Trial Information

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 pain, nausea and vomiting (PONV) are the most common complications after
anesthesia and surgery. 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. Emetic episodes predispose to aspiration of
gastric contents, wound dehiscence, psychological distress, and delayed recovery and
discharge times. 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. Antiserotonins (e.g., ondansetron) are available for the prevention
and treatment of PONV in patients undergoing various types of surgery. However, the use of
prophylactic antiemetic therapy with antiserotonins has been criticized for being too
expensive.

Dexamethasone was first reported to be an effective antiemetic regimen in patients receiving
cancer chemotherapy. Some authors 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. One ot this studies
demostrated that intravenous 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 node dissection.

Patients and Methods Patients Between June and August 2009, 70 patients undergoing
mastectomy with axillary dissection were studied in a prospective, randomized, double-blind
clinical trial. Patients were randomized to receive intravenous dexamethasone (8 mg) or
homologated placebo 60 minutes before skin incision, using an equal number of blinded
envelopes. Patients of American Society of Anesthesiologists classes III and IV were
excluded. Further exclusion criteria were age more than 80 years; pregnancy; active
menstruation; treatment with steroids; severe diabetes mellitus (serum HbA1c > 8%); use of
opioids, sedatives or any kind of analgesics less than one week before mastectomy, or a
history of alcohol or drug abuse. Patients with any history of motion sickness and ⁄or
previous PONV after any surgical procedure were excluded. All patients were admitted to the
hospital one day before the operation and were followed from hospital admission until 30
days after the surgical procedure to detect any medical or surgical morbidity.

Anesthesia and surgery All patients underwent a standardized general anesthesia procedure
and none of them received any preanesthetic medication. Induction used intravenous propofol
(2 mg/kg body weight) and fentanyl (3-5 mcg/kg). Vecuronium bromide (0.1 mg/kg) was used to
facilitate tracheal intubation. Anesthesia was maintained with 2-3% sevoflurane and 66%
nitrous oxide in oxygen. Ventilation was controlled mechanically and maintained constant
throughout surgery using an anesthetic and respiratory gas analyzer for monitoring.

All patients were monitored with indirect determinations of arterial pressure and heart rate
using standard techniques, as well as the expired CO2 content and oxygen blood saturation.
Afterwards, all patients were extubated and transferred to the immediate postsurgical care
unit with cardiovascular and oxygen monitoring.

Surgical procedures All patients were treated according to the preoperative clinical stage
with radical mastectomy or breast conservative surgery with lymph node axillary dissection
by the same surgical team. In all patients, closed suction drains were placed in the region
subjected to surgery and were removed during the following days. Chemotherapy and/or
radiotherapy were administered 3-4 weeks after uncomplicated surgical resections.

Analgesia and antiemetic therapies Pain was assessed immediately on return to the recovery
room and at 6, 12 and 24 h after the operation using a visual analogue scale (VAS; 0 = no
pain to 10 = most severe pain). Analgesia was given as intravenous sodium ketorolac (30 mg
every 8 hours) and intravenous tramadol infusion (50 mg) was used as a backup analgesic
medication. The incidence of PONV was recorded immediately on return to the recovery room
and at 6, 12 and 24 h after the operation, using a three point ordinal scale (0 = none, 1 =
nausea, 2 = retching, 3 = vomiting). Nausea was defined as a subjectively unpleasant
sensation associated with awareness of the urge to vomit, retching was defined as the
labored, spasmodic, rhythmic contraction of the respiratory muscles without the expulsion of
gastric contents, and vomiting was defined as the forceful expulsion of gastric contents
from the mouth. Intravenous ondansetron (4-8 mg) was given for antiemetic treatment on
demand.

Data collection and statistical analysis Postoperative complications were recorded during
hospitalization and the patients were followed up to 30 days after discharge. Additional
data collected included patient age, body mass index (BMI), any history of smoking and
neoadjuvant chemotherapy, anesthesia and operation time and the frequency of use of
analgesic and antiemetic drugs. These parameters were summed and compared between the
dexamethasone and placebo groups.The study endpoints were postoperative nausea and vomiting,
and pain measured by the VAS and the need for additional analgesic and antiemetic drugs.

The sample size was predetermined. We expected a 35% difference in the incidence of nausea
and vomiting between groups. The alpha error was set at 0.05 and beta error at 0.20; n = 35
patients for each group was considered adequate, according to a power analysis. Results are
expressed as percentages and as the mean ± standard deviation (SD). Student's t test, the
Chi-squared test or Fisher's Exact Test were used for the analysis of quantitative and
qualitative data, respectively. Differences were considered statistically significant at p <
0.05.

Ethical considerations The study was conducted according to the principles of the
Declaration of Helsinki of 1989 and the Mexican Health Guidelines. The Ethical and Research
Committees of the Oncologic Institute, approved all protocols. Full, written informed
consent was obtained from all patients before their inclusion in the study.