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Low pressure versus standard pressure pneumoperitoneum in laparoscopic cholecystectomy

  1. Kurinchi Selvan Gurusamy*,
  2. Jessica Vaughan,
  3. Brian R Davidson

Editorial Group: Cochrane Hepato-Biliary Group

Published Online: 18 MAR 2014

Assessed as up-to-date: 19 FEB 2013

DOI: 10.1002/14651858.CD006930.pub3


How to Cite

Gurusamy KS, Vaughan J, Davidson BR. Low pressure versus standard pressure pneumoperitoneum in laparoscopic cholecystectomy. Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No.: CD006930. DOI: 10.1002/14651858.CD006930.pub3.

Author Information

  1. Royal Free Campus, UCL Medical School, Department of Surgery, London, UK

*Kurinchi Selvan Gurusamy, Department of Surgery, Royal Free Campus, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK. k.gurusamy@ucl.ac.uk.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 18 MAR 2014

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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

 
Summary of findings for the main comparison. Low pressure versus standard pressure pneumoperitoneum in laparoscopic cholecystectomy

Low pressure versus standard pressure pneumoperitoneum in laparoscopic cholecystectomy

Patient or population: patients undergoing laparoscopic cholecystectomy.
Settings: secondary or tertiary.
Intervention: low pressure pneumoperitoneum.
Comparison: standard pressure pneumoperitoneum.

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)

Assumed riskCorresponding risk

ControlIntervention

MortalityNo mortality in either groupnot estimable434

(8 studies)
⊕⊝⊝⊝
very low1,2





Serious adverse events3 per 10008 per 1000
(0 to 167)
RR 3
(0.14 to 65.9)
394
(7 studies)
⊕⊝⊝⊝
very low1,2

Conversion to open cholecystectomy7 per 10008 per 1000
(2 to 33)
RR 1.18
(0.29 to 4.72)
556
(10 studies)
⊕⊝⊝⊝
very low1,2

Hospital stayThe mean hospital stay in the control groups was
2 days
The mean hospital stay in the intervention groups was
0.3 lower
(0.63 lower to 0.02 higher)
415
(5 studies)
⊕⊝⊝⊝
very low1,3

Operating timeThe mean operating time in the control groups was
55 minutes
The mean operating time in the intervention groups was
1.51 higher
(0.07 to 2.94 higher)
990
(19 studies)
⊕⊕⊝⊝
low1

*The basis for the assumed risk is the mean control group risk for conversion to open cholecystectomy. Although we planned to use the mean control group risk for serious adverse events also, we could not do so because no serious adverse events were reported in the control group. Overall serious adverse events in both groups were used as the control group risk. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1The trial(s) was (were) at high risk of bias (two points).
2The confidence intervals overlapped 1 and either 0.75 or 1.25 or both. Events in the intervention and control groups were fewer than 300 (two points).
3Severe heterogeneity was noted by the I2 and the lack of overlap of confidence intervals (two points).

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Description of the condition

About 5% to 25% of the adult Western population have gallstones (GREPCO 1984; GREPCO 1988; Bates 1992; Halldestam 2004). The annual incidence of gallstones is about one in 200 people (NIH 1992). Only 2% to 4% of people with gallstones become symptomatic with biliary colic (pain), acute cholecystitis (inflammation), obstructive jaundice, or gallstone pancreatitis within a year (Attili 1995; Halldestam 2004). Cholecystectomy (removal of the gallbladder) is the preferred option in the treatment of symptomatic gallstones (Strasberg 1993). Every year, more than 0.5 million cholecystectomies are performed in the US and 60,000 in the UK (Dolan 2009; HES 2011). Approximately 80% of cholecystectomies are performed laparoscopically (by key-hole surgery) (Ballal 2009). Biliary colic (pain in the right upper abdomen lasting longer than half an hour) is one of the symptoms related to gallstones (Berger 2000) and is the most common indication for cholecystectomy (Glasgow 2000).

 

Description of the intervention

Traditionally, one of the first steps in laparoscopic cholecystectomy is the creation of pneumoperitoneum (Russell 1993) using carbon dioxide (CO2) through a Veress needle (Casati 1997) or through a port (hole) (Alijani 2004) in the abdominal wall. Traditionally, the pressure used is around 15 mm Hg (Russell 1993). The created pneumoperitoneum allows visualisation and manipulation of instruments inside the abdominal cavity. Increased intra-abdominal pressure due to the pneumoperitoneum causes several cardiopulmonary changes. The increased intra-abdominal pressure increases the absorption of CO2, causing hypercapnia and acidosis, which must be avoided by hyperventilation (Henny 2005). It also pushes the diaphragm upwards, decreasing pulmonary compliance (Alijani 2004; Henny 2005), and increases the peak airway pressure (Galizia 2001; Alijani 2004). Increased intra-abdominal pressure increases the venous return due to blood compressed out of the splanchnic vasculature (Henny 2005). Pneumoperitoneum also increases systemic vascular resistance (Galizia 2001; Mertens 2004) and pulmonary vascular resistance (Galizia 2001). Carbon dioxide pneumoperitoneum predisposes to cardiac arrhythmias (Egawa 2006). During the early phase of pneumoperitoneum, cardiac output is reduced (Galizia 2001; Alijani 2004) by decreasing venous return (Neudecker 2002). Although these cardiorespiratory changes may be tolerated by healthy adults with adequate cardiopulmonary reserve, people with cardiopulmonary diseases may not tolerate these cardiopulmonary changes. About 17% of patients undergoing laparoscopic cholecystectomy have an American Society of Anesthesiologists (ASA) status of III or IV (Giger 2006; ASA 2007). Abdominal wall lift, using a special device (eg, Laparolift (Egawa 2006), Laparo-tensor (Alijani 2004)) introduced through a port in the abdominal wall, has been used to decrease the cardiopulmonary changes and has been considered in a different review (Gurusamy 2012). Helium insufflation is an alternative to CO2 insufflation (Neuhaus 2001) and has been reported to have little or no effect on pulmonary function in pigs (Junghans 1997). However, concerns about the solubility of helium in the blood and hence the risk of gas embolism have precluded its routine use in humans (Neuhaus 2001).

 

How the intervention might work

Lower pressure may decrease the effects of pneumoperitoneum. However, the safety of low pressure pneumoperitoneum has not been established.

 

Why it is important to do this review

In our previous version of the review, we found evidence from trials with high risk of bias showing that low pressure pneumoperitoneum decreased pain scores (Gurusamy 2009). However, pain scores are unvalidated surrogate outcomes for pain in people undergoing laparoscopic cholecystectomy, and several Cochrane systematic reviews have demonstrated that pain scores can be decreased with no clinical implications in people undergoing laparoscopic cholecystectomy (Gurusamy 2014a; Gurusamy 2014b; Gurusamy 2014c). In addition, no study has evaluated the level of pain scores that people undergoing laparoscopic cholecystectomy or any other elective or emergency operation consider as important. The minimal clinically important difference in pain scores has also not been established in people undergoing laparoscopic cholecystectomy or any other elective or emergency operation. This update of our previous review includes results from trials that became available since the time of our last review.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

To assess the benefits and harms of low pressure pneumoperitoneum compared with standard pressure pneumoperitoneum in patients undergoing laparoscopic cholecystectomy.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Criteria for considering studies for this review

 

Types of studies

We included all randomised clinical trials that compared different pressures of pneumoperitoneum in participants undergoing laparoscopic cholecystectomy (irrespective of language, blinding, publication status, or sample size, or whether the trials were adequately powered). We did not consider randomised trials that compared abdominal wall lift in combination with pneumoperitoneum versus pneumoperitoneum alone. Such trials were included in the review in which abdominal lift and pneumoperitoneum were compared (Gurusamy 2012).

We excluded quasi-randomised trials (ie, trials in which the method of allocating participants to a treatment were not strictly random, for example, date of birth, hospital record number, or alternation).

 

Types of participants

Patients undergoing laparoscopic cholecystectomy (elective or emergency) for any reason (symptomatic gallstones, acalculous cholecystitis, gallbladder polyp, or any other condition) using four ports, at least two of 10 mm or larger and the remaining two of 5 mm or larger (which is generally considered as standard laparoscopic cholecystectomy). We excluded trials in which fewer ports or smaller ports were used, as the safety of such procedures has not been established (Gurusamy 2013; Gurusamy 2014d). We applied no restriction based on the type of anaesthesia used provided that the same type of anaesthesia was used in both groups.

 

Types of interventions

Trials comparing low pressure (less than 12 mm Hg) versus standard pressure (12 to 16 mm Hg) pneumoperitoneum. We excluded any trials using pressure greater than 16 mm Hg. The definitions of standard (12 mm Hg to 16 mm Hg) and low (less than 12 mm Hg) were chosen arbitrarily and were based on general belief and the review authors' opinions. No universal definitions are available for standard and low.

 

Types of outcome measures

 

Primary outcomes

  1. Mortality (30-day or in-hospital mortality).
  2. Serious adverse events: defined as any events that would increase mortality; are life-threatening; require inpatient hospitalisation; or result in persistent or significant disability; or any important medical events that might have jeopardised the participant or required intervention for prevention. All other adverse events were considered non-serious (ICH-GCP 1997). Combining outcomes of different severity can result in wrong conclusions about the safety and effectiveness of an intervention (Cordoba 2010), and the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) recommends that an exhaustive list of all outcomes should not be included—only important outcomes that are important to patients or health policy-makers; therefore we included only serious adverse events rather than all adverse events.
  3. Quality of life.

 

Secondary outcomes

  1. Conversion to open cholecystectomy.
  2. Hospital stay.
    1. Proportion discharged as day procedure.
    2. Length of hospital stay.
  3. Return to normal activity.
  4. Return to work.
  5. Operating time.

We also collected information on the successful completion of low pressure laparoscopic cholecystectomy.

 

Search methods for identification of studies

 

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded (Royle 2003). We have provided the search strategies in Appendix 1 along with the time span for the searches. Searches were conducted until February 2013.

 

Searching other resources

We also searched the references of identified trials to identify further relevant trials.

 

Data collection and analysis

 

Selection of studies

KSG and JV independently identified the trials for inclusion. We have listed the excluded studies along with the reasons for exclusion.

 

Data extraction and management

KSG and JV independently extracted the following data.

  1. Year and language of publication.
  2. Country.
  3. Year of study.
  4. Inclusion and exclusion criteria.
  5. Sample size.
  6. Population characteristics such as age and sex ratio.
  7. Details of intervention and control.
  8. Co-interventions.
  9. Outcomes (listed above).
  10. Risk of bias (described below).

 

Assessment of risk of bias in included studies

We independently assessed the risk of bias in the trials without masking the trial names. We followed the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and the Cochrane Hepato-Biliary Group Module (Gluud 2012). Based on the risk of biased overestimation of beneficial intervention effects in randomised trials with high risk of bias (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savović 2012; Savović 2012a), we assessed the trials for the following risk of bias domains.

 

Allocation sequence generation

  1. Low risk of bias: Sequence generation was achieved using a 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 person not otherwise involved in the trial.
  2. Uncertain risk of bias: The method of sequence generation was not specified.
  3. High risk of bias: The sequence generation method was not random.

 

Allocation concealment

  1. Low risk of bias: The participant allocations could not have been foreseen in advance of, or during, enrolment. Allocation was controlled by a central and independent randomisation unit. The allocation sequence was unknown to the investigators (eg, if the allocation sequence was hidden in sequentially numbered, opaque, and sealed envelopes).
  2. Uncertain risk of bias: The method used to conceal the allocation was not described, so that intervention allocations may have been foreseen in advance of, or during, enrolment.
  3. High risk of bias: The allocation sequence was likely to be known to the investigators who assigned the participants.

 

Blinding of participants, personnel, and outcome assessors

  1. Low risk of bias: Blinding was performed adequately, or the assessment of outcomes was not likely to be influenced by lack of blinding.
  2. Uncertain risk of bias: Information was insufficient to allow assessment of whether blinding was likely to induce bias on the results.
  3. High risk of bias: No blinding or incomplete blinding was provided, and assessment of outcomes was likely to be influenced by lack of blinding.

 

Incomplete outcome data

  1. Low risk of bias: Missing data were unlikely to make treatment effects depart from plausible values. Sufficient methods, such as multiple imputation, have been employed to handle missing data.
  2. Uncertain risk of bias: Information was insufficient to allow assessment of whether missing data in combination with the method used to handle missing data were likely to induce bias on the results.
  3. High risk of bias: The results were likely to be biased because of missing data.

 

Selective outcome reporting

  1. Low risk of bias: All outcomes were predefined and reported, or all clinically relevant and reasonably expected outcomes were reported.
  2. Uncertain risk of bias: It is unclear whether all predefined and clinically relevant and reasonably expected outcomes were reported. 
  3. High risk of bias: One or more clinically relevant and reasonably expected outcomes were not reported, and data on these outcomes were likely to have been recorded.

 

For-profit bias

  1. Low risk of bias: The trial appears to be free of industry sponsorship or other kinds of for-profit support that may lead to manipulatiion of trial design, conductance, or results. 
  2. Uncertain risk of bias: The trial may or may not be free of for-profit bias, as no information on clinical trial support or sponsorship is provided.
  3. High risk of bias: The trial is sponsored by the industry or has received other kinds of for-profit support.

We considered trials to have a low risk of bias if we assessed all of the above domains as being at low risk of bias. In all other cases, the trials were considered to have a high risk of bias.

 

Measures of treatment effect

For binary outcomes, we calculated the risk ratio (RR) with 95% confidence interval (CI). We also planned to report the risk difference if the conclusions would have changed by using risk difference, because risk difference allows meta-analysis including trials with zero events in both groups. For continuous variables, we calculated the mean difference (MD) with 95% CI for hospital stay as well as standardised mean difference (SMD) with 95% CI for variables such as quality of life.

 

Unit of analysis issues

The unit of analysis was the participant undergoing laparoscopic cholecystectomy.

 

Dealing with missing data

We performed an intention-to-treat analysis (Newell 1992) when possible for binary outcomes. For continuous outcomes, we used available-case analysis in the presence of missing data unless the study authors reported an intention-to-treat analysis based on an appropriate method of imputation of data such as multiple imputation. We planned to use intention-to-treat analysis if such analysis was available. We imputed the standard deviation from P values according to instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011) and used the median for the meta-analysis when the mean was not available. If it was not possible to calculate the standard deviation from the P value or the CIs, we imputed the standard deviation as the highest standard deviation in the other trials included under that outcome, fully recognising that this form of imputation would decrease the weight of the trial for calculation of mean differences and would bias the effect estimate to no effect in the case of standardised mean differences (Higgins 2011).

 

Assessment of heterogeneity

We examined the forest plot to visually assess heterogeneity. We used overlapping of CIs to visually assess heterogeneity. We explored heterogeneity by using the Chi2 test, with significance set at a P value of 0.10, and measured the quantity of heterogeneity using the I2 statistic (Higgins 2002).

 

Assessment of reporting biases

We used a funnel plot to explore bias in the presence of at least 10 trials for the outcome (Egger 1997; Macaskill 2001). We used asymmetry in the funnel plot of trial size against treatment effect to assess this bias. We also used the linear regression approach described by Egger et al to determine the funnel plot asymmetry (Egger 1997).

 

Data synthesis

We performed the meta-analyses according to the recommendations of The Cochrane Collaboration (Higgins 2011) and the Cochrane Hepato-Biliary Group Module (Gluud 2012), using the software package Review Manager 5 (RevMan 2012). We used a random-effects model (DerSimonian 1986) and a fixed-effect model (DeMets 1987). In the case of a discrepancy between the two models, we have reported both results; otherwise, we have reported only the results from the fixed-effect model.

 

Subgroup analysis and investigation of heterogeneity

We planned to perform the following subgroup analyses.

  1. Trials with low risk of bias versus trials with high risk of bias.
  2. Different gases used for pneumoperitoneum.
  3. Different pressures used for pneumoperitoneum (borderline low 10 mm Hg to 11 mm Hg; moderately low 7 mm Hg to 9 mmHg; and very low up to 6 mm Hg). This was defined arbitrarily again based on general belief and on review authors' opinions because no universal definitions are available.
  4. Elective versus emergency cholecystectomy.

We planned to perform the Chi2 test for subgroup differences, setting a P value of 0.05 to identify any differences for the subgroup analyses.

 

Sensitivity analysis

We planned to perform a sensitivity analysis by excluding the trials in which medians or standard deviations were imputed for continuous outcomes.

 

Trial sequential analysis

We planned to use trial sequential analysis to control for random errors due to sparse data and repetitive testing of accumulating data (CTU 2011; Thorlund 2011). The underlying assumption of trial sequential analysis is that testing for significance may be performed each time a new trial is added to the meta-analysis, resulting in an increased risk of random errors. We planned to add the trials according to the year of publication, and if more than one trial was published in a year, we planned to add the trials alphabetically according to the last name of the first author. We planned to construct trial sequential monitoring boundaries on the basis of the required information size. These boundaries determine the statistical inference one may draw regarding the cumulative meta-analysis that has not reached the required information size; if the trial sequential monitoring boundary is crossed before the required information size is reached, firm evidence may perhaps be established and further trials may turn out to be superfluous. On the other hand, if the boundary is not surpassed, it may be necessary to continue doing trials to detect or reject a certain intervention effect (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009, Wetterslev 2009; Thorlund 2010).   

We planned to apply trial sequential analysis (CTU 2011; Thorlund 2011) using a diversity-adjusted required information size (DARIS) calculated from an alpha error of 0.05, a beta error of 0.20, a control event proportion obtained from the results, and a relative risk reduction of 20% for binary outcomes with two or more trials to determine whether more trials on this topic are necessary. Trial sequential analysis cannot be performed for standardised mean difference. So, we did not plan to perform a trial sequential analysis for quality of life. For hospital stay, return to normal activity, and return to work, we planned to calculate the DARIS from an alpha error of 0.05, a beta error of 0.20, the variance estimated from the meta-analysis results of low risk of bias trials (if available), and a minimal clinically relevant difference of one day. For operating time, we planned to calculate the DARIS using a minimal clinically relevant difference of 15 minutes, with remaining parameters the same as for hospital stay.

 

Summary of findings table

We have summarised the results of all outcomes in a 'Summary of findings' table prepared using GRADEPro 3.6 (http://ims.cochrane.org/revman/gradepro).

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Description of studies

 

Results of the search

We identified a total of 1057 bibliographic references through electronic searches of The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (n = 202), MEDLINE (n = 240), EMBASE (n = 233), and Science Citation Index Expanded (n = 382). We excluded 465 duplicates and 555 clearly irrelevant references through reading abstracts. Thirty-eight references were retrieved for further assessment. One reference was identified through contacting experts in the field. No references were identified by scanning reference lists of the identified randomised trials. We excluded 12 references of 11 studies for the reasons listed under the table ‘Characteristics of excluded studies’. Twenty-six references of 24 randomised clinical trials were included in the review. Twenty-one randomised clinical trials provided data for this review. The reference flow is shown in Figure 1. The details of population characteristics, pressure used for pneumoperitoneum, and outcomes reported by individual trials are shown in the table ‘Characteristics of included studies’.

 FigureFigure 1. Study flow diagram.

 

Included studies

A total of 1277 participants were randomly assigned in the 24 trials included in this review (Pier 1994; Unbehaum 1995; Wallace 1997; Dexter 1999; Barczynski 2002; Barczynski 2003; Perrakis 2003; Polat 2003; Sefr 2003; Basgul 2004; Celik 2004; Hasukic 2005; Koc 2005; Chok 2006; Ibraheim 2006; Karagulle 2008; Joshipura 2009; Kanwer 2009; Sandhu 2009; Torres 2009; Celik 2010; Kandil 2010; Topal 2011; Eryilmaz 2012). However, only 21 trials including 1092 participants provided information for this review and further description about participants and interventions (Pier 1994; Unbehaum 1995; Wallace 1997; Dexter 1999; Barczynski 2003; Perrakis 2003; Polat 2003; Sefr 2003; Basgul 2004; Celik 2004; Hasukic 2005; Koc 2005; Chok 2006; Ibraheim 2006; Karagulle 2008; Joshipura 2009; Kanwer 2009; Sandhu 2009; Torres 2009; Celik 2010; Topal 2011). Participants were randomly assigned to the low pressure group (509 participants) and the standard pressure group (583 participants) in the 21 trials (Pier 1994; Unbehaum 1995; Wallace 1997; Dexter 1999; Barczynski 2003; Perrakis 2003; Polat 2003; Sefr 2003; Basgul 2004; Celik 2004; Hasukic 2005; Koc 2005; Chok 2006; Ibraheim 2006; Karagulle 2008; Joshipura 2009; Kanwer 2009; Sandhu 2009; Torres 2009; Celik 2010; Topal 2011). The average age of participants ranged between 42 years and 58 years in the 19 trials that provided this information (Unbehaum 1995; Wallace 1997; Dexter 1999; Barczynski 2003; Perrakis 2003; Polat 2003; Sefr 2003; Basgul 2004; Celik 2004; Hasukic 2005; Koc 2005; Chok 2006; Ibraheim 2006; Karagulle 2008; Joshipura 2009; Sandhu 2009; Torres 2009; Celik 2010; Topal 2011). The proportion of female participants ranged between 21.7% and 100% in the 19 trials that provided this information (Unbehaum 1995; Wallace 1997; Dexter 1999; Barczynski 2003; Perrakis 2003; Polat 2003; Sefr 2003; Basgul 2004; Celik 2004; Hasukic 2005; Koc 2005; Chok 2006; Ibraheim 2006; Karagulle 2008; Joshipura 2009; Sandhu 2009; Torres 2009; Celik 2010; Topal 2011). Twenty trials included only participants undergoing elective laparoscopic cholecystectomy (Pier 1994; Unbehaum 1995; Wallace 1997; Dexter 1999; Barczynski 2003; Perrakis 2003; Sefr 2003; Basgul 2004; Celik 2004; Hasukic 2005; Koc 2005; Chok 2006; Ibraheim 2006; Karagulle 2008; Joshipura 2009; Kanwer 2009; Sandhu 2009; Torres 2009; Celik 2010; Topal 2011). It was not clear whether participants undergoing emergency laparoscopic cholecystectomy were included in one trial (Polat 2003). Eleven trials clearly stated that they included only ASA I or II (low anaesthetic risk) participants (Pier 1994; Dexter 1999; Barczynski 2003; Perrakis 2003; Sefr 2003; Basgul 2004; Hasukic 2005; Chok 2006; Karagulle 2008; Sandhu 2009; Celik 2010). One trial included ASA I to III participants (Koc 2005). This information was not available for the remaining nine trials (Unbehaum 1995; Wallace 1997; Polat 2003; Celik 2004; Ibraheim 2006; Joshipura 2009; Kanwer 2009; Torres 2009; Topal 2011). All 21 trials used carbon dioxide pneumoperitoneum (Pier 1994; Unbehaum 1995; Wallace 1997; Dexter 1999; Barczynski 2003; Perrakis 2003; Polat 2003; Sefr 2003; Basgul 2004; Celik 2004; Hasukic 2005; Koc 2005; Chok 2006; Ibraheim 2006; Karagulle 2008; Joshipura 2009; Kanwer 2009; Sandhu 2009; Torres 2009; Celik 2010; Topal 2011).

 

Interventions

The types of low pressure used in the different trials were as follows.

In the remaining two trials, the pressure used was 8 to 10 mm Hg (Unbehaum 1995; Celik 2004).

In one trial, the trocar was inserted at standard pressure and the operation was performed under low pressure (Joshipura 2009).

 

Risk of bias in included studies

The risk of bias of all trials included in the review is shown in Figure 2. The risk of bias in individual trials is shown in Figure 3. Nine trials had low risk of bias in the allocation sequence generation domain (Wallace 1997; Dexter 1999; Barczynski 2003; Sefr 2003; Hasukic 2005; Chok 2006; Kanwer 2009; Sandhu 2009; Celik 2010). Eleven trials had low risk of bias in the allocation concealment domain (Dexter 1999; Barczynski 2002; Barczynski 2003; Perrakis 2003; Sefr 2003; Hasukic 2005; Koc 2005; Chok 2006; Ibraheim 2006; Joshipura 2009; Sandhu 2009). Three trials had low risk of bias in the blinding of participants, personnel, and outcome assessors domain (Wallace 1997; Joshipura 2009; Sandhu 2009). Ten trials had low risk of bias due to missing outcome data (Wallace 1997; Barczynski 2002; Barczynski 2003; Perrakis 2003; Sefr 2003; Celik 2004; Hasukic 2005; Chok 2006; Joshipura 2009; Sandhu 2009). Seven trials had low risk of bias due to selective outcome reporting (Wallace 1997; Dexter 1999; Hasukic 2005; Chok 2006; Karagulle 2008; Sandhu 2009; Celik 2010). Four trials had low risk of bias in the for-profit bias domain (Barczynski 2002; Chok 2006; Kanwer 2009; Sandhu 2009). Only one trial was considered to be at low risk of bias (Sandhu 2009).

 FigureFigure 2. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
 FigureFigure 3. Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

 

Effects of interventions

See:  Summary of findings for the main comparison Low pressure versus standard pressure pneumoperitoneum in laparoscopic cholecystectomy

The results are summarised in  Summary of findings for the main comparison.

 

Mortality

Mortality was reported in eight trials (Wallace 1997; Dexter 1999; Perrakis 2003; Hasukic 2005; Chok 2006; Karagulle 2008; Sandhu 2009; Celik 2010). No mortality was reported in either the low pressure group (0/199; 0%) or the standard pressure group (0/235; 0%). As no mortality was reported in either group, we were unable to use the control group proportion for calculation of the required information size of the trial sequential analysis. Instead, we used a proportion of 0.2% in the control group based on data from approximately 30,000 patients included in a database in Switzerland (Giger 2011). The proportion of information accrued was only 0.12% of the DARIS, and so the trial sequential monitoring boundaries were not drawn (Figure 4). The cumulative Z-curve does not cross the conventional statistical boundaries.

 FigureFigure 4. Trial sequential analysis of mortality
The diversity-adjusted required information size (DARIS) was calculated to 352,564 participants, based on the proportion of participants in the control group with the outcome of 0.2%, for a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. After accrual of 434 participants in the eight trials, only 0.12% of the DARIS has been reached. To account for zero event groups, a continuity correction of 0.01 was used in the calculation of the cumulative Z-curve (blue line). Accordingly, the trial sequential analysis does not show the required information size and the trial sequential monitoring boundaries. As shown, not even the conventional boundaries (dotted red line) were crossed by the cumulative Z-curve.

 

Serious adverse events

Serious adverse events were reported in seven trials (Wallace 1997; Dexter 1999; Hasukic 2005; Chok 2006; Karagulle 2008; Sandhu 2009; Celik 2010). No significant difference was noted in the proportions of participants with serious adverse events between the low pressure group (1/179; 0.6%) and the standard pressure group (0/215; 0%) (RR 3.00, 95% CI 0.14 to 65.90) ( Analysis 1.1). As only serious adverse events were reported in only one trial, the issue of fixed-effect model versus random-effects model does not arise. As no serious adverse events were reported in the control group, we used the overall proportions in both groups as the control group proportion for performing trial sequential analysis. The proportion of information accrued was only 0.14% of the DARIS, and so the trial sequential monitoring boundaries were not drawn (Figure 5). The cumulative Z-curve does not cross the conventional statistical boundaries.

 FigureFigure 5. Trial sequential analysis of serious adverse events
The diversity-adjusted required information size (DARIS) was calculated to 281,924 participants, based on the proportion of participants in the control group with the outcome of 0.25%, for a relative risk reduction of 20%, an alpha of 5%, a beta of 20% and a diversity of 0%. To account for zero event groups, a continuity correction of 0.01 was used in the calculation of the cumulative Z-curve (blue line). After accrual of 394 participants in the seven trials, only 0.14% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the required information size and the trial sequential monitoring boundaries. As shown, not even the conventional boundaries (dotted red line) were crossed by the cumulative Z-curve.

 

Quality of life

Quality of life was not reported in any of the trials.

 

Conversion to open cholecystectomy

Conversion to open cholecystectomy was reported in 10 trials (Dexter 1999; Barczynski 2003; Perrakis 2003; Sefr 2003; Chok 2006; Ibraheim 2006; Karagulle 2008; Joshipura 2009; Sandhu 2009; Celik 2010). No significant difference in the conversion to open cholecystectomy was observed between the low pressure group (2/269; 0.7%) and the standard pressure group (2/287; 0.7%) (RR 1.18, 95% CI 0.29 to 4.72) ( Analysis 1.2). The trial sequential analysis revealed that the proportion of information accrued was only 0.55% of the DARIS, and so the trial sequential monitoring boundaries were not drawn (Figure 6). The cumulative Z-curve does not cross the conventional statistical boundaries.

 FigureFigure 6. Trial sequential analysis of conversion to open cholecystectomy
The diversity-adjusted required information size (DARIS) was calculated to 100,279 participants, based on the proportion of participants in the control group with the outcome of 0.70%, for a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. To account for zero event groups, a continuity correction of 0.01 was used in the calculation of the cumulative Z-curve (blue line). After accrual of 556 participants in the 10 trials, only 0.55% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the required information size and the trial sequential monitoring boundaries. As shown, not even the conventional boundaries (dotted red line) were crossed by the cumulative Z-curve.

 

Hospital stay

None of the trials reported the proportion discharged as day-procedure laparoscopic cholecystectomy. Length of hospital stay was reported in five trials (Unbehaum 1995; Wallace 1997; Barczynski 2003; Joshipura 2009; Sandhu 2009). Hospital stay was statistically shorter in the low pressure group than in the standard pressure group by the fixed-effect model (MD -0.27 days, 95% CI -0.36 to -0.17) ( Analysis 1.3). This difference was not clinically significant. No significant difference was noted between the groups using the random-effects model (MD -0.30 days, 95% CI -0.63 to 0.02). No imputation of mean or standard deviation was performed, and so the sensitivity analysis was not performed. The trial sequential analysis suggested that it is unlikely that future trials will demonstrate any significant difference in length of hospital stay between low pressure groups and standard pressure groups as the cumulative Z-curve has crossed the DARIS but does not cross the conventional statistical boundaries (Figure 7).

 FigureFigure 7. Trial sequential analysis of hospital stay
The diversity-adjusted required information size (DARIS) was 183 participants based on a minimal relevant difference (MIRD) of one day, a variance (VAR) of 0.47, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 91.83%. Neither the conventional statistical boundaries (dotted red line) nor the trial sequential monitoring boundaries (red line) are crossed by the cumulative Z-curve (blue line), although the DARIS has been reached. The findings are consistent with no significant difference in length of hospital stay between low pressure and standard pressure pneumoperitoneum with low risk of random errors.

 

Return to normal activity

None of the trials reported this outcome.

 

Return to work

None of the trials reported this outcome.

 

Operating time

Operating time was reported in 19 trials (Pier 1994; Wallace 1997; Dexter 1999; Barczynski 2003; Perrakis 2003; Polat 2003; Sefr 2003; Basgul 2004; Celik 2004; Hasukic 2005; Koc 2005; Chok 2006; Ibraheim 2006; Joshipura 2009; Kanwer 2009; Sandhu 2009; Torres 2009; Celik 2010; Topal 2011). Operating time was about two minutes longer in the low pressure group than in the standard pressure group (MD 1.51 minutes, 95% CI 0.07 to 2.94) ( Analysis 1.4). No change in results was noted when the random-effects model was used. The mean or the standard deviation or both were imputed in five trials (Wallace 1997; Dexter 1999; Perrakis 2003; Torres 2009; Celik 2010). Excluding these trials from the analysis did not alter the results. The trial sequential analysis revealed that the DARIS has been crossed. The conventional statistical boundaries were crossed by a cumulative Z-curve favouring standard pressure pneumoperitoneum. Findings were consistent with low pressure pneumoperitoneum resulting in longer operating time compared with standard pressure pneumoperitoneum with low risk of random errors (Figure 8).

 FigureFigure 8. Trial sequential analysis of operating time
The diversity-adjusted required information size (DARIS) was 37 participants based on a minimal relevant difference (MIRD) of 15 minutes, a variance (VAR) of 258.34, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 0%. The conventional statistical boundaries (dotted red line) are crossed by the cumulative Z-curve (blue line) after the fourth trial. The trial sequential monitoring boundary (red line) is crossed by the cumulative Z-curve after the second trial. The findings are consistent with low pressure pneumoperitoneum associated with a longer operating time than standard pressure pneumoperitoneum with low risk of random errors.

 

Successful completion of low pressure laparoscopic cholecystectomy

Successful completion of low pressure laparoscopic cholecystectomy was reported in nine trials (Wallace 1997; Barczynski 2003; Perrakis 2003; Chok 2006; Ibraheim 2006; Joshipura 2009; Kanwer 2009; Sandhu 2009; Celik 2010). The median proportion of successful completion of low pressure laparoscopic cholecystectomy was 90%, with a range between 71.4% and 100%.

 

Subgroup analysis

Only one of the trials was at low risk of bias (Sandhu 2009). So this subgroup analysis was not performed. The remaining subgroup analyses were not performed because of the few trials included in the subgroups for the primary outcomes.

 

Reporting bias

Reporting bias could be assessed for conversion to open cholecystectomy and operating time. Visual inspection of the funnel plot and Egger's linear regression method of assessment of the funnel plot revealed no evidence of reporting bias (conversion to open cholecystectomy: P value 0.50; operating time: P value 0.07).

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Summary of main results

This review compared the safety and effectiveness of low pressure pneumoperitoneum versus standard pressure pneumoperitoneum. No mortality was noted in either group in the eight trials that reported mortality (Wallace 1997; Dexter 1999; Perrakis 2003; Hasukic 2005; Chok 2006; Karagulle 2008; Sandhu 2009; Celik 2010). Serious adverse events were reported in seven trials only (Wallace 1997; Dexter 1999; Hasukic 2005; Chok 2006; Karagulle 2008; Sandhu 2009; Celik 2010). No statistically significant difference was seen in the proportion of participants with serious adverse events between the low pressure group (1/179; 0.6%) and the standard pressure group (0/215; 0%). Conversion to open cholecystectomy was reported in 10 trials (Dexter 1999; Barczynski 2003; Perrakis 2003; Sefr 2003; Chok 2006; Ibraheim 2006; Karagulle 2008; Joshipura 2009; Sandhu 2009; Celik 2010). In many of these trials, the reason for conversion and the outcomes of participants who underwent conversion to open cholecystectomy were not reported (Barczynski 2003; Perrakis 2003; Sefr 2003; Ibraheim 2006; Joshipura 2009). A small proportion of participants who underwent conversion to open cholecystectomy (and for whom the reason for conversion or the outcome was not available) may have been converted to open cholecystectomy because of procedure-related injuries such as injuries to the viscera or bile duct. This possibility has not been ruled out in this review. In addition, the confidence intervals of serious adverse events are wide, and significant increases or decreases in complications due to low pressure pneumoperitoneum cannot be ruled out. Hence, no conclusion can be made about the safety of low pressure pneumoperitoneum.

The potential benefit of using low pressure pneumoperitoneum is reduced cardiopulmonary complications. However, even in trials that reported morbidity, no cardiopulmonary complications were described. This is likely to be due to inclusion of only low anaesthetic risk participants in the trials, as well as the low overall incidence of cardiopulmonary complications (0.5% in a case series of 400 patients, 70% of whom were low anaesthetic risk patients) (Dexter 1997). Information on whether low pressure could be beneficial in patients with cardiopulmonary disease is not available from the trials included in this review and requires investigation in further trials.

Operating time was two minutes longer in the low pressure group, and this finding is not clinically significant. Hospital stay was not different between the two groups using the random-effects model. Although the fixed-effect model showed significantly shorter hospital stay in the low pressure group than in the standard pressure group, this difference is not clinically significant.

Thus no clinical benefit of low pressure pneumoperitoneum is apparent, and information about its safety is lacking.

 

Overall completeness and applicability of evidence

Most of the trials included low anaesthetic risk participants undergoing elective laparoscopic cholecystectomy. So the findings of this review are applicable only to low anaesthetic risk patients undergoing elective laparoscopic cholecystectomy.

 

Quality of the evidence

Only one of the included trials was assessed as having low risk of bias, although it is possible to perform trials with low risk of bias for this comparison as compared with many other comparisons in surgery for which it is not possible to perform trials with low risk of bias (Sandhu 2009). The quality of the evidence is low or very low, as shown in  Summary of findings for the main comparison. However, this is the best quality evidence available on this topic.

 

Potential biases in the review process

We performed a thorough search of the literature. However, some trials may not have been reported by the researchers because of the lack of benefit associated with low pressure pneumoperitoneum. However, this would not have affected the conclusions of this review in that we do not recommend low pressure pneumoperitoneum unless future trials demonstrate clinical benefit.

 

Agreements and disagreements with other studies or reviews

We agree with the findings of our previous version that the safety of low pressure pneumoperitoneum has not been established (Gurusamy 2009).

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

 

Implications for practice

Laparoscopic cholecystectomy can be completed successfully using low pressure in approximately 90% of people undergoing laparoscopic cholecystectomy. However, currently no evidence is available to support the use of low pressure pneumoperitoneum. The safety of low pressure pneumoperitoneum has yet to be established.

 
Implications for research

Further trials with low risk of bias are required for elective laparoscopic cholecystectomy, laparoscopic cholecystectomy in patients with acute cholecystitis, and laparoscopic cholecystectomy in patients with cardiopulmonary disorders.

Future trials need to be designed according to the SPIRIT guidelines (www.spirit-statement.org/) and conducted and reported in accordance with the CONSORT statement (www.consort-statement.org).

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

To the Cochrane Hepato-Biliary Group for the support provided.

Peer Reviewers: Yogesh Puri, UK; Rutger Schols, The Netherlands.
Contact Editor: Steffano Trastulli, Italy.

K Samraj who identified trials and extracted data for the previous version of this review.

This project was funded by the National Institute for Health Research.
Disclaimer of the Department of Health: 'The views and opinions expressed in the review are those of the authors and do not necessarily reflect those of the National Institute for Health Research (NIHR), National Health Services (NHS), or the Department of Health'.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
Download statistical data

 
Comparison 1. Low pressure versus standard pressure pneumoperitoneum

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Serious adverse events7394Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.14, 65.90]

 2 Conversion to open cholecystectomy10556Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.29, 4.72]

 3 Hospital stay5415Mean Difference (IV, Random, 95% CI)-0.30 [-0.63, 0.02]

 4 Operating time19990Mean Difference (IV, Fixed, 95% CI)1.51 [0.07, 2.94]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Appendix 1. Search strategies


DatabasePeriod of SearchSearch Strategy

Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Wiley)Issue 1, 2013#1 MeSH descriptor Cholecystectomy, Laparoscopic explode all trees
#2 (laparoscop* OR coelioscop* OR celioscop* OR peritoneoscop*) AND cholecystectom*
#3 (#1 OR #2)
#4 MeSH descriptor Pneumoperitoneum, Artificial explode all trees
#5 MeSH descriptor Insufflation explode all trees
#6 MeSH descriptor Abdominal Wall explode all trees
#7 pneumoperitoneum OR insufflation OR "abdominal wall lift" OR gasless
#8 (#4 OR #5 OR #6 OR #7)
#9 (#3 AND #8)

MEDLINE (PubMed)1987 to February 2013(laparoscop* OR coelioscop* OR celioscop* OR peritoneoscop*) AND (cholecystectom* OR cholecystectomy, laparoscopic[MeSH]) AND (pneumoperitoneum OR Pneumoperitoneum, Artificial[MeSH] OR insufflation OR insufflation[MeSH] OR "abdominal wall lift" OR Abdominal Wall[MeSH] OR gasless) AND ((randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) AND humans [mh])

EMBASE (Ovid SP)1987 to February 20131 exp CROSSOVER PROCEDURE/
2 exp DOUBLE BLIND PROCEDURE/
3 exp SINGLE BLIND PROCEDURE/
4 exp RANDOMIZED CONTROLLED TRIAL/
5 (((RANDOM* or FACTORIAL* or CROSSOVER* or CROSS) and OVER*) or PLACEBO* or (DOUBL* and BLIND*) or (SINGL* and BLIND*) or ASSIGN* or ALLOCAT* or VOLUNTEER*).af.
6 1 or 2 or 3 or 4 or 5
7 (laparoscop* or coelioscop* or celioscop* or peritoneoscop*).af.
8 "cholecystectom*".af.
9 8 and 7
10 exp Cholecystectomy/
11 exp Laparoscopic Surgery/
12 11 and 10
13 9 or 12
14 (pneumoperitoneum or insufflation or "abdominal wall lift" or gasless).af.
15 exp Pneumoperitoneum/
16 exp Abdominal Wall/
17 16 or 15 or 14
18 6 and 13 and 17

Science Citation Index Expanded (Web of Knowledge)1987 to February 2013#1 TS=(laparoscop* OR coelioscop* OR celioscop* OR peritoneoscop*)
#2 TS=(cholecystectom*)
#3 TS=(pneumoperitoneum OR insufflation OR "abdominal wall lift" OR gasless)
#4 TS=(random* OR blind* OR placebo* OR meta-analysis)
#5 #4 AND #3 AND #2 AND #1



 

What's new

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Last assessed as up-to-date: 19 February 2013.


DateEventDescription

29 March 2013AmendedAuthor list: Kurinchi Selvan Gurusamy, Jessica Vaughan, Brian R Davidson.

29 March 2013New citation required and conclusions have changedThe methods of the review have been revised according to version 5.1.0 of Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

The conclusions now read: "There is currently no evidence to support the use of low pressure pneumoperitoneum. The safety of low pressure pneumoperitoneum has to be established. Further well-designed trials are necessary". The conclusions in the published 2009 version read: "Low pressure pneumoperitoneum appears effective in decreasing pain after laparoscopic cholecystectomy. The safety of low pressure pneumoperitoneum has to be established".

19 February 2013New search has been performedThe search was updated, and nine new trials were included (Karagulle 2008; Kanwer 2009; Sandhu 2009; Joshipura 2009; Torres 2009; Kandil 2010; Celik 2010; Topal 2011; Eryilmaz 2012).



 

History

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Protocol first published: Issue 1, 2008
Review first published: Issue 2, 2009


DateEventDescription

29 October 2008AmendedConverted to new review format.



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

KS Gurusamy wrote the review, assessed the trials for inclusion, and extracted data on included trials. J Vaughan identified trials and extracted data on included trials for this version. BR Davidson provided advice on improving the review.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Internal sources

  • None, Other.

 

External sources

  • None, Other.

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Differences between first and second versions

The methods of the review have been revised according to version 5.1.0 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). This resulted in a change in outcomes and in risk of bias. Outcomes related to pain scores were excluded from the revised version, as the clinical implication of reduction in pain is not clear. A clinically significant reduction in pain score is likely to result in shorter hospital stay, earlier return to normal activity, and earlier return to work, all of which have been included in the revised version.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé scientifique
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Barczynski 2002 {published data only}
  • Barczynski M, Herman RM. Influence of different pressures of pneumoperitoneum on the autonomic system function during laparoscopy. Folia Medica Cracoviensia 2002;43(1-2):51-8.
Barczynski 2003 {published data only}
  • Barczynski M, Herman RM. A prospective randomized trial on comparison of low-pressure (LP) and standard-pressure (SP) pneumoperitoneum for laparoscopic cholecystectomy. Surgical Endoscopy 2003;17(4):533-8.
Basgul 2004 {published data only}
  • Basgul E, Bahadir B, Celiker V, Karagoz AH, Hamaloglu E, Aypar U. Effects of low and high intra-abdominal pressure on immune response in laparoscopic cholecystectomy. Saudi Medical Journal 2004;25(12):1888-91.
Celik 2004 {published data only}
  • Celik V, Salihoglu Z, Demiroluk S, Unal E, Yavuz N, Karaca S, et al. Effect of intra-abdominal pressure level on gastric intramucosal pH during pneumoperitoneum. Surgical Laparoscopy Endoscopy & Percutaneous Techniques 2004;14(5):247-9.
Celik 2010 {published data only}
  • Celik AS, Firat N, Celebi F, Guzey D, Kaplan R, Birol S, et al. Laparoscopic cholecystectomy and postoperative pain: is it affected by intra-abdominal pressure?. Surgical Laparoscopy Endoscopy & Percutaneous Techniques 2010;20(4):220-2.
Chok 2006 {published data only}
  • Chok KS, Yuen WK, Lau H, Fan ST. Prospective randomized trial on low-pressure versus standard-pressure pneumoperitoneum in outpatient laparoscopic cholecystectomy. Surgical Laparoscopy Endoscopy & Percutaneous Techniques 2006;16(6):383-6.
Dexter 1999 {published data only}
Eryilmaz 2012 {published data only}
  • Eryilmaz HB, Memis D, Sezer A, Inal MT. The effects of different insufflation pressures on liver functions assessed with LiMON on patients undergoing laparoscopic cholecystectomy. The Scientific World Journal 2012;2012:172575.
Hasukic 2005 {published data only}
Ibraheim 2006 {published data only}
  • Ibraheim OA, Samarkandi AH, Alshehry H, Faden A, Farouk EO. Lactate and acid base changes during laparoscopic cholecystectomy. Middle East Journal of Anesthesiology 2006;18(4):757-68.
  • Ibraheim OA, Samarkandy AH, Alshehry H, Faden A, Elfarouk EO. Lactate levels and acid-base equilibrium in high- and low-pressure CO2 pneumoperitoneum for laparoscopic cholecystectomy. Egyptian Journal of Anaesthesia 2005;21(4):337-40.
Joshipura 2009 {published data only}
  • Joshipura VP, Haribhakti SP, Patel NR, Naik RP, Soni HN, Patel B, et al. A prospective randomized, controlled study comparing low pressure versus high pressure pneumoperitoneum during laparoscopic cholecystectomy. Surgical Laparoscopy, Endoscopy & Percutaneous Techniques 2009;19(3):234-40.
Kandil 2010 {published data only}
  • Kandil TS, El Hefnawy E. Shoulder pain following laparoscopic cholecystectomy: factors affecting the incidence and severity. Journal of Laparoendoscopic and Advanced Surgical Techniques. Part A 2010;20(8):677-82.
Kanwer 2009 {published data only}
  • Kanwer DB, Kaman L, Nedounsejiane M, Medhi B, Verma GR, Bala I. Comparative study of low pressure versus standard pressure pneumoperitoneum in laparoscopic cholecystectomy—a randomised controlled trial. Tropical Gastroenterology 2009;30(3):171-4.
Karagulle 2008 {published data only}
  • Karagulle E, Turk E, Dogan R, Ekici Z, Moray G. The effects of different abdominal pressures on pulmonary function test results in laparoscopic cholecystectomy. Surgical Laparoscopy, Endoscopy & Percutaneous Techniques 2008;18(4):329-33.
Koc 2005 {published data only}
Perrakis 2003 {published data only}
  • Perrakis E, Vezakis A, Velimezis G, Savanis G, Deverakis S, Antoniades J, et al. Randomized comparison between different insufflation pressures for laparoscopic cholecystectomy. Surgical Laparoscopy Endoscopy & Percutaneous Techniques 2003;13(4):245-9.
Pier 1994 {published data only}
Polat 2003 {published data only}
  • Polat C, Yilmaz S, Serteser M, Koken T, Kahraman A, Dilek ON. The effect of different intraabdominal pressures on lipid peroxidation and protein oxidation status during laparoscopic cholecystectomy. Surgical Endoscopy 2003;17(11):1719-22.
Sandhu 2009 {published data only}
  • Sandhu T, Yamada S, Ariyakachon V, Chakrabandhu T, Chongruksut W, Ko-Iam W. Low-pressure pneumoperitoneum versus standard pneumoperitoneum in laparoscopic cholecystectomy, a prospective randomized clinical trial. Surgical Endoscopy 2009;23(5):1044-7.
Sefr 2003 {published data only}
  • Sefr R, Puszkailer K, Frána J, Penka I. [Effect of carbon dioxide pneumoperitoneum on selected parameters of the acid-base equilibrium in laparoscopic cholecystectomy]. Rozhledy v Chirurgii 2001;80(4):206-12.
  • Sefr R, Puszkailer K, Jagos F. Randomized trial of different intraabdominal pressures and acid-base balance alterations during laparoscopic cholecystectomy. Surgical Endoscopy 2003;17(6):947-50.
Topal 2011 {published data only}
  • Topal A, Celik JB, Tekin A, Yuceaktas A, Otelcioglu S. The effects of 3 different intra-abdominal pressures on the thromboelastographic profile during laparoscopic cholecystectomy. Surgical Laparoscopy, Endoscopy & Percutaneous Techniques 2011;21(6):434-8.
Torres 2009 {published data only}
  • Torres K, Torres A, Staskiewicz GJ, Chroscicki A, Lo T, Maciejewski R. A comparative study of angiogenic and cytokine responses after laparoscopic cholecystectomy performed with standard- and low-pressure pneumoperitoneum. Surgical Endoscopy 2009;23(9):2117-23.
Unbehaum 1995 {published data only}
  • Unbehaum N, Feussner H, Siewert J R. Low-pressure insufflation technique in the laparoscopic cholecystectomy. Minimal Invasive Chirurgie 1995;4:10-5.
Wallace 1997 {published data only}
  • Wallace DH, Serpell MG, Baxter JN, O'Dwyer PJ. Randomized trial of different insufflation pressures for laparoscopic cholecystectomy. British Journal of Surgery 1997;84(4):455-8.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé scientifique
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Barczynski 2004 {published data only}
  • Barczynski M, Herman RM. Low-pressure pneumoperitoneum combined with intraperitoneal saline washout for reduction of pain after laparoscopic cholecystectomy: a prospective randomized study. Surgical Endoscopy 2004;18(9):1368-73.
Beqiri 2012 {published data only}
  • Beqiri AI, Domi RQ, Sula HH, Zaimi EQ, Petrela EY. The combination of infiltrative bupivacaine with low-pressure laparoscopy reduces postcholecystectomy pain. A prospective randomized controlled study. Saudi Medical Journal 2012;33(2):134-8.
Brokelman 2006 {published data only}
  • Brokelman WJA, Holmdahl L, Bergstrom M, Falk P, Klinkenbijl JHG, Reijnen M. Peritoneal fibrinolytic response to various aspects of laparoscopic surgery: a randomized trial. Journal of Surgical Research 2006;136(2):309-13.
  • Brokelman WJA, Holmdahl L, Bergstrom M, Falk P, Klinkonbijl JHG, Reijnen MMPJ. Peritoneal transforming growth factor beta-1 expression during laparoscopic surgery: a clinical trial. Surgical Endoscopy 2007;21(9):1537-41.
Esmat 2006 {published data only}
  • Esmat ME, Elsebae MMA, Nasr MMA, Elsebaie SB. Combined low pressure pneumoperitoneum and intraperitoneal infusion of normal saline for reducing shoulder tip pain following laparoscopic cholecystectomy. World Journal of Surgery 2006;30(11):1969-73.
Giraudo 2001 {published data only}
  • Giraudo G, Brachet Contul R, Caccetta M, Morino M. Gasless laparoscopy could avoid alterations in hepatic function. Surgical Endoscopy 2001;15(7):741-6.
Morino 1998 {published data only}
Parikh 2009 {published data only}
  • Parikh H, Mehta M. A study of QT interval and QT dispersion during laparoscopic cholecystectomy. Indian Journal of Anaesthesia 2009;53(2):193-6.
Sandoval-Jimenez 2009 {published data only}
  • Sandoval-Jimenez C, Mendez-Sashida G, Cruz-Marquez-Rico L, Cardenas-Victorica R, Guzman-Esquivel H, Luna-Silva M, et al. [Postoperative pain in patients undergoing elective laparoscopic cholecystectomy with low versus standard-pressure pneumoperitoneum. A randomized clinical trial.]. Revista de Gastroenterologia de Mexico 2009;74(4):314-20.
Sarli 2000 {published data only}
Tou 2004 {published data only}
Yasir 2012 {published data only}
  • Yasir M, Mehta KS, Banday VH, Aiman A, Masood I, Iqbal B. Evaluation of post operative shoulder tip pain in low pressure versus standard pressure pneumoperitoneum during laparoscopic cholecystectomy. The Surgeon 2012;10(2):71-4.

Additional references

  1. Top of page
  2. AbstractRésumé scientifique
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Alijani 2004
  • Alijani A, Hanna GB, Cuschieri A. Abdominal wall lift versus positive-pressure capnoperitoneum for laparoscopic cholecystectomy - randomized controlled trial. Annals of Surgery 2004;239(3):388-94.
ASA 2007
  • American Association of Anesthiologists. ASA Physical Status Classification System. www.asahq.org/clinical/physicalstatus.htm (accessed 7 August 2013).
Attili 1995
Ballal 2009
Bates 1992
Berger 2000
  • Berger MY, van der Velden JJ, Lijmer JG, de Kort H, Prins A, Bohnen AM. Abdominal symptoms: do they predict gallstones? A systematic review. Scandinavian Journal of Gastroenterology 2000;35(1):70-6.
Brok 2008
  • Brok J, Thorlund K, Gluud C, Wetterslev J. Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses. Journal of Clinical Epidemiology 2008;61:763-9.
Brok 2009
  • Brok J, Thorlund K, Wetterslev J, Gluud C. Apparently conclusive meta-analyses may be inconclusive—Trial sequential analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta-analyses. International Journal of Epidemiology 2009;38(1):287-98.
Casati 1997
  • Casati A, Valentini G, Ferrari S, Senatore R, Zangrillo A, Torri G. Cardiorespiratory changes during gynaecological laparoscopy by abdominal wall elevation: comparison with carbon dioxide pneumoperitoneum. British Journal of Anaesthesia 1997;78(1):51-4.
Cordoba 2010
CTU 2011
  • Copenhagen Trial Unit. TSA - Trial Sequential Analysis. http://ctu.dk/tsa/ 2011 (accessed 7 August 2013).
DeMets 1987
DerSimonian 1986
Dexter 1997
  • Dexter SPL, Martin IG, Marton J, McMahon MJ. Long operation and the risk of complications from laparoscopic cholecystectomy. British Journal of Surgery 1997; Vol. 84, issue 4:464-6. [DOI: 10.1002/bjs.1800840410]
Dolan 2009
  • Dolan JP, Diggs BS, Sheppard BC, Hunter JG. The national mortality burden and significant factors associated with open and laparoscopic cholecystectomy: 1997-2006. Journal of Gastrointestinal Surgery 2009;13(12):2292-301.
Egawa 2006
  • Egawa H, Morita M, Yamaguchi S, Nagao M, Iwasaki T, Hamaguchi S, et al. Comparison between intraperitoneal CO2 insufflation and abdominal wall lift on QT dispersion and rate-corrected QT dispersion during laparoscopic cholecystectomy. Surgical Laparoscopy Endoscopy & Percutaneous Techniques 2006;16(2):78-81.
Egger 1997
  • Egger M, Davey SG, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ (Clinical Research Ed.) 1997;315(7109):629-34.
Galizia 2001
  • Galizia G, Prizio G, Lieto E, Castellano P, Pelosio L, Imperatore V, et al. Hemodynamic and pulmonary changes during open, carbon dioxide pneumoperitoneum and abdominal wall-lifting cholecystectomy. A prospective, randomized study. Surgical Endoscopy 2001;15(5):477-83.
Giger 2006
  • Giger UF, Michel JM, Opitz I, Inderbitzin DT, Kocher T, Krahenbuhl L. Risk factors for perioperative complications in patients undergoing laparoscopic cholecystectomy: analysis of 22,953 consecutive cases from the Swiss Association of Laparoscopic and Thoracoscopic Surgery database. Journal of American College of Surgeons 2006;203(5):723-8.
Giger 2011
Glasgow 2000
  • Glasgow RE, Cho M, Hutter MM, Mulvihill SJ. The spectrum and cost of complicated gallstone disease in California. Archives of Surgery 2000;135(9):1021-5; discussion 1025-7.
Gluud 2012
  • Gluud C, Nikolova D, Klingenberg SL, Alexakis N, Als-Nielsen B, Colli A, et al. Cochrane Hepato-Biliary Group. About The Cochrane Collaboration (Cochrane Review Groups (CRGs)). 2013, Issue 7. Art. No.: LIVER.
GREPCO 1984
  • GREPCO. Prevalence of gallstone disease in an Italian adult female population. Rome group for the epidemiology and prevention of cholelithiasis (GREPCO). American Journal of Epidemiology 1984;119(5):796-805.
GREPCO 1988
  • GREPCO. The epidemiology of gallstone disease in Rome, Italy. Part i. Prevalence data in men. The Rome group for epidemiology and prevention of cholelithiasis (GREPCO). Hepatology 1988;8(4):904-6.
Gurusamy 2012
Gurusamy 2013
Gurusamy 2014a
  • Gurusamy KS, Vaughan J, Toon C, Davidson BR. Pharmacological interventions for prevention or treatment of post-operative pain in patients undergoing laparoscopic cholecystectomy. Cochrane Database of Systematic Reviews 2014, Issue (under editorial). [DOI: 10.1002/14651858.CD008261]
Gurusamy 2014b
Gurusamy 2014c
  • Gurusamy KS, Nagendran M, Guerrini GP, Toon C, Zinnuroglu M, Davidson BR. Intraperitoneal local anaesthetic instillation versus no intraperitoneal local anaesthetic instillation for laparoscopic cholecystectomy. Cochrane Database of Systematic Reviews 2014, Issue 3. [DOI: 10.1002/14651858.CD007337.pub3]
Gurusamy 2014d
Halldestam 2004
Henny 2005
HES 2011
  • HESonline. Hospital Episode Statistics. Main procedures and interventions: 3 character. http://www.hesonline.nhs.uk/Ease/servlet/ContentServer?siteID=1937&categoryID=205 2011 (accessed on 7 August 2013).
Higgins 2002
Higgins 2011
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Colloboration, 2011. www.cochrane-handbook.org.
ICH-GCP 1997
  • International Conference on Harmonisation Expert Working Group. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline. Guideline for good clinical practice CFR & ICH Guidelines. Vol. 1, PA 19063-2043, USA: Barnett International/PAREXEL, 1997.
Junghans 1997
  • Junghans T, Bohm B, Grundel K, Schwenk W. Effects of pneumoperitoneum with carbon dioxide, argon, or helium on hemodynamic and respiratory function. Archives of Surgery 1997;132(3):272-8.
Kjaergard 2001
  • Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Annals of Internal Medicine 2001;135(11):982-9.
Lundh 2012
Macaskill 2001
Mertens 2004
  • Mertens zur Borg IR, Lim A, Verbrugge SJ, Jzermans IJ, Klein J. Effect of intraabdominal pressure elevation and positioning on hemodynamic responses during carbon dioxide pneumoperitoneum for laparoscopic donor nephrectomy: a prospective controlled clinical study. Surgical Endoscopy 2004;18(6):919-23.
Moher 1998
  • Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses?. Lancet 1998;352(9128):609-13.
Neudecker 2002
  • Neudecker J, Sauerland S, Neugebauer E, Bergamaschi R, Bonjer HJ, Cuschieri A, et al. The European Association for Endoscopic Surgery clinical practice guideline on the pneumoperitoneum for laparoscopic surgery. Surgical Endoscopy 2002;16(7):1121-43.
Neuhaus 2001
Newell 1992
NIH 1992
  • NIH. NIH consensus statement on gallstones and laparoscopic cholecystectomy. http://consensus.nih.gov/1992/1992GallstonesLaparoscopy090html.htm 1992 (accessed 7 August 2013).
RevMan 2012
  • The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012.
Royle 2003
  • Royle P, Milne R. Literature searching for randomized controlled trials used in Cochrane reviews: rapid versus exhaustive searches. International Journal of Technology Assessment in Health Care 2003;19(4):591-603.
Russell 1993
  • Russell RC. General surgery: biliary surgery. BMJ (Clinical Research Ed.) 1993;307(6914):1266-9.
Savović 2012
  • Savović J, Jones HE, Altman DG, Harris RJ, Juni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials. Annals of Internal Medicine 2012;157(6):429-38.
Savović 2012a
  • Savović J, Jones HE, Altman DG, Harris RJ, Jüni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials. Health Technology Assessment 2012;16(35):1-82.
Schulz 1995
  • Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273(5):408-12.
Strasberg 1993
Thorlund 2009
  • Thorlund K, Devereaux PJ, Wetterslev J, Guyatt G, Ioannidis JP, Thabane L, et al. Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses. International Journal of Epidemiology 2009;38(1):276-86.
Thorlund 2010
  • Thorlund K, Anema A, Mills E. Interpreting meta-analysis according to the adequacy of sample size. An example using isoniazid chemoprophylaxis for tuberculosis in purified protein derivative negative HIV-infected individuals. Clinical Epidemiology 2010;2:57-66.
Thorlund 2011
  • Thorlund K, Engstrøm J, Wetterslev J, Brok J, Imberger G, Gluud C. User manual for Trial Sequential Analysis (TSA). http://ctu.dk/tsa/files/tsa_manual.pdf 2011 (accessed 7 August 2013).
Wetterslev 2008
  • Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. Journal of Clinical Epidemiology 2008;61(1):64-75.
Wetterslev 2009
Wood 2008
  • Wood L, Egger M, Gluud LL, Schulz KF, Jüni P, Altman GD, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ (Clinical Research Ed.) 2008;336:601-5.