inpatient vs. outpatient), drug

allergies, previous experience with medications, and concurrent

drug therapy. The ASA physical status classification system classifies patients as I through V. ASA-I patients are healthy with

little medical risk, whereas ASA-V patients have little chance of

survival. Severe systemic disorders (e.g., uncontrolled diabetes

mellitus, coronary artery disease) are present in ASA-III through

ASA-V patients. Selection of preoperative medications in this

group of patients will be more difficult. These patients generally have limited physiological reserve; thus, administration of

a cardiovascular depressant agent, for example, can be harmful.

Furthermore, these patients will be taking a significant number of

medications; hence, chances for drug interactions are increased.

The patient’s other medical conditions are important to consider

to prevent the administration of contraindicated medications. For

example, the benzodiazepines are contraindicated in pregnancy.

A patient’s age will play a role in the response seen with premedicant administration. The elderly are often more sensitive

to preoperative opioids and benzodiazepines, as well as to the

central nervous system (CNS) effects of anticholinergic agents.

Familiarity with the surgery to be performed will aid in selecting appropriate premedicants. In surgical cases in which painful

procedures (e.g., vascular cannulation, peripheral nerve block)

will be performed on the patient, an analgesic premedicant may

be warranted. The length and type of the procedure is important to consider when selecting premedicants. For example, a

patient undergoing emergency surgery who has not fasted is

often administered a nonparticulate antacid because of the risk

for aspiration of gastric contents. In outpatient surgery, agents

with a long duration of action should be avoided because residual

150 Section 1 General Care

effects can prolong discharge time. Finally, it is important to

review the patient’s current drug therapy before selecting an

agent to prevent potentially harmful drug interactions.

Timing and Routes of Administration

The timing and route of administration is almost as important

as the choice of the agent. As a general rule, agents administered

by the IV route produce the fastest onset of action and are often

given after the patient arrives in the OR, whereas medications

administered via the oral route are usually administered 30 to

60 minutes before the patient arrives in the OR. If possible, the

intramuscular (IM) route should be avoided because it is painful

and undesirable for the patient.

Administration of Chronic Medications

Before Surgery

CASE 8-1

QUESTION 1: K.J., a 61-year-old man, is scheduled to

undergo a carotid endarterectomy under general anesthesia. K.J.’s past medical history is significant for diabetes,

hypertension, hyperlipidemia, and coronary artery disease.

His current medications are enalapril 20 mg once daily,

metoprolol XL 50 mg once daily, metformin XR 1,000 mg

once daily, atorvastatin 40 mg once daily, aspirin EC 325 mg

once daily, and clopidogrel 75 mg once daily. What medications should K.J. take the morning of surgery?

Consequences of stopping a chronic medication before, or

failing to restart that medication after surgery, can be significant. For example, abrupt discontinuation of a β-blocker during

the perioperative period in a patient who has been on chronic

β-blocker therapy can increase the risk of death in the intraoperative and postoperative period. The American College of

Cardiology/American Heart Association (ACC/AHA) recommends continuation of β-blocker therapy in patients undergoing surgery who are receiving a β-blocker for treatment of

conditions with ACC/AHA Class I guideline indications for the

drugs (e.g., angina, symptomatic arrhythmia, postmyocardial

infarction).5 Angiotensin-converting enzyme inhibitors (ACEIs)

and angiotensin receptor blockers (ARBs) increase the risk of

hypotension after induction of anesthesia when these agents are

not withheld 24 hours before surgery.6 In general, this hypotension is not responsive to conventional vasopressors (ephedrine,

phenylephrine) but will respond to vasopressin.7 Stopping the

ACEI before surgery, however, can result in adverse postoperative effects such as rebound hypertension and atrial fibrillation.

Therefore, the decision to continue or stop the ACEI or ARB

before surgery is made on an individual basis, taking into consideration the indication for the ACEI or ARB and the type of surgery.

Calcium-channel blockers, clonidine, amiodarone, digoxin, and

statins should be continued. Preoperative withdrawal of a statin

in a patient undergoing major vascular surgery, for example,

increases the risk of myocardial infarction and cardiovascular

death after surgery.8 Diuretics are typically held the morning

of surgery to minimize the risk of hypovolemia and electrolyte

abnormalities.

Oral antidiabetic agents and noninsulin injectable agents are

typically held the morning of surgery and not restarted until normal food intake resumes. In patients with renal dysfunction and

those who may receive IV contrast media, metformin should be

discontinued 24 to 48 hours before surgery to reduce the risk

of perioperative lactic acidosis. For patients on insulin therapy,

a portion of the morning dose of intermediate- or long-acting

insulin is generally administered on the day of surgery after a

check of the patient’s blood glucose. Close blood glucose monitoring guides subsequent insulin doses to avoid hypoglycemia.9

Antiepileptics, antipsychotics, benzodiazepines, lithium,

selective serotonin and norepinephrine reuptake inhibitors

(SSRIs and SNRIs), tricyclic antidepressants (TCAs), and carbidopa/levodopa have a greater risk for withdrawal or disease

decompensation than for perioperative complications. These

medications should therefore be continued up to and including

the morning of surgery.

Monoamine oxidase inhibitors (MAOIs) can interact with certain drugs used during anesthesia to produce cardiovascular instability. However, administration of an MAOI-safe anesthetic avoids

the need to stop the MAOI before surgery (and relapse of the

underlying disease) in a patient requiring an MAOI for refractory psychiatric illness.10

Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs)

reversibly inhibit platelet aggregation and are often stopped 1 to

3 days before surgery, depending on the duration of action of

the drug. Celecoxib does not affect platelet aggregation and may

be continued up to and including the day of surgery. Nonselective

NSAIDs and celecoxib should be held if there is a concern for

impaired renal function during or after surgery.

For patients on anticoagulant or antiplatelet therapy, the risks

for thromboembolism must be balanced with the risk for bleeding during and after the surgical procedure. For patients on

warfarin who are at high risk for perioperative thromboembolism, bridging anticoagulation therapy with IV heparin or

low-molecular-weight heparin (LMWH) before surgery is recommended. Warfarin may not need to be discontinued if the

patient is undergoing minor surgery (e.g., certain ophthalmic,

dental, or dermatologic procedures). For patients who have had

coronary stents recently placed, discontinuing antiplatelet therapy prematurely can significantly increase the risk of perioperative stent thrombosis and have catastrophic consequences.11

Traditionally, it was thought that patients who have been taking long-term corticosteroid therapy before surgery will experience adrenal insufficiency in the perioperative period and should

receive a supplemental stress-dose of hydrocortisone or methylprednisolone during and up to 2 to 3 days after surgery.12 A

recent review of the literature, however, found that patients on

long-term corticosteroid therapy only require continuation of

their normal daily dose of corticosteroid in the perioperative

period. These patients are generally able to increase their endogenous adrenal function above their baseline corticosteroid dose

to meet the increased demand from surgery; a supplemental

stress dose of corticosteroid is not necessary. These patients can

be closely monitored, and if hypotension that is refractory to

volume replacement does develop, a stress dose of a corticosteroid should be administered at that time. Patients who have

a known dysfunctional hypothalamic-pituitary-adrenal axis deficiency (e.g., Addison disease), on the other hand, will require

supplemental corticosteroid doses in the perioperative period as

they cannot increase endogenous cortisol production to meet

the increased demand from surgery.13

Opioid-dependent chronic pain patients who undergo surgery

often experience more severe acute pain after surgery. These

patients should receive either their chronic opioid medication or

a comparable dose of an IV opioid the morning of surgery to meet

their daily requirements to avoid uncontrolled pain and opioidwithdrawal symptoms. Opioid-dependent patients being treated

with buprenorphine present a unique challenge for postoperative pain management. Buprenorphine is a partial mu-agonist

and kappa antagonist that tightly binds to these receptors for a

very long time. If buprenorphine is continued up to the morning

151Perioperative Care Chapter 8

of surgery, it prevents a pure mu-agonist such as morphine from

providing effective analgesia. Although buprenorphine produces

analgesia, it only partially stimulates the mu-receptor, resulting

in a ceiling effect for analgesia. Increasing the dose of buprenorphine does not usually provide enough analgesia. In patients

expected to have moderate to severe pain after surgery (requiring the use of an opioid), it is recommended that buprenorphine be discontinued 5 to 7 days before surgery. These patients

may be transitioned to nonopioid pain medications and possibly

methadone, which would then be continued up to and including the morning of surgery. The use of nonopioid analgesics

or analgesic techniques (e.g., acetaminophen, peripheral nerve

blockade, epidural analgesia) for perioperative analgesia should

be maximized, regardless of whether or not buprenorphine is

discontinued prior to surgery.14

For K.J., metformin should be discontinued 24 to 48 hours

before surgery to minimize the risk for lactic acidosis during or

after surgery. Metoprolol, on the other hand, should be taken up

to and including the morning of surgery. K.J. has coronary artery

disease and is undergoing a carotid endarterectomy, which is

a vascular surgical procedure with a high risk of serious cardiovascular complications (such as stroke or myocardial infarction). Based on the ACC/AHA practice guidelines,5 perioperative

β-blocker therapy is recommended for K.J. The decision for K.J.

to take enalapril and atorvastatin the morning of surgery is made

by the anesthesia care provider. For K.T., it is likely that he will

be asked to take his atorvastatin but hold his morning dose of

enalapril to ensure hemodynamic stability during induction of

general anesthesia. The decision for K.J. to take or hold aspirin

and clopidogrel is made by the surgeon, based on risk of bleeding versus the benefit of cardiovascular protection. For K.T., it is

likely that the surgeon will ask him to take the aspirin up to and

including the morning of surgery but hold the clopidogrel for

7 days before surgery.

Aspiration Pneumonitis Prophylaxis

CASE 8-2

QUESTION 1: D.W., a 5-foot 4-inch, 95-kg, 38-year-old

woman, ASA-II, is scheduled to undergo a laparoscopic

cholecystectomy under general anesthesia. D.W. has type

2 diabetes. Physical examination is normal except for an

abnormal airway, which is anticipated to complicate intubation. Her medications include glipizide and an antacid

for dyspepsia. The procedure is scheduled as a same-day

surgery. What factors predispose D.W. to aspiration, and

what premedication, if any, should D.W. receive for aspiration prophylaxis?

DEFINITION

Aspiration pneumonitis, although uncommon, is a potentially

fatal condition that occurs as a result of regurgitation and aspiration of gastric contents. Aspiration of undigested or semidigested

gastric contents into the respiratory tract can cause obstruction

and an inflammatory response. Acute chemical pneumonitis and

subsequent acute lung injury (aspiration pneumonitis) can result

from aspiration of acidic gastric secretions.15 For adult patients,

it is believed that aspiration of more than 25 mL of gastric fluid

with a pH of less than 2.5 places them at greater risk for severe

pneumonitis and pulmonary sequelae should aspiration occur.1

RISK FACTORS

Patients at greatest risk for regurgitation and aspiration include

those with increased gastric acid, elevated intragastric pressure,

gastric or intestinal hypomotility, digestive structural disorders,

neuromuscular incoordination, and depressed sensorium. These

can include pregnant women, obese patients, and patients with

diabetes, as well as patients with a hiatal hernia, gastroesophageal

reflux, esophageal motility disorders, or peptic ulcer disease.1,16

Diabetic patients with reflux symptoms or poor glucose control

may also benefit from pharmacologic prophylaxis. In addition

to having delayed gastric emptying, obese patients will often

present with increased abdominal pressure and an abnormal airway; both factors predispose these individuals to aspiration. Hormonal changes in pregnant women account for delayed gastric

emptying and relaxation of the lower esophageal sphincter. An

increase in intra-abdominal pressure is also seen during pregnancy. Labor can increase gastrin levels, increasing gastric volume and acidity as well as delaying gastric emptying. Patients

undergoing emergency surgery frequently have full stomachs

because they have not had time to fast appropriately.

Rapid sequence induction, effective application of cricoid pressure, maintaining a patent upper airway, avoiding inflation of

the stomach with anesthetic gases, and inserting a large-bore

gastric tube once the airway has been secured, as well as the

use of regional anesthesia when possible, are probably the most

important measures the anesthesia provider can take to reduce

the patient’s risk of aspiration.17 Routine administration of pharmacologic aspiration prophylaxis is not cost-effective and does

not reduce morbidity in healthy patients undergoing elective

surgery.18 Administration of pharmacologic aspiration prophylaxis should, however, be considered to prevent morbidity in

patients at risk for aspiration.

D.W. has several factors that place her at risk for aspiration.

She is obese with an abnormal airway. She also has diabetes

and reports symptoms of dyspepsia that are relieved by antacids.

These conditions will predispose D.W. to increased abdominal

pressure, delayed gastric emptying, and increased risk of regurgitation. Her abnormal airway may delay intubation, increasing

the amount of time D.W. is susceptible to aspiration. Therefore,

aspiration prophylaxis with medications that buffer gastric acid

and reduce gastric volume is prudent for D.W.

MEDICATIONS

Many medications (e.g., antacids, gastric motility stimulants,

H2-receptor antagonists) can reduce the risk of pneumonitis if

aspiration occurs. These drugs, with the possible exception of

metoclopramide, are relatively free of adverse effects and have a

favorable risk-benefit profile.

ANTACIDS

Antacids, effective in raising gastric pH to greater than 2.5, should

be given as a single dose (30 mL) approximately 15 to 30 minutes

before induction of anesthesia. Nonparticulate antacids (e.g., citric acid and sodium citrate) are the agents of choice because

the suspension particles in particulate antacids can act as foci

for an inflammatory reaction if aspirated and increase the risk

of pulmonary damage.1 Antacids have two major advantages

when used for aspiration pneumonitis prophylaxis; there is no

“lag time” for onset of activity, and antacids are effective on the

fluid already in the stomach. Their major disadvantages are (a)

a short-acting buffering effect that is not likely to last as long as

the surgical procedure (citric acid and sodium citrate must be

administered no more than 1 hour before induction of anesthesia, with its duration possibly dependent on gastric emptying);

(b) the potential for emesis (owing to their lack of palatability);

(c) the possibility of incomplete mixing in the stomach; and (d)

their administration adds fluid volume to the stomach.1,18

152 Section 1 General Care

GASTRIC MOTILITY STIMULANTS

The gastric motility stimulant, metoclopramide, has no effect

on gastric pH or acid secretion. This agent reduces gastric volume in predisposed patients (e.g., parturients, obese patients)

by promoting gastric emptying. Preoperative metoclopramide

increases lower esophageal sphincter pressure and reduces gastric

volume.1,18 Metoclopramide should be administered 60 minutes

before induction of anesthesia when given orally. When given

by the IV route, metoclopramide should be slowly (3–5 minutes)

administered 15 to 30 minutes before induction of anesthesia.

The effects of metoclopramide on gastric emptying have been

variable, especially when used with other agents. For example,

the concomitant administration of anticholinergics (e.g., glycopyrrolate, atropine) or prior administration of opioids can reduce

lower esophageal sphincter pressure, which can offset the effects

of metoclopramide on the upper gastrointestinal (GI) tract.1,19

H2-RECEPTOR ANTAGONISTS

H2-receptor antagonists reduce gastric acidity and volume by

decreasing gastric acid secretion. Unlike antacids, the H2-receptor

antagonists do not produce immediate effects. Onset time for

these agents when administered orally is 1 to 3 hours; good effects

will be seen in 30 to 60 minutes when administered IV.3 Duration

of action of H2-receptor antagonists is also important because

the risk of aspiration pneumonitis extends through emergence

from anesthesia. After IV administration, the cimetidine dose

should be repeated in 6 hours if necessary, whereas therapeutic

concentrations of ranitidine and famotidine persist for 8 and

12 hours, respectively.3

PROTON-PUMP INHIBITORS

Proton-pump inhibitors (PPIs; e.g., omeprazole) act at the final

site of gastric acid secretion, making these agents very effective

in suppressing acid secretion. When the effects of preoperative

IV pantoprazole on gastric pH and volume were compared with

IV ranitidine and placebo, both pantoprazole and ranitidine significantly reduced the volume and increased the pH of gastric

contents when compared with placebo (saline). There was no

difference, however, between the pantoprazole and ranitidine

groups.20 Therefore, there appears to be no need to use the

more-expensive PPIs in patients at risk for pulmonary aspiration.

Because D.W.’s surgery is scheduled as a same-day surgery,

D.W. will arrive at the hospital or surgical center approximately

90 minutes before the start of the procedure. A nonparticulate

antacid such as citric acid and sodium citrate solution 30 mL

orally can be administered to D.W. immediately before entering

the OR. The anesthesia care provider may also administer an

H2-receptor antagonist instead of, or in addition to, the nonparticulate antacid.

INTRAVENOUS ANESTHETIC AGENTS

General Anesthesia

General anesthesia is a state of drug-induced unconsciousness.

Other components of general anesthesia include amnesia, analgesia, immobility, and attenuation of autonomic responses to

noxious stimuli.21 Drugs used to induce general anesthesia

should produce unconsciousness rapidly and smoothly while

minimizing any cardiovascular changes. An IV induction agent is

commonly administered for initiation of general anesthesia. The

most common drug used for IV induction is propofol. Methohexital, etomidate, remifentanil, midazolam, and ketamine are

less frequently used. Propofol can also be used to maintain general anesthesia, as drugs that do not accumulate during repeat

or continuous dosing are ideal choices for maintenance therapy.

Mechanisms of Action

Most IV anesthetic agents produce CNS depression by action

on the γ -aminobutyric acid (GABA) benzodiazepine chloride

ion channel receptor. GABA is the principal inhibitory neurotransmitter in the CNS. The barbiturates (methohexital) bind

to a receptor site on the GABA–receptor complex, reducing the

rate of dissociation of GABA from its receptor. This results in

increased chloride conductance through the ion channel, nerve

cell hyperpolarization, and inhibition of nerve impulse transmission. Barbiturates can directly activate the chloride channels by

mimicking the action of GABA. Benzodiazepines (midazolam)

also bind to this GABA–receptor complex, and their subsequent

potentiation of the inhibitory action of GABA is well described.

At large doses, most of the benzodiazepine receptors will be

occupied, and hypnosis (unconsciousness) will occur. The site of

action of etomidate—and propofol—is also at the GABA receptor, with etomidate augmenting GABA-gated chloride currents

and propofol enhancing the activity of the GABA-activated chloride channel. Ketamine acts at a different site than other induction agents. At anesthetic doses, ketamine produces dissociation

between the cortex and the thalamus within the limbic system,

resulting in a dissociative state; that is, the patient appears to be

detached from his or her surroundings. Ketamine also produces

analgesia and amnesia at these doses.22

Pharmacokinetics

The onset and duration of effect are the most important pharmacokinetic properties of IV anesthetic agents when used for induction of anesthesia. In general, the commonly used IV induction

agents have a rapid onset of action and short clinical duration.

 OPIOID THERAPY FOR BREAKTHROUGH PAIN

MANAGEMENT

CASE 7-7, QUESTION 4: What are L.V.’s options for breakthrough pain management?

Breakthrough pain can be classified as spontaneous pain (frequently idiopathic, occurring with no known stimulus), incident

pain (secondary to a stimulus that the patient may or may not

be able to control), or end-of-dose failure (pain at the end of the

dosing interval of the long-acting opioid).161 Incident pain can be

reduced by instructing the patient to take a dose of short-acting

opioid 30 minutes before activity. Spontaneous breakthrough

pain should be treated by administering a short-acting opioid as

soon as the pain is experienced. For patients on long-acting opioid

formulations experiencing end-of-dose failure, APS guidelines

recommend supplementary doses of a short-acting opioid equivalent to 5% to 15% of the total daily dose to be taken every 2 hours

as needed.159 Short-acting opioid/acetaminophen products have

a maximal dose to prevent liver toxicity with acetaminophen, thus

creating a ceiling limit on the analgesic efficacy. Plain short-acting

opioids (e.g., morphine, oxycodone, hydromorphone) should be

used for patients requiring large doses for breakthrough pain.

In L.V.’s case, short-acting opioid solution (morphine, hydromorphone, or oxycodone) should be available for breakthrough

pain before discontinuation of IV hydromorphone. The shortacting opioid can be administered in solution form through the

gastric feeding tube or as oral tablets if L.V. can tolerate swallowing. L.V.’s oncologist would like to use oral morphine solution

for breakthrough pain management. Because the transdermal

fentanyl total daily dose is approximately equal to a total daily

dose of 280 mg of oral morphine (Fig. 7-7), 10% of the total daily

morphine dose would be 28 mg. The dose should be rounded to

the nearest tablet size, which is 30 mg, if L.V. would eventually

take morphine tablets.

If more than two supplemental doses of short-acting morphine 30 mg are required daily to keep L.V.’s pain under control,

an increase in the transdermal fentanyl patch dose should be

tried. For patients with pain rated 4 of 10 or less and not exceeding four supplemental doses per day, the long-acting opioid dose

(e.g., transdermal fentanyl) should be increased by the amount

equal to the daily total of supplemental short-acting opioid taken

for pain. Moderate to severe pain may require an increase in the

opioid total daily dose by 50% to 100%.159

Fentanyl administration by oral transmucosal (Actiq) or buccal (Fentora) routes is approved for breakthrough pain management in cancer patients. The dose of both formulations is

determined by titration (i.e., starting with the lowest dose and

increasing based on pain relief ) rather than a percentage of the

total daily dose.166 Equianalgesic doses of Actiq and Fentora are

given in Table 7-23. The oral transmucosal and buccal routes

would not be preferred in L.V.’s case due to his dry oral mucous

membranes secondary to radiation, which will impact absorption. Xerostomia is a common problem associated with radiation

therapy of the head and neck and occurs in 80% of patients by

week 7 of treatment. Problems related to xerostomia include difficulty speaking, chewing, swallowing, infections; mouth pain;

and dental caries. Reports indicate up to 64% of patients may

experience moderate-to-severe xerostomia 3 years after radiation

treatment.155,167 Chapter 90, Adverse Effects of Chemotherapy

and Targeted Agents, provides information on topical treatment

of mucositis and xerostomia.

METHADONE DOSE CALCULATION

CASE 7-7, QUESTION 5: L.V. has now completed chemoradiation therapy, and the mucositis pain has resolved. He continues to have persistent burning neuropathic pain rated 8

of 10 in the neck and shoulders and is using transdermal

fentanyl 100 mcg/hour along with five doses of immediaterelease oral morphine 30 mg per day. He is also taking

gabapentin 900 mg orally three times a day and using a

Lidoderm patch on each shoulder. L.V.’s oncologist wants

to switch to oral methadone for neuropathic pain management. What is the oral methadone dose L.V. should be

started on?

Methadone is an opioid agonist with analgesic activity at mu

and delta receptors. Additional mechanisms of methadone that

make it unique from other opioids and a good option for neuropathic pain include 5-HT and NE reuptake inhibition and antagonist effects at the NMDA receptor. Rotation to methadone

is recommended when a patient has an inadequate response

to other opioids or experiences intolerable side effects such as

delirium, myoclonus, or nausea. A trial with methadone is warranted for L.V. because his neuropathic pain is not well controlled with transdermal fentanyl and other coanalgesics, including gabapentin and Lidoderm. Refer to Case 7-3 for treatment of

neuropathic pain.

Unlike short-acting opioids, methadone has a long half-life

that ranges from 15 to 60 hours with a duration of action of

6 to 12 hours.159 The conversion to methadone is not proportional like other opioid equianalgesic dose calculations. Older

opioid dosing tables list a single conversion factor as 20 mg of

oral methadone (or 10 mg IV methadone) is equianalgesic to 30

mg of oral morphine. The single methadone conversion factor

was intended for acute pain and does not account for chronic use.

The conversion ratios vary with morphine dose. Contemporary

tables contain three or more morphine to methadone ratios to

adjust for the magnitude of the methadone dose potency with

higher morphine daily dose requirements for chronic nonmalignant and cancer pain. The most commonly used morphine to

methadone conversions are given in Table 7-24.168

L.V.’s total daily dose of morphine is between 340 mg and

390 mg after converting transdermal fentanyl and adding the

immediate-release morphine. Figure 7-8 gives calculations to

convert transdermal fentanyl to oral methadone in L.V. The dose

of oral morphine falls within the dose range of 301 to 600 mg,

which corresponds to a 10:1 oral morphine to oral methadone

ratio (Table 7-24). L.V.’s total daily dose of methadone is approximately 34 mg or 39 mg, depending on the conversion ratio of

transdermal fentanyl used (e.g., 34 mg will be used for this case

based on the Donnor ratio). For most patients, the recommended

methadone dose interval is every 8 hours. Older adults or frail

144 Section 1 General Care

TABLE 7-24

Morphine to Methadone Equianalgesic Dose Ratio168

Oral Morphine Dose (mg/d) <100 101–300 301–600 601–800 801–1000 ≥1001

Oral morphine to oral methadone ratio 3:1 5:1 10:1 12:1 15:1 20:1

patients may need methadone dosed every 12 hours to reduce

the occurrence of side effects such as sedation.159,161

L.V.’s total daily dose of methadone should be divided into

three doses and administered on an 8-hour interval. However,

methadone is available in tablets (5 mg and 10 mg) or oral solution. The problem with L.V.’s total daily methadone dose is that it

does not divide evenly using tablets. Splitting methadone tablets

is not recommended because of the inconsistency in the dose with

unequal tablet portions. Methadone solution is not convenient

to use, and the dose needs to be drawn accurately with an oral

syringe to prevent overdosing. L.V. would need approximately

11 to 13 mg of oral methadone solution per dose, which may

be difficult to calibrate with the oral syringe. Therefore, L.V.’s

methadone dose should be rounded down to the nearest available tablet size (i.e., 10 mg). Using a rapid switch transition from

transdermal fentanyl to methadone, L.V. should be instructed

to remove the transdermal fentanyl patch and begin methadone

10 mg orally every 8 hours approximately 12 hours after the

patch has been removed. L.V. can continue to use morphine

sulfate immediate-release 30 mg every 2 hours as needed for

breakthrough pain. The immediate-release morphine dose may

need to be reduced if L.V. has a good response to methadone.

Because methadone has a long terminal half-life, it will take 4

or more days to achieve steady state. Unless L.V. is experiencing

severe pain, the methadone dose should not be increased before

5 days. L.V. should be encouraged to use the immediate-release

morphine during the transition period. The methadone dose can

be adjusted based on the total daily dose of morphine used for

pain control during the transition period.161

METHADONE TOXICITY SIGNS AND SYMPTOMS

CASE 7-7, QUESTION 6: What are the signs and symptoms

of methadone toxicity that should be communicated to L.V.?

Step 1:

Determine the 24-hour total of the opioid that will be converted. For L.V., the transdermal fentanyl 100 mcg/hour patch will

need to be converted to oral morphine. In addition, L.V. is using 150 mg/day of immediate-release oral morphine.

Donner Study Ratio165

The conversion ratio of 60 mg/day oral morphine to 25 mcg/hour transdermal fentanyl will be used for the calculation.

(25)(X) = (100)(60)

X = 240 mg oral morphine

Therefore, the total daily dose of oral morphine is 390 mg (240 mg + 150 mg)

Breitbart Study Ratio164

The conversion ratio of 2 mg oral morphine to 1 mcg/hour transdermal fentanyl will be used for the calculation.

(1)(X) = (2)(100)

X = 200 mg/day oral morphine

Therefore, the total daily dose of oral morphine is 340 mg (200 mg + 150 mg)

“X” mg total daily dose of new opioid

100 mcg/hour transdermal fentanyl = 60 mg/day oral morphine

25 mcg/hour transdermal fentanyl

“X” mg total daily dose of new opioid

100 mcg/hour transdermal fentanyl = 2 mg oral morphine

1 mcg/hour transdermal fentanyl

Step 2:

Select the equianalgesic dose ratio from the methadone table that corresponds to a total daily morphine use of 390 mg (using

the Donner method in step 1).161,169

According to the methadone dose Table 7-24, morphine doses in the range of 301–600 mg correspond to a 10:1 ratio (oral morphine to

oral methadone).

(10)(X) = (390)(1)

10X = 390

X = 39 mg of oral methadone/day

If the total daily dose of 340 mg oral morphine is used for the calculation, the total daily dose of methadone would be 34 mg.

“X” mg total daily dose oral methadone

390 mg total daily dose oral morphine = 1 mg oral methadone

10 mg oral morphine

FIGURE 7-8 Conversion of L.V. from transdermal fentanyl to oral methadone.

145Pain and Its Management Chapter 7

In 2006, the FDA issued a public health advisory to alert prescribers and patients of the risk of fatal respiratory depression

and QTc interval prolongation associated with methadone.169

L.V. should be instructed to take methadone exactly as prescribed

to prevent serious problems with breathing. He should be told

about the signs and symptoms of methadone toxicity including

shallow breathing, slowed respirations followed by periods of not

breathing, slurred speech or difficulty talking, loud snoring, and

inability to walk normally.161 L.V. should be told to seek medical attention immediately if he experiences any of these signs

and symptoms of methadone toxicity. He should also let family

members living with him know about the risks of methadone

so they can be aware of the signs and symptoms of methadone

toxicity.

METHADONE TOXICITY MONITORING

CASE 7-7, QUESTION 7: What are the recommendations for

monitoring cardiac toxicity associated with methadone?

Methadone can cause prolongation of the QTc interval and

increase the risk for development of torsades de pointes (potentially fatal arrhythmia). Factors associated with QTc prolongation

are methadone doses greater than 100 mg/day, hypokalemia,

low prothrombin level (suggestive of reduced liver function),

and drug interactions involving the cytochrome P-450 3A4

enzyme.168,169

Consensus guidelines have been published on cardiac monitoring for patients taking methadone. The guidelines recommend pretreatment screening, electrocardiogram evaluation,

and risk stratification for QTc intervals exceeding 500 milliseconds. For a QTc interval exceeding 500 milliseconds, the consensus guidelines recommend reducing or discontinuing methadone

(Table 7-25).170

OPIOID SIDE EFFECT MANAGEMENT

CASE 7-7, QUESTION 8: How should opioid side effects be

managed?

Appropriate use of opioids requires minimizing the occurrence of side effects including sedation, nausea, vomiting, pruritus, myoclonus, and cognitive impairment.171 Table 7-26 gives

treatment for common opioid-related side effects. In cancer

patients, multiple factors may contribute to the emergence of

opioid side effects such as renal insufficiency, nausea and vomitTABLE 7-25

Consensus Recommendations for Methadone QTc

Prolongation170

Inform patients of arrhythmia risk before prescribing methadone.

Obtain patient history of structural heart disease, arrhythmia, and

syncope.

Obtain a pretreatment ECG before starting methadone and follow up

30 days after starting methadone. Annual ECG is recommended.

Additional ECG if the methadone dosage exceeds 100 mg/d or

patient has unexplained syncope or seizures.

Reduce or discontinue methadone if the QTc interval exceeds

500 milliseconds.

Screen medication profile use of drugs that also may prolong or slow

the elimination of methadone (i.e., SSRIs, antifungal agents, protease

inhibitors, phenytoin, rifampin, phenobarbital, droperidol).

ECG, electrocardiogram; SSRIs, selective serotonin reuptake inhibitors.

TABLE 7-26

Pharmacological Treatments for Opioid-Related Side

Effects171

Side Effect Treatment

Constipation Stool softener, laxative, methylnaltrexone,

oral naloxone

Sedation Methylphenidate, modafinil

Pruritus Diphenhydramine, hydroxyzine

Nausea Prochlorperazine, haloperidol,

metoclopramide, ondansetron,

antihistamine

Dysphoria Haloperidol, opioid rotation

Cognitive impairment Methylphenidate, modafinil, opioid rotation

Myoclonus Clonazepam, dose reduction, opioid rotation

ing caused by changes in gut motility or chemotherapy, sedation

owing to metabolic disturbances, and concomitant use of other

sedatives or antiemetics. Tolerance to most of the opioid side

effects develops in 3 to 7 days. If the side effects do not diminish

with time, treatment may include switching to a different opioid or adding another medication to counteract the undesired

effect.159,171

Respiratory depression is a serious adverse event and often

is preceded by sedation. With methadone, the peak respiratory

depressant effects typically occur later and persist longer than

with other opioids. Naloxone is an opioid receptor antagonist

that can be used to reverse respiratory depression caused by

opioid medications. Opioid-tolerant patients are exquisitely sensitive to opioid antagonists. If naloxone is necessary, it should be

titrated to effect (i.e., 0.02 mg IV push every 2 minutes) to prevent profound withdrawal, seizures, arrhythmias, and severe pain

(e.g., the analgesic effect of opioids is reversed with naloxone).159

Patients who are overdosed on methadone will require a continuous IV infusion of naloxone for 24 to 36 hours because of the

long elimination half-life of methadone.

REFRACTORY CANCER PAIN MANAGEMENT

CASE 7-7, QUESTION 9: What are other options if pain is

not controlled with conventional pharmacotherapy?

Neuraxial opioid administration (epidural or intrathecal) can

be used to treat cancer pain that is refractory to conventional

therapy with opioids and coanalgesic medications.172 Cancer

patients with a life expectancy less than 3 months typically have

epidural medication administration through a catheter tunneled

under the skin that is connected to an ambulatory infusion pump.

Long-term neuraxial therapy must be administered through an

implantable intrathecal pump to avoid infection complications.

Indications for use of neuraxial therapy include neuropathic

pain, mixed neuropathic-nociceptive pain, radicular pain from

failed back syndrome, and CRPS (refer to Cases 7-1 and 7-4).

Medication selection is based on the patient’s allergy history

and response to a screening trial. Opioids (morphine, hydromorphone, fentanyl), local anesthetics (bupivacaine, ropivacaine), clonidine, ziconotide, and baclofen are commonly used in

neuraxial regimens.172

Complementary and alternative medicine therapies are

widely used by patients in the management of cancer pain, dyspnea, and nausea and vomiting. Auricular acupuncture, therapeutic touch, and hypnosis may help with the management of

cancer pain. Music therapy, massage, meditation, and hypnosis may help to reduce anxiety caused by dyspnea. Acupuncture

146 Section 1 General Care

and guided imagery may be beneficial in treating chemotherapyinduced nausea and vomiting.171

Oral cannabinoid formulations (dronabinol and nabilone) are

approved by the FDA for chemotherapy-induced nausea and

vomiting refractory to conventional antiemetic therapy. Several

studies of the endogenous cannabinoid receptors (CB1 and CB2)

have demonstrated efficacy in the management of pain. In the

CNS, the CB1 receptor is expressed in the areas involved in nociceptive processing, including the periaqueductal gray matter and

dorsal horn of the spinal cord. The CB2 receptor is expressed

on cells of the immune system and is involved in modulation

of inflammation and pain. CB2 receptor activation has been

shown to be analgesic in neuropathic pain models.171,173 Medical

use of cannabinoids has been debated in many states. In October 2009, the Department of Justice issued a memorandum to

US Attorneys stating that federal resources should not be used

to prosecute persons whose actions comply with their state’s

laws permitting medical use of marijuana. Currently, 14 states

allow the use of medical marijuana via inhalation for various diseases and medical conditions including nonmalignant and cancer

pain.174

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT10e. Below are the key references

for this chapter, with the corresponding reference number in this

chapter found in parentheses after the reference.

Key References

American Geriatrics Society Panel on Pharmacological Management of Persistent Pain in Older Persons. Pharmacological management of persistent pain in older persons. J Am Geriatr Soc.

2009;57:1331. (121)

Attal N et al. EFNS guidelines on the pharmacological treatment

of neuropathic pain: 2010 revision. Eur J Neurol. 2010;17:1113. (16)

Carville SF et al. EULAR evidence-based recommendations for

the management of fibromyalgia syndrome. Ann Rheum Dis.

2008;67:536. (69)

Chou R et al. Clinical guidelines for the use of chronic opioid

therapy in chronic noncancer pain. J Pain. 2009;10:113. (144)

Chou R et al. Medications for acute and chronic low back pain:

a review of the evidence for an American Pain Society/American

College of Physicians clinical practice guideline [published correction appears in Ann Intern Med. 2008;148:247]. Ann Intern Med.

2007;147:505. (32)

Chou R et al. Comparative efficacy and safety of skeletal muscle

relaxants for spasticity and musculoskeletal conditions: a systematic review. J Pain Symptom Manage. 2004;28:140. (101)

Drossman DA. Severe and refractory chronic abdominal pain:

treatment strategies. Clin Gastroenterol Hepatol. 2008;6:978. (142)

Dubinsky RM et al. Practice parameter: treatment of postherpetic neuralgia: an evidence-based report of the Quality Standards Subcommittee of the American Academy of Neurology.

Neurology. 2004;63:959. (111)

Dworkin RH et al. Recommendations for the pharmacological

management of neuropathic pain: an overview and literature

update. Mayo Clin Proc. 2010;85(3 Suppl):S3. (104)

Finnerup NB et al. The evidence for pharmacological treatment

of neuropathic pain. Pain. 2010;150:573. (105)

Harvey WF, Hunter DJ. Pharmacologic intervention for

osteoarthritis in older adults. Clin Geriatr Med. 2010;26:503.

(120)

Koes BW et al. An updated overview of clinical guidelines for the

management of non-specific low back pain in primary care. Eur

Spine J. 2010;19:2075. (27)

Miaskowski C et al. Guideline for the Management of Cancer Pain

in Adults and Children, APS Clinical Practice Guideline Series, No. 3.

Glenview, IL: American Pain Society; 2005. (152)

Turk DC et al. Psychological approaches in the treatment of

chronic pain patients—when pills, scalpels and needles are not

enough. Can J Psychiatry. 2008;53:213. (148)

Key Websites

Partners against Pain. www.partnersagainstpain.com.www.

nhpoc.org

Perioperative Care 8

Andrew J. Donnelly, Julie A. Golembiewski, and Andrei M. Rakic

CORE PRINCIPLES

CHAPTER CASES

PREOPERATIVE MEDICATIONS

1 Chronic medications that are necessary to maintain the patient’s underlying

physiological condition are generally administered up to, and including, the day of

surgery. The decision to hold medications that cause bleeding (e.g., warfarin,

clopidogrel), have hemodynamic (e.g., angiotensin-converting enzyme inhibitor) or

hypoglycemic effects (e.g., insulin), or that can potentially interact with

intraoperative and postoperative medications (e.g., buprenorphine) is made on an

individual basis based on risk and benefit.

Case 8-1 (Question 1)

2 Premedication may be administered immediately before surgery to reduce the

patient’s anxiety about the upcoming surgery (e.g., midazolam) or to reduce the

patient’s risk for aspiration (e.g., sodium citrate).

Case 8-2 (Question 1)

INTRAVENOUS ANESTHETIC AGENTS

1 General anesthesia, defined as a state of drug-induced unconsciousness, is most

commonly achieved by the administration of an intravenous anesthetic agent. The

choice of agent is based on patient characteristics.

Case 8-3 (Question 1),

Case 8-4 (Question 1),

Case 8-5 (Question 1)

VOLATILE INHALATION AGENTS

1 Volatile inhalation agents are administered to maintain general anesthesia, although

sevoflurane may also be used to induce general anesthesia (via a face mask). These

agents vary in potency, pharmacokinetics, pharmacologic properties, and cost.

Case 8-7 (Question 1),

Case 8-8 (Question 1)

NEUROMUSCULAR BLOCKING AGENTS

1 Neuromuscular blocking agents (NMBAs) are administered to facilitate

endotracheal intubation and to relax skeletal muscle during surgery.

Succinylcholine, a depolarizing agent, has a fast onset, short duration of action, and

a significant adverse effect profile. The nondepolarizing NMBAs (e.g., rocuronium,

vecuronium, cisatracurium, pancuronium) differ in their routes of elimination and

cardiovascular adverse effect profile.

Case 8-9 (Questions 1, 2),

Case 8-10 (Question 1)

LOCAL ANESTHETICS

1 Local anesthetics are routinely administered in the perioperative setting to provide

local or regional anesthesia. Agents vary in their physiochemical properties, which

account for differences in onset and duration of action. To minimize the risk for

systemic local anesthetic toxicity (which can be life-threatening), attention must be

paid to the total dose administered, the vascularity of the injection site, and patient

characteristics (such as age and the presence of cardiac, renal, or hepatic

dysfunction).

Case 8-11 (Question 1),

Case 8-12 (Question 1)

continued

147

148 Section 1 General Care

CHAPTER CASES

ANTIEMETIC AGENTS AND POSTOPERATIVE NAUSEA AND VOMITING

1 Postoperative nausea and vomiting (PONV) is one of the most common

complications after surgery. Identifying the number of risk factors is critical for

assessing a patient’s risk for experiencing PONV. Patients at moderate or high risk

for experiencing PONV should receive one or more prophylactic antiemetics. If

PONV develops despite antiemetic prophylaxis, administration of an antiemetic

with a different mechanism of action is the most effective treatment.

Case 8-13 (Questions 1–4)

ANALGESIC AGENTS AND POSTOPERATIVE PAIN

1 On-demand administration of an intravenous opioid (patient-controlled analgesia

[PCA]) can provide excellent analgesia with the added benefit of allowing the

patient control over his or her pain management. Appropriate patient selection,

ordering, pump programming, therapy adjustments, monitoring, and patient

education are critical for safe PCA use.

Case 8-14 (Questions 1–7)

2 Epidural analgesia can provide superior pain relief compared with an intravenous

opioid for patients undergoing certain types of major surgery. An opioid and a local

anesthetic are often administered in combination as a continuous infusion through

the epidural catheter. Appropriate patient selection, ordering, pump programming,

therapy adjustments, monitoring, and review of concurrent medications are critical

for safe epidural analgesia.

Case 8-15 (Questions 1–6)

3 The pain management plan should be individualized, taking into consideration the

invasiveness and type or location of the surgery, anticipated pain intensity after

surgery, patient comorbidities, current medications, and previous response to

analgesic medications. Maximizing the use of nonopioid analgesics (such as

acetaminophen, nonsteroidal anti-inflammatory drugs, and local anesthetics) can

improve analgesia and reduce the need for an opioid. Lower opioid use can mean

fewer undesirable adverse effects, particularly nausea, vomiting, and excessive

sedation.

Case 8-16 (Question 1)

The operating room (OR) is one of the most medicationintensive settings in a hospital. During the perioperative period

(broadly defined as the preoperative, intraoperative, and postoperative periods), a patient may receive many medications. Most

of them are used primarily in the OR setting and have limited

application elsewhere in the institution. For other medications,

their use in the OR may differ from that seen in other patient care

areas. The OR is unique in that a significant number of the medications are administered as single doses by the anesthesia care

provider (e.g., physician, nurse anesthetist, anesthesia assistant).

To ensure continuity of care of the surgical patient, health care

providers from all settings (e.g., acute care, home health care,

extended care) should have a basic understanding of perioperative drug therapy.

This chapter reviews seven major classes of medications used

during the perioperative period: preoperative medications, intravenous (IV) anesthetic agents, volatile inhalation agents, neuromuscular blocking agents, local anesthetics, antiemetic agents,

and analgesic agents.

PREOPERATIVE MEDICATIONS

A preoperative evaluation ensures that the patient is medically

prepared for surgery (e.g., pre-existing medical conditions such as

diabetes, hypertension, or asthma are controlled or stable), allows

the provider to discuss the most appropriate anesthetic and postoperative pain management options with the patient, and helps

reassure and educate the patient. Once the plan is made, the anesthesia provider and the surgeon determine whether the patient

should take his or her regularly scheduled medications up to and

including the morning of surgery. These chronic medications

are often necessary to maintain the patient’s physiological condition. The decision to continue or withhold chronic medications before surgery depends on the patient’s current medical

condition and the potential for withdrawal symptoms, worsening

of the patient’s underlying physiological condition, drug interactions with anesthetic medications, perioperative hemodynamic

instability, or postoperative complications such as bleeding.

Administration of preoperative medications (premedicants)

to patients can be thought of as the start of their operative course.

Many different medications are used preoperatively and can be

grouped into the following classes: benzodiazepines, opioids, gastric motility stimulants, H2-receptor antagonists, and antacids.

A key point concerning preoperative medication is that not all

patients will require premedicants. Patients should be assessed

individually regarding their need for pharmacologic premedication. If required, premedicants should be selected based on

patient-specific needs. Administration of a standard preoperative

regimen to all patients should be avoided.

Goals of Premedication

Major goals of premedication are to decrease the patient’s anxiety about the upcoming surgery and to produce sedation. In

addition to relieving anxiety and producing sedation, premedication is occasionally used to provide analgesia, reduce anesthetic requirements, prevent autonomic responses that result in

149Perioperative Care Chapter 8

TABLE 8-1

Indications, Routes of Administration, and Doses of Preoperative Agentsa 1–4

Agent Indications

Routes of

Administration Dosesb

Benzodiazepines

Diazepam Anxiolysis, amnesia, sedation PO Adults: 5–10 mg

Lorazepam Anxiolysis, amnesia, sedation PO 0.025–0.05 mg/kg (range, 1–4 mg for adults)

IV Adults: 0.025–0.04 mg/kg; Pediatrics: 0.01–0.03 mg/kg (titrate

dose; max: 2 mg)

Midazolam Anxiolysis, amnesia, sedation PO Adults: 20 mg; Pediatrics: 0.5–0.75 mg/kg (max: 20 mg)

IM Adults: 0.05–0.08 mg/kg (max: 10 mg); Pediatrics: 0.1–0.15 mg/kg

(max: 10 mg)

IV Adults: 1–2.5 mg (titrate dose); Pediatrics: 0.025–0.05 mg/kg

(titrate dose)

IN Pediatrics: 0.2 mg/kg (max: 15 mg)

Opioids

Morphine Analgesia, sedation IM Adults: 2–4 mg; Pediatrics: 0.02–0.05 mg/kg

IV Titrate dose

Fentanyl Analgesia, sedation IV Adults: 25–100 mcg (titrate dose); Pediatrics: 0.05–2 mcg/kg

Anticholinergics

Atropine (A) Antisialagogue (S > G > A),

sedation (S > A > G)

IM/IV Adults: 0.3–0.6 mg; Pediatrics: 0.02 mg/kg IM, 0.01 mg/kg

IV (max: 0.4 mg)

Scopolamine (S) Sedation, amnesia, antisialagogue IM/IV Adults: 0.1–0.4 mg; Pediatrics: 0.02 mg/kg IM, 0.01 mg/kg

IV (max: 0.4 mg)

Glycopyrrolate (G) Antisialagogue IM/IV Adults: 0.1–0.3 mg; Pediatrics: 0.005–0.01 mg/kg (max: 0.3 mg)

Gastric Motility Stimulants

Metoclopramide Reduce gastric volume,

antiemetic

PO Adults: 10 mg; Pediatrics: 0.15 mg/kg

IV Adults: 0.1–0.2 mg/kg (5–10 mg); Pediatrics: 0.1–0.15 mg/kg

H2-Receptor Antagonists

Cimetidine ↑ Gastric pH PO Adults: 300 mg; Pediatrics: 7.5 mg/kg

IV Adults: 300 mg; Pediatrics: 7.5 mg/kg

Ranitidine ↑ Gastric pH PO Adults: 150 mg; Pediatrics: 2 mg/kg

IV Adults: 50 mg; Pediatrics: 0.5–1 mg/kg

Famotidine ↑ Gastric pH PO Adults: 40 mg; Pediatrics: 0.5 mg/kg

IV Adults: 20 mg; Pediatrics: 0.25 mg/kg

Nizatidine ↑ Gastric pH PO Adults: 150 mg–300 mg

Nonparticulate Antacids

Citric acid and sodium

citrate

↑ Gastric pH PO Adults: 30 mL

aGeneral dosage guidelines; doses must be individualized based on patient-specific parameters.

b Doses listed are for agents when used as sole premedicant; doses may need to be reduced if premedicants are administered in combination (e.g., opioids, benzodiazepines).

IM, intramuscular; IN, intranasal; IV, intravenous; PO, oral.

intraoperative hemodynamic instability, decrease salivation and

secretions, reduce gastric fluid volume, or increase gastric pH.

Table 8-1 lists medications commonly used preoperatively and

their major indications, routes of administration, and dosages.1–4

Midazolam is by far the most commonly used premedicant.

Selection Criteria

Factors to consider when selecting a preoperative drug include

the patient’s American Society of Anesthesiologists (ASA) physical status class,3 medical conditions, degree of anxiety, age,

surgical procedure to be performed, length of procedure, postoperative admission status (e.g.,