Differential Management Strategies and Outcomes in Patients over 65 years with Acute Calculous Biliary Disease—Results and Insights from the ESTES Complicated Biliary Calculous Disease Snapshot Audit

Background: Acute complicated calculous biliary disease (ACCBD) may pose challenges in an ageing population. Frailty and comorbidities increase the potential risks of surgery; thus, surgeons may opt to offer operative treatments less often to their older patients. We set out to capture the incidence and treatment algorithms used across Europe to treat older patients presenting with ACCBD. Methods: Analysis of the European Society of Trauma and Emergency Surgery (ESTES) 2018 Acute Complicated Calculous Biliary Disease audit was performed. Patients undergoing emergency hospital admission with ACCBD between 1 October 2018 and 31 October 2018 were included. The primary outcome measure was operative intervention in patients over and under 65 years of age. Mortalities, postoperative morbidity, time to operative intervention, post-acute disposition and length of hospital stay were measured as secondary outcomes. Results: The median age of the 338 patients admitted to the snapshot was 67 years; 185 patients (54.7%) were over 65 years at time of admission. Signicantly fewer patients over 65 underwent denitive surgical treatment, compared with those under 65 (37.8% vs. 64.7%, p <0.001). Surgical complications were seen more frequently in the over 65 cohort. Post-operative mortality was seen in 2.2% of over 65s versus 0.7% under 65(p=0.253). Mean post-operative length of stay was signicantly longer in the elderly cohort. In patients surviving to discharge, post-acute convalescence or rehabilitation was required in 13.3% in the elderly cohort versus 1.9% of those under 65 (p=0.002). Conclusions: Elderly patients commonly present with ACCBD. Increased frailty and incidence of comorbid disease in this population increases the potential surgical risk. In our snapshot, elderly patients represented the majority, but far fewer were offered denitive surgical treatment. Post-operative mortality, morbidity, length of post-operative in-hospital stay and the requirement for post-discharge convalescence were higher in this group.


Background
Over the last 25 years, the number of older people undergoing emergency non-cardiac surgical procedures has increased faster than the rate of population ageing. Despite advances in peri-operative care, and changing patient expectations, age and pre-existing comorbidities remain the main predictors of adverse postoperative outcomes in the older surgical population [1][2][3][4][5][6][7][8]. In particular, gallbladder surgery has been highlighted as accruing excess morbidity and mortality in the elderly patient [9]. The role of frailty as an independent risk factor for adverse postoperative outcomes is also now emerging [10][11][12][13]. An ageadjusted Charlson co-morbidity index [14][15][16] has been recently validated, while limitations in the discriminating power of the prognostic p-POSSUM score have been recognised in the older patient [17].
Acknowledging that acute complicated calculous biliary disease is a common set of clinical problems which presents frequently to general surgeons, the Cohort Studies Group of the European Society for Trauma and Emergency Surgery set out to capture real-world data on the epidemiology and contemporary management of these patients [18,19]. While traditional medical school teaching identi es the 6Fs (fair, fat, fertile, female, forty and family history) as predictors of the population most likely to present with symptomatic gallstone disease [20], it was notable that the cohort presenting to European emergency departments were older, with a median age of 67 years.
We aimed to assess patterns of surgical practice regarding these older patients as well as collating data on how outcomes differ in this cohort compared with younger patients.

Protocol
This prospective, observational, multi-centre audit was conducted in line with a pre-speci ed protocol which was registered with ClinicalTrials.gov (Trial # NCT03610308).

Centre eligibility
Any unit undertaking adult acute care surgery was eligible to register to enter patients into the study. No minimum case volume, or centre-speci c limitations were applied. The study protocol was disseminated to registered members of the European Society of Trauma and Emergency Surgery (ESTES), and through national surgical societies. Data were recorded contemporaneously and stored on a secure, user-encrypted online platform (REDCap ® ) without patient-identi able information. Centres were asked to validate that all eligible patients during the study period had been entered, and to attain > 95% completeness of data eld entry prior to nal submission. Quality assurance mentorship was provided by at least one consultant/attending-level surgeon at every participating site.

Outcome measure
Outcomes were compared between patients aged over and under 65 years. The primary outcome measure was index admission surgical de nitive treatment (cholecystectomy). The secondary outcome measures were length of stay, the postoperative major complication rate de ned as Clavien-Dindo classi cation grade 3 to 5 (reoperation, reintervention, unplanned admission to intensive care unit, organ support requirement or death), the postoperative length of stay (in whole days), with day of surgery as day zero, and the postoperative mortality rate, de ned as death within 30 days of surgery.

Statistical analysis
The descriptive and inferential statistical analyses were performed using Stata 15.1 (StataCorp LLC, College Station, TX, USA) and the jamovi project (www.jamovi.com, 2019) utilizing the R language for statistical computing. Effect estimates are presented as odds ratios (OR) with 95% con dence intervals and two-tailed P-values. An alpha signi cance level of 0.05 was used through-out. Measures of central tendency were presented as mean (± standard deviation ; median, interquartile range).

Ethical considerations
All 25 participating centres (see Supplemental Table of Collaborators) provided local institutional review board approval or equivalent as a requirement of registration. No patient consent was sought since the current study was purely observational and did not change the medical course of any patient. All data were irrevocably de-identi ed at source when uploaded to the secure study database.

Participating Centres
Following an open call for participation by ESTES in May 2018, 38 centres expressed interest in participating. Of those, 25 centres completed the local ethics approval process and proceeded to enrol patients to the study. These centres came from 9 countries (Austria, Italy, Ireland, Romania, Spain, Sweden, Portugal, United Kingdom, and United States of America).

Diagnosis
Acute calculous cholecystitis was present in 45.9% patients, acute biliary pancreatitis in 20.7%, choledocholithiasis in 31.9% of whom 43.5% had cholangitis. Five patients (1.5%) were admitted for treatment of Mirizzi syndrome or bilioenteric stula. Acute biliary pancreatitis was also graded using the AAST Emergency Surgery grading system. Of total 70 patients with diagnosis of pancreatitis, the majority had interstitial pancreatitis (95.7%), and 3 (4.3%) suffered from necrotising pancreatitis.

Operative Management
Of the 338 patients enrolled in the study, 50% underwent surgical intervention, while 50% had not received operative treatment by the end of the 60-day follow-up period. One hundred and fty-two patients (89.9%) underwent surgical intervention during the index admission, while a further seventeen (10.1%) were operated upon after discharge from index admission but prior to the closure of the study database (with a mean interval to cholecystectomy from index admission being 56±25 days (range 13-97).

Interventional Radiologic Management
Interventional radiologic management of the gallbladder or common bile duct was undertaken in 7.7% (n=26) of patients -11 patients under the age of 65 years and 15 patients over 65 (p=0.830). Cholecystostomy was performed in 23 (88.5%) of these cases, percutaneous radiologic drainage of a collection or abscess was performed in one (3.8%) patient and percutaneous transhepatic cholangiography was performed in two (7.7%). No complication was recorded for patients undergoing interventional radiologic procedures. Mean (±sd; median,IQR) time from admission to endoscopy did not differ between patients over the age of 65 years (4.11±12.3;2,0.25-7 days) compared with patients under 65 (3.65±4.33;2,0-6 days), p=0.738, (Figure 3).

Morbidity and Mortality
Five deaths were recorded (1.4%) in the total cohort-one (1.4%) patient in those with suffering gallstone pancreatitis, two (4.2%) in patients with cholangitis and two (1.2%) patients with acute cholecystitis, both of which had an AAST Grade IV cholecystitis. Only one (0.58%) post-operative mortality was recorded, following cholecystectomy for AAST Grade IV cholecystitis. Four deaths occurred in patients over 65 (2.2%), compared with one (0.7%) under 65 years (p=0.253). Of the 333 patients surviving to discharge, signi cantly more patients over 65 years had ongoing morbidity requiring post-acute convalescence or rehabilitation (13.3%), compared with (1.9%) under the age of 65 (p=0.002).
Post-operative complications were seen more commonly in patients over 65 compared with younger patients (18.5% vs 9%, p=0.102); although it did not achieve statistical signi cance due to a low incidence, bile duct injury and haemorrhage requiring return to the OR were more common in the elderly patients (Table 3). 1. Nineteen patients (5.6%) were admitted to ICU for organ failure during their hospital stay -ten (6.5%) patients under 65 and nine (4.8%) over 65. Thirteen of the 19 patients admitted to ICU (68.4%) required inotropic support, nine (47.4%) required ventilatory support and one (5.3%) required haemodialysis; of these, three (15.8%) had multi-organ failure requiring two or more supports. There was no statistically-signi cant difference between younger and older cohorts in terms of organsupport requirements.

Discussion
There has been a disproportionate increase in the number of elderly people within the population over the last 50 years, with the global population aged 60 years or older projected to treble to nearly 2 billion people within the rst half of this century [21]. In Europe alone, almost 30% of the population is predicted to be aged 65 or over by 2050 [21]. Geriatric patients frequently undergo emergency general surgery and accrue a greater risk of postoperative complications and fatal outcomes than the general population [6,9,11]. It is thus highly relevant to develop the most appropriate care measures and to guide patient-centered decision-making around emergent care [22]. ACCBD is a relatively-frequent diagnosis in patients over 65 years, and while some consensus guidance exists, age is not considered to be a contraindication to operative management [2].
This snapshot audit, a collaborative non-randomized observation study of 338 consecutive patients presenting to 25 hospitals across 9 countries over the period of one month, provides unique granular 'realworld' data on the differing treatment strategies offered to elderly patients, and the disparity in outcomes between these patients and those under 65 years of age.
Snapshot audit, a form of prospective, observational, non-randomised multi-centre cohort study, is a novel methodology for prospective collaborative cohort studies that has allowed detailed, de ned datasets to be accrued in line with a priori analyses stated in pre-publication, open access protocols led with clinical trial repositories 2-4 . This methodology, which is superior in some respects to large retrospective registries, has been recently embraced by surgeons as a pragmatic alternative to randomized controlled trial.
The older patients presented with the burden of cardiovascular, endocrine and renal co-morbidity far in excess of that seen in younger patients, as evidenced by a signi cantly higher CCI [14][15][16]. While a direct correlation has yet to be studied between aaCCI and morbidity and mortality following emergency cholecystectomy, strong evidence exists supporting aaCCI as a robust predictor of poor outcomes following elective gynecologic, oncologic gastrointestinal and emergency orthopedic surgery. Indeed, the observed case fatality rate in this study was 2.2% in patients over 65 years while a post-operative complication occurred in 18%.
Notably, recovery following acute illness and particularly surgical intervention may be prolonged in the elderly population, as a consequence of a loss of strength, mobility, and functional capacity [23][24][25][26]. Frailty may manifest phenotypically as decline in lean body mass, strength, endurance, balance, walking performance and low activity; patients who have three or more of the ve features of slowness, weakness, exhaustion, weight loss and low physical activity are deemed frail, while those who have none of the features are non-frail. Patients who display one or two of the ve features are "pre-frail". The Canadian Study of Health and Aging (CSHA) Frailty Index[25] is based on comprehensive geriatric assessment, calculated by counting the number of de cits present in an individual, divided by the total number of de cits measured. The de cits encompass co-morbidities, physical and cognitive impairments, psychosocial risk factors and common geriatric syndromes. While our snapshot audit was not set up to speci cally capture metrics of frailty, post-operative length of in-patient hospital stay was found to be signi cantly longer in our patients over 65, with ongoing morbidity was reported in 13.5% of these patients and 13% (versus 2% in patients under 65) required discharge from the hospital to a rehabilitation facility before returning home.

Conclusion
Although this study is limited by its intention and design as a descriptive study, granular 'real world' data illustrate the challenges faced by surgeons treating elderly patients. Given the increase in morbidity, mortality, length of post-operative hospital stay and the need for rehabilitation, routine use of prognostic tools (such as p-POSSUM or aaCCI in the case of morbidity and mortality) and frailty indices in mitigating risk, informing consent and in anticipating the requirement for enhanced supports in this patient cohort.  Table of Collaborators) provided local institutional review board approval or equivalent as a requirement of registration. No patient consent was sought since the current study was purely observational and did not change the medical course of any patient. All data were irrevocably de-identi ed at source when uploaded to the secure study database.

Consent for publication
All authors consent to publication. This manuscript is not currently under review elsewhere.

Availability of data and material
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
Prof Shahin Mohseni is a member of the editorial board (Associate Editor) of BMC Surgery

Funding
No funding Authors' contributions GAB, AEG, YC and SM conceived the study, analysed the data and wrote the manuscript. All study collaborators sought local ethics approval, provided the anonymous patient-level data and per protocol are listed as PubMed-indexed authors.