LETTER TO THE EDITOR Fulminant Acute Pancreatitis To the Editor: he recent “determinant-based” classification1 is a welcome advance in the stratification of cases of acute pancreatitis. Central to the categorization as “severe” and “critical” is the concept of persistence of features of organ failure for more than 48 hours. There is a small group of patients, whose clinical course is truly catastrophic. These patients tend to die within the first few days (or even the first day) after presentation either because of respiratory failure or because of an overwhelming systemic inflammatory syndrome in tandem with a huge cytokine storm. I think that it would be worthwhile classifying these patients separately as they often do not survive long enough to have a contrast-enhanced computed tomographic scan at day 3, nor even to develop 48 hours of acute organ failure. Perhaps these patients should be described as “fulminant acute pancreatitis.” Supportive of this approach is earlier work that has shown that patients who develop organ failure early in the course of their disease have a significantly worse prognosis.2

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Andrew Thomson, FRACP Gastroenterology Unit The Canberra Hospital Australian National University Australia [email protected]

REFERENCES 1. Dellinger EP, Forsmark CE, Layer P, et al. Pancreatitis Across Nations Clinical Research and Education Alliance (PANCREA). Determinant-based classification of acute pancreatitis severity: an international multidisciplinary consultation. Ann Surg. 2012;256:875–880. 2. Sharma M, Banerjee D, Garg PK. Characterization of newer subgroups of fulminant and subfulminant pancreatitis associated with a high early mortality. Am J Gastroenterol. 2007;102:2688– 2695.

Disclosure: The authors declare no conflicts of interest. C 2014 by Lippincott Williams & Wilkins Copyright  ISSN: 0003-4932/14/26101-e0023 DOI: 10.1097/SLA.0000000000000647

Reply:

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e appreciate the feedback of colleagues from China, Australia, Italy, India, and Germany to the new determinant-based classification (DBC) of acute pancreatitis severity published under the auspices of the Pancreatitis Across Nations Clinical Research and Education Alliance (PANCREA) in the Annals of Surgery.1 This classification is based on factors that are causally associated with severity, which are called “determinants,” and include both local and systemic factors. The local determinant of severity is necrosis of the pancreas and/or peripancreatic tissue. This is covered by the term “(peri)pancreatic necrosis.” The systemic determinant of severity is organ failure resulting from acute pancreatitis. The definitions used for the categories of severity are based on attributes and interactions of the local determinants [absent, sterile, or infected (peri)pancreatic necrosis] and the systemic determinants (absent, transient, or persistent organ failure). The number of categories was a by-product rather than the objective of this approach.2 There are 3 points in the submitted letters that deserve careful consideration. These relate to the early-onset organ failure in acute pancreatitis, the critical category of severity, and the consultation process. The authors from China and Australia propose the inclusion of the early-onset organ failure into a modified classification of severity. To justify this, there needs to be a careful examination of the impact on the relative risk of mortality for both early-onset and late-onset organ failures. They refer to 3 single-center studies to support the concept of “early” severe acute pancreatitis, but all the 3 studies are encumbered by important limitations.3–5 The definitions used for “organ failure” in one of the referred studies, which include pancreatic bed bleeding and sepsis, are no longer acceptable.3 Furthermore, early open necrosectomy, now abandoned because of a prohibitive mortality rate, was advocated in the other 2 referred studies.4,5 These limitations suggest that we should be circumspect as any mortality difference between the “early” and “late” groups might be attributable to known (as described earlier) or unknown confounders. Furthermore, the 2-phase concept is overly simplistic belying the complexity of acute pancreatitis pathophysiology.6,7 In keeping with severe trauma and septic shock, the proinflammatory and anti-inflammatory responses often occur concurrently in the escalating cascades of cytokine release.8 And in relation to the important determinants of severity, although usually late, infected Disclosure: The author declares no conflicts of interest. 10.1097/SLA.0000000000000508

Annals of Surgery r Volume 261, Number 1, January 2015

pancreatic necrosis can occur early and persistent organ failure can occur late even in the absence of infection.9–12 The designation of an early phase that is sterile and a late phase that is infected is just not tenable. The authors from Italy have raised a question about the necessity of the critical category of severity. The definition of the critical category preceded the development of the DBC. A meta-analysis of more than 1400 patients clearly demonstrated that patients with the combination of local and systemic severity determinants had an extremely severe course of the disease.13 When this occurred, there was a doubling of the mortality. The importance of defining the critical category of acute pancreatitis severity has been confirmed in an independent validation study from India, which highlighted that the mortality rate was 34% for severe acute pancreatitis and 87% for critical acute pancreatitis.14 Furthermore, the study showed a significant difference between these categories in terms of other important clinical endpoints, including computed tomography severity index, need for percutaneous catheter drainage, need for surgical interventions, prevalence of blood infection, Acute Physiology and Chronic Health Evaluation II score, number and duration of stay in intensive care unit, and total length of hospital stay.14 The authors from India and Germany have raised a concern about “the manner” in which the survey was conducted. The method used to conduct the first global survey of pancreatologists was original, taking advantage of being able to access e-mail addresses of all corresponding authors of recent publications relating to clinical acute pancreatitis.15 This was considered an open and unbiased sampling of pancreatologists around the world. As such, this method is more likely to result in a less skewed distribution of pancreatologists than, for instance, contacting the members of certain societies, but we accept that this approach has not been tested. The authors should also note that the term “consensus” has not been used or claimed in our publication, but rather we have deliberately used the more moderate term “consultation.”1 Caution is advised as any claim of “consensus” in other publications in this complex field would likely belie reality. Now that the DBC has been presented, debated in a number of international forums (including a global online survey and a dedicated symposium at the 2011 International Association of Pancreatology meeting), and prospectively validated, the question arises as to whether it surpasses the performances of other classifications.16 The appropriate and validated metric to compare different approaches to classification is net reclassification improvement. This defines the relative www.annalsofsurgery.com | e23

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Annals of Surgery r Volume 261, Number 1, January 2015

improvement in discriminating the event of interest after introducing a new classification scheme.17 The net reclassification improvement of the DBC is +66.4% (a net +17.2% of the patients who died and a net +49.2% of the patients who did not die were reclassified appropriately), and it indicates excellent discriminative ability of the DBC.16 This is compared with the net reclassification improvement of the revised Atlanta classification of only +43.1% (a net −6.9% of the patients who died and a net +50.0% of the patients who did not die were reclassified appropriately), and it indicates that, even in comparison with the original Atlanta classification, the revised Atlanta classification fails to offer any improvement in reclassification of those patients who will eventually die.16 The discriminative ability of the DBC is superior to the one offered by other classifications, and its particular strength lies in considerably improved stratification of the most challenging subgroup of patients with acute pancreatitis— those who are most likely to die. But there is certainly a room for improvement here, and that is why the focus of the next project under the auspices of the PANCREA is the patient characteristics that have a significant impact on mortality in acute pancreatitis.18 A multicenter international study is currently underway, and the first results are expected in the second half of 2014. In conclusion, the DBC offers a superior discriminative ability and is a valid approach that can be used in both clinical practice and clinical research. There is considerable interest in collaborative opportunities to accumulate evidence from around the world on the use of this classification in se-

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lecting a proper study population for clinical trials, evaluating effects of studied treatments, and comparing outcomes of patients between different institutions. Pancreatitis Across Nations Clinical Research and Education Alliance (PANCREA) [email protected]

REFERENCES 1. Dellinger EP, Forsmark CE, Layer P, et al. Pancreatitis Across Nations Clinical Research and Education Alliance (PANCREA). Determinant-based classification of acute pancreatitis severity: an international multidisciplinary consultation. Ann Surg. 2012;256:875–880. 2. Petrov MS, Windsor JA. Conceptual framework for classifying the severity of acute pancreatitis. Clin Res Hepatol Gastroenterol. 2012;36:341– 344. 3. Sharma M, Banerjee D, Garg PK. Characterization of newer subgroups of fulminant and subfulminant pancreatitis associated with a high early mortality. Am J Gastroenterol. 2007;102: 2688–2695. 4. Isenmann R, Rau B, Beger HG. Early severe acute pancreatitis: characteristics of a new subgroup. Pancreas. 2001;22:274–278. 5. Tao HQ, Zhang JX, Zou SC. Clinical characteristics and management of patients with early acute severe pancreatitis: experience from a medical center in China. World J Gastroenterol. 2004;10:919–921. 6. Petrov MS, Windsor JA. Classification of the severity of acute pancreatitis: how many categories make sense? Am J Gastroenterol. 2010;105:74– 76. 7. Mason J, Siriwardena AK. Designing future clinical trials in acute pancreatitis. Pancreatology. 2005;5:113–115. 8. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369: 840–851.

9. Isenmann R, Rau B, Beger HG. Bacterial infection and extent of necrosis are determinants of organ failure in patients with acute necrotizing pancreatitis. Br J Surg. 1999;86:1020–1024. 10. Le Mee J, Paye F, Sauvanet A, et al. Incidence and reversibility of organ failure in the course of sterile or infected necrotizing pancreatitis. Arch Surg. 2001;136:1386–1390. 11. Buchler MW, Gloor B, Muller CA, et al. Acute necrotizing pancreatitis: treatment strategy according to the status of infection. Ann Surg. 2000;232:619–626. 12. Petrov MS, Chong V, Windsor JA. Infected pancreatic necrosis: not necessarily a late event in acute pancreatitis. World J Gastroenterol. 2011;17:3173–3176. 13. Petrov MS, Shanbhag S, Chakraborty M, et al. Organ failure and infection of pancreatic necrosis as determinants of mortality in patients with acute pancreatitis. Gastroenterology. 2010;139:813– 820. 14. Thandassery RB, Yadav TD, Dutta U, et al. Prospective validation of 4-category classification of acute pancreatitis severity. Pancreas. 2013;42: 392–396. 15. Petrov MS, Vege SS, Windsor JA. Global survey of controversies in classifying the severity of acute pancreatitis. Eur J Gastroenterol Hepatol. 2012;24:715–721. ˜ C vy P. Pancreatitis 16. Petrov MS, Windsor JA, LA Across Nations Clinical Research and Education Alliance (PANCREA). New international classification of acute pancreatitis: more than just 4 categories of severity. Pancreas. 2013;42:389–391. 17. Pencina MJ, D’Agostino RB, Sr, Demler OV. Novel metrics for evaluating improvement in discrimination: net reclassification and integrated discrimination improvement for normal variables and nested models. Stat Med. 2012;31:101– 113. 18. Das SL, Papachristou GI, De Campos T, et al. Pancreatitis Across Nations Clinical Research and Education Alliance (PANCREA). Individual patient data meta-analysis of organ failure in acute pancreatitis: protocol of the PANCREA II study. JOP. 2013;14:475–483.

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