Pharmacology of Inhaled Anesthetics



Fig. 10.1
Molecular structure of inhalational anesthetics




Table 10.1
Physical and chemical properties of inhaled anesthetics




















































































 
Nitrous Oxide

Halothane

Methoxyflurane

Enflurane

Isoflurane

Desflurane

Sevoflurane

Molecular weight

44

197

165

184

184

200

168

Boiling point (°C)

−89

51

105

57

48

23

59

Blood:gas coefficient @ 37 °C

0.47

2.5

12

1.9

1.4

0.45

0.65

Oil: gas coefficient @ 37 °C

1.3

197

950

99

97

19

53

Vapor pressure (mmHG @ 20 °C)

Gas

244

22.5

172

240

669

170

MAC % (30–55 year old at 1 atm)

104

0.75

0.2

1.63

1.17

6.0

2.0

Stable in soda lime

Yes

No

Yes

Yes

Yes

Yes

No


Sources: Bovill [2] and Yasuda et al. [3]




10.2.2 Halothane


Halothane is a halogenated alkane (◘ Fig. 10.1) that remains a clear liquid at room temperature. Carbon-fluoride bonds make it nonflammable and non-explosive. It is well tolerated for inhalational inductions with a notable sweet, non-pungent odor. It has a high potency and intermediate solubility, which allows for an intermediate onset and recovery from anesthesia (◘ Table 10.1). Thymol must be added to halothane which also must be stored in amber bottles to prevent spontaneous oxidative decomposition [5, 6].


10.2.3 Enflurane


Enflurane is a halogenated ether (◘ Fig. 10.1) with an ethereal odor that remains a liquid at room temperature. It has an intermediate solubility and high potency allowing for intermediate onset and recovery times from anesthesia (◘ Table 10.1). Enflurane is oxidized in the liver and can produce nephrotoxic fluoride ions [7, 8].


10.2.4 Isoflurane


Isoflurane is a fluorinated methyl ethyl ether (◘ Fig. 10.1) that is a nonflammable liquid at room temperature. Although it is an isomer of enflurane, it has different physiochemical properties and different manufacturing methods. Like enflurane and halothane, it has an intermediate solubility and high potency allowing for intermediate onset and recovery times from anesthesia (◘ Table 10.1). It has a pungent ethereal odor [8].


10.2.5 Sevoflurane


Sevoflurane is a fluorinated methyl isopropyl ether (◘ Fig. 10.1). It has a potency similar to enflurane. However, it has a significantly lower solubility in blood (◘ Table 10.1). This property allows for a rapid increase in alveolar concentration and a rapid on and offset of anesthesia. Combined with its nonpungent odor, these attributes make sevoflurane an ideal inhalational induction agent. Its vapor pressures allow for the use of a conventional vaporizer. Sevoflurane is susceptible to metabolism, with 3–5% undergoing biodegradation. Unlike other volatile agents, sevoflurane is not metabolized to acyl halide intermediates (as with halothane, enflurane, isoflurane, and desflurane), which can potentially cause hepatotoxicity or cross-sensitivity between drugs.


10.2.6 Desflurane


Desflurane is also a fluorinated methyl ethyl ether (◘ Fig. 10.1) that differs from isoflurane only by a substitution of a fluoride for the chlorine atom. The “minor change” of fluorination increases the vapor pressure, enhances molecular stability, and decreases the potency of the drug [9]. Because of its vapor pressure (◘ Table 10.1), desflurane will boil at room temperature at high altitudes. This requires a vaporizer (Tec 6, GE Healthcare, Chicago, IL) designed specifically to handle this inhalational agent. The vaporizer is heated to 39°C and pressurized to 2 atm. No fresh gas flows through the vaporizer pump; rather pure desflurane vapor joins the fresh gas flows before exiting the vaporizer [10]. Low solubility and potency allow for a rapid on and offset of anesthesia. Its lower blood-gas solubility creates precise control and the ability for more rapid recovery times from anesthesia [8]. Desflurane has a pungent odor, which limits its utility for inhalational inductions.


10.2.7 Xenon


Xenon is a noble gas found in the atmosphere; and was recognized as an anesthetic in 1951. It has a MAC value of 71% and can be combined with oxygen to deliver anesthesia. The blood:gas partition coefficient is 0.12, which results in rapid onset and recovery. Xenon depresses post-sympathetic excitatory transmission through N-methyl-D-aspartate (NMDA) receptor blocks. There are minimal cardiovascular side effects, even in the setting of severely limited myocardial reserve. Xenon affects anesthetic-induced preconditioning of the heart and brain against ischemic damage in the same way as volatile agents. Xenon may have neuroprotective action, but it may be offset by an increase in cerebral blood flow. It is a non-irritant to the airway for easy induction. Although a mild respiratory depressant, it decreases respiratory rate and increases tidal volume, in contrast to the volatile agents. Xenon has a high relative density, which causes an increase in pulmonary resistance. Caution is advised in patients who have severe chronic obstructive pulmonary disease (COPD) or in premature infants. It is not metabolized in the liver or kidneys and it does not trigger malignant hyperpyrexia. Xenon is also a potent intraoperative analgesic, attenuating responses to surgical stimuli to a greater extent than sevoflurane.

Xenon anesthesia provides more stable intraoperative blood pressure, lower heart rate, and faster recovery from anesthesia than volatile agents. However, it is associated with higher postoperative nausea and vomiting. The main limitations for wider use are lack of studies, need for hyperbaric conditions, impracticality in surgery, and inefficiency of conventional anesthesia equipment. These limitations make xenon cost prohibitive.



10.3 Mechanism of Action


The exact mechanism of action for volatile anesthetics is complex and still unknown. Currently, the mechanics of inhaled volatile anesthetics is believed to occur through a combined effect by prolongation of inhibitory effects (GABAA and glycine receptors) and inhibition of excitatory effects (nicotinic acetylcholine and glutamate receptors). Typical anesthetic agents produce anesthesia, amnesia, analgesia, and immobilization.

Initially, Meyer and Overton proposed a lipid theory and believed the lipid membrane was the primary site of anesthetic action by correlating inhaled anesthetics potency with their solubility in lipids. They observed a strong correlation between the potency of inhalational anesthetics and their solubility in oil, theorizing they had a nonspecific lipid membrane mechanism of action [11]. Later, researchers demonstrated that proteins may also be the site of action for inhaled anesthetics [12, 13]. Additional research on the mechanism of action for inhaled anesthetics explained ligand gated ion channels proteins are mostly likely the targets of inhaled anesthetics [14].

Electrical activity in human cells is generated through influx and efflux of ions (mostly Na+, Ca2+, Cl− and K+) through a variety of ion channels. Some receptor-mediated ion channels are targets of inhaled anesthetics at clinical anesthetic concentrations, such as serotonin receptors, GABAA receptors, glycine receptors, and NMDA or AMPA (α[alpha]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors (glutamate neurotransmitter) [1518].

GABAA-related anesthetic action is common for all volatile anesthetics due to its abundancy in the brain. Normal physiologic function of GABAA and glycine receptors (Cl− ion channels) is to inhibit the excitation of postsynaptic neurons. At effective clinical concentrations, volatile anesthetics enhance the GABAA receptor-mediated activity by increasing its sensitivity to gamma-aminobutyric acid (GABA) and the sensitized receptors prolong the inhibition of excitatory neurons. Gaseous anesthetics, such as nitrous oxide, have a minimal effect on GABA-related mechanisms [1923]. Normally K+ channels maintain a polarized state of neurons and are targeted sites for isoflurane. Isoflurane activates the K+ channel and leads to a decrease of neuronal excitation [24].

Inhibition of excitatory neurotransmission can be achieved either by inhibition of a neurotransmitter release from presynaptic nerve endings or a postsynaptic receptor blockade. Halothane and isoflurane at clinical concentrations inhibit the NMDA receptor (Na+ ion channel) associated excitation by postsynaptic blockades or decreasing presynaptic glutamate release. The volatile anesthetics also can inhibit the presynaptic release of an excitatory neurotransmitter by blocking presynaptic voltage-gated Na+ channels at clinical concentrations [25]. Excitatory postsynaptic nicotinic acetylcholine receptors and NMDA-sensitive glutamate channels are inhibited by gaseous anesthetics to inhibit the excitation of excitatory neurons [26].

The mechanism of action for immobilization and amnesia occurs at distinct sites. Studies have proven that immobilization to surgical stimulus can be achieved at the spinal cord level without brain involvement. Immobility to surgical stimuli occurs by inhibiting ascending transmission of pain stimuli to the brain from the spinal cord. At the spinal cord level, volatile anesthetics prolong the inhibitory effects of glycine receptors and inhibit the postsynaptic excitatory effects of NMDA and AMPA receptors [2729]. Amnesia can be induced without immobilization at lower clinical concentrations. Specific loci in the brain are responsible for this amnesic effect. Inhaled anesthetics act on nicotinic acetylcholine receptors in the brain and impair the memory process leading to amnesia [3033].

GABA receptors function differently between the growing brain in children and the brain in adults. In the growing brain, GABA receptors function as stimulators and in the adult brain they act as inhibitors; therefore, a neurotoxic effect from anesthetics can be seen in the growing brain. In contrast to its inhibitory action in the adult brain, GABA receptors act as an excitatory neurotransmitter in the growing brain of the child. These GABA receptors generate action potentials directly opening voltage-dependent calcium channels and increase the calcium concentration in the brain. This increase in intracellular calcium can lead to apoptosis. In addition, the mitochondrion appears to be the mediator between anesthesia-induced increased calcium levels and cell apoptosis, leading to mitochondrial damage. Every year, millions of children are treated with anesthetic agents. There is evidence that suggests that exposure to anesthetics may be neurotoxic to the developing brain and lead to long-term neurological effects.

Lithium protects against anesthesia-induced developmental neuroapoptosis along with melatonin. Coadministration of hydrogen gas acts as part of the carrier gas mixture and may suppress neuronal apoptosis. Therefore, there may not be a safe anesthetic, but only safe anesthetic concentrations and exposure durations.


10.4 Systemic Effects of Inhaled Anesthetics


Inhaled anesthetics have several effects on systemic organs. Anesthetics effects on the central nervous system, cardiovascular system, pulmonary function, neuromuscular junction, renal and liver function, and hematology and immune systems have been described in sub-sections and are summarized in ◘ Table 10.2.


Table 10.2
Systemic effects of inhaled anesthetics











































































 
Nitrous oxide

Halothane

Methoxyflurane

Enflurane

Isoflurane

Desflurane

Sevoflurane

Cardiovascular

 HR

 SVR

 CO

 Myocardial contractility




a























b









Respiratory

 TV

 RR

 PaCO2

 PVR

 Airway resistance










↓↓




















Irritant






Cerebral

 Blood flow

 ICP

 CMRO2

 Seizures





↑↑


a





















↓/

Nondepolarizing blockade








Renal

 Blood flow

 GFR

 Urine

















Unknown

Unknown


Unknown

Unknown

Hepatic

 Blood flow









Abbreviations: MAP mean arterial pressure, HR heart rate, SVR systemic vascular resistance, CO cardiac output, TV tidal volume, RR respiratory rate, PaCO 2 partial pressure of carbon dioxide, PVR pulmonary vascular resistance, ICP intracranial pressure, CMRO 2 cerebral metabolic rate of oxygen, GFR glomerular filtration rate

aMinimal

bWith rapid change in inhaled concentration


10.4.1 Effects on Central Nervous System


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.


10.4.2 Effects on Cardiovascular System


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.


10.4.3 Effects on Respiration


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 [5456].


10.4.4 Effects on Neuromuscular Junction


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 [5961]. 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].


10.4.5 Effects on Renal Function


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).


10.4.6 Effects on Hepatic Function


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).


10.4.7 Effects on Hematologic and Immune Systems


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].


10.5 Biotransformation and Toxicity of Inhaled Anesthetics


Inhalational anesthetics undergo biotransformation to many different degrees and locations depending primarily on their lipophilicity and clinical stability. The major organs involved in biotransformation, the liver and kidneys, are exposed to the highest metabolite concentrations, and therefore, are the primary sites of toxicity (see ◘ Table 10.3).


Table 10.3
Biotransformation and toxicity of inhaled anesthetics











































































 
Nitrous oxide

Halothane

Methoxyflurane

Enflurane

Isoflurane

Desflurane

Sevoflurane

Tissue metabolism (%)

0.004

25

70

2.5

0.2

0.02

5

Oxidating enzymes

Anaerobic bacteria in gastrointestinal tract

CYP2E1, CYP2A6

CYP2E1, CYP1A2, CYP2C9/10, CYP2D6

CYP2E1

CYP2E1

CYP2E1

CYP2E1

Principal metabolite

Inactivation of methionine synthetase

TFA, bromine, chloride

Oxalic acid, free fluoride

TFA, small fluoride level rise

TFA, small fluoride level rise

TFA (fluoride levels unchanged from pre-anesthetic levels)

Fluoride

Trifluoroacetylated hepatocellular protein degree of modification

None

++++++

None

++

+

+

None

CO2 stability

Yes

CO from desiccated carbon dioxide absorbent

CO from desiccated carbon dioxide absorbent

CO from desiccated carbon dioxide absorbent

CO from desiccated carbon dioxide absorbent

CO from desiccated carbon dioxide absorbent

Compound A from desiccated carbon dioxide absorbent, heat production

Possibly toxicities

DNA synthesis,

Bone marrow suppression,

Vitamin B12 deficiency

Hepatic (1:20,000 fulminant hepatitis)

Renal, hepatic

Hepatic (1:300,000 fulminant hepatitis)

Hepatic

(rare fulminant hepatitis)

Hepatic

(rare fulminant hepatitis)

Hepatic

(few case reports fulminant hepatitis)


Sources: Yasuda et al. [72, 73]

Abbreviations: TFA trifluoroacetic acid, CO 2 carbon dioxide, CO carbon monoxide


10.5.1 Nitrous Oxide


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.


10.5.2 Halothane


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 [7779]. 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.


10.5.3 Methoxyflurane


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].


10.5.4 Isoflurane


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].


10.5.5 Desflurane


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 [8789].


10.5.6 Sevoflurane


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) [9193]. 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.

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