Acute pancreatitis, the most common pancreatic disorder in childhood,1,2 is a costly and increasingly recognized disease. Studies from the United States, Mexico, and Australia have reported an increasing incidence of pediatric acute pancreatitis over the past two decades, though the reasons for such increases remain unclear.3-9 In the United States, approximately 11,000 children are diagnosed with acute pancreatitis each year, providing a total fiscal burden of more than $200 million/year. The burden, however, is not limited to cost, as pediatric acute pancreatitis is associated with significant morbidity and mortality, with reported mortality rates ranging from 0% to as high as 11%. The incidence of acute pancreatitis is 2 to 13 new cases annually per 100,000 children.4,7,10
Acute pancreatitis is a reversible process characterized by the presence of interstitial edema, infiltration by acute inflammatory cells, and varying degrees of necrosis, apoptosis and hemorrhage.4,11 There are many causes of acute pancreatitis (Table 82-1), but the mechanisms by which these conditions trigger pancreatic inflammation have not been fully elucidated.
TABLE 82-1Causes and Conditions Associated with Pancreatitis ||Download (.pdf) TABLE 82-1 Causes and Conditions Associated with Pancreatitis
|Drugs and Toxins (See Table 82-2) |
|Biliary Disorders |
|Choledochal cyst |
|Biliary sludge |
| Cytomegalovirus |
| Epstein-Barr virus |
| Enterovirus (Coxsackie) |
| Hepatitis A and B |
| Human immunodeficiency virus |
| Influenza A and B |
| Measles |
| Mumps |
| Rubella |
| Rubeola |
| Varicella |
| Campylobacter |
| Escherichia coli |
| Leptospirosis |
| Mycoplasma |
| Yersinia |
| Ascaris lumbricoides (obstructive) |
| Clonorchis sinensis (obstructive) |
| Malaria |
|Systemic Diseases |
|α1-Antitrypsin deficiency |
|Celiac disease |
|Collagen vascular disorders (lupus, polyarteritis nodosa) |
|Cystic fibrosis |
|Diabetes mellitus |
|Envenomation (scorpion, spider) |
|Head trauma |
|Henoch-Schönlein purpura |
|Hemolytic uremic syndrome |
|Hyperlipidemia (see Metabolic disorders/inborn errors of metabolism) |
|Hypertriglyceridemia (see Metabolic disorders/inborn errors of metabolism) |
|Inflammatory bowel disease |
|Intracranial tumors |
|Kawasaki disease |
|Malnutrition (starvation, eating disorders) |
|Metabolic disorders/inborn errors of metabolism |
| Acute intermittent porphyria |
| Apolipoprotein C-II deficiency |
| Apolipoprotein lipase deficiency |
| Branched-chain ketoaciduria (maple syrup urine disease) |
| Cystinuria |
| Familial hypertriglyceridemia and chylomicronemia |
| Glycogen storage disease |
| Hereditary lipoprotein lipase deficiency |
| Homocystinuria |
| Lysinuric protein intolerance |
| Organic aciduria (3-hydroxy-3-methyglutaryl-coenzyme A lyase deficiency) |
| Pyruvate kinase deficiency |
|Renal failure |
|Shock (multiorgan dysfunction syndrome, systemic inflammatory response syndrome) |
|Sickle cell disease (vaso-occlusive) |
|Transplantation (bone marrow, heart, kidney, liver, pancreas) |
|Accidental blunt trauma |
|Child abuse |
|Endoscopic retrograde cholangiopancreatography |
|Surgical trauma |
|Annular pancreas |
|Biliary tract malformations |
|Choledochal cyst |
|Cholelithiasis and choledocholithiasis |
|Duplication cyst |
|Endoscopic retrograde cholangiopancreatography complication |
|Pancreas divisum |
|Pancreatic ductal abnormalities |
|Pancreatic pseudocyst |
|Perforated duodenal ulcer |
|Sphincter of Oddi dysfunction |
|Calcium sensing receptor (CASR) |
|Cationic trypsinogen (PRSS1) |
|Anionic trypsinogen (PRSS2) |
|Chymotrypsinogen C |
|Cystic fibrosis transmembrane conductance regulator (CFTR) |
|Serine protease inhibitor of Kazal 1 (SPINK1) |
|Autoimmune pancreatitis |
While gallstones and alcohol consumption cause most cases in adults, the etiologies in children are more diverse (Table 82-1). The most common causes of acute pancreatitis in children are medications; biliary, idiopathic, and systemic causes; and trauma, followed by infectious, metabolic, and hereditary causes.4,8,12,13
Medications cause almost 30% of cases of acute pancreatitis in children (Table 82-2)4. The most common medications include valproic acid, L-asparaginase, prednisone, 5-ASA derivatives (e.g. sulfasalazine) and 6-mercaptopurine14; however, true causality is difficult to establish because many patients receive concomitant medications (such as 6-mercaptopurine) for systemic illnesses that in and of themselves may predispose to pancreatitis (i.e. inflammatory bowel disease).
TABLE 82-2Drugs Associated with Pancreatitis
Biliary tract disease refers to the presence of gallstones or sludge in the gallbladder. Thirty percent of biliary causes are attributed to sludge, as opposed to formed gallstones,2-4,6,8 in children. In most cases of pediatric biliary pancreatitis, children will have abnormal liver enzymes, particularly transaminase elevation and sometimes mild total hyperbilirubinemia.1,3,5,7-9
Pancreatitis associated with multisystem disease accounts for approximately one-third of the cases in pediatric patients. The most common associated systemic diseases include sepsis, shock with and without sepsis, hemolytic-uremic syndrome, and systemic lupus erythematous.4,6,7 While rare, Kawasaki disease has also been reported as a cause of acute pancreatitis.4,10,11 Trauma, while previously thought to be a leading cause of acute pancreatitis in children, was reported as a precipitating cause in 10% to 40% of patients in case series.4 Most commonly reported examples of trauma include blunt injury related to motor vehicle collisions, sports injuries, accidental falls, and child abuse.4,8,12,13 Despite better imaging modalities and increased awareness, up to one-third of cases of pancreatitis still have unknown etiology (i.e. idiopathic).
Less common causes of acute pancreatitis in children include infectious, metabolic, and hereditary causes. Viral etiologies, especially enteroviruses, tend to predominate with regard to infectious etiologies (Table 82-1); however, causation by any specific pathogen can be difficult to prove. Symptoms of infection and pancreatitis may occur at the same time and be independent events, or an infectious episode may serve as a nonspecific trigger in a host with an underlying predisposition to pancreatitis. The most common metabolic causes of acute pancreatitis in children include diabetic ketoacidosis, followed by hypertriglyceridemia and hypercalcemia.4,14 Most patients with hypertriglyceridemia, when subsequently examined, show evidence of an underlying derangement in lipid metabolism, probably unrelated to pancreatitis. Such patients are prone to recurrent episodes of pancreatitis. Any factor (e.g. drugs, alcohol) that causes an abrupt increase in serum triglycerides can precipitate acute pancreatitis. Most cases of hypercalcemia related pancreatitis are due to hyperparathyroidism.15
Congenital anomalies such as pancreatic divisum, abnormal junction of the common bile duct and main pancreatic duct (common channel syndrome), choledochal cysts, and annular pancreas increase the risk for acute pancreatitis. Pancreas divisum, which is present in approximately 15% of the population, occurs when the dorsal and ventral pancreatic buds fuse incompletely during embryonic development (7th week of gestation). Despite its proposed obstructive mechanism leading to acute pancreatitis, clinical causality remains controversial.16
The pathophysiology of acute pancreatitis remains obscure. Autodigestion is a currently accepted pathogenic theory, whereby pancreatitis results when proteolytic enzymes (e.g. trypsinogen, chymotrypsinogen, proelastase, and additional lipolytic enzymes) are activated in the pancreas acinar cell rather than the intestinal lumen.17
Despite multiple etiologies, inflammation in pancreatitis appears to be the result of a common pathway.4 Current dogma suggests that pancreatitis is a disease that evolves in three phases. The initial phase is characterized by intrapancreatic digestive enzyme activation and acinar cell injury. Aberrant nonphysiological calcium signals within acinar cells are generated first, followed by premature activation of the intraacinar pancreatic proenzymes, or zymogens.18 Acinar cell injury is believed to be the consequence of trypsin activation. The second phase of pancreatitis involves the activation, chemoattraction, and sequestration of leukocytes and macrophages in the pancreas, resulting in an enhanced intrapancreatic inflammatory reaction.17 Production of cytokines such as tumor necrosis factor-α leads to varying degrees of extrapancreatic inflammation and the final phase, in which the ensuing inflammatory cascade leads to fulminant pancreatitis. Here the active enzymes and cytokines digest cellular membranes and cause proteolysis, edema, interstitial hemorrhage, vascular damage, coagulation necrosis, fat necrosis, and parenchymal necrosis. Cellular injury and death result in the release of vasoactive substances and histamines that produce local and distal vasodilation, increased vascular permeability, and edema with effects on other organs. Most notable is the development of the systemic inflammatory response syndrome (SIRS) and acute respiratory distress syndrome (ARDS) as well as multi-organ failure that may occur as a result of this cascade. While rare in children, progression to this final phase results in significant morbidity and mortality.
AUTOPROTECTION OF THE PANCREAS
Autodigestion of the pancreas and associated pancreatitis is prevented by several innate protective mechanisms: (1) the packaging of pancreatic proteases in a precursor (proenzyme) form, (2) intracellular calcium homeostasis, (3) acid–base balance, and (4) the synthesis of endogenous trypsin or protease inhibitors; i.e. pancreatic secretory trypsin inhibitor (PSTI), also known as serine protease inhibitor of Kazal type 1 (SPINK1).
Trypsin activity that might be generated in the acinar cell is reduced by two mechanisms— the trypsin inhibitors (SPINK1) and trypsin-degrading proteases, such as chymotrypsin C (CTRC). Mutations of the proteins involved in these pathways increase the risk of developing pancreatitis since the abnormal proteins are not able to control prematurely activated trypsin within the acinar cell.19
Multiple genetic factors can increase the susceptibility and/or modify the severity of pancreatic injury in acute pancreatitis, recurrent pancreatitis, and chronic pancreatitis. These factors are related to control of trypsin activity within the acinar cell. There are five identified genes, variants of which are associated with increased susceptibility to pancreatitis: (1) cationic trypsinogen mutations (PRSS1), (2) pancreatic secretory trypsin inhibitor (SPINK1), (3) the cystic fibrosis transmembrane conductance regulator (CFTR), (4) the chymotrypsin gene (CTRC), and (5) the calcium sensing receptor (CASR).19
In children, abdominal pain is the major presenting symptom in 80% to 95% of cases.4 Pain is most commonly localized to the epigastrium; however, 20% of patients report diffuse pain, and 10% or less describe the “classical” radiation to the back. Rarely, patients may present complaining only of back pain. In non-verbal children, unusual irritability may be the only clue that the patient is in pain.6 The pain and/or irritability are often worsened by eating and may be more intense when the patient is supine. Patients may obtain some relief by sitting with the trunk flexed and knees drawn up.
The next most common presenting symptom in children is nausea or vomiting, occurring up to 80% of patients.4 Other findings may include fever, jaundice, ascites, or chest pain (the latter due to a pleural effusion). If an abdominal mass can be palpated, consider the possibility of a pseudocyst.
Infants and toddlers may differ in their presentation when compared to children older than 3 years of age. Abdominal distension and fever may be more likely than abdominal pain and nausea.6
In episodes of severe pancreatitis, the systemic inflammatory response syndrome may ensue. Patients can present in multi-organ failure manifested as shock, coagulopathy, hemorrhage, ARDS, renal failure, and secondary infections.
Physical examination frequently reveals a distressed patient. Tachycardia is often present and may be associated with hypotension. Compensated shock is not unusual and may result from (1) hypovolemia secondary to exudation of blood and plasma proteins into the retroperitoneal space, (2) increased formation and release of kinin peptides which cause vasodilation and increased vascular permeability, and (3) systemic effects of proteolytic and lipolytic enzymes released into the circulation.17 Jaundice may occur and is usually due to edema of the head of the pancreas with compression of the intrapancreatic portion of the common bile duct or passage of a biliary stone or sludge. Patients may demonstrate pulmonary findings such as tachypnea, basilar rales, atelectasis, possibly due to the presence of a (usually left-sided) pleural effusion. Abdominal tenderness and rigidity are present to a variable degree but may be hard to illicit depending on the patient’s body habitus. Abdominal distension may also be seen. Cutaneous manifestations termed Grey-Turner’s or Cullen’s sign, secondary to ecchymoses in the flanks or periumbilicus respectively due to hemorrhagic pancreatitis, is rare.12 Rarely, a palpable mass may be appreciated in the upper abdomen later in the course of the disease (i.e. 4–6 weeks) suggestive of a pseudocyst.
The differential diagnosis for abdominal pain in children is very broad and also age specific. Since pancreatitis can present at any age (although it is rare in infants and toddlers), clinical suspicion is required and there should be a low threshold to obtain appropriate laboratory studies (see below). Elevations of serum amylase and lipase are the most common biochemical abnormalities in pancreatitis. However, it is important to be aware they are not 100% specific to acute pancreatitis, as there are other pediatric conditions that can be associated with elevated amylase or lipase (Table 82-3).
TABLE 82-3Pediatric Conditions Associated with Elevation of Amylase or Lipase Levels ||Download (.pdf) TABLE 82-3 Pediatric Conditions Associated with Elevation of Amylase or Lipase Levels
| ||Elevation in Amylase ||Elevation in Lipase |
|Abdominal || || |
|Salivary gland || |
Infection (i.e. mumps)
|Thoracic || |
|Infectious || || |
|Metabolic || |
|Neoplastic || || |
|Drugs || || |
|Trauma || || |
|Renal || |
|Inflammatory || |
|Miscellaneous || || |
After obtaining a history and performing a physical examination that is suggestive, the diagnosis of acute pancreatitis is confirmed based on laboratory investigations. Significant elevations in serum amylase and lipase are typically the initial findings that suggest a diagnosis of pancreatitis. Serum amylase and/or lipase values threefold or more above normal are practically diagnostic if gut perforation, ischemia, and infarction can be excluded. Amylase values remain valuable in diagnosing pancreatitis despite being elevated in only 50% to 85% of cases.4 There are many cases in which an elevated amylase will be the only abnormality, as radiographic evidence of acute pancreatitis is not always found. As noted above, specificity of these biochemical markers is not perfect (Table 82-3), and be aware that increases in pancreatic enzymes have been reported in up to 25% of patients with celiac disease.20
While the serum lipase is generally considered the preferred test due to its greater sensitivity and specificity, there appears to be no definite correlation between the severity of pancreatitis and the degree of enzyme elevation. Total serum amylase values tend to return toward normal after 3 to 7 days, even with continuing clinical or radiographic evidence of pancreatitis. However, pancreatic isoamylase and lipase levels may remain elevated for 7 to 14 days.17
In infants and toddlers, discrepancies between lipase values may occur due to developmental differences in the expression of the pancreatic enzymes during the first few months of life: pancreatic lipase activity is diminished compared with older children, and preduodenal lipases assume greater importance.21 The clinical implication is that a lipase value in an infant may not reach the same levels as seen in an adolescent, and combined testing with amylase may be needed.
An immunoassay for urinary cationic trypsinogen is both sensitive and specific for pancreatitis, but cost and test availability limit use of this test to the setting of diagnostic uncertainty. Its utility in the pediatric population is still under study. Currently, urinary trypsin activation peptide may be the most sensitive diagnostic test for determining the severity of an episode of acute pancreatitis.22
Nonspecific laboratory findings may include leukocytosis, hemoconcentration, increased liver enzymes (particularly elevated γ-glutamyltransferase and bilirubin, which should prompt evaluation for gallstones), decreased calcium and magnesium levels, metabolic alkalosis (as a result of vomiting) or acidosis (severe pancreatitis), hyperglycemia, and evidence of disseminated intravascular coagulation or hypercoagulability. A limited proportion of patients will also demonstrate hypoxemia, which may herald the onset of ARDS.
Radiographic evaluation can include plain films, ultrasound (conventional and endoscopic), computed tomography (CT), magnetic resonance imaging (MRI), endoscopic retrograde cholangiopancreatography (ERCP), and magnetic resonance cholangiopancreatography (MRCP).
Plain films of the abdomen may demonstrate nonspecific findings such as a “sentinel loop” (distention of a loop of small bowel in proximity to the pancreas), dilated transverse colon with the “cutoff” sign (absent colonic gas distal to the transverse colon), paralytic ileus, a diffuse haziness indicative of ascites, calcification of the pancreas, blurring of the left psoas margin, pseudocyst formation, or in cases of severe disease, the presence of extraluminal air. Chest radiography, though not routinely necessary in the absence of hypoxia or respiratory distress, may reveal atelectasis, basilar infiltrates, pleural effusions (usually left-sided), or pulmonary edema.
Ultrasound is particularly appealing as an initial imaging tool because it does not subject children to ionizing radiation and is widely available. Furthermore, it is superior to CT scan in detecting gallstones as a cause of pancreatitis.23 All children whose presentation is suspicious for acute pancreatitis or who have an elevated amylase or lipase in the absence of a known etiology should undergo an abdominal ultrasound. Ultrasound does have some limitations. It is more operator dependent than other modalities, and this can be an issue when young children are being seen outside of pediatric centers. Patient factors such as overlying bowel gas or obesity can obscure the pancreas and hinder image quality. Diagnostic features at presentation on abdominal ultrasound include pancreatic size, ductal anatomy, the presence of gallstones, pancreatic parenchymal changes (heterogeneity, edema, calcifications), and peripancreatitic fluid collections.4 If the ultrasound is equivocal, the decision to obtain additional imaging—i.e. CT or MRI—should be discussed with the appropriate consultative services such as radiology or gastroenterology. Complications from recurrent pancreatitis such as masses, cysts, pseudocysts, or abscesses can also be identified. Abdominal ultrasound can be used to assess interval changes in pancreatic duct size, cyst/pseudocyst size, and stent position serially in patients with chronic pancreatitis without subjecting them to the ionizing radiation of a CT scan.
In most cases, CT is generally not necessary on initial presentation unless the diagnosis is unclear.24 Its utility can be greatest several days into the course if the patient continues to deteriorate, in which case there should be concern for pancreatic necrosis. CT is the optimal modality in detecting problems of perfusion and necrosis within the pancreatic parenchyma.
MRCP is costly, time consuming, and younger patients may need sedation/anesthesia to remain still. Despite these shortcomings, MRCP does provide high-quality imaging of the pancreatic parenchyma as well as duct system if concurrently stimulated with secretin administration. MRCP is the modality of choice for delineating congenital/anatomic or obstructive lesions such as pancreas divisum or pancreaticobiliary junction. It can mitigate the need for ERCP unless cholangitis is suspected, and is useful in distinguishing a pseudocyst from walled-off necrosis (see below). CT scan, however, is superior in the detection of calcifications over MRCP. Currently there are no guidelines regarding the use of MRI in the setting of acute pancreatitis; however, as this modality becomes more accessible and less time consuming, it may have a role in the future.4,25
ERCP has an important role in the diagnosis and treatment of pancreatic and biliary disease in children. Increased awareness of pancreatic diseases in children has led to it becoming an increasingly used therapeutic modality. In settings of ascending cholangitis, its emergent use is indicated. Patients with ductal abnormalities secondary to chronic pancreatitis or trauma may benefit from ERCP, because pancreatic duct dilation, sphincterotomy, stone extraction, lithotripsy, and stent placement are among the therapeutic options available to the advanced endoscopist. Post-ERCP pancreatitis is the most commonly encountered adverse event after the procedure and can lead to significant morbidity. As with MRCP, there is limited data about its use in children, and as more pediatric centers offer this therapeutic modality, more long-term data will be needed to assess its true efficacy.
A child with severe acute pain in the abdomen, with or without emesis, should be evaluated for acute pancreatitis. The diagnosis is established by two of the following three criteria: (1) Abdominal pain suggestive of or compatible with acute pancreatitis (i.e. abdominal pain of acute onset, especially in the epigastric region), (2) serum amylase and/or lipase activity at least three times greater than the upper limit of normal (IU/L), and (3) imaging findings characteristic of or compatible with acute pancreatitis (e.g. using ultrasound, contrast enhanced CT, endoscopic ultrasound, MRI/MRCP).26 As noted earlier, patients may also have associated nausea, emesis, fever, tachycardia, and abnormal findings on abdominal examination. Laboratory studies may reveal leukocytosis, hypocalcemia, and hyperglycemia. While not formally defined in pediatrics, severe pancreatitis may be associated with worsening hemoconcentration (elevated hematocrit), azotemia (elevated BUN, decreased urine output), SIRS, hypoxemia and associated ARDS, and signs of multi-organ failure.
CLINICAL COURSE, DEFINITIONS, AND CLASSIFICATIONS
Relative to adults, there is a lack of literature on the natural history of pediatric pancreatitis. Historically, pediatricians have extrapolated from adult studies and applied adult scoring systems to children. Pediatricians have recently come to realize that adult data and experience may not be completely transferable to children. The most common etiologies are different and vary with age or developmental stage. Environmental exposures in children are also likely to be different (e.g. less alcohol-induced) and this may also influence the presentation, clinical course, and severity of acute pancreatitis.
As a result, strict definitions for severity of acute pancreatitis in children do not currently exist. Nor can the standard classifications of interstitial versus necrotizing pancreatitis be used in children. As more research is being carried out in this field, many pediatricians will continue to base their work on the benchmarks set by adult definitions; however, there is hope that pediatric-specific criteria, classifications, and definitions will soon be available.
Traditional adult scoring systems such as APACHE II and Ranson’s criteria have not been clinically useful in pediatrics. They are cumbersome, require collection of a large amount of clinical and laboratory data over time, and do not have acceptable positive and negative predictive values for severe acute pancreatitis in children. Currently, no validated predictive scoring model exists for pediatric acute pancreatitis.
In the majority of cases of pediatric acute pancreatitis, the disease is self-limited (mild, interstitial disease, no organ failure or persistence of SIRS) and resolves spontaneously. The typical duration of hospitalization for children with pancreatitis is 5 to 8 days.4 More severe cases may have symptomatic local complications and may require clinical stabilization in an intensive care unit with multidisciplinary involvement. Admissions for severe pancreatitis may well last longer than 7 days. The presence of SIRS at admission has been associated with a prolonged length of stay greater than 7 days. The variability in the course of more severe cases of pancreatitis requires a multidisciplinary, personalized management approach to deliver the best care.17
Once the diagnosis has been confirmed, initial measures include the following. (1) Assessment of severity: Is there evidence of SIRS? Is there hemodynamic compromise? Is the patient clinically unstable, necessitating ICU level of care? (2) Initial resuscitation: IV analgesics for pain, aggressive but safe IV fluid administration, and pancreatic rest (nil per os [NPO; i.e. nothing by mouth]). Fluid resuscitation remains an area of some debate; however, an initial challenge of 20 cc/kg followed by a second bolus of 20 cc/kg should be used in almost all cases. Ensuring adequate urine output with serial evaluations of hydration status is imperative. If a patient continues to be hypotensive or tachycardic despite 60 cc/kg of IV fluid, intensive care unit transfer or admission may be warranted, as shock may be present or imminent. Patients with persistent emesis are at risk for electrolyte imbalances. The correction and repletion of any electrolyte abnormalities is important in the initial phase of management. (3) Determination of etiology: Once the patient is stable, be sure there is a thorough history, review of systems, and, importantly, a review of all medications and supplements. Radiologic investigations, mentioned above, such as ultrasound can evaluate for gallstones and assess the pancreatic head and body.
To standardize the approach to the immediate assessment and management of acute pancreatitis, many institutions now implement prestructured “ordersets,” or clinical practice care maps. These ordersets help standardize approach and facilitate optimal management of a disease with the potential for significant morbidity and mortality.
Nutrition has also now emerged as an important area of treatment debate in pancreatitis. While past dogma was that patients with acute pancreatitis should be completely NPO at admission to provide pancreatic rest, several large randomized, controlled trials27-31 of adults with severe acute pancreatitis have shown that early enteral feeding, either jejunal, postpyloric, or continuous nasogastric, reduces complications associated with acute pancreatitis. The intestinal barrier integrity is better maintained when the gut is fed, which results in decreased distal bacterial translocation. Pediatric trials of enteral feeding, however, have never been performed. Total parenteral nutrition (TPN) is generally not recommended unless a patient proves intolerant to enteral feeding. Infants and toddlers, however, are more likely to receive TPN than older children, and this should be considered if a patient is expected to remain NPO for greater than 3 days.
Data from two randomized control trials support early introduction of low-fat solid food (as opposed to “clears”) as the initial meal for adult patients with mild acute pancreatitis.30,31 The use of a polymeric formulation (presumed to stimulate the pancreas) does not increase the risk of feeding intolerance, infectious complications, or mortality in comparison with elemental formula. As data do not currently exist for children, practice variability exists in the initiation of feeding for children with acute pancreatitis.
Pain control can be provided with any opioid derivative. Most often hydromorphone hydrochloride (Dilaudid) is preferred to morphine, given concern for sphincter of Oddi dysfunction. We have found this to be more anecdotal than evidence based, and feel both opioids are safe to use in children for pain in acute pancreatitis. Many patients respond to high-dose nonsteroidal anti-inflammatory drugs such as ketorolac; however, its use must be weighed against the increased risk of bleeding, gastric ulceration, or renal insufficiency. Refractory cases may benefit from consultation from a dedicated pain service when available. Debate exists on the utility of proton pump inhibitors (PPIs) in the acute treatment phase for acute pancreatitis. Although commonly prescribed, currently there are no data indicating that PPI use can favorably alter the course of acute pancreatitis. The decision to initiate, and discharge a patient, on a PPI is therefore based on provider preference or judgment.
Complications can be early and late onset. Early-onset complications primarily include multi-organ dysfunction or shock.32 Patients can develop ARDS, pneumonia, or pleural effusions. Renal failure can also be seen.
Late-onset complications include pancreatic necrosis and pseudocyst formation.32 A sudden rise in pancreatic enzymes, persistent elevation, or worsening/persistence of symptoms suggests the development of a pseudocyst. A pancreatic pseudocyst is defined as an extrapancreatic homogenous collection of fluid rich in pancreatic enzymes and a small amount of debris that lacks an epithelial lining.27 This is different from “walled-off necrosis,” which is a post-necrotic fluid collection that contains heterogenous material including residual necrotic debris. Pseudocysts complicate the course in approximately 10% of patients but may occur in up to 50% of cases due to abdominal trauma. Thus in all but the mildest self-limited cases of acute pancreatitis, it is advisable to repeat an ultrasound after approximately 4 weeks to evaluate for possible pseudocyst formation, as they become evident 2 to 3 weeks after initial presentation. Small, asymptomatic pseudocysts can be managed conservatively; however, intervention is warranted for persistently symptomatic pseudocysts or those with evidence of complications such as infection or bleeding.32 Surgical intervention and/or percutaneous drainage are therapeutic options. In recent years, radiographic, endoscopic, and laparoscopic drainage have played an increasing role in pseudocyst drainage.32
ADMISSION AND DISCHARGE CRITERIA
All pediatric patients with acute or recurrent pancreatitis should be admitted for bowel rest and fluid and electrolyte management. Established criteria for admission to a general pediatric floor versus ICU should be utilized due to the persistence of SIRS despite aggressive fluid resuscitation.
When the child is tolerating adequate intake to sustain hydration and nutrition without pain, discharge home may be considered. Plans for follow-up, including any repeat imaging, should be in place.
Collaboration plus consultation with a pediatric gastroenterologist regarding the acute management and follow-up of patients with pancreatitis is prudent. Surgical consultation may be necessary in cases of confirmed or suspected trauma, pancreaticobiliary anomalies, or stones as potential causes of pancreatitis. The interventional radiologist may also provide valuable guidance and assistance when radioimaging is being considered. The pain service, where available, may assist with pain management, particularly in the acute setting. A genetics evaluation or consultation should be considered in cases of recurrent pancreatitis or in a child with a family history of hereditary pancreatitis.
There is limited literature regarding acute recurrent pancreatitis and chronic pancreatitis in children. The epidemiology and natural history of pediatric acute recurrent pancreatitis and chronic pancreatitis are not well understood, and there are no evidence-based diagnostic, prognostic, and treatment guidelines for these disorders.26 Approximately 25% of adults have recurrence17; however, the predominant etiologies in adults are alcohol and cholelithiasis, which are less commonly seen in children. Data on recurrence rates in children is lacking; however, approximately 15% to 35% of children with acute pancreatitis have recurrence,4 and the average number of recurrences reported was about 2.7 episodes per patient.8 Recurrent pancreatitis was more common in patients with biliary anomalies and metabolic disorders, particularly hypertriglyceridemia.12 Genetic defects associated with hereditary pancreatitis of course are associated with recurrent pancreatitis. The diagnostic criteria for acute recurrent pancreatitis require at least two distinct episodes of acute pancreatitis, along with (1) complete resolution of pain (≥1-month pain-free interval between the diagnoses of acute pancreatitis), or (2) complete normalization of serum pancreatic enzyme levels (amylase and lipase) before the subsequent episode of acute pancreatitis is diagnosed, along with complete resolution of pain symptoms, irrespective of a specific time interval between acute pancreatitis episodes.26
Chronic pancreatitis is a disease process characterized by irreversible damage to the pancreas as distinct from reversible changes noted in acute pancreatitis. Histopathologically, chronic pancreatitis is defined in the same manner as in adults and consists of an inflammatory process characterized by irreversible morphologic changes and fibrotic replacement of the pancreatic parenchyma.26 Irrespective of the mechanism of injury, it is hypothesized that pancreatic stellate cell activation results in cytokine expression and the production of extracellular matrix proteins leading to acute and chronic inflammatory changes and collagen deposition in the pancreas.33 In chronic pancreatitis, fibrosis and ductal obstruction may give rise to radiographically evident calcifications and pancreatic duct irregularities such as strictures and dilations, or histologic evidence of sclerosis/fibrosis, acinar and islet cell loss, inflammatory infiltrates, pancreatic duct abnormalities/scarring, and intraductal calculi.26
Among adults in the United States, alcoholism is the most common cause of clinically apparent chronic pancreatitis, while cystic fibrosis is the most frequent cause in children. The cardinal manifestations of the disease include abdominal pain, steatorrhea, weight loss, and diabetes mellitus.17 Patients with chronic pancreatitis will often seek medical attention for treatment of abdominal pain. The pain may be variable in location, severity, and frequency. It may be constant or intermittent, with frequent pain-free intervals. The development of a chronic abdominal pain syndrome often ensues.
The diagnosis of early or mild chronic pancreatitis is challenging because there is not a biomarker of the disease. Unlike acute pancreatitis, serum amylase and lipase levels are usually not strikingly elevated in chronic pancreatitis.17 Depending on the degree of endocrine and exocrine insufficiency, patients may have impaired glucose tolerance with elevated fasting blood glucose levels. In addition, fecal elastase-1 may be abnormal in patients with pancreatic steatorrhea.
Exocrine insufficiency should be suspected in patients with clinical features of or laboratory test results that suggestion malabsorption. These include diarrhea, steatorrhea, weight loss, metabolic bone disease, or vitamin or mineral deficiency. Treatment of exocrine insufficiency requires pancreatic enzyme replacement. A baseline evaluation of nutritional status is appropriate when patients begin pancreatic enzyme therapy.34 The patient’s anthropometrics should be determined and basic laboratory tests should be performed, including complete blood counts (with differential), comprehensive metabolic panel, international normalized ratio, and levels of albumin, prealbumin, carotene, and vitamin D.
The management of chronic abdominal pain is usually the most challenging problem with chronic pancreatitis. Pain treatment begins with medical therapy, as most patients with chronic pain will require analgesics. Notwithstanding the risk of addiction, the main goal is pain relief. While less-potent opioids are initiated per standard pain ladder algorithms, a number of other agents can be given along with opioids to manage chronic abdominal pain syndromes. These include tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and gabapentoids.34 Consultation with a pediatric pain specialist is advised in cases of chronic pain, and should form part of the multidisciplinary approach to patients with chronic pancreatitis. Recent meta-analyses have shown no consistent benefit of enzyme therapy in relation to pain reduction in chronic pancreatitis.35 Endoscopic treatment of chronic pancreatitis pain may involve sphincterotomy, stenting, stone extraction, and drainage of a pancreatic pseudocyst if present. Finally, a Whipple procedure as well as total pancreatectomy and autologous islet cell transplantation have been used in selected patients with chronic pancreatitis and abdominal pain refractory to conventional therapy. In adult studies, celiac plexus block has not demonstrated long-lasting pain relief.
There is one form of chronic pancreatitis that has specific medical therapy. Autoimmune pancreatitis (AIP) occurs in two forms.36 In type 1 AIP, the pancreas is involved as part of a systemic disease characterized by the presence of immunoglobulin G4-positive plasma cells in affected organs, and some patients have increased serum levels of immunoglobulin G4. A variety of organs can be involved, including salivary glands, bile ducts, kidneys, and lungs. Type 2 is not associated with altered levels of immunoglobulin G4 and involves only the pancreas. It may be seen in association with other diseases of presumed autoimmune etiology. Both types of AIP respond to corticosteroid therapy. Relapse can occur and may require other immunosuppressive therapies. AIP, while reported, is exceedingly rare in pediatric patients.
Chronic pancreatitis that occurs with an autosomal dominant pattern of inheritance has been termed hereditary pancreatitis. This is not to be confused with familial pancreatitis, which refers to pancreatitis from any cause that occurs in a family with an incidence that is greater than would be expected by chance alone, given the size of the family and standardized incidence of pancreatitis within a defined population. Mutations in genes encoding pancreatic proteins can cause inherited forms of chronic pancreatitis or modify the risk for developing chronic pancreatitis. Chronic pancreatitis in children has been associated with mutations in the genes encoding for cationic trypsinogen (serine protease 1, or PRSS1), SPINK1, cystic fibrosis transmembrane conductance regulator (CFTR), and CTRC. Mutations in PRSS1 are transmitted in an autosomal dominant manner, while that of SPINK1 and CFTR are autosomal recessive. Many patients may have recurrent acute or chronic pancreatitis episodes associated with a combination of genetic and environmental factors, as is seen in patients heterozygous for SPINK1 mutations. It is likely that the SPINK1 mutation probably acts as a disease modifier, lowering the threshold for developing pancreatitis from other genetic (e.g. CFTR mutations) or environmental factors. Genetic testing for pancreatitis susceptibility genes should be considered in patients with pancreatitis who fulfill one or more of the following criteria: (1) unexplained documented episode of pancreatitis as a child, (2) idiopathic chronic pancreatitis, particularly when onset is before age 25, (3) a family history of recurrent acute pancreatitis, idiopathic chronic pancreatitis, or childhood pancreatitis without a known cause, (4) relatives known to carry mutations associated with hereditary pancreatitis (i.e. PRSS1 mutations), or (5) recurrent acute attacks of pancreatitis for which there is no identifiable cause.
The diagnosis of pancreatitis should be entertained in a pediatric patient with persistent vomiting, abdominal pain, and anorexia.
Bowel rest, fluid and electrolyte management, and pain control are the mainstays of therapy.
Although complete recovery is usual in children, recurrence suggests underlying pathology, which mandates evaluation for an underlying cause.
Diagnostic imaging may begin with plain films of the abdomen, which may reveal pancreatic calcifications or findings suggestive of pancreatitis as previously discussed. Ultrasound and CT are the preferred studies to diagnose and monitor the course of pancreatitis and pseudocysts.
A pseudocyst complicates the course in approximately 10% of patients unless associated with abdominal trauma, in which case pseudocysts occur in more than 50% of patients.
ERCP may allow endoscopic therapeutic intervention for pancreatitis. MRCP affords anatomic definition of the pancreas while avoiding radiation exposure.
Advances in the understanding of genetic mutations that either produce or predispose an individual to pancreatitis should allow diagnostic insight, provide the framework for interventional strategies, and result in tailoring of management to specific underlying molecular causes. Pediatric risk stratification systems to assist the clinician in assessing the severity of acute pancreatitis are being developed and evaluated.
KM. Acute pancreatitis associated with biliary disease in children. J Gastroenterol Hepatol
SL. Acute pancreatitis. In: Kliegman
BF, eds. Nelson Textbook of Pediatrics. Philadelphia, PA: Saunders; 2007:1653.
BC. Pancreatitis in children. J Pediatr Gastroenterol Nutr
SZ. What have we learned about acute pancreatitis in children? J Pediatr Gastroenterol Nutr
R. Acute and recurrent pancreatitis in children: etiological factors. Acta Paediatr
ME. Etiology and outcome of acute pancreatitis in infants and toddlers. J Pediatr
ME. Increasing incidence of acute pancreatitis at an American pediatric tertiary care center: is greater awareness among physicians responsible? Pancreas
et al. Changing referral trends of acute pancreatitis in children: a 12-year single-center analysis. J Pediatr Gastroenterol Nutr
MR. Changing incidence of acute pancreatitis: 10-year experience at the Royal Children’s Hospital, Melbourne. J Gastroenterol Hepatol
RJ. Pancreatitis in Kawasaki disease. Am J Dis Child
EL. A clinically based classification system for acute pancreatitis. Summary of the International Symposium on Acute Pancreatitis, Atlanta, GA. September 11-13, 1992. 128;1993:586–590.
PR. Acute pancreatitis in childhood. J Pediatr
. 1988;113 (1 Pt 1):24–29.
MR. Childhood pancreatitis. J Gastroenterol Hepatol
et al. Novel characterization of drug-associated pancreatitis in children. J Pediatr Gastroenterol Nutr
DL. Update in acute pancreatitis. Curr Gastroenterol Rep
ME. Pediatric pancreatitis. Pediatr Rev
PA. Acute and chronic pancreatitis. In: Harrison’s Principles of Internal Medicine. Vol 2. 18th ed. McGraw Hill Professional; 2011:2634–2649.
E. The acinar cell and early pancreatitis responses. Clin Gastroenterol Hepatol
. 2009;7(11 Suppl):S10–14.
DC. Genetic aspects of pancreatitis. Annu Rev Med
A, Di Prima
et al. Unexplained elevated serum pancreatic enzymes: a reason to suspect celiac disease. Clin Gastroenterol Hepatol
LT. Measurement of fat digestion in early life using a stable isotope breath test. Arch Dis Child
et al. Prediction of the severity of acute pancreatitis on admission by urinary trypsinogen activation peptide: a meta-analysis. WJG
WT. Acute biliary disease: initial CT and follow-up US versus initial US and follow-up CT. Radiology
ML, the Practice Parameters Committee of the American College of Gastroenterology. Practice Guidelines in Acute Pancreatitis. Am J Gastroenterol
SL. A retrospective assessment of magnetic resonance cholangiopancreatography in children. J Pediatr Gastroenterol Nutr
et al. Definitions of pediatric pancreatitis and survey of present clinical practices. J Pediatr Gastroenterol Nutr
DL. Education practice. Clin Gastroenterol Hepatol
NV. A randomized controlled trial of enteral versus parenteral feeding in patients with predicted severe acute pancreatitis shows a significant reduction in mortality and in infected pancreatic complications with total enteral nutrition. Dig Surg
. 2006;23(5-6):336–344; discussion 344-345.
CD. A randomised clinical trial to assess the effect of total enteral and total parenteral nutritional support on metabolic, inflammatory and oxidative markers in patients with predicted severe acute pancreatitis (APACHE II > or =6). Pancreatology
BC, Vander Vliet
PA. A prospective, randomized trial of clear liquids versus low-fat solid diet as the initial meal in mild acute pancreatitis. Clin Gastroenterol Hepatol
. 2007;5(8):946–951; quiz 886.
RG. Immediate oral feeding in patients with mild acute pancreatitis is safe and may accelerate recovery–a randomized clinical study. Clin Nutr
et al. Classification of acute pancreatitis–2012: revision of the Atlanta classification and definitions by international consensus. Gut
JS. Chronic pancreatitis: challenges and advances in pathogenesis, genetics, diagnosis, and therapy. Gastroenterology
CE. Management of chronic pancreatitis. Gastroenterology
CM. Clinical trials of pancreatic enzyme replacement for painful chronic pancreatitis – a review. Pancreatology
ST. Autoimmune pancreatitis: an update on classification, diagnosis, natural history and management. Curr Gastroenterol Rep