DEXAMETHASONE

Dexamethasone’s mechanism of action as an antiemetic is not

well understood, particularly in the surgical setting. When compared with ondansetron and droperidol, a prophylactic dose of

dexamethasone is as effective in preventing PONV in high-risk

patients.94 Adverse effects in otherwise healthy patients are minimal and include headache, dizziness, drowsiness, constipation,

and muscle pain.95 Unlike droperidol and the serotonin antagonists, dexamethasone is most effective when administered at the

beginning of surgery (immediately before induction).96

PHENOTHIAZINES

Prochlorperazine has been used successfully to prevent PONV.

Prochlorperazine (10 mg IM) was found to have superior efficacy (less nausea and vomiting, as well as less need for rescue

antiemetics) when compared with ondansetron for preventing

PONV.97 Prochlorperazine may cause sedation, EP reactions, and

165Perioperative Care Chapter 8

TABLE 8-11

Classification, Proposed Site(s) of Action, Usual Dose, and Adverse Effects of Select Antiemetic Drugs3,76,78,81,82,85

Antiemetic Drug

Proposed

Receptor Site

of Action Usual Dosea

Duration of

Action Adverse Effects Comments

Butyrophenones

Droperidol D2 Adult: 0.625–1.25 mg IV

Pediatric: 20–50 mcg/

kg IV for prevention;

10–20 mcg/kg IV for

treatment

≤12–24 hours Sedation, restlessness or

agitation, hallucinations,

hypotension (especially

in hypovolemic patients),

EPS

Monitor ECG for QT

prolongation,

torsades de pointes

Phenothiazines

Prochlorperazine D2 Adult: 5–10 mg IM or IV;

25 mg PR

Pediatric:b

0.1–0.15 mg/kg

IM, 0.1–0.13 mg/kg PO,

2.5 mg PR

4–6 hours

(12 hours

when given

PR)

Sedation, hypotension

(especially in

hypovolemic patients),

EPS

Antimuscarinics

Promethazine D2, H1, M1 Adult: 6.25–25 mg IM, IV,

or PRc

4–6 hours Sedation, hypotension

(especially in

hypovolemic patients),

EPS, serious tissue injury

from inadvertent arterial

injection or IV

extravasation

Limit concentration to

25 mg/mL; dilute in

10–20 mL of saline,

inject through a

running line, and

advise patient to

report IV site

discomfort

Diphenhydramine H1, M1 Adult: 12.5–25 mg IM or IV

Pediatric: 1 mg/kg IV, PO

(max: 25 mg for children

younger than 12 years)

4–6 hours Sedation, dry mouth,

blurred vision, urinary

retention

Scopolamine M1 Adult: 1.5 mg transdermal

patch

72 hoursd

Sedation, dry mouth, visual

disturbances, dysphoria,

confusion,

disorientation,

hallucinations

Apply at least 4 hours

before end of

surgery; wash hands

after handling patch;

not appropriate for

children, elderly, or

patients with renal or

hepatic impairment Benzamides

Metoclopramide D2 Adult: 25 mg IV

Pediatric: 0.25 mg/kg IV

≤6 hours Sedation, hypotension, EPS Consider for rescue if

N/V is believed to be

caused by gastric

stasis; reduce dose to

5 mg in renal

impairment; give

slow IV push Serotonin Antagonists

Ondansetron 5-HT3 Adult: 4 mg IV

Pediatric: 0.05–0.1 mg/kg IV

Up to 24 hours Headache, lightheadedness,

constipation, QT

prolongation

Dolasetron 5-HT3 Adult: 12.5 mg IV

Pediatric: 0.35 mg/kg IV

Up to 24 hours Headache, lightheadedness,

constipation, QT

prolongation

Granisetron 5-HT3 Adult: 0.35 mg–1 mg IV

Pediatric: Not known

Up to 24 hours Headache, lightheadedness,

constipation, QT

prolongation

Palonosetron Adult: 0.075 mg IV Up to 24 hours Headache, constipation,

QT prolongation NK1 Antagonists

Aprepitant NK1 Adult: 40 mg PO up to 3

hours before surgery

Up to 24 hours Headache

Other

Dexamethasone Unknown Adult: 4 mg IV

Pediatric: 0.15 mg/kg IV

Up to 24 hours Genital itching, flushing

aUnless otherwise indicated, pediatric doses should not exceed adult doses.

bChildren >10 kg or older than 2 years only. Change from IM to PO as soon as possible. When administering PR, the dosing interval varies from 8 to 24 hours, depending

on the child’s weight.

c Maximum of 12.5 mg in children younger than 12 years.

d Remove after 24 hours. Instruct patient to thoroughly wash the patch site and their hands.

D2, dopamine type 2 receptor; ECG, electrocardiogram; EPS, extrapyramidal symptoms (e.g., motor restlessness or acute dystonia); 5-HT3, serotonin type 3 receptor; H1,

histamine type 1 receptor; IV, intravenous; IM, intramuscular; M1, muscarinic cholinergic type 1; NK1, neurokinin type 1 receptor; N/V, nausea or vomiting; PO, orally (by

mouth); PR, per rectum.

166 Section 1 General Care

cardiovascular effects. Because it has a short duration of action,

multiple doses may be necessary.

ANTIMUSCARINICS

Scopolamine blocks afferent impulses at the vomiting center and

blocks Ach in the vestibular apparatus and CTZ. Transdermal

scopolamine is useful for prevention of nausea, vomiting, and

motion sickness. Compared with placebo, transdermal scopolamine effectively reduces the incidence of emetic symptoms.98

Common side effects include dry mouth and visual disturbances.

Patients can also have trouble correctly applying the patch. It is

important to apply the patch before surgery because its onset

of effect is 4 hours. Patients should also be instructed to wash

their hands after applying the patch and to dispose of the patch

properly.

NEUROKININ-1 ANTAGONISTS

Aprepitant is the first NK1 antagonist to be approved for prevention of PONV. Aprepitant has a long half-life and is administered orally before surgery. For prevention of PONV in patients

undergoing abdominal surgery, aprepitant was similar in efficacy

(defined as no vomiting and no use of rescue antiemetics in the

first 24 hours after surgery) to ondansetron. Aprepitant, however,

was significantly more effective than ondansetron in preventing

vomiting at 24 and 48 hours after surgery. Aprepitant was well

tolerated, with adverse effects similar to ondansetron.99

COMBINATION OF AGENTS

As discussed, droperidol, serotonin antagonists, dexamethasone,

and transdermal scopolamine effectively prevent PONV. However, these agents fail to prevent PONV in approximately 20% to

30% of patients. Most of the agents effectively block one receptor

believed to be involved in the activation of the vomiting center.

However, because the cause of PONV is likely multifactorial, a

combination of antiemetic agents (from different classes) is more

efficacious for preventing PONV in a high-risk patient. In a factorial trial of six interventions for prevention of PONV in more

than 5,000 high-risk patients undergoing surgery, patients were

randomly assigned to 1 of 64 possible combinations of six different prophylactic interventions: 4 mg IV ondansetron or no

ondansetron; 4 mg IV dexamethasone or no dexamethasone;

1.25 mg IV droperidol or no droperidol; propofol or a volatile

inhalation anesthetic agent; nitrous oxide or nitrogen (i.e., no

nitrous oxide); and remifentanil (an ultrashort-acting opioid) or

fentanyl (a short-acting opioid).94 Each antiemetic agent intervention (ondansetron, dexamethasone, droperidol) had similar

efficacy and reduced the risk of PONV by about 26%. The risk

was further reduced when a combination of any two antiemetics

was administered, with no difference among the various combinations of agents. The risk was the lowest when all three

antiemetic agents were administered.

For prophylaxis of PONV, J.E. should receive at least two

antiemetic agents because she is at very high risk for experiencing PONV. Dexamethasone 4 mg IV can be administered at the

beginning of surgery (just after induction of anesthesia) and 4 mg

IV ondansetron (or 0.625 mg droperidol) should be administered

approximately 30 minutes before the end of surgery. If an alternative agent (to ondansetron or droperidol plus dexamethasone)

or third agent is warranted (because she is at such high risk), an

antihistamine or antimuscarinic agent such as 25 mg IV diphenhydramine intraoperatively or a transdermal scopolamine patch,

placed within 2 hours before the induction of general anesthesia,

can be used.

Treatment of Postoperative Nausea and

Vomiting

CASE 8-13, QUESTION 3: J.E. is taken to surgery. Anesthesia is induced with propofol and maintained with

sevoflurane. Fentanyl is administered intraoperatively for

analgesia. A prophylactic dose of dexamethasone is administered at the beginning of surgery, and ondansetron is

administered near the end of surgery. Neuromuscular blockade produced by vecuronium is reversed with neostigmine

and glycopyrrolate. In the recovery room, J.E. becomes nauseated and has several emetic episodes. What is the most

appropriate treatment at this time?

Although dexamethasone and ondansetron are effective for

both prevention and treatment of PONV, a rescue antiemetic is

most efficacious if it works by a different mechanism of action

than the prophylactically administered antiemetics.100 Prophylactic dexamethasone or ondansetron can be effective for up

to 24 hours. If nausea and emetic episodes occur in the recovery room, the prophylactic antiemetic agents were ineffective.

Phenothiazines (prochlorperazine) and benzamides (metoclopramide) block dopaminergic stimulation of the CTZ, making

these agents appropriate for J.E. Prochlorperazine may be preferred because metoclopramide’s primary effect is in the GI tract

rather than the CTZ. Diphenhydramine, which blocks Ach receptors in the vestibular apparatus as well as histamine receptors that

activate the CTZ, would also be an appropriate choice for rescue

for J.E. Because excessive sedation could delay J.E.’s discharge

from the ambulatory surgery center, doses should not exceed

25 mg IV for diphenhydramine. In addition, it is important to

assess J.E. for postoperative factors that could increase the likelihood of PONV. If postural hypotension is present, IV fluids and

ephedrine would be appropriate therapy.

Anesthetic Agents With a Low Incidence

of Postoperative Nausea and Vomiting

CASE 8-13, QUESTION 4: How could J.E.’s anesthetic regimen have been modified to reduce the likelihood of PONV?

Several changes could be made in the anesthetic regimen to

reduce the likelihood of PONV. When propofol is used for both

induction and maintenance of anesthesia, it reduces the risk of

PONV similar to the administration of a single antiemetic.94

Because perioperative administration of opioids is associated

with PONV, the use of NSAIDs (oral agents preoperatively and

postoperatively, parenteral acetaminophen or ketorolac intraoperatively and postoperatively), when appropriate, can reduce the

need for postoperative opioids. In addition, surgical wound infiltration with a long-acting local anesthetic, such as bupivacaine,

should also be used, as needed, to reduce postoperative incisional

pain.

ANALGESIC AGENTS AND

POSTOPERATIVE PAIN

MANAGEMENT

Acute Pain

Surgery causes injury to the body, resulting in acute pain. Specifically, the tissue damage from surgery releases substances that

directly stimulate or sensitize nociceptors (free nerve endings in

167Perioperative Care Chapter 8

the skin, muscle, bone, and connective tissue that detect damaging or unpleasant stimuli). These substances (e.g., bradykinin,

serotonin, prostaglandins, and cytokines) mediate pain impulses,

which then travel from the periphery (surgical incision) to the

dorsal horn of the spinal cord. Glutamate and substance P

are released in the dorsal horn to cause the pain impulses to

ascend to higher centers in the brain. Nerves originating in

the brainstem descend to the spinal cord and release substances

(norepinephrine, serotonin, endogenous opioids) that modulate

(inhibit) pain transmission. The final integration of all these processes is perception—this is when the patient “feels” the pain.

Because cortical and limbic systems are involved, the same

surgery can result in significant individual differences in pain

perception.101,102

Most patients will have pain at rest after surgery, with the magnitude of the pain generally correlating to the invasiveness of the

surgery. More intense pain would be expected after major abdominal surgery than after laparoscopic hernia repair, for example.

In addition, certain types of movement after major surgery (e.g.,

coughing after major upper abdominal surgery or knee flexion

after total knee replacement) can evoke pain that is more intense,

less responsive to opioids, and longer lasting than pain at rest.103

Nerve injury or peripheral or central nerve sensitization can

occur, leading to pain hypersensitivity, pain in response to a stimulus that is not usually painful (allodynia), pain that is difficult to

manage, or chronic pain after surgery. Immobility and body positioning after surgery, for example, can lead to musculoskeletal

pain.103–105 Patients vary in their response to pain (and interventions) and in their personal preferences toward pain management. Acute pain usually resolves when the injury heals (hours

to days). Unrelieved acute postoperative pain has detrimental

physiological and psychological effects, including impaired pulmonary function (leading to pulmonary complications); thromboembolism; tachycardia; hypertension and increased cardiac

work; impairment of the immune system; nausea, vomiting, and

ileus; chronic pain; and anxiety, fatigue, and fear.105

Adequate pain assessment and management are essential

components of perioperative care. Education of patients and families about their roles, as well as the limitations and side effects of

pain treatments, is critical to managing postoperative pain. Pain

management must be planned for and integrated into the perioperative care of patients. Proactive planning includes obtaining

a pain history based on the patient’s own experiences with pain

and a frank discussion of a realistic comfort–function goal for

the patient (e.g., complete pain relief after major surgery is not

a realistic goal). The intensity and quality of pain, as well as the

patient’s response to treatment and the degree to which pain

interferes with normal activities, should be monitored. Ideally,

pain should be prevented by treating it adequately because once

established, severe pain can be difficult to control.

Management Options

Effective postoperative pain management should provide subjective pain relief while minimizing analgesic-related adverse effects,

allow early return to normal daily activities, and minimize the

detrimental effects from unrelieved pain. The following techniques can be used to manage postoperative pain: (a) systemic

administration of opioids, NSAIDs, and acetaminophen; (b) ondemand administration of IV opioids, also known as patientcontrolled analgesia (PCA); (c) epidural analgesia (continuous and

on-demand, usually with an opioid–local anesthetic mixture); (d)

local nerve blockade, such as local infiltration or peripheral nerve

block; and (e) application of heat or cold, guided imagery, music,

relaxation, or other nonpharmacologic intervention. Local anesthetics, opioids, acetaminophen, and NSAIDs can be used alone

or in combination to create the optimal analgesic regimen for

each patient based on factors such as efficacy of the agent to

reduce pain to an acceptable level, type of surgery, underlying

disease, adverse effects, and cost of therapy. For patients experiencing mild to moderate postoperative pain, local anesthetic

wound infiltration, peripheral nerve blockade, or administration

of a nonopioid analgesic such as an NSAID or acetaminophen

are appropriate approaches to analgesia. For moderate or severe

postoperative pain, an opioid is required. The choice of agent,

dose, and route of administration depends on the clinical situation. For example, a patient who cannot take anything by mouth

may receive an IV opioid in a dose appropriate for the severity of the pain and the presence or absence of risk factors for

opioid-induced respiratory depression. A patient who is tolerating crackers and a soft drink before discharge from the surgery

center should receive the first dose of the analgesic that will

be prescribed for the patient at home. This will ensure that the

analgesic (commonly, acetaminophen plus hydrocodone) will

be effective and tolerated by the patient. For moderate to severe

pain after more-invasive surgery, an IV opioid (e.g., morphine,

hydromorphone), an epidural containing a local anesthetic and

opioid, or a peripheral nerve block with local anesthetic is necessary. (For more information about general pain management, see

Chapter 7, Pain and Its Management.) Analgesia for acute pain in

the perioperative setting is best achieved by using a multimodal

(balanced) approach with a combination of two or more analgesic medications or modalities that have different mechanisms

of action to provide additive or synergistic analgesia with fewer

adverse effects when compared with a single analgesic medication or modality.105 Examples of multimodal analgesic regimens used in the perioperative setting include (a) local anesthetic

wound infiltration, acetaminophen, NSAIDs, and if necessary, a

weaker opioid analgesic (e.g., hydrocodone plus acetaminophen)

after laparoscopic cholecystectomy, (b) continuous epidural analgesia (with opioid plus local anesthetic) with IV acetaminophen

and, if necessary, a potent IV opioid for rescue analgesia in an

area not covered by the epidural catheter, and (c) continuous

peripheral nerve blockade, with acetaminophen, NSAIDs, and,

if necessary, an opioid for rescue analgesia in an area not covered

by the nerve block.106

PATIENT-CONTROLLED ANALGESIA

ADVANTAGES

CASE 8-14

QUESTION 1: J.A., a 50-year-old, 5-foot 4-inch, 50-kg

woman, is immediately postoperative from a total abdominal hysterectomy for a neoplasm. Her laboratory values are

remarkable for a serum creatinine of 1.3 mg/dL. She is allergic to penicillin. She will be admitted to the postsurgical

floor for a planned stay of 2 to 3 days. What mode of pain

management should be chosen for J.A.?

PCA is a popular method of administering analgesics and

has been shown to provide an overall improvement in analgesia

and greater patient satisfaction when compared with traditional

intermittent IV opioid injections.107 Patients treated with traditional intermittent IV dosing of opioids “as needed” can experience severe pain because the serum opioid concentration is

allowed to fall to less than the minimum effective analgesic concentration (the concentration that provides approximately 90%

pain relief ). In addition, high peak plasma opioid concentrations

can be seen with this administration method, often resulting in

excessive nausea, vomiting, or sedation, as well as respiratory

depression. Small, frequent opioid doses on demand, as seen in

168 Section 1 General Care

PCA, minimize the peaks and valleys in serum concentrations

seen with relatively larger intermittent IV doses and allow the

patient control over his or her pain management. This is helpful

in minimizing adverse effects associated with high peak serum

concentrations and inadequate pain relief caused by subtherapeutic serum concentrations. Small, frequent, patient-controlled

dosing of opioids is efficacious because opioids have a steep sigmoidal dose–response curve for analgesia, resulting in the ability

of a small opioid dose to move the plasma concentration from

being subtherapeutic to above the minimum effective plasma

concentration that will provide effective pain relief. However,

one must remember that these small, frequent on-demand doses

are intended tomaintain analgesia. The patient should be reasonably comfortable (e.g., from a loading dose) before the initiation

of PCA.108,109 In terms of safety, sedation generally precedes respiratory depression.110 Therefore, if a patient becomes sedated,

self-administration of additional patient-controlled bolus doses

will stop, allowing the serum opioid concentration to fall to a

safe level.

Therapy can be individualized by using small doses of opioids

at preset intervals (e.g., 1 mg of morphine every 10 minutes),

with the patient in control of his or her analgesic administration.

An infusion pump with a programmed on-demand dose (the dose

the patient can self-administer), number of minutes between

allowable doses (lock-out interval), and maximum number of

boluses per hour is equipped with a button that the patient presses

to receive a dose. An IV bolus is the most common PCA route,

with opioids being the drugs of choice to provide analgesia.

If the patient is educated to use PCA properly, it can be used

to alleviate anticipated pain before movement or physical therapy in a pre-emptive fashion. J.A. has undergone a procedure for

which moderate to severe pain is expected in the immediate postoperative period. J.A.’s pain requirement in the immediate

postoperative period could be met with PCA opioid administration after first administering a loading dose of an IV opioid, which is titrated to achieve the appropriate level of analgesia. Analgesia can then be maintained with patient-controlled

bolus doses. When her opioid requirements decline or when

she can tolerate oral intake, she can then be switched to oral

analgesics.

PATIENT SELECTION

CASE 8-14, QUESTION 2: J.A.’s surgeon decides to prescribe PCA for postoperative pain management. How

should J.A. be evaluated for her ability to appropriately participate in her analgesic administration?

Patients receiving PCA therapy must be able to understand

the concept behind PCA and to operate the drug administration button. J.A. must be alert, oriented, and willing to assume

control of her own pain management. She must be able to comprehend the relationships between a stimulus (pain), a response

(pushing the button), and a delayed result (pain relief ). She must

understand verbal or written instructions about the function

and safety features of the infusion pump and how to titrate the

drug as needed for satisfactory analgesia. The anticipated intensity of the patient’s pain after surgery should be such that an

IV opioid would be required for pain management. PCA has

been used successfully in children, generally after ages 8 or 9

(adjusting doses appropriately), and in elderly patients. It is not

indicated in patients who are expected to require parenteral opioids for analgesia for less than 24 hours because these patients

will generally be able to tolerate oral analgesics shortly after

surgery.

PATIENT INSTRUCTIONS

CASE 8-14, QUESTION 3: J.A. is nervous about giving herself an overdose while using PCA. What instructions should

be provided to her?

Patients often worry about the safety of PCA, which can lead

to reluctance to provide themselves with adequate pain relief.

J.A. should be informed that she will be frequently assessed by

the nurse (particularly during the first 24 hours of therapy). If she

becomes sleepy from the opioid, she should not press the button.

When this adverse effect of the opioid has worn off, she will wake

up (plasma opioid level has fallen back into or below the therapeutic range) and she may then press the button to receive a dose

of the opioid if she has pain. This is an important safety feature of

PCA and is the reason family members must not push the button

for the patient. However, J.A. should also know that she may have

to press the button several times (after the lock-out interval has

passed) before her pain is relieved. She must also be informed

that she may require a larger PCA dose, so it is important for

J.A. to assess her pain relief from her current (“usual”) dose that

most patients are initially started on after surgery. Accurate pain

assessment after her prescribed dose is critical for ensuring that

her dose is sufficient to provide the desired level of analgesia. She

should also understand the possible adverse effects of her PCA

medication and what can be done to prevent and treat these

effects, as well as the advantages of providing herself with adequate analgesia (e.g., early ambulation). Finally, she should be

told of the negligible risk of narcotic addiction from short-term

PCA use and be given ample opportunity to ask questions.

CHOICE OF AGENT

CASE 8-14, QUESTION 4: Meperidine is ordered for J.A.’s

PCA. Is this a reasonable drug choice for her?

Ideally, opioids for PCA administration have a rapid onset and

intermediate duration of action (30–60 minutes), with no accumulation or adverse effects. The physicians, nurses, and pharmacists involved with the care of the patient should be familiar

with the drug selected for PCA. Morphine is by far the most

common choice for PCA, although other opioids such as fentanyl and hydromorphone can be used. Drug choice is based

on past patient experiences, allergies, adverse effects, and special

considerations, such as renal function. Meperidine has a metabolite, normeperidine, which is renally excreted, has a long halflife, and can cause cerebral irritation and excitation. Symptoms

of CNS toxicity from normeperidine include agitation, shaky

feelings, delirium, twitching, tremors, and myoclonus or tonicclonic seizures. These symptoms can be seen when meperidine

is administered in higher doses or for a prolonged period.111

The presence of renal insufficiency increases the risk of accumulation of normeperidine.111 Meperidine also inhibits serotonin

reuptake and has a fairly high serotonergic potential. The risk

of a patient developing the serotonin syndrome is greater when

meperidine is coadministered with another drug that has moderate or high serotonergic potential (e.g., fluoxetine, fluvoxamine,

paroxetine, venlafaxine).112 For these reasons, meperidine is a

poor choice for analgesia, particularly for J.A. who has diminished renal function. Morphine is conjugated with glucuronide

in hepatic and extrahepatic sites (particularly the kidney) to its

two major metabolites, morphine-3-glucuronide and morphine6-glucuronide; both metabolites are excreted primarily in the

urine. Morphine-6-glucuronide is an active metabolite that can

accumulate in patients with renal failure, resulting in prolonged

analgesia, sedation, and respiratory depression.113 Because of

169Perioperative Care Chapter 8

TABLE 8-12

Adult Analgesic Dosing Recommendations for Intravenous Patient-Controlled Analgesiaa,102,114,115

Demand Dose (mg)

Drug Usual Concentration Usual Range Lock-Out Interval (minutes)

Fentanyl (as citrate) 10 mcg/mL 0.01–0.02 0.01–0.04 10

Hydromorphone hydrochloride 0.2 mg/mL 0.2–0.3 0.1–0.4 10

Morphine sulfate 1 mg/mL 1–2 0.5–2.5 10

aAnalgesic doses are based on those required by a healthy 55- to 70-kg, opioid-na¨ıve adult. Analgesic requirements vary widely among patients. Doses may need to be

adjusted because of age, condition of the patient, and prior opioid use.

J.A.’s diminished renal function, morphine should probably be

avoided because other options exist. Hydromorphone is not

metabolized to an active 6-glucuronide metabolite, and fentanyl

is metabolized to inactive metabolites. Either hydromorphone

or fentanyl is an appropriate analgesic choice for J.A. Hydromorphone is chosen. Table 8-12 lists common doses and lock-out

intervals for drugs administered by PCA.102,114,115

DOSING

CASE 8-14, QUESTION 5: J.A. was not receiving an opioid before surgery (e.g., she is opioid na¨ıve). What dose of

hydromorphone and what lock-out interval should be used

for her initial PCA pump settings?

If J.A. is experiencing pain before PCA has been initiated,

she should receive a loading dose of IV hydromorphone titrated

to achieve baseline pain relief (may require up to 1 mg). Once

adequate analgesia is achieved, demand doses of 0.2 mg with

a lock-out interval of 10 minutes would be a good choice to

maintain analgesia for this opioid-na¨ıve patient. If J.A.’s pain is

not relieved after two to three demand doses within 1 hour, the

demand dose can be increased to 0.3 mg.

USE OF A BASAL INFUSION

CASE 8-14, QUESTION 6: After the first postoperative

evening, J.A. tells you that she had a terrible time sleeping.

She describes waking up in pain frequently, despite pressing

her PCA button many times. She rates her pain as moderate to severe in intensity and fairly constant. A review of

the history on her PCA device reveals successful delivery of

9 mg of hydromorphone (30 demand doses, 0.3 mg each)

during the past 12 hours. J.A. is not sedated and reports no

adverse effects from hydromorphone. How can J.A.’s pain

management be improved?

Many PCA infusion pumps offer a continuous infusion setting for a basal infusion during intermittent dosing. Use of a basal

(continuous) infusion has not been shown to improve analgesia

and likely increases the risk of adverse effects (owing to the potential of an opioid overdose in some patients). Therefore, routine

basal (continuous) infusion of opioids cannot be recommended

for acute pain management. In an opioid-na¨ıve patient such as

J.A., however, continuing to increase the demand dose increases

the risk of excessive sedation and respiratory depression (owing

to high peak levels). Also, J.A. describes her pain as moderate to

severe in intensity and fairly constant in nature when she does not

regularly push the demand button. For J.A., a continuous infusion

could be beneficial. As a rule of thumb, an opioid-na¨ıve patient

experiencing acute pain (that can change quickly) should receive

no more than one-third of her average hourly usage as a continuous infusion or a maximum of 1 mg/hour of morphine (or its

equivalent, which would be 0.2 mg/hour for hydromorphone).

For J.A., a continuous infusion of 0.2 mg/hour hydromorphone

should be initiated in addition to her demand dose of 0.3 mg

every 8 minutes. Because the onset of action of hydromorphone

is about 5 minutes and the peak effect occurs in 10 to 20 minutes,

shortening the lock-out interval is not recommended because

J.A. could access the next dose of hydromorphone before the

effects of the initial dose can be appreciated. That could lead to

dose-stacking and significant adverse effects, such as excessive

sedation and respiratory depression.

ADVERSE EFFECTS

CASE 8-14, QUESTION 7: The next day, J.A. requested only

a few demand doses and reports adequate pain relief with

her PCA, but now complains of feeling slightly groggy and

nauseated. Bowel sounds are noted on physical examination, and J.A. plans to try to take clear liquids later that

morning. What are the adverse effects of PCA opioids, and

how can J.A.’s complaints be addressed?

Opioids can produce sedation, confusion, euphoria, nausea and vomiting, constipation, urinary retention, and pruritus.

These adverse effects can be managed by dose adjustments or

pharmacologic intervention. Although rare, life-threatening respiratory depression is the most serious adverse effect of opioid

administration.110 Because sedation precedes respiratory depression, systematic assessment of sedation and respiratory parameters should be performed at frequent intervals (every 1 to

2 hours during the first 24 hours of therapy). The patient should

be observed for how quickly he or she arouses when stimulated, and the rate, depth, and regularity of the patient’s respirations should be assessed and compared with the patient’s baseline

status.110,114 Particular attention must be paid to patients at high

risk for respiratory depression from an opioid. These risk factors

include age older than 65 years, obesity, pulmonary disease or

other conditions that reduce ventilatory capacity, and known or

suspected history of sleep apnea.114 Technical problems must also

be ruled out. The PCA pump should be checked to ensure that it

is delivering the correct drug and dose, programming should be

checked for accuracy (e.g., drug concentration, dosing interval),

and the opioid reversal agent naloxone must be readily available. Monitoring for efficacy and adverse effects of PCA therapy

should include pain intensity and quality, response to treatment, number of on-demand requests, analgesic consumption,

BP, heart rate, respiratory rate and effort, and level of sedation,

as well as the presence of other adverse effects of opioids such as

nausea and itching.

J.A.’s PCA hydromorphone dose could be reduced to manage

her sedation and nausea. However, her pain control must be

carefully reassessed to ensure efficacy of the newly lowered dose.

An order for a nonsedating antiemetic (such as ondansetron)

could also be provided. NSAIDs (ketorolac IV or other NSAID

170 Section 1 General Care

orally) or acetaminophen (IV or oral) are not sedating; thus, they

should be added to the analgesic regimen to provide analgesia and

allow a reduction in her opioid dose. However, because of J.A.’s

compromised renal function, acetaminophen is a better choice

than an NSAID. If J.A. is able to take fluids orally, PCA should

be discontinued and oral analgesics administered as needed. As

healing occurs, her pain intensity should lessen, and oral opioid–

acetaminophen products should manage her pain adequately.

EPIDURAL ANALGESIA

CASE 8-15

QUESTION 1: T.M., a 69-year-old man, enters the surgical ICU after surgery for colorectal cancer (lower anterior

resection, urethral stents, ileorectal pull-through). His pain

is managed through a lumbar epidural catheter. What are

the benefits and risks of epidural analgesia, and why was

this approach to postoperative analgesia chosen for T.M.?

ADVANTAGES AND DISADVANTAGES

Epidural analgesia can offer superior pain relief compared with

traditional parenteral (IM, IV, and IV PCA) analgesia116 as well as

facilitate return of GI function, decrease pulmonary complications, and possibly decrease cardiovascular events.117,118 Epidural PCA offers an advantage compared with parenteral opioids

(including IV PCA) because it allows individualization of the

analgesic requirements, lower total drug use, greater patient

satisfaction,119 and improved analgesia.120 Epidural catheter

placement is an invasive procedure that can result in unintentional dural puncture (causing postdural puncture headache),

insertion site inflammation or infection, catheter migration, and,

rarely, epidural hematoma.115

PATIENT SELECTION

Epidural analgesia should be chosen based on the need for good

postoperative pain relief and reduced perioperative physiological

responses. Postoperative pain should be localized at an appropriate level for catheter placement in the lumbar or thoracic location

of the epidural space. Patients undergoing abdominal, gynecologic, obstetric, colorectal, urologic, lower limb (e.g., major vascular), or thoracic surgery are excellent candidates for epidural

pain management. Absolute contraindications to epidural analgesia include severe systemic infection or infection in the area

of catheter insertion, known coagulopathy, clinically significant

abnormal platelet count or function, increased intracranial pressure, patient refusal, and anatomical abnormalities that make

epidural catheter placement difficult or impossible.121 T.M. is

a good candidate for epidural analgesia based on the severity of

pain associated with his surgery and the location and invasiveness

of the surgical procedure.

CHOICE OF AGENT AND MECHANISMS OF ACTION

CASE 8-15, QUESTION 2: What drug or drug combination

can be used for T.M.’s epidural infusion? What are the mechanisms of action of the analgesics commonly administered

in the epidural space?

Most commonly, an opioid and a local anesthetic are administered in combination in the epidural analgesic infusion. Opioids

in the epidural space are transported by passive diffusion and the

vasculature to the spinal cord, where they act at opioid receptors in the dorsal horn. After epidural administration, opioids can

reach brainstem sites by cephalad movement in the cerebrospinal

fluid. In addition, lipophilic opioids (fentanyl, sufentanil) have

substantial systemic absorption from the epidural space.113,122

Opioids selectively block pain transmission and have no effect on

nerve transmission responsible for motor, sensory, or autonomic

function.123 Local anesthetics, however, spread within the epidural space to anesthetize nerve roots as they exit the neural foramina (openings in the spinal column) and block nerve transmission.

Depending on the drug, concentration, and depth of nerve penetration, local anesthetics produce sensory, motor, or autonomic

blockade (see Local Anesthetics section). Table 8-13 describes the

 shorter than the duration of an

intubating dose of rocuronium. Because this procedure will last

longer than the duration of muscle relaxation provided by the

intubating dose of rocuronium, this is not a concern.

Routes of Elimination

CASE 8-10

QUESTION 1: M.M., a 70-year-old woman, ASA-IV, is scheduled to undergo a 2-hour GI procedure. Pertinent laboratory

findings are as follows:

Aspartate aminotransferase, 272 units/L

Alanine aminotransferase, 150 units/L

Blood urea nitrogen, 40 mg/dL

Serum creatinine, 1.8 mg/dL

Albumin, 2.6 g/dL

Which neuromuscular blocking agent would you recommend for M.M.?

When selecting a neuromuscular blocking agent, one of the

factors that must be considered is the patient’s renal and hepatic

function. Neuromuscular blocking agents often depend on the

kidneys and liver for varying amounts of their metabolism and

excretion (Table 8-8).54,55,58 Some agents, however, are primarily

metabolized by plasma cholinesterase (pseudocholinesterase),

Hofmann elimination (a nonbiological process that does not

require renal, hepatic, or enzymatic function), or nonspecific

esterases.

Hofmann elimination is a pH- and temperature-dependent

process unique to atracurium and cisatracurium. One of the

products produced by Hofmann elimination is laudanosine,

a CNS stimulant in high concentrations. Laudanosine undergoes renal and hepatic elimination. Because of the short-term

use of atracurium and cisatracurium in the OR, accumulation of laudanosine with resultant seizure activity is not a concern, even in patients with end-stage renal failure.63 Because

plasma cholinesterase levels may be decreased in patients with

160 Section 1 General Care

TABLE 8-8

Elimination of Neuromuscular Blocking Agents54,55,58

Agent Renal Hepatic Biliary Plasma

Atracurium 10% NS Hofmann elimination, ester hydrolysis

Cisatracurium NS NS Hofmann elimination

Pancuronium 80% 10% 5%–10%

Rocuronium 10%–25% 10%–20% 50%–70%

Succinylcholine Plasma cholinesterase

Vecuronium 15%–25% 20%–30% 40%–75%

NS, not significant.

renal or hepatic dysfunction, the duration of action of succinylcholine could be prolonged. The increased duration of action

of succinylcholine in patients with low levels of normal plasma

cholinesterase is generally not clinically significant. Patients with

atypical plasma cholinesterase, however, cannot hydrolyze the

ester bonds in succinylcholine. This results in a significantly

increased duration of action in these patients.64

Unchanged neuromuscular blocking agents and their metabolites are excreted by the renal or biliary routes. The duration of

action of the renally eliminated agent, pancuronium, will be

increased in patients with renal failure. Vecuronium’s duration

of action can be increased in patients with liver disease, reflecting impaired metabolism or excretion rather than termination

of effect by redistribution.65 Although the main route of elimination of rocuronium is hepatobiliary, the duration of action

of rocuronium can be significantly prolonged in chronic renal

failure.66

Because M.M. has evidence of both significant renal and hepatic impairment, cisatracurium or atracurium would be appropriate choices for a neuromuscular blocking agent because their

properties are not altered significantly by renal and hepatic failure. Furthermore, because these agents have an intermediate

duration of action, they can easily be used in a 2-hour procedure. The availability of generic atracurium makes this agent

a more economical choice; however, the greater propensity of

atracurium to cause histamine release with resultant hypotension makes cisatracurium the most appropriate choice in this

70-year-old, ASA-IV patient.

LOCAL ANESTHETICS

Local and Regional Anesthesia

Some surgical procedures can be performed under regional anesthesia (anesthesia selective for part of the body, such as the

area near the surgical site) rather than general anesthesia (total

body anesthesia with the patient rendered unconscious). Epidural, spinal (intrathecal), peripheral nerve block, or local infiltration anesthesia can be chosen, depending on the location of the

surgical site, extent of the surgery, patient health and physical

characteristics, coagulation status, duration of surgery, and the

desires and cooperativeness of the patient. For epidural anesthesia, the local anesthetic is administered into the epidural space,

which is located between the dura and the ligament covering the

spinal vertebral bodies and discs. To provide spinal anesthesia,

the local anesthetic is injected into the cerebrospinal fluid within

the subarachnoid (intrathecal) space. By injecting a local anesthetic in the tissue near a specific nerve or nerve plexus (peripheral

nerve block), certain types of surgery can be performed under

regional anesthesia rather than general anesthesia. Examples

include carotid endarterectomy (cervical plexus), upper extremity surgery (brachial plexus), and hand surgery (ulnar, median,

or radial nerve). Regional anesthesia can be selected to reduce

or avoid the likelihood of complications such as postoperative

pain, nausea, vomiting, laryngeal irritation, or dental complications, all of which are associated with general anesthesia. Potential advantages of spinal or epidural anesthesia include reduction

of the stress response to surgery, improvement in cardiac function in patients with ischemic heart disease, fewer postoperative

pulmonary complications, and the ability to continue epidural

analgesia into the postoperative period.67 Potential advantages

of peripheral nerve block include continued analgesia into the

postoperative period and fewer side effects or technical problems

than epidural analgesia.68 Disadvantages of spinal, epidural, or

peripheral nerve block include the additional time and manipulations required to perform it, possible complications or pain from

invasive catheter placements or injections, slow onset of effect,

possible failure of technique, and potential toxicity from absorption of the drugs administered. Finally, local infiltration anesthesia can be used to provide localized anesthesia to allow a minor

procedure (e.g., a deep laceration repair) to be performed or to

provide postoperative analgesia at the site of surgical incision.

Uses of Local Anesthetic Agents

Local anesthetics are a mainstay of analgesia because they prevent

the initiation or propagation of the electrical impulses required

for peripheral and spinal nerve conduction. These agents can be

administered by all routes previously discussed, depending on

the drug chosen. Table 8-9 lists the common uses of currently

available local anesthetics.69,70 Local anesthetics are often given

in combination with other agents, such as sodium bicarbonate

(to increase the speed of onset and reduce pain on local infiltration), epinephrine (to prolong the duration of action and to

delay vascular absorption of the local anesthetic, thereby minimizing plasma concentration and systemic toxicity), or opioids

(to provide analgesia by a different mechanism of action).

TABLE 8-9

Clinical Uses of Local Anesthetic Agents69,70

Agent Primary Clinical Use

Esters

Chloroprocaine Epidural

Cocaine Topical

Tetracaine Topical

Amides

Bupivacaine Local infiltration, nerve block, epidural, spinal

Lidocaine Local infiltration, nerve block, spinal, epidural,

topical, intravenous regional

Mepivacaine Local infiltration, nerve block, epidural

Ropivacaine Local infiltration, nerve block, epidural

161Perioperative Care Chapter 8

Mechanism of Action

The two structural classes of local anesthetics are characterized

by the linkage between the molecule’s lipophilic aromatic group

and hydrophilic amine group: amides and esters. Both amide and

ester classes provide anesthesia and analgesia by reversibly binding to and blocking the sodium channels in nerve membranes,

thereby decreasing the rate of rise of the action potential such that

threshold potential is not reached. As a result, propagation of the

electrical impulses required for nerve conduction is prevented.

The axonal membrane blockade that results is selective depending on the drug, the concentration and volume administered,

and the depth of nerve penetration. C fibers (pain transmission

and autonomic activity) appear to be the most easily blocked,

followed by fibers responsible for touch and pressure sensation

(A-α,A-β, and A-δ), and finally, those responsible for motor function (A-α and A-β). At the most commonly used doses and concentrations, some non–pain-transmitting nerve fibers are also

blocked. The blockade of sensory, motor, or autonomic (sympathetic, parasympathetic) fibers may result in adverse effects

such as paresthesia, numbness and inability to move extremities, hypotension, and urinary retention. Systemic effects (e.g.,

seizures or cardiac arrhythmias) are related to the inherent cardiac and CNS safety margins of these drugs.69,70

Ropivacaine, like bupivacaine, has a long duration of action.

Higher plasma concentrations of ropivacaine are required to produce mild CNS toxicity (lightheadedness, tinnitus, numbness of

the tongue) in volunteers when compared with bupivacaine. In

animal studies, ropivacaine was found to be less cardiotoxic than

bupivacaine. As a result, some practitioners believe that ropivacaine is safer than bupivacaine. However, once plasma concentrations reach higher levels, all local anesthetics are capable of

producing severe myocardial depression.71 Prevention of local

anesthetic systemic toxicity (LAST) is key, with attention paid

to early detection of intravascular needle or catheter placement

as well as predictors of local anesthetic plasma levels (e.g., dose,

block site, patient factors, etc.) that will be discussed further in

the Toxicity section.

Allergic Reaction

Localized skin hypersensitivity reactions (e.g., localized rash,

itching, edema, burning) to local anesthetics are the most common types of allergic reactions. Ester-type local anesthetic agents

(e.g., chloroprocaine) produce most of the allergic reactions,

owing to their metabolite, para-aminobenzoic acid (PABA). True

(systemic immunologic) allergy to amide-type local anesthetics

is extremely rare. However, allergic reactions may occur to a

preservative (methylparaben or other substances that are structurally similar to PABA) in the product. Because amide-type local

anesthetics do not undergo metabolism to a PABA metabolite,

a patient with a known allergy to an ester-type local anesthetic

can safely receive an amide-type agent.69,70,72 When selecting a

product, it is best to administer a preservative free, epinephrinefree preparation to a patient with a known allergy to a local

anesthetic.

Toxicity

Factors that influence the toxicity of local anesthetics include

the total amount of drug administered, presence or absence of

epinephrine, vascularity of the injection site, extremities of age

(e.g., <4 months or >70 years of age), and presence of cardiac, renal, or hepatic dysfunction.71 Systemic absorption of the

local anesthetic is positively correlated with the vascularity of the

injection site (IV > epidural > brachial plexus > subcutaneous).

End-stage pregnancy, extremities of age, significant hepatic or

renal dysfunction, and advanced heart failure can result in either

higher peak levels or accumulation of local anesthetic with continued or repeated dosing. In general, local anesthetic doses

should be reduced in patients with these conditions.73

Toxic levels of local anesthetics are most often achieved by

unintentional intravascular injection, which results in excessive

plasma concentrations. Systemic toxicity of local anesthetics

involves the CNS and cardiovascular systems. Patients may initially complain of tinnitus, lightheadedness, metallic taste in the

mouth, tingling, numbness, and dizziness. Hypotension may

occur. These symptoms can quickly be followed by tremors,

seizures, arrhythmias, unconsciousness, and cardiac or respiratory arrest as plasma levels rise.69,74 If signs and symptoms of

LAST occur, treatment includes airway management, benzodiazepines for seizure management, and if a cardiac arrest occurs,

standard Advanced Cardiac Life Support should be initiated

with minor modifications. Small (10–100 mcg) initial epinephrine

doses are preferred, vasopressin is not recommended, calciumchannel blockers and β-blockers should be avoided, and ventricular arrhythmias should be treated with amiodarone. After

airway management, 20% lipid emulsion therapy may be considered at the first signs of LAST (initial IV bolus dose of 1.5

mL/kg followed by 0.25 mL/kg/minute for at least 10 minutes

after circulatory stability is achieved).71

Physicochemical Properties

Affecting Action

The potency of a local anesthetic is primarily determined by the

degree of lipid solubility. Local anesthetics such as bupivacaine

are highly lipid soluble and can be given in concentrations of

0.25% to 0.5%. Less lipid-soluble agents, such as lidocaine, require

concentrations of 1% to 2% for many anesthetic techniques.

Amide-type local anesthetics are metabolized primarily by

microsomal enzymes in the liver. The cytochrome P-450 enzyme

system is involved in the metabolism of lidocaine (CYP3A4)

and ropivacaine (CYP3A2, CYP3A4, and CYP1A2). Agents that

induce or inhibit these enzymes could affect the metabolism,

and therefore the plasma concentration, of these drugs. Estertype local anesthetics are hydrolyzed by plasma cholinesterase

and, to a lesser extent, cholinesterase in the liver.69,70

Differences in the clinical activity of local anesthetics are

explained by other physicochemical properties such as protein

binding and pKa (the pH at which 50% of the drug is present in

the unionized form and 50% in the ionized form). Agents that are

highly protein bound typically have a longer duration of action.

Agents with a lower pKa typically have a faster onset of action.70

Choice of local anesthetic is based on the duration of the surgical procedure (e.g., the duration of analgesia required). Usually,

a local anesthetic that will, at least minimally, outlast the duration

of surgery with a single injection is chosen; a continuous infusion

can also be administered for titration of effect with shorter-acting

agents. Important physicochemical and pharmacokinetic properties of local anesthetics are shown in Table 8-10.69,70

Regional Anesthesia in

High-Risk Patients

CASE 8-11

QUESTION 1: M.S., a 52-year-old, 5-foot 9-inch, 105-kg

black man, is undergoing an emergent minor hand repair

procedure after a fall-related injury. His medical history is

positive for type 1 diabetes mellitus for 41 years, angina,

162 Section 1 General Care

TABLE 8-10

Physicochemical and Pharmacokinetic Properties of Local Anesthetic Agents69,70

Maximum Recommended Doseb

Agent pKa Potency Toxicity Onset Durationa Plain (mg) With Epinephrine (mg)

Esters

Cocainec – – – – – 1.5 mg/kg –

Chloroprocaine 9.1 Low Very low Very fast Short 800 1,000

Tetracaine 8.4 High Moderate Slow Very long 100 (topical) 200

Amides

Bupivacaine 8.1 High High Slow Long 175 225

Lidocaine 7.8 Moderate Moderate Fast Moderate 300 500

Mepivacaine 7.7 Moderate Moderate Moderate Moderate 300 500

Ropivacaine 8.1 High Moderate Slow Long 300 –

aDepends on factors such as injection site, dose, and addition of epinephrine. In general, a short duration is <1 hour, a moderate duration is 1–3 hours, and a long or very

long duration of action is 3–12 hours when the local anesthetic is administered without epinephrine.

b Maximum recommended single dose for infiltration or peripheral nerve block in 70-kg adults.

cTopical use only; concentrations >4% are not recommended owing to increased risk for systemic adverse effects.

and hypertension. On OR admission, laboratory values of

note are plasma glucose, 240 mg/dL, and BP, 145/92 mm

Hg. His sister tells the anesthesia provider that he has been

having increasing difficulty walking up stairs and, of late, is

often short of breath. The anesthesia provider chooses to

provide regional anesthesia via an axillary block; the anticipated duration of surgery is 2 hours. M.S. agrees with this

plan. Why is this a good plan for M.S., and which local anesthetic should be chosen?

With his medical conditions of diabetes, angina, and hypertension, M.S. is at risk for complications from general anesthesia.

General anesthesia is not absolutely necessary in this localized

surgery. Regional anesthesia would be beneficial in M.S. because

it does not disrupt autonomic function. In addition, his diabetes

and obesity, and possibly full stomach (emergency surgery, diabetic gastroparesis), place him at significant risk for aspiration

during both induction and emergence from general anesthesia.

An axillary block with a local anesthetic could provide M.S. with

adequate anesthesia and analgesia during and after his procedure.

The local anesthetic of choice is one with a duration at least

that of the anticipated surgery and with a good safety profile

should systemic absorption inadvertently occur. A local anesthetic containing epinephrine would increase the agent’s duration of action and reduce the systemic absorption; however, such

an agent is not indicated in M.S. because of his diabetes (peripheral vascular effects) and hypertension (added effect from catecholamine administration). Lidocaine as a single injection without epinephrine has a duration of action that may be too short

for M.S.’s procedure. Mepivacaine, an intermediate-acting local

anesthetic, or ropivacaine, a long-acting agent to provide longerlasting postoperative analgesia, would be appropriate choices to

use in M.S.

Alkalinization of Local Anesthetics

CASE 8-12

QUESTION 1: T.F., a 22-year-old man, is scheduled for a hernia repair. He has never undergone surgery and is very anxious. In the preoperative area, the nurse chooses to locally

infiltrate 1% lidocaine to reduce the pain and discomfort

from IV catheter placement. She injects a small amount of

lidocaine under the skin. T.F. flinches and complains of pain

from the injection. Can anything be done to reduce the pain

from injection of lidocaine?

The onset of action of local anesthetics depends on their pKa.

Drugs with pKas closest to body pH (7.4) will have the fastest

onset because a high percentage of the local anesthetic molecules

will be unionized and therefore will be able to cross the nerve

membranes to their intracellular site of action. Local anesthetics are formulated in solutions with acidic pH to optimize their

shelf-lives. When sodium bicarbonate is added to local anesthetic

solutions, the pH is increased, the percentage of unionized drug

is increased, and the onset of local anesthetic action can be shortened considerably. The amount of bicarbonate added to the solution depends on the pH of the local anesthetic agent. Because too

much sodium bicarbonate will precipitate the local anesthetic,

a dose of 0.1 mEq (0.1 mL of a 1-mEq/mL concentration) of

sodium bicarbonate is added to 10 mL of bupivacaine, whereas

1 mEq (1 mL of a 1-mEq/mL concentration) is added to 10 mL of

lidocaine. More importantly, alkalinized lidocaine can be significantly less painful for subcutaneous injection before IV catheter

placement when compared with lidocaine at pH 5 (its pH in

the commercially available vial).75 However, if the lidocaine contains epinephrine, the addition of bicarbonate to the solution

will destroy the activity of epinephrine (which is stable only in

an acidic pH).

ANTIEMETIC AGENTS AND

POSTOPERATIVE NAUSEA AND

VOMITING

Impact of Postoperative Nausea and

Vomiting

The two most common complications after surgery are postoperative pain and PONV. Patients who experience PONV are

greatly dissatisfied with their surgical experience, and require

additional resources such as nursing time, and medical and surgical supplies. Furthermore, vomiting can provoke the rupture

of surgical sutures and cause wound pain and hematomas, and,

if severe, more serious adverse events can occur (e.g., aspiration pneumonitis, increased intraocular pressure leading to loss

of vision). PONV typically lasts less than 24 hours; however,

symptom distress can continue at home, thereby preventing the

163Perioperative Care Chapter 8

patient from resuming normal activities or returning to work.

It is important to remember that nausea is a separate subjective

sensation and is not always followed by vomiting. Nausea can be

more distressing to patients than vomiting.76

Mechanisms of and Factors Affecting

Postoperative Nausea and Vomiting

The vomiting center is reflex activated through the chemoreceptor trigger zone (CTZ). Input from other sources can also

stimulate the vomiting center. Afferent impulses from the periphery (e.g., manipulation of the oropharynx or GI tract), the cerebral cortex (e.g., unpleasant sights or smells, emotions, anxiety,

hypotension, pain), and the endocrine environment (e.g., female

sex) can also stimulate the vomiting center. In addition, disturbances in vestibular function (e.g., movement after surgery, middle ear surgery) can stimulate the vomiting center via direct

central pathways and the CTZ. Neurotransmitter receptors that

play an important role in impulse transmission to the vomiting

center include dopamine type 2 (D2), serotonin (5-HT3), muscarinic cholinergic (M1), histamine type 1 (H1), and neurokinin

type 1 (NK1) (Fig. 8-1).76–80 Opioid analgesics can activate the

CTZ, as well as the vestibular apparatus, to produce nausea and

vomiting.76–80

PONV is probably not caused by a single event, entity, or

mechanism; instead, the cause is likely to be multifactorial. Factors that place adults at risk for developing PONV include female

sex, history of PONV or motion sickness, nonsmoking status,

use of postoperative opioids, duration of anesthesia, and general

anesthesia with inhalation anesthetic agents.81,82 A commonly

used tool for determining an adult patient’s risk of developing

PONV has been developed; one point is assigned to each of the

following risk factors: female sex, nonsmoker, history of PONV,

and postoperative use of opioids.83 The level of risk for developing PONV is low (<20%) for patients with zero or one risk factor

and increases significantly with the presence of each additional

risk factor (2 risk factors, 40%; 3 risk factors, 60%; and 4 risk factors, 80%).83 For children, risk factors for postoperative vomiting

include duration of surgery 30 minutes or longer, age 3 years or

older, strabismus surgery, and a history of postoperative vomiting in the child or PONV in the mother, father, or siblings.84

Similarly to adults, the level of risk for developing postoperative

vomiting is low for children with zero or one risk factor and

increases significantly with the presence of each additional risk

factor (2 risk factors, 30%; 3 risk factors, 55%; and 4 risk factors,

70%).83 In children, nausea is not easily measured and hence not

routinely assessed.

CASE 8-13

QUESTION 1: J.E., a 34-year-old, 55-kg woman, is scheduled to undergo a gynecologic laparoscopy under general inhalation anesthesia on an outpatient basis. She has

had one previous surgery, has no known medication allergies, and is a nonsmoker. On questioning, she reports that

she experienced PONV after her first surgery. Her physical

D2, 5-HT3, M1,

Mu–opioid, NK1

Vestibular center

(movement after surgery,

middle ear surgery)

H1, M1 Endocrine environment

(female sex, pregnancy)

Increased ICP (tumor,

CSF obstruction)

Cerebral cortex (anxiety,

emotions, sights, smells)

Vagal afferents from the

periphery (distension of GI

tract, gastroparesis,

insufflation of the

abdomen during

laparoscopic surgery, early

ingestion of fluids or food)

5-HT3, D2, NK1

D2, 5-HT3, M1,

H1, NK1

Chemoreceptor

Trigger Zone

Nucleus Tractus

Solitarius

Vomiting Center

Upper GI Tract

Motor Response –

Emesis

Hypotension,

hypoxia

FIGURE 8-1 Mechanisms and neurotransmitters of postoperative nausea and vomiting. The chemoreceptor

trigger zone (CTZ) is located in the area postrema of the midbrain. The vomiting center is also located in the

midbrain, close to the nucleus tractus solitarius (NTS) and the area postrema. The CTZ, NTS, and area postrema

are rich in 5-HT3, H1, M1, D2, and mu-opioid receptors. Antiemetic agents used to manage postoperative

nausea and vomiting block one or more of these receptors. 5-HT3, serotonin type 3 receptor; CSF, cerebral

spinal fluid; D2, dopamine type 2 receptor; GI, gastrointestinal; H1, histamine type 1 receptor; ICP, intracranial

pressure; M1, muscarinic cholinergic type 1 receptor; NK1, substance P neurokinin type 1 receptor.

164 Section 1 General Care

examination is unremarkable. Is J.E. a candidate for prophylactic antiemetic therapy?

J.E. has several risk factors that make her susceptible to experiencing PONV. Adult women are two to three times more likely

than adult men to develop PONV. Previous PONV also increases

the likelihood of developing PONV threefold. In addition, a nonsmoking status increases the risk of developing PONV. Using

the simplified risk score for PONV, J.E. has four risk factors,

anticipating that she will require postoperative opioids for pain

management. In addition, the type of procedure J.E. is undergoing (gynecologic laparoscopy) may further increase her risk for

developing PONV. Because of the presence of four risk factors,

J.E. is at very high risk and should be administered at least two

prophylactic antiemetic agents.

Prevention of Postoperative Nausea and

Vomiting: Choice of Agent

CASE 8-13, QUESTION 2: Which antiemetic drugs would be

most appropriate for J.E., and when should they be administered?

Antiemetic drugs can be classified as antimuscarinics (scopolamine, promethazine, diphenhydramine), serotonin antagonists (ondansetron, dolasetron, granisetron, palonosetron),

benzamides (metoclopramide), butyrophenones (droperidol),

phenothiazines (prochlorperazine), and NK1 antagonists (aprepitant). These drugs exert their antiemetic effects primarily

by blocking one central neurotransmitter receptor and exert

their antiemetic effect independently of one another. The

higher a patient’s baseline risk for experiencing PONV, the

more antiemetic agents and interventions must be combined. Dopamine antagonists include the benzamides, butyrophenones, and phenothiazines. Ondansetron, granisetron,

dolasetron, and palonosetron block 5-HT3 receptors of vagal

afferent nerves in the GI tract and in the CTZ. Antimuscarinics

such as scopolamine and diphenhydramine likely exert their

antiemetic effect by blocking Ach in the vestibular apparatus,

vomiting center, and CTZ. The proposed site of action, usual

adult dose, and select adverse effects of the commonly used

antiemetic drugs for prevention and treatment of PONV are

summarized in Table 8-11.3,76,78,81,82,85

BUTYROPHENONES

Droperidol possesses significant antiemetic activity. It effectively

prevents PONV at IV doses of 0.625 to 1.25 mg, with a rapid onset

and short duration of action.86 Therefore, droperidol is most

effective when administered near the end of surgery. Adverse

effects include sedation (especially at doses ≥2.5 mg), hallucinations, hypotension, and, rarely, restlessness or other extrapyramidal (EP) reactions. Because of its effectiveness and cost, droperidol has historically been used extensively as a first-line agent.

However, in December 2001, the FDA strengthened warnings

regarding adverse cardiac events after droperidol administration.

With the new warning to perform continuous 12-lead electrocardiographic monitoring before and for 2 to 3 hours after administration of droperidol, it became an issue, from both expense and

logistical viewpoints, to administer droperidol to an outpatient,

a patient in the PACU (recovery room), or a patient in an unmonitored bed. Because low-dose droperidol has been used for more

than 30 years to prevent PONV, several studies were undertaken

to examine the effect of low-dose droperidol on the QTc interval.

When compared with placebo (saline), low-dose droperidol did

not produce QTc prolongation after surgery.87 When compared

with ondansetron, droperidol produced similar QTc prolongation, and it was concluded that serotonin antagonists may not

be safer than low-dose droperiol.88 Finally, Nuttall et al.89 retrospectively examined whether low-dose droperidol administration increased the incidence of torsades de pointes in patients

undergoing general surgery. Of the 16,791 patients exposed to

droperidol, no patient experienced torsades de pointes. These

authors concluded that the FDA’s black-box warning for lowdose droperidol is excessive and unnecessary.

BENZAMIDES

Metoclopramide, in doses of 10 to 20 mg, has been used in the

prevention and treatment of PONV. However, variable results

have been seen with this agent at these doses.90 For maximal

benefit, metoclopramide should be administered in a dose of

25 mg IV near the end of surgery (secondary to its rapid redistribution after IV administration); 10 mg IV administered at the

beginning of surgery is not effective.91 Adverse effects of metoclopramide include drowsiness and EP reactions, such as anxiety and restlessness. Metoclopramide should be administered

by slow IV injection for at least 2 minutes to minimize the risk

of EP reactions and cardiovascular effects such as hypotension,

bradycardia, and supraventricular tachycardia.

SEROTONIN ANTAGONISTS

Ondansetron (4 mg IV) was the first 5-HT3 antagonist to receive

an indication for PONV. Dolasetron (12.5 mg IV) and granisetron

(1 mg IV) are also approved for preventing and treating PONV.

Palonosetron (0.075 mg IV) is approved for the prevention of

PONV for up to 24 hours after surgery. In general, serotonin

antagonists are consistently more effective in reducing vomiting

rather than nausea.82,92 Ondansetron and dolasetron are equally

efficacious in preventing PONV.93 A single dose of ondansetron,

dolasetron, or granisetron provides acute relief and can protect

against nausea and vomiting for up to 24 hours after administration. Palonosetron is effective when compared with placebo,

but it has not been compared with the older, first-generation

agents (ondansetron, granisetron, dolasetron). For optimal efficacy, serotonin antagonists should be administered near the end

of surgery. Adverse effects are generally minimal and include

headache and constipation; prolongation of the QTc interval can

occur.