The changes in an electroencephalogram (EEG) are noticed after the induction of inhaled anesthetics. At lower clinical concentrations (low MAC), the volatile anesthetics and gaseous anesthetics produce high frequency and low amplitude (Beta waves) waves in the EEG, and are transformed to low frequency and high amplitude waves (Delta waves) at clinical anesthetic concentrations [33]. Some volatile anesthetics, such as isoflurane and desflurane at 1.5–2 MAC anesthetic concentration, cause electrical silence in the EEG [34].

Enflurane has the tendency to induce convulsions (seizures) to decreased PaCO₂, MAC >2, and repetitive auditory stimuli [35]. Isoflurane has anti-convulsive properties, and desflurane does not produce seizures [36, 37]. There are case reports that support that sevoflurane can produce seizure activity [38, 39].

Typically, cerebral blood flow is autoregulated and depends on the cerebral oxygen consumption (CMRO₂), and PaCO₂. All inhaled anesthetics increase cerebral blood flow in a dose-dependent manner despite a decrease in cerebral oxygen consumption. Inhalation agents also partially preserve the autoregulation of CBF to changes in PaCO₂. Desflurane and isoflurane preserve the responsiveness of CBF to changes in PaCO₂ [40]. Cerebral metabolic oxygen requirements are dose-dependent and are decreased with volatile anesthetics [41]. Increased intracranial pressure is seen with halothane use due to significant increases in cerebral blood flow compared to other inhaled anesthetics [42].

Preconditioning and postconditioning is a mechanism for inhaled anesthetics for neuroprotective effects. Inhalational anesthetics provide neuroprotective effects against brain ischemia by pre-, pro- and post-conditionings. Preconditioning is a process where a relatively small amount of inhalational agent is administered prior to the ischemic insult. Postconditioning is applied after the cerebral ischemic event has developed. Many studies have confirmed the protection of pre- and post-conditioning of inhalational anesthetics in their neuroprotection against cerebral ischemia. Sevoflurane preconditioning and early postconditioning reduced both cerebral infract size and neurological defect score at 24 h of reperfusion. Pretreatment with sevoflurane or its early administration at reperfusion provided neuroprotection via mitoKATP in a rat model for focal cerebral ischemia.

Although sevoflurane and isoflurane are similar in their systemic effects, they appear to differ in cerebral circulation. Sevoflurane can maintain cerebral autoregulation up to 1.5 MAC; whereas, isoflurane results in loss of autoregulation. Thus, cerebral autroregulation is better preserved during 1.5 MAC sevoflurane than isoflurane and is a better neuroanesthetic agent.

Volatile anesthetics decrease mean arterial pressure in a dose-dependent manner, which varies with the type of agent used. At clinical anesthetic concentration, halothane decreases the mean arterial pressure by decreasing myocardial contractility and cardiac output; whereas, isoflurane, sevoflurane, and desflurane decrease systemic vascular resistance. Enflurane decreases both systemic vascular resistance and cardiac output. The change in heart rate is variable with type of agent used and the type of pharmacological agent administrated during surgery. The decrease in heart rate is observed with halothane use due to suppression of the carotid sinus to changes in systemic blood pressure and rate of sinus node depolarization. At anesthetic concentrations, the heart rate is increased with desflurane, enflurane, sevoflurane (>1 MAC) and isoflurane use [41, 43]. Nitrous oxide has very little effect in mean arterial pressure and heart rate changes [44, 45]. Significant decrease in cardiac output is noticed with halothane and enflurane, and sevoflurane can decrease cardiac output at MAC between 1 and 1.5. Sevoflurane can prolong the QT interval and should be cautiously used in patients with prolonged QT interval syndrome or patients susceptible to QT interval changes [46]. Volatile agents can induce arrhythmias. Halothane and isoflurane sensitize the heart to epinephrine, compared to desflurane and sevoflurane, and cause cardiac arrhythmias [47, 48]. Coronary steal syndrome, wherein normally responsive coronary anenoles are dilated “stealing” blood from vessels supplying ischemic zones, may be associated with isoflurane [49]. Isoflurane is known to be a potent coronary artery vasodilator. Isoflurane-induced coronary artery vasodilatation can lead to redistribution of coronary blood flow away from diseased areas, which have decreased ability to vasodilate. Thereby, blood is redistributed in greater amounts to areas with normally responsive coronary arteries. However, most clinical studies failed to prove a higher incident of myocardial ischemia due to isoflurane. Sevoflurane and desflurane do not cause coronary steal syndrome.

All volatile agents depress ventilation and blunt responses to changes in PaCO₂. Volatile agents cause rapid, shallow breathing. There is a reduction in the tidal volumes and minute ventilation. The increase in respiratory rate does not adequately compensate for the amount of tidal volume decrease and hence causes an increase in PaCO₂.

Volatile agents reduce minute ventilation by reducing tidal volumes. Reduced tidal volume causes a slight increase in PaCO₂. The agents minimally suppress the responsiveness to increased PaCO₂ (hypercapnia) from decreased tidal volume at central medullary respiratory centers [50, 51]. Nitrous oxide has very little effect in ventilation depression, bronchial muscle tone, and in hypoxic drive [52]. Increases in respiratory rate are associated with all volatile anesthetics. Halothane, isoflurane and sevoflurane decrease airway resistance in COPD and asthmatic patients [53]. Due to low airway irritant effects, nitrous oxide, halothane and sevoflurane can be used for induction of anesthesia. Isoflurane and desflurane can irritate the airways during induction with MAC greater than 1.5 and 1, respectively, but have little or no effect during the maintenance of anesthesia. Desflurane is a pungent gas that can cause airway irritability during induction, manifested as breath-holding, salivation, coughing, and possibly laryngospasm. Small doses of opioid administration and humidification help to reduce irritant properties [54–56].

Volatile anesthetics enhance the effects of neuromuscular blocking drugs by inhibiting nicotinic acetylcholine receptors [57]. Volatile anesthetics produce dose-dependent muscle relaxation; whereas, nitrous oxide can cause skeletal muscle rigidity (>1 MAC) [58]. One potential complication of volatile agents is malignant hyperthermia (MH). Succinylcholine administration with a volatile agent potentiates a patient susceptible to MH. Malignant hyperthermia can occur even without succinylcholine administration in genetically susceptible patients [59–61]. Halothane has a higher tendency to produce MH than other volatile agents. MH can appear hours after uneventful anesthesia with desflurane [62] and sevoflurane [63, 64]. Nitrous oxide does not manifest this complication [11].

Volatile agents have little effect on renal physiology. The decrease in renal blood flow that is clinically observed is a product of their glomerular filtration rate and urine output is systemic vascular effects. There is no direct effect of inhalational agents on renal blood flow. Inorganic fluorides and metabolites, such as compound A, produced from the metabolism of volatile anesthetics can be nephrotoxic; and these effects are further discussed in the next section (Biotransformation and Toxicity of Inhaled Anesthetics).

All inhaled anesthetics reduce the hepatic blood flow. Severe hepatic injury following volatile anesthetics administration is very rare, with a ratio of 1:10,000,000 [65]. Anesthetics agents interfere with hepatic metabolism of other pharmacological agents that are administrated during the anesthesia [66, 67]. Hepatotoxicity can occur with inhaled anesthetics due to inadequate hepatic oxygenation from reduced hepatic blood flow. Hepatotoxicity incidences are higher with halothane induction compared with other inhaled anesthetics. These effects are further discussed in the next section (Biotransformation and Toxicity of Inhaled Anesthetics).

Prolonged exposure to nitrous oxide can interfere with bone marrow function. Nitrous oxide affects DNA synthesis by inhibiting vitamin B₁₂ dependent enzymes (methionine sythetase) [68, 69]. Megaloblastic changes are noticed in patients who receive nitrous oxide for a duration of 24 h. Agranulocytosis occurs in patients with 4 days or longer exposure to nitrous oxide. Volatile anesthetics have an immunosuppressive effect on both innate immunity (neutrophils, NK cells, and macrophages) and cell-mediated immunity (T-cells and B-cells), and are dose-dependent. Volatile agents impair neutrophil, macrophage, dendritic, and T-cell function. The suppressive action on immunity is from a combined exposure of the patient to surgery and anesthesia. Surgery releases stress hormones (catecholamines and corticosteroids) [70]. Inhaled anesthetics inhibit the actions of polymorphonuclear cells such as chemotaxis and phagocytosis. Sevoflurane and isoflurane can induce dose-dependent apoptosis in lymphocytes. Isoflurane and sevoflurane also reduce the expression of adhesion molecules on lymphocytes and macrophages; and thus, decreases the recruitment and accumulation of immune cells at inflammatory sites [71].

Nitrous oxide undergoes very little biotransformation (0.004%) and is almost solely eliminated by exhalation during emergence [8]. Anaerobic bacteria in the gastrointestinal (GI) tract are responsible for the minimal amount of metabolism. Nitrous oxide irreversibly oxidizes the cobalt atom in vitamin B₁₂, including methionine synthetase and thymidylate synthetase. These enzymes are responsible for myelin formation and DNA synthesis; and thus, nitrous oxide has been questioned to cause bone marrow suppression and neurologic deficiencies in prolonged usage.

The liver is the primary site of biotransformation and metabolism for most drugs, particularly lipophilic drugs such as halothane [74, 75]. Approximately 25% of administered halothane is oxidized by an isoenzyme of P450 (CYP2E1) into its principal metabolite trifluoroacetic acid (TFA), as well as lesser amounts of bromide and chloride [76]. The TFA metabolites react with tissue proteins to form trifluoroacetylated protein adducts. Clinical exposure to halothane results in 2 distinct types of hepatitis [77–79]. Type I hepatotoxicity is benign and self-limiting and occurs in 25–30% of patients receiving halothane. Symptoms include transient nausea, fever, and serum transaminase levels. “Halothane hepatitis,” or type II hepatotoxicity, has been reported in 1:5000 to 1:35,000 cases of halothane administration. This immune-mediated reaction is believed to result from the trifluoroacetylated protein adducts in the liver. Clinical symptoms of halothane hepatitis include fever, eosinophilia, and jaundice. Laboratory findings include elevated serum alanine and aspartate transferase and elevated bilirubin. Patients also have a positive IgG against TFA. Severe cases are associated with centrilobular necrosis that may lead to fulminant liver failure with a mortality rate of 50% [80]. Higher rates of halothane hepatitis are found in patients exposed to multiple halothane anesthetics in a short period of time, obese patients, patients >50 years old, female patients, and patients with a history of postanesthetic fever or jaundice.

As the most lipophilic inhaled anesthetic, methoxyflurane undergoes the most biotransformation at an estimated 70% of the drug administered [81]. Only a small amount of the drug, taken into body tissue, is exhaled and respiratory clearance from muscle and fat can extend over a period of several days. Methoxyflurane is metabolized in both the kidneys and the liver, and inorganic fluoride (F-) is produced during its metabolism in clinically significant quantities [82, 83]. Many studies have demonstrated direct links between methoxyflurane dosages, metabolism, and fluoride production. Inorganic fluoride likely causes renal injury with a nephrotoxic threshold of 50 μ(mu)mol/L [84]. Methoxyflurane, the first modern halogenated ether anesthetic, is no longer in clinical use because it is now known to produce polyuric renal insufficiency. More recent anesthetics have been cautiously studied for their renal impairment and fluoride production abilities [85].

The minimal metabolism (0.2%) of isoflurane results in extremely low rates of hepatic or renal impairment. TFA is the primary metabolite, but serum fluoride levels have not been shown to cause renal dysfunction [86].

Desflurane undergoes extremely low metabolism rates in humans (0.02%); and thus, the serum and urine fluoride levels are essentially unchanged from pre-anesthetic levels. More than the other volatile agents (desflurane > enflurane > isoflurane), desflurane is susceptible to degradation in dessicated carbon dioxide absorbancy to carbon monoxide, when water content falls below 1.4% for soda lime and 5% for baralyme. This carbon monoxide can lead to increased levels of blood carboxyhemoglobin [87–89].

Inorganic fluoride ions in plasma concentrations greater than enflurane and hexafluoroisopropanol are produced during the metabolism of sevoflurane in humans. The overall rate of sevoflurane metabolism is more than 10 times that of isoflurane (5%), clinically producing higher serum fluoride levels. Despite this, clinical studies have demonstrated no clinical nephrotoxicity with sevoflurane administration, even with peak concentrations of 50 μ(mu)mol/L. Production of fluoride ions of sevoflurane is mainly in the liver and, therefore, has minimal effect on the kidney function. The liver metabolizes 2–5% of the sevoflurane. Typical fluoride levels after 2–3 MAC hours are 20–30 μ(mu)mol/L [90]. Because of sevoflurane’s low blood:gas solubility and rapid elimination, fluoride concentrations fall quickly and renal toxicity is not clinically present. In the presence of a strong alkali, such as those in carbon dioxide absorbents, sevoflurane has been shown to degrade to compounds toxic to animals, particularly compound A (fluoromethyl-1, 1-difluro-1(trimethyl) vinyl-ether) [91–93]. Larger amounts of compound A are produced with lower gas flows, increased respiratory temperatures, high sevoflurane concentrations, anesthetics of long duration and dessicated soda lime. Amsorb® (Armstrong Ltd., Coleraine, Northern Ireland) is a newer absorbent that does not contain strong base and does not form CO or compound A in vitro. It is clinically recommended to maintain fresh gas flows greater than 2 L/min to limit possible compound A production. Despite proven nephrotoxicity in rats, no postoperative renal impairment or injury has been seen in humans. This difference may be secondary to the lower β(beta)-lyase activity in humans [94]. Degradation of sevoflurane to hydrogen fluoride in the presence of metal and environmental impurities can also occur. Hydrogen fluoride can cause respiratory mucosal burns. Degradation is inhibited through the addition of water in manufacturing and packaging in plastic containers [90]. The US Food and Drug Administration (FDA) recommends the use of sevoflurane with fresh gas flow rates at least 1 L/min for exposure up to 1 h and at least 2 L/min for exposures greater than 1 h.