Dig Dis Sci (2014) 59:1316–1321 DOI 10.1007/s10620-013-3000-7
ORIGINAL ARTICLE
Implementation of the Asia-Pacific Guidelines of Obesity Classification on the APACHE-O Scoring System and Its Role in the Prediction of Outcomes of Acute Pancreatitis: A Study from India Ragesh Babu Thandassery • Sreekanth Appasani • Thakur Deen Yadav • Usha Dutta • Abujam Indrajit Kartar Singh • Rakesh Kochhar
•
Received: 20 September 2013 / Accepted: 11 December 2013 / Published online: 28 December 2013 Ó Springer Science+Business Media New York 2013
Abstract Aims We studied the role of obesity and the Acute Physiology and Chronic Health Evaluation (APACHE) O score in predicting the outcome in patients with acute pancreatitis (AP) using the Asia-Pacific obesity classification. Methods Two hundred eighty AP patients were classified into three different groups, normal weight [body mass index (BMI) = 18.5–22.9 kg/m2], overweight (BMI = 23–24.9 kg/m2) and obese (BMI [ 25 kg/m2), according to the Asia-Pacific obesity classification. For all patients APACHE II scores and modified APACHE O (i.e., APACHE Oap) scores that included a factor for obesity were calculated. The patients were managed using a standard protocol, and the outcome measures were compared for different obesity groups. Results Of the 280 patients (mean age 40.7 years), 46.8 % were normal weight, 29.6 % overweight and 23.6 % obese. Forty-six (16.4 %) patients underwent surgery, and 61 (21.8 %) patients died. Patients with higher BMI had worse radiological indices of severity, more infected necrosis (p \ 0.001), more persistent organ failure (p \ 0.001) and higher requirement for percutaneous drain insertion (p = 0.04), surgery (p = 0.008) and mortality (p \ 0.001). The area under the curve for predicting mortality was 0.879 for APACHE II and 0.886 for APACHE Oap; at a cutoff of 8.5, the APACHE II score had a sensitivity of 88.2 % and specificity of 68.7 %, and APACHE Oap 90.2 and 64.0 %, respectively. Conclusions BMI C 23 kg/m2 was an important predictor of a severe disease course and fatal outcome in patients
R. B. Thandassery S. Appasani T. D. Yadav U. Dutta A. Indrajit K. Singh R. Kochhar (&) Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India e-mail: [email protected]
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with AP. However, the predictive accuracy of APACHE Oap for mortality was similar to APACHE II. Keywords Acute pancreatitis APACHE O Body mass index Obesity
Introduction Acute pancreatitis (AP) is a systemic disease with complex inflammatory cascades. The exact role of individual contributing factors is yet to be clearly defined. Recent studies indicate that among patient characteristics, obesity is an independent risk factor for adverse outcomes in patients with AP [1, 2]. Martinez et al. [3] suggested in a metaanalysis that obesity [body mass index (BMI) [ 30 kg/m2] increased the risk of developing severe AP. The mechanism by which obesity increases the severity of AP is unclear. It is believed that the severity of AP is directly related to the intensity of the immune response and that obese patients are at risk of more severe complications of AP because of a more intense inflammatory response (systemic inflammatory response syndrome, SIRS) to pancreatic injury [4]. It has also been suggested that the higher rate of complications in obese patients could be caused by the existence of obesity-related comorbidity and lower lung compliance [4–6]. Central obesity in particular could lead to a worse prognosis in AP. Adipose tissue is an important source of cytokines, and obesity can be considered a state of chronic inflammation. Obese humans have increased levels of several proinflammatory cytokines including adipocytokines [7]. Serum tumor necrosis factor (TNF-a) [8], C-reactive protein (CRP) [9], interleukin-6 (IL-6) [10] and monocyte chemotactic protein (MCP-1) [11] concentrations are elevated in obese compared to non-
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Table 1 Obesity classification as per WHO and Asia-Pacific guidelines
Normal
WHO (BMI)a
Asia-Pacific (BMI)a
Obesity score
18.5–24.9
18.5–22.9
0
Overweight
25–29.9
23–24.9
1
Obese
[30
[25
2
a
2
BMI body mass index (in kg/m )
obese patients, and they fall after a reduction of adipose tissue depots. The most commonly used multifactorial scoring systems for prediction of the severity of AP are Ranson’s score and the Acute Physiology and Chronic Health Evaluation (APACHE) II score [12–14]. However, regardless of the cutoff selection, their overall accuracy in most of the studies does not exceed 80–85 % [15]. A modification of the APACHE-II scoring system (APACHE O) was proposed that included a factor for obesity. The APACHE-O score adds 1 point for BMI between 26 and 30 kg/m2 (overweight) and 2 points for BMI C 30 kg/m2 (obese) [5, 6]. Different workers have reported variable results in studies evaluating APACHE-O score as a predictor of the severity of pancreatitis and the outcome [5, 6, 16]. In recent years, India and other countries in the Asia-Pacific region have encountered increasing problems related to obesity [17]. An Asia-Pacific consensus meeting has recommended a different obesity grading since the skeletal and muscle mass of patients in the Asia-Pacific region is lower than that in the West (Table 1) [18]. There are limited data from Asia-Pacific region on the interaction between obesity and AP. Shin et al. [19] from Korea followed the Asia-Pacific classification of obesity in a retrospective study of 403 patients and found that being overweight and obese was associated with a higher risk of developing severe acute pancreatitis (SAP). However, in a Chinese cohort, Yeung et al. [20] did not find a similar correlation between obesity and SAP, but they had used the WHO classification of obesity, not the AsiaPacific one. We therefore planned this study to evaluate the role of obesity in defining the outcome of AP using the AsiaPacific classification of obesity. We also aimed at modifying the APACHE O score to incorporate the Asia-Pacific grading of obesity by generating the APACHE Oap score.
2011, 280 consecutive patients with AP were studied. Informed consent was taken from all the patients. The study was approved by the Institute’s Ethics Board, and the Indian Council of Medical Research (ICMR) guidelines for conducting research were followed. The inclusion criteria were (1) patient age over 12 years, (2) AP as defined by (any two of the three): (a) acute abdominal pain, (b) elevated serum amylase of more than thrice the upper limit of normal range and (c) typical appearance on ultrasound (USG) and/or contrast-enhanced computed tomography (CECT) [12]. The patients known to have chronic pancreatitis were excluded. All patients underwent detailed clinical examination and relevant investigations. The APACHE II scores and APACHE Oap scores (combining APACHE II and obesity score as per Asia-Pacific guidelines) were calculated for all patients within 24 h of hospitalization. All patients were subjected to CECT 72 h after the onset of pain when the computed tomography severity index (CTSI) and Balthazar score were calculated. Severity stratification of AP was done retrospectively incorporating the recent modified Atlanta classification [12]. Patients were monitored closely to observe the progression of any local or systemic complications or organ failure (OF). OF was classified into transient and persistent as defined in the modified Atlanta classification. All patients were managed according to a standard protocol, which included intensive resuscitation, fluid and electrolyte monitoring, nutritional support (nasojejunal feeding or total parenteral nutrition) and supportive care [21]. No prophylactic antibiotics were used. Patients with symptomatic or infected fluid collection(s) underwent radiologically guided percutaneous catheter drainage (PCD) using a 10-Fr catheter (with replacement with larger bore catheters or multiple catheters if required) as described in our earlier study [21]. Imageguided fine-needle aspiration (IG-FNA) of pancreatic necrosis was considered when patients had persistent fever and/or leucocytosis after excluding other causes. If IGFNA or the operative specimen showed isolates on bacterial culture and/or gram staining, the patient was defined as having infected pancreatic necrosis (IN). Necrosectomy and closed lesser sac drainage (with additional and/or modified surgical procedures as per the situation) were offered on (1) evidence of IN not responding to conservative management, (2) worsening of OF despite medical management and PCD, and (3) uncontrolled hemorrhage.
Methods Data Analysis In this prospective observational study conducted at the departments of Gastroenterology and General Surgery of the Postgraduate Institute of Medical Education and Research (PGIMER), a tertiary care referral center at Chandigarh, India, between January 2009 and December
Different obesity groups were compared for age, gender and etiology of AP. The obesity groups were compared for markers of disease severity (serum CRP levels, APACHE II, APACHE Oap) and radiological indices [CTSI and
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Balthazar score]. The occurrence of bloodstream infections, infected necrosis (IN), development of persistent OF, requirement for interventions (percutaneous drain placement and surgery) and mortality were compared. APACHE Oap scores were evaluated for predictive accuracy for mortality. Statistical Analysis The data were analyzed using SPSS software (version 18). Data were explored for any outliers, errors and missing values. When data were normally distributed, continuous variables were compared using Student’s t test. For more than two groups. one-way ANOVA was used. Quantitative data were described as mean and standard deviation (SD) with 95 % confidence intervals. Categorical data were shown as proportions. Comparison of different types of OF was carried out for various categorical variables using the chi-square test of association.
Markers of Disease Severity The occurrence of SAP as per the modified Atlanta classification [12] was higher in patients with higher BMIs. Twentyone (16 %) patients with normal BMI, 43 (51.8 %) overweight and 55 (83.3 %) obese patients had SAP (p \ 0.001). The markers of disease severity were different among the three obesity groups (Table 3). Serum CRP levels were different among groups (ANOVA p = 0.04; post hoc analysis, normal vs. overweight p = 0.04; overweight vs. obese p = 0.02). The radiological markers of severity, Balthazar score (p \ 0.001) and CTSI (p \ 0.001) were significantly different among different obesity groups. There was a significant difference in APACHE II scores between different obesity groups (ANOVA p \ 0.001). Post hoc analysis showed a significant difference between normal versus overweight (p = 0.04) as well as overweight versus obese patients (p \ 0.001). The mean APACHE Oap scores were also significantly different among different obesity groups (ANOVA p \ 0.001) and between each other (p \ 0.001).
Results
Infections During the Course of Illness
The mean age of the study group was 40.67 ± 13.12 years (199 males). The most common cause for pancreatitis was alcohol (54.2 %) followed by gall stone disease (36.0 %) (Table 2). The etiology of pancreatitis was comparable among different obesity groups (p = 0.79). Forty-six (16.4 %) patients underwent surgery, and 61 (21.8 %) patients succumbed to the illness.
The occurrence of blood stream infection was significantly different among different obesity groups (ANOVA p = 0.04). Post hoc analysis showed a higher number of blood stream infection in normal compared to overweight (p = 0.042) and overweight compared to obese groups (p = 0.02). The occurrence of IN also followed the same trend (ANOVA, p = 0.03; post hoc analysis, normal versus overweight, p = 0.02; overweight versus obese, p = 0.041).
Table 2 The in-hospital course of 280 patients APACHE II (24 h)a
8.7 ± 6.8 a
APACHE Oap (24 h) 2 a
9.5 ± 7.3
BMI (kg/m )
23.2 ± 2.0
BMI category (0/1/2)b
131/83/66 (46.8/29.6/23.6)
CRP (48 h)a,c
171.5 ± 77.9
Organ failure
189 (67.5)
Severity of acute pancreatitisd
119/69/92
Bloodstream infection Infected necrosis
45 (16.0) 39 (13.9)
PCD requirement
41 (14.6)
Need for surgery
23 (8.2)
Mortality
61 (21.8)
Figures in parentheses show percentage APACHE Acute Physiology and Chronic Health Evaluation, CTSI Computerized Tomography Severity Index, PCD percutaneous drain a b
Mean ± SD 0/1/2 normal/overweight/obese
c
mg/l
d
Modified Atlanta classification (severe/moderate/mild)
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Persistent OF and Requirement for Interventions Ninety (32.1 %) patients had no OF, 79 (25.4 %) patients developed transient OF, and 119 (42.5 %) patients developed persistent OF. Persistent OF occurred more frequently in patients with higher BMI. Twenty-one (16 %) patients with normal BMI, 43 (51.8 %) overweight and 55 (83.3 %) obese patients had persistent OF (p \ 0.001). Requirement for percutaneous drain insertion (PCD) was different among different obesity groups (ANOVA p = 0.004); on post hoc analysis it was significantly higher in normal versus overweight (p = 0.02) and overweight versus obese groups (p = 0.008). Similarly, the requirement for surgery also followed the same trend, ANOVA p = 0.008 (normal vs. overweight, p = 0.04; overweight vs. obese, p = 0.001). Specific indications for surgery (n = 46) were IN and multiple organ dysfunction syndrome in 22, failure of conservative management in 21, emphysematous pancreatitis with persistent sepsis in 2 and pseudoaneurysmal bleed in 1 patient.
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Table 3 Comparison among groups with different grades of BMI as per the Asia-Pacific classification of obesity Normal
Overweight
Obese
p
N
131
83
66
Etiology (1/2/3)a
71/49/11
47/26/10
34/26/6
0.79
Age (years)b
38.8 ± 13.2
42.8 ± 12.6
41.6 ± 13.2
0.28
Serum CRP
b,c
162.2 ± 78.4
171.8 ± 78.0
189.0 ± 76.1
CTSIb
5.3 ± 2.7
5.9 ± 2.6
7.0 ± 3.0
\0.001
0.33
Severe pancreatitis
83 (63.4)
66 (80.5)
59 (89.4)
\0.001
APACHE IIb score
5.1 ± 3.7
9.5 ± 6.3
15.0 ± 7.4
\0.001
APACHE Oapb score
5.2 ± 3.7
10.5 ± 6.4
17.0 ± 7.5
\0.001
Bloodstream infection
14 (10.6)
14 (16.9)
17 (27.8)
0.04
Infected necrosis
9 (6.8)
16 (19.3)
14 (22.9)
\0.001
PCD requirement Need for surgery
12 (9.1) 10 (7.6)
14 (16.9) 14 (16.8)
15 (24.9) 22 (36.0)
0.004 0.008
Total hospital stayb,d
15.6 ± 13.8
14.9 ± 12.8
16.1 ± 18.3
0.88
Total ICU stayb,d
3.2 ± 4.6
7.8 ± 6.4
8.2 ± 7.8
0.08
Mortality
9 (6.8)
12 (14.4)
40 (68)
\0.001
Figures in parentheses show percentage BSI bloodstream infection, CRP C reactive protein, CTSI Computerized Tomography Severity Index, PCD percutaneous drain, SAP severe acute pancreatitis a
1/2/3, alcohol/gallstones/others
b
Mean ± SD mg/l
c d
Duration of stay in days
Outcome The total duration of hospital stay was not significantly different among different obesity groups. However, the total duration of intensive care unit (ICU) stay showed a significant difference (p = 0.08; normal vs. overweight, p = 0.002; overweight vs. obese, p = 0.066). Of the 61 patients who died, 20 had sepsis, 38 multiple organ dysfunction, 1 postoperative bleed and 1 unrelated cause (intracranial bleed). Mortality was significantly higher among groups with high BMI (ANOVA p \ 0.001); 9 (6.8 %) patients with normal BMI and 12 (14.4 %) overweight patients succumbed to illness, p = 0.03. Forty patients (68 %) succumbed in the obese group (overweight vs. obese, p \ 0.001). Overweight patients had twofold and obese patients had tenfold increased mortality when compared to patients with normal BMI. A BMI of C23 therefore conferred a higher risk of mortality. On univariate analysis, the predictors of mortality were high BMI (p = 0.002), high APACHE II score (p \ 0.001), high APACHE Oap score (p \ 0.001), high CTSI (p \ 0.001), occurrence of IN (p \ 0.001) and occurrence of persistent OF (p \ 0.001). Multivariate analysis showed IN (odds ratio 20.60, CI = 3.31–128.26, p = 0.001), APACHE II (odds ratio 6.9, CI = 6.0–7.9, p \ 0.001) and APACHE Oap (odds ratio 7.2,
CI = 6.1–8.1, p \ 0.001) as independent predictors of mortality. The area under the curve (AUC) for predicting mortality was 0.879 for APACHE II [95 % confidence interval (CI) = 0.819–0.938] and 0.886 for APACHE Oap (CI = 0.827–0.944) (Table 4). At a cutoff of 8.5, the APACHE II score had a sensitivity of 88.2 % and specificity of 68.7 %, and APACHE Oap had a sensitivity of 90.2 % and specificity of 64.0 % (Fig. 1).
Discussion In this study of 280 patients of AP, using Asia-Pacific classification of obesity we found that the course in the hospital and overall outcome were significantly different among different obesity groups. Patients with higher BMI had higher serum CRP levels, APACHE II score, APACHE Oap score and radiological indices of severity. The occurrence of bloodstream infections (p = 0.009), persistent OF (p \ 0.001) and IN (p \ 0.001), were significantly higher among patients with higher BMI. Similarly, requirement for PCD insertion (p = 0.04), surgery (p = 0.008) and mortality (p \ 0.001) were significantly higher in groups with higher BMI. Lankisch et al. [22] were the first to identify obesity as a risk factor for SAP. Their observations were validated by other workers thereafter [4–6]. Hong et al. [23] in a recent
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Table 4 Comparison of APACHE Oap with APACHE II scoring systems for prediction of mortality Sensitivity
Specificity
PPV
NPV
LRP
LRN
7.5
92.2
59
38
91.5
2.23
0.13
8.5 9.5
90.2 88.2
64 73
41.1 47.7
95.8 95.8
2.4 3.2
0.15 0.15
7.5
92.2
61
39.4
96.3
2.3
0.13
8.5
88.2
68.7
43.9
95.5
2.8
0.16
9.5
84.5
77
50.4
94.4
3.6
0.21
APACHEOap
APACHE-II
PPV positive predictive value, NPV negative predictive value, LRP likelihood for a positive test, LRN likelihood for a negative test
Fig. 1 Receiver operating characteristic curve (ROC) plot showing the area under the curve (AUC) for predicting outcome in acute pancreatitis. The AUC for predicting mortality was 0.879 for APACHE II (95 % CI = 0.819–0.938) and 0.886 for APACHE Oap (CI = 0.827–0.944)
metaanalysis showed that compared to normal-weight individuals, obese individuals (BMI [ 30 kg/m2) had an increased risk of AP; they developed significantly more severe AP with more systemic and local complications as well as mortality. They concluded that obesity is not only associated with an increased risk of development of AP, but is also a poor prognostic factor. In another metaanalysis of eight studies including 939 patients, Wang et al. [24] found the incidence rates of SAP, local complications and mortality to be increased in overweight (BMI between 25 and 30 kg/m2) patients with AP. However, no difference was detected in the incidence of systemic complications
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between the normal weight and overweight patients. They concluded that overweight status is an additional prognostic factor of severity, local complications and mortality in AP. Johnson et al. [6] incorporated the factor of obesity into the APACHE II scoring system to develop ‘‘APACHE O’’ as a composite multifactorial scoring system in AP. In their study of 106 patients with AP, they found age, BMI and the APACHE II score to be independent predictors of complications, and the APACHE-O score provided greater predictive accuracy. At a cutoff of [8, the APACHE-O score had a sensitivity of 82 %, specificity of 86 %, positive predictive value of 74 %, negative predictive value of 91 % and overall accuracy of 85 %, and at the same cutoff APACHE II had respective values of 70, 78, 63, 84 and 77 %. However, the predictive accuracy of the APACHE O system over APACHE II has been variably reported in the literature. In a study of 102 patients with AP, Papachristou et al. [5] found that admission APACHE-O (AUC 0.895) and APACHE-II (AUC 0.893) showed similar accuracy in predicting severe outcome. Their study validated BMI as a significant risk for SAP (OR 2.8, p = 0.048) and mortality (OR 11.2, p = 0.022). They also reported significantly higher CRP levels (p = 0.0001) as well as Ranson’s score (p = 0.021) in obese patients. Another study from Brazil in patients with acute biliary pancreatitis found Ranson scoring, modified Glasgow scoring, APACHE II and APACHE O scores as having similar sensitivity and specificity in predicting severity [16]. They also did not find a higher accuracy for APACHE O over APACHE II in predicting severity [16]. There is enough evidence to show that the body mass composition of the Asia-Pacific population is different from that of the population in the West [17, 25]. The occurrence of abdominal obesity is higher in the AsiaPacific population [17, 25]. The consensus guidelines of the Asia-Pacific obesity study group regarding BMI grading has been incorporated into the management of hyperlipidemia, metabolic syndrome, type 2 diabetes mellitus and coronary artery disease [18]. However, there are only a few studies on AP from the Asia-Pacific region that have applied the modified obesity grading. Shin et al. [19], in a retrospective study of 403 patients with AP from Korea, found that when compared to normal weight (BMI 18.5–22.9 kg/m2), all categories with a BMI [ 23 kg/m2 had an increased risk of developing SAP, and a BMI [ 25 kg/m2 predicted the severity and more systemic and metabolic complications. Our results are in accordance with those of Shin et al. [17]. However, Yeung et al. [20] from Hong Kong reported that overweight and obesity were not associated with severe pancreatitis. Their study was based on only 101 patients, and they used the WHO classification of obesity, not the one based on the
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Asia-Pacific guidelines. In addition, they admitted that the population represented by the study had a low prevalence of obesity. Our study is the first one from South Asia to have used the Asia-Pacific guidelines of obesity classification in patients with AP. The strength of our study lies in the sizeable number of patients and the fact that we also used the 2013 Atlanta revision to classify our patients into mild, moderate and severe AP. We also had enough patients in each of the three obesity groups. A limitation of our study is the fact that it has the bias of a referral center with 42.5 % of patients having severe AP. It would be interesting to have multicenter studies with patients from different geographic areas. In conclusion, our study correlated obesity (as per the Asia-Pacific obesity guidelines) with disease severity markers, radiological indices of severity, hospital course, requirement for interventions and overall outcome. We have shown that a BMI C23 is associated with higher occurrence of severe acute pancreatitis, higher CRP levels, higher radiological severity indices, higher requirement for interventions, infectious complications, persistent organ failure and mortality. However, APACHE Oap scores had similar predictive values as APACHE II for mortality.
Conflict of interest
None.
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ORIGINAL ARTICLE
Implementation of the Asia-Pacific Guidelines of Obesity Classification on the APACHE-O Scoring System and Its Role in the Prediction of Outcomes of Acute Pancreatitis: A Study from India Ragesh Babu Thandassery • Sreekanth Appasani • Thakur Deen Yadav • Usha Dutta • Abujam Indrajit Kartar Singh • Rakesh Kochhar
•
Received: 20 September 2013 / Accepted: 11 December 2013 / Published online: 28 December 2013 Ó Springer Science+Business Media New York 2013
Abstract Aims We studied the role of obesity and the Acute Physiology and Chronic Health Evaluation (APACHE) O score in predicting the outcome in patients with acute pancreatitis (AP) using the Asia-Pacific obesity classification. Methods Two hundred eighty AP patients were classified into three different groups, normal weight [body mass index (BMI) = 18.5–22.9 kg/m2], overweight (BMI = 23–24.9 kg/m2) and obese (BMI [ 25 kg/m2), according to the Asia-Pacific obesity classification. For all patients APACHE II scores and modified APACHE O (i.e., APACHE Oap) scores that included a factor for obesity were calculated. The patients were managed using a standard protocol, and the outcome measures were compared for different obesity groups. Results Of the 280 patients (mean age 40.7 years), 46.8 % were normal weight, 29.6 % overweight and 23.6 % obese. Forty-six (16.4 %) patients underwent surgery, and 61 (21.8 %) patients died. Patients with higher BMI had worse radiological indices of severity, more infected necrosis (p \ 0.001), more persistent organ failure (p \ 0.001) and higher requirement for percutaneous drain insertion (p = 0.04), surgery (p = 0.008) and mortality (p \ 0.001). The area under the curve for predicting mortality was 0.879 for APACHE II and 0.886 for APACHE Oap; at a cutoff of 8.5, the APACHE II score had a sensitivity of 88.2 % and specificity of 68.7 %, and APACHE Oap 90.2 and 64.0 %, respectively. Conclusions BMI C 23 kg/m2 was an important predictor of a severe disease course and fatal outcome in patients
R. B. Thandassery S. Appasani T. D. Yadav U. Dutta A. Indrajit K. Singh R. Kochhar (&) Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India e-mail: [email protected]
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with AP. However, the predictive accuracy of APACHE Oap for mortality was similar to APACHE II. Keywords Acute pancreatitis APACHE O Body mass index Obesity
Introduction Acute pancreatitis (AP) is a systemic disease with complex inflammatory cascades. The exact role of individual contributing factors is yet to be clearly defined. Recent studies indicate that among patient characteristics, obesity is an independent risk factor for adverse outcomes in patients with AP [1, 2]. Martinez et al. [3] suggested in a metaanalysis that obesity [body mass index (BMI) [ 30 kg/m2] increased the risk of developing severe AP. The mechanism by which obesity increases the severity of AP is unclear. It is believed that the severity of AP is directly related to the intensity of the immune response and that obese patients are at risk of more severe complications of AP because of a more intense inflammatory response (systemic inflammatory response syndrome, SIRS) to pancreatic injury [4]. It has also been suggested that the higher rate of complications in obese patients could be caused by the existence of obesity-related comorbidity and lower lung compliance [4–6]. Central obesity in particular could lead to a worse prognosis in AP. Adipose tissue is an important source of cytokines, and obesity can be considered a state of chronic inflammation. Obese humans have increased levels of several proinflammatory cytokines including adipocytokines [7]. Serum tumor necrosis factor (TNF-a) [8], C-reactive protein (CRP) [9], interleukin-6 (IL-6) [10] and monocyte chemotactic protein (MCP-1) [11] concentrations are elevated in obese compared to non-
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Table 1 Obesity classification as per WHO and Asia-Pacific guidelines
Normal
WHO (BMI)a
Asia-Pacific (BMI)a
Obesity score
18.5–24.9
18.5–22.9
0
Overweight
25–29.9
23–24.9
1
Obese
[30
[25
2
a
2
BMI body mass index (in kg/m )
obese patients, and they fall after a reduction of adipose tissue depots. The most commonly used multifactorial scoring systems for prediction of the severity of AP are Ranson’s score and the Acute Physiology and Chronic Health Evaluation (APACHE) II score [12–14]. However, regardless of the cutoff selection, their overall accuracy in most of the studies does not exceed 80–85 % [15]. A modification of the APACHE-II scoring system (APACHE O) was proposed that included a factor for obesity. The APACHE-O score adds 1 point for BMI between 26 and 30 kg/m2 (overweight) and 2 points for BMI C 30 kg/m2 (obese) [5, 6]. Different workers have reported variable results in studies evaluating APACHE-O score as a predictor of the severity of pancreatitis and the outcome [5, 6, 16]. In recent years, India and other countries in the Asia-Pacific region have encountered increasing problems related to obesity [17]. An Asia-Pacific consensus meeting has recommended a different obesity grading since the skeletal and muscle mass of patients in the Asia-Pacific region is lower than that in the West (Table 1) [18]. There are limited data from Asia-Pacific region on the interaction between obesity and AP. Shin et al. [19] from Korea followed the Asia-Pacific classification of obesity in a retrospective study of 403 patients and found that being overweight and obese was associated with a higher risk of developing severe acute pancreatitis (SAP). However, in a Chinese cohort, Yeung et al. [20] did not find a similar correlation between obesity and SAP, but they had used the WHO classification of obesity, not the AsiaPacific one. We therefore planned this study to evaluate the role of obesity in defining the outcome of AP using the AsiaPacific classification of obesity. We also aimed at modifying the APACHE O score to incorporate the Asia-Pacific grading of obesity by generating the APACHE Oap score.
2011, 280 consecutive patients with AP were studied. Informed consent was taken from all the patients. The study was approved by the Institute’s Ethics Board, and the Indian Council of Medical Research (ICMR) guidelines for conducting research were followed. The inclusion criteria were (1) patient age over 12 years, (2) AP as defined by (any two of the three): (a) acute abdominal pain, (b) elevated serum amylase of more than thrice the upper limit of normal range and (c) typical appearance on ultrasound (USG) and/or contrast-enhanced computed tomography (CECT) [12]. The patients known to have chronic pancreatitis were excluded. All patients underwent detailed clinical examination and relevant investigations. The APACHE II scores and APACHE Oap scores (combining APACHE II and obesity score as per Asia-Pacific guidelines) were calculated for all patients within 24 h of hospitalization. All patients were subjected to CECT 72 h after the onset of pain when the computed tomography severity index (CTSI) and Balthazar score were calculated. Severity stratification of AP was done retrospectively incorporating the recent modified Atlanta classification [12]. Patients were monitored closely to observe the progression of any local or systemic complications or organ failure (OF). OF was classified into transient and persistent as defined in the modified Atlanta classification. All patients were managed according to a standard protocol, which included intensive resuscitation, fluid and electrolyte monitoring, nutritional support (nasojejunal feeding or total parenteral nutrition) and supportive care [21]. No prophylactic antibiotics were used. Patients with symptomatic or infected fluid collection(s) underwent radiologically guided percutaneous catheter drainage (PCD) using a 10-Fr catheter (with replacement with larger bore catheters or multiple catheters if required) as described in our earlier study [21]. Imageguided fine-needle aspiration (IG-FNA) of pancreatic necrosis was considered when patients had persistent fever and/or leucocytosis after excluding other causes. If IGFNA or the operative specimen showed isolates on bacterial culture and/or gram staining, the patient was defined as having infected pancreatic necrosis (IN). Necrosectomy and closed lesser sac drainage (with additional and/or modified surgical procedures as per the situation) were offered on (1) evidence of IN not responding to conservative management, (2) worsening of OF despite medical management and PCD, and (3) uncontrolled hemorrhage.
Methods Data Analysis In this prospective observational study conducted at the departments of Gastroenterology and General Surgery of the Postgraduate Institute of Medical Education and Research (PGIMER), a tertiary care referral center at Chandigarh, India, between January 2009 and December
Different obesity groups were compared for age, gender and etiology of AP. The obesity groups were compared for markers of disease severity (serum CRP levels, APACHE II, APACHE Oap) and radiological indices [CTSI and
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Balthazar score]. The occurrence of bloodstream infections, infected necrosis (IN), development of persistent OF, requirement for interventions (percutaneous drain placement and surgery) and mortality were compared. APACHE Oap scores were evaluated for predictive accuracy for mortality. Statistical Analysis The data were analyzed using SPSS software (version 18). Data were explored for any outliers, errors and missing values. When data were normally distributed, continuous variables were compared using Student’s t test. For more than two groups. one-way ANOVA was used. Quantitative data were described as mean and standard deviation (SD) with 95 % confidence intervals. Categorical data were shown as proportions. Comparison of different types of OF was carried out for various categorical variables using the chi-square test of association.
Markers of Disease Severity The occurrence of SAP as per the modified Atlanta classification [12] was higher in patients with higher BMIs. Twentyone (16 %) patients with normal BMI, 43 (51.8 %) overweight and 55 (83.3 %) obese patients had SAP (p \ 0.001). The markers of disease severity were different among the three obesity groups (Table 3). Serum CRP levels were different among groups (ANOVA p = 0.04; post hoc analysis, normal vs. overweight p = 0.04; overweight vs. obese p = 0.02). The radiological markers of severity, Balthazar score (p \ 0.001) and CTSI (p \ 0.001) were significantly different among different obesity groups. There was a significant difference in APACHE II scores between different obesity groups (ANOVA p \ 0.001). Post hoc analysis showed a significant difference between normal versus overweight (p = 0.04) as well as overweight versus obese patients (p \ 0.001). The mean APACHE Oap scores were also significantly different among different obesity groups (ANOVA p \ 0.001) and between each other (p \ 0.001).
Results
Infections During the Course of Illness
The mean age of the study group was 40.67 ± 13.12 years (199 males). The most common cause for pancreatitis was alcohol (54.2 %) followed by gall stone disease (36.0 %) (Table 2). The etiology of pancreatitis was comparable among different obesity groups (p = 0.79). Forty-six (16.4 %) patients underwent surgery, and 61 (21.8 %) patients succumbed to the illness.
The occurrence of blood stream infection was significantly different among different obesity groups (ANOVA p = 0.04). Post hoc analysis showed a higher number of blood stream infection in normal compared to overweight (p = 0.042) and overweight compared to obese groups (p = 0.02). The occurrence of IN also followed the same trend (ANOVA, p = 0.03; post hoc analysis, normal versus overweight, p = 0.02; overweight versus obese, p = 0.041).
Table 2 The in-hospital course of 280 patients APACHE II (24 h)a
8.7 ± 6.8 a
APACHE Oap (24 h) 2 a
9.5 ± 7.3
BMI (kg/m )
23.2 ± 2.0
BMI category (0/1/2)b
131/83/66 (46.8/29.6/23.6)
CRP (48 h)a,c
171.5 ± 77.9
Organ failure
189 (67.5)
Severity of acute pancreatitisd
119/69/92
Bloodstream infection Infected necrosis
45 (16.0) 39 (13.9)
PCD requirement
41 (14.6)
Need for surgery
23 (8.2)
Mortality
61 (21.8)
Figures in parentheses show percentage APACHE Acute Physiology and Chronic Health Evaluation, CTSI Computerized Tomography Severity Index, PCD percutaneous drain a b
Mean ± SD 0/1/2 normal/overweight/obese
c
mg/l
d
Modified Atlanta classification (severe/moderate/mild)
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Persistent OF and Requirement for Interventions Ninety (32.1 %) patients had no OF, 79 (25.4 %) patients developed transient OF, and 119 (42.5 %) patients developed persistent OF. Persistent OF occurred more frequently in patients with higher BMI. Twenty-one (16 %) patients with normal BMI, 43 (51.8 %) overweight and 55 (83.3 %) obese patients had persistent OF (p \ 0.001). Requirement for percutaneous drain insertion (PCD) was different among different obesity groups (ANOVA p = 0.004); on post hoc analysis it was significantly higher in normal versus overweight (p = 0.02) and overweight versus obese groups (p = 0.008). Similarly, the requirement for surgery also followed the same trend, ANOVA p = 0.008 (normal vs. overweight, p = 0.04; overweight vs. obese, p = 0.001). Specific indications for surgery (n = 46) were IN and multiple organ dysfunction syndrome in 22, failure of conservative management in 21, emphysematous pancreatitis with persistent sepsis in 2 and pseudoaneurysmal bleed in 1 patient.
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Table 3 Comparison among groups with different grades of BMI as per the Asia-Pacific classification of obesity Normal
Overweight
Obese
p
N
131
83
66
Etiology (1/2/3)a
71/49/11
47/26/10
34/26/6
0.79
Age (years)b
38.8 ± 13.2
42.8 ± 12.6
41.6 ± 13.2
0.28
Serum CRP
b,c
162.2 ± 78.4
171.8 ± 78.0
189.0 ± 76.1
CTSIb
5.3 ± 2.7
5.9 ± 2.6
7.0 ± 3.0
\0.001
0.33
Severe pancreatitis
83 (63.4)
66 (80.5)
59 (89.4)
\0.001
APACHE IIb score
5.1 ± 3.7
9.5 ± 6.3
15.0 ± 7.4
\0.001
APACHE Oapb score
5.2 ± 3.7
10.5 ± 6.4
17.0 ± 7.5
\0.001
Bloodstream infection
14 (10.6)
14 (16.9)
17 (27.8)
0.04
Infected necrosis
9 (6.8)
16 (19.3)
14 (22.9)
\0.001
PCD requirement Need for surgery
12 (9.1) 10 (7.6)
14 (16.9) 14 (16.8)
15 (24.9) 22 (36.0)
0.004 0.008
Total hospital stayb,d
15.6 ± 13.8
14.9 ± 12.8
16.1 ± 18.3
0.88
Total ICU stayb,d
3.2 ± 4.6
7.8 ± 6.4
8.2 ± 7.8
0.08
Mortality
9 (6.8)
12 (14.4)
40 (68)
\0.001
Figures in parentheses show percentage BSI bloodstream infection, CRP C reactive protein, CTSI Computerized Tomography Severity Index, PCD percutaneous drain, SAP severe acute pancreatitis a
1/2/3, alcohol/gallstones/others
b
Mean ± SD mg/l
c d
Duration of stay in days
Outcome The total duration of hospital stay was not significantly different among different obesity groups. However, the total duration of intensive care unit (ICU) stay showed a significant difference (p = 0.08; normal vs. overweight, p = 0.002; overweight vs. obese, p = 0.066). Of the 61 patients who died, 20 had sepsis, 38 multiple organ dysfunction, 1 postoperative bleed and 1 unrelated cause (intracranial bleed). Mortality was significantly higher among groups with high BMI (ANOVA p \ 0.001); 9 (6.8 %) patients with normal BMI and 12 (14.4 %) overweight patients succumbed to illness, p = 0.03. Forty patients (68 %) succumbed in the obese group (overweight vs. obese, p \ 0.001). Overweight patients had twofold and obese patients had tenfold increased mortality when compared to patients with normal BMI. A BMI of C23 therefore conferred a higher risk of mortality. On univariate analysis, the predictors of mortality were high BMI (p = 0.002), high APACHE II score (p \ 0.001), high APACHE Oap score (p \ 0.001), high CTSI (p \ 0.001), occurrence of IN (p \ 0.001) and occurrence of persistent OF (p \ 0.001). Multivariate analysis showed IN (odds ratio 20.60, CI = 3.31–128.26, p = 0.001), APACHE II (odds ratio 6.9, CI = 6.0–7.9, p \ 0.001) and APACHE Oap (odds ratio 7.2,
CI = 6.1–8.1, p \ 0.001) as independent predictors of mortality. The area under the curve (AUC) for predicting mortality was 0.879 for APACHE II [95 % confidence interval (CI) = 0.819–0.938] and 0.886 for APACHE Oap (CI = 0.827–0.944) (Table 4). At a cutoff of 8.5, the APACHE II score had a sensitivity of 88.2 % and specificity of 68.7 %, and APACHE Oap had a sensitivity of 90.2 % and specificity of 64.0 % (Fig. 1).
Discussion In this study of 280 patients of AP, using Asia-Pacific classification of obesity we found that the course in the hospital and overall outcome were significantly different among different obesity groups. Patients with higher BMI had higher serum CRP levels, APACHE II score, APACHE Oap score and radiological indices of severity. The occurrence of bloodstream infections (p = 0.009), persistent OF (p \ 0.001) and IN (p \ 0.001), were significantly higher among patients with higher BMI. Similarly, requirement for PCD insertion (p = 0.04), surgery (p = 0.008) and mortality (p \ 0.001) were significantly higher in groups with higher BMI. Lankisch et al. [22] were the first to identify obesity as a risk factor for SAP. Their observations were validated by other workers thereafter [4–6]. Hong et al. [23] in a recent
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Table 4 Comparison of APACHE Oap with APACHE II scoring systems for prediction of mortality Sensitivity
Specificity
PPV
NPV
LRP
LRN
7.5
92.2
59
38
91.5
2.23
0.13
8.5 9.5
90.2 88.2
64 73
41.1 47.7
95.8 95.8
2.4 3.2
0.15 0.15
7.5
92.2
61
39.4
96.3
2.3
0.13
8.5
88.2
68.7
43.9
95.5
2.8
0.16
9.5
84.5
77
50.4
94.4
3.6
0.21
APACHEOap
APACHE-II
PPV positive predictive value, NPV negative predictive value, LRP likelihood for a positive test, LRN likelihood for a negative test
Fig. 1 Receiver operating characteristic curve (ROC) plot showing the area under the curve (AUC) for predicting outcome in acute pancreatitis. The AUC for predicting mortality was 0.879 for APACHE II (95 % CI = 0.819–0.938) and 0.886 for APACHE Oap (CI = 0.827–0.944)
metaanalysis showed that compared to normal-weight individuals, obese individuals (BMI [ 30 kg/m2) had an increased risk of AP; they developed significantly more severe AP with more systemic and local complications as well as mortality. They concluded that obesity is not only associated with an increased risk of development of AP, but is also a poor prognostic factor. In another metaanalysis of eight studies including 939 patients, Wang et al. [24] found the incidence rates of SAP, local complications and mortality to be increased in overweight (BMI between 25 and 30 kg/m2) patients with AP. However, no difference was detected in the incidence of systemic complications
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between the normal weight and overweight patients. They concluded that overweight status is an additional prognostic factor of severity, local complications and mortality in AP. Johnson et al. [6] incorporated the factor of obesity into the APACHE II scoring system to develop ‘‘APACHE O’’ as a composite multifactorial scoring system in AP. In their study of 106 patients with AP, they found age, BMI and the APACHE II score to be independent predictors of complications, and the APACHE-O score provided greater predictive accuracy. At a cutoff of [8, the APACHE-O score had a sensitivity of 82 %, specificity of 86 %, positive predictive value of 74 %, negative predictive value of 91 % and overall accuracy of 85 %, and at the same cutoff APACHE II had respective values of 70, 78, 63, 84 and 77 %. However, the predictive accuracy of the APACHE O system over APACHE II has been variably reported in the literature. In a study of 102 patients with AP, Papachristou et al. [5] found that admission APACHE-O (AUC 0.895) and APACHE-II (AUC 0.893) showed similar accuracy in predicting severe outcome. Their study validated BMI as a significant risk for SAP (OR 2.8, p = 0.048) and mortality (OR 11.2, p = 0.022). They also reported significantly higher CRP levels (p = 0.0001) as well as Ranson’s score (p = 0.021) in obese patients. Another study from Brazil in patients with acute biliary pancreatitis found Ranson scoring, modified Glasgow scoring, APACHE II and APACHE O scores as having similar sensitivity and specificity in predicting severity [16]. They also did not find a higher accuracy for APACHE O over APACHE II in predicting severity [16]. There is enough evidence to show that the body mass composition of the Asia-Pacific population is different from that of the population in the West [17, 25]. The occurrence of abdominal obesity is higher in the AsiaPacific population [17, 25]. The consensus guidelines of the Asia-Pacific obesity study group regarding BMI grading has been incorporated into the management of hyperlipidemia, metabolic syndrome, type 2 diabetes mellitus and coronary artery disease [18]. However, there are only a few studies on AP from the Asia-Pacific region that have applied the modified obesity grading. Shin et al. [19], in a retrospective study of 403 patients with AP from Korea, found that when compared to normal weight (BMI 18.5–22.9 kg/m2), all categories with a BMI [ 23 kg/m2 had an increased risk of developing SAP, and a BMI [ 25 kg/m2 predicted the severity and more systemic and metabolic complications. Our results are in accordance with those of Shin et al. [17]. However, Yeung et al. [20] from Hong Kong reported that overweight and obesity were not associated with severe pancreatitis. Their study was based on only 101 patients, and they used the WHO classification of obesity, not the one based on the
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Asia-Pacific guidelines. In addition, they admitted that the population represented by the study had a low prevalence of obesity. Our study is the first one from South Asia to have used the Asia-Pacific guidelines of obesity classification in patients with AP. The strength of our study lies in the sizeable number of patients and the fact that we also used the 2013 Atlanta revision to classify our patients into mild, moderate and severe AP. We also had enough patients in each of the three obesity groups. A limitation of our study is the fact that it has the bias of a referral center with 42.5 % of patients having severe AP. It would be interesting to have multicenter studies with patients from different geographic areas. In conclusion, our study correlated obesity (as per the Asia-Pacific obesity guidelines) with disease severity markers, radiological indices of severity, hospital course, requirement for interventions and overall outcome. We have shown that a BMI C23 is associated with higher occurrence of severe acute pancreatitis, higher CRP levels, higher radiological severity indices, higher requirement for interventions, infectious complications, persistent organ failure and mortality. However, APACHE Oap scores had similar predictive values as APACHE II for mortality.
Conflict of interest
None.
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