Pediatr Surg Int (2014) 30:1111–1115 DOI 10.1007/s00383-014-3595-6
ORIGINAL ARTICLE
Predictors for mortality following acute pancreatitis in children Qiang Guo • Mao Li • Yang Chen • Hankui Hu Weiming Hu
•
Accepted: 9 September 2014 / Published online: 13 September 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Introduction Although there are several studies focusing on pancreatitis etiology and clinical outcome, no previous report has examined the risk factors for death in children. Patients and methods We reviewed the medical records of all children (ages 0–18 years) admitted to West China Hospital with acute pancreatitis between 2002 and 2012. Independent predictors for death following acute pancreatitis in children were identified using a multivariate logistic regression analysis. Results Biliary diseases (23 %), medications (20 %), idiopathic (19 %), and trauma (11 %) were the most common etiologies for acute pancreatitis in children. The death rate was 5 % and the mean duration of hospital stay was 13 days. Organ failure during admission occurred in 24 of 371 patients and most of them started in 3 days of onset (19/24). Multivariate analysis with logistic regression confirmed that occurrence of SIRS in the first week of onset (OR = 2.12, 95 % CI 1.14–6.32, P \ 0.001), occurrence of organ failure within 3 days of onset (OR = 8.0, 95 % CI 2.2–12.3, P \ 0.001), occurrence of MOF in the first week of onset (OR = 9.4, 95 % CI 2.3–14.6, P \ 0.001), infected necrosis (OR = 1.28, 95 % CI 1.08–1.52, P = 0.02), and idiopathic cause (OR = 17.3, 95 % CI 2.0–60.5, P \ 0.001) were independent risk factors for death in cases with pancreatitis. Conclusions Mortality rate and complication rate of acute pancreatitis in children remains low. Patients with SIRS, early organ failure, MOF, infected necrosis, or idiopathic cause should be well evaluated because they have higher risk of death. Q. Guo M. Li Y. Chen H. Hu W. Hu (&) Hepato-Bilio-Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China e-mail: [email protected]
Keywords Acute pancreatitis Children Mortality Multivariate analysis
Introduction Acute pancreatitis is a common disease with a very varied outcome [1]. In the US, acute pancreatitis is the most common reason of gastrointestinal diseases for hospitalization [2]. In the UK, there are 150–420 clinically diagnosed cases per million residents, and in the US, approximately 233,000 patients are admitted with a new diagnosis of acute pancreatitis each year [3, 4]. The mortality rate ranges from 5.7 to 10 % in patients who are diagnosed with acute pancreatitis [5, 6]. In children, the incidence of acute pancreatitis appears to be on the rise [7]. Although there are several studies focusing on pancreatitis etiology, few have characterized their clinical outcome and no previous report has examined the risk factors for death in children [8, 9]. Herein, we described the characteristics of acute pancreatitis in children and defined independent predictors for early death using a multivariate logistic regression analysis. Since recent reports suggest that there may be important differences in clinical features between infants/toddlers and older children [9], we compared the clinical features and outcomes between different age groups as well.
Materials and methods Identification of patients Data on children (younger than 19 years) admitted to West China Hospital with a first diagnosis of acute pancreatitis
123
1112
from January 2002 to July 2012 were collected. The exclusion criteria were a flare-up of chronic pancreatitis. A diagnosis of acute pancreatitis (AP) was made using a combination of clinical (i.e., the sudden onset of upper abdominal pain), laboratory (more than three times the upper normal limit for amylase and/or lipase levels), and imaging tests (abdominal ultrasound, abdominal computerized tomography, and magnetic resonance imaging) findings [10]. Acute recurrent pancreatitis (ARP) was defined as more than two distinct episodes of AP with intervening return to baseline [10]. Therapeutic strategy After admission, full laboratory and imaging tests were performed to evaluate the severity of the disease. All patients received conservative treatment initially. Antibiotics were administered after admission for no more than 7 days unless they had persistent clinical manifestations of sepsis. Parenteral nutrition was initiated, and after the function of gastrointestinal tract recovered from paralysis, they were fed with enteral nutrition as well as parenteral nutrition. During the conservative treatment, contrastenhanced computed tomography (CECT) was performed when a patient started to have persistent clinical manifestations of sepsis. Patients with suspected infected necrosis were advised to receive surgical intervention. Cultures were taken during all primary procedures to confirm the diagnosis of infected necrosis. Those patients who were extremely weak were treated in the intensive care unit.
Pediatr Surg Int (2014) 30:1111–1115 Table 1 Characteristics of each age group Age group
0–2
3–10
11–20
Total
No. of pancreatitis episodes
3
55
313
371
No. of patients
3
45
243
291
Patients with ARP, no. (%) Females, no. (%)
0 (0)
2 (4)
25 (10)
27 (9)
2 (67)
19 (35)
172 (55)
193 (52)
Cause of pancreatitis, no. (%) Biliary
1 (33)
14 (25)
109 (35)
124 (33)
Medication
1 (33)
12 (22)
62 (20)
75 (20)
Idiopathic
0 (0)
12 (22)
58 (19)
70 (19)
Trauma
1 (33)
7 (13)
32 (10)
40 (11)
Viral
0 (0)
10 (18)
23 (7)
33 (9)
Infected necrosis, no. (%)
0 (0)
0 (0)
7 (2)
7 (2)
Pancreatic pseudocyst, no. (%)
0 (0)
0 (0)
5 (2)
5 (1)
SIRS occurred in the first week of onset, no. (%)
1 (33)
9 (16)
37 (12)
47 (13)
Organ failure at any time during admission, no. (%)
1 (33)
5 (9)
18 (6)
24 (6)
MOF at any time during admission, no. (%) Length of hospital stay, median (range), days
1 (33)
3 (5)
7 (2)
11 (3)
9
14 (1–78)
13 (1–120)
13 (1–120)
Mortality, no. (%)
1 (33)
4 (7)
14 (4)
19 (5)
Complications
(1–28)
Data collection The ID numbers of patients who were identified through a computer database search for acute pancreatitis were obtained for a detailed search. All of the data were reviewed by authors and then entered into a database on a digital case record form. The data collected for each patient included age, sex, etiology, clinical presentation, laboratory tests, and clinical outcomes. All components of the pediatric acute pancreatitis severity (PAPS) scoring system and all signs of systemic inflammatory response syndrome (SIRS) were recorded on admission and by 48 h [11]. Organ failure and multiple organ failure (MOF) statuses were evaluated according to the established score described by Graciano et al. [12]. Severity classification was based on the Revision of the Atlanta Classification system [13]. Statistical analysis Mortality rate was the primary outcome. Complications and length of hospital stay were secondary outcomes. Patients were subdivided by age and characteristics of each
123
age group were analyzed. Potential parameters to predict death were analyzed, too. Data were compiled and analyzed with SPSS (SPSS Inc, Chicago, IL, USA) software. Multivariable analysis was used to determine the impact of the different predictors on mortality. The results were analyzed using standard testing (Mann–Whitney test, Chi square test, linear-by-linear association). Two-sided P \ 0.05 was considered statistically significant.
Results Characteristics of the patients A total of 404 cases were identified from the database; however, 33 of these cases met the exclusion criteria. Of the 371 remaining cases, 178 were male and 193 were female. We divided the patients into three groups based on age, the demographic characteristics of each age group are provided in Table 1. Forty-five percent of cases in the 11–18 years age group were male, lower when compared
Pediatr Surg Int (2014) 30:1111–1115
with 65 % in the 3–10 years age group (P \ 0.05). Concerning etiologies, biliary causes were the most common, found in 124 (33 %) cases. Medications and trauma were also common etiologies for AP, found in 75 (20 %) and 40 (11 %) patients, respectively. In terms of patient distribution, under the RAC system, 6 % (21/371) of the patients were categorized as severe, and the rest were categorized as mild or moderate. Outcomes Overall mortality rate was 5 % (19/371). The mean duration of hospital stay was 13 days. ARP occurred in 27 patients with an average of three recurrent episodes. Death within 7 days of hospitalization occurred in 89 % (17/19) of all fatalities. The death rate and mean duration of hospital stay in the three groups were similar (P [ 0.05). However, patients with infected necrosis, and pancreatic pseudocyst were all observed in the 11–20 years age group. All of the patients with infected necrosis were received open necrosectomy and two of which died because of intra-abdominal bleeding. Organ failure during admission occurred in 24 of 371 patients and most of them started in 3 days of onset (19/ 24) (Table 1). The vast majority death had organ failure during admission as compared with patients without organ failure (17/19 vs 2/19, P \ 0.001). Furthermore, 3 of the 371 cases were misdiagnosed as acute appendicitis initially and thus received appendectomies.
1113 Table 2 Comparison of clinical parameters of the patients with and without death Died (n = 19)
Survived (n = 352)
Age [10 years
14
299
0.188
Females
14
179
0.052
1
26
0.729
3
121
0.094
10
60
\0.001
Patients with recurrence Cause of pancreatitis Biliary Idiopathic
P value
Medication
3
72
0.622
Trauma
2
38
0.971
Viral
1
31
0.592
Ten times higher than the upper normal limit to amylaze and/or lipase levels at admission Median BMI percentile [95 % at admission
7
112
0.648
2
30
0.762
White blood cell count [15, 109/L at admission
8
131
0.668
PAPS score [2
9
122
0.259
Infected necrosis
2
5
0.045
SIRS occurred in the first week of onset
15
32
\0.001
Organ failure occurred within 3 days of onset
15
4
\0.001
MOF occurred in the first week of onset
10
1
\0.001
Predictors for mortality The results of the comparison of clinical parameters of the patients with and without death occurrence are given in Table 2. Results showed that occurrence of SIRS in the first week of onset, occurrence of organ failure within 3 days of onset, occurrence of MOF in the first week of onset, infected necrosis, and idiopathic cause were strongly associated with death development (P \ 0.05). Multivariate analysis with logistic regression confirmed that occurrence of SIRS in the first week of onset (OR = 2.12, 95 % CI 1.14–6.32, P \ 0.001), occurrence of organ failure within 3 days of onset (OR = 8.0, 95 % CI 2.2–12.3, P \ 0.001), occurrence of MOF in the first week of onset (OR = 9.4, 95 % CI 2.3–14.6, P \ 0.001), infected necrosis (OR = 1.28, 95 % CI 1.08–1.52, P = 0.02), and idiopathic cause (OR = 17.3, 95 % CI 2.0–60.5, P \ 0.001) were independent risk factors for death in cases with AP.
Discussion In this study, we report a study regarding clinical outcomes for AP in children on the basis of a 10-year retrospective
analysis. We divided them into three groups by age to describe demographic characteristics and outcomes of them. We also compared the clinical features between those with and without a outcome of death to find out the risk factors to predict death occurrence. Acute pancreatitis in children is a costly and increasingly recognized disease. The incidence of acute pancreatitis in children has documented an increase during the past 10–15 years by several studies [8, 14]. Variation in age, developmental stages, and environmental exposures in children may influence the presentation of children with acute pancreatitis [7]. That is why in our study, 3 of the 371 cases were misdiagnosed as acute appendicitis and received appendectomy. Concerning etiology, biliary tract diseases are still the most common cause for the patients with acute pancreatitis, both in adults and children. In adults, the overwhelming majority of pancreatitis episodes are associated with gallstones or alcohol, however in children the etiologies are much more diverse [1]. Available data suggested that the most common etiologies of acute pancreatitis in children are biliary, medications, idiopathic, systemic disease, and trauma [9, 15], which is similar to our result. The growing
123
1114
incidence leads to a further recognition of etiologies. A previous study underscored the importance of considering drugs as a cause and a contributor to pancreatitis in children, particularly valproic acid in young children [16]. In children, only a small percentage of patients were reported to have severe complications, and the mortality rate ranged from 0 to 11 % [17]. In our study, 2 % of the patients developed infected necrosis or pancreatic pseudocyst, all of the patients were 11 years old or more. All the five patients with pseudocyst were associated with a traumatic etiology, which is similar to a previous study [18]. It should be mentioned that we did not perform CECT routinely during conservative treatment except when a patient started to have persistent clinical manifestations of sepsis, which is why we did not enroll pancreatic necrosis into the complications. Overall mortality rate in our study was 5 % (19/371). The mean duration of hospital stay was 13 days. Death within 7 days of hospitalization occurred in 89 % (17/19) of all fatalities. Most of the patients died followed by early organ failures instead of infected necrosis, which is different from adult patients [19]. Despite traditional measures, including scoring systems (e.g., Ranson, Glasgow, APACHE), serum measurements, and radiological evaluation, acute pancreatitis patients remain challenging to risk-stratify in a consistent and accurate manner [20]. Results of a study showed that commonly used scoring systems have limited ability to predict disease severity in children and adolescents with acute pancreatitis by assessing the accuracy of the Ranson, modified Glasgow, and pediatric acute pancreatitis severity (PAPS) scoring systems for predicting major complications [11]. Careful and repeated evaluations are essential in managing these patients who may develop major complications without early signs. In our study, results showed that early organ failure and idiopathic cause were strongly associated with death development. Multivariate analysis with logistic regression confirmed that SIRS, early organ failure, MOF, infected necrosis, and idiopathic cause instead of PAPS scoring system were independent risk factors for death in cases with pancreatitis. At the beginning of the natural course of acute pancreatitis, systemic inflammatory response syndrome (SIRS) is caused by the activation of an inflammatory cascade mediated by cytokines such as tumor necrosis factor (TNF) and interleukin (IL)-6, mononuclear cells and the complement system [21]. This inflammatory response involves the activation of macrophages, which are recruited into tissues distant to the pancreas and result in the development of multiple organ failure (MOF) [21]. At the same time, release of inflammatory mediators often leads to general derangements including hypovolemia, a hyperdynamic circulatory regulation, fluid loss from the intravascular space, and increased capillary permeability, which would
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Pediatr Surg Int (2014) 30:1111–1115
aggravate MOF [22]. A previous study had revealed that duration of organ failure during the first week of predicted severe acute pancreatitis is strongly associated with the risk of death or local complications; persistent organ failure is a marker for subsequent death or local complications [23]. At the latter stage, infected necrosis is still a main lifethreatening complication with a high risk of death [24]. Furthermore, persistent organ failure, bacteraemia, and age were associated with mortality by using multivariate analysis in adult patients with AP [25]. About 12–37 % of the patients with AP in children had idiopathic cause [26]; however, the pathophysiology of these patients seems as yet unclear although inflammation in acute pancreatitis appears to be the result of a common pathway. In this study, after a review of the cases with an idiopathic cause, we found that there was an increase in serum lipid level (triglyceride levels [130 mg/dL) in some of the patients (22/70), and most (20/22) of which had moderate or severe hypertriglyceridemia (triglyceride levels [200 mg/dL). Deng et al. [27] reviewed 176 adult patients with severe AP, of which 45 had hypertriglyceridemia ([500 mg/dL). On univariate analyses, patients with hypertriglyceridemia had higher prevalence of renal failure, shock, infection, and overall mortality. Logistic regression analysis also showed a positive correlation between admission triglyceride level and 24-h APACHE II score. Recent findings demonstrated a decrease in acinar ATP levels and mitochondrial damage in hypertriglyceridemic mink exocrine pancreas [28]. Besides, higher serum amylase levels and worse histologic damage to the pancreas were observed in hypertriglyceridemic animals [28]. These results might explain why idiopathic cause was an independent risk factor for death in cases with pancreatitis. Although this finding has never been mentioned in previous reports and it is unclear whether there is a connection between hyperlipidemia and higher risk of death, we suggest that hyperlipidemia can be considered to be an independent etiology of the patients with AP in children. Besides, a high prevalence of genetic mutations (CFTR, SPINK1, PRRS1 mutations) was found in those patients without anatomic or metabolic abnormalities known to be associated with pancreatitis [29, 30]. Since genetic tests are not routinely performed in the patients with idiopathic cause, it is unclear whether genetic mutation is another potential reason for the higher mortality rate of idiopathic cause.
Conclusion Our results indicated that biliary causes, medications, and trauma were the most common etiologies for acute pancreatitis in children. The death rate, complication rate, and
Pediatr Surg Int (2014) 30:1111–1115
mean duration of hospital stay were similar in different age groups. Early organ failure, infected necrosis, and idiopathic cause were independent risk factors for death in cases with pancreatitis. However, this series had an unavoidable bias, as its retrospective nature may have led to a potential bias in data collection. In addition, we did not perform follow-up visits; thus, the outcomes that we analyzed were limited. Aside from these clinical implications, further research on the pathophysiology of acute pancreatitis in children should be considered in future studies. Acknowledgments All of the authors contributed to the collection and analysis of the data and to the preparation of the report. The corresponding author had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Part of the study was presented at the 44th Annual Meeting of American Pancreatic Association 2013 (October 30– November 2, Miami, FL, USA). Conflict of interest
The authors declare no conflicts of interest.
References 1. Whitcomb DC (2006) Acute pancreatitis. N Engl J Med 354:2142–2150 2. Peery AF, Dellon ES, Lund J et al (2012) Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology 143:1179–1187 3. Goldacre MJ, Roberts SE (2004) Hospital admission for acute pancreatitis in an English population, 1963–98: database study of incidence and mortality. BMJ 328:1466–1469 4. DeFrances CJ, Lucas CA, Buie VC et al (2008) National Hospital Discharge Survey. Natl Health Stat Report 5:1–20 5. Lankisch PG, Karimi M, Bruns A et al (2009) Temporal trends in incidence and severity of acute pancreatitis in Lu¨neburg County, Germany: a population-based study. Pancreatology 9:420–426 6. Spanier BW, Dijkgraaf MG, Bruno MJ (2008) Trends and forecasts of hospital admissions for acute and chronic pancreatitis in the Netherlands. Eur J Gastroenterol Hepatol 20:653–658 7. Bai HX, Lowe ME, Husain SZ (2011) What have we learned about acute pancreatitis in children? J Pediatr Gastroenterol Nutr 52:262–270 8. Nydegger A, Heine RG, Ranuh R et al (2007) Changing incidence of acute pancreatitis: 10-year experience at the Royal Children’s Hospital, Melbourne. J Gastroenterol Hepatol 22:1313–1316 9. Kandula L, Lowe ME (2008) Etiology and outcome of acute pancreatitis in infants and toddlers. J Pediatr 152:106–110 10. Morinville VD, Husain SZ, Bai H et al (2012) Definitions of pediatric pancreatitis and survey of present clinical practices. J Pediatr Gastroenterol Nutr 55:261–265 11. Lautz TB, Chin AC, Radhakrishnan J (2011) Acute pancreatitis in children: spectrum of disease and predictors of severity. J Pediatr Surg 46:1144–1149
1115 12. Graciano AL, Balko JA, Rahn DS et al (2005) The Pediatric Multiple Organ Dysfunction Score (P-MODS): development and validation of an objective scale to measure the severity of multiple organ dysfunction in critically ill children. Crit Care Med 33:1484–1491 13. Banks PA, Bollen TL, Dervenis C et al (2013) Classification of acute pancreatitis—2012: revision of the Atlanta classification and definitions by international consensus. Gut 62:102–111 14. Lopez MJ (2002) The changing incidence of acute pancreatitis in children: a single-institution perspective. J Pediatr 140:622–624 15. Park AJ, Latif SU, Ahmad MU et al (2010) A comparison of presentation and management trends in acute pancreatitis between infants/toddlers and older children. J Pediatr Gastroenterol Nutr 51:167–170 16. Bai HX, Ma MH, Orabi AI et al (2011) Novel characterization of drug-associated pancreatitis in children. J Pediatr Gastroenterol Nutr 53:423–428 17. Werlin SL, Kugathasan S, Frautschy BC (2003) Pancreatitis in children. J Pediatr Gastroenterol Nutr 37:591–595 18. Yeung CY, Lee HC, Huang FY et al (1996) Pancreatitis in children-experience with 43 cases. Eur J Pediatr 55:458–463 19. Schmid SW, Uhl W, Friess H et al (1999) The role of infection in acute pancreatitis. Gut 45:311 20. James RS, Stephen PP (2008) Acute pancreatitis. Curr Opin Crit Care 14:172–178 21. Mofidi R, Duff MD, Wigmore SJ et al (2006) Association between early systemic inflammatory response, severity of multiorgan dysfunction and death in acute pancreatitis. Br J Surg 93:738–744 22. Norman J (1998) The role of cytokines in the pathogenesis of acute pancreatitis. Am J Surg 175:76–83 23. Johnson CD, Abu-Hilal M (2004) Persistent organ failure during the first week as a marker of fatal outcome in acute pancreatitis. Gut 53:1340–1344 24. Beger HG, Rau B, Mayer J et al (1997) Natural course of acute pancreatitis. World J Surg 21:130–135 25. Besselink MG, van Santvoort HC, Boermeester MA et al (2009) Timing and impact of infections in acute pancreatitis. Br J Surg 96:267–273 26. Javid G, Zargar S, Shah A et al (2013) Etiology and outcome of acute pancreatitis in children in Kashmir (India). An endemic area of hepatobiliary ascariasis. World J Surg 37:1133–1140 27. Deng LH, Xue P, Xia Q et al (2008) Effect of admission hypertriglyceridemia on the episodes of severe acute pancreatitis. World J Gastroenterol 14:4558–4561 28. Scherer J, Singh VP, Pitchumoni CS et al (2014) Issues in hypertriglyceridemic pancreatitis: an update. J Clin Gastroenterol 48:195–203 29. Minen F, De Cunto A, Martelossi S et al (2012) Acute and recurrent pancreatitis in children: exploring etiological factors. Scand J Gastroenterol 47:1501–1504 30. Sultan M, Werlin S, Venkatasubramani N (2012) Genetic prevalence and characteristics in children with recurrent pancreatitis. J Pediatr Gastroenterol Nutr 54:645–650
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ORIGINAL ARTICLE
Predictors for mortality following acute pancreatitis in children Qiang Guo • Mao Li • Yang Chen • Hankui Hu Weiming Hu
•
Accepted: 9 September 2014 / Published online: 13 September 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Introduction Although there are several studies focusing on pancreatitis etiology and clinical outcome, no previous report has examined the risk factors for death in children. Patients and methods We reviewed the medical records of all children (ages 0–18 years) admitted to West China Hospital with acute pancreatitis between 2002 and 2012. Independent predictors for death following acute pancreatitis in children were identified using a multivariate logistic regression analysis. Results Biliary diseases (23 %), medications (20 %), idiopathic (19 %), and trauma (11 %) were the most common etiologies for acute pancreatitis in children. The death rate was 5 % and the mean duration of hospital stay was 13 days. Organ failure during admission occurred in 24 of 371 patients and most of them started in 3 days of onset (19/24). Multivariate analysis with logistic regression confirmed that occurrence of SIRS in the first week of onset (OR = 2.12, 95 % CI 1.14–6.32, P \ 0.001), occurrence of organ failure within 3 days of onset (OR = 8.0, 95 % CI 2.2–12.3, P \ 0.001), occurrence of MOF in the first week of onset (OR = 9.4, 95 % CI 2.3–14.6, P \ 0.001), infected necrosis (OR = 1.28, 95 % CI 1.08–1.52, P = 0.02), and idiopathic cause (OR = 17.3, 95 % CI 2.0–60.5, P \ 0.001) were independent risk factors for death in cases with pancreatitis. Conclusions Mortality rate and complication rate of acute pancreatitis in children remains low. Patients with SIRS, early organ failure, MOF, infected necrosis, or idiopathic cause should be well evaluated because they have higher risk of death. Q. Guo M. Li Y. Chen H. Hu W. Hu (&) Hepato-Bilio-Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China e-mail: [email protected]
Keywords Acute pancreatitis Children Mortality Multivariate analysis
Introduction Acute pancreatitis is a common disease with a very varied outcome [1]. In the US, acute pancreatitis is the most common reason of gastrointestinal diseases for hospitalization [2]. In the UK, there are 150–420 clinically diagnosed cases per million residents, and in the US, approximately 233,000 patients are admitted with a new diagnosis of acute pancreatitis each year [3, 4]. The mortality rate ranges from 5.7 to 10 % in patients who are diagnosed with acute pancreatitis [5, 6]. In children, the incidence of acute pancreatitis appears to be on the rise [7]. Although there are several studies focusing on pancreatitis etiology, few have characterized their clinical outcome and no previous report has examined the risk factors for death in children [8, 9]. Herein, we described the characteristics of acute pancreatitis in children and defined independent predictors for early death using a multivariate logistic regression analysis. Since recent reports suggest that there may be important differences in clinical features between infants/toddlers and older children [9], we compared the clinical features and outcomes between different age groups as well.
Materials and methods Identification of patients Data on children (younger than 19 years) admitted to West China Hospital with a first diagnosis of acute pancreatitis
123
1112
from January 2002 to July 2012 were collected. The exclusion criteria were a flare-up of chronic pancreatitis. A diagnosis of acute pancreatitis (AP) was made using a combination of clinical (i.e., the sudden onset of upper abdominal pain), laboratory (more than three times the upper normal limit for amylase and/or lipase levels), and imaging tests (abdominal ultrasound, abdominal computerized tomography, and magnetic resonance imaging) findings [10]. Acute recurrent pancreatitis (ARP) was defined as more than two distinct episodes of AP with intervening return to baseline [10]. Therapeutic strategy After admission, full laboratory and imaging tests were performed to evaluate the severity of the disease. All patients received conservative treatment initially. Antibiotics were administered after admission for no more than 7 days unless they had persistent clinical manifestations of sepsis. Parenteral nutrition was initiated, and after the function of gastrointestinal tract recovered from paralysis, they were fed with enteral nutrition as well as parenteral nutrition. During the conservative treatment, contrastenhanced computed tomography (CECT) was performed when a patient started to have persistent clinical manifestations of sepsis. Patients with suspected infected necrosis were advised to receive surgical intervention. Cultures were taken during all primary procedures to confirm the diagnosis of infected necrosis. Those patients who were extremely weak were treated in the intensive care unit.
Pediatr Surg Int (2014) 30:1111–1115 Table 1 Characteristics of each age group Age group
0–2
3–10
11–20
Total
No. of pancreatitis episodes
3
55
313
371
No. of patients
3
45
243
291
Patients with ARP, no. (%) Females, no. (%)
0 (0)
2 (4)
25 (10)
27 (9)
2 (67)
19 (35)
172 (55)
193 (52)
Cause of pancreatitis, no. (%) Biliary
1 (33)
14 (25)
109 (35)
124 (33)
Medication
1 (33)
12 (22)
62 (20)
75 (20)
Idiopathic
0 (0)
12 (22)
58 (19)
70 (19)
Trauma
1 (33)
7 (13)
32 (10)
40 (11)
Viral
0 (0)
10 (18)
23 (7)
33 (9)
Infected necrosis, no. (%)
0 (0)
0 (0)
7 (2)
7 (2)
Pancreatic pseudocyst, no. (%)
0 (0)
0 (0)
5 (2)
5 (1)
SIRS occurred in the first week of onset, no. (%)
1 (33)
9 (16)
37 (12)
47 (13)
Organ failure at any time during admission, no. (%)
1 (33)
5 (9)
18 (6)
24 (6)
MOF at any time during admission, no. (%) Length of hospital stay, median (range), days
1 (33)
3 (5)
7 (2)
11 (3)
9
14 (1–78)
13 (1–120)
13 (1–120)
Mortality, no. (%)
1 (33)
4 (7)
14 (4)
19 (5)
Complications
(1–28)
Data collection The ID numbers of patients who were identified through a computer database search for acute pancreatitis were obtained for a detailed search. All of the data were reviewed by authors and then entered into a database on a digital case record form. The data collected for each patient included age, sex, etiology, clinical presentation, laboratory tests, and clinical outcomes. All components of the pediatric acute pancreatitis severity (PAPS) scoring system and all signs of systemic inflammatory response syndrome (SIRS) were recorded on admission and by 48 h [11]. Organ failure and multiple organ failure (MOF) statuses were evaluated according to the established score described by Graciano et al. [12]. Severity classification was based on the Revision of the Atlanta Classification system [13]. Statistical analysis Mortality rate was the primary outcome. Complications and length of hospital stay were secondary outcomes. Patients were subdivided by age and characteristics of each
123
age group were analyzed. Potential parameters to predict death were analyzed, too. Data were compiled and analyzed with SPSS (SPSS Inc, Chicago, IL, USA) software. Multivariable analysis was used to determine the impact of the different predictors on mortality. The results were analyzed using standard testing (Mann–Whitney test, Chi square test, linear-by-linear association). Two-sided P \ 0.05 was considered statistically significant.
Results Characteristics of the patients A total of 404 cases were identified from the database; however, 33 of these cases met the exclusion criteria. Of the 371 remaining cases, 178 were male and 193 were female. We divided the patients into three groups based on age, the demographic characteristics of each age group are provided in Table 1. Forty-five percent of cases in the 11–18 years age group were male, lower when compared
Pediatr Surg Int (2014) 30:1111–1115
with 65 % in the 3–10 years age group (P \ 0.05). Concerning etiologies, biliary causes were the most common, found in 124 (33 %) cases. Medications and trauma were also common etiologies for AP, found in 75 (20 %) and 40 (11 %) patients, respectively. In terms of patient distribution, under the RAC system, 6 % (21/371) of the patients were categorized as severe, and the rest were categorized as mild or moderate. Outcomes Overall mortality rate was 5 % (19/371). The mean duration of hospital stay was 13 days. ARP occurred in 27 patients with an average of three recurrent episodes. Death within 7 days of hospitalization occurred in 89 % (17/19) of all fatalities. The death rate and mean duration of hospital stay in the three groups were similar (P [ 0.05). However, patients with infected necrosis, and pancreatic pseudocyst were all observed in the 11–20 years age group. All of the patients with infected necrosis were received open necrosectomy and two of which died because of intra-abdominal bleeding. Organ failure during admission occurred in 24 of 371 patients and most of them started in 3 days of onset (19/ 24) (Table 1). The vast majority death had organ failure during admission as compared with patients without organ failure (17/19 vs 2/19, P \ 0.001). Furthermore, 3 of the 371 cases were misdiagnosed as acute appendicitis initially and thus received appendectomies.
1113 Table 2 Comparison of clinical parameters of the patients with and without death Died (n = 19)
Survived (n = 352)
Age [10 years
14
299
0.188
Females
14
179
0.052
1
26
0.729
3
121
0.094
10
60
\0.001
Patients with recurrence Cause of pancreatitis Biliary Idiopathic
P value
Medication
3
72
0.622
Trauma
2
38
0.971
Viral
1
31
0.592
Ten times higher than the upper normal limit to amylaze and/or lipase levels at admission Median BMI percentile [95 % at admission
7
112
0.648
2
30
0.762
White blood cell count [15, 109/L at admission
8
131
0.668
PAPS score [2
9
122
0.259
Infected necrosis
2
5
0.045
SIRS occurred in the first week of onset
15
32
\0.001
Organ failure occurred within 3 days of onset
15
4
\0.001
MOF occurred in the first week of onset
10
1
\0.001
Predictors for mortality The results of the comparison of clinical parameters of the patients with and without death occurrence are given in Table 2. Results showed that occurrence of SIRS in the first week of onset, occurrence of organ failure within 3 days of onset, occurrence of MOF in the first week of onset, infected necrosis, and idiopathic cause were strongly associated with death development (P \ 0.05). Multivariate analysis with logistic regression confirmed that occurrence of SIRS in the first week of onset (OR = 2.12, 95 % CI 1.14–6.32, P \ 0.001), occurrence of organ failure within 3 days of onset (OR = 8.0, 95 % CI 2.2–12.3, P \ 0.001), occurrence of MOF in the first week of onset (OR = 9.4, 95 % CI 2.3–14.6, P \ 0.001), infected necrosis (OR = 1.28, 95 % CI 1.08–1.52, P = 0.02), and idiopathic cause (OR = 17.3, 95 % CI 2.0–60.5, P \ 0.001) were independent risk factors for death in cases with AP.
Discussion In this study, we report a study regarding clinical outcomes for AP in children on the basis of a 10-year retrospective
analysis. We divided them into three groups by age to describe demographic characteristics and outcomes of them. We also compared the clinical features between those with and without a outcome of death to find out the risk factors to predict death occurrence. Acute pancreatitis in children is a costly and increasingly recognized disease. The incidence of acute pancreatitis in children has documented an increase during the past 10–15 years by several studies [8, 14]. Variation in age, developmental stages, and environmental exposures in children may influence the presentation of children with acute pancreatitis [7]. That is why in our study, 3 of the 371 cases were misdiagnosed as acute appendicitis and received appendectomy. Concerning etiology, biliary tract diseases are still the most common cause for the patients with acute pancreatitis, both in adults and children. In adults, the overwhelming majority of pancreatitis episodes are associated with gallstones or alcohol, however in children the etiologies are much more diverse [1]. Available data suggested that the most common etiologies of acute pancreatitis in children are biliary, medications, idiopathic, systemic disease, and trauma [9, 15], which is similar to our result. The growing
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incidence leads to a further recognition of etiologies. A previous study underscored the importance of considering drugs as a cause and a contributor to pancreatitis in children, particularly valproic acid in young children [16]. In children, only a small percentage of patients were reported to have severe complications, and the mortality rate ranged from 0 to 11 % [17]. In our study, 2 % of the patients developed infected necrosis or pancreatic pseudocyst, all of the patients were 11 years old or more. All the five patients with pseudocyst were associated with a traumatic etiology, which is similar to a previous study [18]. It should be mentioned that we did not perform CECT routinely during conservative treatment except when a patient started to have persistent clinical manifestations of sepsis, which is why we did not enroll pancreatic necrosis into the complications. Overall mortality rate in our study was 5 % (19/371). The mean duration of hospital stay was 13 days. Death within 7 days of hospitalization occurred in 89 % (17/19) of all fatalities. Most of the patients died followed by early organ failures instead of infected necrosis, which is different from adult patients [19]. Despite traditional measures, including scoring systems (e.g., Ranson, Glasgow, APACHE), serum measurements, and radiological evaluation, acute pancreatitis patients remain challenging to risk-stratify in a consistent and accurate manner [20]. Results of a study showed that commonly used scoring systems have limited ability to predict disease severity in children and adolescents with acute pancreatitis by assessing the accuracy of the Ranson, modified Glasgow, and pediatric acute pancreatitis severity (PAPS) scoring systems for predicting major complications [11]. Careful and repeated evaluations are essential in managing these patients who may develop major complications without early signs. In our study, results showed that early organ failure and idiopathic cause were strongly associated with death development. Multivariate analysis with logistic regression confirmed that SIRS, early organ failure, MOF, infected necrosis, and idiopathic cause instead of PAPS scoring system were independent risk factors for death in cases with pancreatitis. At the beginning of the natural course of acute pancreatitis, systemic inflammatory response syndrome (SIRS) is caused by the activation of an inflammatory cascade mediated by cytokines such as tumor necrosis factor (TNF) and interleukin (IL)-6, mononuclear cells and the complement system [21]. This inflammatory response involves the activation of macrophages, which are recruited into tissues distant to the pancreas and result in the development of multiple organ failure (MOF) [21]. At the same time, release of inflammatory mediators often leads to general derangements including hypovolemia, a hyperdynamic circulatory regulation, fluid loss from the intravascular space, and increased capillary permeability, which would
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aggravate MOF [22]. A previous study had revealed that duration of organ failure during the first week of predicted severe acute pancreatitis is strongly associated with the risk of death or local complications; persistent organ failure is a marker for subsequent death or local complications [23]. At the latter stage, infected necrosis is still a main lifethreatening complication with a high risk of death [24]. Furthermore, persistent organ failure, bacteraemia, and age were associated with mortality by using multivariate analysis in adult patients with AP [25]. About 12–37 % of the patients with AP in children had idiopathic cause [26]; however, the pathophysiology of these patients seems as yet unclear although inflammation in acute pancreatitis appears to be the result of a common pathway. In this study, after a review of the cases with an idiopathic cause, we found that there was an increase in serum lipid level (triglyceride levels [130 mg/dL) in some of the patients (22/70), and most (20/22) of which had moderate or severe hypertriglyceridemia (triglyceride levels [200 mg/dL). Deng et al. [27] reviewed 176 adult patients with severe AP, of which 45 had hypertriglyceridemia ([500 mg/dL). On univariate analyses, patients with hypertriglyceridemia had higher prevalence of renal failure, shock, infection, and overall mortality. Logistic regression analysis also showed a positive correlation between admission triglyceride level and 24-h APACHE II score. Recent findings demonstrated a decrease in acinar ATP levels and mitochondrial damage in hypertriglyceridemic mink exocrine pancreas [28]. Besides, higher serum amylase levels and worse histologic damage to the pancreas were observed in hypertriglyceridemic animals [28]. These results might explain why idiopathic cause was an independent risk factor for death in cases with pancreatitis. Although this finding has never been mentioned in previous reports and it is unclear whether there is a connection between hyperlipidemia and higher risk of death, we suggest that hyperlipidemia can be considered to be an independent etiology of the patients with AP in children. Besides, a high prevalence of genetic mutations (CFTR, SPINK1, PRRS1 mutations) was found in those patients without anatomic or metabolic abnormalities known to be associated with pancreatitis [29, 30]. Since genetic tests are not routinely performed in the patients with idiopathic cause, it is unclear whether genetic mutation is another potential reason for the higher mortality rate of idiopathic cause.
Conclusion Our results indicated that biliary causes, medications, and trauma were the most common etiologies for acute pancreatitis in children. The death rate, complication rate, and
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mean duration of hospital stay were similar in different age groups. Early organ failure, infected necrosis, and idiopathic cause were independent risk factors for death in cases with pancreatitis. However, this series had an unavoidable bias, as its retrospective nature may have led to a potential bias in data collection. In addition, we did not perform follow-up visits; thus, the outcomes that we analyzed were limited. Aside from these clinical implications, further research on the pathophysiology of acute pancreatitis in children should be considered in future studies. Acknowledgments All of the authors contributed to the collection and analysis of the data and to the preparation of the report. The corresponding author had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Part of the study was presented at the 44th Annual Meeting of American Pancreatic Association 2013 (October 30– November 2, Miami, FL, USA). Conflict of interest
The authors declare no conflicts of interest.
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