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OREGON HEALTH AND SCIENCE UNIVERSITY Office of Clinical Integration and Evidence‐Based Practice Acute Pancreatitis Evidence Summary

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Date started: April 2018 Date completed: March 2019 Content Expert Team Members: Angela Alday, MD, Hospital Medicine, Tuality Erin Boyd, MD, Hospitalist, Adventist Christian Crannell, MD, Surgery, OHSU Honora Englander, MD, Hospital Medicine, OHSU Susan Ferguson, RN, Trauma and Surgical ICU, OHSU Jessica Gregg, MD, PhD, General Internal Medicine and Geriatrics, OHSU Shalini Gupta, MD, MPH, Hospital Medicine, OHSU James Heilman, MD, Emergency Medicine, OHSU Timothy Hill, MD, Hospitalist, Adventist Jared Huber, MD, Internal Medicine, OHSU James Lewis, PharmD, Pharmacy Daniel Lincoln, MD, Critical Care, Tuality Robert Martindale, MD, PhD, Gastrointestinal and General Surgery, OHSU Matthias Merkel, MD, PhD, Anesthesiology and Perioperative Medicine, OHSU Patrick O’Leary, MD, General Surgery, Tuality Jen Packer, MSN, RN, CENP, CEN, Tuality Jenna Petersen, MD, Internal Medicine, OHSU Scott Sallay, MD, Hospital Medicine, OHSU

Jackie Sharpe, Pharm D, Pharmacy, OHSU Kaveh Sharzehi, MD, MS, Gastroenterology and Hepatology, OHSU Brett Sheppard, MD, Gastrointestinal and General Surgery, OHSU Payer Representatives: Joe Badolato, MD, Regence Jim Rickards, MD, Moda Amit Shah, MD, Care Oregon

Office of Clinical Integration and Evidence‐Based Practice Team: Marcy Hager, MA, EBP Program Manager Andrew Hamilton, MS/MLS, Liaison Librarian Stephanie Halvorson, MD, Clinical Integration Medical Director/Hospital Medicine Marian McDonagh, PharmD, Associate Director of the

Evidence‐based Practice Center (EPC)

Objective: To critically review the evidence on acute pancreatitis treatment

Inclusion Criteria: ‐Adult patients with acute pancreatitis including, both early phase (within 1 week) and late phase (>1 week).

Exclusion Criteria: ‐Adult patients with chronic pancreatitis and recurrent acute pancreatitis

Definitions: Acute Pancreatitis (AP): A sudden onset and short duration of symptoms. Based on the fulfillment of ‘2 out of 3’ of the following criteria: clinical (upper abdominal pain), laboratory (serum amylase or lipase 3x upper limit of normal) and/or imaging (CT, MRI, ultrasonography) criteria.

Early Phase AP: (within 1 week) Characterized by the systemic inflammatory response syndrome (SIRS) and / or organ failure; Late Phase AP: (>1 week) Characterized by local complications. Mild AP: Lacks both organ failure and local or systemic

complications

Moderately Severe AP: Transient organ failure (organ

failure of <2 days), local complications, and/or

exacerbation of coexistent disease

Severe AP: Presence of persistent organ failure (organ

failure that persists for >/2 days)

Chronic Pancreatitis: Loss of pancreatic function that

develops gradually and worsens over time, resulting in

permanent organ damage.

Local complications: Objective criteria based primarily

on contrast‐enhanced computed tomography; classified

as acute peripancreatic fluid collections, pseudocyst,

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acute (pancreatic/peripancreatic) necrotic collection,

and walled‐off necrosis.

Target Guideline Users: All clinicians caring for patients presenting with acute pancreatitis within the OHSU Health System.


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Quality Measures: Outcome

Length of stay Readmissions Transfers between partner sites

Process

# and timing of imaging

Referrals to Impact % of patients receiving fluid therapy Type and time of antibitiocs prescribed Type of nutrional support # of cholecystectomy

Review Preparation: 1. What is the diagnostic criteria for acute pancreatitis? (Search Strategy: Guidelines) 2. What approach (contrast‐enhanced computed tomography [CECT], magnetic resonance imaging [MRI],

ultrasound) for diagnosing acute pancreatitis is most accurate (sensitivity and specificity)? (Search Strategy: January 2013 – present [since ACG Guideline])

3. What assessment tool (Sequential Organ Failure Assessment [SOFA], Apache, Ranson) is the most accurate in predicting pancreatitis severity? (Search Strategy: last 10 years)

For the following questions clinical outcomes refers to (either some or all of the following): mortality, morbidity, infected pancreatic necrosis, multiple organ failure, single organ failure, hospital length of stay.

4. What is the optimal type (colloid vs. crystalloid) and quantity (per time‐period vs goal‐directed therapy) of intravenous hydration in the initial management (between 48 – 72 hours) of patients with acute pancreatitis, including special populations (patients with congestive heart failure, renal failure, or advanced age)? (Search Strategy: March 2017 – present [since AGA Guideline])

5. When should prophylactic antibiotics be indicated in treatment for acute pancreatitis? If antibiotics are indicated, which antibiotics are associated with the best clinical outcomes (mortality, morbidity, infected pancreatic necrosis, multiple organ failure, single organ failure, hospital length of stay)? (Search Strategy: March 2017 – present [since AGA Guideline])

6. For patients already on antibiotics for treatment of acute pancreatitis, what is the appropriate course of treatment (continuing or tapering)? (Search Strategy: March 2017 – present [since AGA Guideline])

7. Which patients with acute pancreatitis benefit from endoscopic retrograde cholangiopancreatography (ERCP)? (Search Strategy: March 2017 – present [since AGA Guideline])

8. What is the optimal timing, type, and route of nutrition treatment for patients with acute pancreatitis? (Search Strategy: March 2017 – present [since AGA Guideline])

9. Which patients with mild acute biliary pancreatitis benefit from same‐admission vs delayed cholecystectomy? (Search Strategy: March 2017 – present [since AGA Guideline])

10. What is the optimal method and timing of alcohol cessation counseling in patients with acute alcohol‐induced pancreatitis? (Search Strategy: March 2017 – present [since AGA Guideline])

11. Which patients with acute and late‐phase pancreatitis benefit from cross‐sectional (repeat) imaging? What is the optimal method/timing of imaging? (Search Strategy: last 10 years)

12. In patients with complications of late‐phase acute pancreatitis (pancreatic pseudocyst or walled‐off pancreatic necrosis), what is the optimal timing and method of drainage? (Search Strategy: last 10 years)

13. In patients with acute pancreatitis, what pain management strategy is associated with the best clinical outcomes (mortality, morbidity, infected pancreatic necrosis, multiple organ failure, single organ failure, hospital length of stay)? (Search Strategy: last 15 years)

14. What is the criteria to determine appropriate transfers between OHSU, Tuality and Adventist?


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Acute Pancreatitis

Existing External Guidelines/Pathways/Order Sets Existing External Guidelines

External Guideline Organization and Author Last Update

American Gastroenterological Association Institute Guideline on Initial Management of Acute Pancreatitis

American Gastroenterological Association (AGA) 2018

Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N)

Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N)

2016

The role of endoscopy in the diagnosis and treatment of inflammatory pancreatic fluid collections

American Society for Gastrointestinal Endoscopy (ASGE) 2016

Japanese guidelines for the management of acute pancreatitis: Japanese Guidelines 2015

Japanese Society of Hepato‐Biliary‐Pancreatic Surgery 2015

The role of ERCP in benign diseases of the biliary tract American Society for Gastrointestinal Endoscopy (ASGE) 2015

Prophylaxis of post‐ERCP pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) Guideline – Updated June 2014

European Society of Gastrointestinal Endoscopy (ESGE) 2014

IAP/APA evidence‐based guidelines for the management of acute pancreatitis

International Association of Pancreatology (IAP) and the American Pancreatic Association (APA)

2013

American College of Radiology ‐ Clinical Conditions: Acute Pancreatitis American College of Radiology (ACR) 2013

American College of Gastroenterology Guideline: Management of Acute Pancreatitis

American College of Gastroenterology 2013

The Revised Atlanta Classification of Acute Pancreatitis: Its Importance for the Radiologist and Its Effect on Treatment

Atlanta Classification 2012

The ten published clinical guidelines were evaluated for this review using the University of Pennsylvania’s Center for Evidence‐Based Practice Trustworthy Guideline rating scale.

The scale is based on the Institute of Medicine’s “Standards for Developing Trustworthy Clinical Practice Guidelines” (IOM), as well as a review of the AGREE Enterprise and Guidelines

International Network domains.

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See appendix B for full description of the Trustworthy Guideline grading system.

Guideline Issuer and

Date AGA 2018

SCCM and A.S.P.E.N.

2016 ASGE 2016 JSHS ASGE

2015 ESGE 2014

IAP/APA 2013

ACR 2013

ACG 2013

Atlanta 2012

1. Transparency

A A C A C B A C B B

2. Conflict of interest

A A C B C B A NR C B

3. Development group

B B NR B NR B A NR C NR

4. Systematic Review

A A B B B A A B B B

5. Supporting evidence

A A A A A A A A A B

6. Recommendations

A A B A B B A B B C

7. External Review

B A NR A NR NR B NR NR NR

8. Currency and updates

B B B B B B B B B B

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Guideline Evidence Evaluation Systems

AGA 2018

SCCM and A.S.P.E.N. 2016

ASGE 2016

JSHS 2015

ASGE 2015

Evidence Evaluation The AGA process for developing clinical practice guidelines incorporates Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology and best practices as outlined by the Institute of Medicine. GRADE methodology was utilized to prepare the background information for the guideline and the technical review that accompanies it.

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Guideline Evidence Evaluation Systems

ESGE 2014

IAP/APA 2013

ACR 2013

ACG 2013

Atlanta 2012

Evidence Evaluation Categories of evidence

The strength of the evidence used in this guideline was that recommended by the Scottish Intercollegiate Guidelines Network [1]. The ratings of levels of evidence are summarized below:

1++ High quality meta‐analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias

1+ Well‐conducted meta‐analyses, systematic reviews of RCTs, or RCTs with a low risk of bias

1– Meta‐analyses, systematic reviews, or RCTs with a high risk of bias

2++ High quality systematic reviews of case–control or cohort studies; high quality case–control or cohort studies with a very low risk of confounding, bias, or chance, and a high probability that the relationship is causal

2+ Well‐conducted case–control or cohort studies with a low risk of confounding, bias, or chance, and a

a. Recommendation: the GRADE strength of recommendation (1 ¼ strong, 2 ¼ weak) and quality of evidence (A ¼ high, B ¼ moderate, C ¼ low) are provided along with the strength of agreement during plenary voting (strong/weak) (see Appendix). In the absence of studies specifically addressing the question, this had to be stated and the recommendation was then based on related studies or expert opinion.

b. Remarks: these remarks could discuss any relevant aspect regarding the recommendation, such as important exceptions/ contra‐indications, availability, lack of evidence, risks, and costs.

c. A summary table of relevant studies was produced, including columns on outcome assessed (e.g. mortality, infected necrosis), the total number of patients, the number of included studies per outcome, design of the study (e.g. retrospective cohort, prospective cohort, RCT), and critical appraisal of methodology according to the GRADE

International Working Group builds consensus on modifying Atlanta classification terminology and provide simple functional clinical and morphologic classifications

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moderate probability that the relationship is causal

2– Case–control or cohort studies with a high risk of confounding, bias, or chance and a significant risk that the relationship is not causal

3 Non‐analytic studies, e. g. case reports, case series

4 Expert opinion.

Grading of recommendations

Recommendations were based on the level of evidence presented in support and were graded accordingly [1]. This grading is summarized below:

A At least one meta‐analysis, systematic review, or RCT rated as 1++ and directly applicable to the target population; or a systematic review of RCTs; or a body of evidence consisting principally of studies rated as 1+ directly applicable to the target population and demonstrating overall consistency of results

B A body of evidence including studies rated as 2++ directly applicable to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 1++ or 1+

C A body of evidence including studies rated as 2+ directly

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applicable to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 2++

D Evidence level 3 or 4; or extrapolated evidence from studies rated as 2+.

For interventions analyzed in a single study, no recommendation was made.

Review of Relevant Evidence: Search Strategies and Databases Reviewed

Search Strategies Document Strategies Used

Search Terms/Strategies Used:

Database Searched

Years Searched ‐ All Questions

Language English

Age of Subjects

Evidence Found with Searches

Check type of evidence found Summary of Evidence – All Questions Number of articles obtained

Systematic reviews/Meta‐analysis

Randomized controlled trials

Non‐randomized studies

Government/State agency regulations

Professional organization guidelines/white papers, etc.

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Evaluating the Quality of the Evidence The GRADE criteria were used to evaluate the quality of evidence presented in research articles reviewed during the development of this guideline. The table below defines how the quality of the evidence is rated and how a strong versus weak recommendation is established. For more detailed information, see Appendix A.

Question #1. What is the diagnostic criteria for acute pancreatitis?

Guideline Recommendations:

The American Gastroenterological Association (AGA) 2018 guideline follows the Atlanta Classification and includes the following criteria:

The diagnosis of AP requires at least 2 of the following features: characteristic abdominal pain; biochemical evidence of pancreatitis (ie, amylase or lipase elevated >3 times the

upper limit of normal); and/or radiographic evidence of pancreatitis on cross‐sectional imaging. Presentations of AP occur along a clinical spectrum, and can be categorized as mild,

moderately severe, or severe, based on the recent revised Atlanta classification. Most cases of AP (around 80%) are mild, with only interstitial changes of the pancreas without local

or systemic complications. Moderately severe pancreatitis is characterized by transient local or systemic complications or transient organ failure (<48 hours), and severe AP is

associated with persistent organ failure. Necrotizing pancreatitis is characterized by the presence of pancreatic and/or peripancreatic necrosis, and is typically seen in patients with

moderately severe or severe AP. Severity of disease factors into several of the recommendations in this guideline. There are 2 overlapping phases of AP, early and late. The early

phase of AP takes place in the first 2 weeks after disease onset, and the late phase can last weeks to months thereafter. The guideline focuses on the initial management of AP

within the first 48 – 72 hours of admission.

The 2015 Japanese guidelines for the management of acute pancreatitis recommended the following for Diagnosis:

Diagnosis

The measurement of serum lipase is recommended for the diagnosis of acute pancreatitis. However, when the measurement of lipase is difficult, serum amylase (pancreatic

amylase) should be measured. (1B)

Recommendation

STRONG Desirable effects clearly outweigh undesirable effects or vice versa

CONDITIONAL Desirable effects closely balanced with undesirable effects

Quality Type of Evidence

High Further research is very unlikely to change our confidence in the estimate of effect.

Moderate Further research is likely to have an important impact on our confidence in the estimate of effect and may

change the estimate.

Low Further research is very likely to have an important impact on our confidence in the estimate of effect and is

likely to change the estimate.

Very Low Any estimate of effect is very uncertain.

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Urinary trypsinogen‐2 dipstick may be useful for minimally invasive method and rapid diagnosis of acute pancreatitis. However, this is not commercially available in Japan and

therefore it cannot be recommended at this time. (ungraded B)

The 2013 International Association of Pancreatology (IAP) and the American Pancreatic Association (APA) recommends:

Diagnosis of acute pancreatitis and etiology 1. The definition of acute pancreatitis is based on the fulfillment of ‘2 out of 3’ of the following: clinical (upper abdominal pain), laboratory (serum amylase or lipase >3x upper

limit of normal) and/or imaging (CT, MRI, ultrasonography) criteria. (GRADE 1B, strong agreement) 2. On admission, the etiology of acute pancreatitis should be determined using detailed personal (i.e. previous acute pancreatitis, known gallstone disease, alcohol intake,

medication and drug intake, known hyperlipidemia, trauma, recent invasive procedures such as ERCP) and family history of pancreatic disease, physical examination,

laboratory serum tests (i.e. liver enzymes, calcium, triglycerides), and imaging (i.e. right upper quadrant ultrasonography). (GRADE 1B, strong agreement)

3. In patients considered to have idiopathic acute pancreatitis, after negative routine work‐up for biliary etiology, endoscopic ultrasonography (EUS) is recommended as the first

step to assess for occult microlithiasis, neoplasms and chronic pancreatitis. If EUS is negative, (secretin‐stimulated) MRCP is advised as a second step to identify rare

morphologic abnormalities. CT of the abdomen should be performed. If etiology remains unidentified, especially after a second attack of idiopathic pancreatitis, genetic

counseling (not necessarily genetic testing) should be considered. (GRADE 2C, weak agreement)

The 2013 American College of Gastroenterology recommended the following for diagnosis and etiology:

Diagnosis:

The diagnosis of AP is most often established by the presence of 2 of the 3 following criteria: (i) abdominal pain consistent with the disease, (ii) serum amylase and / or lipase

greater than three times the upper limit of normal, and / or (iii) characteristic findings from abdominal imaging (strong recommendation, moderate quality of evidence).

Contrast‐enhanced computed tomography (CECT) and / or magnetic resonance imaging (MRI) of the pancreas should be reserved for patients in whom the diagnosis is unclear

or who fail to improve clinically within the first 48 – 72 h after hospital admission or to evaluate complications (strong recommendation, low quality of evidence).

The revised 2012 Atlanta classification recommends the following:

Clinical Definition: Acute pancreatitis (regardless of presence or absence of chronic pancreatitis) is clinically defined by at least the first two of three features (4): (a) abdominal pain suggestive of pancreatitis (epigastric pain often radiating to the back), with the start of such pain considered to be the onset of acute pancreatitis; (b) serum amylase and lipase levels three or more times normal (imaging is to be used if the elevated values are 3 times normal); and (c) characteristic findings on CT, magnetic resonance (MR) imaging, or transabdominal ultrasonographic (US) studies. If acute pancreatitis is diagnosed on the basis of the first two criteria with no systemic sign of severe systemic inflammatory response syndrome or persistent organ failure, contrast material–enhanced CT may not be necessary for determining patient care. Course and Severity of Disease: The revised Atlanta classification introduces two distinct phases of acute pancreatitis: a first, or early, phase that occurs within the 1st week of onset of disease; and a second, or late, phase that takes place after the 1st week of onset.

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Imaging: According to the revised Atlanta classification, contrast‐enhanced CT is the primary tool for assessing the imaging‐based criteria because it is widely available for these acutely ill patients and has a high degree of accuracy Summary:

The revised Atlanta classification distinguishes an early phase (1st week) in which clinical parameters determine treatment from a later phase (after the 1st week) in which treatment is determined on the basis of clinical parameters and morphologic criteria defined by CT.

Severe acute pancreatitis is defined in the first phase as organ failure lasting more than 48 hours or death; and during the second phase, as persistent organ failure, death, or complications resulting from acute pancreatitis.

Fluid collections are defined by presence or absence of necrosis and infection: acute peripancreatic fluid collections (in the first 4 weeks without necrosis), pseudocysts (encapsulated fluid collections after 4 weeks, without necrosis), acute necrotic collections (ANCs; in first 4 weeks, with necrosis), and walled‐off necrosis (WON; encapsulated collections after 4 weeks, with necrosis).

Intraparenchymal fluid collections due to pancreatitis are referred to as ANCs or WONs, not as pseudocysts.

Pseudocysts rarely become infected or require intervention; for sterile ANC or WON, any need for drainage is based on the clinical information; infected ANCs or WONs usually require intervention.

References:

1. (2013). "IAP/APA evidence‐based guidelines for the management of acute pancreatitis." Pancreatology 13(4 Suppl 2): e1‐15. 2. Banks, P. A., et al. (2013). "Classification of acute pancreatitis‐‐2012: revision of the Atlanta classification and definitions by international consensus." Gut 62(1): 102‐111. 3. Crockett, S. D., et al. (2018). "American Gastroenterological Association Institute Guideline on Initial Management of Acute Pancreatitis." Gastroenterology 154(4): 1096‐1101. 4. Tenner, S., et al. (2013). "American College of Gastroenterology guideline: management of acute pancreatitis." Am J Gastroenterol 108(9): 1400‐1415; 1416. 5. Yokoe, M., et al. (2015). "Japanese guidelines for the management of acute pancreatitis: Japanese Guidelines 2015." Journal of Hepato‐biliary‐pancreatic Sciences 22(6): 405‐432.

Question #2. What approach (contrast‐enhanced computed tomography [CECT], magnetic resonance imaging [MRI], ultrasound) for diagnosing acute pancreatitis is most accurate (sensitivity and specificity)?


The 2015 Japanese guidelines for the management of acute pancreatitis recommended the following for diagnostic imaging:

When acute pancreatitis is suspected, ultrasonography is recommended. (1C)

CT is recommended for the diagnosis of acute pancreatitis. (1C)

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MRI is more useful than CT in diagnosing bile duct stones causing pancreatitis and hemorrhagic necrotizing pancreatitis. (2C)

Contrast‐enhanced CT is useful for the diagnosis of active hemorrhage and thrombosis associated with pancreatitis. (1C)

The 2013 International Association of Pancreatology (IAP) and the American Pancreatic Association (APA) stated that on admission, the etiology of acute pancreatitis should be

determined using detailed personal (i.e. previous acute pancreatitis, known gallstone disease, alcohol intake, medication and drug intake, known hyperlipidemia, trauma, recent invasive

procedures such as ERCP) and family history of pancreatic disease, physical examination, laboratory serum tests (i.e. liver enzymes, calcium, triglycerides), and imaging (i.e. right upper

quadrant ultrasonography). (GRADE 1B, strong agreement) In patients considered to have idiopathic acute pancreatitis, after negative routine work‐up for biliary etiology, endoscopic

ultrasonography (EUS) is recommended as the first step to assess for occult microlithiasis, neoplasms and chronic pancreatitis. If EUS is negative, (secretin‐stimulated) MRCP is advised as a

second step to identify rare morphologic abnormalities. CT of the abdomen should be performed. If etiology remains unidentified, especially after a second attack of idiopathic pancreatitis,

genetic counseling (not necessarily genetic testing) should be considered. (GRADE 2C, weak agreement).

For imaging, the indication for initial CT assessment in acute pancreatitis can be: 1) diagnostic uncertainty, 2) confirmation of severity based on clinical predictors of severe acute

pancreatitis, or 3) failure to respond to conservative treatment or in the setting of clinical deterioration. Optimal timing for initial CT assessment is at least 72‐96 hours after onset of

symptoms. (GRADE 1C, strong agreement) Follow up CT or MR in acute pancreatitis is indicated when there is a lack of clinical improvement, clinical deterioration, or especially when

invasive intervention is considered. (GRADE 1C, strong agreement) It is recommended to perform multidetector CT with thin collimation and slice thickness (i.e. 5mm or less), 100‐150 ml of

non‐ionic intra‐venous contrast material at a rate of 3mL/s, during the pancreatic and/or portal venous phase (i.e. 50‐70 seconds delay). During follow up only a portal venous phase

(monophasic) is generally sufficient. For MR, the recommendation is to perform axial FS‐T2 and FS‐T1 scanning before and after intravenous gadolinium contrast administration. (GRADE 1C,

strong agreement)

The 2013 American College of Radiology recommended:

In the acute setting (<48–72 hours after the onset of symptoms), an enhanced CT should not be performed when a typical clinical presentation and unequivocal elevations of

amylase and lipase are present.

In the acute setting, an enhanced CT should be performed if the clinical presentation and amylase and lipase levels are equivocal.

Early (within the first 72 hours) imaging with CT may underestimate the full severity of the disease.

Enhanced CT after 48–72 hours will detect pancreatic and peripancreatic necrosis as well as acute pancreatic fluid collections.

Delayed enhanced CT (>7–21 days after the onset of symptoms) is very effective in assessing severity and will guide management, including image‐guided aspiration and/or

drainage as well as other forms of minimally invasive drainage.

Enhanced CT should be performed when there is a significant deterioration of the patient’s condition, including an acute drop in hemoglobin and hematocrit, tachycardia, and

hypotension, an abrupt change in fever, or leukocytosis.

CT with IV contrast provides the best overall assessment of the pancreas and complications related to pancreatitis.

US is primarily used to assess for gallstones and should be performed early in patients who present for the first time and in whom the cause is uncertain.

MRI with IV contrast and MRCP have the potential to be an all‐inclusive examination for assessing pancreatitis; however, use may be limited in the acute setting.

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Diagnosis:

The diagnosis of AP is most often established by the presence of 2 of the 3 following criteria: (i) abdominal pain consistent with the disease, (ii) serum amylase and / or lipase

greater than three times the upper limit of normal, and / or (iii) characteristic findings from abdominal imaging (strong recommendation, moderate quality of evidence).



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Etiology:

Transabdominal ultrasound should be performed in all patients with acute pancreatitis (strong recommendation, low quality of evidence).

In the absence of gallstones and / or history of significant history of alcohol use, a serum triglyceride should be obtained and considered the etiology if > 1,000 mg / dl

(conditional recommendation, moderate quality of evidence).

In a patient older than 40 years, a pancreatic tumor should be considered as a possible cause of acute pancreatitis (conditional recommendation, low quality of evidence).

Endoscopic investigation in patients with acute idiopathic pancreatitis should be limited, as the risks and benefits of investigation in these patients are unclear (conditional

recommendation, low quality of evidence).

Patients with idiopathic pancreatitis should be referred to centers of expertise (conditional recommendation, low quality of evidence).

Genetic testing may be considered in young patients (< 30 years old) if no cause is evident and a family history of pancreatic disease is present (conditional recommendation,

low quality of evidence).

According to the revised 2012 Atlanta classification, contrast‐enhanced CT is the primary tool for assessing the imaging‐based criteria because it is widely available for these acutely ill

patients and has a high degree of accuracy

References:

1. (2013). "IAP/APA evidence‐based guidelines for the management of acute pancreatitis." Pancreatology 13(4 Suppl 2): e1‐15. 2. Baker, M. E., et al. (2014). "ACR Appropriateness Criteria(R) acute pancreatitis." Ultrasound Quarterly 30(4): 267‐273. 3. Banks, P. A., et al. (2013). "Classification of acute pancreatitis‐‐2012: revision of the Atlanta classification and definitions by international consensus." Gut 62(1): 102‐111. 4. Crockett, S. D., et al. (2018). "American Gastroenterological Association Institute Guideline on Initial Management of Acute Pancreatitis." Gastroenterology 154(4): 1096‐1101. 5. Tenner, S., et al. (2013). "American College of Gastroenterology guideline: management of acute pancreatitis." Am J Gastroenterol 108(9): 1400‐1415; 1416. 6. Yokoe, M., et al. (2015). "Japanese guidelines for the management of acute pancreatitis: Japanese Guidelines 2015." Journal of Hepato‐biliary‐pancreatic Sciences 22(6): 405‐432.

Primary Literature:

PICO Question: What approach (contrast‐enhanced computed tomography [CECT], magnetic resonance imaging [MRI], ultrasound) for diagnosing acute pancreatitis is most accurate (sensitivity and specificity)?

Low Quality Rating if: Studies inconsistent (wide

variation of treatment effect across studies, population, interventions, or outcomes varied) Studies are indirect (PICO

question is quite different from the available evidence in regard to population, intervention, comparison, or outcome)

Modality: Contrast‐enhanced computer tomography (CECT); Outcome: Prognosis Study Acronym; Author;

Year Published; Location

Aim of Study; Study Type; Study Size (N)

Patient Population Study Intervention (# patients) / Study Comparator

Endpoint Results / Outcome (Absolute Event Rates, P values; OR or RR; & 95% CI)

Design Limitations

Journal: AJR. American Journal of Roentgenology Author: Brand, M., et al. Year Published: 2014 Location: Department of Radiology, University Medical Center

Aim: To determine whether laboratory and clinical findings determined in the early phase of disease and morphologic features on contrast‐enhanced

Inclusion Criteria: All adult patients (age ≥ 18 years) who were treated between January 2005 and December 2010 and had diagnosis code

Intervention: A retrospective analysis of 99 patients with acute necrotizing pancreatitis was performed. Four laboratory variables (albumin, calcium, C‐

Results: 99 patients (63 men, 36 women; median age, 52 years; age range, 18‐84 years), 25 patients (25%) developed infection, 42 patients (42%) experienced organ

Study Limitations: None

Non‐Randomized Studies Failure to develop and

apply appropriate eligibility criteria

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References: 1. Brand, M., et al. (2014). "Acute necrotizing pancreatitis: laboratory, clinical, and imaging findings as predictors of patient outcome." AJR. American Journal of Roentgenology 202(6): 1215‐1231.

Regensburg, Regensburg, Germany

CT (CECT) at the beginning of the late phase of disease are helpful in predicting patient outcome and whether CECT findings provide additional information in establishing prognosis compared with the laboratory and clinical findings. Study Type: Retrospective Study Size: 99 patients

K85, which is defined as “acute pancreatitis” according to the International Statistical Classification of Diseases and Related Health Problems (10th revision, German Modification).

reactive protein, WBC count) and three clinical variables (Acute Physiology, Age, Chronic Health Evaluation [APACHE] II score; Simplified Acute Physiology Score [SAPS] II; persistent organ failure) were assessed. Five morphologic features on CECT including Balthazar grade and CT severity index were reviewed. The endpoints of patient outcome were peripancreatic or pancreatic infection, need for intervention, duration of organ failure, ICU and hospital stays, and death. Based on receiver operating characteristic curve analysis for infection, high‐and low‐risk groups for each prognostic variable were calculated and univariable and multivariable Cox regression analyses were carried out.

failure, and 12 patients (12%) died. Regarding the laboratory and clinical variables, albumin level, APACHE II score, and particularly persistent organ failure were the strongest independent predictors of patient outcome. Regarding the imaging variables, Balthazar grade and a morphologic feature that takes the distribution of intrapancreatic necrosis into account were the strongest independent predictors. In the multivariable analysis of all studied variables, imaging variables were independent and strong predictors of patient outcome and provided additional information in establishing prognosis compared with clinical and laboratory findings.

Flawed measurement of both exposure and outcome Failure to adequately

control confounding Incomplete or

inadequately short follow‐up Differences in

important prognostic factors at baseline

Studies are imprecise (when studies include few patients and few events, and thus have wide confidence intervals, and the results are uncertain) Publication Bias (e.g.

pharmaceutical company sponsors study on effectiveness of drug only small, positive studies found) Increase Quality Rating if: Large effect Dose‐response gradient Plausible confounders or

other biases increase certainty of effect Quality (certainty) of evidence for studies as a whole: High Moderate Low Very Low




question is quite different from the available evidence in regard to population,

Modality; Computed tomography; Outcome: Splenic artery complications Study Acronym; Author;





Design Limitations

Journal: World Journal of Gastroenterology Author: Cai, D.M., et al. Year Published: 2014

Aim: To assess the value of contrast‐enhanced ultrasound (CEUS) in diagnosing splenic artery

Inclusion Criteria: Patients diagnosed with AP by CECT

Intervention: All patients were examined by CEUS and contrast‐enhanced computed tomography (CECT). CECT was

Results: Nine patients were diagnosed as having SACs after AP by CECT among the 118 patients. The patients with SACs


Diagnostic Studies

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References: 1. Cai, D. M., et al. (2014). "Diagnostic value of contrast enhanced ultrasound for splenic artery complications following acute pancreatitis." World Journal of Gastroenterology 20(4): 1088‐1094. 2. Jiang, W., et al. (2014). "Splanchnic vein thrombosis in necrotizing acute pancreatitis: Detection by computed tomographic venography." World Journal of Gastroenterology 20(44): 16698‐16701.

Location: West China Hospital, Sichuan University, China

complications (SACs) after acute pancreatitis (AP). Study Type: Prospective Study Size: 118 patients

Exclusion Criteria: Patients were excluded from the study either because the gray scale sonography of the pancreas hardly displayed meteorism or because patients had a history of splenic disease.

accepted as a gold standard for the diagnosis of SACs in AP. The diagnostic accuracy of splenic CEUS and pancreatic CEUS was compared with that of CECT. Splenic infarction was the diagnostic criterion for splenic artery embolism and local dysperfusion of the splenic parenchyma was the diagnostic criterion for splenic arterial stenosis. The incidence of splenic sub‐capsular hemorrhage, splenic artery aneurysms, and splenic rupture was all lower than that of SACs.

were diagnosed with severe acute pancreatitis (SAP). Among them, 6 lesions were diagnosed as splenic artery embolism, 5 as splenic artery aneurysms, and 1 as splenic arterial stenosis. No lesion was diagnosed by pancreatic CEUS and 5 lesions were diagnosed by splenic CEUS. By splenic CEUS, 4 cases were diagnosed as splenic artery embolism and 1 as splenic arterial stenosis. The accuracy of splenic CEUS in diagnosis of SACs in SAP was 41.7% (5/12), which was higher than that of pancreatic CEUS (0%).

Patients not enrolled in consecutive or random manner Case‐control study No independent, blind

comparison between index test and reference test Not all patients received

reference test

intervention, comparison, or outcome) Studies are imprecise

(when studies include few patients and few events, and thus have wide confidence intervals, and the results are uncertain) Publication Bias (e.g.



Journal: World Journal of Gastroenterology Author: Jiang, W., et al. Year Published: 2014 Location: Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, China

Aim: To assess the diagnostic accuracy of computed tomographic venography (CTV) for splanchnic vein thrombosis (SVT) detection in necrotizing acute pancreatitis (AP) patients Study Type: Retrospective Comparative Study Size: 43 patients

Inclusion Criteria: Patients diagnosed with necrotizing AP from July 1, 2011 to June 30, 2013 undergoing both CTV and DSA within 3 d were included in this study.

Intervention: Patients with necrotizing AP who underwent both CTV and digital subtraction angiography (DSA) within 3 d were analyzed in this retrospective comparative study. All CTV procedures were performed with a dual‐source CT scanner. The presence and location of SVT were determined via blinded imaging data analyses.

Results: According to the DSA results, 17 (39.5%) of the total 43 patients had SVT. The sensitivity, specificity, positive and negative predictive values of CTV for SVT detection were 100% (95%CI: 77.1%‐100%), 92.3% (95%CI: 73.4%‐98.7%), 89.5% (95%CI: 65.5%‐98.2%) and 100% (95%CI: 82.8%‐100%), respectively


Diagnostic Studies Patients not enrolled in

consecutive or random manner Case‐control study No independent, blind


reference test

22

References: 1. de Freitas Tertulino, F., et al. (2015). "Diffusion‐weighted magnetic resonance imaging indicates the severity of acute pancreatitis." Abdominal Imaging 40(2): 265‐271.




question is quite different from the available evidence in regard to population, intervention, comparison, or outcome) Studies are imprecise




Modality: Diffusion‐weighted magnetic resonance imaging; Outcome: Severity of Acute Pancreatitis Study Acronym; Author;





Design Limitations

Journal: Abdominal Imaging Author: de Freitas Tertulino, F., et al. Year Published: 2015 Location: Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, Brazil

Aim: To test the use of diffusion‐weighted magnetic resonance imaging (DW‐MRI) to differentiate between different degrees of severity of acute pancreatitis (AP) Study Type: Prospective, Observational Study Size: 36 patients, 108 segments

Inclusion Criteria: Patients who underwent DW‐MRI and magnetic resonance cholangiopancreatography

Intervention: Patients who underwent DW‐MRI and magnetic resonance cholangiopancreatography were divided into patients with mild AP (mAP, n = 15), patients with necrotizing AP (nAP, n = 8), and patients with a normal pancreas (nP, n = 15; controls). The pancreas was divided into head, body, and tail, and each segment was classified according to image features: pattern 1, normal; pattern 2, mild inflammation; and pattern 3, necrosis. Apparent diffusion coefficients (ADCs) were measured in each segment and correlated with clinical diagnoses.

Results: Twenty‐one patients received a diagnosis of AP: 13 with mAP and 8 with necrotizing AP (nAP). The remaining 15 patients showed a normal pancreas and were therefore considered as controls. Segments classified as pattern 1 in the nP and mAP groups showed similar ADC values (P = 0.29). ADC values calculated for the pancreatic segments grouped according to the different image patterns (1‐3) were significantly different (P < 0.001). Comparisons revealed significant differences in signal intensity between all three patterns (P < 0.05).





reference test

23

References: 1. Fei, Y. and W. Q. Li (2017). "Effectiveness of contrast‐enhanced ultrasound for the diagnosis of acute pancreatitis: A systematic review and meta‐analysis." Digestive & Liver Disease 49(6): 623‐629.








Modality: Contrast‐enhanced ultrasound; Outcome: Diagnostic Accuracy Study Acronym; Author;





Design Limitations

Journal: Digestive & Liver Disease Author: Fei, Y and W.Q. Li Year Published: 2017 Location: Jinling Hospital, Medical School of Nanjing University, Nanjing, China

Aim: To systematically determine the diagnostic value of contrast‐enhanced ultrasound (CEUS) in the assessment of acute pancreatitis Study Type: Systematic Review Size: 7 studies, 421 AP cases

Inclusion Criteria: (1) full text original article; (2) human study; (3)evaluation of CEUS for the AP; (4) inclusion of at least 20 patients;(5) published in English or Chinese

Exclusion Criteria: (1) no evaluation of the value of CEUS for the diagnosis of acute pancreatitis; (2) samples less than 20patients; (3) review article (including meta‐analyses), corresponding letter or editorial not reporting original data; (4) published in abstract form only; (5) published more than once; (6) sufficient data including gender, age, evaluation of the degree of AP and imaging modality for AP were not provided.

Systematic Review

Results: The pooled weighted sensitivity with a corresponding 95% confidence interval (CI) was 0.92 (95% CI: 0.88, 0.95), the specificity was 0.84 (95% CI: 0.78, 0.90), the positive likelihood ratio was 5.38 (95% CI: 3.21, 9.00), the negative likelihood ratio was 0.13 (95% CI: 0.05, 0.36), and the diagnostic odds ratio was 49.37 (95% CI: 14.69, 165.94). The area under the ROC curve was 0.9273 (95% CI: 0.8916, 0.9790). Quality of evidence was rated as moderate due to heterogeneity and publication bias.


Systematic Review Review did not address

focused clinical question Search was not detailed

or exhaustive Quality of the studies

was not appraised or studies were of low quality Methods and/or results

were inconsistent across studies

24








Modality: Endoscopic ultrasound; Outcome: Diagnostic Accuracy Study Acronym; Author;




Endpoint Results / Outcome (Absolute Event Rates, P values; OR or RR;

& 95% CI)

Design Limitations

Journal: Minerva Gastroenterologica e Dietologica Author: Ashkar, M. and T. B. Gardner Year Published: 2014 Location: Elizabeth’s Medical Center, Brighton, MA and Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH

Aim: To systematically review the literature and high‐light the benefit of using EUS in different pancreatic diseases by primarily reviewing its importance in diagnosing, treating pan‐creatic pathologies, comparing its accuracy to other modalities and determining its limi‐tations and complications. Study Type: Systematic Review Size: 75

Inclusion Criteria: All published randomized controlled trials (RCTs), obser‐vational studies, meta‐analyses and review articles that evaluated EUS diagnostic indi‐cations, therapeutic use, limitations, com‐plications and common practice guidelines in relation to several pancreatic pathologies (mainly acute pancreatitis, chronic pancrea‐titis, autoimmune pancreatitis, pancreatic cancer, neuroendocrine pancreatic tumors, pancreatic cysts and pancreatic divisum). No restrictions were placed on each indi‐vidual study age group, gender, ethnicity, race, and sample size or study duration.

Systemic Review Results: In acute biliary pancreatitis, EUS is superior to CT and to magnetic resonance cholangiopancreatography (MRCP) for detection of microlithiasis. EUS‐guided pseudocyst drainage is safe with a high success rate. One randomized controlled trial concluded that EUS‐guided transmural drainage of pancreatic pseudocysts is better than conventional endoscopic transmural drainage. It has a success rate of 94% vs. 72%, better access to non‐bulging pseudocysts, fewer complications (7% vs. 10) and higher pseudocyst resolution rate (97% vs. 91%). Another trial randomized thirty patients to undergo pseudocyst drainage by EUS vs EGD; it resulted in 100% success rate in the EUS group, while only 33% of the cases in the EGD group had a successful pseudocyst drainage. Also, all failed cases from the EGD group where crossed over to EUS‐guided drainage







25

References: 1. Ashkar, M. and T. B. Gardner (2014). "Role of endoscopic ultrasound in pancreatic diseases: a systematic review." Minerva Gastroenterologica e Dietologica 60(4): 227‐245.

group and this achieved 100% suc‐cess rate. A small study evaluated the value of EUS‐guided transmural drainage of pancreatic abscesses and access to pancreatic necrosis for concurrent endoscopic necrosectomy. It noted how promising this approach is in avoiding surgical intervention and promoting pancreatic healing.






pharmaceutical company sponsors study on effectiveness of drug only small, positive studies found) Increase Quality Rating if:

Modality: Dual‐phase multidetector computed tomography (MDCT) over a single‐phase protocol on initial MDCT; Outcome: Diagnostic Success Rate Study Acronym; Author;





Design Limitations

Journal: European Journal of Radiology Author: Avanesov, M., et al. Year Published: 2016 Location: University Medical Center Hamburg‐Eppendorf, Hamburg, Germany

Aim: To evaluate the additional value of dual‐phase multidetector computed tomography (MDCT) protocols over a single‐phase protocol on initial MDCT in patients with acute pancreatitis using three CT‐based pancreatitis severity scores with regard to radiation dose. Study Type: Retrospective Study Size: 102 consecutive patients

Inclusion Criteria: (1) Acute pancreatitis according to the revised Atlanta classification (2) Intravenous contrast‐enhanced dual‐phase abdominal MDCT with evidence of AP and (3) Data available for analysis in our radiological information system(RIS)

Exclusion Criteria: (1) Pregnancy (2) Age below 18 years (3) Less than 3 days delay between onset of symptoms of pancreatitis and MDCT

Intervention: 102 consecutive patients (73 males; 55years, IQR48‐64) with acute pancreatitis. Inclusion criteria were CT findings of interstitial edematous pancreatitis (IP) or necrotizing pancreatitis (NP) and a contrast‐enhanced dual‐phase (arterial phase and portal‐venous phase) abdominal CT performed at >=72h after onset of symptoms. The severity of pancreatic and extrapancreatic changes was independently assessed by 2 observers using 3 validated CT‐based scoring systems (CTSI, mCTSI,

Results: In neither of the CT severity scores a significant difference was observed after application of a dual‐phase protocol compared with a single‐phase protocol (IP: CTSI: 2.7 vs. 2.5, p=0.25; mCTSI: 4.0 vs. 4.0, p=0.10; EPIC: 2.0 vs. 2.0, p=0.41; NP: CTSI: 8.0 vs. 7.0, p=0.64; mCTSI: 8.0 vs. 8.0, p=0.10; EPIC: 3.0 vs. 3.0, p=0.06). The application of a single‐phase CT protocol was associated with a median effective dose reduction of 36% (mean dose reduction





reference test

26

References: 1. Avanesov, M., et al. (2016). "MDCT of acute pancreatitis: Intraindividual comparison of single‐phase versus dual‐phase MDCT for initial assessment of acute pancreatitis using different CT scoring systems."

European Journal of Radiology 85(11): 2014‐2022.

EPIC). All scores were applied to arterial phase and portal venous phase scans and compared to score results of portal venous phase scans, assessed >=14days after initial evaluation. For effective dose estimation, volume CT dose index (CTDIvol) and dose length product (DLP) were recorded in all examinations.

31%) compared to a dual‐phase CT scan.

Large effect Dose‐response gradient Plausible confounders or







pharmaceutical company sponsors study on effectiveness of drug only small, positive studies found) Increase Quality Rating if:

Modality: Acoustic Radiation Force Impulse (ARFI) with sonography and computed tomography (CT); Outcome: Diagnostic Success Rate Study Acronym; Author;





Design Limitations

Journal: Journal of Ultrasound in Medicine Author: Goya, C., et al. Year Published: 2014 Location: Medical School, Dicle University, Diyarbakir, Turkey

Aim: To compare the diagnostic success rate of acoustic radiation force impulse (ARFI) elastography with those of sonography and computed tomography (CT) for acute pancreatitis at hospital admission. ARFI uses Virtual touch tissue quantification and the Virtual Touch imaging to diagnose AP. These elastographic techniques are new radiologic imaging methods that are used to detect changes in the stiffness of tissue

Inclusion Criteria: The patient group was selected on the basis of the following criteria: serum amylase and lipase levels 3 times the upper limit of normal or hither, elevation of white blood cell counts to 20,000 to 50,000, decreases in the echo texture of the pancreas, and increases in the size of the pancreas (both focal and diffuse).

Exclusion Criteria: Patients with chronic pancreatitis, pregnancy, malignancy, chronic liver disease, a history of

Intervention: B‐mode sonography and ARFI elastography were performed on 88 patients with symptoms of acute pancreatitis and 50 healthy control participants who were admitted to our hospital between February 2013 and July 2013. Acute pancreatitis was verified in the 88 patients based on clinical and laboratory findings. Computed tomography was performed on 41 patients, and the CT results from these patients were compared with those of ARFI elastography. The appearances of the

Results: Forty‐six of the 88 patients had a diagnosis of pancreatitis by B‐mode sonography; pancreatitis was diagnosed in all patients by ARFI elastography; and 10 of 41 patients could not be diagnosed by CT. The sensitivity and specificity of Virtual Touch tissue quantification were 100% and 98%, respectively, when a cutoff value of 1.63 m/s was used. The control group had color scores of 1 or 2, whereas all patients with pancreatitis had color scores of 3 to 6





reference test

27

References: 1. Goya, C., et al. (2014). "Use of acoustic radiation force impulse elastography to diagnose acute pancreatitis at hospital admission: comparison with sonography and computed tomography.[Erratum appears

in J Ultrasound Med. 2014 Sep;33(9):1696], [Erratum appears in J Ultrasound Med. 2014 Sep;33(9):1696; PMID: 28027620]." Journal of Ultrasound in Medicine 33(8): 1453‐1460.

by measuring tissue elasticity by a sonographically based method. Study Type: Diagnostic Study Size: 88 patients

pancreatitis, a pancreatic mass, or obesity (body mass index > 30 kg/m2).

pancreases of the patients were classified into 6 groups using visual color encodings obtained with ARFI elastography. The elasticity values of pancreatic head, body, and tail regions were evaluated with Virtual Touch imaging and Virtual Touch tissue quantification (Siemens Medical Solutions, Mountain View, CA). The success rates of sonography, CT, and ARFI elastography for diagnosing acute pancreatitis at hospital admission were compared.

on color scale evaluation with Virtual Touch imaging.

Large effect Dose‐response gradient Plausible confounders or







pharmaceutical company

Modality: microRNA (miRNA); Outcome: Early Diagnosis of AP Study Acronym; Author;





Design Limitations

Journal: Pancreatology Author: Liu, P., et al. Year Published: 2014 Location: The First Affiliated Hospital of Nanchang University, China

Aim: To identify serum microRNA (miRNA) as diagnostic and prognostic biomarkers for acute pancreatitis (AP). Study Type: Diagnostic Study Size: 74 patients clinically classified as AP and 21 healthy volunteers

Inclusion Criteria: Patients clinically diagnosed as having AP

Intervention: Sera microRNA expression was profiled from 12 AP patients with varying disease severity and three healthy controls. Differentially expressed miRNAs were validated in a larger cohort of patients and controls. The diagnostic and prognostic potentials of differentially expressed miRNAs were evaluated using receiver operating characteristic (ROC) curve analysis and

Results: miRNA microarray analyses identified 205 differentially expressed miRNAs between sera from AP patients and that from controls. Nine miRNAs were differentially expressed between severe and mild AP patients. Further validation confirmed the down‐regulation of miR‐92b, miR‐10a, and miR‐7 in AP patients, and ROC analysis revealed that





reference test

28

References: 1. Liu, P., et al. (2014). "Identification of serum microRNAs as diagnostic and prognostic biomarkers for acute pancreatitis." Pancreatology 14(3): 159‐166.

Question #3. What assessment tool (Sequential Organ Failure Assessment [SOFA], Apache, Ranson) is the most accurate in predicting pancreatitis severity?


The 2015 Japanese guidelines for the management of acute pancreatitis recommended the following for severity assessment:

In principle, it is recommended that a severity assessment be made immediately after diagnosis and repeated over time (especially within 48 h of the diagnosis). (1C)

It is recommended that a scoring system is used for severity assessments. (1B)

Contrast‐enhanced CT is recommended for identifying poorly contrasted areas of acute pancreatitis and is also useful in the diagnosis of complications. However, the possibility of

exacerbating pancreatitis and renal function and allergic reactions associated with the contrast must be considered. (2B)

The 2013 International Association of Pancreatology (IAP) and the American Pancreatic Association (APA) stated to determine the prognostication/predication of severity that Systemic inflammatory response syndrome (SIRS) is advised to predict severe acute pancreatitis at admission and persistent SIRS at 48 hours (GRADE 2B, weak agreement). During admission, a 3‐dimension approach is advised to predict outcome of acute pancreatitis combining host risk factors (e.g. age, co‐morbidity, body mass index), clinical risk stratification (e.g. persistent SIRS) and monitoring response to initial therapy (e.g. persistent SIRS, blood urea nitrogen, creatinine) (GRADE 2B, strong agreement). The 2013 American College of Radiology recommended:




compared to that of classic prognostic markers for AP.

these miRNAs can differentiate AP from health cases. Further‐more, the serum miR‐551b‐5p level was significantly higher in patients with disease complications or a low plasma calcium level. ROC analysis showed that the serum miR‐551b‐5p level can distinguish between severe and mild AP.

sponsors study on effectiveness of drug only small, positive studies found) Increase Quality Rating if: Large effect Dose‐response gradient Plausible confounders or


29






31

The 2013 American College of Gastroenterology recommended the following for etiology and initial assessment and risk stratification:

Etiology:


In the absence of gallstones and / or history of significant history of alcohol use, a serum triglyceride should be obtained and considered the etiology if > 1,000 mg / dl (conditional

recommendation, moderate quality of evidence).





Genetic testing may be considered in young patients (< 30 years old) if no cause is evident and a family history of pancreatic disease is present (conditional recommendation, low

quality of evidence).

Initial assessment and risk stratification:

Hemodynamic status should be assessed immediately upon presentation and resuscitative measures begun as needed (strong recommendation, moderate quality of evidence).

32

Risk assessment should be performed to stratify patients into higher‐ and lower‐risk categories to assist triage, such as admission to an intensive care setting (conditional


Patients with organ failure should be admitted to an intensive care unit or intermediary care setting whenever possible (strong recommendation, low quality of evidence).

The revised 2012 Atlanta classification recommends the following:

Clinical Definition: Acute pancreatitis (regardless of presence or absence of chronic pancreatitis) is clinically defined by at least the first two of three features (4): (a) abdominal pain suggestive of pancreatitis (epigastric pain often radiating to the back), with the start of such pain considered to be the onset of acute pancreatitis; (b) serum amylase and lipase levels three or more times normal (imaging is to be used if the elevated values are ,3 times normal); and (c) characteristic findings on CT, magnetic resonance (MR) imaging, or transabdominal ultrasonographic (US) studies. If acute pancreatitis is diagnosed on the basis of the first two criteria with no systemic sign of severe systemic inflammatory response syndrome or persistent organ failure, contrast material–enhanced CT may not be necessary for determining patient care. Course and Severity of Disease: The revised Atlanta classification introduces two distinct phases of acute pancreatitis: a first, or early, phase that occurs within the 1st week of onset of disease; and a second, or late, phase that takes place after the 1st week of onset.

Summary:

The revised Atlanta classification distinguishes an early phase (1st week) in which clinical parameters determine treatment from a later phase (after the 1st week) in which treatment is determined on the basis of clinical parameters and morphologic criteria defined by CT.

Severe acute pancreatitis is defined in the first phase as organ failure lasting more than 48 hours or death; and during the second phase, as persistent organ failure, death, or complications resulting from acute pancreatitis.

Fluid collections are defined by presence or absence of necrosis and infection: acute peripancreatic fluid collections (in the first 4 weeks without necrosis), pseudocysts (encapsulated fluid collections after 4 weeks, without necrosis), acute necrotic collections (ANCs; in first 4 weeks, with necrosis), and walled‐off necrosis (WON; encapsulated collections after 4 weeks, with necrosis).

Intraparenchymal fluid collections due to pancreatitis are referred to as ANCs or WONs, not as pseudocysts.

Pseudocysts rarely become infected or require intervention; for sterile ANC or WON, any need for drainage is based on the clinical information; infected ANCs or WONs usually require intervention.

References:

1. (2013). "IAP/APA evidence‐based guidelines for the management of acute pancreatitis." Pancreatology 13(4 Suppl 2): e1‐15. 2. Baker, M. E., et al. (2014). "ACR Appropriateness Criteria(R) acute pancreatitis." Ultrasound Quarterly 30(4): 267‐273. 3. Banks, P. A., et al. (2013). "Classification of acute pancreatitis‐‐2012: revision of the Atlanta classification and definitions by international consensus." Gut 62(1): 102‐111. 4. Tenner, S., et al. (2013). "American College of Gastroenterology guideline: management of acute pancreatitis." Am J Gastroenterol 108(9): 1400‐1415; 1416. 5. Yokoe, M., et al. (2015). "Japanese guidelines for the management of acute pancreatitis: Japanese Guidelines 2015." Journal of Hepato‐biliary‐pancreatic Sciences 22(6): 405‐432.

33

Primary Literature:

2018 American Gastroenterological Association Institute Technical Review

The technical review summarized the literature and found a recent report actually suggested that current scoring systems have reached their limit to predict persistent organ failure with no

good positive predictive value and future research should include novel approaches. In another recent systematic review included, no single tool is favored and most tools have only

moderate predictive value for predicting development of persistent organ failure or infected pancreatic necrosis. For this reason, there is general consensus from guidelines and among

experts to utilize expert clinical judgment and a variety of predictive tools to best estimate predicted severity. An initial 1260 citations were retrieved from the systematic literature search

and 839 full‐text articles were reviewed. What is lacking in the literature are specific studies focused on whether utilizing a risk severity assessment tool during the early management of AP

impacts outcomes, which would match the aim of the systematic review of identifying interventions or treatments that impact outcomes, and more specifically the a priori‐set objective for

this PICO. A single study that comes closest to addressing this question focused on whether use of tools to predict severity (SIRS, BISAP [Bedside Index for Severity in

Acute Pancreatitis], or transient organ failure) coupled with a structured management approach would impact outcomes. Whereas the structured management of AP compared to usual

care in historical controls has been shown to be associated with a significant reduction in hospital LOS without affecting other major outcomes (eg, persistent organ failure or pancreatic

necrosis), it is difficult to tease apart the individual contribution of such predictors on any clinically important outcome. Moreover, all predictors have tried to prognosticate SAP and the

only study that attempted to predict the moderately severe type of AP found it impossible to distinguish this entity from SAP.

Results of the current systematic review. All of the reasons mentioned, and the absence of any observational study or RCT on the clinical impact of using severity prediction tools,

prevented reviewers from identifying any gradable evidence.

PICO Question: What assessment tool (Sequential Organ Failure Assessment [SOFA], Apache, Ranson) is the most accurate in predicting pancreatitis severity? Low Quality Rating if: Studies inconsistent

(wide variation of treatment effect across studies, population, interventions, or outcomes varied) Studies are indirect

(PICO question is quite different from the available evidence in regard to population, intervention, comparison, or outcome) Studies are imprecise

(when studies include few patients and few events, and thus have wide

Modality: EPIC; Outcome: Organ Failure Study Acronym; Author; Year

Published; Location




& 95% CI)

Design Limitations

Journal: Medicine Author: Chen, C., et al. Year Published: 2017 Location: West China Hospital, Sichuan University, Chengdu, China

Aim: To evaluate the utility of the EPIC score for predicting organ failure in the early phase of AP as defined by the revised Atlanta classification Study Type: Retrospective Study Size: 208

Inclusion Criteria: Patients who underwent abdominal computed tomography (CT) within 24 hours after AP onset and admission

Exclusion Criteria: AP in pregnancy, malignancy, traumatic AP, and acute‐on‐chronic pancreatitis.

Intervention: Each patient’s EPIC score, Balthazar score, bedside index of severity in acute pancreatitis (BISAP), and systemic inflammatory response syndrome (SIRS) score were obtained. Primary endpoints were organ failure occurrence and death. Scores were evaluated by receiver operator characteristic (ROC) curve and area

Results: Median age was 45 years (range: 18–83 years). Forty‐seven patients (22.6%) developed organ failure, and 5 patients (2.4%) developed infection and underwent surgery. Two patients died. The median EPIC score was 2 (range: 0–7). EPIC score accuracy (AUC=0.724) in predicting organ failure was similar to that of BISAP (0.773) and


Diagnostic Studies Patients not enrolled

in consecutive or random manner Case‐control study No independent,

blind comparison between index test and reference test Not all patients

received reference test

34

References: 1. Chen, L., et al. (2013). "Evaluation of the BISAP score in predicting severity and prognoses of acute pancreatitis in Chinese patients." International Surgery 98(1): 6‐12.

under the curve (AUC) analysis.

SIRS (0.801) scores, whereas Balthazar scoring was not significant (P=.293). An EPIC score of 3 or greater had a sensitivity and specificity of 80.65% and 63.16%, respectively. EPIC scores correlated moderately with organ failure severity (Spearman r=0.321) and number of failed organs (r=0.343).

confidence intervals, and the results are uncertain) Publication Bias (e.g.

pharmaceutical company sponsors study on effectiveness of drug only small, positive studies found) Increase Quality Rating if: Large effect Dose‐response

gradient Plausible

confounders or other biases increase certainty of effect Quality (certainty) of evidence for studies as a whole: High Moderate Low Very Low



(PICO question is quite different from the available evidence in regard to population, intervention, comparison, or outcome)

Modality: CCAAB; Outcome: Organ Failure Study Acronym; Author; Year

Published; Location




& 95% CI)

Design Limitations

Journal: Pancreas Author: Wang, X., et al. Year Published: 2013 Location: Fourth Center Hospital, Tianjin, China

Aim: To develop a method that can early, efficiently, and accurately evaluate the in‐hospital organ failure in patients with SAP. Study Type: Validation Study Size: 393 patients

Inclusion Criteria: Patients with SAP admitted in 3 tertiary care center hospitals. AP was diagnosed through the combination of clinical features (epigastric abdominal pain and vomiting), laboratory findings (elevated serum amylase and lipase at least 3 times higher than the normal

Method: Using multivariate logistic regression analysis, the associative factors for in‐hospital organ failure were evaluated retrospectively from conventional data obtained from 393 patients with SAP from 2000 to 2012. In classification and regression tree analysis, a

Results: Laboratory results revealed serum calcium level greater than or equal to 1.84 mmol/L, serum creatinine level greater than or equal to 110 micro mol/L, age greater than or equal to 72 years, activated partial thromboplastin time less than or equal to 30.95 seconds, and Balthazar



apply appropriate eligibility criteria Flawed measurement

of both exposure and outcome

35

References: 1. Wang, X., et al. (2013). "An evidence‐based proposal for predicting organ failure in severe acute pancreatitis." Pancreas 42(8): 1255‐1261.

level), and imaging test findings (abdominal ultrasound, abdominal computed tomography).

new clinical scoring system was developed for the evaluation of in‐hospital organ failure in SAP. The accuracy of the new scoring system was also compared with multiple organ dysfunction score and Acute Physiology and Chronic Health Examination II score by the receiver operating characteristic curve. CCAAB includes serum Ca2+, Serum Cr, age, serum APTT, and Balthazar scores

computed tomography score greater than or equal to 7 (CCAAB) score system, each contributed 1 point for the prediction of organ failure. The area under the curve of the CCAAB score (0.904) system was similar to multiple organ dysfunction scores (0.897) and Acute Physiology and Chronic Health Examination II scores (0.889).

Failure to adequately control confounding Incomplete or





gradient Plausible

confounders or other biases increase certainty of effect Quality (certainty) of evidence for studies as a whole: High Moderate Low Very Low



(PICO question is quite different from the available evidence in regard to

Modality: microRNA (miRNA); Outcome: Early Diagnosis of AP

Study Acronym; Author; Year

Published; Location




Design Limitations

Journal: Pancreatology Author: Liu, P., et al. Year Published: 2014

Aim: To identify serum microRNA (miRNA) as diagnostic and prognostic

Inclusion Criteria: Patients clinically diagnosed as having AP

Intervention: Sera microRNA expression was profiled from 12 AP patients with varying disease severity

Results: miRNA microarray analyses identified 205 differentially expressed


Diagnostic Studies

36

References: 1. Liu, P., et al. (2014). "Identification of serum microRNAs as diagnostic and prognostic biomarkers for acute pancreatitis." Pancreatology 14(3): 159‐166.

Location: The First Affiliated Hospital of Nanchang University, China

biomarkers for acute pancreatitis (AP). Study Type: Diagnostic Study Size: 74 patients clinically classified as AP and 21 healthy volunteers

and three healthy controls. Differentially expressed miRNAs were validated in a larger cohort of patients and controls. The diagnostic and prognostic potentials of differentially expressed miRNAs were evaluated using receiver operating characteristic (ROC) curve analysis and compared to that of classic prognostic markers for AP.

miRNAs between sera from AP patients and that from controls. Nine miRNAs were differentially expressed between severe and mild AP patients. Further validation confirmed the down‐regulation of miR‐92b, miR‐10a, and miR‐7 in AP patients, and ROC analysis revealed that these miRNAs can differentiate AP from health cases. Further‐more, the serum miR‐551b‐5p level was significantly higher in patients with disease complications or a low plasma calcium level. ROC analysis showed that the serum miR‐551b‐5p level can distinguish be‐tween severe and mild AP.

Patients not enrolled in consecutive or random manner Case‐control study No independent,

blind comparison between index test and reference test Not all patients

received reference test

population, intervention, comparison, or outcome) Studies are imprecise



gradient Plausible confounders

or other biases increase certainty of effect Quality (certainty) of evidence for studies as a whole: High Moderate Low Very Low



(PICO question is quite

Modality: SOFA, Ranson, and APACHE II; Outcome: Morality Study Acronym; Author; Year Published; Location



Endpoint Results / Outcome (Absolute Event Rates, P values; OR or

RR; & 95% CI)

Design Limitations

Journal: Turkish Journal of Gastroenterology Author: Adam, F., et al. Year Published: 2013

Aim: To evaluate the role of three scoring systems, i.e. Acute Physiology and Chronic Health

Inclusion Criteria: Patients with severe acute pancreatitis

Intervention: Diagnosis was obtained by clinical symptoms (abdominal pain with nausea and

Results: Thirty‐nine patients were included in the study (65% male, mean age: 61 years). The


Non‐Randomized Studies

37

References: 1. Adam, F., et al. (2013). "Severe acute pancreatitis admitted to intensive care unit: SOFA is superior to Ranson's criteria and APACHE II in determining prognosis." Turkish Journal of Gastroenterology 24(5):

430‐435.

Location: Ege University School of Medicine, Izmir, Turkey

Evaluation, Sequential Organ Failure Assessment, and modified Ranson’s criteria, in predicting mortality rate in patients with severe acute pancreatitis as well as other factors influencing mortality in patients admitted to intensive care unit. Study Type: Retrospective Study Size: 43 patients

Exclusion Criteria: Patients under 18

vomiting), laboratory parameters (3‐fold increase in amylase and lipase levels) and radiological findings (edematous pancreatitis, cholelithiasis, choledocholithiasis, bile sludge with ultrasonography and/or CT‐MRI). Demographic data, co‐existing diseases (metabolic, cardiac, pulmonary, renal, hepatic disorders, and malignancy) on admission and C‐reactive protein (CRP) levels at 24, 48 and 72 hours were recorded. APACHE II, SOFA and modified Ranson’s scores were calculated on admission, and SOFA score was recorded on weekly intervals during the ICU stay. The initial, highest and mean SOFA scores were taken into account.

intensive care unit mortality was 64% and hospital mortality was 71%. Sequential Organ Failure Assessment scores correlated significantly with mortality. All patients with Sequential Organ Failure Assessment score ≥11 at any time during intensive care unit stay had higher mortality (80% sensitivity, 79% specificity, ROC=0,837). Although Acute Physiology and Chronic Health Evaluation II is used to estimate mortality prognosis, we could not find any statistically significant association between Acute Physiology and Chronic Health Evaluation II scores and mortality.

Failure to develop and apply appropriate eligibility criteria Flawed

measurement of both exposure and outcome Failure to adequately




different from the available evidence in regard to population, intervention, comparison, or outcome) Studies are imprecise






(wide variation of treatment effect across studies, population,

Modality: HAPS and Ranson; Outcome: Severity of AP Study Acronym; Author; Year Published; Location




& 95% CI)

Design Limitations

38

References: 1. Al‐Qahtani, H. H., et al. (2017). "Comparison of Harmless Acute Pancreatitis Score with Ranson's Score in Predicting the Severity of Acute Pancreatitis." Jcpsp, Journal of the College of Physicians & Surgeons ‐

Pakistan 27(2): 75‐79.

Journal: Journal of the College of Physicians & Surgeons ‐ Pakistan Author: Al‐Qahtani, H. H., et al. Year Published: 2017 Location: King Saud Medical City, Riyadh, Kingdom of Saudi Arabia

Aim: To determine the predictability of harmless acute pancreatitis score (HAPS) in determining the severity of acute pancreatitis (AP) and compare it with Ranson's score. Study Type: Prospective cohort study Size: 116 patients

Inclusion Criteria: All consecutive patients with a primary diagnosis of first attack of AP, of either gender, over the age of 14 years, were included in the study

Exclusion Criteria: Patients were excluded from the study, if they refused participation, or had recurrent AP, or had known comorbid disorders of respiratory, cardiovascular or renal systems.

Intervention: All patients admitted with AP were assessed with HAPS and Ranson’s score. Predictability values of the two systems were analyzed and compared.

Results: Out of 116 patients studied, 104 (89.6%) were HAPS positive and predicted to have mild disease. Pancreatitis was mild in 101 (87%) but severe in 3 (2.6%) patients who scored >= 3 Ranson's criteria. Among 12 HAPS negative patients, 10 scored >= 3 Ranson's criteria and developed severe pancreatitis while 2 (1.7%) with 2 positive Ranson's criteria developed mild pancreatitis. HAPS correctly predicted the disease severity in 101 (87%) patients, a sensitivity of 98% specificity of 77% and accuracy of 96%. Ranson's system predicted correctly in all but took 48 hours for assessment. Statistical analysis showed moderate agreement (Kappa = 0.776, p < 0.001), and positive relation (rs = 0.777, p < 0.001) between the two scores.


Non‐Randomized Studies Failure to develop

and apply appropriate eligibility criteria Flawed





interventions, or outcomes varied) Studies are indirect






39

References: 1. Bansal, S. S., et al. (2016). "Performance of the revised Atlanta and determinant‐based classifications for severity in acute pancreatitis." British Journal of Surgery 103(4): 427‐433.








Modality: 1992 Atlanta Classification, revised Atlanta 2012 and DBC; Outcome: Severity of AP Study Acronym; Author;





& 95% CI)

Design Limitations

Journal: British Journal of Surgery Author: Bansal, S. S., et al. Year Published: 2016 Location: University Hospitals Birmingham, UK

Aim: To assess the ability of the Atlanta 1992 classification, revised Atlanta 2012 classification and novel determinant‐based classification (DBC) to stratify disease severity among patients with acute pancreatitis Study Type: Observational cohort study Size: 228 patients

Inclusion Criteria: Patients with a diagnosis of acute pancreatitis

Exclusion Criteria: No patients were excluded

Intervention: This was an observational cohort study of patients with acute pancreatitis identified from an institutional database. Cohort characteristics, investigations, interventions and outcomes were identified. Systems were compared using receiver operating characteristic (ROC) analysis and Spearman's correlation coefficients.

Results: The in‐hospital mortality rate was 6.6 per cent (15 of 228 patients). All of the outcomes considered correlated significantly with the three systems, with the exception of the need for surgery in Atlanta 1992. Atlanta 2012 and the DBC had higher area under the curve (AUC) values than Atlanta 1992 for all outcomes. The revised Atlanta and DBC systems both performed similarly with regard to ICU admission (AUC 0.927 and 0.917 respectively; both P < 0.001), need for percutaneous drainage (AUC 0.879 and 0.891; both P < 0.001), need for surgery (AUC 0.827 and 0.845; P=0.006 and P=0.004 respectively) and in‐hospital mortality (0.955 and 0.931; both P < 0.001). However, the critical category in the DBC system identified patients with the most severe disease; seven of eight patients in this group died in hospital, compared with 15 of 34 with severe pancreatitis according to Atlanta 2012.








40








Modality: BISAP Score; Outcome: Severity of AP Study Acronym; Author; Year

Published; Location



Endpoint Results / Outcome (Absolute Event Rates, P

values; OR or RR; & 95% CI)

Design Limitations

Journal: International Surgery Author: Chen, L., et al. Year Published: 2013 Location: Wuxi People’s Hospital Affiliated to Nanjing Medical University, China

Aim: To evaluate the accuracy of bedside index for severity in acute pancreatitis (BISAP) in predicting the severity and prognoses of acute pancreatitis (AP). Study Type: Retrospective Study Size: 497 patients

Inclusion Criteria: Patients with AP, defined based on the presence of the following features: characteristic abdominal pain (occasionally absent); serum amylase level three times the upper limit of normal; the presence or absence of characteristic imaging findings of AP; and exclusion of other diseases.

Exclusion Criteria: Patients with incomplete clinical data, those who presented symptoms for more than 3 days at admission, and patients with chronic pancreatitis were excluded.

Intervention: Clinical data for patients with AP were analyzed retrospectively to compare BISAP with acute physiology and chronic health evaluation II, Ranson, and computed tomography severity index scores in predicting the severity of AP and the occurrence of pancreatic necrosis, mortality, and organ failure in patients with severe AP (SAP) using the area under the receiver‐operating characteristic curve.

Results: 396 patients had mild AP and 101 patients had SAP. There were significant correlations between the scores of any two systems. BISAP performed similarly to other scoring systems in predicting SAP, as well as pancreatic necrosis, mortality, and organ failure in SAP patients, in terms of the area under the receiver‐operating characteristic curve. Receiver‐operating characteristic (ROC) curves yielded an AUC of 0.762 (95% CI, 0.722–0.799) for BISAP, 0.755 (95% CI, 0.714–0.792) for APACHE II, and 0.801 (95% CI, 0.763–0.835) for Ranson in predicting SAP, with no significant differences among the 3 groups (P > 0.05 for all). BISAP, APACHE II, and Ranson scores were significantly higher in the SAP group than in the MAP group (P ¼ 0.000 for all). Spearman correlation coefficient was 0.612 between BISAP and APACHE II scores, 0.568 between BISAP and Ranson scores, and 0.577 between APACHE II and Ranson scores (P = 0.000 for all), suggesting




measurement of both exposure and outcome Failure to

adequately control confounding Incomplete or



41

significant correlations among the 3 scoring systems.

Journal: Korean Journal of Internal Medicine Author: Kim, B.G., et al. Year Published: 2013 Location: Dong‐A University College of Medicine, Busan, Korea

Aim: To compare the accuracies of the BISAP, serum PCT, and other scoring systems in terms of predicting the severity of AP Study Type: Prospective Study Size: 50 patients

Inclusion Criteria: Patients with AP. The diagnosis of AP was based on acute upper abdominal pain associated with a serum amylase level greater than three times the normal value or an elevated serum lipase level and radiological evidence of AP.

Intervention: Blood samples were obtained at admission and after 48 hours and imaging studies were performed within 48 hours of admission. The BISAP score was compared with the serum PCT, Ranson's score, and the acute physiology and chronic health examination (APACHE)‐II, Glasgow, and Balthazar computed tomography severity index (BCTSI) scores. Acute pancreatitis was graded using the Atlanta criteria. The predictive accuracy of the scoring systems was measured using the area under the receiver‐operating curve (AUC).

Results: The accuracy of BISAP (>= 2) at predicting severe acute pancreatitis was 84% and was superior to the serum PCT (>= 3.29 ng/mL, 76%) which was similar to the APACHE‐II score. The best cutoff value of BISAP was 2 (AUC, 0.873; 95% confidence interval, 0.770 to 0.976; p < 0.001). In logistic regression analysis, BISAP had greater statistical significance than serum PCT.








Journal: Hepatobiliary & Pancreatic Diseases International Author: Park, J. Y., et al. Year Published: 2013 Location: Inje University Sanggye Paik Hospital, Seoul, Korea

Aim: To evaluate the comparative usefulness of the BISAP Study Type: Retrospective Study Size: 303 patients

Inclusion Criteria: Patients with AP

Exclusion Criteria: Patients with missing data

Intervention: Patients with acute pancreatitis diagnosed were analyzed. BISAP, APACHE‐II, Ranson criteria, and CT severity index (CTSI) of all patients were calculated. The patients were stratified and the number of patients with severe pancreatitis, pancreatic necrosis, and organ failure as well as the number of deaths by BISAP score. The area under the receiver operating curve (AUC) to compare BISAP with other scoring systems,

Results: Of the 303 patients, 31 (10.2%) were classified as having severe acute pancreatitis. Organ failure occurred in 23 (7.6%) patients, pancreatic necrosis in 40 (13.2%), and death in 6 (2.0%). A BISAP score of 2 was a statistically significant cutoff value for the diagnosis of severe acute pancreatitis, organ failure, and mortality. AUCs for BISAP predicting severe pancreatitis and death were 0.80 and 0.86, respectively, which were similar to those






inadequately short follow‐up

42

References: 1. Chen, L., et al. (2013). "Evaluation of the BISAP score in predicting severity and prognoses of acute pancreatitis in Chinese patients." International Surgery 98(1): 6‐12. 2. Kim, B. G., et al. (2013). "A comparison of the BISAP score and serum procalcitonin for predicting the severity of acute pancreatitis." Korean Journal of Internal Medicine 28(3): 322‐329. 3. Park, J. Y., et al. (2013). "Bedside index for severity in acute pancreatitis: comparison with other scoring systems in predicting severity and organ failure." Hepatobiliary & Pancreatic Diseases International 12(6):

645‐650.

C‐reactive protein (CRP), hematocrit, and body mass index (BMI) with regard to prediction of severe acute pancreatitis, necrosis, organ failure, and death.

for APACHE‐II (0.80, 0.87) and Ranson criteria (0.74, 0.74) and greater than AUCs for CTSI (0.67, 0.42). The AUC for organ failure predicted by BISAP, APACHE‐II, Ranson criteria, and CTSI was 0.93, 0.95, 0.84 and 0.57, respectively. AUCs for BISAP predicting severity, organ failure, and death were greater than those for CRP (0.69, 0.80, 0.72), hematocrit (0.45, 0.35, 0.14), and BMI (0.41, 0.47, 0.17).

Differences in important prognostic factors at baseline




(when studies include few patients and few events, and thus have wide confidence intervals, and the results are uncertain)

Modality: Ranson, APACHE II, and BISAP; Outcome: Severity of AP Study Acronym; Author; Year

Published; Location





Design Limitations

Journal: World Journal of Gastroenterology Author: Cho, J.H., et al. Year Published: 2015 Location: Yeungnam University College of Medicine, South Korea

Aim: To investigate the prognostic usefulness of several existing scoring systems in predicting the severity of acute pancreatitis (AP) Study Type: Retrospective Study Size: 161 patients

Inclusion Criteria: Patients with AP

Intervention: Acute Physiology and Chronic Health Evaluation (APACHE)‐II, and bedside index for severity in acute pancreatitis (BISAP) scores, and computed tomography severity index (CTSI) of all patients with AP were calculated. Serum C‐reactive protein (CRP) levels were measured at admission (CRPi) and after 24 h (CRP24). Severe AP was defined as persistent organ failure for more than 48 h. The predictive

Results: Of 161 patients, 21 (13%) were classified as severe AP, and 3 (1.9%) died. Statistically significant cutoff values for prediction of severe AP were Ranson>=3, BISAP>=2, APACHE‐II>=8, CTSI>=3, and CRP24>=21.4. AUCs for Ranson, BISAP, APACHE‐II, CTSI, and CRP24 in predicting severe AP were 0.69 (95%CI: 0.62‐0.76), 0.74 (95%CI: 0.66‐0.80), 0.78 (95%CI: 0.70‐0.84), 0.69 (95%CI: 0.61‐0.76), and 0.68 (95%CI: 0.57‐0.78), respectively. APACHE‐II






inadequately short follow‐up

43

References: 1. Cho, J. H., et al. (2015). "Comparison of scoring systems in predicting the severity of acute pancreatitis." World Journal of Gastroenterology 21(8): 2387‐2394. 2. Lee, K. J., et al. (2016). "Comparison of Predictive Systems in Severe Acute Pancreatitis According to the Revised Atlanta Classification." Pancreas 45(1): 46‐50.

accuracy of each scoring system was measured by the area under the receiver‐operating curve (AUC).

demonstrated the highest accuracy for prediction of severe AP, however, no statistically significant pairwise differences were observed between APACHE‐II and the other scoring systems, including CRP24.

Differences in important prognostic factors at baseline

Publication Bias (e.g. pharmaceutical company sponsors study on effectiveness of drug only small, positive studies found) Increase Quality Rating if: Large effect Dose‐response



Journal: Pancreas Author: Lee, K.J., et al. Year Published: 2016 Location: Yonsei University Wonju College of Medicine, Incheon, Korea

Aim: To compare the prognostic value of various predictors and complex scoring systems for prediction of severe acute pancreatitis (SAP) according to the revised Atlanta classification Study Type: Prospective Study Size: 146 patients

Inclusion Criteria: Patients with AP. The diagnosis of AP was based on 2 of the following 3 features: (1) acute abdominal pain, (2) at least 3‐fold elevated levels of serum amylase or lipase, and (3) characteristic findings on radiological study

Intervention: C‐reactive protein (CRP) and procalcitonin were obtained on admission, and CRP level 24 hours after admission (CRP2) was measured. Various scoring systems including Ranson, Acute Physiology and Chronic Health Examination (APACHE II), the Bedside Index for Severity in Acute Pancreatitis, and Computed Tomography Severity Index (CTSI) were calculated.

Results: There were 146 patients with acute pancreatitis (mean age, 50.6 +/‐ 18.3 years; 63% male), of which 43 patients (29.5%) received a diagnosis of moderately severe AP, and 17 patients (11.6%) received a diagnosis of SAP. In patients with moderately severe acute pancreatitis to SAP, CTSI (odds ratio [OR], 10.46; 95% confidence interval [CI], 4.3‐25.43; P < 0.001), APACHE II (OR, 3.87; 95% CI, 1.18‐12.64; P = 0.025), and CRP2 (OR, 4.5; 95% CI, 1.53‐13.1; P = 0.006) were strongly related to moderately severe acute pancreatitis and SAP. In patients with SAP compared with mild to moderately severe AP, procalcitonin (OR, 4.36; 95% CI, 1.01‐18.96; P = 0.049) was the only factor strongly associated with SAP.








44

References:








Modality: Panc 3; Outcome: Severity of AP Study Acronym; Author; Year

Published; Location





Design Limitations

Journal: ABCD, Arquivos Brasileiros de Cirurgia Digestiva Author: Beduschi, M. G., et al. Year Published: 2016 Location: Hospital Regional de São José Dr. Homero de Miranda Gomes, São José, SC, Brazil

Aim: To assess the efficacy of the PANC 3 score to predict acute pancreatitis severity and its relation to clinical outcome Study Type: Prospective Study Size: 64 patients

Inclusion Criteria: Patients with diagnosis of acute pancreatitis was made based on the presence of two out of the three following characteristics: 1) epigastric abdominal pain frequently radiating to the back, intense, persistent and of acute onset; 2) serum amylase and/ or lipase levels three‐fold higher than the upper normalcy limit; and 3) computed tomography with characteristic findings.

Exclusion Criteria: Patients who chose not to participate in the study, those referred by other institutions and diagnosed as acute pancreatitis, with no properly collected data for inclusion in the study, and patients who were not duly followed‐up

Intervention: Acute pancreatitis patients were assessed as to sex, age, body mass index (BMI), etiology of pancreatitis, intensive care need, length of stay, length of stay in intensive care unit and mortality. The PANC 3 score was determined within the first 24 hours after diagnosis and compared to acute pancreatitis grade of the Revised Atlanta classification. The PANC 3 score was determined by measuring three variables obtained within the first 24 h after diagnosis of acute pancreatitis: 1) serum hematocrit; 2) body mass index (BMI); and 3) pleural effusion on the chest X‐ray. The case was considered positive if serum hematocrit was >44 mg/dl, BMI>30 kg/m2 , and pleural effusion was detected on the chest X‐ray.

Results: Out of 64 patients diagnosed with acute pancreatitis, 58 met the inclusion criteria. The PANC 3 score was positive in five cases (8.6%), pancreatitis progressed to a severe form in 10 cases (17.2%) and five patients (8.6%) died. Patients with a positive score and severe pancreatitis required intensive care more often, and stayed for a longer period in intensive care units.

The PANC 3 score showed sensitivity of 50%, specificity of 100%, accuracy of 91.4%, positive predictive value of 100% and negative predictive value of 90.6% in prediction of severe acute pancreatitis.



apply appropriate eligibility criteria Flawed measurement of

both exposure and outcome Failure to adequately


inadequately short follow‐up Differences in important

prognostic factors at baseline

45

1. Beduschi, M. G., et al. (2016). "The Panc 3 Score Predicting Severity of Acute Pancreatitis." ABCD, Arquivos Brasileiros de Cirurgia Digestiva 29(1): 5‐8.








Modality: BISAP, Ranson, CTSI, and SIRS; Outcome: Hyperlipidemic Acute Pancreatitis Study Acronym; Author; Year

Published; Location




RR; & 95% CI)

Design Limitations

Journal: Medicine Author: Qiu, L., et al. Year Published: 2015 Location: Shanghai Tenth People’s Hospital, China

Aim: To summarize the clinical characteristics of HLAP and compare the accuracy of conventional scoring systems in predicting the prognosis of HLAP Study Type: Retrospective Study Size: 909 patients

Inclusion Criteria: All patients with AP

Exclusion Criteria: The exclusion criteria included hospitalization discharge with 48 hours, age <18 years, pregnancy, and incomplete information.

Intervention: Analyzed all consecutively diagnosed AP patients and compared the clinical characteristics between HLAP and nonhyperlipidemic acute pancreatitis. The bedside index for severity of acute pancreatitis (BISAP), Ranson, computed tomography severity index (CTSI), and systemic inflammatory response syndrome (SIRS) scores were applied within 48 hours following admission.

Results: Of 909 AP patients, 129 (14.2%) had HLAP, 20 were classified as severe acute pancreatitis (SAP), 8 had pseudocysts, 9 had pancreatic necrosis, 30 had pleural effusions, 33 had SIRS, 14 had persistent organ failure, and there was 1 death. Among the HLAP patients, the area under curves for BISAP, Ranson, SIRS, and CTSI in predicting SAP were 0.905, 0.938, 0.812, and 0.834, 0.874, 0.726, 0.668, and 0.848 for local complications, and 0.904, 0.917, 0.758, and 0.849 for organ failure, respectively. HLAP patients were characterized by younger age at onset, higher recurrence rate, and being more prone to pancreatic necrosis, organ failure, and SAP. BISAP, Ranson, SIRS, and CTSI all have accuracy in predicting the prognosis of HLAP patients, but each has different strengths and weaknesses.








46

References: 1. Qiu, L., et al. (2015). "Comparison of Existing Clinical Scoring Systems in Predicting Severity and Prognoses of Hyperlipidemic Acute Pancreatitis in Chinese Patients: A Retrospective Study." Medicine 94(23):

e957.







or other biases increase certainty of effect

Modality: EPIC, APACHE II, and BISAP; Outcome: Study Acronym; Author;




Endpoint Results / Outcome (Absolute Event Rates, P values;

OR or RR; & 95% CI)

Design Limitations

Journal: Turkish Journal of Gastroenterology Author: Liu, J., et al. Year Published: 2017 Location: Capital Medical University, Beijing, China

Aim: To compare the ability of conventional laboratory markers and scoring systems to early predict organ failure (OF) and to differentiate between transient and persistent OF in patients with acute pancreatitis (AP) using the revised Atlanta classification Study Type: Retrospective Study Size: 214 patients

Inclusion Criteria: The diagnosis of AP based on the basis of the presence of two of the following three criteria: 1) abdominal pain consistent with the disease, 2) serum amylase and/or lipase >3 times the upper limit of normal, and 3) characteristic findings from abdominal imaging Exclusion Criteria: Exclusion criteria were as follows: 1) time from onset to hospital admission was >72 h, 2) unacceptable abdominal computed tomography (CT) immediately before admission or within 72 h after admission, 3) patients diagnosed with OF or those who underwent invasive treatment before admission, and 4) patients who were pregnant or

Intervention: The predictive values of laboratory markers were analyzed in patients with AP. The predictive accuracy of individual markers, extrapancreatic inflammation on computed tomography (EPIC), acute physiology and chronic health evaluation II (APACHE II), and bedside index for severity in acute pancreatitis (BISAP) scores were measured using the area under the receiver operating characteristic curve (AUROC).

Results: OF was diagnosed in 32 (15%) patients and persistent OF in 14 (6.5%). There were statistically significant differences between patients with and without OF with respect to white blood cell count, creatinine, blood urea nitrogen, lactate dehydrogenase, C‐reactive protein, calcium (Ca), arterial partial pressure of oxygen (PaO2), base excess (BE), APACHE II, BISAP scores, and EPIC scores. Logistic regression analysis identified Ca, PaO2, and BE as independent predictors of OF. Using AUROC, the EPIC score had the highest accuracy for the early prediction of OF, which was 0.82. No significant differences were detected between patients with transient and persistent OF.








47

References: 1. Liu, J., et al. (2017). "Early prediction of organ failure under the revised Atlanta classification." Turkish Journal of Gastroenterology 28(1): 46‐52.

aged <18 years. Relapse patients were not excluded. The study design was approved by the ethics committee of our institution

Quality (certainty) of evidence for studies as a whole: High Moderate Low Very Low






gradient

Modality: Risk Factors; Outcome: Severity of AP Study Acronym; Author; Year Published; Location




& 95% CI)

Design Limitations

Journal: Journal of Digestive Diseases Author: Zeng, Y.B., et al. Year Published: 2014 Location: Second Military University, Shanghai, China

Aim: To identify the risk factors for predicting pancreatic infection in patients with severe acute pancreatitis (SAP) Study Type: Prospective Cohort Study Size: 163 patients. Patients were further divided between two groups, that is, the pancreatic infection group (n = 32) and the non‐pancreatic infection group (n=131)

Inclusion Criteria: Patients admitted with SAP.

Intervention: In all, 163 patients with SAP were included and divided into two groups based on the presence or absence of pancreatic infection. Their demographic and clinical characteristics, laboratory examination results, complications and treatment modalities were collected from their medical records. Variables were initially screened by univariate analysis and those with statistical significance were then filtered by multivariate analysis to determine the independent risk factors for pancreatic infection in SAP.

Results: Patients having SAP with pancreatic infection had a lower partial pressure of arterial carbon dioxide (PaCO2 ), peripheral white blood cell count and alkaline phosphatase levels, together with a higher computed tomography severity index (CTSI) than those without pancreatic infection, while their lactate dehydrogenase (LDH) levels and blood urea nitrogen were much higher. Pancreatic infection was also more common in patients receiving late fluid resuscitation than in those receiving early fluid resuscitation. Multivariate analyses revealed that increased LDH level, high CTSI, delayed fluid resuscitation and hypoxemia were independent risk factors








48

References: 1. Zeng, Y. B., et al. (2014). "Risk factors for pancreatic infection in patients with severe acute pancreatitis: an analysis of 163 cases." Journal of Digestive Diseases 15(7): 377‐385.

Question #4. What is the optimal type (colloid vs. crystalloid) and quantity (per time‐period vs goal‐directed therapy) of intravenous hydration in the initial management (between 48 – 72 hours) of patients with acute pancreatitis, including special populations (patients with congestive heart failure, renal failure, or advanced age)?


The American Gastroenterological Association (AGA) 2018 guideline on Initial Management of Acute Pancreatitis suggests to use goal‐directed therapy for fluid management (Conditional

Recommendation, Very Low Quality Evidence). The AGA suggests against the use of hydroxyethyl starch (HES) fluids (Conditional Recommendation, Very Low Quality Evidence).

The 2015 Japanese guidelines for the management of acute pancreatitis recommended the following for fluid therapy:

An extracellular solution (Ringer’s Lactate solution, etc.) is recommended as the initial infusion solution for acute pancreatitis. (1C)

For patients in shock or with dehydration in the early phases of acute pancreatitis, short‐time rapid fluid resuscitation (150–600 mL/h: depending on the presence of shock and the

dehydration level) is recommended. However, this should be carried out with great care in order to avoid excessive fluid infusion. For patients without dehydration, they should be

monitored closely with an appropriate amount of fluid infusion (130–150 mL/h). Particularly for patients with comorbidities such as cardiac or renal failure, the circulating blood

volume should be careful evaluated to determine the rate of fluid infusion. (1C)

If a mean arterial pressure of 65 mmHg or more and a urine output of 0.5 mL/kg per h or more has been secured in patients with acute pancreatitis, rapid fluid infusion should be

discontinued and a reduction of the rate of fluid infusion is suggested. The volume of infusion should be adjusted to maintain these levels. (2C)

The 2013 International Association of Pancreatology (IAP) and the American Pancreatic Association (APA) stated that early fluid resuscitation within the first 24 hours of admission for

acute pancreatitis is associated with decreased rates of persistent SIRS and organ failure (GRADE 1 C, strong agreement). Ringer’s lactate is recommended for initial fluid resuscitation in

for pancreatic infection in SAP. The sensitivity, specificity, positive and negative predictive values for a model combining the parameters in predicting pancreatic infection were 84%, 97%, 88% and 96%, respectively, with a cut‐off value of 0.393, and the area under the receiver operating characteristic curve was 0.923.

Plausible confounders or other biases increase certainty of effect Quality (certainty) of evidence for studies as a whole: High Moderate Low Very Low

49

acute pancreatitis (GRADE 2B, weak agreement). Goal directed intravenous fluid therapy with 5 – 10 ml/kg/h should be used initially until resuscitation goals are reached (GRADE 1B, weak

agreement). The preferred approach to assessing the response to fluid resuscitation should be based on one or more of the following: 1) non‐invasive clinical targets of heart rate <

120/min, mean arterial pressure between 65‐85 mmHg (8.7 – 11.3 kPa), and urinary output > 0.5 – 1 ml/kg/h, 2) invasive clinical targets of stroke volume variation, and intrathoracic blood

volume determination, and 3) biochemical targets of hematocrit 35 – 44% (Grade 2B, weak agreement).

The 2013 American College of Gastroenterology recommended the following for Initial management:

1. Aggressive hydration, defined as 250‐500 ml per hour of isotonic crystalloid solution should be provided to all patients, unless cardiovascular and / or renal comorbidities exist.

Early aggressive intravenous hydration is most beneficial the first 12 – 24 h, and may have little benefit beyond (strong recommendation, moderate quality of evidence).

2. In a patient with severe volume depletion, manifest as hypotension and tachycardia, more rapid repletion (bolus) may be needed (conditional recommendation, moderate quality

of evidence).

3. Lactated Ringer’s solution may be the preferred isotonic crystalloid replacement fluid (conditional recommendation, moderate quality of evidence).

4. Fluid requirements should be reassessed at frequent intervals within 6 h of admission and for the next 24 – 48 h. The goal of aggressive hydration should be to decrease the blood

urea nitrogen (strong recommendation, moderate quality of evidence).

References:

1. (2013). "IAP/APA evidence‐based guidelines for the management of acute pancreatitis." Pancreatology 13(4 Suppl 2): e1‐15. 2. Crockett, S. D., et al. (2018). "American Gastroenterological Association Institute Guideline on Initial Management of Acute Pancreatitis." Gastroenterology 154(4): 1096‐1101. 3. Tenner, S., et al. (2013). "American College of Gastroenterology guideline: management of acute pancreatitis." Am J Gastroenterol 108(9): 1400‐1415; 1416. 4. Yokoe, M., et al. (2015). "Japanese guidelines for the management of acute pancreatitis: Japanese Guidelines 2015." Journal of Hepato‐biliary‐pancreatic Sciences 22(6): 405‐432.

Primary Literature:


The Technical Review concluded there is insufficient evidence to state that goal‐directed therapy, utilizing various parameters to guide fluid administration, reduces the risk of persistent

single or multiple organ system failure, infected (peri) pancreatic necrosis or mortality from AP. Additional, there was no evidence from RCTs determining that any particular type of fluid

therapy (eg, lactated Ringer’s) reduces the risk of mortality or persistent single or multiple organ failure. The additional of HES to usual intravenous fluids does not reduce the risk of

mortality, and may increase the risk of persistent multiple organ system failure in AP.

Four trials (n = 431) examined predefined rapid hydration or gradual hydration. Mortality was not significantly different between groups (4 trials; OR, 1.92; 95% CI 0.69 – 5.37) nor was

infected pancreatic necrosis (1 trial, OR, 3.49; 95% CI, 0.13 – 90.86) or persistent multiple organ failure (PMOF) (1 trial, OR, 0.35; 95% CI, 0.01 – 9.13). An additional trial by Sharma et al

assessed nasojejunal (NJ) goal‐directed therapy compared to intravenous goal‐directed therapy, but the data could not be analyzed with these studies because it compared 2 different goal‐

directed therapies. None of the reported critical outcomes differed between groups in this trial. (Table 2)

50

While lactated Ringer’s has the theoretical benefit of decreasing pancreatic acidosis and reducing trypsin activity, and has been shown to improve outcomes like C‐reactive protein (CRP)

levels and SIRS in some trials, treatment allocation and choice of outcomes did not allow for a determination of the impact of lactated Ringer’s administration for any of the chosen critical

or important outcomes.

In the 2 trials (n = 161) that examined the administration of 6% hydroxyethyl starch (HES, a non‐ionic starch derivative used as a volume expander) compared to fluids without 6% HES,

mortality was not significantly different (2 trials; OR, 0.47; 95% CI, 0.15 – 1.51). Rates of infected pancreatic necrosis, PMOF, and PSOF were not reported in the included trials. MOF was

significantly increased (OR, 3.86; 95% CI, 1.24 – 12.04) with 6% HES administration in 1 trial. (Table 3)

51

Summary of evidence for optimal type and quantity of intravenous hydration

55

Primary Literature published since the 2017 AGA Technical Review

56

PICO Question: What is the optimal type (colloid vs. crystalloid) and quantity (per time‐period vs goal‐directed therapy) of intravenous hydration in the initial management (between 48 – 72 hours) of patients with acute pancreatitis, including special populations (patients with congestive heart failure, renal failure, or advanced age)?







Outcome: Clinical Improvement

Study Acronym; Author; Year Published;

Location




Design Limitations

Journal: American Journal of Gastroenterology Author: Buxbaum, J.L., et al. Year Published: 2017 Location: University of Southern California, Los Angeles

Aim: To compare aggressive intravenous hydration with standard hydration for the management of acute pancreatitis in a randomized controlled trial Study Type: RCT Size: 60 patients; 27 patients allocated to aggressive fluid arm and 33 patients allocated to moderate fluid arm

Inclusion Criteria: Patients were eligible for inclusion if they presented to the emergency department at Los Angeles County and University of Southern California Medical Center with acute pancreatitis as defined by two of three criteria: epigastric abdominal pain; elevated amylase or lipase >3 times the upper limit of normal; or imaging consistent with acute pancreatitis. Eligible patients were required to be evaluated, consented, and randomized within 4 h of diagnosis.

Exclusion Criteria: Systemic inflammatory response syndrome (SIRS) ( 13 ); New York Heart Association Class II or greater heart failure; decompensated cirrhosis (Child’s Class B or C); hypotension (systolic blood pressure <90 mm Hg); renal insufficiency (Cr>2 mg/dl at time of randomization) or dialysis requirement;

Intervention: Patients with acute pancreatitis without systemic inflammatory response syndrome (SIRS) or organ failure were randomized within 4 h of diagnosis to aggressive (20 ml/kg bolus followed by 3 ml/kg/h) vs. standard (10 ml/kg bolus followed by 1.5 mg/kg/h) hydration with Lactated Ringer’s solution. Patients were assessed at 12‐h intervals. At each interval, in both groups, if hematocrit, blood urea nitrogen (BUN), or creatinine was increased, a bolus of 20 ml/kg followed by 3 ml/kg/h was given; if labs were decreased and epigastric pain was decreased (measured on 0–10 visual analog scale), hydration was then given at 1.5 ml/kg/h and clear liquid diet was started. The primary endpoint, clinical improvement within 36 h, was defined as the combination of decreased hematocrit, BUN, and creatinine; improved pain; and tolerance of oral diet.

Results: A higher proportion of patients treated with aggressive vs. standard hydration showed clinical improvement at 36 h: 70 vs. 42% (P =0.03). The rate of clinical improvement was greater with aggressive vs. standard hydration by Cox regression analysis: adjusted hazard ratio=2.32, 95% confidence interval 1.21–4.45. Persistent SIRS occurred less commonly with aggressive hydration (7.4 vs. 21.1%; adjusted odds ratio (OR)=0.12, 0.02–0.94) as did hemoconcentration (11.1 vs. 36.4%, adjusted OR=0.08, 0.01–0.49). No patients developed signs of volume overload.


RCTs Lack of blinding Lack of allocation

concealment Stopped early for

benefit Incorrect analysis of ITT Selective reporting of

measures (e.g., no effect outcome) Large losses to F/U Difference in important


57

References: 1. Buxbaum, J. L., et al. (2017). "Early Aggressive Hydration Hastens Clinical Improvement in Mild Acute Pancreatitis." American Journal of Gastroenterology 112(5): 797‐803.

respiratory insufficiency (oxygen saturation <90% on room air); hyponatremia (sodium <135 meq/l); clinical signs of volume overload (peripheral edema, pulmonary rales, and ascites); gastrointestinal bleeding; pregnancy; and pancreatitis following an endoscopic, radiographic, or surgical procedure. Imaging was not prescribed by the study protocol but if obtained for clinical indications was used as part of the diagnostic criterion: patients were excluded if pancreatic abscess or necrosis was detected on imaging.






Outcome: SIRS Study Acronym; Author;





Design Limitations


Aim: To compare aggressive intravenous hydration with standard hydration for the management of acute pancreatitis in a randomized controlled trial Study Type: RCT

Inclusion Criteria: Patients were eligible for inclusion if they presented to the emergency department at Los Angeles County and University of Southern California Medical Center with acute pancreatitis as defined by two of three criteria: epigastric

Intervention: Patients with acute pancreatitis without systemic inflammatory response syndrome (SIRS) or organ failure were randomized within 4 h of diagnosis to aggressive (20 ml/kg bolus followed by 3 ml/kg/h) vs. standard (10 ml/kg bolus followed by 1.5 mg/kg/h) hydration with Lactated Ringer’s

Results: A higher proportion of patients treated with aggressive vs. standard hydration showed clinical improvement at 36 h: 70 vs. 42% (P =0.03). The rate of clinical improvement was greater with aggressive vs. standard hydration by Cox regression analysis:




benefit Incorrect analysis of ITT Selective reporting of

measures (e.g., no effect outcome)

58

Size: 60 patients; 27 patients allocated to aggressive fluid arm and 33 patients allocated to moderate fluid arm

abdominal pain; elevated amylase or lipase >3 times the upper limit of normal; or imaging consistent with acute pancreatitis. Eligible patients were required to be evaluated, consented, and randomized within 4 h of diagnosis.

Exclusion Criteria: Systemic inflammatory response syndrome (SIRS) ( 13 ); New York Heart Association Class II or greater heart failure; decompensated cirrhosis (Child’s Class B or C); hypotension (systolic blood pressure <90 mm Hg); renal insufficiency (Cr>2 mg/dl at time of randomization) or dialysis requirement; respiratory insufficiency (oxygen saturation <90% on room air); hyponatremia (sodium <135 meq/l); clinical signs of volume overload (peripheral edema, pulmonary rales, and ascites); gastrointestinal bleeding; pregnancy; and pancreatitis following an endoscopic, radiographic, or surgical procedure. Imaging was not prescribed by the study protocol but if obtained for clinical indications was used as part of the diagnostic criterion: patients were

solution. Patients were assessed at 12‐h intervals. At each interval, in both groups, if hematocrit, blood urea nitrogen (BUN), or creatinine was increased, a bolus of 20 ml/kg followed by 3 ml/kg/h was given; if labs were decreased and epigastric pain was decreased (measured on 0–10 visual analog scale), hydration was then given at 1.5 ml/kg/h and clear liquid diet was started. The primary endpoint, clinical improvement within 36 h, was defined as the combination of decreased hematocrit, BUN, and creatinine; improved pain; and tolerance of oral diet.

adjusted hazard ratio=2.32, 95% confidence interval 1.21–4.45. Persistent SIRS occurred less commonly with aggressive hydration (7.4 vs. 21.1%; adjusted odds ratio (OR)=0.12, 0.02–0.94) as did hemoconcentration (11.1 vs. 36.4%, adjusted OR=0.08, 0.01–0.49). No patients developed signs of volume overload.

Large losses to F/U Difference in important


Publication Bias (e.g. pharmaceutical company sponsors study on effectiveness of drug only small, positive studies found) Increase Quality Rating if: Large effect Dose‐response gradient Plausible confounders or


59

References: 1. Buxbaum, J. L., et al. (2017). "Early Aggressive Hydration Hastens Clinical Improvement in Mild Acute Pancreatitis." American Journal of Gastroenterology 112(5): 797-803.

excluded if pancreatic abscess or necrosis was detected on imaging.








Outcome: Volume Overload


Location




Design Limitations


Aim: To compare aggressive intravenous hydration with standard hydration for the management of acute pancreatitis in a randomized controlled trial Study Type: RCT Size: 60 patients; 27 patients allocated to aggressive fluid arm and 33 patients allocated to moderate fluid arm

Inclusion Criteria: Patients were eligible for inclusion if they presented to the emergency department at Los Angeles County and University of Southern California Medical Center with acute pancreatitis as defined by two of three criteria: epigastric abdominal pain; elevated amylase or lipase >3 times the upper limit of normal; or imaging consistent with acute pancreatitis. Eligible patients were required to be evaluated, consented, and randomized within 4 h of diagnosis.

Exclusion Criteria: Systemic inflammatory response syndrome (SIRS) ( 13 ); New York Heart Association Class II or greater heart failure; decompensated

Intervention: Patients with acute pancreatitis without systemic inflammatory response syndrome (SIRS) or organ failure were randomized within 4 h of diagnosis to aggressive (20 ml/kg bolus followed by 3 ml/kg/h) vs. standard (10 ml/kg bolus followed by 1.5 mg/kg/h) hydration with Lactated Ringer’s solution. Patients were assessed at 12‐h intervals. At each interval, in both groups, if hematocrit, blood urea nitrogen (BUN), or creatinine was increased, a bolus of 20 ml/kg followed by 3 ml/kg/h was given; if labs were decreased and epigastric pain was decreased (measured on 0–10 visual analog scale), hydration was then given at 1.5 ml/kg/h and clear liquid diet was started. The primary endpoint, clinical improvement within 36 h, was defined as the

Results: A higher proportion of patients treated with aggressive vs. standard hydration showed clinical improvement at 36 h: 70 vs. 42% (P =0.03). The rate of clinical improvement was greater with aggressive vs. standard hydration by Cox regression analysis: adjusted hazard ratio=2.32, 95% confidence interval 1.21–4.45. Persistent SIRS occurred less commonly with aggressive hydration (7.4 vs. 21.1%; adjusted odds ratio (OR)=0.12, 0.02–0.94) as did hemoconcentration (11.1 vs. 36.4%, adjusted OR=0.08, 0.01–0.49). No patients developed signs of volume overload.




benefit Incorrect analysis of

ITT Selective reporting of

measures (e.g., no effect outcome) Large losses to F/U Difference in


60

References: 1. Buxbaum, J. L., et al. (2017). "Early Aggressive Hydration Hastens Clinical Improvement in Mild Acute Pancreatitis." American Journal of Gastroenterology 112(5): 797-803.

Question #5. When should prophylactic antibiotics be indicated in treatment for acute pancreatitis? If antibiotics are indicated, which antibiotics are associated with the best clinical outcomes (mortality, morbidity, infected pancreatic necrosis, multiple organ failure, single organ failure, hospital length of stay)? and Question #6: For patient already on antibiotics for treatment of acute pancreatitis, what is the appropriate course of treatment (continuing or tapering)?


cirrhosis (Child’s Class B or C); hypotension (systolic blood pressure <90 mm Hg); renal insufficiency (Cr>2 mg/dl at time of randomization) or dialysis requirement; respiratory insufficiency (oxygen saturation <90% on room air); hyponatremia (sodium <135 meq/l); clinical signs of volume overload (peripheral edema, pulmonary rales, and ascites); gastrointestinal bleeding; pregnancy; and pancreatitis following an endoscopic, radiographic, or surgical procedure. Imaging was not prescribed by the study protocol but if obtained for clinical indications was used as part of the diagnostic criterion: patients were excluded if pancreatic abscess or necrosis was detected on imaging.

combination of decreased hematocrit, BUN, and creatinine; improved pain; and tolerance of oral diet.

61

The American Gastroenterological Association (AGA) 2018 guideline on Initial Management of Acute Pancreatitis suggests against the use of prophylactic antibiotics in patients with severe

AP and necrotizing AP (Conditional Recommendation, Low Quality Evidence).

The 2015 Japanese guidelines for the management of acute pancreatitis recommended the following for antibiotics prophylaxis:

The prophylactic administration of antibiotics is not necessary in mild acute pancreatitis, since the incidence and mortality rates of infectious complications from mild acute pancreatitis are low. (1A)

The prophylactic administration of antibiotics in severe acute pancreatitis and necrotizing pancreatitis may improve the prognosis, if carried out in the early phases of pancreatitis (within 72 h of onset). (2B)

No remedial effect of the prophylactic administration of antifungal agents for acute pancreatitis has been observed. Therefore, routine administration is not recommended. (1C)

The 2013 International Association of Pancreatology (IAP) and the American Pancreatic Association (APA) stated that intravenous antibiotic prophylaxis is not recommended for the

prevention of infectious complications in acute pancreatitis (GRADE 1B, strong agreement).

The 2013 American College of Gastroenterology recommended the following for the role of antibiotics in acute pancreatitis:

Antibiotics should be given for an extrapancreatic infection, such as cholangitis, catheter‐acquired infections, bacteremia, urinary tract infections, pneumonia (strong

recommendation, high quality of evidence).

Routine use of prophylactic antibiotics in patients with severe acute pancreatitis is not recommended (strong recommendation, moderate quality of evidence).

The use of antibiotics in patients with sterile necrosis to prevent the development of infected necrosis is not recommended (strong recommendation, moderate quality of

evidence).

Infected necrosis should be considered in patients with pancreatic or extrapancreatic necrosis who deteriorate or fail to improve after 7 – 10 days of hospitalization. In these

patients, either (i) initial CT‐guided fine needle aspiration (FNA) for Gram stain and culture to guide use of appropriate antibiotics or (ii) empiric use of antibiotics without CT FNA

should be given (strong recommendation, low quality of evidence).

In patients with infected necrosis, antibiotics known to penetrate pancreatic necrosis, such as carbapenems, quinolones, and metronidazole, may be useful in delaying or

sometimes totally avoiding intervention, thus decreasing morbidity and mortality (conditional recommendation, low quality of evidence).

Routine administration of antifungal agents along with prophylactic or therapeutic antibiotics is not recommended (conditional recommendation, low quality of evidence).

References:


62

Primary Literature:


Technical review identified 263 citations, with 10 RCTs (n = 701) that addressed the role of prophylactic antibiotic coverage (Table 4). Mortality exhibited a trend toward reduction with the prophylactic use of antibiotics (OR, 0.66; 95% CI, 0.42‐1.04) that disappeared in subgroup analysis among more recent studies (after 2002: OR, 0.85; 95% CI, 0.52‐1.80) (Table 5). Infected peripancreatic necrosis, was significantly lowered with antibiotic prophylaxis (OR, 0.56; 95% CI, 0.36‐0.86), but no difference in this outcome was noted among more recent trials (OR, 0.81; 95% CI, 0.44‐1.49) (Table 5). Similarly, no between‐group differences in mortality or peripancreatic necrosis were noted among higher‐quality trials. Persistent single organ failure was not reduced by prophylaxis antibiotics (OR, 0.19; 95% CI, 0.01‐4.06). No studies reported on the outcome of PMOF. None of the additional important outcomes were significantly improved with prophylactic antibiotic administration, including MOF or multiple organ dysfunction of unclear duration, single organ failure of unclear duration, and hospital LOS (Table 5). The absence of significant findings among more recent and better‐quality trials is likely attributable to the methodologic limitations below, more prominently noted among older trials. Several trials related to the focus of this AGA technical review were of interest but were excluded because the nature of the intervention was not sufficiently comparable to prophylactic intravenous antibiotic treatment trials included in the review, namely intra‐arterial administration of both antibiotics and protease inhibitors and selective decontamination of the gut. Technical review found inherent methodologic problems described by earlier reviews and recent meta‐analysis are most pronounced among older studies and include differences in inclusion criteria, variable prophylactic antibiotic treatment regimens, inconsistent double blinding, and use of non‐placebo controlled study design that compares 2 antibiotics. Hence, recent guidelines do not recommend prophylactic antibiotics to prevent infection in sterile necrosis in AP. A persistent concern in the field is that methodologic problems across trials might mask detection of an important clinical benefit of prophylactic antibiotics, perhaps in certain subgroups with extensive necrosis and persistent organ failure (usually known only after 48 hours).

67

2015 Japanese guidelines systematic review on early prophylactic antibiotics administration for acute necrotizing pancreatitis

Background: The effectiveness of prophylactic antibiotics use for acute necrotizing pancreatitis has been explored and a number of systematic reviews have been published with conflicting results. The timing of antibiotics administration can be fundamental to their effectiveness, but thus far no reviews have focused on the timing of administration. Methods: A systematic review of randomized controlled trials (RCTs) of prophylactic antibiotics for acute necrotizing pancreatitis was conducted using MEDLINE (PubMed), CINAHL and Japana Centra Revuo Medicina. Trials in which antibiotics were administered within 72 h after onset of symptoms or 48 h after admission were included. Our primary outcomes were the mortality rate and the incidence of infected pancreatic necrosis, and secondary outcomes were the incidence of non‐pancreatic infection and the incidence of surgical intervention. Selection Criteria: (1) RCTs of antibiotics administered through intravenous infusion performed in humans; (2) written in any languages; (3) study population comprised patients with acute necrotizing pancreatitis; (4) the timing of administration of antibiotics was described; and (5) antibiotics were commenced within 72 h after onset of symptoms or 48 hr. after hospital admission. No restriction was placed on the choice of antibiotics. Results: The search revealed six RCTs with a total of 397 patients. The mortality rates were significantly different for those taking antibiotics (7.4%), and controls (14.4%) (odds ratio [OR], 0.48; 95% confidence interval [CI], 0.25–0.94). Also, early prophylactic antibiotics use was associated with reduced incidence of infected pancreatic necrosis (antibiotics 16.3%, controls 25.1%; OR, 0.55; 95% CI, 0.33–0.92). Reference:

1. Ukai, T., et al. (2015). "Early prophylactic antibiotics administration for acute necrotizing pancreatitis: a meta-analysis of randomized controlled trials." Journal of Hepato-biliary-pancreatic Sciences 22(4): 316-321.

70

Comparison of the RCTs included in AGA and Japanese Guideline analysis

AGA Sub‐analysis excluded studies prior to 2002

Japanese Guideline

Excluded from AGA sub‐analysis Year: 1993 Author: Pederzoli Number of Patients (intervention: control): 41 : 33 Antibiotic dosage: Imipenem 0.5g, 8 hours Time of administration: Within 72 h after onset Duration of administration: 14 days

Year: 1993 Author: Pederzoli Number of Patients (intervention: control): 41 : 33 Antibiotic dosage: Imipenem 0.5g, 8 hours Time of administration: Within 72 h after onset Duration of administration: 14 days

Excluded from AGA sub‐analysis Year: 1995 Author: Luiten Number of Patients (intervention: control): 50 : 52 Antibiotic dosage: Selective gut – contamination with norfloxacin, colistin, amphotericin, Colistin sulfate: oral 200 Mg, 6 hours; Oral amphotericin 500 mg 6 hours; Oral norfloxacin 50 mg 6 hours; Cefotaxime 500 mg 8 hours

Excluded from Japanese Meta‐analysis

71

Time of administration: Not reported Duration of administration: Until patient extubated and without supplemental oxygen, on regular diet, and out of ICU (time on therapy not reported)

Excluded from AGA sub‐analysis Year: 1996 Author: Delcenserie Number of Patients (intervention: control): 11 : 12 Antibiotic dosage: Ceftazidine, 2 g, 8 hours; metronidazole, 0.5 g, 8 hours; amikacin, 7.5 mg/kg body weight every 12 hours; and medical treatment Time of administration: Not reported Duration of administration: 10 days


Excluded from AGA sub‐analysis Year: 1995 Author: Sainio Number of Patients (intervention: control): 30 : 30 Antibiotic dosage: Cefuroxime 1.5g, 8 hours for 14 days Time of administration: Within 48 h after admission Duration of administration: 14 days

Year: 1995 Author: Sainio Number of Patients (intervention: control): 30 : 30 Antibiotic dosage: Cefuroxime 1.5g, 8 hours for 14 days Time of administration: Within 48 h after admission Duration of administration: 14 days

Excluded from AGA sub‐analysis Year: 2001 Author: Nordback Number of Patients (intervention: control): 25 : 33 Antibiotic dosage: Imipenem 1.0 g, 8 hours Time of administration: Within 72 h after onset Duration of administration: Not reported

Year: 2001 Author: Nordback Number of Patients (intervention: control): 25 : 33 Antibiotic dosage: Imipenem 1.0 g, 8 hours Time of administration: Within 72 h after onset Duration of administration: Not reported

Year: 2004 Author: Isenmann Number of Patients (intervention: control): 41 : 35 Antibiotic dosage: Ciprofloxacin 0.4 g, 12 hours Time of administration: Within 72 h after onset Duration of administration: 14 – 21 days

Year: 2004 Author: Isenmann Number of Patients (intervention: control): 41 : 35 Antibiotic dosage: Ciprofloxacin 0.4 g, 12 hours Time of administration: Within 72 h after onset Duration of administration: 14 – 21 days

72

Year: 2007 Author: Dellinger Number of Patients (intervention: control): 50 : 50 Antibiotic dosage: Meropenem 1 g, 8 hours Time of administration: Not Reported Duration of administration: 7 ‐ 21 days


Year: 2007 Author: Røkke Number of Patients (intervention: control): 36 : 37 Antibiotic dosage: Imipenem 0.5 g, 8 hours Time of administration: Within 72 f after onset Duration of administration: 5 – 7 days

Year: 2007 Author: Røkke Number of Patients (intervention: control): 36 : 37 Antibiotic dosage: Imipenem 0.5 g, 8 hours Time of administration: Within 72 f after onset Duration of administration: 5 – 7 days

Year: 2009 Author: Garcia‐Barrasa Number of Patients (intervention: control) 22 : 19 Antibiotic dosage: IV ciprofloxacin, 300 mg, 12 hours Time of administration: Not Reported Duration of administration: 10 days


Year: 2009 Author: Xue Number of Patients (intervention: control): 29 : 37 Antibiotic dosage: Imipenem 0.5 g, 8 hours Time of administration: Within 72 h after onset Duration of administration: 7 – 10 days

Year: 2009 Author: Xue Number of Patients (intervention: control): 29 : 37 Antibiotic dosage: Imipenem 0.5 g, 8 hours Time of administration: Within 72 h after onset Duration of administration: 7 – 10 days

AGA Meta‐analysis findings Mortality: OR 0.85 (95% CI 0.52 – 1.80) Infected peripancreatic necrosis: OR 0.81 (95% CI 0.44 – 1.49) *Subgroup = Included only studies after 2002

Japanese Guideline’s Meta‐analysis findings Mortality: OR 0.48 (95% CI 0.25 – 0.94) Infected Pancreatic Necrosis: OR 0.55 (95% CI 0.33 = 0.92) *Analysis = Included only studies with dosing within 72 hours of onset of symptoms or 48 hours after admission


PICO Question: When should prophylactic antibiotics be indicated in treatment for acute pancreatitis? If antibiotics are indicated, which antibiotics are associated with the best clinical outcomes (mortality, morbidity, infected pancreatic necrosis, multiple organ failure, single organ failure, hospital length of stay)?

Low Quality Rating if:

73

References: 1. Moggia, E., et al. (2017). "Pharmacological interventions for acute pancreatitis." Cochrane Database of Systematic Reviews 4: CD011384.

Modality: Acute Pancreatitis; Outcome: Short‐term mortality Studies inconsistent (wide variation of treatment effect across studies, population, interventions, or outcomes varied) Studies are indirect (PICO






Location




Design Limitations

Journal: Cochrane Database of Systematic Reviews Author: Moggia, E., et al. Year Published: 2017 Location: IRCCS Humanitas Research Hospital, Milan, Italy

Aim: To assess the effects of different pharmacological interventions in people with acute pancreatitis Study Type: Systematic Review Size: 17 studies, 1058 participants

Inclusion Criteria: RCTs performed in people with acute pancreatitis, irrespective of etiology, severity, presence of infection, language, blinding, or publication status for inclusion in the review

Intervention: Systematic Review

Results: Antibiotics versus control ‐ Odds Ratio (M‐H, Fixed, 95% CI) 0.81 [0.57, 1.15].





was not appraised or studies were of low quality Methods were

inconsistent across studies



74


Modality: Acute Necrotizing Pancreatitis; Outcome: Short‐term mortality Studies inconsistent (wide variation of treatment effect across studies, population, interventions, or outcomes varied) Studies are indirect (PICO






Location



Endpoint Results / Outcome (Absolute Event Rates, P values; OR or RR; &

95% CI)

Design Limitations














75


Modality: Severe Acute Pancreatitis; Outcome: Short‐term morality Studies inconsistent (wide variation of treatment effect across studies, population, interventions, or outcomes varied) Studies are indirect (PICO






Location




& 95% CI)

Design Limitations














76


Modality: Acute Pancreatitis; Outcome: adverse events Studies inconsistent (wide variation of treatment effect across studies, population, interventions, or outcomes varied) Studies are indirect (PICO






Location




OR or RR; & 95% CI)

Design Limitations


Aim: To assess the effects of different pharmacological interventions in people with acute pancreatitis Study Type: Systematic Review Size: Serious Adverse Events Proportion: 5 studies, 304 participants; Number: 12 studies, 716 participants Adverse Events Proportion: 6 studies, 429 participants; Number: 12 studies, 755 participants



Results: Serious adverse events (proportion) Antibiotics versus control ‐ Odds Ratio (M‐H, Fixed, 95% CI) 0.65 [0.37, 1.15].

Serious adverse events (number) Antibiotics versus control – Rate Ratio (Fixed, 95% CI) 0.86 [0.68, 1.07]

Adverse events (proportion) Antibiotics versus control ‐ Odds Ratio (M‐H, Fixed, 95% CI) 0.51 [0.32, 0.80].

Adverse events (number) Antibiotics versus control – Rate Ratio (Fixed, 95% CI) 0.75 [0.58, 0.95]







77









Modality: Acute Necrotising Pancreatitis; Outcome: adverse events Study Acronym; Author;





Design Limitations


Aim: To assess the effects of different pharmacological interventions in people with acute pancreatitis Study Type: Systematic Review Size: Serious Adverse Events Proportion: 4 studies, 281 participants; Number: 7 studies













78


Modality: Severe Acute Pancreatitis; Outcome: adverse events Studies inconsistent (wide variation of treatment effect across studies, population, interventions, or outcomes varied) Studies are indirect (PICO






Location




Design Limitations


Aim: To assess the effects of different pharmacological interventions in people with acute pancreatitis Study Type: Systematic Review Size: Proportion: 3 studies, 164 participants; Number: 5 studies













79


Modality: Acute Pancreatitis; Outcome: Organ Failure Studies inconsistent (wide variation of treatment effect across studies, population, interventions, or outcomes varied) Studies are indirect (PICO






Location



Endpoint Results / Outcome (Absolute

Event Rates, P values; OR or RR; & 95% CI)

Design Limitations














80

References: 1. Moggia, E., et al. (2017). "Pharmacological interventions for acute pancreatitis." Cochrane Database of Systematic Reviews 4: CD011384. 2.

Modality: Acute Necrotising Pancreatitis; Outcome: Organ Failure Studies inconsistent (wide variation of treatment effect across studies, population, interventions, or outcomes varied) Studies are indirect (PICO






Location




Design Limitations














81


Modality: Severe Acute Pancreatitis; Outcome: Organ Failure Studies inconsistent (wide variation of treatment effect across studies, population, interventions, or outcomes varied) Studies are indirect (PICO






Location




Design Limitations














82


Modality: Acute Pancreatitis; Outcome: Infected pancreatic necrosis Studies inconsistent (wide variation of treatment effect across studies, population, interventions, or outcomes varied) Studies are indirect (PICO






Location




Design Limitations














83


Modality: Acute Necrotising Pancreatitis; Outcome: Infected pancreatic necrosis Studies inconsistent (wide variation of treatment effect across studies, population, interventions, or outcomes varied) Studies are indirect (PICO






Location




Design Limitations














84


Modality: Severe Acute Pancreatitis; Outcome: Infected pancreatic necrosis Studies inconsistent (wide variation of treatment effect across studies, population, interventions, or outcomes varied) Studies are indirect (PICO






Location




& 95% CI)

Design Limitations














85


Modality: Acute Pancreatitis; Outcome: Sepsis Studies inconsistent (wide variation of treatment effect across studies, population, interventions, or outcomes varied) Studies are indirect (PICO






Location




RR; & 95% CI)

Design Limitations














86


Modality: Acute Necrotising Pancreatitis; Outcome: Sepsis Studies inconsistent (wide variation of treatment effect across studies, population, interventions, or outcomes varied) Studies are indirect (PICO






Location




Design Limitations














87


Modality: Acute Pancreatitis; Outcome: Requirement for additional invasive intervention Studies inconsistent (wide variation of treatment effect across studies, population, interventions, or outcomes varied) Studies are indirect (PICO






Location



Endpoint Results / Outcome (Absolute

Event Rates, P values; OR or RR; & 95% CI)

Design Limitations














88


Systematic Review Summary

Modality Outcome Odds Ratio & 95% CI Level of Evidence

Modality: Acute Pancreatitis; Outcome: Endoscopic or radiological drainage of collections Studies inconsistent (wide variation of treatment effect across studies, population, interventions, or outcomes varied) Studies are indirect (PICO






Location




& 95% CI)

Design Limitations












89

Acute Pancreatitis Short‐term mortality 0.81 [0.57, 1.15] Low

Serious adverse events (proportion)

0.65 [0.37, 1.15] Low

Serious adverse events (number)

0.86 [0.68, 1.07] Low

Adverse events (proportion) 0.51 [0.32, 0.80] Low

Adverse events (number) 0.75 [0.58, 0.95] Low

Organ Failure 0.78 [0.44, 1.38] Very Low

Infected pancreatic necrosis 0.82 [0.53, 1.25] Very Low

Sepsis 0.42 [0.11, 1.60] Very Low

Requirement for additional invasive intervention

0.82 [ 0.59, 1.13] Low

Endoscopic or radiological drainage of collections

0.33 [0.01, 9.07] Very Low

Acute Necrotizing Pancreatitis Short‐term mortality 0.82 [0.52, 1.30] Low

Serious adverse events 0.84 [0.46, 1.54] Very Low


0.79 [0.59, 1.06] Very Low



Sepsis 0.42 [0.11, 1.60] Very Low

Severe Acute Pancreatitis Short‐term mortality 0.82 [0.53, 1.27] Low

Serious adverse events (proportion)

0.56 [0.27, 1.18] Very Low


0.81 [0.52, 1.25] Very Low



*Adverse events definition was from the International Conference on Harmonisation – Good Clinical Practice guideline: Any untoward medical occurrence that results in

death, is life‐threatening, requires inpatient hospitalization, or prolongation of existing hospitalization, or results in persistent or significant disability/incapacity.

90

Question #7: Which patients with acute pancreatitis benefit from endoscopic retrograde cholangiopancreatography (ERCP)?


The American Gastroenterological Association (AGA) 2018 guideline on Initial Management of Acute Pancreatitis stated in patients with acute biliary pancreatitis and no cholangitis, the

AGA suggests against the routine use of urgent ERCP (Conditional recommendation, Low Quality of Evidence).

The 2015 American Society for Gastrointestinal Endoscopy (ASGE) guideline on the role of ERCP in benign diseases of the biliary tract:

Recommended that ERCP in patients with acute biliary pancreatitis be limited to those with concomitant cholangitis or biliary obstruction. [Quality of Evidence: High]

Recommended rectal indomethacin with or without a pancreatic stent for prophylaxis against post‐ERCP pancreatitis when ERCP is performed in patients with suspected spincter

of Oddi dysfunction (SOD). [Quality of Evidence: Moderate]

The 2015 Japanese guidelines for the management of acute pancreatitis recommended the following for management of biliary pancreatitis:

Early ERCP/ES should be performed in gallstone‐induced acute pancreatitis when complications of cholangitis or prolonged passage disorder of the biliary tract are suspected. (1A)

To prevent the recurrence of gallstone‐induced acute pancreatitis, cholecystectomy is recommended for cases where such surgery is possible. (1B)

A cholecystectomy should be performed as soon as gallstone‐induced acute pancreatitis has been resolved. (1B)

The 2013 International Association of Pancreatology (IAP) and the American Pancreatic Association (APA) stated

ERCP is not indicated in predicted mild biliary pancreatitis without cholangitis. (GRADE 1A, strong agreement). ERCP is probably not indicated in predicted severe biliary

pancreatitis without cholangitis (GRADE 1B, strong agreement). ERCP is probably indicated in biliary pancreatitis with common bile duct obstruction (GRADE 1C, strong

agreement) ERCP is indicated in patients with biliary pancreatitis and cholangitis (GRADE 1B, strong agreement)

Urgent ERCP (<24 hrs) is required in patients with acute cholangitis. Currently, there is no evidence regarding the optimal timing of ERCP in patients with biliary pancreatitis without

cholangitis. (GRADE 2C, strong agreement)

MRCP and EUS may prevent a proportion of ERCPs that would otherwise be performed for suspected common bile duct stones in patients with biliary pancreatitis who do not have

cholangitis, without influencing the clinical course. EUS is superior to MRCP in excluding the presence of small (<5mm) gallstones. MRCP is less invasive, less operator‐dependent

and probably more widely available than EUS. Therefore, in clinical practice there is no clear superiority for either MRCP or EUS. (GRADE 2C, strong agreement)

In patients with biliary pancreatitis who have undergone sphincterotomy and are fit for surgery, cholecystectomy is advised, because ERCP and sphincterotomy prevent recurrence

of biliary pancreatitis but not gallstone related gallbladder disease, i.e. biliary colic and cholecystitis. (GRADE 2B, strong agreement)

The 2013 American College of Gastroenterology recommended the following for ERCP in acute pancreatitis:

Patients with acute pancreatitis and concurrent acute cholangitis should undergo ERCP within 24h of admission (strong recommendation, moderate quality of evidence).

ERCP is not needed in most patients with gallstone pancreatitis who lack laboratory or clinical evidence of ongoing biliary obstruction (strong recommendation, low quality of

evidence).

91

In the absence of cholangitis and / or jaundice, MRCP or endoscopic ultrasound (EUS) rather than diagnostic ERCP should be used to screen for choledocholithiasis if highly

suspected (conditional recommendation, low quality of evidence).

Pancreatic duct stents and / or postprocedure rectal nonsteroidal anti‐inflammatory drug (NSAID) suppositories should be utilized to prevent severe post‐ERCP pancreatitis in high‐

risk patients (conditional recommendation, moderate quality of evidence).

References:

1. (2013). "IAP/APA evidence‐based guidelines for the management of acute pancreatitis." Pancreatology 13(4 Suppl 2): e1‐15. 2. Chathadi, K. V., et al. (2015). "The role of ERCP in benign diseases of the biliary tract." Gastrointestinal Endoscopy 81(4): 795‐803. 3. Crockett, S. D., et al. (2018). "American Gastroenterological Association Institute Guideline on Initial Management of Acute Pancreatitis." Gastroenterology 154(4): 1096‐1101. 4. Tenner, S., et al. (2013). "American College of Gastroenterology guideline: management of acute pancreatitis." Am J Gastroenterol 108(9): 1400‐1415; 1416. 5. Yokoe, M., et al. (2015). "Japanese guidelines for the management of acute pancreatitis: Japanese Guidelines 2015." Journal of Hepato‐biliary‐pancreatic Sciences 22(6): 405‐432.


Technical identified 242 citations, with 8 RCTs (n = 935) that addressed the role of urgent ERCP in acute gallstone pancreatitis (Table 6). Mortality, MOF, single organ failure (respiratory,

renal, circulatory), infected (peri) pancreatic necrosis, and total necrotizing pancreatitis were no different between patients randomized to the urgent ERCP or the conservative

management groups; subgroup analyses that assessed all studies and those having excluded patients with biliary obstruction showed similar findings. In addition, no differences were

attributed to ERCP among patients with pancreatitis and cholangitis, although the outcome was reported in small numbers of patients and in only 1 trial. The only significant difference

in outcomes pertained to LOS that was significantly decreased with urgent ERCP weight mean differences (WMD) = ‐8.8 (95% CI, ‐12.64 to ‐4.96) (1 trial, n = 120 patients).

Although most of the recent trials specifically attempted to exclude patients with suspected cholangitis, there remains marked clinical heterogeneity in adopted selection criteria/definitions

limiting the interpretation of the findings (Table 7).

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References:

PICO Question: Which patients with acute pancreatitis benefit from endoscopic retrograde cholangiopancreatography (ERCP)? Low Quality Rating if: Studies inconsistent (wide






Modality: Indication system for ERCP; Outcome: Choledocholithiasis Study Acronym; Author;





& 95% CI)

Design Limitations

Journal: Scandinavian Journal of Gastroenterology Author: Yuen, N., et al. Year Published: 2017 Location: Australian National University Medical School, Acton, Australia

Aim: To review the prevailing ERCP indications in the literature, and to propose and evaluate a new ERCP indication system, which relies on more objective pre‐procedure parameters Study Type: Systematic review to develop new indication system Size: Systematic Reivew: 12 studies and 53,394 ERCP procedures; Indication system development: 1758 consecutive ERCP procedures

Inclusion Criteria: Search criteria: greater than 500 ERCP cases; consecutive, unselected cases; ERCP carried out in humans; literature published in English; and published in the last 10 years.

Methods: Systematic review and Indiction system: An analysis was conducted on consecutive ERCP procedures, in which contemporaneous use was made of an apriori indication system. Indications were based on the objective pre‐procedure parameters and divided into primary [cholangitis, clinical evidence of biliary leak, acute (biliary) pancreatitis, abnormal intraoperative cholangiogram (IOC), or change/removal of stent for benign/malignant disease] and secondary [combination of two or three of: pain attributable to biliary disease (‘P’), imaging evidence of biliary disease (‘I’), and abnormal liver function tests (LFTs) (‘L’)]. A secondary indication was only used if a primary indication was not present. The relationship between this newly developed classification system and ERCP findings and adverse events was examined.

Results: The indications of cholangitis and positive intraoperative cholangiogram (IOC) were predictive of choledocholithiasis at ERCP (101/154 and 74/141 procedures, respectively). With respect to secondary indications, only if all three of ‘P’, ‘I’,and ‘L’ were present there was a statistically significant association with choledocholithiasis (v2(1) = 35.3, p < .001). Adverse events were associated with an unusual indication leading to greater risk of unplanned hospitalization (v2(1) = 17.0, p < .001).


Systematic Review Review did not

address focused clinical question Search was not

detailed or exhaustive Quality of the studies



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1. Yuen, N., et al. (2017). "New classification system for indications for endoscopic retrograde cholangiopancreatography predicts diagnoses and adverse events." Scandinavian Journal of Gastroenterology 52(12): 1457‐1465.

Question #8: What is the optimal timing, type, and route of nutrition treatment for patients with acute pancreatitis?


The American Gastroenterological Association (AGA) 2018 guideline on Initial Management of Acute Pancreatitis stated:

In patients with AP, the AGA recommends early (within 24 hours) oral feeding as tolerated rather than keeping the patient nil per os. (Strong recommendation, moderate quality

evidence).

In patients with AP and inability to feed orally, the AGA recommends enternal rather than parental nutrition. (Strong recommendation, moderate quality evidence).

In patients with predicted severe or necrotizing pancreatitis requiring enteral tube feeding, the AGA suggest either nasogastric or nasoenternal route. (Conditional

recommendation, low quality evidence)

The 2016 Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) guidelines for the Provision and Assessment of Nutrition Support

Therapy in the Adult Critically Ill Patient stated the following:

Bundle Statements:

Assess patients on admission to the ICU for nutrition risk, and calculate both energy and protein requirements to determine goals of nutrition therapy.

Initiate enteral nutrition (EN) within 24−48 hours following the onset of critical illness and admission to the ICU and increase to goals over the first week of ICU stay.

Take steps as needed to reduce risk of aspiration or improve tolerance to gastric feeding (use prokinetic agent, continuous infusion, chlorhexidine mouthwash, elevate the head of

bed, and divert level of feeding in the gastrointestinal tract).

Implement enteral feeding protocols with institution‐specific strategies to promote delivery of EN.

Do not use gastric residual volumes as part of routine care to monitor ICU patients on EN.

Start parenteral nutrition early when EN is not feasible or sufficient in high‐risk or poorly nourished patients.

Acute Pancreatitis:

Suggest that the initial nutrition assessment in acute pancreatitis evaluate disease severity to direct nutrition therapy. Since disease severity may change quickly,

suggest frequent reassessment of feeding tolerance and need for specialized nutrition therapy. [Expert Consensus]

Suggest NOT providing specialized nutrition therapy to patients with mild acute pancreatitis, instead advancing to an oral diet as tolerated. If an unexpected

complication develops or there is failure to advance to oral diet within 7 days, then specialized nutrition therapy should be considered. [Quality of Evidence: Very

Low]

Suggest that patients with moderate to severe acute pancreatitis should have a naso‐/oroenteric tube placed and EN started at a trophic rate and advanced to goal

as fluid volume resuscitation is completed (within 24–48 hours of admission). [Quality of Evidence: Very Low]

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Suggest using a standard polymeric formula to initiate EN in the patient with severe acute pancreatitis. Although promising, the data are currently insufficient to

recommend placing a patient with severe acute pancreatitis on an immune‐enhancing formulation at this time. [Quality of Evidence: Very Low]

Suggest the use of EN over PN in patients with severe acute pancreatitis who require nutrition therapy. [Quality of Evidence: Low]

Suggest that EN be provided to the patient with severe acute pancreatitis by either the gastric or jejunal route, as there is no difference in tolerance or clinical

outcomes between these two levels of infusion. [Quality of Evidence: Low]

Suggest that, in patients with moderate to severe acute pancreatitis who have intolerance to EN, measures should be taken to improve tolerance. [Expert

Consensus]

Suggest that the use of probiotics be considered in patients with severe acute pancreatitis who are receiving early EN. [Quality of Evidence: Low]

Suggest that, for the patient with severe acute pancreatitis, when EN is not feasible, use of PN should be considered after one week from the onset of the

pancreatitis episode. [Expert Consensus]

The 2015 Japanese guidelines for the management of acute pancreatitis recommended the following for:

Nasogastric tube

No remedial effect of nasogastric tube insertion has been observed for mild acute pancreatitis. Therefore, the routine use of nasogastric suction tubes is not required. (1A)

Nutritional support

Intravenous hyperalimentation is not recommended for mild cases. (1B)

Total parenteral nutrition (not performed with oral or enteral nutrition) should be avoided if possible. (1B)

In severe cases, it is more significant as a measure to prevent infection rather than as a route of nutrition support. It can be applied and implemented for severe cases which do not

have accompanying intestinal complications. (1A)

If initiated in the early phase, enteral nutrition can reduce the incidence of complications and can contribute to an increased rate of survival. Therefore, it is desirable that it be

started within at least 48 h of admission. (2A)

In principle, it is recommended that enteral feeding tubes be inserted into the jejunum through the Treitz ligament. However, if a feeding tube cannot be inserted into the jejunum,

nutrients can be infused into the duodenum or stomach instead. (2B)

The initiation of oral administration should be determined using indicators such as the subsidence of abdominal pain and the serum pancreatic enzyme (especially serum lipase)

level, etc. (2B)

The 2013 International Association of Pancreatology (IAP) and the American Pancreatic Association (APA) stated the following for nutritional support:

Oral feeding in predicted mild pancreatitis can be restarted once abdominal pain is decreasing and inflammatory markers are improving. (GRADE 2B, strong agreement)

Enteral tube feeding should be the primary therapy in patients with predicted severe acute pancreatitis who require nutritional support. (GRADE 1B, strong agreement)

Either elemental or polymeric enteral nutrition formulations can be used in acute pancreatitis. (GRADE 2B, strong agreement)

Enteral nutrition in acute pancreatitis can be administered via either the nasojejunal or nasogastric route. (GRADE 2A, strong agreement)

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Parenteral nutrition can be administered in acute pancreatitis as second‐line therapy if nasojejunal tube feeding is not tolerated and nutritional support is required. (GRADE 2C,

strong agreement)

The 2013 American College of Gastroenterology recommended the following for nutrition in acute pancreatitis:

In mild AP, oral feedings can be started immediately if there is no nausea and vomiting, and abdominal pain has resolved (conditional recommendation, moderate quality of evidence).

In mild AP, initiation of feeding with a low‐fat solid diet appears as safe as a clear liquid diet (conditional recommendations, moderate quality of evidence).

In severe AP, enteral nutrition is recommended to prevent infectious complications. Parenteral nutrition should be avoided unless the enteral route is not available, not tolerated, or not meeting caloric requirements (strong recommendation, high quality of evidence).

Nasogastric delivery and nasojejunal delivery of enteral feeding appear comparable in efficacy and safety (strong recommendation, moderate quality of evidence). References:

1. (2013). "IAP/APA evidence‐based guidelines for the management of acute pancreatitis." Pancreatology 13(4 Suppl 2): e1‐15. 2. Crockett, S. D., et al. (2018). "American Gastroenterological Association Institute Guideline on Initial Management of Acute Pancreatitis." Gastroenterology 154(4): 1096‐1101. 3. McClave, S. A., et al. (2016). "Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient." Journal of Parenteral and Enteral Nutrition

40(2): 159‐211. 4. Tenner, S., et al. (2013). "American College of Gastroenterology guideline: management of acute pancreatitis." Am J Gastroenterol 108(9): 1400‐1415; 1416. 5. Yokoe, M., et al. (2015). "Japanese guidelines for the management of acute pancreatitis: Japanese Guidelines 2015." Journal of Hepato‐biliary‐pancreatic Sciences 22(6): 405‐432.


What is the benefit of early feeding in mild or severe pancreatitis?

From 547 citations, the technical review identified 15 RCTs that addressed the role of early vs delayed feeding (Table 8). Four of the 15 were not included in the analyses because timing of

feeding was not clearly identified. Mortality was not significantly different for delayed compared to early feeding (OR, 0.59; 95% CI, 0.22 ‐ 1.59) or any of the other noted outcomes.

There exists some clinical heterogeneity in the time to feeding that extends beyond the scope of the first 48 hours targeted by this technical review, varying in part according to the severity

of the AP as discussed, but this was not believed to significantly invalidate the results. Subgroup analyses showed no differences in outcomes when comparing npo vs early oral feeding or

enteral feeding (data available upon request). However, in the comparison of npo vs early enteral feeding, the rate of intervention for necrosis was increased (OR, 2.47; 95% CI, 1.41 ‐

4.35) in the npo (fasting) group (1 trial); in the comparison of npo vs TPN, ICU LOS was significantly shorter for the npo (fasting) group WMD = ‐10.5 days (95% CI, ‐15.74 to ‐5.24 days)(1

trial) (Table 9).

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What is the benefit of artificial enternal nutritional support (nasogastric or nasojejunal) compared to total parenteral nutrition in mild or severe pancreatitis?

From 547 citations, the technical review identified 12 RCTs that compared nasogastric (NG) or nasojejunal (NJ) to total parenteral nutrition (TPN) in mild or severe pancreatitis (Table 10).

Mortality was not significantly different in the 2 groups (OR, 0.60; 95% CI, 0.25‐1.43), but multiple organ failure and single organ failure were significantly decreased in the NG or NJ

group compared to TPN (OR, 0.41; 95% CI, 0.27‐0.63) and 0.25 (95% CI, 0.10‐0.62), respectively. The conclusions were unchanged when restricting the analysis to the trials with only SAP

(data available upon request). However, even in severe and necrotizing AP, a proportion of patients can be fed orally, particularly if no significant nausea and vomiting or paralytic ileus is

present (Table 11). The evidence supports the superiority of enteral nutrition in both mild and SAP if patients cannot tolerate oral feeding. TPN is indicated only when enteral route is

not possible or is not able to meet the minimum calorie requirements.

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What is the benefit of the route of nasogastric feeding over nasojejunal feeding in predicted severe and necrotizing pancreatitis?

From 547 citations, the technical review identified 3 RCTs that compared nasojejunal (NJ) compared to nasogastric (NG) in severe acute pancreatitis (SAP) (Table 12). Mortality was not

significantly different between the 2 groups (OR, 1.01; 95%CI, 0.44‐2.30). Similarly, none of the other outcomes were significantly different for NJ compared to NG. Some methodologic

problems exist in these studies, for example, NJ feeding was actually nasoduodenal in 1 study and mortality was higher than usual in the SAP group. Significant weaknesses of these analyses

are that each study used different criteria to define SAP, and data for all major out‐comes except death were derived from only 1 small study each (Table 13).

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PICO Question: What is the optimal timing, type, and route of nutrition treatment for patients with acute pancreatitis? Low Quality Rating if: Studies inconsistent (wide





other biases increase certainty of effect Quality (certainty) of evidence for studies as a whole: High Moderate Low

Modality: Early enternal nutrition versus delayed enternal nutrition; Outcome: Organ Failure


Location




& 95% CI)

Design Limitations

Journal: Medicine Author: Feng, P., et al. Year Published: 2017 Location: University of South China, Hengyang, Hunan, China

Aim: To pool all relevant articles to evaluate the effects of early enternal nutrition (EEN) within 48 hours versus delayed enternal nutrition (DEN) beyond 48 hours on the clinical outcomes of patients with acute pancreatitis Study Type: Systematic review with meta‐analysis Size: 6 studies including 1007 patients; 2 retrospective studies and 4 RCTs

Inclusion Criteria: (1) Randomized comparative trials (RCTs) or retrospective trials with available information; (2) Consecutive patients with acute pancreatitis; and (3) EEN within 48 hours and DEN beyond 48 hours Exclusion Criteria: (1) Duplicate publications; (2) case reports, reviews, meta‐analysis, or guidelines; and (3) contained no available data for this meta‐analysis

Methods: Systematic Review with meta‐analysis

Results: The pooled analysis showed that EEN was related to a reduced risk of multiple organ failure (RR=0.67, 95% CI 0.46‐0.99, P=.04), but not for necrotizing pancreatitis (RR=0.95, 95% CI 0.81‐1.12, P=.57).







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References: 1. Feng, P., et al. (2017). "Early enteral nutrition versus delayed enteral nutrition in acute pancreatitis: A PRISMA‐compliant systematic review and meta‐analysis." Medicine 96(46): e8648.


Very Low







Modality: Early enternal nutrition versus delayed enternal nutrition; Outcome: Systemic Inflammatory Response Syndrome (SIRS) Study Acronym; Author;





& 95% CI)

Design Limitations





Results: There was a tendency for decreased systemic inflammatory response in the EEN group, but the trend was not significant (RR = 0.85, 95% CI 0.71‐1.02, P=0.09).







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Question #9: Which patients with mild acute biliary pancreatitis benefit from same‐admission vs delayed cholecystectomy?







Modality: Early enternal nutrition versus delayed enternal nutrition; Outcome: Mortality


Location




OR or RR; & 95% CI)

Design Limitations





Results: No significant difference was found between the EEN and DEN groups (RR=0.78, 95% CI 0.27‐2.24, P=.64).







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In patients with acute biliary pancreatitis, the AGA recommends cholecystectomy during the initial admission rather than after discharge. (Strong Recommendation, Moderate

Quality of Evidence)

The 2015 Japanese guidelines for the management of acute pancreatitis recommended the following for management of biliary pancreatitis:

To prevent the recurrence of gallstone‐induced acute pancreatitis, cholecystectomy is recommended for cases where such surgery is possible. (1B)

A cholecystectomy should be performed as soon as gallstone‐induced acute pancreatitis has been resolved. (1B)

The 2013 International Association of Pancreatology (IAP) and the American Pancreatic Association (APA) stated the following for timing of cholecystectomy (or endoscopic

sphincterotomy):

Cholecystectomy during index admission for mild biliary pancreatitis appears safe and is recommended. Interval cholecystectomy after mild biliary pancreatitis is associated with a

substantial risk of readmission for recurrent biliary events, especially recurrent biliary pancreatitis. (GRADE 1C, strong agreement)

Cholecystectomy should be delayed in patients with peripancreatic collections until the collections either resolve or if they persist beyond 6 weeks, at which time cholecystectomy

can be performed safely. (GRADE 2C, strong agreement)

In patients with biliary pancreatitis who have undergone sphincterotomy and are fit for surgery, cholecystectomy is advised, because ERCP and sphincterotomy prevent recurrence

of biliary pancreatitis but not gallstone related gallbladder disease, i.e. biliary colic and cholecystitis. (GRADE 2B, strong agreement)

The 2013 American College of Gastroenterology recommended the following for the role of surgery in acute pancreatitis:

In patients with mild AP, found to have gallstones in the gallbladder, a cholecystectomy should be performed before discharge to prevent a recurrence of AP (strong


In a patient with necrotizing biliary AP, in order to prevent infection, cholecystectomy is to be deferred until active inflammation subsides and fluid collections resolve or stabilize

(strong recommendation, moderate quality of evidence).

The presence of asymptomatic pseudocysts and pancreatic and / or extrapancreatic necrosis do not warrant intervention, regardless of size, location, and / or extension (strong


In stable patients with infected necrosis, surgical, radiologic, and / or endoscopic drainage should be delayed preferably for more than 4 weeks to allow liquefication of the

contents and the development of a fibrous wall around the necrosis (walled‐off necrosis) (strong recommendation, low quality of evidence).

In symptomatic patients with infected necrosis, minimally invasive methods of necrosectomy are preferred to open necrosectomy (strong recommendation, low quality of

evidence).

References:

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What is the role of same‐admission vs. delayed cholecystectomy in patients with mild acute gallstone pancreatitis?

From an initial 120 citations, only 1 RCT (n = 264) was identified that addressed the role of same admission vs delayed cholecystectomy in patients with mild acute gallstone pancreatitis (Table 14). Same‐admission cholecystectomy was done within 3 days after randomization. In the interval cholecystectomy group, patients were discharged from hospital and cholecystectomy was electively scheduled 25‐30 days after randomization. Intraoperative cholangiography was not mandatory, with widespread availability of ERCP, if indicated. The primary end point was a composite of gallstone‐related complications or mortality occurring within 6 months after randomization, before or after cholecystectomy, analyzed by intention to treat. Gallstone‐related complications were defined as readmission for recurrent pancreatitis, cholecystitis, cholangitis, choledocholithiasis needing ERCP or gallstone colic. The primary end point occurred in significantly fewer patients in the surgery during the same admission group compared to those undergoing delayed cholecystectomy (OR, 0.24; 95% CI, 0.09‐0.61); no difference was noted in mortality during the 6‐month follow‐up period (OR, 3.21; 95% CI, 0.13‐79.56). Patients undergoing same‐admission cholecystectomy had significantly fewer readmissions for both recurrent pancreatitis and pancreaticobiliary complications compared to those undergoing delayed cholecystectomy (OR, 0.25; 95% CI, 0.07‐0.90 and OR, 0.24; 95% CI, 0.09‐0.61, respectively). There was no difference between conversion to open cholecystectomy or difficulty of cholecystectomy between the 2 groups (Table 15).

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Question #10: What is the optimal method and timing of alcohol cessation counseling in patients with acute alcohol‐induced pancreatitis?

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In patients with acute alcoholic pancreatitis, the AGA recommends brief alcohol intervention during admission (Strong Recommendation, Moderate Quality of Evidence).

References:

1. Crockett, S. D., et al. (2018). "American Gastroenterological Association Institute Guideline on Initial Management of Acute Pancreatitis." Gastroenterology 154(4): 1096‐1101.


What is the role of alcohol counseling in the management of patients with acute pancreatitis?

From 63 citations, only 1 RCT was identified that addressed the role of alcohol counseling on recurrent bouts of AP (Table 16). The included patients had a clear alcohol history and had

undergone a first attack of AP with the exclusion of other possible etiologies. Comparing similar interventions of alcohol counseling as a sole session at the initial hospitalization vs every 6

months for 2 years in a gastrointestinal clinic setting, a strong trend favored the repeated intervention for the outcome of total hospital admission rates (OR, 0.38; 95% CI, 0.14‐1.00),

with nonsignificant differences noted for the other outcomes of a second attack of pancreatitis (OR, 0.34; 95% CI, 0.11‐1.03), definite recurrent pancreatitis (OR, 0.34; 95% CI, 0.11‐1.03),

or 2 or more recurrent attacks of pancreatitis (OR, 0.56; 95% CI, 0.16‐2.03). Additional outcomes were not assessed in the trial (Table 17). An important limitation of this analysis is, of

course, the paucity of randomized trials available in the literature in the context of patients with AP.

A Cochrane review of alcohol‐reduction strategies was also considered; while the trials this systematic review refers to were not carried out in the context of patients presenting with AP,

the effect of an intervention strategy was assessed in a large number of studies (22 RCTs) and evaluated outcomes in >5800 patients. Patients who received a brief intervention had a

significant reduction in alcohol consumption compared with controls after 1 year (‐38 g/wk; 95% CI ‐54 to ‐23 g/wk), although substantial heterogeneity between trials was noted and

the benefit of brief intervention was statistically significant in men but not in women. Extended intervention was associated with a nonsignificantly increased reduction in alcohol

consumption compared with brief intervention. In the absence of any dose threshold linking alcohol intake to AP and its recurrence, and in the absence of any significant untoward effects

related to the proposed intervention, this evidence was applied to the PICO under consideration, while the level of evidence was downgraded for indirectness and chosen outcomes.

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Question #11: Which patients with acute and late‐phase pancreatitis benefit from cross‐sectional (repeat) imaging? What is the optimal method/timing of imaging?


The 2015 Japanese guidelines for the management of acute pancreatitis recommended the following for diagnostic imaging:

MRI is more useful than CT in diagnosing bile duct stones causing pancreatitis and hemorrhagic necrotizing pancreatitis. (2C)

Contrast‐enhanced CT is useful for the diagnosis of active hemorrhage and thrombosis associated with pancreatitis. (1C)

The 2013 International Association of Pancreatology (IAP) and the American Pancreatic Association (APA) stated that in patients considered to have idiopathic acute pancreatitis, after

negative routine work‐up for biliary etiology, endoscopic ultrasonography (EUS) is recommended as the first step to assess for occult microlithiasis, neoplasms and chronic pancreatitis. If

EUS is negative, (secretin‐stimulated) MRCP is advised as a second step to identify rare morphologic abnormalities. CT of the abdomen should be performed. If etiology remains

unidentified, especially after a second attack of idiopathic pancreatitis, genetic counseling (not necessarily genetic testing) should be considered. (GRADE 2C, weak agreement).

For imaging, the indication for initial CT assessment in acute pancreatitis can be: 1) diagnostic uncertainty, 2) confirmation of severity based on clinical predictors of severe acute

pancreatitis, or 3) failure to respond to conservative treatment or in the setting of clinical deterioration. Optimal timing for initial CT assessment is at least 72‐96 hours after onset of

symptoms. (GRADE 1C, strong agreement) Follow up CT or MR in acute pancreatitis is indicated when there is a lack of clinical improvement, clinical deterioration, or especially when

invasive intervention is considered. (GRADE 1C, strong agreement) It is recommended to perform multidetector CT with thin collimation and slice thickness (i.e. 5mm or less), 100‐150 ml of

non‐ionic intravenous contrast material at a rate of 3mL/s, during the pancreatic and/or portal venous phase (i.e. 50‐70 seconds delay). During follow up only a portal venous phase

(monophasic) is generally sufficient. For MR, the recommendation is to perform axial FS‐T2 and FS‐T1 scanning before and after intravenous gadolinium contrast administration. (GRADE 1C,

strong agreement)

The 2013 American College of Radiology recommended:

In the acute setting (<48–72 hours after the onset of symptoms), an enhanced CT should not be performed when a typical clinical presentation and unequivocal elevations of

amylase and lipase are present.

In the acute setting, an enhanced CT should be performed if the clinical presentation and amylase and lipase levels are equivocal.


Enhanced CT after 48–72 hours will detect pancreatic and peripancreatic necrosis as well as acute pancreatic fluid collections.






120



122


Diagnosis:



Etiology:


In the absence of gallstones and / or history of significant history of alcohol use, a serum triglyceride should be obtained and considered the etiology if > 1,000 mg / dl

(conditional recommendation, moderate quality of evidence).


123




Genetic testing may be considered in young patients (< 30 years old) if no cause is evident and a family history of pancreatic disease is present (conditional recommendation,

low quality of evidence).

References:

1. (2013). "IAP/APA evidence‐based guidelines for the management of acute pancreatitis." Pancreatology 13(4 Suppl 2): e1‐15. 2. Baker, M. E., et al. (2014). "ACR Appropriateness Criteria(R) acute pancreatitis." Ultrasound Quarterly 30(4): 267‐273. 3. Tenner, S., et al. (2013). "American College of Gastroenterology guideline: management of acute pancreatitis." Am J Gastroenterol 108(9): 1400‐1415; 1416. 4. Yokoe, M., et al. (2015). "Japanese guidelines for the management of acute pancreatitis: Japanese Guidelines 2015." Journal of Hepato‐biliary‐pancreatic Sciences 22(6): 405‐432.


This review does not address imaging because it is not necessary to obtain a computed tomography scan early on if 2 criteria (typical pain and >/= 3‐fold elevation of pancreatic enzymes)

are present. Also the need for magnetic resonance imaging, endoscopic ultrasound, and repeat computed tomography scan, if one is performed initially, are all beyond the scope of this

review. There is unanimity about routine use of abdominal ultrasound to detect gallstones and sludge (observed in approximately 30%‐40% of all cases of AP).

Question #12: In patients with complications of late‐phase acute pancreatitis (pancreatic pseudocyst or walled‐off pancreatic necrosis), what is the optimal timing and method of

drainage?


The 2016 American Society for Gastrointestinal Endoscopy (ASGE) guideline on the role of endoscopy in the diagnosis and treatment of inflammatory pancreatic fluid collections:

1. Recommended that endoscopic drainage of PFCs be performed only after sufficient exclusion of alternative diagnoses, such as cystic pancreatic neoplasms and pseudoaneurysms.

[Quality of Evidence: High]

2. Recommended waiting for maturation of the cyst wall of PFCs before endoscopic intervention. [Quality of Evidence: Moderate]

3. Recommended drainage of symptomatic pancreatic pseudocysts. [Quality of Evidence: Moderate]

4. Suggested drainage of rapidly enlarging pancreatic pseudocysts. [Quality of Evidence: Low]

5. Recommended drainage of all infected PFCs in patients who fail to improve with conservative management alone. [Quality of Evidence: High]

6. Recommended drainage of symptomatic sterile necrosis lasting more than 8 weeks after the onset of acute pancreatitis. [Quality of Evidence: Moderate]

7. Suggested that routine FNA of PFCs is not required to diagnose infected necrosis. [Quality of Evidence: Low]

8. Recommended that endoscopic drainage be considered for initial therapy before surgical drainage of pancreatic pseudocysts. [Quality of Evidence: Moderate]

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9. Recommended using EUS for transmural drainage of PFCs in the absence of a luminal bulge or when portal hypertension is suspected. [Quality of Evidence: High]

10. Recommended initial endoscopic transmural and/or percutaneous drainage of WON before consideration of endoscopic transmural necrosectomy or surgical drainage. [Quality of

Evidence: Moderate]

11. Recommended that endoscopic drainage of PFCs be performed only with the availability of surgical and interventional radiology support. [Quality of Evidence: High]

12. Suggested using CO2 when performing transmural drainage procedures. [Quality of Evidence: Low]


Interventions for the local complications:

In principle, conservative treatment should first be performed for necrotizing pancreatitis. The best indication for intervention is applied to cases of infected pancreatic necrosis

with suspected or confirmed infection accompanying an aggravated general condition. (1C)

Infected pancreatic necrosis should be suspected when clinical symptoms and blood test findings deteriorate. Routine use of fine needle‐aspiration (FNA) is not required for

diagnosis, and clinical signs and CT should be used for a comprehensive determination. If an aggravated general condition is observed, percutaneous drainage or endoscopic

drainage should be given for diagnosis and treatment. (1C)

If possible, therapeutic intervention for infected pancreatic necrosis should be performed after 4 weeks of onset, when the necrosis has been sufficiently walled off, or in other

words, during WON period. (2C)

During therapeutic intervention for infected pancreatic necrosis, percutaneous (retroperitoneal) drainage or endoscopic transluminal drainage should be first given, and if no

improvement is achieved, necrosectomy should then be performed. Necrosectomy by endoscopic or retroperitoneal approach is recommended. (2B)

The 2013 International Association of Pancreatology (IAP) and the American Pancreatic Association (APA) stated the following:

Intensive Care Management:

Medical treatment of abdominal compartment syndrome (ACS) should target 1) hollow‐viscera volume, 2) intra/extra vascular fluid and 3) abdominal wall expansion. Invasive

treatment should only be used after multidisciplinary discussion in patients with a sustained intra‐abdominal pressure >25mmHg with new onset organ failure refractory to medical

therapy and nasogastric/ rectal decompression. Invasive treatment options include percutaneous catheter drainage of ascites, midline laparostomy, bilateral subcostal

laparostomy, or subcutaneous linea alba fasciotomy. In case of surgical decompression, the retroperitoneal cavity and the omental bursa should be left intact to reduce the risk of

infecting peripancreatic and pancreatic necrosis. (GRADE 2C, strong agreement)

Timing of intervention in necrotizing pancreatitis:

For patients with proven or suspected infected necrotizing pancreatitis, invasive intervention (i.e. percutaneous catheter drainage, endoscopic transluminal

drainage/necrosectomy, minimally invasive or open necrosectomy) should be delayed where possible until at least 4 weeks after initial presentation to allow the collection to

become ‘walled‐off’. (GRADE 1C, strong agreement)

Intervention strategies in necrotizing pancreatitis:

The optimal interventional strategy for patients with suspected or confirmed infected necrotizing pancreatitis is initial image‐guided percutaneous (retroperitoneal) catheter

drainage or endoscopic transluminal drainage, followed, if necessary, by endoscopic or surgical necrosectomy. (GRADE 1A, strong agreement)

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Percutaneous catheter or endoscopic transmural drainage should be the first step in the treatment of patients with suspected or confirmed (walled‐off) infected necrotizing

pancreatitis. (GRADE 1A, strong agreement)

The 2013 American College of Gastroenterology recommended the following for the role of surgery in acute pancreatitis:

In stable patients with infected necrosis, surgical, radiologic, and / or endoscopic drainage should be delayed preferably for more than 4 weeks to allow liquefication of the

contents and the development of a fibrous wall around the necrosis (walled‐off necrosis) (strong recommendation, low quality of evidence).

In symptomatic patients with infected necrosis, minimally invasive methods of necrosectomy are preferred to open necrosectomy (strong recommendation, low quality of

evidence).

References:

1. (2013). "IAP/APA evidence‐based guidelines for the management of acute pancreatitis." Pancreatology 13(4 Suppl 2): e1‐15. 2. Muthusamy, V. R., et al. (2016). "The role of endoscopy in the diagnosis and treatment of inflammatory pancreatic fluid collections." Gastrointestinal Endoscopy 83(3): 481‐488. 3. Tenner, S., et al. (2013). "American College of Gastroenterology guideline: management of acute pancreatitis." Am J Gastroenterol 108(9): 1400‐1415; 1416. 4. Yokoe, M., et al. (2015). "Japanese guidelines for the management of acute pancreatitis: Japanese Guidelines 2015." Journal of Hepato‐biliary‐pancreatic Sciences 22(6): 405‐432.

PICO Question: In patients with complications of late‐phase acute pancreatitis (pancreatic pseudocyst or walled‐off pancreatic necrosis), what is the optimal timing and method of drainage?





pharmaceutical company sponsors study on effectiveness of drug only small, positive studies found)

Modality: Peritoneal lavage vs. open necrosectomy; Outcome: Short‐Term Mortality


Location




& 95% CI)

Design Limitations

Journal: Cochrane Database of Systematic Reviews Author: Gurusamy, K.S., et al. Year Published: 2016 Location: UCL Medical School, London, UK

Aim: To assess the benefits and harms of different interventions in people with acute necrotising pancreatitis Study Type: Systematic review with meta‐analysis Size: 3 studies with 80 participants

Inclusion Criteria: RCTs performed in people with necrotising pancreatitis, irrespective of etiology, presence of infection, language, blinding, or publication status

Methods: Systematic Review with meta‐analysis.

Results: Peritoneal lavage versus open necrosectomy (OR 1.90, 95% CI to 0.73 to 4.94; I2 = 31%).







126

References: 1. Gurusamy, K. S., et al. (2016). "Interventions for necrotising pancreatitis." Cochrane Database of Systematic Reviews 4: CD011383.

Increase Quality Rating if: Large effect Dose‐response gradient Plausible confounders or







pharmaceutical company sponsors study on effectiveness of drug only small, positive studies found) Increase Quality Rating if: Large effect

Modality: Minimally invasive step‐up approach versus open necrosectomy; Outcome: Short‐Term Mortality


Location




& 95% CI)

Design Limitations


Aim: To assess the benefits and harms of different interventions in people with acute necrotising pancreatitis Study Type: Systematic review with meta‐analysis Size: 2 studies with 160 participants



Results: Minimally invasive step‐up approach versus open necrosectomy (OR 0.65, 95% CI 0.32 to 1.34; I2 = 57%).







127


Dose‐response gradient Plausible confounders or




variation of treatment effect across studies, population, interventions, or outcomes varied)

‐ Not available Studies are indirect (PICO



pharmaceutical company sponsors study on effectiveness of drug only small, positive studies found) Increase Quality Rating if: Large effect Dose‐response gradient

Modality: Delayed open necrosectomy vs. early open necrosectomy; Outcome: Short‐Term Mortality


Location




& 95% CI)

Design Limitations


Aim: To assess the benefits and harms of different interventions in people with acute necrotising pancreatitis Study Type: Systematic review with meta‐analysis Size: 1 study with 36 participants



Results: Delayed open necrosectomy versus early open necrosectomy (OR 0.29, 95% CI 0.06 to 1.38).







128










Modality: Video‐assisted vs endoscopic; Outcome: Short‐Term Mortality


Location




& 95% CI)

Design Limitations





Results: Variations in the minimally invasive step‐up approach. Minimally invasive step‐up approach: video‐assisted versus endoscopic (OR 4.50, 95% CI 0.41 to 49.08; 22 participants; 1 study).







129










Modality: Planned surgery vs. continued percutaneous drainage; Outcome: Short‐Term Mortality


Location




& 95% CI)

Design Limitations





Results: Minimally invasive step‐up approach: planned surgery versus continued percutaneous drainage (OR 21.00, 95% CI 0.65 to 689.99; 8 participants, 1 study).







130









other biases increase certainty of effect

Modality: EUS‐guided drainage vs. endoscopic drainage groups; Outcome: Short‐term mortality


Location




& 95% CI)

Design Limitations


Aim: To assess the benefits and harms of different management strategies of pancreatic pseudocysts Study Type: Systematic review with meta‐analysis Size: 2 studies and 89 participants

Inclusion Criteria: RCTs of people with pancreatic pseudocysts, regardless of size, presence of symptoms, or etiology. No restrictions were placed on blinding, language, or publication status of trails.


Results: There was one death reported in the endoscopic drainage group, due to major bleeding. No statistically significant difference was found between EUS‐guided drainage and endoscopic drainage groups (OR 3.00; 95% CI 0.11 to 79.91; participants = 89, studies = 2).







131

References: 1. Gurusamy, K. S., et al. (2016). "Management strategies for pancreatic pseudocysts." Cochrane Database of Systematic Reviews 4: CD011392.





‐ Not Available Studies are indirect (PICO





Modality: Surgical vs. endoscopic drainage; Outcome: Short‐term mortality


Location




& 95% CI)

Design Limitations

Journal: Surgical Endoscopy Author: Saul, A., et al. Year Published: 2016 Location: National Institute of Medical Sciences and Nutrition Salvador Zubiran, Mexico City, Mexico

Aim: To compare surgical versus endoscopic treatment on pancreatic pseudocysts regarding clinical success, complication rate, recurrence, hospital stay, and cost. Study Type: Retrospective Study Size: 64 procedures in 61 patients were included. 21 (33% were drained endoscopically guided by EUS and 43 (67%) cases were drained surgically.

Inclusion Criteria: Patients who provided written informed consent before the procedure, evaluated routinely with CT scan prior to the procedure, treated with endoscopic drainage that were intubated and received 1 g I.V. of ceftazidime 30 min before the procedure.

Methods: A retrospective analysis of data obtained prospectively in paper and electronic records of patients with diagnosis of PPC and endoscopic or surgical treatment was conducted. A PPC was defined as a fluid collection in the pancreatic or peripancreatic area that had a well‐defined wall and contained no solid debris or recognizable parenchymal necrosis. Clinical success was defined as complete resolution or a decrease in size of the PPC to 2 cm or smaller.

Results: The morality rate of the endoscopic group was 0 and 2.3% (1 of 64) for the surgical group (P = 0.4).




of both exposure and outcome Failure to adequately




132

References: 1. Gurusamy, K. S., et al. (2016). "Management strategies for pancreatic pseudocysts." Cochrane Database of Systematic Reviews 4: CD011392. 2. Saul, A., et al. (2016). "EUS-guided drainage of pancreatic pseudocysts offers similar success and complications compared to surgical treatment but with a lower cost." Surgical

Endoscopy 30(4): 1459-1465.









Modality: Different methods of drainage; Outcome: Serious Adverse Events Study Acronym; Author;





& 95% CI)

Design Limitations


Aim: To assess the benefits and harms of different management strategies of pancreatic pseudocysts Study Type: Systematic review with meta‐analysis Size: 3 trails, 129 participants



Results: Adverse events included: bleeding requiring additional intervention, pneumoperitoneum, stent migration, difficulty in eating requiring surgical placement of feeding tube, and pancreatic stricture requiring distal pancreatectomy. 1. EUS‐guided drainage: 3.1% (2/65);

2. Endoscopic drainage: 11.4% (5/44);

3. Open surgical drainage 15.0% (3/20)







133

References: 1. Akshintala, V. S., et al. (2014). "A comparative evaluation of outcomes of endoscopic versus percutaneous drainage for symptomatic pancreatic pseudocysts." Gastrointestinal Endoscopy

79(6): 921-928; quiz 983.e922, 983.e925. 2. Gurusamy, K. S., et al. (2016). "Management strategies for pancreatic pseudocysts." Cochrane Database of Systematic Reviews 4: CD011392.


Journal: Gastrointestinal Endoscopy Author: Akshintala, V.S., et al. Year Published: 2014 Location: John Hopkins Medical Institutions, Baltimore, MD

Aim: To compare the outcomes of endoscopic drainage (ED) versus percutaneous drainage (PD) for symptomatic pseudocysts Study Type: Retrospective Cohort Study Size: 81 patients, 41 underwent ED and 40 underwent PD

Inclusion Criteria: Adult patients with symptomatic pseudocysts within %1 cm of the gastric or duodenal wall who underwent ED or PD between 1993 and 2011. Exclusion Criteria: Patients with walled‐off pancreatic necrosis were excluded.

Methods: Patients who underwent endoscopic drainage or percutaneous drainage for symptomatic pseudocysts were identified from an institutional claims database. Main Outcome Measurements: Rates of technical success, procedural adverse events, clinical success, reinterventions, and failure. Other outcomes included the length of hospital stay and number of follow‐up abdominal imaging studies.

Results: There were no differences in the rates of adverse events (14.6% vs 15%; P = .96) between ED and PD, respectively.













(when studies include few patients and few events, and thus have wide confidence

Modality: Different methods of draining pseudocysts with EUS‐guided drainage; Outcome: Health‐related quality of life (HRQoL)


Location




& 95% CI)

Design Limitations


Aim: To assess the benefits and harms of different management strategies of pancreatic pseudocysts Study Type: Systematic review with meta‐analysis

Inclusion Criteria: RCTs of people with pancreatic pseudocysts, regardless of size, presence of symptoms, or etiology. No restrictions were placed on blinding, language, or


Results: Only one trial reported HRQoL, using the SF‐36 scale. HRQoL was statistically significantly worse in the open surgical drainage group than in the EUS‐guided drainage group (MD ‐21.00; 95% CI ‐33.21 to ‐8.79; participants = 40; studies = 1).





was not appraised or

134


Size: 1 study, 40 participants

publication status of trails.

studies were of low quality Methods were


intervals, and the results are uncertain) Publication Bias (e.g.









Modality: EUS‐guided drainage with nasocystic drainage vs. EUS‐guided drainage; Outcome: Hospital Stay Study Acronym; Author;





& 95% CI)

Design Limitations


Aim: To assess the benefits and harms of different management strategies of pancreatic pseudocysts Study Type: Systematic review with meta‐analysis Size: 1 study, 47 participants



Results: The length of hospital stay was statistically significantly shorter in the EUS‐guided drainage with nasocystic drainage compared to EUS‐guided drainage (MD ‐8.10 days; 95% CI ‐9.79 to ‐6.41).





was not appraised or studies were of low quality

135


Methods were inconsistent across studies

Publication Bias (e.g.








Modality: Surgical drainage group vs. EUS‐guided drainage group; Outcome: Hospital Stay Study Acronym; Author;





& 95% CI)

Design Limitations


Aim: To assess the benefits and harms of different management strategies of pancreatic pseudocysts Study Type: Systematic review with meta‐analysis Size: 1 study; 40 participants



Results: The length of hospital stay was statistically significantly longer in the open surgical drainage group compared to the EUS‐guided drainage group (MD 4.20 days; 95% CI 2.82 to 5.58; participants = 40; studies =1).







136

References: 1. Gurusamy, K. S., et al. (2016). "Management strategies for pancreatic pseudocysts." Cochrane Database of Systematic Reviews 4: CD011392. 2. Saul, A., et al. (2016). "EUS-guided drainage of pancreatic pseudocysts offers similar success and complications compared to surgical treatment but with a lower cost." Surgical

Endoscopy 30(4): 1459-1465




Aim: To compare surgical versus endoscopic treatment on pancreatic pseudocysts regarding clinical success, complication rate, recurrence, hospital stay, and cost. Study Type: Retrospective Study Size: 64 procedures in 61 patients were included. 21 (33% were drained endoscopically guided by EUS and 43 (67%) cases were drained surgically.

Inclusion Criteria: Patients who provided written informed consent before the procedure, evaluated routinely with CT scan prior to the procedure, treated with endoscopic drainage that were intubated and received 1 g I.V. of ceftazidime 30 min before the procedure.

Methods: A retrospective analysis of data obtained prospectively in paper and electronic records of patients with diagnosis of PPC and endoscopic or surgical treatment was conducted. A PPC was defined as a fluid collection in the pancreatic or peripancreatic area that had a well‐defined wall and contained no solid debris or recognizable parenchymal necrosis. Clinical success was defined as complete resolution or a decrease in size of the PPC to 2 cm or smaller.

Results: The hospital stay was lower for the endoscopic group: 0 (0‐10) days compared with 7 (2‐42) days in the surgical group (P < 0.0001).












question is quite different from the available evidence in regard to population, intervention, comparison, or outcome)

Modality: Endoscopic drainage vs. EUS‐guided drainage; Outcome: Hospital Stay Study Acronym; Author;





& 95% CI)

Design Limitations


Aim: To assess the benefits and harms of different management strategies of pancreatic pseudocysts

Inclusion Criteria: RCTs of people with pancreatic pseudocysts, regardless of size, presence of symptoms, or etiology. No


Results: There was no statistically significant difference in the comparison between endoscopic drainage and EUS‐guided drainage (MD ‐1.00 days; 95% CI ‐2.52




detailed or exhaustive

137


Study Type: Systematic review with meta‐analysis Size: 1 study; 29 participants

restrictions were placed on blinding, language, or publication status of trails.

to 0.53; participants = 29; studies = 1).

Quality of the studies was not appraised or studies were of low quality Methods were










(when studies include few

Modality: Endoscopy drainage vs percutaneous drainage; Outcome: Hospital Stay Study Acronym; Author;





& 95% CI)

Design Limitations


Aim: To compare the outcomes of endoscopic drainage (ED) versus percutaneous drainage (PD) for symptomatic psdeudocysts

Inclusion Criteria: Adult patients with symptomatic pseudocysts within %1 cm of the gastric or duodenal wall who underwent ED or PD between 1993 and 2011.

Methods: Patients who underwent endoscopic drainage or percutaneous drainage for symptomatic pseudocysts were identified from an institutional claims database.

Results: Patients who underwent PD had longer length of hospital stay (14.8 +/‐ 14.4 vs 6.5 +/‐ 6.7 days; P = .001) compared with patients who underwent ED.




of both exposure and outcome

138


79(6): 921-928; quiz 983.e922, 983.e925.

Study Type: Retrospective Cohort Study Size: 81 patients, 41 underwent ED and 40 underwent PD

Exclusion Criteria: Patients with walled‐off pancreatic necrosis were excluded.

Main Outcome Measurements: Rates of technical success, procedural adverse events, clinical success, reinterventions, and failure. Other outcomes included the length of hospital stay and number of follow‐up abdominal imaging studies.

Failure to adequately control confounding Incomplete or



patients and few events, and thus have wide confidence intervals, and the results are uncertain) Publication Bias (e.g.







(when studies include few patients and few events, and

Modality: Endoscopic vs. EUS‐guided drainage; Outcome: Additional intervention Study Acronym; Author;





& 95% CI)

Design Limitations



Inclusion Criteria: RCTs of people with pancreatic pseudocysts, regardless of size, presence of symptoms, or etiology. No restrictions were


Results: The proportion of people requiring additional invasive intervention for drainage was statistically significantly higher with endoscopic drainage than EUS‐guided drainage (OR 11.13; 95% CI 2.85 to 43.44).




detailed or exhaustive

139


Size: 2 studies; 89 participants

placed on blinding, language, or publication status of trails.

Quality of the studies was not appraised or studies were of low quality Methods were


thus have wide confidence intervals, and the results are uncertain) Publication Bias (e.g.








(when studies include few patients and few events, and

Modality: Open Surgical vs. EUS‐guided Drainage; Outcome: Additional intervention Study Acronym; Author;





& 95% CI)

Design Limitations



Inclusion Criteria: RCTs of people with pancreatic pseudocysts, regardless of size, presence of symptoms, or etiology. No restrictions were placed on blinding,


Results: There was no statistically significant differences in the need for additional drainage between the open surgical and EUS‐guided drainage groups (OR 0.47; 95% CI 0.04 to 5.69; participants = 40; studies = 1).






140


Size: 1 study; 40 participants

language, or publication status of trails.

studies were of low quality Methods were


thus have wide confidence intervals, and the results are uncertain) Publication Bias (e.g.









Modality: Endoscopic vs. percutaneous drainage; Outcome: Additional intervention Study Acronym; Author;





& 95% CI)

Design Limitations


Aim: To compare the outcomes of endoscopic drainage (ED) versus percutaneous drainage (PD) for symptomatic psdeudocysts Study Type: Retrospective Cohort Study

Inclusion Criteria: Adult patients with symptomatic pseudocysts within %1 cm of the gastric or duodenal wall who underwent ED or PD between 1993 and 2011. Exclusion Criteria: Patients with

Methods: Patients who underwent endoscopic drainage or percutaneous drainage for symptomatic pseudocysts were identified from an institutional claims database. Main Outcome Measurements: Rates of technical success, procedural adverse events, clinical success,

Results: Patients who underwent PD had higher rates of reintervention (42.5% vs 9.8%; P = .001), and median number [quartiles] of follow‐up abdominal imaging studies (6 [3.25, 10] vs 4 [2.5, 6]; P = .02) compared with patients who underwent ED.





control confounding

141


79(6): 921-928; quiz 983.e922, 983.e925.

Size: 81 patients, 41 underwent ED and 40 underwent PD

walled‐off pancreatic necrosis were excluded.

reinterventions, and failure. Other outcomes included the length of hospital stay and number of follow‐up abdominal imaging studies.

Incomplete or inadequately short follow‐up Differences in











Modality: Different methods of draining pseudocysts with EUS‐guided drainage; Outcome: Costs Study Acronym; Author;





& 95% CI)

Design Limitations



Inclusion Criteria: RCTs of people with pancreatic pseudocysts, regardless of size, presence of symptoms, or etiology. No restrictions were placed on blinding, language, or


Results: Only one trial reported costs. Treatment costs were statistically significantly higher in the open drainage group compared to the EUS‐guided drainage group (MD 8040 USD; 95% CI 3020 to 13,060; participants = 40; studies = 1).






142


Size: 4 RCTs with 177 participants. After one participant was excluded, 176 participants were randomised to endoscopic ultrasound (EUS)‐guided drainage (88 participants), endoscopic drainage (44 participants), EUS‐guided drainage with nasocystic drainage (24 participants), and open surgical drainage (20 participants).

publication status of trails.

studies were of low quality Methods and/or

results were inconsistent across studies










Modality: Surgical versus endoscopic treatment on pancreatic pseudocysts; Outcome: Costs Study Acronym; Author;





& 95% CI)

Design Limitations


Aim: To compare surgical versus endoscopic treatment on pancreatic pseudocysts regarding clinical success, complication rate, recurrence, hospital stay, and cost. Study Type: Retrospective Study

Inclusion Criteria: Patients who provided written informed consent before the procedure, evaluated routinely with CT scan prior to the procedure, treated with endoscopic drainage that were intubated and received 1 g I.V.

Methods: A retrospective analysis of data obtained prospectively in paper and electronic records of patients with diagnosis of PPC and endoscopic or surgical treatment was conducted. A PPC was defined as a fluid collection in the pancreatic or peripancreatic area that had a well‐defined wall and contained no solid debris or recognizable parenchymal

Results: The surgical treatment was approximately two times the cost for endoscopic drainage.





control confounding

143

References: 1. Saul, A., et al. (2016). "EUS-guided drainage of pancreatic pseudocysts offers similar success and complications compared to surgical treatment but with a lower cost." Surgical

Endoscopy 30(4): 1459-1465.

Size: 64 procedures in 61 patients were included. 21 (33% were drained endoscopically guided by EUS and 43 (67%) cases were drained surgically.

of ceftazidime 30 min before the procedure.

necrosis. Clinical success was defined as complete resolution or a decrease in size of the PPC to 2 cm or smaller.












Modality: Surgical vs. endoscopic drainage; Outcome: Recurrence Study Acronym; Author;





& 95% CI)

Design Limitations





Results: The recurrence rate was similar in both groups: 9.5 and 4.5% respectively (P = 0.59). The two recurrences found in the endoscopic group were associated with stent migration, and the recurrence in the surgical group was due to the type of surgery performed (open drainage).





control confounding

144


Endoscopy 30(4): 1459-1465.















Modality: Endoscopic vs percutaneous drainage; Outcome: Intervention Success Rate Study Acronym; Author;





& 95% CI)

Design Limitations


Aim: To compare the outcomes of endoscopic drainage (ED) versus percutaneous drainage (PD) for symptomatic psdeudocysts Study Type: Retrospective Cohort Study

Inclusion Criteria: Adult patients with symptomatic pseudocysts within %1 cm of the gastric or duodenal wall who underwent ED or PD between 1993 and 2011. Exclusion Criteria: Patients with walled‐off

Methods: Patients who underwent endoscopic drainage or percutaneous drainage for symptomatic pseudocysts were identified from an institutional claims database. Main Outcome Measurements: Rates of technical success, procedural adverse events, clinical success, reinterventions, and failure.

Results: There were no differences in the rates of technical success (90.2% vs 97.5%; P = .36) and clinical success (70.7% vs 72.5%; P = .86) between ED and PD, respectively





control confounding

145


79(6): 921-928; quiz 983.e922, 983.e925.

Size: 81 patients, 41 underwent ED and 40 underwent PD

pancreatic necrosis were excluded.

Other outcomes included the length of hospital stay and number of follow‐up abdominal imaging studies.












Modality: Endoscopic drainage vs. surgical; Outcome: Intervention Success Rate Study Acronym; Author;





& 95% CI)

Design Limitations





Results: The clinical success of the endoscopic group was 90.5 versus 90.7% for the surgical group (P 0.7), with a complication rate of 23.8 and 25.6%, respectively (P = 0.8).





control confounding

146


Endoscopy 30(4): 1459-1465. Primary Literature Summary

Outcome: Modality: Results: Level of Evidence: Short‐term mortality Peritoneal lavage vs. open necrosectomy OR 1.90, 95% CI 0.73 – 4.94), I2 = 31% Low

Minimally invasive step‐up approach vs. open necrosectomy

OR 0.65, 95% CI 0.32 – 1.34), I2 = 57% Low

Delayed vs early open necrosectomy OR 0.29, 95% CI 0.06 to 1.38 Very Low Video‐assisted vs. endoscopic OR 4.50, 95% CI 0.41 to 49.08 Very Low Planned surgery vs. continued percutaneous drainage

OR 21.00; 95% CI 0.65 to 689.00 Very Low

EUS‐guided drainage vs. endoscopic drainage OR 3.00; 95% CI 0.11 to 79.91 Low Surgical vs. endoscopic drainage Endoscopic = 0; Surgical = 1/64 (2.3%), P = 0.4 Very Low

Serious Adverse Events EUS‐guided drainage 3.1% (2/65) Very Low

Endoscopic drainage SR: 11.4% (5/44); Retrospective Study: 14.6% Very Low

Open surgical drainage 15.0% (3/20) Very Low

Percutaneous drainage 15% Very Low









147

Hospital Stay EUS‐guided with nasocystic drainage vs EUS‐guided drainage

MD ‐8.10 days, 95% CI ‐9.79 to ‐6.41 Very Low

Surgical drainage vs. EUS‐guided drainage SR: MD 4.20 days, 95% CI 2.82 to 5.58; Retrospective Study: endoscopic group = 0; surgical = 7 (2‐42) P < 0.0001)

Low

Endoscopic drainage vs. EUS‐guided drainage MD ‐1.00 days, 95% CI ‐2.52 to 0.53 Very Low

Endoscopy drainage vs. percutaneous drainage

Percutaneous drainage had longer length of stay (14.8 +/‐ 14.4 vs 6.5 +/‐ 6.7 days; P = .001)

Very Low

Additional Intervention Endoscopic vs. EUS‐guided drainage OR 11.13, 95% CI 2.85 to 43.44 Very Low

Open Surgical vs. EUS‐guided drainage OR 0.47, 95% CI 0.04 to 5.69 Very Low

Endoscopic vs. percutaneous drainage Percutaneous has higher rates of reintervention (42.5% vs. 9.8%; P = .001); Follow‐up abdominal imaging studies (6 [3.25, 10] vs 4 [2.5, 6]; P = .02)

Very Low

Intervention Success Rate Endoscopic vs. percutaneous drainage Technical Success: Endoscopic = 90.2% and Percutaneous = 97.5%; P = .36 Clinical Success: Endoscopic = 70.7% and Percutaneous = 72.5%; P = .86

Very Low

Endoscopic drainage vs. surgical Clinical Success: Endoscopic = 90.5% and Surgical = 90.7%; P = 0.8

Very Low

Health‐related quality of life (HRQoL)

Open surgical drainage vs. EUS‐guided drainage group

MD ‐21.00, 95% CI ‐33.21 to ‐8.79 Very Low

Recurrence Surgical vs. endoscopic drainage Surgical = 9.5% and Endoscopic Drainage = 4.5%; P = 0.59 Very Low Question #13: In patients with acute pancreatitis, what pain management strategy is associated with the best clinical outcomes (mortality, morbidity, infected pancreatic necrosis,

multiple organ failure, single organ failure, hospital length of stay)?

Primary Literature

PICO Question: In patients with acute pancreatitis, what pain management strategy is associated with the best clinical outcomes (mortality, morbidity, infected pancreatic necrosis, multiple organ failure, single organ failure, hospital length of stay)?



Modality: Procaine; Outcome: Additional Analgesics Study Acronym; Author;





& 95% CI)

Design Limitations

148

Journal: Digestion Author: Kahl, S., et al. Year Published: 2004 Location: Otto von Guericke University Magdeburg, Magdeburg, Germany

Aim: To evaluate whether procaine hydrochloride is effective for pain treatment Study Type: RCT Size: 107 patients (76 male, 31 female; mean age 45 +/‐ 12 years)

Inclusion Criteria: Acute pancreatitis diagnosed by acute abdominal pain of sudden onset and threefold elevation of serum pancreatic enzymes (pancreatic amylase or lipase), onset of abdominal pain < 72 h prior to hospitalization, no analgesic treatment prior to hospitalization, written informed consent, age > 18 years Exclusion Criteria: Onset of abdominal pain > 72 h prior to hospitalization, any analgesic treatment prior to hospitalization, Age < 18 years, pregnancy, no written informed consent

Methods: Patients were included and randomized either to receive procaine (n = 55) or pentazocine (n = 52) for pain relief. Procaine 2 g/ 24 h was administered by continuous intravenous infusion, pentazocine 30 mg was administered every 6 h as a bolus intravenous injection. Pentazocine was additionally administered on demand whenever required in patients of both treatment groups and its total consumption was recorded. Pain scores were assessed twice daily on a visual analogue scale.

Results: Patients receiving procaine were significantly more likely to request additional analgesics compared to patients treated with pentazocine alone, 98 vs. 44%, respectively (p < 0.001). Procaine did not reduce the amount of pentazocine required for pain control. The amount of pentazocine given in both groups was not statistically significantly different.








Studies are indirect (PICO question is quite different from the available evidence in regard to population, intervention, comparison, or outcome) Studies are imprecise




Journal: Pancreas Author: Layer, P., et al. Year Published: 2011 Location: Israelitic Hospital, Hamburg, Germany

Aim: To evaluate whether intravenous procaine decreases pain and/or necessity for auxiliary analgesic medication and might improve clinical course in patients with acute pancreatitis Study Type: RCT Size: 44 patients

Inclusion Criteria: Acute upper abdominal pain compatible with the clinical suspicion of acute pancreatitis, associated with at least 3‐fold increase in serum lipase and/or amylase levels, and/or typical findings obtained from imaging procedures (abdominal ultrasound,

Methods: Consecutive patients with acute pancreatitis randomly received intravenous procaine (2 g/24 h) or placebo for 72 hours in a double‐blind fashion. Pain severity (visual analog scale, 0‐100), on‐demand pain medication (metamizole and/or buprenorphine), and the clinical course were monitored every 24 hours.

Results: Patients randomized to procaine treatment used less of additional analgesics (P = 0.042) and overall analgesic superiority (P = 0.015).

None RCTs Lack of blinding Lack of allocation






149

References: 1. Kahl, S., et al. (2004). "Procaine hydrochloride fails to relieve pain in patients with acute pancreatitis." Digestion 69(1): 5-9. 2. Layer, P., et al. (2011). "Effects of systemic administration of a local anesthetic on pain in acute pancreatitis: a randomized clinical trial." Pancreas 40(5): 673-679.

computed tomography [CT]). Exclusion Criteria: Aged 18 years and younger or older than 75 years, pregnancy, evidence of malignancy, known cardio morbidity including arrhythmia, severe preexisting liver or kidney disease, leukopenia, allergic asthma, and known allergies against local anesthetics, paraben, metamizole, or buprenorphine






Modality: Procaine; Outcome: Pain Study Acronym; Author;





& 95% CI)

Design Limitations

Journal: Digestion Author: Kahl, S., et al. Year Published: 2004 Location: Otto von Guericke University Magdeburg, Magdeburg, Germany

Aim: To evaluate whether procaine hydrochloride is effective for pain treatment Study Type: RCT Size: 107 patients (76 male, 31 female; mean age 45 +/‐ 12 years)

Inclusion Criteria: Acute pancreatitis diagnosed by acute abdominal pain of sudden onset and threefold elevation of serum pancreatic enzymes (pancreatic amylase or lipase), onset of abdominal pain < 72 h prior to hospitalization, no analgesic treatment

Methods: Patients were included and randomized either to receive procaine (n = 55) or pentazocine (n = 52) for pain relief. Procaine 2 g/ 24 h was administered by continuous intravenous infusion, pentazocine 30 mg was administered every 6 h as a bolus intravenous injection. Pentazocine was additionally administered on demand

Results: Recorded pain scores were significantly lower (p < 0.001) in patients in the pentazocine group during the first 3 days of analgesic treatment. From day 4 on there was no significant difference in pain scores among the two groups.






measures (e.g., no effect outcome)

150

prior to hospitalization, written informed consent, age > 18 years Exclusion Criteria: Onset of abdominal pain > 72 h prior to hospitalization, any analgesic treatment prior to hospitalization, Age < 18 years, pregnancy, no written informed consent

whenever required in patients of both treatment groups and its total consumption was recorded. Pain scores were assessed twice daily on a visual analogue scale.

Large losses to F/U Difference in







Inclusion Criteria: Acute upper abdominal pain compatible with the clinical suspicion of acute pancreatitis, associated with at least 3‐fold increase in serum lipase and/or amylase levels, and/or typical findings obtained from imaging procedures (abdominal ultrasound, computed tomography [CT]). Exclusion Criteria: Aged 18 years and younger or older than 75 years, pregnancy, evidence of malignancy, known cardio morbidity including arrhythmia, severe preexisting liver or kidney disease,


Results: Procaine treatment was associated with a stronger decrease in pain compared with placebo (median visual analog scale decrement, ‐62 vs ‐39, P = 0.025). Moreover, there was a greater proportion of patients with adequate (>= 67%) pain reduction (75% vs 43%, P = 0.018).







151

References: 1. Kahl, S., et al. (2004). "Procaine hydrochloride fails to relieve pain in patients with acute pancreatitis." Digestion 69(1): 5-9. 2. Layer, P., et al. (2011). "Effects of systemic administration of a local anesthetic on pain in acute pancreatitis: a randomized clinical trial." Pancreas 40(5): 673-679.

leukopenia, allergic asthma, and known allergies against local anesthetics, paraben, metamizole, or buprenorphine








Modality: Procaine; Outcome: Hospital Stay Study Acronym; Author;





& 95% CI)

Design Limitations



Inclusion Criteria: Acute upper abdominal pain compatible with the clinical suspicion of acute pancreatitis, associated with at least 3‐fold increase in serum lipase and/or amylase levels, and/or typical findings obtained from imaging procedures (abdominal ultrasound, computed tomography [CT]). Exclusion Criteria: Aged 18 years and younger or older than 75 years, pregnancy, evidence of malignancy, known cardio morbidity including


Results: Compared with placebo, the proportion of patients hospitalized after 2 weeks was reduced by 80% after procaine treatment (P = 0.012).







152

References: 1. Layer, P., et al. (2011). "Effects of systemic administration of a local anesthetic on pain in acute pancreatitis: a randomized clinical trial." Pancreas 40(5): 673-679.

arrhythmia, severe preexisting liver or kidney disease, leukopenia, allergic asthma, and known allergies against local anesthetics, paraben, metamizole, or buprenorphine









Modality: Epidural Anesthesia (EA); Outcome: Pain Study Acronym; Author;





& 95% CI)

Design Limitations

Journal: World Journal of Gastroenterology Author: Sadowski, S. M., et al. Year Published: 2015 Location: University Hospitals of Geneva, Geneva, Switzerland

Aim: To study the safety of epidural anesthesia (EA), its effect on pancreatic perfusion and the outcome of patients with acute pancreatitis (AP) Study Type: RCT Size: 35 patients, 13 to EA group and 22 to control group

Inclusion Criteria: AP [Ranson score ≥ 2, C‐reactive protein > 100 or necrosis on computed tomography (CT)] Exclusion Criteria: Absence of severe pancreatitis as defined previously, patients with contraindications to epidural anesthesia (skin infection of the vertebral region, coagulation disorders, iodine allergy), inability to obtain consent and concurrent participation in another clinical trial.

Methods: Patients were prospectively randomized to either a group receiving EA or a control group treated by patient controlled intravenous analgesia. Pain management was evaluated in the two groups every eight hours using the visual analog pain scale (VAS). Parameters for clinical severity such as length of hospital stay, use of antibiotics, admission to the intensive care unit, radiological/clinical complications and the need for surgical necrosectomy including biochemical data were recorded. A CT scan using a perfusion protocol was performed on admission and at 72 h to evaluate pancreatic blood flow. A significant variation in blood flow was defined as a 20% difference in pancreatic perfusion between

Results: The Balthazar radiological severity score on admission was higher in the EA group than in the control group (mean score 4.15 +/‐ 2.54 vs 3.38 +/‐ 1.75, respectively, P = 0.347) and the median Ranson scores were 3.4 and 2.7 respectively (P = NS). The VAS improved during the first ten days in the EA group compared to the control group (0.2 vs 2.33, P = 0.034 at 10 d). Length of stay and mortality were not statistically different between the 2 groups (26 d vs 30 d, P = 0.65, and 0% for both respectively). The median duration of EA was 5.7 d, and no








153

References: 1. Sadowski, S. M., et al. (2015). "Epidural anesthesia improves pancreatic perfusion and decreases the severity of acute pancreatitis." World Journal of Gastroenterology 21(43): 12448-

12456.

admission and 72 h and was measured in the head, body and tail of the pancreas.

complications of the epidural procedure were reported.




variation of treatment effect across studies, population, interventions, or outcomes varied) – Not Available Studies are indirect (PICO





Modality: Epidural Anesthesia (EA); Outcome: Perfusion of the pancreas Study Acronym; Author;





& 95% CI)

Design Limitations




Methods: Patients were prospectively randomized to either a group receiving EA or a control group treated by patient controlled intravenous analgesia. Pain management was evaluated in the two groups every eight hours using the visual analog pain scale (VAS). Parameters for clinical severity such as length of hospital stay, use of antibiotics, admission to the intensive care unit, radiological/clinical complications and the need for surgical necrosectomy including biochemical data were recorded. A CT scan using a perfusion protocol was performed on admission and at 72 h to evaluate pancreatic blood flow. A significant variation in blood flow was defined as a 20% difference in pancreatic perfusion between admission and 72 h and was

Results: The Balthazar radiological severity score on admission was higher in the EA group than in the control group (mean score 4.15 +/‐ 2.54 vs 3.38 +/‐ 1.75, respectively, P = 0.347) and the median Ranson scores were 3.4 and 2.7 respectively (P = NS). An improvement in perfusion of the pancreas was observed in 13/30 (43%) of measurements in the EA group vs 2/27 (7%) in the control group (P = 0.0025). The median duration of EA was 5.7 d, and no complications of the epidural procedure were reported.








154


12456.

measured in the head, body and tail of the pancreas.









Modality: Epidural Anesthesia (EA); Outcome: Necrosectomy


Location




& 95% CI)

Design Limitations




Methods: Patients were prospectively randomized to either a group receiving EA or a control group treated by patient controlled intravenous analgesia. Pain management was evaluated in the two groups every eight hours using the visual analog pain scale (VAS). Parameters for clinical severity such as length of hospital stay, use of antibiotics, admission to the intensive care unit, radiological/clinical complications and the need for surgical necrosectomy including biochemical data were recorded. A CT scan using a perfusion protocol was performed on admission and at 72 h to evaluate pancreatic blood flow. A significant variation in blood flow was defined as a 20% difference in pancreatic perfusion between admission and 72 h and was

Results: The Balthazar radiological severity score on admission was higher in the EA group than in the control group (mean score 4.15 +/‐ 2.54 vs 3.38 +/‐ 1.75, respectively, P = 0.347) and the median Ranson scores were 3.4 and 2.7 respectively (P = NS). Necrosectomy was performed in 1/13 patients in the EA group vs 4/22 patients in the control group (P = 0.63). The median duration of EA was 5.7 d, and no complications of the epidural procedure were reported.








155


12456.

measured in the head, body and tail of the pancreas.









Modality: Perirenal space blocking; Outcome: Pain Study Acronym; Author;





& 95% CI)

Design Limitations

Journal: World Journal of Gastroenterology Author: Sun, J.J., et al. Year Published: 2013 Location: The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China

Aim: To investigate effects of perirenal space blocking (PSB) of a visceral nerve in the pancreatic region using 1% lidocaine on gastrointestinal function in patients with severe acute pancreatitis (SAP) Study Type: RCT Size: 40 patients

Inclusion Criteria: All adult SAP patients (n = 40) admitted within 3 d after the onset of symptoms to the Department of General Surgery, the First Affiliated Hospital of Henan University of Science and Technology, from January 2012 to March 2013 were included in this study. SAP was defined as the presence of one or more local complications (e.g., pseudocyst, necrosis or abscess) and/or organ failure, and acute physiology and

Methods: Patients with SAP were randomly allocated to receive PSB or no PSB (NPSB). All the SAP patients received specialized medical therapy (SMT). Patients in the PSB group received PSB + SMT when hospitalized and after diagnosis, whereas patients in the NPSB group only received SMT. A modified gastrointestinal failure (GIF) scoring system was used to assess the gastrointestinal function in SAP patients after admission. Pain severity (visual analog scale, 0 to 100) was monitored every 24 h for 72 h.

Results: During the 72‐h study period, pain intensity decreased in both groups. VAS data were depicted as median values (ranges) for the evaluation of pain intensity at specific time points. The median pain decrease (VAS) was significantly greater in the PSB group (‐53) than in the NPSB group (‐23) at 24 h; ‐67 than ‐46 at 48 h; and ‐76 than ‐49 at 72 h. Thus, the magnitude of median pain relief was better in the PSB group compared with the NPSB group.


RCT Lack of blinding Lack of allocation






156

References: 1. Sun, J. J., et al. (2013). "Perirenal space blocking restores gastrointestinal function in patients with severe acute pancreatitis." World Journal of Gastroenterology 19(46): 8752‐8757.

chronic health evaluation APACHE Ⅱ score > 8 according to the widely used Atlanta criteria formulated in 1992. Exclusion Criteria: Age (18 years old and below, or older than 75 years), pregnancy, evidence of malignancy, known cardiac morbidity including arrhythmia, severe pre‐existing liver or kidney disease, leukopenia, allergic asthma, and known allergies.







Modality: Perirenal space blocking; Outcome: Gastrointestinal Function Study Acronym; Author;





& 95% CI)

Design Limitations

Journal: World Journal of Gastroenterology Author: Sun, J.J., et al. Year Published: 2013 Location: The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China

Aim: To investigate effects of perirenal space blocking (PSB) of a visceral nerve in the pancreatic region using 1% lidocaine on gastrointestinal function in patients with severe acute pancreatitis (SAP) Study Type: RCT Size: 40 patients

Inclusion Criteria: All adult SAP patients (n = 40) admitted within 3 d after the onset of symptoms to the Department of General Surgery, the First Affiliated Hospital of Henan University of Science and Technology, from January 2012 to

Methods: Patients with SAP were randomly allocated to receive PSB or no PSB (NPSB). All the SAP patients received specialized medical therapy (SMT). Patients in the PSB group received PSB + SMT when hospitalized and after diagnosis, whereas patients in the NPSB group only received SMT. A modified gastrointestinal failure (GIF) scoring system was used to

Results: During the 10‐d study period, modified GIF score decreased in both groups, from 4.56 to 1.00 in the PSB group and from 4.34 to 2.13 in the NPSB group. The median score decrease was initially significantly greater in the PSB group than in the NPSB group (P = 0.042) after hospitalization for 24 h (PSB was performed as


RCT Lack of blinding Lack of allocation




measures (e.g., no effect outcome) Large losses to F/U

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References: 1. Sun, J. J., et al. (2013). "Perirenal space blocking restores gastrointestinal function in patients with severe acute pancreatitis." World Journal of Gastroenterology 19(46): 8752‐8757.

March 2013 were included in this study. SAP was defined as the presence of one or more local complications (e.g., pseudocyst, necrosis or abscess) and/or organ failure, and acute physiology and chronic health evaluation APACHE Ⅱ score > 8 according to the widely used Atlanta criteria formulated in 1992. Exclusion Criteria: Age (18 years old and below, or older than 75 years), pregnancy, evidence of malignancy, known cardiac morbidity including arrhythmia, severe pre‐existing liver or kidney disease, leukopenia, allergic asthma, and known allergies.

assess the gastrointestinal function in SAP patients after admission. Pain severity (visual analog scale, 0 to 100) was monitored every 24 h for 72 h.

soon as PSB group patients were admitted). The variance tendency of the modified GIF score in the two groups.

Difference in important prognostic factors at baseline



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Question #14: What is the criteria to determine appropriate transfers between OHSU, Tuality and Adventist?



Transfer indication:

Severe cases should be treated immediately at a facility capable of providing treatment for severe acute pancreatitis. Where such treatment is difficult at the facility, it is strongly

recommended that the consideration be given to the immediate transfer of the patient. Even where the case is mild in the early stages, severity assessments should be carried out

repeatedly over time, and when the criteria are met, transfer should be considered. (1C)

Intensive care:

No life‐saving effect has been observed from peritoneal lavage for acute pancreatitis, and therefore it is not recommended. (2B)

For severe cases where circulation dynamics are not stable with anuria even after sufficient initial fluid infusion or cases with abdominal compartment syndrome (ACS), CHF/CHDF

should be introduced. (1C)

The efficacy of CHF/CHDF in cases of severe acute pancreatitis not mentioned above is uncertain. Therefore, routine use is not recommended. (2C)

Continuous Regional Arterial Infusion therapy is reported to be effective in reducing pancreatic infection and mortality rates for severe acute pancreatitis and acute necrotizing

pancreatitis, but its efficacy has not been confirmed. (ungraded B)

The 2013 International Association of Pancreatology (IAP) and the American Pancreatic Association (APA) stated the following:

Intensive care management:

Patients diagnosed with acute pancreatitis and one or more of the parameters identified at admission as defined by the guidelines of the Society of Critical Care Medicine (SCCM).

Furthermore, patients with severe acute pancreatitis as defined by the revised Atlanta Classification (i.e. persistent organ failure) should be treated in an intensive care setting.

(GRADE 1C, strong agreement)

Management in, or referral to, a specialist center is necessary for patients with severe acute pancreatitis and for those who may need interventional radiologic, endoscopic, or

surgical intervention. (GRADE 1C, strong agreement)

A specialist center in the management of acute pancreatitis is defined as a high volume center with up‐to‐date intensive care facilities including options for organ replacement

therapy, and with daily (i.e. 7 days per week) access to interventional radiology, interventional endoscopy with EUS and ERCP assistance as well as surgical expertise in managing

necrotizing pancreatitis. Patients should be enrolled in prospective audits for quality control issues and into clinical trials whenever possible. (GRADE 2C, weak agreement)

Early fluid resuscitation within the first 24 hours of admission for acute pancreatitis is associated with decreased rates of persistent SIRS and organ failure. (GRADE 1C, strong

agreement)

Abdominal compartment syndrome (ACS) is defined as a sustained intra‐abdominal pressure > 20 mmHg that is associated with new onset organ failure. (GRADE 2B, strong

agreement)

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Medical treatment of ACS should target 1) hollow‐viscera volume, 2) intra/extra vascular fluid and 3) abdominal wall expansion. Invasive treatment should only be used after

multidisciplinary discussion in patients with a sustained intra‐abdominal pressure >25mmHg with new onset organ failure refractory to medical therapy and nasogastric/ rectal

decompression. Invasive treatment options include percutaneous catheter drainage of ascites, midline laparostomy, bilateral subcostal laparostomy, or subcutaneous linea alba

fasciotomy. In case of surgical decompression, the retroperitoneal cavity and the omental bursa should be left intact to reduce the risk of infecting peripancreatic and pancreatic

necrosis. (GRADE 2C, strong agreement)

SCCM Guide to Resource Allocation of Intensive Monitoring and Care

The 2013 American College of Gastroenterology recommended the following:

Etiology:


160

Initial assessment and risk stratification:

Risk assessment should be performed to stratify patients into higher‐ and lower‐risk categories to assist triage, such as admission to an intensive care setting (conditional


Patients with organ failure should be admitted to an intensive care unit or intermediary care setting whenever possible (strong recommendation, low quality of evidence).

References:

1. (2013). "IAP/APA evidence‐based guidelines for the management of acute pancreatitis." Pancreatology 13(4 Suppl 2): e1‐15. 2. Task force of the American College of Critical Care Medicine, Society of Critical Care Medicine. Guidelines for intensive care unit admission, discharge, and triage. Crit Care Med

1999; 27:633‐8. 3. Tenner, S., et al. (2013). "American College of Gastroenterology guideline: management of acute pancreatitis." Am J Gastroenterol 108(9): 1400‐1415; 1416. 4. Yokoe, M., et al. (2015). "Japanese guidelines for the management of acute pancreatitis: Japanese Guidelines 2015." Journal of Hepato‐biliary‐pancreatic Sciences 22(6): 405‐432.

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Appendix A. GRADE criteria for rating a body of evidence on an intervention

Developed by the GRADE Working Group Grades and interpretations: High: Further research is very unlikely to change our confidence in the estimate of effect. Moderate: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low: Any estimate of effect is very uncertain.

Type of evidence and starting level Randomized trial–high Observational study–low Any other evidence–very low

Criteria for increasing or decreasing level Reductions Study quality has serious (–1) or very serious (–2) problems Important inconsistency in evidence (–1) Directness is somewhat (–1) or seriously (–2) uncertain Sparse or imprecise data (–1) Reporting bias highly probable (–1) Increases Evidence of association† strong (+1) or very strong (+2) Dose-response gradient evident (+1) All plausible confounders would reduce the effect (+1) †Strong association defined as significant relative risk (factor of 2) based on consistent evidence from two or more studies with no plausible confounders Very strong association defined as significant relative risk (factor of 5) based on direct evidence with no threats to validity.

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Appendix B. Trustworthy Guideline rating scale The University of Pennsylvania’s Center for Evidence-Based Practice Trustworthy Guideline rating scale is based on the Institute of Medicine’s “Standards for Developing Trustworthy Clinical Practice Guidelines” (IOM), as well as a review of the AGREE Enterprise and Guidelines International Network domains. The purpose of this scale is to focus on the weaknesses of a guideline that may reduce the trust a clinical user can have in the guideline, and distinguish weaknesses in documentation (e.g. guide-line does not have a documented updating process) from weaknesses in the guidance itself (e.g. recommendations are outdated). Current quality scales like AGREE emphasize documentation. They are important checklists for developers of new guidelines, but are less useful for grading existing guidelines. These scales also are harder for clinicians and other persons who are not methodology experts to apply, and their length discourages their use outside formal technology assessment reports. This new scale is brief, balanced, and easy and consistent to apply. We do not attempt to convert the results of this assessment into a numeric score. Instead we present a table listing the guidelines and how they are rated on each standard. This facilitates qualitative understanding by the reader, who can see for what areas the guideline base as a whole is weak or strong as well as which guidelines are weaker or stronger. 1. Transparency

A Guideline development methods are fully disclosed. B Guideline development methods are partially disclosed. C Guideline development methods are not disclosed.

The grader must refer to any cited methods supplements or other supporting material when evaluating the guideline. Methods should include: Who wrote the initial draft? How the committee voted on or otherwise approved recommendations Evidence review, external review and methods used for updating are not addressed in this standard. 2. Conflict of interest

A Funding of the guideline project is disclosed, disclosures are made for each individual panelist, and financial or other conflicts do not apply to key authors of the guideline or to more than 1 in 10 panel members).

B Guideline states that there were no conflicts (or fewer than 1 in 10 panel members), but does not disclose funding source. C Lead author, senior author, or guideline panel members (at least 1 in 10) have conflict of interest, or guideline project was funded by

industry sponsor with no assurance of independence. NR Guideline does not report on potential conflict of interests.

For purposes of this checklist, conflicts of interest include employment by, consulting for, or holding stock in companies doing business in fields affected by the guideline, as well as related financial conflicts. This definition should not be considered exclusive. As much as anything, this is a

163

surrogate marker for thorough reporting, since it may be assumed that guideline projects are funded by the sponsoring organization and many authors think it unnecessary to report a non-conflict. 3. Guideline development group

A Guideline development group includes 1) methodological experts and clinicians and 2) representatives of multiple specialties. B Guideline development group includes one of the above, but not both. C Guideline developers all from one specialty or organization, and no methodologists. NR Affiliations of guideline developers not reported

The purpose of this standard is to ensure that supporters of competing procedures, or clinicians with no vested interest in utilization of one procedure or another, are involved in development of the guideline. Both AGREE II and IOM call for patient or public involvement: very few guideline panels have done so to date, so this is not necessary for guidelines to be rated A. Involvement of methodologists or HTA specialists in the systematic review is sufficient involvement in the guideline development group for our purposes. In the absence of any description of the guideline group, assume the named authors are the guideline group. 4. Systematic review

A Guideline includes a systematic review of the evidence or links to a current review. B Guideline is based on a review which may or may not meet systematic review criteria. C Guideline is not based on a review of the evidence.

In order to qualify as a systematic review, the review must do all of the following: Describe itself as systematic or report search strategies using multiple databases Define the scope of the review (including key questions and the applicable population) Either include quantitative or qualitative synthesis of the data or explain why it is not indicated Note: this element does not address the quality of the systematic review: simply whether or not it exists. Concerns about quality or bias of the review will be discussed in text, where the analyst will explain whether the weaknesses of the review weaken the validity or reliability of the guideline. Note: a guideline may be rated B on this domain even if the review on which it is based is not available to us. This potential weakness of the guideline should be discussed in text of the report. 5. Grading the supporting evidence

A Specific supporting evidence (or lack thereof) for each recommendation is cited and graded B Specific supporting evidence (or lack thereof) for each recommendation is cited but the recommendation is not graded. C Recommendations are not supported by specific evidence.

To score a B on this domain there should be specific citations to evidence tables or individual references for each relevant recommendation in the guideline, or an indication that no evidence was available. Any standardized grading system is acceptable for purposes of this rating. If a guideline

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reports that there is no evidence available despite a thorough literature search, it may be scored B on this domain, or even A if evidence for other recommendations is cited and graded. 6. Recommendations

A Considerations for each recommendation are documented (i.e. benefits and harms of a particular action, and/or strength of the evidence); and recommendations are presented in an actionable form.

B Either one or the other of the above criteria is met. C Neither of the above criteria are met

In order to be actionable, the guideline should specify the specific population to which the guideline applies, the specific intervention in question, and the circumstances under which it should be carried out (or not carried out). The language used in the recommendations should also be consistent with the strength of the recommendation (e.g. directive and active language like “should” or “should not” for strong recommendations, and passive language like “consider” for weak recommendations). A figure or algorithm is considered actionable as long as it is complete enough to incorporate all the applicable patients and interventions. Please see the forthcoming NICE manual (24) for a good discussion of actionability in guidelines.

7. External review A Guideline was made available to external groups for review. B Guideline was reviewed by members of the sponsoring body only. C Guideline was not externally reviewed. NR No external review process is described.

8. Updating and currency of guideline

A Guideline is current and an expiration date or update process is specified. B Guideline is current but no expiration date or update process is specified. C Guideline is outdated.

A guideline is considered current if it is within the developers’ stated validity period, or if no period or expiration data is stated, the guideline was published in the past three years (NOTE: the specific period may be changed at the analyst’s discretion, based on whether the technology is mature and whether there is a significant amount of recent evidence). A guideline must address new evidence when it is updated. A guideline which is simply re-endorsed by the panel without searching for new evidence must be considered outdated.

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Appendix C. Search Strategies Dianostic Imaging:



1 exp PANCREATITIS/ (48415) 2 exp Diagnostic Imaging/ (2429938) 3 exp "Sensitivity and Specificity"/ (525318) 4 1 and 2 and 3 (867) 5 (acut* adj3 pancreat* adj7 (diagnos* or detect* or identif* or locat* or confirm*) adj10 (predict* or accura* or specificity)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (132) 6 (acut* adj3 pancreat* adj7 (imag* or scan* or tomogra* or radiogra* or pancreatogra*) adj10 (predict* or accura* or specificity)).mp. (38) 7 (acut* adj3 pancreat* adj7 (diagnos* or detect* or identif* or locat* or confirm*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (2714) 8 3 and 7 (295) 9 (acut* adj3 pancreat* adj7 (imag* or scan* or tomogra* or radiogra* or pancreatogra*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (861) 10 3 and 9 (94) 11 (acut* adj3 pancreat* adj7 (predict* or accura* or specificity)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (774) 12 2 and 11 (212) 13 exp Pancreatitis/dg [Diagnostic Imaging] (3895) 14 3 and 13 (406) 15 exp Diagnostic Errors/ (109179) 16 1 and 2 and 15 (229) 17 9 and 15 (16) 18 4 or 5 or 6 or 8 or 10 or 12 or 14 or 16 or 17 (1407) 19 limit 18 to yr="2013 ‐Current" (318)

Database Searched Ovid Medline

Years Searched ‐ All Questions 1946‐2018

Language English

Age of Subjects >18 years old

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Accurary:



1 exp PANCREATITIS/ (48415) 2 exp patient acuity/ (223010) 3 exp "Sensitivity and Specificity"/ (525318) 4 1 and 2 and 3 (507) 5 (acut* adj3 pancreat* adj7 (prognos* or severe or severity) adj10 (predict* or accura* or specificity)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (503) 6 (acut* adj3 pancreat* adj7 (predict* or accura* or specificity)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (774) 7 2 and 6 (373) 8 (acut* adj3 pancreat* adj7 (prognos* or severe or severity)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (4807) 9 3 and 8 (507) 10 exp pancreatitis/co (10296) 11 3 and 10 (271) 12 4 or 5 or 7 or 9 or 11 (1092) 13 ((Acute Physiology and Chronic Health Evaluation) or apache or bisap or Bedside Index of Severity in Acute Pancreatitis or (ranson* adj2 (score* or valu*)) or Computed Tomography Severity Index or ctsi).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (10414) 14 (((Acute Physiology and Chronic Health Evaluation) or apache or bisap or Bedside Index of Severity in Acute Pancreatitis or (ranson* adj2 (score* or valu*)) or Computed Tomography Severity Index or ctsi) adj7 (predict* or assess* or accura* or specificity)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (1644) 15 1 and 14 (198) 16 1 and 3 and 13 (253) 17 12 or 15 or 16 (1168) 18 limit 17 to yr="2013 ‐Current" (339)



167

Language English


Antibiotics:



1 exp pancreatitis/ (48454) 2 (acut* adj3 pancreatiti*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (23446) 3 1 or 2 (51038) 4 exp Anti‐Bacterial Agents/ (651689) 5 exp Bacterial Infections/dt, pc [Drug Therapy, Prevention & Control] (236812) 6 exp BACTERIA/de [Drug Effects] (222568) 7 4 or 5 or 6 (825591) 8 3 and 7 (1262) 9 limit 8 to yr="2017 ‐Current" (24) 10 ((prevent* or prophyla* or precaution* or pre‐caution* or deter or deterr*) adj5 (bacteria* or infect* or abscess* or antibiot* or anti‐biot*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (79455) 11 3 and 10 (522) 12 limit 11 to yr="2017 ‐Current" (8) 13 9 or 12 (30)



Language English


Fluid Therapy:



1 exp pancreatitis/ (48454) 2 (acut* adj3 pancreatiti*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (23446) 3 1 or 2 (51038)

168

4 exp fluid therapy/ (18479) 5 exp DEHYDRATION/th [Therapy] (1774) 6 exp Rehydration Solutions/ (1398) 7 exp Water‐Electrolyte Imbalance/th [Therapy] (5867) 8 exp OSMOREGULATION/ (31560) 9 4 or 5 or 6 or 7 or 8 (53307) 10 3 and 9 (358) 11 ((iv or intraven* or infus* or (administ* or giv* or prescri* or recommend* or deliver*)) adj5 (hydrat* or rehydrat* or dehydrat* or fluid* or water* or electrolyt* or osmo*) adj10 pancreat*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (140) 12 ((iv or intraven* or infus* or (administ* or giv* or prescri* or recommend* or deliver*)) adj5 (hydrat* or rehydrat* or dehydrat* or fluid* or water* or electrolyt* or osmo*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (45787) 13 3 and 12 (234) 14 10 or 11 or 13 (611) 15 ((iv or intraven* or infus* or (administ* or giv* or prescri* or recommend* or deliver*) or hydrat* or rehydrat* or dehydrat* or fluid* or water* or electrolyt* or osmo*) adj7 (crystallin* or colloid*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (8659) 16 3 and 15 (25) 17 14 or 16 (619) 18 limit 17 to yr="2017 ‐Current" (28) 19 limit 18 to english language (26) 20 limit 18 to abstracts (23) 21 19 or 20 (28) 22 exp pancreatitis/ (48454) 23 (acut* adj3 pancreatiti*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (23446) 24 22 or 23 (51038) 25 exp fluid therapy/ (18479) 26 exp DEHYDRATION/th [Therapy] (1774) 27 exp Rehydration Solutions/ (1398) 28 exp Water‐Electrolyte Imbalance/th [Therapy] (5867) 29 exp OSMOREGULATION/ (31560) 30 25 or 26 or 27 or 28 or 29 (53307)

169

31 24 and 30 (358) 32 ((iv or intraven* or infus* or resuscitat* or (administ* or giv* or prescri* or recommend* or deliver*)) adj5 (hydrat* or rehydrat* or dehydrat* or fluid* or water* or electrolyt* or osmo*) adj10 pancreat*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (195) 33 ((iv or intraven* or infus* or resuscitat* or (administ* or giv* or prescri* or recommend* or deliver*)) adj5 (hydrat* or rehydrat* or dehydrat* or fluid* or water* or electrolyt* or osmo*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (49647) 34 24 and 33 (331) 35 31 or 32 or 34 (670) 36 ((iv or intraven* or infus* or resuscitat* or (administ* or giv* or prescri* or recommend* or deliver*) or hydrat* or rehydrat* or dehydrat* or fluid* or water* or electrolyt* or osmo*) adj7 (crystallin* or colloid*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (8813) 37 24 and 36 (29) 38 35 or 37 (680) 39 limit 38 to yr="2017 ‐Current" (31)



Language English


Pain:



1 exp PANCREATITIS/ (48515) 2 (acut* adj3 pancreat*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (24002) 3 1 or 2 (51443) 4 exp PAIN/ (359294) 5 exp Pain Management/ (28008) 6 exp Pain Measurement/ (77065) 7 exp ANALGESIA/ (40792) 8 exp ANALGESICS/ (494746) 9 4 or 5 or 6 or 7 or 8 (839038)

170

10 3 and 9 (3468) 11 exp MORTALITY/ (343085) 12 exp Vital Statistics/ (836700) 13 exp "Outcome Assessment (Health Care)"/ (939208) 14 exp "Length of Stay"/ (76641) 15 exp "Costs and Cost Analysis"/ (215736) 16 (pancrea* adj5 ((abcess* or infect*) and necro*)).mp. (2370) 17 ((organ* or liver or hepat* or kidney* or renal or heart or cardia*) adj3 fail*).mp. (360417) 18 11 or 12 or 13 or 14 or 15 or 16 or 17 (2179416) 19 10 and 18 (748) 20 limit 19 to yr="2003 ‐Current" (572) 21 limit 20 to (meta analysis or systematic reviews) (44) 22 limit 20 to randomized controlled trial (72) 23 21 or 22 (116) 24 exp PANCREATITIS/ (48515) 25 (acut* adj3 pancreat*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (24002) 26 24 or 25 (51443) 27 exp PAIN/ (359294) 28 exp Pain Management/ (28008) 29 exp Pain Measurement/ (77065) 30 exp ANALGESIA/ (40792) 31 exp ANALGESICS/ (494746) 32 27 or 28 or 29 or 30 or 31 (839038)



Language English


Drainage:



1 exp Pancreatic Cyst/ (7142) 2 exp Pancreatitis, Acute Necrotizing/ (3042) 3 (pancreat* adj5 (cyst* or pseudocyst* or necrot*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol

171

supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (15713) 4 1 or 2 or 3 (15713) 5 exp Drainage/ (54824) 6 (drain* or ((remov* or releas* or suction* or evacua*) adj3 (pressur* or fluid* or accumulat*))).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (128611) 7 5 or 6 (141559) 8 4 and 7 (2995) 9 limit 8 to yr="2008 ‐Current" (983) 10 ((drain* or ((remov* or releas* or suction* or evacua*) adj3 (pressur* or fluid* or accumulat*))) adj10 (pancreat* adj5 (cyst* or pseudocyst* or necrot*))).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (1006) 11 limit 10 to yr="2008 ‐Current" (298)



Language English


Repeat Imaging:



1 exp PANCREATITIS/ (48515) 2 ((acut* or (late* adj3 (phas* or stag*))) adj3 pancreatiti*).mp. (23499) 3 1 or 2 (51109) 4 exp DIAGNOSTIC IMAGING/ (2434864) 5 dg.fs. (1042571) 6 4 or 5 (2452608) 7 exp TIME/ (1280039) 8 ((cross or section* or repeat*) adj5 (imag* or scan* or radiogra* or x‐ray* or tomogra*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (30200) 9 3 and 7 (2676) 10 3 and 8 (133) 11 9 or 10 (2804) 12 limit 11 to yr="2008 ‐Current" (946)

172

13 exp Vital Statistics/ (836700) 14 exp "OUTCOME ASSESSMENT (HEALTH CARE)"/ (939208) 15 exp Cost‐Benefit Analysis/ (73070) 16 13 or 14 or 15 (1735781) 17 11 and 16 (644) 18 limit 17 to yr="2008 ‐Current" (432) 19 ((cross or section* or repeat*) adj5 (imag* or scan* or radiogra* or x‐ray* or tomogra*) adj10 pancreatit*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (32) 20 ((cross or section* or repeat*) adj5 (imag* or scan* or radiogra* or x‐ray* or tomogra*) adj10 (time or times or timing* or frequen* or schedul* or multip*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (1920) 21 3 and 20 (12) 22 19 or 21 (43) 23 limit 22 to yr="2008 ‐Current" (20) 24 18 or 23 (449)



Language English


Alcohol:



1 exp pancreatitis/ (48515) 2 (acut* adj3 pancreatiti*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (23489) 3 1 or 2 (51108) 4 exp ETHANOL/ (103467) 5 exp Alcohol Drinking/ (62824) 6 exp ALCOHOLISM/ (71993) 7 4 or 5 or 6 (212455) 8 3 and 7 (2376)

173

9 limit 8 to yr="2017 ‐Current" (35) 10 limit 9 to humans (32) 11 ((drink* or drank or drunk or consum* or imbib* or stop* or ceas* or cessat* or quit*) adj5 (alcohol* or ethanol* or liquor* or beer* or wine*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (93932) 12 3 and 11 (872) 13 limit 12 to yr="2017 ‐Current" (37) 14 9 or 13 (50) 15 ((quit* or stop* or ceas* or cessat* or rehab* or (giv* adj up)) adj5 (alcohol* or ethanol* or liquor* or beer* or wine*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (2476) 16 3 and 15 (46) 17 limit 16 to yr="2017 ‐Current" (2) 18 14 or 17 (50)



Language English


Nutrition:



1 exp pancreatitis/ (48515) 2 (acut* adj3 pancreatiti*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (23489) 3 1 or 2 (51108) 4 exp Nutrition Therapy/ (93022) 5 exp nutrition assessment/ (13206) 6 exp Feeding Methods/ (41784) 7 exp DIET/ (250204) 8 exp Energy Metabolism/ (344516) 9 4 or 5 or 6 or 7 or 8 (634261) 10 3 and 9 (1786) 11 limit 10 to yr="2017 ‐Current" (43)

174

12 ((nutri* or feed* or food* or diet*) adj7 (therap* or treat* or interven* or support or regimen*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (171143) 13 3 and 12 (1089) 14 limit 13 to yr="2017 ‐Current" (36) 15 11 or 14 (57) 16 ((nutri* or feed* or food* or diet*) adj7 (oral* or enteral* or parenteral* or therap* or treat* or interven* or support or regimen*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (217760) 17 3 and 16 (1753) 18 limit 17 to yr="2017 ‐Current" (56) 19 15 or 18 (66)



Language English


ERCP:



1 exp pancreatitis/ (48515) 2 (acut* adj3 pancreatiti*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (23489) 3 1 or 2 (51108) 4 exp Cholangiopancreatography, Endoscopic Retrograde/ (15170) 5 ERCP.mp. (7829) 6 (endoscop* adj3 retrograd* adj5 cholangiopancreat*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub‐heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (17194) 7 4 or 5 or 6 (18511) 8 3 and 7 (4785) 9 limit 8 to yr="2017 ‐Current" (141) 10 limit 9 to english language (133) 11 limit 9 to abstracts (105) 12 10 or 11 (137)



175

Language English


acute pancreatitis evidence summary 4.1 pancreatitis evidence summary...13. in patients with acute...

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