Fast Track Pathway to Accelerated Cholecystectomy Versus Standard of Care for Acute Cholecystitis (FAST) pilot trial

Abstract

Background:

Timing to surgery for acute cholecystitis remains variable, ranging from early (< 7 d) to delayed surgery (> 7 d). Accelerated surgery may result in better outcomes owing to reduced exposure to hypercoagulable and inflammatory states. We sought to determine the feasibility of a trial comparing accelerated surgery with standard care among patients with calculous acute cholecystitis.

Methods:

We conducted a multicentre pilot randomized controlled trial. We randomly assigned adult patients with acute cholecystitis to receive accelerated surgery (i.e., goal of surgery within 6 hours of diagnosis) or standard care. The primary feasibility outcome included recruitment of 60 patients, randomly assigning the equivalent of 1 patient per site per month, and 95% follow-up at 90 days.

Results:

Sixty patients (mean age 61.7, standard deviation [SD] 13.5, yr; 27 [45%] female) were randomly assigned to accelerated surgery (n = 31) or standard care (n = 29) from December 2019 to December 2021, with 2 recruitment pauses due to the COVID-19 pandemic. The median time from diagnosis to surgery was 5.8 (interquartile range [IQR] 4.4–11.1) hours in the accelerated care arm and 20.3 (IQR 6.8–26.8) hours in the standard care arm. Across 4 sites, 4.6 patients per month were randomly assigned. All patients completed the 90-day follow up.

Conclusion:

In our pilot trial, we found that accelerated cholecystectomy was achievable. These results show the feasibility of a trial comparing accelerated and standard care among patients requiring surgery for acute cholecystitis and support a definitive trial.

Trial registration:

ClinicalTrials.gov, no. NCT04033822.

The prevalence of gallstones in the general population is 10%–15%. Approximately 10%–15% of these patients will develop calculous acute cholecystitis.¹ Every year, more than 200 000 people in the United States are diagnosed with acute cholecystitis, which represents a large burden of treatable disease.¹ Surgery is the only definitive treatment and is considered standard of care for acute cholecystitis.^2,3 The optimal timing for operative intervention is unclear. On the basis of observational data, it was previously believed that delayed surgery could decrease complications like bile duct injuries by avoiding surgery in active inflammation.⁴ However, recent evidence has questioned this theory. On the basis of evidence from small randomized trials showing decreased length of stay and possibly reduced morbidity, guidelines now recommend early timing of laparoscopic cholecystectomy.^5–7

Despite those recommendations, there is no clear definition for “early” surgery. Across existing studies, early surgery has ranged from 24 hours to 7 days from the time of symptom onset or from the time of hospital admission.^5,6,8–15 Existing trials evaluating the optimal timing of surgery for acute cholecystitis have been limited by small samples and are underpowered for major outcomes.^5,12–15 Guidance from Tokyo suggests that early cholecystectomy should be performed as soon as possible or at least within 72 hours of symptom onset.⁶ Without clear evidence for optimal time to surgery, there remains large variations in clinical practice worldwide.^16–19

Acute cholecystitis initiates inflammatory, hypercoagulable, and stress states that can cause medical complications.^20,21 Accelerated surgical treatment will reduce the time patients are exposed to these harmful states and therefore may reduce the risk of adverse outcomes, especially among frail and comorbid patients. Moreover, accelerated surgery may further reduce the cumulative length of hospital stay, which may lower overall costs.^1,5,13,22 Across existing studies, the earliest time to surgery that has been investigated is within 24 hours of symptom onset.^5,12–15 Accelerated surgical intervention for acute cholecystitis, such as surgery within 6 hours of diagnosis, has not yet been studied.^1,20,21,23 In populations with hip fracture requiring surgery, a large international trial has successfully been conducted evaluating accelerated surgery within 6 hours of diagnosis and demonstrated reductions in delirium, urinary tract infections, and pain, and more rapid mobilization, weight bearing, and discharge from hospital.²⁴ Through a similar model, our group ultimately seeks to investigate the impact of accelerated surgery in patients with acute cholecystitis. Before undertaking a large trial, there is a need to establish the feasibility of such a trial. Therefore, we undertook the pilot trial herein. The primary objective was to determine the feasibility of a large-scale trial evaluating accelerated surgery within 6 hours of diagnosis, compared with the current standard of care, among patients with acute cholecystitis.

Methods

We reported the study according to the Pilot Study Reporting Recommendation Checklist adopted from the Consolidated Standards of Reporting Trials statement.²⁵ All patients provided informed consent before random assignment.

Study design

This was a multicentre parallel pilot randomized controlled trial (RCT) that compared accelerated surgery and standard of care among adult patients with calculous acute cholecystitis. All 4 participating sites were tertiary care hospitals in Ontario, Canada (Juravinski Hospital, St. Joseph’s Healthcare Hamilton, Hamilton General Hospital, and London Health Sciences). By nature of the intervention, it was not possible for patients, health care providers, or data collectors to be unaware of study group assignment; however, all outcome adjudicators were unaware of study group allocation.

Randomization

Random assignment occurred immediately after a patient was deemed eligible and written informed consent had been obtained. If a patient was unable to provide consent, then consent was obtained from a substitute legal decision-maker. Research personnel randomly assigned patients using an interactive Web-based randomization Internet system, maintained by the coordinating centre at the Population Health Research Institute in Hamilton, Ontario. Patients were stratified by centre. Randomization was stratified by centre, and block randomization within strata with randomly varying block sizes was used. We randomly assigned participants in a 1:1 ratio to receive accelerated surgery versus standard care.

Patient inclusion and exclusion

Patients with a diagnosis of acute calculous cholecystitis and aged 45 years and older or between the ages of 18 and 45 years with at least 1 comorbidity (reported in Table 1) were considered for inclusion. Inclusion was restricted to working hours, as per each local site, to enhance the potential for surgical and anesthetic team availability and operating room access for participants assigned to accelerated care, as per previous trials led by our group.^24,26 Further details regarding the inclusion and exclusion criteria are reported in Table 1.

Table 1.

Details of inclusion and exclusion criteria

Inclusion criteria

Age ≥ 45 years, or age ≥ 18 years to < 45 years with at least 1 of the following comorbidities: diabetes or chronic respiratory, cardiovascular, or renal disease, or baseline NT-proBNP ≥ 200 ng/L; Diagnosis of acute cholecystitis defined by the presence of at least 2 of the following: Abdominal pain, Murphy sign, Leukocytosis > 10 × 109/L, or Oral temperature < 36.5°C or > 38°C; Cholelithiasis (stones or sludge); Ultrasonography signs of cholecystitis or in a setting where ultrasonography was suboptimal (e.g., obesity), then computed tomography signs of cholecystitis as interpreted by a surgeon or radiologist: Thickened gallbladder wall, Sonographic Murphy sign, or Pericholecystitic fluid; Acute cholecystitis that requires surgery and was diagnosed during working hours; Expected to have required at least an overnight hospital admission after surgery; and Provided written informed consent to participate in the trial.

Exclusion criteria

Patients who required emergent surgery or emergent interventions (e.g., abdominal pathology requiring urgent laparotomy, coronary revascularization, or pacemaker-implantation); Patients whose therapeutic anticoagulation was not reversible; Patients with a history of heparin-induced thrombocytopenia who were taking warfarin with an INR ≥ 1.5; Pregnant patients; and Patients who had previously participated in the trial.

INR = international normalized ratio; NT-proBNP = N-terminal pro-B-type natriuretic peptide.

Trial intervention

Once a patient was diagnosed with acute cholecystitis by the general surgery team, research personnel assessed the patient’s eligibility for study inclusion, obtained consent, and randomly assigned the patient to either the accelerated surgery or standard care group. If deemed relevant, the general surgery team could consult the medical clearance team — including perioperative care physicians, general internists, or cardiologists, as per each local site policy — to assess and, if appropriate, clear the patient for surgery. For patients in the accelerated surgery group, the goal was to have patients assessed and cleared for surgery within 2 hours of a surgeon consulting the medical clearance team.

If the patient was randomly assigned to accelerated surgical care, they were to be booked as the next case in the general surgery operating room (OR). These participants were booked at a higher category of priority (i.e., surgery within 8 hours) than is usual according to our institutional protocol (i.e., surgery within 48 hours), with the goal of surgery within 6 hours of diagnosis by a staff surgeon. They were also given priority over scheduled elective surgeries, if possible. Although this was uncommon, scheduled cases that were shifted for the study participant were rescheduled to the next OR slot later in the day and were completed a few hours later than originally planned. Costs incurred from these scenarios were covered by the study funds to ensure that no elective surgeries were cancelled. Availability of the OR was determined by readiness of the OR staff, anesthesiology staff, and general surgeons. Sites also used the trauma room when it was available for some of the accelerated surgical cases.

Participants who were randomly assigned to the standard care group underwent surgery following each institutions’ standard processes and timing of care. All participating hospitals had a dedicated emergency general surgery service. One of these centres had dedicated OR time for emergency general surgery cases, including cholecystectomies, once a week. All other perioperative management (monitoring, fluids, type of anesthesia, analgesia) and postoperative care were at the discretion of the attending anesthesiologists, surgeons, and medicine physicians. All co-interventions were recorded.

Follow-up

Participants in both arms of the trial received the same follow-up from research personnel. All participants had daily measurements of troponin and creatinine while in hospital, up to and including day 3 after surgery. Participants were also screened for postoperative delirium while in hospital, twice daily during the first 3 days after surgery or until discharge, whichever occurred first, by research personnel trained on the 3D-Confusion Assessment Method.²⁷ Participants were followed daily and contacted by telephone at 90 days after random assignment. All study outcomes were recorded. All outcome assessors were unaware of the treatment allocation.

Trial outcomes

The primary outcome was the feasibility of a large-scale trial. We judged the trial as feasible if we were able to recruit 60 participants across all sites, the equivalent of 1 patient per site per month, and if 95% or more of participants completed the follow-up at 90 days after random assignment.

The exploratory clinical outcomes included major perioperative complication (i.e., a composite of death; nonfatal sepsis; surgical site infection; pneumonia; Clostridium difficile–associated diarrhea; intra-abdominal abscess; bile duct injury; cystic duct stump leak; conversion to open surgery; intra-abdominal reoperation; intra-abdominal percutaneous or endoscopic reintervention, including placement of drain, embolization, and endoscopic retrograde cholangiopancreatography [ERCP]; cholangitis; pancreatitis; myocardial injury not meeting definition of myocardial infarction; myocardial infarction; stroke; symptomatic proximal venous thromboembolism; new atrial fibrillation; acute congestive heart failure; new acute renal injury requiring dialysis; and major bleeding) within 90 days of random assignment. Secondary clinical outcomes of interest at 90 days after random assignment included individual components of the composite outcome, cumulative length of stay, days alive at home, length of surgical procedure, postoperative ileus, acute kidney injury, admission to the intensive care unit, number of hospital readmissions, peripheral arterial thrombosis, intraoperative cholangiography, postoperative delirium, and feasibility of drawing preoperative N-terminal pro-B-type natriuretic peptide (NT-proBNP) in 90% of participants. Outcomes are defined in Appendix 1 and Appendix 2, available at www.canjsurg.ca/lookup/doi/10.1503/cjs.016423/tab-related-content.

Statistical analysis

We enrolled a convenience sample of 60 participants in this pilot trial. All analyses included all randomly assigned participants by the treatment groups to which they were originally allocated in accordance with the intention-to-treat principle. We used descriptive statistics to assess baseline characteristics and the primary feasibility outcomes. We reported categorical variables as counts and proportions in each group. We reported continuous variables as means with standard deviations (SDs) or medians with interquartile ranges (IQRs) in each group, as appropriate.

We compared secondary exploratory clinical outcomes between the accelerated surgery and standard care groups using Cox proportional hazards models. We plotted the time to first occurrence of a major perioperative complication for each treatment group using the Kaplan–Meier method, and we used the log-rank test to compare the event rates between the 2 groups. We used the Student t test or Mann–Whitney test to compare surgery duration, length of stay, and days alive at home, as appropriate. For binary outcomes without time to event, we used a logistic regression model. All tests were 2-sided with a significance level of 0.05. We used SAS version 9.4 to perform statistical analyses.

Ethics approval

The local institutional review board (Hamilton Integrated Research Ethics Board, 2019–5948-GRA) gave ethics approval. We registered the trial with ClinicalTrials.gov (NCT04033822).

Results

Recruitment and feasibility outcomes

The flow of participants through the trial is shown in Figure 1. Across the 4 participating centres, 60 participants were randomly assigned into the trial starting from December 2019 to December 2021. Owing to the COVID-19 pandemic, there were 2 periods of recruitment pauses from Mar. 17, 2020, to Oct. 11, 2020, and from Dec. 15, 2020, to July 18, 2021, spanning 30 and 31 weeks, respectively. There were 392 patients screened, with 89 patients identified to be eligible for inclusion. Six patients were excluded because their therapeutic anticoagulation was not reversible. Four patients were excluded because they required emergency surgery or emergent interventions. One patient was excluded because she was pregnant. There were 29 patients who were not randomly assigned, mostly owing to issues with OR availability (n = 13) and choledocholithiasis requiring preoperative intervention (n = 3). In all, 60% of patients eligible for inclusion were consented and randomly assigned for participation in the trial. There was an average of 4.6 participants recruited per month across all sites, and all randomly assigned participants completed the 90-day follow-up.

Fig. 1.

Recruitment feasibility. CT = computed tomography; NT-proBNP = N-terminal pro-B-type natriuretic peptide; OR = operating room.

Baseline demographic characteristics

The mean age of the overall group was 61.7 (SD 13.5) years, and 27 (45%) were female. Table 2 shows the baseline demographic characteristics by treatment group. There were 31 participants randomly assigned to the accelerated surgery group and 29 assigned to the standard care group. The accelerated surgery group had a mean age of 60.5 (SD 12.9) years and included 13 females (42%). The standard care group had a mean age of 62.9 (SD 14.0) years and included 14 females (48%). Overall, 50% of participants had a history of hypertension and 22% had diabetes. A total of 18% of participants had a history of choledocholithiasis, and 10% of participants had a previous acute cholecystitis event. A total of 28% of participants had a prior open abdominal surgery, and 10% had a prior laparoscopic surgery. The mean total bilirubin measurement was 16.6 (SD 9.0) μmol/L, and the direct bilirubin measurement was 12.8 (SD 7.4) μmol/L. Among the 57 participants who had measured preoperative NTproBNP, 8 of 57 (14%) had preoperative NT-proBNP levels from 100 ng/L to less than 200 ng/L, and 35 of 57 (61%) had preoperative NTproBNP levels of 200 ng/L or greater. The severity of acute cholecystitis was reported as mild (44%), moderate (44%), and severe (22%).

Table 2.

Participant demographic and medical baseline characteristics, by treatment group (n = 60)

Characteristic	No. (%)*
	Accelerated surgery n = 31	Standard care n = 29
Age, mean ± SD, yr	60.5 ± 12.9	62.9 ± 14.0
Sex, female	13 (42)	14 (48)
History of coronary revascularization, PCI, or CABG	2 (6)	4 (14)
History of congestive heart failure	1 (3)	0 (0)
History of atrial fibrillation	1 (3)	2 (7)
History of hypertension	13 (42)	17 (59)
History of deep venous thrombosis	0 (0)	0 (0)
History of pulmonary embolism	0 (0)	1 (3)
History of renal failure with dialysis	0 (0)	0 (0)
History of chronic obstructive pulmonary disease	2 (6)	1 (3)
Current smoker	5 (16)	6 (21)
History of obstructive sleep apnea	2 (6)	3 (10)
History of diabetes	6 (19)	7 (24)
History of choledocholithiasis	5 (16)	6 (21)
Previous acute cholecystitis event	4 (13)	2 (7)
Previous abdominal surgery
Open intra-abdominal surgery	9 (29)	8 (28)
Laparoscopic surgery	3 (10)	3 (10)
History of cholangitis	0 (0)	1 (3)
Active cancer	0 (0)	1 (3)
Preoperative baseline laboratory results
Hemoglobin, g/L, mean ± SD	138.4 ± 19.2	134.7 ± 22.7
Leucocytes × 109/L, mean ± SD	12.3 ± 3.7	12.4 ± 5.1
Creatinine, mmol/L, mean ± SD	84.6 ± 30.8	79.2 ± 30.6
Troponin elevation before random assignment, n = 58	1 (3)	0 (0)
Aspartate transferase, U/L, median (IQR), n = 17	27.0 (25.0–60.0)	31.0 (23.0–54.0)
Alanine transaminase, U/L, median (IQR)	23.0 (18.0–30.0)	28.0 (20.0–60.0)
γ-Glutamyltransferase, U/L, median (IQR), n = 56	42.0 (25.0–83.0)	35.0 (20.0–87.0)
Alkaline phosphate, U/L, mean ± SD, n = 58	89.6 ± 37.6	89.0 ± 42.2
Total bilirubin, μmol/L, mean ± SD	17.2 ± 10.1	16.0 ± 7.6
Lactate, μmol/dL, mean ± SD, n = 21	1.5 ± 0.5	1.4 ± 0.3
Lipase, U/L, median (IQR), n = 56	56.0 (27.0–92.0)	70.0 (21.0–113.0)
NT-proBNP, ng/L, median (IQR), n = 57	255.0 (98.0–578.0)	340.0 (171.0–805.0)
NT-proBNP categories, ng/L, n = 57
< 100	9 (30)	5 (18)
≥ 100 to < 200	3 (10)	5 (18)
≥ 200 to < 1500	16 (53)	13 (48)
≥ 1500	2 (7)	4 (1)
Acute cholecystitis severity, n = 45
Mild	11 (52)	9 (37)
Moderate	7 (33)	8 (33)
Severe	3 (14)	7 (29)
Systolic blood pressure, mm Hg, mean ± SD	135.8 ± 28.4	141.6 ± 19.2
Heart rate, bpm, mean ± SD	81.4 ± 11.8	79.0 ± 11.8
Intraoperative characteristics
Surgery duration, min, mean ± SD	86.8 ± 30.0	86.4 ± 32.3
Open surgery	0 (0)	1 (3)
Laparoscopic surgery	30 (97)	28 (97)
Laparoscopic converted to open	1 (3)	0 (0)
Intra-operative cholangiography	4 (13)	3 (10)

CABG = coronary artery bypass surgery; IQR = interquartile range; NT-proBNP = N-terminal pro-B-type natriuretic peptide; PCI = percutaneous coronary intervention; SD = standard deviation.

^*Unless stated otherwise.

Timelines of care pathway

Table 3 describes the timelines of emergency department arrival, diagnosis, and time to surgery, by treatment group. The median time from acute cholecystitis diagnosis to surgery was 5.8 (IQR 4.4–11.1) hours in the accelerated surgery group and 20.3 (IQR 6.8–26.8) hours in the standard care group. There were 16 (51.6%) participants in the accelerated care group who underwent surgery within 6 hours of diagnosis, and there were 5 (17.2%) in the standard care group.

Table 3.

Timelines of emergency department arrival, diagnosis, and surgery, by treatment group

Variable	Median (IQR) or no. (%)
	Total n = 60	Accelerated surgery n = 31	Standard care n = 29
Time from symptom onset to emergency department arrival, h	26.4 (9.9–77.8)	22.5 (9.8–67.7)	35.7 (10.6–78.2)
Time from emergency department arrival to acute cholecystitis diagnosis, h	7.0 (4.1–12.2)	5.8 (3.7–11.8)	7.9 (4.1–12.4)
Time from acute cholecystitis diagnosis to surgery, h	8.1 (5.3–21.6)	5.8 (4.4–11.1)	20.3 (6.8–26.8)
Surgery within 6 hours of diagnosis	21 (35)	16 (52)	5 (17)

IQR = interquartile range.

Intraoperative characteristics

The mean duration of surgery was 86.8 (SD 30.0) minutes in the accelerated surgery group and 86.4 (SD 32.3) minutes in the standard care group. One patient in the standard care group required an open surgery, and 1 patient in the accelerated care group started the surgery laparoscopically but was converted to an open procedure. The rest of the surgeries were completed laparoscopically from beginning to end. Intraoperative cholangiography was performed in 4 (13%) participants in the accelerated care group and 3 (10%) in the standard care group.

Secondary exploratory outcomes

Appendix 1, Supplementary Table 1 details the clinical outcomes by treatment group. A major perioperative complication within 90 days postrandomization occurred in 9 (29%) participants in the accelerated surgery group and 4 (14%) participants in the standard care group (hazard ratio [HR] 2.42, 95% confidence interval [CI] 0.74–7.91; p = 0.1). Five (16%) participants in the accelerated surgery group and 1 (3%) in the standard care group required postoperative ERCP (HR 5.11, 95% CI 0.60–43.9). The 1 patient from the standard care group required ERCP for ascending cholangitis. In the accelerated surgery group, 1 patient required ERCP for a bile leak from the liver bed and another patient underwent an ERCP following intraoperative cholangiography with incomplete transit of contrast into the duodenum. Both patients recovered well following ERCP. The remaining 3 participants in the accelerated surgery group required ERCP for postoperative obstructive jaundice. Two participants in the accelerated group and 1 patient in the standard care group experienced myocardial injury after noncardiac surgery (HR 1.91, 95% CI 0.17–21.9). There were no differences between the 2 groups across the individual components of the composite of major complications outcome.

Two (6%) participants in the accelerated surgery group and 4 (14%) in the standard care group required a hospital readmission (HR 0.47, 95% CI 0.09–2.56). The median length of stay from emergency department admission to discharge was 2 (IQR 1–3) days in the accelerated surgery group and 2 (IQR 2–3) days in the standard care group (p = 0.08). There was 1 patient in each group that met the criteria for postoperative delirium (OR 0.86, 95% CI 0.05–14.5). There were no differences in days alive at home (median 88 days in the accelerated care group v. 87 days in the standard care arm). No deaths occurred in either group throughout the study.

All participants completed 90-day follow-up, and blood was drawn for preoperative NT-proBNP testing in 57 of 60 (95%) participants (Appendix 1, Table 2).

Discussion

This pilot RCT, conducted across 4 Canadian academic institutions, determined the feasibility of a large trial comparing accelerated surgery and standard of care for adult patients with calculous acute cholecystitis. The predetermined threshold for feasibility was met, as 60 patients were recruited, with random assignment of 1 or more patients per site per month across all sites, and all participants completed follow-up at 90 days after randomization. Among those randomly assigned to the intervention arm, the feasibility of accelerated surgery (i.e., surgery within 6 hours of diagnosis) was established, as median time to surgery was 5.8 (IQR 4.4–11.1) hours.

To our knowledge, this is the earliest timing of surgical intervention in acute cholecystitis that has been studied to date.^5,13 Among existing studies comparing early and delayed surgery for acute cholecystitis, the earliest timing for “early surgery” has been within 24 hours of admission.^12–15 In a recent systematic review comparing early and delayed surgery, cholecystectomy within 24 hours of admission did not significantly reduce postoperative complications (relative risk 1.89, 95% CI, 0.76–4.71).⁵ However, only 3 of the 15 included trials considered early surgery to be within 24 hours of admission.^5,12,14,15 Furthermore, these trials were powered for the primary outcome of conversion to open surgeries and had small samples of 100, 60, and 40 patients, respectively.^12,14,15 The 12 other trials included in the systematic review considered early surgery to be within 48–72 hours of admission.⁵ The ACDC (Acute Cholecystitis — Early Laparoscopic Surgery Versus Antibiotic Therapy and Delayed Elective Cholecystectomy) trial was not included in that systematic review, but it is the largest study to date comparing early surgery within 24 hours of admission and delayed surgery, with the inclusion of 618 patients.¹³ Still, it was underpowered for major outcomes and had a concerning imbalance of baseline prognostic factors between the randomized groups. The pilot trial herein established the feasibility of accelerated surgery, that is, surgery within 6 hours of acute cholecystitis diagnosis.

A clinical perioperative outcome was reported in 21.7% of all enrolled participants within 90 days after random assignment. This is consistent with recent literature reporting rates of 11%–27% of perioperative complications among patients undergoing emergency cholecystectomy, with follow-up periods ranging from 30 to 75 days.^1,13–16,22 The RCTs by Lai and colleagues (n = 100 patients) and Kolla and colleagues (n = 40 patients) did not report differences in perioperative complications between delayed and early surgery.^12,15 Ozkardes and colleagues found a 26.7% rate of complications (bile duct injury, bleeding, gallbladder perforation, lung infection, atelectasis, and surgical site infection) in the early group compared with 0% in the delayed group.¹⁴ However, it should be noted that only 30 participants were included per arm, and therefore, the study was severely underpowered for this outcome.¹⁴ The ACDC trial, which included more than 600 patients, found that early surgery was associated with less morbidity (11.8% v. 34.4%, p < 0.001), shorter cumulative length of stay (5.4 v. 10.0 d, p < 0.001), and lower cost (€2919 v. €4262, p < 0.001).¹³ However, in addition to the aforementioned limitations of this trial, there were large differences in time to surgery between the early (median 1.0, range 0.0–4.0, d) and delayed groups (median 23.0, range 1.0–99.0, d). Considering the acceptance of early surgery over delayed surgery, this does not inform the question of whether accelerated surgery provides health benefits, and the median time to delayed surgery in the ACDC trial did not represent standard care. With the lack of clear timelines on what is considered “early” surgery, in conjunction with conflicting evidence, substantial variations in clinical practice have persisted.¹⁶

If accelerated surgery is beneficial, there may be certain populations in which accelerated surgery is more beneficial than others. Current evidence shows that there is significantly greater morbidity in acute cholecystitis with advanced age.^1,5,28 The CHOCOLATE (Laparoscopic Cholecystectomy Versus Percutaneous Catheter Drainage for Acute Cholecystitis in High Risk Patients) trial compared cholecystectomy versus percutaneous cholecystostomy tube for patients who were comorbid (i.e., Acute Physiology and Chronic Health Evaluation [APACHE] score 7) with mean age 71.4 (SD 10.6) years.² This trial demonstrated the stark health benefits of surgical intervention over percutaneous drainage among patients with acute cholecystitis and comorbidities. Similarly, the older patient populations with more comorbidites may stand to benefit most from accelerated surgery, especially with their lower reserve to withstand and recover from prolonged periods of exposure to inflammation.²⁹ These points informed the selection of our inclusion and exclusion criteria, which intentionally excluded younger and healthier patients, as the benefit of accelerated surgery may not be evident in these low-risk patients.

Among the participants who experienced the composite of major complications, this was most commonly due to the component outcome of postoperative re-intervention. All re-interventions were ERCPs, which were mostly performed for choledocholithiasis and, on 1 occasion, for ascending cholangitis in a patient in the standard care arm. None of these participants had elevated bilirubin levels preoperatively, and all participants recovered following their ERCPs. It is theoretically possible that accelerated surgery may lead to missed asymptomatic choledocholithiasis that would have been identified on bilirubin trending, while a patient awaits “delayed” surgery. However, the study is underpowered to draw meaningful conclusions from these outcomes, and the statistical test showed that the results are consistent with chance. Indeed, no participants in the standard care group required preoperative ERCP, and rates of intraoperative cholangiography were similar between the 2 groups (4 participants in the accelerated surgery group v. 3 in the standard care group). Currently, there is controversy regarding selective versus routine use of intraoperative cholangiography to reduce bile duct injuries.⁶ As intraoperative cholangiography can detect asymptomatic bile duct stones, which can present in up to 5% of patients undergoing cholecystectomy, it is possible that an accelerated pathway combined with routine intraoperative cholangiography may be an optimal treatment option.^6,30

Limitations

This pilot trial is unable to inform the clinical question of whether accelerated surgery benefits patients. Although there were no differences seen in the measured clinical outcomes, the study was underpowered to detect differences should they exist. Pursuit of a large trial would inform the effects of accelerated surgery versus standard care. There were also limitations from conducting the trial throughout the COVID-19 pandemic. Patient satisfaction was not collected, and so patient perspectives on the intervention and current standard of care protocol were not captured. Future trials should incorporate patient satisfaction to inform the value of accelerated care from the patient perspective.

Although our feasibility goals were met, the event and recruitment rates in this pilot trial highlight the need for a large sample for the full trial. It should be noted that some feasibility elements may have been affected by the COVID-19 pandemic. For instance, cancellation of elective surgeries allowed for more resources to be allotted to the emergency surgery rooms, leading to faster times to operation for the standard care group than would normally be expected. Furthermore, the limitations on research personnel on hospital premises during the pandemic may have slowed recruitment. Achieving feasibility during the pandemic combined with our group’s success in conducting the multicentre, international HIP ATTACK (Accelerated Surgery Versus Standard Care in Hip Fracture) trials suggests the generalizability of our feasibility results to other tertiary centres across Canada and internationally.²⁴

Our recruitment rate was high, and this likely reflects that most patients want accelerated surgery. Our standard of care median timelines from diagnosis to surgery were around 24 hours. It is possible that sicker patients for whom surgeons planned to wait longer periods to perform surgery as per their usual practice were not included in the study. Despite these limitations, to our knowledge, this is the first study to formally investigate an accelerated pathway for surgical intervention in acute cholecystitis. It was a multicentre study that was successfully conducted across 4 sites with a carefully developed protocol through interdisciplinary collaboration.

Conclusion

In this pilot study, we found that accelerated cholecystectomy was achievable. These results show the feasibility of a large trial comparing accelerated surgery within 6 hours of diagnosis versus standard of care timing for surgery in adult patients with acute cholecystitis.