ORIGINAL ARTICLE

Decreased Severity in Recurrent Versus Initial Episodes of Acute Pancreatitis Peter J.W. Lee, MD,* Amit Bhatt, MD,* Jordan Holmes, MD,* Amareshwar Podugu, MD,* Rocio Lopez, MS, MPH,† Matthew Walsh, MD,* and Tyler Stevens, MD* Objectives: The comparative outcomes of initial versus recurrent acute pancreatitis (AP) have not been clearly established. Aim: The aim was to compare the clinical outcomes of those with an initial episode of AP to those with recurrent AP stratified by the number of prior episodes. Methods: This retrospective cohort study included consecutive patients with AP admitted to the Cleveland Clinic between 2008 and 2011. The odds of severe AP, multisystem organ failure, ICU admission, new local complications, elevated blood urea nitrogen and bedside index for severity in acute pancreatitis score, systemic inflammatory response syndrome, and mortality were compared using univariable and multivariable logistic regression. Results: Two hundred and ninety two patients were included, of which 213 (72%) were admitted on their initial AP episode. Mortality in patients experiencing first episode was 4.7%, compared to 0% in patients with recurrent attack of pancreatitis (P = 0.047). Prior episodes of AP were found to be protective against multisystem organ failure (odds ratio, 0.14 for each prior episode; confidence interval, 0.01–0.76) and intensive care unit admission (0.24, confidence interval, 0.06–0.91), adjusting for potential confounding factors such as transfer status and obesity. Conclusions: Patients presenting with recurrent AP may be at decreased risk of a clinically severe course and incur decreased mortality. Key Words: recurrent pancreatitis, acute pancreatitis, mortality, severe pancreatitis Abbreviations: AP - acute pancreatitis, MSOF - multisystem organ failure, SIRS - systemic inflammatory response syndrome, ICU - intensive care unit, CP - chronic pancreatitis, CCI - Charlson comorbidity index (Pancreas 2015;44: 896–900)

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he United States has one of the highest admission rates for acute pancreatitis (AP) among Western countries, and its estimated total direct cost exceeds two billion dollars annually.1,2 The incidence has been rising over the past 2 decades, and AP was the number one cause of gastrointestinal-related hospitalizations in 2012. 2,3 Moreover, AP has a recurrence rate ranging between 10.9% and 27%, amplifying the cost burden. Recurrence is most common when the underlying cause cannot be found or is not eliminated.4–6 The morbidity, mortality, and costs related to AP are closely correlated to the severity of the attack. Severity is determined by persistent organ failure, persistent systemic inflammatory From the *Digestive Disease Institute, and †Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH. Received for publication April 28, 2014; accepted January 13, 2015. Reprints: Tyler Stevens, MD, Digestive Disease Institute, 9500 Euclid Ave, Desk Q3, Cleveland Clinic, Cleveland, OH 44195 (e‐mail: [email protected]). The authors declare no conflict of interest. Guarantor of the article: Tyler Stevens, MD. Specific author contributions: Peter Lee, study concept, acquisition of data, interpretation of data, and drafting of the paper; Amit Bhatt, acquisition of data, concept, and study design; Jordan Holmes and Amareshwar Podugu, acquisition of data; Richard Walsh, revision of the paper; Rocio Lopez, statistical analysis and interpretation of data; and Tyler Stevens, drafting of the paper and critical revision. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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response syndrome (SIRS), and the presence of infected necrosis.7 Patients with mild pancreatitis who lack these features usually recover within 4 days without the development of other organ manifestations and have negligible mortality.8 Observational studies have reported that recurrent pancreatitis may run a milder clinical course than an index episode.9,10 However, existing literature has yet to clearly characterize in-hospital outcomes such as mortality, rates of multisystem organ failure (MSOF), and intensive care unit (ICU) admissions, or to demonstrate an association between number of attacks and severity. Accurate knowledge of these clinical outcomes of recurrent pancreatitis has important implications for health care resource allocations. In this study, we retrospectively compared the outcomes of patients presenting with their first versus subsequent attack of AP to determine the impact of recurrence on severity.

MATERIALS AND METHODS A single-center historical cohort study was conducted using our institutional review board–approved AP database (Cleveland Clinic Institutional Review Board 10-779). The study was approved with a waiver of informed consent owing to its retrospective nature. The database was designed to examine and improve the quality of care of patients admitted with AP. Consecutive subjects were identified who had a primary or secondary discharge diagnosis of AP (International Classification of Diseases, Ninth Revision, 577.0) from years 2008 to 2011. Study data were collected and managed using REDCap electronic data capture tools hosted at Cleveland Clinic. 11 Thirty-six demographic, clinical, etiologic, laboratory, imaging, and outcome variables were collected by manual abstraction of the electronic and written medical records. The diagnosis of AP was confirmed based on the American College of Gastroenterology guidelines, which require 2 or the following 3 features: (1) typical abdominal pain, (2) increased serum amylase and/or lipase >3 times the upper limit of normal, (3) CT or ultrasound imaging features of AP. 12 Patients were excluded if AP occurred during a hospitalization for another acute illness. Recurrent AP was defined as AP occurring at least 2 months after the previous episode. The number of prior attacks was determined based on the admitting history and physical note and past medical records. The Charlson comorbidity index (CCI) was calculated for all patients to summarize their underlying age- and health-related comorbidities. Patients with chronic pancreatitis (CP) were excluded. The presence of CP was determined based on one or more of the following criteria: (1) computed tomographic evidence of pancreatic calcifications, ductal dilation or strictures without a mass, or atrophy, (2) magnetic resonance cholangiopancreatography or endoscopic retrograde cholangiopancreatography showing Cambridge class 3 or 4 ductal changes, and (3) EUS showing 4 or more standard criteria or “suggestive/most consistent” based on Rosemont scoring. Several outcomes related to AP severity were examined. These were severity as defined by the revised Atlanta criteria, 7 organ failure as determined by the modified Marshall score, multisystem organ failure (MSOF), AP-related mortality, systemic inflammatory response syndrome (SIRS), elevated blood urea Pancreas • Volume 44, Number 6, August 2015

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Pancreas • Volume 44, Number 6, August 2015

Reduced Severity in Recurrent Pancreatitis

nitrogen (BUN) upon admission, and elevated bedside index for severity in acute pancreatitis (BISAP) score of 3 or higher upon admission.7,13

Statistical Analysis Data are presented as mean ± standard deviation, median [25th, 75th percentiles], or N (%). For the univariable analysis, the Cochran-Armitage test for trend was used for binary variables and Jonckheere-Terpstra test was used for all other variables. Multivariable logistic regression analysis was used to assess associations between episode number and ICU admission, MSOF, and severe AP. Proportional odds regression was used for BISAP score on day 1 and linear regression was used to assess associations with change in BUN at the time of admission. A natural logarithm transformation was used for BUN. An automated stepwise variable selection method performed on 1000 bootstrap samples was used to choose the final models. Episode number was forced into the model; and age, sex, body mass index (BMI), smoking, CCI, and transfer patients were among the variables considered for inclusion. The “10 events per variable” rule was used to limit the final number of variables in each model and the x variables with highest inclusion rates were kept in the final model. P < 0.05 was considered statistically significant. Survival analysis was performed to assess AP-related death rates. A Kaplan-Meier plot was constructed, and a log-rank test was used to compare the groups. All analyses were performed using SAS software version 9.2 (SAS Institute, Cary, NC) and R version 3.0.1 (The R Foundation for Statistical Computing, Vienna, Austria).

of Gastroenterology criteria for AP. Six patients were excluded because they had an attack within 2 months or were admitted for a complication of previous AP. Forty-two patients were excluded based on a history of CP. This left 294 patients who were included in the final analysis, of which 72% were admitted with their first episode. Severe AP occurred in 27 patients (10%), MOSF in 17 patients (5%), and in-hospital mortality in 10 patients (3%). Tables 1 and 2 present the results of the univariable analysis. Patients were classified in 4 groups based on episode number. Younger age, lower BMI, male sex, and lower CCI were significantly associated with more episodes of AP (Table 1). The percentage with unknown etiology seemed to be higher in those with recurrent AP, although the trend was not statistically significant. Patients with recurrent AP had lower admitting BUN levels (P ≤ 0.001), fewer ICU admissions (P = 0.019), decreased likelihood of severe AP (P = 0.003), decreased incidence of MSOF (P = 0.009), and fewer deaths (P = 0.047) compared to initial AP (Fig. 1). Ten patients (5%) admitted for their initial AP episode had an AP-related death compared to none of those admitted for recurrent AP. A statistically significant increase in the risk of death was found in those presenting with a first compared to a recurrent attack (Fig. 2). The results of the multivariable models are shown in Table 3. For each additional episode of AP, the adjusted odds of severe AP decreased by 55%, the odds of MSOF decreased by 86%, and the odds of ICU stay decreased by 76%. The odds of MSOF remained significantly decreased even when adjusted for obesity and transfer status.

DISCUSSION

RESULTS Three hundred and eighty admissions in 342 patients were identified between 2008 and 2011 that met the American College

Despite the perception that recurrent AP has a better prognosis than initial AP, the evidence has been inconsistent. Whereas past studies in Europe and in the United States demonstrated lower

TABLE 1. Demographic and Clinical Characteristics First (n = 213) Factor Age BMI Male Smoking Current smoker Ex-smoker Never smoker Any alcohol consumption Etiology Alcohol Gallstones Triglycerides Drug induced Post ERCP Other Unknown CCI Transfer patient

Second (n = 44)

Third (n = 14)

>3 episodes (n = 23)

n

Summary

n

Summary

n

Summary

n

Summary

P

211 203 213 196

55.5 ± 16.6 29.0 ± 6.7 105 (49.3)

44 42 44 39

53.8 ± 18.5 27.3 ± 8.1 25 (56.8)

13 14 14 13

45.2 ± 12.4 29.1 ± 7.0 7 (50.0)

23 22 23 21

45.7 ± 16.5 25.9 ± 7.4 18 (78.3)

0.013 20 on days 1 and 2 ICU admission Length of stay, days Diet at discharge Tube feed dependency Liquid diet Solid diet Deceased AP-related death

Summary

213

Second (n = 44) n

172 (80.8) 16 (7.5) 25 (11.7) 213 213 213 213 213 213 213

6 (2.8) 7 (3.3) 10 (4.7) 25 (11.7) 16 (7.5) 26 (12.2)

4

44 44 44 44 44 44 44

0 (0.0) 4 (9.1) 3 (6.8) 1 (2.3) 0 (0.0) 1 (2.3)

213 211 186 213 204

87 (40.8) 82 (38.5) 23 (10.8) 15 (7.0) 6 (2.8) 44 (20.7) 15.0 [11.0, 22.0] 44 (23.7) 26 (12.2) 5.0 [2.0, 8.0]

213 213 213 213 213

10 (4.7) 12 (5.6) 116 (54.5) 37 (17.4) 10 (4.7)

43 44 44

Summary

44 44 39 44 44

25 (56.8) 9 (20.5) 8 (18.2) 2 (4.5) 0 (0.0) 10 (22.7) 12.0 [9.5, 19.0] 8 (20.5) 2 (4.5) 4.0 [2.0, 7.0]

44 44 44 44 44

3 (6.8) 6 (13.6) 27 (61.4) 8 (18.2) 0 (0.0)

n

14 14 14 14 14 14 14

0 (0.0) 1 (7.1) 2 (14.3) 0 (0.0) 0 (0.0) 0 (0.0)

P 0.45

19 (82.6) 3 (13.0) 1 (4.3) 23 23 23 23 23 23 23

0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 14 (100.0)

14 14 14

Summary

23

0 0 (0.0) 2 (50.0) 2 (50.0) 0 (0.0) 4 (9.3) 8 (18.2)

>3 episodes (n = 23)

11 (78.6) 3 (21.4) 0 (0.0)

0 (0.0) 1 (2.3) 1 (2.3) 2 (4.5) 40 (90.9) 4

2 (50.0) 1 (25.0) 0 (0.0) 1 (25.0) 48 (24.4) 62 (29.1)

n 14

36 (81.8) 7 (15.9) 1 (2.3)

1 (0.47) 0 (0.0) 1 (0.47) 2 (0.94) 209 (98.1)

197 213 213

Summary

44

Third (n = 14)

0 (0.0) 3 (13.0) 0 (0.0) 1 (4.3) 0 (0.0) 1 (4.3)

0.11 0.002 0.51 0.004 0.009 0.003 0.27

1 (4.3) 0 (0.0) 0 (0.0) 0 (0.0) 22 (95.7) 1

— — — — 5 (35.7) 5 (35.7)

19 23 23

14 14 12 14 14

9 (64.3) 3 (21.4) 2 (14.3) 0 (0.0) 0 (0.0) 2 (14.3) 13.0 [11.0, 16.0] 0 (0.0) 0 (0.0) 5.0 [3.0, 5.0]

23 23 17 23 23

14 14 14 14 14

0 (0.0) 1 (7.1) 11 (78.6) 2 (14.3) 0 (0.0)

23 23 23 23 23

0 (0.0) 1 (100.0) 0 (0.0) 0 (0.0) 3 (15.8) 7 (30.4)

0.1 0.96 0.032

13 (56.5) 5 (21.7) 4 (17.4) 1 (4.3) 0 (0.0) 5 (21.7) 0.16 14.0 [9.0, 15.0]

Decreased Severity in Recurrent Versus Initial Episodes of Acute Pancreatitis.

The comparative outcomes of initial versus recurrent acute pancreatitis (AP) have not been clearly established...
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