Introduction

Acute inflammation of the pancreas produces a spec-trum of symptoms, which may be mild and self-limit-ing, or reflect severe disease that leads rapidly to mul-tiple organ failure and death. In a majority of patientsa treatable underlying cause is identified. Althoughmild, interstitial, oedematous pancreatitis is morecommon; the more severe form, acute necrotising pan-creatitis (ANP) is associated with a mortality of27±45 % [1]. Management of patients with severeANP is time-consuming, and labour and resource in-tensive. Long-term follow-up suggests that those whodo survive maintain a good quality of life, althoughsome suffer permanent exocrine and endocrine insuffi-ciency [2].

In the last 20 years there has been a gradual move to-wards aggressive supportive therapy for ANP. Numer-ous putative therapeutic interventions have been tried,but few have provided any objective evidence of clinicalbenefit. Thus clear treatment guidelines based on com-pelling data do not exist.

Objective

This paper has been prepared from a continuous reviewof publications in intensive care, gastroenterological,surgical and general medical journals concerning man-agement aspects of ANP supplemented by a formal

MEDLINE search using the following key words: pan-creatitis, necrotising pancreatitis, pancreatic necrosis,surgery, octreotide, somatostatin, protease inhibitors,enteral nutrition (EN), total parenteral nutrition(TPN) and selective decontamination. Papers were se-lected and employed according to an evidence-gradingsystem based upon the methodology of Sackett [3]. Par-ticular attention was paid to areas of intensive care man-agement considered controversial, especially regardingpancreatic imaging, surgical intervention in ANP, theuse of nutritional support and the role of prophylacticantibiotic therapy. Finally, data covering the applicationof new therapies was assessed for each specific area ofcontroversy, where possible `evidence-based' recom-mendations based on this evidence are made for themanagement of these patients in intensive care.

Material and methods

Sackett's original methodology

How should a clinician decide between the uncontrolled expe-rience of seasoned clinicians and the validated results of a blindedrandomised trial? In 1989 Sackett suggested that rules should belaid down for the interpretation of the results of clinical trials [3].He argued that this was vital in order that clinicians are able tomaximise their evaluation of the possible benefits arising fromstudies of potential or unproven remedies. His methodology wasnot designed to discard a large body of uncontrolled clinical obser-vations, but rather to place in context and to qualify the `Level ofEvidence' available for an individual therapy.

Modified methodology

A recent Consensus conference [4] modified Sackett's original evi-dence-based approach in order to grade more precisely the levelsof evidence. The three grades originally cited (A, B, and C) wereexpanded to A, B, C, D, and E (Table 1). The grade allocated tothe response to a given question reflects the quality of evidencecurrently available to answer that question. The answers `Yes',

D.L. Wyncoll The management of severe acutenecrotising pancreatitis: an evidence-based review of the literature

Accepted: 18 August 1998

D.L. Wyncoll ())Department of Intensive Care,Royal Brompton Hospital,Sydney Street, London SW3 6NP, UK

Intensive Care Med (1999) 25: 146±156Ó Springer-Verlag 1999 REVIEW

`No' and `Uncertain' are used and a grade provided which is select-ed according to whether the answer is based upon well-designed,randomised, controlled trials (Level I data) at one extreme; to ananswer that is based upon case series, uncontrolled studies and ex-pert opinion only (Level V data). Thus the validity of a given an-swer to a question must be interpreted in the context of a givengrade. For each question area, recommendations for clinical prac-tice are made based on the available evidence.

Diagnostic approach

Severe acute pancreatitis and scoring systems

Ranson's criteria

Although the overall mortality rate for acute pancreati-tis is approximately 10%, the vast majority of deaths oc-cur in the 25% of patients who suffer the severe form ofthe disease. Since 1974 the standard means of docu-menting the severity of disease and risk of mortalityhas been through the use of Ranson's criteria [5] (Ta-ble 2). These factors were determined following theanalysis of 100 patients with predominantly alcohol-in-duced pancreatitis using clinical and laboratory data ob-tained on admission and after 48 h, and the number ofpositive criteria should predict outcome. In 1984, thesecriteria were re-evaluated and the first eight of Ranson'scriteria were found to be most predictive [6], nowknown as the Glasgow criteria, or Imrie score.

More recently, others have attempted to determinefactors associated with mortality in ANP more accurate-ly [7]. Ranson scores for all patients studied were un-available, but mortality was not associated with whiteblood cell count, respiratory failure, serum calcium con-centration or insulin requirements at ICU admission, al-though these are all Ranson criteria. Neither was therean association between death and systolic blood pres-sure, heart rate, haemoglobin level, platelet count, posi-tive blood cultures, infected pancreatic necrosis or ab-dominal surgery for pancreatitis. However, death wasassociated with higher age, higher serum creatinine, theuse of inotropic and/or vasopressor support and renalfailure during ICU stay.

APACHE

The Acute Physiology and Chronic Health Evaluation(APACHE) II scoring system has also been used in pre-dicting the severity of pancreatitis, and can be used dailythroughout the patient's hospital admission rather thansolely within the first 48 h, thus potentially documentingprogress or deterioration. However, such scoring sys-tems are complex to perform and have only been evalu-ated prospectively 24±48 h after the onset of pancreatit-is, which means that the criteria may not be valid for pa-

tients admitted to the ICU subsequently. In a multicen-tre study from Spain [8], 233 patients with severe ANPand a mortality of 26.6 % were reviewed. Those factorswith most predictive value for mortality included ad-vanced age, presence of renal or respiratory insufficien-cy, and presence of shock.

The scoring of patients with acute pancreatitis is im-portant for a number of reasons. Firstly, the cliniciancan be alerted to the presence of potentially severe dis-ease. Secondly, comparisons of severity can be madeboth within and between patient series and, thirdly, ra-tional selection of patients can be made for inclusion intrials of potential new treatments or interventions. Un-fortunately the scoring systems used at present are ofteninadequate in patients with severe ANP, which is char-

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Table 1 Grading of responses to questions and levels of evidence[4]

Grading of responses to questionsA Supported by at least two level I investigationsB Supported by only one level I investigationC Supported by level II investigations onlyD Supported by at least one level III investigationE Supported by level IV or level V evidence

Levels of evidenceLevel I Large, randomised trials with clear-cut results; low risk

of false-positive (a) error or false-negative (b) errorLevel II Small, randomised trials with uncertain results; mode-

rate to high risk of false-positive (a) and/or false-nega-tive (b) error

Level III Non-randomised, contemporaneous controlsLevel IV Non-randomised, historical controls and expert

opinionLevel V Case series, uncontrolled studies, and expert opinion

Table 2 Adverse prognostic factors in acute pancreatitis: Ranson'sscore [5]

On admission Age > 55 yearsWhite cell count > 16,000/mm3

Glucose > 11 mmol/lLDH > 400 IU/lAST > 250 IU/l

Within 48 hof hospitalisation

Decrease in Hct > 10%Increase in blood urea > 1.8 mmol/lCalcium < 2 mmol/lPaO2 < 8 kPaBase deficit > 4 mmol/lFluid deficit > 6 l

Risk factors Mortality rate0±2 < 1%3±4 > 15%5±6 > 40%> 6 > 100%

Blamey et al. [6] found only eight variables (not LDH, base deficit& fluid deficit) were predictive and these are often referred to asthe Glasgow criteria or Imrie score

acterised by rapidly progressive multiple system organdysfunction. In this setting, the Ranson criteria andAPACHE score do not take account of the effects oftreatment upon measured parameters. The way forwardmay be to use a combination of the Ranson score, theradiological scoring systems (vide infra) and an organfailure score such as the Sepsis-related Organ FailureAssessment [9].

The role of computed tomography in the diagnosis andmanagement of ANP

An International Symposium was held in Atlanta in1992 to discuss the diagnostic evaluation and manage-ment of acute pancreatitis and to agree upon an accept-able series of clinical definitions for classifying the dis-ease and its complications [10]. Forty internationallyrecognised experts from 15 countries attended and con-cluded that, of the imaging techniques readily available,dynamic contrast-enhanced computed tomography(CT) provides the best means of accurately visualisingthe pancreas and diagnosing pancreatitis and its localcomplications. It also may be used for guiding percuta-neous catheter drainage. Guidelines [11] were suggestedfor the efficacious use of CT scanning in such cases, andare shown in Table 3.

In severe acute pancreatitis, there is lack of normalenhancement to contrast of the gland or a portion there-of. This is consistent with pancreatic necrosis, defined asdiffuse or focal areas of non-viable parenchyma. Micro-

scopically there is evidence of damage to the parenchy-mal network, acinar cells and pancreatic ductal systemand necrosis of perilobular fat. Areas of necrosis are of-ten multifocal and rarely involve the whole gland, andmay be confined to the periphery with preservation ofthe core. Necrosis develops early in the course of the dis-ease and is usually established 96 h after the onset ofsymptoms [12]. The extent of pancreatic necrosis andthe degree of peripancreatic inflammation have beenused to determine outcome. Necrosis is estimated as lessthan 30%, 30±50%, and more than 50% of the pancreat-ic gland, and categories A to E represent the radiologi-cally determined spectrum of peripancreatic inflamma-tion (Table 4). A grading system combining the two CTprognostic indicators (the extent of necrosis and thegrade of peripancreatic inflammation) has been devel-oped to give the `CT severity index'. Most complicationsof acute pancreatitis occur in patients in whom the initialdiagnosis is based upon peripancreatic fluid collections(grade D or E) and an excellent correlation has been es-tablished between the CT depiction of necrosis and thedevelopment of complications and death [13].

More recently, localisation of the exact site of necro-sis has been shown to enhance accuracy in the predictionof outcome [14]. One hundred and sixty-one primary CTscans of patients with ANP were analysed retrospective-ly. The anatomical site of necrosis was a better indicatorthan the extent of necrosis for predicting the risk of com-plications and, for patients with necrosis in the pancreat-ic head, the outcome was as severe as when the entirepancreas was affected. By contrast, for patients with ne-crosis in only the distal portion of the gland, the out-come was favourable with few complications. This sug-gests that necrosis in the head of the pancreas may causeobstruction of the pancreatic duct and so produce a risein pressure in the acinar cells leading to damage andleakage and activation of destructive proteases.

Following the initial CT scan, additional scanning isonly indicated if the patient's clinical condition deterio-rates, usually through the development of pancreaticnecrosis, abscess or pancreatic pseudocyst, haemor-rhage or colonic ischaemia or perforation.

Evidence-based evaluation

The role of surgery in ANP

Historical perspective

The role of surgery remains the most controversial areain the management of severe ANP. Earlier this centurymost patients with acute pancreatitis of even moderateseverity underwent operative intervention. The resultswere poor, with mortality rates in excess of 50%,although this was without ICU facilities. In 1972 this

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Table 3 Guidelines for efficacious use of CT scanning in suspectedacute pancreatitis [11]

a) Patients in whom the clinical diagnosis is in doubt

b) Patients with hyperamylasaemia and severe clinical pancreati-tis, abdominal distension, tenderness, high fever (> 39�C) andleukocytosis

c) Patients with Ranson score > 3 or APACHE II > 8

d) Patients showing lack of improvement after 72 h of initial con-servative therapy

e) Acute deterioration following initial clinical improvement

Table 4 Grades of peripancreatic inflammation by CT scanning[13]

A Normal pancreas

B Focal or diffuse enlargement of the pancreas

C Pancreatic gland abnormalities associated with peripancreaticinflammation

D Fluid collection in a single location

E Two or more fluid collections and/or the presence of gas in oradjacent to the pancreas

feeling was summarised in a cynical comment that aª10-minute surgical discussion of acute pancreatitisshould probably include 9 minutes of silenceº [15]. Theconservative, non-surgical approach to severe pancre-atitis persisted for many years. During the past decade,however, it has become clear that certain patients withsevere pancreatitis do benefit from operative interven-tion, and that they will not survive without [16]. Never-theless, the decision regarding whether to and when tooperate is often difficult and requires careful clinicaljudgement.

Present-day surgical management

It is accepted that laparotomy for an acute abdomen isessential when the diagnosis of pancreatitis is in doubt,especially since the procedure is unlikely to exacerbatethe condition if present. Surgery may increase the inci-dence of subsequent infection, but this risk is probablyoutweighed by the dangers of delaying diagnosis andthe treatment of other serious intra-abdominal condi-tions. In a recent review, indications for surgery in se-vere ANP were proposed (Table 5) [17]. If severe acutepancreatitis is an unsuspected `chance' finding at lapa-rotomy, a T-tube may be inserted into the common bileduct, particularly if it has been explored and the oppor-tunity taken for placement of a feeding jejunostomytube [18]. Others oppose this approach, as opening ahollow viscus risks peritonitis.

Endoscopic retrograde cholangiopancreatography(ERCP) represents an alternative approach, particular-ly for patients with severe biliary pancreatitis. Threeprospective randomised studies have been carried outto compare early ERCP with conservative treatment inacute biliary pancreatitis [19±21]. Although the studiesare not entirely consistent, ERCP and papillotomyseem to be beneficial in severe biliary pancreatitis if un-dertaken by a skilled operator, whereas in mild pancre-atitis the risks of the treatment probably outweigh thebenefits.

The presence of infected pancreatic necrosis seemsto be an undisputed indication for urgent surgery [22].Necrosis is documented by contrast-enhanced CT scan,and infection proved by percutaneous aspiration of lo-calised fluid collections or of the necrotic tissue. Allsuch patients require some form of surgical treatment,

although whether this should consist of debridementand gravity drainage, continuous closed lavage of thelesser sac, staged repeated laparotomy or open packingremains to be established. Non-operative methods forthe treatment of infected pancreatic necrosis, such as ra-diological placement of drainage tubes, are doomed tofailure because of repeated blockage due to the viscidnature of the infected material.

Pancreatic abscesses are circumscribed collections ofpus containing little or no pancreatic necrosis, whicharise as a later consequence of acute pancreatitis or pan-creatic trauma [10]. They commonly occur 4 weeks ormore after the onset of severe pancreatitis, and CTscan most accurately makes the diagnosis. If the appro-priate expertise is available, percutaneous catheterdrainage may be successful, although the most recentseries still reports a 40% failure rate [23]. Consequently,proceeding to open surgical drainage is often used as theinitial procedure.

Surgical intervention in sterile ANP

The observation that some patients with severe ANPsurvive without becoming infected and avoiding surgeryis well known. Moreover, operating upon patients whohave sterile ANP hypothetically may be meddlesomeby increasing the risk of subsequent infection and of itsassociated mortality. This is the basis of the critical deci-sion as to whether patients with sterile ANP should un-dergo operative intervention.

Question 1: Do patients with sterile pancreatic necrosisbenefit from early surgery?

Answer: Uncertain; Grade: D

Rationale. In 1991 a review of 194 patients with acutepancreatitis, all of whom were treated medically, pan-creatic necrosis (documented by CT scan) developed in38 (20 %) [24]. Infected ANP was demonstrated in 27/38 (71 %). This was treated by open drainage, yieldinga mortality of 4/27 (15 %). Those patients (n = 11) withdocumented sterile ANP were all treated successfullywithout surgical intervention. This seemed to suggestthat sterile ANP is better treated by medical meansalone. However, of the 156 (80 %) `non-necrosis' pa-tients 17 died, yielding a mortality of 11% (17/156), sim-ilar to that in the `necrosis' group (10.5 %). This paper isoften quoted in support of a conservative non-surgicalapproach, yet the `non-necrosis' (i. e. acute interstitialpancreatitis) group had a higher mortality than the med-ically treated `necrosis' group.

Another paper [25] promotes the view that persistingor increasing multiple organ failure (MOF) despite in-tensive care is an indication for surgery in sterile ANP.Patients admitted with a diagnosis of ANP were re-

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Table 5 Indications for surgery in severe acute pancreatitis [17]

Accepted Controversial

Differential diagnosis > 50 % Sterile pancreatic necrosisPersistent biliary pancreatitis Stable but persistent necrosisInfected pancreatic necrosis Deterioration in clinical coursePancreatic abscess Organ system failure

viewed, of whom 172 (69 %) were found, either at oper-ation or by needle aspiration, to have sterile necrosis.All were initially treated conservatively but 107 devel-oped abdominal or organ complications which necessi-tated surgery. The remaining patients were treated con-servatively throughout their illness. The surgically treat-ed patients had significantly more severe disease asjudged by admission C-reactive protein level, Ranson(median 4.7 versus 3.0) and APACHE II (median 11versus 8) scores. In the surgical group there was a trendtowards a higher incidence of pulmonary and renal in-sufficiency, and shock, and their APACHE II scores in-creased post operatively. The mortality rate of the pa-tients treated surgically was 14/107 (13 %) comparedwith 4/65 (6.2 %) for those treated conservatively, anon-significant difference. The increased incidence ofcomplications in the surgical group may have been ac-counted for by their greater severity of disease. Unfor-tunately, the question as to whether surgery is indicatedin sterile necrosis remains unanswered.

The largest prospective study of surgical interventionfor ANP is from Paris [26]. Debridement of necroticperipancreatic tissue, prolonged closed lavage with spi-ral drains, enteral nutrition (EN) via a jejunostomy andloop ileostomy (to prevent the complication of colonicischaemia) was performed in 157 patients with severeANP defined at laparotomy. The overall mortality was18% and the mortality in primary (non-referred) pa-tients was 13%. The category of primary patients repre-sented 2 % of all patients admitted for acute pancreatitisover the same period. Although these data are just acase series, the results compare favourably.

Recommendation. It is not possible to draw any firm sci-entific conclusions. However, a repeated concern frompublished reviews and investigations is that severeANP should be treated in specialised referral centres.This would give the potential to observe adequately theimpact of different surgical strategies upon the diseaseprocess, whilst maintaining control over other aspectsof supportive care.

Pharmacological agents in the treatment of ANP

Introduction

Theories regarding the pathogenesis of acute pancreati-tis have promoted the concept that autodigestion of thegland and peri-pancreatic tissue by activated pancreaticenzymes is a central component. This has led to the sug-gestion that the reduction of pancreatic exocrine secre-tion, thereby `resting the pancreas', might improve out-come. The problem is that the secretory status of thepancreas in severe ANP is not known. Consequently, itis not clear whether inhibition of secretion actually oc-

curs or whether this is beneficial. Therapies designed toinhibit pancreatic secretion, such as cimetidine, atro-pine, calcitonin, glucagon and fluorouracil do not alterthe course of the disease. However, other pharmacolog-ical therapies such as aprotonin and gabexate mesilate,both protease inhibitors, and somatostatin and octreo-tide are in widespread use in the hope of improving theoutcome.

Somatostatin and octreotide

Somatostatin and its long-acting analogue octreotideare potent inhibitors of pancreatic secretion. They alsostimulate activity of the reticuloendothelial system andplay a regulatory role, mostly inhibitory, in the modula-tion of the immune response via autocrine and neu-roendocrine pathways. Both are cytoprotective with re-spect to the pancreas [27]. Somatostatin has also beenshown to block the release of the cytokines tumour ne-crosis factor and interferon-gamma by peripheralmononuclear cells. Furthermore, octreotide increasesthe phagocytotic activity of monocytes [28]. These ac-tions may be important in the modulation of the patho-genesis of ARDS and septic shock, both of which cancomplicate severe ANP. Both agents are effective in ex-perimental pancreatitis [29], and in the prevention ofcomplications in human patients undergoing surgeryfor chronic pancreatitis [30]. Yet, these beneficial ac-tions depend upon pre-emptive administration prior toany cytotoxic challenge, and this is obviously not possi-ble in the clinical situation. Both agents are powerfulsplanchnic vasoconstrictors and have been proposed aspotential therapies for the treatment of bleedingoesophageal varices. Moreover, the development ofpancreatic necrosis has been linked to hypoperfusionof the gland and vasoconstrictors have been shown toworsen the histological severity of experimental pan-creatitis [31]. Consequently, these agents have benefi-cial and detrimental effects.

Question 2: Does the use of somatostatin or octreotideimprove outcome in ANP?

Answer: No; Grade: B

Rationale. Since 1975 four randomised trials of soma-tostatin for the treatment of acute pancreatitis havebeen carried out. None has demonstrated a beneficialeffect on survival, although the trials were not of suffi-cient size to exclude benefit. Furthermore, the studiesincluded patients of low disease severity and the lowmorbidity makes the results of these studies uncertainand difficult to interpret. A meta-analysis of six trialsof somatostatin, involving a total of over 400 patients,which individually recorded no significant benefit withrespect to mortality, suggested an overall improvement

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in outcome [32]. Because of the overall low mortality(10 %) of the studies included, the relevance of themeta-analysis to the treatment of patients with severeANP remains uncertain.

Preliminary results of an ongoing study [33] havesuggested that octreotide may be beneficial in the treat-ment of patients with severe ANP. This prospective, un-blinded study randomised patients to receive 100 mg oc-treotide subcutaneously 8 hourly for up to 14 days.Both active and placebo groups received indentical con-servative treatment including fluid resuscitation, totalparenteral nutrition (TPN), broad-spectrum antibiotics(ampicillin, gentamicin and metronidazole) and intrave-nous H2-receptor antagonists. The incidence of sepsiswas lower in treatment group (26 % versus 74%), andhospital stay was shorter (18 versus 34 days). Mortalitywas 2/19 patients in the treatment group and 6/19 in thecontrol group: a non-significant difference.

A case-matched study using historical controls [34]examined the effect of octreotide in patients with ANPand pulmonary failure, and also showed potentially ben-eficial results. Thirty-nine patients received octreotide(100 mg intravenously [iv], 8 hourly for 10 days) in addi-tion to standard intensive care. There was no differencein the development of renal, hepatic, gastrointestinal,haemostatic, neurological or local complications, butthe frequency of ARDS and circulatory shock was sig-nificantly lower in the treatment group. Furthermore,mortality was 26 % (10/39) in the octreotide group and61% (33/54) in the control group (p < 0.01). The sameinvestigators have initiated a prospective, double-blind,placebo-controlled trial.

The most recently completed study in this field was arandomised, placebo-controlled, multicentre trial of oc-treotide in 58 patients with moderate to severe pancre-atitis [35]. A larger dose was administered (40 mg/h fora 5-day period by continuous infusion) than in previousstudies. Severity of illness was judged by the admissionAPACHE II score and only those patients with a scorehigher than 5 were entered into the study. Mortalitywas similar in the two groups 5/28, 18 % for octreotideversus placebo group 6/30, 20 %. Complications such asrespiratory failure, acute renal failure, MOF and pan-creatic necrosis were higher in the treatment group(36 % versus 20 %), although this was not significant.

Recommendation. There is insufficient evidence at pre-sent to support the use of octreotide or somatostatin inthe treatment of patients with moderate to severe acutepancreatitis. Additionally, the therapeutic effect of oc-treotide, if present at all, is probably very small andtherefore unlikely to make any significant impact onthe management of patients with ANP.

Protease inhibitors in ANP

One of the mechanisms involved in the pathophysiologyof acute pancreatitis is autodigestion of the pancreas bythe activation of proteases. More accurately it has beenobserved that there is an imbalance between proteasesand anti-proteases. Aprotinin and gabexate mesilateare proteolytic enzyme inhibitors that inhibit a numberof serine-proteases such as trypsin, phospholipase A2,kallikrein, plasmin, thrombin and C1 r and C1 s ester-ases.

Question 3: Does the use of protease inhibitors improveoutcome in ANP?

Answer: No; Grade: A

Rationale. The largest double-blind study of aprotininwas carried out in 161 patients with acute pancreatitis,randomly allocated to receive either aprotinin (500,000units bolus and then 200,000 units 6 hourly for 5 days)or placebo, in addition to conservative treatment [36].Severe pancreatitis, defined as a Ranson score of 3 ormore, was present in 37% of patients who were equallydistributed between the two groups. There were 14deaths, 7 in each group, and there was no difference inthe complication rate.

A second, multicentre, randomised double-blindstudy, included 223 patients with moderate or severepancreatitis [37]. Patients received placebo or gabexatemesilate (4 g per day i. v. for 7 days). There was no dif-ference between the groups with regard to mortality(15 % versus 16%), complications or the need for sur-gery.

The reason why these agents did not have the expect-ed beneficial effect on outcome has been proposed to bethe lag time between the onset of pancreatitis and drugadministration. Additionally, derangement to the mi-crovascular control of the pancreas along with increasedvascular permeability may be contributory. It has beenhypothesised that administration of potential therapiesby continuous regional arterial infusion or the intraperi-toneal route may be advantageous. So far, trials usingthese modes of administration have only been in studiesincorporating small numbers of patients [38] or of poorstudy design.

Recommendation. There is insufficient evidence at pre-sent to recommend that patients with severe ANPshould be treated with protease inhibitors.

The role of prophylactic antibiotics in ANP

Bacterial infection of necrotic pancreatic tissue occursin approximately 40±70 % of patients with ANP, and in-fection is the major cause of morbidity and mortality

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[39]. Early studies investigating the potential role of an-tibiotics in the prevention of infection in pancreatitisshowed no benefit [40], but most included patients witha low level of disease severity and employed agents(e. g. ampicillin) with inefficient penetration into pan-creatic tissue. Subsequent experimental animal and hu-man work in this field is more encouraging.

Question 4: Is the administration of prophylactic antibi-otics beneficial in ANP?

Answers: Reduced complications-Yes; Grade: B. Re-duced mortality-Uncertain; Grade: C

Rationale. Early pancreatic infection, in a rat model ofANP, can be reduced with an antibiotic concentratedby the pancreas, such as imipenem, or with a gut decon-tamination regimen [41]. Oral antibiotics alone are inef-fective, as is intravenous cefotaxime, an antibiotic whichis not concentrated by pancreatic tissue. Using the samerat model, extended studies have found in favour of pro-phylactic systemic antibiotic therapy in ANP [42]. Bothimipenem and ciprofloxacin reduced the number of in-fected pancreatic specimens and bacterial counts com-pared to controls at 1 week. At 3 weeks, pancreatic ab-scess formation and infected pseudocysts were also lessprevalent, and survival was significantly improved, ineach of the antibiotic-treated groups.

An open, randomised, multicentre, clinical trial ofimipenem in 74 patients with CT scans demonstratingmild, moderate or severe necrotising pancreatitis within72 h of onset, assigned them to receive no antibiotic orprophylactic imipenem (500 mg i.v. 8 hourly for14 days) [43]. Imipenem has exceptional penetrationinto pancreatic tissues and broad activity against mostof the common pathogens encountered in this disease.The severity of illness was assessed by Ranson scores,which ranged from 3 to 6 (mean 3.7). The incidence ofseptic complications was significantly reduced in thetreated group (12.2 % versus 30.3%), although therewas only a trend towards decreased mortality (7 % ver-sus 12%). This result may be more impressive than itfirst seems since, despite randomisation, the two groupsof patients were not well matched for the extent of pan-creatic necrosis. The imipenem group contained a sig-nificantly greater number of patients with severe( > 50 %) ANP and therefore would have had a higherpredicted mortality rate than the controls. All patientsunderwent `standard intensive medical treatment' in-cluding analgesics, nasogastric suction, H2-receptor an-tagonists and antiprotease drugs, and received TPN.This is interesting since very few of these therapiesstand up to evidence-based evaluation.

In another randomised study of 60 patients with etha-nol-induced ANP, confirmed by contrast enhanced CTscan, 30 patients were assigned to receive cefuroxime(4.5 grams/day i. v.) prophylactically [44]. There were

more infectious complications in the non-antibioticgroup (mean per patient 1.8 versus 1.0 for those receiv-ing cefuroxime; p < 0.01). Mortality was also higher inthe non-antibiotic group (7 versus 1 death in the antibi-otic group; p = 0.03). This is the first study showing a dif-ference in mortality. It is also surprising, as it would beexpected that an antibiotic which was effective in ANPwould be one which penetrated pancreatic tissue effi-ciently and was effective against the organisms most fre-quently isolated. In fact, cefuroxime does not readilyachieve high concentrations in pancreatic tissue andthe commonest organism responsible for an infectiousepisode in the control group was Staphylococcus epider-midis, which is of uncertain pathogenicity and is normal-ly resistant to cefuroxime. This observation has led tothe suggestion that the improvement in outcome maybe due to the antioxidant properties of this drug identifi-able at this large dose [45].

Recommendation. The evidence at present suggests thatadministration of an i. v. antibiotic such as high dose ce-furoxime, a quinolone or a carbapenem to patientswith ANP is beneficial. Because of deficiencies in thedesign of the studies presently available (primarily alack of blinding), it would not be unreasonable to repeatthese trials with an improved design.

Selective decontamination of the gut in ANP

The original selective digestive decontamination (SDD)strategy contained three components: oropharyngealand gastric decontamination with polymyxin E, tobra-micin, and amphoteracin B and intravenous cefotaximefor 4 days [46]. With this regimen it was hoped that ef-fective elimination of aerobic Gram-negative bacteriacould be achieved with a significant reduction in Gram-negative complications. There is ongoing debate as tothe effectiveness of this strategy and results are conflict-ing regarding any reduction in mortality, particularlywhen applied to a general critically ill population. How-ever, more promising results have been seen in specificpatient populations (e. g. multiple trauma victims andthose with acute liver failure).

The hypothesis that acute pancreatitis promotesbacterial translocation, leading to infection of the in-flamed pancreas and peripancreatic tissue, was testedin rats fed with fluorescent beads; sensitive inert mark-ers of translocation [47]. Following the induction ofnon-lethal pancreatitis in the experimental rats, livebacteria were recovered from 33% of the pancreas ofrats with acute pancreatitis but from none of the con-trols. Moreover, beads were visualised in 91% of thepancreas of rats with acute pancreatitis but from noneof the control animals. Beads were not visualised inthe mesenteric lymph nodes, suggesting a transperito-

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neal route of translocated bacteria for pancreatic infec-tion.

Such results have encouraged investigators to persistwith trials of SDD and/or peritoneal lavage in cases ofsevere ANP. It should be remembered that althoughSDD is often attempted, true decontamination is infre-quently achieved.

Question 5: Does the use of SDD improve outcome inANP?

Answer: Yes; Grade: C

Rationale. The only controlled trial of SDD in these cir-cumstances was performed in 102 patients with ANP[48]. Patients were randomised to receive SDD (oralcolistin, amphoteracin and norfloxacin with addition ofa daily dose of the three drugs given as a rectal enemaand systemic cefotaxime {500 mg i. v. 8 hourly} untilGram-negative bacteria were successfully eliminatedfrom the oral cavity and rectum) or control treatment.Surveillance samples were taken regularly to assesswhether any subsequent infection was of exogenous orendogenous origin. All patients were fed enterally,which was only replaced with TPN if recurrent gastricretention was present. There were 18 deaths (35 %) inthe control group, compared with 11 (22 %) in theSDD group (p < 0.05). This difference was caused by afall in late mortality due to significant reduction in theincidence of Gram-negative pancreatic infection. Therewas also a reduction in the mean number of laparoto-mies in the SDD patients. Since the SDD regimen usedin this study incorporated i. v. cefotaxime, it could be ar-gued that the improvement in outcome was not due tothe colistin, amphoteracin, and norfloxacin compo-nents, but merely due to a systemic antibiotic effect.

Recommendation. It is likely that the use of SDD is as-sociated with a reduction in the incidence of respiratorytract infections. Meta-analyses of SDD suggest thatthere are clear trends towards a reduction in mortalityin critically ill patients [49]. However, evidence thatSDD reduces mortality is clearest in specific subsetsand severe ANP may represent another such subset.The use of this policy has been associated with the emer-gence of resistant Gram-positive cocci, particularly themethicillin-resistant Staphylococcus aureus and thuscaution must be exercised. It is likely that this reasonand the inconvenience associated with its administra-tion are why this therapy is not more enthusiasticallyemployed.

Nutritional support in ANP

The provision of nutritional support for the patient withANP is an essential component of supportive therapy,

especially since many patients with pancreatitis are nu-tritionally depleted prior to their illness and face in-creased metabolic demands throughout the course oftheir disorder [50]. Failure to reverse or prevent malnu-trition, and a prolonged negative nitrogen balance, in-creases mortality rates. The route by which nutrition isadministered is, however, still hotly debated. In the lastdecade there has been a trend away from the use ofTPN in favour of EN in the support of the critically illin general. Studies suggest that early EN started within24 h of admission to ICU, compared with TPN or de-layed EN, is associated with improved wound healingand decreased septic morbidity [51]. Additionally, thereis increasing evidence of negative effects of TPN, suchas increased gut permeability, increased catheter-relat-ed sepsis, an immunosuppressive effect [52], increasedincidence of septic complications [53] and greatly in-creased costs.

Question 6: Does the use of TPN improve outcome inANP?

Answer: Uncertain; Grade: CQuestion 7: Can EN be provided safely in patients

with ANP?Answer: Yes; Grade: C

Rationale. Severe pancreatitis is often quoted as an ab-solute contraindication to EN, and TPN is considered`standard' therapy in most recently reported trials. Thisis largely because it is regarded as a way of `resting thepancreas', although this is based on an assumption thatthe necrotic pancreas is still a secretor of activated en-zymes. In fact, the secretory state of the pancreas hasnever been prospectively studied in severe necrosis.Moreover, several retrospective evaluations of TPN inacute pancreatitis have failed to demonstrate conclu-sively an effect on survival, or on the incidence and se-verity of organ failure. The largest reported prospectiveseries of the use of TPN in the treatment of pancreatitiswas carried out over 2 years [54]. The authors concludedthat TPN was safe, based on 73 patients who had a meanRanson score of 2.5 and an overall mortality of 11%.They argued that this mortality rate was similar to thatpredicted by the Ranson score from other contempora-neous studies. In a second prospective, randomised trialcomparing TPN with no nutrition in 54 patients with alow severity of illness, there was no difference in out-come between the two groups (one patient died in eachgroup). However, strong trends emerged in favour ofthe control group in terms of resolution of pancreatitisand shorter hospital stay [55]. There was also a signifi-cantly increased rate of catheter-related sepsis in theTPN group.

There are an increasing number of reports on the useof EN in severe ANP challenging the persisting dogmaregarding the use of TPN in this condition. When EN is

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given it has been suggested that it should be delivereddistal to the ligament of Treitz (below the area of thecholecystokinin (CCK) cells distal to the third part ofthe duodenum) as CCK stimulation may worsen thecourse of the disease [56]. For a long time it has beenknown that intragastric delivery of nutrients results inan increased volume of pancreatic secretion with in-creased protein and bicarbonate secretion. By contrast,jejunal nutrient delivery is not associated with any in-crease in pancreatic exocrine secretory volume, proteinor bicarbonate secretion.

Jejunal tube feeding as far distally as possible in theupper gastrointestinal tract, therefore conforms to theconcept of `pancreatic rest'. Feeding jejunostomiesplaced in 11 patients undergoing laparotomy for compli-cations of pancreatitis caused no exacerbation of thecondition and only one patient developed a jejunal leaknear the placement of the catheter [57]. Others haveconfirmed the safety of this technique, with patientsshowing a high degree of tolerance of EN and no aggra-vation of the disease process [58].

A comparison of EN with TPN has been made inmild acute pancreatitis [59]. Thirty patients receivedEN (via a nasojejunal tube) on 16 admissions, and TPNon 16. There were no deaths and no differences in serialpain scores, days to normalisation of amylase, days todiet by mouth, or percent of nosocomial pneumonia.However, serial Ranson, APACHE III and MOF scoresrecorded every 2±3 days decreased in the EN group, yetincreased in the TPN group.

There are two randomised studies comparing ENwith TPN in severe ANP. The first allocated 18 patientsto receive EN via a nasojejunal tube with a semi-ele-mental diet, while 20 received TPN through a centralvenous line [60]. EN was well tolerated without adverseeffects on the course of the disease. Patients who receiv-ed EN experienced fewer total complications (p < 0.01)and were at lower risk of developing septic complica-tions (p < 0.01) than those receiving TPN. Three pa-tients died, one in the EN and two in the TPN group.The cause of death in all cases was sepsis and MOF.

A second study of 34 patients with acute pancreatitislooked specifically at the effect of the route of nutrition-al support on the acute phase response. Disease severityscores including APACHE II and C-reactive protein fellin the EN group whereas there was no change but an in-crease in endotoxin core antibody levels and a fall in to-

tal antioxidant capacity in those receiving TPN [61]. ENseems to modulate the inflammatory and sepsis re-sponse beneficially, and appears to be superior to TPNin this regard.

Recommendation. The beneficial effects of EN overTPN shown in other groups of critically ill patients can-not be indiscriminately extrapolated to patients with se-vere ANP. However the presently available data suggestthat EN is no more harmful than TPN and may be advan-tageous. A number of recommendations can be made:

1. Most patients with mild uncomplicated pancreatitisdo not benefit from nutritional support.

2. Patients who require an operation for diagnosis ortreatment should have a jejunal tube placed at thetime of surgery (62).

3. Patients who have moderate to severe pancreatitis(Ranson score > 2) should begin nutritional supportearly in the course of the disease process. A trial ofEN via a nasojejunal feeding tube should be initiatedand TPN only given if this not tolerated.

Summary and conclusion

Clearly the main determinant of outcome in severeacute pancreatitis is the extent of pancreatic necrosisand the subsequent risk for the development of infectednecrosis. A thorough assessment using appropriate scor-ing systems and the early use of dynamic contrast-en-hanced CT will highlight those patients likely to benefitfrom higher dependency or intensive care. Despite nu-merous suggested specific therapies there is still noGrade A evidence that any confers a significant mortal-ity benefit. However, general supportive measuresshould include vigorous replacement of fluid losses tocorrect the circulating volume, correction of electrolyteand glucose abnormalities, and respiratory, cardiovascu-lar and renal support as necessary. Those patients withinfected pancreatic necrosis or deteriorating organ sys-tems should undergo surgery. Patients with sterile ne-crosis should receive a broad-spectrum prophylactic an-tibiotic which adequately penetrates pancreatic tissue.Due attention should also be paid to nutritional support,for which a jejunal feeding tube with EN is recommend-ed as early as is achievable.

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