Author Affiliations: Department of Preventive Medicine and Community Health, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan (Murata A, Ohtani M, Muramatsu K and Matsuda S)

Corresponding Author: Atsuhiko Murata, MD, Department of Preventive Medicine and Community Health, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan (Tel: +81-93-6917244; Fax: +81- 93-6034307; Email: amurata@med.uoeh-u.ac.jp)

 

© 2015, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(15)60398-8

Published online July 14, 2015.

 

 

Contributors: MA proposed the study. OM and MK collected, and MA and MS analyzed the data. MA drafted the article and all authors revised it critically for important intellectual content and approved the final version submitted for publication. MA is the guarantor.

Funding: This study was supported by grants-in-aid from the Research on Policy Planning and Evaluation from the Ministry of Health, Labor and Welfare, Japan.

Ethical approval: The study was approved by the Ethics Committee of Medical Care and Research of the University of Occupational and Environmental Health, Kitakyushu, Japan.

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.

 

BACKGROUND: Little information is available on the influence of comorbidities on outcomes of older patients with acute pancreatitis. This study aimed to investigate the influence of comorbidities on outcomes of older patients with acute pancreatitis using data from a national Japanese administrative database.

 

METHODS: A total of 14 322 older patients (≥70 years) with acute pancreatitis were referred to 1090 hospitals between 2010 and 2012 in Japan. We collected patients' data from the administrative database to compare the in-hospital mortality and length of stay of older patients with acute pancreatitis. The patients were categorized into four groups according to comorbidity level using the Charlson Comorbidity Index (CCI): none (CCI score=0; n=6890); mild (1; n=3874); moderate (2; n=2192) and severe (≥3; n=1366).

 

RESULTS: Multiple logistic and linear regression analyses revealed that severe comorbidity was significantly associated with higher in-hospital mortality and longer length of stay [odds ratio (OR)=2.26; 95% confidence interval (CI): 1.75-2.92, P<0.001 and coefficient 4.37 days; 95% CI: 2.89-5.85, P<0.001, respectively]. In addition, cardiovascular and renal diseases were the most significant comorbidities affecting outcomes of the older patients. ORs of cardiovascular and renal diseases for mortality were 1.44 (95% CI: 1.13-1.85, P=0.003) and 2.69 (95% CI: 1.88-3.85, P<0.001), respectively, and coefficients for length of stay were 3.01 days (95% CI: 1.34-4.67, P<0.001) and 3.72 days (95% CI: 1.01-6.42, P=0.007), respectively.

 

CONCLUSION: This study demonstrated that comorbidities significantly influenced outcomes of older patients with acute pancreatitis and cardiovascular and renal comorbidities were significant factors affecting outcomes.

 

(Hepatobiliary Pancreat Dis Int 2015;14:422-428)

 

KEY WORDS: acute pancreatitis; comorbidity; length of stay; databases

Acute pancreatitis is characterized by a local and systemic inflammatory response, which results in pancreatic microvascular and parenchymal tissue injury as well as alterations in remote organs.^[1-3] The number of patients with acute pancreatitis has been increasing. In the United States, acute pancreatitis leads to 270 000 hospital admissions annually, and inpatient costs exceed 2.5 billion dollars.^[4] Two Japanese nationwide epidemiological surveys^{[5, 6]} have shown that the estimated total number of patients with acute pancreatitis increased from 57 560 in 2007 to 63 080 in 2011. Roberts et al^[7] reported that the prevalence of acute pancreatitis significantly increased from 27.6 per 100 000 in 1999 to 36.4 per 100 000 in 2010. Therefore, acute pancreatitis is a significant health and economic burden in developed countries.

 

The World Health Report has highlighted the acceleration of population aging worldwide, with marked increases in the numbers of older people in many countries.^[8] Increasing life expectancy and an aging population will inevitably lead to a growing number of older patients. At the same time, the number of patients with comorbidities is rapidly increasing in some developed countries as the population of older patients increases.^[9,10] In a cross-sectional study, Wolff et al^[9] reported that most older patients have at least one chronic comorbid condition, and that medical expenditure increases in line with the number of chronic comorbidities.

 

However, little information is available on the influence of comorbidities on outcomes of older patients with acute pancreatitis. Clarification of the influence of comorbidities could contribute to improvements in the quality of management of older patients with acute pancreatitis, which could have significant implications for healthcare policy decision-making. In this study, we investigated the influence of comorbidities on outcomes of older patients with acute pancreatitis. This influence was determined by analyzing a large quantity of patient data from the national, administrative, Japanese case-mix discharge database named the Diagnosis Procedure Combination (DPC).

 

 

The healthcare system of Japan has severe financial difficulties related to the costs of new medical technology, a rapidly aging society, and extended patient hospitalization duration.^[11-15] To address these issues, the Ministry of Health, Labor and Welfare and its affiliated research institute have begun investigating whether the Japanese case-mix classification system, namely the DPC, can be used to standardize medical profiling and payments.^[11-15] The DPC system was introduced to 82 academic hospitals (the National Cancer Center, the National Cardiovascular Center, and 80 university hospitals) in 2003.^[11-15] Reimbursement from health insurance using the DPC system is common practice in Japan. According to the DPC administrative database, the number of participating acute-care hospitals has increased, and enormous amounts of inpatient data are collected annually from approximately 90% of the total acute-care inpatient hospitalizations nationwide.^[11-15] The DPC database compiled inpatient data during 9 months (from July to the following March) until 2010 and then all year round since 2011.

 

The DPC system collects important patient data during hospitalization in addition to specific data for reimbursement. Each patient's financial data, claim information, and discharge summary (including the principal diagnosis, complications, and comorbidities during hospitalization) are meticulously recorded in the database. These data are coded according to the International Classification of Diseases and Injuries, 10th Revision (ICD-10) code. Additionally, this database contains comprehensive medical information, including all interventional or surgical procedures, and medications that are indexed in original Japanese codes assigned by the Ministry of Health, Labor and Welfare of Japan.^[11-15] The date and amount of daily care delivered during hospitalization are also recorded in the DPC administrative database.^[11-15]

 

From the DPC database, we collected data of patients with acute pancreatitis (K85) as the principal diagnosis during hospitalization. A total of 47 247 patients with acute pancreatitis were identified in the database for the years 2010, 2011 and 2012. We excluded 7535 patients with missing or unknown data. The main population of interest in this investigation was older patients, defined as patients aged ≥70 years in the Japanese Clinical Practice Guidelines for Acute Pancreatitis;^[16] therefore 25 390 patients aged <70 years were excluded. A total of 14 322 patients were identified as having acute pancreatitis, and were included in the analysis (Fig.). The severity of chronic comorbid conditions was assessed using the Charlson Comorbidity Index (CCI), which has been widely used for analyzing comorbidities and has been validated in various studies.^[17] The CCI score was calculated for each patient according to the method used in a previous study, which demonstrated the association between the CCI and ICD-10 code.^[17] The CCI was expressed as the score of all comorbid conditions and was initially evaluated as a continuous variable. These patients were categorized into four groups according to the level of comorbidity: none (CCI score=0; n=6890), mild (1; n=3874), moderate (2; n=2192), and severe (≥3; n=1366) (Fig.). The patients had been admitted to 1090 hospitals participating in the DPC (83 academic and 1007 community hospitals) from 2010 to 2012.

 

The use of DPC data was permitted by all institutions and hospitals that provided the data. The research protocol of the study was approved by the Ethics Committee of Medical Care and Research of the University of Occupational and Environmental Health, Kitakyushu, Japan.

 

Study variables included age, severity of acute pancreatitis, gender, body mass index (BMI), use of ambulance transportation, admission to the intensive care unit, treatments for acute pancreatitis (total parenteral nutrition or enteral nutrition, use of antimicrobial drugs or protease inhibitors, continuous intra-arterial infusion, surgical drainage and necrosectomy), treatments for organ support (continuous hemodiafiltration, mechanical ventilation and use of vasopressor), hospital type, size and region, hospitals with emergency centers, in-hospital mortality, and length of stay (LOS).

 

Age categories were stratified as follows: 70-79 years, 80-89 years, and ≥90 years. Japanese clinical practice guidelines have introduced a scoring system to determine the severity of acute pancreatitis.^[16] This unique scoring system consists of nine prognostic scores and three computed tomography grades, and severe acute pancreatitis is defined as a prognostic score of 3 or more or computed tomography severity grade of 2 or more.^[16] Using the prognostic scores and computed tomography severity grades recorded in the DPC database, patients were divided into two categories, mild and severe. BMI was classified into two groups: <30 and ≥30 kg/m². We referred to the Japanese clinical practice guidelines for acute pancreatitis regarding treatments or procedures.^[18-20] Hospital type was classified as academic or community.^[11-15] Hospital size was categorized into three groups according to the number of hospital beds as follows: small (<200 beds), medium (200-600 beds), and large (>600 beds).^[11-15] Hospital region was classified as urban or rural. We defined an urban region as a prefecture with a population concentration of ≥50% and a rural region as a prefecture with a population concentration of <50%, as reported previously.^[21]

 

We used the Chi-square test for categorical data and one-way analysis of variance for continuous variables. Additionally, we used multiple logistic regression models to estimate the odds ratios (ORs) and their 95% confidence intervals (CIs) for in-hospital mortality, with the mild comorbidity group as the reference group. Age, severity of acute pancreatitis, gender, BMI, use of ambulance transportation, intensive care unit admission, and treatments for acute pancreatitis as well as organ support were considered to be potential confounders. Hospital characteristics such as hospital type, size and region, and hospitals with emergency centers were also considered as confounding factors in the multiple logistic regression models. A multiple linear regression model was also used to confirm the influence of comorbidity on LOS, incorporating the above-mentioned confounding factors. In addition, using multiple logistic and linear regression models, we investigated the effect of each comorbidity such as cardiovascular diseases, cerebrovascular diseases, diabetes mellitus, digestive and liver diseases, malignant diseases, pulmonary diseases, renal diseases, and other diseases as described in CCI.^[17]

 

All statistical analyses were performed using the Stata statistical software package version 11.0 (Stata Corp., College Station, TX, USA). A P<0.05 was considered statistically significant.

 

 

Of 14 322 patients in this study, 6890 patients had no comorbidity, 3874 patients had mild comorbidity, 2192 patients had moderate comorbidity, and 1366 patients had severe comorbidity. The total in-hospital mortality was 5.3%, while the mean LOS of all patients was 23.2 days.

 

The clinical characteristics of the patients and hospitals are shown in Table 1. The proportion of male patients, and rate of total parenteral nutrition were significantly higher in patients with severe comorbidity. The proportions of patients in academic hospitals or large-sized hospitals were also significantly higher for those with severe comorbidity. There was a significant difference with regard to in-hospital mortality (4.7% vs 4.6% vs 6.1% vs 8.6%, P<0.001). The LOS in patients with severe comorbidity was also longer than in those with mild or moderate comorbidity (none: 22.0 days; mild: 23.5 days; moderate: 23.7 days; severe: 27.4 days; P<0.001).

 

Multiple logistic regression analysis of in-hospital mortality according to level and type of comorbidity is presented in Table 2. After adjustment for patient characteristics as well as hospital characteristics, a significant association was seen between in-hospital mortality and comorbidity level (OR for moderate comorbidity: 1.42, 95% CI: 1.11-1.80, P=0.004; OR for severe comorbidity: 2.26, 95% CI: 1.75-2.92, P<0.001). Regarding the type of comorbidity, cardiovascular, malignant and renal diseases were significantly associated with higher in-hospital mortality in older patients with acute pancreatitis [OR=1.44 (95% CI: 1.13-1.85, P=0.003), 1.68 (95% CI: 1.29-2.20, P<0.001), and 2.69 (95% CI: 1.88-3.85, P<0.001), respectively].

 

Multiple linear regression analysis of LOS according to level and type of comorbidity is shown in Table 3. After adjustment for patients and hospital characteristics, severe comorbidity was significantly associated with a longer LOS. The coefficient was 4.37 days (95% CI: 2.89-5.85, P<0.001). Multiple linear regressions also revealed that cardiovascular and renal diseases were significant factors affecting LOS. The coefficient of cardiovascular disease was 3.01 days (95% CI: 1.34-4.67, P<0.001) while those of renal disease was and 3.72 days (95% CI: 1.01-6.42, P=0.007), respectively.

 

 

Using a national administrative database, we investigated the influence of comorbidity on outcomes of older patients with acute pancreatitis. Our study demonstrated that the comorbidity level significantly influenced outcomes, and that cardiovascular and renal comorbidities were associated with higher mortality and longer LOS.

 

Recently, a number of studies have reported the influence of comorbidities on various aspects of acute pancreatitis.^{[22, 23]} In an epidemiological study, Akshintala et al^[22] reported that comorbidity increased the risk of severity of acute on chronic pancreatitis. Singh et al^[23] also revealed that the mortality of patients with interstitial pancreatitis was strongly associated with their comorbidities. Thus, comorbidity has been recognized as an important factor in patients with acute pancreatitis. However, while some studies have focused on the effect of comorbidities on outcomes of patients with acute pancreatitis, studies using the CCI score to evaluate the influence of comorbidities are rare. Only one report of CCI in patients with acute pancreatitis has been published. McNabb-Baltar et al^[24] investigated the relationship between the incidence and severity of comorbidity using CCI, and found that patients with a CCI≥3 were more likely to be admitted to the emergency department. In this study, we defined the level and type of comorbidity using the CCI because this score reflects the sum of a patient's weighted comorbidities and predicts mortality.^{[25, 26]} Use of the CCI score may be advantageous in assessing the impact of comorbidity on outcomes of patients. In addition, we focused on older patients, whose comorbidities can have a greater influence on outcomes compared with younger patients. Thus, information on the effects of comorbidities in this population is essential for targeting future improvements in the quality of care of older patients with acute pancreatitis.

 

In the present study, older patients with severe comorbidity had approximately twice the risk of in-hospital mortality, and longer hospitalization of 4 days compared with those without comorbidity. In a previous study, Frey et al^[27] found that the increasing number of chronic comorbid medical conditions, particularly three or more, was a very strong predictor of death in patients with acute pancreatitis. Li et al^[28] also noted that the number of comorbidities was correlated with the increased rate of organ failure in patients with acute pancreatitis. The current findings suggested that patient outcomes were strongly associated with the level of comorbidity in acute pancreatitis. In addition, cardiovascular and renal diseases were significant factors affecting both in-hospital mortality and LOS of older patients with acute pancreatitis. These results are consistent with some previous studies and it is reasonable that the infusion volume may influence the outcomes of older patients with acute pancreatitis.^{[29, 30]} However, the validity of high-volume fluid administration remains controversial. In a recent study, Warndorf et al^[31] found that early fluid resuscitation reduced the incidence of systemic inflammatory response syndrome and organ failure. Gardner et al^[32] also showed that patients who did not receive sufficient intravenous fluid volume during the first 24 hours had a greater risk of death than those who were resuscitated more aggressively. Conversely, some studies^{[33, 34]} reported that a large quantity or early administration of fluid led to poorer outcomes in patients with acute pancreatitis. Indeed, early and aggressive infusion may be associated with the acute exacerbation of cardiovascular and renal diseases or a deterioration in heart or kidney function. Thus, these discrepancies suggest the difficulty in determining appropriate fluid administration in patients with acute pancreatitis as well as cardiovascular and renal diseases. However, to our knowledge, there has been no study focusing on the efficacy and safety of early and adequate infusion in older patients with acute pancreatitis and comorbid cardiovascular and renal disease. Prospective or randomized studies are needed to investigate the effect of infusion on the outcomes of such patients.

 

However, pulmonary diseases were not significant predictors of in-hospital mortality or LOS in older patients with acute pancreatitis in this study. One possible explanation is that all pulmonary diseases in the CCI are classified as chronic and severe conditions such as pulmonary edema or adult respiratory distress syndrome, and are thus not specified.^[17] Pulmonary diseases are assigned a lower score in the CCI compared with renal diseases or malignant diseases. Therefore, the selection in the CCI may obscure the real influence of pulmonary diseases on outcomes of patients with acute pancreatitis. Future studies using other methods to classify comorbidity should be conducted.

 

The data source represents a major strength of the current study. One of the benefits of a national database is that it enables evaluation of a large number of hospitals in an unbiased manner. Our investigation involved a nationally representative sample of patients who underwent treatments for acute pancreatitis within their community.^[11-15] Furthermore, detailed daily medical data were available for each patient.^[11-15] Therefore, this administrative database also allows evaluation of the clinical outcomes of individual medical treatments.

 

Some potential limitations of this study also warrant mention. First, the data were obtained from only DPC-participating hospitals, which may have introduced selection bias. Furthermore, we excluded 7535 of 47 247 patients, approximately 16% of all patients with acute pancreatitis, because of incomplete data. Data from non-DPC-participating hospitals and improvement in patient data collection would reduce possible bias. Second, we could not identify the etiology of acute pancreatitis, such as idiopathic, alcoholic, gallstones, or endoscopic retrograde cholangiopancreaticography-related. In addition, we also could not identify those patients who had more severe conditions such as necrotizing pancreatitis or systemic inflammatory response syndrome because these had not been assigned an ICD-10 code. The etiologies or conditions of patients with acute pancreatitis may influence the outcomes of these patients. Therefore, further clinical studies on the effect of comorbidity on outcomes of older patients with acute pancreatitis may be required, taking into account more detailed clinical data.

 

In conclusion, we demonstrated that comorbidity significantly influenced the outcomes of older patients with acute pancreatitis, and that comorbid cardiovascular and renal diseases were significant factors affecting in-hospital mortality and LOS. More attention should be given to the care of older acute pancreatitis patients with severe comorbidity, and especially those with cardiovascular or renal diseases. In addition, further studies on the effect and safety of fluid volume for acute pancreatitis in these patients should be needed in the future.

 

 

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