The Relationship Between Patient Risk Factors and Early Versus Late Postoperative Emetic Symptoms

Paul F. White, PhD, MD, FANZCA Ozlem Sacan, MD Nina Nuangchamnong, MS Tiffany Sun, MS Matthew R. Eng, MS
BACKGROUND: Postoperative nausea and vomiting (PONV) remain common complications after elective surgery. Prophylactic antiemetic drugs are frequently administered to patients with well known risk factors for developing PONV. We designed this prospective observational study to assess the relationship between common patient risk factors for developing PONV and the occurrence of early (0 24 h) versus late (24 72 h) emetic symptoms. METHODS: One hundred thirty patients undergoing elective laparoscopic (n 88) or plastic (n 42) surgery were assigned a risk score for developing PONV based on the Apfel risk scoring system, which assigns one point each for female gender, nonsmoking status, history of PONV or motion sickness, and postoperative opioid use. It was assumed that all patients would receive an opioid analgesic in the postoperative period. The patients received 0, 1, 2, or 3 antiemetic drugs for prophylaxis. The occurrence of nausea, vomiting, and need for rescue antiemetics was assessed at specific time intervals from 0 to 6, 6 24, and 24 72 h after surgery. In addition, the impact of PONV on recovery of normal activities of daily living was assessed using a standardized patient questionnaire. RESULTS: One or more prophylactic antiemetics were administered to 87%, 90%, and 95% of the patients in the two, three, and four Apfel risk-factor groups, respectively. In the presence of three or four risk factors, 2 antiemetics were administered to 56% and 75% of the patients, respectively. Vomiting was reported in 11% and 22% of patients in the three and four risk factor groups compared with 6% in the two risk factor group at 0 6 h, and 13% and 27% (vs 0%) at 6 24 h, respectively. However, in the 24 72 h postoperative period, the incidences of emesis were low and did not differ in the three risk groups (9%, 5%, and 11%, respectively). The occurrence of moderate-to-severe nausea was increased in the higher risk groups at 0 6 h and 6 24 h (19%28% vs 6% and 20%30% vs 9%, respectively). However, the incidences of nausea in the 24 72 h period in the three and four risk factor groups were not different from the two-risk factor group (5% and 8% vs 6%, respectively). The need for rescue antiemetics and interference of emetic symptoms with normal activities was greater in the four risk factor group compared with the two and three risk factor groups. CONCLUSION: Despite the frequent use of multiple antiemetic drugs for prophylaxis, an Apfel risk score of three or four (vs 2) was associated with a higher incidence of emetic sequelae in the first 24 h after surgery. However, the occurrence of late (24 72 h) emetic symptoms was low and appeared to be unrelated to the patients Apfel risk score.
(Anesth Analg 2008;107:459 63)

ostoperative nausea and vomiting (PONV) is a long-standing problem for anesthesia practitioners.1

From the Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, Texas. Accepted for publication April 4, 2008. Dr. Paul F. White, Section Editor for Special Project, was recused from all editorial decisions related to this manuscript. Supported by endowment funds from the Margaret Milam McDermott Distinguished Chair in Anesthesiology, and UT Southwestern Medical Student Summer Research Program, and the White Mountain Institute, a non-for profit private foundation (Dr. P.F.W., President). Address correspondence and reprint requests to Dr. Paul F. White, PhD, MD, FANZCA, Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9068. Address e-mail to paul.white@utsouthwestern.edu. Copyright 2008 International Anesthesia Research Society
DOI: 10.1213/ane.0b013e31817aa6e4

The incidence of PONV remains high despite the frequent use of prophylactic antiemetics (e.g., 5-HT3 antagonists, glucocorticoids, dopamine antagonists), shorter-acting anesthetics and analgesics (e.g., propofol, desflurane, remifentanil), and less invasive surgical techniques (e.g., laparoscopic procedures). Patient, anesthetic and surgical factors all contribute to the persistently frequent incidence of emetic symptoms in the postoperative period.1 With the increasingly emphasis on earlier mobilization and discharge (fasttracking) after both minor and major operations,2 postural hypotension and oral opioid containing analgesics may become more important contributors to PONV. In a recent analysis of factors influencing postanesthesia recovery, Edler et al.3 reported that the number of episodes of PONV contributes significantly to prolonging the patients length of stay in the hospital.
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Use of antiemetic prophylaxis has been shown to improve patient satisfaction and speed of recovery compared to simply treating the symptoms when they occur in the postoperative period.4 6 Therefore, antiemetic drugs are now commonly administered both at the start and end of surgery to patients considered to be at increased risk of developing PONV.7 In fact, combinations of antiemetic drugs are now routinely administered as part of a multimodal strategy for reducing postoperative emetic symptoms in at risk patient populations.8 10 Apfel et al.11 have developed a simplified scoring system which has favorable discriminating and calibrating properties for predicting an individual patients risk for developing PONV.12 This prospective observational study was designed to assess the relationship between the patients Apfel risk score for developing PONV and the occurrence of early ( 24 h) and late (24 72 h) emetic symptoms in at risk surgical populations receiving frequent multimodal antiemetic prophylaxis.

METHODS
One hundred thirty healthy patients (18 75 yr) undergoing major laparoscopic (n 88) or plastic (n 42) surgery under general anesthesia were enrolled in this IRB-approved prospective observational study after obtaining written, informed consent. Patients were excluded from this study if they had received any antiemetic medications within 24 h of their surgery, had any unstable preexisting medical conditions, received an investigational medication within 30 of their surgery, or had a recent ( 6 mo) history of alcohol or drug abuse. All patients entered into this study were expected to receive postoperative opioid analgesics, and had at least one additional risk factor (i.e., minimum Apfel score of two). Patients with an Apfel score of three or four were considered to be at high risk for developing PONV. All patients received a standardized general anesthetic technique consisting of IV midazolam 20 g/kg, for premedication; propofol 12 mg/kg, fentanyl 12 g/kg, and rocuronium 0.6 0.8 mg/kg IV for induction, and desflurane 4% 8% inspired in a 50:50 air:oxygen mixture for maintenance of anesthesia. Residual neuromuscular blockade was reversed at the end of surgery with a combination of neostigmine 2 4 mg IV, and glycopyrolate, 0.4 0.6 mg IV. Antiemetic prophylaxis was administered at the discretion of the attending anesthesiologist, and when administered, consisted of one or more of the following IV medications: ondansetron 4 mg, dexamethasone 4 mg, and/or droperidol 0.625 mg. In the postanesthesia care unit (PACU), pain relief was initially provided with fentanyl, 2550 g IV. In the postdischarge period, patients were prescribed oral opioidcontaining analgesics (e.g., Lortab or Vicodin) to treat moderate-to-severe pain. Ondansetron, 4 mg IV, was
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administered as the initial rescue antiemetic medication in the PACU (unless it had been used for antiemetic prophylaxis). Promethazine, 12.5 mg IV, was used as the rescue antiemetic if ondansetron failed to prevent (or relieve) early postoperative emetic symptoms. Prochlorperazine suppositories were prescribed for treating PONV in the postdischarge period. An emetic episode was defined as any number of vomits (or retches) in a single 5 min period or a sequence of vomits in close succession not relieved by a 2 min period of relaxation. If the patient complained of nausea at any of the assessment intervals, they were asked to quantify the severity of the nausea using a four-point Likert scale, with 0 none, 1 mild, 2 moderate, 3 severe. If the patient complained of moderate-to-severe nausea lasting 15 min or experienced repeated episodes of emesis (or retching), they were given the option of receiving a rescue antiemetic. Rescue antiemetic drugs were administered by the PACU and short-stay unit nurses who were unaware of the patients Apfel risk scores. Follow-up evaluations were performed by one of the investigators at 24, 48, and 72 h intervals after surgery to inquire about the occurrence of emetic symptoms and need for rescue analgesic and/or antiemetic medications. Using a structured questionnaire format, all patients were asked if the occurrence of PONV had any impact on their ability to resume normal activities of daily living (e.g., ability to consume liquids and solid food, ambulate without assistance). Simple yes or no responses to the questions were recorded). At the time of discharge, patients were instructed to contact the investigator directly if they experienced any emetic symptoms after discharge from the hospital and were prescribed prochlorperazine suppositories if their emetic symptoms persisted. In evaluating these outcome data, patients were assigned to one of three risk groups based on their simplified Apfel score.11 This validated risk scoring system assigns one point for each of the following factors: 1) female gender, 2) nonsmoking status, 3) history of PONV or motion sickness, and 4) use of opioid analgesics in the postoperative period. Data are presented as means ( sd) for continuous data or relative and absolute frequencies for discrete (categorical) data. For statistical analysis, Fishers exact test was used to analyze all categorical data. A significant difference was defined as a P value 0.05 when comparing data from the three different risk factor groups.

RESULTS
Patient demographic characteristics are summarized in Table 1. Demographic characteristics for patients with two risk factors were significantly different from those in the Apfel three or four risk factor groups (e.g., larger proportion of women, nonsmokers and nondrinkers, history of PONV, and motion sickness).
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Table 1. Demographic and Baseline Characteristics of Patients with 2, 3 or 4 Risk Factors for Developing Postoperative Nausea and Vomiting (PONV) According to the Apfel Scoring System11,12a Risk factors for PONVb Two (n
Mean age, range (yr) Sex (M/F) (n) No smoking history (%) No alcohol consumption (%) History of PONV (%) History of motion sickness (%) Mean anesthesia time (min) Mean surgery time (min)

32)

Three (n
48 (3264) 16/45c 60 54c 20c 21c 177 92 157 87

61)

Four (n

37)

51 (3268) 4/28 50 19 3 3 165 79 148 31

54 (4167) 1/36c 73c 43c 68c 62c 146 86 130 71

M male; F female. a Values are means (range or SD), numbers (n), or percentages (%). b Apfel scoring system (4 points): 1) female gender, 2) history of PONV or motion sickness, 3) non-smoking status, 4) use of postoperative opioid analgesics. c P 0.05 vs 2 risk factor group.

Table 2. Use of Prophylactic Antiemetics and Incidences of Postoperative Vomiting or Retching and Moderate-to-Severe Nausea, as well as Requirement for Rescue Antiemetic Drugs And Interference of Postoperative Nausea and Vomiting (PONV) in Return to Normal Activities in The Three Risk Groupsa Risk factors for PONV (n)c Two (n
Prophylactic antiemetics (n, %) Zero One Two Three Vomiting or retching (n, %) 06 h interval 624 h interval 2472 h interval Moderate-severe nausea (n, %)c 06 h interval 624 h interval 2472 h interval Rescue antiemetic administered (n, %) 06 h interval 624 h interval 2472 h interval Emetic symptoms interfered with normal activities (n, %) 06 h interval 624 h interval 2472 h interval
a

32)

Three (n
6, 10 21, 34 15, 25 19, 31 7, 11 8, 13 3, 5 17, 28b 12, 20 3, 5 12, 20 9, 15 5, 8 5, 8 8, 13 3, 5

61)

Four (n
2, 5b 7, 19 6, 16 22, 59b 8, 22b 10, 27b 4, 11 7, 19 11, 30b 3, 8 8, 22b 12, 32b 7, 19 6, 16b 12, 32b 4, 11

37)

4, 13 19, 59 5, 16 4, 13 2, 6 0, 0 3, 9 2, 6 3, 9 2, 6 4, 13 2, 6 3, 9 1, 3 0, 0 3, 9

Values are numbers (n), percentages (%). P 0.05 vs 2 risk factors. c Nausea severity scale: 0 none, 1 mild, 2
b

moderate, 3

severe.

All patients received opioid analgesics in the postoperative period. Prophylactic antiemetics were administered to 88%, 90% and 95% of the patients in the two, three, and four risk factor groups, respectively (Table 1). Of importance, 2 antiemetic drugs were administered to 29%, 56% and 75% of the patients with two, three, and four risk factors, respectively. However, 44% and 24% of the patients in the three and four risk groups, respectively, received one (or zero) prophylactic antiemetic drugs (Table 2). Postoperative vomiting was reported in 11% and 22% in the three and four risk factor groups, respectively, compared to only 6% in the two risk factor group during the early (0 6 h) postoperative period
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(Table 2). The occurrence of moderate or severe nausea at 0 6 h was also more frequent in the two higher risk groups (28 and 19% vs 6%, respectively). Requirements for rescue antiemetic in the 0 6 h postoperative period were 13%, 20%, and 22% in the two, three, and four risk factor groups, respectively. All the patients in the three and four risk factor groups who required rescue antiemetics received either no or only one prophylactic antiemetic drug. In the first 24 h after surgery, symptoms of vomiting (6%, 24%, and 49%), moderate-to-severe nausea (15%, 48%, and 49%), and the need for rescue antiemetics (19%, 35%, and 54%) increased in proportion to the number of Apfel risk factors (i.e., two, three, and
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four, respectively). However, in the late (24 72 h) postoperative period, there was no apparent relationship between PONV symptoms and the number of Apfel risk factors (Table 2). Importantly, the incidence of PONV varied from only 5% to 11% during the late recovery period (24 72 h). In assessing the percentage of patients who reported that PONV negatively impacted upon their recovery within the first 24 h after surgery, a greater impact was observed in the groups with higher risk scores (21 and 48 vs 3% in the 3 and 4 vs 2 risk factor groups, respectively). In the late recovery period (24 72 h), there were no significant differences among the three risk factor groups with respect to any of the outcome measures (Table 2).

DISCUSSION
These prospective data suggest that PONV remains a common problem for high-risk surgical populations despite the frequent use of two or more antiemetic drugs for prophylaxis. Multimodal approaches involving the use of two or more prophylactic antiemetic drugs, avoiding highly emetogenic anesthetics and analgesics, and insuring adequate hydration are strongly recommended for all patients at increased risk of developing PONV.8 10 The use of multimodal strategies has assumed increased importance in the current health care environment in order to facilitate a fast-track recovery after surgery.2 Apfels simplified risk scoring system11 has been shown to provide clinically useful information for predicting PONV within 24 h after surgery in patients not receiving prophylactic antiemetic drugs.12 Compared to predicting a patients risk for PONV based on a history of PONV or the type of surgery alone, the use of this simplified risk scoring system has been found to be more sensitive and specific.13 In fact, a study confirmed that administering prophylactic antiemetics to high-risk patients using this simplified scoring system reduced institutional rates of PONV.14 However, the utility of the Apfel scoring system for predicting early ( 24 h) and late (24 72 h) emetic symptoms has not been examined in patients receiving multimodal antiemetic prophylaxis. Despite the frequent use of prophylactic antiemetics in our at-risk study population, the Apfel scoring system was highly predictive of emetic symptoms within 24 h after surgery. However, these data failed to find a correlation between the incidence of late PONV ( 24 h after surgery) and patients Apfel risk score. This finding may reflect the lower than expected incidence of PONV symptoms during the 24 72 h postoperative evaluation interval (due to the frequent use of prophylactic antiemetics and rescue treatment in the pre-discharge period). The incidence of late PONV in our study is less than the 35% incidence reported by Carroll et al.,15 but similar to the findings in the systematic literature review by Wu et al.16
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Another factor which may explain the lack of differences among the three risk factor groups in the 24 72 h period is the potentially confounding effect of patients self-administering oral opioid-containing analgesics in the post-discharge period.10 It has been suggested that the use of oral opioid-containing analgesics may be a significant contributing factor to postdischarge nausea and vomiting.2 Post-discharge nausea and vomiting remains common after outpatient (and short-stay) surgery, and contributes to significant patient distress and can impair resumption of normal activities of daily living.15,16 Although more than 60% of the high-risk patients (with three or four risk factors) in our study received multiple ( 2) antiemetic medications for prophylaxis, most of these patients still required a rescue antiemetic in the postoperative period. More than 25% of the lower risk patients (with only two risk factors) also required a rescue antiemetic even though that over 80% of these patients received at least one prophylactic antiemetic drug. In contrast to the recommendation of Apfel et al.,13,14 these data suggest that even lower risk patient populations (e.g., those with two risk factors) may benefit from multimodal antiemetic prophylaxis if they are undergoing major laparoscopic or plastic surgery procedures. Surprisingly, 24% of the patients in the highest risk group received either nothing or only one antiemetic drug for prophylaxis. A major deficiency in this observational study was related to the fact that the use of prophylactic antiemetic therapy was left to the discretion of the anesthesiologist. However, this study was designed to evaluate current antiemetic practices in two higherrisk surgical populations, and to assess whether individual patient risk information provided by the Apfel risk scoring system would have predictive value despite the frequent use of prophylactic antiemetic drugs. A second deficiency of this analysis relates to the fact that we only included patients with two or more risk factors. However, we would agree with Apfel et al.17 that patients with 0 1 risk factors are less likely to benefit from the routine use of prophylactic antiemetics. Finally, our failure to quantify the amount of perioperative fluid administered and the number of oral opioid-containing analgesics consumed in the post-discharge period are also deficiencies in the study design. Although prophylaxis per se does not alter the predictive value of the Apfel risk criteria for early PONV, these data suggest that there remains a need to develop improved antiemetic and anti-nausea therapeutic regimens which are effective during both the early postoperative period, as well as after the patient has been discharged home. Although the use of allegedly longer-acting antiemetics (e.g., aprepitant, palonosetron, transdermal scopolamine)18 21 for prophylaxis might be capable of providing greater protection against emetic symptoms in the post-discharge period,
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additional well-controlled studies are needed to support their use in routine clinical practice.22 In conclusion, the Apfel risk scoring system was predictive of PONV within 24 h after surgery even in the presence of multimodal antiemetic prophylaxis. However, the Apfel risk score was not predictive of post-discharge emetic symptoms. The inability to discriminate among the various risk groups after 24 h may be related to the low incidence of emetic symptoms (5%11% at 24 72 h), and the confounding effect of oral opioid analgesic medications in the postdischarge period. We conclude that pharmacological management of PONV should be tailored to the patients risk level using the Apfel scoring system to minimize the potential for adverse side effects in the postoperative period. REFERENCES
1. Watcha MF, White PF. Postoperative nausea and vomiting: its etiology, treatment and prevention. Anesthesiology 1992;77: 162 84 2. White PF, Kehlet H, Neal JM, Schricker T, Carr DB, Carli F, Fast-Track Surgery Study Group. The expanding role of anesthesiology in fast-track surgery: from multimodal analgesia to perioperative medical care. Anesth Analg 2007;104:1380 96 3. Edler AA, Mariano ER, Golianu B, Kuan C, Pentcheva K. An analysis of factors influencing postanesthesia recovery after pediatric ambulatory tonsillectomy and adenoidectomy. Anesth Analg 2007;104:784 9 4. Tang J, Wang B, White, PF, Watcha MF, Qi J, Wender RH. The effect of timing on ondansetron administration on its efficacy, cost-effectiveness, and cost-benefit as a prophylactic antiemetic in ambulatory setting. Anesth Analg 1999;88:11912 5. Sadhasivam S, Saxena A, Kathirvel S, Kannan TR, Trikha A, Mohan V. The safety and efficacy of prophylactic ondansetron in patients undergoing radical mastectomy. Anesth Analg 1999;89:1340 5 6. Sennaraj B, Shende D, Hadhasivam S, Ilavajady S, Jagan D. Management of post-strabismus nausea and vomiting in children using ondansetron: a value-based comparison of outcomes. Br J Anaesth 2002;89:473 8 7. White PF, Watcha MF. Postoperative nausea and vomiting; prophylaxis versus treatment. Anesth Analg 1999;89:11379 8. Scuderi PE, James RL, Harris L, Mims GR. Multimodal antiemetic management prevents early postoperative vomiting after outpatient laparoscopy. Anesth Analg 2000;91:1408 14 9. Habib AS, White WD, Eubanks S, Pappas TN, Gan TJ. A randomized comparison of multimodal management strategy versus combination antiemetics for the prevention of postoperative nausea and vomiting. Anesth Analg 2004;99:77 81

10. White PF. Prevention of postoperative nausea and vomiting- a multimodal solution to a persistent problem. N Engl J Med 2004;350:25112 11. Apfel CC, Laara E, Koivuranta M, Greim CA, Roewer N. A simplified risk score for predicting postoperative nausea and vomiting: conclusions from cross-validations between two centers. Anesthesiology 1999;91:693700 12. Pierre S, Benais H, Pouymayou J. Apfels simplified score may favourably predict the risk of postoperative nausea and vomiting. Can J Anaesth 2002;49:237 42 13. Apfel CC, Kranke P, Eberhart LHJ. Comparison of surgical site and patients history with a simplified risk score for the prediction of postoperative nausea and vomiting. Anaesthesia 2004;59:1078 82 14. Biedler A, Wermelt J, Kunitz O, Muller A, Wilhelm W, Dethling J, Apfel CC. A risk adapted approach reduces the overall institutional incidence of postoperative nausea and vomiting. Can J Anaesth 2004;51:139 15. Carroll NV, Miederhoff P, Cox FM, Hirsch JD. Postoperative nausea and vomiting after discharge from outpatient surgery centers. Anesth Analg 1995;80:9039 16. Wu CL, Berenholtz SM, Pronovost PJ, Fleisher LA. Systematic review and analysis of postdischarge symptoms after outpatient surgery. Anesthesiology 2002;96:994 1003 17. Apfel CC, Bacher A, Biedler A, Danner K, Danzeisen O, Eberhart LH, Forst H, Fritz G, Hergert M, Frings G, Goebel A, Hopf HB, Kerger H, Kranke P, Lange M, Mertzlufft F, Motsch J, Paura A, Roewer N, Schneider E, Stoecklein K, Wermelt J, Zernak C. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. Anaesthesist 2005;54:2019 18. Tang J, DAngelo R, White PF, Scuderi PE. The efficacy of RS-25259, a long-acting selective 5-HT3 receptor antagonist, for preventing postoperative nausea and vomiting after hysterectomy procedures. Anesth Analg 1998;87:4627 19. Gesztesi Z, Scuderi PE, White PF, Wright W, Wender RH, DAngelo R, Black LS, Dalby PL, MacLean D. Substance P (Neurokinin-1) antagonist prevents postoperative vomiting after abdominal hysterectomy procedures. Anesthesiology 2000;93:9317 20. White PF, Tang J, Song D, Coleman JE, Wender RH, Ogunnaike B, Sloninsky A, Kapu R, Shah M, Webb T. Transdermal scopolamine: an alternative to ondansetron and droperidol for the prevention of postoperative emetic symptoms. Anesth Analg 2007;104:92 6 21. Gan TJ, Apfel CC, Kovac A, Philip BK, Singla N, Minkowitz H, Habib AS, Knighton J, Carides AD, Zhang H, Horgan KJ, Evans JK, Lawson FC, Aprepitant-PONV Study Group. A randomized, double-blind comparison of the NK1 antagonist, aprepitant, versus ondansetron for the prevention of postoperative nausea and vomiting. Anesth Analg 2007;104:10829 22. Glass PS, White PF. Practice guidelines for the management of postoperative nausea and vomiting: past, present, and future. Anesth Analg 2007;105:1528 9

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