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View larger version:In a new windowDownload as PowerPoint SlideFig 1 Flow diagram of studiesView this table:View PopupView InlineTable 1 Characteristics of included studies in meta-analysisStudy characteristicsOf the included studies, 24 were published in English, and one each in Turkish,34 Korean,39 Spanish,54 Chinese,29 and Hebrew.38 Ten studies were conducted in North America,30 31 32 33 35 40 47 53 54 55 12 in Asia,28 29 34 37 38 39 41 45 46 49 50 51 four in Europe,12 42 43 52 two in Australia,36 48 and one in Africa.44 All studies were presented as full publications. In two studies, dexamethasone was provided by pharmaceutical companies,12 32 and one of these studies specified that the funding organisation had no role in the design or conduct of the study.12Nineteen studies were performed in children, six in adults only, and four included both children and adults. Twenty four studies compared the effects of systemic steroids with placebo12 28 29 30 31 32 33 34 35 37 40 41 43 46 47 48 50 51 53 54 55 or no intervention (neither a placebo nor any intervention in the control group).38 39 45 Six studies compared systemic steroids with other treatments (tropisetron, ondansetron, droperidol, piroxicam, bilateral glossopharyngeal nerve block with bupivacaine, or paracetamol).Dexamethasone was used in 28 studies, while prednisolone was administered in the remaining study.48 In 18 studies, the dexamethasone dose was calculated according to the patient’s weight (mg/kg) and varied from 0.05 mg/kg 12 to 1.0 mg/kg. In the remaining studies, the steroid dose was fixed29 31 40 42 43 50 52 55; based on the patient’s body surface (mg/m²)32; or either fixed or based on weight (mg/kg), according to patient’s age.48 49 Systemic steroids were administrated as a single dose, or repeated doses over a specific period of time: 16 h,54 three days,40 four days,29 seven days,48 or eight days.52 In these studies, the total dose was taken into account.In most studies, the main outcomes were the effect of steroids on pain,12 28 29 30 31 32 33 35 37 38 39 40 41 42 43 44 45 47 48 50 51 52 53 54 55 nausea and vomiting,12 28 30 33 34 35 36 37 38 39 41 43 45 46 47 48 49 50 51 52 53 and oral intake 12 28 30 32 35 37 38 39 41 43 45 46 47 48 50 51 53 55 after tonsillectomy. Other main outcome measures of included studies were the effect of steroids on oedema, fever, trismus, halitosis, and level of activity.Twenty six studies reported data for post-tonsillectomy bleeding. Through private communications with authors, we obtained details pertaining to the severity of and to interventions related to the bleeding episodes for three of these studies,40 42 53 and obtained unpublished data on bleeding episodes for three additional studies.43 44 49 Eight studies reported no postoperative bleeding episodes or mentioned uneventful surgeries.29 37 43 44 48 49 51 54 Among studies reporting bleeding episodes, 18 specified the timing of occurrence,12 28 30 31 32 33 34 35 36 39 41 42 45 46 47 50 52 53 nine reported the need for admission due to bleeding,12 28 30 31 35 46 47 50 53 and 12 reported data for reintervention.12 30 32 34 39 40 42 46 47 50 52 55 No study reported transfusion of red blood cells or mortality.A clear definition of post-tonsillectomy bleeding was presented in two of 29 studies.12 42 Eight studies stated that bleeding episodes were going to be reported,12 28 31 32 33 35 37 41 while six clearly questioned their patients about postoperative bleeding or provided instructions in the event of unexpected bleeding.12 28 35 37 41 42 No study described a systematic method to evaluate postoperative bleeding.Validity assessmentA low risk of bias was attributed to seven studies 33 35 36 40 41 42 50 (table 2?). Fifteen studies had an adequate sequence generation,12 30 31 33 35 36 37 40 41 42 43 50 51 52 54 and 15 had an appropriate method of allocation concealment.12 30 33 35 36 40 41 42 43 47 48 50 52 53 55 Six studies were not blinded,28 38 39 45 46 49 and blinding was unclear in another study.34 One study was terminated early because of an increased incidence of post-tonsillectomy bleeding in the intervention group.12 Fourteen studies 12 31 32 33 36 38 40 41 42 43 47 52 53 55 reported losses to follow-up that varied from 2.7%12 to 36.1%,43 and losses to follow-up were unclear in four studies.29 39 45 48 Eight studies had a follow-up period of 24 h or less.30 34 37 44 45 46 49 51 Two studies reported performing an intention to treat analysis.12 40 Five studies did not report all outcomes stated in their methods.32 45 46 51 54View this table:View PopupView InlineTable 2 Risk of bias and methodological quality assessment of included studiesPost-tonsillectomy bleeding episodesThe administration of steroids did not increase the incidence of bleeding events after tonsillectomy, based on pooled data from the 29 studies (n=2674, odds ratio 0.96, 95% confidence intervals 0.66 to 1.40, I²=0%), of which eight did not observe any bleeding episodes29 37 43 44 48 49 51 54 (fig 2?). Sensitivity analyses including trials with low risk of bias, observers blinded to the intervention, larger population, or longer follow-up periods yielded similar results (table 3?). Results were also comparable regardless of the population age, surgical technique, steroid dose, or concomitant administration of non-steroidal anti-inflammatory drugs. When we analysed primary and secondary bleeding events separately, we observed no increase in bleeding incident with the administration of steroids.
View larger version:In a new windowDownload as PowerPoint SlideFig 2 Post-tonsillectomy bleeding. For Peto odds ratio, continuity correction k=0.5 was used when there was no event in both groupsView this table:View PopupView InlineTable 3 Sensitivity analysis of post-tonsillectomy bleeding outcomeHospital admissionSeventeen studies reported data for admission12 28 30 31 35 46 47 50 53 or reinterventions34 36 39 40 42 45 52 55 that required admission (fig 3?). The incidence of admission due to a bleeding episode did not increase in the steroid group (17 studies, n=1722 patients, odds ratio 1.16, 95% confidence interval 0.68 to 2.00, I²=19%). All sensitivity analyses accorded with this finding (data not shown).
View larger version:In a new windowDownload as PowerPoint SlideFig 3 Admission for post-tonsillectomy bleedingReintervention for a bleeding episodeThe incidence of operative reintervention for bleeding episodes was significantly increased in the steroid group (12 studies, n=1178; odds ratio 2.27, 95% confidence interval 1.03 to 4.99, I2=0%; fig 4?). The average incidence of reintervention due to bleeding in patients receiving steroids was 3.0% versus 1.5% in controls. Sensitivity analyses were performed to evaluate the incidence of reintervention for bleeding episodes among different subgroups (table 4?). We observed a significant increase of reinterventions in children (eight studies12 30 32 34 39 46 47 55; 3.43, 1.29 to 9.13, I²=0%) but not in adults (four40 42 50 52; 1.07, 0.29 to 4.03, I²=0%). A dose effect was not observed. We found an increased incidence of reinterventions among patients receiving non-steroidal anti-inflammatory drugs (three12 39 52; 4.10, 0.99 to 16.97, I²=0%). No significant association was seen among double blinded studies (nine12 30 32 40 42 47 50 52 55; 2.22, 0.95 to 5.18, I2=0%) and those with longer follow-up periods (nine12 32 39 40 42 47 50 52 55; 2.16, 0.92 to 5.06, I2=0%). In each case, the incidence of reinterventions for bleeding episodes was increased in the steroid group compared with the control group without reaching significance (P=0.07 for double blinding, P=0.08 for longer follow-up periods), although the results suggested a strong trend. Studies with low risk of bias showed no clear association between steroids use and the incidence of operative reintervention (three studies40 42 50; 0.91, 0.22 to 3.68, I²=0%).
View larger version:In a new windowDownload as PowerPoint SlideFig 4 Reintervention for post-tonsillectomy bleeding. For Peto odds ratio, continuity correction k=0.5 was used when there was no event in both groupsView this table:View PopupView InlineTable 4 Sensitivity analysis of operative reintervention to treat post-tonsillectomy bleedingAllogenic transfusion and mortalityNone of the included studies reported transfusion of red blood cells or mortality. Publication bias and quality of evidence We evaluated the presence of potential publication bias using a funnel plot of intervention effect estimates versus the standard error for studies presenting data for bleeding episodes. Visual inspection of the funnel plot did not reveal evidence of publication bias (web figure). According to the GRADE methodology, the quality of the evidence for bleeding and admission outcomes after tonsillectomy was low; however, the association between post-tonsillectomy reintervention and systemic steroids was considered to be of high quality (table 5?).View this table:View PopupView InlineTable 5 Summary of evidence for key outcomes Discussion In this systematic review, we did not observe an increased incidence of postoperative bleeding events after perioperative administration of systemic steroids in patients undergoing tonsillectomy. However, we did observe a significant increase in the incidence of operative reinterventions needed to manage clinically significant bleeding episodes in patients who received systemic steroids. The quality of the evidence according to the GRADE approach was high for this specific outcome. This raised incidence of reinterventions was significantly increased in children.Strengths and limitations if the studyAn important limitation of our study concerned the data available within included publications. None of the included studies was designed to evaluate adverse complications of steroids use after tonsillectomy, and no study systematically screened for bleeding events after tonsillectomy. Therefore, the incidence of this complication could have been systematically underestimated. Moreover, only two studies presented a clear definition of post-tonsillectomy bleeding. Bleeding episodes of varying severity may not have received equal consideration across all studies, which could lead to an underestimation of overall bleeding episodes. This could explain why we did not observe a significant association between steroids use and bleeding events, while we did observe an association with reintervention for bleeding events. On the other hand, the inclusion in meta-analyses of studies reporting no bleeding event in either group using a continuity correction could have underestimated the association. The majority of included studies were of limited methodological quality, and many studies had substantial numbers of patients who were lost to follow-up. These factors provide further concern that bleeding episodes may have been missed. A significant proportion of studies had a very limited follow-up period precluding the evaluation of the incidence of secondary bleeding episodes. Since bleeding episodes are relatively rare events, unreported episodes could greatly affect the study results. Despite of known limitations, our systematic review had important strengths. Firstly, the extensive search strategy using different databases, including the grey literature and conference proceedings, allowed us to retrieve a comprehensive list of the studies performed on the topic. Importantly, the decision to evaluate the incidence of reinterventions for bleeding episodes, as opposed to only bleeding episodes, allowed us to summarise the effect of clinically significant bleeding events with greater fidelity. We believe that operative reintervention for bleeding episodes represents a more reliable and clinically meaningful endpoint than bleeding episodes. Severe enough bleeding events to require operative reintervention are less likely to have been overlooked and may therefore represent the optimal clinical outcome to understand the impact of systemic steroids in tonsillectomy.Comparison with other studiesOverall, the mean incidence of post-tonsillectomy bleeding events observed in our systematic review was 4.4%, which is consistent with the current literature.56 57 58 59 60 Our results on postoperative bleeding are in accordance with a recent systematic review.15 However, this previous meta-analysis identified half the number of studies as compared with our study, and did not evaluate other clinically significant outcomes such as operative reinterventions for bleeding and hospital admission. The increased incidence of reintervention observed in a recent landmark study by Czarnetzki and colleagues12 was also seen in our pooled analysis. But our systematic review did not confirm the higher incidence of bleeding episodes associated with perioperative steroids use in tonsillectomy procedures, as observed in this trial.The increased incidence of reinterventions associated with steroids occurred in the absence of increased bleeding events, and thus probably represents an increased severity of bleeding when steroids are administered. Although no study specified indications to undergo a reintervention in the event of bleeding, this procedure usually suggests that the bleeding was significant enough to require an emergency procedure. Bleeding events requiring reintervention are more likely to be noticed and reported in a publication as opposed to minor events. Therefore, reinterventions to manage bleeding events may be a more objective and reliable outcome to assess clinically significant bleeding events after tonsillectomy.Conclusions and policy implicationsWe did not observe an increased incidence of postoperative bleeding events following administration of systemic steroids during tonsillectomy. We did, however, observe a significant increase in the incidence of operative reintervention associated with the use of steroids, which may be related to an increased severity of a given bleeding episode. Considering the potential for harm and the availability of other drugs to prevent postoperative nausea and vomiting, we recommend that steroids should be used with caution; risks and benefits must be weighted; and steroids should not be used routinely for such purposes, especially in children. Further studies should be designed to answer concerns about the safety of the perioperative use of steroids in tonsillectomy procedures.What is already known on this topicTonsillectomy is one of the most commonly performed ear, nose, and throat surgeries worldwide, but has a high underlying risk of postoperative nausea and vomitingSystemic use of steroids to reduce postoperative nausea and vomiting is increasing, and recommended in addition to the use of 5-HT3 antagonists in recent guidelinesA recent study has linked such use of steroids with an increased incidence of postoperative bleeding after tonsillectomyWhat this study addsOverall, the risk of postoperative bleeding did not increase after perioperative administration of systemic steroids in patients undergoing tonsillectomyHowever, the incidence of reinterventions for bleeding episodes did increase overall with steroids, and especially among children, which could represent a greater severity of bleeding associated with use of steroids Systemic steroids should be used with caution; risks and benefits must be weighted, and steroids should not be used routinely to prevent postoperative nausea and vomiting after tonsillectomy, especially in childrenNotesCite this as: BMJ 2012;345:e5389FootnotesWe thank Lucie Côté from the Library of the Centre Hospitalier Affilié Universitaire de Québec, Enfant-Jésus Hospital, for her help with the retrieval of study publications.Contributors: JP, AFT, RZ, FL, LM, and DAF contributed to the conception and design of the study. JP and LV determined eligibility of search results and extracted data from included studies. JP, AB, and AFT performed and reviewed the analyses, and drafted the manuscript. All authors participated in the interpretation of the data and the critical review of the manuscript, and approved the version to be published. AFT is the guarantor.Funding: This study was funded by personal funds. AFT and FL are recipients of a research career award from the Fonds de Recherche Québec-Santé. AFT and FL are supported by the Traumatology Research Consortium of the Fonds de Recherche Québec-Santé. LM and DAF are recipients of New Investigator Awards from the Canadian Institutes for Health Research. RZ is a recipient of a randomised controlled trials mentorship award from the Canadian Institutes for Health Research.Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.Ethical approval: This study did not require ethical approval.Data sharing: No additional data available.This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. 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