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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