Chapter 19: General Anesthetics and Therapeutic Gases

Historical Perspectives. Crawford Long, a physician in rural Georgia, first used ether anesthesia in 1842. William T.G. Morton, a Boston dentist and medical student, performed the first public demonstration of general anesthesia using diethyl ether in 1846 when Gilbert Abbott underwent surgical excision of a neck tumor at the Massachusetts General Hospital in the operating room now known as "the ether dome." The era of modern anesthesia and a revolution in the medical care of the surgical patient had begun.

Ether was the ideal "first" anesthetic. A liquid at room temperature, it readily vaporized, and was easy to administer. Ether, unlike nitrous oxide, was potent and could produce anesthesia without diluting room air to hypoxic levels. It was relatively nontoxic and produced limited respiratory or circulatory compromise. Ether maintained a role in clinical anesthesia until the 1950s.

Horace Wells, a dentist, noted at a stage show that an injured participant under the influence of nitrous oxide felt no pain. The next day Wells had a tooth extracted while breathing nitrous oxide. An attempt in 1845 by Wells to demonstrate his discovery at the Massachusetts General Hospital in Boston ended in failure when the patient cried out and nitrous oxide fell into disuse. In 1868, Edmond Andrews, a Chicago surgeon, described the co-administration of nitrous oxide and oxygen, a practice that continues to this day.

The Scottish obstetrician James Simpson introduced chloroform in 1847. Chloroform had a more pleasant odor than ether and was nonflammable. It was, however, a hepatotoxin and a severe cardiovascular depressant, which limited its ultimate utility. Despite incidents of intraoperative and postoperative deaths associated with chloroform, its use continued, especially in Great Britain, for nearly 100 years.

The anesthetic properties of cyclopropane were discovered accidentally in 1929 by chemists analyzing impurities in propylene. Cyclopropane is a pleasant-smelling gas that produces rapid anesthetic induction and recovery, and was widely used as a general anesthetic for over 30 years. However, cyclopropane is explosive when mixed with air, oxygen, or nitrous oxide. In 1956 came the introduction of halothane, a nonflammable volatile halogenated alkane that quickly became the dominant anesthetic.

In 1935, Lundy demonstrated the clinical usefulness of thiopental, a rapidly acting agent that could be administered intravenously; however, anesthetic doses of thiopental resulted in serious depression of the circulatory, respiratory, and nervous systems. The further development of intravenous anesthetic agents such as propofol, combined with other intravenous anesthetic adjuncts such as midazolam, dexmedetomidine, and remifentanil, has led to the use of total intravenous anesthesia (TIVA) as a clinically useful tool in modern anesthetic practice.

Even small drops in body temperatures may lead to an increase in perioperative morbidity, including cardiac complications, wound infections, and impaired coagulation. Prevention of hypothermia has emerged as a major goal of anesthetic care. Modalities to maintain normothermia include using warm intravenous fluids, heat exchangers in the anesthesia circuit, forced-warm-air covers, and new technology involving water-filled garments with microprocessor feedback control to a core temperature set point.

Other Emergence and Postoperative Phenomena. Hypertension and tachycardia are common as the sympathetic nervous system regains its tone and is enhanced by pain. Myocardial ischemia can appear or markedly worsen during emergence in patients with coronary artery disease. Emergence excitement occurs in 5-30% of patients and is characterized by tachycardia, restlessness, crying, moaning, and thrashing. A variety of neurologic signs, including delirium, spasticity, hyperreflexia, and Babinski sign, are often manifest in the patient emerging from anesthesia. Postanesthesia shivering occurs frequently because of core hypothermia. A small dose of meperidine (12.5 mg) lowers the shivering trigger temperature and effectively stops the activity. The incidence of all of these emergence phenomena is greatly reduced when opioids and α₂ agonists (dexmedetomidine) are employed as part of the intraoperative regimen.

Airway obstruction may occur during the postoperative period because residual anesthetic effects continue to partially obtund consciousness and reflexes (especially in patients who normally snore or who have sleep apnea). Strong inspiratory efforts against a closed glottis can lead to negative-pressure pulmonary edema. Pulmonary function is reduced postoperatively following all types of anesthesia and surgery, and hypoxemia may occur. Hypertension can be prodigious, often requiring aggressive treatment.

Pain control can be complicated in the immediate postoperative period. The respiratory suppression associated with opioids can be problematic among postoperative patients who still have a substantial residual anesthetic effect. Patients can alternate between states of excruciating pain to somnolence with airway obstruction, all in a matter of moments. The nonsteroidal anti-inflammatory agent ketorolac (30-60 mg intravenously) frequently is effective, and the development of injectable cyclooxygenase-2 inhibitors (Chapter 34) holds promise for analgesia without respiratory depression. In addition, regional anesthetic techniques are an important part of a perioperative multimodal approach that employs local anesthetic wound infiltration; epidural, spinal, and plexus blocks; and nonsteroidal anti-inflammatory drugs, opioids, α₂ adrenergic receptor agonists, and NMDA-receptor antagonists. Patient-controlled administration of intravenous and epidural analgesics makes use of small, computerized pumps activated on demand but programmed with safety limits to prevent overdose. The agents used are opioids (frequently morphine) by the intravenous route, and an opioid, local anesthetic, or both by the epidural route. These techniques have revolutionized postoperative pain management, can be continued for hours or days, and promote ambulation and improved bowel function until oral pain medications are initiated.

An alternative way of defining the anesthetic state is to consider it as a collection of "component" changes in behavior or perception. The components of the anesthetic state include:

• amnesia

• immobility in response to noxious stimulation

• attenuation of autonomic responses to noxious stimulation

• analgesia

• unconsciousness

It is important to remember that general anesthesia is useful only insofar as it facilitates the performance of surgery or other noxious procedures. The performance of surgery usually requires an immobilized patient who does not have an excessive autonomic response to surgery (blood pressure and heart rate) and who has amnesia for the procedure. Indeed, if an anesthetic produces profound amnesia, it can be difficult in principle to determine if it also produces either analgesia or unconsciousness.

The strengths of MAC as a measurement are that:

• alveolar concentrations can be monitored continuously by measuring end-tidal anesthetic concentration using infrared spectroscopy or mass spectrometry

• it provides a direct correlate of the free concentration of the anesthetic at its site(s) of action in the CNS

• it is a simple-to-measure end point that reflects an important clinical goal

End points other than immobilization also can be used to measure anesthetic potency. For example, the ability to respond to verbal commands (MAC_awake) and the ability to form memories also have been correlated with alveolar anesthetic concentration. Interestingly, verbal response and memory formation both are suppressed at a fraction of MAC. Furthermore, the ratio of the anesthetic concentrations required to produce amnesia and immobility vary significantly among different inhalational anesthetic agents (nitrous oxide versus isoflurane) (Table 19–1), suggesting that anesthetic agents may produce these behavioral end points through different cellular and molecular mechanisms. The potency of intravenous anesthetic agents is somewhat more difficult to measure; we lack methods to measure blood or plasma anesthetic concentration continuously, and we cannot determine the free concentration of the drug at its site of action. Generally, the potency of intravenous agents is defined as the free plasma concentration (at equilibrium) that produces loss of response to surgical incision (or other end points) in 50% of subjects.

A substantial body of work indicates that an anesthetic agent produces different components of the anesthetic state by means of actions at different anatomic loci in the nervous system and may produce these component effects through different cellular and molecular actions. Moreover, increasing evidence supports the hypothesis that different anesthetic agents produce specific components of anesthesia by actions at different molecular targets. Given these insights, the unitary theory of anesthesia has been largely discarded.

The inhalational anesthetics inhibit excitatory synapses and enhance inhibitory synapses in various preparations. These effects likely are produced by both pre- and postsynaptic actions of the inhalational anesthetics. The inhalational anesthetic isoflurane clearly can inhibit neurotransmitter release, while the small reduction in presynaptic action potential amplitude produced by isoflurane (3% reduction at MAC concentration) substantially inhibits neurotransmitter release (Wu et al., 2004b). The latter effect occurs because the reduction in the presynaptic action potential is amplified into a much larger reduction in presynaptic Ca²⁺ influx, which in turn is amplified into an even greater reduction in transmitter release. This effect may account for the majority of the reduction in transmitter release by inhalational anesthetics at some excitatory synapses. Inhalational anesthetics also can act postsynaptically, altering the response to released neurotransmitter. These actions are thought to be due to specific interactions of anesthetic agents with neurotransmitter receptors.

The intravenous anesthetics produce a narrower range of physiological effects. Their predominant actions are at the synapse, where they have profound and relatively specific effects on the postsynaptic response to released neurotransmitter. Most of the intravenous agents act predominantly by enhancing inhibitory neurotransmission, whereas ketamine predominantly inhibits excitatory neurotransmission at glutamatergic synapses.

Anatomic Sites of Anesthetic Action. In principle, general anesthetics could interrupt nervous system function at myriad levels, including peripheral sensory neurons, the spinal cord, the brainstem, and the cerebral cortex. Delineation of the precise anatomic sites of action is difficult because many anesthetics diffusely inhibit electrical activity in the CNS. For example, isoflurane at 2 MAC can cause electrical silence in the brain. However, in vitro studies show that specific cortical pathways exhibit markedly different sensitivities to both inhalational and intravenous anesthetics (MacIver and Roth, 1988), suggesting that anesthetics produce specific components of the anesthetic state through actions at specific sites in the CNS. Consistent with this possibility, inhalational anesthetics produce immobilization in response to a surgical incision (the end point used in determining MAC) by action on the spinal cord (Rampil, 1994). Given that amnesia or unconsciousness cannot result from anesthetic actions in the spinal cord, one concludes that different components of anesthesia are produced at different sites in the CNS. Indeed, recent studies show that the sedative effects of pentobarbital and propofol (GABA-ergic anesthetics) are mediated by GABA_A receptors in the tuberomammillary nucleus (Nelson et al., 2002), and the sedative effects of the intravenous anesthetic dexmedetomidine (an α₂ adrenergic receptor agonist) are produced by actions in the locus ceruleus (Mizobe et al., 1996). These findings suggest that the sedative actions of some anesthetics share the neuronal pathways involved in endogenous sleep.

Functional imaging studies of the awake and anesthetized brain have revealed that most anesthetics cause, with some exceptions, a global reduction in cerebral metabolic rate (CMR) and in cerebral blood flow (CBF); agent-specific effects on CMR and CBF will be described later in the chapter. A consistent feature of general anesthesia is a suppression of metabolism in the thalamus (Alkire et al., 2008). This is not surprising given the demonstration that inhalational anesthetics depress the excitability of thalamic neurons. The thalamus serves as a major relay by which sensory input from the periphery ascends to the cortex. Suppression of thalamic activity might isolate the cortex from ascending input. Thus, the thalamus may serve as a switch between the awake and anesthetized states (Franks, 2008). In addition, general anesthesia results in the suppression of activity in specific regions of the cortex, including the mesial parietal cortex, posterior cingulate cortex, precuneus, and inferior parietal cortex. Of interest is the recent observation that electrical activity in the cortex is suppressed before that in the thalamus. This suggests that it is cortical suppression that, via the corticothalamic fibers, leads to thalamic suppression, thereby making the cortex the primary target of anesthetics (Alkire et al., 2008). However, the temporal relationships between thalamus and cortical activity (and deactivation) under general anesthesia need further clarification before the relative importance of each site to anesthetic induced loss of consciousness is known (Franks, 2008).

The similarities between natural sleep and the anesthetized state suggest that anesthetics might also modulate endogenous sleep regulating pathways, which include ventrolateral preoptic (VLPO) and tuberomammillary nuclei. VLPO projects inhibitory GABA-ergic fibers to ascending arousal nuclei, which in turn project to the cortex, forebrain, and subcortical areas; release of histamine, 5-HT, orexin, NE, and ACh mediate wakefulness (Sanders and Maze, 2007). Intravenous and inhalational agents with activity at GABA_A receptors can increase the inhibitory effects of VLPO, thereby suppressing consciousness. Dexmedetomidine, an α₂ agonist, also increases VLPO-mediated inhibition by suppressing the inhibitory effect of locus ceruleus neurons on VLPO (Sanders et al., 2007). Finally, both intravenous and inhalational anesthetics depress hippocampal neurotransmission (Kendig et al., 1991), a probable locus for their amnestic effects.

The typical induction dose (3-4 mg/kg) of thiopental produces unconsciousness in 10-30 seconds with a peak effect in 1 minute and duration of anesthesia of 5-8 minutes. Neonates and infants usually require a higher induction dose (5-8 mg/kg), whereas elderly and pregnant patients require less (1-3 mg/kg) (Gin et al., 1997). Dosage calculation based on lean body mass reduces individual variation in dosage requirements. Doses can be reduced by 10-50% after premedication with benzodiazepines, opiates, or α₂ adrenergic agonists, because of their additive hypnotic effect (Nishina et al., 1994; Short et al., 1991; Wang et al., 1996). Thiamylal is approximately equipotent with and in all aspects similar to thiopental. Methohexital (brevital) is 3-fold more potent but otherwise similar to thiopental in onset and duration of action. Thiopental and thiamylal produce little to no pain on injection; methohexital elicits mild pain. Veno-irritation can be reduced by injection into larger non-hand veins and by prior intravenous injection of lidocaine (0.5-1 mg/ kg). For induction of pediatric patients without IV access, any of the three drugs can be given off-label per rectum at ~ 10-fold the IV dose.

Pharmacokinetics and Metabolism. Pharmacokinetic parameters for parenteral anesthetics are given in Table 19–2. As already discussed, the principal mechanism limiting anesthetic duration after single doses is redistribution of these hydrophobic drugs from the brain to other tissues. However, after multiple doses or infusions, the duration of action of the barbiturates varies considerably depending on their clearances.

Methohexital differs from the other two intravenous barbiturates in its much more rapid clearance; thus, it accumulates less during prolonged infusions. Because of their slow elimination and large volumes of distribution, prolonged infusions or very large doses of thiopental and thiamylal can produce unconsciousness lasting several days. Even single induction doses of thiopental and to a lesser degree methohexital can produce psychomotor impairment lasting up to 8 hours (Beskow et al., 1995). Propofol has largely supplanted methohexital for outpatient procedures that require a rapid return to an alert state (see "Propofol" later in the chapter).

All three barbiturates are primarily eliminated by hepatic metabolism and renal excretion of inactive metabolites; a small fraction of thiopental undergoes desulfuration to the longer-acting hypnotic pentobarbital. In patients with cirrhosis, a larger volume of distribution combined with a reduction in clearance can result in prolongation of the clinical action of barbiturates. These drugs are highly protein bound (Table 19–2). Hepatic disease or other conditions that reduce serum protein concentration will increase the initial free concentration and hypnotic effect of an induction dose; this is noted in patients with advanced cirrhosis in whom the protein synthesis capacity of the liver is greatly compromised.

Side Effects

Nervous System. Barbiturates suppress the EEG and can produce burst suppression of the EEG. They reduce the cerebral metabolic rate, as measured by cerebral O₂ consumption (CMRO₂), in a dose-dependent manner. Induction doses of thiopental reduce CMRO₂ by 25-30%, with a maximal decrease of 55% occurring at two to five times that dose (Stullken et al., 1977). As a consequence of the decrease in CMRO₂, cerebral blood flow and intracranial pressure are similarly reduced.

Because it markedly lowers cerebral metabolism, thiopental has been used as a protectant against cerebral ischemia; however, the large doses required and the subsequent prolonged sedation have precluded its use clinically for this purpose. Thiopental also reduces intraocular pressure. Presumably in part due to their CNS depressant activity, barbiturates are effective anticonvulsants. Thiopental in particular is a proven medication in the treatment of status epilepticus. Methohexital can increase ictal activity, and seizures have been described in patients who received doses sufficient to produce burst suppression of the EEG (Todd et al., 1984). This property makes methohexital a good choice for anesthesia in patients who undergo electroconvulsive therapy.

Cardiovascular System. The anesthetic barbiturates produce dose-dependent decreases in blood pressure. The effect is due primarily to vasodilation, particularly venodilation, and to a lesser degree to a direct decrease in cardiac contractility. Typically, heart rate increases as a compensatory response to a lower blood pressure, although barbiturates also blunt the baroreceptor reflex. Thiopental maintains the ratio of myocardial O₂ supply to demand in patients with coronary artery disease within a normal blood pressure range.

Hypotension can be severe in patients with an impaired ability to compensate for venodilation such as those with hypovolemia, cardiomyopathy, valvular heart disease, coronary artery disease, cardiac tamponade, or β adrenergic blockade. None of the barbiturates has been shown to be arrhythmogenic.

Respiratory System. Barbiturates are respiratory depressants. Induction doses of thiopental decrease minute ventilation and tidal volume, with a smaller and inconsistent decrease in respiratory rate (Grounds et al., 1987). Reflex responses to hypercarbia and hypoxia are diminished by anesthetic barbiturates (Hirshman et al., 1975); and at higher doses or in the presence of other respiratory depressants such as opiates, apnea can result. With the exception of uncommon anaphylactoid reactions, these drugs have little effect on bronchomotor tone (Kingston and Hirshman, 1984). Compared to propofol, barbiturates produce a higher incidence of wheezing in asthmatics, attributed to histamine release from mast cells, during induction of anesthesia (Pizov et al., 1995).

Other Side Effects. Short-term administration of barbiturates has no clinically significant effect on the hepatic, renal, or endocrine systems. A single induction dose of thiopental does not alter tone of the gravid uterus, but may produce mild transient depression of newborn activity. True allergies to barbiturates are rare; however, direct drug-induced histamine release is occasionally seen (Sprung et al., 1997).

Barbiturates can induce fatal attacks of porphyria in patients with acute intermittent or variegate porphyria and are contraindicated in such patients. The abnormal synthesis of protoporphyrin (important in hemoglobin production) results in excess porphobilinogen. Barbiturates induce aminolevulinic acid synthase, an enzyme responsible for phophobilinogen synthesis. This leads to excessive porphobilinogen levels and can precipitate acute porphyric crises that are manifested by severe abdominal pain, nausea, vomiting, psychiatric disorders, and neurologic abnormalities.

Methohexital can produce pain on injection to a greater degree than thiopental. Inadvertent intra-arterial injection of thiobarbiturates can induce a severe inflammatory and potentially necrotic reaction that can threaten limb survival. Methohexital and to a lesser degree other barbiturates can produce excitatory symptoms on induction such as cough, hiccup, muscle tremors, twitching, and hypertonus.

Unlike inhalational anesthetics and succinylcholine, barbiturates and all other parenteral anesthetics apparently do not trigger malignant hyperthermia (Rosenberg et al., 1997).

Chemistry and Formulations. The active ingredient in propofol, 2,6-diisopropylphenol, is an oil at room temperature and insoluble in aqueous solutions. Propofol is formulated for IV administration as a 1% (10 mg/mL) emulsion in 10% soybean oil, 2.25% glycerol, and 1.2% purified egg phosphatide. In the U.S., disodium EDTA (0.05 mg/mL) or sodium metabisulfite (0.25 mg/mL) is added to inhibit bacterial growth. Nevertheless, significant bacterial contamination of open containers has been associated with serious patient infections; propofol should be administered within 4 hours of its removal from sterile packaging; unused drug should be discarded.

The lipid emulsion formulation of propofol is associated with significant pain on injection and hyperlipidemia. A new aqueous formulation of propofol, fospropofol, which is not associated with these adverse effects, has recently been approved for use for sedation in patients undergoing diagnostic procedures. Fospropofol, which itself is inactive, is a phosphate ester prodrug of propofol that is hydrolyzed by endothelial alkaline phosphatases to yield propofol, phosphate, and formaldehyde. The formaldehyde is rapidly converted to formic acid, which then is metabolized by tetrahydrofolate dehydrogenase to CO₂ and water (Fechner et al., 2008).

Dosage and Clinical Use. The induction dose of propofol (diprivan, others) in a healthy adult is 2-2.5 mg/kg and it has an onset and duration of anesthesia similar to thiopental (Table 19–2). As with barbiturates, dosages should be reduced in the elderly and in the presence of other sedatives and increased in young children. Because of its reasonably short elimination t_1/2, propofol often is used for maintenance of anesthesia as well as for induction. For short procedures, small boluses (10-50% of the induction dose) every 5 minutes or as needed are effective. An infusion of propofol produces a more stable drug level (100-300 μg/kg per minute) and is better suited for longer-term anesthetic maintenance. Infusion rates should be tailored to patient response and the levels of other hypnotics. Sedating doses of propofol are 20-50% of those required for general anesthesia. However, even at these lower doses, caregivers should be vigilant and prepared for all of the side effects of propofol discussed below, particularly airway obstruction and apnea.

Fospropofol produces dose-dependent sedation and can be administered in otherwise healthy individuals at 2-8 mg/kg intravenously (delivered either as a bolus or by a short infusion over 5-10 min). The optimum dose for sedation is ~6.5 mg/kg. This results in a loss of consciousness in ~10 minutes. The duration of the sedative effect is ~45 min.

Pharmacokinetics and Metabolism. The pharmacokinetics of propofol are governed by the same principles that apply to barbiturates. Onset and duration of anesthesia after a single bolus are similar to thiopental. Recovery after multiple doses or continuous infusion has been shown to be much faster after propofol than after thiopental or even methohexital. Propofol has a context-sensitive t_1/2 of ~10 min with an infusion lasting 3 hours and ~40 minutes for infusions lasting up to 8 hours (Figure 19–3). Propofol's shorter duration of action after infusion can be explained by its very high clearance, coupled with the slow diffusion of drug from the peripheral to the central compartment (Figure 19–3). The rapid clearance of propofol explains the more rapid emergence from anesthesia in comparison to barbiturates; this facilitates a more rapid discharge from the recovery room.

Propofol is metabolized in the liver by conjugation to sulfate and glucunoride to less active metabolites that are renally excreted; however, its clearance exceeds hepatic blood flow, and anhepatic metabolism, particularly in the lungs and kidneys, has been demonstrated (Veroli et al., 1992). In patients with moderate cirrhosis, the volume of distribution of propofol is increased significantly. However, terminal elimination t_1/2 and emergence from propofol anesthesia is not substantially different from healthy patients (Servin et al., 1990). Propofol is highly protein bound, and its pharmacokinetics, like those of the barbiturates, may be affected by conditions that alter serum protein levels.

Clearance of propofol is reduced in the elderly; given that the central volume of distribution of propofol is also reduced, the required dose of propofol for both induction and maintenance of anesthesia may be decreased. In neonates, propofol clearance is also reduced (Allegaert et al., 2007). Infusion of propofol in neonates therefore has the potential for substantial accumulation and a consequent delay in emergence from anesthesia or sedation. By contrast, in young children, a more rapid clearance in combination with a larger central volume may necessitate larger doses of propofol for induction and maintenance of anesthesia (Kataria et al., 1994).

The t_1/2 for hydrolysis of fospropofol is 8 min. Fospropofol has a small volume of distribution and a terminal t_1/2 ~46 min. The currently published pharmacokinetic data on fospropofol were derived using an analytical method that has now been shown to be inaccurate; correct pharmacokinetic data are not yet available (Fechner et al., 2008).

Pharmacology and Side Effects

Nervous System. The sedation and hypnotic actions of propofol are mediated by its action on GABA_A receptors; agonism at these receptors results in an increased chloride conduction and hyperpolarization of neurons. Propofol suppresses the EEG, and in sufficient doses, can produce burst suppression of the EEG. Propofol decreases CMRO₂, cerebral blood flow, and intracranial and intraocular pressures by about the same amount as thiopental. Like thiopental, propofol has been used in patients at risk for cerebral ischemia; however, no human outcome studies have been performed to determine its efficacy as a neuroprotectant. Excitatory phenomena, such as choreiform movements and opisthotonus, have been observed after propofol injection with the same frequency as that seen with thiopental but less than with methohexital. These movements, which are transient, are not associated with seizure activity. Results from studies on the anticonvulsant effects of propofol have been mixed; some data even suggest it has proconvulsant activity when combined with other drugs. However, propofol has been shown to suppress seizure activity in experimental models and has been used for the treatment of status epilepticus in humans (Parviainen et al., 2007).

Cardiovascular System. Propofol produces a dose-dependent decrease in blood pressure that is significantly greater than that produced by thiopental. The fall in blood pressure can be explained by both vasodilation and possibly mild depression of myocardial contractility. Propofol appears to blunt the baroreceptor reflex and reduce sympathetic nerve activity (Ebert and Muzi, 1994). As with thiopental, propofol should be used with caution in patients at risk for or intolerant of decreases in blood pressure; these include patients with significant blood loss and hypovolemia.

Respiratory System. At equipotent doses, propofol produces a slightly greater degree of respiratory depression than thiopental (Blouin et al., 1991). Patients given propofol should be monitored to ensure adequate oxygenation and ventilation. Propofol appears to be less likely than barbiturates to provoke bronchospasm and may be the induction agent of choice in asthmatics (Pizov et al., 1995). The bronchodilator properties of propofol may be attenuated by the metabisulfite preservative in some propofol formulations (Brown et al., 2001).

Other Side Effects. Propofol has no clinically significant effects on hepatic, renal, or endocrine organ systems. Unlike thiopental, propofol does not have an anti-analgesic effect. It has a significant anti-emetic action. Propofol elicits pain on injection that can be reduced with lidocaine and the use of larger arm and antecubital veins. Propofol provokes anaphylactoid reactions at about the same low frequency as thiopental; the histamine release (in the absence of anaphylactic or anaphylactoid reactions) that occurs with thiopental administration is greater than that with propofol. Although propofol does cross placental membranes, it is considered safe for use in pregnant women; like thiopental, propofol only transiently depresses activity in the newborn (Abboud et al., 1995). Propofol does not trigger malignant hyperthermia.

A rare but potentially fatal complication, termed propofol infusion syndrome (PRIS), has been described primarily in prolonged, higher-dose infusions of propofol in young or head-injured patients. The syndrome is characterized by metabolic acidosis, hyperlipidemia, rhabdomyolysis, and an enlarged liver. While the precise mechanisms by which PRIS occurs are not clear, alterations in mitochondrial metabolism and electron transport chain function have been described (Kam and Cardone, 2007).

The side-effect profile of fospropofol is similar to that of propofol. Fospropofol's slower onset of sedation (due to the need for hydrolysis of the prodrug) results in a lower incidence of hypotension, respiratory depression, apnea, and loss of airway patency. Nonetheless, unintended deep levels of sedation can occur with fospropofol, and the drug should therefore be used only by individuals who can maintain an adequate airway and support cardiorespiratory function.

Whether fospropofol can also cause PRIS is not currently known (Fechner et al., 2008). A metabolic byproduct of fospropofol is formic acid. This is degraded to CO₂ and water by tetrahydrofolate dehydrogenase, an enzyme that requires folate as a co-factor. In patients who have a folate deficiency, there is a theoretical risk of formic acid accumulation; to date, such an adverse event has not been reported.

Nervous System. Etomidate produces hypnosis and has no analgesic effects. The effects of etomidate on cerebral blood flow, metabolism, and intracranial and intraocular pressures are similar to those of thiopental (without dropping mean arterial blood pressure) (Modica and Tempelhoff, 1992). Etomidate has been used as a protectant against cerebral ischemia; however, animal studies have failed to show a consistent beneficial effect (Drummond et al., 1995), and no controlled human trials have been performed. Etomidate produces increased EEG activity in epileptogenic foci and has been associated with seizures (Ebrahim et al., 1986).

Cardiovascular System. Cardiovascular stability after induction is a major advantage of etomidate over either barbiturates or propofol. Induction doses of etomidate typically produce a small increase in heart rate and little or no decrease in blood pressure or cardiac output Etomidate has little effect on coronary perfusion pressure while reducing myocardial O₂ consumption (Kettler et al., 1974). Thus, of all induction agents, etomidate is best suited to maintain cardiovascular stability in patients with coronary artery disease, cardiomyopathy, cerebral vascular disease, or hypovolemia.

Respiratory and Other Side Effects. The degree of respiratory depression due to etomidate appears to be less than that due to thiopental. Like methohexital, etomidate may induce hiccups but does not significantly stimulate histamine release. Despite minimal cardiac and respiratory effects, etomidate does have two major drawbacks. Etomidate has been associated with nausea and vomiting. The drug also inhibits adrenal biosynthetic enzymes required for the production of cortisol and some other steroids. Single induction doses of etomidate may mildly and transiently reduce cortisol levels but no significant differences in outcome after short-term administration have been found, even for variables specifically known to be associated with adrenocortical suppression (Wagner et al., 1984). Thus, while etomidate is not recommended for long-term infusion, it appears safe for anesthetic induction and has some unique advantages in patients prone to hemodynamic instability. A rapidly metabolized and ultra-short-acting analog, methoxycarbonyl-etomidate, has been developed that retains the favorable pharmacological properties of etomidate but does not produce adrenocortical suppression after bolus dosing (Cotton and Claing, 2009).

Ketamine is supplied as a mixture of the R+ and S- isomers even though the S- isomer is more potent with fewer side effects. Although more lipophilic than thiopental, ketamine is water soluble and available as 10-, 50-, and 100-mg/mL solutions in sodium chloride plus the preservative benzethonium chloride.

Dosage and Clinical Use. Ketamine (ketalar, others) has unique properties that make it useful for anesthetizing patients at risk for hypotension and bronchospasm and for certain pediatric procedures. However, significant side effects limit its routine use. Ketamine rapidly produces a hypnotic state quite distinct from that of other anesthetics. Patients have profound analgesia, unresponsiveness to commands, and amnesia, but may have their eyes open, move their limbs involuntarily, and breathe spontaneously. This cataleptic state has been termed dissociative anesthesia. The administration of ketamine has been shown to reduce the development of tolerance to long-term opioid use. Low-dose ketamine infusion for this purpose has been advocated in patients who have developed significant tolerance to opioids (Himmelseher and Durieux, 2005).

Ketamine typically is administered intravenously but also is effective by intramuscular, oral, and rectal routes. The induction doses are 0.5-1.5 mg/kg IV, 4-6 mg/kg IM, and 8-10 mg/kg PR. Onset of action after an intravenous dose is similar to that of the other parenteral anesthetics, but the duration of anesthesia of a single dose is longer (Table 19–2). For anesthetic maintenance, ketamine occasionally is continued as an infusion (25-100 μg/kg per minute). Ketamine does not elicit pain on injection or true excitatory behavior as described for methohexital, although involuntary movements produced by ketamine can be mistaken for anesthetic excitement.

Pharmacokinetics and Metabolism. The onset and duration of an induction dose of ketamine are determined by the same distribution/redistribution mechanisms operant for all the other parenteral anesthetics.

Ketamine is hepatically metabolized to norketamine, which has reduced CNS activity; norketamine is further metabolized and excreted in urine and bile. Ketamine has a large volume of distribution and rapid clearance that make it suitable for continuous infusion without the lengthening in duration of action seen with thiopental (Table 19–2 and Figure 19–3). Protein binding is much lower with ketamine than with the other parenteral anesthetics (Table 19–2).

Side Effects

Nervous System. Ketamine has indirect sympathomimetic activity and can support blood pressure on anesthetic induction in patients who are at risk of developing significant hypotension. Ketamine's behavioral effects are distinct from those of other anesthetics. The ketamine-induced cataleptic state is accompanied by nystagmus with pupillary dilation, salivation, lacrimation, and spontaneous limb movements with increased overall muscle tone. Although ketamine does not produce the classic anesthetic state, patients are amnestic and unresponsive to painful stimuli. Ketamine produces profound analgesia, a distinct advantage over other parenteral anesthetics.

Unlike other parenteral anesthetics, ketamine increases cerebral blood flow and intracranial pressure (ICP) with minimal alteration of cerebral metabolism. The racemic mixture of ketamine can increase cerebral metabolic rate (CMR) and cerebral blood flow (CBF), particularly in the anterior cingulate and frontal cortex, thalamus, and putamen (Langsjo et al., 2004). S ketamine produces similar changes in CBF and CMR whereas R+ ketamine reduces both CMR and CBF (Vollenweider et al., 1997). These properties of ketamine have raised a concern that ICP can increase in patients with compromised intracranial compliance. However, ketamine does not increase ICP in patients with intracranial hypertension (Bourgoin et al., 2005). Moreover, the effects of ketamine on CBF can be readily attenuated by the simultaneous administration of sedative hyponotics (propofol, midazolam, barbiturates). In aggregate, the available data suggest that the contraindication of ketamine in patients with intracranial pathology or cerebral ischemia needs re-evaluation (Himmelseher et al., 2005).

In some studies, ketamine increased intraocular pressure, and its use for induction of patients with open eye injuries is controversial (Whitacre and Ellis, 1984). The effects of ketamine on seizure activity appear mixed, without either strong pro- or anticonvulsant activity. Emergence delirium, characterized by hallucinations, vivid dreams, and delusions, is a frequent complication of ketamine that can result in serious patient dissatisfaction and can complicate postoperative management. Delirium symptoms are most frequent in the first hour after emergence and appear to occur less frequently in children. Benzodiazepines reduce the incidence of emergence delirium (Dundee and Lilburn, 1978).

Cardiovascular System. Unlike other anesthetics, induction doses of ketamine typically increase blood pressure, heart rate, and cardiac output. The cardiovascular effects are indirect and are most likely mediated by inhibition of both central and peripheral catecholamine reuptake. Ketamine has direct negative inotropic and vasodilating activity, but these effects usually are overwhelmed by the indirect sympathomimetic action (Pagel et al., 1992). Thus, ketamine is a useful drug, along with etomidate, for patients at risk for hypotension during anesthesia. While not arrhythmogenic, ketamine increases myocardial O₂ consumption and is not an ideal drug for patients at risk for myocardial ischemia.

Respiratory System. The respiratory effects of ketamine are perhaps the best indication for its use. Induction doses of ketamine produce small and transient decreases in minute ventilation, but respiratory depression is less severe than with other general anesthetics. Ketamine is a potent bronchodilator due to its indirect sympathomimetic activity and perhaps some direct bronchodilating activity. Thus, ketamine is particularly well-suited for anesthetizing patients at high risk for bronchospasm. Increased salivation that attends ketamine administration can be effectively prevented by anticholinergic agents such as glycopyrrolate.

Approximately 60-80% of halothane taken up by the body is eliminated unchanged by the lungs in the first 24 hours after its administration. A substantial amount of the halothane not eliminated in exhaled gas is biotransformed by hepatic CYPs. The major metabolite of halothane is trifluoroacetic acid, which is formed by removal of bromine and chlorine ions. Trifluoroacetic acid, bromine, and chlorine all can be detected in the urine. Trifluoroacetylchloride, an intermediate in oxidative metabolism of halothane, can trifluoroacetylate several proteins in the liver. An immune reaction to these altered proteins may be responsible for the rare cases of fulminant halothane-induced hepatic necrosis. A minor reductive pathway accounts for ~1% of halothane metabolism that generally is observed only under hypoxic conditions.

Cardiovascular System. The most predictable side effect of halothane is a dose-dependent reduction in arterial blood pressure. Mean arterial pressure typically decreases ~20-25% at MAC concentrations of halothane. This reduction in blood pressure is primarily the result of direct myocardial depression leading to reduced cardiac output (Figure 19–6). Myocardial depression is thought to result from attenuation of depolarization-induced intracellular calcium transients. Halothane-induced hypotension usually is accompanied by either bradycardia or a normal heart rate. Attenuation of baroreceptor reflex function decreases the chronotropic and inotropic responses to a reduction in blood pressure (Constant et al., 2004). Heart rate can be increased during halothane anesthesia by exogenous catecholamine or by sympathoadrenal stimulation. Halothane-induced reductions in blood pressure and heart rate generally disappear after several hours of constant halothane administration, presumably because of progressive sympathetic stimulation.

Halothane does not cause a significant change in systemic vascular resistance. Nonetheless, it does alter the resistance and autoregulation of specific vascular beds, leading to redistribution of blood flow. The vascular beds of the skin and brain are dilated directly by halothane, leading to increased cerebral blood flow and skin perfusion. Conversely, autoregulation of renal, splanchnic, and cerebral blood flow is inhibited by halothane, leading to reduced perfusion of these organs in the face of reduced blood pressure. Coronary autoregulation is largely preserved during halothane anesthesia. Finally, halothane inhibits hypoxic pulmonary vasoconstriction, leading to increased perfusion to poorly ventilated regions of the lung and an increased alveolar:arterial O₂ gradient.

Halothane also has significant effects on cardiac rhythm. Sinus bradycardia and atrioventricular rhythms occur frequently during halothane anesthesia but usually are benign. These rhythms result mainly from a direct depressive effect of halothane on sinoatrial node discharge. Halothane also can sensitize the myocardium to the arrhythmogenic effects of epinephrine (Sumikawa et al., 1983). Premature ventricular contractions and sustained ventricular tachycardia can be observed during halothane anesthesia when exogenous administration or endogenous adrenal production elevates plasma epinephrine levels.

Respiratory System. Spontaneous respiration is rapid and shallow during halothane anesthesia. The decreased alveolar ventilation results in an elevation in arterial CO₂ tension from 40 mm Hg to >50 mm Hg at 1 MAC (Figure 19–7). The elevated CO₂ does not provoke a compensatory increase in ventilation, because halothane causes a concentration-dependent inhibition of the ventilatory response to CO₂. This action of halothane is thought to be mediated by depression of central chemoceptor mechanisms. Halothane also inhibits peripheral chemoceptor responses to arterial hypoxemia. Thus, neither hemodynamic (tachycardia and hypertension) nor ventilatory responses to hypoxemia are observed during halothane anesthesia, making it prudent to monitor arterial O₂ directly. Halothane also is an effective bronchodilator (Yamakage, 1992) and has been effectively used as a treatment of last resort in patients with status asthmaticus (Gold and Helrich, 1970).

Nervous System. Halothane dilates the cerebral vasculature, increasing cerebral blood flow and cerebral blood volume. This can result in an increase in intracranial pressure, especially in patients with space-occupying intracranial masses, brain edema, or preexisting intracranial hypertension. Halothane attenuates autoregulation of cerebral blood flow in a dose-dependent manner. Hence, cerebral blood flow can increase even with a modest reduction in arterial pressure. With a reduction of arterial pressure that is below the lower limit of autoregulation, cerebral blood flow can decrease significantly. Halothane suppresses cerebral metabolism and cerebral metabolic rate is decreased.

Muscle. Halothane causes some relaxation of skeletal muscle by its central depressant effects. Halothane also potentiates the actions of non-depolarizing muscle relaxants (curariform drugs; Chapter 11), increasing both their duration of action and the magnitude of their effect. Halothane and the other halogenated inhalational anesthetics can trigger malignant hyperthermia, a syndrome characterized by severe muscle contraction, rapid development of hyperthermia, and a massive increase in metabolic rate in genetically susceptible patients. This syndrome frequently is fatal and is treated by immediate discontinuation of the anesthetic and administration of dantrolene.

Uterine smooth muscle is relaxed by halothane. This is a useful property for manipulation of the fetus (version) in the prenatal period and for delivery of retained placenta postnatally. However, halothane inhibits uterine contractions during parturition, prolonging labor and increasing blood loss, and therefore is not used as an analgesic or anesthetic for labor and vaginal delivery.

Kidney. Patients anesthetized with halothane usually produce a small volume of concentrated urine. This is the consequence of halothane-induced reduction of renal blood flow and glomerular filtration rate, which may be reduced by 40-50% at 1 MAC. Halothane-induced changes in renal function are fully reversible and are not associated with long-term nephrotoxicity.

Liver and GI Tract. Halothane reduces splanchnic and hepatic blood flow as a consequence of reduced perfusion pressure, as discussed above. This reduced blood flow has not been shown to produce detrimental effects on hepatic or GI function.

Halothane can produce fulminant hepatic necrosis in a small number of patients. This syndrome generally is characterized by fever, anorexia, nausea, and vomiting, developing several days after anesthesia and can be accompanied by a rash and peripheral eosinophilia. There is a rapid progression to hepatic failure, with a fatality rate of ~50%. This syndrome occurs in ~1 in 10,000 patients receiving halothane and is referred to as halothane hepatitis (Study, 1966). Current thinking is that halothane hepatitis is the result of an immune response to hepatic proteins that become trifluoroacetylated as a consequence of halothane metabolism (see the "Pharmacokinetics" section for halothane earlier in the chapter).

More than 99% of inhaled isoflurane is excreted unchanged by the lungs. Approximately 0.2% of absorbed isoflurane is metabolized by CYP2E1. This small amount of isoflurane degradation products produced is insufficient to produce any renal, hepatic, or other organ toxicity. Isoflurane does not appear to be a mutagen, teratogen, or carcinogen.

It is typically used for maintenance of anesthesia after induction with other agents because of its pungent odor, but induction of anesthesia can be achieved in < 10 minutes with an inhaled concentration of 3% isoflurane in O₂; this concentration is reduced to 1-2% (~1-2 MAC) for maintenance of anesthesia. The use of other drugs such as opioids or nitrous oxide reduces the concentration of isoflurane required for surgical anesthesia.

Side Effects

Cardiovascular System. Isoflurane produces a concentration-dependent decrease in arterial blood pressure. Unlike halothane, cardiac output is well maintained with isoflurane, and hypotension is the result of decreased systemic vascular resistance (Figure 19–6). Isoflurane produces vasodilation in most vascular beds, with particularly pronounced effects in skin and muscle. Isoflurane is a potent coronary vasodilator, simultaneously producing increased coronary blood flow and decreased myocardial O₂ consumption. In theory, this makes isoflurane a particularly safe anesthetic to use for patients with ischemic heart disease. Concern that isoflurane might produce myocardial ischemia by inducing "coronary steal" has not been substantiated in animal and human studies. Isoflurane significantly attenuates baroreceptor function. Patients anesthetized with isoflurane generally have mildly elevated heart rates as a compensatory response to reduced blood pressure; however, rapid changes in isoflurane concentration can produce both transient tachycardia and hypertension due to isoflurane-induced sympathetic stimulation.

Respiratory System. Isoflurane produces concentration-dependent depression of ventilation. Patients spontaneously breathing isoflurane have a normal respiration rate but a reduced tidal volume, resulting in a marked reduction in alveolar ventilation and an increase in arterial CO₂ tension (Figure 19–7). Isoflurane is particularly effective at depressing the ventilatory response to hypercapnia and hypoxia (Hirshman et al., 1977). While isoflurane is an effective bronchodilator, it also is an airway irritant and can stimulate airway reflexes during induction of anesthesia, producing coughing and laryngospasm.

Nervous System. Isoflurane dilates the cerebral vasculature, producing increased cerebral blood flow; this vasodilating activity is less than that of either halothane or enflurane (Drummond et al., 1983). There is a modest risk of an increase in intracranial pressure in patients with preexisting intracranial hypertension. Isoflurane reduces cerebral metabolic O₂ consumption in a dose dependent manner. At 1.5-2.0 MAC, isoflurane produces burst suppression of the EEG and reduces cerebral metabolic rate by ~50%. The modest effects of isoflurane on cerebral blood flow can be reversed readily by hyperventilation (McPherson et al., 1989).

Muscle. Isoflurane produces some relaxation of skeletal muscle by its central effects. It also enhances the effects of both depolarizing and non-depolarizing muscle relaxants. Isoflurane is more potent than halothane in its potentiation of neuromuscular blocking agents. Like other halogenated inhalational anesthetics, isoflurane relaxes uterine smooth muscle and is not recommended for analgesia or anesthesia for labor and vaginal delivery.

Kidney. Isoflurane reduces renal blood flow and glomerular filtration rate, resulting in a small volume of concentrated urine. Changes in renal function observed during isoflurane anesthesia are rapidly reversed, with no long-term renal sequelae or toxicities.

Liver and Gastrointestinal Tract. Splanchnic and hepatic blood flows are reduced with increasing doses of isoflurane as systemic arterial pressure decreases. Liver function tests are minimally affected by isoflurane, with no reported incidence of hepatic toxicity.

It is a clear, colorless liquid at room temperature with a mild, sweet odor. Like other inhalational anesthetics, it is volatile and must be stored in a sealed bottle. It is nonflammable and non-explosive in mixtures of air or oxygen.

Enflurane is metabolized to a modest extent, with 2-8% of absorbed enflurane undergoing oxidative metabolism in the liver by CYP2E1. Fluoride ions are a by-product of enflurane metabolism, but plasma fluoride levels are low and nontoxic. Patients taking isoniazid exhibit enhanced metabolism of enflurane with significantly elevated serum fluoride concentrations (Mazze et al., 1982).

Surgical anesthesia can be induced with enflurane in < 10 minutes with an inhaled concentration of 4% in oxygen. Anesthesia can be maintained with concentrations from 1.5-3%. As with other anesthetics, the enflurane concentrations required to produce anesthesia are reduced when it is co-administered with nitrous oxide or opioids. With the advent of new inhalational agents, enflurane is rarely used for clinical anesthesia in developed countries.

Side Effects

Cardiovascular System. Enflurane causes a concentration-dependent decrease in arterial blood pressure. Hypotension is due in part to depression of myocardial contractility, with some contribution from peripheral vasodilation (Figure 19–6). Enflurane has minimal effects on heart rate and produces neither the bradycardia seen with halothane nor the tachycardia seen with isoflurane.

Respiratory System. The respiratory effects of enflurane are similar to those of halothane. Spontaneous ventilation with enflurane produces a pattern of rapid, shallow breathing. Minute ventilation is markedly decreased, and a Pa_CO2 of 60 mm Hg can be seen with 1 MAC of enflurane (Figure 19–7). Enflurane produces a greater depression of the ventilatory responses to hypoxia and hypercarbia than do either halothane or isoflurane (Hirshman et al., 1977). Enflurane, like other inhalational anesthetics, is an effective bronchodilator.

Nervous System. Enflurane is a cerebral vasodilator and thus can increase intracranial pressure in some patients. Like other inhalational anesthetics, enflurane reduces cerebral metabolic O₂ consumption. Enflurane has an unusual property of producing electrical seizure activity. High concentrations of enflurane or profound hypocarbia during enflurane anesthesia result in a characteristic high-voltage, high-frequency electroencephalographic (EEG) pattern that progresses to spike-and-dome complexes. The spike-and-dome pattern can be punctuated by frank seizure activity that may or may not be accompanied by peripheral motor manifestations of seizure activity. The seizures are self-limited and are not thought to produce permanent damage. Epileptic patients are not particularly susceptible to enflurane-induced seizures. Nonetheless, enflurane generally is not used in patients with seizure disorders.

Muscle. Enflurane produces significant skeletal muscle relaxation in the absence of muscle relaxants. It also significantly enhances the effects of non-depolarizing muscle relaxants. As with other inhalational agents, enflurane relaxes uterine smooth muscle. It is not widely used for obstetric anesthesia.

Kidney. Like other inhalational anesthetics, enflurane reduces renal blood flow, glomerular filtration rate, and urinary output. These effects are rapidly reversed upon drug discontinuation. Enflurane metabolism produces significant plasma levels of fluoride ions (20-40 μmol) and can produce transient urinary-concentrating defects following prolonged administration (Mazze et al., 1977). There is scant evidence of long-term nephrotoxicity following enflurane use, and it is safe to use in patients with renal impairment, provided that the depth of enflurane anesthesia and the duration of administration are not excessive.

Liver and GI Tract. Enflurane reduces splanchnic and hepatic blood flow in proportion to reduced arterial blood pressure. Enflurane does not appear to alter liver function or to be hepatotoxic.

Delivery of a precise concentration of desflurane requires the use of a specially heated vaporizer that delivers pure vapor that then is diluted appropriately with other gases (O₂, air, or N₂O). Desflurane is nonflammable and non-explosive in mixtures of air or oxygen.

Indeed, within 5 minutes of administration, the alveolar concentration reaches 80% of the inspired concentration. This provides for a very rapid induction of anesthesia and for rapid changes in depth of anesthesia following changes in the inspired concentration. Emergence from anesthesia also is very rapid with desflurane. The time to awakening following desflurane is shorter than with halothane or sevoflurane and usually does not exceed 5-10 minutes in the absence of other sedative agents (La Colla et al., 2007).

Clinical Use. Desflurane is a widely used anesthetic for outpatient surgery because of its rapid onset of action and rapid recovery. The drug irritates the tracheobronchial tree and can provoke coughing, salivation, and bronchospasm. Anesthesia therefore usually is induced with an intravenous agent, with desflurane subsequently administered for maintenance of anesthesia. Maintenance of anesthesia usually requires inhaled concentrations of 6-8% (~1 MAC). Lower concentrations of desflurane are required if it is co-administered with nitrous oxide or opioids.

Side Effects

Cardiovascular System. Desflurane, like all inhalational anesthetics, causes a concentration-dependent decrease in blood pressure. Desflurane has a very modest negative inotropic effect and produces hypotension primarily by decreasing systemic vascular resistance (Eger, 1994) (Figure 19–6). Thus, cardiac output is well preserved during desflurane anesthesia, as is blood flow to the major organ beds (splanchnic, renal, cerebral, and coronary). Marked increases in heart rate often are noted during induction of desflurane anesthesia and during abrupt increases in the delivered concentration of desflurane. This transient tachycardia results from desflurane-induced stimulation of the sympathetic nervous system (Ebert and Muzi, 1993). Unlike some inhalational anesthetics, the hypotensive effects of desflurane do not wane with increasing duration of administration.

Respiratory System. Similarly to halothane and enflurane, desflurane causes a concentration-dependent increase in respiratory rate and a decrease in tidal volume. At low concentrations (< 1 MAC) the net effect is to preserve minute ventilation. At desflurane concentrations > 1 MAC, minute ventilation is markedly depressed, resulting in elevated arterial CO₂ tension (Pa_CO2) (Figure 19–7). Patients spontaneously breathing desflurane at concentrations > 1.5 MAC will have extreme elevations of Paco₂ and may become apneic. Desflurane, like other inhalational agents, is a bronchodilator. However, it also is a strong airway irritant, and can cause coughing, breath-holding, laryngospasm, and excessive respiratory secretions. Because of its irritant properties, desflurane is not used for induction of anesthesia.

Nervous System. Desflurane decreases cerebral vascular resistance and cerebral metabolic O₂ consumption. Burst suppression of the EEG is achieved with ~ 2 MAC desflurane; at this level, CMRO₂ is reduced by ~ 50%. Under conditions of normocapnia and normotension, desflurane produces an increase in cerebral blood flow and can increase intracranial pressure in patients with poor intracranial compliance. The vasoconstrictive response to hypocapnia is preserved during desflurane anesthesia, and increases in intracranial pressure thus can be prevented by hyperventilation.

Muscle. Desflurane produces direct skeletal muscle relaxation as well as enhancing the effects of non-depolarizing and depolarizing neuromuscular blocking agents (Caldwell et al., 1991).

Kidney. Consistent with its minimal metabolic degradation, desflurane has no reported nephrotoxicity.

Liver and GI Tract. Desflurane is not known to affect liver function tests or to cause hepatotoxicity.

Desflurane and Carbon Monoxide. Inhaled anesthetics are administered via a circle system circuit that permits unidirectional flow of gas. This systems permits rebreathing of exhaled gases that contain CO₂. To prevent rebreathing of CO₂ (which can lead to hypercarbia), CO₂ absorbers are incorporated into the anesthesia delivery circuits. These CO₂ absorbers contained either Ca(OH)₂ or Ba(OH)₂ and smaller quantities of more potent alkalis, NaOH and KOH. Interaction of inhaled anesthetics with these strong alkalis results in the formation of CO. The amount of CO produced is insignificant as long as the CO₂ absorbent is sufficiently hydrated. With almost complete dessication of the CO₂ absorbents, substantial quantities of CO can be produced. This effect is greatest with desflurane and can be prevented by the use of well-hydrated, fresh CO₂ absorbent.

Approximately 3% of absorbed sevoflurane is biotransformed. Sevoflurane is metabolized in the liver by CYP2E1, with the predominant product being hexafluoroisopropanol (Kharasch et al., 1995). Hepatic metabolism of sevoflurane also produces inorganic fluoride. Serum fluoride concentrations peak shortly after surgery and decline rapidly. Interaction of sevoflurane with soda lime also produces decomposition products. The major product of interest is referred to as compound A, pentafluoroisopropenyl fluoromethyl ether (see "Kidney" under "Side Effects") (Hanaki et al., 1987).

Clinical Use. Sevoflurane is widely used, particularly for outpatient anesthesia, because of its rapid recovery profile. It is well-suited for inhalation induction of anesthesia (particularly in children) because it is not irritating to the airway. Induction of anesthesia is rapidly achieved using inhaled concentrations of 2-4% sevoflurane.

Side Effects

Cardiovascular System. Sevoflurane, like all other halogenated inhalational anesthetics, produces a concentration-dependent decrease in arterial blood pressure. This hypotensive effect primarily is due to systemic vasodilation, although sevoflurane also produces a concentration-dependent decrease in cardiac output (Figure 19–6). Unlike isoflurane or desflurane, sevoflurane does not produce tachycardia and thus may be a preferable agent in patients prone to myocardial ischemia.

Respiratory System. Sevoflurane produces a concentration-dependent reduction in tidal volume and increase in respiratory rate in spontaneously breathing patients. The increased respiratory frequency does not compensate for reduced tidal volume, with the net effect being a reduction in minute ventilation and an increase in Pa_CO2 (Doi and Ikeda, 1987) (Figure 19–7). Sevoflurane is not irritating to the airway and is a potent bronchodilator. Because of this combination of properties, sevoflurane is the most effective clinical bronchodilator of the inhalational anesthetics (Rooke et al., 1997).

Nervous System. Sevoflurane produces effects on cerebral vascular resistance, cerebral metabolic O₂ consumption, and cerebral blood flow that are very similar to those produced by isoflurane and desflurane. Its cerebral vasodilating capacity is less than that of isoflurane, and particularly desflurane. At ~2 MAC anesthesia, sevoflurane produces burst suppression of the EEG, and at this level, CMRO₂ is reduced by ~50%. While sevoflurane can increase intracranial pressure in patients with poor intracranial compliance, the response to hypocapnia is preserved during sevoflurane anesthesia, and increases in intracranial pressure can be prevented by hyperventilation. In children, sevoflurane is associated with delirium upon emergence from anesthesia. This delirium, the causes of which are not clear, is short lived and without any reported adverse long-term sequelae.

Muscle. Sevoflurane produces skeletal muscle relaxation and enhances the effects of non-depolarizing and depolarizing neuromuscular blocking agents. Its effects are similar to those of other halogenated inhalational anesthetics.

Kidney. Controversy has surrounded the potential nephrotoxicity of compound A, the degradation product produced by interaction of sevoflurane with the CO₂ absorbent soda lime. Biochemical evidence of transient renal injury has been reported in human volunteers (Eger et al., 1997). Large clinical studies have shown no evidence of increased serum creatinine, blood urea nitrogen, or any other evidence of renal impairment following sevoflurane administration (Mazze et al., 2000). The FDA recommends that sevoflurane be administered with fresh gas flows of at least 2 L/min to minimize accumulation of compound A.

Liver and GI Tract. Sevoflurane is not known to cause hepatotoxicity or alterations of hepatic function tests.

N₂O is sold in steel cylinders and must be delivered through calibrated flow meters provided on all anesthesia machines. Nitrous oxide is neither flammable nor explosive, but it does support combustion as actively as oxygen does when it is present in proper concentration with a flammable anesthetic or material.

The rapid uptake of N₂O from alveolar gas serves to concentrate co-administered halogenated anesthetics; this effect (the "second gas effect") speeds induction of anesthesia. On discontinuation of N₂O administration, nitrous oxide gas can diffuse from blood to the alveoli, diluting O₂ in the lung. This can produce an effect called diffusional hypoxia. To avoid hypoxia, 100% O₂ rather than air should be administered when N₂O is discontinued.

Nitrous oxide is almost completely eliminated by the lungs, with some minimal diffusion through the skin. Nitrous oxide is not biotransformed by enzymatic action in human tissue, and 99.9% of absorbed nitrous oxide is eliminated unchanged. N₂O can oxidize the cobalt I (Co⁺) form of vitamin B₁₂ to Co³⁺ (Sanders et al., 2007), thereby preventing vitamin B₁₂ from acting as a co-factor for methionine synthetase. The latter is important in the synthesis of a number of products including DNA, RNA, and myelin. Indeed, methionine synthetase activity is dramatically reduced after 3-4 hours of N₂O exposure; activity of the enzyme is restored in 3-4 days. Inactivation of methionine synthetase can produce signs of vitamin B₁₂ deficiency, including megaloblastic anemia and peripheral neuropathy. This is of particular concern in patients with malnutrition, vitamin B₁₂ deficiency, or alcoholism. For this reason, N₂O is not used as a chronic analgesic or as a sedative in critical care settings.

The analgesic property of N₂O is a function of the activation of opioidergic neurons in the periacqueductal gray matter (Fang et al., 1997) and the adrenergic neurons in the locus ceruleus (Sawamura et al., 2000). At least part of the activation of the locus ceruleus is due to release of corticotrophin-releasing factor from the hypothalamus as a result of antagonism of the NMDA receptor.

In doses approaching 70-80%, significant sedation is produced. Therefore, N₂O is frequently used in concentrations of ~50% to provide analgesia and mild sedation in outpatient dentistry. Nitrous oxide cannot be used at concentrations > 80% because this limits the delivery of adequate O₂. Because of this limitation, nitrous oxide is used primarily as an adjunct to other inhalational or intravenous anesthetics. Nitrous oxide substantially reduces the requirement for inhalational anesthetics. For example, at 70% nitrous oxide, the MAC for other inhalational agents is reduced by ~60%, allowing for lower concentrations of halogenated anesthetics and a lesser degree of side effects.

One major problem with N₂O is that it will exchange with N₂ in any air-containing cavity in the body. Moreover, because of their differential blood:gas partition coefficients, nitrous oxide will enter the cavity faster than nitrogen escapes, thereby increasing the volume and/or pressure in this cavity. Examples of air collections that can be expanded by nitrous oxide include a pneumothorax, an obstructed middle ear, an air embolus, an obstructed loop of bowel, an intraocular air bubble, a pulmonary bulla, and intracranial air. Nitrous oxide should be avoided in these clinical settings.

Side Effects

Cardiovascular System. Although N₂O produces a negative inotropic effect on heart muscle in vitro, depressant effects on cardiac function generally are not observed in patients because of the stimulatory effects of nitrous oxide on the sympathetic nervous system. The cardiovascular effects of nitrous oxide also are heavily influenced by the concomitant administration of other anesthetic agents. When nitrous oxide is co-administered with halogenated inhalational anesthetics, it generally produces an increase in heart rate, arterial blood pressure, and cardiac output. In contrast, when nitrous oxide is co-administered with an opioid, it generally decreases arterial blood pressure and cardiac output. Nitrous oxide also increases venous tone in both the peripheral and pulmonary vasculature. The effects of N₂O on pulmonary vascular resistance can be exaggerated in patients with preexisting pulmonary hypertension; thus, the drug generally is not used in these patients.

Respiratory System. N₂O causes modest increases in respiratory rate and decreases in tidal volume in spontaneously breathing patients. The net effect is that minute ventilation is not significantly changed and PaCO₂ remains normal. However, even modest concentrations of nitrous oxide markedly depress the ventilatory response to hypoxia. Thus, it is prudent to monitor arterial O₂ saturation directly in patients receiving or recovering from nitrous oxide.

Nervous System. When administered alone, nitrous oxide can significantly increase cerebral blood flow and intracranial pressure. This cerebral vasodilatory capacity of N₂O is significantly attenuated by the simultaneous administration of intravenous agents such as opiates and propofol. By contrast, the combination of N₂O and inhaled agents results in greater vasodilation than the administration of the inhaled agent alone at equivalent anesthetic depth.

Muscle. Nitrous oxide does not relax skeletal muscle and does not enhance the effects of neuromuscular blocking drugs. Unlike the halogenated anesthetics, nitrous oxide does not trigger malignant hyperthermia.

Kidney, Liver, and GI Tract. Nitrous oxide is not known to produce any changes in renal or hepatic function and is neither nephrotoxic nor hepatotoxic.

Cardiovascular System. Xenon has minimal effects on cardiovascular function. Arterial pressure, unlike the situation with other anesthetic agents, is well maintained. Left ventricular contractility is not affected and heart rate and systemic vascular resistance are essentially unchanged. Autonomic function is better maintained under xenon anesthesia than under anesthesia with propofol and inhaled anesthetics (Hanss et al., 2006). Even in patients with significant cardiac disease, xenon maintains a favorable profile (Lockwood et al., 2006).

Respiratory System. Under xenon anesthesia, respiratory rate is reduced slightly. However, an increase in tidal volume maintains minute ventilation, indicating that there is minimal respiratory depression. An increase in airway pressure does occur; this has been attributed to the greater density and viscosity of xenon (compared to oxygen) and not due to changes in bronchomotor tone (Baumert et al., 2002).

Central Nervous System. Like other anesthetic agents, xenon reduces cerebral metabolism by 25-30%. This reduction in metabolism is accompanied by a corresponding reduction in cerebral blood flow. Consequently, xenon is not expected to increase intracranial pressure.

Liver, Kidney, and GI Tract. Xenon is an inert agent and does not undergo metabolism. Hepatic or renal toxicity with its use have not been reported.

Midazolam is water soluble and typically is administered intravenously but also can be given orally, intramuscularly, or rectally; oral midazolam is particularly useful for sedation of young children. Midazolam produces minimal venous irritation as opposed to diazepam and lorazepam, which are formulated in propylene glycol and are painful on injection, sometimes producing thrombophlebitis. Midazolam has the pharmacokinetic advantage, particularly over lorazepam, of being more rapid in onset and shorter in duration of effect. Sedative doses of midazolam (0.01-0.05 mg/kg intravenously) reach peak effect in ~2 minutes and provide sedation for ~30 minutes. Elderly patients tend to be more sensitive to and have a slower recovery from benzodiazepines (Jacobs et al., 1995); thus, titration to the desired effect of smaller doses in this age group is prudent. Midazolam is hepatically metabolized with a clearance (6-11 mL/min per kg), similar to that of methohexital and ~20 and 7 times higher than those of diazepam and lorazepam, respectively. Either for prolonged sedation or for general anesthetic maintenance, midazolam is more suitable for infusion than are other benzodiazepines, although its duration of action does significantly increase with prolonged infusions (Figure 19–3). Benzodiazepines reduce both cerebral blood flow and metabolism but at equi-anesthetic doses are less potent in this respect than are barbiturates. They are effective anticonvulsants and sometimes are given to treat status epilepticus. Benzodiazepines modestly decrease blood pressure and respiratory drive, occasionally resulting in apnea. Thus, blood pressure and respiratory rate should be monitored in patients sedated with intravenous benzodiazepines.

The most common side effects of dexmedetomidine include hypotension and bradycardia, both of which are attributed to decreased catecholamine release by activation peripherally and in the CNS of the α_2A receptor (Lakhlani et al., 1997). Nausea and dry mouth also are common untoward reactions. At higher drug concentrations, the α_2B subtype is activated, resulting in hypertension and a further decrease in heart rate and cardiac output. Dexmedetomidine has the very useful property of producing sedation and analgesia with minimal respiratory depression (Belleville et al., 1992); thus, it is particularly valuable in sedation of patients who are not endotracheally intubated and mechanically ventilated. The sedation produced by dexmedetomidine has been noted to be more akin to natural sleep, with patients relatively easy to arouse (Hall et al., 2000). However, dexmedetomidine does not appear to provide reliable amnesia and additional agents may need to be employed if lack of recall is desirable.

Dexmedetomidine is supplied as an aqueous solution of the hydrochloride salt and should be diluted in normal saline to a final concentration of 4 μg/mL for intravenous delivery, the only approved route of administration. The recommended loading dose is 1 μg/kg given over 10 minutes, followed by infusion at a rate of 0.2-0.7 μg/kg per hour. Reduced doses should be considered in patients with risk factors for severe hypotension. The distribution and terminal half-lives are 6 minutes and 2 hours, respectively. Dexmedetomidine is highly protein bound and is primarily hepatically metabolized; the glucuronide and methyl conjugates are excreted in the urine.

The choice of a perioperative opioid is based primarily on duration of action, since, at appropriate doses, all produce similar analgesia and side effects. Remifentanil has an ultrashort duration of action (~10 minutes) and accumulates minimally with repeated doses or infusion; it is particularly well suited for procedures that are briefly painful, but for which little analgesia is required postoperatively. Single doses of fentanyl, alfentanil, and sufentanil all have similar intermediate durations of action (30, 20, and 15 minutes, respectively), but recovery after prolonged administration varies considerably. Fentanyl's duration of action lengthens the most with infusion, sufentanil's much less so, and alfentanil's the least. Except for remifentanil, all of the above-mentioned opioids are metabolized in the liver, followed by renal and biliary excretion of the metabolites. Remifentanil is hydrolyzed by tissue and plasma esterases. Given its rapid elimination, termination of the effects of remifentanil can result in significant pain in the surgical patient. Consequently, longer-acting opiates are often given prior to discontinuation of remifentanil.

During the perioperative period, opioids often are given at induction to preempt responses to predictable painful stimuli (e.g., endotracheal intubation and surgical incision). Subsequent doses either by bolus or infusion are titrated to the surgical stimulus and the patient's hemodynamic response. Marked decreases in respiratory rate and heart rate with much smaller reductions in blood pressure are seen to varying degrees with all opioids. Muscle rigidity that can impair ventilation sometimes accompanies larger doses of opioids. The incidence of sphincter of Oddi spasm is increased with all opioids, although morphine appears to be more potent in this regard (Hahn et al., 1988). The frequency and severity of nausea, vomiting, and pruritus after emergence from anesthesia are increased by all opioids to about the same degree. A useful side effect of meperidine is its capacity to reduce shivering, a common problem during emergence from anesthesia (Pauca et al., 1984); other opioids are not as efficacious against shivering, perhaps due to less κ receptor agonism. Finally, opioids often are administered intrathecally and epidurally for management of acute and chronic pain (Chapter 18). Neuraxial opioids with or without local anesthetics can provide profound analgesia for many surgical procedures; however, respiratory depression and pruritus usually limit their use to major operations.

By contrast, anesthetics reduce ischemic injury to a variety of tissues, including the brain and heart. This protective effect is robust and results in better functional outcomes in comparison to ischemic injury that occurs in unanesthetized awake subjects. With respect to ischemic injury of the brain, anesthetics (inhalational agents, propofol, barbiturates, ketamine, lidocaine, midazolam) suppress excitotoxic injury produced by excessive glutamate release, reduce inflammation, and promote pro-survival signaling (Head et al., 2007). In addition, exposure to anesthesia results in the activation of plasmalemmal and mitochondrial ATP-dependent K⁺ channels, activation of signal transduction pathways (NO synthase, MAP kinases), and protein synthesis that render the brain less vulnerable to subsequent ischemic injury. In a similar fashion, volatile anesthetics and, under some conditions, propofol and barbiturates, reduce myocardial ischemia-reperfusion injury (Frassdorf et al., 2009). The molecular mechanisms leading to cardiac protection by volatile anesthetics involve activation of "classical" preconditioning signaling pathways (e.g., GPCRs, endothelial NO synthase, survival protein kinases, PKC, reactive oxygen species, ATP-dependent K⁺ channels, and the mitochondrial permeability transition pore) (Hausenloy and Scorrano, 2007). Propofol and barbiturates may induce specific components of the "classical" pathways involved in cardiac protection; however, there is debate as to whether these agents are truly protective or injurious to the ischemic myocardium (Frassdorf et al., 2009).

The PO₂ in arterial blood, however, is further reduced by venous admixture (shunt), the addition of mixed venous blood from the pulmonary artery, which has a PO₂ of ~5.3 kPa (40 mm Hg). Together, the diffusional barrier, ventilation–perfusion mismatches, and the shunt fraction are the major causes of the alveolar-to-arterial oxygen gradient, which is normally 1.3-1.6 kPa (10-12 mm Hg) when air is breathed and 4.0-6.6 kPa (30-50 mm Hg) when 100% oxygen is breathed.

Oxygen is delivered to the tissue capillary beds by the circulation and again follows a gradient out of the blood and into cells. Tissue extraction of oxygen typically reduces the PO₂ of venous blood by an additional 7.3 kPa (55 mm Hg). Although the PO₂ at the site of cellular oxygen utilization—the mitochondria—is not known, oxidative phosphorylation can continue at a PO₂ of only a few mm Hg.

In the blood, oxygen is carried primarily in chemical combination with hemoglobin and is to a small extent dissolved in solution. The quantity of oxygen combined with hemoglobin depends on the PO₂, as illustrated by the sigmoidal oxyhemoglobin dissociation curve (Figure 19–8). Hemoglobin is ~98% saturated with oxygen when air is breathed under normal circumstances, and it binds 1.3 mL of oxygen per gram when fully saturated. The steep slope of this curve with falling PO₂ facilitates unloading of oxygen from hemoglobin at the tissue level and reloading when desaturated mixed venous blood arrives at the lung. Shifting of the curve to the right with increasing temperature, increasing PCO₂, and decreasing pH, as is found in metabolically active tissues, lowers the oxygen saturation for the same PO₂ and thus delivers additional oxygen where and when it is most needed. However, the flattening of the curve with higher PO₂ indicates that increasing blood PO₂ by inspiring oxygen-enriched mixtures can increase the amount of oxygen carried by hemoglobin only minimally. Further increases in blood oxygen content can occur only by increasing the amount of oxygen dissolved in plasma. Because of the low solubility of oxygen (0.226 mL/L per kPa or 0.03 mL/L per mm Hg at 37°C), breathing 100% oxygen can increase the amount of oxygen dissolved in blood by only 15 mL/L, less than one-third of normal metabolic demands. However, if the inspired PO₂ is increased to 3 atm (304 kPa) in a hyperbaric chamber, the amount of dissolved oxygen is sufficient to meet normal metabolic demands even in the absence of hemoglobin (Table 19–4).

Low FI_O2 is a cause of hypoxemia only at high altitude or in the event of equipment failure, such as a gas blender malfunction or a mislabeled compressed-gas tank. An increase in the barrier to diffusion of oxygen within the lung is rarely a cause of hypoxemia in a resting subject, except in end-stage parenchymal lung disease. Both these problems may be alleviated with administration of supplemental oxygen, the former by definition and the latter by increasing the gradient driving diffusion.

Hypoventilation causes hypoxemia by reducing the alveolar PO₂ in proportion to the buildup of CO₂ in the alveoli. During hypoventilation, there is decreased delivery of oxygen to the alveoli, whereas its removal by the blood remains the same, causing its alveolar concentration to fall. The opposite occurs with carbon dioxide. This is described by the alveolar gas equation:

where PA_O2 and PA_CO2 are the alveolar partial pressures of oxygen and carbon dioxide, PI_O2 is the partial pressure of oxygen in the inspired gas, and R the respiratory quotient.

Under normal conditions, breathing room air at sea level (corrected for the partial pressure of water vapor), the PI_O2 is ~ 20 kPa (150 mm Hg), the PA_CO2 ~ 5.3 kPa (40 mm Hg), R is 0.8, and thus the PA_O2 is normally around 13.3 kPa (100 mm Hg). It would require substantial hypoventilation, with the PA_CO2 rising to over 9.8 kPa (72 mm Hg), to cause the PA_O2 to fall below 7.8 kPa (60 mm Hg). This cause of hypoxemia is readily prevented by administration of even small amounts of supplemental O₂.

Shunt and V̇/Q̇ mismatch are related causes of hypoxemia but with an important distinction in their responses to supplemental oxygen. Optimal gas exchange occurs when blood flow (Q̇) and ventilation (V̇) are matched quantitatively. However, regional variations in V̇/Q̇ matching typically exist within the lung, particularly in the presence of lung disease. As ventilation increases relative to blood flow, the alveolar PO₂ (PA_O2) increases; because of the flat shape of the oxyhemoglobin dissociation curve at high PO₂ (Figure 19–8), this increased PA_O2 does not contribute much to the oxygen content of the blood. Conversely, as the V̇/Q̇ ratio falls and perfusion increases relative to ventilation, the PA_O2 of the blood leaving these regions falls relative to regions with better matched ventilation and perfusion. Since the oxyhemoglobin dissociation curve is steep at these lower PO₂ values, the oxygen saturation and content of the pulmonary venous blood falls significantly. At the extreme of low V̇/Q̇ ratios, there is no ventilation to a perfused region, and a pure shunt results; thus the blood leaving the region has the same low PO₂ and high PA_CO2 as mixed venous blood.

The deleterious effect of V̇/Q̇ mismatch on arterial oxygenation is a direct result of the asymmetry of the oxyhemoglobin dissociation curve. Adding supplemental oxygen generally will make up for the fall in PA_O2 in low V̇/Q̇ units and thereby improve arterial oxygenation. However, since there is no ventilation to units with pure shunt, supplemental oxygen will not be effective in reversing hypoxemia from this cause. Because of the steep oxyhemoglobin dissociation curve at low PO₂, even moderate amounts of pure shunt will cause significant hypoxemia despite oxygen therapy (Figure 19–9). For the same reason, factors that decrease mixed venous PO₂, such as decreased cardiac output or increased O₂ consumption, enhance the hypoxemic effects of mismatch and shunt.

Nonpulmonary Causes of Hypoxia. In addition to failure of the respiratory system to oxygenate the blood adequately, a number of other factors can contribute to hypoxia at the tissue level. These may be divided into categories of O₂ delivery and O₂ utilization. Oxygen delivery decreases globally when cardiac output falls or locally when regional blood flow is compromised, such as from a vascular occlusion (e.g., stenosis, thrombosis, or microvascular occlusion) or increased downstream pressure (e.g., compartment syndrome, venous stasis, or venous hypertension). Decreased O₂-carrying capacity of the blood likewise will reduce oxygen delivery, such as occurs with anemia, CO poisoning, or hemoglobinopathy. Finally, hypoxia may occur when transport of O₂ from the capillaries to the tissues is decreased (edema) or utilization of the O₂ by the cells is impaired (CN⁻ toxicity).

Effects of Hypoxia. There has been a considerable increase in our understanding of the cellular and biochemical changes that occur after acute and chronic hypoxia. Regardless of the cause, hypoxia produces a marked alteration in gene expression, mediated in part by hypoxia inducible factor-1α (Brahimi-Horn and Pouyssegur, 2009). Ultimately, hypoxia results in the cessation of aerobic metabolism, exhaustion of high-energy intracellular stores, cellular dysfunction, and death. The time course of cellular demise depends on the tissue's relative metabolic requirements, O₂ and energy stores, and anaerobic capacity. Survival times (the time from the onset of circulatory arrest to significant organ dysfunction) range from 1-2 minutes in the cerebral cortex to around 5 minutes in the heart and 10 minutes in the kidneys and liver, with the potential for some degree of recovery if reperfused. Revival times (the duration of hypoxia beyond which recovery is no longer possible) are ~4 to 5 times longer. Less severe degrees of hypoxia have progressive physiological effects on different organ systems (Nunn, 2005b). Responses of individual organ systems to hypoxia are summarized next.

Respiratory System. Hypoxia stimulates the carotid and aortic baroreceptors to cause increases in both the rate and depth of ventilation. Minute volume almost doubles when normal individuals inspire gas with a PO₂ of 6.6 kPa (50 mm Hg). Dyspnea is not always experienced with simple hypoxia but occurs when the respiratory minute volume approaches half the maximal breathing capacity; this may occur with minimum exertion in patients in whom maximal breathing capacity is reduced by lung disease. In general, little warning precedes the loss of consciousness resulting from hypoxia.

Cardiovascular System. Hypoxia causes reflex activation of the sympathetic nervous system by both autonomic and humoral mechanisms, resulting in tachycardia and increased cardiac output. Peripheral vascular resistance, however, decreases primarily through local autoregulatory mechanisms, with the net result that blood pressure generally is maintained unless hypoxia is prolonged or severe. In contrast to the systemic circulation, hypoxia causes pulmonary vasoconstriction and hypertension, an extension of the normal regional vascular response that matches perfusion with ventilation to optimize gas exchange in the lung (hypoxic pulmonary vasoconstriction).

CNS. The CNS is least able to tolerate hypoxia. Hypoxia is manifest initially by decreased intellectual capacity and impaired judgment and psychomotor ability. This state progresses to confusion and restlessness and ultimately to stupor, coma, and death as the arterial PO₂ decreases below 4-5.3 kPa (30-40 mm Hg). Victims often are unaware of this progression.

Cellular and Metabolic Effects. When the mitochondrial PO₂ falls below ~ 0.13 kPa (1 mm Hg), aerobic metabolism stops, and the less efficient anaerobic pathways of glycolysis become responsible for the production of cellular energy. End products of anaerobic metabolism, such as lactic acid, are released into the circulation in measurable quantities. Energy-dependent ion pumps slow, and transmembrane ion gradients dissipate. Intracellular concentrations of Na⁺, Ca²⁺, and H⁺ increase, finally leading to cell death. The time course of cellular demise depends on the relative metabolic demands, oxygen storage capacity, and anaerobic capacity of the individual organs. Restoration of perfusion and oxygenation prior to hypoxic cell death paradoxically can result in an accelerated form of cell injury (ischemia–reperfusion syndrome), which is thought to result from the generation of highly reactive oxygen free radicals.

Adaptation to Hypoxia. Long-term hypoxia results in adaptive physiological changes; these have been studied most thoroughly in persons exposed to high altitude. Adaptations include increased numbers of pulmonary alveoli, increased concentrations of hemoglobin in blood and myoglobin in muscle, and a decreased ventilatory response to hypoxia. Short-term exposure to high altitude produces similar adaptive changes. In susceptible individuals, however, acute exposure to high altitude may produce acute mountain sickness, a syndrome characterized by headache, nausea, dyspnea, sleep disturbances, and impaired judgment progressing to pulmonary and cerebral edema. Mountain sickness is treated with rest and analgesics when mild or supplemental oxygen, descent to lower altitude, or an increase in ambient pressure when more severe. Acetazolamide (a carbonic anhydrase inhibitor) and dexamethasone also may be helpful. The syndrome usually can be avoided by a slow ascent to altitude, adequate hydration, and prophylactic use of acetazolamide or dexamethasone.

Certain aspects of fetal and newborn physiology are strongly reminiscent of adaptation mechanisms found in hypoxia-tolerant animals (Mortola, 1999), including shifts in the oxyhemoglobin dissociation curve (fetal hemoglobin), reductions in metabolic rate and body temperature (hibernation-like mode), reductions in heart rate and circulatory redistribution (as in diving mammals), and redirection of energy utilization from growth to maintenance metabolism. These adaptations probably account for the relative tolerance of the fetus and neonate to both chronic (uterine insufficiency) and short-term hypoxia.

Respiratory System. Inhalation of O₂ at 1 atm or above causes a small degree of respiratory depression in normal subjects, presumably as a result of loss of tonic chemoreceptor activity. However, ventilation typically increases within a few minutes of O₂ inhalation because of a paradoxical increase in the tension of CO₂ in tissues. This increase results from the increased concentration of oxyhemoglobin in venous blood, which causes less efficient removal of carbon dioxide from the tissues.

In a small number of patients whose respiratory center is depressed by long-term retention of CO₂, injury, or drugs, ventilation is maintained largely by stimulation of carotid and aortic chemoreceptors, commonly referred to as the hypoxic drive. The provision of too much oxygen can depress this drive, resulting in respiratory acidosis. In these cases, supplemental oxygen should be titrated carefully to ensure adequate arterial saturation. If hypoventilation results, then mechanical ventilatory support with or without tracheal intubation should be provided.

Expansion of poorly ventilated alveoli is maintained in part by the nitrogen content of alveolar gas; nitrogen is poorly soluble and thus remains in the airspaces while oxygen is absorbed. High oxygen concentrations delivered to poorly ventilated lung regions dilute the nitrogen content and can promote absorption atelectasis, occasionally resulting in an increase in shunt and a paradoxical worsening of hypoxemia after a period of oxygen administration.

Cardiovascular System. Aside from reversing the effects of hypoxia, the physiological consequences of oxygen inhalation on the cardiovascular system are of little significance. Heart rate and cardiac output are slightly reduced when 100% O₂ is breathed; blood pressure changes little. While pulmonary arterial pressure changes little in normal subjects with oxygen inhalation, elevated pulmonary artery pressures in patients living at high altitude who have chronic hypoxic pulmonary hypertension may reverse with oxygen therapy or return to sea level. In particular, in neonates with congenital heart disease and left-to-right shunting of cardiac output, oxygen supplementation must be regulated carefully because of the risk of further reducing pulmonary vascular resistance and increasing pulmonary blood flow.

Metabolism. Inhalation of 100% O₂ does not produce detectable changes in O₂ consumption, CO₂ production, respiratory quotient, or glucose utilization.

Low-Flow Systems. Low-flow systems, in which the oxygen flow is lower than the inspiratory flow rate, have a limited ability to raise the FI_O2 because they depend on entrained room air to make up the balance of the inspired gas. The FI_O2 of these systems is extremely sensitive to small changes in the ventilatory pattern. Nasal cannulae—small, flexible prongs that sit just inside each naris—deliver oxygen at 1-6 L/min. The nasopharynx acts as a reservoir for storing the oxygen, and patients may breathe through either the mouth or nose as long as the nasal passages remain patent. These devices typically deliver 24-28% FI_O2 at 2-3 L/min. Up to 40% FI_O2 is possible at higher flow rates, although this is poorly tolerated for more than brief periods because of mucosal drying. The simple face mask, a clear plastic mask with side holes for clearance of expiratory gas and inspiratory air entrainment, is used when higher concentrations of oxygen delivered without tight control are desired. The maximum FI_O2 of a face mask can be increased from around 60% at 6-15 L/min to > 85% by adding a 600- to 1000-mL reservoir bag. With this partial rebreathing mask, most of the inspired volume is drawn from the reservoir, avoiding dilution by entrainment of room air.

High-Flow Systems. The most commonly used high-flow oxygen delivery device is the Venturi-style mask, which uses a specially designed mask insert to entrain room air reliably in a fixed ratio and thus provides a relatively constant FI_O2 at relatively high flow rates. Typically, each insert is designed to operate at a specific oxygen flow rate, and different inserts are required to change the FI_O2. Lower delivered FI_O2 values use greater entrainment ratios, resulting in higher total (oxygen plus entrained air) flows to the patient, ranging from 80 L/min for 24% FI_O2 to 40 L/min at 50% FI_O2. While these flow rates are much higher than those obtained with low-flow devices, they still may be lower than the peak inspiratory flows for patients in respiratory distress, and thus the actual delivered O₂ concentration may be lower than the nominal value. Oxygen nebulizers, another type of Venturi-style device, provide patients with humidified oxygen at 35-100% FI_O2 at high flow rates. Finally, oxygen blenders provide high inspired oxygen concentrations at very high flow rates. These devices mix high-pressure compressed air and oxygen to achieve any concentration of O₂ from 21-100% at flow rates of up to 100 L/min. These same blenders are used to provide control of FI_O2 for ventilators, CPAP/BiPAP machines, oxygenators, and other devices with similar requirements. Again, despite the high flows, the delivery of high FI_O2 to an individual patient also depends on maintaining a tight-fitting seal to the airway and/or the use of reservoirs to minimize entrainment of diluting room air.

Monitoring of Oxygenation. Monitoring and titration are required to meet the therapeutic goal of oxygen therapy and to avoid complications and side effects. Although cyanosis is a physical finding of substantial clinical importance, it is not an early, sensitive, or reliable index of oxygenation. Cyanosis appears when ~5 g/dL of deoxyhemoglobin is present in arterial blood, representing an oxygen saturation of ~67% when a normal amount of hemoglobin (15 g/dL) is present. However, when anemia lowers the hemoglobin to 10 g/dL, then cyanosis does not appear until the arterial blood saturation has decreased to 50%. Invasive approaches for monitoring oxygenation include intermittent laboratory analysis of arterial or mixed venous blood gases and placement of intravascular cannulae capable of continuous measurement of oxygen tension. The latter method, which relies on fiber-optic oximetry, is used frequently for the continuous measurement of mixed venous hemoglobin saturation as an index of tissue extraction of oxygen, usually in critically ill patients.

Noninvasive monitoring of arterial oxygen saturation can be achieved using transcutaneous pulse oximetry, in which oxygen saturation is measured from the differential absorption of light by oxyhemoglobin and deoxyhemoglobin and the arterial saturation determined from the pulsatile component of this signal. Application is simple, and calibration is not required. Pulse oximetry measures hemoglobin saturation and not PO₂. It is not sensitive to increases in PO₂ that exceed levels required to saturate the blood fully. Pulse oximetry is very useful for monitoring the adequacy of oxygenation during procedures requiring sedation or anesthesia, rapid evaluation and monitoring of potentially compromised patients, and titrating oxygen therapy in situations where toxicity from oxygen or side effects of excess oxygen are of concern. Near infrared spectroscopy (NIRS) is a noninvasive technique being used to monitor oxygen content in the cerebral cortex. Unlike pulse oximetry NIRS measures all reflected light in both pulsatile arterial blood and nonpulsatile venous blood, the primary compartment in the cerebral vascular bed. NIRS is useful to monitor cerebral oxygenation in surgical procedures involving cardiopulmonary bypass and circulatory arrest (Guarracino, 2008).

Complications of Oxygen Therapy. Administration of supplemental oxygen is not without potential complications. In addition to the potential to promote absorption atelectasis and depress ventilation (discussed earlier), high flows of dry oxygen can dry out and irritate mucosal surfaces of the airway and the eyes, as well as decrease mucociliary transport and clearance of secretions. Humidified oxygen thus should be used when prolonged therapy (>1 hour) is required. Finally, any oxygen-enriched atmosphere constitutes a fire hazard, and appropriate precautions must be taken both in the operating room and for patients on oxygen at home.

It is important to realize that hypoxemia still can occur despite the administration of supplemental oxygen. Furthermore, when supplemental oxygen is administered, desaturation occurs at a later time after airway obstruction or hypoventilation, potentially delaying the detection of these critical events. Therefore, whether or not oxygen is administered to a patient at risk for these problems, it is essential that both O₂ saturation and adequacy of ventilation be assessed frequently.

Therapeutic Uses of Oxygen

Correction of Hypoxia. The primary therapeutic use of oxygen is to correct hypoxia. Hypoxia is most commonly a manifestation of an underlying disease, and administration of oxygen thus should be viewed as temporizing therapy. Efforts must be directed at correcting the cause of the hypoxia. For example, airway obstruction is unlikely to respond to an increase in inspired oxygen tension without relief of the obstruction. More important, while hypoxemia owing to hypoventilation after a narcotic overdose can be improved with supplemental oxygen administration, the patient remains at risk for respiratory failure if ventilation is not increased through stimulation, narcotic reversal, or mechanical ventilation. Hypoxia resulting from most pulmonary diseases can be alleviated at least partially by administration of oxygen, allowing time for definitive therapy to reverse the primary process. Thus, administration of oxygen is basic and important treatment for all forms of hypoxia.

Reduction of Partial Pressure of an Inert Gas. Since nitrogen constitutes some 79% of ambient air, it also is the predominant gas in most gas-filled spaces in the body. In situations such as bowel distension from obstruction or ileus, intravascular air embolism, or pneumothorax, it is desirable to reduce the volume of air-filled spaces. Since nitrogen is relatively insoluble, inhalation of high concentrations of oxygen (and thus low concentrations of nitrogen) rapidly lowers the total-body partial pressure of nitrogen and provides a substantial gradient for the removal of nitrogen from gas spaces. Administration of oxygen for air embolism is additionally beneficial because it helps to relieve localized hypoxia distal to the vascular obstruction. In the case of decompression sickness, or bends, lowering the inert gas tension in blood and tissues by oxygen inhalation prior to or during a barometric decompression reduces the supersaturation that occurs after decompression so that bubbles do not form. If bubbles do form in either tissues or the vasculature, administration of oxygen is based on the same rationale as that described for gas embolism.

Hyperbaric Oxygen Therapy. Oxygen can be administered at greater than atmospheric pressure in hyerbaric chambers (Thom, 2009). Clinical uses of hyperbaric oxygen therapy include the treatment of trauma, burns, radiation damage, infections, non-healing ulcers, skin grafts, spasticity, and other neurological conditions. Hyperbaric chambers can withstand pressures that range from 200 to 600 kPa (2-6 atm), although inhaled oxygen tension that exceeds 300 kPa (3 atm) rarely is used. Chambers range from single-person units to multiroom establishments housing complex medical equipment.

Hyperbaric oxygen therapy has two components: increased hydrostatic pressure and increased O₂ pressure. Both factors are necessary for the treatment of decompression sickness and air embolism. The hydrostatic pressure reduces bubble volume, and the absence of inspired nitrogen increases the gradient for elimination of nitrogen and reduces hypoxia in downstream tissues. Increased oxygen pressure at the tissue is the primary therapeutic goal for other indications for hyperbaric O₂. A small increase in PO₂ in ischemic areas enhances the bactericidal activity of leukocytes and increases angiogenesis. Repetitive brief exposures to hyperbaric oxygen may enhance therapy for chronic refractory osteomyelitis, osteoradionecrosis, crush injury, or the recovery of compromised skin and tissue grafts. Increased O₂ tension can be bacteriostatic and useful in the treatment for the spread of infection with Clostridium perfringens and clostridial myonecrosis (gas gangrene).

Hyperbaric oxygen may be useful in generalized hypoxia. In CO poisoning, hemoglobin (Hb) and myoglobin become unavailable for O₂ binding because of the high affinity of these proteins for CO. Affinity for CO is ~250 times greater than the affinity for O₂; thus, an alveolar concentration of CO = 0.4 mm Hg (1/250th that of alveolar O₂, which is ~100 mm Hg), will compete equally with O₂ for binding sites on Hb. High Po₂ facilitates competition of O₂ for Hb binding sites as CO is exchanged in the alveoli. In addition, hyperbaric O₂ increases the availability of dissolved O₂ in the blood (Table 19–4). In a randomized clinical trial (Weaver et al., 2002), hyperbaric O₂ decreased the incidence of long- and short-term neurological sequelae after CO intoxication. The occasional use of hyperbaric oxygen in cyanide poisoning has a similar rationale. Hyperbaric oxygen may be useful in severe short-term anemia since sufficient oxygen can be dissolved in the plasma at 3 atm to meet metabolic demand. Such treatment must be limited because oxygen toxicity depends on increased Po₂, not on the oxygen content of the blood.

Adverse effects of hyperbaric oxygen therapy include middle ear barotrauma, CNS toxicity, seizures, lung toxicity, and aspiration pneumonia. Contraindications to hyperbaric oxygen therapy include pneumothorax and concurrent doxorubicin, bleomycin, or disulfiram therapy. Relative contraindications include respiratory tract infections, severe obstructive lung disease, fever, seizure disorders, optic neuritis, pregnancy, concurrent steroid use, and claustrophobia.

Respiratory Tract. The pulmonary system is usually the first to exhibit toxicity, a function of its continuous exposure to the highest oxygen tensions in the body. Subtle changes in pulmonary function can occur within 8-12 hours of exposure to 100% O₂. Increases in capillary permeability, which will increase the alveolar/arterial oxygen gradient and ultimately lead to further hypoxemia, and decreased pulmonary function can be seen after only 18 hours of exposure (Clark, 1988). Serious injury and death, however, require much longer exposures. Pulmonary damage is directly related to the inspired oxygen tension, and concentrations of < 0.5 atm appear to be safe over long time periods. The capillary endothelium is the most sensitive tissue of the lung. Endothelial injury results in loss of surface area from interstitial edema and leaks into the alveoli.

Decreases of inspired oxygen concentrations remain the cornerstone of therapy for oxygen toxicity. Tolerance also may play a role in protection from oxygen toxicity; animals exposed briefly to high O₂ tensions are subsequently more resistant to toxicity. Sensitivity in humans also can be altered by preexposure to both high and low O₂ concentrations (Clark, 1988). These studies strongly suggest that changes in alveolar surfactant and cellular levels of antioxidant enzymes play a role in protection from oxygen toxicity.

Nervous System. Retinopathy of prematurity (ROP) is an eye disease in premature infants involving abnormal vascularization of the developing retina that can result from oxygen toxicity or relative hypoxia (Lutty et al., 2006). Retinal changes can progress to blindness and are likely caused by fibrovascular proliferation. Central nervous system problems are rare, and toxicity occurs only under hyperbaric conditions where exposure exceeds 200 kPa (2 atm). Symptoms include seizures and visual changes, which resolve when oxygen tension is returned to normal. Increased inspired oxygen concentrations are often administered to patients who have sustained acute ischemic central nervous system injury. In premature neonates and those who have sustained in utero asphyxia, hyperoxia and hypocapnia are associated with worse neurologic outcomes (Klinger et al., 2005). Similarly, in preclinical studies, resuscitation from cardiac arrest with high inspired oxygen concentrations leads to worse outcomes (Balan et al., 2006). These data indicate that oxygen therapy should be titrated to maintain an acceptable Po₂ and that hyperoxemia should be avoided (Sola, 2008).

Respiration. CO₂ is a rapid, potent stimulus to ventilation in direct proportion to the inspired CO₂. Inhalation of 10% carbon dioxide can produce minute volumes of 75 L/min in normal individuals. CO₂ stimulates breathing by acidifying central chemoreceptors and the peripheral carotid bodies (Guyenet, 2008). Elevated Pco₂ causes bronchodilation, whereas hypocarbia causes constriction of airway smooth muscle; these responses may play a role in matching pulmonary ventilation and perfusion (Duane et al., 1979).

Circulation. The circulatory effects of CO₂ result from the combination of its direct local effects and its centrally mediated effects on the autonomic nervous system. The direct effect of CO₂ on the heart, diminished contractility, results from pH changes and a decreased myofilament Ca²⁺ responsiveness (van den Bos et al., 1979). The direct effect on systemic blood vessels results in vasodilation. CO₂ causes widespread activation of the sympathetic nervous system and an increase in the plasma concentrations of epinephrine, norepinephrine, angiotensin, and other vasoactive peptides. The results of sympathetic nervous system activation generally are opposite to the local effects of carbon dioxide. The sympathetic effects consist of increases in cardiac contractility, heart rate, and vasoconstriction (Chapter 12).

The balance of opposing local and sympathetic effects, therefore, determines the total circulatory response to CO₂. The net effect of CO₂ inhalation is an increase in cardiac output, heart rate, and blood pressure. In blood vessels, however, the direct vasodilating actions of CO₂ appear more important, and total peripheral resistance decreases when the PCO₂ is increased. CO₂ also is a potent coronary vasodilator. Cardiac arrhythmias associated with increased PCO₂ are due to the release of catecholamines.

Hypocarbia results in opposite effects: decreased blood pressure and vasoconstriction in skin, intestine, brain, kidney, and heart. These actions are exploited clinically in the use of hyperventilation to diminish intracranial hypertension.

CNS. Hypercarbia depresses the excitability of the cerebral cortex and increases the cutaneous pain threshold through a central action. This central depression has therapeutic importance. For example, in patients who are hypoventilating from narcotics or anesthetics, increasing Pco₂ may result in further CNS depression, which in turn may worsen the respiratory depression. This positive-feedback cycle can have lethal consequences. The inhalation of high concentrations of carbon dioxide (~50%) produces marked cortical and subcortical depression of a type similar to that produced by anesthetic agents.

Methods of Administration. CO₂ is marketed in gray metal cylinders as the pure gas or as CO₂ mixed with oxygen. It usually is administered at a concentration of 5-10% in combination with O₂ by means of a face mask. Another method for the temporary administration of CO₂ is by rebreathing, such as from an anesthesia breathing circuit when the soda lime canister is bypassed or from something as simple as a paper bag. A potential safety issue exists in that tanks containing carbon dioxide plus oxygen are the same color as those containing 100% CO₂. When tanks containing CO₂ and O₂ have been used inadvertently where a fire hazard exists (e.g., in the presence of electrocautery during laparoscopic surgery), explosions and fires have resulted.

Therapeutic Uses. CO₂ is used for insufflation during endoscopic procedures (e.g., laparoscopic surgery) because it is highly soluble and does not support combustion. Inadvertent gas emboli thus are dissolved and eliminated more easily by the respiratory system. CO₂ can be used to flood the surgical field during cardiac surgery. Because of its density, carbon dioxide displaces the air surrounding the open heart so that any gas bubbles trapped in the heart are carbon dioxide rather than insoluble nitrogen (Nadolny and Svensson, 2000). Similarly, CO₂ is used to de-bubble cardiopulmonary bypass and extracorporeal membrane oxygenation (ECMO) circuits. It is used to adjust pH during cardiopulmonary bypass procedures when a patient is cooled.

Hypocarbia, with its attendant respiratory alkalosis, still has some uses in anesthesia. It constricts cerebral vessels, decreasing brain size slightly, and thus may facilitate the performance of neurosurgical operations. While short-term hypocarbia is effective for this purpose, sustained hypocarbia has been associated with worse outcomes in patients with head injury (Muizelaar et al., 1991). Consequently, hypocarbia should be instituted with a clearly defined indication and normocarbia should be re-established as soon the indication for hypocabia no longer applies.

Endogenous NO is produced from L-arginine by a family of enzymes called NO synthases (neural, inducible and endothelial). NO is both an intra-cellular and a cell-cell messenger implicated in a wide range of physiological and pathophysiological events in numerous cell types, including the cardiovascular, immune, and nervous systems. NO activates the soluble guanylyl cyclase, increasing cellular cyclic GMP (Chapter 3). In the vasculature, basal release of NO produced by endothelial cells is a primary determinant of resting vascular tone; NO causes vasodilation when synthesized in response to shear stress or a variety of vasodilating agents (Chapter 27). It also inhibits platelet aggregation and adhesion. Impaired NO production has been implicated in diseases such as atherosclerosis, hypertension, cerebral and coronary vasospasm, and ischemia–reperfusion injury. In the immune system, NO serves as an effector of macrophage-induced cytotoxicity, and overproduction of NO is a mediator of inflammation. In neurons, NO acts as a mediator of long-term potentiation, cytotoxicity resulting from N-methyl-D-aspartate (NMDA), and non-adrenergic non-cholinergic neurotransmission; NO has been implicated in mediating central nociceptive pathways (Chapters 8 and 18).

NO is rapidly inactivated in the circulation by oxyhemoglobin and by the reaction of NO with the heme iron, leading to the formation of nitrosyl-hemoglobin. Small quantities of methemoglobin are also produced and these are converted to the ferrous form of heme iron by cytochrome b5 reductase. The majority of inhaled NO is excreted in the urine in the form of nitrate. Rapid withdrawal of NO can result in a rebound increase in pulmonary pressure; gradual withdrawal should minimize rebound phenomena (Griffiths and Evans, 2005).

Inhaled NO (iNO) has potential as a therapy for numerous diseases associated with increased pulmonary vascular resistance. In patients with adult respiratory distress syndrome (ARDS), iNO is more often used to improve oxygenation rather than reducing pulmonary pressure. NO does improve oxygenation but this effect is transient. Moreover, the use of iNO therapy is not associated with either a reduction in the duration of mechanical ventilation or in morbidity or mortality (Taylor et al., 2004). iNO-mediated reductions in pulmonary pressure have prompted its use in patients with pulmonary hypertension in other clinical settings. Transient reduction in pulmonary pressure have been reported in patients undergoing cardiac surgery (Winterhalter et al., 2008) and pulmonary transplantation (Ardehali et al., 2001). Although transient physiologic improvements do occur, long-term outcome is essentially unchanged (Meade et al., 2003). Several small studies and case reports have suggested potential benefits of inhaled NO in a variety of conditions, including pulmonary hypertension and right heart failure associated with orthotopic heart transplantation, weaning from cardiopulmonary bypass in adult and congenital heart disease patients, ventricular assist device placement, primary pulmonary hypertension, pulmonary embolism, acute chest syndrome in sickle-cell patients, congenital diaphragmatic hernia, high-altitude pulmonary edema, and lung transplantation (Haddad et al., 2000). Larger prospective, randomized studies for these disease conditions either have not yet been performed or have failed to confirm any changes in outcome.

Inhaled NO is FDA-approved for only one indication, persistent pulmonary hypertension of the newborn (Mourani et al., 2004). A recent systematic review of the available data in neonates has shown that in very sick neonates with poor oxygenation, iNO does improve oxygenation but it does not improve mortality, reduce the incidence of bronchopulmonary dysplasia that is common in this population, or reduce the incidence of brain injury (Hintz et al., 2007, Su and Chen, 2008). Whether there are subsets of patients who may have a favorable response to iNO remains to be determined.

Diagnostic Uses. Inhaled NO also is used in several diagnostic applications. Inhaled NO can be used during cardiac catheterization to safely and selectively evaluate the pulmonary vasodilating capacity of patients with heart failure and infants with congenital heart disease. Inhaled NO also is used to determine the diffusion capacity (DL) across the alveolar–capillary unit. NO is more effective than carbon dioxide in this regard because of its greater affinity for hemoglobin and its higher water solubility at body temperature (Haddad et al., 2000).

NO is produced from the nasal passages and from the lungs of normal human subjects and can be detected in exhaled gas. The measurement of fractional exhaled NO (FeNO) is a noninvasive marker for airway inflammation with utility in the assessment of respiratory tract diseases including asthma, respiratory tract infection and chronic lung diseases (Taylor et al., 2006).

Toxicity. Administered at low concentrations (0.1-50 ppm), inhaled NO appears to be safe and without significant side effects. Pulmonary toxicity can occur with levels higher than 50-100 ppm. In the context of NO as an atmospheric pollutant, the Occupational Safety and Health Administration places the 7-hour exposure limit at 50 ppm. Part of the toxicity of NO may be related to its further oxidation to nitrogen dioxide (NO₂) in the presence of high concentrations of O₂. Even low concentrations of NO₂ (2 ppm) have been shown to be highly toxic in animal models, with observed changes in lung histopathology, including loss of cilia, hypertrophy, and focal hyperplasia in the epithelium of terminal bronchioles. It is important, therefore, to keep NO₂ formation during NO therapy at a low level. This can be achieved by the administration of NO at a site in the respiratory circuit as close to the patient as possible and timing the delivery of NO to inspiration. Laboratory studies have suggested potential additional toxic effects of chronic low doses of inhaled NO, including surfactant inactivation and the formation of peroxynitrite by interaction with superoxide. Nitric oxide and peroxynitrite have been implicated in cellular mechanisms of oxygen toxicity in the lung and central nervous system (Allen et al., 2009). The ability of NO to inhibit or alter the function of a number of iron- and heme-containing proteins, including cyclooxygenase, lipoxygenases, and oxidative cytochromes, as well as its interactions with ADP-ribosylation, suggests a need for further investigation of the toxic potential of NO under therapeutic conditions (Haddad et al., 2000).

The development of methemoglobinemia is a significant complication of inhaled NO at higher concentrations, and rare deaths have been reported with overdoses of NO. The blood content of methemoglobin, however, generally will not increase to toxic levels with appropriate use of inhaled NO. Methemoglobin concentrations should be monitored intermittently during NO inhalation (Haddad et al., 2000).

Inhaled NO can inhibit platelet function and has been shown to increase bleeding time in some clinical studies, although bleeding complications have not been reported.

In patients with impaired function of the left ventricle, NO has a potential to further impair left ventricular performance by dilating the pulmonary circulation and increasing the blood flow to the left ventricle, thereby increasing left atrial pressure and promoting pulmonary edema formation. Careful monitoring of cardiac output, left atrial pressure, or pulmonary capillary wedge pressure is important in this situation.

Despite these concerns, there are limited reports of inhaled NO-related toxicity in humans. The most important requirements for safe NO inhalation therapy include:

• continuous measurement of NO and NO₂ concentrations using either chemiluminescence or electrochemical analyzers

• frequent calibration of monitoring equipment

• intermittent analysis of blood methemoglobin levels

• the use of certified tanks of NO

• administration of the lowest NO concentration required for therapeutic effect

Methods of Administration. Courses of treatment of patients with inhaled NO are highly varied, extending from 0.1 to 40 ppm in dose and for periods of a few hours to several weeks in duration. The minimum effective inhaled NO concentration should be determined for each patient to minimize the chance for toxicity. Given that sensitivity to NO can vary in the patient during the course of administration, the determination of dose response relationship on a frequent basis should assist in the titration of the optimum dose of NO. Commercial NO systems are available that will accurately deliver inspired NO concentrations between 0.1 and 80 ppm and simultaneously measure NO and NO₂ concentrations. A constant inspired concentration of NO is obtained by administering NO in nitrogen to the inspiratory limb of the ventilator circuit in either a pulse or continuous mode. While inhaled NO may be administered to spontaneously breathing patients by a closely fitting mask, it usually is delivered during mechanical ventilation. Nasal prong administration is being employed in therapeutic trials of home administration for treatment of primary pulmonary hypertension (Griffiths et al., 2005).

Pulmonary gas flow normally is laminar. With increased flow rates or a narrowed flow pathway, a component of pulmonary gas flow becomes turbulent. Helium can be added to oxygen to reduce turbulence due to airway obstruction since the density of helium is less than that of air and the viscosity of helium is greater than that of air. Addition of helium reduces the Reynolds number of the mixture (the Reynolds number is proportional to density and inversely proportional to viscosity), thereby reducing turbulence. Mixtures of helium and oxygen reduce the work of breathing. The utility of helium/oxygen mixtures is limited by the fact that oxygenation often accompanies airway obstruction. The need for increased inspired O₂ concentration limits the fraction of helium that can be used. Furthermore, even though helium reduces the Reynolds number of the gas mixture, the viscosity of helium is greater than that of air, and the increased viscosity increases the resistance to flow according to Poiseuille's law, whereby flow is inversely proportional to viscosity.

Helium has high thermal conductivity, making it useful during laser surgery on the airway. This more rapid conduction of heat away from the point of contact of the laser beam reduces the spread of tissue damage and the likelihood that the ignition point of flammable materials in the airway will be reached. Its low density improves the flow through the small endotracheal tubes typically used in such procedures. However, its use for this purpose is rare.

Laser-polarized helium is used as an inhalational contrast agent for pulmonary magnetic resonance imaging. Optical pumping of hyperpolarized helium increases the signal from the gas in the lung to permit detailed imaging of the airways and inspired airflow patterns (Hopkins et al., 2007).

Hyperbaric Applications. The depth and duration of diving activity are limited by oxygen toxicity, inert gas (nitrogen) narcosis, and nitrogen supersaturation when decompressing. Oxygen toxicity is a problem with prolonged exposure to compressed air at 500 kPa (5 atm) or more. This problem can be minimized by dilution of oxygen with helium, which lacks narcotic potential even at very high pressures and is quite insoluble in body tissues. This low solubility reduces the likelihood of bubble formation after decompression, which therefore can be achieved more rapidly. The low density of helium also reduces the work of breathing in the otherwise dense hyperbaric atmosphere. The lower heat capacity of helium also decreases respiratory heat loss, which can be significant when diving at depth.