Abstract

Postoperative nausea and vomiting (PONV) is a common annoying experience after surgery. The overall incidence of PONV in adults is 20–30%; the incidence rate in patients of high-risk groups can be as high as 70–80%. Children are not exempted from attacking either; the incidence rate in children above the age of 3 is more than 40%. The incidence slowly drops after puberty, sharing the same rate with adults. Dexamethasone can be effective in preventing PONV in adults and children. Compared with other preventive medications, dexamethasone has equal or even better efficacy in reducing the incidence of PONV and has the advantages of low cost and longer effectiveness as well. Although the action mechanism of dexamethasone is hitherto not fully understood, animal studies have confirmed that the vomiting center in the brain stem plays a central role. A combination of dexamethasone with other antiemetics is more effective than any single drug alone. Additionally, the use of dexamethasone to prevent nausea and vomiting triggered by intravenous or epidural morphine for pain control can also offer a good therapeutic effect. To date, clinically, dexamethasone as a preventative drug against PONV has not caused fatal outcome; therefore, it is generally considered to be an effective and safe antiemetic. Nevertheless, its use in this regard may lead to adverse effects, principally postoperative hyperglycemia and infection.

Keywords

antiemetics; dexamethasone; glucocorticoids; postoperative complications;

1. Introduction

Postoperative nausea and vomiting (PONV) is a common postoperative unpleasant experience. Although improvement of various anesthetics and the identification of patient-, anesthesia-, and surgery-related risk factors for PONV have helped to develop many preventive strategies in recent years, the overall incidence of PONV in the adult population still remains at 20–30%.1, 2 The PONV incidence rate in patients of high-risk groups could be as high as 70–80%.² Additionally, children are not exemptible from PONV. The incidence rate for children above the age of 3 exceeds 40%.² It is not until they have reached puberty does the incidence rate begin to decline. PONV is highly troubling: it not only results in delayed discharge from the hospital, leading to lavishing medical resources, but also reduces patient satisfaction. Traditional preventive treatment of PONV includes: serotonin Type 3 receptor antagonist (ondansetron, dolasetron, and granisetron), dopamine Type 2 receptor antagonist (droperidol and metoclopramide), muscarinic cholinergic Type 1 receptor antagonist (scopolamine), and histamine Type 1 receptor antagonist (promethazine and prochlorperazine).² Since the mid 1980s, studies have shown that dexamethasone can reduce vomiting in patients after chemotherapy.3, 4, 5, 6 Subsequent studies have also found that dexamethasone can effectively prevent PONV7, 8, 9 induced by epidural morphine used to reduce postoperative pain.¹⁰ A decade ago, results from meta-analysis have further suggested that the preventive effect of dexamethasone against PONV is similar to ondansetron.¹¹ Because of its low cost and safety in use, dexamethasone may well be the first drug of choice in preventing PONV.11, 12, 13 Clearly, it should be noted that none of the aforementioned drugs could completely prevent PONV. Here, we report the latest findings on dexamethasone as a preventive drug against PONV and its potential adverse effects.

1.1. Possible action mechanism of dexamethasone in PONV prevention

At present, the action mechanism of dexamethasone in PONV prevention is still not fully understood. Dexamethasone is a synthetic form of adrenocorticoid, and acts mainly as a glucocorticoid receptor with almost no mineralocorticoid receptor functions.¹⁴ The physiological effect of dexamethasone is the result of its action with glucocorticoid receptor. Numerous cells with this type of receptor exist in the body.¹⁴ Some glucocorticoid receptors are related to the physiological conduction path for vomiting.15, 16 The glucocorticoid receptors exist in the part of the brain stem where the nucleus of solitary tract and area postrema reside.¹⁷ Recent animal experiments have proved that glucocorticoid receptors on both sides of the nucleus of the solitary tract, not area postrema, in the brain stem act to conduct the main antiemetic effect of dexamethasone.18, 19, 20 Other possible explanations for dexamethasone preventing PONV include central inhibition of prostaglandin synthesis, reduction of central serotonin activity, and change of permeability of blood-brain barrier to plasma proteins.¹¹ However, all aforementioned explanations lack direct experimental evidence. Beyond these possible explanations for dexamethasone preventing PONV, the anti-inflammatory effect of dexamethasone is even stronger. Dexamethasone can effectively reduce local inflammatory reactions after surgery; this may reduce the inflammation triggered by afferent stimulation of parasympathetic nervous system to the vomiting center, thereby reducing PONV. Additionally, dexamethasone increases synthesis of endorphin in the body,¹⁴ uplifting moods and appetite.²¹

1.2. Dosage and timing of administration of dexamethasone

The recommended intravenous dose of dexamethasone for prevention of PONV in adults is 2.5–10 mg22, 23; its recommended dose for children is 0.15–1 mg.²⁴ Adult dosage studies have determined that a minimum of 2.5 mg of an intravenous injection of dexamethasone for PONV prevention is required after gynecological surgery (abdominal total hysterectomy, myomectomy, and radical hysterectomy),²² and a minimum of 5 mg of an intravenous dose of dexamethasone after thyroidectomy.²³ Dexamethasone has also demonstrated preventive effects against nausea and vomiting induced by intravenous or epidural morphine for postoperative pain control.10, 25, 26, 27 The respective minimum doses were 8 mg (to prevent nausea and vomiting triggered by intravenous injection of morphine)²⁵ and 5 mg (to prevent nausea and vomiting triggered by epidural injection of morphine).26, 27 As a result, different optimal doses of dexamethasone are used to treat nausea and vomiting caused by various emetic factors.

The timing of administration of dexamethasone is crucial for preventing PONV. Intravenous dexamethasone generally requires a longer period of time to take effect and a time lag of 12–24 hours to achieve the maximal result¹⁴; and its physiological effect in the body can remain for 36–72 hours.¹⁴ In terms of these pharmacological properties, the characteristic of dexamethasone is clearly a drug with the slow onset time and long duration of action. Studies have showed that the antiemetic effect of dexamethasone begins approximately 2 hours after intravenous injection.28, 29 Chemotherapy patients have also reported that dexamethasone is effective in preventing a late onset of vomiting.⁵ In preventing an early onset of PONV (nausea and vomiting occurring 0–6 hours after surgery is considered an early onset of PONV; nausea and vomiting occurring after 6–24 hours is considered to be a late onset of PONV), dexamethasone should be given before or immediately after induction of anesthesia rather than waiting until the surgery is nearly completed. However, no studies have touched the duration of antiemetic effect of dexamethasone, but a duration of up to 24 hours after surgery is generally accepted as a fact.11, 12, 13

1.3. The effect of dexamethasone for the prevention of PONV

As the preventive effect of dexamethasone against chemotherapy induced nausea and vomiting was real, many studies on dexamethasone in preventing PONV in various surgical procedures have discovered that the results are generally quite favorable. These procedures have included laparoscopic cholecystectomy, laparoscopic tubal ligation, hysterectomy, thyroidectomy, ear surgery, total knee replacement, tonsillectomy, and strabismus surgery.11, 12, 13, 30

On an average, in every 3.8 children receiving treatment against vomiting, early and late vomiting is prevented in one instance.¹¹ For adults, early and late vomiting could be prevented in 1 of 7.1 patients, and 1 of 4.3 patients for late onset of nausea.¹¹ The effect of dexamethasone in preventing nausea and vomiting was identical or better when compared with that of other antiemetic drugs, such as droperidol or ondansetron.11, 12

Additionally, in patients who used epidural morphine for postoperative analgesia, the incidence of nausea and vomiting was approximately 40–60%.26, 27, 31 Some studies have investigated the relative effectiveness of dexamethasone, saline, droperidol, and tropisetron in treating nausea and vomiting caused by epidural morphine. Dexamethasone has been shown to reduce the incidence rate by approximately 30–40%.26, 27 One study on dosage discovered that a 5 mg intravenous dexamethasone is as effective as 10 mg, such dosages are as effective as 1.25 mg of droperidol for treating nausea and vomiting caused by epidural morphine.²⁷ In contrast, tropisetron had no significant effect in preventing nausea and vomiting caused by epidural morphine.³²

1.4. Use of dexamethasone in combination with other antiemetics

The vomiting center is a region of indefinite boundary in the medulla oblongata close to the nucleus of the solitary tract and area postrema15, 16 The vomiting center receives emetic message peripherally from the surrounding 9^th and 10^th cranial nerves. Vomiting center messages also come centrally from the chemoreceptive trigger zone, vestibular nucleus, nucleus of solitary tract, cerebellum, and higher cerebral cortex.¹⁶ Nausea and vomiting related functional receptors in the above-described emesis-stimulating pathway include the serotonin Type 3 receptor, dopamine Type 2 receptor, muscarinic cholinergic Type 1 receptor, histamine Type 1 receptor, and opioid receptor. Therefore, drugs used to treat PONV are developed from pharmacology research on the antagonistic substances of these receptors.2, 15, 16 Because of the various causes of PONV, antinausea and vomiting treatment from a combination of multiple antiemetic drugs may be more effective than a single antiemetic drug. Numerous researches have been conducted on this subject. Relevant studies have confirmed the combined effectiveness of dexamethasone with serotonin antagonists (ondansetron and granisetron), droperidol, and metoclopramide.¹¹

An intravenous injection of 4 mg of ondansetron and 8 mg of dexamethasone is the most commonly used drug combination to treat PONV. This combination has been used in major gynecological surgery, as well as for patients receiving diagnostic laparoscopy. The results show that the combined use of the two drugs in reducing the incidence of PONV is more effective than the use of either one antiemetic drug alone or a placebo.11, 12 A combination of 3 mg of granisetrone and 8 mg of dexamethasone can also effectively reduce the incidence of PONV.11, 12 The combination has proven to be effective in many surgical operations such as tonsillectomy, breast surgery, laparoscopic cholecystectomy, gynecologic surgery, and caesarean sections.11, 12 The combination of dexamethasone and serotonin antagonists could prevent one of 4 patients from early nausea and vomiting, late nausea could be prevented in one of 3.7 patients, and in late vomiting one of 5.5 patients.11, 12

The combination of 8 mg of dexamethasone with 50 mg of metoclopramide or with 25 mg, can effectively reduce the incidence of PONV.³³ These surgical procedures include thyroidectomy, ear surgery, cholecystectomy, hysterectomy, hernia repair, total knee replacement, and knee arthroscopy.³³ However, only patient groups using 50 mg metoclopramide combined with dexamethasone can effectively reduce a late (occurring 12 hours after surgery) incidence of nausea and vomiting.³³ For an early (occurring postoperatively from 0 to 12 hours) incidence of nausea and vomiting, 25 mg and 50 mg of metoclopramide in combination with dexamethasone are equally effective, causing fewer adverse effects.³³

In December 2001, the U.S. Food and Drug Administration issued a black box warning, stating that the use of droperidol (butyrophenone class of drugs) may be related to fatal arrhythmia (torsade de pointes).³⁴ As a result, two recent studies have explored the use of haloperidol (butyrophenone class of drugs) as an alternative to droperidol to determine whether its combination with dexamethasone can effectively reduce the incidence of PONV.35, 36 The combined use of 2 mg of haloperidol with 5 mg of dexamethasone in laparoscopically assisted vaginal hysterectomy,³⁵ and the combined use of 1.5 mg of haloperidol with 8 mg of dexamethasone in plastic and otorhinolaryngologic procedures³⁶ are both effective in reducing the incidence of PONV. It is noteworthy that patients using haloperidol may also be subjected to fatal arrhythmia (torsade de pointes).³⁷

1.5. Use of dexamethasone in children

The recommended dose of dexamethasone for use in children to prevent PONV is 0.15–1.0 mg/kg.²⁴ This measure is also effective in patients receiving tonsillectomy and strabismus surgery.24, 38, 39 After the induction of anesthesia, an intravenous injection of 1.0 mg/kg of dexamethasone to prevent PONV is more cost-effective than 100 μg/kg of ondansetron.²⁴ Moreover, dexamethasone has the additional advantage of extending the antiemetic effect (up to 6–24 hours after surgery).²⁴ In one study on the effective and safe dosage range of the drugs used,³⁸ data were collected from 168 child patients undergoing strabismus surgery. The study discovered that using 0.25 mg/kg of dexamethasone for the prevention of PONV was more effective than saline. However, increase in dosage of dexamethasone did not increase the antiemetic effect. In that experiment, nine children received more than 20 mg of dexamethasone without adverse effect, 7 days after surgery. According to the results, if dexamethasone is to be used to prevent one case of severe PONV in child patients, it is necessary at least to triplcate the treatment cases to achieve this goal.³⁸ A recent large-scale study,³⁹ whose data were collected from 215 children undergoing tonsillectomy surgery, discovered that a low-dose of dexamethasone (0.05 mg/kg) was already effective in preventing PONV, whereas the use of 0.5 mg/kg of dexamethasone would increase the risk of wound bleeding. However, should a single use of a low-dose dexamethasone actually produce adverse effects with grave influence on the prognosis for patients, the clarification of this predicament relies on further large-scale clinical trials.

1.6. The potential adverse effects of using dexamethasone

Adverse effects from using large amounts of dexamethasone may include difficulty in controlling blood sugar levels, wound infections, delayed wound healing, gastric ulcers, and avascular necrosis. These are potential adverse effects of long-term use of dexamethasone.11, 13, 14 Recent studies have shown that although a single use of a low-dose of dexamethasone is effective in preventing PONV, its use can slightly increase blood glucose levels within 24 hours (Table 1)40, 41, 42, 43, 44, 45; after 24 hours, there is a severe drop in cortisol in the blood.⁴³ Whether a low-dose of dexamethasone alone leads to any increase in postoperative infections, has yet to be determined by an academic institution that used different research methods in the study (retrospective cohort study vs. matched case-control study) in which the conclusions made were both positive and negative (Table 2).46, 47 Furthermore, in numerous studies on prevention of PONV with dexamethasone, no fatal outcomes have been reported.11, 12, 13, 14 Therefore, dexamethasone is generally considered a safe antiemetic. However, if a single use of a low-dose of dexamethasone could really produce adverse effects that influence the prognosis for patients, the solution of the riddle depends on further large-scale clinical trials.

Table 1. Summary of included studies evaluating the postoperative glycemia after antiemetic doses of dexamethasone.

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Table 2. Summary of included studies evaluating the postoperative infection after antiemetic doses of dexamethasone.

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2. Conclusion

The use of dexamethasone for the prevention of PONV is effective and safe. The most commonly used intravenous dose is 5–10 mg for adults and 0.15–1 mg/kg for children. It is recommended that dexamethasone be administered before or after the induction of anesthesia or right at the beginning of surgery. Dexamethasone is highly effective in preventing a late onset of PONV, mainly because the onset of the effect of dexamethasone usually takes much longer time. For this reason, dexamethasone is not considered as an effective drug for immediate relief of existing PONV. To date, a combination of dexamethasone and serotonin antagonist may be the most effective treatment of preventing PONV. Although no fatal outcomes have been reported from single use of dexamethasone at low-dose, this preventive antiemetic might bring about adverse effects such as postoperative hyperglycemia and infection.

Acknowledgments

This work was supported, in part, by grants (V97C1-005, V98C1-049, V99C1-008, V100C-022) from the Taipei Veterans General Hospital, Taipei, Taiwan.