Sheung-Tat Fan China : I wondered if dosage should be expressed in terms of the body weight — kilograms — rather than absolute amount. I see that there is a difference in body size between Asians and Americans, so there may be a difference. We have to be more realistic; that means we have to talk about the body weight, rather than absolute amount. Harumi Gomi: For example, 30 kg — for these low-body-weight patients, we may have to use FDA-approved pediatric dosage.
Harumi Gomi: The major reasons for proposals on appropriate dosing regimens are as follows:. Best available medical treatment with appropriate antimicrobial dosing regimens should be provided to patients, when possibile, to avoid inadequate clinical response. Overuse or unnecessary use of broader-spectrum antimicrobial agents, such as carbapenems, should be avoided in Japan. Medical professionals in Japan should be aware of scientifically sound or appropriate antimicrobial dosing regimens on the basis of pharmacokinetics and pharmacodynamics of the agents.
To make the appropriate dosing regimens available in Japan, legal action or policy-making is required. We would like to express our deep gratitude to the Japanese Society for Abdominal Emergency Medicine, the Japan Biliary Association, and the Japanese Society of Hepato-Biliary-Pancreatic Surgery, who provided us with great support and guidance in the preparation of the Guidelines.
We also truly appreciate the panelists who cooperated with and contributed significantly to the International Consensus Meeting, held on April 1 and 2, National Center for Biotechnology Information , U. Journal of Hepato-Biliary-Pancreatic Surgery.
J Hepatobiliary Pancreat Surg. Published online Jan Solomkin , Steven Strasberg , Henry A. Henry A. Serafin C.
Author information Article notes Copyright and License information Disclaimer. Corresponding author. Received May 31; Accepted Aug 6. This article has been cited by other articles in PMC. Abstract Acute cholecystitis consists of various morbid conditions, ranging from mild cases that are relieved by the oral administration of antimicrobial drugs or that resolve even without antimicrobials to severe cases complicated by biliary peritonitis.
Introduction Acute cholecystitis consists of various morbid conditions, ranging from mild cases that are relieved by the oral administration of antimicrobial drugs or that resolve even without antimicrobials to severe cases complicated by biliary peritonitis, each of which requires a different treatment strategy. What microbiological studies should be performed in acute cholecystitis? Open in a separate window.
How should antimicrobial agents be used in patients with acute cholecystitis? Is the administration of NSAIDs to patients suffering from an attack of biliary colic effective to prevent the development of acute cholecystitis? What are the important factors for consideration in antimicrobial drug selection? Should penetration into the bile or gallbladder wall be considered important in the selection of therapeutic antimicrobials in acute cholecystitis?
What are the results of clinical trials regarding antimicrobial therapy for acute cholecystitis? Table 3 Comparative clinical tests of antimicrobial drugs in cholecystitis. What are the current recommendations for antimicrobial therapy in acute cholecystitis?
Antimicrobial drugs should be selected according to the severity assessment. Table 4 Antibacterials for mild grade I acute cholecystitis.
What is the appropriate antimicrobial dosing regimen? Discussion at the Tokyo International Consensus Meeting Community-acquired or hospital-acquired biliary infections Henry Pitt USA : We should talk about community-acquired or hospital-acquired infections. Duration of antimicrobial therapy Henry Pitt: I think in particular, for the acute cholecystitis, if you do a cholecystectomy, that you can often get away with a very short course, especially if it is a mild case, which meant most of the cases.
Drug selection on the basis of severity assessment Joseph S. Drug dosage and cost Joseph S. Henry Pitt: I think that the issue of cost should be in our guidelines as well. Harumi Gomi: The major reasons for proposals on appropriate dosing regimens are as follows: Best available medical treatment with appropriate antimicrobial dosing regimens should be provided to patients, when possibile, to avoid inadequate clinical response Overuse or unnecessary use of broader-spectrum antimicrobial agents, such as carbapenems, should be avoided in Japan.
Medical professionals in Japan should be aware of scientifically sound or appropriate antimicrobial dosing regimens on the basis of pharmacokinetics and pharmacodynamics of the agents To make the appropriate dosing regimens available in Japan, legal action or policy-making is required.
Acknowledgment We would like to express our deep gratitude to the Japanese Society for Abdominal Emergency Medicine, the Japan Biliary Association, and the Japanese Society of Hepato-Biliary-Pancreatic Surgery, who provided us with great support and guidance in the preparation of the Guidelines.
References 1. Consequences of preoperative cholangitis and its treatment on the outcome of operation for choledocholithiasis. Bacteriological study of choledochal bile in patients with common bile duct stones, with or without acute suppurative cholangitis.
Kaohsiung J Med Sci. Simultaneous bacteriologic assessment of bile from gallbladder and common bile duct in control subjects and patients with gallstones and common duct stones. Arch Surg.
Counts of bacteria and pyocites of choledochal bile in controls and in patients with gallstones or common bile duct stones with or without acute cholangitis. Bacteriological studies of bile from the gallbladder in patients with carcinoma of the gallbladder, cholelithiasis, common bile duct stones and no gallstones disease. Eur J Surg. Bacteriology of the gallbladder bile in normal subjects. Am J Surg. Kune G, Schutz E.
Bacteria in the billary tract. A study of their frequency and type. Med J Aust. Treatment of biliary colic with diclofenac: a randomized, double-blind, placebo-controlled study.
Biliary colic treatment and acute cholecystitis prevention by prostaglandin inhibitor. Dig Dis Sci. However, gram-negative microorganisms, commonly found in the intestinal tract, such as Enterobacteriales were frequently isolated from patients with biliary infection Owing to the development of defense mechanisms, Enterobacteriales, especially Escherichia , became more resistant to bile than gram-positive microorganisms, thus becoming less sensitive to the deleterious effects of bile so that they frequently colonized the gallbladder and became an important reservoir for biliary infections 13 , The proportion of infections caused by the gram-positive microorganisms including enterococci significantly declined over time, whereas the gram-negative microorganisms, especially Enterobacteriales are becoming more prevalent, and most commonly isolated among patients with acute cholecystitis in this study.
There might have several reasons for these changes. At first, it might be associated with the recent extensive use of oral fluoroquinolone for urinary tract infections, pneumonia, and skin or soft tissue infections in the community. Although enterococci were intrinsically less susceptible to fluoroquinolones, gut microbiota, specifically enterococcal populations, were highly impacted by ciprofloxacin, with a decrease observed in their density and diversity in healthy volunteers Second, the duration of preoperative antibiotic therapy would be related with these changes because most of recommended antibiotics for biliary infection were susceptible to Enterobacteriales other than enterococci.
In this study, the duration of preoperative antibiotic therapy was consistently decreased from the second period to the recent period. Third, the frequency of biliary intervention either PTBD or ERCP, performed for patients with combined common bile duct stone would be associated with these changes.
A previous study had shown that enterococci were commonly isolated from the bile of patients with stents or from those who had undergone PTBD In contrast, patients who underwent ECRP might have more chances of ascending infection from the microorganisms of intestinal tract, as Enterobacteriales. However, the frequency of those procedures were reversed in the recent period that it might be a reason for a recent resurgence of gram-positive microorganisms, including enterococci in this study.
Although penicillin and ampicillin provide good coverage against non- faecium enterococci, such as E. Therefore, vancomycin is recommended for infections with E. The first detection of VREFM in this study was from samples obtained during the later years — of the investigated period, and nearly all of these patients had grade II acute cholecystitis Hence, other antibiotics, including linezolid and tigecycline, which provide good coverage against VREFM, should be considered for patients with such advanced infections.
Although one report noted the poor effectiveness of tigecycline for severely ill patients with septic shock 17 , tigecycline can be used in several other cases because of its broad spectrum of effectiveness against gram-negative microorganisms, including ESBL-producing bacteria.
As enterococci have seldom been associated with bacteremia, it is still controversial to administer antibiotics when enterococci are isolated from culture samples. However, antimicrobial therapy should be strongly considered for high-risk patients such as immunocompromised patients with nosocomial infections, severely ill patients with a history of taking broad-spectrum antibiotics, and patients at high risk of endocarditis 18 , For gram-negative microorganisms, piperacillin-tazobactam and third- or fourth-generation cephalosporins are recommended as the first drugs of choice, and fluoroquinolones and carbapenems are recommended as the second choice, depending on the severity of the illness and antimicrobial susceptibility patterns 8.
However, this study has demonstrated a significant increasing frequency of ciprofloxacin-resistant Enterobacteriales infections, likely, at least partly, because of its extensive usage in the community. Therefore, these antibiotics are not appropriate for initial empiric antimicrobial therapy, and piperacillin-tazobactam or cefepime, which have broader spectra and lower resistance rates, would be more appropriate, especially for patients with severe infections.
For patients who have been recently exposed to serial antimicrobial therapy, carbapenem or tigecycline should be used, considering the possibility of infection with ESBL-producing gram-negative bacteria. CRE species have emerged as important healthcare-associated pathogens because of extensive drug resistance and associated high morbidity and mortality rates One case of CRE was detected in this study; continuous monitoring for these bacteria is required.
The role of antimicrobial therapy varies depending on the severity of the illness and etiologic characteristics. In grade I acute cholecystitis, as it is not obvious whether bacteria play a significant role, antimicrobial therapy is administered to prevent progression to infection before cholecystectomy. For grade II acute cholecystitis, antimicrobial therapy is therapeutic and required until the gallbladder is removed 8 , In this study, in contrast to patients with grade I and II acute cholecystitis, bacteremia, or VREFM infection, patients who did not receive early appropriate antibiotics did not require additional antibiotic treatment or postoperative hospitalization.
Thus, surgery might be more important for the treatment of grade I and II acute cholecystitis, even as an infection control measure. Although the analysis of patients with bacteremia did not reach statistical significance, because of the small number of patients in this study, early appropriate antimicrobial therapy for those patients seems to be important as we observed marked differences in operation times, estimated blood loss, open conversion rate, and postoperative hospitalization duration according to the bacteremia status.
Most patients with bacteremia might have clinical deterioration and can be classified as grade III acute cholecystitis and are therefore not suitable for surgery.
Hence, only a small number of those patients, who were in relatively good condition, were included in this study. This study has several limitations. First, this was a retrospective study because of which the accuracy of the data analyzed relied on the completeness of the medical records. Second, because of differences in bacterial growth and other parameters, more experimental evidence would be needed to determine or confirm antibiotic resistance in the future. Furthermore, over time, there were changes in the list of antibiotic resistance tests available at our hospital, rendering the data on some antibiotics to be insufficient for analysis.
Finally, the results of our microbiological and antibiotic resistance analyses may be different because of regional and institutional differences. In conclusion, the incidence of frequently isolated microorganisms and their antibiotic resistance profiles changed over time.
The frequency of infections caused by gram-positive microorganisms, including enterococci, significantly declined during the period under study, whereas infections caused by gram-negative microorganisms, including Enterobacteriales, especially Escherichia , showed a significant increasing trend. Of the antibiotics previously recommended for acute cholecystitis, ciprofloxacin and ceftriaxone were among the agents that were no longer as effective and hence, are inappropriate for initial empiric antimicrobial therapy.
For grade I and II acute cholecystitis, surgery might be crucial for treatment and infection control. We retrospectively reviewed positive bile cultures from patients who underwent cholecystectomy for acute cholecystitis between January and December at our hospital.
The diagnostic criteria and severity assessment criteria for acute cholecystitis provided by the Tokyo Guidelines 8 were used. The following clinical and demographic data were captured for all patients: age, sex, cause of acute cholecystitis calculous or acalculous , grade of acute cholecystitis, and initial laboratory findings WBC count, total bilirubin, direct bilirubin, AST, ALT, and ALP.
To validate the clinical significance of early and appropriate antimicrobial therapy by acute cholecystitis grade, we compared the perioperative outcomes operation time, estimated blood loss, open conversion rate, indwelling drain catheter insertion rate, presence of wound infection, major postoperative complications [classified according to a modified version of the original Clavien system], duration of preoperative antibiotics, and postoperative hospital stay of patients who received and did not receive early appropriate antimicrobial therapy.
As this was a retrospective cohort study, the requirement for written informed consent was waived by the institutional review board. All methods were carried out in accordance with relevant guidelines and regulations. Bile was swabbed in an aseptic manner for microbial assessment immediately after intraoperative retrieval of the gallbladder specimen.
The specimens were inoculated on blood agar, chocolate agar, and MacConkey agar. Antibiotic susceptibilities were reported as follows: susceptible S meant that poor bacterial growth was detected with adequate antibiotics; indeterminate I meant that an inappropriate antibiotic was used; and resistant R meant that the bacterial colony continued to grow despite the presence of a normally effective antibiotic.
For intergroup comparisons, the distribution of data was first evaluated for normality using the Shapiro—Wilk test.
The test for trend was performed by linear-by-linear association. Indar, A. Acute cholecystitis. BMJ , — Article Google Scholar. Darkahi, B. Biliary microflora in patients undergoing cholecystectomy. Galili, O. The effect of bactibilia on the course and outcome of laparoscopic cholecystectomy. Role of antibiotics in the treatment and prevention of acute and recurrent cholangitis. Rhodes, A. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock: Care Med.
Yun, S. Clinical aspects of bile culture in patients undergoing laparoscopic cholecystectomy. Kwon, W. Changing trend in bile microbiology and antibiotic susceptibilities: Over 12 years of experience.
Hwang et al. However, based on the inclusion criteria, generalisability of findings may be an issue in applying the findings to routine clinical practice [ 24 ]. The study of Yokoe et al evaluated the Tokyo guidelines criteria and found a sensitivity of Different clinical, laboratory, and imaging findings are combined in the Tokyo guidelines, giving a larger probability to reach the diagnosis.
However, the different combinations were not defined in this report. As previously stated, generalisability of these findings to routine clinical practice may be problematic because of the inclusion criteria used in this study. A full clinical examination should be performed and recorded. This should be combined with laboratory tests for inflammation and AUS. In case of uncertainty in AUS imaging but with a clinical suspicion of ACC, there is no definitive evidence on whether to perform a high cost although highly accurate investigation or to treat the patient empirically as if he or she had ACC.
The opportunity to dissolve gallstones by medication or break them by ESWL, or combination of both, instead of mechanical removal, has never been tested in the setting of ACC. Strict selection is required to obtain satisfactory results from these therapeutic options: less than 5 mm stone, single stone, cholesterol gallstones, functional gallbladder, and integrity of gallbladder wall when applying external wave to the gallbladder [ 25 ].
Ursodeoxycholic acid was ineffective in a large randomized, double-blind, placebo-controlled trial in patients waiting for elective cholecystectomy in the setting of biliary colic [ 27 ]. After gallstone disappearance, the persistence of the same pathogenic factors that induced gallstone formation is primarily responsible for their recurrence after non-surgical treatments of gallstones [ 28 ].
The opportunity to remove the gallstones in a different way than cholecystectomy has never been tested in the acute setting and the report of this technique are very few. In Yong et al published the results of consecutive laparoscopic gallbladder-preserving cholelithotomy. The required main patient selection criteria is the functioning gallbladder; this condition is not present in ACC [ 29 ].
We found only one prospective randomized study comparing observation to surgery after ACC, published in by Shmidt [ 30 ]. The population size was 33 patients assigned to observation versus 31 assigned to surgery. After five years the relapse of symptoms was described as negligible. Despite the value of a long follow-up, the study is underpowered as recognized by the authors themselves. Furthermore, of the eligible patients, From the economic point of view, the frequency of surgery in the observational group with the need for readmission slightly favoured surgery.
The authors concluded with words of caution because the number of patients was small. In addition, not all aspects were analysed e. Although ACC is an inflammatory process at the beginning, a secondary infection can occur in the case of continuous bile stasis due to cystic duct occlusion by calculus and oedema, which can lead to sepsis.
While many clinicians advocate routine administration of antibiotics in all patients diagnosed with acute cholecystitis, others restrict the antibiotics to patients likely to develop sepsis on the basis of clinical, laboratory, and imaging findings [ 35 ]. As a consequence, antibiotics constitute the primary therapy in patients undergoing delayed surgery or observation. In a meta-analysis including 9 RCT on early or delayed cholecystectomy, Papi et al.
The rate of unplanned surgery was Similar results were reported later in the Cochrane review including only laparoscopic cholecystectomy by Gurusamy in Approximately, In de Mestral et al. They collected 25, patients with ACC. Gallstone-related events were measured at 6 weeks, 12 weeks and at 1 year. Gallstone-related events were more frequent in patients aged between 18 and 34 years old [ 10 ]. Non-surgical options such as gallbladder drainage can be considered in surgical high risk patients.
The role of non-surgical options will be analysed in a different section. Therapy with appropriate antimicrobial agents is an important component in the management of patients with ACC [ 38 , 39 ]. Antibiotics are always recommended in complicated cholecystitis and in delayed management of uncomplicated cholecystitis.
In a recently published prospective randomised controlled trial [ 40 ], a total of patients treated at 17 medical French centres for grade I or II ACC and who received 2 g of amoxicillin plus clavulanic acid three times a day and once at the time of surgery were randomized after surgery to an open-label, non-inferiority, randomized clinical trial between May and August Patients were randomized to either no antibiotics after surgery or continuation with the preoperative antibiotic regimen three times daily for 5 days.
Among patients with mild or ACC who received preoperative and intra-operative antibiotics, lack of postoperative treatment with amoxicillin plus clavulanic acid did not result in a greater incidence of postoperative infections. The principles of empiric antibiotic treatment should be defined according to the most frequently isolated microbes, always taking into consideration the local trend of antibiotic resistance.
Organisms most often isolated in biliary infections are the gram-negative aerobes, Escherichia coli and Klebsiella pneumonia and anaerobes, especially Bacteroides fragilis [ 41 , 42 ]. Pathogenicity of Enterococci in biliary tract infections remains unclear and specific coverage against these microorganisms is not routinely suggested for community-acquired biliary infections [ 43 ]. For selected immunosuppressed patients, i. The main antimicrobial resistance is due to extended spectrum beta-lactamase ESBL producing Enterobacteriaceae.
It is found frequently in community acquired infections in patients with co-morbidities requiring frequent exposure to antibiotic treatments [ 41 , 42 ]. Health care-related infections are commonly caused by more resistant strains. For these infections, complex regimens with broader spectra are recommended as adequate empiric therapy appears to be a crucial factor affecting postoperative complications and mortality rates, especially in critically ill patients [ 44 ].
Although there are no clinical or experimental data to support the use of antibiotics with biliary penetration for these patients, the efficacy of antibiotics in the treatment of biliary infections may depend on effective biliary antibiotic concentrations too.
However, in patients with obstructed bile ducts, the biliary penetration of antibiotics may be poor and effective biliary concentrations are reached only in a minority of patients [ 45 ]. Antibiotics biliary penetration ability indicated as the ratio of bile to serum concentrations are listed in Table 2 [ 46 ]. The choice of the antimicrobial regimen may be problematic in the management of critically ill patients with ACC. In patients with severe sepsis or septic shock of abdominal origin, early correct empirical antimicrobial therapy has a significant impact on the outcome [ 47 ].
Recent international guidelines for the management of severe sepsis and septic shock Surviving Sepsis Campaign [ 49 ] recommend broad-spectrum intravenous antibiotics with good penetration into the presumed site of infection within the first hour.
In the event of biliary sepsis, drug pharmacokinetics may be altered significantly in patients with severe sepsis and septic shock. Dosage of antibiotics should be reassessed daily, based on both the pathophysiological status of the patient and the pharmacokinetic properties of the employed antibiotics [ 50 ].
Identifying the causative organism s is an essential step in the management of ACC, especially in patients at high risk for antimicrobial resistance such as healthcare-associated infections. In Table 3 are reported the antimicrobial regimens suggested for ACC. ACC is a heterogeneous condition.
The severity of inflammation and its life-threatening potential is strongly determined by the general status of the patient. It could be argued that alternative treatment to early cholecystectomy could be of benefit for patients with reduced functional reserve. Our search reviewed the available literature to identify the parameters to stratify the risk of surgery in this population and verify if there is any available method to select the best course of action in selected high-risk groups.
Several studies identify old age as a perioperative risk factor for cholecystectomy. However, it is not clear if early laparoscopic cholecystectomy is the best treatment option for elderly patients with ACC. In the retrospective cohort study by Kirshtein et al, the age groups above and below 75 showed a significant difference in mortality 4. A recent study by Nielsen et al reported that the odds ratio for mortality in ACC patients older than 80 years with low anaesthetic risk American Score of Anaesthesiologist I-II ASA was significantly higher than in the age groups of 65 to 79 and 50 to 64 In the case series by Lupinacci et al, mortality of patients older than 80 years was Statistically significant differences were also demonstrated in morbidity and length of hospital stay.
Few retrospective cohort studies compare the outcome of early versus delayed cholecystectomy in aged ACC patients. They fail to demonstrate a significant difference in mortality and postoperative complications [ 63 — 66 ]. A study by Cull et al showed that recurrent episodes of pancreatitis, cholecystitis, and cholangitis were significantly less likely after early than delayed cholecystectomy, irrespective of whether delayed cholecystectomy was preceded by percutaneous cholecystostomy [ 65 ].
These findings confirmed the results of a recent population-based analysis on a sample of the Medicare Claims Data System. In , Shpitz et al showed a greater incidence of cardiovascular disease and associated bacterobilia in diabetics who underwent urgent cholecystectomy for ACC; however, they did not report a significant difference in the postoperative outcome [ 68 ].
A recent analysis of a large ACC cholecystectomy series from the American College of Surgeons National Surgical Quality Improvement Program database demonstrated that diabetes increased the risk of mortality 4.
A second study on the same series showed that delay in surgery in diabetic patients was associated with significantly higher odds of developing surgical site infections and a longer hospital stay. The same findings were not found in the non-diabetic patients of the same series [ 70 ], suggesting that a prompt course of action is appropriate in diabetics.
None of the available clinical scores for the evaluation of surgical risk for acute conditions has been validated for ACC. Recently, the Tokyo guidelines attempted to address the heterogeneity of the ACC population with a therapeutic algorithm that includes some elements of risk stratification. They suggest a staging system based upon severity assessment criteria such as degree of local inflammation and patient conditions, without including any of the most commonly adopted risk stratification scores [ 71 ].
However, their classification lacks a clinical validation and has not been validated by studies showing an improved outcome after its introduction. In fact, a retrospective series failed to find any significant benefit [ 13 ].
In , Yi et al stratified the risk in relation to the ASA score. The study highlights a significant association of the three scores with morbidity and mortality. Finally, we would like to point out that the usefulness of any score is to add but not to trump surgical judgement: in other words not all patient variables e. Several randomised controlled trials have investigated early laparoscopic cholecystectomy versus delayed laparoscopic cholecystectomy [ 74 — 82 ].
Early and delayed laparoscopic cholecystectomy have been defined differently in different trials. In general, early laparoscopic cholecystectomy has been defined variably as that performed in patients with acute cholecystitis with symptoms less than 72 h or symptoms less than 7 days but within 4 to 6 days of diagnosis. This roughly translates to 10 days from onset of symptoms. The delayed laparoscopic cholecystectomy is defined variably as that performed between 7 days to 45 days and that performed at least 6 weeks after initial diagnosis.
Different patients were included in the trial and the definitions of early laparoscopic cholecystectomy used by these trials comparing early laparoscopic cholecystectomy versus delayed laparoscopic cholecystectomy performed within 6 weeks after initial diagnosis were different in various studies. Six trials provided clinical results. Overall, the systematic review and meta-analysis of randomised controlled trials which included clinical data from five of these six trials demonstrated no significant difference in the complication rate or conversion to open cholecystectomy between early and delayed laparoscopic cholecystectomy and a hospital stay which was statistically shorter by 4 days in the early laparoscopic cholecystectomy group compared to the delayed laparoscopic cholecystectomy group [ 37 ].
One trial which was not included in the systematic review also showed similar results as the systematic review i. One trial compared early laparoscopic cholecystectomy versus delayed laparoscopic cholecystectomy performed between 7 days and 45 days after initial diagnosis [ 83 ]. In this trial, the duration of symptoms in the participants was not reported. This trial demonstrated that the morbidity was higher in the delayed laparoscopic cholecystectomy compared to early laparoscopic cholecystectomy group and the length of hospital stay was 5 days longer in the delayed laparoscopic cholecystectomy group compared to early laparoscopic cholecystectomy group [ 83 ].
There was no significant difference in the conversion to open cholecystectomy between the two groups [ 83 ]. One randomised controlled trial compared early laparoscopic cholecystectomy as soon as surgical schedule allows with early laparoscopic cholecystectomy after resolution of symptoms but within 5 days of admission [ 74 ] in patients with ACC.
The duration of symptoms prior to admission was not reported in this trial. There was no statistically difference in the complication rate or conversion to open cholecystectomy between patients who underwent surgery as soon as the scheduling allowed compared to those who underwent surgery after resolution of symptoms but within 5 days of admission [ 74 ].
However, the length of hospital stay was shorter in patients who underwent surgery as soon as the scheduling allowed compared to those who underwent surgery after resolution of symptoms but within 5 days of admission [ 74 ].
Evidence from a large database review including approximately 95, patients with ACC demonstrated that patients who had surgery within 2 days of admission had fewer complications than those who underwent surgery between 2 and 5 days of admission, and those who had surgery between 6 days and 10 days of presentation.
There was no significant difference in the groups between conversion to open surgery [ 84 ]. Finally, several studies suggest that cholecystectomy performed as soon as possible, especially in the scenario of an Acute Care Surgery Service, is cost-effective [ 83 , 85 , 86 ]. According to Tokyo Guidelines TG13 , laparoscopic cholecystectomy is now accepted as a safe surgical technique when it is performed by expert surgeons even in the setting of ACC. TG13 described the surgical treatment of ACC according to the degree of severity of the disease.
For patients with severe local complications such as biliary peritonitis, emphysematous cholecystitis, gangrenous cholecystitis and purulent cholecystitis, emergency surgery is conducted open or laparoscopic along with the usual supportive measures.
Some Scientific Societies also support, more strongly than TG13, laparoscopic cholecystectomy in ACC as the first line approach [ 87 — 89 ]. Although Borzellino et al. A recently published meta-analysis demonstrated that laparoscopic cholecystectomy in ACC is the preferable approach with lower mortality and morbidity, significantly shorter postoperative hospital stay and reduced rate of pneumonia and wound infections, compared to the open technique.
Some studies suggested that laparoscopic cholecystectomy should be the first line approach in specific categories of patients such as the elderly or pregnant women [ , ]. According to meta-analysis published by de Goede et al. According to Lucidi et al. Cirrhosis is a major risk factor for surgery.
Laparoscopic cholecystectomy-related morbidity in cirrhotic patients is directly related to the Child Pugh score [ , ]. Subtotal cholecystectomy can avoid many of these difficulties [ ]. In conclusion, laparoscopic approach should be the first choice for the cholecystectomy in Child A and B patients. The approach to patients with Child Pugh C no-compensated cirrhosis remains a matter of debate. As a first recommendation, cholecystectomy should be avoided in these patients, unless clearly indicated, such as in ACC not responding to antibiotics [ ].
A recent systematic review with meta-analysis by Elshaer et al. The most common indications were severe cholecystitis They concluded that subtotal cholecystectomy is an important tool in the difficult cholecystectomy and achieves morbidity rates comparable to those reported for total cholecystectomy in simple cases [ ].
Alternative surgical strategy is the fundus first approach to reach progressively the infundibulum, cystic duct and artery: also by using this thecnique the risk of lesions must be always kept in mind [ , ].
Tang et al. Single factors that appear to be important include male gender, extreme old age, morbid obesity, cirrhosis, previous upper abdominal surgery, severe acute and chronic cholecystitis, and emergency laparoscopic cholecystectomy. The combination of patient and disease related risk factors increases the conversion rate [ ]. According to Giger et al. Therefore, conversion to open surgery is strongly recommended to secure patient safety in such difficult conditions [ ].
Sugrue et al. According to Eldar et al. In conclusion gangrenous gallbladder, obscure anatomy, bleeding, bile duct injuries, adhesions and previous upper abdominal surgery represent clinical conditions for which conversion to open cholecystectomy should be strongly considered [ ]. Choledocholithiasis, i. Investigation for CBDS require time and can delay the surgical intervention. Due to the relatively low incidence of CBDS during ACC, the issue is to select patients with a high likelihood of CBDS who would benefit from further diagnostic tests and eventually the removal of the stones.
Liver biochemical tests historically have a great utility in determining the presence of CBDS. However, the majority of published studies are not in patients with ACC and also include asymptomatic cholelithiasis. In fact, in ACC, liver biochemical tests may be altered due to the acute inflammatory process of the gallbladder and the biliary tree.
Song et al demonstrated that of patients with ACC had increased liver tests alanine transaminase ALT , aspartate transaminase AST greater than twice normal levels. However, increased bilirubin levels with leukocytosis may predict gangrenous cholecystitis [ ]. By multivariate analysis increased common bile duct size and elevated ALT and ALP were predictors of choledocholithiasis [ ]. The diagnostic accuracy increases for cholestasis tests such serum bilirubin with the duration and the severity of obstruction.
In a prospective study, Silvestein reported the diagnostic accuracy of serum bilirubin and serum ALP at two cut-offs for each test. Serum bilirubin at a cut-off of greater than Bilirubin at a cut-off of greater than twice the normal limit, had a sensitivity of 0. For ALP at a cut-off of greater than twice the normal limit, sensitivity was 0. Simultaneously, the common bile duct can be visualized and investigated. A recently published meta-analysis investigated the diagnostic potential of ultrasound [ ]: sensitivity ranged from 0.
The implementation of these predictive scores in clinical practice is poor [ , — ]. All combine the same clinical variables differently. This proposed classification has clear clinical implications. Patients with a low risk of CBDS should be operated upon without further investigation. Patients with moderate risk should be interrogated with a second level examination: preoperatively by endoscopic ultrasound EUS or magnetic resonance cholangiopancreatography MRCP or intraoperatively by laparoscopic ultrasound or laparoscopic cholangiography, to select patients who need stone removal prior, during or after surgery.
See Table 4 for the modified risk stratification. These diagnostic tools, according to the ASGE guidelines [ ] should be reserved for patients with moderate risk for choledocholithiasis and have been shown to delay definitive ACC treatment [ ].
On the other hand, these tests could exclude the presence of CBDS with high diagnostic accuracy, thereby avoiding further invasive procedures such ERCP or intraoperative cholangiography and their complications. As noted by some authors interpreting similar results, considerations other than diagnostic efficacy local availability, costs, expertise, delay of surgery might be important when deciding which imaging method to use [ ].
ERCP has both a diagnostic and therapeutic role in the management of choledocholithiasis but is an invasive procedure with potential severe complications. The literature emphasizes that diagnostic ERCP has risks.
Morbidity associated with diagnostic ERCP includes pancreatitis, cholangitis, haemorrhage, duodenal perforation, or allergy to contrast. On the other hand intraoperative cholangiography significantly increases the length of surgery [ ] and requires dedicated staff in the operating room. This is not always available, especially in the acute setting with non-planned operation as in ACC. Positive findings on intraoperative cholangiography lead to intraoperative management of CBDS with additional operative time.
A recently published meta-analysis compared the two techniques [ ]: for ERCP, the summary sensitivity was 0. For intraoperative cholangiography, the summary sensitivity was 0. A recent meta-analysis has shown that intraoperative cholangiography and Laparoscopic ultrasound have the same pooled sensitivity and similar pooled specificity for the detection of CBDS [ ].
As in the case of intraoperative cholangiography, intraoperative evidence of CBDS leads to intraoperative management of common bile duct with additional operating time. A systematic review assessed the difference between these different techniques [ ].
No differences in terms of morbidity, mortality and success rate were reported comparing these methods. Therefore, these techniques should be considered suitable options. Another meta-analysis investigated two different techniques for ERCP plus sphincterotomy: preoperative or intraoperative with the rendezvous technique [ ].
These two techniques were equal in safety and efficacy; intraoperative technique reduced the risk for post-ERCP pancreatitis, but obviously requires dedicated staff in the theatre and prolongs the length of surgery. As already stated, the definitive treatment of ACC is early laparoscopic cholecystectomy.
However some patients may not be suitable candidates for surgery, due to co-morbidities. Recently published articles show that emergency cholecystectomy for ACC could be considered a feasible and safe procedure [ 89 , — ]. Gallbladder drainage decompresses the infected bile or pus in the gallbladder, removing the infected collection without removing the gallbladder. The removal of the infected material, in addition to antimicrobial therapy, can result in a reduced inflammation with an improvement of the clinical condition.
Several case series, retrospective and observational studies exist on cholecystostomy. A systematic review of the literature included 53 studies with patients outlining a high success rate of the procedure A major limitation of the study was the inclusion of patients with both acute acalcolus cholecystitis and ACC.
After the aforementioned review, about 27 further observational studies have been published, confirming that the groups considered in the studies, their inclusion criteria, the results and even the conclusions reached by different authors are largely non-homogeneous [ ].
Cholecystostomy can be performed with several different techniques as summarized well by the TG [ ]. These include PTGBD, percutaneous transhepatic gallbladder aspiration PTGBA , endoscopic naso-biliary gallbladder drainage, endoscopic gallbladder stenting, and EUS-guided gallbladder drainage via the antrum of the stomach and the duodenum. A controlled trial by Ito et al. PTGBD was superior to gallbladder aspiration in terms of clinical effectiveness with the same complication rate as gallbladder aspiration.
However this trial included high risk and low risk patients. No other good quality evidence exists on which is the best gallbladder drainage technique. Finally, in case of evidence of cystic duct obstruction, PTGDB should be, even more, the preferred technique for gallbladder drainage. TG on ACC [ 11 ] consider the gallbladder drainage as mandatory in the severe grade according to the Tokyo classification [ 12 ] acute cholecystitis and also suggest its use in the moderate grade if conservative treatment fails.
The panel of the Tokyo Guidelines states that it is known to be an effective option in critically ill patients, especially in elderly patients and patients with complications; however, there is a lack of good quality evidence to support the statement. Hatzidakis et al. Akyurek et al published in a trial where patients with ACC were randomized to receive PC followed by early laparoscopic cholecystectomy or conservative treatment followed by delayed laparoscopic cholecystectomy [ ].
There were no differences in term of mortality and morbidity; PC plus early laparoscopic cholecystectomy resulted in a reduction of the length of stay and of costs. Melloul et al. A Spanish retrospective study [ ] compared critically ill patients with ACC who underwent PC or early laparoscopic cholecystectomy. They found a significantly higher mortality rate in the PC group; however this study is of poor quality and has several limitations such as the retrospective study design and the selection bias.
A Cochrane systematic review by Gurusamy et al. Gallbladder drainage has been even described as a procedure reserved for those patients who failed the conservative treatment after a variable time of 24 to 48 h.
A prospective study by Barak et al. There is no specific antibiotic regimen to be prescribed alongside PC. None of the examined studies reported the specific drug agent. No evidence exists supporting the need for a peculiar antibiotic regimen. For the antimicrobial therapy, please see the dedicated section. At the present time, PC seems to be a safe and effective procedure in critically ill patients with ACC.
However, no evidence supports its superiority toward the conservative treatment or early laparoscopic cholecystectomy. De Mestral et al. No randomized trial comparing the need for delayed laparoscopic cholecystectomy exists currently. Based on the evidence included in the present guidelines, it can be stated that early laparoscopic cholecystectomy is the best therapeutic approach for ACC and that post-operative antibiotics are not necessary in cases of uncomplicated cholecystitis.
Moreover, studies providing a high level of evidence on the management of associated CBDS have also been published. However in both cases intra-operative exploration according to the local expertise has been reported as a recommended option with a high level of evidence. Furthermore we observed lack of studies investigating the cost savings of transcystic duct common bile duct removal of small stones. The recommendations on the surgical treatment of ACC are however limited to patients who may be good candidates for urgent surgery.
Grey areas still remain in the cases of patients not fit for urgent surgery or for laparoscopic surgery secondary to general conditions. Diagnosis may be assessed by clinical, laboratory data and AUS but with such a diagnostic approach results appear controversial and supported by a limited number of high quality studies. A radiological investigation such as HIDA may be required to reach a diagnostic certainty.
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