Antiemetic Agents and Postoperative Nausea and Vomiting

Antiemetic Agents and Postoperative Nausea and Vomiting

Impact of Postoperative Nausea and Vomiting

PONV is a relatively common (overall incidence, 25%-30%) yet highly undesirable anesthetic and surgical outcome. Patients who develop PONV are greatly dissatisfied with their surgical experience and require additional resources such as nursing time and medical/surgical supplies. PONV typically lasts <24 hours; however, symptom distress can continue at home, thereby preventing the patient from resuming normal activities or returning to work.¹¹⁹ It is important to remember that nausea is a separate subjective sensation and is not always followed by vomiting. Nausea can be as or more distressing to patients as vomiting.

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 tastes, sights, smells, emotions, hypotension, pain), and the endocrine environment (e.g., female gender) 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 (5HT₃), muscarinic cholinergic (M₁), histamine type 1 (H₁), and neurokinin type 1 (NK₁) (Fig. 9-1).^{119,120,121,122,123,124,125} The vestibular apparatus is rich in M₁ and H₁ receptors. Opioid analgesics can activate the CTZ, as well as the vestibular apparatus, to produce nausea and vomiting.^{119,120,121,122}

PONV is probably not caused by a single event, entity, or mechanism; instead, the cause is likely to be multifactorial. Factors that place a patient at risk for developing PONV in adults include female gender, history of PONV and/or motion sickness, nonsmoking status, use of opioids, type of surgery, duration of surgery, and general anesthesia with inhalation anesthetic agents and/or nitrous oxide.¹²⁶ For children, risk factors for postoperative vomiting include duration of surgery ≥30 minutes, age ≥3 years, strabismus surgery, and a history of postoperative vomiting in the child or PONV in the mother, father, or siblings.¹²⁵ Unlike adults, nausea is not easily measured in children and hence not routinely assessed.

18. J.E., a 34-year-old, 55-kg woman, is scheduled to undergo a gynecologic laparoscopy under general 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 developed PONV following her first surgery. Her physical examination is unremarkable. Is J.E. a candidate for prophylactic antiemetic therapy?

J.E. has several risk factors that make her susceptible to developing 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. The type of procedure J.E. is undergoing (gynecologic laparoscopy) places her at a higher risk for developing PONV. Finally, J.E. is scheduled for general anesthesia, which is also associated with a greater risk of PONV when compared with regional anesthesia. Because of the presence of many risk factors, J.E. is at high risk and should be administered at least two prophylactic antiemetic agents. Patients undergoing surgery view PONV as a highly undesirable consequence, thereby reducing their overall level of satisfaction.

Figure 9-1 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 solaritus (NTS) and the area postrema. The CTZ, NTS, and area postrema are rich in 5-HT3, H1, M1, D2, and µ-opioid receptors. Antiemetic agents used to manage postoperative nausea and vomiting block one or more of these receptors. D2, dopamine type 2 receptor; 5-HT3, serotonin type 3 receptor; M1, muscarinic cholinergic type 1 receptor; NK1, neurokinin type 1 receptor; H1, histamine type 1 receptor; GI, gastrointestinal; ICP, intracranial pressure; CSF, cerebral spinal fluid. Source: Adapted from references 119, 120, 121, 122, 123, 124, 125.

Prevention of Postoperative Nausea and Vomiting: Choice of Agent

19. 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), benzamides (metoclopramide), butyrophenones (droperidol), phenothiazines (prochlorperazine), and the NK₁ antagonist, aprepitant. These drugs exert their antiemetic effects primarily by blocking one central neurotransmitter receptor. Dopamine antagonists include the benzamides, butyrophenones, and phenothiazines. Ondansetron, granisetron, and dolasetron block 5HT₃ receptors of vagal afferent nerves in the GI tract and in the CTZ. Antimuscarinics 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 9-15.^{3,119,121,125-127}

Butyrophenones

Droperidol possesses significant antiemetic activity, with IV doses of 0.625 to 1.25 mg effectively preventing PONV. Droperidol is more effective for nausea than vomiting, even at a dose as low as 0.3 mg. Droperidol has an onset of action of 3 to 10 minutes, with peak effects seen at 30 minutes. Doses of 0.625 or 1.25 mg often prevent PONV for up to 24 hours.

 

The duration of action of a 0.3-mg dose, however, is short lived, with repeated doses often necessary. Droperidol is most effective when administered near the end of surgery. Adverse effects include sedation (especially at doses ≥2.5 mg), anxiety, hypotension, and, rarely, restlessness or other extrapyramidal (EP) reactions.¹²⁸ 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 following droperidol administration. With the new warning to perform continuous 12-lead electrocardiographic monitoring before and for 2 to 3 hours following administration of droperidol, it became an issue, from both expense and logistical viewpoints, to administer droperidol to an outpatient, patient in the PACU (recovery room), or patient in an unmonitored bed. Because low-dose droperidol has been used for >30 years to prevent PONV, many anesthesia providers challenged the decision of the FDA to issue this “black box” warning.¹²⁹ Nuttall et al.¹³⁰ retrospectively examined whether low-dose droperidol 

administration increased the incidence of torsades de pointes (TdP) in patients undergoing general surgery. Of the 16,791 patients exposed to droperidol, no patient experienced TdP. The authors concluded that the FDA's black box warning for low-dose droperidol is excessive and unnecessary.

Table 9-15 Classification, Proposed Site(s) of Action, Usual Dose, and Adverse Effects of Select Antiemetic Drugs

Antiemetic Drug Proposed Receptor Site of Action Usual Dosea Duration of Action Adverse Effects Comments Butyrophenones Droperidol (Inapsine) D2 Adult: 0.625–1.25 mg IV Pediatric: 20–50 µg/kg IV for prevention; 10-20 mcg/kg IV for treatment ≤12–24 hr Sedation, dizziness, anxiety, hypotension (especially in hypovolemic patients), EPS Monitor ECG for QT prolongation/torsades de pointes Phenothiazines Prochlorperazine (Compazine) D2 Adult: 5–10 mg IM or IV; 25 mg PR Pediatricb: 0.1-0.15 mg/kg IM, 0.1–0.13 mg/kg PO, 2.5 mg PR 4–6 hr (12 hr when given PR) Sedation, hypotension (especially in hypovolemic patients), EPS   Antimuscarinics Promethazine (Phenergan) D2, H1, M1 Adult: 6.25–25 mg IM, IV, or PRc 4-6 hr 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 saline, inject through a running line, and advise patient to report IV site discomfort Diphenhydramine (Benadryl) H1, M1 Adult: 12.5–50 mg IM or IV 4–6 hr Sedation, dry mouth, blurred vision, urinary retention       Pediatric: 1 mg/kg IV, PO (max: 25 mg for children younger than 12 years)       Scopolamine (Transderm Scop) M1 Adult: 1.5 mg transdermal patch 72 hrd Sedation, dry mouth, visual disturbances, dysphoria, confusion, disorientation, hallucinations Apply at least 4 hr before end of surgery; wash hands after handling patch; not appropriate for children, elderly, or patients with renal/hepatic impairment Benzamides Metoclopramide (Reglan) D2 Adult: 10-20 mg IV Pediatric: 0.25 mg/kg IV ≤6 hr Sedation, hypotension, EPS Consider for rescue if N/V is believed to be due to gastric stasis; reduce dose to 5 mg in renal impairment; give slow IV push Serotonin Antagonists Ondansetron (Zofran) 5-HT3 Adult: 4 mg IV Up to 24 hr Headache, lightheadedness, QT prolongation       Pediatric: 0.05–0.1 mg/kg IV       Dolasetron (Anzemet) 5-HT3 Adult: 12.5 mg IV Up to 24 hr Headache, lightheadedness, QT prolongation       Pediatric: 0.35 mg/kg IV       Granisetron (Kytril) 5-HT3 Adult: 0.35 mg-1 mg IV Pediatric: Not known Up to 24 hr Headache, lightheadedness, QT prolongation   Palonosetron (Aloxi)   Adult: 0.075 mg IV Up to 24 hr Bradychardia, headache, QT prolongation   NK1 Antagonists Aprepitant (Emend) NK1 Adult: 40 mg PO up to 3 hr before surgery Up to 24 hr Headache   Other Dexamethasone (Decadron) None Adult: 4–8 mg IV Pediatric: 0.15 mg/kg IV Up to 24 hr Genital itching, flushing, hyperglycemia   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. cMaximum of 12.5 mg in children younger than 12 years. dRemove after 24 hours. Instruct patient to thoroughly wash the patch site and their hands. 5-HT3, serotonin type 3 receptor; D2, dopamine type 2 receptor; ECG, electrocardiogram; EPS, extrapyramidal symptoms (e.g., motor restlessness or acute dystonia); H1, histamine type 1 receptor; IV, intravenous; IM, intramuscular; M1, muscarinic cholinergic type 1; N/A, not applicable; N/V, nausea and/or vomiting; PO, orally (by mouth); PR, per rectum. Adapted from references 3, 119, 121, and 125, 126, 127.

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.¹³¹ For maximum benefit, metoclopramide must be administered 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. Adverse effects of metoclopramide include drowsiness and EP reactions, such as anxiety and restlessness. Metoclopramide should be administered by slow intravenous injection over 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 5HT₃ 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 following surgery. As a general rule, serotonin antagonists are consistently more effective in reducing vomiting rather than nausea.¹³² Ondansetron and dolasetron are equally efficacious in preventing PONV.¹³³ 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. For optimal efficacy, serotonin antagonists should be administered near the end of surgery. Adverse effects are minimal and include headache, constipation, and elevated liver enzymes. Because of their good efficacy and adverse effect profile, serotonin antagonists are recommended as first-line therapy.¹²⁵

Dexamethasone

Dexamethasone is frequently used as an antiemetic in patients undergoing highly emetogenic chemotherapy. Its mechanism of action as an antiemetic is not well understood, particularly in the surgical setting. When compared to placebo, a prophylactic dose of dexamethasone is antiemetic in high-risk patients. It is most effective in preventing late PONV (up to 24 hours). Adverse effects in otherwise healthy patients are minimal and include headache, dizziness, drowsiness, constipation, and muscle pain.¹³⁴ Because of its good efficacy and adverse effect profile (from a single dose), dexamethasone is also recommended as first-line therapy.¹²⁵ Unlike droperidol and the serotonin antagonists, dexamethasone is most effective when administered at the beginning of surgery (immediately before induction).¹³⁵

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.¹³⁶ Prochlorperazine may cause sedation, EP reactions, and 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.¹³⁷ 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 prior to 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 following 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.¹³⁸

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).¹³⁹ 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 between 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 high risk for developing PONV. Dexamethasone 4 mg IV can be administered at the beginning of surgery (just after induction of anesthesia) and 4 mg IV ondansetron should be administered approximately 30 minutes before the end of surgery. If an alternative agent (to ondansetron and dexamethasone) or third agent is warranted, a transdermal scopolamine patch can be placed within 2 hours before the induction of general anesthesia. The addition of transdermal scopolamine to ondansetron for prevention of PONV significantly reduces PONV, as well as supplemental antiemetic requirements.¹⁴⁰

Treatment of Postoperative Nausea and Vomiting

20. 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.D. becomes nauseated and has several emetic episodes. What do you recommend?

Although dexamethasone and ondansetron are effective for both prevention and treatment of PONV, a rescue antiemetic is more efficacious if it works by a different mechanism of action.¹⁴¹ Prophylactic dexamethasone and/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 or promethazine, which blocks Ach receptors in the vestibular apparatus, as well as histamine receptors that activate the CTZ, would also be appropriate choices 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 promethazine and 50 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. Postoperative pain must also be assessed because PONV is directly related to the degree of postoperative pain; a threefold higher frequency of PONV has been reported in ambulatory surgery patients with postoperative pain.¹⁴²

Anesthetic Agents With a Low Incidence of Postoperative Nausea and Vomiting

21. 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.¹³⁹ Because perioperative administration of opioids is associated with PONV, the use of NSAIDs (oral agents preoperatively and postoperatively, parenteral 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 trauma from surgery directly stimulate nociceptors (receptors in the periphery that detect damaging or unpleasant stimuli, inflammation, pressure, and/or temperature). In addition, tissue injury causes the release of inflammatory mediators (e.g., prostaglandins, substance P) that sensitize and activate nociceptors. Sensitized nociceptors amplify the pain impulse by generating nerve impulses more readily and more often; this is called “peripheral sensitization.” The pain impulse then travels from the periphery to the dorsal horn of the spinal cord. From here, the pain impulse ascends to higher centers in the brain, which results in the patient “feeling” the pain. Because both cortical and limbic systems are involved and social and environmental influences are present, the same surgery can result in significant individual differences in pain perception. Persistent bombardment of the dorsal horn with pain impulses from the periphery results in central sensitization (“wind-up”), where there is increased firing of dorsal horn neurons. Clinically, when these two processes occur, the patient will experience a lower pain threshold, both at the site of injury and in the surrounding tissue. When this occurs, pain may be prolonged beyond the usual expected duration following surgery. If central sensitization is prolonged, permanent changes in the CNS can occur. Clinically, this can result in postoperative pain that is hard to manage.^143,144

The degree of pain usually depends on the magnitude of the surgery¹⁴⁵ and the patient's level of fear and anxiety. 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.¹⁴⁶

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; determining the patient's pain goal; and anticipating preoperative, intraoperative, and postoperative pain therapies. 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) on-demand administration of IV opioids, also known as patient-controlled 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 or peripheral nerve blockade, or administration of a nonopioid analgesic such as an NSAID or acetaminophen are appropriate approaches to analgesia. For moderate postoperative pain, a less potent oral opioid, such as hydrocodone or codeine, is added. For moderate to severe pain following 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 8.) 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 agents that have different mechanisms of action or that are administered by different techniques.¹⁴⁶

Posted in: General Care,Perioperative Care