Victoria F. Ferraresi

CORE PRINCIPLES

CHAPTER CASES

1 End-of-life care consists of palliative and hospice care. It is ideally introduced early

in the disease progression to provide support to patients of all ages with a serious

chronic or life-threatening illness. Medicare patients who enter a hospice program

agree to relinquish their regular Medicare benefits as they relate to the terminal

illness, and accept the palliative rather than curative approach that will be provided

by hospice. The hospice provides all care related to the hospice diagnosis under a

managed-care model at a fixed reimbursement.

Case 5-1 (Question 1)

2 In 2008, the Hospice Conditions of Participation were updated to include a review

of the medication profile as part of the initial assessment of new patients. The

medication regimens of hospice patients should be continually reviewed and

updated, with unnecessary, ineffective, or duplicative medications discontinued.

Case 5-1 (Question 2)

3 Patients near end of life can experience a number of distressing symptoms. These

should be anticipated and treated in a timely manner that is acceptable to the

patients and their families.

Case 5-1 (Question 3)

4 Well-trained pharmacists can improve medication management for hospice

patients, while helping the hospice manage their drug costs.

Case 5-1 (Question 2)

5 Many barriers exist regarding pain management and the use of opioids. Case 5-1 (Question 4)

6 Effective pain management uses a variety of approaches. Case 5-2 (Question 1)

7 Pain and symptom management may at times require an aggressive approach. Case 5-3 (Questions 1–3)

HOSPICE AND PALLIATIVE CARE

Terminology

Hospice care and palliative care are similar, but distinct, terms

sharing the common belief that the relief of suffering is a longstanding, central, and fully legitimate aim of medicine. End-of-life

carerefers to both hospice care and palliative care. The basic principle of end-of-life care is to optimize the quality of life for the

patient and family in the last weeks and months of life, as well

as to provide support for the family beyond the end of life into

bereavement.

Palliative care, which includes hospice care, is ideally introduced early in the disease progression to provide support to

patients of all ages with a serious chronic or life-threatening illness. It can be provided concurrently with other treatments to

cure or reduce disease, or it can be provided independently. The

word palliation, derived from the Latin word pallium(a cloak), has

been defined as “treatment to reduce the violence of a disease.”

The World Health Organization and the National Consensus

Project define palliative care as an approach that improves the

quality of life of patients and their families who are facing a lifethreatening illness, by preventing and relieving suffering through

early identification and impeccable assessment and treatment of

pain and other physical, psychosocial, and spiritual problems.1–4

Palliative care:

 Affirms life and regards dying as a normal process

 Provides relief from pain and other distressing symptoms

 Intends neither to hasten nor postpone death

 Integrates the psychological and spiritual aspects of patient

care

 Offers a support system to help patients live as actively as

possible until death

 Uses a multidisciplinary team approach to address the needs

of the patient and his or her family during the patient’s illness

and

 Provides bereavement counseling when indicated.3

88

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.

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