Management of Postoperative Nausea and Vomiting in Ambulatory Surgery The Big Little Problem

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1 Management of Postoperative Nausea and Vomiting in Ambulatory Surgery The Big Little Problem Mary Keyes, MD KEYWORDS Postoperative nausea and vomiting PONV prophylaxis PONV in ambulatory surgery KEY POINTS The Consensus Guidelines for Managing Postoperative Nausea and Vomiting (PONV) provides an evidence-based management strategy for clinicians. Although the exact cause of PONV is unknown, many receptors, pathways, and neurotransmitters are likely involved. Because of the multitude of inputs that may be causal, single therapies are often inadequate. An individual s risk for PONV is best predicted by using a simplified risk score of independent predictors: female gender, nonsmoking status, history of PONV or motion sickness, and postoperative opioid use. Although some types of surgery, plastic surgery among them, are associated with higher PONV risk, risk scores that include type of surgery provide no greater predictive value. Strategies that avoid inhaled anesthetics such as total intravenous anesthesia (TIVA), elimination of nitrous oxide, and minimal opioid use reduce risk. Multimodal regimens involving TIVA with propofol, combination antiemetic prophylaxis, hydration, and nonnarcotic analgesics, are the most effective way to prevent PONV in high-risk patients. Postdischarge nausea and vomiting is common in ambulatory surgery patients. Those who have nausea in the postanesthesia care unit (PACU) are particularly at risk. Which agents in addition to dexamethasone are effective remains to be determined. Considerable progress has been made in the management of postoperative nausea and vomiting (PONV) since it was labeled the big little problem over 20 years ago by Kapur. 1 Although usually self-limited, it is distressing to patients who, in some studies, state they would pay up to $ out of pocket for a drug to avoid it. 2 PONV can lead to dehydration, electrolyte disturbances, and the inability to take vital oral medications and fluids after surgery. The act of vomiting can cause suture disruption, lead to hematoma formation, and be a risk factor for pulmonary aspiration. Its occurrence often delays discharge from ambulatory settings and is a leading cause of unanticipated hospital admission escalating health care costs. With most surgeries now being done on an outpatient or ambulatory basis, considerable attention is being given to this issue. The Consensus Guidelines for Managing Postoperative Nausea and Vomiting authored by an international panel of experts created an evidencebased management strategy for clinicians. 3 These UCLA Department of Anesthesiology, Ronald Reagan UCLA Medical Center, 757 Westwood Plaza, Suite 3325, Los Angeles, CA , USA address: mkeyes@mednet.ucla.edu Clin Plastic Surg 40 (2013) /13/$ see front matter Published by Elsevier Inc. plasticsurgery.theclinics.com

2 448 Keyes guidelines have been the foundation for the improved understanding and recent advances gained regarding this common, undesirable perioperative experience. However, there is still room for improvement, particularly in the area of postdischarge nausea and vomiting (PDNV), which occurred in up to 37% of ambulatory patients in a recently published study. 4 PATHOPHYSIOLOGY OF NAUSEA AND VOMITING Various stimuli that produce nausea and vomiting converge in an area of the medulla known as the emetic center. This center is not a discrete nucleus but rather a collection of neurons controlled by a central pattern generator. Input to the emetic center comes from a variety of pathways: the visceral afferent nerves of the gastrointestinal tract, the chemoreceptor trigger zone (CTZ), the cerebral cortex, and the vestibular apparatus. Each of these systems is modulated by specific receptors and neurotransmitters. The CTZ is located in the fourth ventricle of the brainstem but, because of its uniquely permeable membrane, it is outside the blood-brain barrier, which allows detection of toxins and drugs in the circulation. Stimulation of dopamine, opioid, histamine, acetylcholine, serotonin type 3 receptors, or neurokinin-1 receptors in the emetic center initiates the vomiting reflex. Therapies that interfere with each of these neurotransmitter-receptor interactions are used to prevent nausea and vomiting in clinical practice. Because of the multitude of inputs that may be causal in the production of nausea and vomiting, single therapies are often inadequate. ASSESSING RISK FOR PONV The important first step in managing PONV is to assess risk for each patient. In doing so, there are 3 categories of factors to consider: Patient-specific factors: 1. Female gender 2. Nonsmoking status 3. History of PONV or motion sickness Anesthesia-related factors: 1. Use of volatile anesthetics 2. Use of nitrous oxide 3. Perioperative opioid use Surgery-related factors: 1. Duration and invasiveness of surgery 2. Type of surgery A simplified risk score of independent predictors by Apfel and colleagues 5 has gained widespread recognition and implementation by anesthesia providers. Although some types of surgery (plastic, strabismus, gynecologic, laparoscopic, urologic) are known to be associated with a higher PONV risk, risk scores that include type of surgery provide no greater predictive value than a simplified version. For example, hysterectomy is known to have a higher PONV risk. It may be that this increased risk is a reflection of the patient population who are female (the strongest risk factor) rather than the surgery itself. Patients having plastic surgery are predominantly women, making them inherently at higher risk. The simplified risk score for an adult having a balanced inhalational anesthetic consists of the following 4 factors: female gender, nonsmoking status, previous history of PONV or motion sickness, and postoperative opioid use. The presence of 1 risk factor correlates with a risk of 20% for PONV. Each additional risk factor adds 20%, so that patients with all 4 have an 80% risk of developing PONV (Fig. 1). REDUCING RISK There are often strategies that can be incorporated into the anesthesia and surgical plan to reduce the probability of developing PONV: 1. Total intravenous anesthesia (TIVA) with propofol reduces PONV risk about 19% from a patient s baseline risk. 6 Impediments to the use of propofol have been cost, the lack of ability to monitor depth of anesthesia, and the need for an infusion pump. Propofol is now a generic drug, making the cost difference between it and a volatile agent much less significant. The cost savings gained in having less PONV and improved patient satisfaction may justify the increased cost. 2. Nitrous oxide use is a risk factor for PONV, although not as significant as the volatile anesthetic agents. Both propofol anesthesia and inhalational anesthesia are more emetogenic when N 2 O is used in combination. There is no difference in emetogenicity between isoflurane, desflurane, and sevoflurane. One of the findings of the International Multicenter Protocol to assess Antiemetic Combinations Trial (IMPACT) was that, by eliminating N 2 O as the carrier gas, PONV risk is reduced by about 12% Minimization of perioperative opioids reduces PONV risk. Infiltration with local anesthetics and the use of alternative nonnarcotic analgesics are opioid sparing. Ketorolac has been available and in use for more than a decade.

3 Postoperative Nausea and Vomiting 449 Fig. 1. Risk factors for developing PONV. (From Apfel CC, Läärä E, Koivuranta M, et al. A simplified risk score for predicting postoperative nausea and vomiting: conclusions from cross-validations between two centers. Anesthesiology 1999;91(3): ; with permission.) Some surgeons are reluctant to use it because it causes inhibition of platelet aggregation by inhibiting cyclooxygenase. Although the increased incidence of bleeding is small, when surgical outcome is jeopardized, many surgeons avoid using it. Intravenous acetaminophen (Ofirmev) was approved by the US Food and Drug Administration (FDA) in late Most studies of Ofirmev use report less opioid consumption and a lower percentage of patients requiring rescue medications. The rapid blood level achieved by the intravenous route provides an excellent alternative or adjunct for those patients requiring mild to moderate pain relief. 4. Regional anesthesia is associated with a marked reduction in PONV risk compared with general inhalational anesthesia by avoiding exposure to volatile anesthetics and narcotics. PONV PROPHYLAXIS Serotonin Antagonists The serotonin antagonists have become one of the foundation drug classes in the treatment of PONV. Much of what is known about antiemetic prophylaxis has come from therapies effective in chemotherapy-induced nausea and vomiting. Cytotoxic chemotherapy is associated with release of serotonin from the gut. This released serotonin may stimulate vagal afferents in the gut through 5-hydroxytryptamine (5-HT3) receptors and initiate vomiting. Serotonin is also found throughout the central nervous system, including the CTZ. The 5-HT3 receptor antagonists (5-HT3-RAs) include ondansetron (Zofran), dolasetron (Anzemet), granisetron (Kytril), and, most recently, palonosetron (Aloxi). All are approved for use in the United States. In general, all are considered safe and equally effective. Ondansetron was the first of its class and the most widely studied. The most common side effects (headache, constipation, and diarrhea) occur at a low rate. These drugs are not sedating and do not cause extrapyramidal side effects, which makes them particularly useful. It is recommended that ondansetron 4 mg (and other drugs in this class) be given 20 to 30 minutes before the end of surgery to provide prophylaxis for 4 to 6 hours after surgery in the case of ondansetron. The variable chemical structures of each of these drugs may explain the minor differences in dose response and duration of action. Palonosetron is unique in this group, with a long half-life of about 40 hours, which may make it useful in the prevention of PDNV. Steroids Dexamethasone is effective in the management of PONV. It has a slow onset of action and consequently the recommendation is to administer it immediately following induction of anesthesia. Although the mechanism of action is not completely known, it is thought that steroids inhibit prostaglandin synthesis centrally or lead to endorphin release. The Society for Ambulatory Anesthesia (SAMBA) guidelines endorse the use of 4 to 5 mg of dexamethasone, whereas other studies have determined that higher doses (8 mg) are more effective. 7,8 There seems to be no clinical toxicity associated with the use of dexamethasone for PONV prophylaxis. Dopamine Antagonists There are several groups of drugs that are dopamine antagonists. The two most common in the

4 450 Keyes class of butyrophenones are droperidol and haloperidol. In addition to blocking D 2 receptors, these drugs cause alpha blockade, which can lead to sedation and extrapyramidal symptoms, although not commonly at the small doses given for PONV prophylaxis (0.625/1.25 mg). The efficacy of droperidol as a cost-effective antiemetic has been well established. It would be considered by many anesthesia providers to be first-line therapy if not for the black-box warning imposed by the FDA in The concern regarding prolongation of the QT interval has been implicated in the development of torsades de pointes; although evidence of this effect with small antiemetic doses is lacking. Most other currently available antiemetics also cause QT prolongation, including the phenothiazines, antihistamines, and the 5- HT3-RA, ondansetron. Hypothermia and the duration of general anesthesia are also associated with QT prolongation. There has been a drastic decline in the use of droperidol since this warning. In our institution, droperidol use is limited to high-risk patients who will have cardiac monitoring for at least 2 hours from the time of drug administration. Although effective, haloperidol can only be given by the intramuscular route because of similar concerns of cardiac dysrhythmia. The phenothiazines, promethazine (Phenergan) and prochlorperazine (Compazine) are commonly used antiemetics. Because of numerous adverse effects such as agitation, somnolence, and extrapyramidal effects, their use is not considered first-line therapy. A retrospective review comparing the efficacy of a repeat dose of ondansetron for established PONV versus 6.25 mg of promethazine showed greater efficacy with promethazine. Higher doses of promethazine did not increase efficacy. 9 This finding supports the recommendations by experts to choose a drug from another class when the first drug fails, because the receptors targeted by the first drug given are already blocked. The use of intravenous promethazine is associated with a small but serious risk of venous thrombosis and inflammation. It is essential to ensure that promethazine is administered slowly in a wellfunctioning intravenous line. Although commonly used, Compazine has not been well studied for effectiveness. The benzamide, metoclopramide, blocks both central and peripheral D 2 receptors. At the commonly used 10-mg dose, numerous studies have failed to show antiemetic efficacy and it is therefore not recommended for PONV prophylaxis. 10 Higher doses may be effective but lead to an unacceptably high incidence of extrapyramidal symptoms. Antihistamines Diphenhydramine (Benadryl) is an H 1 blocker with antiemetic effects at the recommended dose of 1 mg/kg intravenously. Its use in PONV prophylaxis has not been well studied. The anticholinergic side effects of dry mouth, blurred vision, and urinary retention limit its use. Cholinergic Antagonists Scopolamine and atropine block cholinergic muscarinic emetic receptors in the central nervous system. Because of its weaker antiemetic properties and resultant tachycardia, atropine is not used for PONV prophylaxis. Transdermal scopolamine has been shown to be effective as an antiemetic. 11 Its anticholinergic side effects of blurred vision, dry mouth, and restlessness, as well as its 2-hour to 4-hour onset of action, limit its use. It may be useful in combination with other agents in high-risk patients and in the prevention of PDNV. MANAGEMENT STRATEGIES The IMPACT study established that the three most commonly used antiemetics, ondansetron 4 mg, dexamethasone 4 mg, and droperidol 1.25 mg, are equally effective for PONV prophylaxis. 6 Various combinations of these three interventions were examined and each antiemetic was found to act independently and to reduce risk by about 26%. It was also shown that the efficacy of these drugs is primarily dependent on the baseline risk rather than on which antiemetic was given. The first antiemetic has the greatest impact on reducing risk; additional antiemetics in a combination regimen add less and less benefit as the baseline risk decreases, as shown in Table 1. Also shown in the table is that those with the greatest risk benefit the most from PONV prophylaxis, whereas those with already low risk, benefit little. For example, a patient with no risk factors has a 10% baseline risk for PONV. If this patient receives 1 intervention, the risk for PONV is reduced only to about 7%, which demonstrates why prophylaxis is not generally recommended in this group of patients (Fig. 2). Low Risk These patients have 0 to 1 risk factor for PONV. A reasonable approach to these patients is to either use a single antiemetic agent or none at all if the procedure is short, not invasive, and there are no serious medical or surgical consequences to consider. Dexamethasone and the 5-HT3-RA are considered first-line therapy. Because dexamethasone is not immediately effective, it should be

5 Postoperative Nausea and Vomiting 451 Table 1 Estimated PONV incidence as a function of baseline risk, assuming each intervention reduces relative risk by 26% (values given as %) given following induction. Ondansetron (or other 5- HT3-RAs) are reserved for rescue treatment; this group of drugs is effective for established PONV. 12 Intermediate Risk Number of Interventions None a One Two Three Four a The baseline risk levels of 10%, 20%, 40%, 60%, and 80% reflect 0, 1, 2, 3, and 4 risk factors considered in a simplified risk score. From Apfel CC, Korttila K, Abdalla M, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med 2004;350:2449; with permission. These patients have 2 to 3 risk factors. For example, a nonsmoking woman has 2 risk factors from the outset. Female gender is the strongest risk factor for PONV and the risk persists long after menopause. It is generally recommended that patients with intermediate risk have at least 2 interventions. These interventions could be either combination antiemetics, such as dexamethasone and a 5-HT3-RA, or a propofol-based anesthetic with dexamethasone. Measures to minimize opioid use, such as the use of local anesthetics when appropriate and nonnarcotic analgesics (Ketorolac or Ofirmev), reduce risk. If ondansetron (or other 5-HT3-RA) has been used during the course of anesthesia and the patient develops PONV in the PACU (postanesthesia care unit), a drug from another class should be chosen because the serotonin receptors are already blocked. Promethazine at a dose of 6.25 mg may be used as rescue therapy in this case. 9 Droperidol could also be given if the patient can be monitored on a cardiac monitor for 2 hours. A second dose of ondansetron can be given if 4 to 6 hours have passed since the initial dose. High Risk Patients with 3 or 4 risk factors require a multimodal approach because no combination of 2 or even 3 antiemetics eliminates the possibility of developing PONV. Scuderi and colleagues 13 introduced the concept of multimodal therapy in high-risk patients, which included propofol and remifentanil intravenous anesthesia (TIVA), dual antiemetic prophylaxis with droperidol (0.625 mg) and dexamethasone (10 mg), ketorolac, hydration with 25 ml/kg total fluids, and 1 mg ondansetron at the end of the case. Only 1 patient required treatment of nausea in Fig. 2. Risk factors and PONV management strategy.

6 452 Keyes the PACU and this was treated with 12.5 mg of diphenhydramine. This study was able to show that it is possible to decrease PONV to a low level in high-risk patients but it requires the increased expertise needed to perform TIVA rather than the relative ease of providing general anesthesia with a vaporizer. PDNV In a recently published prospective multicenter study of ambulatory surgery patients having general anesthesia, Apfel and colleagues found a remarkably high incidence of 37% for nausea and/or vomiting following discharge. This is in contrast to the approximately 21% of the same group having nausea and/or vomiting in the PACU. 4 They found 5 independent risk factors for PDNV: female gender, age less than 50 years, history of PONV, opioids administered in the PACU, and nausea in the PACU. These risks factors are similar to those found to predict PONV. The most significant finding is that patients who experience nausea in the PACU have a 3-fold higher risk for developing PDNV. Ondansetron administered during surgery and a TIVA with propofol are not protective for PDNV because of the short half-lives of both of these drugs. The agents or combinations of agents that will prove useful in PDNV prevention remain unclear at this time. In the study by Apfel and colleagues, 4 dexamethasone significantly reduced PDNV. The first FDA-approved neurokinin-1 receptor antagonist aprepitant (Emend) has been found to be superior to ondansetron in the prevention of vomiting in the first 24 to 48 hours following surgery. 14 Aprepitant is well tolerated and comes in oral and intravenous forms that may be useful when other agents have failed. The second-generation 5-HT3-RA palonosetron has a significantly longer half-life than ondansetron and consequently may be efficacious in reducing PDNV. SUMMARY Identifying those patients with the highest risk leads to the greatest success in reducing PONV by modifying the anesthetic plan to decrease baseline risk, and implementing the appropriate use of prophylaxis. The strategies that will be effective in the reduction of PDNV are currently under investigation. REFERENCES 1. Kapur PA. The big little problem [editorial]. Anesth Analg 1991;73: Gan T, Sloan F, Dear G, et al. How much are patients willing to pay to avoid postoperative nausea and vomiting? Anesth Analg 2001;92: Gan TJ, Meyer T, Apfel CC, et al. Consensus guidelines for managing postoperative nausea and vomiting. Anesth Analg 2003;97: Apfel CC, Philip BK, Cakmakkaya OS, et al. Who is at risk for postoperative nausea and vomiting after ambulatory surgery? Anesthesiology 2012;117: Apfel CC, Läärä E, Koivuranta M, et al. A simplified risk score for predicting postoperative nausea and vomiting: conclusions from cross-validations between two centers. Anesthesiology 1999;91(3): Apfel CC, Korttila K, Abdalla M, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med 2004;350: Gan TJ, Meyer T, Apfel CC, et al. Society for ambulatory anesthesia guidelines for the management of postoperative nausea and vomiting. Anesth Analg 2007;105: Elhakim M, Nafie M, Mahmoud K, et al. Dexamethasone 8 mg in combination with ondansetron 4 mg appears to be the optimal dose for the prevention of nausea and vomiting after laparoscopic cholecystectomy. Can J Anaesth 2002; 49(9): Habib AS, Reuveni J, Taguchi A, et al. A comparison of ondansetron with promethazine for treating postoperative nausea and vomiting in patients who received prophylaxis with ondansetron: a retrospective database analysis. Anesth Analg 2007;104(3): Henzi I, Walder B, Tramer MR. Metochlopramide in the preventions of postoperative nausea and vomiting: a quantitative systematic review of randomized placebo-controlled studies. Br J Anaesth 1999; 83(5): Carlisle J, Stevenson C. Drugs for preventing postoperative nausea and vomiting. Cochrane Database Syst Rev 2006;(3):CD Kazemi-Kjellberg F, Henzi I, Tramer MR. Treatment of established postoperative nausea and vomiting: a quantitative systematic review. BMC Anesthesiol 2001;1(1): Scuderi PE, James RL, Harris L, et al. Multimodal Antiemetic Management Prevents Early Postoperative Vomiting After Outpatient Laparoscopy. Anesth Analg 2000;91(6): Gan TJ, Apfel CC, Kovac A, et al. A randomized, double-blind comparison of the NK1 antagonist, aprepitant, versus ondansetron for the prevention of postoperative nausea and vomiting. Anesth Analg 2007;105(5):