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From the Department of Anesthesiology, Buddhist Tzu-Chi Medical Center, Tzu-Chi University School of Medicine, Hualien, Taiwan
Address correspondence to Ming-Hwang Shyr, MD, PhD, Department of Anesthesiology, Buddhist Tzu-chi Medical Center, Tzu-chi University School of Medicine, No. 707, Sec 3, Chung-Yang Road, Hualien, 970, Taiwan. Address reprint requests to Yi Lee, MD, Department of Anesthesiology, Tzu-Chi Medical Center, Tzu-Chi University School of Medicine, no. 707, Sec 3, Chung-Yang Road, Hualien, Taiwan, ROC. Address e-mail to dr.stone{at}msa.hinet.net or drleeyi@sinamail.com.
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Abstract |
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IMPLICATIONS: Morphine administration by patient-controlled analgesia (PCA) is often associated nausea and vomiting. In this double-blind study, the minimum effective dose of dexamethasone for reducing this complication was 8 mg. This was as effective as adding droperidol 0.1 mg/mL to the morphine PCA without causing drowsiness, restlessness or arrhythmias.
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Introduction |
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Droperidol is antiemetic even when small doses (<1 mg) are used (2). However, the effect is short-lived, suggesting that a repeated bolus of small doses of droperidol should be used to achieve the best antiemetic effect (2,3). Tramèr and Walder (1) suggested that concomitant use of a small dose of droperidol with morphine is an effective means to prevent nausea and vomiting. Lamond et al. (4) demonstrated that droperidol 0.10 mg/mL with morphine 1 mg/mL in the PCA container is the optimal dose for preventing PONV.
Dexamethasone has been effective in decreasing PONV after general anesthesia (5,6). Recently, we (7) have found that dexamethasone 8 mg administered IV immediately before induction of anesthesia significantly decreases the incidence of PCA-morphine related nausea and vomiting. Despite this antiemetic effect, however, the optimal dose of dexamethasone for this purpose has not been determined.
In this randomized, double-blind, placebo-controlled study, we evaluated the antiemetic effects of four different doses of dexamethasone (2, 4, 8, and 12 mg) on PCA morphine-related nausea and vomiting. Droperidol (0.10 mg/mL) and saline were used as controls.
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Methods |
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Patients were randomly assigned to 1 of 6 groups (n = 40 each) using a computer-generated random number table. The study medication (3 mL), containing 0.9% saline for the droperidol and saline-control groups and 2 mg, 4 mg, 8 mg, and 12 mg of dexamethasone for the four dexamethasone groups, was administered IV immediately before induction of anesthesia. Postoperatively, the dexamethasone and saline-control groups received PCA morphine 1 mg/mL. The droperidol-control group received the same concentration of morphine combined with droperidol 0.1 mg/mL. All patients were blinded to the nature of the drug administered. The study medication preparations were performed by a specially trained nurse-anesthetist who was not involved in any subsequent assessments.
The anesthesia was standardized for all patients. Glycopyrrolate 0.2 mg, fentanyl 2 µg/kg, and thiopental 5 mg/kg were used for the induction of anesthesia. Tracheal intubation was facilitated by administration of rocuronium 0.8 mg/kg. Anesthesia was maintained by sevoflurane 2%–5% (inspired concentrations) and 50% nitrous oxide in oxygen. Ventilation was mechanically controlled and adjusted to maintain end-tidal CO2 values between 4 and 5.3 kPa throughout the surgery. Additional rocuronium was administered as required. All patients received ketorolac 30 mg IV approximately 30 min before the end of surgery. For reversal of residual muscle relaxation, the combination of glycopyrrolate 0.6 mg and neostigmine 3 mg were administered IV and the trachea was extubated. No opioids were given during the operation.
Postoperatively, all patients received an initial dose of morphine (0.05 mg/kg) immediately before initiation of PCA. The PCA device was programmed to deliver a 1-mL bolus of morphine solution (with or without addition of droperidol), with a 5-min lockout interval. No background infusion was used. Rescue medication (metoclopramide 10 mg) was given IV if the patient experienced more than 15 min of nausea, had experienced an emetic episode, or if the patient requested antiemetic medication. The treatment was repeated if necessary.
The incidence of PONV and the amount of morphine used were recorded by specially trained nurse anesthetists who were blinded as to the treatment groups at 2, 12, and 24 h after operation. Nausea was measured using an 11-point numerical rating scale with 0 = no nausea and 10 = nausea as bad as it can be. A score of 
8 was considered severe, 4 to 7 = moderate, and 
3 = mild nausea. In this study, retching and vomiting were grouped together under the common term "emetic episodes" (8). An emetic episode was defined as vomiting/retching events occurring in rapid sequence within a 1-min period. If the interval between 2 bouts of emesis exceeded 1 min, they were considered separate episodes. If there were more than 4 episodes within the 24-h observation period, the emesis was considered severe (9).
Our primary efficacy end-point was complete response, defined as patients who stayed completely free from PONV and had no rescue antiemetic requirement during the first 24-h observation period.
Pain intensity was rated by the patients using an 11-point numerical rating scale similar to that used for nausea, where 0 symbolized no pain and 10 represented the worst pain imaginable. At the end of the observation period, all patients would be asked whether they were satisfied with the PCA procedure.
The satisfaction on PCA was also assessed using the similar 11-point numerical rating scale. A score of 10 denoted the highest level of satisfaction, and patient satisfaction was defined as high if the score was 8 or more (10).
The severity of sedation was classified into 5 categories: 0 = fully awake; 1 = drowsy, closed eyes; 2 = asleep, rousable; 3 = asleep, unrousable, answer to touch or pain; 4 = does not respond. Other side effects such as restlessness (felt nervous or jumpy), visual disturbance, headache, or extrapyramidal symptoms were also considered at 2, 12, and 24 h postoperatively.
Sample size calculation was performed before starting the trials by using a statistical power analysis. Based on an 
error of 0.05 and ß error of 0.20, 30 patients were estimated to be needed in each group to have a 90% chance with an error of 5% to detect a decrease in total PONV incidence from 60% to 40% after treatment (11). To compensate for patients not completing the study, we randomized 40 patients to each group. Data were analyzed using one-way analysis of variance with a linear contrast, 
2 test with Yates’ correction, and Mann-Whitney U-test as appropriate. Data are expressed as mean values with SD or number and percentage. A P value <0.05 was considered statistically significant. Commercial software SPSS 10.0 (SPSS Inc., Chicago, IL) for Windows was used for data processing.
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Results |
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4; P = 0.046, 0.041, and 0.011 respectively) than did those in the saline group.
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8) in comparison to those who received placebo (P = 0.033, 0.019, and 0.004 respectively). No significant differences were found among the dexamethasone 8 and 12 mg and droperidol groups. Dexamethasone 2 and 4 mg provided no better PONV protection than saline alone. The morphine consumption was not different among groups.
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Discussion |
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Study designs that analyze only one type of surgery or restricted patient populations have recently been criticized (16,17). In fact, large prospective investigations have shown that the different incidences of PONV are mainly caused by the associated risk factors and less by the operation itself (17). Therefore, we used Apfel’s simplified risk score instead of selecting patients undergoing just one type of surgery to identify patients with an increased risk. In this study, the types of surgery and the number of risk factors were similar among groups (Table 1). We believe that the difference in the six groups with respect to PONV was directly related to the drug tested. We also found that the incidence of PONV in the droperidol and saline-controlled groups were comparable with previously published data (1,4).
Droperidol is effective in reducing the incidence of PONV when given concomitantly with a PCA device with morphine (1,4). However, the side effects in the postoperative setting remains a concern even when antiemetic treatment with droperidol is administered in small doses (18–20). Lamond et al. (4) found that these previous patients were administered an initial loading bolus dose of droperidol as part of the anesthetic technique, with the result that patients often received large doses of droperidol. Gan et al. (21) noted that administration of an initial loading dose of droperidol before addition of droperidol in PCA should be avoided, as it resulted in more sedation. Lamond et al. (4) demonstrated that when given without an initial loading dose, a PCA bolus dose of droperidol of 0.1 mg/mL appears to provide the optimal balance between antiemetic efficacy and an acceptable incidence of side effects. In the current study, we found that a total dose of droperidol of between 2.0 and 5.3 mg in 24 h was associated with an acceptable rate of PONV (18.9%), which was similar to dexamethasone 8 and 12 mg. The levels of sedation were not different among groups, although the small size of the groups could also be the cause. Nevertheless, one in six patients (6 of 37 patients) in the droperidol group reported side effects at 24 h after operation. Four of these patients had restlessness, a common droperidol-related side effect, after administration of 35, 36, 40, and 43 mg of morphine (3.5, 3.6, 4.0, and 4.3 mg droperidol) respectively. None of these patients found the experience disturbing. However, PCA treatment had to be stopped in 2 patients after administration of total doses of 42 and 51 mg morphine (4.2 and 5.1 mg droperidol) because of being asleep and only awakened by touch. We could not establish whether the symptoms were caused by the droperidol, the morphine, or the combination of the two. However, Roberts et al. (19) found a significant increase in sedation associated with PCA droperidol. Tramèr and Walder (1) also noted that adverse events are likely when the droperidol dosage exceeds 4–6 mg per day. Of note is that these side effects were not reported in any of the dexamethasone-treated patients.
Droperidol has been used for the prophylaxis and treatment of PONV for over 30 years (22). On December 5, 2001, the US Food and Drug Administration issued a "black box" warning regarding the risk of cardiac arrhythmias during droperidol administration (23). However, White et al. (22) stated that there is not even a single case report indicating that droperidol in doses used for the management of PONV has been associated with cardiac arrest or arrhythmias. After conducting an extensive literature research, we were also unable to find a report of arrhythmias or cardiac arrest associated with the use of droperidol with morphine PCA. In fact, continuing 12-lead electrocardiogram (ECG) monitoring for all elective surgery patients during the postoperative PCA period is clinically impractical. Thus, patients in the droperidol group in the current study were not monitored by continuous ECG in ward. Although no discernible cardiac arrhythmia accompanying 0.1 mg/mL droperidol in the PCA was found, further detailed investigation and a longer follow-up would be needed to prove this.
Baxendale et al. (24) reported that dexamethasone might reduce pain intensity after tooth extraction. In this study, we found that both morphine consumption and pain severity were similar in the dexamethasone and saline control groups. These results indicate that dexamethasone might not alter the intensity of pain after surgery, nor did it enhance the efficacy of PCA-morphine.
Patient satisfaction should be an important consideration in antiemetic selection for PONV treatment. Fisher (25) indicated that patient satisfaction, rather than PONV, should be advocated as the main outcome. In this study, a higher satisfaction score was reported for patients treated with dexamethasone 8 or 12 mg or droperidol in comparison with those who received saline. Further, more than half of the subjects in these groups (dexamethasone 8/12 mg, 61.1/63.2%; droperidol, 70.3%) were highly satisfied (satisfaction score 8). With a similar pain score at all times in the 6 groups, we believe that the degree of satisfaction was mainly associated with the severity and incidence of PONV during PCA. Hence, dexamethasone 8 or 12 mg IV not only reduced the incidence of PCA-related PONV, but also provided a similar level of patient satisfaction as droperidol treatment.
In this study, patients who received dexamethasone 8 or 12 mg or droperidol had less frequent incidence of nausea than those who received saline (Table 2). However, the differences were not statistically significant. The a priori defined outcome in this study was the total incidence of PONV and the sample size estimation assumed to be 
60%. As the incidence of nausea in the saline group was significantly less (25.7%) than this estimation, the power of the study to detect such differences was not sufficient. Thus, more patients were needed to detect the same relative reduction in nausea.
Although complications from corticosteroid use, such as delayed healing, additional wound infection, peptic-ulcer perforation, or adrenal suppression, are usually related to its long-term therapy, we avoided its use in patients who were immunosuppressed or who had peptic ulcer disease, diabetes, Cushing’s syndrome, or recent tuberculosis to minimize the risk of exacerbating their underlying diseases. In previous studies, a single dose of dexamethasone was considered safe (3–7,10). In this study, no apparent adverse effects, such as peptic ulcer perforation, were noted. However, we do not know if a single dose of dexamethasone would suppress adrenal function or have clinical significance (for instance, if it would increase the risk of wound infection) in healthy patients during surgical stress. This needs to be studied further.
In conclusion, this study has demonstrated that the preinduction administration of dexamethasone 8 mg IV was the smallest effective dose for the reduction of PCA morphine-related PONV. Moreover, this was as effective as adding droperidol 0.1 mg/mL to the morphine PCA without causing drowsiness, restlessness, or arrhythmias.
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