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