Introduction
About 10–15 percent of the adult Western population has gallstones. Between 1 and 4 percent become symptomatic each year. Acute cholecystitis is one of the main reasons of cholecystectomies which is usually performed using laparoscopic cholecystectomies. There is considerable controversy over the timing of laparoscopic cholecystectomy in. 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). Delaying surgery increases the risks of further gallstone-related complications. With laparoscopic cholecystectomy, there are concerns about higher morbidity rates in an emergency procedure and the higher conversion rate to an open procedure during the acute phase. The main reason for conversion in early laparoscopic cholecystectomy (ELC) is inflammation obscuring the view of Calot’s triangle, whereas in delayed laparoscopic cholecystectomy (DLC) it is fibrotic adhesions. Severe inflammation and fibrotic adhesions are associated with bile duct injury. Usually about 20-30 percent of patients with acute cholecystitis undergo cholecystectomy during the acute attack. The remainder allows the symptoms to settle for at least 6 weeks before performing DLC.
Methods
Metaanalysis is refered to the studies that use specific statistical methods to select a group of studies among a pool of studies with a single focus and aggregate the results that indicate the most potential for generalization. A metaanalysis published in 2010 summarized the outcomes of comparisons between early (ELC, performed up to one week since the appearance of the symptoms) and late (allow the symptoms to settle for at least 6 weeks before surgery) laparoscopic cholecystectomy. In this metaanalysis a total of 535 references were identified through the electronic searches. No new trials were identified by searching references. In total, seven publications describing five completed randomized trials fulfilled the inclusion criteria. All the trials included patients with acute cholecystitis due to gallstones. Two trials excluded patients with common bile duct stones. Some 223 patients were randomized to ELC and 228 to DLC.
Results
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 complicatio. The bile duct injury rate was 0.5 percent (one of 222) in the early groupversus 1.4 percent (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. Some 3.2 percent (seven of 222) required ERCP in the early group compared with 0 percent (none of 216) in the delayed group.
Other complications
There was no significant difference between the two groups regarding intra-abdominal collections requiring intervention, superficial wound infections or deep wound infections, 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 percent) 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
Conversion to open cholecystectomy
There was no significant difference between the two groups regarding conversion to open cholecystectomy. The conversion rate was 20.3 percent (45 of 222) in the early group and 23.6 percent (51 of 216) in the delayed group. 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. Two trials included only patients fewer than 4 days from onset of symptoms and three included patients fewer than 7 days from onset of symptoms. There was no significant difference in the conversion or complication 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 reported the mean and three 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. The median operating time reported in two trials was longer in the early group than in the delayed group by 21 min and 30 min. 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. Excluding this trial, the total operating time was longer in the early group than in the delayed group. Excluding the three trials that reported median values, mean operating time was longer in the ELC group.
Incidence of common bile duct stones
Two trials excluded patients with common bile duct stones. Meta-analysis of the remaining trials showed no significant difference in the incidence of common bile duct stones.
Hospital stay
The mean total hospital stay ranged from 4.1 to 7.6 days in the early group and from 8.0 to 11.6 days in the delayed group. One trial did not report total hospital stay. Two trials reported the mean (s.d.) hospital stay and two provided a median value. The median was used in the metaanalysis 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. The median hospital stay reported in two trials was shorter in the early group than in the delayed group by 3 days and 5 days. Excluding these trials did not alter the mean difference in the total hospital stay.
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 that reported this outcome in 36 patients who were in active employment during the trial period (15 versus 26 days).
Quality of life
Only one trial reported this outcome. 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 (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.
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 6–12 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.
Bile duct injury is the most feared complication during cholecystectomy and can be fatal. Corrective surgery for bile duct injury has a high morbidity rate and is not without mortality; quality of life can be poor even 3 years after corrective surgery. Cholecystitis has been considered as a risk factor for bile duct injury. Observational studies have suggested a larger number of bile duct injuries 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 percent of laparoscopic cholecystectomies. These are usually due to cystic stump leaks and the majority are successfully managed by endoscopic sphincterotomy with or without a temporary stent. In the present analysis, leaks occurred in about 3 percent 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 percent) 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. Patients awaiting surgery for longer than 12 weeks have a significant risk of developing complications of gallstones.
Observational studies have suggested a higher conversion rate to open surgery in the early group whereas randomized trials have shown no difference between the groups. This may be due to lack of intention-to-treat analysis in observational studies, with patients from the delayed surgery group who had to undergo emergency surgery being included in the early surgery group (treatmentreceived 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.
Although there are reports of an increased conversion rate if cholecystectomy is delayed for more than 48–96 h after the onset of symptoms, this has not been confirmed in other studies. 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. Although subgroup analysis did not reveal a significant difference in outcomes after early versusdelayed 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. Laparoscopic cholecystectomy performed by upper gastrointestinal surgeons has a lower rate of conversion to open cholecystectomy and shorter hospital stay than that performed by non-upper gastrointestinal surgeons. 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 thereafter40. 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. 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.
New trials with adequate sample size are needed to decrease the risk of type I and type II errors. 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.
Reference
K. Gurusamy, et al., “Meta‐analysis of randomized controlled trials on the safety and effectiveness of early versus delayed laparoscopic cholecystectomy for acute cholecystitis”, British Journal of Surgery, vol. 97, pp. 141-150, 2010.
