coMpliAnce With evideNce-based cliniCal Guidelines in the managemenT of Acute biliaRy pancreAtitis

Background

Acute pancreatitis (AP) is an inflammatory disease of the pancreas, most commonly caused by
gallstones, or excessive use of alcohol. It represents a management challenge and a
significant healthcare burden. The incidence of AP ranges globally from 5 to 30 cases per
100.000 inhabitants/year, and there is evidence that the incidence has been rising in recent
years. The overall case-fatality rate for AP is roughly 5%, and it is expectedly higher for
more severe stages of the disease. In most cases (80%), the outcome of AP is rapidly
favorable. However, acute necrotizing pancreatitis (ANP) may develop in up to 20% of cases,
and is associated with significant rates of early organ failure (38%), needing some type of
surgical/endoscopic intervention (38%) and death (15%).

In the United States, AP is a leading cause of inpatient care among gastrointestinal
conditions: more than 270.000 patients are hospitalized for AP annually, at an aggregate cost
of over 2.5 billion dollars per year. In Europe, the UK incidence of AP is estimated as 15-42
cases per 100.000/year and is rising by 2.7% each year.

Several scientific societies published their clinical practice guidelines making
recommendations on the management of AP. The main topics of these guidelines are the
diagnosis, antibiotic treatment, management in the intensive care unit, surgical and
operative management, and open abdomen management.

Audits about biliary AP have been performed in Italy, Germany, France, and England, with
quite disappointing results. Indeed, in these audits, the treatment of biliary AP differed
substantially from the recommendations. For example, less than 15% of the responders stated
that they strictly followed all recommendations included in the guidelines in Germany and
25.8% of patients did not receive definitive treatment for biliary AP within 1 year in the
UK.

A recent study from Singapore aiming to review the clinical management of patients with AP in
an HPB referral center in the light of assessing the compliance to the 2013 International
Association of Pancreatology (IAP)/American Pancreatic Association (APA) and the 2015
Japanese guidelines found that only 50% of patients received Ringer lactate for initial fluid
resuscitation, 38.7% received antibiotics as prophylaxis, 21.4% of patients with severe AP
had early enteral nutrition, and only 21.4% patients with biliary AP had index admission
cholecystectomy despite the recommendations. In another recent study by a Canadian group,
only 25% of patients with gallstones AP underwent a cholecystectomy on the same admission.
Furthermore, only one-quarter of patients in whom an index admission cholecystectomy was not
possible underwent ERCP with sphincterotomy, and only one-third of patients with gallstones
AP and an imaging-confirmed obstructed common bile duct had an ERCP and sphincterotomy. Slow
implementation of the recommendation on early cholecystectomy has been reported also in a
Danish survey seeking compliance with the recommendations of the national reference program
for the treatment of patients with gallstone disease, and a similar lack of compliance with
guidelines was found in Italy, mainly regarding indications for endoscopic and surgical
management.

Conversely, a recent study from Sweden has shown that by improved compliance to current AP
guidelines, recurrence rate and associated costs can be reduced. The authors found that 80%
of patients with biliary AP underwent definitive treatment during their first attack (68%
cholecystectomy, 17% ERCP and sphincterotomy, 15% both interventions).

Moreover, significant overall differences between the practice of HPB specialists and
non-specialists in gallstone AP have been reported, especially regarding severity assessment,
indication and timing of requesting CT scan, nutritional support, and in common bile duct
assessment prior to cholecystectomy.

These findings support the view that publication alone of nationally or internationally
developed and approved guidelines is insufficient to modify the practice of non-specialists
and raises the question of how best to spread guideline recommendations. Previous reports,
including the one from France in 2012 have shown that major changes in biliary AP patients
management were noticed since the publication of the French guidelines. In particular, after
the publication of the mentioned guidelines, lipase levels were measured for establishing AP
diagnosis by 99% (vs. 83% pre-guidelines) and a CT scan was performed at 48h by 69% (vs. 29%
pre-guidelines) to evaluate AP severity. Antibiotic prophylaxis and enteral nutrition were
proposed by 20% (vs. 57% pre-guidelines) and 58% (vs. 25% pre-guidelines) for necrotizing AP.

Management of pancreatic necrosis Infection of pancreatic necrosis is the predominant driver
of sustained morbidity and late mortality in patients with severe AP. The subset of patients
with ANP may face a complex and prolonged clinical course, with an associated mortality of up
to 30% if an infection develops in the necrotic collection. Optimal management of patients
with pancreatic necrosis requires a multidisciplinary approach, and specific guidelines for
this specific subgroup of patients have been recently released. Although antibiotic
prophylaxis may prevent or reduce colonization of necrosis, the results of RCTs evaluating
this approach and meta-analyses do not support prophylaxis. Consequently, internationally
applicable recommendations are that intravenous antibiotic prophylaxis is not recommended for
the prevention of infectious complications in AP. However, several global overviews assessing
reports from across the world of the use of antibiotics in prophylaxis in AP have shown a
spread diffusion of such behavior.

COVID-19 and management of AP In 2020, the spread of the virus Covid-19 has represented a
pandemic that also had a profound impact on the surgical community. The constant increase in
the number of patients requiring treatment has represented a huge challenge for the
healthcare systems of many involved countries and could be their breaking point. In an
emergency situation, resources must be concentrated and used rationally, both to handle the
pandemic and to continue handling the pre-existing diseases. In this context, the majority of
surgical departments were forced to re-schedule their activity giving priority to
urgent/emergent surgical cases and to non-deferrable oncological cases. There are many ways
through which the outbreak of the Covid-19 pandemic could have influenced daily clinical
practice for patients with biliary AP also leading to a failure to adhere to the
recommendations coming from the guidelines, especially those regarding the early and
definitive treatment with cholecystectomy or ERCP and sphincterotomy. First of all, the
recommendation to postpone all non-urgent endoscopic procedures during the peak of the
pandemic. Second, the recommendation to conservatively treat inflammatory conditions such as
acute cholecystitis and acute appendicitis wherever possible.

The rationale for the study Despite existing evidence-based practice guidelines for the
management of biliary AP, in Europe clinical compliance with recommendations is poor. Studies
in this field have identified major discrepancies between evidence-based recommendations and
daily clinical practice.

It is believed by many that clinical guidelines would help to decrease inappropriate
variation in practice, that they provide a rational basis for referral, and that they would
help to reduce uncertainty in the management of some conditions. Clinical guidelines also
provide a basis for continuing medical education and can improve control of healthcare costs.
However, the value of national and/or international guidelines is very much dependent on a
strategy for their implementation.

Although different guidelines for the management of biliary AP have been published, they have
not been properly investigated and compliance has generally been unsatisfactory. Deficiencies
and lack of standardization of the management of AP worldwide have been reported.

The most commonly reported gaps between clinical practice and guidelines on AP include the
indications for CT scan, need and timing of artificial nutritional support, indications for
antibiotics, and surgical/endoscopic management of biliary AP.

The MANCTRA-1 can identify a number of areas for quality improvement that will require new
implementation strategies.

Aim of the study Since the clinical compliance with recommendations about AP is poor and the
impact of implementing guideline recommendations in biliary AP has not been well studied on a
global basis, the MANCTRA-1 study has been launched with the aim to demonstrate areas where
there is currently a sub-optimal implementation of contemporary guidelines on biliary AP. The
main areas of sub-optimal care due to the lack of compliance with current guidelines will be
investigated to provide the basis for introducing a number of bundles in the management of AP
patients to be implemented during the next years. Moreover, during the Covid-19 pandemic, the
tendency to disregard the guidelines recommendations may have been more marked than usual.
The study will try to find out if AP patients' care during the Covid-19 pandemic resulted in
a higher rate of adverse outcomes compared to non-pandemic times due to the lack of
compliance with the guidelines.

Primary objective To evaluate which items of the current AP guidelines, if disregarded,
correlate with negative clinical outcomes according to the different clinical presentations
of the disease

Secondary objectives To assess the compliance of surgeons worldwide to the most up-to-date
international guidelines on biliary AP.

To evaluate the medical and surgical practice in the management of biliary AP during the
non-pandemic (2019) and pandemic Covid-19 periods (2020).

To investigate outcomes of patients with biliary AP treatment during the two study periods.

Study design The MANCTRA-1 study (coMpliAnce with evideNce-based cliniCal guidelines in the
managemenT of acute biliaRy pancreAtitis) is an international multicenter, retrospective
cohort study to assess the outcomes of patients admitted to hospital with a diagnosis of
biliary AP and the compliance of surgeons worldwide to the most up-to-date international
guidelines on biliary AP. The study compares data collected in 2019 (pre-pandemic period)
with those of 2020 (Covid-19 pandemic period).

Study population All consecutive adult patients admitted to the participating surgical
departments with a clinical and radiological diagnosis of biliary AP (with and without
concomitant cholecystitis) between 01/01/2019 and 31/12/2020. Patient data will be
retrospectively analyzed and demographic characteristics, comorbidity status, clinical and
radiological findings, treatment strategies, 30-day morbidity, and mortality will be
evaluated.

Study periods The pre-pandemic period runs from 01/01/2019 to 31/12/2019. The Covid-19
pandemic period runs from 01/01/2020 to 31/12/2020. Data will be entered in the database from
01/03/2021 to 31/08/2021.

Data collection All epidemiological, clinical, and surgical data will be collected on a CFR
that will be completed by accessing a protected data system. The link for accessing the
completion of the CFR will be sent via email to only one contact person (Local Lead) of each
participating center.

Sample size Studies on biliary AP found a mortality rate of approximately 10%. Patients with
biliary AP tend to have higher mortality than patients with alcoholic pancreatitis. However,
this rate has been falling over the last 2 decades as improvements in supportive care have
been initiated. In patients with severe disease (organ failure), who account for about 20% of
presentations, mortality is approximately 30%. This rate has not decreased in the past 10
years.

We estimate that a minimum of 200 patients per group (2019 vs. 2020) would yield a power of
0.80 (1-ß) to establish whether changes in clinical care for patients with biliary AP during
the Covid-19 pandemic has impacted on overall mortality using a one-sided significance ɑ
level of 0.05 (5%) with power sample size calculator (sealedenvelope.com).

Statistical analysis The dichotomous variables will be expressed as numbers and percentages,
while continuous variables will be expressed as mean and SD, or median and IQR (minimum and
maximum values). Student's t-test or ANOVA will be used for comparisons of continuous
variables between groups. Chi-squared test or Fisher's exact test, as appropriate, will be
used for the analysis of categorical data. Multi logistics regression models will be used to
investigate clinical, laboratory, and radiologic variables predictive of morbidity and
mortality. A value of P < 0.05 will be considered statistically significant.

Ethical aspects This is an international observational study, it will not attempt to change
or modify the clinical practice of the participating physicians. The study will meet and
conform to the standards outlined in the Declaration of Helsinki and Good Epidemiological
Practices. Every clinical center attending the study is responsible for Ethics Committee
approval depending on the local policy for observational and non-interventional studies. All
surgeons involved in the patients' recruitment will be included in the research authorship.

Publication policy The Local Lead and two Collaborators from each center will be listed as
Co-authors in the final publications. Data will be published as a pool from all participating
surgical units. Data that emerged from the MANCTRA-1 study will be published irrespective of
findings. Results will be published on ClinicalTrials.Gov and each manuscript that is
generated based on the registry will be disseminated to all participating centers before
final publication.

Safety issues None.

Data collection In each center, the coordinator will collect and compile data in an online
case report system. Data will be recorded contemporaneously on a dedicated, secure server
that allows collaborators to enter and store data in a secure system. No patient identifiable
data (name, date of birth, address, telephone number, etc.) will be recorded.

Informed consent Due to its retrospective design, this observational study will not attempt
to change or modify the laboratory or clinical practices of the participating physicians.
Consequently, informed consent will not be required.

Data management Every local investigator is responsible for entering data on an online case
report form for every patient included in the study.

Funding This research has not received any specific grant from funding agencies in the
public, commercial, or not-for-profit sectors.

Financial and Insurance Not applicable.