- Email: [email protected]
Validation of the moderate severity category of acute pancreatitis defined by determinant-based classification
Moderate category Originalseverity Article / Pancreasof acute pancreatitis
Validation of the moderate severity category of acute pancreatitis defined by determinant-based classification Tao Jin, Wei Huang, Xiao-Nan Yang, Ping Xue, Muhammad A Javed, Kiran Altaf, Robert Sutton and Qing Xia Chengdu, China
BACKGROUND: Recent international multidisciplinary consulta tion proposed the use of local (sterile or infected pancreatic necrosis) and/or systemic determinants (organ failure) in the stratification of acute pancreatitis. The present study was to validate the moderate severity category by international multidisciplinary consultation definitions. METHODS: Ninety-two consecutive patients with severe acute pancreatitis (according to the 1992 Atlanta classification) were classified into (i) moderate acute pancreatitis group with the presence of sterile (peri-) pancreatic necrosis and/or transient organ failure; and (ii) severe/critical acute pancreatitis group with the presence of sterile or infected pancreatic necrosis and/ or persistent organ failure. Demographic and clinical outcomes were compared between the two groups.
CONCLUSIONS: Our data suggest that the definition of moderate acute pancreatitis, as suggested by the international multidisciplinary consultation as sterile (peri-) pancreatic necrosis and/or transient organ failure, is an accurate category of acute pancreatitis. (Hepatobiliary Pancreat Dis Int 2014;13:323-327) KEY WORDS: acute pancreatitis; pancreatic necrosis; organ failure; determinant-based classification
Introduction
A
cute pancreatitis is the most common pancreatic RESULTS: Compared with the severe/critical group (n=59), the moderate group (n=33) had lower clinical and computerized disease and leads to 210 000 hospitalizations tomographic scores (both P<0.05). They also had a lower in the United States annually.[1] According to incidence of pancreatic necrosis (45.5% vs 71.2%, P=0.015), the Atlanta classification,[2] which was introduced in infection (9.1% vs 37.3%, P=0.004), ICU admission (0% vs 1992, acute pancreatitis can be classified as mild or 27.1%, P=0.001), and shorter hospital stay (15±5 vs 27±12 days; P<0.001). A subgroup analysis showed that the moderate severe. This classification however does not rank the group also had significantly lower ICU admission rates, shorter severity between organ failure and local complications, hospital stay and lower rate of infection compared with the such as necrosis, abscess, or pseudocyst. Clinical severe group (n=51). No patients died in the moderate group but evidence shows that the mortality in patients with 7 patients died in the severe/critical group (4 for severe group). acute pancreatitis without organ failure is rare, whereas
Author Affiliations: Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Center, West China Hospital, Sichuan University, Chengdu 610041, China (Jin T, Huang W, Yang XN, Xue P and Xia Q); NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool and Broadgreen University Hospitals Trust and University of Liverpool, Liverpool L69 3GA, UK (Huang W, Javed MA, Altaf K and Sutton R) Corresponding Author: Qing Xia, MD, Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Center, West China Hospital, Sichuan University, Chengdu 610041, China (Tel: 86-28-85423373; Fax: 86-28-85423028; Email: [email protected]) © 2014, Hepatobiliary Pancreat Dis Int. All rights reserved. doi: 10.1016/S1499-3872(14)60255-1
patients with persistent organ failure have a relatively high mortality.[3-8] Therefore, the current Atlanta classification overestimates the clinical outcomes of severe acute pancreatitis. Indeed, a considerable number of patients with severe acute pancreatitis defined by the Atlanta classification belong to a unique classification, the moderate category of severity of acute pancreatitis, which differs from its mild and severe counterparts. Vege et al[9] retrospectively reviewed 207 patients with severe acute pancreatitis (defined by the Atlanta classification) and found that the subgroup without organ failure, categorized as moderately severe acute pancreatitis, had a high morbidity and a low mortality.
Hepatobiliary Pancreat Dis Int，Vol 13，No 3 • June 15，2014 • www.hbpdint.com • 323
Hepatobiliary & Pancreatic Diseases International
Two further prospective studies[10, 11] have also identified such group based on the presence of local complications but the absence of organ failure. Efforts have been made to establish a new classification system by a recent international multi disciplinary consultation (IMC)[12] which proposes pancreatic necrosis (sterile or infected) and organ failure (respiratory, cardiovascular and renal failure) as determinants in stratification of the severity of acute pancreatitis. However, the IMC classification does not include pancreatic abscess, fluid collection and pseudocyst but defines moderate acute pancreatitis as sterile (peri-) pancreatic necrosis and/or transient organ failure. In this study, we have validated the clinical practicality of the IMC for moderate acute pancreatitis in a cohort of patients with severe acute pancreatitis defined by the Atlanta classification.
Methods Study population A retrospective analysis was performed on patients with severe acute pancreatitis (defined by the Atlanta classification) admitted between April 2008 and September 2010. A database had been collated during this period for an ethically approved randomized clinical trial at Sichuan Provincial Pancreatitis Center, West China Hospital, Sichuan University, Chengdu, China. All patients were admitted within 72 hours of symptom onset. Ninety-two patients were included and categorized into: (i) a group with moderate acute pancreatitis, sterile (peri-) pancreatic necrosis and/or transient organ failure; and (ii) a group with severe/critical acute pancreatitis, persistent organ failure and/or infected pancreatic necrosis (IPN).[12] Persistent organ failure was defined as persistent failure (≥48 hours) of one or more of respiratory, cardiovascular and renal systems with a sepsis-related organ failure assessment (SOFA) score ≥ 2.[13] Transient organ failure was defined as organ failure that lasted for less than 48 hours. Single organ failure was that only one organ was affected, whereas multiple organ failure was defined as two or more affected organs at the same time.
scans were taken on admission for differential diagnoses when necessary. Contrast enhanced CT (CECT) scans were taken for every patient within a week of admission [median 6 days (range: 5-8)] and pancreatic necrosis was defined as lack of parenchymal enhancement on arterial phase of CECT.[17] Multiple CT scoring systems [CT severity index (CTSI),[18] modified CTSI (MCTSI),[19] extrapancreatic inflammation on CT (EPIC)[20]] were scored by two independent blinded abdominal radiologists. Patients were treated in a medical ward unless transfer to the intensive care unit (ICU) due to clinical need. Initial fluid resuscitation and non-invasive positive pressure ventilation (NIPPV) were provided in the ward in some cases with severe acute pancreatitis. Decision for ICU care was based on a persistent systolic blood pressure <90 mmHg despite fluid resuscitation; persistent respiratory failure requiring intubation and ventilation was marked by hypoxia, hypercapnea or acidosis with a failed response to NIPPV; and persistent renal failure was defined by metabolic acidosis, hyperkalemia and/or anuria, which need hemodialysis. Extrapancreatic infection was defined by positive microbiology culture obtained from blood, body fluid or tissue. IPN was defined on the basis of the presence of at least one of the followings:[12] (1) gas bubbles within pancreatic necrosis on CECT; and (2) a positive culture of pancreatic necrosis obtained by image guided fine-needle aspiration or during drainage and/or necrosectomy. Any infection was defined as either infected pancreatic necrosis or extrapancreatic infection or both.
Statistical analysis Statistical analysis was performed using SPSS 20.0 in the National Institute for Health Research (NIHR) Pancreas Biomedical Research Unit, University of Liverpool, UK. Continuous variables were expressed as mean±standard deviation or median±interquartile range and categorical variables were expressed as proportions. For group comparisons, a one-way ANOVA or the Kruskal-Wallis test was used, depending on the pattern of distribution. Categorical outcomes were compared using the Chi-square or Fisher's exact test. Only the two-tailed P values were considered to determine statistical significance. A P value less than 0.05 was considered statistically significant.
Outcome definition and data collection Demographic, clinical, radiological and laboratory data of all study participants were recorded. Acute physiology and chronic health evaluation II (APACHE Results II)[14] and bedside index for severity in acute pancreatitis [15, 16] scores were calculated within 24 hours after Baseline characteristics (BISAP) admission. Non-enhanced computed tomography (CT) The study population contains 41 females and 51 males, 324 • Hepatobiliary Pancreat Dis Int，Vol 13，No 3 • June 15，2014 • www.hbpdint.com
Moderate severity category of acute pancreatitis
Table 1. Demographic and clinical variables of patients Age (yr) Gender (F/M) Etiology (n, %) Biliary Alcoholic Hyperlipidemia Miscellaneous
Moderate (n=33) Severe/critical (n=59) P value 45.1±12.1 45.8±10.1 0.761 16/17 25/34 0.572 14 (42.4) 4 (12.1) 10 (30.3) 5 (15.2)
23 (39.0) 12 (20.3) 16 (27.1) 8 (13.6)
0.747 0.366 0.770 0.764
with a mean age of 45.6±10.9 years. The median time from onset of symptoms to admission was 48 hours (range 24-70). The etiologies were biliary in 37 patients, alcoholic in 16, hyperlipidemia in 26 and miscellaneous in 13 (Table 1). There were no significant differences in age, gender ratio and etiology between the two groups (all P>0.05).
Table 2. Comparison of biomarkers, clinical and computerized tomographic scores between moderate and severe/critical AP groups Biomarkers WBC BUN Creatinine Hematocrit CRP Clinical scores APACHE II BISAP CT scores CTSI MCTSI EPIC
Moderate (n=33)
Severe/critical (n=59)
P value
14.1±3.9 4.2 (2.9-6.3) 67.8 (52.1-76.0) 38.5 (34.0-46.8) 189.3±95.9
15.0±5.7 4.8 (3.0-7.4) 76.5 (55.0-115.5) 44.0 (37.0-48.0) 225.7±100.6
0.397 0.210 0.064 0.221 0.118
7.8±4.2 2.0±0.5
11.0±5.1 2.3±0.6
0.003 0.006
5.2±1.6 7.0±1.6 4.0±1.8
6.1±2.0 7.9±1.7 5.5±1.4
0.015 0.008 0.000
WBC: white blood cell; BUN: blood urea nitrogen; CRP: C-reactive protein.
Comparison of biomarkers, clinical scores and CT Table 3. Comparison of clinical outcomes of patients between moderate and severe/critical AP groups (n, %) scores Moderate Severe/critical P value Within 24 hours of admission, the biomarkers (n=33) (n=59) were not significantly different between the two Any pancreatic necrosis 15 (45.5) 42 (71.2) 0.015 groups (P>0.05). However, APACHE II (P=0.003) and Pancreatic necrosis ≥30% 4 (12.1) 17 (28.8) 0.067 BISAP (P=0.006) scores were significantly lower in Infected pancreatic necrosis 0 (0) 10 (16.9) 0.031 the moderate group compared with the severe/critical Any infection* 3 (9.1) 22 (37.3) 0.004 group. In line with the clinical scores, CTSI (P=0.015), Hospital stay (d) 15±5 27±12 <0.001 MCTSI (P=0.008) and EPIC scores (P=0.000) were also Need for ICU care 0 (0) 16 (27.1) 0.001 significantly lower in the moderate group (Table 2). Need for surgery 0 (0) 4 (6.8) 0.339 Mortality
Comparison of clinical outcomes There were 33 patients in the moderate group, 15 of them developed pancreatic necrosis, 22 had transient organ failure and 4 had both. There were 59 patients in the severe/critical group with 51 severe (49 had persistent organ failure only and 2 had IPN only) patients, and 8 critical ones with both persistent organ failure and IPN. The infection was complicated in 3 patients in the moderate group (all extrapancreatic infections: sputum 2, and urine 1) and 22 in the severe/ critical group (IPN 10, sputum 20, urine 3, blood 5, and others 3). No mortality was seen in the moderate group, but 7 patients died in the severe/critical group. Compared with those in the severe/critical group, patients in the moderate group had a lower incidence of pancreatic necrosis (45.5% vs 71.2%, P=0.015) and infection (9.1% vs 37.3%, P=0.004), and required ICU admission (0% vs 27.1%, P=0.001) and shorter hospital stay (15±5 vs 27±12 days; P<0.001) (Table 3). A subgroup analysis also showed that patients in the moderate group had significantly lower ICU admissions (0% vs 19.2%,
0 (0)
7 (11.9)
0.047
*: Any infection includes both infected pancreatic necrosis and extrapancreatic infections.
P=0.04), shorter hospital stay (15±5 vs 25±11 days, P<0.001) and a lower rate of any infection (9.0% vs 27.4%, P=0.014) compared with the severe group.
Discussion Acute pancreatitis has the least predictable course of any digestive disease and it is recognized that organ failure[8] and IPN[4] are the main causes of death in patients with acute pancreatitis. From a clinical perspective, it is crucial to identify those patients with severe acute pancreatitis who are at risk of developing significant complications and mortality earlier in the course of the disease, so that appropriate management can be instituted.[21] The current categorization of severe acute pancreatitis by the Atlanta classification consists of a heterogeneous patient population with variable outcomes. Local pancreatic complications are
Hepatobiliary Pancreat Dis Int，Vol 13，No 3 • June 15，2014 • www.hbpdint.com • 325
Hepatobiliary & Pancreatic Diseases International
not associated with mortality in acute pancreatitis at the absence of persistent organ failure.[10, 11, 21] The current IMC guidelines highlight the utility of local (IPN) and systemic determinants (organ failure) to stratify and define acute pancreatitis into mild (no pancreatic necrosis or organ failure), moderate [sterile (peri-) pancreatic necrosis and/or transient organ failure], severe (IPN or persistent organ failure) and critical (IPN and persistent organ failure) categories.[12] There are existing published data advocating a distinct new category of acute pancreatitis called the moderately severe acute pancreatitis.[10, 11, 21] Although there is no general consensus on this classification, this group of patients has been characterized by the presence of local complications but the absence of organ failure. In contrast to the previous studies which require more than 30% of non-enhancement to diagnose (peri-) pancreatic necrosis, the IMC defines that any area of non-enhancement of the pancreatic tissue by CECT is diagnosable. We divided 92 patients who were classified with severe acute pancreatitis by the Atlanta classification into two groups, moderate and severe/ critical. It was shown that within 24 hours of admission, the APACHE II and BISAP scores were significantly lower in the moderate group compared with the severe/ critical group. Moreover, at approximately a week post admission, CT scores in the moderate group were also significantly lower. These findings suggest that the clinical scores may differentiate the moderate group at an earlier stage of the disease from those who would develop a more severe form of the disease. Patients in the moderate group also had a significantly higher Ranson score, white blood cell count, and longer hospital stay, compared with those diagnosed with mild acute pancreatitis (data not shown).[22] Our study showed that patients in the moderate group had a lower incidence of pancreatic necrosis, extrapancreatic infection and IPN, shorter hospital stay and no mortality. All these results indicated that stratification of acute pancreatitis by sterile (peri-) pancreatic necrosis and/or transient organ failure (defined by IMC) can identify different severity. This stratification may benefit the interpretation of data from clinical trials for new drugs by providing more homogenous subgroups. To our knowledge, this was the first study using clinical data from severe patients with acute pancreatitis (defined by Atlanta classification) to evaluate the efficacy of IMC in stratification of the severity of acute pancreatitis. The local and systemic determinants provide a moderate category of patients, initially proposed by previous studies, which may be differentiated from severe/critical cases by clinical scores at an early stage of disease
progression. The overall mortality in our study was 11.9% in the severe/critical group, which is relatively lower than that reported previously.[23] The inconsistence may be due to the following factors: West China Hospital is one of the largest tertiary centers in China where experienced doctors deal with more than 1500 patients with acute pancreatitis per year; the multidisciplinary team approach with workable treatment strategy might benefit patients significantly.[24] Alongside updated guidelines, patients are also routinely treated with traditional Chinese medicine from the time of admission, and patients in this study were all admitted within 72 hours of symptom onset. Double-blinded randomized clinical trail is ongoing to justify the effects of traditional Chinese medicine. It is of note that the severe and critical[7] groups had a mortality of 7.8% and 37.5%, respectively, highlighting the combination of persistent organ failure and IPN in the diagnosis of severe acute pancreatitis. In summary, this study validates a moderate category of acute pancreatitis severity which differs from severe or severe/critical categories by using IMC definitions. Further studies are needed to validate the critical group defined by IMC. Acknowledgements: The authors thank Drs Li ZY, Guo J, Bharucha S, Johnstone M, Mukherjee R, Lin ZQ, Huang ZX, Song B, Zou K, Huang L, Jiang K and Wen L for their supports to this work. Contributors: XP, SR and XQ designed the study. JT, HW, YXN, XP and JMA collected the data. JT, HW and AK analyzed the data and drafted the manuscript. XP, SR and XQ made critical revisions and approved the paper. JT and HW contributed equally to this work. XQ is the guarantor. Funding: This study was supported by grants from Science and Technology Support Program of Sichuan (2009SZ0201, 2010SZ0068 and 2011SZ0291) and National Institute for Health Research, UK. Ethical approval: Not needed. Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
References 1 Swaroop VS, Chari ST, Clain JE. Severe acute pancreatitis. JAMA 2004;291:2865-2868. 2 Bradley EL 3rd. A clinically based classification system for acute pancreatitis. Summary of the International Symposium on Acute Pancreatitis, Atlanta, Ga, September 11 through 13, 1992. Arch Surg 1993;128:586-590. 3 Bollen TL, van Santvoort HC, Besselink MG, van Leeuwen MS, Horvath KD, Freeny PC, et al. The Atlanta Classification of acute pancreatitis revisited. Br J Surg 2008;95:6-21. 4 Petrov MS, Shanbhag S, Chakraborty M, Phillips AR, Windsor JA. Organ failure and infection of pancreatic necrosis as determinants of mortality in patients with acute
326 • Hepatobiliary Pancreat Dis Int，Vol 13，No 3 • June 15，2014 • www.hbpdint.com
Moderate severity category of acute pancreatitis
pancreatitis. Gastroenterology 2010;139:813-820. 5 Mofidi R, Duff MD, Wigmore SJ, Madhavan KK, Garden OJ, Parks RW. Association between early systemic inflammatory response, severity of multiorgan dysfunction and death in acute pancreatitis. Br J Surg 2006;93:738-744. 6 Buter A, Imrie CW, Carter CR, Evans S, McKay CJ. Dynamic nature of early organ dysfunction determines outcome in acute pancreatitis. Br J Surg 2002;89:298-302. 7 McKay CJ, Imrie CW. The continuing challenge of early mortality in acute pancreatitis. Br J Surg 2004;91:1243-1244. 8 Vege SS, Chari ST. Organ failure as an indicator of severity of acute pancreatitis: time to revisit the Atlanta classification. Gastroenterology 2005;128:1133-1135. 9 Vege SS, Gardner TB, Chari ST, Munukuti P, Pearson RK, Clain JE, et al. Low mortality and high morbidity in severe acute pancreatitis without organ failure: a case for revising the Atlanta classification to include "moderately severe acute pancreatitis". Am J Gastroenterol 2009;104:710-715. 10 Talukdar R, Clemens M, Vege SS. Moderately severe acute pancreatitis: prospective validation of this new subgroup of acute pancreatitis. Pancreas 2012;41:306-309. 11 de-Madaria E, Soler-Sala G, Lopez-Font I, Zapater P, Martínez J, Gómez-Escolar L, et al. Update of the Atlanta Classification of severity of acute pancreatitis: should a moderate category be included? Pancreatology 2010;10:613619. 12 Dellinger EP, Forsmark CE, Layer P, Lévy P, Maraví-Poma E, Petrov MS, et al. Determinant-based classification of acute pancreatitis severity: an international multidisciplinary consultation. Ann Surg 2012;256:875-880. 13 Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996;22:707-710. 14 Larvin M, McMahon MJ. APACHE-II score for assessment and monitoring of acute pancreatitis. Lancet 1989;2:201-205. 15 Singh VK, Wu BU, Bollen TL, Repas K, Maurer R, Johannes RS, et al. A prospective evaluation of the bedside index for
severity in acute pancreatitis score in assessing mortality and intermediate markers of severity in acute pancreatitis. Am J Gastroenterol 2009;104:966-971. 16 Wu BU, Johannes RS, Sun X, Tabak Y, Conwell DL, Banks PA. The early prediction of mortality in acute pancreatitis: a large population-based study. Gut 2008;57:1698-1703. 17 Papachristou GI, Muddana V, Yadav D, O'Connell M, Sanders MK, Slivka A, et al. Comparison of BISAP, Ranson's, APACHE-II, and CTSI scores in predicting organ failure, complications, and mortality in acute pancreatitis. Am J Gastroenterol 2010;105:435-442. 18 Balthazar EJ, Robinson DL, Megibow AJ, Ranson JH. Acute pancreatitis: value of CT in establishing prognosis. Radiology 1990;174:331-336. 19 Mortele KJ, Wiesner W, Intriere L, Shankar S, Zou KH, Kalantari BN, et al. A modified CT severity index for evaluating acute pancreatitis: improved correlation with patient outcome. AJR Am J Roentgenol 2004;183:1261-1265. 20 Bollen TL, Singh VK, Maurer R, Repas K, van Es HW, Banks PA, et al. A comparative evaluation of radiologic and clinical scoring systems in the early prediction of severity in acute pancreatitis. Am J Gastroenterol 2012;107:612-619. 21 Petrov MS, Windsor JA. Classification of the severity of acute pancreatitis: how many categories make sense? Am J Gastroenterol 2010;105:74-76. 22 Li J, Xue GJ, Liu YL, Javed MA, Zhao XL, Wan MH, et al. Early oral refeeding wisdom in patients with mild acute pancreatitis. Pancreas 2013;42:88-91. 23 Banks PA, Freeman ML; Practice Parameters Committee of the American College of Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol 2006;101: 2379-2400. 24 Murata A, Matsuda S, Mayumi T, Yokoe M, Kuwabara K, Ichimiya Y, et al. Effect of hospital volume on clinical outcome in patients with acute pancreatitis, based on a national administrative database. Pancreas 2011;40:1018-1023. Received July 23, 2012 Accepted after revision September 4, 2013
Hepatobiliary Pancreat Dis Int，Vol 13，No 3 • June 15，2014 • www.hbpdint.com • 327
Validation of the moderate severity category of acute pancreatitis defined by determinant-based classification Tao Jin, Wei Huang, Xiao-Nan Yang, Ping Xue, Muhammad A Javed, Kiran Altaf, Robert Sutton and Qing Xia Chengdu, China
BACKGROUND: Recent international multidisciplinary consulta tion proposed the use of local (sterile or infected pancreatic necrosis) and/or systemic determinants (organ failure) in the stratification of acute pancreatitis. The present study was to validate the moderate severity category by international multidisciplinary consultation definitions. METHODS: Ninety-two consecutive patients with severe acute pancreatitis (according to the 1992 Atlanta classification) were classified into (i) moderate acute pancreatitis group with the presence of sterile (peri-) pancreatic necrosis and/or transient organ failure; and (ii) severe/critical acute pancreatitis group with the presence of sterile or infected pancreatic necrosis and/ or persistent organ failure. Demographic and clinical outcomes were compared between the two groups.
CONCLUSIONS: Our data suggest that the definition of moderate acute pancreatitis, as suggested by the international multidisciplinary consultation as sterile (peri-) pancreatic necrosis and/or transient organ failure, is an accurate category of acute pancreatitis. (Hepatobiliary Pancreat Dis Int 2014;13:323-327) KEY WORDS: acute pancreatitis; pancreatic necrosis; organ failure; determinant-based classification
Introduction
A
cute pancreatitis is the most common pancreatic RESULTS: Compared with the severe/critical group (n=59), the moderate group (n=33) had lower clinical and computerized disease and leads to 210 000 hospitalizations tomographic scores (both P<0.05). They also had a lower in the United States annually.[1] According to incidence of pancreatic necrosis (45.5% vs 71.2%, P=0.015), the Atlanta classification,[2] which was introduced in infection (9.1% vs 37.3%, P=0.004), ICU admission (0% vs 1992, acute pancreatitis can be classified as mild or 27.1%, P=0.001), and shorter hospital stay (15±5 vs 27±12 days; P<0.001). A subgroup analysis showed that the moderate severe. This classification however does not rank the group also had significantly lower ICU admission rates, shorter severity between organ failure and local complications, hospital stay and lower rate of infection compared with the such as necrosis, abscess, or pseudocyst. Clinical severe group (n=51). No patients died in the moderate group but evidence shows that the mortality in patients with 7 patients died in the severe/critical group (4 for severe group). acute pancreatitis without organ failure is rare, whereas
Author Affiliations: Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Center, West China Hospital, Sichuan University, Chengdu 610041, China (Jin T, Huang W, Yang XN, Xue P and Xia Q); NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool and Broadgreen University Hospitals Trust and University of Liverpool, Liverpool L69 3GA, UK (Huang W, Javed MA, Altaf K and Sutton R) Corresponding Author: Qing Xia, MD, Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Center, West China Hospital, Sichuan University, Chengdu 610041, China (Tel: 86-28-85423373; Fax: 86-28-85423028; Email: [email protected]) © 2014, Hepatobiliary Pancreat Dis Int. All rights reserved. doi: 10.1016/S1499-3872(14)60255-1
patients with persistent organ failure have a relatively high mortality.[3-8] Therefore, the current Atlanta classification overestimates the clinical outcomes of severe acute pancreatitis. Indeed, a considerable number of patients with severe acute pancreatitis defined by the Atlanta classification belong to a unique classification, the moderate category of severity of acute pancreatitis, which differs from its mild and severe counterparts. Vege et al[9] retrospectively reviewed 207 patients with severe acute pancreatitis (defined by the Atlanta classification) and found that the subgroup without organ failure, categorized as moderately severe acute pancreatitis, had a high morbidity and a low mortality.
Hepatobiliary Pancreat Dis Int，Vol 13，No 3 • June 15，2014 • www.hbpdint.com • 323
Hepatobiliary & Pancreatic Diseases International
Two further prospective studies[10, 11] have also identified such group based on the presence of local complications but the absence of organ failure. Efforts have been made to establish a new classification system by a recent international multi disciplinary consultation (IMC)[12] which proposes pancreatic necrosis (sterile or infected) and organ failure (respiratory, cardiovascular and renal failure) as determinants in stratification of the severity of acute pancreatitis. However, the IMC classification does not include pancreatic abscess, fluid collection and pseudocyst but defines moderate acute pancreatitis as sterile (peri-) pancreatic necrosis and/or transient organ failure. In this study, we have validated the clinical practicality of the IMC for moderate acute pancreatitis in a cohort of patients with severe acute pancreatitis defined by the Atlanta classification.
Methods Study population A retrospective analysis was performed on patients with severe acute pancreatitis (defined by the Atlanta classification) admitted between April 2008 and September 2010. A database had been collated during this period for an ethically approved randomized clinical trial at Sichuan Provincial Pancreatitis Center, West China Hospital, Sichuan University, Chengdu, China. All patients were admitted within 72 hours of symptom onset. Ninety-two patients were included and categorized into: (i) a group with moderate acute pancreatitis, sterile (peri-) pancreatic necrosis and/or transient organ failure; and (ii) a group with severe/critical acute pancreatitis, persistent organ failure and/or infected pancreatic necrosis (IPN).[12] Persistent organ failure was defined as persistent failure (≥48 hours) of one or more of respiratory, cardiovascular and renal systems with a sepsis-related organ failure assessment (SOFA) score ≥ 2.[13] Transient organ failure was defined as organ failure that lasted for less than 48 hours. Single organ failure was that only one organ was affected, whereas multiple organ failure was defined as two or more affected organs at the same time.
scans were taken on admission for differential diagnoses when necessary. Contrast enhanced CT (CECT) scans were taken for every patient within a week of admission [median 6 days (range: 5-8)] and pancreatic necrosis was defined as lack of parenchymal enhancement on arterial phase of CECT.[17] Multiple CT scoring systems [CT severity index (CTSI),[18] modified CTSI (MCTSI),[19] extrapancreatic inflammation on CT (EPIC)[20]] were scored by two independent blinded abdominal radiologists. Patients were treated in a medical ward unless transfer to the intensive care unit (ICU) due to clinical need. Initial fluid resuscitation and non-invasive positive pressure ventilation (NIPPV) were provided in the ward in some cases with severe acute pancreatitis. Decision for ICU care was based on a persistent systolic blood pressure <90 mmHg despite fluid resuscitation; persistent respiratory failure requiring intubation and ventilation was marked by hypoxia, hypercapnea or acidosis with a failed response to NIPPV; and persistent renal failure was defined by metabolic acidosis, hyperkalemia and/or anuria, which need hemodialysis. Extrapancreatic infection was defined by positive microbiology culture obtained from blood, body fluid or tissue. IPN was defined on the basis of the presence of at least one of the followings:[12] (1) gas bubbles within pancreatic necrosis on CECT; and (2) a positive culture of pancreatic necrosis obtained by image guided fine-needle aspiration or during drainage and/or necrosectomy. Any infection was defined as either infected pancreatic necrosis or extrapancreatic infection or both.
Statistical analysis Statistical analysis was performed using SPSS 20.0 in the National Institute for Health Research (NIHR) Pancreas Biomedical Research Unit, University of Liverpool, UK. Continuous variables were expressed as mean±standard deviation or median±interquartile range and categorical variables were expressed as proportions. For group comparisons, a one-way ANOVA or the Kruskal-Wallis test was used, depending on the pattern of distribution. Categorical outcomes were compared using the Chi-square or Fisher's exact test. Only the two-tailed P values were considered to determine statistical significance. A P value less than 0.05 was considered statistically significant.
Outcome definition and data collection Demographic, clinical, radiological and laboratory data of all study participants were recorded. Acute physiology and chronic health evaluation II (APACHE Results II)[14] and bedside index for severity in acute pancreatitis [15, 16] scores were calculated within 24 hours after Baseline characteristics (BISAP) admission. Non-enhanced computed tomography (CT) The study population contains 41 females and 51 males, 324 • Hepatobiliary Pancreat Dis Int，Vol 13，No 3 • June 15，2014 • www.hbpdint.com
Moderate severity category of acute pancreatitis
Table 1. Demographic and clinical variables of patients Age (yr) Gender (F/M) Etiology (n, %) Biliary Alcoholic Hyperlipidemia Miscellaneous
Moderate (n=33) Severe/critical (n=59) P value 45.1±12.1 45.8±10.1 0.761 16/17 25/34 0.572 14 (42.4) 4 (12.1) 10 (30.3) 5 (15.2)
23 (39.0) 12 (20.3) 16 (27.1) 8 (13.6)
0.747 0.366 0.770 0.764
with a mean age of 45.6±10.9 years. The median time from onset of symptoms to admission was 48 hours (range 24-70). The etiologies were biliary in 37 patients, alcoholic in 16, hyperlipidemia in 26 and miscellaneous in 13 (Table 1). There were no significant differences in age, gender ratio and etiology between the two groups (all P>0.05).
Table 2. Comparison of biomarkers, clinical and computerized tomographic scores between moderate and severe/critical AP groups Biomarkers WBC BUN Creatinine Hematocrit CRP Clinical scores APACHE II BISAP CT scores CTSI MCTSI EPIC
Moderate (n=33)
Severe/critical (n=59)
P value
14.1±3.9 4.2 (2.9-6.3) 67.8 (52.1-76.0) 38.5 (34.0-46.8) 189.3±95.9
15.0±5.7 4.8 (3.0-7.4) 76.5 (55.0-115.5) 44.0 (37.0-48.0) 225.7±100.6
0.397 0.210 0.064 0.221 0.118
7.8±4.2 2.0±0.5
11.0±5.1 2.3±0.6
0.003 0.006
5.2±1.6 7.0±1.6 4.0±1.8
6.1±2.0 7.9±1.7 5.5±1.4
0.015 0.008 0.000
WBC: white blood cell; BUN: blood urea nitrogen; CRP: C-reactive protein.
Comparison of biomarkers, clinical scores and CT Table 3. Comparison of clinical outcomes of patients between moderate and severe/critical AP groups (n, %) scores Moderate Severe/critical P value Within 24 hours of admission, the biomarkers (n=33) (n=59) were not significantly different between the two Any pancreatic necrosis 15 (45.5) 42 (71.2) 0.015 groups (P>0.05). However, APACHE II (P=0.003) and Pancreatic necrosis ≥30% 4 (12.1) 17 (28.8) 0.067 BISAP (P=0.006) scores were significantly lower in Infected pancreatic necrosis 0 (0) 10 (16.9) 0.031 the moderate group compared with the severe/critical Any infection* 3 (9.1) 22 (37.3) 0.004 group. In line with the clinical scores, CTSI (P=0.015), Hospital stay (d) 15±5 27±12 <0.001 MCTSI (P=0.008) and EPIC scores (P=0.000) were also Need for ICU care 0 (0) 16 (27.1) 0.001 significantly lower in the moderate group (Table 2). Need for surgery 0 (0) 4 (6.8) 0.339 Mortality
Comparison of clinical outcomes There were 33 patients in the moderate group, 15 of them developed pancreatic necrosis, 22 had transient organ failure and 4 had both. There were 59 patients in the severe/critical group with 51 severe (49 had persistent organ failure only and 2 had IPN only) patients, and 8 critical ones with both persistent organ failure and IPN. The infection was complicated in 3 patients in the moderate group (all extrapancreatic infections: sputum 2, and urine 1) and 22 in the severe/ critical group (IPN 10, sputum 20, urine 3, blood 5, and others 3). No mortality was seen in the moderate group, but 7 patients died in the severe/critical group. Compared with those in the severe/critical group, patients in the moderate group had a lower incidence of pancreatic necrosis (45.5% vs 71.2%, P=0.015) and infection (9.1% vs 37.3%, P=0.004), and required ICU admission (0% vs 27.1%, P=0.001) and shorter hospital stay (15±5 vs 27±12 days; P<0.001) (Table 3). A subgroup analysis also showed that patients in the moderate group had significantly lower ICU admissions (0% vs 19.2%,
0 (0)
7 (11.9)
0.047
*: Any infection includes both infected pancreatic necrosis and extrapancreatic infections.
P=0.04), shorter hospital stay (15±5 vs 25±11 days, P<0.001) and a lower rate of any infection (9.0% vs 27.4%, P=0.014) compared with the severe group.
Discussion Acute pancreatitis has the least predictable course of any digestive disease and it is recognized that organ failure[8] and IPN[4] are the main causes of death in patients with acute pancreatitis. From a clinical perspective, it is crucial to identify those patients with severe acute pancreatitis who are at risk of developing significant complications and mortality earlier in the course of the disease, so that appropriate management can be instituted.[21] The current categorization of severe acute pancreatitis by the Atlanta classification consists of a heterogeneous patient population with variable outcomes. Local pancreatic complications are
Hepatobiliary Pancreat Dis Int，Vol 13，No 3 • June 15，2014 • www.hbpdint.com • 325
Hepatobiliary & Pancreatic Diseases International
not associated with mortality in acute pancreatitis at the absence of persistent organ failure.[10, 11, 21] The current IMC guidelines highlight the utility of local (IPN) and systemic determinants (organ failure) to stratify and define acute pancreatitis into mild (no pancreatic necrosis or organ failure), moderate [sterile (peri-) pancreatic necrosis and/or transient organ failure], severe (IPN or persistent organ failure) and critical (IPN and persistent organ failure) categories.[12] There are existing published data advocating a distinct new category of acute pancreatitis called the moderately severe acute pancreatitis.[10, 11, 21] Although there is no general consensus on this classification, this group of patients has been characterized by the presence of local complications but the absence of organ failure. In contrast to the previous studies which require more than 30% of non-enhancement to diagnose (peri-) pancreatic necrosis, the IMC defines that any area of non-enhancement of the pancreatic tissue by CECT is diagnosable. We divided 92 patients who were classified with severe acute pancreatitis by the Atlanta classification into two groups, moderate and severe/ critical. It was shown that within 24 hours of admission, the APACHE II and BISAP scores were significantly lower in the moderate group compared with the severe/ critical group. Moreover, at approximately a week post admission, CT scores in the moderate group were also significantly lower. These findings suggest that the clinical scores may differentiate the moderate group at an earlier stage of the disease from those who would develop a more severe form of the disease. Patients in the moderate group also had a significantly higher Ranson score, white blood cell count, and longer hospital stay, compared with those diagnosed with mild acute pancreatitis (data not shown).[22] Our study showed that patients in the moderate group had a lower incidence of pancreatic necrosis, extrapancreatic infection and IPN, shorter hospital stay and no mortality. All these results indicated that stratification of acute pancreatitis by sterile (peri-) pancreatic necrosis and/or transient organ failure (defined by IMC) can identify different severity. This stratification may benefit the interpretation of data from clinical trials for new drugs by providing more homogenous subgroups. To our knowledge, this was the first study using clinical data from severe patients with acute pancreatitis (defined by Atlanta classification) to evaluate the efficacy of IMC in stratification of the severity of acute pancreatitis. The local and systemic determinants provide a moderate category of patients, initially proposed by previous studies, which may be differentiated from severe/critical cases by clinical scores at an early stage of disease
progression. The overall mortality in our study was 11.9% in the severe/critical group, which is relatively lower than that reported previously.[23] The inconsistence may be due to the following factors: West China Hospital is one of the largest tertiary centers in China where experienced doctors deal with more than 1500 patients with acute pancreatitis per year; the multidisciplinary team approach with workable treatment strategy might benefit patients significantly.[24] Alongside updated guidelines, patients are also routinely treated with traditional Chinese medicine from the time of admission, and patients in this study were all admitted within 72 hours of symptom onset. Double-blinded randomized clinical trail is ongoing to justify the effects of traditional Chinese medicine. It is of note that the severe and critical[7] groups had a mortality of 7.8% and 37.5%, respectively, highlighting the combination of persistent organ failure and IPN in the diagnosis of severe acute pancreatitis. In summary, this study validates a moderate category of acute pancreatitis severity which differs from severe or severe/critical categories by using IMC definitions. Further studies are needed to validate the critical group defined by IMC. Acknowledgements: The authors thank Drs Li ZY, Guo J, Bharucha S, Johnstone M, Mukherjee R, Lin ZQ, Huang ZX, Song B, Zou K, Huang L, Jiang K and Wen L for their supports to this work. Contributors: XP, SR and XQ designed the study. JT, HW, YXN, XP and JMA collected the data. JT, HW and AK analyzed the data and drafted the manuscript. XP, SR and XQ made critical revisions and approved the paper. JT and HW contributed equally to this work. XQ is the guarantor. Funding: This study was supported by grants from Science and Technology Support Program of Sichuan (2009SZ0201, 2010SZ0068 and 2011SZ0291) and National Institute for Health Research, UK. Ethical approval: Not needed. Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
References 1 Swaroop VS, Chari ST, Clain JE. Severe acute pancreatitis. JAMA 2004;291:2865-2868. 2 Bradley EL 3rd. A clinically based classification system for acute pancreatitis. Summary of the International Symposium on Acute Pancreatitis, Atlanta, Ga, September 11 through 13, 1992. Arch Surg 1993;128:586-590. 3 Bollen TL, van Santvoort HC, Besselink MG, van Leeuwen MS, Horvath KD, Freeny PC, et al. The Atlanta Classification of acute pancreatitis revisited. Br J Surg 2008;95:6-21. 4 Petrov MS, Shanbhag S, Chakraborty M, Phillips AR, Windsor JA. Organ failure and infection of pancreatic necrosis as determinants of mortality in patients with acute
326 • Hepatobiliary Pancreat Dis Int，Vol 13，No 3 • June 15，2014 • www.hbpdint.com
Moderate severity category of acute pancreatitis
pancreatitis. Gastroenterology 2010;139:813-820. 5 Mofidi R, Duff MD, Wigmore SJ, Madhavan KK, Garden OJ, Parks RW. Association between early systemic inflammatory response, severity of multiorgan dysfunction and death in acute pancreatitis. Br J Surg 2006;93:738-744. 6 Buter A, Imrie CW, Carter CR, Evans S, McKay CJ. Dynamic nature of early organ dysfunction determines outcome in acute pancreatitis. Br J Surg 2002;89:298-302. 7 McKay CJ, Imrie CW. The continuing challenge of early mortality in acute pancreatitis. Br J Surg 2004;91:1243-1244. 8 Vege SS, Chari ST. Organ failure as an indicator of severity of acute pancreatitis: time to revisit the Atlanta classification. Gastroenterology 2005;128:1133-1135. 9 Vege SS, Gardner TB, Chari ST, Munukuti P, Pearson RK, Clain JE, et al. Low mortality and high morbidity in severe acute pancreatitis without organ failure: a case for revising the Atlanta classification to include "moderately severe acute pancreatitis". Am J Gastroenterol 2009;104:710-715. 10 Talukdar R, Clemens M, Vege SS. Moderately severe acute pancreatitis: prospective validation of this new subgroup of acute pancreatitis. Pancreas 2012;41:306-309. 11 de-Madaria E, Soler-Sala G, Lopez-Font I, Zapater P, Martínez J, Gómez-Escolar L, et al. Update of the Atlanta Classification of severity of acute pancreatitis: should a moderate category be included? Pancreatology 2010;10:613619. 12 Dellinger EP, Forsmark CE, Layer P, Lévy P, Maraví-Poma E, Petrov MS, et al. Determinant-based classification of acute pancreatitis severity: an international multidisciplinary consultation. Ann Surg 2012;256:875-880. 13 Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996;22:707-710. 14 Larvin M, McMahon MJ. APACHE-II score for assessment and monitoring of acute pancreatitis. Lancet 1989;2:201-205. 15 Singh VK, Wu BU, Bollen TL, Repas K, Maurer R, Johannes RS, et al. A prospective evaluation of the bedside index for
severity in acute pancreatitis score in assessing mortality and intermediate markers of severity in acute pancreatitis. Am J Gastroenterol 2009;104:966-971. 16 Wu BU, Johannes RS, Sun X, Tabak Y, Conwell DL, Banks PA. The early prediction of mortality in acute pancreatitis: a large population-based study. Gut 2008;57:1698-1703. 17 Papachristou GI, Muddana V, Yadav D, O'Connell M, Sanders MK, Slivka A, et al. Comparison of BISAP, Ranson's, APACHE-II, and CTSI scores in predicting organ failure, complications, and mortality in acute pancreatitis. Am J Gastroenterol 2010;105:435-442. 18 Balthazar EJ, Robinson DL, Megibow AJ, Ranson JH. Acute pancreatitis: value of CT in establishing prognosis. Radiology 1990;174:331-336. 19 Mortele KJ, Wiesner W, Intriere L, Shankar S, Zou KH, Kalantari BN, et al. A modified CT severity index for evaluating acute pancreatitis: improved correlation with patient outcome. AJR Am J Roentgenol 2004;183:1261-1265. 20 Bollen TL, Singh VK, Maurer R, Repas K, van Es HW, Banks PA, et al. A comparative evaluation of radiologic and clinical scoring systems in the early prediction of severity in acute pancreatitis. Am J Gastroenterol 2012;107:612-619. 21 Petrov MS, Windsor JA. Classification of the severity of acute pancreatitis: how many categories make sense? Am J Gastroenterol 2010;105:74-76. 22 Li J, Xue GJ, Liu YL, Javed MA, Zhao XL, Wan MH, et al. Early oral refeeding wisdom in patients with mild acute pancreatitis. Pancreas 2013;42:88-91. 23 Banks PA, Freeman ML; Practice Parameters Committee of the American College of Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol 2006;101: 2379-2400. 24 Murata A, Matsuda S, Mayumi T, Yokoe M, Kuwabara K, Ichimiya Y, et al. Effect of hospital volume on clinical outcome in patients with acute pancreatitis, based on a national administrative database. Pancreas 2011;40:1018-1023. Received July 23, 2012 Accepted after revision September 4, 2013
Hepatobiliary Pancreat Dis Int，Vol 13，No 3 • June 15，2014 • www.hbpdint.com • 327