Acute Pancreatitis

Enteral feeding in acute pancreatitisSubhajit Sarkar MDDivision of Hospital MedicineUniversity of New MexicoAugust 2011Role of enteral feeding in acute pancreatitisQ1. How important is nutritional support?Q2. When should it be started?Q3. What is the best route?The pancreas0.1% total body weightEndocrine pancrease (insulin production) - 80%Exocrine pancreas (manufacture and secretion of digestive enzymes) 20%13 times the protein producing capacity of the liver and RES combined15 different types of digestive enzymes RER > golgi > zymogens (pro-enzymes) Meal > vagal nerve, VIP, GRP, secretin, CCK and encephalins > enzymatic release into pancreatic duct > brush border of duodenum Trypsinongen + enterokinase > trypsinTrypsin > activates other proenzymes

Protection from autodigestionNegative feedback stops enzyme activation elevated trypsin > decreases CCK and secretinProtective mechanisms proteins are translated into the inactive pro-enzymesposttranslational modification in the Golgi > segregation into the unique zymogen granulesparacrystalline arrangement with protease inhibitors.acidic pH and a low calcium concentrationWhen these protective mechanisms are disrupted > intracellular enzyme activation > pancreatic autodigestion > leading to acute pancreatitis.

PathophysiologyTriggers hypothesizedExtracellular factors (eg, neural response, vascular response)Intracellular factors (eg, intracellular digestive enzyme activation, increased calcium signaling, heat shock protein activation) Delayed or absent enzymatic secretion, such as with the CFTR gene mutation.> (1) lysosomal and zymogen granule compartments fuse, enabling activation of trypsinogen to trypsin> (2) intracellular trypsin triggers the entire zymogen activation cascade> (3) secretory vesicles are extruded across the basolateral membrane into the interstitium > molecular fragments act as chemoattractants for inflammatory cells

Pathophysiology> Activated neutrophils > superoxide + proteolytic enzymes (cathepsins B, D, and G; collagenase; and elastase)> macrophages > cytokines (tumor necrosis factor-alpha, interleukin-6, and interleukin-8)> increased pancreatic vascular permeability > hemorrhage, edema > necrosis> systemic complications from mediators> SIRS > shock > death bacteremia due to gut flora translocationARDS pleural effusionsgastrointestinal hemorrhagerenal failure. CausesBiliary tract disease (40%): occult microlithiasis is probably responsible for most cases (70%) of idiopathic acute pancreatitis.Alcohol (35%): Post-ERCP (4%)Idiopathic (10%)Trauma (1.5%)Drugs (2%)azathioprine, sulfonamides, sulindac, tetracycline, valproic acid, didanosine, methyldopa, estrogens, furosemide, 6-mercaptopurine, pentamidine, 5-aminosalicylic acid compounds, corticosteroids, and octreotide.CausesInfection (< 1%)Viral, Bacterial (Mycoplasma pneumoniae, Salmonella, Campylobacter, and TB)Ascariasis Hereditary pancreatitis (< 1%) : AD, cationic trypsinogen gene (PRSS1)> premature activation of trypsinogen to trypsin.CFTR mutation > abnormalities of ductal secretionHypercalcemia (< 1%)Developmental abnormalities of the pancreas (< 1%): pancreas divisum and annular pancreas.Hypertriglyceridemia (< 1%)Tumor (< 1%)Toxins (< 1%) organophosphate insecticideScorpion Tityus trinitatis (Trinidad)Postoperative (< 1%)Vascular abnormalities/vasculitis (< 1%)Autoimmune pancreatitis (< 1%)EpidemiologyIncidence: 17/100000100,000 hospitalizations/year80% mild, 20% severe (necrotizing)Mortality (per ACG paper 2007)All cases5%Interstitial (mild)3%Necrotizing17%Infected necrosis30%Sterile necrosis12%

EpidemiologyAge median agesAlcohol-related - 39 yearsBiliary tractrelated - 69 yearsTrauma-related - 66 yearsDrug-induced etiology - 42 yearsEndoscopic retrograde cholangiopancreatography (ERCP)related - 58 yearsAIDS-related - 31 yearsVasculitis-related - 36 years

HistoryAbdominal painsudden onset, dull, boring, and steadyupper abdomen, usually in the epigastric region, but it may be perceived more on the left or right sideRadiates directly through the abdomen to the back in approximately one half of cases.Nausea + vomiting + anorexiaDiscomfort frequently improves with the patient in the supine position

Physical signsFever (76%) Tachycardia (65%)Abdominal tenderness, muscular guarding (68%), and distension (65%)Hypoactive bowel sounds (ileus)Jaundice (28%).Dyspnea (10%) diaphragmitis, pleural effusion, ARDSHemodynamic instability (10%)Hematemesis or melena (5%)Severe acute pancreatitis: pale, diaphoretic, and listless.Severe necrotizing pancreatitisCullen signGrey-Turner signErythematous skin nodules (extensor skin surface-fat necrosis), polyarthritisPurtscher retinopathy

DiagnosisAmylase Non-specific also elevated in SBO, mesenteric ischemia, tubo-ovarian disease, renal insufficiency, macroamylasemia, parotitisShort half-life - daysLipase More specific; Longer half-life? recheck lipase level does not indicate whether the disease is mild, moderate, or severe, and monitoring levels serially during the course of hospitalization does not offer insight into prognosis.LFTFor gall stone disease: ALT > 150 s.o gallstone panc and more fluminant disease

Ca, TGCauses, complication (hypocalcemia from saponification); TG can be falsely lowered Chem7 Electrolyte imbalances, renal failure, endocrine dysfunctionCBCa negative predictor, that is, a lack of hemoconcentration effectively rules out severe disease.CRP24-48 hours after presentation to provide some indication of prognosis. Higher levels have been shown to correlate with a propensity toward organ failure.A CRP value in double figures strongly indicates severe pancreatitis. ABGIf dyspneicLDH, BUN (on admission and 48 hours)Ranson criteriaIgG4to evaluate for autoimmune pancreatitis. not specificTrypsin, trypsinogen-2, trypsinogen activation peptidediagnose acute pancreatitis and to help determine severityMCP-1 gene polymorphismmay also predict severityDiagnosisAbdominal radiographya colon cut-off sign, a sentinel loop, or an ileus; calcificationsAbdominal ultrasonographyAbdominal CT scanningGenrallt not indicated for patients with mild pancreatitis Usually at 72 hours in severe pancreatitisBalthazar scaleA - NormalB - Enlargement C - Peripancreatic inflammationD - Single fluid collectionE - Multiple fluid collections

MRCPEndoscopic ultrasonographyERCP +/ manometryCT or EUS guided aspiration/drainagePRSS1mutations CFTRgeneSPINK1gene

ComplicationsAcute fluid collectionsEarly in the course of acute pancreatitis; usually regress spontaneouslyMost require no specific therapy.Pseudocystcollection of pancreatic fluid enclosed by a wall of granulation tissue and requires 4 or more weeks to develop.Intra-abdominal infectionsFirst 1-3 weeks, fluid collections or pancreatic necrosis can become infected and jeopardize clinical outcome.3-6 weeks, pseudocysts may become infected or a pancreatic abscess may develop. Escherichia coli(26%),Pseudomonasspecies (16%),Staphylococcusspecies (15%),Klebsiellaspecies (10%),Proteusspecies (10%),Streptococcusspecies (4%),Enterobacterspecies (3%), and anaerobic organisms (16%).Fungal superinfections may occur weeks or months into the course of severe necrotizing pancreatitis.Pancreatic necrosisSterile pancreatic necrosis is usually treated with aggressive medical managementInfected pancreatic necrosis require surgical debridement or percutaneous drainage if they are to survive.If the pancreatitis was moderate to severe and associated with peripancreatic fluid collections, subsequent imaging studies are indicated to determine if a pseudocyst has developed.

Staging severityDifferences in managementMild: interstitial edema and an inflammatory infiltrate without hemorrhage or necrosis, usually with minimal or no organ dysfunction. Severe (necrotizing): extensive inflammation and necrosis of the pancreatic parenchyma , often associated with severe gland dysfunction and multiorgan system failure.Infected necrosisAssessing severityClinical criteriaRanson APACHE II (>8)GlasgowAtlantaBISAPBalthazar CRP: level greater than 6 at 24 hours, or greater than 7 at 48 hours, is consistent with severe acute pancreatitis.Hematocrit: negative predictor for necrosis in patients without hemoconcentration. Pertioneal lavagetrypsin activation peptide, polymorphonuclear elastase, interleukin-6, and phospholipase A2. Polymorphisms (MCP-1) gene

APACHE IIDoes the patient have a history of chronic organ insufficiency or immunocompromise?Yes, and is s/p emergency surgery.Yes, but is not s/p operation.Yes, and is s/p elective surgery.No.Does the patient have acute renal failure?Yes.Ageyears oldTemperature (Rectal, Celsius)C or F (yes, either!)Mean arterial pressure (MAP)pH (Arterial)Heart RatebpmRespiratory Rate (either ventilated or spontaneous)bpmSodium (Serum)mg/dL Potassium (Serum)mg/dL Creatinine (Serum)mg/dLHematocrit White Blood Cell Countx103cells / mmGCS pointsA-a gradient (if FiO2 0.5)mm HgPaO2 (if FiO2 < 0.5)mm HgRanson criteriaAt admission:age in years > 55 yearswhite blood cell count > 16000 cells/mm3blood glucose > 10 mmol/L (> 200 mg/dL)serum AST > 250 IU/Lserum LDH > 350 IU/LAt 48 hours:Calcium (serum calcium < 2.0 mmol/L (< 8.0 mg/dL)Hematocrit fall > 10%Oxygen (hypoxemia PO2 < 60 mmHg)BUN increased by 1.8 or more mmol/L (5 or more mg/dL) after IV fluid hydrationBase deficit (negative base excess) > 4 mEq/LSequestration of fluids > 6 L

AGA 2007Clinicians should define severe disease by mortality or by the presence of organ failure and/or local pancreatic complications including pseudocyst, necrosis, or abscess. Multiorgan system failure and persistent or progressive organ failure are most closely predictive of mortality and are the most reliable markers of severe disease. The prediction of severe disease, before its onset, is best achieved by careful ongoing clinical assessment coupled with the use of a multiple factor scoring system and imaging studies. The Acute Physiology and Chronic Health Evaluation (APACHE) II system is preferred, utilizing a cutoff of 8. Those with predicted or actual severe disease, and those with other severe comorbid medical conditions, should be strongly considered for triage to an intensive care unit or intermediate medical care unit. Rapid-bolus contrast-enhanced CT should be performed after 72 hours of illness to assess the degree of pancreatic necrosis in patients with predicted severe disease (APACHE II score 8) and in those with evidence of organ failure during the initial 72 hours. CT should be used selectively based on clinical features in those patients not satisfying these criteria. Laboratory tests may be used as an adjunct to clinical judgment, multiple factor scoring systems, and CT to guide clinical triage decisions. A serum C-reactive protein level >150 mg/L at 48 hours after disease onset is preferred.TreatmentNPO vs early nutritionIVFAnalgesicsUS for gallstonesSevere acute pancreatitis may require intensive care.Aggressive supportive care, to decrease inflammation, to limit infection or superinfection, and to identify and treat complications as appropriateResuscitation should be enough to maintain hemodynamic stability, which is usually an initial several liter fluid bolus followed by 250-500 cc/h continuous infusion.

TreatmentAntibioticsInfected pancreatic necrosis. Not be given routinely for feversRoutine use of antibiotics as prophylaxis against infection in severe acute pancreatitis is not recommended.ERCPsevere acute gallstone pancreatitis that is not responding to supportive therapy or with ascending cholangitis with worsening signs and symptoms of obstruction, early ERCP with sphincterotomy and stone extraction is indicatedSurgery for infected necrosisDrainage of organised collections

NPO for pancreatic rest?Rationale for a period of NPO is the idea of pancreatic restAssumption that enteral feeding may stimulate pancreasAlso NPO due to anorexia, nausea and painTPN was originally the route of choice NJ feeding used in most studiesRagins et al canine modelJejunal feeding did not stimulate pancreatic secretionIntragastric and intraduodenal didIn humans feeding into the jejunum past the ligament of Treitz less likely to stimulate CCK and secretin and may stimulate inhibiting polypeptidesPancreatic enzyme production increased significantly at LOT whereas no increase 60 cm beyond thisElemental formula (low fat, free amino acids) cause trypsin levels to fall and less stomach acidAnimal and human studies suggest exocrine secretions and response to CCK are suppressed (thus EN may not cause increased secretion)May be pancreatic rest is not as crucial as once thought.Q1. How important is nutritional support ?Pancreatitis is a systemic disease with cytokine productionBacterial translocation is involved in the etiology of infected necrosisMochizuki et al 1984: ginea pig burn model. If gastric feeding started at 2 hours rather than 72 hours > reduced hypermetabolic response and most survived.- feedings preserved gut integrity and aborted early cytokine responseBenefit of TPN in reducing mortality established early in severe disease (was previous gold standard)Feller et al (1974) reported reduced mortality and complications in patients with parenteral nutrition vs no nutritionQ1. How important is nutritional support ?Mild disease : generally improves within days and studies do not show benefit of additional support.Sax et al (1987): randomised 54 pts: Mild pancreatitis (Ranson 1.1) no differences in TPN vs standard IVFin total hospital days, number of complications or days to oral intake.

Q1. How important is nutritional support ?Petrov et al (2008) Systematic review: nutritional support in acute pancreatitis.

Systematic review of the data from 15 RTCS in acute pancreatitis that compares enteral nutrition with no supplementary nutrition, parenteral nutrition with no supplementary nutrition and enteral nutrition with parenteral nutrition.Enteral nutrition, when compared with no supplementary nutrition, was associated with no significant change in infectious complications, but a significant reduction in mortality: ratio of RR 0.22, 95% CI 0.07-0.70, P = 0.01. Parenteral nutrition, when compared with no supplementary nutrition, was associated with no significant change in infectious complications,but a significant reduction in mortality: RR 0.36, 95% CI 0.13-0.97, P = 0.04. Enteral nutrition, when compared with parenteral nutrition, was associated with a significant reduction in infectious complications: RR 0.41, 95% CI 0.30-0.57, P 24% reduction in infectious complications, 32% reduction in mortality compared to delayed feedingMarik and Zaloga (2001)Metaanalysis: early EN vs PN < 36 hours vs > 36 hours in ICU patientsReduced infectious complications and LOSFor AP: Petrov et al (2008)Systematic review of RTCs comparing EN and TPN EN started within 48 hours of admission -> significant reduction in MOF, pancreatic infection complications and mortalityDifferences diminished after 48 hours of admissionTherefore EN started within 48 hours may be beneficial but more directed RTC is neededEckerwall et al (2007)60 pts; immediate oral feeding vs fastingImmediate group > shorter period of IVF, 2 day earlier solid food, 2 day shorter LOSNo difference in symptoms, complications, recurrencesAgain does pancreatic rest make any difference?

Q3. What is the best route?Windsor at al (1998): first trial of NJ-EN in severe disease (Glasgow score >3)- 34 patients amylase > 1000- enteral vs parenteral- SIRS and organ failure, hospital stay reduced in enteral groupPetrov et al (2008): 69 pts NJ-EN vs PN in SAP (APACHE II>8)- less infected necrosis (47% vs 20%, p= 0.02)- less septic complications (32% vs 11%, p= 0.04)- MOF and overal mortality (35% vs 6%, p=0.003)- overall mortality of 20%Enteral feeding via NJ tube thought to increase antioxidant activity, reduce acute phase reaction, cytokine production and maintain gut integrity reducing bacterial translocation Multiple studies now show that NJ-EN is superior to TPN in severe APAl-Omran (2010) metaanalysis of 8 trials: EN significantly reduced mortality, multiple organ failure, systemic infections, and the need for surgery compared with those who received PNMcClave et al (2006): metaanalysis of 7 trials comparing enteral to parenteral nutrition showed a significant reduction in infectious morbidity (291 patients, risk ratio (RR) = 0.5) and hospital length of stay (202 patients, mean difference (-) 4 days), and a trend toward reduced organ failure.

Q3. What is the best route?Eatock et al (2005): RTC of early NG vs NJ feeding in severe APFound NG feeding as well tolerated as NJStudy limitation: NJ tubes not fluroscopically confirmed to be in jejunum2 metaanalyses of NG vs NJ feeding in SAPJiang et al (2007): 3 RTC: no difference in mortality, LOS, infectious complications, MOF, ICU admission or surgeryPetrov et al (2008): 4 RTC: no differences in mortality or tolerancehowever small numbers and very wide confidence intervals.Both studies say well-powered RTC neededExisiting guidelinesThese guidelines may be out of dateACG (2006): Banks et alMild AP : just oral intake, no nutritional supportSevere AP: nutrional support should be initiated when it becomes clear that the patient will not be able to comsume nourishment by mouth for several weeksThis assessment can usually be made within 3-4 daysAGA (2007): AGA Institute medical position statement on acute pancreatitisNutritional support should be provided in those patients likely to remain "nothing by mouth" for more than 7 days. Nasojejunal tube feeding, using an elemental or semielemental formula, is preferred over total parenteral nutrition. Total parenteral nutrition should be used in those unable to tolerate enteral nutrition.Uptodate:Mild AP: oral dietSevere AP: enteral nutrition within 72 hours, if possible beyond ligament of Treitz; TPN to be used if not tolerated or does not need nutritional goals within 2 days

Proposed UNM Best PracticeMild APNPO, IVF, initiate oral diet when anorexia, nausea, pain resolveIf not eating > 5-7 days, initiate enteral feeding with NJ or NG tubeSevere APInitiate EN within 48 hours of admissionIf possible NJ, otherwise NG if significant delayTPN only if EN not tolerated or not meeting nutritional goals after 2 days