Peter O’Leary 12/1/09

1. Evidence Based Treatment of Acute PancreatitisA Look at Established ParadigmsStefan Heinrich, MD, Markus Schäfer, MD, Valentin Rousson, PhD, and Pierre-Alain Clavien, MD, PhD Peter O’Leary 12/1/09

2. Introduction • Gallstone disease and excessive alcohol are the predominant causes of acute pancreatitis • During the past two decades there has been • Improved management (better diagnostic and treatment modalities) • Reduction in disease related mortality • An increase in the overall incidence • One fifth of patients develop a severe form of pancreatitis • Associated mortality rate of 30% • Associated necrosis • Necrosis best assessed using contrast enhanced computed tomography • Balthazar score most commonly used to define extent of necrosis • MRI may be used where CT is contraindicated • Atlanta classification describes acute pancreatitis as severe if it is accompanied by • Single or multi-organ failure • or Local complications • or Ransons criteria score of 3 or more • or an Apache score of 8 or more

3. Intoduction • Over the past few decades, management of acute pancreatitis has been biased by unproven paradigms which were generated by theories of the pathophysiology • These paradigms have been questioned in recent years, resulting in changes in treatment which were again based on personal experience and opinions rather than convincing scientific evidence

4. Aim • To assess the clinical value of different newer treatment modalities by reviewing the current literature on the treatment of acute pancreatitis • The evidence based approach of Sackett was used to analyse the literature of the last decade

5. Methods • Treatment of acute pancreatitis involves multiple modalities • Study focused on the values of • Antibiotic prophylaxis • Medical treatments • Enteral nutrition • Endoscopic and surgical interventions • Study designs excluded from review were • Review articles • Retrospective analysis • Studies only reported as abstracts • Articles included were published in the • English language • Between January 1990 and October 2004

6. Methods cont… • Literature research • Electronic search of Medline database and Cochrane library for publications on acute pancreatitis • Only publications that fulfilled the inclusion criteria and addressed the clinical question were further assessed • Each selected publication was independantly reviewed by 2 of the authors • Relevant data including authors, title, study design, methodology, main results and conclusions were extracted and documented on a separate data sheet for each publication

7. Methods cont… • Literature classification

8. Methods cont… • Statistical analysis • If several level I and II trials were available for a specific topic, own meta analysis was performed • This was done if identified trials were not included in previous meta-analyses or if pre-existing meta-analysis reported controversial results • All meta-analyses were performed on studies which compare 2 groups with respect to a dichotomous endpoint (eg. Mortality and sepsis) • Thus, each study provides estimates of 2 proportions, one in each group • The goal was to obtain global estimates of these proportions and to test whether they significantly differ • Heterogeneity between studies was evaluated using the χ2- based Q statistic proposed by cochrane • The random effects model was used to account for the variability between studies • The treatment effects were characterised by the logarithm of the odds ratio such that values less than zero indicated a positive treatment effect • P values <0.05 were considered statistically significant

9. Results • Does medical treatment influence the course of established acute pancreatitis? • Uncontrolled activation of pancreatic proteases and platelet activating factor are considered key features of pancreatic necrosis development • Several drugs have been tested in clinical trials which interfere with the putative mechanisms

10. Results cont… • Gabexate Mesilate • One level I trial, two meta-analysis were eligible • Valderrama et al and one level III were excluded as they did not meet inclusion criteria • Meta-analysis of Buchler et al and Chen et al was performed • Need for surgery (26.9% versus 22.7%, P=0.46) • Mortality rates (17.9% versus 14.2%, P=0.46) • Neither were reduced by Gabexate treatment • Conclude that Gabexate mesilate does not improve outcomes of patients with severe acute pancreatitis • Routine use in patients with pancreatitis is not recommended

11. Results cont… • Aprotinin • One double-blind randomised trial (intra-peritoneal) and one randomised study (intra-venous) • Neither intra-peritoneal nor intra-venous aprotinin improved outcome of patients with severe acute pancreatitis • Its routine use is thus not recommended

12. Results cont… • Lexipafant • Two randomised double blind placebo controlled trials • Johnson et al • significantly lower incidence of sepsis • MOF and local complications remained unaffected • McKay et al • Significantly higher reduction in MOF • Length of hospital stay, mortality rates were not improved • Both Trials were meta-analysed • Incidence of MOF and mortality rates were extracted from both trials • No significant difference in MOF (27.7% versus 21.7%, P=0.37) or mortality (17.3% versus 10.3%, P=0.07) • Not enough evidence in current literature to recommend routine use of Lexipafant

13. Results cont… • Octreotide • Following were identified • One meta analysis • Three placebo controlled randomised studies • Three randomised open labelled studies • One prospective matched • Three prospective non-randomised trials • Meta-analysis of 4 eligible trials • No reduction in • Surgical intervention (23.3% versus 16.3%, p=0.09) • Sepsis (28.7% versus 21.1%, p=0.25) • Mortality (20.6% versus 17.7%, p=0.34) • Overall complication rate (70.6% versus 63.2%, p=0.2) • No significant difference between subcutaneous and intra-venous application detected • Routine use of Octreotide in patients with severe acute pancreatitis is not recommended

14. Results cont… • Does early nasojejunal nutrition influence morbidity or mortality of patients with acute pancreatitis? • Suppression of pancreatic enzyme secretion by ‘resting the bowel’ was an old strategy used in treating acute pancreatitis • Newer studies have shown that enteral nutrition is safe and is associated with a lower rate of infection • Animal and human studies show that the intestinal mucosa atrophies during fasting periods, while it is preserved during enteral nutrition • Infection of pancreatic necrosis is thought to be derived from the gastro-intestinal tract, and enteral nutrition might therefore decrease this complication rate • In contrast to initial concerns, enteral nutrition does not stimulate the exocrine function of the pancreas, if the feeding tube is positioned in the jejenum

15. Results cont… • Does early nasojejunal nutrition influence morbidity or mortality of patients with acute pancreatitis? • Studies identified • Two level I • Six level II • Two level III • All studies used NJ feeding except Eatock et al which used NG feeding and matched with patients receiving TPN • Meta-anlysis of six Level II trials • Multi organ failure (11.5% versus 19.8%, p=0.3) • and • Mortality (10.3% versus 11.6%, p=0.38) • Not significantly different • Central line infections (3.5% versus 26.1%, p=0.01) • Sepsis (12.9% versus 27.9, p=0.02) • Significantly lower in the enteral nutrition group

16. Results cont… • Does early nasojejunal nutrition influence morbidity or mortality of patients with acute pancreatitis? • Results were also separated and evaluated for mild and severe acute pancreatitis • Mortality rates were the only uniform parameter • Mortality rates did not differ significantly between enteral nutrition and TPN • Mild (8.9% versus 5.4%, p=0.38) nor for severe (15.8% versus 20.9%, p=0.6) • As meta-analysis shows equal mortality rates but less infectious complications for enteral nutrition, it is concluded that patients with acute pancreatitis should receive enteral nutrition preferably • NG use appears feasible but requires further investigation • Supplementation of enteral feeds with probiotics was shown to decrease septic complications, but this was only documented in one study

17. Results cont… • Does antibiotic prophylaxis reduce morbidity and mortality in acute pancreatitis? • Meta-analysis carried out on 5 trials • Overall, antibiotic prophylaxis significantly reduced sepsis and mortality but did not prevent infection of necrosis • A subgroup analysis demonstrates a significant reduction in infected necrosis for patients receiving prophylactic imipenam (36.4% versus 10.6%, p=0.002) in contrast to those receiving quinolones and metronidazole • Conclude that antibiotic prophylaxis is superior to antibiotic treatment in necrotising acute pancreatitis • Patients with proven pancreatic necrosis should receive antibiotic prophylaxis using imipenam or meropenam

19. Results cont… • Which is the antibiotic regimen for antibiotic prophylaxis • Bassi et al • Randomised 60 patients with necrotising acute pancreatitis to perfloxacin or imipenam over 14 days • Less infected necrosis for imipenam (34% versus 10%, p=0.03) but difference in mortality was not significant (24% versus 10%, p=0.18) • Manes et al • Randomised 176 patients to meropenam or imipenam for at least 14 days • No significant difference regarding septic complications, indications for surgery or mortality rates (13.4% versus 11.4%) • Conclude that imipenam is superior to perfloxacin and is equally effective as meropenam

20. Results cont… • Does antibiotic prophylaxis promote fungal infections? • Four randomised trials using antibiotic prophylaxis disclosed the incidence of fungal super-infection • Trials were meta-analysed • Fungal infection rate was not different between patients receiving antibiotics, 4.9%, and those in the control group, 6.7% (p=0.99) • Conclude that antibiotic prophylaxis does not result in an increased fungal infection incidence

21. Results cont… • Should emergency ERC and Sphincterotomy be performed for biliary acute pancreatitis? • One meta-analysis and four randomised trials were identified • Meta-analysis was carried out on three of the randomised trials • Emergency ERC and Sphincterotomy significantly reduced overall complication rate (41.8% versus 31.3%, p=0.03) • No significant effect on mortality (7.2% versus 6.4%, p=0.46) • Sub-group analysis shows no differences in overall complications or mortality in mild biliary acute pancreatitis • However, ERC significantly reduced both the overall complication rate (57.1% versus 18.2%, p=0.0001) and mortality rate (17.9% versus 3.6%, p=0.03) in patients with severe biliary acute pancreatitis • Conclude, emergency ERC does not influence the course of mild biliary acute pancreatitis • And • Emergency ERC and Sphincterotomy should be strongly considered in patients with severe biliary acute pancreatitis

22. Emergency ERC for acute AP. The 95% confidence intervals (95% CI) for the logarithm of the odd ratios for mortality and local complications of emergency ERC in patients with acute AP. Heterogeneity between studies was evaluated using the χ2 based Q statistic, and the results are provided in the right column of this figure: ⋄, Fan et al;78 ○, Fölsch et al;79 ▵, Neoptolemos et al;80 , meta-analysis.

23. Results cont… • What is the best treatment in acute pancreatitis? Primary cholecystectomy or ERC and sphincterotomy? • Four Level I trials, one level II • Conclude, patients with mild biliary acute pancreatitis are best treated by primary lap chole with intra-operative cholangiography • ERC should be conducted post-operatively if cholangiography reveals CBD stones

24. Results cont… • Is cholecystectomy indicated after successful ERCP and Sphincterotomy • 3 level III trials • Conclude • Cholecystectomy is indicated after sphincterotomy for symptomatic CBD stones or biliary acute pancreatitis in patients with an ASA score of I to III • Current literature does not support lap chole on patients with ASA grades IV and V but a ‘wait and see’ policy after ERC and sphincterotomy

25. Results cont… • Should all patients with necrotising acute pancreatitis be operated on? • Conclude • Detection of necrosis alone is not an indication for surgery, contrary to earlier studies which indicate it is • Surgery is required for reasons secondary to necrosis formation (eg compartment syndrome or failure of conservative treatment)

26. Results cont… • Do patients with infected necrosis require immediate surgery? • Infection of necrosis was an absolute indication in all studies on surgery for necrotising acute pancreatitis • 2 studies did not require infection of necrosis as a strict indication for surgery • Based on these results, the authors conclude that surgery should not be performed in the early phase of acute pancreatitis • But • Most cases of infected necrosis will require surgery

27. Discussion • Systematic review provides the best evidence for defining the optimal treatment strategy of acute pancreatitis patients • A major challenge experienced was in the comparability of the included studies as they have been performed using • Different patient populations • Different inclusion criteria • Hospitals with differing standards of care • Mortality rates were often the only objective and convincing parameter • These methodologic limitations were addressed using strict inclusion criteria and using the random effects model in statistical analysis • Publications prior to 1990 were excluded as crucial treatment modalities (eg ICU) have markedly changed over the past 20 years • Abstract publications were excluded, as comparability of results cannot be ascertained without availability of complete inclusion criteria and patient characteristics • The application of these evidence based recommendations to an individual case needs to be performed in a multi-disciplinary setting

28. Critique • Overall, comprehensive systematic review of acute pancreatitis • Aimed to provide the highest level of evidence available for each clinical question • Reveals weaknesses in current literature which should help direct future research into acute pancreatitis • Authors admit that a major challenge for this study was comparability of included studies • Definitions of disease severity were not uniformly used before the consensus conference of Atlanta in 1992

29. Thank you