Glucocorticoids have a number of beneficial properties in a surgical setting. In addition to being antiemetic, they are antiinflammatory, analgesic, antipyretic, and antiallergic. The mechanism by which glucocorticoids exert their action has been elucidated.1 Glucocorticoids reduce prostaglandin synthesis by inhibiting both phospholipase enzyme and cyclooxygenase Type II and by decreasing the products of cyclooxygenase-2, but have only a minor effect on cyclooxygenase-1.2 They also modulate the inflammatory response by inhibiting tumor necrosis factor-α, interleukin 1β, interleukin 6, c-reactive protein, and leukocyte receptors.3
The analgesic effect of glucocorticoids was first shown with betamethasone in patients undergoing third molar extraction.4 During the past 10 yr, the analgesic effect of betamethasone, dexamethasone, and methylprednisolone has been demonstrated in a variety of surgical procedures.5–9 In fact, all of the three drugs possess a strong antiinflammatory effect and a negligible sodium-retaining effect compared with other glucocorticoids.10 We chose to investigate the analgesic potency of different doses of dexamethasone, because its use as a basic antiemetic in surgical settings is established.11,12
The optimal analgesic dose of dexamethasone has not been determined. For the prevention of postoperative nausea and vomiting (PONV), the effective dose was reported to range from 2.5 mg after major gynecological surgery13 to 5 mg after thyroidectomy.14 A larger dose of dexamethasone has been used for postoperative pain management, ranging from 8 to 40 mg.6,8 This dose-finding study was designed to determine the smallest effective analgesic dose of dexamethasone, in a randomized, double-blind comparison with placebo in women undergoing laparoscopic hysterectomy.
After the study design was approved by the Ethics Committee and the National Agency of Medicines, we obtained the written informed consent of 129 Finnish-speaking women with ASA physical status I/II/III and body mass index <35 kg/m2, who were scheduled for laparoscopic hysterectomy with or without salpingo-oophorectomy. The study period lasted 14 mo, starting in October 2006. The exclusion criteria were diabetes, a history of gastric or duodenal ulcer, or contraindication to the use of any of the study medications.
The hospital pharmacy performed the randomization using a computer-generated random number table. Each consenting patient received a consecutive randomization number. The study medication was prepared by a person not involved with the perioperative or postoperative care of the patient, according to the following instructions: in the placebo group, the study medication consisted of 3 mL of saline, in the D5 group of dexamethasone 5 mg (5 mg/mL) diluted with 2 mL of saline, in the D10 group of dexamethasone 10 mg diluted with 1 mL of saline, and in the D15 group of dexamethasone 15 mg. In all cases, the total volume was 3 mL in a 5 mL syringe.
The study patients were premedicated orally 1 h before surgery with diazepam 10 mg. In the operating room, standard monitoring was started and the study medication was administered in a double-blind fashion as soon as an IV access was established. Anesthesia was induced immediately afterward using a target-controlled infusion pump (Orchestra™ Base Primea, Fresenius Vial, Brezins, France) with a target of 3 ng/kg for remifentanil and 6–8 μg/kg for propofol. Tracheal intubation was facilitated with rocuronium 0.6 mg/kg, and the patients' lungs were mechanically ventilated with a mixture of oxygen and nitrous oxide (0.5 L:0.5 L) to maintain end-tidal CO2 at the level of 4.5–5.0 kPa. After intubation, a gastric tube was inserted to deflate the stomach; the tube was aspirated and removed before extubation. The propofol infusion was adjusted to maintain the level of hypnosis at a fixed level; State Entropy (SE™, Entropy, General Electrics Healthcare, Helsinki, Finland)15 was used for monitoring hypnosis to maintain it between 45 and 55. The remifentanil infusion was adjusted to maintain noninvasive arterial blood pressure at −15% to +15% of the baseline value minus 20 mm Hg. To prevent PONV, all patients received droperidol 10 μg/kg (0.5–0.75 mg) IV in combination with ondansetron 4 mg IV at the end of surgery. When the operation was completed, the remifentanil infusion was discontinued and a 0.07 mg/kg IV bolus of oxycodone was given. During the closure of skin, the propofol infusion was stopped and neostigmine 2.5 mg with glycopyrrolate 0.5 mg IV was administered to reverse neuromuscular blockade. The total amounts of remifentanil and propofol infused, and the average values of SE™ during the anesthesia were recorded.
In the postanesthesia care unit, patients requesting analgesia or with a visual analog scale (VAS) ≥4 received oxycodone 0.04 mg/kg doses of oxycodone IV q 10 min. When the patients were alert, patient-controlled analgesia (PCA; CADD-Legacy™, SIMS Deltec, St. Paul, MN) with oxycodone 1 mg/mL was initiated (oxycodone 100 mg in combination with droperidol 5 mg diluted with saline) using a 0.04 mg/kg bolus of oxycodone and a lockout time of 8–10 min. The next morning the PCA was discontinued, and the total amount of oxycodone consumed was recorded. Before stopping the PCA, regular oral pain medication with ibuprofen 800 mg twice a day was started. Combination tablets of acetaminophen 500 mg and codeine 30 mg were given to treat breakthrough pain, and the patients were advised to take one to two tablets every 6 h, when needed. Although the patients still had an IV line, the rescue antiemetic medication was droperidol 0.5 mg IV or ondansetron 4 mg IV. After the IV line was removed, the patients received an ondansetron disintegrating tablet to treat a possible episode of PONV.
Postoperative pain was assessed at rest, with leg raising and with coughing using an 11-point scale VAS, which the patients were trained to use before premedication. In addition to recording pain scores, VAS scores (none—most severe imaginable) for side effects, including PONV, drowsiness, dizziness, lack of concentration, blurred vision, and itching, as well as the number of episodes of postoperative vomiting were recorded at 2, 4, 6, 8, 12, and 24 h after surgery. The patients were telephoned on the 3rd, 4th, or 5th day after discharge from hospital and interviewed by the study nurse or one of the investigators. A structured questionnaire was used to inquire about the patients' scores for pain using an 11-point scale (number rating scale [NRS]), total amounts of analgesics used, NRS scores for side effects during the first 3 days after surgery, and the patients' satisfaction with the anesthesia and pain treatment. For the presentation of the results, the VAS and the NRS scores for side effects ≥1 were considered positive, and the patient was considered to suffer from the symptom.
A power analysis was performed using a power of 80% and an α of 0.05. We anticipated that the consumption of oxycodone would be 0.50 mg/kg after perioperative administration of placebo, and 0.35 mg/kg after perioperative administration of dexamethasone 15 mg, with a sd of 0.15 mg/kg. Based on these assumptions, a sample size of 16 patients per group was required. When we estimated the sample size using VAS scores, we assumed a pain score of 30 mm after administration of saline, and a pain score of 15 mm after perioperative administration of dexamethasone 15 mg. With a sd of 20 mm, the sample size was calculated to be 28 patients per study group. Using these two calculations, we decided to randomize 32 patients into each group to cover the possible dropouts.
The patients' demographic data including ASA physical status classification, smoking habits, and history of PONV or motion sickness, characteristics of the surgery, including different types of surgery, and the incidence of side effects were analyzed using a χ2 test. The demographic data including age and body mass index, and clinical data including duration of anesthesia and surgery, doses of remifentanil and propofol, average SE™ value during anesthesia, were compared using analysis of variance. A post hoc analysis using Tukey adjustment was performed. The times to the first dose of rescue analgesic, and the amounts of postoperative analgesics were compared using Kruskal–Wallis test. The pairwise comparisons using Mann–Whitney U-test were performed. For multiple tests, the Bonferroni correction was applied and P < 0.0083 was considered a statistically significant difference. The VAS scores for pain and side effects were evaluated using repeated measures analysis of variance. The statistical analysis was performed using the Statistical Package for Social Sciences (SPSS™), Windows versions 14.0, 15.0, and 16.0 (SPSS, Chicago, IL).
The study was performed in the operating room and the gynecological ward in Helsinki University Hospital in Helsinki, Finland. One hundred twenty-nine patients were randomized in the study, 124 of whom received the study drug. In the final analysis, there were 120 patients in the data for the first 24 h after surgery, and 119 patients in the data for the first three postoperative days. Patient flow through the trial, including the reasons for exclusion, is presented in Figure 1.
Patient characteristics did not differ among the four study groups (Table 1). Distribution of the different laparoscopic procedures was similar in the four study groups, as was the duration of anesthesia and surgery. The amounts of remifentanil and propofol administered were equal, and the average SE™ values did not differ among the four groups.
The times to the first rescue analgesic dose were equal in the four study groups (Table 2). The total dose of oxycodone (0–24 h after surgery) was smaller in the D15 group than in the placebo group (P = 0.027, Kruskal–Wallis test, P = 0.003; pairwise comparison with Mann–Whitney U-test, with Bonferroni correction P < 0.0083 considered significant) (Table 2, Fig. 2). The doses of oxycodone during Hours 0–2 in the postanesthesia care unit were smaller in the D10 and D15 study groups than in the placebo group (P < 0.001, Kruskal–Wallis test, P < 0.001 D15 versus placebo, P = 0.001 D10 versus placebo; pairwise comparison with Mann–Whitney U-test, with Bonferroni correction P < 0.0083 considered significant) and the D5 group (P = 0.008, D15 versus D5; pairwise comparison with Mann–Whitney U-test, with Bonferroni correction P < 0.0083 considered significant) (Table 2). The dose of oxycodone during Hours 2–24 after surgery was equal in all four groups (Table 2). The number of patients taking paracetamol with codeine did not differ among the four study groups. The VAS scores for pain at rest (Fig. 3), pain in motion (Fig. 4), and when coughing (Fig. 5) during the whole recovery period were similar in the four study groups. Satisfaction with anesthesia and pain medication was equal in all four study groups.
The incidence of PONV or postoperative vomiting (Table 3) and the number of patients needing rescue antiemetics (data not shown) did not differ in the four study groups. Of the side effects, the incidence of drowsiness (data not shown), headache, lack of concentration, blurred vision, and pruritus did not differ among the four study groups (Table 3). The incidence of dizziness was less frequent in the D15 group than in the placebo group (P = 0.001; χ2 test), the D5 group (P = 0.006; χ2 test), and the D10 group (P = 0.030; χ2 test) during the first 24 h after surgery (Table 3). During the later course of recovery, the incidence of dizziness did not differ among the four study groups.
According to our results, the opioid-sparing potency of dexamethasone is dose dependent. The effect of the 5 mg dose on postoperative oxycodone consumption was negligible, whereas the 10 and 15 mg doses reduced oxycodone consumption during the first 2 h after surgery. Our finding is in accordance with the data available. An antiemetic dose (4 mg) of dexamethasone was not shown to have an effect on postoperative pain, although it did have other beneficial effects on hospital discharge.16 On the other hand, a 16 mg dose of dexamethasone, combined with rofecoxib, was demonstrated to have a prolonged analgesic effect.7 The widely studied 125 mg dose of methylprednisolone9,17,18 is equivalent to 20–25 mg of dexamethasone.10 Hence, it is possible that even larger doses of dexamethasone than the ones chosen in this study would result in a better opioid-sparing effect.
In this study, we demonstrated that the high dose of dexamethasone had an apparent opioid-sparing effect, but no effect on VAS scores of pain at rest or of evoked pain. This was probably due to the postoperative pain management achieved with IV oxycodone using the PCA technique, which allows the patient to dose the opioid to the level of pain relief she desires. It is also possible that the lack of effect of dexamethasone on the pain scores in our study reflects the low degree of invasiveness and weak inflammatory response of laparoscopic hysterectomy compared with other operations.
In this study, the onset of the analgesic effect of 10 and 15 mg of dexamethasone was fast, as the dose of rescue oxycodone was smaller in the dexamethasone 15 mg group in the early phase of recovery during Hours 0–2 after surgery, corresponding to the time period 2–4 h after administration of the drug. This finding is consistent with the results of Romundstad et al.,9 who showed that the analgesic effect of methylprednisolone 125 mg IV was evident at 60 min after administration of the drug, compared with placebo. The early response in our study probably reflects the rapid action of dexamethasone mediated via membrane-bound receptors, shown in experimental studies.19,20 However, there is also strong evidence of the traditional delayed onset of the beneficial effects of glucocorticoids.1 The effect of a 12 mg dose of betamethasone was not apparent until 3 h after surgery,5 that of a 4 mg dose of dexamethasone was more pronounced after discharge,16 and after a 16 mg dose of dexamethasone there was no effect until 5–6 h after IV administration.7 The delayed onset of analgesic action and the extended duration of the effect can be explained by the slower action of glucocorticoids via modification of the transcription of DNA in the cell nucleus,1 which is a time-consuming process and lasts longer than what is expected regarding the plasma elimination half-life of about 6 h.21
The perioperative single dose of dexamethasone did not result in a higher incidence of adverse effects, which is consistent with the published data. A perioperative single dose of glucocorticoid was not associated with adverse effects in a quantitative systematic review of 598 surgical patients receiving dexamethasone 4 mg as an antiemetic12 or in a randomized controlled trial, in which 2617 surgical patients received dexamethasone 4 mg as an antiemetic.11 There were also no adverse events reported in a meta-analysis of 1900 patients in which methylprednisolone was used even in high doses (30 mg/kg) perioperatively.22 In a nonrandomized study, however, a 10 mg dose of dexamethasone was shown to increase blood glucose level in both nondiabetic and Type 2 diabetic surgical patients for 240 min after administration.23 In this study, we did not measure the blood glucose levels routinely, as patients with diabetes were excluded from our study. Everything considered, the potential effect of dexamethasone on carbohydrate metabolism may limit the use of larger doses than those used in this study.
Interestingly, the 15 mg dose of dexamethasone, but not the lower doses, reduced the incidence of dizziness in our patients during the first 24 h after surgery. Dizziness was defined to patients as vertigo, disequilibrium, or spinning. The patients were asked to assess dizziness using the VAS when resting or sitting. It is possible that the difference in the incidence of dizziness resulted from a Type 2 error, because this finding has not been previously reported. However, dizziness is a common side effect of all opioids. The lower incidence of dizziness may reflect the smaller dose of oxycodone required in the dexamethasone 15 mg group. Everything considered, a lower incidence of dizziness may be associated with earlier home readiness and a better sense of well-being shown in patients undergoing ambulatory surgery.16 Certainly, it facilitates faster ambulation and convalescence.
Although dexamethasone is an antiemetic, we did not anticipate any differences in the incidence of PONV in our study. The study was far too underpowered in this context. Furthermore, we used all possible methods to prevent PONV: we anesthetized the patients using propofol, administered ondansetron and droperidol for antiemetic prophylaxis, and added droperidol as an adjuvant to the oxycodone-PCA.
In our center, the cost of a single 15 mg dose of dexamethasone is €7.50 ($12) corresponding to the cost of a 1 g dose of paracetamol, which is often administered four times a day to surgical patients. In fact, the extra cost of the effective analgesic dose of dexamethasone remains at €5 after subtracting the cost of the 5 mg dose (€2.5) used as antiemetic prophylaxis. The cost of the drugs used for anesthesia constitutes only a small fraction of the total cost of the procedure. Considering the multifaceted action of dexamethasone, the cost is very reasonable.
In conclusion, IV administration of dexamethasone 15 mg before induction of anesthesia decreases oxycodone consumption during the first 24 h after laparoscopic hysterectomy, compared with placebo. During first 2 h after surgery, dexamethasone 10 mg reduces oxycodone consumption as effectively as the 15 mg dose.
We want to thank M.Sc. Antti Nevanlinna in Helsinki University IT Department for statistical advice. We are grateful to Ms. Maria Jokilehto, RN, and Ms. Eija Ruoppa, RN, as well as the entire staff of the operation theater and gynecological ward in Women's Hospital, Helsinki University Hospital, for taking excellent care of our patients.
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© 2009 International Anesthesia Research Society
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