Glucocorticosteroids for patients undergoing laparoscopic cholecystectomy

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To determine the beneficial and harmful effects of glucocorticoids for reducing PONV or both in patients undergoing laparoscopic cholecystectomy relative to placebo or alternative antiemetic agents.

Background

Description of the condition

Laparoscopic cholecystectomy is a widely performed surgical procedure associated with post-operative nausea and vomiting (PONV) in as many as 75% of patients (Erhan 2008). PONV contributes to postoperative morbidity and has been labelled as the 'big little problem in ambulatory surgery' by Kapur 1991. In an era of increasing day care laparoscopic cholecystectomy, PONV increases the likelihood of unanticipated admissions postoperatively (Lau 2001).

There are several classes of antiemetic agents for therapeutic and prophylactic use for PONV. A meta-analysis by Carlisle 2006 found that certain medications reduced PONV after surgery compared to placebo. These included dexamethasone, metoclopramide, domperidone, 5HT3-antagonists (ondansetron, tropisetron, dolasetron, granisetron), cyclizine, and droperidol. Subgroup analysis of operation type comparing 'general' surgical versus other procedures showed that dexamethasone prevented nausea (RR = 0.59, 0.48 to 0.72), vomiting (RR = 0.51, 0.40 to 0.66), and nausea or vomiting (RR = 0.47, 0.29 to 0.76) compared with placebo after 'general' surgery. However, they did not evaluate the benefits and harms of antiemetic drugs specifically after laparoscopic cholecystectomy.

Laparoscopic cholecystectomy - along with gynaecological and ophthalmic surgery - is more likely to cause PONV compared to other operations (Kapur 1991; Watcha 1992; Carlisle 2006; Sweeney 2006). The mechanisms producing PONV after laparoscopic cholecystectomy may be different from those producing this complication after other operations. Therefore, drugs that are effective in other situations may not have the same effect after laparoscopic cholecystectomy.

Description of the intervention

Glucocorticoids are well-known antiemesis agents with an established role in patients undergoing chemotherapy (Aapro 1981; Aranda Aguilar 2005). They have been used at anaesthetic induction via the intravenous (Wang 1999; Wallenborn 2006), epidural (Thomas 2006), intramuscular (Thagaard 2007), and oral (Bisgaard 2008) routes in patients having laparoscopic cholecystectomy. Dexamethasone is the most widely studied glucocorticoid and has been administered at doses from 2 mg to 16 mg (Elhakim 2002; Bisgaard 2003; Antonetti 2007).

How the intervention might work

The exact mechanism of antiemetic action of glucocorticosteroids in humans is unclear though prostaglandin antagonism, release of endorphins, and tryptophan depletion have been postulated as having a role (Aouad 2001). One indirect antiemetic effect may be via a reduction in overall pain and opioid requirements during the first 24 hours after surgery reducing the likelihood of opioid induced vomiting (Bisgaard 2003).

Why it is important to do this review

Some randomised clinical trials support glucocorticosteroids as a perioperative antiemetic following laparoscopic cholecystectomy. The Carlisle 2006 study included trials only up to 2004 and was not able to comment specifically on antiemesis after laparoscopic cholecystectomy. In 2008, Karanicolas et al published a meta-analysis of 16 randomised clinical trials specifically looking at steroids for laparoscopic cholecystectomy (Karanicolas 2008). They included trials published to April 2007 and found a beneficial effect of glucocorticosteroids on nausea, vomiting and nausea, or vomiting outcomes. No differences in side effects between placebo and glucocorticosteroids were found. Since then, at least a further 20 randomised trials have been published on the topic, and until present, there is no other review published assessing the risk of bias of all the performed trials, collecting and pooling the data from all the available evidence. It is unknown what impact these additional trials will have on the original findings and if glucocorticosteroids use as a perioperative antiemetic following laparoscopic cholecystectomy will still be supported.

Objectives

To determine the beneficial and harmful effects of glucocorticoids for reducing PONV or both in patients undergoing laparoscopic cholecystectomy relative to placebo or alternative antiemetic agents.

Methods

Criteria for considering studies for this review

Types of studies

All randomised clinical trials comparing individuals undergoing laparoscopic cholecystectomy receiving corticosteroids perioperatively versus those receiving placebo or alternative anti-emetic agents. Quasi-randomised studies and other non-randomised studies retrieved with the searches for identification of trials for this review will be excluded for evaluation of the beneficial effects of the glucocorticosteroids or corticosteroids, but data on the reported harmful effects may be extracted.

Types of participants

Participants will be patients of any age or ethnic origin who are undergoing a laparoscopic cholecystectomy for gallbladder disease. Open cholecystectomy will not be included in the review. Trials incorporating patients who convert to an open procedure will be included in the analysis.

Types of interventions

  • Glucocorticosteroids versus no intervention or placebo, or glucocorticosteroids versus alternative antiemetic agents are to be included in the review. The test group will have received a glucocorticosteroid during the perioperative period.

  • Studies that include a range of treatment dosages and those administrating multiple treatments will also be included.

  • Co-interventions will be allowed if received equally between the intervention groups in a trial.

Types of outcome measures

Primary outcomes
  1. Reported postoperative nausea.

  2. Reported postoperative vomiting.

  3. Reported postoperative nausea and vomiting.

  4. Number and type of adverse events. According to the ICH-GCP guidelines, the adverse events are subdivided into serious and non-serious adverse events (ICH-GCP 1997). Serious adverse events are defined as any event that has led to death, was life-threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability or congenital anomaly/birth defect, any important medical event, which might have jeopardized the patient or required intervention to prevent it.

Secondary outcomes
  1. Requirement for post-operative rescue antiemetics.

  2. Duration of intravenous hydration.

  3. Postoperative pain measured on a visual analogue or verbal rating scale.

  4. Postoperative opioids for pain relief.

  5. Length of hospital stay.

Search methods for identification of studies

Both electronic and paper journals will be searched. There will be no limits on language, and form or date of publication.

Electronic searches

The following sources will be searched to identify studies to be considered in this review:

The Cochrane Hepato-Biliary Group Controlled Trials Register (Gluud 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library; MEDLINE, EMBASE, Science Citation Index Expanded, CIHAHL, LILACS, Chinese Database of Medicine (TCMLARS), Scopus, and Google Scholar will be searched during the review preparation (Royle 2003). Preliminary search strategies with the expected time span of the searches are given in Appendix 1. The first laparoscopic cholecystectomy was performed in 1985 (Mühe 1986) and, therefore, only articles from that year onwards will be included. No language restriction will be applied.

Searching other resources

Further potentially relevant studies will be searched for by cross checking the reference lists of published randomised clinical trials and systematic reviews. The proceedings of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), the Association of Laparoscopic Surgeons of Great Britain and Ireland (ALSGBI), the European Association for Endoscopic Surgery, and Other Interventional Techniques (EAES) will be searched for any unpublished randomised trials during the last three years. These will be included provided adequate additional quality data are available from the authors.

Data collection and analysis

Selection of studies

At least two authors will independently review each title and abstract, and, on determining that a study fulfils the inclusion criteria, obtain full text of the study for further review. Excluded studies will be documented and the reasons for exclusion stated. Any differences in opinion will be resolved by arbitration within the group alongside the senior author (RLN).

Data extraction and management

Data will be extracted on study participants' age, sex, and glucocorticoid use including type of glucocorticoid utilised, timing of glucocorticoid administration (preoperative, intraoperative, or postoperative), the route of glucocorticoid administration, and actual dose used. Data on any intervention in the control group and any co-interventions will be extracted. Additionally, we will collect data on the primary and secondary outcomes already listed. A data extraction form will be used. Data will be collected from each study by at least two authors to ensure concordance. Disagreements will be resolved by arbitration within the group alongside the senior author.

Assessment of risk of bias in included studies

This will include assessment of the methods regarding design and performance of the trials (see further down the text). We will also record whether there was a sample size calculation, whether withdrawal rate was less than 10%, whether a clear explanation was given for any drop-outs in the study groups, whether intention-to-treat analysis was performed, whether inclusion and exclusion criteria were clearly defined, and whether authors gave an adequate definition of nausea and vomiting (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Higgins 2009).

We will assess the reports of the trials and their performance - we will also attempt to contact authors of the trials for the latter - by making judgements on the listed below risk of bias domains:

Sequence allocation generation

  • Low risk of bias. Sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards, and throwing dice are adequate if performed by an independent adjudicator.

  • Uncertain risk of bias. The trial is described as randomised, but the method of sequence generation was not specified.

  • High risk of bias. The sequence generation method is not, or may not be, random. Quasi-randomised studies, those using dates, names, or admittance numbers in order to allocate patients are inadequate studies for our review and will be excluded for the assessment of benefits but not for harms.

Allocation concealment

  • Low risk of bias. Allocation was controlled by a central and independent randomisation unit, opaque, sealed, and serially numbered envelopes or similar, so that intervention allocations could not have been foreseen in advance of, or, during enrolment.

  • Uncertain risk of bias. The trial was described as randomised, but the method used to conceal the allocation was not described, so that intervention allocations may have been foreseen in advance of, or during enrolment.

  • High risk of bias, if the allocation sequence was known to the investigators who assigned participants, or if the study was quasi-randomised. Quasi-randomised studies will be excluded for the assessment of benefits but not for harms.

Blinding of participants, personnel, and outcome assessors

  • Low risk of bias. Blinding was performed adequately, or the outcome measurement is not likely to be influenced by lack of blinding.

  • Uncertain risk of bias. There is insufficient information to assess whether the type of blinding used is likely to induce bias on the estimate of effect.

  • High risk of bias. There is no blinding or incomplete blinding, and the outcome or the outcome measurement is likely to be influenced by lack of blinding.

Incomplete outcome data

  • Low risk of bias. The underlying reasons for missingness are unlikely to make treatment effects departure from plausible values, or proper methods have been employed to handle missing data.

  • Uncertain risk of bias. There is insufficient information to assess whether the missing data mechanism in combination with the method used to handle missing data is likely to induce bias on the estimate of effect.

  • High risk of bias. The crude estimate of effects (eg, complete case estimate) will clearly be biased due to the underlying reasons for missingness, and the methods used to handle missing data are unsatisfactory.

Selective outcome reporting

  • Low risk of bias. The trial protocol is available and all of the trial's pre-specified outcomes that are of interest in the review have been reported or similar.

  • Uncertain risk of bias. There is insufficient information to assess whether the magnitude and direction of the observed effect is related to selective outcome reporting.

  • High risk of bias. Not all of the trial's pre-specified primary outcomes have been reported or similar.

Baseline imbalance

  • Low risk of bias. There was no baseline imbalance in important characteristics.

  • Uncertain risk of bias. The baseline characteristics were not reported.

  • High risk of bias. There was a baseline imbalance due to chance, or due to imbalanced exclusion after randomisation.

Other bias risks

  • Low risk of bias. The trial appears to be free of other components that could put it at risk of bias.

  • Uncertain risk of bias. The trial may or may not be free of other components that could put it at risk of bias.

  • High risk of bias. There are other factors in the trial that could put it at risk of bias, eg, for-profit involvement, authors have conducted trials on the same topic etc.

Two authors will, independently of each other, judge the above listed domains for risk of bias. In case of disagreements, a third author will serve as an arbiter.

For a trial to be classified as a trial with low risk of bias, it must be judged with low risk of bias in all domains.

Measures of treatment effect

Dichotomous variables will be presented as relative risk (RR) and continuous variables as mean difference (MD), both with 95% confidence intervals (CI). A P value of 0.05 or less will be considered significant. Treatment effect will be determined as successful where a patient does not report nausea or vomiting or both.

Dealing with missing data

Where data for an outcome are missing, authors of the trial will be contacted in an attempt to obtain the relevant information. If the data are unobtainable, then an attempt will be made to impute the missing data provided it is statistically robust, eg, standard deviation calculated from the variance. If the data are unobtainable, there is uncertainty in relation to the accuracy of a potential imputation, and the missing data are too large to ignore, then that particular trial may have to be excluded from that analysis and the implications of this mentioned in the discussion. Sensitivity analyses will be done assuming best- and worst-case scenarios to see how such variations impact on the overall treatment effect. Overall intention-to-treat analysis will be undertaken when dealing with randomised participants lost to follow-up or from whom no outcome was obtained (Higgins 2009).

Assessment of heterogeneity

Statistical heterogeneity will be sought for by calculating the Chi2 test for heterogeneity and the I2 statistic along with its confidence interval utilising RevMan 5 (RevMan 2008) software as per the Cochrane Handbook (Higgins 2009).

Assessment of reporting biases

When there are more than 10 trials included in the review, then data will be entered into a funnel plot to investigate the possibility of publication bias and other bias (Egger 1997; Higgins 2009).

Data synthesis

The statistical package Review Manager provided by The Cochrane Collaboration will be used for statistical analyses (RevMan 2008). A fixed- effect model will be used if there is no heterogeneity present and a random-effects model utilised if heterogeneity is seen. However, when the two models give different results, both results will be reported.

Subgroup analysis and investigation of heterogeneity

Subgroup analyses are planned according to route, timing, and dosage of glucocorticosteroid administration, co-intervention, male compared to female patients, doses of opoid analgesia received, conversion rate to open surgery, and any other clinically relevant areas. Sources of heterogeneity will be investigated by analysis using the RevMan 2008 software.

Sensitivity analysis

A sensitivity analysis is planned to compare low risk of bias trials compared to high risk of bias trials (Kjaergard 2001; Wood 2008). Additionally, data on different doses of a given agent will be pooled together, but then sensitivity analyses will be performed to determine if the findings are altered by pooling of high doses compared with low doses of the drug in question.

Acknowledgements

Peer Reviewers: Steven R Brown, UK; PJ Karanicolas, Canada; E Tiippana, Finland.
Contact Editor: Brian Davidson, UK.

Appendices

Appendix 1. Databases and Search Terms

DatabaseTime spanSearch strategy
Cochrane Hepato-Biliary Group Controlled Trials RegisterDate will be given at review stage.cholecystectom* AND (vomiting OR nausea OR (postop* nausea and vomiting)) AND (glucocorticoid* OR steroid* OR dexamethasone OR prednis* OR hydrocortisone)
Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane LibraryLatest issue.#1 MeSH descriptor Cholecystectomy, Laparoscopic explode all trees
#2 cholecystectom*
#3 (#1 OR #2)
#4 MeSH descriptor Postoperative Nausea and Vomiting explode all trees
#5 (vomiting OR nausea OR (postop* nausea and vomiting))
#6 (#4 OR #5)
#7 MeSH descriptor Glucocorticoidsexplode all trees
#8 (glucocorticoid* OR steroid* OR dexamethasone OR prednis* OR hydrocortisone)
#9 (#7 OR #8)
#10 (#3 AND #6 AND #9), from 1985 to 2010
Pubmed/MEDLINE (http://www.ncbi.nlm.nih.gov/sites/entrez)1985 to the date the search is performed.cholecystectom* AND (vomiting OR nausea OR (postop* nausea and vomiting)) AND (glucocorticoid* OR steroids* OR dexamethasone OR prednis* OR hydrocortisone)
EMBASE (OvidSP)1985 to the date the search is performed.(cholecystectomy AND (vomiting OR nausea OR (postoperative nausea AND vomiting)) AND (glucocorticoid OR dexamethasone OR prednisolone OR prednisone OR hydrocortisone) AND (random* OR controlled OR controls OR RCT)).ti,ab [Limit to: Publication Year 1985-Current]
Science Citation Index
(http://science.thomsonreuters.com/cgi-bin/jrnlst/jloptions.cgi?PC=D)
1985 to the date the search is performed.#1 TS=cholecystectom*
#2 TS=(vomiting OR nausea OR (postop* nausea and vomiting))
#3 TS=(glucocorticoid* OR steroids* OR dexamethasone OR prednis* OR hydrocortisone)
#4 #3 AND #2 AND #1
#5 TS=(random* OR blind* OR placebo* OR meta-analysis)
#6 #5 AND #4
CINAHL (http://www.library.nhs.uk/booksandjournals/Default.aspx)1985 to the date the search is performed.((cholecystectomy AND (vomiting OR nausea OR (postoperative nausea AND vomiting)) AND (glucocorticoids OR dexamethasone OR prednisolone OR prednisone OR hydrocortisone) AND (random* OR controlled OR controls OR RCT))).ti,ab [Limit to: Publication Year 1985-2009]
LILACS(http://bases.bvsalud.org/public/scripts/php/page_show_main.php?home=true&lang=en&form=simple)1985 to the date the search is performed.(((Pt RANDOMIZED CONTROLLED TRIAL OR Pt CONTROLLED CLINICAL TRIAL OR Mh RANDOMIZED CONTROLLED TRIALS OR Mh RANDOM ALLOCATION OR Mh DOUBLE-BLIND METHOD OR Mh SINGLE-BLIND METHOD OR Pt MULTICENTER STUDY) OR ((tw ensaio or tw ensayo or tw trial) and (tw azar or tw acaso or tw placebo or tw control$ or tw aleat$ or tw random$ or (tw duplo and tw cego) or (tw doble and tw ciego) or (tw double and tw blind)) and tw clinic$)) AND NOT ((CT ANIMALS OR MH ANIMALS OR CT RABBITS OR CT MICE OR MH RATS OR MH PRIMATES OR MH DOGS OR MH RABBITS OR MH SWINE) AND NOT (CT HUMAN AND CT ANIMALS)) [Palavras] ) AND cholecystectomy AND (nausea OR vomiting OR (nausea and vomiting)) AND (steroid* OR glucocorticoid* OR dexamethasone OR prednisolone OR prednisone OR hydrocortisone)
TCMLARS (http://www.cintcm.com/index.htm)1985 to the date the search is performed.((cholecystectomy AND (vomiting OR nausea OR (postoperative nausea AND vomiting)) AND (glucocorticoids OR dexamethasone OR prednisolone OR prednisone OR hydrocortisone) AND (random* OR controlled OR controls OR RCT)))
SCOPUS (http://www.scopus.com/home.url)1996 to the date the search is performed.((cholecystectomy AND (vomiting OR nausea OR (postoperative nausea AND vomiting)) AND (glucocorticoids OR dexamethasone OR prednisolone OR prednisone OR hydrocortisone) AND (random* OR controlled OR controls OR RCT)))
Google Scholar (http://scholar.google.co.uk/)1985 to the date the search is performed.((cholecystectomy AND (vomiting OR nausea OR (postoperative nausea AND vomiting)) AND (glucocorticoids OR dexamethasone OR prednisolone OR prednisone OR hydrocortisone) AND (random* OR controlled OR controls OR RCT)))

Contributions of authors

AIM came up with the idea for the review and registered the title with The Cochrane Hepato-Biliary Group along with ST and RLN. RLN is the senior author who has supervised the development of the protocol and is the final arbiter for any conflicting ideas between the authors. All the authors (AIM, SIT, JER, NLH, RM, SLC, NUM, SSA, SEE, and RLN) have equally contributed to developing the draft protocol and have been involved in responding to the early feedback from The Hepato-Biliary Group Editorial Office.

Declarations of interest

No declarations of interest.

Sources of support

Internal sources

  • No sources of support declared, Not specified.

External sources

  • No sources of support declared, Not specified.

Ancillary