manejo crtico de la pancreatitis

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2004 Lippincott Williams & Wilkins, Inc. Volume 32(12), December 2004, pp

2524-2536Management of the critically ill patient with severe acute

pancreatitis[Special Article]

Nathens, Avery B. MD, PhD; Curtis, J Randall MD, MPH; Beale, Richard J.MBBS; Cook, Deborah J. MD; Moreno, Rui P. MD, PhD; Romand, Jacques-Andre MD, FCCM; Skerrett, Shawn J. MD; Stapleton, Renee D. MD; Ware,

Lorraine B. MD; Waldmann, Carl S. MD

From the University of Washington (ABN, JRC, SJS, RDS) Seattle, WA; SaintThomas' Hospital (RJB), London, UK; McMaster University (DJC), Hamilton,ON, Canada; Unidade de Cuidados Intensivos Polivalente (RPM), Hospital deSanto Antnio dos Capuchos, Centro Hospitalar de Lisboa (Zona Central),Lisboa, Portugal; University Hospital of Geneva (J-AR), Geneva, Switzerland;Vanderbilt University School of Medicine (LBW), Nashville, TN; and the RoyalBerkshire Hospital (CSW), Reading, UK.

Abstract

Objective: Acute pancreatitis represents a spectrum of disease ranging from a

mild, self-limited course requiring only brief hospitalization to a rapidlyprogressive, fulminant illness resulting in the multiple organ dysfunctionsyndrome (MODS), with or without accompanying sepsis. The goal of thisconsensus statement is to provide recommendations regarding themanagement of the critically ill patient with severe acute pancreatitis (SAP).

Data Sources and Methods: An international consensus conference was held inApril 2004 to develop recommendations for the management of the critically illpatient with SAP. Evidence-based recommendations were developed by a juryof ten persons representing surgery, internal medicine, and critical care after

conferring with experts and reviewing the pertinent literature to addressspecific questions concerning the management of patients with severe acutepancreatitis.

Data Synthesis: There were a total of 23 recommendations developed toprovide guidance to critical care clinicians caring for the patient with SAP.Topics addressed were as follows. 1) When should the patient admitted withacute pancreatitis be monitored in an ICU or stepdown unit? 2) Should patientswith severe acute pancreatitis receive prophylactic antibiotics? 3) What is theoptimal mode and timing of nutritional support for the patient with SAP? 4)What are the indications for surgery in acute pancreatitis, what is the optimaltiming for intervention, and what are the roles for less invasive approachesincluding percutaneous drainage and laparoscopy? 5) Under what


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circumstances should patients with gallstone pancreatitis undergo interventionsfor clearance of the bile duct? 6) Is there a role for therapy targeting theinflammatory response in the patient with SAP? Some of the recommendationsincluded a recommendation against the routine use of prophylactic systemicantibacterial or antifungal agents in patients with necrotizing pancreatitis. Thejury also recommended against pancreatic debridement or drainage for sterile

necrosis, limiting debridement or drainage to those with infected pancreaticnecrosis and/or abscess confirmed by radiologic evidence of gas or results orfine needle aspirate. Furthermore, the jury recommended that wheneverpossible, operative necrosectomy and/or drainage be delayed at least 23 wkto allow for demarcation of the necrotic pancreas.

Conclusions: This consensus statement provides 23 different recommendationsconcerning the management of patients with SAP. These recommendationsdiffer in several ways from previous recommendations because of the releaseof recent data concerning the management of these patients and also because

of the focus on the critically ill patient. There are a number of importantquestions that could not be answered using an evidence-based approach, andareas in need of further research were identified.

Acute pancreatitis represents a spectrum of disease ranging from a mild, self-limited course requiring only brief hospitalization to a rapidly progressive,fulminant illness resulting in the multiple organ dysfunction syndrome with orwithout accompanying sepsis. This consensus statement focuses on the

management of the critically ill patient with severe acute pancreatitis (SAP).Only a minority of patients with pancreatitis have disease severe enough torequire admission to an intensive care unit (ICU). These patients havemortality rates in the range of 3050% and a mean hospital length of stay >1month, attesting to the severity of pancreatitis at this end of the spectrum (1).

An established definition of SAP was developed by consensus in 1992 and iswidely used throughout the literature. Using this definition, SAP is acutepancreatitis associated with complications that are either local (e.g.,peripancreatic fluid collection, necrosis, abscess, pseudocyst) or systemic (e.g.,

organ dysfunction). However, the definitions used previously for organdysfunction are not consistent with current criteria that necessitate organsupport or ICU admission today. To better identify patients who have severesystemic manifestations of pancreatitis from a critical care perspective, we usethe term severe acute pancreatitis to represent pancreatitis in the context oftrue organ dysfunction, irrespective of the local complications. In this regard,SAP is to pancreatitis as severe sepsis is to sepsis (2).

An international consensus conference was held in April 2004 to developguidelines for the management of the critically ill patient with SAP. Theseguidelines differ from those previously published by focusing on the challengesof caring for the patient with severe pancreatitis in the critical careenvironment. A jury of ten persons representing surgery, internal medicine,and critical care attended the presentations of 24 experts in the field of
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pancreatitis. Experts were asked to address several specific questions posed bythe conference organizers and scientific advisors. These questions included thefollowing: a) When should the patient admitted with acute pancreatitis bemonitored in an ICU or step-down unit? b) Should patients with SAP receiveprophylactic antibiotics? c) What are the optimal mode and timing of nutritionalsupport for the patient with SAP? d) What are the indications for surgery in

acute pancreatitis, what is the optimal timing for intervention, and what arethe roles for less invasive approaches including percutaneous drainage andlaparoscopy? e) Under what circumstances should patients with gallstonepancreatitis undergo interventions for clearance of the bile duct? and f) Isthere a role for therapy targeting the inflammatory response in the patientwith SAP?

Following the formal presentations, the jury met to review the pertinentliterature. One pair of jury members addressed each question, summarizingthe level of evidence and making recommendations for consideration and

discussion among all jury members using the approach promulgated by theCenter for Evidence Based Medicine, Oxford, United Kingdom (3). Since thefocus on this consensus conference was critically ill patients with SAP and sincea number of recent studies address some of these questions, some statementsin this document vary from previously published recommendations (4).

Question 1: When Should the Patient Admitted With Acute

Pancreatitis Be Monitored in an ICU or Step-Down Unit?Rationale

Patients with SAP may benefit from an environment with more intensivemonitoring given their potential for progressive organ dysfunction and/or life-threatening local complications. Since the availability of critical care beds islimited, it is important to identify appropriate patients for ICU admission.Additionally, avoiding unnecessary ICU admission may limit the risk ofnosocomial infections and iatrogenic complications.

Evidence

One of the most important determinants of poor outcome in SAP is the early

development and persistence of organ dysfunction. Although a variety ofscoring systems, biomarkers, and radiological findings can help to identifypatients at risk of organ dysfunction, these do not substitute for frequentclinical assessment and monitoring. Therefore, the cornerstone of managementin early pancreatitis is fluid resuscitation and close monitoring for earlymanifestations of organ dysfunction. In addition to frequent assessment ofvital signs, monitoring should be directed toward the repeated evaluation ofintravascular volume status by means of physical examination and monitoringof urine output and the early identification of hypoxemia through either pulseoximetry or arterial blood gas analysis.

Several disease-specific scoring systems have been developed to help identifythe patient at risk for adverse outcomes, such as the Ranson criteria (5) and
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the Glasgow Score (6). Of the 11 Ranson criteria, four are directly related tofluid resuscitation (urea, net fluid sequestration, base deficit, and decreasedhematocrit) and are independent predictors of mortality (7). In a report of 49patients with acute pancreatitis, generic measures of disease severity such asthe Acute Physiology and Chronic Health Evaluation II or Simplified AcutePhysiology Score II score were superior to disease-specific scoring systems in

predicting mortality (8). These scoring systems describe patients in the first2448 hrs after their presentation. However, evolving organ dysfunctionappears to be a better predictor of outcome than a one-time assessment,suggesting that dynamic scores might be more useful (9).

A variety of serum biomarkers are associated with the severity and prognosisof acute pancreatitis (10). C-reactive protein (CRP), an acute phase reactant, ismost widely used. Although high levels of CRP have been associated withpancreatic necrosis (11, 12), there is a 24- to 48-hr latency before CRPincreases, limiting its utility as an early predictor (10). Of the many cytokines

evaluated, interleukin (IL)-6 appears to hold the most promise as an earlypredictor of severe disease, but more definitive studies are needed (10).Trypsinogen activation peptide is a pancreatic protease that is released early inacute pancreatitis. In a study of 172 patients designed to evaluate the utility oftrypsinogen activation peptide and CRP in identifying patients with severedisease, the discriminatory ability of either was poor. The area under thereceiver operating curve at 24 hrs from symptom onset for trypsinogenactivation peptide and CRP was only 0.69 and 0.40, respectively. At 24 hrsfollowing hospital admission, their ability to discriminate mild from severedisease was only slightly better, with the area under the receiver operating

curve of 0.78 and 0.65 for trypsinogen activation peptide and CRP, respectively(13). Procalcitonin (14) and numerous other markers also have been studied insmall groups of patients (10). In general, although some of these markers areused to follow patients with pancreatitis, they are of limited clinical utility inpredicting outcome or to triage patients for admission to an ICU.

Radiographic imaging frequently is necessary to both diagnose and stage theseverity of acute pancreatitis. In patients with abdominal pain of unclearetiology, computed tomography (CT) of the abdomen can confirm thediagnosis of pancreatitis and identify other causes of pain. When intravenous

radiocontrast media are contraindicated, the diagnosis of acute pancreatitiscan be inferred from homogeneous glandular enlargement and the presence ofperipancreatic fluid collections (15). CT with nonionic intravenous radiocontrastis preferred. The radiocontrast is necessary to identify pancreatic necrosis,which appears as focal or diffuse zones of nonenhanced parenchyma. Necrosismay not be evident until 4872 hrs after presentation. If the patient isclinically stable, magnetic resonance imaging is an alternative to CT whencontrast dye is contraindicated and an assessment of the presence of necrosisis necessary. The extent of pancreatic necrosis appears to be a usefuldeterminant of prognosis, with mortality increasing markedly in patients withnecrosis involving >30% of the gland (1619).

The availability of critical care services may ensure optimal fluid resuscitationin order to prevent, reverse, or attenuate organ dysfunction and facilitate
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timely use of advanced life support. Thresholds for admission to an ICU varywidely and are dependent on the availability of beds, alternative venues (suchas step-down units), and whether frequent monitoring and appropriatemanagement can occur on the ward. Patients with SAP who fulfill conventionalcriteria for ICU admission (20) should be admitted if possible, as well as thosepatients at high risk of rapid deterioration such as the elderly (21), those with

significant obesity (e.g., body mass index >30 kg/m2) (22), patients requiringongoing volume resuscitation, and patients with evidence of substantialpancreatic necrosis (>30%).

There are no studies evaluating the relationship between different models ofcritical care delivery and outcomes in patients with SAP. However, a systematicreview of 26 observational studies showed that a heterogeneous group ofcritically ill patients cared for by an intensivist or using an intensivistconsultant model in a closed ICU had a shorter duration of ICU stay and lowermortality than similar patients cared for in units without such staffing patterns

(23).

Jury RecommendationsRecommendation 1.

We recommend ICU admission for patients meeting conventional criteria foradmission to a critical care unit. In addition, a step-down unit or ICU should beconsidered for patients who are at high risk of rapid deterioration such as theelderly, the obese, patients requiring ongoing volume resuscitation, andpatients with substantial pancreatic necrosis (level 5 evidence, grade D

recommendation).

Recommendation 2.

We recommend that when feasible, critically ill patients with pancreatitis becared for by an intensivist-led multidisciplinary team with ready access tophysicians skilled in endoscopy, endoscopic retrogradecholangiopancreatography (ERCP), surgery, and interventional radiology (level3a evidence, grade B recommendation).

Recommendation 3.

We recommend close clinical observation of patients with pancreatitisregardless of their venue of care. These patients usually require early andaggressive fluid resuscitation. They are at risk for the early development oforgan dysfunction as a result of inadequate resuscitation and the systemic andlocal complications of pancreatitis. Clinical monitoring should focus onintravascular volume assessment (e.g., physical examination, urine output,and acid-base status) and pulmonary function (e.g., hypoxemia). Disease-specific scoring systems and global illness severity scores may be usefuladjuncts to identify patients at high risk of complications; however, thesemodels should not replace frequent serial clinical assessments (level 5evidence, grade D recommendation).
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Recommendation 4.

We recommend against the routine use of markers such as CRP orprocalcitonin to guide clinical decision making, predict the clinical course ofpancreatitis, or triage patients (level 5 evidence, grade D recommendation).

Recommendation 5.

We recommend that in the presence of diagnostic uncertainty at the time ofinitial presentation, a CT scan of the abdomen (with intravenous contrast in theabsence of contraindications) be performed after adequate fluid resuscitationto confirm the diagnosis of pancreatitis and to rule out alternate diagnoses. Anadmission CT scan may also serve as a baseline for future scans (level 5evidence, grade D recommendation).

Recommendation 6.

We recommend that CT to identify local complications be delayed for 4872hrs when possible, as necrosis might not be visualized earlier (level 5evidence, grade D recommendation).

Question 2: Should Patients With Severe AcutePancreatitis Receive Prophylactic Antibiotics?Rationale

Infection of the necrotic pancreas develops in 3050% of patients with

necrosis documented by CT or operation (2427). Although infection mightoccur within the first week following initial presentation, its incidence tends topeak in the third week of the disease (28). Rates of organ failure and mortalityappear to be highest among patients with infected pancreatic necrosis.

The mechanism by which the necrotic pancreas becomes infected is unclear,but experimental and clinical data suggest that the gastrointestinal tract is thelikely source of organisms, since intestinal colonization by pathogens oftenprecedes pancreatic infection (2933). These data, combined with the adverseoutcomes associated with the development of infected pancreatic necrosis,

underlie the rationale for the use of either prophylactic intravenous or oral,nonabsorbable antimicrobials. Different regimens have been proposed, butmost have a spectrum of activity that includes Gram-negative organisms.There is no justification for antimicrobial prophylaxis in patients withoutnecrosis, given the relatively low incidence of infectious complications in thissetting.

EvidenceIntravenous Antimicrobial Prophylaxis.

Three randomized controlled studies tested the efficacy of parenteral ampicillin(1 g every 6 hrs for 57 days) in unselected patients with acute pancreatitis.There were no differences in outcomes (infectious complications, deaths, or


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hospital length of stay) between treatment and control groups in all threestudies. However, there were no major pancreatic complications and only onedeath in these trials, indicating that the majority of these patients had mildpancreatitis (3436).

More recent studies have targeted patients at greater risk of pancreatic

infection, using high levels of CRP and/or evidence of pancreatic necrosis on CTas inclusion criteria. Six randomized controlled trials have tested the efficacy ofprophylactic systemic antibiotics in this higher risk group (3742) (Table 1).These trials differ in their inclusion criteria and the choice of antimicrobials.Two studies demonstrated reduced rates of pancreatic infection (37, 39). Onlyone of these trials was adequately powered to demonstrate a statisticallysignificant decrease in this end point, and in this study the reduction ininfection rates was not associated with a reduction in the number ofoperations, organ failure, or mortality (37). The other four studies did notdemonstrate a significant reduction in rates of pancreatic infection with

prophylaxis (38, 4042). The report by Sainio and colleagues (38) is the solestudy demonstrating a reduction in mortality in the treatment arm, but anexcess of early deaths in the control group, unrelated to infection, suggests animbalance in randomization. In this study, prophylaxis was associated withfewer urinary tract infections and fewer operative interventions; however,many of the operations were directed toward the debridement of noninfectedpancreatic necrosis. In the Schwarz et al. (41) trial, there was a trend towardbenefit but the study was underpowered to derive definitive conclusions. In thetrial by Nordback et al. (42), in which patients with CRP >150 and pancreaticnecrosis by CT were randomized to prophylaxis or standard care, there was

less organ failure with a trend toward fewer pancreatic infections in thetreatment arm, without significant effects on operative interventions ormortality. However, >40% of the patients in the control arm of this study wereconverted to imipenem therapy because of suspicion of infection (42). Thefourth study, with the highest methodological quality, yet with a relativelysmall proportion of patients with necrosis, demonstrated no differences inoutcome (40).
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Table 1. Summary of randomized trials examining routine prophylacticantibiotics for necrotizing pancreatitis

Three meta-analyses have been published (4345), none of which included themost recently published randomized controlled trial by Isenmann. All of theseanalyses have concluded that prophylactic antimicrobial therapy is beneficial innecrotizing pancreatitis with either trends or statistically significant reductionsin mortality, rates of infection, or surgical intervention. In each of these meta-analyses, the results were influenced by the inclusion of the trial with a highearly mortality in the control arm by Sainio and colleagues (38), describedpreviously. After excluding this report, one meta-analysis showed no beneficialeffect to prophylactic antimicrobial therapy (44). Another meta-analysis waslimited to the three studies in which acute necrotizing pancreatitis was anentry criterion (45). In this analysis, the pooled estimates suggested a trendtoward a decrease in the risk of local pancreatic infections. However, asignificant reduction in mortality was evident. The improvement in mortality

without a reduction in rates of pancreatic infection suggests that theantimicrobials might have exerted their beneficial effects through othermechanisms, the most likely of which is earlier treatment of other nosocomialinfections.

The lack of any consistent benefit across studies, their variable inclusioncriteria, variable methodological quality, different antimicrobial regimens, andthe significant potential for harm preclude a recommendation for routineintravenous prophylactic antimicrobial therapy in patients with SAP with orwithout necrosis. Furthermore, prophylactic antimicrobials have been

associated with a change in the spectrum of pancreatic isolates from entericGram-negatives to fungi and Gram-positive organisms (46, 47). A large,multiple-center, double-blind, randomized controlled trial of meropenem vs.placebo is underway and might provide additional insight into the risks andbenefits of systemic antimicrobial prophylaxis.

Prophylactic Antifungal Therapy.

The practice of routine antibacterial prophylaxis for SAP is associated with anincreasing number of reports of pancreatic necrosis infected with Candida

species (24, 46, 48). These infections are associated with a higher mortalitythan bacterial infections, although this finding is not consistent across allstudies (4852). One observational study with historical controls suggested thatprophylaxis or early preemptive treatment (in the setting ofCandidacolonization) with fluconazole might prevent fungal pancreatic infections (51).However, given the limited data available, there is insufficient evidence tosupport a recommendation of routine antifungal prophylaxis in patients withSAP.

Selective Decontamination of the Digestive Tract.

Another strategy for infection prophylaxis is the use of selectivedecontamination of the digestive tract. Given that the source of pathogens is
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thought to be the gastrointestinal tract, this approach offers a sound biologicalrationale. In a multiple-center, randomized controlled trial, Luiten et al. (53)studied 102 patients with severe pancreatitis defined by an Imrie (Glasgow)score >=3 and/or one or more peripancreatic fluid collections on CT. Thetreatment group received an oral and rectal regimen of colistin, amphotericin,and norfloxacin. In addition, intravenous cefotaxime was administered until

Gram-negative bacteria were eliminated from oral and rectal cultures. Theprophylaxis regimen was associated with a significant reduction in pancreaticinfections, particularly those due to Gram-negative organisms (54). Thenumber of patients requiring surgical intervention was no different, but thenumber of operations per patient was reduced in the treatment arm. Overallmortality and length of stay were not affected by the prophylaxis regimen, butpost hocanalysis suggested a mortality benefit among patients with thehighest severity scores. This study suggests that selective decontamination ofthe digestive tract is a promising modality worthy of further study, but thedata are insufficient to warrant a specific recommendation.


We recommend against the routine use of prophylactic systemic antibacterialor antifungal agents in patients with necrotizing pancreatitis in light ofinconclusive evidence and divided expert opinion. Subsets of patients whobenefit from prophylactic antibiotics may be identified by further investigation(level 2b evidence, grade B recommendation).

Recommendation 8.

We recommend against the routine use of selective decontamination of thedigestive tract in the management of necrotizing pancreatitis. Furtherinvestigation of this promising strategy in SAP is warranted.

Question 3: What Is the Optimal Mode and Timing ofNutritional Support for the Patient With Severe AcutePancreatitis?Rationale

Patients with SAP are frequently hypercatabolic; timely institution of feeding isimportant if malnutrition is to be avoided or treated. Local complications ofpancreatitis might cause upper gastrointestinal tract obstruction, makingenteral nutrition problematic. There are also concerns that enteral nutritionmay exacerbate the severity of SAP through further pancreatic stimulation andenzyme release. These considerations have led to a widespread reliance onparenteral nutrition as the main nutritional support modality in SAP.

A large body of evidence suggests that there are several potential benefits to

enteral nutrition compared with parenteral nutrition including a reduction inmicrobial translocation, improvements in gut blood flow, and preservation ofgut mucosal surface immunity. Furthermore, since altered gut microbiological
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flora and barrier function may contribute to the development of infectedpancreatic necrosis, there are theoretical advantages to enteral feeding in SAP.Prior guidelines advocate jejunal rather than gastric administration of enteralnutrition in patients with acute pancreatitis to limit the potential for pancreaticstimulation, although this requires either endoscopic or radiological feedingtube placement (55).

EvidenceRole of Feeding in Exacerbation of SAP.

In 20% of patients with resolving pancreatitis, abdominal symptoms recurfollowing the introduction of oral intake (56). The likelihood of relapse appearsgreatest in patients with pancreatic necrosis or those with longer periods ofpain before the reintroduction of enteral nutrition. Observations such as thesehave led to a belief that enteral nutrition might exacerbate SAP by stimulatingthe inflamed pancreas and that recovery could be hastened with pancreatic

rest achieved through the cessation of enteral intake. Studies in healthyvolunteers confirm that pancreatic secretions are stimulated by feeding directlyinto the stomach, duodenum, and jejunum (57). The effects on pancreaticsecretion are mitigated when feeding occurs significantly beyond the ligamentof Treitz (58).

The benefits of enteral nutrition vs. parenteral nutrition in the general criticallyill population have encouraged an increasing number of investigators to useenteral nutrition as the preferred mode of nutritional support in SAP. Data fromrelatively small case series suggest that jejunal feeds are relatively well

tolerated without adverse effects (59, 60). Pupelis and colleagues (61)randomized 60 patients undergoing laparotomy for management of peritonitisor SAP (n = 42 patients) to receive early jejunal feeding with a standardformula via a nasojejunal tube or intravenous fluids alone. Patients in thejejunal feeding group required fewer laparotomies and had more rapidrecovery of bowel transit and a lower mortality rate (61). This is a very selectpopulation of patients with SAP, making extrapolation to all those with SAPdifficult, but there was no suggestion of harm associated with the use ofenteral nutrition.

The limited evidence suggests that jejunal feeding is not likely to be harmful inpatients with SAP. However, placing a feeding tube into this position is oftendifficult or impractical, raising the question whether more proximal feeding isfeasible. In a small case series without controls, Eatock et al. (62) found thatnasogastric feeding was tolerated and did not appear to exacerbatepancreatitis. In a randomized controlled trial (n = 50) available only in abstractform, investigators reported similar CRP levels and pain scores after theintroduction of nasogastric compared with nasojejunal feeds (63).

Enteral Nutrition Vs. Parenteral Nutrition.

Eight trials have directly compared enteral nutrition and parenteral nutrition inpatients with pancreatitis. Two of these studies demonstrated an attenuatedinflammatory response in enterally fed patients as measured by resolution of
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systemic inflammatory response syndrome or reduction in circulating levels ofCRP, tumor necrosis factor (TNF)-[alpha], or IL-6 (64, 65). In all the remainingstudies, the majority of which compared total parenteral nutrition with jejunalfeeds, outcomes related to infections, organ failure, and mortality were eithersimilar (66) or lower in enterally fed patients (6771). Results of a meta-analysis of six trials in which patients (n = 263) were randomized to receive

either nasojejunal enteral feeds or parenteral nutrition within 48 hrs ofadmission suggested significant benefit for those fed enterally (72). In thisanalysis, infection rates, rates of surgical intervention, and length of stay weresignificantly lower in this group, whereas a mortality benefit did not reachstatistical significance.

These studies of enteral vs. parenteral nutrition were performed before theunderstanding of the merits of strict glycemic control for critically ill patients inreducing infectious complications and mortality (73). As parenteral nutrition isoften accompanied by some degree of hyperglycemia, it is likely that the

results of many of these studies are confounded by the higher glucose levels inthe parenterally supported patients. Consequently, all critically ill patients withSAP, and particularly those receiving parenteral nutrition, should be managedusing protocols for strict glycemic control.

Role of Glutamine Supplementation, Immunonutrition, or Probiotics.

Experimental data in animal models of SAP suggest that glutamine-enrichedparenteral nutrition reduces bacterial translocation (74, 75). The data availablein patients with SAP are limited. De Beaux et al. (76) randomized 14 patients

with SAP to receive either standard parenteral nutrition or isonitrogenousparenteral nutrition enriched with glutamine and reported less monocyte IL-8production in the glutamine group. In a similar study, Ockenga et al. (77)reported an increase in albumin with a reduction in CRP levels in patientsreceiving glutamine-enriched parenteral nutrition. These studies, althoughsmall and inconclusive, are consistent with the larger body of literaturesuggesting that glutamine supplementation of parenteral nutrition is beneficialin the critically ill.

There is a single study of glutamine-enriched enteral nutrition in SAP (78).

Sixteen patients with SAP were randomized to receive standard enteralnutrition or a glutamine-enriched immune-enhancing enteral nutritionpreparation. Patients in the latter group experienced significant elevations inserum immunoglobulin G and retinol binding protein and significantly morerapid recovery than those receiving standard enteral feeds.

The use of probiotics in SAP has also been studied. Treatment with specificfiber-fermenting lactobacillus and fermentable fiber is designed to modifypotentially pathogenic bacterial overgrowth in the gut, reduce bacterialtranslocation, and improve immune function. This approach is conceptuallysound given the mechanism by which it is believed the necrotic pancreasbecomes infected, but the approach is supported by very limited experimentaldata (79). In the only available clinical trial evaluating this approach, 45patients with pancreatitis were randomized to receive either the probiotic
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regimen delivered via a nasojejunal tube or a similar preparation in which thelactobacillus had been heat-inactivated (80). There were no differences inmortality rate, yet infected pancreatic necrosis was significantly less frequentin patients receiving the probiotic preparation. These results suggest thatprobiotics are worthy of further study in SAP, but current data are not strongenough support their use.


We recommend that enteral nutrition be used in preference to parenteralnutrition in patients with SAP. Enteral nutrition should be initiated after initialresuscitation. The jejunal route should be used if possible (level 1a evidence,grade A recommendation).

Recommendation 10.

We recommend parenteral nutrition only be used when attempts at enteralnutrition have failed after a 5- to 7-day trial (level 5 evidence, grade Drecommendation).

Recommendation 11.

We recommend that, when used, parenteral nutrition should be enriched withglutamine (level 5 evidence, grade D recommendation).

Recommendation 12.

We recommend that patients, both enterally and parenterally fed, be managedwith protocols ensuring strict glycemic control (level 1b evidence, grade Arecommendation).

Recommendation 13.

We recommend against the routine use of immune-enhancing enteral feedformulas or probiotics (level 5 evidence, grade D recommendation).

Question 4: What Are the Indications for Surgery in AcutePancreatitis and What Is the Optimal Timing forIntervention? What Are the Roles for Less Invasive

Approaches Including Percutaneous Drainage andLaparoscopy?Rationale

There are several incontrovertible indications for operative intervention inpatients with SAP: suspected or confirmed intra-abdominal catastrophe

including intestinal infarction or perforation, exsanguinating hemorrhage, orabdominal compartment syndrome. The patient with SAP must be assessed
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daily for deterioration with these possibilities in mind since timely operativeintervention is essential.

In acute pancreatitis, the extensive inflammatory process in theretroperitoneum leads to the development of peripancreatic fluid collectionsand pancreatic necrosis (81). Routine operative or percutaneous drainage of

the former is not necessary and may infect otherwise sterile tissues. Necrosisdevelops in approximately 1020% of patients with acute pancreatitis and in asignificantly greater proportion of those with severe clinical disease (16).Putatively, the presence of tissue necrosis further exacerbates or impairs theresolution of the local and systemic inflammatory response. Nonviable tissuealso might be seeded by enteric organisms, resulting in infected pancreaticnecrosis.

Necrosis in the context of severe clinical disease mandates repeatedassessment of the need for intervention, which in many cases involves

operative debridement of the pancreas and peripancreatic tissues. Later in thedisease, the necrotic pancreas demarcates from viable tissue, leading to aneasier and safer debridement with a greater likelihood of sparing pancreatictissue. Over time, this area of necrosis undergoes liquefaction, resulting in apancreatic abscess that might be more amenable to percutaneous, rather thanoperative drainage. Thus, the optimal type of the intervention depends on theclinical course of the patient and the precise timing of the intervention. In thereview of evidence that follows, we use the terms debridement and/ordrainage to reflect this continuum.

EvidenceDiscrimination Between Sterile and Infected Pancreatic Necrosis.

Severe acute pancreatitis represents one of the archetypical examples of asterile inflammatory process leading to organ dysfunction (82). The clinicalpicture is often one of the systemic inflammatory response syndrome and canbe indistinguishable from severe sepsis. The potential for development ofinfected pancreatic necrosis and/or extrapancreatic sites of infection furthercomplicates the management of these patients. A deteriorating clinical pictureor the development of new or progressive signs of infection suggests the need

for microbial sampling as clinically indicated. The use of empirical antimicrobialtherapy while awaiting the results of cultures should be based on the rate ofclinical deterioration, with deescalation once results are available and cessationof antimicrobials in the absence of proven infection.

In the critically ill patient with evidence of systemic inflammatory responsesyndrome or sepsis, it is critical to discriminate between sterile and infectedpancreatic necrosis. In this regard, CT is helpful, because the finding ofretroperitoneal air is generally indicative of the presence of gas-formingorganisms and thus infected necrosis. However, the presence of retroperitonealair in patients with infected pancreatic necrosis is rare, rendering CT arelatively insensitive diagnostic test. In the absence of retroperitoneal gas,ultrasound- or CT-guided fine needle aspiration (FNA) of the necrotic tissuewith Gram-negative stain and culture can discriminate between sterile and


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infected pancreatic necrosis. In two studies comparing FNA results with thereference standard of tissue cultures obtained following percutaneous oroperative intervention among patients with a clinical suspicion of pancreaticinfection (25, 26), the positive and negative predictive values of FNAapproached or exceeded 90% (Table 2). However, many patients with negativecultures obtained through FNA who had a benign clinical course did not

undergo operative or percutaneous intervention and were assumed to havesterile pancreatic necrosis. Acknowledging these limitations and the lack of ablinded, uniformly applied reference standard, the use of cultures obtainedthrough FNA is recommended for the discrimination of sterile and infectedpancreatic necrosis.

Table 2. Diagnostic utility of fine needle aspiration in patients with pancreaticnecrosis and clinically suspected infection

Management of Sterile Pancreatic Necrosis.

Several case series describe the course of patients with SAP and sterilepancreatic necrosis treated without debridement (24, 8385). From these data,it is clear that patients without evidence of pancreatic infection can bemanaged without operation with low rates of mortality and morbidity, even inthe face of organ dysfunction. Clinical deterioration is not necessarily anindication for operative debridement. The significant risk of iatrogenic bowelinjuries, hemorrhage, an open abdomen, and infecting sterile pancreaticnecrosis should be considered and balanced against the low probability of afalse-negative FNA before proceeding with operative debridement of sterilenecrosis.

Management of Infected Pancreatic Necrosis.

Several large cases series suggest that the diagnosis of infected pancreaticnecrosis warrants consideration of a single or a series of interventionsdesigned to achieve the goal of pancreatic debridement and/or drainage (83,84, 8690). There are no reports suggesting that antimicrobial therapy alone isadequate. Percutaneous drainage may be the only intervention necessary if thenecrosis has demarcated and liquefied to an extent that the imagingcharacteristics are more consistent with a pancreatic abscess. Several caseseries suggest that necrosectomy should be delayed to achieve this end (89, 91,92). These studies suggest a reduction in the relative risk of death of 3769%in patients in whom necrosectomy is performed at least 23 wks afterpresentation. However, these results are all confounded by the indication for
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surgery, since most critically ill patients at highest risk of death undergooperation earlier in the course of their disease.

In a small clinical trial in an era of mandatory operative necrosectomypredating the use of FNA (93), 36 critically ill patients with pancreatic necrosiswere randomized to early (12 days) intervention. There

was a trend toward lower mortality and a need for fewer debridements inpatients assigned to delayed intervention who underwent an operation (27%vs. 56%). Importantly, a significant minority (20%) of those randomized tolate necrosectomy improved without operation. There was an imbalance ofrandomization such that there was an excess of patients with more severedisease in the early intervention arm. Acknowledging the limitations of theavailable data, it seems likely that there is some benefit to delayingintervention if the clinical setting permits.

Access to the retroperitoneum via laparotomy or flank incision represents the

conventional operative approach and is considered the gold standard forachieving retroperitoneal debridement and drainage. Repeated operativeinterventions are frequently necessary to accomplish an adequatedebridement. There are recent reports of selected, relatively stable patientsundergoing laparoscopic retroperitoneal debridement in conjunction withpercutaneous drainage (94). Percutaneous drainage, with or withoutpercutaneous debridement, might also offer advantages by minimizing themorbidity of laparotomy or temporizing until the retroperitoneal process hassufficiently demarcated such that operative management, when necessary, isfacilitated (95). Case series of percutaneous interventions suggest that as

many as 53100% of highly selected patients might be spared an operativenecrosectomy (9699). Endoscopic transgastric debridement and drainage alsohave been reported and appear to reduce the need for operative debridement(100). These reports emphasize the need for repeated interventions andimaging studies over a prolonged period of days to weeks to accomplishdebridement and retroperitoneal drainage with frequent reassessment of theclinical and radiological response. A delay in achieving definitive control of theinfected necrotizing process is not prudent in deteriorating patients withmultiple organ failure; thus, the clinical scenario must be considered beforeembarking on a course of minimally invasive operative or percutaneous

interventions.


We recommend sonographic- or CT-guided FNA with Gram stain and culture ofpancreatic or peripancreatic tissue to discriminate between sterile and infectednecrosis in patients with radiological evidence of pancreatic necrosis andclinical features consistent with infection (level 4 evidence, grade Crecommendation).

Recommendation 15.
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We recommend against debridement and/or drainage in patients with sterilenecrosis (level 4 evidence, grade C recommendation).

Recommendation 16.

We recommend pancreatic debridement or drainage in patients with infected

pancreatic necrosis and/or abscess confirmed by radiological evidence of gas orresults of FNA. The gold standard for achieving this goal is open operativedebridement. Minimally invasive techniques including laparoscopic and/orpercutaneous interventions might be effective in selected patients (level 4evidence, grade C recommendation).

Recommendation 17.

We recommend that when possible, operative necrosectomy and/or drainagebe delayed at least 23 wks to allow for demarcation of the necrotic pancreas.

However, the clinical picture (severity and evolution) should be the primarydeterminant of the timing of intervention (level 4 evidence, grade Crecommendation).

Question 5: Under What Circumstances Should Patients

With Gallstone Pancreatitis Undergo Interventions forClearance of the Bile Duct?Rationale

Gallstones represent one of the most common etiologies of acute pancreatitis,accounting for 4060% of all cases (101). All patients with pancreatitis shouldbe evaluated for the presence of gallstones since this etiology has specifictherapeutic implications. The mechanism by which gallstones initiate theprocess of pancreatitis is by temporary or persistent obstruction of thesphincter of Oddi, leading to an increase in pancreatic ductal pressure andinitiation of the inflammatory cascade through mechanisms that have not beenfully elucidated (102104). Given this purported mechanism, it has beenpostulated that prompt removal of the impacted stone would attenuate theinflammatory response. However, in most cases the obstruction is onlytransient; the stone has often spontaneously passed before attempts at

removal. Nevertheless, this is the rationale for early biliary clearance inpatients with gallstone pancreatitis.

EvidenceIdentification of the Patient With Biliary Pancreatitis.

Ultrasonography should be performed to assess for gallstones as a potentialcause of pancreatitis, and the abdominal CT scan should be reviewed with thisin mind. The sensitivity of ultrasound for identification of cholelithiasis in thepresence of acute pancreatitis is approximately 85%, whereas the sensitivity

for choledocholithiasis is


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the identification of cholelithiasis and offers comparable sensitivity to ERCP forthe identification of choledocholithiasis in patients with acute pancreatitis (105,106). Serum biochemistry also might offer some predictive utility indifferentiating biliary pancreatitis from other etiologies. For example, in onemeta-analysis, a three-fold or greater increase in alanine aminotransferase hada positive predictive value of 95% in identifying pancreatitis with a biliary

etiology (107). Timing of presentation will influence the predictive utility ofdiagnostic tests; thus, gallstones should be considered the presumptiveetiology in those without an alternate diagnosis.

Timing of Biliary Clearance.

For patients with severe acute gallstone pancreatitis, urgent biliary drainageand clearance of the bile duct must be considered. There is general consensusthat patients with severe acute gallstone pancreatitis with obstructive jaundiceshould undergo urgent ERCP and, if gallstones are identified, endoscopic

sphincterotomy should be performed. The role of urgent ERCP and endoscopicsphincterotomy in the setting of acute pancreatitis due to suspected or provengallstones but without obstructive jaundice is more controversial. Fourrandomized trials have been conducted comparing early ERCP (defined aswithin 24 of admission or within 72 hrs symptom onset) to delayed or nobiliary drainage. Three of the four trials have been published (108110) and thefourth has been presented only in abstract form (111) (Table 3). In addition, asystematic review has been performed on all four trials (112). Two of thepublished trials suggested that patients benefit from early ERCP with reducedmorbidity (108) or reduced mortality (113). The third trial showed no benefit of

ERCP and a significant increase in the development of respiratory failure with atrend toward increased mortality (110). The fourth trial suggested a lowermortality in patients undergoing ERCP, but the limited information in theabstract precludes making any definitive conclusions. Taken together in theform of a meta-analysis, these trials suggested a significant reduction inmortality and morbidity in subjects receiving early ERCP (112). In two trials,subjects were stratified by severity of pancreatitis (108, 109). In both of thesereports, the benefits were limited to those with severe disease. Importantly,the negative study by Folsch et al. (110) had the lowest proportion of patientswith severe pancreatitis, emphasizing the importance of disease severity as an

indicator of those likely to benefit from early ERCP.

Table 3. Summary of randomized controlled trials comparing early ERCPwithin 72 hrs of presentation or 24 hrs of symptom onset in acute pancreatitis
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Based on the preceding evidence, it is recommended that patients with severeacute gallstone pancreatitis undergo early ERCP and, if indicated, endoscopicsphincterotomy. This recommendation differs from prior consensus guidelines(4) because it takes into account the systematic review (112) and unpublisheddata (111) and because of the focus on this consensus document on critically ill

patients with SAP.

Among patients who undergo ERCP with endoscopic sphincterotomy and havesubsequently recovered from their critical illness, there are case series tosuggest that cholecystectomy should be performed at the earliest possible timedue to the relatively high risk of subsequent gallbladder symptoms (114117).However, one case series suggests that older patients with successfulendoscopic sphincterotomy may have a low incidence of further attacks ofacute pancreatitis and may not need cholecystectomy (118).


We recommend that gallstone pancreatitis be suspected in all patients withSAP and therefore all patients should have evaluation with sonography andbiochemical tests (level 4 evidence, grade C recommendation).

Recommendation 19.

In the setting of obstructive jaundice (or other evidence of acute obstruction of

the biliary and/or pancreatic tract) and acute pancreatitis due to suspected orconfirmed gallstones, we recommend that urgent ERCP should be performedwithin 72 hrs of onset of symptoms. If ERCP cannot be accomplished becauseit is not technically feasible or available, alternative methods of biliary drainagemust be considered (level 5 evidence, grade D recommendation).

Recommendation 20.

In the absence of obstructive jaundice, but with SAP due to suspected orconfirmed gallstones, we recommend that ERCP be strongly considered within72 hrs of onset of symptoms (level 1c evidence, grade B recommendation).

Question 6: Is There a Role for Therapy Targeting the

Inflammatory Response in the Patient With Severe AcutePancreatitis?Rationale

It is commonly accepted that the physiologic response and many of thecomplications of SAP occur as a result of an uncontrolled inflammatoryresponse. Potentially, there may be a therapeutic window between onset of

symptoms and development of organ failure during which anti-inflammatorytherapy may be successful. Recent therapeutic strategies have been directedtoward interrupting the systemic inflammatory response to mitigate the
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development of organ dysfunction. The role of many inflammatory mediators inSAP has been investigated, including TNF-[alpha], IL-1[beta], IL-6, IL-8,cytokine-induced neutrophil chemoattractant/ growth-related oncogen-[alpha],macrophage chemoattractant protein-1, platelet activating factor (PAF), IL-10,CD40L, C5a, intracellular adhesion molecule-1, substance P, and caspase-1(119). Therapies targeting several of these mediators have been studied in

animal models, but there are limited human data. Additionally, recombinanthuman activated protein C (rh-APC) has been shown in a large multiple-centertrial to reduce mortality from severe sepsis (120), leading to the question of itsrole in SAP.

The host response during SAP is complex and varies during the course ofdisease. It has been shown that the inflammatory response is likelycompartmentalized, with a local proinflammatory response and a systemicanti-inflammatory response (121). If the area of pancreatic necrosis becomesinfected, additional host responses triggered by the microorganisms will further

alter the inflammatory response. These variations make the targeting ofspecific mediators during the course of SAP difficult.

EvidenceTNF-[alpha] Blockade.

TNF-[alpha], derived predominantly from activated macrophages, is thought tobe a key mediator in shock and is found in high circulating concentrations inacute pancreatitis (122). In animal models, administration of anti-TNF-[alpha]has been shown to attenuate pancreatic injury and reduce mortality (123).

Although anti-TNF-[alpha] therapy is now a well-accepted treatment modalityfor both Crohn's disease and rheumatoid arthritis (124), there are no dataavailable on its effectiveness in patients with SAP.

PAF Blockade.

PAF, a potent activator of leukocytes and a chemoattractant, is present at highconcentrations in the inflamed pancreas, and its systemic administration hasbeen reported to induce pancreatitis in experimental models (125).Furthermore, PAF antagonists have been shown to attenuate the inflammatory

response in animal models of pancreatitis (126). Lexipafant is the only PAFantagonist to be evaluated in clinical trials of patients with pancreatitis.Lexipafant appeared to lower the incidence of organ dysfunction in tworelatively small trials; both were underpowered to assess mortality (127, 128).In a large European randomized controlled trial (n = 286), patients with SAP(Simplified Acute Physiology component of the Acute Physiology and ChronicHealth Evaluation II) scores >6 within 72 hrs of symptom onset receivinglexipafant had lower organ failure scores and a trend toward lower mortality(129). The greatest benefit appeared when patients received treatment within48 hrs of onset. In a subsequent randomized controlled study (Larvin,unpublished), 1,500 patients with SAP score >5 within 48 hrs of symptomonset were randomized to lexipafant or placebo. However, in contrast to priortrials, lexipafant had no effect on organ failure or mortality.
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Modulation of the Coagulation Cascade.

Recombinant human activated protein C has proven effectiveness in reducingmortality in patients with severe sepsis (120). Sixty-two patients withpancreatitis were enrolled in this trial; mortality was 24% in the placebo armand 15% in those receiving rh-APC. All enrolled patients had a known or

suspected source of infection, which is not the case in many patients with SAP.There are no studies of rh-APC in patients with SAP who do not have adocumented source of infection. Given the absence of available data in SAPwithout infection, its use in this context is not recommended. Furthermore,even in patients with established infection, rh-APC should be used with cautiondue to the theoretical potential for significant retroperitoneal bleeding.

Jury Recommendations Recommendation 21.

General supportive measures used in the critically ill should be employed in

patients with SAP, as these interventions might play an important role inattenuating the inflammatory response. Thus we recommend the use of earlyvolume resuscitation (130) (level 1b, grade A recommendation) and lung-protective ventilation strategies for patients with acute lung injury (131) (level1b evidence, grade A recommendation).

Recommendation 22.

Once the presence of infection is documented or highly suspected and thepatient with SAP meets the definition of severe sepsis (2), we recommend that

management according to current sepsis guidelines be initiated (132, 133).These therapies include the use of rh-APC (120) (level 1b, grade Arecommendation) and low-dose corticosteroids for vasopressor-dependentshock (134) (level 1b evidence, grade B recommendation). We recommend thatcareful consideration be used before the administration of rh-APC based on thetheoretical but unproven concern of retroperitoneal hemorrhage (level 5evidence, grade D recommendation).

Recommendation 23.

We recommend against the use of other immune-modulating therapiestargeting inflammatory mediators in SAP, such as anti-TNF-[alpha] therapyand lexipafant (level 1b, grade A recommendation for lexipafant; level 5evidence, grade D recommendation for all other therapies).

Opportunities for Research

Several aspects of care in patients with SAP require further evaluation in theform of well-designed clinical trials. Specifically, the benefits of prophylacticintravenous or oral antimicrobial therapy need to be further assessed. Themerits of enteral over parenteral nutrition require reevaluation in the contextof strict glycemic control. The consequences of gastric vs. jejunal feeds shouldbe tested in further randomized trials. Given the many uncertainties about the
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pathophysiology of pancreatitis and the promising value of novel therapies inanimal models, we recommend that research continue in these areas.Application of anti-inflammatory mediator therapy in small human trials beforeprogressing to larger international cooperative trials is paramount to thedevelopment of innovative treatment approaches. The formation ofcollaborative research networks that prioritize clinical questions and

collaboratively conduct multiple-center studies would help to generate high-quality evidence in sufficiently powered studies to help improve themanagement of patients with SAP.

ACKNOWLEDGMENTS

Sponsored by the American Thoracic (ATS), the European Respiratory Society(ERS), the European Society of Intensive Care Medicine (ESICM), the Societyof Critical Care Medicine (SCCM) and the Socit de Ranimation de LangueFranaise (SRLF).

Scientific Advisors: John C. Marshall, MD, Toronto General Hospital, Toronto,ON, Canada; Graham Ramsay, MD, Atrium Medisch Centrum, Heerlen, TheNetherlands.

Scientific Experts: John C. Alverdy, MD, University of Chicago, Chicago, IL; E.J. Balthazar, MD, New York University School of Medicine, New York, NY; PhilipS. Barie, MD, MBA, FCCM, Weill Medical College of Cornell University, NewYork, NY; Hans Beger, MD, University of Ulm, Ulm, Germany; Stig Bengmark,MD, Lund University, Lund, Sweden; E. Patchen Dellinger, MD, University of

Washington, Seattle, WA; Thierry Dugernier, MD, St. Luc University Hospital,Brussels, Belgium; Mitchell P. Fink, MD, FCCM, University of Pittsburgh MedicalCenter; Pittsburgh, PA; Beat Gloor, MD, Inselspital/University Berne, Bern,Switzerland; Peter Gotzinger; University of Vienna/General Hospital Vienna,Vienna, Austria; Clement W. Imrie, Glasgow Royal Infirmary, Glasgow,Scotland; Khursheed N. Jeejeebhoy, MB, BS, PhD, St. Michael's Hospital,Toronto, ON, Canada; Colin D. Johnson, Southampton General Hospital,Southampton, UK; E. J. Luiten, Johan de Wittlaan, Rotterdam-Dijkzigt,Netherlands; Stephen McClave, MD, University of Louisville;, Louisville, KY;John Neoptolemos, MD, University of Liverpool, Liverpool, UK; James Norman,

MD, Tampa General Hospital;, Tampa, FL; Grant Edward O'Keefe, MD,University of Washington, Seattle, WA; Jerome Pugin, MD, University Hospital,Geneva, Switzerland; Daniel Sleeman, MD, University of Miami School ofMedicine, Miami, FL; Joseph S. Solomkin, MD, University of Cincinnati MedicalCenter, Cincinnati, OH; Bettina Rau, University of the Saarland, KirrbergerStrasse, Germany; Ori D. Rotstein, MD, Toronto General Hospital, Toronto, ON,Canada; Michael A. West, MD, PhD, FCCM; Northwestern University School ofMedicine; Chicago, IL.

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manejo crtico de la pancreatitis

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