Clinical Tberapeudcs/Volume 27, Number 6, 2005

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1 Clinical Tberapeudcs/Volume 27, Number 6, 2005 Effects of Dexamethasone in Preventing Postoperative Emetic Symptoms After Total Knee Replacement Surgery: A Prospective, Randomized, Double-Blind, Vehicle-Controlled Trial in Adult Japanese Patients Yoshitaka Fujii, MD; and Masahiro Nakayama, MD Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, Tsukuba, Japan ABSTRACT Background: Postoperative emetic symptoms (nausea, retching, and vomiting) are common following total joint replacement, with an incidence as high as 83% when no prophylactic antiemetic is provided. However, most antiemetics currently used in Japan, such as antihistamines (eg, hydroxyzine), butyrophenones (eg, dropefidol), and dopamine receptor antagonists (eg, metoclopramide), have been associated with adverse effects (AEs), such as excessive sedation, hypotension, dry mouth, dysphoria, hallucinations, and extrap/ramidal symptoms. Objective The aim of this study was to assess the efficacy and tolerabifity of 3 doses of intravenous dexamethasone monotherapy versus vehicle in preventing emetic symptoms after total knee replacement performed under combined general and epidural anesthesia. Methods: This prospective, randomized, doubleblind, vehicle-controlled trial was conducted at the Department of Anesthesiology, University of Tsul<uba Institute of Clinical Medicine, Tsukuba, Japan. Adult Japanese patients scheduled to undergo total knee replacement were eligible. Patients were randomly as. signed to 1 of 4 treatment groups: dexamethasone 4, 8, or 16 mg, or vehicle (control). Patients received combination anesthesia with sevoflurane and nitrous oxide in pure oxygen (general) and lidocaine (epidural). Study drugs were administered intravenously after the completion of surgery. An investigator blinded to treatment assignment monitored patients for emetic symptoms for 24 hours after the patient awoke. Patients rated their satisfaction with the study drug using a linear, 11-point scale (0 = complete satisfaction to 10 = complete dissatisfaction). Tolerability was as. sessed by the study investigator using spontaneous reporting and patient interview. Results: A total of 80 patients were enrolled (58 women, 22 men; mean [SD] age, 59 [10] years; mean [SD] height, 154 [7] cm; rrcan [SD] body weight, 55 [7] leg; 20 patients per treatment group). The demographic, clinical, and surgical data were comparable between the 4 treatment groups. The rates of emesis`free patients were 35% (7 patients), 70% (14), and 75% (15) with dexamethasone 4, 8, and 16 rag, respectively, compared with 30% (6) with vehicle (P = NS, 0.013, and 0.005, respectively). Median (range) patient satisfaction scores were significantly higher in the groups receiving dexamethasone 8 and 16 rng (both, 0.0 [0-9]) compared with controls (6.0 [0-10]) (P = and 0.008, respectively). This effect was not found with the 4--rag dose. No clinically serious AEs attributed to the study drug were observed in any of the 4 treatment groups. Condusions: In this study of a small, select group of adult Japanese patients undergoing total knee replacement, the rates of emesis-free patients were higher with dexamethasone 8 and 16 mg compared with vehicle 24 hours after anesthesia induction. This effect was not found with the 4-mg dose. All treatments were well tolerated. (CJ/n Tber ,27: ) Cop/- right 2005 Excerpta Medica, Inc. Key words: complications, nausea, vomiting, antiemetics, dexamethasone, knee. INTRODUCTION Postoperative emetic symptoms (nausea, retching, and vomiting) are common following total joint replace- A~I [orpubli~tion ~ 4, doi: /j.clinchera.200S Primed in the USA. Reproduction in whole or part is no{ permitted. Copyright 2005 Excerlxa Medica, Inc. 740 Volume 27, Number 6

2 Y. Fujii and M. N~lmy~ma meat, with an incidence as high as 83% (worldwide) when no prophylactic antiemetic is provided, l,z However, most antiemetics currently used in Japan, such as antihistamines (eg, hydroxyzine), butyropbenones (eg, droperidol), and dopamine receptor antagonists (eg, metoclopramide), have been associated with adverse effects (AEs), such as excessive sedation, hypotension, dry mouth, dysphoria, hallucinations, and extrapyramidal symptoms.; Ondansetron is a selective serotonin receptor antagonist used for preventing emetic symptoms following joint replacement. 4 However, several investigations have criticized ondansetron use because of its high cost (3-rag dose, US $100.30). s.6 In fact, the use of ondansetron is limited in Japan due to its cost. At the University of Tsuknba Institute of Clinical Medicine, Tsukuba, Japan, the less-expensive corticosteroid dexamethasone is most commonly used for preventing postoperative emetic symptoms (cost of a comparable 8-rag dose, US $5.30). 7 In a meta-analysis of 17 studies (1946 patients) of dexamethasone, Henzi et als concluded that dexamethasone at doses of 8 to 10 mg in adults and 1.0 to 1.5 mg/kg in children was efficacious. A MEDLINE search (key terms: complications, nausea, vomiting, antiemetics, dexametbasone, and knee; years: ) revealed no studies of dexamethasone in the prevention of emetic symptoms following total knee replacement, and no consensus guidelines for managing postoperative emetic symptoms in Japanese patients. Thus, the aim of this study was to assess the efficacy and tolerability of 3 doses of intravenous dexamethasone versus vehicle in preventing emetic symptoms in adult Japanese patients undergoing total knee replacement performed under combined general and epidural anesthesia. PATIENTS AND METHODS This prospective, randomized, double-blind, vehiclecontrolled trial was conducted at the Department of Anesthesiology, University of Tsukuba Institute. The study protocol was approved by the institutional ethics committee at the university, and verbal informed consent was obtained from all study patients. Inclusion and Exclusion Criteria Japanese patients aged ~18 years who were American Society of Anesthesiologists physical status I (no organic, physiologic, biochemical, or psychiatric disturbance) 9 or II (mild to moderate systemic disturbance that may or may not be related to the reason for surgery) 9 and scheduled to undergo elective total knee replacement surgery were eligible. Patients with a history of gastrointestinal disease, motion sickness, and/or postoperative emesis were excluded. Patients who had received an antiemetic agent within 24 hours before surgery also were excluded. Pregnant, possibly pregnant, and breastfeeding patients were excluded, as were patients who were menstruating on the day of surgery. Study Drug Administration Using a computer-generated fist of random numberg patients were assigned to 1 of 4 treatment groups: dexamethasone 4, 8, or 16 rag, or vehicle. Study drugs were administered intravenously by an orthopedic surgeon at the completion of surgery. To maintain blinding of the investigators, study drugs were administered using identical syringes prepared by personnel not involved in the study. If the volume to be administered was <4 ml, isotonic saline solution was added to achieve a total volume of 4 ml. Anesthesia Induction and Surgical Procedures To maintain the integrity of the study results, antiemetic agents other than the study drugs were not permitted. Patient monitoring consisted of electrocardiography, nonmvasive arterial blood pressure measurement, and pulse oximetry. An epidural catheter was inserted at the level of L1-2 or I..2-3 and was placed cephalad (-5 cm). Correct placement was confirmed by the administration of fidocaine 1.5% 2 ml plus epinephrine 10 pg (ie, test dose). Anesthesia was induced using propofol 2 mg/kg IV, and vecuronium 0.2 mg/kg IV was used to facilitate tracheal intuhation. After intuhation, anesthesia was maintained using sevoflurane 1.0% to 3.0% (inspired concentration) and nitrous oxide (N20) 66% in oxygen. Ventilation was mechanically controlled and adjusted to maintain an end-tidal carbon dioxide concentration of 35 to 40 mm Hg throughout surgery, as measured using an anesthetic/respiratory gas analyzer (Ultima, Datex-Ohmeda, Helsinki, Finland). When hemodynamic variables (heart rate and blood pressure) were stable, lidocaine 1.5% 10 to 20 ml was injected through the epidural catheter during surgery. Neuromuscular blockade was achieved using vecuronium, as required. Body temperature was monitored rectally and maintained at 36 C to 37 C throughout surgery using a heating pad. June

3 Clinical Tlm'apma~ At the end of surgery, sevoflurane and NzO administration was discontinued, and atropine 0.02 ms/kg IV and neostigmine 0.04 mg/kg IV were administered for reversal of muscle relaxation. The trachea was extubated when the patient awoke. For postoperative analgesia, a continuous epidural infusion of combination bupivacaine 0.125% 100 ml plus morphine 0.1 mg/kg was started at a rate of 2 ml/h through a balloon catheter. Patients whose pain was perceived as intolerable were allowed to receive indomethacin 50 mg PR (rescue medication). Ffffic.aq Assessment Patients were monitored for emetic symptoms for 24 hours after the patient awoke. An investigator (M.N.) bfinded to treatment assignment asked the patients whether nausea, retching, or vomiting had occurred, with only 2 possible answers (yes or no). Nausea was defined subjectively as an unpleasant sensation combined with an urge to vomit) Retching was defined as the la bored spasmodic, rhythmic contraction of the respiratory muscles without expulsion of gastric contents) Vomiting was defined as a forceful expulsion of gastric contents from the mouth) Vomiting was considered the most severe emetic symptom, followed by retching and nausea. If a patient had >1 emetic symptom, he or she was categorized as having experienced the most severe symptom (vomiting). This categorization has been used in a number of previous reports assessing postoperative emetic symptoms. 1,z,4,7,~ -~3 The primary end point was the rate of emesis-free patients. Patients rated their satisfaction with the study drug at the end of the observation period, using a finear 11- point scale (0 = complete satisfaction to 10 = complete dissatisfaction). Tohrabiliw ~ment The details of any other AEs, obtained by spontaneons reporting and patient interview, were recorded by the study investigator. Sc~ti ~ Analysis Based on previous studies, l,z a sample of 20 patients per treatment group was required to demonstrate a 30% between-group difference in rates of emetic symptoms at an 0~ level of 0.05 and a power (1-~8) of 0.8 (ie, power analysis). Baseline demographic and clinical data were compared between the 4 treatment groups using analysis of variance with the Bonferroni adjustment for mukipie comparisons and the chi-squared test. The incidences of emetic episodes and AEs were compared using the Fisher exact test. Patient satisfaction ratings were analyzed using the Mann-Whitney U test. P < 0.05 was considered statistically significant. RESULTS Study Population Ninety patients were screened to obtain a sample population of 80 patients (58 women, 22 men; mean [SD] age, 59 [10] years; mean [SD] height, 154 [7] crrg mean [SD] body weight, 55 [7] kg; 20 patients per treatment group). No significant differences in demographic, clinical, or surgical data were observed between the 4 treatment groups (Table l). Efficacy The rates of emesis-free patients were 35% (7 patients), 70% (14), 75% (15) with dexamethasone 4, 8, and 16 rag, respectively, compared with vehicle (30% [6]) (P = NS, 0.013, and 0.005, respectively) (Table ll). Median (range) patient satisfaction ratings were higher in patients who received dexamethasone 8 or 16 mg (both, 0.0 [0-9]) compared with those who had received vehicle (6.0 [0-10]) (P = and 0.008, respectively) (Table ill). Tohrability No clinically serious AEs attributed to the study drug were observed in any of the 4 treatment groups. DISCUSSION The incidence of emetic symptoms after total joint replacement surgery varies from 68% to 83% when no prophylactic antiemetic is provided, l,z This incidence justifies the use of prophylactic antiemetics after total joint replacement. The etiology of postoperative emetic symptoms in patients undergoing total joint replacement remains unclear, but is probably multifactorial. ~ A number of factors, including age, sex, obesity, a history of motion sickness and/or postoperative emesis, time after menstrual cycle, type of surgery, anesthetic technique, and postoperative pain, are considered to increase the risk for postoperative emetic symptoms) However, in the present study, patients with a history of motion sickness and/or postoperative emesis were excluded because they had a relatively high risk for postoperative emetic symptoms, 3 and the remaining 742 Volume 27, Number 6

4 . r-ujii and M. Nakayama Table I. Demographic, clinical, and surgical data of the study population (N - 80).* Dexamethasone 4 mg 8 mg 16 mg Vehicle Characteristic (n - 20) (n - 20) (n - 20) (n - 20) Age, y Mean (SD) 60 (10) 57 (10) 61 (9) 57 (11) Range Sex, no. (%) Female 14 (70) 14 (70) 15 (75) 15 (75) Male 6 (30) 6 (30) 5 (25) 5 (25) Height, cm Mean (SO) 153 (10) 152 (12) 151 (11 ) 154 (10) Range Body weight, kg Mean (SO) 54 (7) 55 (8) 54 (7) 53 (5) Range Duration of'surgery, min Mean (SO) 151 (21) 155 (20) 146 (25) 148 (33) Range Duration of anesthesia, min Mean (SD) 185 (27) 172 (23) 175 (25) 178 (29) Range Postoperative analgesic t dose, mg Mean (SD) 5 (2) 5 (2) 5 (1) 5 (1) Range Rescue medicationt use, no. (%) 2 (10) 3 (15) 3 (15) 3 (15) *No significant between-group differences were found. tcondnuous epidural infusion of combination bupivacaine 0.125% 100 ml plus morphine 0.1 mg/kg. $1ndomethacin 50 mg PI~ Table II. Incidence of emetic symptoms after a~.aanent with daxamethasone or vehicle for the prevention of emetic symptoms after total knee replacement surgery (N - 80). Dexamethasone 4 mg (n - 20) 8 mg (n - 20) 16 mg (n - 20) No. of P vs No. of P vs No. of P vs Vehicle Parameter Patients (%) Vehicle Patients (%) Vehicle Patients (%) Vehicle (n - 20) No emetic symptoms 7 (35) (70) (75) (30) Nausea 7 (35) (10) (15) (30) Vomiting 5 (25) (15) (10) (30) Retching 1 (5) (5) (0) (10) June

5 Clinical Table III. I~tient satisfaction (PS) ratings* of clexamethasone versus vehicle in the prevention of emetic symprorns after total knee replacement surgen/(n - 80). Paramecer Median Range Dexamechasone 4 mg (n - 20) 8 mg (n - 20) 16 mg (n - 20) PS P vs PS P vs PS P vs Vehicle Raring Vehicle Raring Vehicle Raring Vehicle (n - 20) *Scale: 0 - complete satisfaction to 10 - complete dissatisfaction. factors were statistically similar between the 4 treatment groups. Therefore, the between-group differences in the incidence of emetic symptoms found in this study can be attributed to the study drug. Dexamethasone is effective for the control of emetic symptoms in patients receiving chemotherapy for cancer. 14 Several investigations have shown that dexamethasone reduces the incidence of emetic symptoms after major gynecologic surgery, 10 laparoscopic cholecystectomy, l t thyroidectomy,12 and pediatric tonsillectomy. t~ The precise antiemetic mechanism of dexamethasone remains unclear, but suggestions include central or peripheral inhibition of the production or secretion of serotonin, is central inhibition of prostaglandin synthesis, 16 and changes in the permeabihty of the blood-brain barrier to serum proteins. 17 The literature search revealed no studies determining the minimum effective dose of dexamethasone for the prevention of emetic symptoms in patients undergoing total knee replacement. In the present study, the rates of emesis-free patients with prophylactic dexamethasone at 8 and 16 mg were lower than with the 4-rag dose and vehicle after total knee replacement, with no clinically important AEs. These results suggest that the 8-rag dose may be effective, and that increasing the dose to 16 mg provides no further chnical benefit. Dexamethasone has not been associated with the sedative, dysphoric, and extrapyramidal AEs associated with the traditional antiemetics droperidol and metoclopramide) However, long-term dexamethasone treatment may cause AEs, such as an increased risk for infection, impaired glucose tolerance, delayed wound heahng, superficial ulceration of the gastric mucosa, and/or adrenal suppression, is These AEs were not found with the single doses of dexamethasone administered in the present study. Clinically serious AEs previously associated with dexamethasone (eg, psychiatric disturbance 18) were not observed in any of the 4 treatment groups. The choice of antiemetics should not only consider patient outcome but also cost. The pharmacy at the University of Tsukuba Institute of Cfinical Medicine pays US $5.30 per 8-rag dose of dexamethasone, which is a bit more expensive than 2 other commonly used and well-estabfished antiemetics, droperidol (US $1.80 for 1.25 rag) and metoclopramide (US $0.60 for 10 rag). However, the use of droperidol or metoclopramide as an antiemetic has been limited worldwide because these drugs have been associated with a low incidence of excessive sedation and/or extrapyramidal signs. 3 The US Food and Drug Administration has issued a warning about the risk for dysrhythmogenic effects with droperidol use, such as a prolonged QT interval. 19 Among the currently used antiemetics, ondansetron is effective for prophylaxis against postoperative emetic symptoms, 4 but its high cost in Japan (US $ for 3 rag) prohibits its clinical appfication. One fimitation of this study was the lack of an active-control group (eg, ondansetron because its use is fimited in Japan due to cost). None of the antiemetics available worldwide are entirely effective, perhaps because most of them act through the blockade of only 1 receptor. Combination therapy with antiemetics with different sites of activity might be more effective than monotherapy for prophylaxis against postoperative emetic symptoms, z In the present study, dexamethasone 8 mg did not completely control postoperative emetic symptoms after 744 Volume 27, Number 6

6 Y, Fujii and M. Nakayama total knee replacement. Further studies are needed to assess the efficacy of combination antiemetic regimens that include dexamethasone and other antiemetics. CONCLUSIONS In this study of a small, select group of adult Japanese patients undergoing total knee replacement, the rates of emesis-free patients with dexamethasone 8 and 16 mg were higher compared with vehicle 24. hours after anesthesia induction. This effect was not found with the 4-mg dose. All treatments were well tolerated. REFERENCES 1, Gan TJ, Alexander R, Fennelly M, Rubin AP. Comparison of'different methods of administering droperidol in Patientcontrolled analgesia in the prevention of postoperative nausea and vomiting. An~sth Anal ;80:81-85, 2. Kauste A, Tuominen M, Heikkinen H, et al. Droperidol, alizapricle and metodopramide in the prevention and treatment of post-operative emetic sequelae. EurJ Ana~t/nsio/. 1986;3: Watcha MF, White PF. Postoperative nausea and vomiting. Its etiology, treatment, and prevention. Anc.~thesi0/0~,. 1992;77: Gan "l'j, Collis R, Hetreed M. Double-blind comparison of ondansetron, droperidol and saline in the prevention of postoperative nausea and vomiting. BrJAna~h. 1994;72: S. White PF, Watcha MF. Are new drugs cost-effective for Patients undergoing ambulatory surgery? Anc.~thesi0/0~,. 1993;78: Lerman J. Are antiemedcs cost-effective for children? C~n J At~cst, h. 1995;42: Liu K, Hsc CC, Chia W. Effect ofdexamethasone on postoperative emesis and pain. BrJ Anaesth. 1998;80: Henzi I, Walder B, Trainer MR. Dexamethasone for the prevention ofpostoparadve nausea and vomiting: A quantitative systematic review. Ane~'h Ano/~. 2000;90: Fleischer LA. Preoperative evaluation. In: Barash PG, Cullen BF, Stoeking RK, eds. C/klk~l An~sthcs~. 3rd ed. Philadelphia, Pa: Lippincorr-Raven; 1996: Uu K, Hsu CC, Chia YY. Effect of dexamethasone on postoperative emesis and pain. BrjAnaesth. 1998;80: Wang 11, Ho ST, Liu YI-I, er al. Dexamethasone reduces nausea and vomiting after laparoscopic cholecystectomy. BrJ Anoesth. 1999;83: Wang JJ, Ho ST, Lee SC, e al. The prophylactic effect of dexamethasone on postoperative nausea and vomiting in women undergoing byroidectomy: A comparison of droperidol with saline. Aeesth Ana/g. 1999;89: Splinter WM, Roberts DJ. Dexamerhasone decreases yoreking by children after tonsillectomy. Anesth AnN$. 1996;83: , 14. Sekine I, Nishiwaki Y, Kakinuma R, er al. Phase II study of high-dose dexamerhasone-based association in acute and delayed high-dose cispladn-induced emesis-jcog study BrJ C~n0er. 1997;76: Fredrikson M, Hursd T, Fursr CJ, er al. Nausea in cancer chemotherapy is inversely related to urinary cortisol excretion. BrJ C~n0er. 1992;65: Aapro MS, Rezia PM, Alberts DS, er al. Double-blind crossover study of the antiemetic efficacy of" high-dose dexamethasone versus high-dose metoclopramide. J C//n Oncd. 1984;2: Livera P, Trojano M, Simone IL, et al. Acute changes in blood-cgf barrier permselecdvity to serum protein after intrathecal merhotrexare and CNS irradiation. J Ne~'~/. 1985;231: Schimmer BP, Parker KL. Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibkors of the synthesis and actions of adrenocortical hormones. In: Hardman JG, Limbird LE, Molinoff PB, e al, eds. Goodman #]" Gilman's The Pl~rmrtcdo~l Baals of Therapeutics. 9th ed. New York: McGraw-Hill; 1996: McCormick CG. FDA alert: Current FDA report on droparidol status and basis for 'Black Box' waming. ASA News/. 2002;66: Rowborham DJ. Current management of postoperative nausea and vomiting. Brj Anaesth. 1992;69(Suppl 1):40S- SgS. Address correspondence to: Yoshitaka Fujii, MD, Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, Tsukuba City, Ibaraki , Japan. E-maih yfujii@m&tsukuba.ac.jp June