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A systematic review of the extra-pancreatic infectious complications in acute pancreatitis
Accepted Manuscript A systematic review of the extra-pancreatic infectious complications in acute pancreatitis Lisa A. Brown, MBChB Todd A. Hore, MBChB, FRACS Anthony RJ. Phillips, BSc, MBChB, PhD John A. Windsor, MBChB, MD, FRACS Maxim S. Petrov, MD, MPH, PhD, Dr PII:
S1424-3903(14)00995-8
DOI:
10.1016/j.pan.2014.09.010
Reference:
PAN 320
To appear in:
Pancreatology
Please cite this article as: Brown LA, Hore TA, Phillips AR, Windsor JA, Petrov MS, A systematic review of the extra-pancreatic infectious complications in acute pancreatitis, Pancreatology (2014), doi: 10.1016/j.pan.2014.09.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT A systematic review of the extra-pancreatic infectious complications in acute pancreatitis Authors: Lisa A Brown1, MBChB, [email protected] Todd A Hore1, MBChB, FRACS [email protected]
John A Windsor1, MBChB, MD, FRACS [email protected] Maxim S Petrov1, MD, MPH, PhD [email protected]
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Anthony R J Phillips1, BSc, MBChB, PhD [email protected]
1 The Department of Surgery, The University of Auckland, Auckland, New Zealand
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Corresponding author: Dr Maxim S Petrov Department of Surgery
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The University of Auckland Room 12.092, Level 12 Auckland City Hospital Private Bag 92019
Auckland 1142 New Zealand [email protected]
Fax: +64 09 377 9656
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Short Title:
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Phone: +64 09 373 7999
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Victoria Street West
Extra-pancreatic infection in acute pancreatitis
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ACCEPTED MANUSCRIPT Abstract Background and Aim: Extra-pancreatic infectious complications in acute pancreatitis increases morbidity and mortality, but their incidence and association with infected pancreatic necrosis is unknown. Half of bacterial cultures of pancreatic necrosis are of non-enteric origin, raising the possibility of other sources of infection. The
pancreatitis, their timing, and relation to severity of pancreatitis and mortality.
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aim of this systematic review was to assess the incidence of extra-pancreatic infectious complications in acute
Methods: A systematic review was performed using Ovid MEDLINE, Embase and Cochrane Libraries,
following PRISMA guidelines. Search terms were “Pancreatitis” AND “Infection” AND (“Complication” OR
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“Outcome”).
Results: 19 studies with 1,741 patients were included. Extra-pancreatic infectious complication incidence was 32% (95% CI 23 - 41%), with the commonest being respiratory infection (9.2%) and bacteraemia (8.4%). Extra-
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pancreatic infectious complications were not associated with the predicted severity or the mortality of acute pancreatitis. Only 3 studies reported a relation of timing between extra-pancreatic and pancreatic infectious complications.
Conclusions: This is the first systematic review to evaluate the incidence of extra-pancreatic infectious complications in acute pancreatitis, which a third of patients with acute pancreatitis will develop. Implications
pancreatic necrosis.
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Keywords:
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are vigilance and prompt treatment of extra-pancreatic infection, to reduce possibility of progression to infected
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Pancreatitis, Infection, Complications, Outcome
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ACCEPTED MANUSCRIPT Introduction Acute pancreatitis is a complex disease, with an overall mortality rate of 5-10% that may increase up to 30% in the presence of infected necrosis[1, 2]. The main determinants of pancreatitis severity are persistent organ failure and infected (peri)pancreatic necrosis [1]. However, the presence of extra-pancreatic infectious complications (EPIC) in patients with acute pancreatitis has also been shown to influence morbidity and
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mortality [3-5].
The pathogenesis of infection of pancreatic necrosis is currently not completely understood. However, enteric translocation of bacteria by portal blood or mesenteric lymph has been proposed as a possible cause [6, 7]. On
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review of the bacteriology of infected pancreatic necrosis, close to half of the bacteria were not of enteric origin [8]. This suggests that other concurrent infections might be alternative bacterial sources for seeding pancreatic
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infection. The incidence and impact of pancreatic infectious complications has been extensively studied [1], but there has been no systematic study on the incidence and impact of EPIC or its temporal relationship to the development of infected pancreatic necrosis[9, 10].
The aim of this systematic review was to assess the incidence of EPIC in patients with acute pancreatitis, the
pancreatitis and mortality.
Methods
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Literature search
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timing of EPIC and pancreatic infection, and its potential impact on outcome in relation to severity of
An extensive search was performed of Ovid MEDLINE (1946 to present), Embase (1980 to present) and
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Cochrane Libraries. The search terms used were “Pancreatitis” AND “Infection” AND (“Complication” OR “Outcome”). Studies were limited to English language and human studies only. Papers were screened for eligibility by two authors independently (L.B. & T.H.) and any disagreement over study inclusion or exclusion was resolved by a third author (M.S.P.). References were also reviewed and eligible papers sought. Papers were reviewed by date and location. If duplicates were identified, in which two studies reported on an overlapping series of patients over the same time period, the study with the greatest patient catchment was used. The last date of the literature search was 6th September 2013. Any queries related to specific points in papers were resolved by contacting corresponding authors. The method of this systematic review was based on that of the PRISMA Statement[11].
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ACCEPTED MANUSCRIPT Selection criteria Papers were included that reported the presence of extra-pancreatic infection in patients with acute pancreatitis. Prospective clinical studies (both interventional and observational) were included, but review articles, metaanalyses and population based studies were excluded. Control groups only were included from interventional trials thus all studies were treated as prospective observational. Patients included were over age 15 years.
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Patients whom had recurrent or chronic pancreatitis or were commenced on antibiotics from the day of
admission were excluded. The primary endpoint of the study was the number of patients with a confirmed extra pancreatic infection, with secondary endpoints of site of origin of EPIC, time to onset of infection, pancreatitis
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severity and mortality within this group.
Data extraction
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Data was extracted using a proforma that included baseline clinical characteristics, measures of pancreatitis severity, degree of necrosis, presence and origin of extra pancreatic infection, time to both EPIC and pancreatic infection and mortality rates.
Quality Assessment
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The quality of studies were assessed by the Newcastle-Ottawa Scale [12]. This used three categorical scoring systems of selection (representativeness, exposure determinance), comparability (controlling factors) and outcome (follow-up) to compare studies. A maximum of four ‘stars’ can be awarded for selection, three for
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outcome and two stars for comparability category, with an overall maximal score possible of nine. Follow-up of
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>90% of patients was considered acceptable.
Statistical analysis
Statistical analysis was undertaken using statistical software Stats Direct Version 2.7.9 [13]. A random effects model was used to provide the most conservative estimate. Data extracted from studies were of absolute values from reported individual and group infection rates. Studies were pooled to determine the pooled incidence and corresponding 95% confidence intervals. Subgroup analysis according to the proportion of patients with pancreatic necrosis (<50%, 50-99%, 100%) and mortality (0-5%, 6-10%, >11%) were conducted. Also, a sensitivity analysis constrained to patients with predicted severe acute pancreatitis (as defined within individual
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ACCEPTED MANUSCRIPT studies as one of either Atlanta criteria[14], Ranson score ≥ 3, CRP > 150, presence of necrosis) were conducted. P-values < 0.05 were deemed significant.
Results Study Identification
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A total of 1041 papers were initially screened, from which 1002 papers were excluded after abstract review. Thirty-nine full text articles were assessed for eligibility (Figure 1), with a further 20 articles excluded because the article was a meta-analysis [15], a population based study [5], only reported infections after surgery [16],
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and because prophylactic antibiotics were used from the time of admission as either a treatment group or as part of a hospital protocol [4, 17-31]. The final analysis included 19 studies.
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Baseline characteristics
Demographics of the studies are shown in Table 1. The 19 studies included a total of 1,741 patients (range 19 – 731) per study. The overall median age of patients was 47 years (range 15 - 91) with a predominance of male patients (2.3 : 1). Alcohol (42%) was the most common cause of acute pancreatitis, followed by gallstones (30%). The quality of the included studies was high with a median total score of 8.6 / 10 (range 8 - 9), using
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The Newcastle-Ottawa Scale, with the breakdown shown in Table 1.
Severity prediction and overall mortality of patients in the included studies
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There was a range of methods used to predict pancreatitis severity including the Ranson score [32-36], APACHE II/III score [3, 37-44], CTSI score [45], Glasgow score [46, 47], Modified Glasgow score [48], and
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CRP [49]. A total of 11 studies only enrolled patients with predicted severe pancreatitis (n = 456) [33-36, 38, 40, 43-46, 48] and six studies only enrolled patients with pancreatic necrosis (n = 696, 40%). The overall median percentage of those patients with infection of pancreatic necrosis was 34% (9-80%). The overall median mortality rate in all included studies was 10% (0 – 30%), in the studies of patients with predicted severe AP it was 13% (7 – 30%), and in studies of patients with necrotizing pancreatitis it was 12% (3 – 30%). Details of severity prediction and mortality are given in Table 2.
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ACCEPTED MANUSCRIPT Incidence of extra pancreatic infectious complications The overall incidence of EPIC was 32% (95% CI 23 - 41%) from all included studies (Figure 2). The I2 as a test of heterogeneity was performed for the incidence of EPIC, which was 87.2%, thus there is substantial heterogeneity within the studies included. For those studies with only patients with predicted severe pancreatitis the incidence of EPIC was 40% (95% CI 23 - 57%) (Figure 3). The incidence of EPIC was analyzed in relation
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to the proportion of patients within each study whom had the presence of necrosis. In studies with patients with overall <50% necrosis had an incidence of EPIC of 33% (95% CI 13 – 56%), those with 50-99% necrosis had an incidence of 29% (95% CI 19 – 39%), and the incidence was 31% (95% CI 15 – 50%) in those in whom all
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patients had necrotizing pancreatitis (Figure 4). The incidence of EPIC was analyzed in relation to mortality. In studies with a mortality of 0-5% the incidence of EPIC was 26% (95% CI 6 – 53%); in those with mortality of 6-10% the incidence was 28% (95% CI 16 – 41%), and in those with greater than 10% mortality it was 36%
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(95% CI 20 – 55%). When the first two categories were combined, for an incidence of 27% (95% CI 17 – 38%), there was no significant difference (p = 0.54, unpaired T test, df=15).
Type of infection
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The most common EPICs were respiratory infection (9.2%), bacteraemia (8.4%), and urinary tract infection (2.6%). Pancreatic infectious complications (12%) were reported in 13 studies [32, 36, 41-43, 46]. Bacteraemia was recorded directly from the studies, where it was reported as a specific group with the term “bacteraemia”.
symptoms.
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The definition in the studies, if outlined, was due to the presence of a positive blood culture +/- clinical
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The causative organisms of EPIC alone were not separately recorded as this was only reported in two of the 19 studies. Two studies reported the presence of the same bacterial culture in both pancreatic necrosis and EPIC. Besselink et al [3] reported that 31 of 51 patients had the same bacterial culture from both sources (necrosis and bacteraemia), and Dellinger et al [37] reported that 3 of 50 patients had the same culture from both EIC (bloodstream, urinary, respiratory tract infection) and pancreatic necrosis. This included both control group and treatment patients whom were on prophylactic antibiotics.
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ACCEPTED MANUSCRIPT Timing of infection Three studies reported a relation of timing between extra pancreatic infection and pancreatic infection. Besselink et al [3] reported that previous bacteraemia in patients with parenchymal necrosis had an increased risk of developing infected necrosis (P=0.002). Dellinger et al [37] found that 13/15 (87%) patients with
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pancreatic infection had an extra pancreatic infection, in five (38%) the EPIC occurred first between 2-28 days prior to the pancreatic infection. In three (23%) patients the pancreatic infection occurred first, 2-12 days before the EPIC.
Two studies, including 781 patients [3, 37], reported time to diagnosis of EPIC with a weighted mean time of
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47.3 days. Four studies [33, 35, 38, 45] reported a time to diagnosis of an unspecified infection (pancreatic or extra-pancreatic) with weighted mean time of 22.9 days, with one study[43] reporting that 14/37 patients were
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diagnosed in week 1, with 2/37 patients diagnosed in week 2. Four studies[3, 34, 37, 45], including 843 patients, reported time to diagnosis of pancreatic infectious complication alone, with weighted mean time of 55.1 days reported in two studies (n= 781 patients) [3, 37]. Pederzoli et al [34] reported diagnosis of pancreatic infection was made within 1-3 weeks and Manes et al [45] reported 4/9 patients developed a pancreatic infection
Discussion
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in the second week, 3/9 in the third week, and 2/9 in the fourth week.
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This is the first systematic review to evaluate the incidence of EPIC in acute pancreatitis, to investigate the timing of EPIC and pancreatic infection, and the relation of EPIC to severity of pancreatitis and mortality. It has
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shown that EPIC is common, with an overall incidence of 32% and does not appear to be related to the predicted severity or the mortality of acute pancreatitis. An association between the EPIC and pancreatic infectious complications has been suggested by some studies [3, 4], with pancreatic infection known as a determinant of mortality in patients with acute pancreatitis.
There are several factors which may promote EPICs in patients with acute pancreatitis including lengthy hospital stays, admission to high dependency or intensive care units, multiple interventions and insertion of foreign materials such as central lines, tracheal tubes, catheters or feeding tubes [5]. Respiratory infection and bacteraemia are the most common EPICs. The predominance of respiratory infection has been corroborated in other large-scale studies evaluating the rate of infectious complications after elective surgery and in studies
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ACCEPTED MANUSCRIPT within the intensive care environment [50]. The predominance of respiratory infections could be related to the proportion of patients within an intensive care environment on respiratory support. Of the 19 studies reviewed, three [4, 14, 27] reported that a median of 17% (range 11-23) were admitted to an intensive care unit (ICU). Xue et al [5] found that those patients with infection (both pancreatic and extra-pancreatic) were more likely to be on respiratory support (34.1% vs 12.5%, P < 0.05) than those without infection [5]. Murine studies have
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demonstrated that the concurrent pneumonia resulted in prolonged, more severe, episodes of pancreatitis [51]. However, Besselink et al [3] found that prior diagnosis of pneumonia did not significantly increase risk of
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infection of pancreatic necrosis (57% vs 42.9%, p = 0.147).
Given that a third of patients develop EPIC and that it can promote infected pancreatic necrosis, preventative strategies should be considered. The role of prophylactic antibiotics has been extensively studied, but not
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specifically in those patients at particular risk of EPIC, including those within the intensive care environment, or whom have insertion of tubes, lines and catheters. We excluded all patients whom were commenced on prophylactic antibiotics in this study and only control groups, not on antibiotics, were included from antibiotic intervention studies. A randomized controlled trial by Manes et al [45], comparing the timing of antibiotic use with Meropenem in acute pancreatitis, found that fewer patients developed an EPIC when they had been
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commenced on antibiotics upon admission (n = 5), compared to those commenced on antibiotics upon confirmation of necrosis (n = 13, p<0.03). A recent Cochrane Review [2] found that the prophylactic use of antibiotic therapy did not significantly reduce the occurrence of pancreatic or EPIC. However, the studies were
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generally poorly powered, with 5 of the 7 studies including rates of EPIC.
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Another strategy to reduce the incidence of EPIC is the use of enteral feeding which has been shown in a recent meta-analysis [52] to reduce the occurrence of all infections (EPIC and pancreatic) and catheter related septic complications though it must be acknowledged that the comparator has been parenteral feeding or delayed enteral feeding, not no feeding. Anyway, based on the best available studies, the maximum benefits of enteral feeding are seen when administered in 24-48 hours but not within the first 24 hours [53-55]. The earlier observation that there is a reduction in the early incidence, but not overall incidence, of infections in acute pancreatitis [9] raises the questions about when to start enteral feeding, what to give, and when to stop it.
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ACCEPTED MANUSCRIPT If a cause-effect relationship is to be established then it is necessary to prove that EPIC precedes infection of pancreatic necrosis [9]. This is made difficult by a possible difference between the actual time of onset and any delay in reporting these clinical events. There is suggestion that the time to the onset of infected necrosis appears to be later than the development of EPIC in a study which investigated the cause and timing of fever in 75 patients with acute pancreatitis [56]. They found that the majority of patients with fever (37/45, 82%) did not
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have infected pancreatic necrosis and (17/45, 38%) had extra-pancreatic infection. Of those patients with infected necrosis, fever was seen in the 2nd or 3rd week of admission, compared to those with EPIC who
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developed fever earlier, in the 1st or 2nd week of the illness.
Two studies [3, 37] included in this systematic review reported that the weighted mean time to diagnosis of EPIC was 47.3 days, compared to the time to the diagnosis of pancreatic infection at a weighted mean time of
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55.1 days. Two further studies [34, 45] reported an association between EPIC and infected necrosis. In a retrospective study [18], excluded from this systematic review because of the use of prophylactic antibiotics, found that EPIC occurred in a cohort of 212 patients at a median of 4 days and prior to infection of pancreatic necrosis. Another excluded study [5] of 11,046 patients found that the onset of pneumonia (median 10.7 ± 2.5 days), bacteraemia (13.7 ± 1.5 days) and gastrointestinal tract infection (16.8 ± 3.9 days) occurred before the
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infection of necrosis (17.6 ± 2.9 days). It appears that patients are more likely to have both infection of necrosis and EIC combined, than EPIC alone with Manes et al [45] reporting that 10/13 (77%) patients with pancreatic infection developed an EPIC, compared with 9/46 (20%) patients without pancreatic infection that developed an
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EPIC (p < 0.001).
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This more typical temporal pattern, of EPIC developing before infected pancreatic necrosis, leads to the hypothesis that EPICs may seed pancreatic infection, but this is by no means proven. It might also be that the different mechanisms of infection might account for earlier EPIC and be quite unrelated to onset of pancreatic infection. Further research is required to determine the extent to which EPICs are responsible for infection of the pancreas.
Two factors that might be related to the role of EPIC in infection of necrosis are immunosuppression [57, 58] and gut barrier dysfunction [6, 59], both of which are features of early acute pancreatitis. The immunosuppression might predispose to EPIC and early onset. The gut barrier dysfunction promotes the
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ACCEPTED MANUSCRIPT translocation of bacteria from gut lumen to pancreatic necrosis, by a number of different potential routes including portal venous blood and mesenteric lymph [7, 60]. However the bacteriology of infected pancreatic necrosis and extra-pancreatic sites indicate that around half of the organisms are not of enteric origin [8].
Other evidence supporting a role for EPIC in promoting pancreatic infection might be derived from bacteriology
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studies, but this systematic review did not primarily evaluate this as an endpoint. The predominant infecting organisms cultured from EPIC and pancreatic infections on review of the included papers were common
intestinal gram negative bacteria and staphylococcus which is in accordance with previous studies evaluating the
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microbiology of pancreatic infections [61]. It has been found that staphylococcal infections are more common following antibiotic therapy [62], which may partly explain the frequency of staphylococci found in the included studies. To further explore the potential causal link between the bacteriology of EPIC and pancreatic infections
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will require improved documentation, including typing of different strains, in future studies. Unfortunately, the current reporting of the presence, timing and bacteriology of EPIC in acute pancreatitis is extremely poor. Many authors have not deemed this an important point to report on and this may be due to poor recording of this initially in clinical notes. This needs to be a fundamental data point to be collected in the future.
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Thus the main limitation of the study is the lack of endpoint priority given to EPIC in the published literature, which prohibits a definitive determination of whether EPIC promote pancreatic infections. Because prophylactic antibiotics would confound the incidence of EPIC, studies that used them were excluded. The
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incidence of EPIC when prophylactic antibiotics are used has not been examined in this study. Because EPIC was not the primary endpoint in the included studies, there is a risk of bias, including selection and incomplete
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outcome reporting. The lack of published bacteriological data in most of the studies is a reason for why it is not possible to determine whether the bacteraemia is a primary EPIC or secondary to infected pancreatic necrosis. There was statistical heterogeneity in relation to the primary endpoint. However, the inferences remain unchanged after pre-specified subgroup and sensitivity analyses. This study includes a high proportion of patients with severe pancreatitis, reflecting the search strategy, and may not be representative of all patients with acute pancreatitis.
In conclusion, this systematic review has found that 32% of patients with acute pancreatitis develop an EPIC during hospitalization. There is currently a lack of recording of the presence, timing and bacteriology of EPIC
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ACCEPTED MANUSCRIPT in acute pancreatitis in the literature. The presence of non-enteric bacteria in pancreatic infection and, in general, the earlier onset of EPIC, suggests a possible causal role in seeding pancreatic infection, but this is not yet proven. The clinical implication of this, if proven by further studies with detailed bacteriology, is that vigilance for early diagnosis and prompt treatment of EPIC may reduce the likelihood of subsequent infection of
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pancreatic necrosis.
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Rokke O, Harbitz TB, Liljedal J, et al. Early treatment of severe pancreatitis with imipenem: a
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43.
prospective randomized clinical trial. Scandinavian Journal of Gastroenterology. 2007;42:771-6. 44.
Xue P, Deng L-H, Zhang Z-D, et al. Effect of antibiotic prophylaxis on acute necrotizing pancreatitis:
45.
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Results of a randomized controlled trial. Journal of Gastroenterology and Hepatology. 2009;24:736-42. Manes G, Uomo I, Menchise A, et al. Timing of antibiotic prophylaxis in acute pancreatitis: a
controlled randomized study with Meropenem. American Journal of Gastroenterology. 2006;101:1348-53. 46.
Nordback I, Sand J, Saaristo R, et al. Early treatment with antibiotics reduces the need for surgery in
acute necrotizing pancreatitis - a single-center randomized study. J Gastrointest Surg. 2001;5:113-20. Olah A, Belagyi T, Issekutz A, et al. Randomized clinical trial of specific lactobacillus and fibre
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47.
supplement to early enteral nutrition in patients with acute pancreatitis. British Journal of Surgery. 2002;89:1103-7.
Olah A, Belagyi T, Poto L, et al. Synbiotic control of inflammation and infection in severe acute
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pancreatitis: a prospective, randomized, double blind study. Hepato-gastroenterology. 2007;54:590-4. Tiengou L-E, Gloro R, Pouzoulet J, et al. Semi-elemental formula or polymeric formula: Is there a
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49.
better choice for enteral nutrition in acute pancreatitis? Randomized comparative study. Journal of Parenteral and Enteral Nutrition. 2006;30(1):1-5. 50.
Markogiannakis H, Pachylaki N, Samara E, et al. Infections in a surgical intensive care unit of a
university hospital in Greece. International Journal of Infectious Diseases. 2009;13(2):145-53. 51.
Westerloo DJv, Schultz MJ, Bruno MJ, et al. Acute pancreatitis in mice impairs bacterial clearance
from the lungs, whereas concurrent pneumonia prolongs the course of pancreatitis. Crit Care Med. 2004;32(10):1997-2001.
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Li J-y, Yu T, Chen G-C, et al. Enteral nutrition within 48 hours of admission improves clinical
outcomes of acute pancreatitis by reducing complications: A meta-analysis. PLOS One. 2013;8(6):e64926. 53.
Zou L, Ke L, Li W, et al. Enteral nutrition within 72h after onset of acute pancreatitis vs delayed
initiation. Eur J Clin Nutr. 2014. Sun J, Mu X, Li W, et al. Effects of early enteral nutrition on immune function of severe acute
pancreatitis patients. World J Gastroenterol. 2013;19:917-22.
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54.
Petrov M. Gastric feeding and ‘gut rousing’ in acute pancreatitis. Nutr Clin Pract. 2014;29:287-90.
56.
Bohidar NP, Garg PK, Khanna S, et al. Incidence, etiology, and impact of fever in patients with acute
pancreatitis. Pancreatology. 2002;3:9-13. 57.
Ueda T, Takeyama Y, Yasuda T, et al. Immunosuppression in patients with severe acute pancreatitis.
Journal of gastroenterology. 2006 Aug;41(8):779-84.
Kylanpaa ML, Repo H, Puolakkainen PA. Inflammation and immunosuppression in severe acute
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58.
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pancreatitis. World journal of gastroenterology : WJG. 2010 Jun 21;16(23):2867-72. 59.
Liu H, Li W, Wang X, et al. Early gut mucosal dysfunction in patients with acute pancreatitis. Pancreas.
2008 Mar;36(2):192-6. 60.
Deitch EA. Gut lymph and lymphatics: a source of factors leading to organ injury and dysfunction.
61.
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Annals of the New York Academy of Sciences. 2010 Oct;1207(Suppl 1):E103-11. Israil AM, Palade R, Chifiriuc M, et al. Spectrum, antibiotic susceptibility and virulence factors of
bacterial infections complicating severe acute pancreatitis. Chirurgia. 2011;106(6):743-52. Behrman SW, Bahr MH, Dickson PV, et al. The microbiology of secondary and postoperative
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pancreatic infections. Arch Surgery. 2011;146(5):613-9.
Acknowledgements:
Lisa Brown was funded for her research during the time of performing this study by the Health Research Council of New Zealand and The Royal Australasian College of Surgeons.
Disclosure statement: There are no conflicts of interest to disclose.
16
ACCEPTED MANUSCRIPT
No. of
Gender patients
Abou-Assi et al.
Jan 2000 – 156 Dec 2000
Besselink et al.
(21-91)
March 2004 - March Netherlands
731 2007
Dellinger et al.
North America &
Feb 2003 –
2007[37]
Europe
Dec 2004
Garcia-Barrasa et
May 1999 – Spain
Garg et al.
Jan 1997 – India
2001[39]
Isenmann et al.
Germany
Male 55%
(42-71)
Female 45%
50yrs
Male 76%
(18-84)
Female 24%
67 yrs
Male 79%
(38-79)
Female 21%
41yrs
Male 69%
(15-80)
Female 31%
169
June 2000
Jan 1999 –
56
46yrs
(Newcastle-Ottawa)
Biliary 18%
Selection ***
Alcohol 62%
Comparability **
Other 16%
Outcome ***
Biliary 54%
Selection ****
Alcohol 18%
Comparability **
Other 28%
Outcome ***
Biliary 24%
Selection ****
Alcohol 52%
Comparability **
Other 24%
Outcome **
Biliary 58%
Selection ****
Alcohol 26%
Comparability **
Other 16%
Outcome ***
Biliary 49%
Selection ****
Alcohol 24%
Comparability **
Other 27%
Outcome ***
Biliary 16%
Selection ****
Female 36%
19
Dec 2003
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al. 2009[38]
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50
Quality Assessment Scale
Aetiology
Male 64%
58yrs
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2009[3]
Mean (range)
46yrs
United States 2002[32]
Age
Years of study
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Setting
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Study
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Table 1. Study Characteristics
Male 79%
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Kumar et al.
(22– 78)
Sep 2002 – India
2006[40]
30
39yrs
Italy
57yrs 29
Other 24%
Outcome ***
Biliary 37%
Selection ***
Alcohol 27%
Comparability **
Other 36%
Outcome ***
Biliary 55%
Selection ****
(38-74)
Alcohol 21%
Comparability **
Other 24%
Outcome ***
Male 62%
Female 38%
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Nov 2005
McClave et al.
Selection ****
Male 75%
United States
Not reported
30
46yrs
Alcohol 69%
Comparability **
Female 25%
Nordback et al.
Sep 1995 – Finland
33 May 1999
Olah et al.
July 2001 – Hungary
Olah et al. Hungary
45
2001
Italy
Biliary 6%
Selection ***
Alcohol 76%
Comparability **
Other 18%
Outcome ***
Male 85%
46 yrs
Female 15%
Selection ***
47 yrs
Male 84%
Alcohol 58%
(19-81)
Female 16%
Other 42%
Comparability ** Outcome*** Selection ***
Jan 1999 - March
2002[47]
Outcome ***
62
July 2004
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2007[48]
EP
2001[46]
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1997[41]
Pederzoli et al.
Comparability **
Female 17%
Jan 2002 –
2006[45]
Alcohol 60%
Male 83%
Dec 2003
Manes et al.
Female 21%
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June 2002
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2004[33]
Jan 1989 - July
33
Male 73%
Alcohol 64%
Female 27%
Other 36%
45yrs
Comparability ** Outcome ***
50 yrs
Male 61%
Biliary 49%
Selection ****
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Female 39%
Feb 2002 - March Qin et al. 2008[42]
China
74
56 yrs
57 yrs 1997 - 2002
37 (29-84)
July 1989 - Nov Finland
30
47yrs
Male 56%
(17-82)
Female 44%
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China
100
One year period
30
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2006[49]
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Tiengou et al.
27
2007
Comparability ** Outcome ***
Biliary 46%
Selection ****
Alcohol 27%
Comparability **
Other 27%
Outcome *** Selection ****
Alcohol 100%
Comparability ** Outcome *** Selection ****
Not reported
Comparability ** Outcome ***
Biliary 17%
Selection ***
Alcohol 73%
Comparability **
Other 10%
Outcome ***
Biliary 54%
Selection ***
Alcohol 8%
Comparability **
Other 38%
Outcome ***
Male 80% 46 yrs Female 20%
Jan 2007 - Dec China
Alcohol 4%
Female 13%
2002
Xue et al. 2009[44]
Selection ****
Female 30%
39yrs
1993
France
Biliary 96%
Male 87%
Jan 1997 – Oct Sun et al. 2004[36]
Outcome ***
Male 70%
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2007[43]
1995[35]
Others 18%
Female 69%
Rokke et al.
Sainio et al.
Comparability **
Male 31%
2006
Norway
Alcohol 33%
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1991
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1993[34]
Male 52% 48yrs Female 48%
ACCEPTED MANUSCRIPT
Study
No. of patients
No. with necrosis,
No. with ICU admission,
Mortality
N (%)
N (%)
N (%)
23 (15%)
14 (9%)
Severity (predicted)
Ranson <3(Mild) 136 156
Ranson 3-5(Mod) 15
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Ranson >5 (Severe) 5
6 (4%)
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Abou-Assi et al. 2002[32]
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Table 2. Severity and Mortality
731
APACHE II 6(4-10)
154 (21%)
168 (23%)
61 (8%)
Dellinger et al. 2007[37]
50
APACHE II 9 (0-39)
41 (82%)
Not reported
9 (18%)
19
APACHE II 14
19 (100%)
Not reported
2 (10%)
66 (39%)
Not reported
20 (12%)
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2009[38]
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Garcia-Barrasa et al.
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Besselink et al. 2009[3]
APACHE II
Garg et al. 2001[39]
169
110 mild 39 severe
Isenmann et al. 2004[33]
56
Ranson 2 (0-7)
35 (63%)
4 (7%)
Kumar et al. 2006[40]
30
APACHE II 10
22 (73%)
Not reported
9 (30%)
Manes et al. 2006[45]
29
CECT Score 5 +/- 2
29 (100%)
Not reported
3 (10%)
McClave et al. 1997[41]
30
APACHE III 19.95
Not reported
Not reported
0 (0%)
Nordback et al. 2001[46]
33
Glasgow Score 3 (1-7)
33 (100%)
Not reported
5 (15%)
Olah et al. 2007[48]
62
Mean Imrie Score 3.0
38 (61%)
Not reported
8 (13%)
Olah et al. 2002[47]
45
Mean Glasgow Score 2.7
20 (44%)
Not reported
3 (7%)
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Not reported
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ACCEPTED MANUSCRIPT
Pederzoli et al. 1993[34]
33
Mean Ranson Score 3.6
33 (100%)
4 (12%)
Qin et al. 2008[42]
74
APACHE II 8.9
Not reported
Not reported
0 (0%)
Rokke et al. 2007[43]
37
APACHE II 6 (1-15)
28 (76%)
7 (19%)
4 (11%)
Sainio et al. 1995[35]
30
Mean Ranson Score 5.7
15 (50%)
Not reported
7 (23%)
Sun et al. 2004[36]
100
Mean Ranson Score 4.6
100 (100%)
Not reported
17 (17%)
Tiengou et al. 2006[49]
30
CRP 33
30 (100%)
Not reported
1 (3%)
Xue et al. 2009[44]
27
APACHE II 11.9
27 (100%)
Not reported
4 (14%)
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Not reported
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ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT Figure 1. Study selection.
1041 papers screened
1002 papers excluded due to only including pancreatic infectious complications, duplicates and not in English language.
20 full-text articles excluded due to being review articles/metaanalyses, a population based study, reporting infections post surgery or using prophylactic antibiotics.
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39 full-text articles assessed for eligibility
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2 additional papers identified on screening references
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1039 papers identified on database searching
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19 studies included in analysis
ACCEPTED MANUSCRIPT Figure 2. Incidence of extra-pancreatic infectious complications across all studies.
0.0641 (0.0312, 0.1147)
Besselink 2009
0.2613 (0.2298, 0.2947)
Dellinger 2007
0.4800 (0.3366, 0.6258)
Garcia-Barrasa 2009
0.5263 (0.2886, 0.7555)
Garg 2001
0.1183 (0.0738, 0.1768)
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Abou-Assi 2002
Isenmann 2004
0.2143 (0.1159, 0.3444)
Kumar 2006
0.2333 (0.0993, 0.4228)
Manes 2006
0.5517 (0.3569, 0.7355)
McClave 1997
0.4000 (0.2266, 0.5940)
0.0606 (0.0074, 0.2023)
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Nordback 2001 Olah 2007
0.1935 (0.1042, 0.3137) 0.2222 (0.1120, 0.3709)
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Olah 2002 Pederzoli 1993 Qin 2008 Rokke 2007 Sainio 1995 Sun 2004
Xue 2009 combined 0.0
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Tiengou 2006
0.2
0.4
0.6
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EP
proportion (95% confidence interval)
0.4848 (0.3080, 0.6646) 0.3919 (0.2804, 0.5123) 0.3243 (0.1801, 0.4979) 1.0000 (0.8843, 1.0000) 0.1800 (0.1103, 0.2695) 0.0333 (0.0008, 0.1722) 0.5556 (0.3533, 0.7452) 0.3179 (0.2293, 0.4137)
0.8
1.0
ACCEPTED MANUSCRIPT Figure 3. Incidence of extra-pancreatic infectious complications in predicted severe pancreatitis.
0.526 (0.289, 0.756)
Isenmann 2004
0.214 (0.116, 0.344)
Kumar 2006
0.233 (0.099, 0.423)
Manes 2006
0.552 (0.357, 0.736)
Nordback 2001
0.061 (0.007, 0.202)
Olah 2007
0.194 (0.104, 0.314)
Pederzoli 1993
0.485 (0.308, 0.665)
Rokke 2007
0.324 (0.180, 0.498)
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Garcia-Barrasa 2009
Sainio 1995
1.000 (0.884, 1.000)
Sun 2004
0.180 (0.110, 0.269) 0.556 (0.353, 0.745)
combined
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Xue 2009
0.395 (0.231, 0.573)
0.0
0.2
0.4
0.6
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proportion (95% confidence interval)
0.8
1.0
ACCEPTED MANUSCRIPT Figure 4. Incidence of extra-pancreatic infectious complications based on proportion of patients with
0.06 (0.03, 0.11)
Besselink 2009
0.26 (0.23, 0.29)
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Abou-Assi 2002
Garg 2001
0.12 (0.07, 0.18)
Olah 2002
0.22 (0.11, 0.37)
Sainio 1995
1.00 (0.88, 1.00)
combined
0.33 (0.14, 0.56)
0.0
0.2
0.4
0.6
0.8
1.0
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0.48 (0.34, 0.63)
Isenmann 2004
Kumar 2006
Olah 2007
0.21 (0.12, 0.34)
0.23 (0.10, 0.42)
0.19 (0.10, 0.31)
Rokke 2007
0.32 (0.18, 0.50)
combined
0.0
0.2
0.4
0.29 (0.19, 0.40)
0.6
0.8
1.0
0.5263 (0.2886, 0.7555)
EP
Garcia-Barrasa 2009
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50 – 99% of patients with necrosis
Dellinger 2007
Manes 2006
0.5517 (0.3569, 0.7355)
Nordback 2001
0.0606 (0.0074, 0.2023)
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100% of patients with necrosis
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Less than 50% of patients with necrosis
pancreatic necrosis.
Pederzoli 1993
0.4848 (0.3080, 0.6646)
Sun 2004
0.1800 (0.1103, 0.2695)
Tiengou 2006
0.0333 (0.0008, 0.1722)
Xue 2009
0.5556 (0.3533, 0.7452)
combined
0.3132 (0.1518, 0.5024) 0.0
0.2
0.4
0.6
proportion (95% confidence interval)
0.8
1.0
S1424-3903(14)00995-8
DOI:
10.1016/j.pan.2014.09.010
Reference:
PAN 320
To appear in:
Pancreatology
Please cite this article as: Brown LA, Hore TA, Phillips AR, Windsor JA, Petrov MS, A systematic review of the extra-pancreatic infectious complications in acute pancreatitis, Pancreatology (2014), doi: 10.1016/j.pan.2014.09.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT A systematic review of the extra-pancreatic infectious complications in acute pancreatitis Authors: Lisa A Brown1, MBChB, [email protected] Todd A Hore1, MBChB, FRACS [email protected]
John A Windsor1, MBChB, MD, FRACS [email protected] Maxim S Petrov1, MD, MPH, PhD [email protected]
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Anthony R J Phillips1, BSc, MBChB, PhD [email protected]
1 The Department of Surgery, The University of Auckland, Auckland, New Zealand
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Corresponding author: Dr Maxim S Petrov Department of Surgery
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The University of Auckland Room 12.092, Level 12 Auckland City Hospital Private Bag 92019
Auckland 1142 New Zealand [email protected]
Fax: +64 09 377 9656
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Short Title:
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Phone: +64 09 373 7999
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Victoria Street West
Extra-pancreatic infection in acute pancreatitis
1
ACCEPTED MANUSCRIPT Abstract Background and Aim: Extra-pancreatic infectious complications in acute pancreatitis increases morbidity and mortality, but their incidence and association with infected pancreatic necrosis is unknown. Half of bacterial cultures of pancreatic necrosis are of non-enteric origin, raising the possibility of other sources of infection. The
pancreatitis, their timing, and relation to severity of pancreatitis and mortality.
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aim of this systematic review was to assess the incidence of extra-pancreatic infectious complications in acute
Methods: A systematic review was performed using Ovid MEDLINE, Embase and Cochrane Libraries,
following PRISMA guidelines. Search terms were “Pancreatitis” AND “Infection” AND (“Complication” OR
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“Outcome”).
Results: 19 studies with 1,741 patients were included. Extra-pancreatic infectious complication incidence was 32% (95% CI 23 - 41%), with the commonest being respiratory infection (9.2%) and bacteraemia (8.4%). Extra-
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pancreatic infectious complications were not associated with the predicted severity or the mortality of acute pancreatitis. Only 3 studies reported a relation of timing between extra-pancreatic and pancreatic infectious complications.
Conclusions: This is the first systematic review to evaluate the incidence of extra-pancreatic infectious complications in acute pancreatitis, which a third of patients with acute pancreatitis will develop. Implications
pancreatic necrosis.
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Keywords:
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are vigilance and prompt treatment of extra-pancreatic infection, to reduce possibility of progression to infected
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Pancreatitis, Infection, Complications, Outcome
2
ACCEPTED MANUSCRIPT Introduction Acute pancreatitis is a complex disease, with an overall mortality rate of 5-10% that may increase up to 30% in the presence of infected necrosis[1, 2]. The main determinants of pancreatitis severity are persistent organ failure and infected (peri)pancreatic necrosis [1]. However, the presence of extra-pancreatic infectious complications (EPIC) in patients with acute pancreatitis has also been shown to influence morbidity and
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mortality [3-5].
The pathogenesis of infection of pancreatic necrosis is currently not completely understood. However, enteric translocation of bacteria by portal blood or mesenteric lymph has been proposed as a possible cause [6, 7]. On
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review of the bacteriology of infected pancreatic necrosis, close to half of the bacteria were not of enteric origin [8]. This suggests that other concurrent infections might be alternative bacterial sources for seeding pancreatic
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infection. The incidence and impact of pancreatic infectious complications has been extensively studied [1], but there has been no systematic study on the incidence and impact of EPIC or its temporal relationship to the development of infected pancreatic necrosis[9, 10].
The aim of this systematic review was to assess the incidence of EPIC in patients with acute pancreatitis, the
pancreatitis and mortality.
Methods
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Literature search
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timing of EPIC and pancreatic infection, and its potential impact on outcome in relation to severity of
An extensive search was performed of Ovid MEDLINE (1946 to present), Embase (1980 to present) and
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Cochrane Libraries. The search terms used were “Pancreatitis” AND “Infection” AND (“Complication” OR “Outcome”). Studies were limited to English language and human studies only. Papers were screened for eligibility by two authors independently (L.B. & T.H.) and any disagreement over study inclusion or exclusion was resolved by a third author (M.S.P.). References were also reviewed and eligible papers sought. Papers were reviewed by date and location. If duplicates were identified, in which two studies reported on an overlapping series of patients over the same time period, the study with the greatest patient catchment was used. The last date of the literature search was 6th September 2013. Any queries related to specific points in papers were resolved by contacting corresponding authors. The method of this systematic review was based on that of the PRISMA Statement[11].
3
ACCEPTED MANUSCRIPT Selection criteria Papers were included that reported the presence of extra-pancreatic infection in patients with acute pancreatitis. Prospective clinical studies (both interventional and observational) were included, but review articles, metaanalyses and population based studies were excluded. Control groups only were included from interventional trials thus all studies were treated as prospective observational. Patients included were over age 15 years.
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Patients whom had recurrent or chronic pancreatitis or were commenced on antibiotics from the day of
admission were excluded. The primary endpoint of the study was the number of patients with a confirmed extra pancreatic infection, with secondary endpoints of site of origin of EPIC, time to onset of infection, pancreatitis
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severity and mortality within this group.
Data extraction
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Data was extracted using a proforma that included baseline clinical characteristics, measures of pancreatitis severity, degree of necrosis, presence and origin of extra pancreatic infection, time to both EPIC and pancreatic infection and mortality rates.
Quality Assessment
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The quality of studies were assessed by the Newcastle-Ottawa Scale [12]. This used three categorical scoring systems of selection (representativeness, exposure determinance), comparability (controlling factors) and outcome (follow-up) to compare studies. A maximum of four ‘stars’ can be awarded for selection, three for
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outcome and two stars for comparability category, with an overall maximal score possible of nine. Follow-up of
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>90% of patients was considered acceptable.
Statistical analysis
Statistical analysis was undertaken using statistical software Stats Direct Version 2.7.9 [13]. A random effects model was used to provide the most conservative estimate. Data extracted from studies were of absolute values from reported individual and group infection rates. Studies were pooled to determine the pooled incidence and corresponding 95% confidence intervals. Subgroup analysis according to the proportion of patients with pancreatic necrosis (<50%, 50-99%, 100%) and mortality (0-5%, 6-10%, >11%) were conducted. Also, a sensitivity analysis constrained to patients with predicted severe acute pancreatitis (as defined within individual
4
ACCEPTED MANUSCRIPT studies as one of either Atlanta criteria[14], Ranson score ≥ 3, CRP > 150, presence of necrosis) were conducted. P-values < 0.05 were deemed significant.
Results Study Identification
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A total of 1041 papers were initially screened, from which 1002 papers were excluded after abstract review. Thirty-nine full text articles were assessed for eligibility (Figure 1), with a further 20 articles excluded because the article was a meta-analysis [15], a population based study [5], only reported infections after surgery [16],
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and because prophylactic antibiotics were used from the time of admission as either a treatment group or as part of a hospital protocol [4, 17-31]. The final analysis included 19 studies.
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Baseline characteristics
Demographics of the studies are shown in Table 1. The 19 studies included a total of 1,741 patients (range 19 – 731) per study. The overall median age of patients was 47 years (range 15 - 91) with a predominance of male patients (2.3 : 1). Alcohol (42%) was the most common cause of acute pancreatitis, followed by gallstones (30%). The quality of the included studies was high with a median total score of 8.6 / 10 (range 8 - 9), using
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The Newcastle-Ottawa Scale, with the breakdown shown in Table 1.
Severity prediction and overall mortality of patients in the included studies
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There was a range of methods used to predict pancreatitis severity including the Ranson score [32-36], APACHE II/III score [3, 37-44], CTSI score [45], Glasgow score [46, 47], Modified Glasgow score [48], and
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CRP [49]. A total of 11 studies only enrolled patients with predicted severe pancreatitis (n = 456) [33-36, 38, 40, 43-46, 48] and six studies only enrolled patients with pancreatic necrosis (n = 696, 40%). The overall median percentage of those patients with infection of pancreatic necrosis was 34% (9-80%). The overall median mortality rate in all included studies was 10% (0 – 30%), in the studies of patients with predicted severe AP it was 13% (7 – 30%), and in studies of patients with necrotizing pancreatitis it was 12% (3 – 30%). Details of severity prediction and mortality are given in Table 2.
5
ACCEPTED MANUSCRIPT Incidence of extra pancreatic infectious complications The overall incidence of EPIC was 32% (95% CI 23 - 41%) from all included studies (Figure 2). The I2 as a test of heterogeneity was performed for the incidence of EPIC, which was 87.2%, thus there is substantial heterogeneity within the studies included. For those studies with only patients with predicted severe pancreatitis the incidence of EPIC was 40% (95% CI 23 - 57%) (Figure 3). The incidence of EPIC was analyzed in relation
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to the proportion of patients within each study whom had the presence of necrosis. In studies with patients with overall <50% necrosis had an incidence of EPIC of 33% (95% CI 13 – 56%), those with 50-99% necrosis had an incidence of 29% (95% CI 19 – 39%), and the incidence was 31% (95% CI 15 – 50%) in those in whom all
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patients had necrotizing pancreatitis (Figure 4). The incidence of EPIC was analyzed in relation to mortality. In studies with a mortality of 0-5% the incidence of EPIC was 26% (95% CI 6 – 53%); in those with mortality of 6-10% the incidence was 28% (95% CI 16 – 41%), and in those with greater than 10% mortality it was 36%
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(95% CI 20 – 55%). When the first two categories were combined, for an incidence of 27% (95% CI 17 – 38%), there was no significant difference (p = 0.54, unpaired T test, df=15).
Type of infection
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The most common EPICs were respiratory infection (9.2%), bacteraemia (8.4%), and urinary tract infection (2.6%). Pancreatic infectious complications (12%) were reported in 13 studies [32, 36, 41-43, 46]. Bacteraemia was recorded directly from the studies, where it was reported as a specific group with the term “bacteraemia”.
symptoms.
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The definition in the studies, if outlined, was due to the presence of a positive blood culture +/- clinical
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The causative organisms of EPIC alone were not separately recorded as this was only reported in two of the 19 studies. Two studies reported the presence of the same bacterial culture in both pancreatic necrosis and EPIC. Besselink et al [3] reported that 31 of 51 patients had the same bacterial culture from both sources (necrosis and bacteraemia), and Dellinger et al [37] reported that 3 of 50 patients had the same culture from both EIC (bloodstream, urinary, respiratory tract infection) and pancreatic necrosis. This included both control group and treatment patients whom were on prophylactic antibiotics.
6
ACCEPTED MANUSCRIPT Timing of infection Three studies reported a relation of timing between extra pancreatic infection and pancreatic infection. Besselink et al [3] reported that previous bacteraemia in patients with parenchymal necrosis had an increased risk of developing infected necrosis (P=0.002). Dellinger et al [37] found that 13/15 (87%) patients with
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pancreatic infection had an extra pancreatic infection, in five (38%) the EPIC occurred first between 2-28 days prior to the pancreatic infection. In three (23%) patients the pancreatic infection occurred first, 2-12 days before the EPIC.
Two studies, including 781 patients [3, 37], reported time to diagnosis of EPIC with a weighted mean time of
SC
47.3 days. Four studies [33, 35, 38, 45] reported a time to diagnosis of an unspecified infection (pancreatic or extra-pancreatic) with weighted mean time of 22.9 days, with one study[43] reporting that 14/37 patients were
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diagnosed in week 1, with 2/37 patients diagnosed in week 2. Four studies[3, 34, 37, 45], including 843 patients, reported time to diagnosis of pancreatic infectious complication alone, with weighted mean time of 55.1 days reported in two studies (n= 781 patients) [3, 37]. Pederzoli et al [34] reported diagnosis of pancreatic infection was made within 1-3 weeks and Manes et al [45] reported 4/9 patients developed a pancreatic infection
Discussion
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in the second week, 3/9 in the third week, and 2/9 in the fourth week.
EP
This is the first systematic review to evaluate the incidence of EPIC in acute pancreatitis, to investigate the timing of EPIC and pancreatic infection, and the relation of EPIC to severity of pancreatitis and mortality. It has
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shown that EPIC is common, with an overall incidence of 32% and does not appear to be related to the predicted severity or the mortality of acute pancreatitis. An association between the EPIC and pancreatic infectious complications has been suggested by some studies [3, 4], with pancreatic infection known as a determinant of mortality in patients with acute pancreatitis.
There are several factors which may promote EPICs in patients with acute pancreatitis including lengthy hospital stays, admission to high dependency or intensive care units, multiple interventions and insertion of foreign materials such as central lines, tracheal tubes, catheters or feeding tubes [5]. Respiratory infection and bacteraemia are the most common EPICs. The predominance of respiratory infection has been corroborated in other large-scale studies evaluating the rate of infectious complications after elective surgery and in studies
7
ACCEPTED MANUSCRIPT within the intensive care environment [50]. The predominance of respiratory infections could be related to the proportion of patients within an intensive care environment on respiratory support. Of the 19 studies reviewed, three [4, 14, 27] reported that a median of 17% (range 11-23) were admitted to an intensive care unit (ICU). Xue et al [5] found that those patients with infection (both pancreatic and extra-pancreatic) were more likely to be on respiratory support (34.1% vs 12.5%, P < 0.05) than those without infection [5]. Murine studies have
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demonstrated that the concurrent pneumonia resulted in prolonged, more severe, episodes of pancreatitis [51]. However, Besselink et al [3] found that prior diagnosis of pneumonia did not significantly increase risk of
SC
infection of pancreatic necrosis (57% vs 42.9%, p = 0.147).
Given that a third of patients develop EPIC and that it can promote infected pancreatic necrosis, preventative strategies should be considered. The role of prophylactic antibiotics has been extensively studied, but not
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specifically in those patients at particular risk of EPIC, including those within the intensive care environment, or whom have insertion of tubes, lines and catheters. We excluded all patients whom were commenced on prophylactic antibiotics in this study and only control groups, not on antibiotics, were included from antibiotic intervention studies. A randomized controlled trial by Manes et al [45], comparing the timing of antibiotic use with Meropenem in acute pancreatitis, found that fewer patients developed an EPIC when they had been
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commenced on antibiotics upon admission (n = 5), compared to those commenced on antibiotics upon confirmation of necrosis (n = 13, p<0.03). A recent Cochrane Review [2] found that the prophylactic use of antibiotic therapy did not significantly reduce the occurrence of pancreatic or EPIC. However, the studies were
EP
generally poorly powered, with 5 of the 7 studies including rates of EPIC.
AC C
Another strategy to reduce the incidence of EPIC is the use of enteral feeding which has been shown in a recent meta-analysis [52] to reduce the occurrence of all infections (EPIC and pancreatic) and catheter related septic complications though it must be acknowledged that the comparator has been parenteral feeding or delayed enteral feeding, not no feeding. Anyway, based on the best available studies, the maximum benefits of enteral feeding are seen when administered in 24-48 hours but not within the first 24 hours [53-55]. The earlier observation that there is a reduction in the early incidence, but not overall incidence, of infections in acute pancreatitis [9] raises the questions about when to start enteral feeding, what to give, and when to stop it.
8
ACCEPTED MANUSCRIPT If a cause-effect relationship is to be established then it is necessary to prove that EPIC precedes infection of pancreatic necrosis [9]. This is made difficult by a possible difference between the actual time of onset and any delay in reporting these clinical events. There is suggestion that the time to the onset of infected necrosis appears to be later than the development of EPIC in a study which investigated the cause and timing of fever in 75 patients with acute pancreatitis [56]. They found that the majority of patients with fever (37/45, 82%) did not
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have infected pancreatic necrosis and (17/45, 38%) had extra-pancreatic infection. Of those patients with infected necrosis, fever was seen in the 2nd or 3rd week of admission, compared to those with EPIC who
SC
developed fever earlier, in the 1st or 2nd week of the illness.
Two studies [3, 37] included in this systematic review reported that the weighted mean time to diagnosis of EPIC was 47.3 days, compared to the time to the diagnosis of pancreatic infection at a weighted mean time of
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55.1 days. Two further studies [34, 45] reported an association between EPIC and infected necrosis. In a retrospective study [18], excluded from this systematic review because of the use of prophylactic antibiotics, found that EPIC occurred in a cohort of 212 patients at a median of 4 days and prior to infection of pancreatic necrosis. Another excluded study [5] of 11,046 patients found that the onset of pneumonia (median 10.7 ± 2.5 days), bacteraemia (13.7 ± 1.5 days) and gastrointestinal tract infection (16.8 ± 3.9 days) occurred before the
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infection of necrosis (17.6 ± 2.9 days). It appears that patients are more likely to have both infection of necrosis and EIC combined, than EPIC alone with Manes et al [45] reporting that 10/13 (77%) patients with pancreatic infection developed an EPIC, compared with 9/46 (20%) patients without pancreatic infection that developed an
EP
EPIC (p < 0.001).
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This more typical temporal pattern, of EPIC developing before infected pancreatic necrosis, leads to the hypothesis that EPICs may seed pancreatic infection, but this is by no means proven. It might also be that the different mechanisms of infection might account for earlier EPIC and be quite unrelated to onset of pancreatic infection. Further research is required to determine the extent to which EPICs are responsible for infection of the pancreas.
Two factors that might be related to the role of EPIC in infection of necrosis are immunosuppression [57, 58] and gut barrier dysfunction [6, 59], both of which are features of early acute pancreatitis. The immunosuppression might predispose to EPIC and early onset. The gut barrier dysfunction promotes the
9
ACCEPTED MANUSCRIPT translocation of bacteria from gut lumen to pancreatic necrosis, by a number of different potential routes including portal venous blood and mesenteric lymph [7, 60]. However the bacteriology of infected pancreatic necrosis and extra-pancreatic sites indicate that around half of the organisms are not of enteric origin [8].
Other evidence supporting a role for EPIC in promoting pancreatic infection might be derived from bacteriology
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studies, but this systematic review did not primarily evaluate this as an endpoint. The predominant infecting organisms cultured from EPIC and pancreatic infections on review of the included papers were common
intestinal gram negative bacteria and staphylococcus which is in accordance with previous studies evaluating the
SC
microbiology of pancreatic infections [61]. It has been found that staphylococcal infections are more common following antibiotic therapy [62], which may partly explain the frequency of staphylococci found in the included studies. To further explore the potential causal link between the bacteriology of EPIC and pancreatic infections
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will require improved documentation, including typing of different strains, in future studies. Unfortunately, the current reporting of the presence, timing and bacteriology of EPIC in acute pancreatitis is extremely poor. Many authors have not deemed this an important point to report on and this may be due to poor recording of this initially in clinical notes. This needs to be a fundamental data point to be collected in the future.
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Thus the main limitation of the study is the lack of endpoint priority given to EPIC in the published literature, which prohibits a definitive determination of whether EPIC promote pancreatic infections. Because prophylactic antibiotics would confound the incidence of EPIC, studies that used them were excluded. The
EP
incidence of EPIC when prophylactic antibiotics are used has not been examined in this study. Because EPIC was not the primary endpoint in the included studies, there is a risk of bias, including selection and incomplete
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outcome reporting. The lack of published bacteriological data in most of the studies is a reason for why it is not possible to determine whether the bacteraemia is a primary EPIC or secondary to infected pancreatic necrosis. There was statistical heterogeneity in relation to the primary endpoint. However, the inferences remain unchanged after pre-specified subgroup and sensitivity analyses. This study includes a high proportion of patients with severe pancreatitis, reflecting the search strategy, and may not be representative of all patients with acute pancreatitis.
In conclusion, this systematic review has found that 32% of patients with acute pancreatitis develop an EPIC during hospitalization. There is currently a lack of recording of the presence, timing and bacteriology of EPIC
10
ACCEPTED MANUSCRIPT in acute pancreatitis in the literature. The presence of non-enteric bacteria in pancreatic infection and, in general, the earlier onset of EPIC, suggests a possible causal role in seeding pancreatic infection, but this is not yet proven. The clinical implication of this, if proven by further studies with detailed bacteriology, is that vigilance for early diagnosis and prompt treatment of EPIC may reduce the likelihood of subsequent infection of
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EP
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pancreatic necrosis.
11
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Abou-Assi S, Craig K, O'Keefe SJD. Hypocaloric jejunal feeding is better than total parenteral
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Sainio V, Kemppainen E, Puolakkainen P, et al. Early antibiotic treatment in acute necrotising
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Ciprofloxacin prophylaxis in patients with acute necrotizing pancreatitis. J Gastrointest Surg. 2009;13:768-74. 39.
Garg PK, Khanna S, Bohidar NP, et al. Incidence, spectrum and antibiotic sensitivity pattern of
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ACCEPTED MANUSCRIPT 52.
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bacterial infections complicating severe acute pancreatitis. Chirurgia. 2011;106(6):743-52. Behrman SW, Bahr MH, Dickson PV, et al. The microbiology of secondary and postoperative
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Acknowledgements:
Lisa Brown was funded for her research during the time of performing this study by the Health Research Council of New Zealand and The Royal Australasian College of Surgeons.
Disclosure statement: There are no conflicts of interest to disclose.
16
ACCEPTED MANUSCRIPT
No. of
Gender patients
Abou-Assi et al.
Jan 2000 – 156 Dec 2000
Besselink et al.
(21-91)
March 2004 - March Netherlands
731 2007
Dellinger et al.
North America &
Feb 2003 –
2007[37]
Europe
Dec 2004
Garcia-Barrasa et
May 1999 – Spain
Garg et al.
Jan 1997 – India
2001[39]
Isenmann et al.
Germany
Male 55%
(42-71)
Female 45%
50yrs
Male 76%
(18-84)
Female 24%
67 yrs
Male 79%
(38-79)
Female 21%
41yrs
Male 69%
(15-80)
Female 31%
169
June 2000
Jan 1999 –
56
46yrs
(Newcastle-Ottawa)
Biliary 18%
Selection ***
Alcohol 62%
Comparability **
Other 16%
Outcome ***
Biliary 54%
Selection ****
Alcohol 18%
Comparability **
Other 28%
Outcome ***
Biliary 24%
Selection ****
Alcohol 52%
Comparability **
Other 24%
Outcome **
Biliary 58%
Selection ****
Alcohol 26%
Comparability **
Other 16%
Outcome ***
Biliary 49%
Selection ****
Alcohol 24%
Comparability **
Other 27%
Outcome ***
Biliary 16%
Selection ****
Female 36%
19
Dec 2003
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al. 2009[38]
EP
50
Quality Assessment Scale
Aetiology
Male 64%
58yrs
TE D
2009[3]
Mean (range)
46yrs
United States 2002[32]
Age
Years of study
SC
Setting
M AN U
Study
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Table 1. Study Characteristics
Male 79%
ACCEPTED MANUSCRIPT
Kumar et al.
(22– 78)
Sep 2002 – India
2006[40]
30
39yrs
Italy
57yrs 29
Other 24%
Outcome ***
Biliary 37%
Selection ***
Alcohol 27%
Comparability **
Other 36%
Outcome ***
Biliary 55%
Selection ****
(38-74)
Alcohol 21%
Comparability **
Other 24%
Outcome ***
Male 62%
Female 38%
M AN U
Nov 2005
McClave et al.
Selection ****
Male 75%
United States
Not reported
30
46yrs
Alcohol 69%
Comparability **
Female 25%
Nordback et al.
Sep 1995 – Finland
33 May 1999
Olah et al.
July 2001 – Hungary
Olah et al. Hungary
45
2001
Italy
Biliary 6%
Selection ***
Alcohol 76%
Comparability **
Other 18%
Outcome ***
Male 85%
46 yrs
Female 15%
Selection ***
47 yrs
Male 84%
Alcohol 58%
(19-81)
Female 16%
Other 42%
Comparability ** Outcome*** Selection ***
Jan 1999 - March
2002[47]
Outcome ***
62
July 2004
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2007[48]
EP
2001[46]
TE D
1997[41]
Pederzoli et al.
Comparability **
Female 17%
Jan 2002 –
2006[45]
Alcohol 60%
Male 83%
Dec 2003
Manes et al.
Female 21%
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June 2002
SC
2004[33]
Jan 1989 - July
33
Male 73%
Alcohol 64%
Female 27%
Other 36%
45yrs
Comparability ** Outcome ***
50 yrs
Male 61%
Biliary 49%
Selection ****
ACCEPTED MANUSCRIPT
Female 39%
Feb 2002 - March Qin et al. 2008[42]
China
74
56 yrs
57 yrs 1997 - 2002
37 (29-84)
July 1989 - Nov Finland
30
47yrs
Male 56%
(17-82)
Female 44%
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China
100
One year period
30
AC C
2006[49]
EP
Tiengou et al.
27
2007
Comparability ** Outcome ***
Biliary 46%
Selection ****
Alcohol 27%
Comparability **
Other 27%
Outcome *** Selection ****
Alcohol 100%
Comparability ** Outcome *** Selection ****
Not reported
Comparability ** Outcome ***
Biliary 17%
Selection ***
Alcohol 73%
Comparability **
Other 10%
Outcome ***
Biliary 54%
Selection ***
Alcohol 8%
Comparability **
Other 38%
Outcome ***
Male 80% 46 yrs Female 20%
Jan 2007 - Dec China
Alcohol 4%
Female 13%
2002
Xue et al. 2009[44]
Selection ****
Female 30%
39yrs
1993
France
Biliary 96%
Male 87%
Jan 1997 – Oct Sun et al. 2004[36]
Outcome ***
Male 70%
M AN U
2007[43]
1995[35]
Others 18%
Female 69%
Rokke et al.
Sainio et al.
Comparability **
Male 31%
2006
Norway
Alcohol 33%
RI PT
1991
SC
1993[34]
Male 52% 48yrs Female 48%
ACCEPTED MANUSCRIPT
Study
No. of patients
No. with necrosis,
No. with ICU admission,
Mortality
N (%)
N (%)
N (%)
23 (15%)
14 (9%)
Severity (predicted)
Ranson <3(Mild) 136 156
Ranson 3-5(Mod) 15
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Ranson >5 (Severe) 5
6 (4%)
SC
Abou-Assi et al. 2002[32]
RI PT
Table 2. Severity and Mortality
731
APACHE II 6(4-10)
154 (21%)
168 (23%)
61 (8%)
Dellinger et al. 2007[37]
50
APACHE II 9 (0-39)
41 (82%)
Not reported
9 (18%)
19
APACHE II 14
19 (100%)
Not reported
2 (10%)
66 (39%)
Not reported
20 (12%)
EP
2009[38]
AC C
Garcia-Barrasa et al.
TE D
Besselink et al. 2009[3]
APACHE II
Garg et al. 2001[39]
169
110 mild 39 severe
Isenmann et al. 2004[33]
56
Ranson 2 (0-7)
35 (63%)
4 (7%)
Kumar et al. 2006[40]
30
APACHE II 10
22 (73%)
Not reported
9 (30%)
Manes et al. 2006[45]
29
CECT Score 5 +/- 2
29 (100%)
Not reported
3 (10%)
McClave et al. 1997[41]
30
APACHE III 19.95
Not reported
Not reported
0 (0%)
Nordback et al. 2001[46]
33
Glasgow Score 3 (1-7)
33 (100%)
Not reported
5 (15%)
Olah et al. 2007[48]
62
Mean Imrie Score 3.0
38 (61%)
Not reported
8 (13%)
Olah et al. 2002[47]
45
Mean Glasgow Score 2.7
20 (44%)
Not reported
3 (7%)
AC C
EP
TE D
M AN U
RI PT
Not reported
SC
ACCEPTED MANUSCRIPT
Pederzoli et al. 1993[34]
33
Mean Ranson Score 3.6
33 (100%)
4 (12%)
Qin et al. 2008[42]
74
APACHE II 8.9
Not reported
Not reported
0 (0%)
Rokke et al. 2007[43]
37
APACHE II 6 (1-15)
28 (76%)
7 (19%)
4 (11%)
Sainio et al. 1995[35]
30
Mean Ranson Score 5.7
15 (50%)
Not reported
7 (23%)
Sun et al. 2004[36]
100
Mean Ranson Score 4.6
100 (100%)
Not reported
17 (17%)
Tiengou et al. 2006[49]
30
CRP 33
30 (100%)
Not reported
1 (3%)
Xue et al. 2009[44]
27
APACHE II 11.9
27 (100%)
Not reported
4 (14%)
AC C
EP
TE D
M AN U
RI PT
Not reported
SC
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT Figure 1. Study selection.
1041 papers screened
1002 papers excluded due to only including pancreatic infectious complications, duplicates and not in English language.
20 full-text articles excluded due to being review articles/metaanalyses, a population based study, reporting infections post surgery or using prophylactic antibiotics.
M AN U
39 full-text articles assessed for eligibility
RI PT
2 additional papers identified on screening references
SC
1039 papers identified on database searching
AC C
EP
TE D
19 studies included in analysis
ACCEPTED MANUSCRIPT Figure 2. Incidence of extra-pancreatic infectious complications across all studies.
0.0641 (0.0312, 0.1147)
Besselink 2009
0.2613 (0.2298, 0.2947)
Dellinger 2007
0.4800 (0.3366, 0.6258)
Garcia-Barrasa 2009
0.5263 (0.2886, 0.7555)
Garg 2001
0.1183 (0.0738, 0.1768)
RI PT
Abou-Assi 2002
Isenmann 2004
0.2143 (0.1159, 0.3444)
Kumar 2006
0.2333 (0.0993, 0.4228)
Manes 2006
0.5517 (0.3569, 0.7355)
McClave 1997
0.4000 (0.2266, 0.5940)
0.0606 (0.0074, 0.2023)
SC
Nordback 2001 Olah 2007
0.1935 (0.1042, 0.3137) 0.2222 (0.1120, 0.3709)
M AN U
Olah 2002 Pederzoli 1993 Qin 2008 Rokke 2007 Sainio 1995 Sun 2004
Xue 2009 combined 0.0
TE D
Tiengou 2006
0.2
0.4
0.6
AC C
EP
proportion (95% confidence interval)
0.4848 (0.3080, 0.6646) 0.3919 (0.2804, 0.5123) 0.3243 (0.1801, 0.4979) 1.0000 (0.8843, 1.0000) 0.1800 (0.1103, 0.2695) 0.0333 (0.0008, 0.1722) 0.5556 (0.3533, 0.7452) 0.3179 (0.2293, 0.4137)
0.8
1.0
ACCEPTED MANUSCRIPT Figure 3. Incidence of extra-pancreatic infectious complications in predicted severe pancreatitis.
0.526 (0.289, 0.756)
Isenmann 2004
0.214 (0.116, 0.344)
Kumar 2006
0.233 (0.099, 0.423)
Manes 2006
0.552 (0.357, 0.736)
Nordback 2001
0.061 (0.007, 0.202)
Olah 2007
0.194 (0.104, 0.314)
Pederzoli 1993
0.485 (0.308, 0.665)
Rokke 2007
0.324 (0.180, 0.498)
SC
RI PT
Garcia-Barrasa 2009
Sainio 1995
1.000 (0.884, 1.000)
Sun 2004
0.180 (0.110, 0.269) 0.556 (0.353, 0.745)
combined
M AN U
Xue 2009
0.395 (0.231, 0.573)
0.0
0.2
0.4
0.6
AC C
EP
TE D
proportion (95% confidence interval)
0.8
1.0
ACCEPTED MANUSCRIPT Figure 4. Incidence of extra-pancreatic infectious complications based on proportion of patients with
0.06 (0.03, 0.11)
Besselink 2009
0.26 (0.23, 0.29)
RI PT
Abou-Assi 2002
Garg 2001
0.12 (0.07, 0.18)
Olah 2002
0.22 (0.11, 0.37)
Sainio 1995
1.00 (0.88, 1.00)
combined
0.33 (0.14, 0.56)
0.0
0.2
0.4
0.6
0.8
1.0
M AN U
0.48 (0.34, 0.63)
Isenmann 2004
Kumar 2006
Olah 2007
0.21 (0.12, 0.34)
0.23 (0.10, 0.42)
0.19 (0.10, 0.31)
Rokke 2007
0.32 (0.18, 0.50)
combined
0.0
0.2
0.4
0.29 (0.19, 0.40)
0.6
0.8
1.0
0.5263 (0.2886, 0.7555)
EP
Garcia-Barrasa 2009
TE D
50 – 99% of patients with necrosis
Dellinger 2007
Manes 2006
0.5517 (0.3569, 0.7355)
Nordback 2001
0.0606 (0.0074, 0.2023)
AC C
100% of patients with necrosis
SC
Less than 50% of patients with necrosis
pancreatic necrosis.
Pederzoli 1993
0.4848 (0.3080, 0.6646)
Sun 2004
0.1800 (0.1103, 0.2695)
Tiengou 2006
0.0333 (0.0008, 0.1722)
Xue 2009
0.5556 (0.3533, 0.7452)
combined
0.3132 (0.1518, 0.5024) 0.0
0.2
0.4
0.6
proportion (95% confidence interval)
0.8
1.0