Pancreatitis

Reviewed and revised 14 December 2016

OVERVIEW

Pancreatitis is inflammation of the pancreas and involves activation of proteolytic enzymes that may progress to haemorrhagic necrosis of the pancreatic parenchyma

• Diagnosis is made when 2 out of 3 criteria are met:
  • Symptoms consistent with pancreatitis (e.g. epigastric pain)
  • Elevation of serum amylase or lipase (to 3 times normal level)
  • Radiological features consistent with pancreatitis (e.g. CT or MRI)
• Severity ranges from mild to severe (acute necrotising pancreatitis)
  • 15-25% of pancreatitis is severe
  • overall mortality of severe acute pancreatitis is about 15%

DEFINITIONS

Atlanta criteria 2012 revision

• Mild acute pancreatitis
  • No organ failure
  • No local or systemic complications
• Moderately severe acute pancreatitis
  • Transient organ failure (<48 hours) and/or
  • Local or systemic complications without persistent organ failure
• Severe acute pancreatitis
  • Persistent organ failure (>48 hours) — single organ or multiorgan

Definitions based on imaging

• Necrotizing pancreatitis
  • in the absence of laparotomy or autopsy, the presence of 30% (or greater) of the pancreas that is non-enhancing on contrast-enhance CT or MRI with gadolinium
• Interstitial edematous pancreatitis
  • lack of evidence of necrotizing pancreatitis on imaging

Local complications of pancreatitis

• acute pancreatic fluid collection
  • peripancreatic fluid collection occurring within 4 weeks and lacking a defined wall
• pancreatic pseudocyst
  • acute pancreatic fluid collection that has persisted >4 weeks and developed a well-defined wall
• acute necrotic collection
  • pancreatic fluid collection with areas of necrosis occurring within 4 weeks and lacking a defined wall
  • may be isolated to pancreas or be peripancreatic
  • sterile or infected
  • patients may appear ill with MODS, or may initially appear well
• walled off necrosis
  • acute necrotic collection that has persisted >4 weeks and developed a well-defined wall
  • sterile or infected

Note that these terms are imprecise and have fallen out of favour:

• pancreatic abscess
• pancreatic sequestration
• necroma
• organized pancreatic necrosis

CAUSES

Ethanol and biliary disease accounts for 70% of cases of acute pancreatitis

A useful mnemonic for the potential causes of acute pancreatitis is “I GET SMASHED”

• Idiopathic
• Gall stones
• Ethanol
• Trauma
• Steroids
• Mumps and other viruses (EBV, CMV, HIV)
• Autoimmune diseases (SLE, polyarteritis nodosa, pregnancy)
• Scorpion stings
• Hypercalcaemia, hyperlipidaemia, hypothermia, hypotension (ischemia)
• ERCP, emboli
• Drugs (SAND + MR VET)
  • sulphasalazine, azathioprine, NSAIDS, diuretics + metronidazole, raniditine, valproate, erthyromycin, tetracyclines

or

• Idiopathic
• Obstructive
  • stones
  • neoplasm
  • sludge
  • congenital
• Parenchymal
  • local
    • trauma
    • ischaemia
    • autoimmune
  • global
    • hypothermia
    • hypotension

ASSESSMENT

History

• severe upper abdominal pain
  • may be epigatric, RUQ or even LUQ
  • rapid onset over ~20 minutes is typical
  • gradually increases to a peak over several hours
  • continuous and boring in nature
  • usually moderate to severe intensity; can be minor in mild cases
  • little change with position
  • bandlike radiation to the back (~50%)
  • pain is absent in 5-10% of cases and can be a feature of fatal disease
• nausea and vomiting
• anorexia
• fever and chills
• dyspnoea
• steatorrhoea

Examination

• Appearance may vary from well to seriously ill
• SIRS: tachycardia, tachypnoea, pyrexia
• jaundice
• evidence of retroperitoneal haemorrhage (<1%, poor prognosis)
  • flank echymosis (Grey-Turner sign)
  • peri-umbilical echymosis (Cullen sign)
• tenderness and guarding
• distention (e.g. ileus, fluid collections)
• hypotension (may have pain-induced hypertension initially)
• oliguria
• respiratory failure
• altered mental state, delirium, coma

Laboratory

• increased amylase (> 3 x normal)
• increased lipase (more specific, longer half life) (>3 x normal)
• elevated liver enzymes
• increased WBC
• hyperglycaemia
• hypocalcaemia

Imaging

• CXR (e.g. raised hemidiaphragm, pleural effusion, APO, ARDS, atelectasis)
• AXR (e.g. localised ileus, exclusion of bowel obstruction)
• Ultrasound (e.g. gallstones and biliary obstruction)
• CT (dynamic contrast-enhanced)
  • pancreatic oedema and haemorrhage, necrosis, viable and non-viable tissue, CBD diameter
  • CT severity index uses (1) extent of necrosis (2) peripancreatic inflammation
  • can be used to determine whether necrosis is sterile or infected
  • typically performed if:
    • diagnostic uncertainty
    • severe acute pancreatitis
    • suspicion of complications
• MRI
  • better than CT for distinguishing uncomplicated pseudocyst from walled off necrosis
• MRCP and ERCP (obstruction and stone removal)

Other

• CT-guided FNA
  • 95% sensitive for infected pancreatic necrosis
  • can be repeated after 4-7 days if negative and infection is still suspected

PROGNOSIS AND GRADING

Other indicators of severity

• Glasogow or  Imrie score
• Multi-organ dysfunction on Marshall Score
• SOFA score
• 3 or more Ranson’s riteria
• APACHE score >8
• CRP
• CT severity index

Ranson’s score (+1 for each criterion met)

• On admission
  • Age > 55 yrs
  • WCC > 16,000
  • LDH > 600 U/I
  • AST > 120 U/I
  • Glucose > 10 mmol/L
• Within 48 hours
  • Haematocrit fall > 10%
  • Urea rise > 0.9 mmol/L
  • Calcium < 2 mmol/L
  • pO2 < 60mmHg
  • Base deficit > 4
  • Fluid sequestration > 6 L
• Mortality based on score
  • < 3  =  1%
  • 3-4  =  15%
  • 5-6  =  40%
  • > 6  =  100%

Glasgow criteria or Imrie score

• On admission
  • age > 55 years
  • WCC > 16
  • glucose > 11
  • AST > 250
• Within 48 hours
  • decrease in HCT by > 10%
  • increase in urea by > 1.8
  • Ca2+ < 2, PaO2 < 60mmHg
• Mortality based on score
  • 0-2 risk factors: mortality < 1%
  • > 6 risk factors: mortality around 100%

COMPLICATIONS

General/ systemic complications

• pain
• SIRS
• renal failure, liver failure and MODS
• metabolic derangement (e.g. metabolic acidosis, electrolyte abnormalities)
• ileus
• infection
  • pancreatic (e.g. gut transolcation leading to infected pancreatic necrosis)
  • extra-pancreatic
• Hypotension and shock
  • “Third space losses” (capillary leak, particularly sequestration in the abdomen)
  • Systemic inflammatory response (systemic cytokine release)
  • Gastrointestinal losses (e.g. vomiting, diarrhoea, decreased oral intake, and gastric bleeding)
  • Retroperitoeal hematoma (haemorrhagic pancreatitis, splenic artery psueudoaneurysm formation and rupture)
  • Decreased preload (hypovolaemia, abdominal compartment syndrome
  • Impaired cardiac contractility (acidaemia and SIRS-associated cardiomyopathy)
• Hypoxaemia and respiratory failure
  • Atelectasis (abdominal pain and distension)
  • ARDS (systemic cytokine release)
  • Pleural effusions (“third spacing” and fluid resuscitation)
  • Pulmonary oedema (decreased cardiac contractility, capillary leak, fluid resuscitation)
  • Aspiration pneumonia (decreased level of consciousness, history of vomiting)

Local complications (may be sterile or infected)

• Pancreatic fluid collections
  • acute pancreatic fluid collection (<4 weeks)
  • pancreatic pseudocyst (>4 weeks)
• Pancreatic necrosis
  • diffuse (<4 weeks)
  • walled off necrosis (>4 weeks)

MANAGEMENT

Resuscitation

• A – intubation may be required for aspiration risk, severe respiratory failure and haemodynamic instability
• B – protective lung ventilation (VT 6 mL/kg PBW with Pplat <30cmH2)) with optimal PEEP +/- permissive hypercapnia (pH>7.15) required because of hypoxic respiratory failure and to decrease O2 consumption from respiratory work; prolonged mechanical ventilation may require tracheostomy
• C – aggressive fluid resuscitation and vasoactive support
• D – sedation and analgesia required to minimise oxygen consumption and optimise respiratory function (especially in the non-intubated patient)
• E – temperature control (e.g. consider active cooling if T>39.5C)

Specific treatment

• consider role of antibiotics for confirmed or suspected infection (see below – prophylactic antibiotics are not indicated)
• consider role of interventions (e.g. surgery) to manage specific local complications (see below)
• treat underlying cause
  • alcohol cessation and manage withdrawal
  • treat biliary obstruction
  • plasmapheresis for severe hypertriglyceridaemia

Supportive care and monitoring

• severe acute pancreatitis typically requires invasive monitoring (arterial line, CVC)
• address nutrition (see below)
• analgesia and sedation
• stress ulter prophylaxis
• glucose control
• consider IDC and maintain adequate urine output +/- RRT as indicated
• fluid balance can be difficult to manage due to initial resuscitation and capillary leak
• correction of coagulopathy
• thromboprophylaxis

Disposition

• HDU/ ICU admission is usually appropriate for:
  • severe pancreatitis
  • pancreatitis with evidence of organ dysfunction

NUTRITION IN SEVERE ACUTE PANCREATITIS

No evidence that “pancreatic rest” is beneficial, early enteral nutrition is preferred

• the concept of “pancreatic rest”
  • parenteral nutrition and jejunal administration of food avoids stimulation of pancreatic exocrine secretion by bypassing the cells that secrete cholecystokinin
  • clinical effectiveness is unproven
  • necrotic pancreas is likely less responsive to secretory stimuli
  • patients with mild pancreatitis can usually be safely fasted for up to 3-4 days (2012 International guidelines)
  • patients with severe acute pancreatitis benefit from early enteral nutrition

Enteral nutrition (EN)

• Enteral nutrition prevents intestinal atrophy, improves gut mucosal function and may reduce SIRS response and bacterial translocation from the GI tract
  • no evidence of clinical benefit in mild/moderate pancreatitis
  • beneficial in severe acute pancreatitis
• 3 RCT’s have shown that EN (compared to PN) results in
  • fewer infections and complications
  • more safety
  • less cost
• or mild/moderate pancreatitis, enteral feeding should be:
  • started at 5-7 days if there is failure to resume a normal diet
• For severe acute pancreatitis, enteral feeding should be:
  • started early
  • protocolised
  • tailored to the individual
  • reassessed daily
  • supplemented with PN to reach nutritional targets if required
• Route
  • Feeds via the gastric route (e.g. nasogastric tube) are successful in 90% of cases
  • jejunal route is an alternative if increased abdominal pain or failure of gastric feeding
• Requirements (2012 International guidelines)
  • 25-35kcal/kg/day
  • 1.2-1.5g/kg/day of protein
• Management of feed intolerance – consider
  • continuous rather than bolus feeding
  • advancing the gastric tube into the jejenum (post-pyloric feeding)
  • change to elemental feeds (e.g. small peptides, medium-chain triglycerides) (these are preferred in the 2012 International guidelines anyway)
• Prolonged artificial nutrition is commonly required for severe acute pancreatitis, especially if complicated by necrosis (e.g. 4-6 weeks)

Parental nutrition (PN)

• 2012 international guidelines recommend PN “when EN is contraindicated or not well tolerated”
• ASPEN guidelines recommend waiting for 5 days of trialling EN before resorting to TPN

In practice

• mild/ moderate pancreatitis cases can be safely fasted for up to a week
• in severe acute pancreatitis
  • feed via gastric tube or jejunal tube early
  • supplement or replace EN with PN if EN is not tolerated or contraindicated
• control glucose (e.g. insulin infusion to target glucose 6-10 mmol/L)

ROLE OF ANTIBIOTICS IN PANCREATITIS

Potential uses of antimicrobials in pancreatitis

• Prophylaxis
  • prevent infection in necrotizing pancreatitis
  • prevent infection of a pancreatic pseudocyst
• Treatment
  • of infected necrotizing pancreatitis
  • of coexistent extrapancreatic infection

Prophylactic antibiotics for severe acute pancreatitis

• SCCM (2004) Consensus Conference recommends against the use of routine prophylactic antibiotics, which is supported by a 2010 Conhrane review which found no benefit for prophylactic antibiotics for necrotizing pancreatitis
• Arguments for
  • Pancreatic necrosis promotes bacterial growth
  • Surgical source control is difficult or impossible
  • Diagnosis of sepsis is difficult (in the presence of SIRS)
  • Sepsis is a major cause of death in severe pancreatitis
  • Non-pancreatic infection plays a major role in this mortality.
  • Thus, prophylactic antibiotics should reduce mortality, even if by treating extrapancreatic infections
  • This practice is common: Baltatziz et al (2016) found antibiotic prophylaxis was used in 44-88% of the surveyed units.
• Arguments against
  • Antibiotic penetration into necrotic tissue is typically poor
  • Antibiotic overuse for treatment of extrapancreatic infections that have higher pancreatic penetrance (e.g. carbapenems)
  • Overgrowth and selection of resistant organisms and fungi

Treatment of coexistent extrapancreatic infection (Brown et al, 2014)

• Infectious complications occur affect 32% of acute pancreatitis cases
• Commonly respiratory infections (9.2%) or bacteraemia (8.4%)
• About 50% of bacterial cultures from necrotic pancreatic tissue are of non-enteric origin, suggesting infection from extrapancreatic sources
• Extrapancreatic infections should be promptly identified and treated to prevent spread to pancreatic tissue

Treatment of infected pancreatic necrosis (Brown et al, 2014)

• 8-12% of patients develop infected necrosis (Mike Larvin et al, 2008)
  • rare in first 7 days
  • tends to be confirmed late (e.g. 19-21 days following onset)
  • Survivors from early organ system failure may still die if pancreatic necrosis later becomes infected
  • Organ system failure tends to be worse and mortality tends to be higher
• Confirmation of the diagnosis is invasive, i.e. by samples and culture
  • consider FNA of the necrotic area if fever and leukocytosis persists beyond 7-10 days without an obvious source of infection
  • imaging helps determine if the infection is pancreatic or peripancreatic
  • CT-guided aspiration has pros (Banks, 2005) and cons (Pappas, 2005)
  • If the patient is haemodynamically unstable and the infected pancreas is held responsible, CT-guided or gastroscopic drainage offers both a diagnosis (confirming infection) and source control
• If infection is confirmed by Gram stain, the best choice of antibiotics is usually meropenem

Antibiotic choice

• Choose an antibiotic with optimal pancreatic penetration (e.g. carbapenem)
• All antibiotics penetrate the necrotic tissue to some extent, but most end up not achieving MIC (Bassi et al, 1994)
• Drugs that achieve high concentrations in pancreatic tissue :
  • Imipenem and meropenem
  • Metronidazole
  • Fluoroquinolones
• Drugs that penetrate poorly:
  • Aminoglycosides
  • Beta-lactams

Prophylactic Antifungals

• 25% of patients get a fungal infection independent of antibiotic use
• fungal infection is associated with increased mortality
• no clear evidence in severe acute pancreatitis

ROLE OF SURGERY AND OTHER INVASIVE INTERVENTIONS IN SEVERE ACUTE PANCREATITIS

Intervention for complications of severe acute pancreatitis remains controversial

• pancreatic debridement is required in <1% of cases of necrotizing pancreatitis (~15% mortality)
• if can perform minimally invasive surgery then preferred option (Hjalmar, NEJM, 2010) – avoid open necrosectomy if possible — options include:
  • percutaneous catheter drainage (~35-90% success rate)
  • endoscopic transluminal drainage (~80% success rate)
  • video-assisted retroperitoneal or endoscopic debridement
• antibiotics may allow infected necrotizing pancreatitis to become walled off necrosis, allowing minimally invasive techniques (e.g. laparoscopic, endoscopic or percutaneous approaches)
• success rates for interventions vary according to different centers and case series

Accepted indications for surgery:

• debridement of infected necrosis (better if done at 4 weeks once more organized)
• persistent bilary pancreatitis (or ERCP)
  • e.g. cholecystectomy after recovery from acute inflammatory response
• walled off necrosis (“abscess”)
• intra-abdominal hypertension

Controversial indications for surgery:

• > 50% sterile pancreatic necrosis (5% mortality for sterile pancreatic necrosis without surgery)
• stable, but persistent necrosis
• deterioration
• organ failure

ERCP

• urgent ERCP is required for an impacted gallstone with ascending cholangitis
• early removal of a possibly impacted gallstone causing gallstone pancreatitis in the absence of ascending cholangitis is controversial (unclear risk-benefit ratio)

OTHER CONTROVERSIAL THERAPIES IN SEVERE ACUTE PANCREATITIS

• Selective Digestive Decontamination (no clear, high-level evidence in pancreatitis)
• Anti-inflammatory agents
  • target TNF alpha, IL-1B, IL-6, 8, 10
  • activated protein C
    • PROWESS showed a reduction in mortality and sepsis and pancreatitis (but no proven source of infection)
    • since taken off the market
  • corticosteroids (no trials in patients with pancreatitis)
• Agents to decrease pancreatic enzyme production
  • e.g. glucagons, somatostatin, octreotide, H2 blockers, atropine, calcitonin, fluorouracil
  • not shown to alter the course of the disease
• Agents to ameliorate pancreatic enzyme damage
  • serine protease inhibitors (block trypsin, PLA2, plasmin, thrombin)
  • e.g. aprotonin, gabexate or lexipafant
  • not shown to improve outcomes

EVIDENCE

Prophylactic antibiotics for sterile necrotizing pancreatitis

• Early trials: suggested benefit (reduced infections, improved outcomes) however poor quality
• Recent higher quality RCTs (Isenmann 2004, Dellinger, 2007 and others): no effect on outcome or rate of infection when prophylactic antibiotics used in necrotic pancreatitis
• SCCM (2004) Consensus Conference recommends against the use of routine prophylactic antibiotics, supported by the 2010 Cochrane systematic review by Villatoro et al (see below)

Antibiotic therapy for prophylaxis against infection of pancreatic necrosis in acute pancreatitis (Villatoro et al, 2010)

• Cochrane systematic review of 7 trials (n=404)
• No statistically significant difference between prophylactic antibiotics and controls for:
  • mortality (8.4% vs 14.4%)
  • infected pancreatic necrosis rates (19.7% vs 24.4%)
  • non-pancreatic infection rates (23.7% vs 36%)
  • incidence of overall infections (37.5% vs 51.9%)
  • operative treatment
  • fungal infections
• No statistically significant difference between prophylactic beta-lactams and controls for:
  • mortality (9.4% vs 15%)
  • infected pancreatic necrosis rates (16.8% vs 24.2%)
  • overall infections (34.4% vs 52.8%)
  • operative treatment rates
• No statistically significant differences between prophylactic quinolone plus imidazole and controls
• Imipenem as sole prophylaxis versus control
  • no difference in the incidence of mortality
  • significant reduction in the rate of pancreatic infection (p=0.02; RR 0.34, 95% CI 0.13 to 0.84)
• Insufficient data available concerning antibiotic resistance
• Author’s conclusions
  • No benefit of antibiotics in preventing infection of pancreatic necrosis or mortality was found, except for when imipenem (a beta-lactam) was considered on its own, where a significantly decrease in pancreatic infection was found
  • None of the studies included were adequately powered

Enteral verus parenteral nutrition (Al-Omran et al, 2010)

• Cochrane systematic review of 8 trials (n=348)
• EN versus TPN for acute pancreatitis favoured EN (relative risk (RR)):
  • mortality 0.50 (95% CI 0.28 to 0.91)
  • multiple organ failure (MOF) 0.55 (95% CI 0.37 to 0.81)
  • systemic infection 0.39 (95% CI 0.23 to 0.65)
  • operative interventions 0.44 (95% CI 0.29 to 0.67)
  • local septic complications 0.74 (95% CI 0.40 to 1.35)
  • other local complications 0.70 (95% CI 0.43 to 1.13)
• Mean length of hospital stay was reduced by 2.37 days in EN vs TPN groups (95% CI -7.18 to 2.44)
• Subgroup analysis for EN vs TPN in patients with severe acute pancreatitis also favoured EN (RR)
  • mortality 0.18 (95% CI 0.06 to 0.58)
  • MOF 0.46 (95% CI 0.16 to 1.29)
• Author’s conclusion
  • EN should be considered the standard of care for patients with acute pancreatitis requiring nutritional support.

Enteral nutrition formulations (Poropat et al, 2015)

• Cochrane systematic review of 15 trials (n=1376)
• Low-quality evidence suggests that immunonutrition decreases all-cause mortality (RR 0.49, 95% CI 0.29 to 0.80) – further research required
• very low-quality evidence for the effects of probiotics
• Studies assessing probiotics yielded inconsistent and almost contrary results – routine use of EN enriched with probiotics in clinical practice is not indicated at present
• Evidence remains insufficient to support the use of a specific EN formulation

References

Journal articles and textbooks

• Al-Omran M, Albalawi ZH, Tashkandi MF, Al-Ansary LA. Enteral versus parenteral nutrition for acute pancreatitis. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD002837. Review. PubMed PMID: 20091534.
• Brown LA, Hore TA, Phillips AR, et al. A systematic review of the extra-pancreatic infectious complications in acute pancreatitis. Pancreatology. 14(6):436-43. 2014. [pubmed]
• Dellinger EP, Tellado JM, Soto NE, Ashley SW, Barie PS, Dugernier T, Imrie CW, Johnson CD, Knaebel HP, Laterre PF, Maravi-Poma E, Kissler JJ, Sanchez-Garcia M, Utzolino S. Early antibiotic treatment for severe acute necrotizing pancreatitis: a randomized, double-blind, placebo-controlled study. Ann Surg. 2007 May;245(5):674-83. PubMed PMID: 17457158; PubMed Central PMCID: PMC1877078.
• Isenmann R, Rünzi M, Kron M, Kahl S, Kraus D, Jung N, Maier L, Malfertheiner P, Goebell H, Beger HG; German Antibiotics in Severe Acute Pancreatitis Study Group. Prophylactic antibiotic treatment in patients with predicted severe acute pancreatitis: a placebo-controlled, double-blind trial. Gastroenterology. 2004 Apr;126(4):997-1004. PubMed PMID: 15057739.
• Jiang K, Huang W, Yang XN, Xia Q. Present and future of prophylactic antibiotics for severe acute pancreatitis. World J Gastroenterol. 2012 Jan 21;18(3):279-84. Review. PubMed PMID: 22294832; PubMed Central PMCID: PMC3261546.
• Lodewijkx PJ, Besselink MG, Witteman BJ. Nutrition in acute pancreatitis: a critical review. Expert review of gastroenterology & hepatology. 10(5):571-80. 2016. [pubmed]
• Marik PE, Zaloga GP. Meta-analysis of parenteral nutrition versus enteral nutrition in patients with acute pancreatitis. BMJ. 2004 Jun 12;328(7453):1407. Epub 2004 Jun 2. Review. PubMed PMID: 15175229; PubMed Central PMCID: PMC421778.
• McClave SA, Chang WK, Dhaliwal R, Heyland DK. Nutrition support in acute pancreatitis: a systematic review of the literature. JPEN. Journal of parenteral and enteral nutrition. 30(2):143-56. 2006. [pubmed]
• Meier R, Beglinger C, Layer P. ESPEN guidelines on nutrition in acute pancreatitis. European Society of Parenteral and Enteral Nutrition. Clinical nutrition (Edinburgh, Scotland). 21(2):173-83. 2002. [pubmed]
• Poropat G, Giljaca V, Hauser G, Štimac D. Enteral nutrition formulations for acute pancreatitis. The Cochrane database of systematic reviews. 2015. [pubmed]
• Spanier BW, Bruno MJ, Mathus-Vliegen EM. Enteral nutrition and acute pancreatitis: a review. Gastroenterology research and practice. 2011:. 2011. [pubmed] [free full-text]
• Villatoro E, Mulla M, Larvin M. Antibiotic therapy for prophylaxis against infection of pancreatic necrosis in acute pancreatitis. The Cochrane database of systematic reviews. 2010. [pubmed]
• Yentis, S.M., et al (2004)“Anaesthesia and Intensive Care A-Z: An Encyclopaedia of Principles and Practice” Elsevier, 3rd Edition