Anesthesia & Analgesia:
Cancer Recurrence and Hyperglycemia with Dexamethasone for Postoperative Nausea and Vomiting Prophylaxis: More Moot Points?
Colin, Brian MD; Gan, Tong J. MD, MHS, FRCA
From the Anesthesiology Department, Duke University Medical Center, Durham, North Carolina.
Accepted for publication February 7, 2014.
Conflicts of Interest: See Disclosures at the end of the article.
Reprints will not be available from the authors.
Address correspondence to Tong J. Gan, MD, MHS, FRCA, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710. Address e-mail to firstname.lastname@example.org.
The routine use of dexamethasone for the prophylaxis of postoperative nausea and vomiting (PONV) has been controversial and debated among anesthesiologists and anesthesia providers for many years. Why is this? There are clear data to support that dexamethasone, with its relative low cost and high efficacy, is a preferred antiemetic for the prevention of PONV, as recommended by the PONV Consensus Guidelines.1 Compared with ondansetron, a 5-HT-3 receptor antagonist, which is likely the most commonly used antiemetic to prevent and treat PONV, the number needed-to-treat to prevent PONV for dexamethasone is 4, compared with 6 to 7 for ondansetron.2,3 The ideal prophylactic dosage appears to be 4 mg IV at induction of anesthesia;4 however, 8 mg IV may provide the additional benefit of pain relief because of opioid-sparing effects5 as well as shorten recovery time.6
The reason for this controversy, of course, is that dexamethasone is a glucocorticoid with many feared side effects when used in the perioperative patient population. There have been concerns regarding the risk of wound infections, wound healing, perioperative bleeding, cortisol suppression, neuromuscular weakness, high blood glucose levels, and even cancer recurrence.7–10 In this issue of Anesthesia & Analgesia, 2 concerns of dexamethasone, the association with steroids and the recurrence of cancer, as well as the concern for the induction of perioperative hyperglycemia, are examined.
Glucocorticoids and their use in cancer patients have long been a topic of concern in the perioperative setting. Surgical excision is the primary definitive treatment for many forms of cancer, with tumor recurrence and metastatic disease being the most important cause of mortality in surgical cancer patients. The suppression of host defenses in the perioperative period, as well as the role of anesthetic techniques and drug choices, are becoming increasingly scrutinized regarding their effect on host immunity.11 Dexamethasone has been shown to suppress T cell function as well as natural killer cell development,12,13 both of which are known to participate in antitumor immune responses.14 Despite these findings, there are few data at this point regarding corticosteroid use and cancer recurrence.
In this issue, De Oliveira et al.15 present a retrospective observational study that analyzes the effect of perioperative systemic dexamethasone (4–10 mg) for PONV prophylaxis in women who underwent primary ovarian cytoreductive surgery for ovarian cancer and the risk of ovarian cancer recurrence. The primary aim was to determine the overall increase in the risk of ovarian cancer recurrence in these patients by determining tumor recurrence in women given perioperative dexamethasone versus those who did not receive the medication. Of 260 women included in the study, 178 had cancer recurrence; 102 of these patients received dexamethasone. The study ultimately found no significant association between perioperative dexamethasone use and ovarian cancer recurrence after primary surgical treatment and therefore does not support the avoidance of single-dose dexamethasone for PONV prophylaxis. There are some acknowledged weaknesses to the study, such as a small sample size and a lack of standardization of intraoperative and postoperative analgesic management. This is particularly important in that several studies have suggested that the use of opioids in the perioperative setting may have an effect on angiogenesis and cancer outcomes. Opioids have been found to regulate the growth of neoplastic cells through the modulation of cell proliferation and apoptosis; they cause immunosuppression, as well as modulate angiogenesis, aiding tumor metastasis and growth through activation of vascular growth cell receptors such as vascular endothelial growth factor and platelet derived growth factor.16 Another study presented evidence that opioids may have a direct effect on lung cancer progression through interaction with the μ-opioid receptor.17 In cancer recurrence from single-dose dexamethasone, there is no clinical evidence in the literature to refute the above findings. In fact, Egberts et al.18 created an animal model in which dexamethasone had utility in preventing the recurrence and metastasis of pancreatic cancer. A study by Munstedt et al.19 found that dexamethasone used along with chemotherapy did not affect ovarian cancer outcomes but may have protective effects on bone marrow.
Another often-touted risk of dexamethasone use is the concern for intraoperative and postoperative hyperglycemia, with several previous studies demonstrating a transient rise in glucose levels with the use of glucocorticoids.20,21 Glucocorticoids are known to increase hepatic glucose production, while increasing insulin resistance and decreasing glucose oxidation and uptake.22 These hyperglycemic effects may be associated with adverse outcomes in the critically ill and postsurgical patients, such as suppression of immune function, increase in proinflammatory cytokines, increased systemic vascular resistance, osmotic diuresis, and electrolyte as well as acid–base imbalances.23
Murphy et al.24 address this concern in this issue with a randomized, placebo-controlled trial to address the effect of dexamethasone on blood glucose concentration in the perioperative environment for gynecologic surgical patients. The primary outcome was to determine the effect of a single low-dose dexamethasone therapy (4 and 8 mg) on blood glucose concentrations during the first 24 hours following administration and to record the incidence of hyperglycemic events (blood glucose level >180 mg/dL). Patients presenting for elective hysterectomies were randomized to receive saline, dexamethasone 4 mg, or dexamethasone 8 mg, with blood glucose measurements at specified times for each group within a 24-hour perioperative period. The study found that while blood glucose concentrations increased significantly in all control and dexamethasone groups, they did not differ significantly between the dexamethasone and saline control groups at any time within the 24-hour perioperative period. Therefore, the results suggest that low-dose dexamethasone used for PONV prophylaxis should not be avoided because of concerns for hyperglycemic events. This finding is supported by other evidence in the literature. One study by Abdelmalak et al.25 showed that while patients undergoing major noncardiac surgery had higher blood glucose levels after receiving dexamethasone 8 mg versus placebo, the effect was very limited in both diabetic and nondiabetic patients. A similar study by Nazar et al.26 investigated a group of 40 nondiabetic and 30 type-2 diabetic patients undergoing laparoscopic cholecystectomy. Patients were randomized to receive either saline or dexamethasone 8 mg, and the results showed that there was no higher susceptibility in the type-2 diabetic patients than the nondiabetic patients to develop perioperative hyperglycemia following PONV doses of dexamethasone.
Our group recently wrote an editorial in this journal with the title: Wound complications with dexamethasone for postoperative nausea and vomiting prophylaxis: a moot point?27 We concluded that the current literature does not support the concern that single-dose use of intraoperative dexamethasone contributes to a statistically significant increase in the incidence of wound complications or time to complete wound healing.27 This, along with the above evaluations of the concerns of the use of single-dose dexamethasone for PONV and the recurrence of cancer or intraoperative hyperglycemia, suggest again that anesthesiologists can safely use dexamethasone 4 to 8 mg doses for PONV prophylaxis.
Name: Brian Colin, MD.
Contribution: The author helped write the manuscript.
Conflicts of Interest: The author has no conflicts of interest to declare.
Name: Tong J. Gan, MD, MHS, FRCA.
Contribution: The author helped write the manuscript.
Conflicts of Interest: Research Support from: Pacira, Covidien, Fresenius, Merck, Purdue, AcelRx, Acacia. Honoraria received from: Merck, Cadence, Edwards, Covidien.
This manuscript was handled by: Sorin J. Brull, MD, FCARCSI (Hon).
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