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Society for Obstetric Anesthesia and Perinatology Section Editor: Cynthia A. WongDexamethasone for the Prophylaxis of PostoperativeNausea and Vomiting Associated with NeuraxialMorphine Administration: A Systematic Reviewand Meta-AnalysisTerrence K. Allen, MBBS, FRCA, Cheryl A. Jones, MD, DVM, and Ashraf S. Habib, MBBCh, MSc, MHS, FRCA BACKGROUND: We performed a systematic review to assess the efﬁcacy of dexamethasone in reducing postoperative nausea, vomiting (PONV), pruritus, and enhancing postoperative analgesia in patients receiving neuraxial anesthesia with neuraxial morphine. METHODS: We searched Medline (1966 –2011), the Cochrane Central Register of Controlled Trials, EMBASE, and Web of Science for all randomized controlled trials comparing dexamethasone with placebo for the prevention of PONV and/or pruritus in patients receiving neuraxial morphine as part of a neuraxial anesthetic technique. Data were extracted independently by the authors on the incidence of PONV, pruritus, pain scores at 4 and 24 hours, and use of rescue antiemetics, antipruritics, and analgesics. RESULTS: Eight randomized controlled trials (4 cesarean deliveries, 4 total abdominal hyster- ectomies) were included. From these trials, 768 patients were analyzed with 473 receiving dexamethasone and 295 receiving placebo. The doses of dexamethasone investigated ranged from 2.5 to 10 mg. Dexamethasone reduced the incidence of postoperative nausea (relative risk, RR [95% conﬁdence interval, CI] ϭ 0.57 [0.45, 0.72]), vomiting (RR [95% CI] ϭ 0.56 [0.43, 0.72]), and the use of rescue antiemetic therapy (RR [95% CI] ϭ 0.47 [0.36, 0.61]) compared with placebo. There was no evidence of dose responsiveness with respect to its antiemetic effect. Dexamethasone also reduced 24-hour visual analog pain scores (measured on an 11-point scale [0 –10]) (mean difference [95% CI] ϭ Ϫ0.30 [Ϫ0.46, Ϫ0.13]) and the use of rescue analgesics (RR [95% CI] ϭ 0.72 [0.52, 0.98]). Dexamethasone did not reduce the incidence of pruritus (RR [95% CI] ϭ 0.98 [0.84, 1.15]). Examination of the funnel plots and Egger’s test revealed evidence of publication bias in the primary outcomes. CONCLUSION: Dexamethasone is an effective antiemetic for patients receiving neuraxial morphine for cesarean delivery and abdominal hysterectomy. In addition, the doses used for antiemetic prophylaxis enhanced postoperative analgesia compared with placebo. However, dexamethasone was not effective for the prophylaxis against neuraxial morphine–induced pruritus. (Anesth Analg 2012;114:813–22)D examethasone is an effective antiemetic when administered prophylactically in patients receiving general anesthesia.1– 4 However, its role as an anti-emetic in patients receiving neuraxial anesthesia is not well local anesthetics provides effective long-lasting postoperative analgesia.5 However, neuraxial morphine has been associated with a frequent incidence of postoperative nausea, vomiting (PONV) and pruritus.6described. Neuraxial anesthesia is frequently used for We performed this systematic review and meta-analysiscesarean delivery and other lower abdominal and lower primarily to assess the efficacy of dexamethasone prophy-limb procedures. The addition of neuraxial morphine to laxis in reducing the overall incidence of postoperative nausea (PON) and postoperative vomiting (POV). Second- arily, we also planned to assess its role in preventingFrom the Department of Anesthesiology, Duke University Medical Center, pruritus and enhancing postoperative analgesia in patientsDurham, North Carolina. receiving neuraxial morphine as a part of a neuraxialAccepted for publication December 9, 2011. anesthetic technique.Supported solely by funding from the Duke University Medical Center’sDepartment of Anesthesiology, Women’s Anesthesia and Critical CareDivision. METHODSThe authors declare no conflicts of interest. We followed the recommendations of the PRISMAThis report was previously presented, in part, at the American Society of statement.7Anesthesia’s Annual Meeting in New Orleans, LA, October 2009.Reprints will not be available from the authors. Eligibility CriteriaAddress correspondence to Terrence K. Allen, MBBS, FRCA, Duke Univer- We performed a literature search of all published reports ofsity Medical System, Box 3094, Durham, NC 27710. Address e-mail toterrence.allen@duke.edu. randomized controlled trials that compared a single dose ofCopyright © 2012 International Anesthesia Research Society IV dexamethasone with placebo primarily for the preven-DOI: 10.1213/ANE.0b013e318247f628 tion of PONV in patients who received a single dose ofApril 2012 • Volume 114 • Number 4 www.anesthesia-analgesia.org 813

Dexamethasone and Neuraxial Morphine–Induced PONVneuraxial preservative-free morphine as an adjunct to a mean difference (MD) with 95% CI. If the 95% CI includedneuraxial anesthetic technique. In addition, we collected a value of 0, it was assumed that there was no differencedata on the incidence of pruritus and/or need for rescue between the groups. Mean and standard deviations wereantipruritic treatment, as well as pain scores and/or the estimated from studies reporting outcomes as median andneed for rescue analgesics. The primary anesthetic tech- range as recommended by Hozo et al.9 A fixed effectsnique had to be neuraxial anesthesia. model was used by default. Significant heterogeneity was defined as I2 Ͼ 50%, and in such cases, the reason forLiterature Search and Study Selection heterogeneity was explored. Forest plots were used toWe searched Medline (1966 –2011), the Cochrane Central graphically represent and evaluate treatment effects. TheRegister of Controlled Trials, EMBASE, and Web of Science number needed to treat was calculated to estimate theusing the terms “dexamethasone,“ “postoperative,” “nausea,” overall clinical impact of any statistically significant inter-“vomiting,” “emesis,” “morphine,” “epidural,” “extradural,” ventions for dichotomous data for the primary outcomes.“spinal,” “intrathecal,” “neuraxial,” “an(a)esthesia,” “analge- To assess whether there was a dose-response relationshipsia” and/or “pruritus,” and their combinations in all fields for the antiemetic efficacy of dexamethasone, we per-without language restriction up to February 2011. The bibli- formed a meta-regression in which the outcome variableographies of retrieved trials were used to identify other was the log (RR) for PON or POV and the predictorrelevant articles. variable was dexamethasone dose. A fixed effect regression The methodological quality of the included studies was model was used. Publication bias was assessed usingassessed using the risk of bias tool recommended by the funnel plots for the primary outcomes and the regressionCochrane Collaboration.8 Two of the authors scored the test described by Egger et al.10 When outcomes were notincluded studies independently (TKA and CAJ). Any dis- consistently reported and quantitative analysis was inap-crepancies were resolved by discussion with the third propriate, they were reviewed qualitatively.author (ASH). Analyses were performed using Review Manager Software (Review Manager [Revman] Version 5.0. Co-Data Collection and Presentation penhagen: The Nordic Cochrane Centre, The CochraneOne author (TKA) extracted the data. A data collection Collaboration, 2008), and Comprehensive Meta-Analysissheet was used to collect the following data: (i) authors, (ii) software (Version 2.2.050).year of publication, (iii) primary country of origin, (iv) typeof surgery, (v) anesthetic technique, (vi) dose, timing, and RESULTSroute of administration of neuraxial morphine, (vii) dose We initially identified 191 publications but subsequentlyand time of administration of dexamethasone, (viii) out- excluded 178 articles (Fig. 1). Of the remaining 13 potentiallycome measures including the incidence of PONV, pruritus, relevant articles, 8 were eventually analyzed.11–18 Of thepain intensity, and the use of rescue antiemetics, antipru- excluded studies, no neuraxial morphine was administered inritics, and analgesics postoperatively, and (ix) side effects. 2 studies,19,20 intrathecal neostigmine was administered in 1Two authors (CAJ and ASH) independently checked the study,21 intrathecal meperidine was administered in an-extracted data for accuracy. When studies included mul- other,22 and there was no placebo group in the remainingtiple group comparisons, only data from the dexametha- study.23 Seven of the studies were performed in Taiwan,sone and placebo groups were extracted. For studies not Republic of China11–16,18 and the remaining study in thereporting an overall incidence of PONV but instead report- United Kingdom.17 Authors of 2 publications were con-ing PON and POV at different time intervals, we recorded tacted and provided missing data.14,17 The details of thethe highest incidence for both outcomes. Pain intensity was included trials are shown in Table 1. The methodologicalrecorded at 4 hours (early) and 24 hours (late) or the closest quality of the included studies is summarized in the risk ofreported time intervals in the included studies. Pain scores bias table (Table 2). There were no discrepancies betweenwere assumed to be at rest unless stated otherwise. We also the authors in the assessment of the methodological qualitycollected the highest pain scores reported in each study of the included studies. The 8 randomized controlled trialsregardless of the reported time interval. Pain scores reported included 1014 patients; 246 of these patients receivedas a 0- to 100-mm visual analog scale were converted to an another antiemetic (tropisetron,12 droperidol,11,15,18 cycliz-11-point scale (0 ϭ no pain to 10 ϭ worst pain). We also ine,17 and metoclopramide16) either alone or in combina-performed a subgroup analysis of different dexamethasone tion with dexamethasone. These patients were not includeddoses, surgical procedures, and route of administration of in the analysis. Of the remaining 768 patients, 473 receivedneuraxial morphine for the relevant outcomes when reported IV dexamethasone and 295 received a placebo. Neuraxialby 2 or more studies. Authors were contacted to provide morphine was administered for abdominal hysterectomiesadditional information or clarification when necessary. in 4 studies12,14,16,18 and cesarean deliveries in the remaining 4 studies.11,13,15,17 Epidural anesthesia was the primaryMeta-Analysis anesthetic technique in 6 studies,12–16,18 combined spinal-Dichotomous data were extracted and summarized using epidural anesthesia in 1 study,17 and spinal anesthesia inrelative risks (RRs) with 95% confidence intervals (CIs). If the remaining study.11 The dose of epidural morphine wasthe 95% CI included a value of 1, it was assumed that there 3 mg12–16,18 and the dose of intrathecal morphine was 0.2was no statistically significant difference between dexa- mg.11,17 The doses and time of administration of dexameth-methasone and placebo. Continuous data were extracted as asone in each individual trial are listed in Table 1. Six stud-mean and standard deviations and summarized using ies investigated a single dose of dexamethasone11,12,14 –17814 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA

Figure 1. Flow chart of screened, excluded, andincluded trials. The included trials investigateddexamethasone as an antiemetic in patients receiv-ing neuraxial morphine who also had neuraxialanesthesia as the primary anesthetic technique.RCTs ϭ randomized controlled trials.whereas 2 dose ranging studies compared 3 doses with a There was no evidence of heterogeneity observed with thisplacebo group.13,18 Dexamethasone was used at a dose of outcome (I2 [95% CI] ϭ 32% [0%, 70%]). A fixed effect2.5 mg in 2 studies,13,18 5 mg in 4 studies,12,13,16,18 8 mg in meta-regression demonstrated no evidence of dose-4 studies,11,14,15,17 and 10 mg in 2 studies13,18 (Tables 1 and responsiveness for PON. The slope (95% CI) was 0.011603). Dexamethasone was administered before neuraxial mor- (Ϫ0.09684, 0.12003) log RR per milligram of dexamethasonephine in 6 studies12–16,18 and after in 2 studies.11,17 In 7 of (P ϭ 0.83). In a subgroup analysis by type of surgery,the 8 studies,11–16,18 dexamethasone was administered as dexamethasone significantly reduced the incidence of PONan IV bolus, and in the remaining study,17 the drug was compared with placebo in patients having abdominal hys-administered as an infusion. Visual examination of the terectomy (15% vs 32%, RR [95% CI] ϭ 0.46 [0.31, 0.68]) andfunnel plots for both PON (Fig. 2) and POV (not shown) cesarean delivery (23% vs 41%, RR [95% CI] ϭ 0.68 [0.51,revealed evidence of publication bias. Egger’s test was also 0.90]). In a subgroup analysis by route of administration ofstatistically significant for both PON (intercept [95% CI] ϭ neuraxial morphine, dexamethasone significantly reducedϪ2.84 [Ϫ4.26, Ϫ1.42], P ϭ 0.002) and POV (intercept [95% PON compared with placebo in patients receiving epiduralCI] ϭ Ϫ2.80 [Ϫ3.87, Ϫ1.73], P Ͻ 0.001). morphine (14% vs 31%, RR [95% CI] ϭ 0.45 [0.32, 0.62]). In these studies, dexamethasone was also administered beforePostoperative Nausea and Vomiting epidural morphine. In the studies in which intrathecalPostoperative Nausea morphine was administered, there was no difference inAll 8 studies reported on the incidence of PON PON between the groups (52% vs 58%, RR [95% CI] ϭ 0.89(Table 3).11–18 Overall, when all doses of dexamethasone for [0.64, 1.22]).all included studies were combined, there was a significantreduction in the incidence of PON compared with placebo Postoperative Vomiting(19% vs 36%, RR [95% CI] ϭ 0.57 [0.45, 0.72]). Doses of 5, 8, POV was investigated in all 8 studies (Table 3).11–18 Overall,and 10 mg significantly reduced the incidence of PON when all doses of dexamethasone were combined, there wascompared with placebo. However, the lowest dose of 2.5 a significant reduction in the incidence of POV compared withmg did not significantly reduce the incidence of PON. placebo (15% vs 30%, RR [95% CI]) ϭ 0.56 [0.43, 0.72]). DosesApril 2012 • Volume 114 • Number 4 www.anesthesia-analgesia.org 815

816 Table 1. Characteristics of Included Trials Time of Timing of dexamethasone Dose and route Postoperative Postoperative Postoperative First author, year administration administration in relation Type of Anesthetic of neuraxial rescue rescue rescue of publication Study groups (n) of study drug to neuraxial morphine surgery technique morphine antiemetic antipruritic analgesic Outcomes analyzed Wang, 199914 Dexamethasone 8 mg End of surgery Before TAH Epidural 3 mg epidural Metoclopramide Diphenhydramine Diclofenac 75 PON, POV, use of rescue antiemetics, (38), saline (36) 10 mg IV 20 mg IM mg IM VAS pain scores,a use of rescue analgesia, incidence of pruritus, use of rescue antipruritica Tzeng, 200015 Dexamethasone 8 mg End of surgery Before Cesarean Epidural 3 mg epidural Metoclopramide Diphenhydramine Diclofenac 75 PON, POV, use of rescue antiemetics, (38), droperidol delivery 10 mg IV 20 mg IM mg IM use of rescue analgesia, incidence 1.25 mg (38), of pruritus, incidence of side saline (37) effects Ho, 200118 Dexamethasone End of surgery Before TAH Epidural 3 mg epidural Ondansetron 4 Diclofenac 75 PON, POV, use of rescue antiemetic, 2.5 mg (43), mg IV mg IM VAS pain scores, use of rescuewww.anesthesia-analgesia.org dexamethasone antiemetic, incidence of side 5 mg (42), effects dexamethasone 10 mg (44), droperidol 1.25 mg (42), saline (43) Dexamethasone and Neuraxial Morphine–Induced PONV Wang, 200113 Dexamethasone 2.5 End of surgery Before Cesarean Epidural 3 mg epidural Ondansetron 4 Diphenhydramine Tenoxicam 20 PON, POV, use of rescue antiemetics, mg (44), delivery mg IV 20 mg IM mg IV VAS pain scores, use of rescue dexamethasone 5 analgesics, incidence of pruritus, mg (44), use of rescue antipruritics, dexamethasone 10 incidence of side effects mg (43), saline (44) Tzeng, 200216 Dexamethasone 5 mg End of surgery Before TAH Epidural 3 mg epidural Ondansetron 4 Diclofenac 75 PON, POV, use of rescue antiemetics, (38), mg IV mg IM VAS pain scores, use of rescue metoclopramide 10 analgesia, incidence of side mg (39), saline effects (38) Wang, 200212 Dexamethasone 5 mg End of surgery Before TAH Epidural 3 mg epidural Droperidol 1.25 Diphenhydramine Diclofenac 75 PON, POV, use of rescue antiemetics, (38), tropisetron 5 mg IV 20 mg IV mg IM VAS pain scores, use of rescue mg (38), saline analgesia, incidence of pruritus, (37) use of rescue antipruritics, incidence of side effects Nortcliffe, 200317 Dexamethasone 8 mg In recovery After Cesarean CSE 0.2 mg intrathecal Prochlorperazine Chlorpheniramine Acetaminophen PON, POV, use of rescue antiemetics, (30), cyclizine 50 room delivery 12.5 mg IM 4 mg orally 500 mg/ VAS pain scores, use of rescue mg (30), saline codeine 30 analgesia, incidence of pruritus,a (30) mg orally use of rescue antipruritics, incidence of side effects Wu, 200711 Dexamethasone 8 mg Before skin After Cesarean Spinal 0.2 mg intrathecal Ondansetron 4 Diphenhydramine Diclofenac 75 PON, POV, use of rescue antiemetics, (30), droperidol incision delivery mg 20 mg IV mg IM VAS pain scores, use of rescue 1.25 mg (30), analgesics, incidence of pruritus, dexamethasone 8 incidence of side effects mg ϩ droperidol 1.25 mg (30), saline (30) TAH ϭ total abdominal hysterectomy; CSE ϭ combined spinal-epidural; PON ϭ postoperative nausea; POV ϭ postoperative vomiting; VAS ϭ visual analog scale. a Additional data obtained from authors.ANESTHESIA & ANALGESIA

Table 2. Risk of Bias Adequate sequence Allocation Incomplete data Free of selectiveIncluded studies generation concealment Blinding addressed reportingWang, 199914 Yes No Yes Yes YesTzeng, 200015 Yes No Yes Yes YesHo, 200118 Unclear No Yes Yes YesWang, 200113 Unclear No Yes No YesTzeng, 200216 Yes No Yes Yes YesWang, 200212 Yes No Yes Yes YesNortcliffe, 200317 Yes Yes Yes Yes YesWu, 200711 Yes No Yes Yes YesEach study risk of bias was assessed as Yes (low risk of bias), No (high risk of bias), or Unclear for each question-based entry. Table 3. The Effect of Dexamethasone on the Incidence of Postoperative Nausea, Vomiting, Pruritus, and the Use of Rescue Antiemetics and Antipruritics Risk of treatment group Risk of control group RR (95% CI) NNT (95% CI)Incidence of postoperative nausea Dexamethasone 2.5 mg13,18 19/87 (22%) 26/87 (30%) 0.73 (0.44, 1.22) — Dexamethasone 5 mg12,13,16,18 21/163 (13%) 50/162 (31%) 0.42 (0.26, 0.66) 6 (4, 11) Dexamethasone 8 mg11,14,15,17 39/136 (29%) 57/133 (43%) 0.68 (0.50, 0.92) 8 (4, 35) Dexamethasone 10 mg13,18 10/87 (12%) 26/87 (30%) 0.38 (0.20, 0.75) 5 (3, 15) All studies combined11–18 89/473 (19%) 107/295 (36%) 0.57 (0.45, 0.72) 6 (4, 9)Incidence of postoperative vomiting Dexamethasone 2.5 mg13,18 14/87 (16%) 20/87 (23%) 0.70 (0.38, 1.29) — Dexamethasone 5 mg12,13,16,18 14/163 (9%) 39/162 (24%) 0.36 (0.20, 0.63) 7 (4, 13) Dexamethasone 8 mg11,14,15,17 35/136 (26%) 50/133 (38%) 0.69 (0.50, 0.96) 9 (4, 121) Dexamethasone 10 mg13,18 6/87 (7%) 20/87 (23%) 0.30 (0.13, 0.71) 7 (4, 17) All studies combined11–18 69/473 (15%) 89/295 (30%) 0.56 (0.43, 0.72) 7 (5, 11)Use of rescue antiemetics Dexamethasone 2.5 mg13,18 19/87 (22%) 28/87 (32%) 0.68 (0.41, 1.12) — Dexamethasone 5 mg12,13,16,18 20/163 (12%) 56/162 (35%) 0.35 (0.22, 0.56) 5 (3, 8) Dexamethasone 8 mg11,14,15,17 26/136 (19%) 46/133 (35%) 0.56 (0.38, 0.82) 6 (4, 15) Dexamethasone 10 mg13,18 9/87 (10%) 28/87 (32%) 0.32 (0.16, 0.64) 5 (3, 10) All studies combined11–18 74/473 (16%) 102/295 (35%) 0.47 (0.32, 0.69) 6 (4, 8)Incidence of pruritus All studies combined11–15,17 158/306 (52%) 120/214 (56%) 0.98 (0.84, 1.15) —Use of rescue antipruritic All studies combined12–14,17 29/238 (12%) 26/147 (18%) 0.71 (0.43, 1.18) —RR ϭ relative risk; CI ϭ conﬁdence interval; NNT ϭ number needed to treat.Figure 2. A funnel plot of all included studiesinvestigating dexamethasone for the prevention ofpostoperative nausea.of 5, 8 and 10 mg significantly reduced the incidence of POV surgery, dexamethasone significantly reduced the inci-when compared with placebo (Table 1). There was no evidence of POV compared with placebo in patients havingdence of heterogeneity among the trials (I2 [95% CI] ϭ 44% total abdominal hysterectomy (9% vs 25%, RR [95% CI] ϭ[0%, 75%]). A fixed effect meta-regression demonstrated no 0.36 [0.22, 0.61]) and cesarean delivery (20% vs 36%, RRevidence of a dose-response relationship. The slope (95% CI) [95% CI] ϭ 0.70 [0.52, 0.96]). In a subgroup analysis bywas 0.1127 (Ϫ0.0244, 0.2498) log RR per milligram of dexa- route of administration of neuraxial morphine, dexa-methasone (P ϭ 0.11). In a subgroup analysis by the type of methasone significantly reduced the incidence of POV inApril 2012 • Volume 114 • Number 4 www.anesthesia-analgesia.org 817

Dexamethasone and Neuraxial Morphine–Induced PONVFigure 3. Forest plots showing the effect of dexamethasone on (A) early pain scores (4 hours), (B) late pain scores (24 hours) (measured onan 11-point scale [0 –10]), and (C) use of rescue analgesics. M-H ϭ Mantel-Haenszel; IV ϭ inverse variance.those patients receiving epidural morphine compared subgroup analysis by route of administration of neuraxialwith placebo (9% vs 24%, RR [95% CI] ϭ 0.38 [0.25, 0.57]). morphine, dexamethasone significantly reduced the use ofHowever, in the studies in which intrathecal morphine postoperative rescue antiemetic therapy in those patientswas administered, there was no difference in POV be- receiving epidural morphine compared with placebotween the groups (50% vs 55%, RR [95% CI ϭ 0.91 [0.65, (12.8% vs 32.8%, RR [95% CI] ϭ 0.37 [0.26, 0.52]). A similar1.28]). effect was not observed in patients receiving intrathecal morphine (35% vs 42%, RR [95% CI ϭ 0.84 [0.56, 1.26]).Use of Postoperative Rescue Antiemetic TreatmentAll 8 studies investigated the use of postoperative rescueantiemetic therapy (Table 3).11–18 Ondansetron 4 mg was Postoperative Painthe rescue antiemetic used in 4 studies,11,13,16,18 metoclo- Postoperative Pain Intensitypramide 10 mg in 2 studies,14,15 droperidol 1.25 mg in 1 Seven studies reported on postoperative pain intensity instudy,12 and prochlorperazine 12.5 mg in the remaining patients receiving dexamethasone for PONV prophy-study.17 Overall, when all doses of dexamethasone were laxis.11–14,16 –18 Six of these studies reported early paincombined, there was a significant reduction in the use of scores at or around 4 hours (Fig. 3A).11–14,16,18 Five studiespostoperative rescue antiemetic therapy when comparedwith placebo (16% vs 35%, RR [95% CI] ϭ 0.47 [0.36, 0.61]). reported late postoperative pain scores at 24 hours (Fig.There was no evidence of significant heterogeneity (I2 ϭ 3B).11–13,16,18 One study reported highest and lowest pain47%). Dexamethasone at doses of 5, 8, and 10 mg also scores only, without specifying a time period.17 There weresignificantly reduced the need for a rescue antiemetic no differences in early pain scores in patients receivingtherapy (Table 2). In a subgroup analysis by the type of dexamethasone compared with those receiving placebo.surgery, dexamethasone reduced the need for postopera- Overall, when all doses were combined, dexamethasonetive rescue antiemetic therapy in patients undergoing total reduced postoperative pain scores at 24 hours when com-abdominal hysterectomy (13% vs 31%, RR [95% CI] ϭ 0.38 pared with the placebo group (MD [95% CI] ϭ Ϫ0.30[0.25, 0.59]) and cesarean delivery (18% vs 38%, RR [95% [Ϫ0.46, Ϫ0.13]). There was evidence of significant hetero-CI] ϭ 0.53 [0.29, 0.98]) compared with placebo. In a geneity among the included trials (I2 ϭ 72%). Removing the818 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA

only study11 in which intrathecal morphine was adminis- not consistently reported quantitatively and so were re-tered abolished this heterogeneity (I2 ϭ 0). When combin- viewed qualitatively. Five studies investigated delayeding the remaining studies, there was still a reduction in wound healing as a possible side effect during the patient’spain scores (MD [95% CI] ϭ Ϫ0.20 [Ϫ0.37, Ϫ0.02]). Doses of postoperative stay.11,13,15,16,18 There were no reported casesdexamethasone of 5 mg (MD [95% CI] ϭ Ϫ0.19 [Ϫ0.37, in either the treatment or placebo groups. Similarly, thereϪ0.01]) and 8 mg (MD [95% CI] ϭ Ϫ1.00 [Ϫ1.45, Ϫ0.55]) were 5 studies investigating wound infection,11,13,15,16,18significantly reduced pain scores at 24 hours compared with no reported cases in either the treatment or interven-with placebo. No conclusion could be drawn for the tion group. Other less relevant side effects investigatedcomparison of the highest reported pain scores between depended on the antiemetics being investigated in conjunc-patients receiving dexamethasone and those in the placebo tion with dexamethasone. Three studies comparing thegroup because of the wide CIs of the pooled results (MD antiemetic efficacy of droperidol alone or in combination[95% CI] ϭ Ϫ1.87 [Ϫ4.16, 0.41]). with dexamethasone reported no difference in the incidence of restlessness between the dexamethasone andUse of Postoperative Rescue Analgesics placebo groups.11,15,18 In 2 of these studies, there was noAll 8 studies reported on the use of rescue analgesics in reported incidence of this side effect in any patient.11,15patients receiving dexamethasone for PONV prophy- Two studies assessed and reported postoperative seda-laxis.11–18 In 6 of the studies, diclofenac 75 mg IM was used tion.11,17 One study compared droperidol alone or in com-as the rescue analgesic.11,12,14 –16,18 IV tenoxicam 20 mg was bination with dexamethasone11 whereas the other usedadministered in 1 study13 and oral acetaminophen 500 cyclizine.17 Both studies used a 4-point sedation scale andmg/codeine 30 mg in the other.17 Overall, dexamethasone reported no difference in sedation scores over the studyreduced the use of postoperative rescue analgesics com- period between the dexamethasone and placebo groups.pared with placebo (27% vs 38%, RR [95% CI] ϭ 0.76 [0.62, One study investigating the antiemetic efficacy of tropise-0.93]) (Fig. 3C). In subgroup analysis by dexamethasone tron reported an incidence of headaches of 5% in both thedose, only dexamethasone at a dose of 5 mg significantly dexamethasone and placebo groups.12 Another study com-reduced the need for rescue analgesia when compared with paring dexamethasone with metoclopramide reported noplacebo (27% vs 38%, RR [95% CI] ϭ 0.72 [0.52, 0.98]). There cases of extrapyramidal side effects in the dexamethasonewas no evidence of heterogeneity among the trials (I2 ϭ 0). and placebo groups.16In a subgroup analysis by type of surgery, dexamethasonecompared with placebo reduced the need for postoperativerescue analgesia in patients undergoing total abdominal DISCUSSIONhysterectomy (28% vs 40%, RR [95% CI] ϭ 0.74 [0.56, 0.99]) The results of this systematic review indicate that a singlebut not after cesarean delivery. In a subgroup analysis by dose of IV dexamethasone is an effective antiemetic inroute of administration, dexamethasone was effective in patients receiving neuraxial morphine as part of a neuraxialsignificantly reducing the use of postoperative rescue an- anesthetic technique. In addition, dexamethasone pro-algesia after epidural morphine administration (26% vs duced a small but statistically significant reduction in37%, RR [95% CI] ϭ 0.74 [0.59, 0.95]). However, in patients 24-hour postoperative pain scores and reduced the need forreceiving intrathecal morphine, no conclusion could be rescue analgesics when compared with placebo. Dexameth-made regarding the use of postoperative rescue analgesics asone, however, did not reduce the incidence of neuraxialbetween the treatment and placebo groups (35% vs 43%, RR morphine–induced pruritus when compared with placebo.[95% CI] ϭ 0.81 [0.55, 1.18]). Dexamethasone has a well-established role as a prophylactic antiemetic in children and adults receiving generalPruritus anesthesia.1– 4,24 However, PON and POV are also frequentSix studies reported the incidence of pruritus associated adverse effects after neuraxial morphine administration.with neuraxial morphine in patients receiving dexametha- Dahl et al.6 reported that the number needed to harm forsone or placebo.11–15,17 Overall, dexamethasone did not PON and POV in patients receiving intrathecal morphinesignificantly reduce the incidence of pruritus when com- for cesarean delivery under spinal anesthesia was 6.3 andpared with placebo (Table 3). 10.1, respectively. The mechanism for the antiemetic effect Four studies reported the use of rescue antipruritic of dexamethasone remains unknown. The ability of dexa-medication after the administration of neuraxial mor- methasone to deplete ␥-aminobutyric acid stores, reducephine.11,12,14,17 IM diphenhydramine 20 mg was the rescue the blood-brain barrier’s permeability to emetic toxins,antipruritic in 3 studies12–14 and oral chlorpheniramine 4 inhibit brainstem enkephalin release, central prostaglandinmg was the rescue drug in the remaining study.17 Overall, synthesis, and serotonin synthesis and release are amongno conclusion could be made regarding the impact of the proposed mechanisms.25,26 Its long duration of actiondexamethasone on the use of rescue antipruritic medication makes it an ideal drug for prophylaxis in patients receivingwhen compared with placebo because of the wide CIs of long-acting neuraxial opioids.1 In this patient population,pooled results (Table 3). There was no evidence of hetero- dexamethasone reduced the overall incidence of PON. Thegeneity for the trials included for both outcomes. lowest effective dose for the prevention of PON and POV was 5 mg. The lowest effective dose of dexamethasone forSide Effects PONV prophylaxis in patients receiving neuraxial mor-Seven of the 8 studies investigated and reported possible phine has not been established but at least one study foundside effects of dexamethasone.11–13,15–18 Side effects were doses as low as 2.5 mg to be an effective antiemetic in adultApril 2012 • Volume 114 • Number 4 www.anesthesia-analgesia.org 819

Dexamethasone and Neuraxial Morphine–Induced PONVpatients receiving general anesthesia.27 Published consen- Pruritus is a common adverse effect of neuraxial mor-sus guidelines for the management of PONV recommend phine but currently there seem to be no consistentlydoses of 4 to 5 mg for antiemetic prophylaxis.24 effective therapies.36 The lack of an antipruritic effect of Interestingly, dexamethasone was an effective anti- dexamethasone is disappointing in light of its antiemeticemetic in patients receiving epidural morphine but ineffec- and antiinflammatory properties. However, dexametha-tive in patients receiving intrathecal morphine. However, sone administration has been associated with perinealbased on the small sample size of the pooled results in the pruritus, a poorly understood phenomenon that is associ-intrathecal morphine subgroup analysis, the power to ated with bolus administration and more frequently re-detect a difference may have been inadequate (type II ported in females.37,38error). We pooled both epidural and intrathecal adminis- This meta-analysis has several limitations. We identifiedtration of morphine for this meta-analysis based on studies evidence of publication bias. Of the 8 trials included in thisthat reported no difference in the incidence of PONV when review, 6 were able to demonstrate some degree of anti-comparing comparable doses using both routes.28,29 In this emetic efficacy of single-dose dexamethasone. The causesreview, the overall incidence of PON and POV in the of publication bias have been highlighted in previouscontrol groups in both trials in which intrathecal morphine publications and its presence may make the validity of thewas administered was 58% and 55%, respectively, which is findings of this review questionable.3,10 However, tests ofmuch higher than the corresponding incidence of 31% and publication bias are unreliable in meta-analyses based24%, respectively, in the trials investigating epidural mor- exclusively on multiple small trials and therefore the re-phine. It is possible that the mechanism of PONV in sults of these tests should be interpreted with caution.10patients receiving intrathecal and epidural opioids may not Another limitation is that 7 of the 8 studies were performedbe similar. In addition, the pharmacokinetics of both routes in Taiwan, Republic of China. In fact, the studies seemed toof administration differs significantly, potentially leading have been performed at the same institution and the studyto more rapid rostral spread and higher intrathecal concen- population also only included female patients. The resultstrations after direct intrathecal administration compared may therefore not be applicable to the male population orwith administration by the epidural route.5,30,31 The intra- those of different ethnicity. With respect to the studythecal morphine dose may also have had a role. Doses of design, in the majority of the studies, dexamethasone wasintrathecal morphine as high as 0.2 mg are associated with administered at the end of surgery or postoperatively. Thisan increase in the incidence of PONV, compared with lower is in contradiction to evidence suggesting a superior anti-doses, without providing any additional analgesic effi- emetic efficacy of dexamethasone when administered at thecacy.32,33 The timing of administration of dexamethasone in induction of anesthesia rather than at the end of surgery inrelation to the administration of neuraxial morphine may patients receiving general anesthesia.24,34 The optimal tim-also have accounted for the observed difference. Dexameth- ing of administration of dexamethasone in patients receiv-asone was administered before morphine in the epidural ing neuraxial anesthesia has not been determined but isstudies but after its administration in the intrathecal stud- likely similar to general anesthesia given the slow onset ofies. With the onset of action of the antiemetic effect of action of dexamethasone. Pain was a secondary end pointdexamethasone estimated to be 2 hours and the possibility in the included trials and details about postoperativeof a more rapid onset of emetic symptoms after intrathecal analgesia were mainly reported as number of patientsmorphine administration, it may have been more prudent requiring rescue and not consistently as doses of rescueto administer the prophylactic drug before initiation of drugs given. Overall, side effects were poorly reported inspinal anesthesia.31,34 the included trials. Adverse effects such as wound infection Dexamethasone reduced pain scores and need for rescue and delayed wound healing are of interest but were inad-analgesics in this systematic review. None of the trials equately reported. Increased risk of bleeding after a singleindividually reported any reduction in postoperative pain dose of dexamethasone in pediatric tonsillectomies has alsointensity or need for rescue analgesia between the treat- been reported, but this risk was not explored in any of thement and placebo groups. However, analgesic outcomes studies.39 Future studies should accurately report sidewere not a primary end point in any of the studies and the effects so that the overall safety of dexamethasone can bestudies were probably not powered to detect this end point. established.The reduction in 24-hour pain scores highlights the slow Further research is needed to determine the role ofonset and long duration of action of dexamethasone and a dexamethasone as an antiemetic in patients receiving intra-possible synergistic action between neuraxial morphine thecal morphine after neuraxial anesthesia. With the popu-and dexamethasone. The administration of a single dose of larity of intrathecal morphine for postcesarean analgesia,dexamethasone has been associated with a reduction in the efficacy of dexamethasone as an antiemetic, particularlytissue inflammatory mediators, including bradykinin, pros- in this at-risk population, needs further investigation. Stud-taglandins, and other nociception-promoting neuropep- ies investigating dexamethasone in combination with othertides; this may contribute to its analgesic properties.35 pharmacological and nonpharmacological antiemeticDexamethasone has been shown to significantly reduce therapy are also needed. Dexamethasone’s role as an anal-postoperative peritoneal inflammation and abdominal pain gesic has been extensively investigated in patients receivingafter colectomy.35 However, although the overall reduction general anesthesia but its role as an analgesic adjunct inin late pain scores was statistically significant, it was small patients receiving neuraxial anesthesia remains less clear.and may not be clinically relevant, especially in patient Studies investigating the analgesic effect of dexamethasonepopulations in which the pain scores were low. in this patient population as a primary outcome are needed.820 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA

In conclusion this systematic review presents relatively 7. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred report-strong evidence that a single IV dose of dexamethasone 5 to ing items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 2009;62:1006 –1210 mg was an effective antiemetic for women receiving 8. Higgins JPT, Green S, eds. Cochrane Handbook for System-neuraxial morphine for cesarean delivery or abdominal atic Reviews of Interventions. Version 5.0.2 (updated Sep-hysterectomy. Although this review suggests that dexa- tember 2009). The Cochrane Collaboration, 2008. Availablemethasone may not be effective in patients receiving intra- at: www.cochrane-handbook.com; accessed March 30, 2011 9. Hozo S, Djulbegovic B, Hozo I. Estimating the mean andthecal morphine, this should be interpreted with caution variance from the median, range, and the size of a sample.because of the small number of patients receiving intrathe- BMC Med Res Methodol 2005;5:13cal morphine that were included in the analysis. There is 10. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysisalso some evidence that the doses used for antiemetic detected by a simple, graphical test. BMJ 1997; 315:629–34prophylaxis also improved postoperative analgesia, al- 11. Wu JI, Lo Y, Chia YY, Liu K, Fong WP, Yang LC, Tan PH. Prevention of postoperative nausea and vomiting after intra-though the reduction in pain scores was small and may not thecal morphine for cesarean section: a randomized compari-be clinically significant. There was no evidence that dexa- son of dexamethasone, droperidol, and a combination. Int Jmethasone was an effective antipruritic. Further studies are Obstet Anesth 2007;16:122–7needed to investigate this drug’s safety profile and its 12. Wang JJ, Tzeng JI, Ho ST, Chen JY, Chu CC, So EC. The prophylactic effect of tropisetron on epidural morphine-relatedefficacy in patients receiving intrathecal morphine. In light nausea and vomiting: a comparison of dexamethasone withof possible publication bias, these findings need to be saline. Anesth Analg 2002;94:749 –53interpreted with caution. 13. Wang JJ, Ho ST, Wong CS, Tzeng JI, Liu HS, Ger LP. Dexa- methasone prophylaxis of nausea and vomiting after epidural morphine for post-cesarean analgesia. Can J Anaesth 2001;DISCLOSURES 48:185–90Name: Terrence K. Allen, MBBS, FRCA. 14. Wang JJ, Ho ST, Liu YH, Ho CM, Liu K, Chia YY. Dexameth-Contribution: This author helped design the study, analyze asone decreases epidural morphine-related nausea and vomit-the data, and write the manuscript. ing. Anesth Analg 1999;89:117–20 15. Tzeng JI, Wang JJ, Ho ST, Tang CS, Liu YC, Lee SC. Dexameth-Attestation: Terrence K. Allen has seen the original study data, asone for prophylaxis of nausea and vomiting after epiduralreviewed the analysis of the data, approved the final manu- morphine for post-cesarean section analgesia: comparison ofscript, and is the author responsible for archiving the study droperidol and saline. Br J Anaesth 2000;85:865– 8files. 16. Tzeng JI, Hsing CH, Chu CC, Chen YH, Wang JJ. Low-doseName: Cheryl A. Jones, MD, DVM. dexamethasone reduces nausea and vomiting after epiduralContribution: This author helped conduct the study and write morphine: a comparison of metoclopramide with saline. J Clin Anesth 2002;14:19 –23the manuscript. 17. Nortcliffe SA, Shah J, Buggy DJ. Prevention of postoperativeAttestation: Cheryl A. Jones has seen the original study data, nausea and vomiting after spinal morphine for caesareanreviewed the analysis of the data, and approved the final section: comparison of cyclizine, dexamethasone and placebo.manuscript. Br J Anaesth 2003;90:665–70Name: Ashraf S. Habib, MBBCh, MSc, MHS, FRCA. 18. Ho ST, Wang JJ, Tzeng JI, Liu HS, Ger LP, Liaw WJ. Dexameth-Contribution: This author helped design the study, conduct asone for preventing nausea and vomiting associated with epidural morphine: a dose-ranging study. Anesth Analgthe study, and write the manuscript. 2001;92:745– 8Attestation: Ashraf S. Habib has seen the original study data, 19. Clarke H, Pereira S, Kennedy D, Andrion J, Mitsakakis N,reviewed the analysis of the data, and approved the final Gollish J, Katz J, Kay J. Adding gabapentin to a multimodalmanuscript. regimen does not reduce acute pain, opioid consumption orThis manuscript was handled by: Cynthia A. Wong, MD. chronic pain after total hip arthroplasty. Acta Anaesthesiol Scand 2009;53:1073– 83 20. Mathiesen O, Jacobsen LS, Holm HE, Randall S, Adamiec-REFERENCES Malmstroem L, Graungaard BK, Holst PE, Hilsted KL, Dahl JB. 1. Henzi I, Walder B, Tramer MR. 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