Early Versus Delayed Cholecystectomy for Acute Calculous Cholecystitis

Transcription

1 Early Versus Delayed Cholecystectomy for Acute Calculous Cholecystitis by Charles William Armand de Mestral A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of the Institute of Medical Science University of Toronto Copyright by Charles William Armand de Mestral 2013

2 Early Versus Delayed Cholecystectomy for Acute Calculous Cholecystitis Charles de Mestral Doctor of Philosophy The Institute of Medical Science University of Toronto 2013 ABSTRACT Introduction: Despite evidence in favour of cholecystectomy early during first presenting admission for most patients with acute calculous cholecystitis, variation in the timing of cholecystectomy remains evident worldwide. This dissertation characterizes the extent of variation within a large regional healthcare system, as well as addresses gaps in our current understanding of the clinical consequences and costs associated with early versus delayed cholecystectomy for acute cholecystitis. Methods: A population-based retrospective cohort of patients admitted emergently with acute cholecystitis was identified from administrative databases for the province of Ontario, Canada. First, the extent of variation across hospitals in the performance of early cholecystectomy (within 7 days of emergency department presentation) was characterized. Second, among patients discharged without cholecystectomy following index admission, the risk of recurrent gallstone symptoms over time was quantified. Third, operative outcomes of early cholecystectomy were compared to those of delayed cholecystectomy. Finally, a cost-utility analysis compared healthcare costs and quality-adjusted life-year gains associated with three management strategies ii

3 for acute cholecystitis: early cholecystectomy, delayed cholecystectomy and watchful waiting, where cholecystectomy is performed urgently if recurrent gallstone symptoms arise. Results: The rate of early cholecystectomy varied widely across hospitals in Ontario (median rate 51%, interquartile range 25-71%), even after adjusting for patient characteristics (median odds ratio 3.7). Among patients discharged without cholecystectomy following an index cholecystitis admission, the probability of a gallstone-related emergency department visit or hospital admission was 19% by 12 weeks following discharge. Early cholecystectomy was associated with a lower risk of major bile duct injury (0.28% vs. 0.53%, RR=0.53, 95% CI , p=0.025). No significant differences were observed in terms of open cholecystectomy (15% vs. 14%, RR=1.07, 95% CI , p=0.10) or in conversion among laparoscopic cases (11% vs. 10%, RR=1.02, 95% CI , p=0.68). Early cholecystectomy was on average less costly ($6,905 per person) and more effective (4.20 QALYs per person) than delayed cholecystectomy ($8,511; 4.18 QALYs per person) or watchful waiting ($7,274; 3.99 QALYs per person). Conclusions: Early cholecystectomy offers a benefit over delayed cholecystectomy in terms of major bile duct injury, mitigates the risk of recurrent symptoms, and is associated with the greatest QALY gains at the least cost. iii

4 Acknowledgments I wish to thank the following people and organizations who generously provided invaluable support for my thesis work: My supervisor Dr. Avery Nathens, for consistently using his experience, enthusiasm and resources to support my success over the last 3 years. My thesis committee members, Dr. Jeffrey Hoch, Dr. Andreas Laupacis and Dr. Ori Rotstein, for their steadfast support and sound advice. Brandon Zagorksi, for helping me navigate the complexities of accessing and analyzing ICES data. My fellow graduate students Barbara Haas, David Gomez, Marvin Hsiao, Sunjay Sharma, Aziz Alali, Chethan Sathya and Debbie Li as well as our lab s research manager Jennifer Bridge, for the insightful input on my work and for creating a great work environment. Harindra Wijeysundera and Murray Krahn, for their help with my Markov model. The University of Toronto Department of Surgery, Division of General Surgery, Dr. George Hiraki and the Clinician Investigator Program, for supporting my training in the Surgeon- Scientist Training Program. The Canadian Association of General Surgeons, Physician Services Inc. Foundation and the Institute for Clinical Evaluative Sciences for financially supporting this thesis work. iv

5 Funding This graduate work was financially supported by an Ontario Doctoral Award, the Chikai and Sawa Hiraki Surgeon-Scientist fellowship, a Clinician-Investigator Program Award from the Ontario Ministry of Health as well as funds from the Division of General Surgery and Department of Surgery of the University of Toronto. Operating costs were covered by a grant from the Canadian Surgical Research Fund and a Resident Research Grant from Physician Services Inc. Foundation. In addition, this work was supported by the Institute for Clinical Evaluative Sciences, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. The opinions, results and conclusions reported in this thesis are those of the author and are independent from the funding sources. No endorsement by the Canadian Institutes of Health Research, the Institute for Clinical Evaluative Sciences or the Ontario Ministry of Health and Long-Term Care is intended or should be inferred. The author has no other financial disclosures or any conflict of interest to declare. v

6 Table of Contents Abstract... ii Acknowledgments... iv Funding... v Table of Contents... vi List of Tables... x List of Figures... xii List of Abbreviations...xiii Chapter 1 - Thesis Overview, Hypotheses and Specific Aims Thesis Overview Rationale Hypotheses Research Aims Contributions...5 Chapter 2 - Background Epidemiology of Gallstone Disease and Acute Cholecystitis Pathogensis of Gallstones and Acute Calculous Cholecystitis Diagnosis and Severity Surgical Management of Acute Cholecystitis Rationale for Surgical Management of Acute Cholecystitis Surgical Approach Complications of Cholecystectomy Laparoscopic Cholecystectomy in the Setting of Acute Cholecystitis Timing of Cholecystectomyfor Acute Cholecystitis...16 vi

7 2.4.6 Timing of Cholecystectomy and Clinical Outcomes Timing of Cholecystectomy and Economic Outcomes Management Guidelines for Acute Cholecystitis Variation in Practice Worldwide Summary of Gaps in Current Knowledge Tables for Chapter Figures for Chapter Chapter 3 - General Methods Strengths of Ontario's Administrative Health Data Description of Data Sources Data Validity Approach to Costing with Ontario's Administrative Data Analytic Considerations...36 Chapter 4 - Variation in Early Cholecystectomy for Acute Cholecystitis in Ontario Summary Background Methods Results Discussion Tables for Chapter Figures for Chapter Chapter 5 - The Risk of Recurrent Symptoms if Cholecystectomy is Delayed Summary Background Methods Results...68 vii

8 5.5 Discussion Tables for Chapter Figures for Chapter Chapter 6 - Comparative Operative Outcomes of Early and Delayed Cholecystectomy Summary Background Methods Results Discussion Tables for Chapter Figures for Chapter Chapter 7 - Cost-utility Analysis of Alternative Timeframes of Cholecystectomy for Acute Cholecystitis Summary Background Methods Results Discussion Tables for Chapter Figures for Chapter Supplemental data for Chapter Chapter 8 - General Discussion Thesis summary Implications Thesis Limitations Chapter 9 - Future Directions viii

9 9.1 Understanding the Context-Specific Determinants of Management Knowledge Translation Plan Ongoing Evaluation of Patient Outcomes and Preference References ix

10 List of Tables Table Acute cholecystitis severity classification from the Tokyo Guidelines...24 Table 2.2. Major sources of morbidity and resource utilization to consider when comparing early to delayed cholecystectomy..25 Table Summary of randomized controlled trials comparing early to delayed cholecystectomy for acute cholecystitis...26 Table Distribution of patient characteristics.56 Table Distribution of hospital characteristics...57 Table Multilevel multivariable logistic regression results showing association of patient and hospital characteristics with early cholecystectomy...58 Table Probability of a gallstone-related event by time from discharge 73 Table Multivariable time to event analysis showing adjusted risk of gallstone-related event across patient characteristics..74 Table Probability of a gallstone-related event by time from discharge in competing risk time-to-event analysis 75 Table 5.4- Probability of a gallstone-related event by 12 weeks across age groups in competing risk time-to-event analysis 76 Table Baseline characteristics of patients and their surgeon before matching.93 Table Baseline characteristics of patients and their surgeon after matching 94 Table Outcome frequency and relative risk before and after matching...95 Table Baseline characteristics of patients and their surgeon in synthetic cohort after weighting on the inverse probability of treatment received...96 Table Relative risk of outcome after weighting on inverse probability of treatment...97 x

11 Table Relative risk of outcomes when defining early cholecystectomy as occurring within 3 days of emergency department presentation..98 Table Relative risk of outcome when excluding delayed cholecystectomy later than 1 year after discharge 99 Table Model parameter inputs with sources and threshold analysis results Table Average costs and quality-adjusted life-year gains and associated increments Table 7.S1 - Baseline characteristics of patients and their surgeon before matching.130 Table 7.S2 - Baseline characteristics of patients and their surgeon after matching 131 Table 7.S3 - Baseline characteristics of patients before matching..132 Table 7.S4 - Baseline characteristics of patients after matching.133 xi

12 List of Figures Figure Depiction of anatomy of gallbladder, cystic duct and common bile duct.27 Figure Depiction of laparoscopic and open cholecystectomy..28 Figure Patient eligibility flowchart...59 Figure Variation in the rate of early cholecystectomy across hospitals (N=24,437 patients, 106 hospitals).60 Figure Variation in the rate of early cholecystectomy rate across hospitals among young (<50 years) healthy patients without concurrent biliary tract obstruction or pancreatitis (N=2,894 patients, 102 hospitals)...61 Figure Unadjusted probability of a gallstone-related event across age groups in the first year following discharge Figure Patient eligibility flowchart.100 Figure Simplified representation of model state transition diagram Figure Cost-effectiveness plane of Monte-Carlo probabilistic analysis results (10,000 iterations).122 Figure Incremental cost-effectiveness plane comparing early to delayed cholecystectomy Figure Cost-effectiveness acceptability curve derived from Monte-Carlo probabilistic sensitivity analysis Figure 7.S1 - Example of two-way sensitivity analysis results xii

13 ADG - Aggregated Diagnosis Group List of Abbreviations QALY - Quality-Adjusted Life-Year CBD - Common Bile Duct CI - Confidence Interval CIHI - Canadian Institute for Health Information CPWC - Cost Per Weighted Case DAD - Discharge Abstract Database ED - Emergency Department ICES - Institute for Clinical Evaluative Sciences IQR - Interquartile Range ISPOR - International Society for Pharmacoeconomics and Outcomes Research KM - Kaplan Meier MOR - Median Odds Ratio NACRS - National Ambulatory Care Reporting System NMB - Net Monetary Benefit OHIP - Ontario Health Insurance Plan xiii

14 OR - Odds Ratio PSA - Probabilistic Sensitivity Analysis RIW - Resource Intensity Weight RPDB - Registered Person Database RR - Relative Risk SD - Standard Deviation SMDM - Society for Medical Decision Making WTP - Willingness-To-Pay xiv

15 1 Chapter 1 Thesis Overview, Hypotheses, and Specific Aims The purpose of this chapter is to: I. Provide an overview of the thesis structure II. III. IV. Describe the rationale for the thesis focus Provide the research hypotheses List the overarching objective and specific aims V. Detail all contributions to this thesis work

16 2 1.1 Thesis Overview In Chapter 1, I outline the structure of this dissertation as well as present the rationale, hypotheses and specific aims of the thesis. In Chapter 2, I detail the relevant epidemiology, pathophysiology and severity classification of acute cholecystitis. I then review the rationale for surgical management of acute cholecystitis as well as the historical and clinical context of the controversy concerning the optimal timing of cholecystectomy for acute cholecystitis. Existing evidence comparing the clinical and economic outcomes of early and delayed cholecystectomy are then described followed by a description of practice worldwide. Chapter 3 is a discussion of general methods applicable to all specific aims. First, details on the contents and validity of administrative databases utilized are provided. Second, major analytic concepts relevant to each specific aim are discussed. Chapters 4, 5, 6 and 7 reflect the four specific aims of this thesis in manuscript format. The final two chapters summarize the thesis results, place the implications in the context of general limitations, and proposes ideas for future directions. Chapter 4 has been accepted for publication by the Canadian Medical Association Journal Open and Chapter 5 has been published in the Journal of Trauma and Acute Care Surgery. Chapter 6 is currently under review by Annals of Surgery. 1.2 Rationale As detailed in Chapter 2, cholecystectomy early on first admission is recommended over delayed elective cholecystectomy for most patients with acute cholecystitis, based on randomized trials and meta-analyses. However, recent reports reveal inconsistency in following

17 3 this recommendation internationally, suggesting that the timing of cholecystectomy remains controversial. In order to generate local solutions for quality improvement, a setting-specific understanding of the extent and potential underlying etiology for the inconsistent application of early cholecystectomy is required. In addition, important limitations of current knowledge should be addressed in order to better inform best practice with regards to the surgical care of acute cholecystitis. In fact, randomized trials comparing early to delayed surgery suffer from limited contemporary external validity and no study to date has been large enough to compare rare but serious operative complications such as bile duct injury or death. Large population-based analyses undertaken in this thesis offer the unique opportunity to address these limitations. Finally, given the constrained nature of healthcare budgets, costs should be considered alongside the clinical consequences of alternative management strategies being considered. Setting-specific economic evaluations incorporating contemporary data will provide critical supplemental evidence with which to inform decision making. 1.3 Hypotheses We first hypothesize that there is considerable variation in the rate of early cholecystectomy for acute cholecystitis across hospitals in Ontario. Second, we hypothesize that early cholecystectomy is associated with similar operative outcomes as delayed cholecystectomy but confers less morbidity by mitigating the risk of recurrent gallstone-related symptoms. Finally, we hypothesize that in Ontario, early cholecystectomy is cost saving and is associated with greater quality-adjusted life year gains compared to delayed laparoscopic cholecystectomy.

18 4 1.4 Research Aims The overarching research objective of this thesis is to investigate the clinical outcomes and costs associated with early and delayed cholecystectomy for acute cholecystitis, using a population-based approach. Given our overarching objective and hypotheses, this thesis is structured around the following four specific aims: Specific Aim #1: To characterize the extent and potential sources of variation in the performance of early cholecystectomy for acute cholecystitis in Ontario. Specific Aim #2: To determine the probability of gallstone-related complications in patients discharged home without cholecystectomy on first admission. Specific Aim #3: To compare the frequency of operative outcomes between early and delayed cholecystectomy. Specific Aim #4: To conduct an economic evaluation comparing different timeframes of cholecystectomy for acute cholecystitis.

19 5 1.5 Contributions My contributions I was involved in every stage of this thesis work with the support and guidance of my program advisory committee. I developed the specific research aims with my supervisor and program advisory committee. I was responsible for creating the population-based cohorts with assistance from an analyst at the Institute for Clinical Evaluative Sciences (ICES). Based on the previous work and input of ICES scientists, I performed and take responsibility for all statistical analyses and the accuracy of the reports. I created the Markov model used in the economic evaluation with input from experts in medical decision modeling and my program advisory committee members. I am the first author of all four manuscripts resulting from this thesis. Specific contribution of others to each specific aim Avery Nathens, Ori Rotstein, Andrea Laupacis, Jeffrey Hoch contributed to the design of all four specific aims. Brandon Zagorski was involved in helping me create the cohorts for each specific aim. Input on statistical analysis was provided by Barbara Haas (specific aim 1), David Gomez (specific aim 1), Aziz Alali (specific aim 3), Jeffrey Hoch (specific aims 1,3,4), Brandon Zagorki (specific aims 1,2,3) and Avery Nathens (all specific aims). Harindra Wijeysundera and Murray Krahn provided input in the development of the Markov model for specific aim 4. All co-authors provided critical revisions on manuscripts.

20 6 Chapter 2 Background The purpose of this chapter is to: I. Describe the epidemiology, pathogenesis and severity classification of acute cholecystitis II. III. Review the role of surgery for acute cholecystitis Review current knowledge with respect to the impact of timing of cholecystectomy on clinical outcomes and healthcare costs. IV. Describe the extent of variation in the timing of cholecystectomy worldwide. V. Provide a summary of gaps in current knowledge

21 7 2.1 Epidemiology of gallstone disease and acute cholecystitis Large screening ultrasound studies have shown that gallstones are present in 5% to 20% of adults 1-3. The prevalence ranges widely across ethnicities 1,3 and is approximately twice as high in women as in men 4-6. In addition to the important influence of ethnicity and sex on prevalence, other non-modifiable risk factors for gallstones include older age, family history and genetic predisposition 2. Modifiable risk factors include obesity, rapid weight loss and a high calorie diet. Furthermore, certain drugs (e.g. estrogen replacement therapy, thiazide diuretics) promote gallstone formation 2 whereas others such as statins, inhibitors of HMG-CoA reductase, have been shown to reduce the risk of gallstone disease 7-9. The previously mentioned risk factors are most applicable to the formation of cholesterol gallstones, which account for 90% of gallstones in Western nations 10. Pigment stones are more common in eastern Asia and more frequently present as stones in the bile duct (choledocholithiasis) as opposed to in the gallbladder (cholelithiasis) 2,10. Pigment stones are associated with states of increased bilirubin excretion (e.g. hemolysis, cirrhosis, bile salt malabsorption) in the case of black pigment stones, or with biliary tract infection and inflammation (cholangitis) in the case of brown pigment stones 2,10. The large majority of patients with gallstones will remain asymptomatic. However, 1% to 3% of patients per year will develop symptoms of gallstone disease 11,12. Symptomatic gallstone disease can present as biliary colic, a short-lived episode of right upper quadrant abdominal pain due to temporary obstruction of outflow from the gallbladder by a gallstone. Acute cholecystitis is a more severe manifestation of cholelithiasis and results from prolonged gallbladder outflow obstruction giving rise to an inflammatory reaction described in the next section. Patients present

22 8 with pain of longer duration than biliary colic and with local and system signs of inflammation. Stones can also escape the gallbladder into the biliary tract (choledocholithiasis) leading to obstruction of the common bile duct with or without infection (cholangitis) or to an inflammatory process in the pancreas (gallstone pancreatitis). The incidence of acute cholecystitis decreased by 18% in Canada in the 1990s as elective laparoscopic cholecystectomy was increasingly performed for symptomatic gallstones 13. However, acute cholecystitis remains prevalent and is in fact the most common reason for hospitalization among all digestive diseases in the United States 14. Between 90% and 95% of cases of acute cholecystitis are due to gallstones, more accurately referred to as acute calculous cholecystitis 10,15. Gallbladder outflow obstruction may however also occur due to malignancy, gallbladder polyps and parasites 16. More commonly, acalculous cholecystitis arises in association with predisposition to gallbladder ischemia or instances of reduced gallbladder motility (e.g. critical illness, sepsis, burns, major surgery, total parenteral nutrition) 10,16. This thesis work focuses on the management of acute cholecystitis due to gallstones. 2.2 Pathogenesis of gallstones and acute calculous cholecystitis Gallstones form from the precipitation of bile solutes. Bile is produced in the liver by hepatocytes and is stored in the gallbladder (Figure 2.1). After ingestion of a meal, neurohormonal signals lead to contraction of the gallbladder and excretion of bile into the gastrointestinal tract where it functions to facilitate the digestion of fats by emulsifying lipids

23 9 into micelles. In its role as a reservoir for bile, the gallbladder is the primary site of gallstone formation. The major solutes of bile include cholesterol, water-soluble bile salts and water-insoluble phospholipids (lecithins) 10. The formation of cholesterol gallstones is promoted by a number of processes. First, cholesterol precipitates into crystals when its concentration in bile exceeds the solubilizing capacity of bile salts and phospholipids. Bile stasis with gallbladder hypomotility supports the nucleation of cholesterol crystals and mucous hypersecretion by the gallbladder epithelium facilitates the formation of stones 10,17,18. Acute calculus cholecystitis develops as a result of gallstone obstruction of the cystic duct leading to impaired bile outflow from the gallbladder and increased pressure within the gallbladder. Gallbladder wall inflammation results from progressive mucosal ischemia exacerbated by the release of inflammatory prostaglandins, leading to the compromise of the glycoprotein mucous layer protecting the gallbladder epithelium 10. While infection is not present at the onset of acute cholecystitis, secondary superinfection is identified on biliary or gallbladder cultures in 29% to 54% of cases of acute cholecystitis 19. Gram negative organisms (E. coli, Klebsiella spp., Pseudomonas spp., Enterobacter spp.) are most frequently involved as well as anaerobes (Bacteroides, Clostridium) and gram positive cocci (Enterococcus, Streptococcus) 16,19. Acute cholecystitis therefore includes a pathologic spectrum ranging from mild inflammation with sterile bile to gangrenous cholecystitis with necrosis, empyema of the gallbladder or emphysematous cholecystitis from gas-forming organisms. Untreated acute cholecystitis can also progress to perforation of the gallbladder leading to bile peritonitis or a

24 10 pericholecystic abscess 15. The formation of a biliary fistula between the gallbladder and duodenum is also a well-documented complication Diagnosis and severity In an effort to standardize nomenclature, inform best practices and facilitate research efforts, an international consensus conference focusing on the topics of acute cholecystitis and cholangitis was organized in Toyko, Japan, in A panel of international experts in surgery, internal medicine (including infectious diseases and gastroenterology), critical care and radiology participated in performing systematic reviews and discussions ultimately leading to a guidelines on the diagnosis and management of acute cholecystitis in This series of publications, known as the Tokyo guidelines, were updated in January 2013, and lay out diagnostic criteria and a clinical severity classification system for acute cholecystitis 20. As per the 2013 Toyko guidelines, the diagnosis of acute cholecystitis can be suspected given one local sign of gallbladder inflammation (either Murphy s sign on physical exam or right upper quadrant mass/pain/tenderness) and one systemic sign of inflammation (either fever, an elevated C reactive protein or a white blood cell count >12,000/mm3) 20. A definite diagnosis is achieved when, in addition to the two previous criteria, imaging findings characteristic of acute cholecystitis are present 20. In a retrospective validation study, these criteria had a 91% sensitivity and 97% specificity for a definite diagnosis of acute cholecystitis 20. The pathologic spectrum of acute cholecystitis mentioned previously is reflected by a range in severity of clinical presentation. In patients with acute cholecystitis, the Tokyo guidelines describe three levels of severity (Table 2.1). Mild cholecystitis involves meeting the

25 11 cholecystitis diagnostic criteria without any markers of greater severity. Moderate cholecystitis reflects a greater degree of inflammation as suggested by a patient s history, physical exam or investigations. Finally, the definition of severe cholecystitis mirrors that of severe sepsis in so far as the criteria are all markers of organ dysfunction. Approximately 95% of patients with acute cholecystitis have mild or moderate cholecystitis 21. Several patient characteristics are frequently cited as associated with more severe cholecystitis. However, no published studies have identified predictors of greater cholecystitis severity in the context of the Toyko guidelines severity classification system. Furthermore, the conclusion of an association between a patient characteristic and more severe cholecystitis has been based on a range of metrics including clinical presentation, pre-operative imaging findings, intraoperative findings, pathology or operative outcomes. With these caveats in mind, the characteristics most consistently associated with more severe cholecystitis include older age, male sex and diabetes Surgical Management of Acute Cholecystitis Rationale for surgical management of acute cholecystitis Current management of acute cholecystitis is predominantly surgical for two main reasons. First, cholecystectomy is the only definitive management of acute cholecystitis since it manages the inflamed organ and, by removing the site of gallstone formation, prevents recurrent symptoms. Second, the advent of laparoscopic cholecystectomy in 1990 has reduced the

26 12 morbidity associated with surgery thereby increasing the proportion of patients to whom definitive surgery can be offered 13. The majority of cases of acute cholecystitis, if managed non-operatively, will settle. In these patients, the need for definitive management is justified based on the risk of recurrent gallstone-related symptoms. In the era when open cholecystectomy was the only surgical approach, alternatives to cholecystectomy such as gallstone lithotripsy and pharmacologic dissolution were extensively investigated for patients with symptomatic gallstones, outside of the acute setting 28. A high rate of recurrent or residual stones, high cost, applicability to only a small proportion of patients and, ultimately, the advent of laparoscopic technique limited the uptake of these nonsurgical treatments Laparoscopic cholecystectomy therefore became the predominant treatment of symptomatic gallstone disease and the number of cholecystectomies performed annually rose significantly in the 1990s 13. In a small proportion of cases of acute cholecystitis initially managed nonoperatively, symptoms will fail to settle and worsening sepsis, gangrenous cholecystitis, or gallbladder perforation may ensue. Urgent surgical intervention is justified in these cases. An alternative to surgery in the acute phase for patients with severe or worsening cholecystitis is gallbladder decompression, generally via placement of a percutaneous drain known as a cholecystostomy drain. Cholecystostomy placement is very effective in settling the acute inflammation however, unlike surgery, does not prevent recurrence of symptom in the future 32, Surgical approach Historically, cholecystectomy was performed via a subcostal incision (open approach). Since the advent of laparoscopy in the late 1980s, laparoscopic cholecystectomy,

27 13 performed through 5-10mm incisions, has become the standard surgical approach (Figure 2.2). In the non-emergent setting, the benefits of laparoscopic over open cholecystectomy include a shorter hospital stay, faster return to work as well as better cosmesis, less post-operative pain and a reduced incidence of surgical site infection As a result, by year 2000, over 90% of elective cholecystectomies were started via a laparoscopic approach in Ontario 13. However, in the event of technical difficulty, conversion from laparoscopic to standard open technique is safe practice Complications of cholecystectomy Removing the gallbladder first involves entering the abdominal cavity, either through an open subcostal incision or laparoscopic instrument port placement (Figure 2.2), and dissecting off omentum or bowel that is adherent to the gallbladder due to the inflammatory process. The cystic duct, which connects the gallbladder to the common bile duct, and the cystic artery, which supplies blood to the gallbladder, are then carefully identified, ligated and then divided (Figure 2.1). The gallbladder is then free to be dissected off the liver bed. As with any invasive surgery, cholecystectomy carries certain risks. Operation-specific complications include surgical site infection, bile leak, bile duct injury, bowel injury, vascular injury and vasculo-biliary injuries. Medical complications include myocardial infarction, pneumonia, urinary tract infection and venous thromboembolism. While rare, death may result from any of these or other rarer complications. The frequency of surgical site infection ranges from 1% to 10% and the risk is related to surgical approach (laparoscopic or open cholecystectomy) and the degree of contamination (e.g. gangrenous cholecystitis, leakage of infected bile, occurrence of a bile duct or bowel injury) 37. More specifically, when characterized according to the Center for Disease Control s levels of

28 14 surgical site infection, the frequency of infection is 1% - 5%, 0.1% - 1% and 0.3% - 2.5% for superficial incisional surgical site infection, deep incisional surgical site infection and organ space surgical site infection respectively 37,38. Appropriate management is usually based on the nature and severity of infection. Antibiotics or simply opening the surgical wound will treat a superficial surgical site infection. Percutaneous drainage or re-operation and washout are required for more extensive or deep organ-space infections. Bile leaks and bile duct injuries represent a spectrum of injury to the biliary tract. Strasberg et al. proposed a classification system most applicable to the laparosopic era that classifies injuries based on the length, circumference and level of the injury involved and whether the main duct (common hepatic and common bile duct) versus an accessory or the cystic duct are injured 39. With respect to associated morbidity and impact on quality of life, injury to the biliary tract can be considered in two broad categories: bile leaks and bile duct injuries requiring operative intervention. Leaks may result from injury to a side branch of the biliary tree, the cystic duct stump or a non-circumferential injury to the main ductal system. These may be managed with endoscopic cholangiopancreatography and stent placement, possibly in association with percutaneous drainage 40. Major bile duct injuries require operative repair or reconstruction of the biliary tract and are therefore associated with the greatest morbidity 40. In fact bile duct injuries are associated with reduced long term survival and are a major cause of litigation against general surgeons Leaks occur in approximately 1-3% of laparoscopic cholecystectomies whereas injuries complicate only % of cholecystectomies 41, In addition, vasculobiliary injuries have recently received greater attention and refer to an extreme case of major bile duct injury that occurs in conjunction with injury to a hepatic artery and/or portal vein 49,50. This devastating injury accounts for only 2% of major bile duct injuries 51.

29 15 The frequency of bowel injuries is not well characterized but results from dissection of the colon, small bowel or duodenum adhered to an inflamed gallbladder or from inadvertent cautery burn. Primary repair is generally possible if recognized early; otherwise, patients will present later with peritonitis necessitating a return visit to the operating room. A small proportion of cholecystectomies for symptomatic gallstones lead to medical complications. Based on data from the National Surgery Quality Improvement Program (NSQIP) of the American College of Surgeons, a procedure-specific registry, medical complications such as myocardial infarction, pneumonia, urinary tract infection and venous thromboembolism respectively occur in 0.2%-1%, 0.4%-4%, 0.7%-2% and 0.2%-1% patients respectively 37. The frequency of such complications might reasonably be expected to be higher in patients operated on for acute cholecystitis. Finally, mortality for patients with acute cholecystitis is under 1% 15 and mortality attributable to cholecystectomy (within 30 days or same admission) ranges between 0.3% and 3% 15,37,52, Laparoscopic cholecystectomy in the setting of acute cholecystitis The initial experience with laparoscopic cholecystectomy was in the elective setting for patients suffering from biliary colic, where transient gallbladder outflow obstruction occurs without gallbladder inflammation. In fact, acute cholecystitis was initially considered a contraindication to laparoscopic surgery based on the argument that laparoscopy in the setting of acute inflammation would translate into high rates of operative complications 54. High common bile duct injury rates (5.5%) and high rates of conversion to open approach (15%-33%) were indeed initially seen with laparoscopic cholecystectomy in the setting of acute cholecystitis

30 16 However, in a randomized trial comparing laparoscopic to open cholecystectomy in the setting of acute cholecystitis, laparoscopy was associated with less morbidity, shorter hospital stay and more rapid return to work 57. More recent evidence suggests an improvement in rates of bile duct injury as surgeons experience and comfort with laparoscopy has grown. In fact, large scale analyses of laparoscopic cholecystectomy in patients with prior acute cholecystitis showed a 0.3% common bile duct injury rate with conversion rates remaining high in the order of 15% 58. Given the benefits of laparoscopy over an open approach, as well as evidence of improvement in outcomes with experience, laparoscopic cholecystectomy has become the standard initial surgical approach for acute cholecystitis. As mentioned previously, in the event of operative difficulty, conversion from laparoscopic to an open approach should be undertaken to prevent complications such as bile duct injury. A number of preoperative factors have been associated with an increased probability of conversion from laparoscopic to open surgery. These include male sex, older age, the presence or history of obstructive jaundice, an elevated white blood cell count and a longer duration of symptoms 22,49. Nevertheless, the degree of inflammation encountered intra-operatively (particularly in the area known as Calot s triangle, where the cystic duct, cystic artery and common hepatic duct are found) remains challenging to predict preoperatively. Furthermore, the surgeon s comfort with difficult laparoscopic cholecystetomy is also a critical determinant of the probability of conversion Timing of cholecystectomy for acute cholecystitis While laparoscopic cholecystectomy was established as superior to open cholecystectomy for patients with acute cholecystitis, the timing of operative intervention in the laparoscopic era remained controversial in the late 1990s. Two broad strategies exist: urgent

31 17 early cholecystectomy and delayed elective cholecystectomy. Early cholecystectomy, while variably defined throughout the surgical literature, most generally refers to cholecystectomy performed on the initial admission within up to 7 days from symptom onset 22,59,60. With delayed intervention, acute inflammation is allowed to settle before proceeding with cholecystectomy some 6 to 12 weeks after the initial admission. In the pre-laparoscopy era, early open cholecystectomy for acute cholecystitis was supported by randomized prospective trials 59,61,62. However with laparoscopy, it was not initially known how conversion rates and operative complications would compare between early and delayed cholecystectomy. Performing a delayed cholecystectomy when the gallbladder is no longer acutely inflamed and friable might reasonably be safer. Conversely, if delayed cholecystectomy allows for the formation of fibrosis in and around Calot s triangle, the operation may prove more difficult resulting in a higher rate of conversion and complicatio ns. Also, patients managed with the intention of delayed cholecystectomy, who are discharged home once their acute symptoms improve, remain at risk of recurrent gallstone-related symptoms until their scheduled elective cholecystectomy. Table 2.2 lists the major sources of morbidity and resource use to consider when comparing early to delayed cholecystectomy Timing of cholecystectomy and clinical outcomes Starting in the late 1990s multiple studies prospectively examined the timing of laparoscopic cholecystectomy in acute cholecystitis. Five randomized prospective trials compare the outcomes of laparoscopic cholecystectomy performed on first presentation compared to a delayed procedure and are synthesized in Table 2.3. The results of these trials show that laparoscopic cholecystectomy within 7 days of symptom onset or diagnosis is associated with a significantly reduced total hospital stay and a similar conversion rate as delayed cholecystectomy

32 18 46, Furthermore, with respect to the clinical course of patients managed with delayed cholecystectomy, trial data and retrospective studies of selected patient samples suggest that delayed management is associated with a 0% to 38% readmission rate for gallstone related complications 46, This range of estimates also provides insight into our contemporary understanding of the natural history of untreated acute cholecystitis. As such, early cholecystectomy for most patients with acute cholecystitis has been promoted based on the findings of a similar conversion rate, shorter hospital length of stay and avoidance of recurrent gallstone symptoms. However, the randomized trials suffer from many limitations. First, they were published from 1998 to 2004 and certain exclusion criteria such as suitability for laparoscopy are unlikely to apply today as experience with difficult laparoscopic cholecystectomy has grown. Second, the trials were powered to compare conversion rates in the order of 20% but were too small to compare rare but devastating complications such as bile duct injury or mortality. A recent meta-analysis of the trials data remains underpowered to offer a conclusive comparison of the frequency of bile duct injury (1 in 232 early cases versus 3 in 219 delayed cases) 71. Finally, the studies originate from single academic centers and therefore may not provide estimates of outcomes and recurrent gallstone symptoms that can be generalized to a broader sphere of practice. The only published population-based data on recurrent gallstone complication rates, in patients discharged home without cholecystectomy, is limited to capturing admissions in patients over the age of Timing of cholecystectomy and economic outcomes The timing of laparoscopic cholecystectomy for acute cholecystitis has important ramifications in terms of resource utilization and associated costs. Clinical studies suggest lower healthcare costs with early cholecystectomy based on a reduction in total hospital length of

33 19 stay 46,69. However, only two formal economic evaluations have focused on the timing of cholecystectomy in acute cholecystitis. A complete economic evaluation requires consideration of both the costs and clinical consequences of alternative management strategies 72. The results of an economic evaluation can help a decision maker, such as a third party payer, decide whether the clinical benefit of one treatment over the other is worth any additional cost. Furthermore, quantifying the amount of uncertainty around the results is an integral component of economic evaluations and remains relevant even in situations where a treatment is more effective and less costly than its alternative. In the first published economic evaluation on this topic, Wilson et al. undertook a costutility analysis using a decision tree framework to compared early cholecystectomy, performed within up to 7 days symptom onset, to delayed elective cholecystectomy 73. Costs were calculated from the perspective of the United Kingdom Ministry of Health and the metric of clinical effectiveness was the quality-adjusted life-year (QALY). Their analysis showed that early laparoscopic cholecystectomy was less costly ( 820 per patient) and associated with greater QALY gains (+0.05QALYs per patient) for patients with acute cholecystitis. On probabilistic sensitivity analysis, they reported an 80% probability that early laparoscopic cholecystectomy was cost-effective given a Ministry of Health willingness-to-pay 20,000 per additional qualityadjusted life-year. In a similar cost-utility analysis, Johner and colleagues reached the same conclusion, but included only costs from the perspective of a single academic hospital in British Columbia, Canada 74. However, the outcomes probabilities that informed both group s decision tree models input parameters were derived from the existing randomized trials comparing early to delayed cholecystectomy. As a result, both studies are hindered by the previously mentioned limited contemporary external validity and constraints related to the small sample size of the trials.

34 20 In addition to these two similar model-based studies, a person-level cost-utility analysis was also published by MaCafee et al. that compared early to delayed cholecystectomy for patients with biliary or acute cholecystitis 75. They performed a small randomized trial capturing patients quality of life days after surgery as well as costs from a National Health Service and societal perspective. Although no significant differences in costs or quality of life were observed, the marginally higher quality of life 30 days after delayed surgery (vs. early surgery) was associated with minimal additional cost. Since the risk of operative complications and recurrent symptoms is lower with biliary colic than acute cholecystitis, the lack of a subgroup analysis focused on patients with acute cholecystitis limits direct application of these results to the central question of this thesis. Furthermore, temporary reductions in quality of life while awaiting delayed elective cholecystectomy were not captured in Macafee s analysis and are a critical consideration. 2.5 Management guidelines for acute cholecystitis The previously described Tokyo consensus guidelines represent the most detailed guidelines for the management of acute cholecystitis 49. Based on existing evidence and consensus among the expert panel members, the 2013 Tokyo guidelines support early surgery on first presenting admission as the optimal management strategy for patients with non-severe acute cholecystitis. This recommendation is also consistent with the Society of American Gastrointestinal and Endoscopic Surgeon s (SAGES) guidelines for the clinical application of laparoscopic biliary surgery 76. While much less detailed, SAGES endorses early laparoscopic cholecystectomy within 24 to 72 hours of diagnosis for patients with acute cholecystitis.

35 21 The Tokyo guidelines also provide recommendations specific to the grade of cholecystitis severity. Since the severity classification system was published relatively recently, grade-specific recommendations do not have a strong evidence base. However, the recommendations are informed by consensus of international experts that participated in the development of these guidelines. Patients with mild (grade I) acute cholecystitis should be managed with cholecystectomy early on first presenting admission. For patients with moderate cholecystitis (grade II), early cholecystectomy is also recommended as the preferred management strategy. However, the 2013 version of the guidelines, more so than the 2007 version, stresses the point that, at the surgeon-level, delaying surgery may be reasonable if the surgeon is not comfortable with difficult laparoscopic cholecystectomy where severe local inflammation is encountered. Conversely, the point is also made that a minority of cases of moderate cholecystitis involving gallbladder perforation, grangrenous cholecystitis or emphysematous cholecystitis may require urgent early surgery or gallbladder drainage. Finally, for patients with severe cholecystitis, intervention is required given the organ dysfunction resulting from the acute cholecystitis. Percutaneous cholecystostomy followed by delayed cholecystectomy is recommended as the optimal management for these patients. 2.6 Variation in practice As described, best available evidence can be interpreted as supportive of early cholecystectomy for most patients with acute cholecystitis based on a similar conversion rate, shorter total hospital length of stay and elimination of the risk of recurrent gallstone symptoms associated with delayed cholecystectomy. While the clinical trials were published between 1998

36 22 and 2004, practice patterns have not universally followed suit. In studies published between 2004 and 2007, only 11% to 55% of surgeons surveyed in the UK, Japan and Australia reported having a preference for early laparoscopic cholecystectomy Further support in the literature for early cholecystectomy was provided in when a Cochrane Collaborative metaanalysis of the randomized trial data was published as well as the Tokyo consensus guidelines for the management of acute cholecystitis. However, studies published between 2006 and 2012 in the USA, UK and Japan have shown that 36-88% of patients with acute cholecystitis actually undergo early cholecystectomy 69,70, Clearly practice patterns remain variable across hospitals worldwide. However, because of differences in the setting and cohort characteristics across published studies, our understanding of the extent and underlying etiology of the inconsistent application of early cholecystectomy remains circumstantial. 2.7 Summary of gaps in knowledge In summary, important gaps remain in the clinical evidence comparing early to delayed cholecystectomy for acute cholecystitis. The main gaps include: (1) The need for a contemporary comparison of the rate of conversion from laparoscopic to open cholecystectomy in real world practice. (2) The lack of an accurate comparison of rare but devastating operative complications including bile duct injury and death. (3) The need for estimates of the risk of recurrent symptoms if cholecystectomy is delayed, that can be generalized to a broad range of patients.

37 23 Furthermore, published reports suggest variation in the application of early cholecystectomy across different contexts of care. Therefore, in order to effectively translate clinical evidence into practice within a given healthcare system such as Ontario s, a detailed understanding of the local context of practice is required. Finally, given the constrained nature of healthcare budgets, economic evaluations can provide useful information for decision making by explicitly presenting the costs of alternative treatments relative to the associated clinical consequences. Setting-specific cost estimates as well as clinical outcome estimates addressing previously mentioned knowledge gaps will best inform decision making.

38 Tables for Chapter 2 Table 2.1 Acute cholecystitis severity classification from the Tokyo Guidelines 20 Severity level Mild cholecystitis Moderate cholecystitis Severe cholecystitis Criteria Not meeting criteria for moderate or severe cholecystitis Any one of the following conditions: 1. Elevated WBC count (>18,000/mm3) 2. Palpable tender mass in the right upper abdominal quadrant 3. Duration of complaints > 72 hours 4. Marked local inflammation (gangrenous cholecystitis, pericholecystic abscess, hepatic abscess, biliary peritonitis, emphysematous cholecystitis) Dysfunction in any one of the following organs/systems: 1. Cardiovascular dysfunction: Hypotension requiring treatment with dopamine 5 lg/kg per min, or any dose of norepinephrine 2. Neurological dysfunction: Decreased level of consciousness 3. Respiratory dysfunction: PaO2/FiO2 ratio < Renal dysfunction: Oliguria, creatinine> 2.0 mg/dl 5. Hepatic dysfunction: PT-INR> Hematological dysfunction Platelet count<100,000/mm3

39 25 Table 2.2 Major sources of morbidity and resource utilization to consider when comparing early and delayed cholecystectomy Early cholecystectomy Delayed cholecystectomy 1) Operative events: - Conversion to open cholecystectomy - Major bile duct injury (requiring surgical reconstruction) - Bile leak (requiring endoscopic intervention) - Other complications: surgical site infection, vascular injury, bowel injury, medical complications - Death 2) Hospital length of stay 1) Operative events: - Conversion to open cholecystectomy - Major bile duct injury (requiring surgical reconstruction) - Bile leak (requiring endoscopic intervention) - Other complications: surgical site infection, vascular injury, bowel injury, medical complications - Death 2) Gallstone-related symptoms while awaiting elective operation: - Biliary colic, recurrent cholecystitis, gallstone pancreatitis, choledocholithiasis, cholangitis, gallstone ileus 3) Hospital length of stay

40 Table 2.3- Summary of randomized controlled trials comparing early to delayed laparoscopic cholecystectomy for acute cholecystitis Outcomes Study characteristics Early vs. Delayed Delayed group Study Country Early Delayed (weeks) Exclusions Surgeons experience Number of patients (Early / delayed) Conversion (%) - 1ry outcome Major bile duct injury (N) Total hospital length of stay in days (median) Non-resolving or recurrent symptoms (%) Kolla, 2004 India 48hrs from randomization 6-12 * Symptoms for >96hrs * Prior upper abdominal surgery * Unfit for laparoscopic surgery *concurrent CBD stones NR 20 / vs vs. 0 4 vs. 10 0% Johansson, 2003 Sweden 48hrs from randomization 6-8 Symptoms for > 7 days >25 LCs 74 / vs vs. 1 5 vs. 8 25% Davila, 1999 Spain 4 days from symptom onset 8 NR NR 36 / 27 4 vs vs vs % Lai, 1998 Hong Kong, China 24hrs from randomization 6-8 * Symptoms > 1 week * Prior upper abdominal surgery * Unfit for laparoscopic surgery * Concurrent CBD stones >50 LCs 53 / vs vs. 0 8 vs % Lo, 1998 Hong Kong, China 72 hrs from admission 8-12 * Symptoms > 7days * Prior upper abdominal surgery * unfit for laparoscopic surgery * Concomittant malignancy >300 LCs 49 / vs vs. 1 6 vs % LC=laparoscopic cholecystectomies, CBD= common bile duct, NR=Not reported

41 Figures for Chapter 2 Figure Depiction of anatomy of gallbladder, cystic duct and common bile duct (copyright A.D.A.M)

42 Figure Depiction of laparoscopic and open cholecystectomy 28