Gurusamy K, Samraj K, Gluud C, et al. Meta-analysis of randomized controlled trials on the safety and effectiveness of early versus delayed laparoscopic cholecystectomy for acute cholecystitis

Hepatopancreatobiliary and Liver Transplant Surgery, University Department of Surgery, Royal Free and University College School of Medicine, London, UK.
British Journal of Surgery (Impact Factor: 5.54). 02/2010; 97(2):141-50. DOI: 10.1002/bjs.6870
Source: PubMed
ABSTRACT
: In many countries laparoscopic cholecystectomy for acute cholecystitis is mainly performed after the acute episode has settled because of the anticipated increased risk of morbidity and higher conversion rate from laparoscopic to open cholecystectomy.
: A systematic review was performed with meta-analysis of randomized clinical trials of early laparoscopic cholecystectomy (ELC; performed within 1 week of onset of symptoms) versus delayed laparoscopic cholecystectomy (performed at least 6 weeks after symptoms settled) for acute cholecystitis. Trials were identified from The Cochrane Library trials register, Medline, Embase, Science Citation Index Expanded and reference lists. Risk ratio (RR) or mean difference was calculated with 95 per cent confidence intervals (c.i.) based on intention-to-treat analysis.
: Five trials with 451 patients were included. There was no significant difference between the two groups in terms of bile duct injury (RR 0.64 (95 per cent c.i. 0.15 to 2.65)) or conversion to open cholecystectomy (RR 0.88 (95 per cent c.i. 0.62 to 1.25)). The total hospital stay was shorter by 4 days for ELC (mean difference -4.12 (95 per cent c.i. -5.22 to -3.03) days).
: ELC during acute cholecystitis appears safe and shortens the total hospital stay.

Full-text

Available from: Christian Gluud, Aug 06, 2014
Meta-analysis
Meta-analysis of randomized controlled trials on the safety
and effectiveness of early versus delayed laparoscopic
cholecystectomy for acute cholecystitis
K. Gurusamy
1
,K.Samraj
2
,C.Gluud
4
,E.Wilson
3
and B. R. Davidson
1
1
Hepatopancreatobiliary and Liver Transplant Surgery, University Department of Surgery, Royal Free and University College School of Medicine,
London,
2
Department of Surgery, Milton Keynes General Hospital, Milton Keynes, and
3
Health Economics Group, School of Medicine, Health Policy
and Practice, University of East Anglia, Norwich, UK, and
4
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet,
Copenhagen University Hospital, Copenhagen, Denmark
Correspondence to: Mr K. Gurusamy, c/o Professor B. R. Davidson, 9th Floor, University Department of Surgery, Royal Free Hospital, Pond Street,
London NW3 2QG, UK (e-mail: kurinchi2k@hotmail.com)
Background:
In many countries laparoscopic cholecystectomy for acute cholecystitis i s mainly performed
after the acute episode has settled because of the anticipated increased risk of morbidity and higher
conversion rate from laparoscopic to open cholecystectomy.
Methods: A systematic review was performed with meta-analysis of randomized clinical trials of early
laparoscopic cholecystectomy (ELC; performed within 1 week of onset of symptoms) versus delayed
laparoscopic cholecystectomy (performed at least 6 weeks after symptoms settled) for acute cholecystitis.
Trials were identified from The Cochrane Library trials register, Medline, Embase, Science Citation
Index Expanded and reference lists. R isk ratio (RR) or mean difference was calculated with 95 per cent
confidence intervals (c.i.) based on intention-to-treat analysis.
Results: Five trials with 451 patients were included. There was no significant difference between the
two groups in terms of bile duct injury (RR 0·64 (95 per cent c.i. 0·15 to 2·65)) or c onversion to open
cholecystectomy (RR 0·88 (95 per cent c.i. 0·62 to 1·25)). The total hospital stay was shorter by 4 days
for ELC (mean difference 4·12 (95 per cent c.i. 5·22 to 3·03) days).
Conclusion: ELC during acute cholecystitis appears safe and shortens the total hospital stay.
Paper accepted 27 August 2009
Published online 24 December 2009 in Wiley InterScience (www.bjs.co.uk). DOI: 10.1002/bjs.6870
Introduction
About 1015 per cent of the adult Western population
have gallstones
1–4
. Between 1 and 4 per cent become
symptomatic each year
4,5
. In the UK, some 50 000
cholecystectomies are performed annually
6
,ofwhich
7090 per cent are carried out laparoscopically
7–10
and
a third are performed for acute cholecystitis
11
. Thus,
approximately 13 000 laparoscopic cholecystectomies are
performed annually in the UK for acute cholecystitis.
There is considerable controversy over the timing of
laparoscopic cholecystectomy in acute cholecystitis. In
the era of open cholecystectomy, early surgery (within
7 days of onset of symptoms) had no increased morbidity
or mortality over delayed surgery (at least 6 weeks
after symptoms settled)
12
. Delaying surgery increases the
risks of further gallstone-related complications
12,13
.With
laparoscopic cholecystectomy, there are concerns about
higher morbidity rates in an emergency procedure
14 16
and
the higher conversion rate to an open procedure during
the acute phase
8,17
. The main reason for conversion in
early laparoscopic cholecystectomy (ELC) is inflammation
obscuring the view of Calot’s triangle
18
, whereas in
delayed laparoscopic cholecystectomy (DLC) it is fibrotic
adhesions
18,19
. Severe inflammation and fibrotic adhesions
are associated with bile duct injury
20
.
In the USA, about 30 per cent of patients with acute
cholecystitis undergo cholecystectomy during the acute
attack
8
. In the UK, only 20 per cent of surgeons perform
laparoscopic cholecystectomy during acute cholecystitis
21
.
The remainder allow the symptoms to settle for at
least 6 weeks before performing DLC
21
. Meta-analyses
Copyright 2009 British Journal of Surgery Society Ltd British Journal of Surgery 2010; 97: 141150
Published by John Wiley & Sons Ltd
Page 1
142 K. Gurusamy, K. Samraj, C. Gluud, E. Wilson and B. R. Davidson
of randomized clinical trials (RCTs) of ELC versus DLC
during acute cholecystitis have concluded that ELC is safe
and decreases the length of hospital stay
22,23
. The present
article is an update of the authors’ Cochrane Hepato-
Biliary Group (CHBG) systematic review published in
2006
22
, with additional outcomes included. The aim of
this systematic review with meta-analysis was to determine
whether patients with acute cholecystitis should be offered
ELC or should undergo a delayed procedure.
Methods
Identification of trials and data extraction
Only RCTs (irrespective of language, blinding, sample
size or publication status) that compared ELC (within
7 days of onset of symptoms) with DLC (intended to be
performed after an interval of at least 6 weeks after the
index attack of acute cholecystitis) were included. Quasi-
randomized trials (in which the methods of allocating
participants to a treatment were not strictly random, such
as by date of birth, hospital record number or alternation)
were excluded. Only trials that reported at least one of the
primary outcomes (mortality; surgery-related morbidity
such as bile duct injury, bile leak, reoperation rate,
infection, bleeding; complications during waiting time
such as pancreatitis, recurrent episodes of cholecystitis,
obstructive jaundice; conversion to open cholecystectomy)
or secondary outcomes (operating time, incidence of
common bile duct stones, hospital stay, number of work
days lost, quality of life) were included. Hospital stay was
defined as the time spent in hospital from all hospital
admissions starting from the onset of symptoms until the
completion of surgery, including those for surgery- and
disease-related complications.
The CHBG Controlled Trials Register, the Cochrane
Central Register of Controlled Trials (CENTRAL) in
The Cochrane Library, Medline, Embase and Science
Citation Index Expanded were searched up to November
2008 using the medical subject headings (MeSH) terms
‘cholecystectomy, laparoscopic’ and ‘cholecystitis, acute’.
Equivalent free text search terms were used in the search
strategy. A filter for identifying RCTs recommended by
The Cochrane Collaboration
24
was used to filter out
non-randomized studies in Medline and Embase. The
references of the included trials were searched to identify
further trials.
Two authors (K.G. and K.S.) independently identified
the trials for inclusion, extracted data related to the
outcomes mentioned above and assessed the risk of bias
in trials as described below. There were no discrepancies
in the selection of the trials or in data extraction between
the reviewers except in the assessment of blinding. Both
reviewers agreed that blinding was unethical or impossible
to achieve. However, there was disagreement with regard
to whether the trials should be classified as having a high
or low risk of bias. Primary outcomes such as surgical
morbidity and decision to convert to open cholecystectomy
are based on subjective criteria and lack of blinding is a
potential source of bias for these outcomes. It was therefore
agreed that lack of blinding would result in the trials
being classified as having a high risk of bias. Any unclear
or missing information was obtained by contacting the
authors of the individual trials.
Assessment of risk of bias
There is a risk of overestimation of beneficial treatment
effects in RCTs with a high risk of bias
25 28
. The risk
of bias was assessed according to the guidelines of The
Cochrane Collaboration and the CHBG Module
24,29,30
.
The assessment of risk of bias in the trials was based on
sequence generation; allocation concealment; blinding of
participants, personnel and outcome assessors; incomplete
outcome data; selective outcome reporting; and other
sources of bias such as baseline imbalance, early stopping
bias, academic bias and source of funding bias
24,29,30
.
Considering that the period of follow-up was short and
the incidence of complications low, any trial that reported
loss to follow-up of any patient was considered to suffer
from bias owing to incomplete outcome data.
Statistical analysis
The software package RevMan 5
31
provided by The
Cochrane Collaboration was used for analysis. The risk
ratio (RR) with 95 per cent confidence interval (c.i.)
was calculated for dichotomous variables, and the mean
difference with 95 per cent c.i. for continuous variables.
If the mean values were not available for continuous
outcomes, median values were used for meta-analysis.
If the standard deviation was not available, it was
calculated according to the guidelines of The Cochrane
Collaboration
24
. This involves assumptions that both
groups have the same variance, which may not be true.
The random-effects model
32
and the fixed-effect model
33
were used. In case of heterogeneity only the results of
the random-effects model were reported. Heterogeneity
was explored using the χ
2
test, with significance set at
P < 0·100, and quantified
34
using I
2
, with a maximum
value of 30 per cent identifying low heterogeneity
24
.
All analyses were based on the intention-to-treat
principle
35
using good-outcome analysis (assuming that
Copyright 2009 British Journal of Surgery Society Ltd www.bjs.co.uk British Journal of Surgery 2010; 97: 141150
Published by John Wiley & Sons Ltd
Page 2
Early versus delayed laparoscopic cholecystectomy for acute cholecystitis 143
Potentially relevant RCTs identified and
screened for retrieval
n
= 535
RCTs excluded
n
= 524
Duplicates
n
= 158
Irrelevant from titles and abstracts
n
= 366
RCTs excluded
n
= 4
Non-randomized
n
= 1
Out of scope
n
= 3
RCTs excluded from meta-analysis
n
= 2
Multiple reports
n
= 2
RCTs withdrawn, by outcome
n
= 0
RCTs retrieved for more detailed
evaluation
n
= 11
Potentially appropriate RCTs to be
included in the meta-analysis
n
= 7
RCTs included in meta-analysis
n
= 5
RCTs with usable information, by
outcome
n
= 5
Fig. 1 QUOROM diagram for the study. *Interventions did not fall within the definitions used for ‘early’ and/or ‘delayed’ laparoscopic
cholecystectomy in this review. RCT, randomized controlled trial
morbidity would not have occurred in patients who
dropped out after randomization and did not actually
undergo surgery) for all outcomes, except conversion
to open cholecystectomy where different scenarios were
used, such as good-outcome analysis (none of the
postrandomization dropouts in either group would have
required conversion to open cholecystectomy), poor-
outcome analysis (all postrandomization dropouts in
both groups would have required conversion to open
cholecystectomy), extreme case favouring ELC (none
of the postrandomization dropouts in the early group
would have required conversion to open cholecystectomy
but all those in the delayed group would have required
conversion) and extreme case favouring DLC (the opposite
of extreme case favouring ELC). This is because of
the low incidence of morbidity in both groups in the
authors’ previous review
22
, leaving ‘conversion to open
cholecystectomy’ the only primary outcome suitable for the
other scenarios. ‘Available-case analysis’
24
of the primary
outcomes was also performed to check whether the results
changed.
A subgroup analysis of the primary outcomes was
performed to determine whether trials that included
only patients who had symptoms for less than 4 days
yielded different results from those that included patients
with symptoms for 7 days. A further subgroup analysis
examined whether the results varied with surgical
experience. The χ
2
test of subgroup differences was
used to identify differences in the effect estimates in the
subgroups
24
. Sensitivity analysis (reanalysis of the data
after excluding one or more trials to assess whether the
effect estimates are altered) was carried out, with inclusion
of trials with a low risk of bias in domains other than
blinding.
A funnel plot was used to explore publication bias
36,37
.
Asymmetry in the funnel plot of study size against
treatment effect was used to identify publication bias.
Results
A total of 535 references were identified through the
electronic searches (Fig. 1). No new trials were identified by
searching references. In total, seven publications describing
five completed randomized trials fulfilled the inclusion
criteria
19,38 43
.
All the trials included patients with acute cholecystitis
due to gallstones. Two trials excluded patients with
common bile duct stones
42,43
. Some 223 patients were
randomized to ELC and 228 to DLC. There was no
Copyright 2009 British Journal of Surgery Society Ltd www.bjs.co.uk British Journal of Surgery 2010; 97: 141150
Published by John Wiley & Sons Ltd
Page 3
144 K. Gurusamy, K. Samraj, C. Gluud, E. Wilson and B. R. Davidson
Table 1
Characteristics of included trials
Reference Year
Timing
of ELC
(days)
Timing
of DLC
(weeks)
Surgeon’s
experience
No. of
patients
(ELC : DLC)
Postrandomization
dropouts
(ELC : DLC)*
Early
surgery
required in
DLC group
D
´
avila et al.
38
1999 < 4 8 Not stated 27 : 36 NS 5 (14)
Johansson et al.
39
2003 < 7 68 Minimum 25 laparoscopic cholecystectomies 74 : 71 0 : 2 18 (25)
Kolla et al.
42
2004 < 4 612 Surgical consultant 20 : 20 0 : 0 0 (0)
Lai et al.
43
1998 < 7 68 Minimum 50 laparoscopic cholecystectomies 53 : 51 0 : 5 8 (16)
Lo et al.
19
1998 < 7 812 More than 300 laparoscopic cholecystectomies 49 : 50 1 : 5 9 (18)
Values in parentheses are percentages. *Did not have surgery. Those belonging to the delayed laparoscopic cholecystectomy (DLC) group who had
worsening, non-resolution or recurrence of acute cholecystitis had to undergo emergency surgery; there was no crossover from early laparoscopic
cholecystectomy (ELC) to DLC. NS, not stated.
Table 2 Risk of bias in included trials
Adequate
sequence
generation
Allocation
concealment Blinding
Incomplete
outcome
data
addressed
Free
from
selective
reporting
Free
from
early
stopping
Free from
baseline
imbalance
Free
from
academic
bias
Source
of
funding
bias
D
´
avila et al.
38
?? ? + ??+ ?
Johansson et al.
39
++++? ++?
Kolla et al.
42
++++? ++?
Lai et al.
43
+++++++?
Lo et al.
19
+++++++?
+, Low risk of bias; , high risk of bias; ?, risk of bias unclear.
baseline imbalance in age or sex between the two groups.
Trial details are shown in Table 1.
Risk of bias of included studies
The risk of bias is summarized in Table 2. Four of the five
trials were at low risk of bias in the important domains,
except blinding
19,39,42,43
. As blinding was not performed
in any study, all trials were considered to be at high risk of
bias. All five trials were graded as ‘risk of bias unclear’ with
regard to source of funding as the funding source was not
stated in any of the trial reports.
Effect estimates
There was no heterogeneity among the trials as denoted
by the χ
2
and I
2
values. The results of the fixed-effect
model are presented. Results were not altered by adopting
the random-effects model. Results of the intention-to-treat
analysis are presented for the meta-analysis. Results did not
change by adopting the available-case analysis (including
only patients who actually underwent surgery). The crude
rates are presented for those who had surgery (222 patients
in ELC group and 216 in DLC group).
Primary outcomes
Mortality
No participant in any of the trials died.
Bile duct injury
The trials reported bile duct injury requiring reoperation.
There was no significant difference between the two groups
with respect to this complication (RR 0·64 (95 per cent c.i.
0·15 to 2·65); P = 0·54) (Fig. 2). The bile duct injury rate
was 0·5 per cent (one of 222) in the early group versus
1·4 per cent (three of 216) in the delayed group (Table 3).
Bile leak requiring endoscopic retrograde
cholangiopancreatography
There was a trend towards a difference between the two
groups in the proportion developing bile leak requiring
endoscopic retrograde cholangiopancreatography (ERCP),
but it did not reach statistical significance (RR 5·50
(95 per cent c.i. 0·98 to 30·83); P = 0·05). An exact
meta-analysis using the fixed-effect conditional maximum
likelihood method was performed using StatsDirect
statistical software version 2.7.2 (StatsDirect, Altrincham,
UK) as the P value was 0·05 (no statistically significant risk
difference) and because of the rare events. Odds ratio was
Copyright 2009 British Journal of Surgery Society Ltd www.bjs.co.uk British Journal of Surgery 2010; 97: 141150
Published by John Wiley & Sons Ltd
Page 4
Early versus delayed laparoscopic cholecystectomy for acute cholecystitis 145
Reference
Dávila
et al
.
38
Johansson
et al
.
39
Kolla
et al
.
42
Lai
et al
.
43
Lo
et al
.
19
Total
Heterogeneity: χ
2
= 1
·
32, 3 d.f.,
P
= 0
·
73,
I
2
= 0%
Test for overall effect:
Z
= 0
·
62,
P
= 0
·
54
Bile duct injury
ELC
0 of 27
0 of 74
1 of 20
0 of 53
0 of 49
1 of 223
1 of 36
26
·
90
·
44 (0
·
02, 10
·
41)
0
·
32 (0
·
01, 7
·
73)
3
·
00 (0
·
13, 69
·
52)
Not estimable
0
·
34 (0
·
01, 8
·
15)
0
·
64 (0
·
15, 2
·
65)
0
·
01 0
·
1
Favours ELC Favours DLC
1 10 100
31
·
8
10
·
4
30
·
9
100
·
0
1 of 71
0 of 20
0 of 51
1 of 50
3 of 228
DLC
Weight (%)
Risk ratio Risk ratio
Fig. 2 Meta-analysis of bile duct injury in early (ELC) versus delayed (DLC) laparoscopic cholecystectomy groups. Risk ratios are shown
with 95 per cent confidence intervals
Table 3 Conversion and bile duct injury
Conversion to open surgery Bile duct injury
Reference ELC DLC Crossover* Elective ELC DLC
D
´
avila et al.
38
1of27(4) 6of36(17) 4of5(80) 2of31(6) 0of27(0) 1of36(3)
Johansson et al.
39
23 of 74 (31) 20 of 69 (29) 10 of 18 (56) 10 of 51 (20) 0 of 74 (0) 1 of 69 (1)
Kolla et al.
42
5 of 20 (25) 5 of 20 (25) 0 of 20 (0) 5 of 20 (25) 1 of 20 (5) 0 of 20 (0)
Lai et al.
43
11 of 53 (21) 11 of 46 (24) 2 of 8 (25) 9 of 38 (24) 0 of 53 (0) 0 of 46 (0)
Lo et al.
19
5 of 48 (10) 9 of 45 (20) 2 of 9 (22) 7 of 36 (19) 0 of 48 (0) 1 of 45 (2)
All studies 45 of 222 (20·3) 51 of 216 (23·6) 18 of 40 (45) 33 of 176 (18·8) 1 of 222 (0·5) 3 of 216 (1·4)
Values in parentheses are percentages. Dropouts (did not undergo surgery) were excluded. *Those belonging to the delayed laparoscopic cholecystectomy
(DLC) group who had worsening, non-resolution or recurrence of acute cholecystitis. Those belonging to DLC group who were successfully managed
conservatively. ELC, early laparoscopic cholecystectomy.
calculated for these purposes. The pooled odds ratio was
infinity (95 per cent c.i. 1·42 to infinity; P = 0·01). The
pooled odds ratio was infinity because this complication
did not occur in any patient undergoing DLC. Some
3·2 per cent (seven of 222) required ERCP in the early
group compared with 0 per cent (none of 216) in the
delayed group.
Other complications
There was no significant difference between the two
groups regarding intra-abdominal collections requiring
intervention (RR 1·82 (95 per cent c.i. 0·57 to 5·87); P =
0·31), superficial wound infections (RR 1·37 (95 per cent
c.i. 0·58 to 3·23); P = 0·48) or deep wound infections (RR
0·44 (95 per cent c.i. 0·10 to 1·96); P = 0·28).
Gallstone-related morbidity during waiting period
Two patients in the delayed group developed cholangitis
during the waiting time, but there were no reports of
pancreatitis. In 40 (17·5 per cent) of 228 patients in the
DLC group symptoms either did not resolve or recurred
before the planned operation and emergency laparoscopic
cholecystectomy was necessary. The proportion of
operations converted to open cholecystectomy was 18 of
40 in this group (Table 3).
Conversion to open cholecystectomy
There was no significant difference between the two groups
regarding conversion to open cholecystectomy (RR 0·88
(95 per cent c.i. 0·62 to 1·25); P = 0·47) (Fig. 3). The
conversion rate was 20·3 per cent (45 of 222) in the early
group and 23·6 per cent (51 of 216) in the delayed group
(Table 3). There was no change in the results when two
scenarios of the intention-to-treat analysis were applied:
‘poor-outcome’ analysis and ‘worst-case ELC’ analysis.
However, in the ‘best-case ELC’ analysis, the rate of
conversion to open cholecystectomy was significantly lower
in the early group than in the delayed group (RR 0· 71
(95 per cent c.i. 0·51 to 0·99); P = 0·04).
Two trials included only patients fewer than 4 days from
onset of symptoms
38,42
and three included patients fewer
than 7 days from onset of symptoms
19,39,43
.Therewasno
significant difference in the conversion or complication
Copyright 2009 British Journal of Surgery Society Ltd www.bjs.co.uk British Journal of Surgery 2010; 97: 141150
Published by John Wiley & Sons Ltd
Page 5
146 K. Gurusamy, K. Samraj, C. Gluud, E. Wilson and B. R. Davidson
Reference
Dávila
et al
.
38
Johansson
et al
.
39
Kolla
et al
.
42
Lai
et al
.
43
Lo
et al
.
19
Total
Heterogeneity: χ
2
= 3
·
33, 4 d.f.,
P
= 0
·
50,
I
2
= 0%
Test for overall effect:
Z
= 0
·
72,
P
= 0
·
47
Conversion
ELC
1 of 27
23 of 74
5 of 20
11 of 53
5 of 49
45 of 223
6 of 36
10
·
10
·
22 (0
·
03, 1
·
74)
1
·
10 (0
·
67, 1
·
82)
1
·
00 (0
·
34, 2
·
93)
0
·
96 (0
·
46, 2
·
02)
0
·
57 (0
·
20, 1
·
57)
0
·
88 (0
·
62, 1
·
25)
0
·
05 0
·
2
Favours ELC Favours DLC
1520
40
·
3
9
·
9
22
·
1
17
·
6
100
·
0
20 of 71
5 of 20
11 of 51
9 of 50
51 of 228
DLC
Weight (%)
Risk ratio Risk ratio
Fig. 3 Meta-analysis of bile duct injury in early (ELC) versus delayed (DLC) laparoscopic cholecystectomy groups. Risk ratios are shown
with 95 per cent confidence intervals
Reference
Johansson
et al
.
39
Kolla
et al
.
42
Lai
et al
.
43
Lo
et al
.
19
Total
Heterogeneity: χ
2
= 1
·
57, 3 d.f.,
P
= 0
·
67,
I
2
= 0%
Test for overall effect:
Z
= 7
·
38,
P
< 0
·
001
ELC
n
74
20
53
49
5
·
0(9
·
1) 13
·
7
3
·
00 (5
·
96, 0
·
04)
6
·
00 (10
·
62, 1
·
38)
4
·
00 (5
·
35, 2
·
65)
5
·
00 (7
·
88, 2
·
12)
4
·
12 (5
·
22, 3
·
03)
Favours ELC Favours DLC
0
510
510
5
·
6
66
·
2
14
·
5
100
·
0
4
·
1(8
·
6)
7
·
6(3
·
6)
6
·
0(7
·
3)
71
20
51
50
8
·
0(9
·
1)
10
·
1(6
·
1)
11
·
6(3
·
4)
11
·
0(7
·
3)
192196
Mean(s.d.) (days)
Weight (%) Mean difference (days) Mean difference (days)
DLC
n
Mean(s.d.) (days)
Fig. 4 Meta-analysis of hospital stay in early (ELC) versus delayed (DLC) laparoscopic cholecystectomy groups. Mean differences are
shown with 95 per cent confidence intervals
rate in the patients operated on fewer than 4 days or fewer
than 7 days after the onset of symptoms.
Secondary outcomes
Operating time
Two trials
42,43
reported the mean and three
19,38,39
the
median operating time. The median was used in the
meta-analysis. There was no significant difference in the
operating time between the two groups (mean difference
1·33 (95 per cent c.i. 3· 25 to 0·59) days; P = 0·18).
The median operating time reported in two trials was
longer in the early group than in the delayed group
by 21 min
19
and 30 min
38
. The median operating time
in one trial, in which laparoscopic common bile duct
exploration was used for suspected common bile duct
stones on routine peroperative cholangiography (with
surgical residents carrying out these procedures), was 2 min
shorter in the early group
39
. Excluding this trial, the total
operating time was longer in the early group than in the
delayed group (mean difference 18·36 (95 per cent c.i. 7·78
to 28·95) min; P < 0·001). Excluding the three trials that
reported median values, mean operating time was longer
in the ELC group (mean difference 15·10 (95 per cent c.i.
2·58 to 27·62) min; P = 0·02).
Incidence of common bile duct stones
Two trials excluded patients with common bile duct
stones
42,43
. Meta-analysis of the remaining trials showed no
significant difference in the incidence of common bile duct
stones (RR 0·90 (95 per cent c.i. 0·32 to 2·57); P = 0·84).
Hospital stay
The mean total hospital stay ranged from 4·1to7·6days
in the early group and from 8·0to11·6 days in the delayed
group. One trial did not report total hospital stay
38
.Two
trials
42,43
reported the mean(s.d.) hospital stay and two
19,39
provided a median value. The median was used in the meta-
analysis after imputing the standard deviation from the P
value. The total hospital stay was shorter in the early group
than in the delayed group by 4 days (mean difference 4·12
(95 per cent c.i. 5·22 to 3· 03); P < 0·001) (Fig. 4). The
Copyright 2009 British Journal of Surgery Society Ltd www.bjs.co.uk British Journal of Surgery 2010; 97: 141150
Published by John Wiley & Sons Ltd
Page 6
Early versus delayed laparoscopic cholecystectomy for acute cholecystitis 147
median hospital stay reported in two trials was shorter
in the early group than in the delayed group by 3 days
19
and 5 days
39
. Excluding these trials did not alter the mean
difference in the total hospital stay (4·16 (95 per cent c.i.
5·45 to 2·86); P < 0· 001).
Number of work days lost
The total number of work days lost was significantly lower
with ELC than DLC by 11 days in the only trial
19
that
reported this outcome in 36 patients who were in active
employment during the trial period (15 versus 26 days;
mean difference 11·00 (95 per cent c.i. 19·61 to 2·39);
P = 0·01)
19
.
Quality of life
Only one trial reported this outcome
40
. Quality of life was
measured 1, 3 and 6 months after surgery in both groups
using a gastrointestinal symptom rating scale and generic
psychological well-being index. At 1 month after operation,
quality of life measured by means of the gastrointestinal
symptom rating scale was significantly better after ELC
than DLC (P < 0·01 in the dimensions of indigestion,
diarrhoea and abdominal pain). There was no significant
difference in the scores on this scale between the groups
at 3 and 6 months, nor was there any difference in the
psychological well-being index at any time (P = 0·11).
Heterogeneity
Subgroup and sensitivity analyses
All the trials had a high risk of bias. This was mainly
due to the lack of blinding. Considering that blinding
is unethical or impossible to achieve in this setting, a
sensitivity analysis was performed of trials that had a low
risk of bias in other important domains
19,39,42,43
.Thisdid
not change the results.
Subgroup analysis of trials including only patients with
fewer than 4 days since onset of symptoms and those also
including patients with symptoms for more than 4 days in
the early group showed no significant difference between
the ELC and DLC groups in any of the outcome measures.
Subgroup analysis was performed of trials in which
the surgeons had experience of a minimum of 2550
laparoscopic cholecystectomies. There was no significant
difference between the early and delayed group in any
outcome measure in spite of the varying surgical experience
of the surgeons.
Funnel plot
The funnel plot did not reveal any publication bias.
However, there were too few trials to perform the Egger’s
test for exploration of bias.
Discussion
This systematic review with meta-analysis of RCTs found
no significant difference in complication or conversion
rates whether laparoscopic cholecystectomy had been
performed at presentation with acute cholecystitis or
612 weeks after the symptoms had settled. The early
strategy had the advantage of decreased hospital stay and
avoided the risk of emergency surgery for non-resolved or
recurrent symptoms with a high rate of conversion to open
cholecystectomy. Open cholecystectomy is associated with
an increase in morbidity, pain and time to return to work
44
.
Bile duct injury is the most feared complication during
cholecystectomy and can be fatal
45
. Corrective surgery
for bile duct injury has a high morbidity rate and is
not without mortality
45,46
; quality of life can be poor
even 3 years after corrective surgery
47
. Cholecystitis has
been considered as a risk factor for bile duct injury
20,48
.
Observational studies have suggested a larger number of
bile duct injuries
49,50
with early surgery, but this was
not evident from the randomized trials. Larger studies
are required to demonstrate small differences in bile duct
injury rates between an early or delayed approach to acute
cholecystitis.
Bile leakage is a complication in about 1 per cent of
laparoscopic cholecystectomies
51,52
. These are usually due
to cystic stump leaks
52 54
and the majority are successfully
managed by endoscopic sphincterotomy with or without a
temporary stent
53,54
. In the present analysis, leaks occurred
in about 3 per cent of patients in the ELC group and
were successfully managed endoscopically. No patient in
the delayed group experienced this complication. Possible
reasons for this difference in bile leakage between the
groups include the friability of the oedematous tissue or a
lower threshold for ERCP for suspected bile leaks in the
early group.
Another important issue is gallstone-related morbidity
during the waiting period for cholecystectomy. The
most important is the non-resolution or recurrence of
cholecystitis. Forty patients (17·5 per cent) in the delayed
group underwent emergency surgery during the waiting
period, with a very high conversion rate. Although there
were few instances of gallstone-related morbidity in the
trials included in the meta-analysis, cholecystectomy in
the delayed group was performed within 12 weeks in all
the trials. However, the reality of elective cholecystectomy
outside trials is likely to be different
11,13
. Patients awaiting
surgery for longer than 12 weeks have a significant risk of
developing complications of gallstones
13,55
.
Observational studies have suggested a higher conver-
sion rate to open surgery in the early group whereas
randomized trials have shown no difference between the
Copyright 2009 British Journal of Surgery Society Ltd www.bjs.co.uk British Journal of Surgery 2010; 97: 141150
Published by John Wiley & Sons Ltd
Page 7
148 K. Gurusamy, K. Samraj, C. Gluud, E. Wilson and B. R. Davidson
groups. This may be due to lack of intention-to-treat analy-
sis in observational studies, with patients from the delayed
surgery group who had to undergo emergency surgery
being included in the early surgery group (treatment-
received analysis).
The total hospital stay was shorter by 4 days with ELC
than with delayed surgery. This was due to patients in
the delayed group requiring two treatment episodes, one
for the conservative treatment of acute cholecystitis and
another for definitive surgical treatment. In addition, many
of the patients in the delayed group required emergency
readmission owing to recurrent symptoms. The number of
work days lost was also less with ELC in the only trial that
reported this outcome
19
.
Although there are reports of an increased conversion
rate if cholecystectomy is delayed for more than 4896 h
after the onset of symptoms
18,56 58
, this has not been
confirmed in other studies
59,60
. In this review comparable
results were found for patients operated on within 4 days
or within 7 days after symptom onset, suggesting that
laparoscopic cholecystectomy is possible and appropriate
up to 7 days after the onset of symptoms.
Another issue is experience of the surgeons
39
. Although
subgroup analysis did not reveal a significant difference
in outcomes after early versus delayed cholecystectomy in
relation to the experience of the surgeons, the techniques
had to be modified and gallbladder decompression was
necessary more often in the early group than in the
delayed group, suggesting more complex surgery
19,42,43
.
Laparoscopic cholecystectomy performed by upper gastro-
intestinal surgeons has a lower rate of conversion to
open cholecystectomy and shorter hospital stay than that
performed by non-upper gastrointestinal surgeons
61
. ELC
should therefore be performed in units with appropriate
surgical expertise.
The quality-of-life data reported in this meta-analysis
included postoperative quality of life in only one
trial. This demonstrated better quality of life in terms
of gastrointestinal symptoms 1 month after ELC than
DLC, but no differences thereafter
40
. Considering costs
incurred up to 1 year after presentation, ELC could save
approximately £8 million (
¤8·95 million) annually in the
UK National Health Service
62
. The recommendation of
the economic analysis is, therefore, that a policy of ELC
should be adopted in preference to DLC.
All the trials in this review had a high risk of bias.
However, blinding can be impossible to achieve in this
situation and it is unlikely that trials with a low risk of bias
can be designed. There is a high risk of type I (erroneously
concluding that an intervention is beneficial when it is not)
and type II (erroneously concluding that an intervention
is not beneficial when it actually is) errors because of the
few trials included and the small sample size in each trial
63
.
New trials with adequate sample size are needed to decrease
theriskoftypeIandtypeIIerrors.
The findings of this review are applicable to patients
with acute cholecystitis due to gallstones, who are eligible
for laparoscopic cholecystectomy and have had symptoms
for fewer than 7 days, with or without common bile
duct stones. ELC during acute cholecystitis appears to
be safe and shortens the total hospital stay. Surgery is
more complex and conversion rates are higher in acute
cholecystitis than in uncomplicated symptomatic gallstone
disease. Although this meta-analysis showed no effect of
surgeon’s experience between early and delayed surgery on
any of the outcome measures, including bile duct injury
and conversion to open operation, surgeons with adequate
laparoscopic experience are likely to perform better when
dealing with acute cholecystitis.
Acknowledgements
This paper is a substantially shortened version of a
Cochrane review submitted to the CHBG. Cochrane
reviews are regularly updated as new evidence emerges,
and in response to comments and criticisms. The
Cochrane Library should be consulted for the most
recent version of the review. The results of a Cochrane
review can be interpreted differently, depending on
people’s perspectives and circumstances. Please consider
the conclusions presented carefully. They are the opinions
of authors, and are not necessarily shared by The Cochrane
Collaboration.
The authors thank the CHBG for the support and advice
that they provided for the preparation of this review. The
authors declare no conflict of interest.
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  • [Show abstract] [Hide abstract] ABSTRACT: A total of 100 consecutive patients with perforated duodenal or juxtapyloric ulcers were treated by: laparotomy and omental patch repair (group 1, n = 44); laparoscopic suture patch repair (group 2, n = 35); and laparoscopic fibrin glue repair (group 3, n = 21). The three groups were comparable in Acute Physiology And Chronic Health Evaluation II score and in other known operative risk factors such as shock on admission, delayed presentation and associated underlying medical illness. Operative mortality and morbidity data were identical in all groups. The mean operating time was 52.1, 101.3 and 61.1 min respectively in the three groups (group 1 versus group 2, group 2 versus group 3, and group 1 versus groups 2 and 3 combined, P < 0.001). The median number of doses of analgesia required after operation was 4, 3 and 1 respectively (group 1 versus groups 2 and 3, P < 0.05). Conversion to laparotomy was necessary in six patients in group 2 and in one in group 3 (P not significant). The median hospital stay was 5 days in all three groups. Patients who underwent laparoscopic repair of perforated peptic ulcer required fewer postoperative doses of analgesia than those who had open repair. Laparoscopic glue repair has the additional advantage over laparoscopic suture of being technically simpler; it also takes less time to perform.
    No preview · Article · Jul 1995 · British Journal of Surgery
  • [Show abstract] [Hide abstract] ABSTRACT: : A recent systematic review found early laparoscopic cholecystectomy (ELC) to be safe and to shorten total hospital stay compared with delayed laparoscopic cholecystectomy (DLC) for acute cholecystitis. The cost-effectiveness of ELC versus DLC for acute cholecystitis is unknown. : A decision tree model estimating and comparing costs to the UK National Health Service (NHS) and quality-adjusted life years (QALYs) gained following a policy of either ELC or DLC was developed with a time horizon of 1 year. Uncertainty was investigated with probabilistic sensitivity analysis, and value-of-information analysis estimated the likely return from further investment in research in this area. : ELC is less costly (approximately - pound820 per patient) and results in better quality of life (+0.05 QALYs per patient) than DLC. Given a willingness-to-pay threshold of pound20 000 per QALY gained, there is a 70.9 per cent probability that ELC is cost effective compared with DLC. Full implementation of ELC could save the NHS pound8.5 million per annum. : The results of this decision analytic modelling study suggest that on average ELC is less expensive and results in better quality of life than DLC. Future research should focus on quality-of-life measures alone.
    No preview · Article · Feb 2010 · British Journal of Surgery
  • [Show abstract] [Hide abstract] ABSTRACT: IntroductionAn iterative approach to evidence gathering and decision makingApproaches to setting research prioritiesValue of information analysisDiscussionConclusion AppendixReferences
    No preview · Chapter · May 2010
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