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Special Article
Management of the critically ill patient with severe acute pancreatitis
Avery B. Nathens, MD, PhD; J. Randall Curtis, MD, MPH; Richard J. Beale, MBBS; Deborah J. Cook, MD;Rui P. Moreno, MD, PhD; Jacques-Andre Romand, MD, FCCM; Shawn J. Skerrett, MD;Renee D. Stapleton, MD; Lorraine B. Ware, MD; Carl S. Waldmann, MD
Acute pancreatitis represents aspectrum of disease rangingfr om a mild, s elf- limitedcourse requiring only brief
hospitalization to a rapidly progressive,fulminant illness resulting in the multi-ple organ dysfunction syndrome with orwithout accompanying sepsis. This con-
sensus statement focuses on the manage-ment of the critically ill patient with se-vere acute pancreatitis (SAP). Only aminority of patients with pancreatitishave disease severe enough to requireadmission to an intensive care unit (ICU).These patients have mortality rates in therange of 3050% and a mean hospitallength of stay 1 month, attesting to the
severity of pancreatitis at this end of thespectrum (1).
An established definition of SAP wasdeveloped by consensus in 1992 and iswidely used throughout the literature.Using this definition, SAP is acute pan-creatitis associated with complicationsthat are either local (e.g., peripancreaticfluid collection, necrosis, abscess,pseudocyst) or systemic (e.g., organ dys-function). However, the definitions usedpreviously for organ dysfunction are not
consistent with current criteria that ne-cessitate organ support or ICU admissiontoday. To better identify patients whohave severe systemic manifestations ofpancreatitis from a critical care perspec-tive, we use the term severe acute pan-creatitis to represent pancreatitis in thecontext of true organ dysfunction, irre-spective of the local complications. In
this regard, SAP is to pancreatitis as se-vere sepsis is to sepsis (2).
An international consensus confer-ence was held in April 2004 to developguidelines for the management of thecritically ill patient with SAP. Theseguidelines differ from those previouslypublished by focusing on the challengesof caring for the patient with severe pan-creatitis in the critical care environment.A jury of ten persons representing sur-gery, internal medicine, and critical care
From the University of Washington (ABN, JRC, SJS,RDS) Seattle, WA; Saint Thomas Hospital (RJB), Lon-don, UK; McMaster University (DJC), Hamilton, ON,Canada; Unidade de Cuidados Intensivos Polivalente(RPM), Hospital de Santo Antnio dos Capuchos, Cen-tro Hospitalar de Lisboa (Zona Central), Lisboa, Portu-gal; University Hospital of Geneva (J-AR), Geneva,Switzerland; Vanderbilt University School of Medicine(LBW), Nashville, TN; and the Royal Berkshire Hospital(CSW), Reading, UK.
Copyright 2004 by the Society of Critical CareMedicine and Lippincott Williams & Wilkins
DOI: 10.1097/01.CCM.0000148222.09869.92
Objective: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 (MODS), with or
without accompanying sepsis. The goal of this consensus state-
ment is to provide recommendations regarding the management
of the critically ill patient with severe acute pancreatitis (SAP).
Data Sources and Methods:An international consensus con-
ference was held in April 2004 to develop recommendations for
the management of the critically ill patient with SAP. Evidence-
based recommendations were developed by a jury of ten personsrepresenting surgery, internal medicine, and critical care after
conferring with experts and reviewing the pertinent literature to
address specific questions concerning the management of pa-
tients with severe acute pancreatitis.
Data Synthesis: There were a total of 23 recommendations
developed to provide guidance to critical care clinicians caring for
the patient with SAP. Topics addressed were as follows. 1) When
should the patient admitted with acute pancreatitis be monitored
in an ICU or stepdown unit? 2) Should patients with severe acute
pancreatitis receive prophylactic antibiotics? 3) What is the op-
timal mode and timing of nutritional support for the patient with
SAP? 4) What are the indications for surgery in acute pancreatitis,
what is the optimal timing for intervention, and what are the rolesfor less invasive approaches including percutaneous drainage
and laparoscopy? 5) Under what circumstances should patients
with gallstone pancreatitis undergo interventions for clearance of
the bile duct? 6) Is there a role for therapy targeting the inflam-
matory response in the patient with SAP? Some of the recom-
mendations included a recommendation against the routine use of
prophylactic systemic antibacterial or antifungal agents in pa-
tients with necrotizing pancreatitis. The jury also recommended
against pancreatic debridement or drainage for sterile necrosis,
limiting debridement or drainage to those with infected pancre-
atic necrosis and/or abscess confirmed by radiologic evidence of
gas or results or fine needle aspirate. Furthermore, the juryrecommended that whenever possible, operative necrosectomy
and/or drainage be delayed at least 23 wk to allow for demar-
cation of the necrotic pancreas.
Conclusions:This consensus statement provides 23 different
recommendations concerning the management of patients with
SAP. These recommendations differ in several ways from previous
recommendations because of the release of recent data concern-
ing the management of these patients and also because of the
focus on the critically ill patient. There are a number of important
questions that could not be answered using an evidence-based
approach, and areas in need of further research were identified.
(Crit Care Med 2004; 32:25242536)
KEY WORDS: acute pancreatitis; multiple organ dysfunction syn-drome; sepsis; critically ill patient; evidence-based recommendations
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attended the presentations of 24 expertsin the field of pancreatitis. Experts wereasked to address several specific ques-tions posed by the conference organizersand scientific advisors. These questionsincluded the following: a) When shouldthe patient admitted with acute pancre-atitis be monitored in an ICU or step-down unit? b) Should patients with SAPreceive prophylactic antibiotics? c) What
are the optimal mode and timing of nu-tritional support for the patient withSAP? d) What are the indications for sur-gery in acute pancreatitis, what is theoptimal timing for intervention, andwhat are the roles for less invasive ap-proaches including percutaneous drain-age and laparoscopy? e) Under what cir-c umstan ce s s ho uld p atie nts withgallstone pancreatitis undergo interven-tions for clearance of the bile duct? and f)Is there a role for therapy targeting theinflammatory response in the patient
with SAP?Following the formal presentations,the jury met to review the pertinent lit-erature. One pair of jury members ad-dressed each question, summarizing thelevel of evidence and making recommen-dations for consideration and discussionamong all jury members using the ap-proach promulgated by the Center forEvidence Based Medicine, Oxford, UnitedKingdom (3). Since the focus on this con-sensus conference was critically ill pa-tients with SAP and since a number ofrecent studies address some of thesequestions, some statements in this docu-ment vary from previously published rec-ommendations (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 anenvironment with more intensive moni-toring given their potential for progres-sive organ dysfunction and/or life-threatening local complications. Sincethe availability of critical care beds islimited, it is important to identify appro-priate patients for ICU admission. Addi-tionally, avoiding unnecessary ICU ad-mission may limit the risk of nosocomialinfections and iatrogenic complications.
Evidence
One of the most important determi-nants of poor outcome in SAP is the earlydevelopment and persistence of organ dys-function. Although a variety of scoring sys-tems, biomarkers, and radiological findingscan help to identify patients at risk of organdysfunction, these do not substitute for fre-quent clinical assessment and monitoring.
Therefore, the cornerstone of managementin early pancreatitis is fluid resuscitationand close monitoring for early manifesta-tions of organ dysfunction. In addition tofrequent assessment of vital signs, monitor-ing should be directed toward the repeatedevaluation of intravascular volume statusby means of physical examination andmonitoring of urine output and the earlyidentification of hypoxemia through eitherpulse oximetry or arterial blood gas analy-sis.
Several disease-specific scoring sys-tems have been developed to help identifythe patient at risk for adverse outcomes,such as the Ranson criteria (5) and theGlasgow Score (6). Of the 11 Ranson cri-teria, four are directly related to fluidresuscitation (urea, net fluid sequestra-tion, base deficit, and decreased hemato-crit) and are independent predictors ofmortality (7). In a report of 49 patientswith acute pancreatitis, generic measuresof disease severity such as the AcutePhysiology and Chronic Health Evalua-tion II or Simplified Acute PhysiologyScore II score were superior to disease-
specific scoring systems in predictingmortality (8). These scoring systems de-scribe patients in the first 24 48 hrs aftertheir presentation. However, evolving or-gan dysfunction appears to be a betterpredictor of outcome than a one-time as-sessment, suggesting that dynamicscores might be more useful (9).
A variety of serum biomarkers are as-sociated with the severity and prognosisof acute pancreatitis (10). C-reactive pro-tein (CRP), an acute phase reactant, ismost widely used. Although high levels of
CRP have been associated with pancreaticnecrosis (11, 12), there is a 24- to 48-hrlatency before CRP increases, limiting itsutility as an early predictor (10). Of themany cytokines evaluated, interleukin(IL)-6 appears to hold the most promiseas an early predictor of severe disease, butmore definitive studies are needed (10).Trypsinogen activation peptide is a pan-creatic protease that is released early inacute pancreatitis. In a study of 172 pa-tients designed to evaluate the utility of
trypsinogen activation peptide and CRPin identifying patients with severe dis-ease, the discriminatory ability of eitherwas poor. The area under the receiveroperating curve at 24 hrs from symptomonset for trypsinogen activation peptideand CRP was only 0.69 and 0.40, respec-tively. At 24 hrs following hospital admis-sion, their ability to discriminate mildfrom severe disease was only slightly bet-
ter, with the area under the receiver op-erating curve of 0.78 and 0.65 fortrypsinogen activation peptide and CRP,respectively (13). Procalcitonin (14) andnumerous other markers also have beenstudied in small groups of patients (10).In general, although some of these mark-ers are used to follow patients with pan-creatitis, they are of limited clinical util-ity in predicting outcome or to triagepatients for admission to an ICU.
Radiographic imaging frequently isnecessary to both diagnose and stage theseverity of acute pancreatitis. In patientswith abdominal pain of unclear etiology,computed tomography (CT) of the abdo-men can confirm the diagnosis of pancre-atitis and identify other causes of pain.When intravenous radiocontrast mediaare contraindicated, the diagnosis ofacute pancreatitis can be inferred fromhomogeneous glandular enlargementand the presence of peripancreatic fluidcollections (15). CT with nonionic intra-venous radiocontrast is preferred. The ra-diocontrast is necessary to identify pan-creatic necrosis, which appears as focal or
diffuse zones of nonenhanced paren-chyma. Necrosis may not be evident until4872 hrs after presentation. If the pa-tient is clinically stable, magnetic reso-nance imaging is an alternative to CTwhen contrast dye is contraindicated andan assessment of the presence of necrosisis necessary. The extent of pancreatic ne-crosis appears to be a useful determinantof prognosis, with mortality increasingmarkedly in patients with necrosis in-volving 30% of the gland (1619).
The availability of critical care services
may ensure optimal fluid resuscitation inorder to prevent, reverse, or attenuateorgan dysfunction and facilitate timelyuse of advanced life support. Thresholdsfor admission to an ICU vary widely andare dependent on the availability of beds,alternative venues (such as step-downunits), and whether frequent monitoringand appropriate management can occuron the ward. Patients with SAP who fulfillconventional criteria for ICU admission(20) should be admitted if possible, as
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well as those patients at high risk of rapiddeterioration such as the elderly (21),those with significant obesity (e.g., bodymass index 30 kg/m2) (22), patients re-quiring ongoing volume resuscitation,and patients with evidence of substantialpancreatic necrosis (30%).
There are no studies evaluating therelationship between different models ofcritical care delivery and outcomes in pa-
tients with SAP. However, a systematicreview of 26 observational studies showedthat a heterogeneous group of criticallyill patients cared for by an intensivist orusing an intensivist consultant model ina closed ICU had a shorter duration ofICU stay and lower mortality than similarpatients cared for in units without suchstaffing patterns (23).
Jury Recommendations
Recommendation 1. We recommendICU admission for patients meeting con-
ventional criteria for admission to a criticalcare unit. In addition, a step-down unit orICU should be considered for patients whoare at high risk of rapid deterioration suchas the elderly, the obese, patients requiringongoing volume resuscitation, and patientswith substantial pancreatic necrosis (level 5evidence, grade D recommendation).
Recommendation 2. We recommendthat when feasible, critically ill patientswith pancreatitis be cared for by an in-tensivist-led multidisciplinary team withready access to physicians skilled in en-
doscopy, endoscopic retrograde cholan-giopancreatography (ERCP), surgery, andinterventional radiology (level 3a evi-dence, grade B recommendation).
Recommendation 3. We recommendclose clinical observation of patients withpancreatitis regardless of their venue ofcare. These patients usually require earlyand aggressive fluid resuscitation. Theyare at risk for the early development oforgan dysfunction as a result of inade-quate resuscitation and the systemic andlocal complications of pancreatitis. Clin-ical monitoring should focus on intravas-
cular volume assessment (e.g., physicalexamination, urine output, and acid-base status) and pulmonary function(e.g., hypoxemia). Disease-specific scor-ing systems and global illness severityscores may be useful adjuncts to iden-tify patients at high risk of complica-tions; however, these models shouldnot replace frequent serial clinical as-sessments (level 5 evidence, grade Drecommendation).
Recommendation 4. We recommendagainst the routine use of markers such
as CRP or procalcitonin to guide clinicaldecision making, predict the clinicalcourse of pancreatitis, or triage patients(level 5 evidence, grade D recommenda-tion).
Recommendation 5. We recommendthat in the presence of diagnostic uncer-tainty at the time of initial presentation, aCT scan of the abdomen (with intrave-nous contrast in the absence of contrain-dications) be performed after adequatefluid resuscitation to confirm the diagno-sis of pancreatitis and to rule out alter-
nate diagnoses. An admission CT scanmay also serve as a baseline for futurescans (level 5 evidence, grade D recom-mendation).
Recommendation 6. We recommendthat CT to identify local complications bedelayed for 4872 hrs when possible, asnecrosis might not be visualized earlier(level 5 evidence, grade D recommenda-tion).
QUESTION 2: SHOULD
PATIENTS WITH SEVERE
ACUTE PANCREATITIS RECEIVE
PROPHYLACTIC ANTIBIOTICS?
Rationale
Infection of the necrotic pancreas de-velops in 30 50% of patients with necro-sis documented by CT or operation (2427). Although infection might occurwithin the first week following initial pre-sentation, its incidence tends to peak inthe third week of the disease (28). Ratesof organ failure and mortality appear tobe highest among patients with infected
pancreatic necrosis.The mechanism by which the necrotic
pancreas becomes infected is unclear, butexperimental and clinical data suggestthat the gastrointestinal tract is the likelysource of organisms, since intestinal col-onization by pathogens often precedespancreatic infection (2933). These data,combined with the adverse outcomes as-sociated with the development of infectedpancreatic necrosis, underlie the ratio-nale for the use of either prophylacticintravenous or oral, nonabsorbable anti-
microbials. Different regimens have beenproposed, but most have a spectrum ofactivity that includes Gram-negative or-ganisms. There is no justification for an-
Table 1. Summary of randomized trials examining routine prophylactic antibiotics for necrotizing pancreatitis
Study Blinded Intervention n
Ranson Score,
Mean
Infected
Pancreatic
Necrosis, %
Surgery,
%
Mean Length
of Stay, Days
Mortality,
%
Pederzoli et al. (37) No None 33 3.6 30 33 NA 12Imipenem 41 3.7 12a 29 7
Sainio et al. (38) No None 30 5.7 40 47 44 23Cefuroxime 30 5.3 30 23a 33 3a
Delcenserie et al. (39) No None 12 2.1 33b 25 28 25Ceftazidime and amikacin and
metronidazole
11 2.5 0 0 22 9
Schwarz et al. (41) No None 13 4.5 54 NA NA 15Ofloxacin and metronidazole 13 5.0 62 0
Nordback et al. (42) No None 33 NA 18 15 21 15Imipenem 25 4 8 17 8
Isenmann et al. (40) Double Placebo 35 2.0 9 17 23 4Ciprofloxacin and metronidazole 41 3.0 12 24 22 3
NA, not applicable.ap .05; b end point is severe sepsis or infected pancreatic necrosis.
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timicrobial prophylaxis in patients with-out necrosis, given the relatively lowincidence of infectious complications inthis setting.
Evidence
Intravenous Antimicrobial Prophy-laxis. Three randomized controlled stud-ies tested the efficacy of parenteral ampi-
cillin (1 g every 6 hrs for 57 days) inunselected patients with acute pancreati-tis. There were no differences in out-comes (infectious complications, deaths,or hospital length of stay) between treat-ment and control groups in all threestudies. However, there were no majorpancreatic complications and only onedeath in these trials, indicating that themajority of these patients had mild pan-creatitis (3436).
More recent studies have targeted pa-tients at greater risk of pancreatic infec-tion, using high levels of CRP and/or ev-idence of pancreatic necrosis on CT asinclusion criteria. Six randomized con-trolled trials have tested the efficacy ofprophylactic systemic antibiotics in thishigher risk group (37 42) (Table 1).These trials differ in their inclusion cri-teria and the choice of antimicrobials.Two studies demonstrated reduced ratesof pancreatic infection (37, 39). Only oneof these trials was adequately powered todemonstrate a statistically significant de-crease in this end point, and in this studythe reduction in infection rates was not
associated with a reduction in the num-ber of operations, organ failure, or mor-tality (37). The other four studies did notdemonstrate a significant reduction inrates of pancreatic infection with prophy-laxis (38, 4042). The report by Sainioand colleagues (38) is the sole study dem-onstrating a reduction in mortality in thetreatment arm, but an excess of earlydeaths in the control group, unrelated toinfection, suggests an imbalance in ran-domization. In this study, prophylaxiswas associated with fewer urinary tract
infections and fewer operative interven-tions; however, many of the operationswere directed toward the debridement ofnoninfected pancreatic necrosis. In theSchwarz et al. (41) trial, there was a trendtoward benefit but the study was under-powered to derive definitive conclusions.In the trial by Nordback et al. (42), inwhich patients with CRP 150 and pan-creatic necrosis by CT were randomizedto prophylaxis or standard care, there wasless organ failure with a trend toward
fewer pancreatic infections in the treat-ment arm, without significant effects onoperative interventions or mortality.However, 40% of the patients in thecontrol arm of this study were convertedto imipenem therapy because of suspi-cion of infection (42). The fourth study,with the highest methodological quality,yet with a relatively small proportion ofpatients with necrosis, demonstrated no
differences in outcome (40).Three meta-analyses have been pub-lished (4345), none of which includedthe most recently published randomizedcontrolled trial by Isenmann. All of theseanalyses have concluded that prophylac-tic antimicrobial therapy is beneficial innecrotizing pancreatitis with eithertrends or statistically significant reduc-tions in mortality, rates of infection, orsurgical intervention. In each of thesemeta-analyses, the results were influ-enced by the inclusion of the trial with ahigh early mortality in the control arm bySainio and colleagues (38), described pre-viously. After excluding this report, onemeta-analysis showed no beneficial effectto prophylactic antimicrobial therapy(44). Another meta-analysis was limitedto the three studies in which acute ne-crotizing pancreatitis was an entry crite-rion (45). In this analysis, the pooled es-timates suggested a trend toward adecrease in the risk of local pancreaticinfections. However, a significant reduc-tion in mortality was evident. The im-provement in mortality without a reduc-
tion in rates of pancreatic infectionsuggests that the antimicrobials mighthave exerted their beneficial effectsthrough other mechanisms, the mostlikely of which is earlier treatment ofother nosocomial infections.
The lack of any consistent benefitacross studies, their variable inclusioncriteria, variable methodological quality,different antimicrobial regimens, and thesignificant potential for harm preclude arecommendation for routine intravenousprophylactic antimicrobial therapy in pa-
tients with SAP with or without necrosis.Furthermore, prophylactic antimicrobi-als have been associated with a change inthe spectrum of pancreatic isolates fromenteric Gram-negatives to fungi andGram-positive organisms (46, 47). Alarge, multiple-center, double-blind, ran-domized controlled trial of meropenemvs. placebo is underway and might pro-vide additional insight into the risks andbenefits of systemic antimicrobial pro-phylaxis.
Prophylactic Antifungal Therapy. Thepractice of routine antibacterial prophy-laxis for SAP is associated with an in-creasing number of reports of pancreaticnecrosis infected with Candida species(24, 46, 48). These infections are associ-ated with a higher mortality than bacte-rial infections, although this finding isnot consistent across all studies (4852).One observational study with historical
controls suggested that prophylaxis orearly preemptive treatment (in the set-ting of Candida colonization) with flu-conazole might prevent fungal pancreaticinfections (51). However, given the lim-ited data available, there is insufficientevidence to support a recommendation ofroutine antifungal prophylaxis in patientswith SAP.
Selective Decontamination of the Di-gestive Tract.Another strategy for infec-tion prophylaxis is the use of selectivedecontamination of the digestive tract.Given that the source of pathogens isthought to be the gastrointestinal tract,this approach offers a sound biologicalrationale. In a multiple-center, random-ized controlled trial, Luiten et al. (53)studied 102 patients with severe pancre-atitis defined by an Imrie (Glasgow) score3 and/or one or more peripancreaticfluid collections on CT. The treatmentgroup received an oral and rectal regimenof colistin, amphotericin, and norfloxa-cin. In addition, intravenous cefotaximewas administered until Gram-negativebacteria were eliminated from oral and
rectal cultures. The prophylaxis regimenwas associated with a significant reduc-tion in pancreatic infections, particularlythose due to Gram-negative organisms(54). The number of patients requiringsurgical intervention was no different,but the number of operations per patientwas reduced in the treatment arm. Over-all mortality and length of stay were notaffected by the prophylaxis regimen, but
post hoc analysis suggested a mortalitybenefit among patients with the highestseverity scores. This study suggests that
selective decontamination of the diges-tive tract is a promising modality worthyof further study, but the data are insuffi-cient to warrant a specific recommenda-tion.
Jury Recommendations
Recommendation 7. We recommendagainst the routine use of prophylacticsystemic antibacterial or antifungalagents in patients with necrotizing pan-
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creatitis in light of inconclusive evidenceand divided expert opinion. Subsets ofpatients who benefit from prophylacticantibiotics may be identified by furtherinvestigation (level 2b evidence, grade Brecommendation).
Recommendation 8. We recommendagainst the routine use of selective de-contamination of the digestive tract inthe management of necrotizing pancre-
atitis. Further investigation of this prom-ising strategy in SAP is warranted.
QUESTION 3: WHAT IS THE
OPTIMAL MODE AND TIMING
OF NUTRITIONAL SUPPORT
FOR THE PATIENT WITH
SEVERE ACUTE PANCREATITIS?
Rationale
Patients with SAP are frequently hy-percatabolic; timely institution of feeding
is important if malnutrition is to beavoided or treated. Local complications ofpancreatitis might cause upper gastroin-testinal tract obstruction, making enteralnutrition problematic. There are alsoconcerns that enteral nutrition may ex-acerbate the severity of SAP through fur-ther pancreatic stimulation and enzymerelease. These considerations have led toa widespread reliance on parenteral nu-trition as the main nutritional supportmodality in SAP.
A large body of evidence suggests thatthere are several potential benefits to en-teral nutrition compared with parenteralnutrition including a reduction in micro-bial translocation, improvements in gutblood flow, and preservation of gut mu-cosal surface immunity. Furthermore,since altered gut microbiological floraand barrier function may contribute tothe development of infected pancreaticnecrosis, there are theoretical advantagesto enteral feeding in SAP. Prior guide-lines advocate jejunal rather than gastricadministration of enteral nutrition in pa-tients with acute pancreatitis to limit the
potential for pancreatic stimulation, al-though this requires either endoscopic orradiological feeding tube placement (55).
Evidence
Role of Feeding in Exacerbation ofSAP. In 20% of patients with resolvingpancreatitis, abdominal symptoms recurfollowing the introduction of oral intake(56). The likelihood of relapse appearsgreatest in patients with pancreatic ne-
crosis or those with longer periods ofpain before the reintroduction of enteralnutrition. Observations such as thesehave led to a belief that enteral nutritionmight exacerbate SAP by stimulating theinflamed pancreas and that recoverycould be hastened with pancreatic restachieved through the cessation of enteralintake. Studies in healthy volunteers con-firm that pancreatic secretions are stim-
ulated by feeding directly into the stom-ach, duodenum, and jejunum (57). Theeffects on pancreatic secretion are miti-gated when feeding occurs significantlybeyond the ligament of Treitz (58).
The benefits of enteral nutrition vs.parenteral nutrition in the general criti-cally ill population have encouraged anincreasing number of investigators to useenteral nutrition as the preferred mode ofnutritional support in SAP. Data fromrelatively small case series suggest thatjejunal feeds are relatively well toleratedwithout adverse effects (59, 60). Pupelisand colleagues (61) randomized 60 pa-tients undergoing laparotomy for man-agement of peritonitis or SAP (n 42patients) to receive early jejunal feedingwith a standard formula via a nasojejunaltube or intravenous fluids alone. Patientsin the jejunal feeding group requiredfewer laparotomies and had more rapidrecovery of bowel transit and a lowermortality rate (61). This is a very selectpopulation of patients with SAP, makingextrapolation to all those with SAP diffi-cult, but there was no suggestion of harm
associated with the use of enteral nutri-tion.
The limited evidence suggests that je-junal feeding is not likely to be harmfulin patients with SAP. However, placing afeeding tube into this position is oftendifficult or impractical, raising the ques-tion whether more proximal feeding isfeasible. In a small case series withoutcontrols, Eatock et al. (62) found thatnasogastric feeding was tolerated and didnot appear to exacerbate pancreatitis. In arandomized controlled trial (n 50)
available only in abstract form, investiga-tors reported similar CRP levels and painscores after the introduction of nasogas-tric compared with nasojejunal feeds(63).
Enteral Nutrition Vs. Parenteral Nu-trition. Eight trials have directly com-pared enteral nutrition and parenteralnutrition in patients with pancreatitis.Two of these studies demonstrated an at-tenuated inflammatory response in enter-ally fed patients as measured by resolu-
tion of systemic inflammatory responsesyndrome or reduction in circulating lev-e ls o f C RP , tumor n ec ro sis fac to r(TNF)-, or IL-6 (64, 65). In all the re-maining studies, the majority of whichcompared total parenteral nutrition withjejunal feeds, outcomes related to infec-tions, organ failure, and mortality wereeither similar (66) or lower in enterallyfed patients (6771). Results of a meta-
analysis of six trials in which patients (n 263) were randomized to receive eithernasojejunal enteral feeds or parenteralnutrition within 48 hrs of admission sug-gested significant benefit for those fedenterally (72). In this analysis, infectionrates, rates of surgical intervention, andlength of stay were significantly lower inthis group, whereas a mortality benefitdid not reach statistical significance.
These studies of enteral vs. parenteralnutrition were performed before the un-derstanding of the merits of strict glyce-mic control for critically ill patients inreducing infectious complications andmortality (73). As parenteral nutrition isoften accompanied by some degree of hy-perglycemia, it is likely that the results ofmany of these studies are confounded bythe higher glucose levels in the parenter-ally supported patients. Consequently, allcritically ill patients with SAP, and par-ticularly those receiving parenteral nutri-tion, should be managed using protocolsfor strict glycemic control.
Role of Glutamine Supplementation,Immunonutrition, or Probiotics.Experi-
mental data in animal models of SAPsuggest that glutamine-enriched paren-teral nutrition reduces bacterial translo-cation (74, 75). The data available in pa-tients with SAP are limited. De Beaux etal. (76) randomized 14 patients with SAPto receive either standard parenteral nu-trition or isonitrogenous parenteral nu-trition enriched with glutamine and re-ported less monocyte IL-8 production inthe glutamine group. In a similar study,Ockenga et al. (77) reported an increasein albumin with a reduction in CRP levels
in patients receiving glutamine-enrichedparenteral nutrition. These studies, al-though small and inconclusive, are con-sistent with the larger body of literaturesuggesting that glutamine supplementa-tion 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 random-ized to receive standard enteral nutritionor a glutamine-enriched immune-
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enhancing enteral nutrition prepara-tion. Patients in the latter group experi-enced significant elevations in serumimmunoglobulin G and retinol bindingprotein and significantly more rapid re-covery than those receiving standard en-teral feeds.
The use of probiotics in SAP has alsobeen studied. Treatment with specific fi-ber-fermenting lactobacillus and fer-
mentable fiber is designed to modify po-tentially pathogenic bacterial overgrowthin the gut, reduce bacterial translocation,and improve immune function. This ap-proach is conceptually sound given themechanism by which it is believed thenecrotic pancreas becomes infected, butthe approach is supported by very limitedexperimental data (79). In the only avail-able clinical trial evaluating this ap-proach, 45 patients with pancreatitiswere randomized to receive either theprobiotic regimen delivered via a nasoje-
junal tube or a similar preparation inwhich the lactobacillus had been heat-inactivated (80). There were no differ-ences in mortality rate, yet infected pan-creatic necrosis was significantly lessfrequent in patients receiving the probi-otic preparation. These results suggestthat probiotics are worthy of furtherstudy in SAP, but current data are notstrong enough support their use.
Jury Recommendations
Recommendation 9. We recommendthat enteral nutrition be used in prefer-ence to parenteral nutrition in patientswith SAP. Enteral nutrition should beinitiated after initial resuscitation. Thejejunal route should be used if possible(level 1a evidence, grade A recommenda-tion).
Recommendation 10. We recommendparenteral nutrition only be used whenattempts at enteral nutrition have failedafter a 5- to 7-day trial (level 5 evidence,grade D recommendation).
Recommendation 11. We recommendthat, when used, parenteral nutritionshould be enriched with glutamine (level5 evidence, grade D recommendation).
Recommendation 12. We recommendthat patients, both enterally and paren-terally fed, be managed with protocolsensuring strict glycemic control (level 1bevidence, grade A recommendation).
Recommendation 13. We recommendagainst the routine use of immune-enhancing enteral feed formulas or pro-
biotics (level 5 evidence, grade D recom-mendation).
QUESTION 4: WHAT ARE THE
INDICATIONS FOR SURGERY IN
ACUTE PANCREATITIS AND
WHAT IS THE OPTIMAL TIMING
FOR INTERVENTION? WHAT ARE
THE ROLES FOR LESS INVASIVE
APPROACHES INCLUDINGPERCUTANEOUS DRAINAGE
AND LAPAROSCOPY?
Rationale
There are several incontrovertible in-dications for operative intervention in pa-tients with SAP: suspected or confirmedintra-abdominal catastrophe includingintestinal infarction or perforation, ex-sanguinating hemorrhage, or abdominalcompartment syndrome. The patientwith SAP must be assessed daily for de-terioration with these possibilities inmind since timely operative interventionis essential.
In acute pancreatitis, the extensive in-flammatory process in the retroperito-neum leads to the development ofperipancreatic fluid collections and pan-creatic necrosis (81). Routine operativeor percutaneous drainage of the former isnot necessary and may infect otherwisesterile tissues. Necrosis develops in ap-proximately 10 20% of patients withacute pancreatitis and in a significantly
greater proportion of those with severeclinical disease (16). Putatively, the pres-ence of tissue necrosis further exacer-bates or impairs the resolution of thelocal and systemic inflammatory re-sponse. Nonviable tissue also might beseeded by enteric organisms, resulting ininfected pancreatic necrosis.
Necrosis in the context of severe clin-ical disease mandates repeated assess-ment of the need for intervention, whichin many cases involves operative debride-ment of the pancreas and peripancreatic
tissues. Later in the disease, the necrotic
pancreas demarcates from viable tissue,leading to an easier and safer debride-ment with a greater likelihood of sparingpancreatic tissue. Over time, this area ofnecrosis undergoes liquefaction, result-ing in a pancreatic abscess that might bemore amenable to percutaneous, ratherthan operative drainage. Thus, the opti-mal type of the intervention depends onthe clinical course of the patient and the
precise timing of the intervention. In thereview of evidence that follows, we usethe terms debridement and/or drainageto reflect this continuum.
Evidence
Discrimination Between Sterile andInfe cted Pancrea tic Necrosis. Severeacute pancreatitis represents one of thearchetypical examples of a sterile inflam-matory process leading to organ dysfunc-tion (82). The clinical picture is often oneof the systemic inflammatory responsesyndrome and can be indistinguishablefrom severe sepsis. The potential for de-velopment of infected pancreatic necrosisand/or extrapancreatic sites of infectionfurther complicates the management ofthese patients. A deteriorating clinicalpicture or the development of new orprogressive signs of infection suggeststhe need for microbial sampling as clini-cally indicated. The use of empirical an-timicrobial therapy while awaiting the re-sults of cultures should be based on therate of clinical deterioration, with dees-
calation once results are available andcessation of antimicrobials in the absenceof proven infection.
In the critically ill patient with evi-dence of systemic inflammatory responsesyndrome or sepsis, it is critical to dis-criminate between sterile and infectedpancreatic necrosis. In this regard, CT ishelpful, because the finding of retroperi-toneal air is generally indicative of thepresence of gas-forming organisms andthus infected necrosis. However, thepresence of retroperitoneal air in patients
with infected pancreatic necrosis is rare,
Table 2.Diagnostic utility of fine needle aspiration in patients with pancreatic necrosis and clinically
suspected infection
n
Prevalence of
Infection, %
Sensitivity,
%
Specificity,
%
Positive
Predictive
Value, %
Negative
Predictive
Value, %
Rau et al. (26) 94 37 83 93 88 90Gerzof et al. (25) 60 46 100 100 100 100
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rendering CT a relatively insensitive di-agnostic test. In the absence of retroper-itoneal gas, ultrasound- or CT-guidedfine needle aspiration (FNA) of the ne-crotic tissue with Gram-negative stainand culture can discriminate betweensterile and infected pancreatic necrosis.In two studies comparing FNA resultswith the reference standard of tissue cul-tures obtained following percutaneous or
operative intervention among patientswith a clinical suspicion of pancreatic in-fection (25, 26), the positive and negativepredictive values of FNA approached orexceeded 90% (Table 2). However, manypatients with negative cultures obtainedthrough FNA who had a benign clinicalcourse did not undergo operative or per-cutaneous intervention and were as-sumed to have sterile pancreatic necrosis.Acknowledging these limitations and thelack of a blinded, uniformly applied ref-erence standard, the use of cultures ob-tained through FNA is recommended forthe discrimination of sterile and infectedpancreatic necrosis.
Management of Sterile Pancreatic Ne-crosis. Several case series describe thecourse of patients with SAP and sterilepancreatic necrosis treated without de-bridement (24, 8385). From these data,it is clear that patients without evidenceof pancreatic infection can be managedwithout operation with low rates of mor-tality and morbidity, even in the face oforgan dysfunction. Clinical deteriorationis not necessarily an indication for oper-
ative debridement. The significant risk ofiatrogenic bowel injuries, hemorrhage,an open abdomen, and infecting sterilepancreatic necrosis should be consideredand balanced against the low probabilityof a false-negative FNA before proceedingwith operative debridement of sterile ne-crosis.
Management of Infected PancreaticNecrosis. Several large cases series sug-gest that the diagnosis of infected pancre-atic necrosis warrants consideration of asingle or a series of interventions de-
signed to achieve the goal of pancreaticdebridement and/or drainage (83, 84, 8690). There are no reports suggesting thatantimicrobial therapy alone is adequate.Percutaneous drainage may be the onlyintervention necessary if the necrosis hasdemarcated and liquefied to an extentthat the imaging characteristics are moreconsistent with a pancreatic abscess. Sev-eral case series suggest that necrosec-tomy should be delayed to achieve thisend (89, 91, 92). These studies suggest a
reduction in the relative risk of death of3769% in patients in whom necrosec-tomy is performed at least 23 wks afterpresentation. However, these results areall confounded by the indication for sur-gery, since most critically ill patients athighest risk of death undergo operationearlier in the course of their disease.
In a small clinical trial in an era ofmandatory operative necrosectomy pre-
dating the use of FNA (93), 36 critically illpatients with pancreatic necrosis wererandomized to early (72 hrs) or delayed(12 days) intervention. There was atrend toward lower mortality and a needfor fewer debridements in patients as-signed to delayed intervention who un-derwent an operation (27% vs. 56%). Im-portantly, a significant minority (20%) ofthose randomized to late necrosectomyimproved without operation. There wasan imbalance of randomization such thatthere was an excess of patients with moresevere disease in the early interventionarm. Acknowledging the limitations ofthe available data, it seems likely thatthere is some benefit to delaying inter-vention if the clinical setting permits.
Access to the retroperitoneum via lap-arotomy or flank incision represents theconventional operative approach and isconsidered the gold standard for achiev-ing retroperitoneal debridement anddrainage. Repeated operative interven-tions are frequently necessary to accom-plish an adequate debridement. There arerecent reports of selected, relatively sta-
ble patients undergoing laparoscopic ret-roperitoneal debridement in conjunctionwith percutaneous drainage (94). Percu-taneous drainage, with or without percu-taneous debridement, might also offeradvantages by minimizing the morbidityof laparotomy or temporizing until theretroperitoneal process has sufficientlydemarcated such that operative manage-ment, when necessary, is facilitated (95).Case series of percutaneous interventionssuggest that as many as 53100% ofhighly selected patients might be spared
an operative necrosectomy (9699). En-doscopic transgastric debridement anddrainage also have been reported and ap-pear to reduce the need for operative de-bridement (100). These reports empha-size the need for repeated interventionsand imaging studies over a prolonged pe-riod of days to weeks to accomplish de-bridement and retroperitoneal drainagewith frequent reassessment of the clinicaland radiological response. A delay inachieving definitive control of the in-
fected necrotizing process is not prudentin deteriorating patients with multipleorgan failure; thus, the clinical scenariomust be considered before embarking ona course of minimally invasive operativeor percutaneous interventions.
Jury Recommendations
Recommendation 14. We recommend
sonographic- or CT-guided FNA withGram stain and culture of pancreatic orperipancreatic tissue to discriminate be-tween sterile and infected necrosis in pa-tients with radiological evidence of pan-creatic necrosis and clinical featuresconsistent with infection (level 4 evi-dence, grade C recommendation).
Recommendation 15. We recommendagainst debridement and/or drainage inpatients with sterile necrosis (level 4 ev-idence, grade C recommendation).
Recommendation 16. We recommendpancreatic debridement or drainage inpatients with infected pancreatic necrosisand/or abscess confirmed by radiologicalevidence of gas or results of FNA. Thegold standard for achieving this goal isopen operative debridement. Minimallyinvasive techniques including laparo-scopic and/or percutaneous interventionsmight be effective in selected patients(level 4 evidence, grade C recommenda-tion).
Recommendation 17. We recommendthat when possible, operative necrosec-tomy and/or drainage be delayed at least
23 wks to allow for demarcation of thenecrotic pancreas. However, the clinicalpicture (severity and evolution) should bethe primary determinant of the timing ofintervention (level 4 evidence, grade Crecommendation).
QUESTION 5: UNDER WHAT
CIRCUMSTANCES SHOULD
PATIENTS WITH GALLSTONE
PANCREATITIS UNDERGO
INTERVENTIONS FOR
CLEARANCE OF THE BILEDUCT?
Rationale
Gallstones represent one of the mostcommon etiologies of acute pancreatitis,accounting for 40 60% of all cases (101).All patients with pancreatitis should beevaluated for the presence of gallstonessince this etiology has specific therapeu-tic implications. The mechanism by
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which gallstones initiate the process ofpancreatitis is by temporary or persistentobstruction of the sphincter of Oddi,leading to an increase in pancreatic duc-tal pressure and initiation of the inflam-matory cascade through mechanismsthat have not been fully elucidated (102104). Given this purported mechanism, ithas been postulated that prompt removalof the impacted stone would attenuate
the inflammatory response. However, inmost cases the obstruction is only tran-sient; the stone has often spontaneouslypassed before attempts at removal. Nev-ertheless, this is the rationale for earlybiliary clearance in patients with gall-stone pancreatitis.
Evidence
Identification of the Patient With Bil-iary Pancreatitis. Ultrasonographyshould be performed to assess for gall-stones as a potential cause of pancreatitis,and the abdominal CT scan should bereviewed with this in mind. The sensitiv-ity of ultrasound for identification of cho-lelithiasis in the presence of acute pan-creatitis is approximately 85%, whereasthe sensitivity for choledocholithiasis is50% (105, 106). The limited sensitivityis likely due to the obscuration of thebiliary tree by bowel gas. Recent reportssuggest that endoscopic ultrasound offerssignificantly greater sensitivity and spec-ificity for the identification of cholelithi-asis and offers comparable sensitivity to
ERCP for the identification of chole-docholithiasis in patients with acute pan-creatitis (105, 106). Serum biochemistryalso might offer some predictive utility indifferentiating biliary pancreatitis fromother etiologies. For example, in onemeta-analysis, a three-fold or greater in-crease in alanine aminotransferase had apositive predictive value of 95% in iden-
tifying pancreatitis with a biliary etiology(107). Timing of presentation will influ-ence the predictive utility of diagnostictests; thus, gallstones should be consid-ered the presumptive etiology in thosewithout an alternate diagnosis.
Timing of Biliary Clearance. For pa-tients with severe acute gallstone pancre-atitis, urgent biliary drainage and clear-ance of the bile duct must be considered.
There is general consensus that patientswith severe acute gallstone pancreatitiswith obstructive jaundice should undergourgent ERCP and, if gallstones are iden-tified, endoscopic sphincterotomy shouldbe performed. The role of urgent ERCPand endoscopic sphincterotomy in thesetting of acute pancreatitis due to sus-pected or proven gallstones but withoutobstructive jaundice is more controver-sial. Four randomized trials have beenconducted comparing early ERCP (de-fined as within 24 of admission or within72 hrs symptom onset) to delayed or nobiliary drainage. Three of the four trialshave been published (108110) and thefourth has been presented only in ab-stract form (111) (Table 3). In addition, asystematic review has been performed onall four trials (112). Two of the publishedtrials suggested that patients benefit fromearly ERCP with reduced morbidity (108)or reduced mortality (113). The thirdtrial showed no benefit of ERCP and asignificant increase in the development ofrespiratory failure with a trend towardincreased mortality (110). The fourth
trial suggested a lower mortality in pa-tients undergoing ERCP, but the limitedinformation in the abstract precludesmaking any definitive conclusions. Takentogether in the form of a meta-analysis,these trials suggested a significant reduc-tion in mortality and morbidity in sub-jects receiving early ERCP (112). In twotrials, subjects were stratified by severity
of pancreatitis (108, 109). In both of thesereports, the benefits were limited to thosewith severe disease. Importantly, the neg-ative study by Folsch et al. (110) had thelowest proportion of patients with severepancreatitis, emphasizing the importanceof disease severity as an indicator of thoselikely to benefit from early ERCP.
Based on the preceding evidence, it isrecommended that patients with severe
acute gallstone pancreatitis undergoearly ERCP and, if indicated, endoscopicsphincterotomy. This recommendationdiffers from prior consensus guidelines(4) because it takes into account the sys-tematic review (112) and unpublisheddata (111) and because of the focus onthis consensus document on critically illpatients with SAP.
Among patients who undergo ERCPwith endo scopic sphincter otomy andhave subsequently recovered from theircritical illness, there are case series tosuggest that cholecystectomy should beperformed at the earliest possible timedue to the relatively high risk of subse-quent gallbladder symptoms (114117).However, one case series suggests thatolder patients with successful endoscopicsphincterotomy may have a low incidenceof further attacks of acute pancreatitisand may not need cholecystectomy (118).
Jury Recommendations
Recommendation 18. We recommendthat gallstone pancreatitis be suspected
in all patients with SAP and therefore allpatients should have evaluation withsonography and biochemical tests (level 4evidence, grade C recommendation).
Recommendation 19. In the setting ofobstructive jaundice (or other evidence ofacute obstruction of the biliary and/orpancreatic tract) and acute pancreatitisdue to suspected or confirmed gallstones,
Table 3.Summary of randomized controlled trials comparing early ERCP within 72 hrs of presentation or 24 hrs of symptom onset in acute pancreatitis
Study Intervention nSevere Pancreatitis,
%Gallstones Present,
%Complications,
%Mortality,
%
Neoptolemos et al. (109) None 59 44 85 34 8ERCP/ES 62 17a 2
Fan et al. (108) None 98 42 66 29 9ERCP/ES 97 18 5
Folsch et al. (110) None 112 14 46 51 6ERCP/ES 126 46 11
Nowak et al. (111) None 102 Not reported Not reported 36 13ERCP/ES 178 17a 2
ERCP, endoscopic retrograde cholangiopan creatography; ES, endoscopic sphincterotomy.ap .05.
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we recommend that urgent ERCP shouldbe performed within 72 hrs of onset ofsymptoms. If ERCP cannot be accom-plished because it is not technically fea-sible or available, alternative methods ofbiliary drainage must be considered (level5 evidence, grade D recommendation).
Recommendation 20. In the absenceof obstructive jaundice, but with SAP dueto suspected or confirmed gallstones, we
recommend that ERCP be strongly con-sidered within 72 hrs of onset of symp-toms (level 1c evidence, grade B recom-mendation).
QUESTION 6: IS THERE A ROLE
FOR THERAPY TARGETING THE
INFLAMMATORY RESPONSE IN
THE PATIENT WITH SEVERE
ACUTE PANCREATITIS?
Rationale
It is commonly accepted that thephysiologic response and many of thecomplications of SAP occur as a result ofan uncontrolled inflammatory response.Potentially, there may be a therapeuticwindow between onset of symptoms anddevelopment of organ failure duringwhich anti-inflammatory therapy may besuccessful. Recent therapeutic strategieshave been directed toward interruptingthe systemic inflammatory response tomitigate the development of organ dys-function. The role of many inflammatory
mediators in SAP has been investigated,including TNF-, IL-1, IL-6, IL-8, cyto-kine-induced neutrophil chemoattractant/growth-related oncogen-, macrophagechemoattractant protein-1, platelet acti-vating factor (PAF), IL-10, CD40L, C5a,intracellular adhesion molecule-1, sub-stance P, and caspase-1 (119). Therapiestargeting several of these mediators havebeen studied in animal models, but thereare limited human data. Additionally, re-combinant human activated protein C(rh-APC) has been shown in a large mul-
tiple-center trial to reduce mortality fromsevere sepsis (120), leading to the ques-tion of its role in SAP.
The host response during SAP iscomplex and varies during the course ofdisease. It has been shown that the in-flammatory response is likely compart-mentalized, with a local proinflammatoryresponse and a systemic anti-inflamma-tory response (121). If the area of pancre-atic necrosis becomes infected, additionalhost responses triggered by the microor-
ganisms will further alter the inflamma-tory response. These variations make thetargeting of specific mediators during thecourse of SAP difficult.
Evidence
TNF- Blockade. TNF-, derived pre-dominantly from activated macrophages,is thought to be a key mediator in shock
and is found in high circulating concen-trations in acute pancreatitis (122). Inanimal models, administration of anti-TNF- has been shown to attenuate pan-creatic injury and reduce mortality (123).Although anti-TNF- therapy is now awell-accept ed treatment moda lity forboth Crohns disease and rheumatoid ar-thritis (124), there are no data availableon its effectiveness in patients with SAP.
PAF Blockade.PAF, a potent activatorof leukocytes and a chemoattractant, ispresent at high concentrations in the in-flamed pancreas, and its systemic admin-istration has been reported to inducepancreatitis in experimental models(125). Furthermore, PAF antagonistshave been shown to attenuate the inflam-matory response in animal models ofpancreatitis (126). Lexipafant is the onlyPAF antagonist to be evaluated in clinicaltrials of patients with pancreatitis.Lexipafant appeared to lower the inci-dence of organ dysfunction in two rela-tively small trials; both were underpow-ered to assess mortality (127, 128). In alarge European randomized controlled
trial (n 286), patients with SAP (Sim-plified Acute Physiology component ofthe Acute Physiology and Chronic HealthEvaluation II) scores 6 within 72 hrs ofsymptom onset receiving lexipafant hadlower organ failure scores and a trendtoward lower mortality (129). The great-est benefit appeared when patients re-ceived treatment within 48 hrs of onset.In a subsequent randomized controlledstudy (Larvin, unpublished), 1,500 pa-tients with SAP score5 within 48 hrs ofsymptom onset were randomized to
lexipafant or placebo. However, in con-trast to prior trials, lexipafant had noeffect on organ failure or mortality.
Modulation of the Coagulation Cas-cade.Recombinant human activated pro-tein C has proven effectiveness in reduc-ing mortality in patients with severesepsis (120). Sixty-two patients with pan-creatitis were enrolled in this trial; mor-tality was 24% in the placebo arm and15% in those receiving rh-APC. All en-rolled patients had a known or suspected
source of infection, which is not the casein many patients with SAP. There are nostudies of rh-APC in patients with SAPwho do not have a documented source ofinfection. Given the absence of availabledata in SAP without infection, its use inthis context is not recommended. Fur-thermore, even in patients with estab-lished infection, rh-APC should be usedwith caution due to the theoretical po-
tential for significant retroperitonealbleeding.
Jury Recommendations
Recommendation 21. General sup-portive measures used in the critically illshould be employed in patients with SAP,as these interventions might play an im-portant role in attenuating the inflamma-tory response. Thus we recommend theuse of early volume resuscitation (130)(level 1b, grade A recommendation) andlung-protective ventilation strategies for
patients with acute lung injury (131)(level 1b evidence, grade A recommenda-tion).
Recommendation 22. Once the pres-ence of infection is documented or highlysuspected and the patient with SAP meetsthe definition of severe sepsis (2), we rec-ommend that management according tocurrent sepsis guidelines be initiated(132, 133). These therapies include theuse of rh-APC (120) (level 1b, grade Arecommendation) and low-dose cortico-steroids for vasopressor-dependent shock
(134) (level 1b evidence, grade B recom-mendation). We recommend that carefulconsideration be used before the admin-istration of rh-APC based on the theoret-ical but unproven concern of retroperito-neal hemorrhage (level 5 evidence, gradeD recommendation).
Recommendation 23. We recommendagainst the use of other immune-modu-lating therapies targeting inflammatorymediators in SAP, such as anti-TNF-therapy and lexipafant (level 1b, grade Arecommendation for lexipafant; level 5
evidence, grade D recommendation forall other therapies).
OPPORTUNITIES FOR
RESEARCH
Several aspects of care in patients withSAP require further evaluation in theform of well-designed clinical trials. Spe-cifically, the benefits of prophylactic in-travenous or oral antimicrobial therapyneed to be further assessed. The merits of
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enteral over parenteral nutrition requirereevaluation in the context of strict gly-cemic control. The consequences of gas-tric vs. jejunal feeds should be tested infurther randomized trials. Given themany uncertainties about the pathophys-iology of pancreatitis and the promisingvalue of novel therapies in animal mod-els, we recommend that research con-tinue in these areas. Application of anti-
inflammatory mediator therapy in smallhuman trials before progressing to largerinternational cooperative trials is para-mount to the development of innovativetreatment approaches. The formation ofcollaborative research networks that pri-oritize clinical questions and collabora-tively conduct multiple-center studieswould help to generate high-quality evi-dence in sufficiently powered studies tohelp improve the management of patientswith SAP.
ACKNOWLEDGMENTSSponsored by the American Thoracic
(ATS), the European Respiratory Society(ERS), the European Society of IntensiveCare Medicine (ESICM), the Society ofCritical Care Medicine (SCCM) and theSocit 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 UniversitySchool of Medicine, New York, NY; PhilipS. Barie, MD, MBA, FCCM, Weill MedicalCollege of Cornell University, New York,NY; Hans Beger, MD, University of Ulm,Ulm, Germany; Stig Bengmark, MD,Lund University, Lund, Sweden; E.Patchen Dellinger, MD, University ofWashington, Seattle, WA; Thierry Dug-ernier, 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, Swit-zerland; Peter Gotzinger; University of Vi-enna/General Hospital Vienna, Vienna,Aus tri a; Clemen t W. Imr ie, Gla sgowRoyal Infirmary, Glasgow, Scotland;Khursheed N. Jeejeebhoy, MB, BS, PhD,St. Michaels Hospital, Toronto, ON, Can-ada; Colin D. Johnson, SouthamptonGeneral Hospital, Southampton, UK; E. J.Luiten, Johan de Wittlaan, Rotterdam-
Dijkzigt, Netherlands; Stephen McClave,MD, University of Louisville;, Louisville,KY; John Neoptolemos, MD, University ofLiverpool, Liverpool, UK; James Norman,MD, Tampa General Hospital;, Tampa,FL; Grant Edward OKeefe, MD, Univer-sity of Washington, Seattle, WA; JeromePugin, MD, University Hospital, Geneva,Switzerland; Daniel Sleeman, MD, Uni-versity of Miami School of Medicine, Mi-
ami, FL; Joseph S. Solomkin, MD, Uni-versity of Cincinnati Medical Center,Cincinnati, OH; Bettina Rau, Universityof the Saarland, Kirrberger Strasse, Ger-many; Ori D. Rotstein, MD, Toronto Gen-eral Hospital, Toronto, ON, Canada; Mi-c ha el A . W es t, M D, P hD , F CC M;Northwestern University School of Medi-cine; Chicago, IL.
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