Acute cholecystitis in high risk surgical patients: percutaneous cholecystostomy versus laparoscopic cholecystectomy (CHOCOLATE trial): Study protocol for a randomized controlled trial

Kirsten Kortram 2 Bert van Ramshorst 2 Thomas L Bollen 1 Marc GH Besselink 2 Dirk J Gouma 0 Tom Karsten 3 Philip M Kruyt Grard AP Nieuwenhuijzen Johannes C Kelder Ellen Tromp Djamila Boerma 2 0 Dept. of Surgery, Academic Medical Centre Amsterdam 1 Dept. of Radiology, St. Antonius Hospital Nieuwegein 2 Dept. of Surgery, St. Antonius Hospital Nieuwegein 3 Dept. of Surgery, Onze Lieve Vrouwe Gasthuis Amsterdam Background: Laparoscopic cholecystectomy in acute calculous cholecystitis in high risk patients can lead to significant morbidity and mortality. Percutaneous cholecystostomy may be an alternative treatment option but the current literature does not provide the surgical community with evidence based advice. Methods/Design: The CHOCOLATE trial is a randomised controlled, parallel-group, superiority multicenter trial. High risk patients, defined as APACHE-II score 7-14, with acute calculous cholecystitis will be randomised to laparoscopic cholecystectomy or percutaneous cholecystostomy. During a two year period 284 patients will be enrolled from 30 high volume teaching hospitals. The primary endpoint is a composite endpoint of major complications within three months following randomization and need for re-intervention and mortality during the follow-up period of one year. Secondary endpoints include all other complications, duration of hospital admission, difficulty of procedures and total costs. Discussion: The CHOCOLATE trial is designed to provide the surgical community with an evidence based guideline in the treatment of acute calculous cholecystitis in high risk patients. Trial Registration: Netherlands Trial Register (NTR): NTR2666 - Background Acute calculous cholecystitis (ACC) is a frequently encountered disease in the general surgical practice. In young, otherwise healthy patients laparoscopic cholecystectomy (LC) is the treatment of choice [1]. In elderly patients with major comorbidity and seriously ill patients, especially those already admitted to an intensive care unit, percutaneous cholecystostomy (PC) seems preferable since acute LC in these patients can result in serious morbidity (up to 41% [2-7]) and mortality (up to 4.5% [2-6,8]). But there is a remaining subgroup of patients who can be defined as high risk patients based on their comorbidity * Correspondence: 1Dept. of Surgery, St. Antonius Hospital Nieuwegein Full list of author information is available at the end of the article or disease severity but do not fit in either of the two aforementioned categories. Both LC and PC are often used in this subgroup of patients but clear selection criteria for either treatment are lacking and a number of questions regarding the safety and efficacy of PC remain. In the Dutch guidelines for the treatment of gallstone disease [9] PC is indicated as a useful treatment option in patients deemed unfit for surgery but it is left open to discussion whether routine use of PC has additional value over antibiotic treatment in the therapy of ACC in the general population. Little evidence is provided to support this statement. Most studies in the current literature addressing PC as a therapeutic option in ACC in high risk patients are retrospective with limited population sizes. Success rates are fairly high, but mortality rates of PC (range 4-12.7% [6]) are higher than those for LC. This could be attributed to selection bias as it is to be expected that those patients treated with PC were in a worse clinical condition than those treated with LC. A systematic review conducted in 2007 [6] analyzed the safety and efficacy of PC in elderly and critically ill patients. The review identified no clinical trials comparing PC with LC and the included studies were mostly retrospective and involved small patient populations. With a success rate of 91% in patients with confirmed ACC and a procedure related mortality of 0.4% results of PC seemed promising. The overall mortality was 12.7% and the overall complication rate was reported to be 6.2%. Complication rates were not included in more than half of the studies thus leading to an underestimation of the actual complication rate. We performed a retrospective review of all patients undergoing PC for acute calculous cholecystitis between January 2009 and June 2010 [10]. A total of 27 patients were included with a median age of 83 years. PC was performed because of either comorbidity/age or duration of symptoms. The success rate was 92.6% (N = 25) but the complication rate was 22.2% (N = 6). The overall mortality rate was 14.8% (n = 4) and the procedure related mortality rate 3.7% (N = 1). With a mean follow-up of eight weeks three patients developed recurrent cholecystitis and four patients underwent an interval cholecystectomy. Current literature and data from our own clinical experience fail to answer the question which therapy is the best option in ACC in high risk patients. At present both treatment strategies are used in this patient category and the preference and expertise of the responsible surgeon or the general opinion within the hospital usually determines the choice of treatment. The CHOCOLATE trial is designed to assess which treatment modality is best suited for high risk patients with ACC, with the aim to prove superiority of the laparoscopic cholecystectomy. Methods Design The CHOCOLATE trial is a randomised controlled, open, parallel, superiority multicenter study. Patients will be randomly allocated to undergo either laparoscopic cholecystectomy or percutaneous drainage. The aim of this study is to test the hypothesis that laparoscopic cholecystectomy will lead to a reduction in morbidity and mortality compared to percutaneous drainage in high risk patients with acute calculous cholecystitis. Primary & Secondary endpoints The primary endpoint is a composite endpoint of all major morbidity, re-intervention and mortality. Table 1 provides an overview of the definitions. Complications occurring during the first 30 days subsequent to randomisation and need for reintervention and mortality during the one year follow-up period will be compared. The secondary endpoints include all individual components of the primary endpoint and in addition all minor complications including wound infection, bleeding without need for transfusion or intervention and urinary tract infection, difficulty of cholecystectomy (as scored by VAS 1-10), total length of hospital stay, emergency room visits for related medical problems, readmissions, duration of hospital and intensive care stay and total (direct and indirect) costs. Study Population All patients presenting with ACC as defined according tot the Tokyo Guidelines [12] to one of the participating hospitals will be assessed for eligibility on presentation. If patients meet the inclusion criteria they will be stratified for hospital and randomised to undergo either LC or PC. The in- and exclusion criteria are presented in table 2. Randomisation Patients will be random (...truncated)