aThe greater the blood–gas partition coefficient, the greater the blood solubility.

bThe greater the brain–blood partition coefficient, the greater the brain solubility.

cThe greater the muscle–blood partition coefficient, the greater the muscle solubility.

dThe greater the fat–blood partition coefficient, the greater the fat solubility.

e Density determined at 25◦C for desflurane, isoflurane, and enflurane and at 20◦C for sevoflurane.

MAC, minimum alveolar concentration to prevent movement in 50% of subjects.

156 Section 1 General Care

volatile inhalation agents, in addition to metabolism and extent

of tissue equilibration. Low-solubility agents are more rapidly

washed out (eliminated) because more of the agent is removed

from the blood in one passage through the lungs.29 As can be

seen in Table 8-4, desflurane has the lowest solubility of any of

the volatile inhalation agents, with sevoflurane’s solubility being

lower than isoflurane’s for blood. As a result of their low solubility, quicker responses to intraoperative concentration changes

are seen with desflurane and sevoflurane as well as a faster emergence and awakening from anesthesia and a more rapid return

to normal motor function and judgment when compared with

isoflurane.37–39

As seen in Table 8-4, the metabolism of the volatile inhalation

agents varies (e.g., desflurane is metabolized least). An important point is that metabolism does not alter the rate of induction or maintenance of anesthesia because the amount of anesthetic administered to the patient greatly exceeds its uptake.29

Metabolism of sevoflurane has resulted in peak inorganic fluoride levels greater than 100 μM.33 Historically, a fluoride level

of 50 μM has been used as a cut-off for potential nephrotoxicity

based on reports of methoxyflurane-associated nephrotoxicity

at levels greater than 50 μM.40 Despite this, sevoflurane has not

been demonstrated to produce nephrotoxicity. Potential reasons

for this include the fact that sevoflurane’s low blood gas solubility

may limit the degree of its metabolism once the anesthetic is discontinued and that sevoflurane, unlike methoxyflurane, undergoes minimal renal defluorination.41

Pharmacologic Properties

All volatile inhalation agents depress ventilation (with an elevation of PaCO2) and dilate constricted bronchial musculature in a

dose-dependent manner. As mentioned previously, sevoflurane

can be used for mask induction of general anesthesia because it

is not as pungent as desflurane, isoflurane, or enflurane. Administration of a pungent agent by mask for induction can cause

coughing, breath-holding, laryngospasm, and salivation in the

patient. All volatile inhalation agents depress myocardial contractility and decrease arterial BP in a dose-dependent manner.

Isoflurane can increase heart rate, so cardiac output is usually

maintained. Sevoflurane produces little increase in heart rate, so

cardiac output may not be as well maintained as with isoflurane.

Although enflurane can increase heart rate, cardiac output is

usually decreased. Desflurane can produce sympathetic nervous

system activation, resulting in a transient increase in BP and

heart rate when concentrations are rapidly increased.29,40 The

sympathetic nervous system activation may be caused by stimulation of medullary centers via receptors in the upper airway and

lungs.42 Enflurane can sensitize the myocardium to the arrhythmogenic effects of epinephrine. The volatile inhalation agents

decrease cerebral metabolic rate and produce cerebral vasodilation, resulting in increased cerebral blood flow and volume.

Enflurane can cause epileptiform activity that can result in clinical tonic-clonic seizures. All volatile inhalation agents produce

muscle relaxation and potentiate the actions of the neuromuscular blocking agents. The volatile inhalation agents relax uterine

smooth muscle, which can contribute to perinatal blood loss.

All volatile inhalation agents have been implicated as triggers of

malignant hyperthermia (MH) and are contraindicated in MHsusceptible patients. Finally, all volatile inhalation agents are associated with postoperative nausea, vomiting, and shivering.29,40

Drug Interactions

Opioids, benzodiazepines, α2-adrenergic agonists, and neuromuscular blocking agents potentiate the effects of the volatile

inhalation agents. Thus, their administration permits use of

lower dosages of the volatile inhalation agents, thereby reducing

their potential for adverse effects.

Economic Considerations

The following items must be considered when examining the

costs associated with the administration of volatile inhalation

agents from an institutional perspective: cost of the volatile

inhalation agent (including waste), cost of the equipment necessary to administer the volatile inhalation agent, cost of adjuvants

used to treat adverse effects of the volatile agent, and time spent

in the OR and PACU.

The cost of a volatile agent depends on (a) the cost per milliliter

of the liquid anesthetic, (b) the amount of vapor generated per

milliliter, (c) the amount of volatile agent that must be delivered

from the anesthesia machine to sustain the desired alveolar concentration, and (d) the flow rate of the background gases.43–45

The use of low flow rates can result in substantial reductions in

the volatile anesthetic drug cost per case. An important point

to keep in mind when comparing only the cost of the volatile

inhalation agents themselves (e.g., excluding any benefits in

terms of cost reduction that may be realized by a quicker discharge from the recovery room) is that the low-solubility volatile

agents have to be administered at low flow rates to prevent their

cost from being substantially higher than that of the more traditional agents (e.g., isoflurane) when administered at rates of 2 to

3 L/minute.

The cost of purchasing new vaporizers and upgrading or

replacing agent analyzers that are used to administer and monitor

volatile inhalation agents, respectively, can be significant. These

costs become a concern when a new product is introduced onto

the market.

Medications used to treat adverse effects associated with the

volatile inhalation agents include β-blockers, opioids, benzodiazepines, vasopressors, and antiemetic agents. Antiemetic agents

are routinely used to prevent or treat the PONV seen with the

volatile inhalation agents. Intraoperative use of volatile inhalation agents is a leading cause of early (within the first 2 hours after

surgery) postoperative vomiting.46 Although the administration

of an antiemetic agent adds to the cost, it is significantly less than

the cost of an unanticipated admission to the hospital secondary

to PONV.

Desflurane Use for Maintenance of

General Anesthesia

SYMPATHETIC NERVOUS SYSTEM ACTIVATION

CASE 8-7

QUESTION 1: C.K., a 26-year-old man, ASA-I, is scheduled

to undergo a laparoscopic hernia repair on an outpatient

basis. During his preoperative evaluation on the morning

of surgery, his BP was 115/75 mm Hg, and his heart rate

was 70 beats/minute. The surgery is expected to last less

than 2 hours, so a propofol induction is planned followed by

maintenance of general anesthesia with desflurane without

nitrous oxide. After induction of anesthesia, the desflurane

concentration on the vaporizer was rapidly increased to 8%.

Within 1 minute of the concentration increase, C.K.’s BP

increased to 148/110 mm Hg, and his heart rate increased

to 112 beats/minute. What could be causing C.K.’s

increased BP and heart rate, and how could it have been

prevented?

157Perioperative Care Chapter 8

Desflurane can produce sympathetic nervous system activation with a resultant increase in BP and heart rate under certain

circumstances. One of these is the rapid increase of desflurane

concentration to 1.1 MAC as seen with C.K.47 This hemodynamic response can be attenuated by the IV administration of

fentanyl approximately 5 minutes before the increase in desflurane concentration.48 Fentanyl is a good choice because it effectively blunts the increase in heart rate and BP, while having minimal cardiovascular depressant and postoperative sedative effects.

Alternatively, nitrous oxide can be administered with desflurane,

thereby allowing the desflurane concentration to be maintained

at less than 1 MAC (6%).

Emergence Agitation in Children

CASE 8-8

QUESTION 1: P.F., a 3-year-old child, ASA-I, is undergoing a

tonsillectomy. General anesthesia will be induced and maintained with sevoflurane and nitrous oxide. His surgery was

uneventful, with a duration of 30 minutes. He was awakened

from anesthesia and transferred to the PACU to recover.

Shortly after he arrived, P.F. became extremely restless and

began crying. The nurse and his mother were unable to console him. Could this reaction be attributed to sevoflurane,

and if so, can it be prevented?

Emergence agitation after the administration of the shortacting inhaled anesthetics, desflurane and sevoflurane, is fairly

common, with a reported incidence as high as 80%.49 Emergence agitation is more common in young children, and its cause

is not clear. Children become restless, cry, and exhibit involuntary physical activity that can result in self-injury. Caring for a

child experiencing emergence agitation is difficult and very upsetting to the caregiver and the parents of the child. Premedication

with oral midazolam50 and administering analgesics to minimize

postoperative pain51 may reduce the incidence. A small dose of

dexmedetomidine (0.3 mcg/kg IV), an α2-agonist with sedative

and analgesic properties, after induction of anesthesia reduces

the incidence of emergence agitation without prolonging recovery in children undergoing sevoflurane anesthesia.52 Although

desflurane cannot be used to induce general anesthesia, switching to desflurane for maintenance of anesthesia after sevoflurane

induction has been reported to reduce the severity of emergence

agitation when it occurs.53

NEUROMUSCULAR BLOCKING

AGENTS

Uses

Neuromuscular blocking agents are one of the most commonly

used classes of drugs in the OR. They are used primarily as an

adjunct to general anesthesia to facilitate endotracheal intubation and to relax skeletal muscle during surgery under general

anesthesia.54 Skeletal muscle relaxation optimizes the surgical

field for the surgeon and prevents patient movement as a reflex

response to surgical stimulation. Neuromuscular blocking agents

are also used in the intensive care unit (ICU) to paralyze mechanically ventilated patients.55 An important point to remember is

that neuromuscular blocking agents have no known effect on

consciousness or pain threshold. Consequently, adequate sedation (or anesthesia) and analgesia must be ensured when neuromuscular blocking agents are administered.

Mechanism of Action

When two molecules of acetylcholine (Ach) bind to the Ach subunits of the nicotinic cholinergic receptors located on the motor

nerve endplate, the Ach receptor undergoes a conformational

change that allows the influx of sodium and potassium into the

muscle cell, the membrane depolarizes, and the muscle contracts.

Neuromuscular blocking agents bind to these subunits and effectively block normal neuromuscular transmission. Two classes of

neuromuscular blocking agents exist based on their mechanism

of action: depolarizing and nondepolarizing. Succinylcholine, the

only depolarizing neuromuscular blocking agent in clinical use

today, acts like Ach to depolarize the membrane. Because succinylcholine is not metabolized as quickly as Ach at the neuromuscular junction, its action at the nicotinic receptor persists

longer than Ach. Succinylcholine causes a persistent depolarization of the motor endplate because the sodium channels cannot reopen until the motor endplate repolarizes, producing a

sustained skeletal muscle paralysis. The paralysis produced by

depolarizing agents is preceded initially by fasciculations (transient twitching of skeletal muscle). The nondepolarizing neuromuscular blocking agents act as competitive antagonists to Ach

at the Ach subunits of the nicotinic cholinergic receptors, thereby

preventing Ach from binding and causing depolarization of the

muscle membrane and muscle contraction.54,56

Monitoring Neuromuscular Blockade

In addition to clinical assessment (e.g., lack of movement) by the

anesthesia provider and the surgeon, the degree of neuromuscular blockade produced by neuromuscular blocking agents is

monitored by nerve stimulation with a peripheral nerve stimulator. Most commonly, the ulnar nerve is electrically stimulated,

and the response of the innervated muscle, the adductor pollicis in the thumb, is visually assessed. Adequate neuromuscular

blockade is present when the train-of-four (four electrical stimulations of 2 Hz delivered every 0.5 seconds) count is 1/4 or 2/4

(one or two visible muscle twitches of a possible four twitches).55

Classification

Neuromuscular blocking agents are commonly classified by the

type of blockade produced (depolarizing vs. nondepolarizing),

chemical structure (steroidal compound, Ach-like, benzylisoquinolinium compound), or duration of action (ultrashort, intermediate, long), as listed in Table 8-5.57

Adverse Effects

The underlying mechanisms for the cardiovascular adverse

effects of neuromuscular blocking agents are listed in Table 8-6

and include blockade of autonomic ganglia (hypotension), blockade of muscarinic receptors (tachycardia), and release of histamine from circulating mast cells (hypotension).56–58 In general,

the steroidal compounds exhibit varying degrees of vagolytic

effect, whereas the benzylisoquinolinium compounds are associated with varying degrees of histamine release. Although not

reported as a problem when used short term in the OR, the use

of neuromuscular blocking agents in ICU patients for extended

periods can result in prolonged neuromuscular blockade or

acute quadriplegic myopathy syndrome, albeit infrequently.56

Of the currently available neuromuscular blocking agents,

cisatracurium and vecuronium are devoid of clinically significant

cardiovascular effects and are the agents of choice for patients

with unstable cardiovascular profiles.54,56,57 Succinylcholine is

associated with a significant number of adverse effects, including

158 Section 1 General Care

TABLE 8-5

Classification of Neuromuscular Blocking Agents57

Agent Type of Block Clinical Duration of Actiona Structure

Atracurium (Tracrium) – Intermediate Benzylisoquinolinium

Cisatracurium (Nimbex) – Intermediate Benzylisoquinolinium

Pancuronium (Pavulon) – Long Steroidal

Rocuronium (Zemuron) – Intermediate Steroidal

Succinylcholine (Anectine, Quelicin) + Ultrashort Acetylcholine like

Vecuronium (Norcuron) – Intermediate Steroidal

aTime from injection of agent to return to twitch height to 25% of control (time at which another dose of agent will need to be administered to maintain paralysis); in

general, clinical duration of a standard intubating dose of ultrashort agents ranges from 3 to 5 minutes, intermediate agents from 30 to 40 minutes, and long agents from 60

to 120 minutes.

+, depolarizing; –, nondepolarizing.

hyperkalemia, arrhythmias, fasciculations, muscle pain, myoglobinuria, trismus, phase II block, and increased intraocular,

intragastric, and intracranial pressures.57,58 Succinylcholine, like

inhalational anesthetics, can trigger MH.56 Of these adverse

effects, bradycardia, hyperkalemia (which can trigger arrhythmias and cardiac arrest in patients at risk), and MH crisis are

severe and potentially life-threatening reactions. Nevertheless,

succinylcholine is still used today because of its rapid onset and

ultrashort duration of action as well as its ability to be administered IM in children in an emergent situation when IV access has

not been established.

Drug Interactions

Several drugs interact with neuromuscular blocking agents. The

volatile inhalation agents potentiate the neuromuscular blockade

produced by nondepolarizing agents, thereby allowing a lower

dose of the latter to be used when administered concomitantly.

Other agents reported to potentiate the effects of neuromuscular

blocking agents include the aminoglycosides, clindamycin, magnesium sulfate, quinidine, furosemide, lidocaine, amphotericin

B, and dantrolene. Carbamazepine, phenytoin, corticosteroids

(chronic administration), and theophylline antagonize the effects

of neuromuscular blocking agents.56,57 By appropriately monitoring the patient and dosing the neuromuscular blocking agent

to effect, significant problems from drug interactions can be minimized.

Reversal of Neuromuscular Blockade

The action of neuromuscular blocking agents ceases spontaneously as plasma concentrations decline or when anticholinesterases (e.g., neostigmine, edrophonium, pyridostigmine) are administered. Anticholinesterases inhibit the enzyme

acetylcholinesterase, which degrades Ach, and are used to reverse

paralysis produced by nondepolarizing agents. Anticholinergic

agents are coadministered (in the same syringe) with the anticholinesterases to minimize other cholinergic effects (e.g., bradycardia, bronchoconstriction, salivation, increased peristalsis, nausea, vomiting) caused by the increase in Ach concentration.

Atropine is routinely administered with edrophonium, and glycopyrrolate with neostigmine or pyridostigmine, to take advantage of similar onset times and durations of action.54,55,57 Reversal

of neuromuscular blockade, as a general rule, is not attempted

until spontaneous recovery is well established. Before extubation, adequacy of reversal is assessed with the use of a peripheral

nerve stimulator and by clinical assessment of the patient (e.g.,

ability to sustain head lift for 5 seconds).57,58

Pharmacokinetics and

Pharmacodynamics

RAPID SEQUENCE INDUCTION

CASE 8-9

QUESTION 1: R.D., a 36-year-old man, ASA-I, is admitted through the emergency department for an emergency

appendectomy. R.D. is otherwise healthy, has no drug allergies, and is currently taking no medications. All laboratory

values are normal. Admission notes reveal that R.D. ate dinner approximately 2 hours earlier. Because of this, the anesthesia provider plans to perform a rapid sequence induction

using the Sellick maneuver. Which neuromuscular blocking

agent would be most appropriate for R.D.?

Rapid sequence induction is indicated for patients at risk for

aspiration of gastric contents should regurgitation occur. Patients

who have recently eaten (with a full stomach), morbidly obese

TABLE 8-6

Causes of Cardiovascular Adverse Effects of Neuromuscular Blocking Agents56–58

Agent Histamine Releasea Autonomic Ganglia Vagolytic Activity Sympathetic Stimulation

Atracuriuma

++ –– –

Cisatracurium – – – –

Pancuronium – Weak block ++ ++

Rocuroniumb

– – + –

Succinylcholine + Stimulates – –

Vecuronium – – – –

aHistamine release is dose and rate related; cardiovascular changes can be lessened by minimizing dose and injecting agent slowly.

b Produces an increase in heart rate of approximately 18% with intubating dose of 0.6 mg/kg; effect usually transient and resolves spontaneously.

+ – ++, likelihood of developing the cardiovascular adverse effect relative to the other agents; –, no effect.

159Perioperative Care Chapter 8

TABLE 8-7

Pharmacokinetic and Pharmacodynamic Parameters of Action of Neuromuscular Blocking Agents55–58

Agent

Cl

(mL/kg/min)

Vdss

(L/kg)

Half-Life

(minutes)

ED95

(mg/kg)

Intubating Dose

(mg/kg)a,b

Onset

(minutes)c

Clinical Duration of Action

of Initial Dose (minutes)

Atracuriumd

5–7 0.2 20 0.2–0.25 0.4–0.5 2–3 25–30

Cisatracurium 4.6 0.15 22 0.05 0.15–0.2 2–2.5 50–60

Pancuronium 1–2 0.3 80–120 0.07 0.04–0.1 3–5 80–100

Rocuroniumd

4.0 0.3 60–70 0.3 0.6–1.2 1–1.5 30–60

Succinylcholined

37 0.04 0.65 0.25 1.5 1 5–10

Vecuroniumd

4.5 0.4 50–70 0.05–0.06 0.1 2–3 25–30

aDose when nitrous oxide–opioid technique is used.

b Intermittent maintenance doses to maintain paralysis, as a general rule, will be approximately 20% to 25% of the initial dose.

cTime to intubation.

dAlso can be administered as a continuous infusion to maintain paralysis. Suggested infusion ranges under balanced anesthesia are atracurium, 4–12 mcg/kg/min;

cisatracurium, 1–2 mcg/kg/min; rocuronium, 6–14 mcg/kg/min; succinylcholine, 50–100 mcg/kg/min; vecuronium, 0.8–2 mcg/kg/min.

Cl, clearance; ED95, effective dose causing 95% muscle paralysis; Vdss, steady-state volume of distribution.

patients, or patients with a history of gastroesophageal reflux are

at risk for aspiration, as is the case for R.D. The goal of rapid

sequence induction is to minimize the time during which the

airway is unprotected by intubating the patient as fast as possible

(e.g., within 60 seconds). In this technique, the patient is preoxygenated, after which an IV induction agent is administered, followed immediately by a neuromuscular blocking agent. Manual

ventilation of the patient is not attempted after administration of

these agents. Apnea occurs as the neuromuscular blocking agent

takes effect; therefore, a neuromuscular blocking agent with as

rapid an onset as possible is required to produce adequate intubating conditions as quickly as possible. The Sellick maneuver is

often used during rapid sequence induction. It is performed by

placing downward pressure on the cricoid cartilage, which compresses and occludes the esophagus and helps prevent passive

regurgitation of gastric contents into the trachea. Intubation is

then performed within 60 seconds.

Table 8-7 lists the onset times of normal intubating doses

and other information pertaining to the use of neuromuscular

blocking agents.55–58 Succinylcholine has the fastest onset time,

which makes it an appropriate agent to use in rapid sequence

induction.59

Because R.D. is an otherwise healthy man with no contraindications to the use of succinylcholine, this agent should be used.

DEPOLARIZING AGENT CONTRAINDICATIONS

CASE 8-9, QUESTION 2: What would be the most appropriate choice of a neuromuscular blocking agent if R.D.

presents with a history of susceptibility to MH, and why?

Succinylcholine is contraindicated in patients with skeletal

muscle myopathies; after the acute phase of injury (i.e., 5–70

days after injury) after major burns, multiple trauma, extensive

denervation of skeletal muscle, or upper motor neuron injury;

in children and adolescents (except when used for emergency

tracheal intubation or when the immediate securing of the airway is necessary); and in patients with a hypersensitivity to the

drug.54,57 Succinylcholine can also trigger MH and is absolutely

contraindicated in MH-susceptible patients.60

The nondepolarizing neuromuscular blocking agents are safe

to use in MH-susceptible patients.61 Rocuronium has the fastest

onset time of the nondepolarizing agents, although it is slightly

slower than succinylcholine.58 The onsets of the remaining

intermediate- and long-duration agents can be shortened by

increasing the dose, which not only results in a faster onset

of action but also prolongs the duration of action. Rocuronium’s time to maximal blockade, for example, can be reduced to

60 seconds with an initial dose of 1.2 mg/kg (vs. a normal initial dose of 0.6 mg/kg). Increasing the dose from 0.6 mg/kg to

1.2 mg/kg, however, will prolong the clinical duration from

approximately 30 minutes to at least 60 minutes.62 Rocuronium,

with its rapid onset of action, would be a suitable alternative

to succinylcholine in R.D.’s case. Its longer clinical duration of

action could be a concern if the airway cannot be secured immediately or if the procedure is 

 

The degree to which metabolism plays a role in the clinical duration of IV induction agents is variable; rapid metabolism can

be a significant factor in the relatively shorter duration to full

recovery of propofol.22 Table 8-2 compares the pharmacokinetic

properties of IV anesthetic agents.22–24

Adverse and Beneficial Effects

IV anesthetic agents can produce a variety of adverse and beneficial effects other than loss of consciousness (e.g., cardiovascular depression or stimulation, pain on injection, nausea and

vomiting, respiratory depression or stimulation, CNS cerebroprotection or excitation, adrenocorticoid suppression, anxiolysis, amnesia, analgesia). Table 8-3 compares the relative significance of these effects among available agents.22–24 The most

TABLE 8-2

Pharmacokinetic Comparison of Common Intravenous

Anesthetic Agents22–24

Drug

Half-Life

(hours)

Onset

(seconds)

Clinical

Duration

(minutes)a

Hangover

Effectb

Etomidate 2–5 ≤30 3–12 +

Ketamine 1–3 30–60 10–20 ++ – +++c

Methohexital 4 ≤30 5–10 +

Midazolam 1–4 30–90 10–20 +++d

Propofol 0.5–7 ≤45 5–10 0 – +

aTime from injection of agent to return to conscious state.

bResidual psychomotor impairment after awakening from induction dose.

cWhen ketamine is administered as the induction agent (e.g., 5–10 mg/kg IM).

dWhen midazolam is administered as the induction agent (e.g., 0.15 mg/kg IV).

153Perioperative Care Chapter 8

TABLE 8-3

Effects of Intravenous Induction Agents22–24

Adverse Effect Etomidate Ketamine Methohexital Midazolam Propofol Remifentanil

Adrenocorticoid suppression + – – –– –

Cerebral protection + – + ++ –

Cardiovascular depression – – ++ + ++ –/+a

Emergence delirium or euphoria – ++ – – + –

Myoclonus +++ + ++ – + –/+a

Nausea/vomiting +++ ++ ++ + –

b

++

Pain on injection ++ – + – ++ –

Respiratory depression ++ – ++ +/++ ++ +/++a

Anxiolysis/amnesia – –/+a

– ++++ –/+a

–

Analgesia – +++ – –– ++++

aDose-dependent effects.

bHas antiemetic effects

+ to ++++, likelihood of adverse effect relative to other agents; –, no effect.

troublesome are usually cardiovascular effects or CNS excitation

reactions. Contribution to postoperative nausea and vomiting

(PONV) and delirium, for example, can be significant and may

delay full recovery and patient discharge from the postanesthesia

care unit (PACU). This is of particular concern in the ambulatory

surgery setting because the patient will be discharged home. CNS

effects can include hiccups, myoclonus, seizure activity, euphoria,

hallucinations, and emergence delirium. The cerebroprotective

effect produced by methohexital, etomidate, and propofol results

from a reduction in cerebral blood flow secondary to cerebral

vasoconstriction. As a result, cerebral metabolic rate, cerebral

blood flow, and intracranial pressure are reduced.22–24 This effect

is useful if these drugs are available in therapeutic concentrations

at a time of potential cerebral ischemia.

Agent Selection

The selection of an IV anesthetic agent should be determined

based on patient characteristics, which may include history

of PONV, allergy profile, psychiatric history, or cardiovascular

status.

Propofol: Antiemetic Effect and

Full Recovery Characteristics

CASE 8-3

QUESTION 1: K.T., a 19-year-old woman, ASA-I, is admitted to the ambulatory surgery center for strabismus surgery

to correct misalignment of her extraocular muscles. She

is otherwise healthy, and all laboratory values obtained

before surgery are within normal limits. The duration of

K.T.’s surgery is anticipated to be approximately 90 minutes. Which IV induction agent should be used?

Propofol is a good choice here for several reasons. Strabismus surgery is considered highly emetogenic because operative

manipulation of extraocular muscles can trigger the oculoemetic

reflex. Therefore, precautions should be taken to reduce the possibility of nausea and vomiting postoperatively. Propofol produces the lowest incidence of PONV when compared with other

IV induction agents and the volatile inhalation agents; it has even

been associated with a direct antiemetic effect.25 This effect does

not preclude the need for prophylactic antiemetic therapy, but

may contribute to the avoidance of emesis in K.T. immediately

after surgery. Furthermore, ambulatory surgery demands rapid,

full recovery from general anesthesia. Propofol, in particular, is

associated with a more rapid recovery of psychomotor function

and a patient-perceived superior quality of recovery.24

Etomidate Use in

Cardiovascular Disease

CASE 8-4

QUESTION 1: L.M., a 73-year-old man, ASA-IV, is in need of

repair of an abdominal aortic aneurysm. During a preoperative evaluation a few days before surgery, his blood pressure

(BP) was 160/102 mm Hg, and his medical records revealed

hypertension that was poorly controlled by hydrochlorothiazide 25 mg daily and metoprolol XL (Toprol) 100 mg

daily. He also has angina that occasionally requires treatment with sublingual nitroglycerin. An exercise stress test

showed electrocardiogram changes at a moderate exercise load. Two days before the elective aneurysm repair

was scheduled, L.M. presented to the emergency department with a 4-hour history of severe back pain. His surgeon

believes that there is a high likelihood that the aneurysm

is leaking or expanding and schedules surgery immediately.

What is the best plan for L.M.’s anesthetic induction and

maintenance?

L.M. has significant cardiovascular disease, and care should

be taken to minimize any cardiovascular depression, tachycardia,

or hypertension during induction and maintenance of anesthesia. Of the currently available induction agents, etomidate has

the most stable cardiovascular profile24 and is associated with

minimal cardiovascular depression. Opioids generally produce

minimal cardiovascular effects and could potentially be used

for induction. Propofol and ketamine can cause hemodynamic

changes and are best avoided in L.M. Etomidate would be an

excellent choice for induction, followed by an inhaled anesthetic

agent such as sevoflurane or isoflurane to maintain anesthesia.

Methohexital for Electroconvulsive

Therapy

CASE 8-5

QUESTION 1: T.B., a 33-year-old woman, ASA-I, will

undergo an electroconvulsive therapy (ECT) procedure for

treatment of her severe, medication-resistant depression.

T.B. is scheduled to go home within 1 to 2 hours after the

154 Section 1 General Care

procedure, which will be performed under general anesthesia. What IV induction agent should be used?

ECT procedures are an important method of treatment of

severe and medication-resistant depression, mania, and other

serious psychiatric conditions. During the ECT procedure, an

electrical current is applied to the brain, resulting in an electroencephalographic spike and wave activity, a generalized motor

seizure, and acute cardiovascular response. For an optimal therapeutic (antidepressant) response, T.B.’s seizure activity should

last from 25 to 50 seconds. General anesthesia is administered

to ensure amnesia, prevent bodily injury from the seizure, and

control the hemodynamic changes. When selecting an IV induction agent, its effect on electroencephalographic seizure activity,

its ability to blunt the hemodynamic response to ECT, and its

recovery profile (e.g., short time to discharge, nonemetogenic)

are important considerations. Because most IV induction agents

have anticonvulsant properties, small doses must be used to allow

adequate seizure duration. Methohexital is considered the gold

standard.26,27 Propofol, in smaller doses, can also be used. Combining a short-acting opioid such as remifentanil with propofol

will allow a small dose of propofol to be used and the seizure

duration to be prolonged. Although etomidate does not adversely

affect the seizure duration, the hemodynamic response to ECT is

accentuated because etomidate is cardiovascularly stable and cannot blunt the cardiovascular response to ECT. In addition, it can

cause nausea and vomiting, resulting in delayed recovery. Midazolam reduces seizure activity, and ketamine increases the risk of

delayed recovery by producing nausea and ataxia.26,27 Therefore,

methohexital, in a dose of 0.75 to 1 mg/kg IV, can be administered

because it will not affect the seizure duration or prolong T.B.’s

recovery time. Alternatively, a small dose of propofol (0.75 mg/

kg) and remifentanil (up to 1 mcg/kg) are also appropriate.

Ketamine Use in Pediatrics

CASE 8-6

QUESTION 1: R.L., a 4-year-old boy, ASA-II, is scheduled

for a painful debridement and dressing change that is anticipated to take approximately 15 minutes. He is brought to

the procedure room near the OR along with his parents and

is in distress over parting from them. He currently has no

IV line in place and will not take any oral medication. How

could sedation and analgesia be provided to R.L.?

Although ketamine can be given IM, administration by this

route is painful and not optimal. However, it might be preferable

to starting an IV in R.L. for a short, painful procedure. At a dose

of 3 or 4 mg/kg IM, ketamine produces sedation with amnesia and analgesia. Intubation is unnecessary because ketamine

causes little or no respiratory depression. However, this dose of

ketamine produces a dissociative stare or trance (eyes are open

but patient does not respond) and nystagmus generally lasting

30 to 60 minutes. R.L.’s parents should be informed about these

potential effects. Ketamine may also be safely used in the emergency department to provide dissociative sedation for short,

painful procedures in children (e.g., fracture reduction, laceration repair, abscess drainage). Appropriate guidelines for use of

ketamine in this setting should be followed.28

VOLATILE INHALATION AGENTS

Currently, four volatile inhalation agents are available for use in

the United States: desflurane, sevoflurane, isoflurane, and enflurane, with the latter being rarely used in clinical practice. The

volatile inhalation agents are unique in that they can produce

all components of the anesthetic state, to varying degrees (e.g.,

minimal, if any, analgesia). Immobility to surgical stimuli and

amnesia are postulated to be the predominant effects produced

by these agents. Unlike IV anesthetic agents, these drugs are

administered into the lungs via an anesthesia machine, and as a

result, it is easy to increase or decrease drug levels in the body.

The anesthesia care provider can estimate, with the use of technology, the anesthetic partial pressure at the site of action (brain);

this helps the anesthesia care provider maintain an optimal depth

of anesthesia.29

Although the volatile inhalation agents could, theoretically,

be used to produce general anesthesia by themselves, it is much

more common to use a combination of drugs intended to take

advantage of smaller doses of each drug while avoiding the disadvantages of high doses of individual agents. This practice is

referred to as balanced anesthesia. For example, midazolam is

used routinely to produce sedation, anxiolysis, and amnesia,

whereas the administration of an IV anesthetic agent (e.g., propofol), followed by administration of a neuromuscular blocking

agent (e.g., succinylcholine), can produce rapid loss of consciousness and muscle relaxation to facilitate endotracheal intubation.

Volatile inhalation agents provide maintenance of general anesthesia, along with reflex suppression (e.g., lowering BP and heart

rate) and some muscle relaxation. Opioids (e.g., fentanyl) also

can induce reflex suppression, thereby lowering total anesthetic

requirements. Subsequent doses of a nondepolarizing neuromuscular blocking drug might be necessary to provide adequate relaxation for the surgical procedure.

Uses

The volatile inhalation agents are primarily used in clinical practice to maintain general anesthesia. Sevoflurane also can be

used to induce general anesthesia via a face mask because of

its low pungency. Desflurane and sevoflurane, because of their

low blood solubility, are ideally suited for maintenance of general anesthesia in ambulatory surgery patients and for inpatients

when rapid wake-up is desired (e.g., neurosurgery procedures).

Site and Mechanism of Action

The goal of inhalation anesthesia is to develop and maintain a

satisfactory (anesthetizing) partial pressure of anesthetic in the

brain, which is the site of anesthetic action.29 Although the mechanism of action of the volatile inhalation agents is not fully understood, these agents are believed to disrupt neuronal transmission

in discrete areas throughout the CNS by either blocking excitatory, or enhancing inhibitory, transmission through synapses. Ion

channels (especially GABA receptors) are likely targets of volatile

inhalation anesthetic agent action.21

Anesthesia Machine and Circuit

A basic understanding of the anesthesia machine and circuit

is helpful to understanding many of the concepts associated

with the administration of volatile inhalation agents. Three parts

of the anesthesia machine are critically important for the administration of volatile inhalation anesthetics. The flowmeters regulate

the amount of nitrous oxide (an anesthetic gas), air, and oxygen

delivered to the patient. The vaporizers regulate the concentration of volatile inhalation agent administered to the patient, and

the carbon dioxide absorber, which contains either soda lime or

barium hydroxide lime, removes carbon dioxide from exhaled

air. The first step in the administration of a volatile inhalation

agent to a patient is to begin the flow of background gases. Flow

155Perioperative Care Chapter 8

is measured in liters per minute. A mixture of nitrous oxide and

oxygen is commonly used. This gas mixture flows to one of

the vaporizers, where a portion of it enters the vaporizer and

“picks up” the anesthetic vapor of the volatile inhalation agent.

The concentration of volatile inhalation agent delivered by the

vaporizer is proportional to the amount of gas mixture passing

through it, which is regulated by adjusting the vaporizer’s concentration dial. The gas and anesthetic vapor mixture exits the

vaporizer and continues through the anesthetic circuit, where it

is ultimately delivered to the patient via an endotracheal tube

or face mask. The exhaled air from the patient, which contains

the volatile inhalation agent and carbon dioxide, is returned to

the circuit. If a semiclosed-circuit breathing system is being used,

rebreathing of the exhaled volatile agent can occur if the fresh

gas flow rate is low enough (e.g., ≤2 L/minute).30

Potency

Potency of the volatile inhalation agents is compared in terms

of minimum alveolar concentration (MAC). MAC is the alveolar concentration of anesthetic at 1 atmosphere that prevents

movement in 50% of subjects in response to a painful stimulus

(e.g., surgical skin incision).29 The lower an agent’s MAC, the

greater is the anesthetic potency. A value of 1.3 MAC is required

to produce immobility in 95% of patients, whereas 1.5 MAC is

required to block the adrenergic response to noxious stimuli.29

Furthermore, the inhalation agents are additive in their effects

on MAC; the addition of a second agent reduces the required

concentration of the first agent. For example, when desflurane,

isoflurane, and sevoflurane are administered with 60% to 70%

nitrous oxide, their MAC values decrease from 6%, 1.15%, and

1.71% to 2.38%, 0.56%, and 0.66%, respectively.29 Of the volatile

inhalation agents routinely used, isoflurane has the lowest MAC

and desflurane the highest (Table 8-4).29

Chemical Stability

Desflurane and isoflurane are very stable compounds and are

not broken down by the moist soda lime or barium hydroxide

lime contained in the carbon dioxide absorber of the anesthesia

machine. Sevoflurane degrades in the presence of carbon dioxide

absorbent to multiple by-products, with compound A being most

important. In rats, compound A has caused nephrotoxicity,31 but

no clinically significant changes in serum creatinine and blood

urea nitrogen have been demonstrated in human studies.32–34

The administration of sevoflurane at low flow rates is one of the

major factors that increases compound A concentration. The US

Food and Drug Administration (FDA) requires that the sevoflurane package insert contain a warning that sevoflurane exposure

should not exceed 2 MAC hours at flow rates of 1 to less than

2 L/minute, and flow rates less than 1 L/minute are not recommended. Nevertheless, even when low fresh gas flows are used

for long periods and exposure to compound A is high, the levels

of compound A are much less than what is believed to be a toxic

level.35

If the carbon dioxide absorber (soda lime or barium hydroxide

lime) is excessively dry, carbon monoxide can be produced when

the volatile inhalation agents pass through the dry absorbent.

This situation is most commonly encountered on a Monday

morning in an anesthesia machine that has been idle during the

weekend and has had a continuous flow of fresh gas through the

absorbent. Carbon monoxide production can be prevented by

ensuring that the vaporizer is turned off when not in use and at

the end of the day.

AMSORB PLUS, an alkali hydroxidefree carbon dioxide

absorbent containing calcium hydroxide (vs. sodium, barium,

or potassium hydroxide), makes the chemical stability of volatile

inhalation agents in the absorbent not a clinical concern. It does

not generate compound A when used with sevoflurane or carbon

monoxide under any clinical conditions.36

Pharmacokinetics

A series of anesthetic partial pressure gradients beginning at the

anesthesia machine serve to drive the volatile inhalation agent

across barriers to the brain. These gradients are as follows: anesthesia machine > delivered > inspired > alveolar > arterial >

brain. The alveolar partial pressure provides an indirect measurement of the anesthetic partial pressure in the brain because the

alveolar, arterial, and brain partial pressures rapidly equilibrate.29

Factors that influence the uptake and distribution of a volatile

inhalation agent include the inspired concentration of the agent,

alveolar ventilation, solubility of the agent in the blood (blood–

gas partition coefficient), blood flow through the lungs, distribution of blood to individual organs (levels rise most rapidly in

highly perfused organs—brain, kidney, heart, liver), solubility of

the agent in tissue (tissue–blood partition coefficient), and mass

of tissue.29 If all other factors are equal, agents with low solubilities will equilibrate quickly and, as a result, have a faster

wash-in (onset). Solubility is also a factor in the elimination of

TABLE 8-4

Pharmacologic and Pharmacokinetic Properties of the Volatile Inhalation Agents29

Property or Effect Desflurane Sevoflurane Isoflurane Enflurane

MAC in O2 (adults) 6.0 1.71 1.15 1.7

Blood–gas partition coefficienta

0.42 0.69 1.46 1.91

Brain–blood partition coefficientb

1.29 1.7 1.6 1.4

Muscle–blood partition coefficientc

2.02 3.13 2.9 1.7

Fat–blood partition coefficientd

27.2 47.5 45 36

Metabolism 0.02% 3% 0.2% 2%

Molecular weight (g) 168 201 184.5 184.5

Liquid densitye

1.45 1.505 1.496 1.517