Postoperative Nausea and Vomiting
All 8 studies reported on the incidence of PON (Table 3).11–18 Overall, when all doses of dexamethasone for all included studies were combined, there was a significant reduction in the incidence of PON compared with placebo (19% vs 36%, RR [95% CI] = 0.57 [0.45, 0.72]). Doses of 5, 8, and 10 mg significantly reduced the incidence of PON compared with placebo. However, the lowest dose of 2.5 mg did not significantly reduce the incidence of PON. There was no evidence of heterogeneity observed with this outcome (I2 [95% CI] = 32% [0%, 70%]). A fixed effect meta-regression demonstrated no evidence of dose-responsiveness for PON. The slope (95% CI) was 0.01160 (−0.09684, 0.12003) log RR per milligram of dexamethasone (P = 0.83). In a subgroup analysis by type of surgery, dexamethasone significantly reduced the incidence of PON compared with placebo in patients having abdominal hysterectomy (15% vs 32%, RR [95% CI] = 0.46 [0.31, 0.68]) and cesarean delivery (23% vs 41%, RR [95% CI] = 0.68 [0.51, 0.90]). In a subgroup analysis by route of administration of neuraxial morphine, dexamethasone significantly reduced PON compared with placebo in patients receiving epidural morphine (14% vs 31%, RR [95% CI] = 0.45 [0.32, 0.62]). In these studies, dexamethasone was also administered before epidural morphine. In the studies in which intrathecal morphine was administered, there was no difference in PON between the groups (52% vs 58%, RR [95% CI] = 0.89 [0.64, 1.22]).
POV was investigated in all 8 studies (Table 3).11–18 Overall, when all doses of dexamethasone were combined, there was a significant reduction in the incidence of POV compared with placebo (15% vs 30%, RR [95% CI]) = 0.56 [0.43, 0.72]). Doses of 5, 8 and 10 mg significantly reduced the incidence of POV when compared with placebo (Table 1). There was no evidence of heterogeneity among the trials (I2 [95% CI] = 44% [0%, 75%]). A fixed effect meta-regression demonstrated no evidence of a dose-response relationship. The slope (95% CI) was 0.1127 (−0.0244, 0.2498) log RR per milligram of dexamethasone (P = 0.11). In a subgroup analysis by the type of surgery, dexamethasone significantly reduced the incidence of POV compared with placebo in patients having total abdominal hysterectomy (9% vs 25%, RR [95% CI] = 0.36 [0.22, 0.61]) and cesarean delivery (20% vs 36%, RR [95% CI] = 0.70 [0.52, 0.96]). In a subgroup analysis by route of administration of neuraxial morphine, dexamethasone significantly reduced the incidence of POV in those patients receiving epidural morphine compared with placebo (9% vs 24%, RR [95% CI] = 0.38 [0.25, 0.57]). However, in the studies in which intrathecal morphine was administered, there was no difference in POV between the groups (50% vs 55%, RR [95% CI = 0.91 [0.65, 1.28]).
Use of Postoperative Rescue Antiemetic Treatment
All 8 studies investigated the use of postoperative rescue antiemetic therapy (Table 3).11–18 Ondansetron 4 mg was the rescue antiemetic used in 4 studies,11,13,16,18 metoclopramide 10 mg in 2 studies,14,15 droperidol 1.25 mg in 1 study,12 and prochlorperazine 12.5 mg in the remaining study.17 Overall, when all doses of dexamethasone were combined, there was a significant reduction in the use of postoperative rescue antiemetic therapy when compared with placebo (16% vs 35%, RR [95% CI] = 0.47 [0.36, 0.61]). There was no evidence of significant heterogeneity (I2 = 47%). Dexamethasone at doses of 5, 8, and 10 mg also significantly reduced the need for a rescue antiemetic therapy (Table 2). In a subgroup analysis by the type of surgery, dexamethasone reduced the need for postoperative rescue antiemetic therapy in patients undergoing total abdominal hysterectomy (13% vs 31%, RR [95% CI] = 0.38 [0.25, 0.59]) and cesarean delivery (18% vs 38%, RR [95% CI] = 0.53 [0.29, 0.98]) compared with placebo. In a subgroup analysis by route of administration of neuraxial morphine, dexamethasone significantly reduced the use of postoperative rescue antiemetic therapy in those patients receiving epidural morphine compared with placebo (12.8% vs 32.8%, RR [95% CI] = 0.37 [0.26, 0.52]). A similar effect was not observed in patients receiving intrathecal morphine (35% vs 42%, RR [95% CI = 0.84 [0.56, 1.26]).
Postoperative Pain Intensity
Seven studies reported on postoperative pain intensity in patients receiving dexamethasone for PONV prophylaxis.11–14,16–18 Six of these studies reported early pain scores at or around 4 hours (Fig. 3A).11–14,16,18 Five studies reported late postoperative pain scores at 24 hours (Fig. 3B).11–13,16,18 One study reported highest and lowest pain scores only, without specifying a time period.17 There were no differences in early pain scores in patients receiving dexamethasone compared with those receiving placebo. Overall, when all doses were combined, dexamethasone reduced postoperative pain scores at 24 hours when compared with the placebo group (MD [95% CI] = −0.30 [−0.46, −0.13]). There was evidence of significant heterogeneity among the included trials (I2 = 72%). Removing the only study11 in which intrathecal morphine was administered abolished this heterogeneity (I2 = 0). When combining the remaining studies, there was still a reduction in pain scores (MD [95% CI] = −0.20 [−0.37, −0.02]). Doses of dexamethasone of 5 mg (MD [95% CI] = −0.19 [−0.37, −0.01]) and 8 mg (MD [95% CI] = −1.00 [−1.45, −0.55]) significantly reduced pain scores at 24 hours compared with placebo. No conclusion could be drawn for the comparison of the highest reported pain scores between patients receiving dexamethasone and those in the placebo group because of the wide CIs of the pooled results (MD [95% CI] = −1.87 [−4.16, 0.41]).
Use of Postoperative Rescue Analgesics
All 8 studies reported on the use of rescue analgesics in patients receiving dexamethasone for PONV prophylaxis.11–18 In 6 of the studies, diclofenac 75 mg IM was used as the rescue analgesic.11,12,14–16,18 IV tenoxicam 20 mg was administered in 1 study13 and oral acetaminophen 500 mg/codeine 30 mg in the other.17 Overall, dexamethasone reduced the use of postoperative rescue analgesics compared with placebo (27% vs 38%, RR [95% CI] = 0.76 [0.62, 0.93]) (Fig. 3C). In subgroup analysis by dexamethasone dose, only dexamethasone at a dose of 5 mg significantly reduced the need for rescue analgesia when compared with placebo (27% vs 38%, RR [95% CI] = 0.72 [0.52, 0.98]). There was no evidence of heterogeneity among the trials (I2 = 0). In a subgroup analysis by type of surgery, dexamethasone compared with placebo reduced the need for postoperative rescue analgesia in patients undergoing total abdominal hysterectomy (28% vs 40%, RR [95% CI] = 0.74 [0.56, 0.99]) but not after cesarean delivery. In a subgroup analysis by route of administration, dexamethasone was effective in significantly reducing the use of postoperative rescue analgesia after epidural morphine administration (26% vs 37%, RR [95% CI] = 0.74 [0.59, 0.95]). However, in patients receiving intrathecal morphine, no conclusion could be made regarding the use of postoperative rescue analgesics between the treatment and placebo groups (35% vs 43%, RR [95% CI] = 0.81 [0.55, 1.18]).
Six studies reported the incidence of pruritus associated with neuraxial morphine in patients receiving dexamethasone or placebo.11–15,17 Overall, dexamethasone did not significantly reduce the incidence of pruritus when compared with placebo (Table 3).
Four studies reported the use of rescue antipruritic medication after the administration of neuraxial morphine.11,12,14,17 IM diphenhydramine 20 mg was the rescue antipruritic in 3 studies12–14 and oral chlorpheniramine 4 mg was the rescue drug in the remaining study.17 Overall, no conclusion could be made regarding the impact of dexamethasone on the use of rescue antipruritic medication when compared with placebo because of the wide CIs of pooled results (Table 3). There was no evidence of heterogeneity for the trials included for both outcomes.
Seven of the 8 studies investigated and reported possible side effects of dexamethasone.11–13,15–18 Side effects were not consistently reported quantitatively and so were reviewed qualitatively. Five studies investigated delayed wound healing as a possible side effect during the patient's postoperative stay.11,13,15,16,18 There were no reported cases in either the treatment or placebo groups. Similarly, there were 5 studies investigating wound infection,11,13,15,16,18 with no reported cases in either the treatment or intervention group. Other less relevant side effects investigated depended on the antiemetics being investigated in conjunction with dexamethasone. Three studies comparing the antiemetic efficacy of droperidol alone or in combination with dexamethasone reported no difference in the incidence of restlessness between the dexamethasone and placebo groups.11,15,18 In 2 of these studies, there was no reported incidence of this side effect in any patient.11,15 Two studies assessed and reported postoperative sedation.11,17 One study compared droperidol alone or in combination with dexamethasone11 whereas the other used cyclizine.17 Both studies used a 4-point sedation scale and reported no difference in sedation scores over the study period between the dexamethasone and placebo groups. One study investigating the antiemetic efficacy of tropisetron reported an incidence of headaches of 5% in both the dexamethasone and placebo groups.12 Another study comparing dexamethasone with metoclopramide reported no cases of extrapyramidal side effects in the dexamethasone and placebo groups.16
The results of this systematic review indicate that a single dose of IV dexamethasone is an effective antiemetic in patients receiving neuraxial morphine as part of a neuraxial anesthetic technique. In addition, dexamethasone produced a small but statistically significant reduction in 24-hour postoperative pain scores and reduced the need for rescue analgesics when compared with placebo. Dexamethasone, however, did not reduce the incidence of neuraxial morphine–induced pruritus when compared with placebo.
Dexamethasone has a well-established role as a prophylactic antiemetic in children and adults receiving general anesthesia.1–4,24 However, PON and POV are also frequent adverse effects after neuraxial morphine administration. Dahl et al.6 reported that the number needed to harm for PON and POV in patients receiving intrathecal morphine for cesarean delivery under spinal anesthesia was 6.3 and 10.1, respectively. The mechanism for the antiemetic effect of dexamethasone remains unknown. The ability of dexamethasone to deplete γ-aminobutyric acid stores, reduce the blood-brain barrier's permeability to emetic toxins, inhibit brainstem enkephalin release, central prostaglandin synthesis, and serotonin synthesis and release are among the proposed mechanisms.25,26 Its long duration of action makes it an ideal drug for prophylaxis in patients receiving long-acting neuraxial opioids.1 In this patient population, dexamethasone reduced the overall incidence of PON. The lowest effective dose for the prevention of PON and POW was 5 mg. The lowest effective dose of dexamethasone for PONV prophylaxis in patients receiving neuraxial morphine has not been established but at least one other study found doses as low as 2.5 mg to be an effective antiemetic in adult patients receiving general anesthesia.27 Published consensus guidelines for the management of PONV recommend doses of 4 to 5 mg for antiemetic prophylaxis.24
Interestingly, dexamethasone was an effective antiemetic in patients receiving epidural morphine but ineffective in patients receiving intrathecal morphine. However, based on the small sample size of the pooled results in the intrathecal morphine subgroup analysis, the power to detect a difference may have been inadequate (type II error). We pooled both epidural and intrathecal administration of morphine for this meta-analysis based on studies that reported no difference in the incidence of PONV when comparing comparable doses using both routes.28,29 In this review, the overall incidence of PON and POV in the control groups in both trials in which intrathecal morphine was administered was 58% and 55%, respectively, which is much higher than the corresponding incidence of 31% and 24%, respectively, in the trials investigating epidural morphine. It is possible that the mechanism of PONV in patients receiving intrathecal and epidural opioids may not be similar. In addition, the pharmacokinetics of both routes of administration differs significantly, potentially leading to more rapid rostral spread and higher intrathecal concentrations after direct intrathecal administration compared with administration by the epidural route.5,30,31 The intrathecal morphine dose may also have had a role. Doses of intrathecal morphine as high as 0.2 mg are associated with an increase in the incidence of PONV, compared with lower doses, without providing any additional analgesic efficacy.32,33 The timing of administration of dexamethasone in relation to the administration of neuraxial morphine may also have accounted for the observed difference. Dexamethasone was administered before morphine in the epidural studies but after its administration in the intrathecal studies. With the onset of action of the antiemetic effect of dexamethasone estimated to be 2 hours and the possibility of a more rapid onset of emetic symptoms after intrathecal morphine administration, it may have been more prudent to administer the prophylactic drug before initiation of spinal anesthesia.31,34
Dexamethasone reduced pain scores and need for rescue analgesics in this systematic review. None of the trials individually reported any reduction in postoperative pain intensity or need for rescue analgesia between the treatment and placebo groups. However, analgesic outcomes were not a primary end point in any of the studies and the studies were probably not powered to detect this end point. The reduction in 24-hour pain scores highlights the slow onset and long duration of action of dexamethasone and a possible synergistic action between neuraxial morphine and dexamethasone. The administration of a single dose of dexamethasone has been associated with a reduction in tissue inflammatory mediators, including bradykinin, prostaglandins, and other nociception-promoting neuropeptides; this may contribute to its analgesic properties.35 Dexamethasone has been shown to significantly reduce postoperative peritoneal inflammation and abdominal pain after colectomy.35 However, although the overall reduction in late pain scores was statistically significant, it was small and may not be clinically relevant, especially in patient populations in which the pain scores were low.
Pruritus is a common adverse effect of neuraxial morphine but currently there seem to be no consistently effective therapies.36 The lack of an antipruritic effect of dexamethasone is disappointing in light of its antiemetic and antiinflammatory properties. However, dexamethasone administration has been associated with perineal pruritus, a poorly understood phenomenon that is associated with bolus administration and more frequently reported in females.37,38
This meta-analysis has several limitations. We identified evidence of publication bias. Of the 8 trials included in this review, 6 were able to demonstrate some degree of antiemetic efficacy of single-dose dexamethasone. The causes of publication bias have been highlighted in previous publications and its presence may make the validity of the findings of this review questionable.3,10 However, tests of publication bias are unreliable in meta-analyses based exclusively on multiple small trials and therefore the results of these tests should be interpreted with caution.10 Another limitation is that 7 of the 8 studies were performed in Taiwan, Republic of China. In fact, the studies seemed to have been performed at the same institution and the study population also only included female patients. The results may therefore not be applicable to the male population or those of different ethnicity. With respect to the study design, in the majority of the studies, dexamethasone was administered at the end of surgery or postoperatively. This is in contradiction to evidence suggesting a superior antiemetic efficacy of dexamethasone when administered at the induction of anesthesia rather than at the end of surgery in patients receiving general anesthesia.24,34 The optimal timing of administration of dexamethasone in patients receiving neuraxial anesthesia has not been determined but is likely similar to general anesthesia given the slow onset of action of dexamethasone. Pain was a secondary end point in the included trials and details about postoperative analgesia were mainly reported as number of patients requiring rescue and not consistently as doses of rescue drugs given. Overall, side effects were poorly reported in the included trials. Adverse effects such as wound infection and delayed wound healing are of interest but were inadequately reported. Increased risk of bleeding after a single dose of dexamethasone in pediatric tonsillectomies has also been reported, but this risk was not explored in any of the studies.39 Future studies should accurately report side effects so that the overall safety of dexamethasone can be established.
Further research is needed to determine the role of dexamethasone as an antiemetic in patients receiving intrathecal morphine after neuraxial anesthesia. With the popularity of intrathecal morphine for postcesarean analgesia, the efficacy of dexamethasone as an antiemetic, particularly in this at-risk population, needs further investigation. Studies investigating dexamethasone in combination with other pharmacological and nonpharmacological antiemetic therapy are also needed. Dexamethasone's role as an analgesic has been extensively investigated in patients receiving general anesthesia but its role as an analgesic adjunct in patients receiving neuraxial anesthesia remains less clear. Studies investigating the analgesic effect of dexamethasone in this patient population as a primary outcome are needed.
In conclusion this systematic review presents relatively strong evidence that a single IV dose of dexamethasone 5 to 10 mg was an effective antiemetic for women receiving neuraxial morphine for cesarean delivery or abdominal hysterectomy. Although this review suggests that dexamethasone may not be effective in patients receiving intrathecal morphine, this should be interpreted with caution because of the small number of patients receiving intrathecal morphine that were included in the analysis. There is also some evidence that the doses used for antiemetic prophylaxis also improved postoperative analgesia, although the reduction in pain scores was small and may not be clinically significant. There was no evidence that dexamethasone was an effective antipruritic. Further studies are needed to investigate this drug's safety profile and its efficacy in patients receiving intrathecal morphine. In light of possible publication bias, these findings need to be interpreted with caution.
Name: Terrence K. Allen, MBBS, FRCA.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Attestation: Terrence K. Allen has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Cheryl A. Jones, MD, DVM.
Contribution: This author helped conduct the study and write the manuscript.
Attestation: Cheryl A. Jones has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Ashraf S. Habib, MBBCh, MSc, MHS, FRCA.
Contribution: This author helped design the study, conduct the study, and write the manuscript.
Attestation: Ashraf S. Habib has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
This manuscript was handled by: Cynthia A. Wong, MD.
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