Goodman and Gilman Manual of Pharmacology and Therapeutics

Section II
Neuropharmacology

chapter 19
General Anesthetics and Therapeutic Gases

General Anesthetics

General anesthetics depress the central nervous system to a sufficient degree to permit the performance of surgery and unpleasant procedures. General anesthetics have low therapeutic indices and thus require great care in administration. The selection of specific drugs and routes of administration to produce general anesthesia is based on their pharmacokinetic properties and on the secondary effects of the various drugs, in the context of the proposed diagnostic or surgical procedure and with the consideration of the individual patient’s age, and associated medical condition.

GENERAL PRINCIPLES OF SURGICAL ANESTHESIA

The administration of general anesthesia is driven by 3 general objectives:

1. Minimizing the potentially deleterious direct and indirect effects of anesthetic agents and techniques

2. Sustaining physiologic homeostasis during surgical procedures that may involve major blood loss, tissue ischemia, reperfusion of ischemic tissue, fluid shifts, exposure to a cold environment, and impaired coagulation

3. Improving postoperative outcomes by choosing techniques that block or treat components of the surgical stress response, which may lead to short- or long-term sequelae

HEMODYNAMIC EFFECTS OF GENERAL ANESTHESIA. The most prominent physiological effect of anesthesia induction is a decrease in systemic arterial blood pressure. The causes include direct vasodilation, myocardial depression, or both; a blunting of baroreceptor control; and a generalized decrease in central sympathetic tone. Agents vary in the magnitude of their specific effects, but in all cases the hypotensive response is enhanced by underlying volume depletion or preexisting myocardial dysfunction.

RESPIRATORY EFFECTS OF GENERAL ANESTHESIA. Nearly all general anesthetics reduce or eliminate both ventilatory drive and the reflexes that maintain airway patency. Therefore, ventilation generally must be assisted or controlled for at least some period during surgery. The gag reflex is lost, and the stimulus to cough is blunted. Lower esophageal sphincter tone also is reduced, so both passive and active regurgitation may occur. Endotracheal intubation has been a major reason for a decline in the number of aspiration deaths during general anesthesia. Muscle relaxation is valuable during the induction of general anesthesia where it facilitates management of the airway, including endotracheal intubation. Neuromuscular blocking agents commonly are used to effect such relaxation (see Chapter 11). Alternatives to an endotracheal tube include a face mask and a laryngeal mask, an inflatable mask placed in the oropharynx forming a seal around the glottis.

HYPOTHERMIA. Patients commonly develop hypothermia (body temperature <36°C) during surgery. The reasons include low ambient temperature, exposed body cavities, cold intravenous (IV) fluids, altered thermoregulatory control, and reduced metabolic rate. Metabolic rate and total body oxygen consumption decrease with general anesthesia by ~30%, reducing heat generation. Hypothermia may lead to an increase in perioperative morbidity. Prevention of hypothermia is a major goal of anesthetic care.

NAUSEA AND VOMITING. Nausea and vomiting continue to be significant problems following general anesthesia and are caused by an action of anesthetics on the chemoreceptor trigger zone and the brainstem vomiting center, which are modulated by serotonin (5HT), histamine, ACh, and dopamine (DA). The 5HT3 receptor antagonists, ondansetron and dolasetron (see Chapters 13 and 46), are very effective in suppressing nausea and vomiting. Common treatments also include droperidol, metoclopramide, dexamethasone, and avoidance of N2O. The use of propofol as an induction agent and the nonsteroidal anti-inflammatory drug ketorolac as a substitute for opioids may decrease the incidence and severity of postoperative nausea and vomiting.

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 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. 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 with opioids and α2 agonists (dexmedetomidine).

Airway obstruction may occur during the postoperative period because residual anesthetic effects. Pulmonary function is reduced following all types of anesthesia and surgery, and hypoxemia may occur. Pain control can be complicated in the immediate postoperative period and respiratory suppression associated with opioids can be problematic. Regional anesthetic techniques are an important part of a perioperative 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.

ACTIONS AND MECHANISMS OF GENERAL ANESTHETICS

THE ANESTHETIC STATE

The components of the anesthetic state include:

• Amnesia

• Immobility in response to noxious stimulation

• Attenuation of autonomic responses to noxious stimulation

• Analgesia

• Unconsciousness

The potency of general anesthetic agents is measured by determining the concentration of general anesthetic that prevents movement in response to surgical stimulation. For inhalational anesthetics, anesthetic potency is measured in MAC units, with 1 MAC defined as the minimum alveolar concentration that prevents movement in response to surgical stimulation in 50% of subjects. 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 (MACawake) and the ability to form memories also have been correlated with alveolar anesthetic concentration. Verbal response and memory formation are suppressed at a fraction of MAC. The ratio of the anesthetic concentrations required to produce amnesia and immobility vary significantly among different inhalational anesthetic agents (nitrous oxide versus isoflurane).

Generally, the potency of IV 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.

MECHANISMS OF ANESTHESIA

CELLULAR MECHANISMS OF ANESTHESIA. General anesthetics produce 2 important physiologic effects at the cellular level:

• The inhalational anesthetics can hyperpolarize neurons. This may be an important effect on neurons serving a pacemaker role and on pattern-generating circuits.

• Both inhalational and IV anesthetics have substantial effects on synaptic transmission and much smaller effects on action-potential generation or propagation.

Inhalational anesthetics inhibit excitatory synapses and enhance inhibitory synapses in various preparations. 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. 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.

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 IV agents act predominantly by enhancing inhibitory neurotransmission, whereas ketamine predominantly inhibits excitatory neurotransmission at glutamatergic synapses.

MOLECULAR ACTIONS OF GENERAL ANESTHETICS. Most IV general anesthetics act predominantly through GABAA receptors and perhaps through some interactions with other ligand-gated ion channels such as NMDA receptors and 2-pore K+ channels.

Chloride channels gated by the inhibitory GABAA receptors (see Figures 14–3 and 14–6) are sensitive to a wide variety of anesthetics, including the halogenated inhalational agents and many IV agents (propofol, barbiturates, etomidate, and neurosteroids). At clinical concentrations, general anesthetics increase the sensitivity of the GABAA receptor to GABA, thus enhancing inhibitory neurotransmission and depressing nervous system activity. The action of anesthetics on the GABAA receptor probably is mediated by binding of the anesthetics to specific sites on the GABAA-receptor protein (but they do not compete with GABA for its binding site on the receptor). The capacity of propofol and etomidate to inhibit the response to noxious stimuli is mediated by a specific site on the β3 subunit of the GABAAreceptor, whereas the sedative effects of these anesthetics are mediated by on the β2 subunit.

Structurally related to the GABAA receptors are other ligand-gated ion channels including glycine receptors and neuronal nicotinic ACh receptors. Glycine receptors may play a role in mediating inhibition by anesthetics of responses to noxious stimuli. Inhalational anesthetics enhance the capacity of glycine to activate glycine-gated chloride channels (glycine receptors), which play an important role in inhibitory neurotransmission in the spinal cord and brainstem. Propofol, neurosteroids, and barbiturates also potentiate glycine-activated currents, whereas etomidate and ketamine do not. Subanesthetic concentrations of the inhalational anesthetics inhibit some classes of neuronal nicotinic ACh receptors, which seem to mediate other components of anesthesia such as analgesia or amnesia.

Ketamine, nitrous oxide, cyclopropane, and xenon are the only general anesthetics that do not have significant effects on GABAA or glycine receptors. These agents inhibit a different type of ligand-gated ion channel, the NMDA receptor (see Figure 14–7 and Table 14–1). NMDA receptors are glutamate-gated cation channels that are somewhat selective for Ca++ and are involved in long-term modulation of synaptic responses (long-term potentiation) and glutamate-mediated neurotoxicity.

Halogenated inhalational anesthetics activate some members of a class of K+ channels known as 2-pore domain channels; other 2-pore domain channel family members are activated by xenon, nitrous oxide, and cyclopropane. These channels are located in both presynaptic and postsynaptic sites. The postsynaptic channels may be the molecular locus through which these agents hyperpolarize neurons.

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. Most anesthetics cause, with some exceptions, a global reduction in cerebral metabolic rate (CMR) and in cerebral blood flow (CBF). A consistent feature of general anesthesia is a suppression of metabolism in the thalamus, which serves as a major relay by which sensory input from the periphery ascends to the cortex. Suppression of thalamic activity may serve as a switch between the awake and anesthetized states. General anesthesia also 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.

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, 5HT, orexin, NE, and ACh mediate wakefulness. Intravenous and inhalational agents with activity at GABAA 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. Finally, both IV and inhalational anesthetics depress hippocampal neurotransmission, a probable locus for their amnestic effects.

PARENTERAL ANESTHETICS

Parenteral anesthetics are the most common drugs used for anesthetic induction of adults. Their lipophilicity, coupled with the relatively high perfusion of the brain and spinal cord, results in rapid onset and short duration after a single bolus dose. These drugs ultimately accumulate in fatty tissue. Each anesthetic has its own unique set of properties and side effects (Tables 19–1 and 19–2). Propofol and thiopental are the 2 most commonly used parenteral agents. Propofol is advantageous for procedures where rapid return to a preoperative mental status is desirable. Thiopental has a long-established track record of safety. Etomidate usually is reserved for patients at risk for hypotension and/or myocardial ischemia. Ketamine is best suited for patients with asthma or for children undergoing short, painful procedures.

Table 19–1

Pharmacological Properties of Parenteral Anesthetics

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Table 19–2

Some Pharmacological Effects of Parenteral Anestheticsa

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PHARMACOKINETIC PRINCIPLES

Parenteral anesthetics are small, hydrophobic, substituted aromatic or heterocyclic compounds (Figure 19–1). Hydrophobicity is the key factor governing their pharmacokinetics. After a single IV bolus, these drugs preferentially partition into the highly perfused and lipophilic tissues of the brain and spinal cord where they produce anesthesia within a single circulation time. Subsequently blood levels fall rapidly, resulting in drug redistribution out of the CNS back into the blood. The anesthetic then diffuses into less perfused tissues such as muscle and viscera, and at a slower rate into the poorly perfused but very hydrophobic adipose tissue. Termination of anesthesia after single boluses of parenteral anesthetics primarily reflects redistribution out of the CNS rather than metabolism (Figure 19–2).

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Figure 19–1 Structures of some parenteral anesthetics.

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Figure 19–2 Thiopental serum levels after a single intravenous induction dose. Thiopental serum levels after a bolus can be described by two time constants, t1/2 α and t1/2 β. The initial fall is rapid (t1/2α<10 min) and is due to redistribution of drug from the plasma and the highly perfused brain and spinal cord into less well-perfused tissues such as muscle and fat. During this redistribution phase, serum thiopental concentration falls to levels at which patients awaken (AL, awakening level; see inset—the average thiopental serum concentration in 12 patients after a 6-mg/kg intravenous bolus of thiopental). Subsequent metabolism and elimination is much slower and is characterized by a half-life (t1/2 β) of more than 10 hours. (Adapted with permission from Burch PG, and Stanski DR, The role of metabolism and protein binding in thiopental anesthesia. Anesthesiology1983, 58:146–152. Copyright Lippincott Williams & Wilkins. http://lww.com.)

After redistribution, anesthetic blood levels fall according to a complex interaction between the metabolic rate and the amount and lipophilicity of the drug stored in the peripheral compartments. Thus, parenteral anesthetic half-life are “context-sensitive,” and the degree to which a t1/2 is contextual varies greatly from drug to drug, as might be predicted based on their differing hydrophobicities and metabolic clearances (Figure 19–3see Table 19–1). For example, after a single bolus of thiopental, patients usually emerge from anesthesia within 10 min; however, a patient may require more than a day to awaken from a prolonged thiopental infusion. Most individual variability in sensitivity to parenteral anesthetics can be accounted for by pharmacokinetic factors. For example, in patients with lower cardiac output, the relative perfusion of the brain and the fraction of anesthetic dose delivered to the brain are higher; thus, patients in septic shock or with cardiomyopathy usually require lower doses of anesthetic. The elderly also typically require a smaller anesthetic dose, primarily because of a smaller initial volume of distribution.

Table 19–3

Properties of Inhalational Anesthetic Agents

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Figure 19–3 Context-sensitive half-time of general anesthetics. The duration of action of single intravenous doses of anesthetic/hypnotic drugs is similarly short for all and is determined by redistribution of the drugs away from their active sites (see Figure 19–2). However, after prolonged infusions, drug half-lives and durations of action are dependent on a complex interaction between the rate of redistribution of the drug, the amount of drug accumulated in fat, and the drug’s metabolic rate. This phenomenon has been termed the context-sensitive half-time; that is, the t1/2 of a drug can be estimated only if one knows the context—the total dose and over what time period it has been given. Note that the half-times of some drugs such as etomidate, propofol, and ketamine increase only modestly with prolonged infusions; others (e.g., diazepam and thiopental) increase dramatically. (Reproduced with permission from Reves JG, Glass PSA, Lubarsky DA, et al: Intravenous anesthetics, in Miller RD, et al, (eds):Miller’s Anesthesia, 7th ed. Philadelphia: Churchill Livingstone, 2010, p 718. Copyright © Elsevier.)

SPECIFIC PARENTERAL AGENTS

PROPOFOL, FOSPROPOFOL

Propofol is the most commonly used parenteral anesthetic in the U.S. Fospropofol is a prodrug form that is converted to propofol in vivo. The clinical pharmacological properties of propofol are summarized in Table 19–1.

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. Propofol should be administered within 4 h 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.

DOSAGE AND CLINICAL USE. The induction dose of propofol (DIPRIVAN, others) in a healthy adult is 2-2.5 mg/kg. 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 t1/2, 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 min or as needed are effective. An infusion of propofol produces a more stable drug level (100-300 µg/kg/min) and is better suited for longer-term anesthetic maintenance. Sedating doses of propofol are 20-50% of those required for general anesthesia. 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 min. The duration of the sedative effect is ∼45 min.

PHARMACOKINETICS AND METABOLISM. Onset and duration of anesthesia after a single bolus are similar to thiopental. Propofol has a context-sensitive t1/2 of 10 min with an infusion lasting 3 h and∼40 min for infusions lasting up to 8 h (see 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.

Propofol is metabolized in the liver by conjugation to sulfate and glucuronide to less active metabolites that are renally excreted. 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. In neonates, propofol clearance is also reduced. 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.

The t1/2 for hydrolysis of fospropofol is 8 min; the drug has a small volume of distribution and a terminal t1/2 ∼46 min.

SIDE EFFECTS

Nervous System. The sedation and hypnotic actions of propofol are mediated by its action on GABAA 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 cerebral metabolic rate of O2 consumption (CMRO2), CBF, 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.

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. As with thiopental, propofol should be used with caution in patients at risk for or intolerant of decreases in blood pressure.

Respiratory System. Propofol produces a slightly greater degree of respiratory depression than thiopental. 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. The bronchodilator properties of propofol may be attenuated by the metabisulfite preservative in some propofol formulations.

Other Side Effects. Propofol has a significant antiemetic action. Propofol elicits pain on injection that can be reduced with lidocaine and the use of larger arm and antecubital veins. 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. The side-effect profile of fospropofol is similar to that of propofol.

ETOMIDATE

Etomidate is a substituted imidazole that is supplied as the active d-isomer. Etomidate is poorly soluble in water and is formulated as a 2 mg/mL solution in 35% propylene glycol. Unlike thiopental, etomidate does not induce precipitation of neuromuscular blockers or other drugs frequently given during anesthetic induction.

DOSAGE AND CLINICAL USE. Etomidate (AMIDATE, others) is primarily used for anesthetic induction of patients at risk for hypotension. Induction doses of etomidate (see Table 19–1) are accompanied by a high incidence of pain on injection and myoclonic movements. Lidocaine effectively reduces the pain of injection, while myoclonic movements can be reduced by premedication with either benzodiazepines or opiates. Etomidate is pharmacokinetically suitable for off-label infusion for anesthetic maintenance (10 μg/kg/min) or sedation (5 μg/kg/min); however, long-term infusions are not recommended.

PHARMACOKINETICS AND METABOLISM. An induction dose of etomidate has a rapid onset; redistribution limits the duration of action. Metabolism occurs in the liver, primarily to inactive compounds. Elimination is both renal (78%) and biliary (22%). Compared to thiopental, the duration of action of etomidate increases less with repeated doses (see Figure 19–3).

SIDE EFFECTS

Nervous System. Etomidate produces hypnosis and has no analgesic effects. The effects of etomidate on CBF, metabolism, and intracranial and intraocular pressures are similar to those of thiopental (without dropping mean arterial blood pressure). Etomidate produces increased EEG activity in epileptogenic foci and has been associated with seizures.

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.

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. 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. 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.

KETAMINE

Ketamine is an arylcyclohexylamine, a congener of phencyclidine. 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.

DOSAGE AND CLINICAL USE. Ketamine (KETALAR, others) 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. Ketamine typically is administered intravenously but also is effective by intramuscular, oral, and rectal routes. 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 (see Table 19–1 and Figure 19–3). Protein binding is much lower with ketamine than with the other parenteral anesthetics.

SIDE EFFECTS

Nervous System. Ketamine has indirect sympathomimetic activity and produces distinct behavioral effects. The ketamine-induced cataleptic state is accompanied by nystagmus with pupillary dilation, salivation, lacrimation, and spontaneous limb movements with increased overall muscle tone. 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 CBF and intracranial pressure (ICP) with minimal alteration of cerebral metabolism. The effects of ketamine on CBF can be readily attenuated by the simultaneous administration of sedative-hypnotic agents.

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. Benzodiazepines reduce the incidence of emergence delirium.

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. Thus, ketamine is a useful drug, along with etomidate, for patients at risk for hypotension during anesthesia. While not arrhythmogenic, ketamine increases myocardial O2consumption 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 and is particularly well suited for anesthetizing patients at high risk for bronchospasm.

BARBITURATES

CHEMISTRY AND FORMULATIONS. Barbiturates are derivatives of barbituric acid with either an oxygen or a sulfur at the 2-position (see Figure 19–1 and Chapter 17). The 3 barbiturates most commonly used in clinical anesthesia are sodium thiopental, thiamylal, and methohexital. Sodium thiopental (PENTOTHAL, others) has been used most frequently for inducing anesthesia. Thiamylal (SURITAL) is licensed in the U.S. only for veterinary use. Barbiturates are supplied as racemic mixtures despite enantioselectivity in their anesthetic potency. Barbiturates are formulated as the sodium salts with 6% sodium carbonate and reconstituted in water or isotonic saline to produce 2.5% (thiopental), 2% (thiamylal), or 1% (methohexital) alkaline solutions (10 ≤ pH ≤ 11). Mixing barbiturates with drugs in acidic solutions during anesthetic induction can result in precipitation of the barbiturate as the free acid; thus, standard practice is to delay the administration of other drugs until the barbiturate has cleared the IV tubing.

PHARMACOLOGICAL PROPERTIES. The pharmacological properties and other therapeutic uses of the barbiturates are presented in Chapter 17Table 17–2 lists the common barbiturates with their clinical pharmacological properties.

DOSAGES AND CLINICAL USE. Recommended IV dosing for parenteral barbiturates in a healthy young adult is given in Table 19–1.

PHARMACOKINETICS AND METABOLISM. 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. See Table 19–1 for pharmacokinetic parameters.

Methohexital differs from the other two IV 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. All 3 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. These drugs are highly protein bound. Hepatic disease or other conditions that reduce serum protein concentration will increase the initial free concentration and hypnotic effect of an induction dose.

SIDE EFFECTS

Nervous System. Barbiturates suppress the EEG and can produce burst suppression of the EEG. They reduce the CMR, as measured by CMRO2, in a dose-dependent manner. As a consequence of the decrease in CMRO2, CBF and ICP are similarly reduced. 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. 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. Reflex responses to hypercarbia and hypoxia are diminished by anesthetic barbiturates; at higher doses or in the presence of other respiratory depressants such as opiates, apnea can result. Compared to propofol, barbiturates produce a higher incidence of wheezing in asthmatics, attributed to histamine release from mast cells, during induction of anesthesia.

Other Side Effects. Short-term administration of barbiturates has no clinically significant effect on the hepatic, renal, or endocrine systems. True allergies to barbiturates are rare; however, direct drug-induced histamine release is occasionally seen. Barbiturates can induce fatal attacks of porphyria in patients with acute intermittent or variegate porphyria and are contraindicated in such patients. Methohexital can produce pain on injection to a greater degree than thiopental. Inadvertent intraarterial 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.

INHALATIONAL ANESTHETICS

A wide variety of gases and volatile liquids can produce anesthesia. The structures of the currently used inhalational anesthetics are shown in Figure 19–4. The inhalational anesthetics have therapeutic indices (LD50/ED50) that range from 2-4, making these among the most dangerous drugs in clinical use. The toxicity of these drugs is largely a function of their side effects, and each of the inhalational anesthetics has a unique side-effect profile. Hence, the selection of an inhalational anesthetic often is based on matching a patient’s pathophysiology with drug side-effect profiles.

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Figure 19–4 Structures of inhalational general anesthetics. Note that all inhalational general anesthetic agents except nitrous oxide and halothane are ethers, and that fluorine progressively replaces other halogens in the development of the halogenated agents. All structural differences are associated with important differences in pharmacological properties.

Table 19–3 lists the widely varying physical properties of the inhalational agents in clinical use. Ideally, an inhalational agent would produce a rapid induction of anesthesia and a rapid recovery following discontinuation.

PHARMACOKINETIC PRINCIPLES

Inhalational agents behave as gases rather than as liquids and thus require different pharmacokinetic constructs to be used in analyzing their uptake and distribution. Inhalational anesthetics distribute between tissues (or between blood and gas) such that equilibrium is achieved when the partial pressure of anesthetic gas is equal in the 2 tissues. When a person has breathed an inhalational anesthetic for a sufficiently long time that all tissues are equilibrated with the anesthetic, the partial pressure of the anesthetic in all tissues will be equal to the partial pressure of the anesthetic in inspired gas. While the partial pressure of the anesthetic may be equal in all tissues, the concentration of anesthetic in each tissue will be different. Indeed, anesthetic partition coefficients are defined as the ratio of anesthetic concentration in 2 tissues when the partial pressures of anesthetic are equal in the 2 tissues. Blood:gas, brain:blood, and fat:blood partition coefficients for the various inhalational agents are listed in Table 19–3. These partition coefficients show that inhalational anesthetics are more soluble in some tissues (e.g., fat) than they are in others (e.g., blood).

In clinical practice, equilibrium is achieved when the partial pressure in inspired gas is equal to the partial pressure in end-tidal (alveolar) gas. For inhalational agents that are not very soluble in blood or any other tissue, equilibrium is achieved quickly, as illustrated for nitrous oxide in Figure 19–5. If an agent is more soluble in a tissue such as fat, equilibrium may take many hours to reach. This occurs because fat represents a huge anesthetic reservoir that will be filled slowly because of the modest blood flow to fat. Anesthesia is produced when anesthetic partial pressure in brain is equal to or greater than MAC. Because the brain is well perfused, anesthetic partial pressure in brain becomes equal to the partial pressure in alveolar gas (and in blood) over the course of several minutes. Therefore, anesthesia is achieved shortly after alveolar partial pressure reaches MAC.

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Figure 19–5 Uptake of inhalational general anesthetics. The rise in end-tidal alveolar (FA) anesthetic concentration toward the inspired (FI) concentration is most rapid with the least soluble anesthetics, nitrous oxide and desflurane, and slowest with the most soluble anesthetic, halothane. All data are from human studies. (Reproduced with permission from Eger EI, II. Inhaled anesthetics: Uptake and distribution, in Miller RD et al, eds. Miller’s Anesthesia, 7th ed. Philadelphia: Churchill Livingstone, 2010, p 540. Copyright, Elsevier.)

Elimination of inhalational anesthetics is largely the reverse process of uptake. For inhalational agents with high blood and tissue solubility, recovery will be a function of the duration of anesthetic administration. This occurs because the accumulated amounts of anesthetic in the fat reservoir will prevent blood (and therefore alveolar) partial pressures from falling rapidly. Patients will be arousable when alveolar partial pressure reaches MACawake, a partial pressure somewhat lower than MAC (see Table 19–3).

HALOTHANE

Halothane is a volatile liquid at room temperature and must be stored in a sealed container. Because halothane is a light-sensitive compound, it is marketed in amber bottles with thymol added as a preservative. Mixtures of halothane with O2 or air are neither flammable nor explosive.

PHARMACOKINETICS. Halothane has a relatively high blood:gas partition coefficient and high fat:blood partition coefficient. Induction with halothane is relatively slow, and the alveolar halothane concentration remains substantially lower than the inspired halothane concentration for many hours of administration. Because halothane is soluble in fat and other body tissues, it will accumulate during prolonged administration.

Approximately 60-80% of halothane taken up by the body is eliminated unchanged by the lungs in the first 24 h 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.

CLINICAL USE. Halothane is used for maintenance of anesthesia. It is well tolerated for inhalation induction of anesthesia, most commonly in children. The use of halothane in the U.S. has diminished because of the introduction of newer inhalational agents with better pharmacokinetic and side-effect profiles. Halothane continues to be extensively used in children because it is well tolerated and its side effects appear to be diminished in children. Halothane has a low cost and is still widely used in developing countries.

SIDE EFFECTS

Cardiovascular System. Halothane induces a dose-dependent reduction in arterial blood pressure. Mean arterial pressure typically decreases ~20-25% at MAC concentrations of halothane, primarily as a result of direct myocardial depression leading to reduced cardiac output and attenuation of baroreceptor reflex function. 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 but does dilates the vascular beds of the skin and brain. Halothane inhibits autoregulation of renal, splanchnic, and CBF, leading to reduced perfusion of these organs in the face of reduced blood pressure. Coronary autoregulation is largely preserved during halothane anesthesia. Halothane inhibits hypoxic pulmonary vasoconstriction, leading to increased perfusion to poorly ventilated regions of the lung and an increased alveolar:arterial O2 gradient. 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.

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. 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.

Nervous System. Halothane dilates the cerebral vasculature, increasing CBF and cerebral blood volume. This can result in an increase in ICP, especially in patients with space-occupying intracranial masses, brain edema, or preexisting intracranial hypertension. Halothane attenuates autoregulation of CBF in a dose-dependent manner.

Muscle. Halothane causes some relaxation of skeletal muscle by its central depressant effects. Halothane also potentiates the actions of nondepolarizing muscle relaxants (curariform drugs; see 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. This syndrome frequently is fatal and is treated by immediate discontinuation of the anesthetic and administration of dantrolene. Halothane relaxes uterine smooth muscle, a useful property for manipulation of the fetus (version) in the prenatal period and for delivery of retained placenta.

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. Halothane can produce fulminant hepatic necrosis (halothane hepatitis) in ~1 in 10,000 patients receiving halothane and is referred to as halothane hepatitis. This syndrome (with a 50% fatality rate) is characterized by fever, anorexia, nausea, and vomiting, developing several days after anesthesia and can be accompanied by a rash and peripheral eosinophilia. Halothane hepatitis may be the result of an immune response to hepatic proteins that become trifluoroacetylated as a consequence of halothane metabolism.

ISOFLURANE

Isoflurane (FORANE, others) is a volatile liquid at room temperature and is neither flammable nor explosive in mixtures of air or oxygen.

PHARMACOKINETICS. Isoflurane has a blood:gas partition coefficient substantially lower than that of halothane or enflurane. Consequently, induction with isoflurane and recovery from isoflurane are relatively faster. More than 99% of inhaled isoflurane is excreted unchanged by the lungs. Isoflurane does not appear to be a mutagen, teratogen, or carcinogen.

CLINICAL USE. Isoflurane is a commonly used inhalational anesthetic worldwide. 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 min 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 adjunct agents 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; cardiac output is well maintained; hypotension is the result of decreased systemic vascular resistance. 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. 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. Isoflurane is particularly effective at depressing the ventilatory response to hypercapnia and hypoxia. Although 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 CBF; this vasodilating activity is less than that of either halothane or enflurane. There is a modest risk of an increase in ICP in patients with preexisting intracranial hypertension. Isoflurane reduces CMRO2 in a dose-dependent manner.

Muscle. Isoflurane produces some relaxation of skeletal muscle by its central effects. It also enhances the effects of both depolarizing and nondepolarizing muscle relaxants. 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.

Liver and GI Tract. Splanchnic and hepatic blood flows are reduced with increasing doses of isoflurane as systemic arterial pressure decreases. There are no reported incidences of hepatic toxicity.

ENFLURANE

Enflurane (ETHRANE, others) 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 nonexplosive in mixtures of air or oxygen.

PHARMACOKINETICS. Because of its relatively high blood:gas partition coefficient, induction of anesthesia and recovery from enflurane are relatively slow. 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 consequent elevation of serum fluoride.

CLINICAL USE. Isoflurane is primarily utilized for maintenance rather than induction of anesthesia. Surgical anesthesia can be induced with enflurane in <10 min with an inhaled concentration of 4% in oxygen, and maintained with concentrations from 1.5-3%. Enflurane concentrations required to produce anesthesia are reduced when it is coadministered with nitrous oxide or opioids.

SIDE EFFECTS

Cardiovascular System. Enflurane causes a concentration-dependent decrease in arterial blood pressure, due in part, to depression of myocardial contractility, with some contribution from peripheral vasodilation. Enflurane has minimal effects on heart rate.

Respiratory System. The respiratory effects of enflurane are similar to those of halothane. Enflurane produces a greater depression of the ventilatory responses to hypoxia and hypercarbia than do either halothane or isoflurane. Enflurane, like other inhalational anesthetics, is an effective bronchodilator.

Nervous System. Enflurane is a cerebral vasodilator and can increase ICP in some patients; it also reduces CMRO2. High concentrations of enflurane or profound hypocarbia during enflurane anesthesia can result in electrical seizure activity that may be accompanied by peripheral motor manifestations. 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 nondepolarizing muscle relaxants. As with other inhalational agents, enflurane relaxes uterine smooth muscle.

Kidney. Enflurane reduces renal blood flow, glomerular filtration rate, and urinary output. These effects are rapidly reversed upon drug discontinuation. 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.

DESFLURANE

Desflurane (SUPRANE) is a highly volatile liquid at room temperature (vapor pressure = 681 mm Hg) and must be stored in tightly sealed bottles. 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 nonexplosive in mixtures of air or O2.

PHARMACOKINETICS. Desflurane has a very low blood:gas partition coefficient (0.42) and also is not very soluble in fat or other peripheral tissues. Thus, the alveolar and blood concentrations rapidly rise to the level of inspired concentration, providing rapid induction of anesthesia and rapid changes in depth of anesthesia following changes in the inspired concentration. Emergence from desflurane anesthesia also is very rapid. Desflurane is minimally metabolized; >99% of absorbed desflurane is eliminated unchanged through the lungs.

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 IV 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 coadministered with nitrous oxide or opioids.

SIDE EFFECTS

Cardiovascular System. Desflurane produces hypotension primarily by decreasing systemic vascular resistance. Cardiac output is well preserved, as is blood flow to the major organ beds (splanchnic, renal, cerebral, and coronary). Transient tachycardia is often noted with abrupt increases in desflurane’s delivered concentration, a result of this desflurane-induced stimulation of the sympathetic nervous system. The hypotensive effects of desflurane do not wane with increasing duration of administration.

Respiratory System. 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. Desflurane concentrations >1 MAC depress minute ventilation, resulting in elevated arterial CO2 tension (PaCO2). Desflurane 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 CMRO2. 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 CBF and can increase ICP in patients with poor intracranial compliance. The vasoconstrictive response to hypocapnia is preserved during desflurane anesthesia, and increases in ICP thus can be prevented by hyperventilation.

Muscle, Kidney, Liver and GI Tract. Desflurane produces direct skeletal muscle relaxation as well as enhancing the effects of nondepolarizing and depolarizing neuromuscular blocking agents. Consistent with its minimal metabolic degradation, desflurane has no reported nephrotoxicity or hepatotoxicity.

Desflurane and Carbon Monoxide. Inhaled anesthetics are administered via a system that permits unidirectional flow of gas and rebreathing of exhaled gases. To prevent rebreathing of CO2 (which can lead to hypercarbia), CO2 absorbers are incorporated into the anesthesia delivery circuits. With almost complete desiccation 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.

SEVOFLURANE

Sevoflurane (ULTANE, others) is a clear, colorless, volatile liquid at room temperature and must be stored in a sealed bottle. It is nonflammable and nonexplosive in mixtures of air or oxygen. However, sevoflurane can undergo an exothermic reaction with desiccated CO2 absorbent (BARALYME) to produce airway burns or spontaneous ignition, explosion, and fire.

Sevoflurane must not be not used with an anesthesia machine in which the CO2 absorbent has been dried by prolonged gas flow through the absorbent. The reaction of sevoflurane with desiccated CO2absorbent also can produce CO, which can result in serious patient injury.

PHARMACOKINETICS. The low solubility of sevoflurane in blood and other tissues provides for rapid induction of anesthesia and rapid changes in anesthetic depth following changes in delivered concentration. Approximately 3% of absorbed sevoflurane is metabolized in the liver by CYP2E1, with the predominant product being hexafluoroisopropanol. Hepatic metabolism of sevoflurane also produces inorganic fluoride. Interaction of sevoflurane with soda lime also produces decomposition products that may be toxic such as compound A, pentafluoroisopropenyl fluoromethyl ether (see“Kidney” under “Side Effects”).

CLINICAL USE. Sevoflurane is widely used, particularly for outpatient anesthesia, because of its rapid recovery profile, and 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 produces concentration-dependent decreases in arterial blood pressure (due to systemic vasodilation) and cardiac output. 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 PaCO2. Sevoflurane is not irritating to the airway and is a potent bronchodilator. As a result, sevoflurane is the most effective clinical bronchodilator of the inhalational anesthetics.

Nervous System. Sevoflurane produces effects on cerebral vascular resistance, CMRO2, and CBF that are very similar to those produced by isoflurane and desflurane. Sevoflurane can increase ICP in patients with poor intracranial compliance, the response to hypocapnia is preserved during sevoflurane anesthesia, and increases in ICP can be prevented by hyperventilation. In children, sevoflurane is associated with delirium upon emergence from anesthesia. This delirium is short lived and without any reported adverse long-term sequelae.

Muscle. Sevoflurane produces skeletal muscle relaxation and enhances the effects of nondepolarizing and depolarizing neuromuscular blocking agents.

Kidney. Controversy has surrounded the potential nephrotoxicity of compound A, which is produced by interaction of sevoflurane with the CO2-absorbent soda lime. Biochemical evidence of transient renal injury has been reported in human volunteers. Large clinical studies have shown no evidence of increased serum creatinine, blood urea nitrogen, or any other evidence of renal impairment following sevoflurane administration. 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.

NITROUS OXIDE

Nitrous oxide (N2O) is a colorless, odorless gas at room temperature. N2O is sold in steel cylinders and must be delivered through calibrated flow meters provided on all anesthesia machines. N2O 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.

PHARMACOKINETICS. N2O is very insoluble in blood and other tissues. This results in rapid equilibration between delivered and alveolar anesthetic concentrations and provides for rapid induction of anesthesia and rapid emergence following discontinuation of administration. The rapid uptake of N2O from alveolar gas serves to concentrate coadministered halogenated anesthetics; this effect (the “second gas effect”) speeds induction of anesthesia. On discontinuation of N2O administration, N2O 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.

Almost all (99.9%) of the absorbed N2O is eliminated unchanged by the lungs. N2O can interact with the cobalt of vitamin B12, thereby preventing vitamin B12 from acting as a cofactor for methionine synthase. Inactivation of methionine synthase can produce signs of vitamin B12 deficiency, including megaloblastic anemia and peripheral neuropathy, a 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.

CLINICAL USE. N2O is a weak anesthetic agent that has significant analgesic effects. Surgical anesthetic depth is only achieved under hyperbaric conditions. By contrast, analgesia is produced at concentrations as low as 20%. The analgesic property of N2O is a function of the activation of opioidergic neurons in the periaqueductal gray matter and the adrenergic neurons in the locus ceruleus. N2O is frequently used in concentrations of ~50% to provide analgesia and mild sedation in outpatient dentistry. N2O cannot be used at concentrations >80% because this limits the delivery of adequate O2. Because of this limitation, N2O is used primarily as an adjunct to other inhalational or IV anesthetics.

A 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, N2O will enter the cavity faster than N2 escapes, thereby increasing the volume and/or pressure in this cavity. Examples of air collections that can be expanded by N2O 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. N2O 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 N2O on the sympathetic nervous system. The cardiovascular effects of N2O also are heavily influenced by the concomitant administration of other anesthetic agents. When N2O is coadministered with halogenated inhalational anesthetics, it produces an increase in heart rate, arterial blood pressure, and cardiac output. In contrast, when N2O is coadministered with an opioid, it generally decreases arterial blood pressure and cardiac output. N2O 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. Even modest concentrations of N2O markedly depress the ventilatory response to hypoxia. Thus, it is prudent to monitor arterial O2 saturation directly in patients receiving or recovering from N2O.

Nervous System. N2O can significantly increase CBF and ICP. This cerebral vasodilatory capacity of N2O is significantly attenuated by the simultaneous administration of IV 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. N2O does not relax skeletal muscle and does not enhance the effects of neuromuscular blocking drugs.

Kidney, Liver, and GI Tract. N2O is not known have nephrotoxic or hepatotoxic effects.

XENON

Xenon (Xe), an inert gaseous element, is not approved for use in the U.S. and is unlikely to enjoy widespread use because it is a rare gas that cannot be manufactured and must be extracted from air; thus, xenon is expensive and available in limited quantities. Xenon, unlike other anesthetic agents, has minimal cardiorespiratory and other side effects.

Xenon is extremely insoluble in blood and other tissues, providing for rapid induction and emergence from anesthesia. It is sufficiently potent to produce surgical anesthesia when administered with 30% oxygen. However, supplementation with an IV agent such as propofol appears to be required for clinical anesthesia. Xenon is well tolerated in patients of advanced age. No long-term side effects from xenon anesthesia have been reported.

ANESTHETIC ADJUNCTS

A general anesthetic is usually given with adjuncts to augment specific components of anesthesia, permitting lower doses of general anesthetics with fewer side effects.

BENZODIAZEPINES

Benzodiazepines (see Chapter 17) can produce anesthesia similar to that of barbiturates, they are more commonly used for sedation rather than general anesthesia because prolonged amnesia and sedation may result from anesthetizing doses. As adjuncts, benzodiazepines are used for anxiolysis, amnesia, and sedation prior to induction of anesthesia or for sedation during procedures not requiring general anesthesia. The benzodiazepine most frequently used in the perioperative period is midazolam followed distantly by diazepam (VALIUM, others), and lorazepam (ATIVAN, others).

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 min and provide sedation for ~30 min. Elderly patients tend to be more sensitive to and have a slower recovery from benzodiazepines. Midazolam is hepatically metabolized. 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 (see Figure 19–3). Benzodiazepines reduce CBF and metabolism but at equianesthetic doses are less potent in this respect than are barbiturates. Benzodiazepines modestly decrease blood pressure and respiratory drive, occasionally resulting in apnea.

α2 ADRENERGIC AGONISTS. Dexmedetomidine (PRECEDEX) is a highly selective α2 adrenergic receptor agonist used for short-term (<24 h) sedation of critically ill adults and for sedation prior to and during surgical or other medical procedures in nonintubated patients. Activation of the α2A adrenergic receptor by dexmedetomidine produces both sedation and analgesia.

The recommended loading dose is 1 μg/kg given over 10 min, followed by infusion at a rate of 0.2-0.7 μg/kg/h. Reduced doses should be considered in patients with risk factors for severe hypotension. Dexmedetomidine is highly protein bound and is metabolized primarily in the liver; the glucuronide and methyl conjugates are excreted in the urine. Common side effects of dexmedetomidine include hypotension and bradycardia, attributed to decreased catecholamine release by activation peripherally and in the CNS of the α2A receptor. Nausea and dry mouth also are common untoward reactions. At higher drug concentrations, the α2B subtype is activated, resulting in hypertension and a further decrease in heart rate and cardiac output. Dexmedetomidine provides sedation and analgesia with minimal respiratory depression. However, dexmedetomidine does not appear to provide reliable amnesia and additional agents may be needed.

ANALGESICS

With the exception of ketamine, neither parenteral nor currently available inhalational anesthetics are effective analgesics. Analgesics typically are administered with general anesthetics to reduce anesthetic requirement and minimize hemodynamic changes produced by painful stimuli. Nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, and acetaminophen (see Chapter 34) sometimes provide adequate analgesia for minor surgical procedures. However, opioids are the primary analgesics used during the perioperative period because of the rapid and profound analgesia they produce. Fentanyl (SUBLIMAZE, others), sufentanil (SUFENTA, others), alfentanil (ALFENTA, others), remifentanil (ULTIVA), meperidine (DEMEROL, others), and morphine are the major parenteral opioids used in the perioperative period. The primary analgesic activity of each of these drugs is produced by agonist activity at μ-opioid receptors (see Chapter 18).

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 min), accumulates minimally with repeated doses, and is particularly well suited for procedures that are briefly painful. Single doses of fentanyl, alfentanil, and sufentanil all have similar intermediate durations of action (30, 20, and 15 min, 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.

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; 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 (see 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.

NEUROMUSCULAR-BLOCKING AGENTS

The practical aspects of the use of neuromuscular blockers as anesthetic adjuncts are briefly described here. The detailed pharmacology of this drug class is presented in Chapter 11.

Depolarizing (e.g., succinylcholine) and nondepolarizing muscle relaxants (e.g., vecuronium) often are administered during the induction of anesthesia to relax muscles of the jaw, neck, and airway and thereby facilitate laryngoscopy and endotracheal intubation. Barbiturates will precipitate when mixed with muscle relaxants and should be allowed to clear from the IV line prior to injection of a muscle relaxant. The action of nondepolarizing muscle relaxants usually is antagonized, once muscle paralysis is no longer desired, with an acetylcholinesterase inhibitor such as neostigmine or edrophonium (seeChapter 10), in combination with a muscarinic receptor antagonist (e.g., glycopyrrolate or atropine; see Chapter 9) to offset the muscarinic activation resulting from esterase inhibition. Other than histamine release by some agents, nondepolarizing muscle relaxants used in this manner have few side effects. However, succinylcholine has multiple serious side effects (bradycardia, hyperkalemia, and severe myalgia) including induction of malignant hyperthermia in susceptible individuals.

Therapeutic Gases

OXYGEN

Oxygen (O2) is essential to life. Hypoxia is a life-threatening condition in which O2 delivery is inadequate to meet the metabolic demands of the tissues. Hypoxia may result from alterations in tissue perfusion, decreased O2 tension in the blood, or decreased O2 carrying capacity. In addition, hypoxia may result from restricted O2 transport from the microvasculature to cells or impaired utilization within the cell. An inadequate supply of O2 ultimately results in the cessation of aerobic metabolism and oxidative phosphorylation, depletion of high-energy compounds, cellular dysfunction, and death.

NORMAL OXYGENATION

O2 makes up 21% of air, which at sea level represents a partial pressure of 21 kPa (158 mm Hg). While the fraction (percentage) of O2 remains constant regardless of atmospheric pressure, the partial pressure of O2 (PO2) decreases with lower atmospheric pressure. Ascent to elevated altitude reduces the uptake and delivery of O2 to the tissues, whereas, increases in atmospheric pressure (e.g., hyperbaric therapy or breathing at depth) raise the PO2 in inspired air and increase gas uptake. As the air is delivered to the distal airways and alveoli, the PO2 decreases by dilution with CO2 and water vapor and by uptake into the blood.

Under ideal conditions, when ventilation and perfusion are well matched, the alveolar PO2 will be ~14.6 kPa (110 mm Hg). The corresponding alveolar partial pressures of water and CO2 are 6.2 kPa (47 mm Hg) and 5.3 kPa (40 mm Hg), respectively. Under normal conditions, there is complete equilibration of alveolar gas and capillary blood, and the PO2 in end-capillary blood is typically within a fraction of a kPa of that in the alveoli. 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 O2 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% O2 is breathed. O2 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 O2 typically reduces the PO2 of venous blood by an additional 7.3 kPa (55 mm Hg). Although the PO2 at the site of cellular O2 utilization—the mitochondria—is not known, oxidative phosphorylation can continue at a PO2 of only a few mm Hg.

In the blood, O2 is carried primarily in chemical combination with hemoglobin and is to a small extent dissolved in solution. The quantity of O2 combined with hemoglobin depends on the PO2, as illustrated by the sigmoidal oxyhemoglobin dissociation curve (Figure 19–6). Hemoglobin is ~98% saturated with O2 when air is breathed under normal circumstances, and it binds 1.3 mL of O2 per gram when fully saturated. The steep slope of this curve with falling PO2 facilitates unloading of O2 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 O2 saturation for the same PO2 and thus delivers additional O2where and when it is most needed. However, the flattening of the curve with higher PO2 indicates that increasing blood PO2 by inspiring O2-enriched mixtures can increase the amount of O2 carried by hemoglobin only minimally. Because of the low solubility of O2 (0.226 mL/L per kPa or 0.03 mL/L per mm Hg at 37°C), breathing 100% O2 can increase the amount of O2 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 O2 is sufficient to meet normal metabolic demands even in the absence of hemoglobin (Table 19–4).

images

Figure 19–6 Oxyhemoglobin dissociation curve for whole blood. The relationship between PO2 and hemoglobin (Hb) saturation is shown. The P50, or the PO2 resulting in 50% saturation, is indicated. An increase in temperature or a decrease in pH (as in working muscle) shifts this relationship to the right, reducing the hemoglobin saturation at the same PO2 and thus aiding in the delivery of O2 to the tissues.

Table 19–4

The Carriage of Oxygen in Blooda

images

OXYGEN DEPRIVATION. Hypoxemia generally implies a failure of the respiratory system to oxygenate arterial blood. Classically, there are 5 causes of hypoxemia:

• Low inspired O2 fraction (images)

• Increased diffusion barrier

• Hypoventilation

• Ventilation–perfusion mismatch

• Shunt or venous admixture

The term hypoxia denotes insufficient oxygenation of the tissues. 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. O2 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 O2carrying capacity of the blood likewise will reduce O2 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). Hypoxia produces a marked alteration in gene expression, mediated in part by hypoxia inducible factor-1α. The cellular consequences are discussed in Chapter 19 of the 12th edition of the parent text.

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 O2, descent to lower altitude, or an increase in ambient pressure when more severe. Acetazolamide (a carbonic anhydrase inhibitor) and dexamethasone also may be helpful.

OXYGEN INHALATION

PHYSIOLOGICAL EFFECTS OF OXYGEN INHALATION. O2 inhalation is used primarily to reverse or prevent the development of hypoxia. However, when O2 is breathed in excessive amounts or for prolonged periods, secondary physiological changes and toxic effects can occur.

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. 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 O2 is absorbed. High O2 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 O2 administration.

CARDIOVASCULAR SYSTEM. Heart rate and cardiac output are slightly reduced when 100% O2 is breathed; blood pressure changes little. Elevated pulmonary artery pressures in patients living at high altitude who have chronic hypoxic pulmonary hypertension may reverse with O2 therapy or return to sea level. In neonates with congenital heart disease and left-to-right shunting of cardiac output, O2supplementation 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.

OXYGEN ADMINISTRATION

O2 is supplied as a compressed gas in steel cylinders; purity of 99% is medical grade. For safety, O2 cylinders and piping are color-coded (green in the U.S.), and some form of mechanical indexing of valve connections is used to prevent the connection of other gases to O2 systems.

O2 is delivered by inhalation except during extracorporeal circulation, when it is dissolved directly into the circulating blood. Only a closed delivery system with an airtight seal to the patient’s airway and complete separation of inspired from expired gases can precisely control images. In all other systems, the actual delivered images will depend on the ventilatory pattern (i.e., rate, tidal volume, inspiratory–expiratory time ratio, and inspiratory flow) and delivery system characteristics.

LOW-FLOW SYSTEMS. Low-flow systems, in which the O2 flow is lower than the inspiratory flow rate, have a limited ability to raise the images because they depend on entrained room air to make up the balance of the inspired gas. These devices typically deliver 24-28% images at 2-3 L/min. Up to 40% images is possible at higher flow rates, although this is poorly tolerated for more than brief periods because of mucosal drying.

HIGH-FLOW SYSTEMS. The most commonly used high-flow O2 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 images at relatively high flow rates. Typically, each insert is designed to operate at a specific O2 flow rate, and different inserts are required to change the images. Lower deliveredimages values use greater entrainment ratios, resulting in higher total (O2 plus entrained air) flows to the patient, ranging from 80 L/min for 24% images to 40 L/min at 50% images. O2 nebulizers, another type of Venturi-style device, provide patients with humidified O2 at 35-100% images at high flow rates. Finally, O2 blenders provide high inspired O2 concentrations at very high flow rates. These devices mix high-pressure compressed air and O2 to achieve any concentration of O2 from 21-100% at flow rates of up to 100 L/min. Despite the high flows, the delivery of high images 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 O2 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. Noninvasive monitoring of arterial O2 saturation can be achieved using transcutaneous pulse oximetry, in which O2 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. 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 O2 therapy in situations where toxicity from O2 or side effects of excess O2 are of concern.

COMPLICATIONS OF OXYGEN THERAPY. In addition to the potential to promote absorption atelectasis and depress ventilation, high flows of dry O2 can dry out and irritate mucosal surfaces of the airway and the eyes, as well as decrease mucociliary transport and clearance of secretions. Humidified O2 thus should be used when prolonged therapy (>1 h) is required. Finally, any O2-enriched atmosphere constitutes a fire hazard, and appropriate precautions must be taken. Hypoxemia can occur despite the administration of supplemental O2. Therefore, 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 O2 is to correct hypoxia. Hypoxia is most commonly a manifestation of an underlying disease, and administration of O2 thus should be viewed as temporizing therapy. Efforts must be directed at correcting the cause of the hypoxia. Hypoxia resulting from most pulmonary diseases can be alleviated at least partially by administration of O2, allowing time for definitive therapy to reverse the primary process.

Reduction of Partial Pressure of an Inert Gas. Because 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. Because nitrogen is relatively insoluble, inhalation of high concentrations of O2 (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 O2 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 O2 inhalation prior to or during a barometric decompression reduces the supersaturation that occurs after decompression so that bubbles do not form.

Hyperbaric Oxygen Therapy. O2 can be administered at greater than atmospheric pressure in hyperbaric chambers. Clinical uses of hyperbaric O2 therapy include the treatment of trauma, burns, radiation damage, infections, nonhealing ulcers, skin grafts, spasticity, and other neurological conditions. Hyperbaric O2 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. 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 (see Table 19–4). Adverse effects of hyperbaric O2 therapy include middle ear barotrauma, CNS toxicity, seizures, lung toxicity, and aspiration pneumonia.

Hyperbaric O2 therapy has 2 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 O2 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 O2 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).

OXYGEN TOXICITY

O2 can have deleterious actions at the cellular level. O2 toxicity may result from increased production of hydrogen peroxide and reactive intermediates such as superoxide anion, singlet oxygen, and hydroxyl radicals that attack and damage lipids, proteins, and other macromolecules, especially those in biological membranes. A number of factors limit the toxicity of oxygen-derived reactive agents, including enzymes such as superoxide dismutase, glutathione peroxidase, and catalase, which scavenge toxic oxygen by-products, and reducing agents such as iron, glutathione, and ascorbate. These factors, however, are insufficient to limit the destructive actions of oxygen when patients are exposed to high concentrations over an extended time period. Tissues show differential sensitivity to oxygen toxicity, which is likely the result of differences in both their production of reactive compounds and their protective mechanisms.

RESPIRATORY TRACT. The pulmonary system is usually the first to exhibit toxicity, a function of its continuous exposure to the highest O2 tensions in the body. Subtle changes in pulmonary function can occur within 8-12 h of exposure to 100% O2. Increases in capillary permeability, which will increase the alveolar/arterial O2 gradient and ultimately lead to further hypoxemia, and decreased pulmonary function can be seen after only 18 h of exposure. Serious injury and death, however, require much longer exposures. Pulmonary damage is directly related to the inspired O2 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.

NERVOUS SYSTEM. Retinopathy of prematurity (ROP) is an eye disease in premature infants involving abnormal vascularization of the developing retina that can result from O2 toxicity or relative hypoxia. CNS 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 O2tension is returned to normal. In premature neonates and those who have sustained in utero asphyxia, hyperoxia and hypocapnia are associated with worse neurologic outcomes.

CARBON DIOXIDE

CO2 is produced by metabolism at approximately the same rate as O2 is consumed. At rest, this value is ~3 mL/kg/min, but it may increase dramatically with exercise. CO2 diffuses readily from the cells into the blood, where it is carried partly as bicarbonate ion (HCO3), partly in chemical combination with hemoglobin and plasma proteins, and partly in solution at a partial pressure of ~6 kPa (46 mm Hg) in mixed venous blood. CO2 is transported to the lung, where it is normally exhaled at the rate it is produced, leaving a partial pressure of ~5.2 kPa (40 mm Hg) in the alveoli and in arterial blood. An increase in PCO2 results in a respiratory acidosis and may be due to decreased ventilation or the inhalation of CO2, whereas an increase in ventilation results in decreased PCO2 and a respiratory alkalosis. Since CO2 is freely diffusible, the changes in blood PCO2 and pH soon are reflected by intracellular changes in PCO2 and pH and by widespread effects in the body, especially on respiration, circulation, and the CNS.

RESPIRATION. CO2 is a rapid, potent stimulus to ventilation in direct proportion to the inspired CO2. CO2 stimulates breathing by acidifying central chemoreceptors and the peripheral carotid bodies. Elevated Pco2 causes bronchodilation, whereas hypocarbia causes constriction of airway smooth muscle; these responses may play a role in matching pulmonary ventilation and perfusion.

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. The direct effect on systemic blood vessels results in vasodilation. CO2 causes widespread activation of the sympathetic nervous system. 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 (see 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.

METHODS OF ADMINISTRATION. CO2 is marketed in gray metal cylinders as the pure gas or as CO2 mixed with O2. 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 or from something as simple as a paper bag.

THERAPEUTIC USES. CO2 is used for insufflation during endoscopic procedures (e.g., laparoscopic surgery) because it is highly soluble and does not support combustion. CO2 can be used to flood the surgical field during cardiac surgery. Because of its density, CO2 displaces the air surrounding the open heart so that any gas bubbles trapped in the heart are CO2 rather than insoluble N2. It is used to adjust pH during cardiopulmonary bypass procedures when a patient is cooled.

Hypocarbia 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. Hypocarbia should be instituted with a clearly defined indication and normocarbia should be reestablished as soon the indication for hypocarbia no longer applies.

NITRIC OXIDE

Nitric oxide (NO) is a free-radical gas now known as a critical endogenous cell-signaling molecule with an increasing number of potential therapeutic applications.

Endogenous NO is produced from L-arginine by NO synthases (neural, inducible and endothelial) (see Chapter 3). In the vasculature, basal production of NO by endothelial cells is a primary determinant of resting vascular tone. NO causes vasodilation of smooth muscle cells and inhibition of platelet aggregation and adhesion. Impaired NO production is implicated in atherosclerosis, hypertension, cerebral and coronary vasospasm, ischemia–reperfusion injury, inflammation, and in mediating central nociceptive pathways. 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.

THERAPEUTIC USES. Inhaled NO (iNO) selectively dilates the pulmonary vasculature and has potential as a therapy for numerous diseases associated with increased pulmonary vascular resistance. Inhaled NO is FDA-approved for only 1 indication, persistent pulmonary hypertension of the newborn.

DIAGNOSTIC USES. Inhaled NO can be used during cardiac catheterization to 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 CO2 in this regard because of its greater affinity for hemoglobin and its higher water solubility at body temperature. 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 disease.

TOXICITY. Administered at low concentrations (0.1-50 ppm), iNO appears to be safe and without significant side effects. Pulmonary toxicity can occur with levels higher than 50-100 ppm. NO is an atmospheric pollutant; the Occupational Safety and Health Administration places the 7-h 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.

The development of methemoglobinemia is a significant complication of inhaled NO at higher concentrations, and rare deaths have been reported with overdoses of NO. Methemoglobin concentrations should be monitored intermittently during NO inhalation. 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.

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 0.1-40 ppm in dose and for periods of a few hours to several weeks in duration. 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.

HELIUM

Helium (He) is an inert gas whose low density, low solubility, and high thermal conductivity provide the basis for its medical and diagnostic uses. Helium can be mixed with O2 and administered by mask or endotracheal tube. Under hyperbaric conditions, it can be substituted for the bulk of other gases, resulting in a mixture of much lower density that is easier to breathe.

The primary uses of helium are in pulmonary function testing, the treatment of respiratory obstruction, laser airway surgery, as a label in imaging studies, and for diving at depth. Helium is also suited for determinations of residual lung volume, functional residual capacity, and related lung volumes. These measurements require a highly diffusible nontoxic gas that is insoluble and does not leave the lung by the bloodstream so that, by dilution, the lung volume can be measured. Helium can be added to O2 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. Mixtures of helium and O2 reduce the work of breathing. Helium has high thermal conductivity, making it useful during laser surgery on the airway. 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.

HYDROGEN SULFIDE

Hydrogen sulfide (H2S), which has a characteristic rotten egg smell, is a colorless, flammable, water-soluble gas that is primarily considered a toxic agent due to its ability to inhibit mitochondrial respiration through blockade of cytochrome c oxidase. Inhibition of respiration is potentially toxic; however, if depression of respiration occurs in a controlled manner, it may allow nonhibernating species exposed to inhaled H2S to enter a state akin to suspended animation (i.e., a slowing of cellular activity to a point where metabolic processes are inhibited but not terminal) and thereby increase tolerance to stress. H2S also may cause activation of ATP-dependent K+ channels, cause vasodilation properties, and serve as a free radical scavenger. H2S has been shown to protect against whole-body hypoxia, lethal hemorrhage, and ischemia-reperfusion injury in various organs including the kidney, lung, liver, and heart. Currently, effort is underway for development of gas-releasing molecules that could deliver H2S and other therapeutic gases to diseased tissue. H2S in low quantities may have the potential to limit cell death.