Recent Advances in Pediatrics—16 Suraj Gupte
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Acute Pancreatitis: Management1

KarolyHorvath,
DevendraMehta
 
INTRODUCTION
Pancreatitis must be considered in the evaluation of any acutely ill child who has severe abdominal pain. The differential diagnosis of acute pancreatitis in children includes the following diseases:
  • Perforation (e.g. peptic ulcer)
  • Intestinal obstruction
  • Malrotation with bowel infarction
  • Acute cholecystitis
  • Renal colic
  • Pneumonia
  • Diabetic ketoacidosis
  • Vasculitis
Data reported from large teaching hospitals1-3 suggest that the prevalence of pancreatitis is increasing in childhood. Based on 3 recent larger pediatric reports,1-3 the causes of pancreatitis in children in decreasing order are systemic diseases, idiopathic (unknown etiology), trauma, medications, structural abnormalities of the pancreas, gallstones, infections, post-procedure (iatrogenic) and familial pancreatitis. Table 1.1 lists the most frequent causes of acute pancreatitis in children. Pancreatitis due to systemic illness represents the most frequent cause. Among drugs valproic acid is responsible for the most cases. Child abuse now is recognized as a major cause of traumatic pancreatitis in young children. As the childhood obesity became an epidemic in the USA, the childhood cases of gallstones pancreatitis, increased. Because in adults gallstone is the most frequent cause of pancreatitis, a recent UK recommendation states that the diagnosis of “idiopathic pancreatitis should not be accepted in the absence of a vigorous search for gallstones.”4 The gene for hereditary pancreatitis was identified at chromosome 7q35.5 Milder forms of cystic fibrosis, and carriers of cystic fibrosis gene mutations also have higher risk of developing idiopathic, acute pancreatitis.6
2
TABLE 1.1   Causes of acute pancreatitis in children
Cause
Examples
Systemic disorders
Reye syndrome; sepsis; shock; hemolytic-uremic syndrome
Trauma
Bike injury; child abuse in younger children
Medications
Valproic acid; Furosemide; Azathioprine; sulfonamides;
Tetracycline; Halothane; Estrogens;
Didanosine; Pentamidine (intravenous);
Mainly in HIV infected persons: Isoniazid, Rifampin, Erythromycin
Structural causes
Pancreas divisum; Trauma-with formation post-traumatic strictures; Pancreatic pseudocyst
Gallstones
Small stones (< 4 mm)40; Biliary sludge41
Infections
Viral: Mumps, Coxsackie B4, CMV, HIV,
In HIV infected persons: Toxoplasma, Mycobacterium avium,
Mycobacterium intracellulare, Cryptosporidium
Post-procedure
Post-ERCP; Post-spinal fusion surgery
Hereditary
Most frequent mutations in cationic trypsinogen gene (PRSS1) are R122H, R122C, and N29I. The activated trypsin is resistant to auto-digestion and inactivation
Other causes
Alcohol; Hypertriglyceridemia > 500 mg/dL; Hypercalcemia; Hyperparathyroidism; Scorpion stings; Ascaris infection; Periarteritis nodosa; CFTR gene mutations
 
PATHOMECHANISM
All of the major digestive enzymes, except amylase and lipase, are synthesized as proenzymes or zymogens that require activation by trypsin. Normally, trypsinogen is activated in the duodenum by the brush border enzyme, enterokinase, or by the trypsin itself.
Recent experimental studies indicate that trypsinogen activation is the main starting event in the development of acute pancreatitis. Studies in hereditary pancreatitis also support that the primary auto-activation of trypsin 7 is the first step. Activated trypsin is capable initiating the systemic inflammatory response8 in animal studies while the inactive trypsinogen itself does not. The role of early trypsinogen activation is also supported by studies showing that pancreatitis associated with endoscopic retrograde cholangiopancreatography (ERCP) can be attenuated by pretreatment with trypsin inhibitor (gabexate).9 However, once the inflammation started the infusion of trypsin inhibitors is not able to influence the cascade of events. The healthy pancreas is protected against the activation of trypsinogen by multiple mechanisms:
  • Pancreatic proteases synthesized as inactive proenzymes
  • 3Digestive enzymes segregated into secretory granules, stored in membrane-bound vesicular compartments and isolated from potential activators within the cell
  • Protease inhibitors are co-localized with pancreatic trypsinogen in the zymogen granules
  • There is an intracellular proteolytic degradation mechanism for the activated trypsin.
There is a balance between autoactivation and degradation of trypsinogen at cellular level. If trypsinogen is activated inside the cell, trypsin is inhibited by the pancreatic secretory trypsin inhibitor (PSTI), which is also known as serine protease inhibitor (SPINK1).
If the above listed protective mechanisms fail then the activated trypsin triggers inflammatory response first locally in the pancreas and if the process does not stop the activated enzymes and circulating cytokines provoke severe systemic inflammatory response. Three phases characterize the pathophysiology of acute pancreatitis.10
  • First, multiple causes can initiate an imbalance between trypsinogen activation and degradation in the acinar cells and the onset of acute pancreatitis. Activation may occur either from direct acinar injury from viruses, drugs and toxins, or increased ductal pressure from biliary stones or sludge, anatomical malformations such as pancreas divisum, ERCP or trauma. Reflux of bile into the pancreatic duct has also been proposed.
  • In the second phase, a series of intra-acinar cell events produce cellular injury and local tissue damage, which activates immune response.
  • In the third phase the damage of acinar cells progresses from the local inflammatory and circulatory response to a systemic response, including the production of cytokines, the generation of reactive oxygen species, and abnormalities in the systemic circulation. The severity of the clinical course is determined by the magnitude of the systemic inflammatory response.
It was shown that active digestive enzymes are potent stimulators of macrophages and can induce the production of such pro-inflammatory cytokines as tumor necrosis factor (TNF-α) and interleukin (IL-1β) in experimental systems.8 Levels of circulating cytokines correlate with the severity of the disease.11,12
Studies on animal models of pancreatitis showed that administration of anti-inflammatory cytokines such as IL1013 can decrease the severity of experimental pancreatitis in animals. Inhibition of NFkappa/beta has been shown to ameliorate experimental acute pancreatitis.14 These experimental approaches may lead to clinical therapies for the prevention of the systemic effects of acute pancreatitis.
Decreased perfusion due to fluid loss or shift to third spaces can be a contributing factor in pancreatitis. In experimental pancreatitis, regions 4of the organ with good perfusion are less likely injured than regions with hypoperfusion. This observation emphasizes the role of early fluid resuscitation in the initial management of acute pancreatitis.
 
DIAGNOSIS
 
Symptoms and Signs
The typical initial symptom is a sudden onset sharp, knife-like epigastric pain, which usually radiates to the back. It is a constant pain and can progress to diffuse abdominal pain syndrome. The pain is associated with nausea, anorexia and vomiting, which as progresses results in dehydration, tachycardia, weakness, light headedness and lethargy. In severe cases due to third spacing of fluid evident signs of hypovolemia and decrease in blood pressure may develop.
 
Physical Examination
On examination there is moderate/severe epigastric/periumbilical tenderness with decreased or absent bowel sounds and with or without abdominal distension. Signs of dehydration also can be noticed. In severe hemorrhagic pancreatitis bluish discoloration around the umbilicus (Cullen = sign) or flanks (Gray-Turner = sign) can be present.
 
Laboratory Evaluation
The typical serum test used for the diagnosis of acute pancreatitis is the measurement of serum amylase and lipase. However, none of them is specific for pancreas injury as amylase is present in the salivary gland and lipase is present in the glands of tongue and the gastric mucosa. Lipase will generally be increased in all forms of pancreatitis, while hypertriglyceridemia frequently does not cause amylase increase. Both amylase and lipase can be bound to immunoglobulins by forming macroamylase and macrolipase, because these complexes are detected by the clinical laboratory assays as amylase and lipase and have a long half-life therefore their presence falsely can be interpreted as ongoing pancreatitis. Table 1.2 lists conditions with elevated serum amylase and lipase.
Typically, the serum amylase level is elevated for 4 to 5 days, whereas the lipase is increased for 8 to 14 days. Lipase measurement is more specific than amylase for pancreatitis.
In addition to the enzyme tests the following tests should be routinely ordered:
  • Hemoglobin and hematocrit. Initially they may indicate hemoconcentration due to dehydration and shift of the fluid to the peritoneum. Untreated hemoconcentration increases the risk for necrotic pancreatitis.
    5
    TABLE 1.2   Differential diagnosis of elevated serum amylase and lipase
    Amylase elevation
    Lipase elevation
    Macroamylase
    Macrolipase
    Intestinal obstruction, infarction, perforation
    Intestinal obstruction, infarction, perforation
    Renal failure
    Critically ill patients (ICU patients)42
    Ruptured ectopic pregnancy
    Pancreatic carcinoma
    Diabetic ketoacidosis
    Diabetic ketoacidosis
    Burn patients
    Salivary adenitis; Parotid disease
  • CBC and differential. Significant leukocytosis is typically present.
  • Blood glucose level. Hyperglycemia can be present up to 25 percent of the patients.
  • Serum albumin. Decreased if ascites and/or pleural effusion develop.
  • Serum calcium.
  • Serum sodium and potassium.
  • AST, ALT and serum bilirubin: Liver function test abnormalities may signify common duct disease.
  • Triglycerides. High blood levels predispose for pancreatitis.
There are other, not routinely used laboratory tests:
  • Urinary trypsinogen-2 (Trypsinogen Activation Peptide, TAP).15,16 Urinary dipstick test was developed for detection of trypsinogen-2 (TAP). It is very useful screening for acute pancreatitis and has a sensitivity of 94 percent and specificity of 95 percent for acute pancreatitis. Levels of TAP correlate with severity of disease. It can be used in emergency room patients with acute abdominal pain to rule out acute pancreatitis.
  • In a pediatric series on 61 patients elevated cationic trypsinogen17 was superior to amylase in the early diagnosis of acute pancreatitis, and was more consistently elevated during the first 5 days in the hospital.
  • A leukocyte marker, polymorphonuclear leukocyte [PMN]-elastase, alone has sensitivity and specificity above 90 percent. The positive predictive value of the test was 98 percent if the cut-off is set at 200 μg/L.18
  • There are other factors from the pancreas, such as phospholipase A2, trypsin, and elastase, that they are elevated in acute pancreatitis, but none of them has gained widespread use in the clinical laboratories.
 
Imaging Studies
Abdominal X-ray is useful to rule out the possibility of perforation. In case of acute pancreatitis it may show ileus, sentinel loop of small bowel and calcification in case of chronic pancreatitis.
6Imaging studies are crucial in the diagnosis of acute pancreatitis, pancreatic necrosis and pseudocyst.
Abdominal ultrasonography is the initial imaging study for children because it is rapid, accurate, and noninvasive, and sedation is not required. The typical sonographic findings are enlarged, hypoechogenic pancreas or pancreatic head, pancreatic duct dilatation and peripancreatic and peritoneal fluid. However, it is most useful for the images of gallbladder and liver and helps to rule out gallstone as possible cause of the pancreatic inflammation. The UK Working Group recommendation is to repeat the abdominal US if the etiology is unknown.4 As far as the pancreatic US imaging concerned it may be impaired by intestinal gas. Pancreatic necrosis and pseudocyst can be identified more accurately by CT or magnetic resonance imaging.
Endoscopic ultrasonography is a recently introduced method, not generally available especially for pediatric practices. It allows a direct imaging of the pancreatic head without the interference of intestine and gas.
Dynamic intravenous contrast enhanced computerized tomography (CECT) is very specific and sensitive as initial evaluation after the first 24 hours and later for the complication of pancreatitis. In early stage it requires oral contrast, which may be difficult to give to the children with nausea and abdominal pain. The extent of necrosis is best assessed by this method. In severe pancreatitis, early CECT can differentiate between sterile necrosis and infected necrosis or abscess, and direct subsequent interventions. Baltazar et al.19 have published a CT grading system for acute pancreatitis (Table 1.3).
TABLE 1.3   CT grading system for acute pancratitis
Grade A
normal pancreas consistent with mild pancreatitis
Grade B
focal or diffuse enlargement of the gland, including contour irregularities and inhomogeneous attenuation but without peripancreatic inflammation
Grade C
abnormalities seen in grade B plus peripancreatic inflammation
Grade D
grade C plus associated single fluid collection
Grade E
grade C plus two or more peripancreatic fluid collections or gas in the pancreas or retroperitoneum
It has been shown that CECT provided a diagnostic sensitivity of 87 percent and an overall detection rate of 90 percent for pancreatic necrosis.20
Magnetic resonance cholangiopancreatograhy (MRCP) is a non-invasive method; it does not require administration of any contrast dye. It is best for evaluation of biliary tract and provides visualization similar to ERCP, although it does not evaluate the ampulla as well as ERCP. In our experience MRCP can miss pancreatic duct anomalies in 7children, which otherwise was seen with ERCP. The sensitivity and visualization of pancreas can be increased after IV secretin administration.
Endoscopic retrograde cholangiopancreatography allows imaging the biliary tree and pancreatic duct(s), while provides therapeutic options by removing gallstones, performing sphincterotomy if common bile duct stones are present. Biliary fluid may also be collected for microlithiasis.
 
MANAGEMENT
Once a diagnosis of pancreatitis has been established, the management consists of the followings:
  • Fluid therapy and treatment of organ dysfunction
  • Early recognition of signs and symptoms of severe acute pancreatitis
  • Identification and treatment of the underlying cause
  • Prevention and treatment of infected necrosis
  • Nutritional support.
 
Fluid Therapy and Treatment of Organ Dysfunction
Patients with acute pancreatitis are usually dehydrated due to vomiting and third space losses. Maintaining an adequate intravascular volume is probably the most essential therapeutic goal in the initial treatment. Rapid fluid boluses are necessary to prevent hemoconcentration. It was reported that a hematocrit over 44 is a predictor for necrotizing pancreatitis.21 Hemoconcentration with an admission hematocrit > or = 44 percent and/or failure of admission hematocrit to decrease at approximately 24 hours was associated with the development of necrotizing pancreatitis and organ failure. The negative predictive value of hematocrit by 24 hours was 96 percent for necrotizing pancreatitis and 97 percent for organ failure.21 An admission serum hematocrit level of 40 or less predicted a low risk of pancreatic necrosis.22 The mainstay of therapy remains early recognition, appropriate and aggressive fluid resuscitation and hemodynamic monitoring Animal studies indicate that ischemia and reperfusion also trigger pancreatitis. Therefore, it is very important to correct hypovolemia and electrolyte abnormalities.
To ensure that the fluid resuscitation is adequate, the urine specific gravity can be measured. If indicated urinary catheter should be inserted. If the patient's condition worsen more invasive monitoring and central venous line may be required. Because it is important to recognize associated organ dysfunction, which can progress to organ failure, full blood count, electrolytes, liver function tests, and arterial blood gases should be performed.
Patients with worsening clinical and laboratory parameters should be managed in intensive care units due to the danger of multiorgan failure.
8In the typical, uncomplicated cases of acute pancreatitis the treatment consists of:
  • Complete bowel rest initially, which followed by the reintroduction of enteral feeding as soon as the patient's condition allows starting it.
  • Nasogastric suction is indicated only in symptomatic patients with paralytic ileus. It is useful to control vomiting but does not influence the resolution of the underlying pancreatitis.
  • Intravenous fluid (Hct < 40)
  • Electrolyte and glucose monitoring
  • Meperidine for severe pain. Morphine is not recommended because it causes Oddi sphincter spasm.
 
Determination and Treatment of the Underlying Cause
After the initial stabilization of patients the next important task is to determine the cause of pancreatitis, e.g. an early ascertainment of the gallstone pancreatitis (the most common cause in adults) may change the approach to clinical management. Ultrasound is recommended as the initial investigation to rule out gallstone. This may need to be repeated as visualization of the biliary tree is often poor with distension, and stones can be missed. If available it can be replaced with magnetic resonance cholangiopancreatography (MRCP), which provides accurate and noninvasive assessment of the main bile duct.
Early endoscopic sphincterotomy (ES) with stone removal is main indication for emergent ERCP. A recent review of three randomized controlled trials concluded that early ERCP and ES are indicated in patients with associated cholangitis or increasing jaundice.23
A meta analysis reported that an elevation of ALT/AST 3-4 times above the normal is strongly associated with gallstones pancreatitis.24
There is a consensus that patients with mild acute gallstone pancreatitis should undergo cholecystectomy before discharge because of the high incidence of recurrent pancreatitis.
If a child has gallstone as the cause of abdominal pain it is important to recognize that multiple small stones represent a high risk for pancreatitis and an elective cholecystectomy should be considered to prevent gallstone pancreatitis.
 
Early Identification of Those at Risks for Severe Acute Necrotizing Pancreatitis
Several clinical, biochemical (inflammatory or pancreatic breakdown products), and radiological prognostic scoring systems have been proposed to identify those who are at risk for severe disease. There are no specific score systems for children. The adult score systems (Ranson's Criteria, Glasgow Score and APACHE II Score) may not have a better predictive value than the good clinical judgment.
9For pediatricians it is important to have a score system, which predicts severe pancreatitis within the first 2 days of the disease. DeBanto et al1 used 8 parameters and the cut-off for predicting a severe outcome was set at 3 criteria. They reported that their score system was more sensitive (70%) and have higher negative (91%) predictive values than the adult score systems, the Ranson and Glasgow scores. The following parameters were used:
  • age (< 7 yr)
  • weight (< 23 kg)
  • admission WBC (> 18,500)
  • admission LDH (> 2,000)
  • 48-h trough Ca2+ (< 8.3 mg/dl)
  • 48-h trough albumin (< 2.6 g/dl)
  • 48-h fluid sequestration (> 75 ml/ kg/48 h), and
  • 48-h rise in BUN (> 5 mg/dl).
In addition to lab indicators the most useful is a good clinical assessment by a physician experienced in the management of pancreatitis.
It seems that at 48 hours of the inflammation C-reactive protein greater than 150 mg/L is reliable marker for severe pancreatitis, although urinary trypsinogen activation peptide (TAP) or serum amyloid A may be better if confirmed by future studies.
Riche et al25 found that elevated IL-6 and procalcitonin soon after hospital admission were predictors of infected necrosis and that low levels had a high negative predictive value for infected necrosis.
 
Prevention and Treatment of Infection
There is no uniformly accepted practice regarding prophylactic antibiotic treatment. Recent multicenter randomized, controlled trial has found no evidence to support the use of prophylactic antibiotics.26 The International Association of Pancreatology recommends antibiotics only for patients with CT-proven necrosis.27 The development of fungal infection is associated with prolonged courses of antibiotics.
The predominant bacterial strains found in pancreatic tissue or blood cultures from pancreatitis patients are Escherichia coli, Klebsiella, Staphylococcus, and Pseudomonas. The agent selected should have a good tissue penetration and cover the intestinal flora. Imipenem or a quinolone, have good peripancreatic tissue penetration and broad spectrum against likely pathogens.28 Imipenem-cilastatin is recommended in acute necrotizing pancreatitis.
The role of selective bowel decontamination is unknown and the evidence that it reduces pancreatic infection is lacking, while the concerns over the selection of multiresistant organisms remain.
 
Nutritional Support
10Traditionally bowel rest was ordered for all patients with acute pancreatitis. The approach of “resting the pancreas” is based on physiologic evidence that nutrients in the duodenum stimulate pancreatic secretion by releasing secretin and cholecystokinin. However, the acinar and duct cell stimulation occur with amino acids, peptides and fatty acids and hydrochloric acid (Figure 1.1). Therefore, formulas with higher (>50%) carbohydrate content can be used.
zoom view
FIGURE 1.1: Nutrients stimulating the pancreatic acinar and ductal cell secretions
Over the past decade this approach changed and early enteral feeding was introduced in patients with severe acute pancreatitis. While both total parenteral nutrition and enteral nutrition are capable to provide optimal nutrition while minimizing pancreatic exocrine activity it is evident that nasoenteric feeding is less expensive, safer, more physiologic than parenteral nutrition and it reduces the risk of septic complications.29 It is also established that enteral nutrition plays an important role in modulating bacterial translocation.
A recent double-blind, randomized, controlled trial comparing early enteral nutrition supplemented with lactobacillus and fiber to fiber supplementation only in patients with acute pancreatitis found a reduction in pancreatic sepsis in the first treatment group.30 Further studies are required regarding fiber and probiotic addition to the enteral nutrition in patients with acute pancreatitis.
11Once the serum enzyme levels decreased to close to normal, children can start oral feeding. The evidence for the necessity of a low-fat diet in the initial period is lacking.
Figure 1.2 provides a summary algorithm for the management of acute pancreatitis.
zoom view
FIGURE 1.2: Algorithm for the management of acute pancreatitis in children
 
MANAGEMENT OF COMPLICATIONS
Severe acute pancreatitis may results in various complications in the pancreas and other organs.
Pancreatic complications are hemorrhagic pancreatitis, pseudocyst, abscess, pancreatic necrosis, and phlegmon. Extensive pancreatic necrosis results in pancreatic insufficiency and diabetes mellitus if more than 95 percent of the pancreas is damaged.
Abscess is arising in phlegmon or area of pseudocyst and requires drainage.
Pseudocyst is a pancreatic fluid filled cavity without true lining epithelium. Most of the pseudocysts are asymptomatic and resolve. A conservative management more likely results in spontaneous resolution in children than adults, especially when the pseudocyst is less than 5 cm in diameter. A report showed that Octreotide (somatostatin analog) has efficacy in reducing cyst fluid production.31 Recurrence in children is rare.32 Complications of pancreatic pseudocysts include spontaneous rupture, infection, internal hemorrhage, erosion into surrounding organs, and biliary or gastric outlet obstruction. Persistent pseudocysts and/or 12those that cause symptoms require decompression. This can be performed endoscopically,33 34 surgically,35 laparoscopically36 or by US-guided transgastric drainage.37 When the pseudocyst becomes infected or too large both internal (duodenal, gastric)38 (Figures 1.3A and B) or external drainage can be performed in children.
zoom view
FIGURES 1.3A and B: CT imaging of a pancreatic pseudocyst before (A) and after (B) endoscopic gastric drainage
13Extrapancreatic complications are sepsis, adult respiratory distress syndrome and pleural fluid. Pleural fistula results in pleural effusion and can be diagnosed by measuring amylase in the pleural effusion.
Biliary duct stricture occurs in ~14 percent patients with chronic pancreatitis. It may result in hepatic fibrosis and secondary biliary cirrhosis. Endoscopic biliary drainage is necessary in these cases.
 
PROGNOSIS
In 80 percent of adult patients with acute pancreatitis the disease resolves without complications. Approximately 20 percent of patients develop severe form of the disease with systemic organ failure and/or extensive pancreatic necrosis, which is associated with a significant mortality. The mortality rate in the severe group can be close to 50 percent.39
Werlin et al3 reported that 11 out of 180 children (6.1%) died, all from underlying systemic illnesses. Weizman et al17 reported that 13 out of 61 patients (21.3%) died and all of them had multisystem disorders.
In the early period (first 14 days) of severe acute pancreatitis a systemic inflammatory response leads multiorgan dysfunction resulting in death. After two weeks the multiorgan failure is usually secondary to sepsis from infected pancreatic necrosis and without surgery, the mortality of these patients approaches 100 percent, while with surgery the mortality rate can be reduced significantly.
In children recurrences of acute pancreatitis typically occur in the following cases: idiopathic pancreatitis, structural anomalies of the pancreaticobiliary tree, metabolic disorders, and familial pancreatitis.
 
CONCLUSIONS
The prevalence of childhood pancreatitis is on the increase in the Western part of the world in the past 15 years. Concurrently, there has been a significant improvement in understanding of the pathophysiology and natural history of acute pancreatitis.
Experimental and trypsinogen gene mutation studies support that trypsinogen activation is the initial step in acute pancreatitis. If the local defense factors are not able to stop this activation an initial local inflammatory response develops that can progress to systemic inflammatory response syndrome. This understanding of this progression may result in the development of new management approaches including specific drug therapies.
It is important to recognize the early signs of a severe acute pancreatitis. The management should include an aggressive fluid resuscitation, pain management, recognition of the underlying cause, treatment of secondary infections and nutritional support.
14

Vital Learning Points

  • Early fluid resuscitation is crucial in the prevention of necrotizing pancreatitis.
  • Children with severe symptoms and initial hemoconcentration
    (Hct = 44) should be managed in intensive care setting.
  • The prevalence of gallstone pancreatitis increases in children. If it is the cause, an early ERCP with sphincterotomy may prevent complications of acute pancreatitis.
  • Patients who had resolved gallstone pancreatitis should have cholecystectomy before discharge.
  • Genetic tests are available for children with recurrent, acute pancreatitis.
  • Elevation in serum amylase and lipase may not represent pancreatitis.
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