuli, but lower concentrations can actually cause hyperalgesia with a peak effect at 0.1 times MAC (Sonner et al., 1998; Zhang et al., 2000) due to potent nicotinic cholinergic receptor inhibition (Flood et al., 2002). In contrast, the gaseous anesthetics xenon and nitrous oxide produce analgesia via glutamatergic receptor inhibition (Yamakura and Harris, 2000), and in the case of nitrous oxide, through additional modulation of noradrenergic–opioid receptor pathways (Zhang et al., 1999). Anatomically, analgesic actions occur both supraspinally and within the dorsal horn of the spinal cord, and are likely responsible for greater blunting of autonomic responses associated with these gases as compared to the modern volatile agents (Nakata et al., 1999).

Unconsciousness, at least insofar as it may be correlated with loss of the righting reflex and spontaneous movement (Quasha et al., 1980), may occur at yet other sites within the CNS. Nicotine injections into the central medial thalamus causes partial-to-full arousal in rats lightly anesthetized with sevoflurane, suggesting a role of nicotinic acetylcholine receptors within this region (Alkire et al., 2007). Within the midbrain, electrical stimulation (Solt et al., 2014) or injection of D₁ receptor agonists (Taylor et al., 2013) into the ventral tegmental area reverses the immobilizing effects of isoflurane in rats, thus indicating a role for dopamine receptors. Presumably, thalamic and brainstem arousal allows subsequent activation of other cortical regions responsible for information processing and integration, a hallmark of consciousness (Tononi, 2008).

Of the contemporary inhaled anesthetics, enflurane (Joas et al., 1971; Neigh et al., 1971) and sevoflurane (Adachi et al., 1992; Komatsu et al., 1994; Osawa et al., 1994; Woodforth et al., 1997; Hilty and Drummond, 2000) are capable of producing epileptiform activity during electroencephalography. However, tonic–clonic muscle activity is typically only observed with enflurane, whereas sevoflurane may actually raise the threshold for seizure manifestation (Karasawa, 1991; Fukuda et al., 1996; Murao et al., 2000a), although perhaps less so than other inhaled agents (Murao et al., 2002). Isoflurane (Koblin et al., 1981; Fukuda et al., 1996; Murao et al., 2000a, 2000b) and desflurane (Fang et al., 1997b) suppress convulsive activity induced by such drugs as bupivacaine, lidocaine, and penicillin.

Inhalation anesthetics are cerebral vasodilators and tend to increase cerebral blood flow and interfere with normal cerebral vascular autoregulation. These effects are agent dependent (less with sevoflurane) (Conzen et al., 1992; Gupta et al., 1997; Matta et al., 1999; Nishiyama et al., 1999; Summors et al., 1999; Bedforth et al., 2000), dose dependent (less at sub-MAC concentrations) (Bundgaard et al., 1998; Matta et al., 1999; Werner et al., 2005), and species dependent (autoregulation better preserved in horses than humans and small animals) (Brosnan et al., 2011). Cerebrovasodilation increases intracranial blood volume and pressure, resulting in increased intracranial pressure that is exacerbated by head-down body positioning (Brosnan et al., 2002a, 2002b), hypercapnia (Brosnan et al., 2003a, 2003b), prolonged anesthetic duration (Brosnan et al., 2003a), and pathophysiological changes associated with increased intracranial elastance (Brosnan et al., 2004), such as intracranial masses, hemorrhage, edema, and hydrocephalus (North and Reilly, 1990). Severe and uncompensated increases in intracranial pressure can cause cerebral herniation and also decrease the extracranial-to-intracranial pressure gradient, defined as the cerebral perfusion pressure, resulting in cerebral ischemia.

In the adult, inhaled anesthetic preconditioning offers some degree of neuroprotection during subsequent hypoxic or ischemic insults (Xiong et al., 2003; Kehl et al., 2004; Zheng and Zuo, 2004; Payne et al., 2005; Li et al., 2008; Li and Zuo, 2009; Yang et al., 2011). However, in neonates, many inhaled agents can adversely affect neural viability or neural development. Contemporary volatile anesthetics have been associated with neuronal apoptosis in the brains and spinal cords of neonatal rats (Sanders et al., 2008b; Istaphanous et al., 2011) and monkeys (Brambrink et al., 2010, 2012); the longer-term clinical consequences for behavioral changes or learning and memory deficits are presently unresolved (Jevtovic-Todorovic et al., 2003b; Culley et al., 2004; Loepke et al., 2009; Satomoto et al., 2009; Kodama et al., 2011). In the aged, inhaled agents have been associated with postanesthetic cognitive dysfunction (Culley et al., 2003; Zhang et al., 2012) with the suggestion that impairment could be secondary to accumulation of amyloid protein within the brain (Xie et al., 2006). Although important in animals, implications of these potential side effects are even greater for humans.

Inhalation anesthetics may produce drug specific and/or dose-related effect. Such effects may manifest as changes in arterial blood pressure, cardiac output, stroke volume, heart rate, and/or rhythm of heart beat. Such changes may be caused by effects on myocardial contractility, peripheral vascular smooth muscle, and/or autonomic nervous system tone. Effects imposed by inhalation anesthetics may be further impacted by controlled versus spontaneous ventilation, concurrently administered drugs with direct or indirect hemodynamic actions, and preexisting cardiovascular disease.

Hepatocellular injury may result as a general consequence of a reduction in hepatic blood flow or by direct volatile anesthetic agent toxicity. The chlorinated methanes, including chloroform, remain a classic research model for induction of hepatic injury (Plaa, 2000). However, of the contemporary volatile agents, liver injury is occasionally reported with halothane (Pohl et al., 1989; Kenna and Jones, 1995). Newer ether-type anesthetics have much less pronounced effects on hepatic blood flow (Merin et al., 1991; Bernard et al., 1992; Crawford et al., 1992; Frink et al., 1992b; Hartman et al., 1992), and isoflurane and desflurane undergo comparatively trivial biotransformation (Holaday et al., 1975; Ghantous et al., 1991; Njoku et al., 1997; Eger et al., 2002).

Although inhaled agents are commonly associated with postanesthetic nausea and vomiting in people, emesis in the recovery period appears uncommon in most domestic animals.