Gastroenterology
Volume 139, Issue 3 , Pages 813-820, September 2010

Organ Failure and Infection of Pancreatic Necrosis as Determinants of Mortality in Patients With Acute Pancreatitis

Department of Surgery, The University of Auckland, Auckland, New Zealand

Received 21 January 2010; accepted 3 June 2010. published online 10 June 2010.

Article Outline

Background & Aims

There is no consistency between the individual studies in the literature on whether organ failure (OF) or infected pancreatic necrosis (IPN) is the main determinant of severity in acute pancreatitis. We aimed to statistically aggregate the available data and determine the pooled influence of OF and IPN on mortality in patients with acute pancreatitis.

Methods

The search for relevant observational studies was undertaken in the MEDLINE, EMBASE, and Scopus electronic databases, as well as in the proceedings of major gastroenterology meetings. The summary estimates are presented as relative risk (RR) and 95% confidence interval (CI).

Results

Fourteen studies comprising 1478 patients with acute pancreatitis were meta-analyzed. A total of 600 patients developed OF and 179 of them died (mortality, 30%); 314 patients developed IPN and 102 of them died (mortality, 32%). In a stratified analysis, patients with OF and IPN had a significantly higher risk of death in comparison with patients with OF and no IPN (RR = 1.94; 95% CI: 1.32−2.85; P = .0007) and in comparison with patients with IPN and no OF (RR = 2.65; 95% CI: 1.30−5.40; P = .0007).

Conclusions

In patients with acute pancreatitis, the absolute influence of OF and IPN on mortality is comparable and thus the presence of either indicates severe disease. The relative risk of mortality doubles when OF and IPN are both present and indicates extremely severe disease or critical acute pancreatitis.

Keywords: Acute Pancreatitis, Organ Failure, Pancreatic Infection, Mortality

Abbreviations used in this paper: CI, confidence interval, IPN, infected pancreatic necrosis, OF, organ failure, RR, relative risk

 

Acute pancreatitis is a protean disease that varies locally from mild pancreatic edema and inflammation to extensive infected pancreatic and peripancreatic necrosis, and systemically from a mild hypoxemia to multiple organ failure. Determinants of disease severity in acute pancreatitis continue to be the subject of debate. Fitz, at the end of 19th century, believed that pancreatic hemorrhage and disseminated fat necrosis were the determinants of severity.1 A century later, the Atlanta classification stated that the presence of local pancreatic complications and extrapancreatic organ failure (OF) were the determinants of severity.2 More recently, it has been postulated that OF is the key determinant of severity regardless of the presence or absence of local pancreatic complications.3, 4, 5, 6

It has also been appreciated that local pancreatic complications, such as fluid collections, pseudocysts, and necrosis, are not all equal contributors to disease severity. The widespread introduction of fine-needle aspiration of pancreatic tissue has helped to highlight the importance of pancreatic infection, particularly infected pancreatic necrosis (IPN), as a key determinant of disease severity.7, 8, 9 However, studies that have examined the relationship between pancreatic infection and mortality are not all in agreement. Some have demonstrated a strong association between the infection status of pancreatic necrosis and mortality,10, 11, 12 while others have failed to do so.13, 14, 15 There may be a number of legitimate reasons for the lack of accord between these studies, including heterogeneous study population of patients with and without OF and small sample size of the studies.

The aim of this study was to conduct a meta-analysis of published clinical studies to determine the influence of OF and IPN, both individually and combined, on the mortality in patients with acute pancreatitis.

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Methods 

Study Identification 

Relevant publications were identified using electronic databases (MEDLINE, Scopus, and EMBASE) to search for studies published between January 1, 1993 (when the current Atlanta classification became available), and August 1, 2009, with no geographic or language restrictions. The search terms used were acute pancreatitis, organ failure, and infection. The search was limited to human adults. The references cited in published original and review articles were searched to identify additional studies. An additional manual search was done using the abstracts of major gastroenterological meetings (Digestive Disease Week and United European Gastroenterology Week) from 2005 to 2009.

Study Selection Criteria 

To be included, studies had to meet the following criteria:

1.Design: prospective and retrospective cohort studies

2.Population: patients with acute pancreatitis

3.Exposure:

a. IPN vs no IPN in patients with OF; IPN had to be confirmed by a positive culture result from fine-needle aspiration, swab at the time of surgery, or culture from the removed necrosis

b. OF vs no OF (as defined by the authors of the primary studies) in patients with IPN

c. OF without IPN vs IPN without OF in patients with acute pancreatitis


4.Outcome: in-hospital mortality.

Wherever multiple publications of the same study population were available, the publication with the most complete and relevant set of data was chosen. Studies that assessed a specific prophylaxis or treatment were excluded.

Data Abstraction 

Full-text articles of the studies that met all the inclusion criteria were retrieved. Qualitative and quantitative information was abstracted independently by 2 reviewers (M.S.P., S.S.) using a standardized data collection form. Inconsistencies were resolved through discussion until a consensus was reached. Authors of studies published on acute pancreatitis that mentioned pancreatic infection or OF but did not provide data were contacted to request the data necessary to include them in the meta-analysis. All non-English articles have been translated by native speakers who are experienced gastroenterologists or surgeons.

Quality Assessment 

Methodological quality was assessed independently by 2 reviewers (M.S.P., M.C.) using the Newcastle-Ottawa Scale.16 A quality score was calculated on the basis of the following components: selection of the study groups (0–4 points), quality of the adjustment for confounding (0–2 points), and ascertainment of the outcomes of interest in the cohort (0–3 points). A higher score represented better methodological quality.

Statistical Analysis 

Relative risk (RR) of in-hospital mortality was used as the primary effect estimate in this meta-analysis. From the eligible studies that met the inclusion criteria, estimates of RR and its associated 95% confidence interval (CI) were calculated using the Review Manager software (Version 5.0 for Windows, Copenhagen, Denmark; The Nordic Cochrane Centre, The Cochrane Collaboration, 2008). Data that could not be obtained directly were reconstructed independently by two reviewers (M.S.P., S.S.) when necessary.

Prespecified subgroup analyses were performed according to the number of failed organs (single vs multiple), definition of OF (according to the Atlanta classification vs others), indications for surgery (IPN only vs others), year of publication (before 2007 vs in or after 2007), study type (prospective vs retrospective cohorts), study countries (North America and Western Europe vs other countries), and language of publication (English vs non-English). Besides, prespecified sensitivity analysis constrained to patients with pancreatic necrosis only (confirmed by computed tomography) was conducted.

The between-study heterogeneity was appraised using the Q measure for statistical significance and the I2 measure for the amount of heterogeneity, with P < .10 being statistically significant and I2 >25% showing important heterogeneity. If there was no heterogeneity, a fixed effects model based on the Mantel and Haenszel estimator was used; otherwise, a random effect model based on the DerSimonian and Laird estimator was used.17 To assess the potential for publication bias, we performed the Begg's test and the Harbord's modified test for small-study effect, with P < .05 being statistically significant.18 The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines19 were used to report the results of this study.

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Results 

Study Characteristics and Methodological Quality 

From the initial literature search, we identified and screened 513 abstracts (Figure 1). Sixty-one articles were considered of potential value and the full text was retrieved for detailed evaluation. Forty-seven of these 61 articles were subsequently excluded from the meta-analysis (42 did not satisfy inclusion criteria, 5 were based on the same study populations). Fourteen original reports (9 prospective and 5 retrospective cohort studies) provided data to investigate the influence of OF and infection status of pancreatic necrosis on mortality.20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 The included studies were published between 1997 and 2009 (Table 1). Seven studies were conducted in Europe, 3 in North America, 2 in Asia, and 2 in Central and Latin America. Eleven were written in English, 1 in Russian, 1 in Spanish, and 1 in Turkish. Table 2 displays the methodological quality of the included studies.

Table 1. Characteristics of the Included Studies
Study first author, yearSettingStudy designTotal no. of patientsPatients with organ failurePatients with infected pancreatic necrosisOverall mortality
n%n%n%
Tenner, 199720USARetrospective512651183548
Büchler, 200021SwitzerlandProspective2047436291494
Le Mée, 200122FranceProspective434310027631023
Perez, 200223USARetrospective99515237371414
Garg, 200524IndiaProspective104373630292423
Remes-Troche, 200625MexicoRetrospective165493014885
Tireli, 200626TurkeyProspective3814371334924
Rau, 200727EuropeaProspective1046865171688
Sharma, 200729IndiaProspective282943357205720
Lutfarakhmanov, 200728RussiaProspective72395426361724
Lytras, 200830GreeceProspective6433521727914
Rocha, 200931IndiaRetrospective64365615231016
Pellegrini, 200932ArgentinaRetrospective9712124444
Radenkovich, 200933SerbiaProspective912426101189
Overall 1478600403142119113

aInternational multicenter trial from Germany, Finland, Switzerland, and Italy.

Table 2. Quality Assessment of Included Studies Based on the Newcastle-Ottawa Scale
Study first author, yearSelectionComparabilityOutcome
Tenner, 199720403
Büchler, 200021403
Le Mée, 200122403
Perez, 200223403
Garg, 200524423
Remes-Troche, 200625413
Tireli, 200626403
Rau, 200727403
Sharma, 200729423
Lutfarakhmanov, 200728413
Lytras, 200830423
Rocha, 200931403
Pellegrini, 200932403
Radenkovich, 200933403

Publication Bias Assessment 

There was no statistical evidence of publication bias among the included studies by using Begg's test (P = .27) and Harbord's test (P = .35).

Overall Patient Characteristics 

The 14 studies encompassed a total of 1478 patients with acute pancreatitis, including 876 patients with confirmed pancreatic necrosis.20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 The prevalence of OF was 40% (600 of 1478 patients) and prevalence of IPN was 21% (314 of 1478 patients) (Table 1). Overall mortality was 13% (191 of 1478 patients), of which 30% (179 of 600 patients) were in all patients with OF, regardless of the presence or absence of IPN, and 32% (102 of 314 patients) in all patients with IPN, regardless of the presence or absence of OF.

Influence of Pancreatic Infection on Mortality in Patients With OF 

The 14 studies provided data for determining the relationship between presence or absence of pancreatic infection and mortality in patients with OF.20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 Mortality was 43% (92 of 213) in patients with OF and confirmed IPN, as opposed to only 22% (87 of 387) in those with OF and no IPN. The presence of IPN was associated with a significantly increased risk of death in patients with OF (RR = 1.94; 95% CI: 1.32−2.85; P = .0007) (Figure 2). A significant heterogeneity was observed (P = .02; I2 = 48%). This heterogeneity was eliminated when a prespecified sensitivity analysis of only patients with confirmed pancreatic necrosis was conducted (P = .50; I2 = 0). Infected, when compared with sterile, pancreatic necrosis was associated with a significantly increased risk of death (RR = 1.84; 95% CI: 1.40−2.41; P < .0001).

  • View full-size image.
  • Figure 2. 

    Forest plot for mortality associated with infected pancreatic necrosis (IPN) compared with no IPN in patients with organ failure (OF). CI, confidence interval.

The pooled estimate was remarkably robust: omission of a primary study resulted in the range of RR between 1.72 (95% CI: 1.31−2.26), after omission of the study by Lytras et al30 and 1.99 (95% CI: 1.48−2.68), after omission of the study by Lutfarakhmanov et al.28 In the prespecified subgroup analyses, the effect did not appear to depend on the number of failed distant organs, definition of OF, indications for surgery, type of study, year of publication, and study setting (data not shown). At the same time, when stratifying for language of publication, risk estimate was only statistically significant in articles published in English as opposed to non-English language (data not shown).

Influence of OF on Mortality in Patients With IPN 

Ten studies provided data for determining the relationship between the presence or absence of OF and mortality in patients with IPN.20, 21, 23, 24, 25, 26, 27, 29, 30, 31 Mortality was 11% (10 of 93) in patients with confirmed IPN but no OF. Figure 3 shows the Forest plot with the pooled estimate for risk of death in patients with IPN and OF compared with those with IPN and no OF. The OF group was associated with a significantly increased risk of death (RR = 2.65; 95% CI: 1.30−5.40; P = .0007). A minimal heterogeneity was observed (I2 = 35%). The pooled estimate was robust: omission of a primary study resulted in the range of RR between 2.26 (95% CI: 1.17−4.37) after omission of the study by Garg et al24 and 3.22 (95% CI: 1.23−8.41) after omission of the study by Sharma et al.29 The prespecified subgroup analyses did not reveal a statistically significant difference between the risk estimates (data not shown).

  • View full-size image.
  • Figure 3. 

    Forest plot for mortality associated with organ failure (OF) compared with no OF in patients with infected pancreatic necrosis (IPN). CI, confidence interval.

Influence of OF vs Pancreatic Infection on Mortality in Patients With Acute Pancreatitis 

Ten studies provided data to compare mortality of patients with OF and no IPN vs those with IPN and no OF.20, 21, 23, 24, 25, 26, 27, 29, 30, 31 Figure 4 shows the Forest plot with no statistically significant difference in risk of death between these 2 groups (RR = 1.44; 95% CI: 0.53−3.93). A moderate heterogeneity was observed (I2 = 51%). Sensitivity analysis constrained to patients with confirmed pancreatic necrosis also did not reveal a significant difference between the groups (RR = 1.66; 95% CI: 0.68−4.04). The prespecified subgroup analyses did not show a statistically significant difference between the risk estimates (data not shown).

  • View full-size image.
  • Figure 4. 

    Forest plot for mortality associated with organ failure (OF) without infected pancreatic necrosis (IPN), compared with that of IPN without OF, in patients with acute pancreatitis. CI, confidence interval.

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Discussion 

This is the first study to have specifically investigated the influence of OF and IPN, both individually and combined, on the mortality of patients with acute pancreatitis. It was found that the presence of OF, regardless of the presence or absence of IPN, led to mortality in 30% of patients and that the presence of IPN, regardless of the presence or absence of OF, led to mortality in 32% of patients. Notably, risk of death was 2 times higher in patients with both OF and IPN in comparison with patients with OF and no IPN and in comparison with patients with IPN and no OF. These findings have both theoretical and practical importance.

From a theoretical perspective, this study sheds more light on the cause−effect relationship between OF and IPN in patients with acute pancreatitis. Several studies during the last decade found that patients with IPN develop OF more often than those with sterile pancreatic necrosis and suggested that infection of pancreatic necrosis is a risk factor for OF and a major determinant of severity in acute pancreatitis.24, 25, 34, 35, 36 By contrast, a number of studies have also found the converse, that OF is a risk factor for development of IPN and a major determinant of severity.23, 37, 38 Both these approaches are too simplistic, making the assumption that there is a single major determinant of severity. Importantly, an interaction between determinants, when the 2 variables modify the effect of each other with regard to the outcome, has never been properly investigated in the setting of acute pancreatitis. This study indicates that OF and IPN accentuate the effect of each other on mortality. This suggests that there is a positive interaction (synergism) between OF and pancreatic infection in patients with acute pancreatitis.

From a practical perspective, this study identifies a subgroup of patients with acute pancreatitis with both OF and IPN who have a substantially higher mortality. This finding is consistent with the Atlanta classification that admits that the presence of OF and/or IPN determines severity.2 The present study takes this further by demonstrating that both OF and IPN are equivalent determinants of severity, as their presence is associated with a mortality rate of 30% and 32%, respectively. Organ failure and IPN present together during the course of acute pancreatitis are associated with more severe disease and an even higher mortality rate (43%). This subgroup comprises a quarter of patients with acute necrotizing pancreatitis (24%; 213 of 876 patients in the present study) and has nearly double the mortality of patients with OF and no IPN. This finding provides strong justification for the introduction of a new category of severity in acute pancreatitis, with this worst prognosis group being termed critical acute pancreatitis.39

The original Atlanta classification defined 2 categories of patients with acute pancreatitis, those with mild and severe disease.2 There has been a recent suggestion for a third category of patients.39, 40, 41 This moderate category of acute pancreatitis includes patients with local noninfectious complications42, 43, 44 and those with transient OF.45 Based on the presence of local (absence, sterile, infectious) and systemic (absence, transient, persistent) complications of acute pancreatitis, there are now 4 categories of severity in acute pancreatitis that have been defined robustly, have strong epidemiological ground to support them, and, most importantly, have clinical relevance.39 Use of these categories will improve clinical assessment of individual patients during the course of acute pancreatitis, communication between caregivers and comparison between groups in clinical studies.

The present study has several important strengths. To our knowledge, this is the first meta-analysis on major determinants of mortality in patients with acute pancreatitis. Use of meta-analytic techniques allows an increase in the statistical power, which is of paramount importance, considering that the prevalence of IPN and OF in patients with acute pancreatitis is relatively low. In fact, most primary studies had inadequate statistical power to estimate all of the determinants of mortality. Our study employed explicit eligibility criteria and a comprehensive search in 3 major electronic databases, as well as in the gray literature, with no language restriction. The majority of the included studies had adequate overall methodological quality according to the Newcastle-Ottawa scale. The effect was very consistent over all published studies and the pooled estimates had narrow confidence intervals. Furthermore, we performed a prespecified sensitivity analysis constrained to patients with confirmed necrotizing pancreatitis only and a number of subgroup analyses to make sure that certain characteristics of the primary studies had not influenced the pooled estimates.

There are a number of possible limitations with this study, and these need to be acknowledged. First, our analysis was based solely on observational studies that might be subject to confounding. While, in general, confounders are best addressed by randomized controlled trials, studies of this design would not be able to address a research question related to the natural course of the disease, particularly one related to the relationship between OF and pancreatic infection in acute pancreatitis. Second, there are potential problems in relation to the different definitions of OF and the different indications for surgical intervention across the primary studies. We addressed this issue by means of prespecified subgroup analyses, which confirmed the robustness of our findings regardless of the definition of OF used and indications for surgery. Third, in recent years, it has been appreciated that the dynamic nature of OF is important, as persistent OF has a worse prognosis than transient OF.3, 5, 46 Unfortunately, only a few of the primary studies included data on the dynamic nature of OF and thus it was not possible to analyze this aspect. However, it is worth mentioning that the biggest study to date on this topic47 reported a 35% (36 of 103 patients) mortality rate in patients who developed persistent OF, but did not report on the influence of pancreatic infection. This is very consistent with the 30% (179 of 600 patients) mortality in patients with OF regardless of the presence or absence of pancreatic infection in the present study. Importantly, having stratified these patients according to the infection status of pancreatic necrosis, we found the mortality rate of 43% in patients with OF and IPN compared with 22% in patients with OF and no IPN. Fourth, we were not able to investigate the effect of early vs late OF in the present study, as the data were not available. However, to the best of our knowledge, no studies demonstrated that early OF is more ominous than late OF in patients with acute pancreatitis. Lastly, as is always the case in meta-analyses, results are susceptible to publication bias, such that studies showing a significant effect are more likely to be published. We believe this bias is minimal, as the relationship between infection status of pancreatic necrosis and presence or absence of OF was not the primary outcome of interest in any of the studies in this meta-analysis. Moreover, 2 different statistical tests used to examine the issue of publication bias were performed and revealed no statistical evidence for significant publication bias.

In summary, this study has demonstrated that OF and IPN are independent and equivalent determinants of mortality in patients with acute pancreatitis. There is a 2-fold increase in the risk of death when both OF and IPN are present. This finding highlights the positive interaction between OF and IPN as determinants of severity in acute pancreatitis. It also provides justification for the inclusion of the new category of “critical” acute pancreatitis in the revision of the current Atlanta classification.

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Acknowledgments 

The study was presented in part at the joint meeting of the World Gastroenterology Organisation and the United European Gastroenterology Federation (November 2009, London, UK) and the 9th World Congress of the International Hepato-Pancreato-Biliary Association (April 2010, Buenos Aires, Argentina).

The authors are thankful to Dr Garg (All India Institute of Medical Sciences, New Delhi, India), Dr Pellegrini (Hospital Británico, Buenos Aires, Argentina), Dr Radenkovich (University of Belgrade, Belgrade, Serbia), and Dr Tireli (Celal Bayar University, Manisa, Turkey) for providing additional data on their studies.

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 This article has an accompanying continuing medical education activity on page e13. Learning Objective: Upon completion of this exercise, successful learners will be able to recognize the major determinants of severity for acute pancreatitis.

 View this article's video abstract at www.gastrojournal.org

 Conflicts of interest The authors disclose no conflicts.

PII: S0016-5085(10)00864-4

doi:10.1053/j.gastro.2010.06.010

Gastroenterology
Volume 139, Issue 3 , Pages 813-820, September 2010

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