Acute Pancreatitis Evidence Based Approach

Acute Pancreatitis Evidence Based Approach
Pankaj Singh MD Director of Gastrointestinal Endoscopy Central Texas VA Health System, TX Assistant Professor Texas A&M University

Clinical Case 32-year-old man
c/o acute onset abdominal pain (presumed pancreatic origin) h/o alcohol intake A 32-year-old man is admitted to the hospital with acute onset abdominal pain of presumed pancreatic origin.

What do you think? Amylase or lipase Ultrasound or CT scan
If yes, When? ICU or medical ward Enteral nutrition or TPN Antibiotics ERCP Surgery

Evidence A. Proven > 2 well designed trials, randomized
B. Possible/ Probable 1 well designed study, randomized C. Consensus agreed opinion with no supportive evidence

Guidelines Atlanta British Society of Gastroenterology
International Association of Pancreas Santorini Conference World Congress of Gastroenterology The evidence based guidelines are the result of five different international associations/ conference that are well known for their expertise on pancreatitis

Background Potentially fatal Mortality – 0-25%
Necrosis determines the prognosis Acute pancreatitis is a potentially fatal disease, with reported mortality rates ranging from zero to almost 25%, depending on severity. Severity itself depends greatly on whether or not pancreatic necrosis is present. Since majority of the patients with mild acute pancreatitis recover without any short term complications or long term sequelae. So majority of the studies have focussed on management of acute necrotizing pancreatitis. I would also Panreas

Background Mild AP (no necrosis) – 0% Sterile necrosis – 10%
Since majority of the patients with mild acute pancreatitis recover without any short term complications or long term sequelae. So majority of the studies have focussed on management of acute necrotizing pancreatitis. I would also Sterile necrosis – 10% Infected necrosis – 25%

Diagnosis Laboratory Amylase Lipase Radiological US CT scan

Blood tests Amylase and lipase Plasma level peak within 24 hours
t1/2 of amylase << lipase Sensitivity Specificity Amylase 67-100 85-98 Lipase 82-100 86-100 Amylase and lipase are both enzymes released from the pancreas during acute pancreatitis. Plasma levels of both enzymes peak within the first 24 hours of symptoms, but the half life of amylase is shorter than that of lipase. Analysis of all published series shows that lipase estimation has slightly sensitivity and specificity and greater overall accuracy than amylase. This difference becomes more marked when there is delay in initial blood sampling. The difference in performance of these two tests, though small, is definite (evidence category A). Gut 1997,41:431-35; Br J Surg 1998,84:

Lipase has slightly higher sensitivity and specificity and greater overall accuracy than amylase (Evidence category A)

Ultra Sound (US) Little part in the diagnosis of the acute pancreatitis Role in biliary pancreatitis Stones in gallbladder Common Bile Duct dilation It is accepted that ultrasonography plays little part in the diagnosis or staging of acute pancreatitis. This is because of the high frequency of the incomplete examination, owing to overlying bowel gas. Early ultrasonography is, however, useful in the determination of the gallstone etiology, by the demonstration of the stones in the gallbladder, or by common bile duct dilation Br J Surg 1982;69:369-72

US findings should be examined in all patients with possible acute pancreatitis on admission (Evidence category B)

CT scan Not necessary for the diagnosis Diagnostic doubt
Atypical presentations Asymptomatic hyperamylasaemia or hyperlipasemia On the other hand, although CT scan is useful in the assessment of the severity of acute pancreatitis, it is not necsaary for the diagnosis itself of the acute pancreatitis. In case of the diagnostic doubt, particularly with atypical presentations when abdominal pain is not a feature or when hyperamylasaemia or hyperlipasaemia have been discovered unexpectedly, pancreatic imaging by CT provides good evidence of the presence or absence of the pancreatitis. Gastroenterol Clin N Am 1990;19:811-42

Routine use of CT scan within 24-48 hours of admission (Evidence category C)

Initial Management Monitoring – temp., pulse, blood pressure, and urine output Treatment – Cardiopulmonary care Sufficient fluid resuscitation Pain control

Severity Stratification
Rationale Differentiate mild from severe acute pancreatitis

Desirable features of Markers of Severity
Accuracy - High sensitivity & PPV Predictability within 24 hours of admission Easy to use

Clinical Features Clinical examination
Age > 70 years Abdominal findings increased tenderness rebound distension hypoactive bowel sounds In first 24 hours of admission - unreliable After 48 hours- as accurate as Ranson score Obesity Clinical examination in the first 24 hours of admission is unreliable After 48 hours, clinical assessment is almost as accurate as the Ransons or Glasgow scores 48 hours after admission is too late to begin specific therapy

Multiple Factors Scoring System
Ranson Separate for alcohol and gallstone etiology Score > 3 = severe acute pancreatitis Glasgow valid in all types of pancreatitis Both of these systems require 48 hours from the admission for full assessment In the 1970s, two systems were developed to assist in the categorization of the patients with acute pancreatitis. Though Ranson system is easy to use and became quite popular, the system was complicated by the requirement for two separate systems dependent on alcohol or gallstone etiology. The Glasgow system, works well in all types of pancreatitis. However, both these systems require 48 hrs from admission for full assessment. There are several scoring systems described after Ranson’s first attempt [1], many of them, e.g. the scoring systems from Glasgow and Hong Kong are variants of Ranson’s scoring system [56, 57]. Two general types of scoring systems have been applied to pancreatitis: one that correlates laboratory and clinical markers specific to pancreatitis to subsequent outcome, and the other correlating non-specific physiological variables to outcome. Examples of the latter are the Acute Physiology and Chronic Health Evaluation (APACHE) II and III, which are built up from a more generalized point: the severely ill patient [58]. When comparing the Ranson score to APACHE III prospectively in an appropriate patient population, with 21% mortality, due to acute pancreatitis, the Ranson score remained a valid predictor of outcome [59]. Today, it seems as if there is only little more information to be gained from the scoring system than what was found by Ranson in 1974, which might indicate that more attention should be paid to what is measured rather than how to combine variables. Can J Gastroent

APACHE II Acute Physiology and Chronic Health Evaluation
as good as the Ranson or Glasgow at 24 and 48 hours of the admission APACHE II score > 8 = Severe acute pancreatitis Cumbersome to use if one does not use a pc or palm - where the formula is easily downloaded Larvin and McMohan group compared Ranson and Glasgow with APACHE II and showed that at 48 hours APACHE II is as good as other two systems. However, the major advantage of the APACHE II was that prediction using this system at 24 hour was as effective as the other scores at 48 hrs. The superiority and early assessment of APACHE II have been confirmed. Br J Surg 1997,84:

If a multiple factor scoring system is to be used, the best choice at present appears to be APACHE II calculated at 24 hours Evidence category A

Tests Trypsinogen Trypsinogen activation peptide (TAP) I Trypsin
Inflammatory cascade (IL6, IL-8, TNF-) II C - reactive protein III Pancreatic injury Amylase, Lipase, Trypsinogen IV

Markers for Leakage of Pancreatic Enzymes
Amylase/ Lipase Degree of elevation shows little correlation with disease severity and prognosis May have an inverse relationship with severity Trypsinogen 2 Excreted into the urine Used as a screening test for acute pancreatitis Amylase. It is generally accepted that the degree of elevation of the amylase levels in serum and urine shows little correlation with disease severity and prognosis. If anything, amylase levels may have an inverse relationship with severity in that some patients with severe disease have normal or only modestly elevated amylase values when first seen [49, 50]. Trypsinogen 2 increases considerably more than trypsinogen 1 (cationic trypsinogen) in serum in acute pancreatitis High serum levels of trypsinogen 2 have been shown to predict complications in patients with acute pancreatitis and also to predict severity after ERCP-induced pancreatitis In acute pancreatitis, trypsinogen 2 is also excreted into the urine in large amounts. A rapid dipstick method for the measurement of trypsinogen 2 in urine has been developed [39]. This can be used as a screening test for acute pancreatitis.

Trypsinogen activation peptide (TAP)
Small peptide Advantage Appear very early during the disease Disadvantage Limited "diagnostic window". decrease very quickly irrespective of the course of the disease Not suitable for rapid simple analysis small peptide (eight amino acids, molecular weight approximately 900 daltons), which is cleaved from the amino-terminal end of trypsinogen during activation. Among the markers for trypsinogen activation TAP is the most thoroughly studied variable [32]. Elevated levels are seen early after onset of symptoms and are usually maximal within hours. Carboxypeptidase B activation peptide (CAPAP) in urine and serum. This is the largest activation peptide (molecular weight approximately 10,000 daltons) released from any pancreatic proenzyme. This peptide is very stable in serum and urine. Three retrospective studies have been published Markers for trypsinogen activation have one major advantage as markers for severity, that is that they appear very early during the disease. They are maximal 1-2 days after onset of pain and then decrease very quickly irrespective of the course of the disease. After 3-4 days these variables are not useful. This rapid decrease give these markers a limited "diagnostic window". Many patients with acute pancreatitis are admitted rather late and they usually appear at tertiary referral centers long after the 3-4th day. It is also important to realize that these markers are not suitable to use as monitors of disease activity during the course of the disease. The tests for these markers are usually immunological and are not completely suitable for rapid simple analysis although rapid strip tests are starting to emerge for these kind of markers.

Markers of Inflammation
TNF-alpha Major role in mediating inflammatory response Conflicting reports as a predictor of severity Interleukin-6 and 8. Principal cytokine mediator Measured in serum and urine Discriminate severe from mild cases on day 1 TNF-alpha is a pleiotrophic predominantly macrophage-derived cytokine which is believed to play a major role in mediating many of the pathophysiologic responses of an organism to injury and sepsis [43]. There are reports of a correlation between TNF-alpha and the severity of acute pancreatitis in some publications [44, 45, 46] but not in others [47]. Interleukin-6 is the principal cytokine mediator of the synthesis of acute phase proteins such as fibrinogen and CRP, and can be measured in serum and urine with a commercially available RIA. Interleukins are known to degrade very rapidly in the circulation. For interleukin-6, however, the samples can be stored at –20 °C for up to six months before analysis provided that the samples are centrifuged and frozen immediately after sampling. Interleukin-6 levels in serum are reported to discriminate severe from mild cases on day 1, and maximal levels are seen on day 1 or 2. Most patients with mild disease have undetectable serum levels of interleukin-6 and thus serum levels have been shown to reflect the severity of an attack of acute pancreatitis [23, 24, 26]. Interleukin-8 is thought to be the principal secondary mediator of TNF-alpha-induced neutrophil activation [43]. Serum interleukin-8 has been shown to be elevated in the course of acute pancreatitis in several studies [24, 25] and to correlate to the clinical course [25]. C-reactive protein (CRP) is an acute phase reactant which is synthesized by the hepatocytes. This synthesis is induced by the release of interleukin 1 and 6. Thus the CRP peak in serum is usually not maximal until about day three after the onset of pain, and is always later than the peak of these interleukins. CRP is the most popular single test severity marker used today. The problem is that CRP is a rather late severity marker (day 2-4) as compared to the other markers in this overview. Cut-off levels have been discussed in the literature, and levels between 120 and 210 mg/L have generally been agreed upon as distinguishing between the mild and the severe disease [3, 27, 32]. Levels above 120 mg/L after one week also distinguish severity well but this is much too late for an early marker of severity [27, 43].

C-reactive protein (CRP)
Acute phase reactant Synthesized by the hepatocytes Synthesis is induced by the release of interleukin 1 and 6 Peak in serum is three days after the onset of pain Most popular single test severity marker used today C-reactive protein (CRP) is an acute phase reactant which is synthesized by the hepatocytes. This synthesis is induced by the release of interleukin 1 and 6. Thus the CRP peak in serum is usually not maximal until about day three after the onset of pain, and is always later than the peak of these interleukins. CRP is the most popular single test severity marker used today. The problem is that CRP is a rather late severity marker (day 2-4) as compared to the other markers in this overview. Cut-off levels have been discussed in the literature, and levels between 120 and 210 mg/L have generally been agreed upon as distinguishing between the mild and the severe disease [3, 27, 32]. Levels above 120 mg/L after one week also distinguish severity well but this is much too late for an early marker of severity [27, 43]. Isenmann et al Pancreas 1993;8:358-61

Gold standard for the prediction of the necrotizing course of the disease Accuracy of 86% Readily available Cut-off levels between 120 and 210 mg/L distinguish between the mild and the severe disease Is the gold standard laboratory marker for the prediction of the necrotizing course of the disease Sensitivity & specificity of > 80% Accuracy of 86% Readily available No correlation has been found between serum CRP levels and the presence of infected necrosis

Advantage Used to monitor the clinical course of the disease Disadvantage Not always present on admission Lack specificity Advantage these markers can be used to monitor the clinical course of the disease Disadvantage not always present on admission but develop later during the course of the disease lack specificity

Recommendations CRP is currently the gold standard
Amylase and lipase of no value High likelihood that IL-6/ TAP will replace the CRP

CT Scan Normal Abnormal Sensitivity of 90-95% Specificity – 100%
Homogeneous enhancement of the whole pancreas Abnormal Non-visualization of a part of the pancreas Sensitivity of 90-95% Specificity – 100%

Interstitial pancreatitis – Unenhanced CT scan obtained on the third day of illness. The pancreas is not clearly defined, and diffuse peripancreatic inflammation extends into the lesser sac (curved arrow), left anterior pararenal space, and adjacent to the left colon. Dynamic contrast-enhanced CT scan performed on the same day. There is uniform enhancement of the pancreas (arrows) without necrosis.

Pancreatic necrosis and pancreatic pseudocyst
Pancreatic necrosis and pancreatic pseudocyst. Dynamic contrast enhanced CT scan was performed on the second hospital day. There is an enlarged body and tail of the pancreas that enhances normally. Enhancement is heterogeneous in the more proximal portion of the pancreas (vertical arrows). Inflammatory changes are extensive in the anterior pararenal space surrounding the pancreas. A small amount of ascites surrounds the liver. The heterogeneous enhancement of the proximal portion of the pancreas is not dignostic of pancreatic necrosis and could represent severe interstitial edema. CT scan performed three weeks later. There is 12 cms x 15 cms low-attenuation mass that replaces the body of the pancreas and extends into the lesser sac, displacing the stomach anteriorly. A portion of the pancreas enhances normally. The overall appearance of the mass appears homogeneous, but the absence of the enhancement of the body of the pancreas indicates that this portion of the gland is necrotic and that the mass is the combination of the pancreatic necrosis and fluid in the lesser sac.

Recommendation A dynamic CT scan should be performed in all (predicted) severe cases between 3 and 10 days after admission (Evidence grade B)

Is It Possible to Predict Severity Early in Acute Pancreatitis?
Good clinical judgment Specificity - 80% Sensitivity - 40% Scoring or biochemical methods Specificity – 60% Sensitivity – 95% The answer to this question could be both yes and no depending on what you demand of the test. With good clinical judgement, an attack of acute pancreatitis predicted severe on admission, will turn out to be severe 8 out of ten times but you will miss two-thirds of the severe cases. With the best available scoring systems or biochemical methods today only 6 out of 10 cases predicted severe will turn out to be severe but the test will miss only 2-4 severe cases out of 100.

Etiological Assessment
Needed in all patients Differentiate biliary from alcoholic pancreatitis Early abdominal US is recommended in all patients (Evidence category A) Because the etiology of an attack of acute pancreatitis affects decision-making and further therapeutic interventions, etiological assessment is needed in all patients. Early abdominal US is recommended in all patients to detect gallstones and dilation of the bile duct. In complicated gallstone pancreatitis, urgent ERCP with or without sphincterotomyis proven to decrease the complications and mortality. (1b) Severe gallstone pancreatitis or gallstone pancreatitis with cholangitis or obstruction of the biliary tract, emergent ERCP is recommended (grade B)

Initial Management of acute pancreatitis
Nutrition Prophylactic Antibiotics Acid suppression ERCP Surgery

Nutrition - Rationale Hyper metabolic state Nutrition depletion
Total energy expenditure 1.5 x resting energy requirement Nutrition depletion Starvation Preexisting protein-calorie malnutrition & micronutrient deficiency Acute pancreatitis is a hypermetabolic state. The total energy expenditure has been calculated to be 1.5 times the predicted resting energy expenditure. Impaired gastric emptying, ileus and abdominal compartment syndrome impair oral feeding leading to starvation. Preexisting protein-calorie malnutrition and micronutrient deficiency are common in chronic ethanol addiction and acute on chronic pancreatitis. The effect of increased metabolic demand and compounded by inadequate nutritional intake leads to a negative nitrogen balance which has been associated with worse outcome as compared to positive nitrogen balance. Nutrition depletion impairs host defenses, immune competence, and resistance to nosocomial infections, complication the course of severe acute pancreatitis. Crit care Med 1991;19:484-90; J parenter Enter Nutr 1989;13:26-29.

Nutrition – who needs it?
Mild AP 70-80% recover within 4-7 days Moderate to severe AP Ranson score > 3 APACHE II > 8 Necrotic pancreas Organ failure Mild AP resolve in 4-7 days and generally do not require no nutritional intervention. The patients with moderate to severe AP have a protracted hospital course and require aggressive nutritional support. Patient with severe disease who will be without oral nutrition for 7-10 days. Windsor et al. Gut 1998,42:431-35; Kalfatentzos et al. Br J Surg 1997,84:

Parenteral nutrition Rationale for - Pancreatic rest
Inability to tolerate enteric feeding

Parenteral Nutrition Rationale against Pancreatic rest
Poorly defined Increased risk of sepsis Gut atrophy - increased bacterial translocation Hyperglycemia Greater costs Rationale against - Pancreatic rest Poorly defined & difficult to measure Increased risk of septic complications Gut atrophy - Mucosal atrophy, loss of gut integrity, and increased translocation of the bacteria Hyperglycemia Greater costs

Parenteral Nutrition Nine uncontrolled retrospective studies
Safe, well tolerated with few complications No impact on the outcome Nine uncontrolled retrospective studies on TPN in AP Safe, well tolerated with few complications Mortality reduced from 22% to 2 %

TPN Prospective randomized controlled trial 54 TPN IV F
Duration of hospital stay Line sepsis Sax et al conducted a RCT of early parenteral nutrition in the acute pancreatitis. TPN started within 24 hours of the hospital admission was compared with no nutritional support in 54 patients. The patients had mild AP. The TPN group had a significantly longer hospital stay compared with patients receiving iv fluids and an increased rate of catheter related sepsis comapred with those who received TPN without pancreatitis (10 vs 1). The authors questioned whether the widespread use of TPN was warranted. Sax et al. Am J Surg 1987,153:117-22

Enteral Nutrition Radiographically verified placement of an endoscopically placed, combined NG-J tube with the gastric-jejunal junction in the antrum and the distal tip past the ligament of Treitz

Enteral Nutrition Rationale for
Minimal effect on pancreatic secretions Prevention of gut mucosal atrophy Avoid TPN related complications Line sepsis Hyperglycemia Rationale for Minimal effect on pancreatic secretions Prevention of mucosal atrophy Maintenance of gut barrier function Avoid TPN related complications Line sepsis Hyperglycemia Arch Surg 1999;134:

Enteral Nutrition Rationale against
Small degree of pancreatic stimulation Proximal displacement of the feeding tube may worsen the disease outcome Rationale against Small degree of pancreatic stimulation Lack of conclusive data that enteral nutrition will lower clinically significant infections Proximal displacement of the feeding tube may worsen the disease outcome

Enteral nutrition 4 prospective randomized controlled trials
Significantly lower Line sepsis Infections per patients Hyperglycemic episodes Cost was significantly higher in TPN No difference in mortality, ICU admissions, multi-organ failure 4 prospective randomized controlled trials compared Enteral versus TPN Significantly lower Line sepsis Hyperglycemic episodes Infections per patients Cost was significantly higher in TPN No difference in mortality, ICU admissions, multi-organ failure Gut 1998,42:431-35; Br J Surg 1997,84: JPEN 1997,21:14-20; J Submicrosc Cytol Pathol 1996,28:61-74.

Enteric feeding Enteral nutrition is feasible, well tolerated and improves nutritional status Enteral nutrition is certainly no worse than TPN and is less costly Enteral nutrition delivered into the jejunum is feasible, and well tolerated nad improves nutritional status. Enteral nutrition is certainly no worse than TPN and is less costly.

How about Nasogastric feeding ?
Aim Assess the safety and practicability of NG feeding in severe acute pancreatitis Methods Prospective study 26 patients with severe acute pancreatitis NG feeding within 48 hours of admission Aim To assess the safety and practicability of NG feeding in patients with severe acute pancreatitis Methods Prospective study 26 patients were enrolled Objective evidence of severe acute pancreatitis NG feeding within 48 hours of admission to our unit Eatock et al. International Journal of Pancreatology, 2000

Result Feeding Pancreatic necrosis – 15 patients
Severe organ failure - 11 patients Feeding Well tolerated in 22 patients No evidence of clinical or biochemical deterioration on commencing NG feeding Result Pancreatic necrosis – 15 patients Severe organ failure necessitating ventilatory support – 11 patients Feeding well tolerated in 22 patients In 3 patients gastric stasis proved troublesome No evidence of clinical or biochemical deterioration on commencing NG feeding

NG feeding appears safe, is well tolerated and is possible in severe acute pancreatitis
Further randomized controlled studies would be required to confirm the results of this study.

Evolution in Nutrition
Fasting TPN is better Early jejunal feeding is safe Early jejunal feeding is superior Gastric feeding is as good as jejunal feeding The classical management recommends that patients presenting with acute pancreatitis be fasted until symptoms begin to resolve. In recent years, following work by Sitzman and others suggesting improvement in outcome, it become common pracitice to institute total parenteral nutrition in those with severe disease. The risk of reccurrence of abdominal pain on refeeding is well known and this together with the presumed presence of the gastroparesis and the intestinal ileus, has resulted in the avoidance of the enteral feeding.

Current Recommendations
Mild to moderate Ranson < APACHE II < do not require nutritional support Severe Ranson > APACHE II > Organ failure Pancreatic necrosis nutritional support

Current Recommendations
Jejunal feeding should be started within 48 hours The optimal feeding formulae is unknown Ensure the jejunal placement of the tube Monitor for Hypertryglyceridemia/ hyperglycemia TPN in patients who do not tolerate enteral feeding Jejunal feeding should be started within 48 hours of the admisssion. Because data suggests increased benefit a a lower cost. Patients in whom enteral nutrition cannot be achieved or maintained, or in whom intolearnce develops, should be considered for TPN. Fat should not be comprised of more than 15-30% of nonprotein calories. Parenteral and enteral routes can be combined early in the hospital course if enteral tolearnce is limited, with enteral nutrition increased as the patient becomes able. Appropriate safeguards should be taken to ensure the jejunal placement of the tube and to avoid vomiting and aspiration if ileus is present

Antibiotics Sepsis Intestinal flora
Accounts for > 80% of deaths Intestinal flora Gram negative bacteria Mechanism – translocation of the bacteria across the gut wall In severe acute pancreatitis, sepsis mainly due to pancreatic or peri-pancreatic infection have emerged as the most serious complications and now account for more than 80% of the deaths. 40% of the patients with infected pancreas die. Studies that have isolated the organisms from the infected pancreas have shown that most of the organisms are from the intestinal flora. The proposed mechanisms is the translocation of bacteria across the gut wall.

Antibiotics - Rationale
Early (1 week) Sterile necrosis Massive inflammatory response – multi-system organ failure (SIRS) Late – Infected necrosis Mortality due to SAP can be divided into early I.e. within one week and late I.e. after three weeks. Early death due to SAP are generally caused by the massive inflammatory resposne that results in multi-system organ failure. This inflammatory response is very similar to SIRS, which is responsible for multisystem organ failre in cases of severe sepsis and trauma. Infected necrosis is the commonest cause of death after 2-3 weeks. Infected pancreatic necrosis can be difficult to diagnose clinically because definite diagnosis requires a CT-guided FNA. Unfortuantely, the mortality associated with infected necrosis is extremely high (20-30%) and surgery is the only definite treatment. Mortality cause by infected pancreatic necrosis usually occurs 2-3 weeks after presentation, and is the leading cause of death in persons with SAP. Because infection has a considerable impact on risk of mortality with in tose with SAP, the prevention and/or early identification and treatment of infection is an extremely important clinical challenge and that’s where the role of prophylactic administration comes.

Why the controversy ? Early trials in 1970’s did not show the benefit of antibiotics Antibiotics that did not penetrated the pancreatic tissue The value of prophylactic antibitics in severe pancreatitis has been continuously debated for more than half a century. During the early 1970’s there were 3 clinical trials that examined the efficacy of the administration of antibiotics prophylaxis. In patients with AP. These trials failed to show a survival benefit associated with antibiotic prophylaxis. Majority of the subjects enrolled in these trials had only mild interstitial acute pancreatitis and were thus highly unlikely to develop a pancreatic infection. Of nore ampicillin was used in these trials. Seminal work by Buchler et al. showed that the pancreas was highly impeneterable to a number of antibiotics, including ampicillin. Further studies showed that that the degree of antibiotic peneterance correlated highly with its ability to eradicate infection in the pancreatic tissue. The antibiotics with the greatest peneterance and the bactericidal properties were the carbapenems and fluoroquinolones and the cephalosporins, respectively. Furthermore, there emerged the concept of interstitial pancreatic and SAP associated with pancreatic necrosis. This new knowledge had a significant impact on the quality of the subsequent studies trials in this area.

Evidence 8 clinical trials
Five of these trials showed a significant reduction in the incidence of pancreatic infections 1 trial showed a significant reduction in mortality Limitations Small sample size None were double blinded randomized placebo controlled trials 8 clinical trials that addressed the role of prophylactic antibiotics Five of these trials showed a significant reduction in the incidence of pancreatic infections 1 trial showed a significant reduction in mortality Limitations Small sample size inadequate power None were double blinded randomized placebo controlled trials

Recommendations Prophylactic antibacterial treatment is strongly recommended in severe pancreatitis (Evidence B) No evidence when to start prophylactic treatment or how long to continue therapy Appropriate antibiotics are those that are active against in particular gram-negative organisms Commence as early as possible after the identification of a severe attack Regardless of the criticism that may be made of each of these clinical studies, taken together, they indicate prophylactic antibacterial treatment is strongly recommended in severe pancreatitis (B1). However, it remains to be decided which drugs should be used, and whether they should be given alone or in combination, or together with gut decontamination. There is no evidence when to start prophylactic treatment or how long to continue therapy. Appropriate antibiotics are those that are active against a wide variety of organisms, in particulkar gram-negative organisms. Antibacteial therapy should be commneced as early as possible after the identification of a severe attack ©.

Is there a downside with antibiotics ?
Increased risk of fungal infections Associate with mortality as high as 85%

Fungal Infection Candida Torulopsis
Commensal organism found in human gastrointestinal tract Incidence 10-40% The most frequent causes of pancreatic fungal infections are Candida species organisms, followed by the Torulopsis sp. Organisms. Torulopsis is closey related to the Candida, it ha no hyphae or pseudohyphae and may differ in its sensitivity to antifungal agents. It reproduces by budding yeast. Both of these are the normal commensals of the human GI tract.

Fungal infection 92 patients with infected pancreatic necrosis
22 patients (24%) with Candida infection Patients with Candida infections Suffered higher mortality (64% vs. 19%, p=.0001) More systemic complications Were given preoperative antibiotics for a longer period (19 vs 6 days; p=.0001) Candida is a commensal organism frequently found in the human GI tract. Its clinical relevance in intraabdominal infection has been a matter of investigation during the past years, and enhanced mortality was demonstrated in patients with intraabdominal Candida infection. For necrotizing pancreatitis there have been only sporadic case reports and only two controlled studies. 92 patients with infected pancreatic necrosis were reviewed for the candida infection 22 patients (24%) with Candida infection Patients with Candida infections Suffered higher mortality (64% vs 19%, p=.0001) More systemic complications Preoperative antibiotics were given for a longer period to Candida infection (19 vs 6 days; p=.0001) World J. Surg. 25,372-76

Fungal Infection Antibiotics predispose to candida infection of the pancreatic tissue which increases the mortality substantially

Therapy Treatment Antifungal therapy – definite role
Antifungal therapy should be instituted as soon as the Candida infection is suspected. Whether prophylaxis with anti-fungal therapy is benefecial is unclear. The current widespread use of antibiotics in AP is not without risk and therefore …….should be reserved for…………….

Acid suppression Several RCT’s of H 2 receptor antagonists failed to show any clinical benefits

Management of the Biliary Pancreatitis
Passage or impaction of a stone Women (age of 50-70) Mortality 6% Passage or impaction of a stone is generally accepted as an event common to all patients with with gallstone pancreatitis Incidence of biliary pancreatitis parallels that of gallstone disease More common in women between the age of 50-70 Patients with biliary pancreatitis are as likely as those with pancreatitis of other etiologies to develop severe disease Mortality averages approx. 6%

? What are the diagnostic criteria of biliary pancreatitis ?
What is the optimal method for biliary tract imaging ? When is early ERCP indicated ? What are the biochemical, and radiologic criteria for the diagnosis of biliary pancreatitis in patients with AP ? What is the optimal method for biliary tract imaging ? When is early ERCP indicated ? What is the optimal timing for the cholecystectomy in ANP? Is cholecystectomy necessary in patients who already have undergone endoscopic sphincterotomy ?

What are the diagnostic criteria of biliary pancreatitis in patients with AP ?
Abnormal liver function tests ALT elevation of > 3 x normal Ultrasound Gallstone Differentiation of biliary from other forms of pancreatitis is based on the combination of serum testing and imaging. Abnormalities in the liver function tests, in particular a threefold elevation of the alanine aminotransferase (ALT), are very specific for the diagnosis. Ultrasound will detect gallstones in 70%-80% of those with acute bilairy pancreatitis. The combination of both the tests is highly accurate for the diagnosis of acute biliary pancreatitis.

What is the optimal method for biliary tract imaging ?
ERCP Ultrasound MRCP EUS Data are insufficient to define the optimal method for biliary tract imaging in setting of acute pancreatitis particulary in ANP. ERCP has been the “gold standard” and also has therapeutic potentials. However, it is an invasive test with a high cost and potential serious complications., especialliy in patients with pancreatitis. Ultrasound remains the test of choice for the detection of cholelithiasis and bile duct dilation, but has a very low sensitivity for common bile duct stones. MRCP has now become more widely available and has a sensitivity of more than 90% for choledocholithiasis. However, the utility of these tests have not been validated in the setting of acute necrotizing pancreatitis. Many prospective studies, using ERCP as the gold standard have shown that EUS is extremely accurate for the detection of the choledocholithiasis. Sensitivty of > 90% and specificity of > %. However, the evidence of simiar accuracy in the setting of acute pacnreatitis is limited.

Endoscopic Retrograde Cholangiopancreatography (ERCP)
Gold standard Potential serious complications The corresponding ERCP image shows the same two stones (7 mm stone, thin arrow; 9 mm stone, thick arrow) in the same location

Abdominal Ultrasound Sensitivity GB stone 60-80% CBD stone 30-60%
Sagittal sonogram of the abdomen demonstrates dilatation of the proximal one half of the extrahepatic bile duct (arrow). The distal one half of the extrahepatic bile duct is obscured by bowel gas

Magnetic Resonance Cholangio-Pancreatography (MRCP)
Sensitivity of > 90% Coronal-oblique MRCP reveals a stone (arrow) impacted in the distal bile duct that has resulted in dilatation of the extrahepatic and intrahepatic bile ducts. The gallbladder (G) and pancreatic duct (arrowhead) are shown. MRCP is useful in identifying the cause and level of biliary obstruction in the setting of a nondiagnostic sonogram.

Endoscopy Ultrasound (EUS)
Sensitivity of > 95% Specificity of > % Many prospective studies, using ERCP as the gold standard have shown that EUS is extremely accurate for the detection of the choledocholithiasis. Sensitivity of > 90% and specificity of > %. EUS image of a nondilated common bile duct with echogenic 7 mm (thin arrow) and 9 mm stones (thick arrow) with posterior acoustic shadowing not seen by transabdominal US.

When is early ERCP indicated ?
Concomitant cholangitis (Evidence A) Significant persistent biliary obstruction (bilirubin > 5 mg/ dl) (Evidence A) ERCP in severe biliary pancreatitis without biliary sepsis or obstruction (Evidence B) Early ERCP with sphincterotomy and stone extraction is indicated for patients with pancreatitis and concomitant cholangitis or significant persistent bilairy obstruction (usually serum bilirubin > 5 mg/ Dl). Achieving adequate biliary drainage folowing the procedure is paramount, and therefore ERCP should be attempted only in settings where appropriate expertise is available. Evidence to support the use of ERCP in severe biliary pancreatitis without bilairy sepsis or obstruction is conflicting. There are no data to support or refute the use of sphincterotomy if, at the time of ERCP doen for suspected bilairy pancreatitis, no stone is found. ERCP should not be performed acutely in patients with mild pancreatitis of suspected or proven bilairy etiology in the absence of the biliary obstruction. Neoptolemos et al 1988; Fan NEJM 1993; Folsch NEJM 1997

When is early ERCP NOT indicated ?
Mild pancreatitis of suspected or proven biliary etiology in the absence of the biliary obstruction (Evidence A) ERCP should not be performed acutely in patients with mild pancreatitis of suspected or proven biliary etiology in the absence of the biliary obstruction Neoptolemos et al 1988; Fan NEJM 1993; Folsch NEJM 1997

Pancreatic necrosis Sterile necrosis – Systemic Inflammatory Response Syndrome (SIRS) (First week) Mortality rate of 10-40% Infected necrosis – Sepsis (After 3 weeks) Mortality – 20-70%

Sterile necrosis Sterile pancreatic necrosis – surgery in selected cases Selected cases Massive pancreatic necrosis (>50%) with a deteriorating clinical course (Evidence C) Patients with progression of organ dysfunction No signs of the improvement (grade B) Sterile pancreatic necrosis as defined by negative fine needle aspiration should be managed conservatively and only undergo surgical intervention in selected cases Selected cases Massive pancreatic necrosis (>50%) with a deteriorating clinical course (Evidence C) Patients with progression of organ dysfunction No signs of the improvement (grade B)

Infected necrosis CT guided FNA with gram stain and culture is a confirmatory test (Evidence A)

Infected Necrosis A dynamic contrast-enhanced CT scan performed on the 14th day in a 40 year old man with alcoholic pancreatitis. The scan reveals enhancement of the head and proximal body of the pancreas (arrows) but no enhancement of the distal body and tail of the pancreas. This is severe pancreatitis with 40-50% necrosis. CT guided aspiration. There are two needles inserted percutaneously. Three mls of brownish material was aspirated from the distal body of the pancreas. A gram stain revealed gram-positive cocci in clusters and pairs, and culture revealed Staphylococcus aureus.

Infected necrosis Suspect if: Exacerbation of clinical signs
Laboratory blood test changes Shift to immature cells Elevation of CRP Increased APACHE II Positive blood culture Indication for Fine Needle Asperation (FNA)

Infected Necrosis Necrosectomy is indicated in a confirmed infected pancreatic necrosis (Evidence A)

Management of Acute Pancreatitis

7th of June, 323 BC June 10, 323 BC, Alexander the Great died at the age of 33. June 10, 323 BC

ALCOHOLIC PANCREATITIS
Clinical Case 32-year-old man c/o acute onset abdominal pain (presumed pancreatic origin) h/o alcohol intake ALEXANDER THE GREAT – DIAGNOSIS: ALCOHOLIC PANCREATITIS A 32-year-old man is admitted to the hospital with acute onset abdominal pain of presumed pancreatic origin.

The End To take the post test for credit of attendance
Download the post test, complete and Return to Dr. S.K. Oliver at

Post test question one Which of the following has an Evidence category A: Lipase has slightly higher sensitivity and specificity and greater overall accuracy than amylase Amylase has higher sensitivity and specificity and greater overall accuracy than lipase US findings should be examined in all patients with possible acute pancreatitis on admission Routine use of CT scan within hours of admission

Post test question two Which of the following is the most popular single test severity marker used today? Trypsinogen activation peptide TNF- alpha C Reactive Protein Interleukin 6&8

Post test question three
Which of the following is associated with gut atrophy? NG feedings Jejunal feedings Parenteral feedings Enteric feedings

Post test question four
When is early ERCP not indicated? Concomitant cholangitis Mild pancreatitis of suspected or proven biliary etiology in the absence of the biliary obstruction Significant persistent biliary obstruction (bilirubin > 5 mg/ dl) ERCP in severe biliary pancreatitis without biliary sepsis or obstruction

The End

Acute Pancreatitis Evidence Based Approach

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Acute Pancreatitis Evidence Based Approach

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Presentation on theme: "Acute Pancreatitis Evidence Based Approach"— Presentation transcript:

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