Preoperative dexamethasone reduces postoperative pain, nausea and vomiting following mastectomy for breast cancer

Breast cancer is the most frequent malignant neoplasm worldwide. In emerging countries such as Mexico, there has been an increase in its frequency and mortality [1, 2] and it is the second most frequent neoplasm after cervical carcinoma. Between 25,000 and 30,000 new cases are diagnosed annually. Unfortunately, only a few women have regular mammography screening so the proportion of patients with locally advanced disease at diagnosis is high. In 2003, only 5-10% of newly diagnosed cases in Mexico were clinical stages 0 or I [2]. Surgical resection with axillary lymph node dissection constitutes the treatment of choice associated with neoadjuvant therapy and postoperative chemotherapy and/or radiation therapy.

Postoperative nausea and vomiting (PONV) are the most common complications after anesthesia and surgery [3, 4]. Women undergoing mastectomy with axillary dissection are at a particularly high risk for the development of PONV and an incidence of 60-80% in patients receiving no antiemetic has been reported [5–7]. Emetic episodes predispose to aspiration of gastric contents, wound dehiscence, psychological distress, and delayed recovery and discharge times [3]. These justify the use of prophylactic antiemetics in women scheduled for mastectomy. Most of the currently used antiemetics, including antihistamines, butyrophenones and dopamine receptor antagonists have been reported to cause occasional undesirable adverse effects, such as excessive sedation, hypotension, dry mouth, dysphoria, hallucinations and extrapyramidal signs [3]. Antiserotonins (e.g., ondansetron) are available for the prevention and treatment of PONV in patients undergoing various types of surgery [4]. However, the use of prophylactic antiemetic therapy with antiserotonins has been criticized for being too expensive [8, 9].

Dexamethasone was first reported to be an effective antiemetic regimen in patients receiving cancer chemotherapy [10]. Holte et al. [11] have reviewed the available randomized trials (1996-2001) regarding perioperative single-dose steroid administration and found that dexamethasone had antiemetic and analgesic effects in various types of operations. Wattwil et al. [12] showed that dexamethasone at 4 mg was effective for the prevention of PONV following breast surgery but they could not demonstrate any difference in postoperative pain.

The purpose of this study was to evaluate the efficacy of dexamethasone treatment for reducing pain and PONV as well as analgesic and antiemetic requirements in women undergoing general anesthesia for mastectomy with axillary lymph node dissection.

There were no significant differences between the two groups with regard to mean age, weight, height, BMI, neoadjuvant chemotherapy, type of surgical procedure, length of surgical procedures, length of anesthesia or operative bleeding (Table 1). Figure 1 shows the median VAS values for pain. Dexamethasone significantly reduced postoperative pain just after surgery (VAS score, 4.54 ± 1.55 vs. 5.83 ± 2.00; p = 0.004), 6 h after the operation (VAS score, 3.03 ± 1.20 vs. 4.17 ± 1.24; p < 0.0005) and 12 h after the breast surgery (VAS score, 2.09 ± 0.85 vs. 2.54 ± 0.98; p = 0.04). No difference was observed 24 h after the operation (1.23 ± 0.42 vs.1.43 ± 0.55; p = 0.09). Analgesics were required in more patients of the control group than in the dexamethasone group (21 vs. 10; p = 0.008). The mean dose of intravenous tramadol was lower in the study group (36.01 ± 12.62 vs. 55.74 ± 27.36; p = 0.03).

	Placebo group (n = 35)	Dexamethasone group (n = 35)
Age (years)a	49.89 ± 10.58	50.11 ± 12.37
Weight (kg)a	67.94 ± 9.91	69.52 ± 13.63
Height (cm)a	158.14 ± 6.33	157.31 ± 6.57
Body mass indexa	27.20 ± 4.29	28.20 ± 6.38
Normal weight 20-25 (%)	11 (31.4%)	12 (34.3%)
Overweight 25.1-29.9 (%)	15 (42.9%)	14 (40%)
Obesity grade I 30-34.9 (%)	7 (20%)	5 (14.3%)
Obesity grade II 35-39.9 (%)	2 (5.7%)	2 (5.7%)
Obesity grade III >40 (%)	0	2 (5.7%)
Smoking (%)	2 (5.7%)	4 (11.4%)
Neoadjuvant chemotherapy (%)	13 (37.1%)	15 (42.8%)
Surgical procedure
Radical mastectomy + axillary dissection (%)	32 (91.4%)	34 (97.1%)
Quadrantectomy + axillary dissection (%)	3 (8.6%)	1 (2.9%)
Surgery time (min)a	119.42 ± 26.97	120.54 ± 30.34
Length of anesthesia (min)a	140.71 ± 26.76	139.60 ± 34.56
Bleeding (ml)a	165.85 ± 61.10	156.85 ± 60.11

^aValues are expressed as the mean ± standard deviation.

The hospital stay was 1-3 days. No morbidity was observed during the follow up period. Drains were removed when the fluid output was less than 50 ml/24 h. One patient in the control group developed a generalized rash before the skin incision was started. The adverse event was treated with intravenous antihistaminic and hydrocortisone with complete resolution. This case was excluded and substituted with a new candidate. There was no mortality.

In this randomized, double-blind, placebo-controlled study, preoperative dexamethasone (8 mg) significantly reduced the incidence of pain, PONV and analgesic and antiemetic requirements after breast surgery for cancer. PONV is an unpleasant, distressing and exhausting complication for patients. It can prolong recovery time, delay patient discharge and increase hospital costs [13]. The etiology of PONV after breast surgery is not entirely clear. Factors affecting PONV after breast surgery are those related to the patients, those related to the surgical procedure and the anesthetic technique and the postoperative care [14]. Risk-scoring systems have been proposed based on logistic regression modeling to select patients for prophylaxis against PONV [15, 16]. Complicated formulations were simplified establishing four predictor factors: a) female sex; b) a history of motion sickness and/or PONV; c) absence of a smoking habit and d) any use of opioids [17]. If none, one, two, three or four of these factors were present, the incidence of PONV was 10%, 23%, 39%, 61% and 79% respectively [17]. Breast surgery inherently caters to high-risk patients and being female was an independent predictor for PONV in multivariate analysis [15, 16]. In our study patients with history of motion sickness and/or PONV were not included and only a few of our patients were active smokers. The first condition lowers the threshold for vomiting [18] and smoking provides some protection against it [3]. The length of the surgical procedure also increases the risk of PONV. As established by Sinclair et al. [16], each 30 min increase in the duration of surgery increases the incidence of PONV by 60%. Anesthetic-related factors have a strong influence on the incidence of PONV because the use of opioids as premedications or to maintain anesthesia stimulates central nervous system (CNS) opioid receptors [19]. Nitrous oxide causes PONV by stimulating the CNS with catecholamine release and changes in middle-air pressure with subsequent stimulation of the vestibular system and elevation of abdominal pressure as a consequence of the exchange of nitrous oxide and nitrogen in gas introduced into the gastrointestinal tract during mask ventilation [20–24]. The use of propofol for maintaining anesthesia has a positive effect on reducing PONV [25]. Postoperatively, the administration of opioids might contribute to these episodes [26].

Since the original description of dexamethasone as an effective antiemetic drug [10], studies have reported it to be effective for the prevention of nausea and vomiting after different surgical procedures. The biological action of a glucocorticoid begins 1-2 h after administration [27]. The antiemetic mechanism of dexamethasone is not known. However, central inhibition of prostaglandin synthesis, inhibition of endogenous opioid release and changes in the permeability of the blood-brain barrier to serum proteins have been suggested [27, 28]. The analgesic effects of glucocorticoids are mainly provided through the peripheral inhibition of phospholipase, thereby decreasing the products of the cyclooxygenase and lipoxygenase pathways in the inflammatory response [29].

In this trial, a variety of risk factors were present in both groups of patients. This included being female, nonsmoking, receiving neoadjuvant chemotherapy, undergoing an operative procedure and anesthesia, the presence of postoperative pain and the use of opioids. All of these factors are considered to affect the incidence of PONV; however, they were well balanced between the placebo and dexamethasone treatment groups. Therefore, the difference in the rate of patients experiencing PONV among the groups can be attributed to the use of dexamethasone.

Our results are similar to those reported by Fujii and Nakayama [30]. They designed a randomized clinical trial with 90 patients submitted to breast surgery (24% of them treated without axillary lymph node dissection). They divided the patients into three groups of 30. Patients received intravenous dexamethasone at doses of 4 or 8 mg preoperatively and the control group received placebo. They evaluated the incidence of PONV and analgesic requirements until 24 h after the surgical procedure. The incidence of PONV was 67% in the placebo group versus 33% and 27% in the 4 mg and 8 mg dexamethasone groups (p = 0.01 and 0.002, respectively). The need for rectally administered indomethacin for relieving intolerable pain was less in patients who had received 8 mg dexamethasone than in those who received placebo (p = 0.001) or dexamethasone at 4 mg (p = 0.034). No difference in analgesic requirement was found between the 4 mg dexamethasone and placebo groups (p = 0.18). They concluded that dexamethasone at 8 mg effectively decreased PONV and analgesic requirements in women undergoing general anesthesia.

Our results suggest that preoperative dexamethasone at 8 mg ameliorates nausea, vomiting, pain and reduces the analgesic and antiemetic requirements of women after breast surgery for cancer without apparent side effects. It appears to be a valuable treatment for preventing such adverse postoperative symptoms.

Breast Tumor Clinic. Oncologic Institute of Jalisco, Health Secretary. Calle Coronel Calderon 715, Colonia El Retiro. Postal code 44280, Guadalajara, Jalisco. Mexico.

Research Unit in Clinical Epidemiology, Specialties Hospital, Western Medical Center. Mexican Institute of Social Security. Avenida Belisario Dominguez 1000, Colonia Independencia. Postal code 44340, Guadalajara, Jalisco. Mexico.