Management of Acute Pancreatitis in the Pediatric Population

Home , Gastroenterology, Pancreatic pseudocyst

SOCIETY PAPER

Management of Acute Pancreatitis in the Pediatric Population: A Clinical Report From the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Pancreas Committee

Maisam Abu-El-Haija, ySoma Kumar, zJose Antonio Quiros, §Keshawadhana Balakrishnan, jjBradley Barth, ôSamuel Bitton, #John F. Eisses, Elsie Jazmin Foglio, yyVictor Fox, zzDenease Francis, §§Alvin Jay Freeman, jjjjTanja Gonska, yyAmit S. Grover, #Sohail Z. Husain, ôôRakesh Kumar, ##Sameer Lapsia, Tom Lin, Quin Y. Liu, yyyAsim Maqbool, zzzZachary M. Sellers, §§§Flora Szabo, jjjjjjAliye Uc, ôôôSteven L. Werlin, and ###Veronique D. Morinville

ABSTRACT

Background: Although the incidence of acute pancreatitis (AP) in children What Is Known is increasing, management recommendations rely on adult published guidelines. Pediatric-specific recommendations are needed. Methods: The North American Society for Pediatric Gastroenterology, Pediatric acute pancreatitis incidence is increasing. Hepatology and Nutrition Pancreas committee performed a MEDLINE review A subset of children develop local and systemic using several preselected key terms relating to management considerations in complications of acute pancreatitis. adult and pediatric AP. The literature was summarized, quality of evidence No guidelines exist for management of pediatric reviewed, and statements of recommendations developed. The authorship met acute pancreatitis in North America. to discuss the evidence, statements, and voted on recommendations. A consensus of at least 75% was required to approve a recommendation. What Is New Results: The diagnosis of pediatric AP should follow the published INternational Study Group of Pediatric Pancreatitis: In Search for a Recommendations for management of pediatric CuRE definitions (by meeting at least 2 out of 3 criteria: (1) abdominal acute pancreatitis manifestations are provided, pain compatible with AP, (2) serum amylase and/or lipase values 3 times including aggressive early fluid administration, care- upper limits of normal, (3) imaging findings consistent with AP). Adequate ful monitoring, pain control, early enteral nutrition, fluid resuscitation with crystalloid appears key especially within the first and indications for endoscopic and surgical 24 hours. Analgesia may include opioid medications when opioid-sparing procedures. measures are inadequate. Pulmonary, cardiovascular, and renal status should Evidence for use of antibiotics and protease inhibitors be closely monitored particularly within the first 48 hours. Enteral nutrition for pediatric acute pancreatitis is limited. should be started as early as tolerated, whether through oral, gastric, or jejunal route. Little evidence supports the use of prophylactic antibiotics, antioxidants, probiotics, and protease inhibitors. Esophago-gastroduodenoscopy, endoscopic retrograde cholangiopancreatography, and endoscopic ultrasonography have limited roles in diagnosis and cute pancreatitis (AP) has been increasingly diagnosed in management. Children should be carefully followed for development of A children in recent decades (1–3). A variety of etiologies can early or late complications and recurrent attacks of AP. result in AP in children, including structural/anatomic, obstructive/ Conclusions: This clinical report represents the first English-language biliary, trauma, infections, toxins, metabolic, systemic illness, recommendations for the management of pediatric AP. Future aims inborn errors of metabolism, and genetic predispositions. These should include prospective multicenter pediatric studies to further are a more prevalent compared with adult AP, when biliary and validate these recommendations and optimize care for children with AP. alcoholic causes are well recognized to be the 2 primary AP risk factors (4). Key Words: endoscopy, fluid management, nutrition, pain control, Most of the literature regarding management of AP describes protease inhibitors, surgery adult experience. Recommendations for fluid resuscitation, prognosis based on markers of severity/signs of multiorgan failure, and (JPGN 2018;66: 159–176) management thereof are all based on adult criteria and experience,

Received March 29, 2017; accepted August 3, 2017. Rady Children’s Hospital, San Diego, CA, the zDivision of From the Division of Gastroenterology Hepatology and Nutrition, Pediatric Gastroenterology, Medical University of South Carolina Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, the Children’s Hospital, Charleston, SC, the §Division of Pediatric yDivision of Pediatric Gastroenterology, Hepatology and Nutrition, Gastroenterology, Maria Fareri Children’s Hospital, Valhalla, NY,

JPGN Volume 66, Number 1, January 2018 159

Copyright © ESPGHAN and NASPGHAN. All rights reserved. Abu-El-Haija et al JPGN Volume 66, Number 1, January 2018 and reflect experience with etiologies leading to AP in adults. For A face-to-face meeting was held at the 2016 World Congress the reasons listed above, adult recommendations cannot be applied of Pediatric Gastroenterology, Hepatology and Nutrition in Mon- directly to the pediatric population diagnosed with AP. treal, Quebec, Canada in October 2016. Each subgroup presented Although pediatric pancreatologists may be consulted during pertinent literature review, and proposed statements to vote upon for an AP hospitalization, a child will typically be initially and primar- each element being considered. The evidence presented and sum- ily handled by a pediatrician and/or a general pediatric gastroen- mary statements/recommendations were discussed and modified terologist at the first episode of AP. Thus, broader awareness of based on the feedback of attendees. Strength of scientific evidence available published evidence/gaps/recommendations for managing was reviewed. both the early and later phases of AP in children are needed. It had been initially anticipated that the group would grade the The aims of the current clinical report consist mainly to quality of evidence to support each recommendation, utilizing the review published evidence for management of AP in children, Grading of Recommendations, Assessment, Development, and Eval- compare and contrast pediatric to adult literature, identify gaps uation system (6). Upon review of the literature by the group at the and limitations in the available literature and knowledge, and make World Congress, it was, however, deemed that the overall quantity recommendations for providers for a unified approach to help guide and quality of pediatric data were so limited that it was decided that all clinical management of children with AP. recommendations could only be stated to have either (1) ‘‘low’’ quality of evidence- meaning that further research is likely to impact our confidence in the estimate of effect and likely to change the METHODS estimate, or (2) ‘‘very low’’ quality of evidence so that any estimate of The working group involved in the development of this effect is uncertain. Hence, recommendations were not individually NASPGHAN clinical report included members of the NASPGHAN labeled with quality of evidence. Subsequent to group discussion, Pancreas Committee in early 2016, under the leadership of the each summary statement was voted upon, using a 5-point scale (5— Pancreas Committee chair (V.D.M.). strongly agree; 4—agree; 3—neutral: neither agree nor disagree; 2— Three subgroups were created, headed by the 3 co-first disagree; 1—strongly disagree). It had been agreed ahead of time that authors (M.A.E.H., S.K., J.A.Q.), who provided guidance on the consensus could only be reached if at least 75% of the participants main topics of interest to be subdivided for thorough review of the voted ‘‘4’’ (agree) or ‘‘5’’ (strongly agree) on a statement. Voting was available literature. Topics were selected ahead of time through anonymous, and no justification was requested for what response group discussions. Keywords included pediatrics, acute pancreati- category was selected. Members that could not physically be present tis, diagnosis, management, intravenous (IV) fluids, enteral nutri- were encouraged to participate by phone/by Internet during the tion (EN), parenteral nutrition (PN), pain management, antibiotics, process. For those who could not participate via these methods, probiotics, antioxidants, anti-proteases, endoscopy, endoscopyc the manuscript draft and recommendations were re-circulated by ultrasonography (EUS), endoscopic retrograde cholangiopancrea- e-mail, with request to vote upon each statement within 1-week. tography (ERCP), surgery, outcomes, and complications. Subsequent to the October 2016 face-to-face meeting, sub- All available adult and pediatric publications were reviewed group leaders re-edited their respective manuscript sections, sum- after each subgroup conducted Medline searches using the above mary and statement wording was finalized, and the updated draft keywords to generate output to end date July 2016. All English was circulated amongst all authors for a second round of voting via literature was reviewed, and 1 foreign language (5) document was Internet in February 2017. The same 5-point scale was utilized, and translated and reviewed (5). Regular calls and e-mail correspon- authors were instructed to answer within 14-days Twenty-four dences were conducted between the subgroup leaders and commit- authors were eligible to vote. Results were tabulated and included tee chair. Section paragraphs were written by subgroup members. within the manuscript. The updated draft of the manuscript was re- Subsections were assembled by the subgroup leaders and senior circulated to all participating committee members for further review author. Tentative summary statements and recommendations were and editing until a final manuscript draft was agreed upon by all written. The first manuscript draft was circulated among all authors authors. The final version was reviewed and approved by the in August to September 2016. NASPGHAN Council.

the jjUniversity of Texas Southwestern Medical School, Dallas, TX, the Alto, CA, the §§§Division of Pediatric Gastroenterology, Hepatology and ôPediatric Gastroenterology and Nutrition, Steven & Alexandra Cohen Nutrition, Children’s Hospital, Richmond Virginia Commonwealth Med- Children’s Medical Center of New York, Hofstra Northwell School of ical Center, Richmond, VA, the jjjjjjUniversity of Iowa Carver College of Medicine, Hempstead, NY, the #Division of Pediatric Gastroenterology, Medicine, Iowa City, IA, the ôôôMedical College of Wisconsin, Mil- Hepatology and Nutrition, Children’ Hospital of Pittsburgh, University of waukee, WI, and the ###Division of Pediatric Gastroenterology and Pittsburgh School of Medicine, Pittsburgh, PA, the Pediatric Gastro- Nutrition, Montreal Children’s Hospital, McGill University Health Cen- enterology, The Children’s Hospital of New Jersey at Newark Beth Israel tre, Montreal, QC, Canada. Medical Center, Newark, NJ, the yyDivision of Gastroenterology, Hepa- Address correspondence and reprint requests to Veronique D. Morinville, tology and Nutrition, Boston Children’s Hospital, Harvard Medical MDCM, FRCPC, Division of Pediatric Gastroenterology and Nutrition, School, Boston, MA, the zzPediatric Gastroenterology, Stony Brook Montreal Children’s Hospital, McGill University Health Centre, University, NY, the §§Division of Gastroenterology, Hepatology and B04.2443, 1001 Blvd Decarie, Montreal, QC, Canada, H4A 3J1 Nutrition, Emory University School of Medicine, Atlanta, GA, the (e-mail: [email protected]). jjjjPediatric Gastroenterology, Toronto Hospital for Sick Children, Tor- This publication was supported by the North American Society for Pediatric onto, ON, Canada, the ôôDivision of Pediatric Gastroenterology, Hepa- Gastroenterology, Hepatology and Nutrition (NASPGHAN); M.A.E.H. tology and Nutrition, University of Oklahoma Health Sciences Centre, by the National Institutes of Diabetes and Digestive and Kidney Diseases Oklahoma City, OK, the ##Gastroenterology, Hepatology and Nutrition, (NIDDK) under award number R43 DK105640-01. Children’s Hospital of the King’s Daughters, Norfolk, VA, the Drs Abu-El-Haija, Kumar, and Quiros contributed equally to the article. Digestive Disease Center, Cedars-Sinai Medical Center, Los The authors report no conﬂicts of interest. Angeles, CA, the yyyGastroenterology, Hepatology and Nutrition, The Copyright # 2017 by European Society for Pediatric Gastroenterology, Children’s Hospital of Philadelphia, University of Pennsylvania Perel- Hepatology, and Nutrition and North American Society for Pediatric man School of Medicine, Philadelphia, PA, the zzzDivision of Pediatric Gastroenterology, Hepatology, and Nutrition Gastroenterology, Hepatology, and Nutrition, Stanford University, Palo DOI: 10.1097/MPG.0000000000001715

160 www.jpgn.org

RESULTS Serum Biomarkers Acute pancreatitis is primarily a clinical diagnosis that relies 1. INITIAL EVALUATION AND DIAGNOSIS OF on the presence of at least 2 of 3 criteria as published by the PEDIATRIC ACUTE PANCREATITIS INSPPIRE and the Atlanta classification (8,9). Without 2 of these 3 Recent studies estimate the incidence of acute pancreatitis criteria fulfilled, it is difficult to make the diagnosis of AP. The (AP) at 1/10,000 children per year (2,7), an incidence approaching main biochemical markers used to diagnose AP include serum that of adults. There are no evidence-based diagnostic guidelines for lipase and serum amylase. As a serum lipase or amylase level of at AP in children. The INSPPIRE (INternational Study Group of least 3 times the upper limit of normal is considered consistent with Pediatric Pancreatitis: In Search for a CuRE) definition of pediatric pancreatitis, it is important to know a laboratory’s reference values AP is an expert definition modeled after the Atlanta criteria in adults to determine this threshold. Both amylase and lipase are usually (8). As per INSPPIRE criteria, a diagnosis of AP requires at least 2 elevated early in the disease course. Correlation of serum lipase or of the following: (1) abdominal pain compatible with AP, (2) serum amylase levels and severity of disease is, however, poor (24,31,32). amylase and/or lipase values 3 times upper limits of normal, (3) Lipase is primarily secreted from the pancreas, although other imaging findings consistent with AP (9,10). INSPPIRE or other sources of lipase include gastric and lingual lipases. In AP, lipase is criteria do not address phases (early or late) of AP in children or usually increased within 6 hours of symptoms; serum levels peak at types (interstitial edematous pancreatitis, necrotizing pancreatitis, 24 to 30 hours and can remain elevated for more than 1 week (33). infected pancreatic necrosis) or severity of AP (mild, moderate or Some advocate that serum lipase without serum amylase is suffi- severe AP with multisystem organ failure). cient to diagnose AP, as lipase is a more sensitive and specific Pediatric AP diagnosis is typically suspected clinically with marker of AP (87%–100% and 95%–100%, respectively) (34– compatible symptom presentations, and confirmed by laboratory 37). Lipase, in addition, stays elevated longer than amylase, which and/or radiological studies. Abdominal pain and/or irritability are is useful in cases of delayed presentation (33,38,39). Lipase levels the most common findings of AP in children, followed by epigastric are also less altered by etiology of AP in contrast to amylase tenderness, nausea, and vomiting (11,12). In infants and toddlers, especially in the case of ethanol (36,40) or hyperlipidemia (41,42). symptoms may be subtle; therefore, the diagnosis requires a high Butcautionininterpretinglevelsinchildrenmustbeexercised, level of suspicion. Biliary/obstructive factors, medications and asnormallipasevalueshavebeendemonstratedtorelatetothe systemic diseases are the main causes of childhood AP age of a child, rising from newborn to child to adult (43,44). (1,4,9,12–23) and knowledge of these possible etiologies will guide Amylase is secreted from several organs, primarily the salivary the initial investigations. glands and the pancreas. Most laboratories measure total amylase The percentage of children who develop ‘‘severe’’ acute levels, which contain both s-amylase (salivary) and p-amylase pancreatitis is variable in published series (6–33), but children with (pancreas) isoforms (45). Laboratory tests exist to fractionate p- AP in general have a mild course (11,16,24). In a subset of patients, and s-amylase, but this practice is less available. Amylase refer- AP may have a severe course (8), but no established clinical tools ence values are different depending on the laboratory test used, but predict this outcome. The scoring systems to assess severity of AP in also vary with age and gender (46,47). Serum amylase levels can be adults (Ranson, Glasgow, modified Glasgow, Bedside Index of altered by the etiology of pancreatitis as noted above. Amylase Severity in Acute Pancreatitis (BISAP) and Acute Physiology and levels rise faster than lipase levels and often can normalize by Chronic Health Evaluation II (APACHE II)) are not easily applicable 24 hours after onset of symptoms limiting usefulness in patients to children for several reasons (25). DeBanto’s pediatric acute with a delayed presentation to a medical facility (33). As the pancreatitis score (PAPS) (26) was assessed in children but has kidneys excrete amylase and lipase, nonpancreatic-based eleva- low sensitivity and requires 48 hours for risk prediction. Likewise, tions of these enzymes may be seen in patients with renal injury or the computed tomography severity index or Balthazar score (27), disease (45). relies on radiologic appearance and thus not desirable in the pediatric Several nonpancreatitis conditions cause elevations of pan- age group due to radiation exposure. With its wide availability, lipase creatic serum amylase and/or lipase, including decompensated liver is an attractive marker to identify severe cases of AP (24), but may failure, renal failure, intestinal inflammation (including celiac identify many false positives because of its low positive predictive disease and inflammatory bowel disease), abdominal trauma, dia- value and specificity. Coffey et al (24) found that serum lipase 7-fold betic ketoacidosis, and head trauma (48). In addition to this, some above the upper limit of normal within 24 hours of presentation individuals produce large complexes of amylase or lipase with helped predict acute pancreatitis severity. This is a retrospective immunoglobulins (termed macroamylase and macrolipase) that are study evaluating 211 children and has not been, however, validated in poorly filtered and excreted due to the large size, that will lead to larger study groups. Suzuki et al (28), in Japan, developed a pediatric- elevated values if the enzyme level is measured in blood, despite not friendly severity scoring system using 9 parameters, but this was also being related to inflammation of the pancreas (49). a retrospective study that only evaluated 145 patients, and the authors Other biomarkers for diagnosis and management of pancre- concluded that results may not be broadly applicable to the pediatric atitis have been proposed and studied in animal models or small population. More recently, Szabo et al (29) reported that an early clinical trials (reviewed in (45,50,51)). None has, however, gained severity prognostic model using serum albumin, lipase, and white prominence and many have yet to be validated for general blood cell count obtained within 24 hours demonstrated a positive clinical use. predictive value of 35% and negative predictive value of 91%. Several laboratory tests are helpful for monitoring the course Further prospective studies are necessary to determine the of AP (52). In general, serum electrolytes, blood urea nitrogen clinical utility of any of these tools. The above-mentioned studies (BUN) and creatinine and a complete blood cell count are important utilized various definitions of severity of AP, limiting the capacity to monitor fluid/hydration status and renal function. A hepatic to make comparisons across studies. A recent publication by the enzyme panel is indicated to seek biliary or gallstone etiology NASPGHAN Pancreas Committee addressed the need to have a and to assess for organ involvement. Calcium and triglyceride levels well-defined classification of severity of AP by proposing defini- should be considered baseline investigations (9). Monitoring respi- tions for mild, moderately severe, and severe AP to improve ratory status can alert the clinician to the progression from mild to homogeneity among studies (30). moderately severe or severe AP. www.jpgn.org 161

Etiologies gave a sensitivity, specificity, positive predictive value, and negative predictive value of 81%, 76%, 62%, and 90%, respectively, for As mentioned previously, anatomic, obstructive (including severity, in a retrospective study evaluating 64 children (60). biliary), infectious, trauma, toxic, metabolic, systemic illness, Ultrasound is used extensively in cases when there is a high inborn errors of metabolism, genetic predispositions, and idiopathic suspicion of biliary pancreatitis, where it is useful early to deter- have all been described as potential etiologies in pediatric AP, acute mine the need for therapeutic intervention (32,57). Ultrasound has recurrent pancreatitis (ARP) and chronic pancreatitis (CP) (3,4,53). an excellent safety profile, is noninvasive and does not utilize The review by Lowe and Morinville (3) summarized the top 6 radiation. Ultrasound utility can, however, be limited in the assess- overall etiological categories in published reviews as being idio- ment of the pancreas due to interfering structures, such as the bowel pathic/other in 24%, trauma in 17%, systemic illness in 15%, gas in the intestine and obesity, and has a lower sensitivity in structural abnormalities in 14%, drugs in 10%, and infections in visualizing the pancreas compared to CECT. 8%. Considering more common etiologies and those for which Magnetic resonance imaging (MRI) is typically not utilized as directed therapies exist, a 2012 manuscript by Morinville et al initial imaging technique in AP but can be useful for late complica- presented a survey of pediatric gastroenterologists providing pan- tions (58). It can be particularly useful in young or pregnant patients creatology care and proposed the following workup in first cases of (intent to limit radiation) and can allow alternative IV contrast pancreatitis: serum liver enzymes, triglyceride and calcium levels, methods in patients with impaired renal function or allergies to and abdominal ultrasound. They suggested reserving testing for iodinated contrast (59). MRI may also be more sensitive in evaluating genetic causes/predispositions (which at the time consisted of necrotic tissue as compared to CECT (58,60). Magnetic resonance CFTR (cystic fibrosis transmembrane conductance regulator), cholangiopancreatography (MRCP) in AP is most often employed in SPINK1 (serine protease inhibitor Kazal type 1) and PRSS1 detecting distal common bile duct stones and diagnosing biliary (cationic trypsinogen)), sweat chloride, and more detailed imaging causes of AP. MRI/MRCP using secretin is helpful in examining for cases of ARP, CP, or first instances of AP with increased the ductular system in the pancreas as well as common bile duct concern for underlying risk for recurrence based on presentation, abnormalities including strictures or stones (61,62). To optimize medical history, or family history (9). As appropriate, a search can detection of ductal abnormalities, MRCP may be performed after be conducted for particular toxic-metabolic risk factors (54). A an attack of AP has resolved as acute edema may obscure the recent publication by Gariepy et al (55) focused on the causal visualization of the ducts. The use of secretin-enhanced MRCP in evaluation of ARP and CP in children, which tends to be more pediatric pancreatic disease has not been fully established (63) and expansive due to the recurrent/chronic nature of the presentation. access to secretin is not uniform across institutions and countries. Lin Autoimmune pancreatitis (AIP) types 1 and 2 are rarely diagnosed et al (64) detail the use of MRI and MRCP in children requiring but represent distinct types of pancreatitis with specific histological pancreatic imaging and overall imaging considerations in AP. findings in the context of suggestive symptoms, imaging, laboratory Recommendation 1a: Diagnosis of pediatric acute pan- results, and response to therapy. Should AIP be suspected as the creatitis should be as per previously published INSPPIRE etiology of AP, further supportive evaluation is necessary. Inter- criteria. ested readers are directed to a recent publication on pediatric AIP by Diagnosis of AP in pediatric patients requires at least 2 of Scheers et al (56). the following: (1) abdominal pain compatible with AP, (2) serum amylase and/or lipase values 3 times upper limits of Imaging normal, (3) imaging findings consistent with AP. 24/24 U 100% agreement with recommendation. Imaging in the early phase of AP usually is not required if history/presenting symptoms and biochemical serum markers are Voting results: Strongly agree ¼ 22; agree ¼ 2; neutral ¼ 0; present to make a diagnosis. Imaging becomes relevant to document disagree ¼ 0; strongly disagree ¼ 0. pancreatic necrosis, complications of pancreatitis including fluid Recommendation 1b: Initial imaging may be accom- collections, and etiology or pancreatitis such as gallstones/biliary plished via transabdominal ultrasonography, with other imag- disease or anatomic abnormalities. ing (CT, MRI) reserved for more complicated cases W tailored The criterion standard for diagnostic imaging remains the to suspected etiology. contrast enhanced computed tomography (CECT) and several scor- 24/24 U 100% agreement with recommendation. ing systems have been developed (57). Despite CETC being the Voting results: Strongly agree ¼ 20; agree ¼ 4; neutral ¼ 0; imaging criterion standard, it is, however, frequently not indicated disagree ¼ 0; strongly disagree ¼ 0. nor necessary for the diagnosis or management of pediatric AP. In cases that are ambiguous for a diagnosis of AP, such as in a delayed Recommendation 1c: Based on most frequent etiologies presentation when serum markers may be low, a CECT may be and those for which therapeutic options exist, first-time attack required to confirm AP. IV contrast is key to distinguish necrotic of acute pancreatitis testing should include liver enzymes (ala- areas in the pancreas (58). As early imaging may underestimate extent nine aminotransferase, aspartate aminotransferase, gamma- of disease and because complications evolve over time and findings glutamyl transferase, alkaline phosphatase, bilirubin), triglyceride level, and calcium level. may not be present in the early phase of the disease, CETC ideally U should be delayed at least 96 hours after onset of symptoms (8,59). In 23/24 96% agreement with recommendation. mild cases, CECT may show homogenous organ enhancement, Voting results: Strongly agree ¼ 20; agree ¼ 3; neutral ¼ 1; inflammatory changes of peripancreatic fat or fluid surrounding disagree ¼ 0; strongly disagree ¼ 0. the pancreas (58). In severe cases, CECT may show heterogeneous organ enhancement, necrosis within the pancreas or in the surround- 2. MANAGEMENT CONSIDERATIONS IN ing peripancreatic tissue. In addition, CECT can also identify peri- PEDIATRIC ACUTE PANCREATITIS pancreatic fluid collections or pseudocysts. CECT should be reconsidered when the patient’s clinical condition deteriorates or 2a. Fluid Management in Acute Pancreatitis is persistently severe (8). Lautz et al found that the computed IV fluid therapy is a mainstay of treatment during an episode tomography severity index (or Balthazar score) in pediatric patients of AP. Fluid resuscitation maintains adequate fluid status and urine

162 www.jpgn.org

Copyright © ESPGHAN and NASPGHAN. All rights reserved. JPGN Volume 66, Number 1, January 2018 Management of Acute Pancreatitis in the Pediatric Population output, but recently attention has focused on the use of IV fluids to 24 hours. The group receiving the highest volume, >4.1 L, had an prevent potential complications in AP, such as necrosis and organ increased rate of persistent organ failure. Weitz et al (78), reviewed failure. The pathogenesis of AP and progression to severe forms is 391 cases of AP and found the use of aggressive fluids (approximately thought to be secondary to alteration in the microcirculation of the 5 L) was associated with increased severity of disease and local pancreas by events including hypovolemia, increased capillary complications. Concerns about this latter group of studies are that permeability and formation of microthrombi. Fluid resuscitation they have primarily involved sicker patients and fluid regimens were is thought not only to correct hypovolemia but to help preserve not restricted to the first 24 hours of resuscitation. pancreatic microcirculation by providing adequate perfusion and Several experts and groups have since made recommenda- preventing possible microthrombi formation and thus preventing tions for the rate of fluid resuscitation in the first 24 to 48 hours in complications and progression to severe disease (65). adults with AP. The IAP/APA guidelines recommend that patients receive 5 to 10 mL kg1 h1 until resuscitation goals are achieved Type of Fluid with regard to improvements in heart rate, urine output, mean arterial pressure and/or hematocrit (69). The American College Consensus is lacking regarding the ideal amount and type of of Gastroenterology (ACG) recommends an initial rate of 250 to fluid to use during an episode of AP in adult practice, and even less 500 mL/h, in addition to boluses of fluid if hypotension or tachy- data exist pertaining to fluids in the pediatric population. Crystal- cardia is present, and using BUN to direct therapy (32). Similar loid has been the most recommended type of fluid in adult guide- recommendations are made in a review by Whitcomb (79). Aggar- lines (32,66–69). A major benefit of crystalloid is that it is readily wal et al (80) advises 3 to 4 L of fluid in the first 24 hours (not and quickly available. Normal saline (NS) has long been the to exceed 4 L) with an initial 1 L bolus and to follow with 1 1 crystalloid of choice for initial fluid resuscitation in general but 3mL kg h for the first 24 to 48 hours. Nasr (81) recommend some adult literature suggests Lactated Ringers (LR) as more 1 to 2 L boluses initially and 150 to 300 mL/h to follow. Subse- 1 1 optimal in AP. In a small randomized controlled trial (RCT) of quently, they recommend 2 mL kg h if the patient responds to 1 1 40 adults with AP, Wu et al (70) showed that LR decreased the the initial resuscitation, but otherwise to use 3 mL kg h (81). incidence of the systemic inflammatory response syndrome (SIRS) Only 1 pediatric study evaluated different rates of maintenance and C-reactive protein levels at 24 hours compared with NS. By fluid administration, involving 201 patients with AP (68). This study contrast, a retrospective review of 103 patients failed to show any showed that a combination of early EN (<48 hours) and aggressive significant difference between LR and NS as the initial resuscitation fluids (>1.5–2 times maintenance in the first 24 hours) decreased LOS fluid in adults with varying severities of pancreatitis (71). LR has and the occurrence of severe disease versus more conventional histori- been recommended over NS in the International Association of cal management. Aggressive IV fluids did not adversely affect out- Pancreatology/American Pancreatic Association (IAP/APA) guide- comes (primarily pulmonary complications or readmission rates). No lines, but the American Gastroenterology Association (AGA) studies specify the ideal rate of maintenance fluids in AP following the guidelines only state that LR may be a better choice but was not initial resuscitation (>24–48 hours), although Szabo et al (72), sug- a strong recommendation (67,69). In pediatrics, it has been shown gested that 1.5 to 2 times maintenance was safe in their patient that aggressive fluid management within the first 24 hours with NS population. No pediatric studies compare initial resuscitation volumes. with dextrose 5% is a safe and well-tolerated option (72), but this Summary: In the initial resuscitation phase of acute pan- was not compared to other types of IV fluids (such as LR). creatitis, theoretical and potential clinical advantages favor LR Colloids (such as albumin, fresh frozen plasma, or packed red above NS based on adult data, but pediatric data are lacking. blood cells) have not been recommended as the initial resuscitation Recommendation 2ai: Children with acute pancreatitis fluid in AP. Colloid components stay within the intravascular space should be initially resuscitated with crystalloids, either with LR because of larger size and can draw fluid into the circulation from or NS in the acute setting. Based on assessment of hydration the interstitium secondary to osmotic effect. The guidelines from status/hemodynamic status, if evidence of hemodynamic com- the AGA recommend colloid in specific situations when the hemat- promise, a bolus of 10 to 20 mL/kg is recommended. ocrit is <25% or albumin is <2 g/dL (67), with another publication 24/24 U 100% agreement with recommendation. recommending a ratio of 3:1 of crystalloid to colloid (73). Voting results: Strongly agree ¼ 22; agree ¼ 2; neutral ¼ 0; disagree ¼ 0; strongly disagree ¼ 0. Rate of Fluid Administration Summary: Pediatric literature is sparse regarding fluid resuscitation and rate of fluid administration in acute pancrea- The aggressiveness of fluid resuscitation in AP has also been titis. The adult literature suggests boluses of 250 to 1000 mL debated. The timing of intervention of aggressive fluid therapy may initially, and up to 3 to 4 L fluids within first 24 hours. be key. Adult studies in favor of early and aggressive fluids in AP Recommendation 2aii: Children with diagnosis of acute include several retrospective studies that utilized different strategies pancreatitis should be provided 1.5 to 2 times maintenance IV such as providing > versus <33% of total fluids within the first fluids with monitoring of urine output over the next 24 to 24 hours, and another providing 3.5 L versus 2.4 L IV within the first 48 hours. 24 hours (74). In general, those receiving more aggressive IV fluid 22/24 U 92% agreement with recommendation. volumes within the first 24 hours tend to have improved outcomes Voting results: Strongly agree ¼ 12; agree ¼ 10; neutral ¼ 2; including mortality, but even within the various studies, findings are disagree ¼ 0; strongly disagree ¼ 0. inconsistent as to whether higher early IV fluids reduced rates of necrosis, SIRS, and length of stay (LOS) (75). In contrast, Mao et al (76), reported an RCT of 76 patients with severe AP assigned to slow 2b. Monitoring of Children Diagnosed With hemodilution (5–10 mL kg1 h1) or rapid hemodilution (10– AP/Extra-Pancreatic Manifestations of Acute 15 mL kg1 h1) demonstrating that rapid aggressive early fluid Pancreatitis administration yielded higher sepsis rates and mortality. de-Madaria et al (77) conducted a prospective study of 247 patients dividing Although not well studied in pediatric patients, multiorgan patients based on the amount of fluid administered in the first disease in adult patients with AP is associated with worse clinical www.jpgn.org 163

Copyright © ESPGHAN and NASPGHAN. All rights reserved. Abu-El-Haija et al JPGN Volume 66, Number 1, January 2018 outcomes with over half of AP-related deaths occurring within hydration (70,80,97). Although no guidelines document the fre- 1 week of the onset of multiorgan dysfunction (82). Cardiac, quency of monitoring these parameters, 8 to 12 hours was used in 1 pulmonary and renal involvement comprise key components of study to determine responsiveness to fluid management (70). adult scoring systems used to predict severity of an AP episode Guidelines from the ACG stress the importance in decreasing including the modified Atlanta Classification, Ranson criteria, the BUN and maintaining a normal creatinine within the first Japanese Severity Assessment, Glasgow Score, BISAP, and 24 hours so early monitoring is essential (32). In rare cases, APACHE II (8,83–86). Pediatric models predicting severity of continuous veno-venous hemofiltration is required to prevent AP have also placed importance on multiorgan involvement but further kidney damage, prevent abdominal compartment syn- have proven to be less reliable (87) or have not yet been prospec- drome, and/or removae inflammatory cytokines, but its use has tively validated (28). Increased endothelial barrier permeability and not been studied in pediatric patients with AP (99). It may be profound cytokine release associated with SIRS combined with necessary to install a urinary catheter to accurately document aggressive hydration theoretically increases a patient’s risk for urinary output, particularly in a sedated child within the third-spacing fluids and developing extrapancreatic manifestations ICU setting. of AP. Appropriate monitoring is vital to balance appropriate fluid resuscitation while attempting to prevent cardiac, pulmonary, and Summary: Monitoring of patients with acute pancreatitis renal complications (88). can provide indicators of complications arising, including SIRS and organ dysfunction/failure. Cardiac, respiratory, and renal status should be followed particularly closely within the first Cardiovascular Monitoring 48 hours after presentation as most complications will have their onset within that time frame. Urine output is an Hypovolemia at admission is a strong predictor of morbidity important marker of adequate fluid resuscitation, with adult and mortality among adults with AP and appears to be correlated S S literature suggesting benefit to aim for >0.5 to 1 mL kg 1 h 1 with the magnitude of the SIRS (88). Tachycardia has been utilized (IAP/APA guidelines). in both adult and pediatric scoring systems to predict severity of AP, and its improvement has been utilized to confirm adequate fluid Recommendation 2bi: In patients admitted to an inpa- resuscitation in addition to monitoring urine output and skin turgor tient ward, vitals should be obtained at least every 4 hours (70,80). Routine adult cardiac monitoring for non-intensive care during the first 48 hours of admission and during periods of unit (ICU) patients includes routine vitals every 8 hours to access aggressive hydration to monitor oxygen saturation, blood pres- cardiovascular status (70). In addition to this, rare cases of cardiac sure, and respiratory rate. Frequency to be adjusted based on tamponade and atrial fibrillation have been reported in AP and clinical status. Abnormalities of vital signs should prompt should be considered during standard cardiac workup initiated in specialist assessment. patients with unexplained hypotension, shortness of breath and/or 22/24 U 92% agreement with recommendation. chest pain (89–92). Voting results: Strongly agree ¼ 16; agree ¼ 6; neutral ¼ 1; disagree ¼ 1; strongly disagree ¼ 0. Recommendation 2bii: BUN, creatinine, and urine output Pulmonary Monitoring should be monitored routinely during the first 48 hours as Both adult studies and animal models show acute respiratory marker of appropriate fluid management and to screen for distress syndrome, pneumonia, and pulmonary edema/effusions as AKI. Abnormalities should prompt nephrology assessment. U early complications of AP, typically within the first 48 hours 22/24 92% agreement with recommendation (15,93). As acute respiratory distress syndrome is the most common Voting results: Strongly agree ¼ 18; agree ¼ 4; neutral ¼ 1; critical complication of severe AP associated with multiorgan disagree ¼ 1; strongly disagree ¼ 0. dysfunction in adults (94), abnormal PaO2 or abnormal pulmonary imaging are components of all commonly used scoring systems to 2c. Pain Management in Acute Pancreatitis predict severity of an AP episode (8,28,83–86). Routine monitoring of oxygen saturation during aggressive hydration is typically Abdominal pain is the most common presenting symptom of implemented, with some advocating patient beds be elevated at AP. In pediatric AP studies, 80% to 95% of patients presented with 30-degree angle to decrease likelihood of pulmonary sequestration abdominal pain. Patients present with epigastric pain in 62% to 89% (70). Standard pulmonary workup and care should be considered in and diffusely in 12% to 20%. The ‘‘classic’’ presentation of any patient with unexplained shortness of breath, worsening cough epigastric pain radiating to the back occurs in only 1.6% to and/or difficulty breathing (93). 5.6% of pediatric patients (15,16). The pathophysiology of AP is characterized by a loss of Renal Monitoring intracellular and extracellular compartmentalization, which could result from different mechanisms: obstruction of pancreatic secre- Acute kidney injury (AKI) via abdominal compartment tory transport; activation of enzymes; or inability to stop the syndrome (82,95) or inflammatory-driven damage to the proximal activation cascade. AP occurs in genetically susceptible individu- convoluted tubule (96) marked by elevation of BUN and creatinine, als in whom the inflammatory reaction causes pancreatitis. This in along with decreased urine output, is a known early complication of turn stimulates visceral pancreatic and somatic peritoneal pain AP in children and factors prominently in AP scoring systems to receptors (100). Other postulated mechanisms causing AP pain predict disease severity (8,15,28,83–86). BUN alone in some adult include high pressures within the gland or pancreatic duct and studies has been shown to be as effective in predicting disease subsequent gland ischemia. Pain in AP is also likely related to the severity as more advanced scoring systems (97) and AKI has been release of tachykinin substance P and calcitonin-gene-related associated with a 10-fold increased risk of mortality in severe AP peptide. Factors that stimulate primary sensory neurons include (98). Therefore, BUN and creatinine are considered important hydrogen ions, heat, leukotrienes, arachidonic acid metabolites, markers to follow in assessing fluid management and to monitor bradykinins and proteases, such as trypsin, released during for AKI in adults during the first 48 hours and during aggressive AP (101).

164 www.jpgn.org

Control of pain is an important therapeutic goal in the perfusion studies, and improve clinical outcomes (decreased management of AP and commonly involves use of peripherally requirement for necrosectomy) (112). And, a prospective study and centrally acting analgesics. No data are published on optimal of 121 patients demonstrated good efficacy and safety of EA in pain management in pediatric AP, and studies in adults have not adult AP (113). identified a single superior medication (66). Summary: No data provide guidance for optimal pain management in pediatric AP. Studies in adults have not identi- Opioid Analgesics fied a single superior medication. No evidence exists supporting the contention that morphine causes adverse events on the Because classic peripherally acting analgesics (such as acet- sphincter of Oddi. aminophen) often are insufficient in severe pancreatitis, opiates are Recommendations 2ci: IV morphine or other opioid required frequently to control pain. Morphine or related opioids should be used for acute pancreatitis pain not responding to were utilized by 94% of respondents to manage children with AP acetaminophen or NSAIDs. according to the 2012 INSPPIRE physician questionnaire (102). 24/24 U 100% agreement with recommendation Morphine had been reported to cause sphincter of Oddi dysfunction Voting results: Strongly agree ¼ 18; agree ¼ 6; neutral ¼ 0; after systemic administration (103). No clear evidence, however, disagree ¼ 0; strongly disagree ¼ 0. supports this theory and morphine can be used safely in patients with AP (104). Meperidine has been used in adults with AP but Recommendation 2cii: Acute pain specialist services drawbacks include its short half-life and potential of neurotoxicity should ideally be consulted in cases of more severe pain to optimize pain management. through the buildup of toxic neurometabolites that can lead to U seizures, myoclonus, and tremors (105). A review of narcotics and 23/24 96% agreement with recommendation sphincter of Oddi function by Thompson (106), documents that no Voting results: Strongly agree ¼ 18; agree ¼ 5; neutral ¼ 1; studies to date directly compare the effects of meperidine and disagree ¼ 0; strongly disagree ¼ 0. morphine on sphincter of Oddi manometry and no comparative studies exist in patients with AP. Furthermore, no studies or 2d. Enteral and Parenteral Nutrition in evidence exist to indicate morphine is contraindicated for use in Pediatric Acute Pancreatitis AP. A Cochrane review from 2013 includes 5 studies with a total of 227 subjects to assess the efficacy and safety of several opioids. Oral and Enteral Nutrition Medications included were buprenorphine, pethidine, pentazocine, Traditionally, AP patients were managed by keeping nil per fentanyl and morphine. The overall conclusion is that opioids may os (114) and giving PN (115). It was hypothesized that by resting be an appropriate choice in the treatment of pain related to AP and the gut, the pancreas was allowed to ‘‘rest’’ and thus heal more they may decrease the need for supplementary analgesia. In addi- rapidly. The rationale behind this theory was that presence of tion to this, the risk of pancreatitis-associated complications or food in the intestines would stimulate cholecystokinin (CCK) clinically serious adverse events is not different comparing opioids release, which in turn would stimulate pancreatic enzyme secre- and other analgesic agents (107). tion, which could lead to further activation of proteolytic enzymes and exaggerate the autodigestionprocessandworsentheinjury (116,117). Opioid-sparing Analgesics In adults, a number of controlled studies, reviews and meta- analyses pertain to nutritional therapy in both severe and mild AP, NSAIDs have been hypothesized to be potential contributors including a review by the Dutch Pancreatitis Study Group and to the development of AP but have also shown benefit in AP pain consensus guidelines published by the International Consensus management. Prophylactic NSAIDs including indomethacin and Guideline Committee (118). Lodewijkx et al (119), support EN diclofenac have been shown to be useful in several studies in the as being superior to PN, and an on-demand feeding strategy in prevention of post-ERCP pancreatitis (108,109). With respect to predicted severe AP. Mirtallo et al (118) reviewed 8 societal reports pain management post AP diagnosis, indomethacin has been found in order to develop international consensus guidelines for nutrition to be superior to placebo and did not show an increased risk of GI therapy in AP. They concluded that in adult AP, EN was preferable bleeding in a small study (110). When compared with morphine, to PN and should be used first even in the presence of fistulas, metamizole showed improved pain relief at 24 hours, but the ascites and pseudocysts. difference did not reach statistical significance (104). The timing of EN initiation has been advocated to be as early Systemic administration of local anesthetics, mainly pro- as possible, especially as 1 of the goals of EN is to prevent bacterial caine, has been advocated as basic analgesia for AP. IV procaine is translocation and thereby prevent the development of SIRS. Early proposed to decrease pain and/or the necessity for auxiliary anal- nutritional therapy is also purported to decrease cytokine response gesic medication and possibly improve the clinical course of AP. In and incidence of gastroparesis and intestinal ileus. Although some 1 controlled trial, systemic administration of procaine in pancreati- studies (120) show no difference in outcomes when EN was tis improved and accelerated postoperative recovery after major initiated before or after 72 hours of presentation, a 2008 meta- abdominal surgery, including diminished pain, improved cognitive analysis examining 11 RCTs demonstrated that EN started within function, and shortened duration of ileus as well as overall hospi- 48 hours of presentation significantly decreased rates of mortality, talization (111). But evidence is limited and there is lack of placebo- infections and multiorgan failure compared with PN (121). These controlled data. effects were diminished when EN was started after 48 hours. In a Epidural anesthesia (EA) widely used to induce analgesia in 2011 review of nutritional support of adult AP, it was concluded the perioperative period and has also been used to decrease pain in that early nutritional support, particularly EN, but also PN, reduced patients with AP. The mode of action has been attributed to a complications and improved survival (122). This review stated that sympathetic nerve blockade that redistributes splanchnic blood flow to be effective, nutritional support had to begin within 72 hours. It to nonperfused pancreatic regions. In a study of 35 patients with has been stated that EN should be considered ‘‘an active therapeutic predicted severe AP, EA was shown to significantly decrease pain intervention that improves the outcome of patients with pancreati- scores, improve pancreatic perfusion based on radiological tis’’ (123). www.jpgn.org 165

Clinical studies comparing the outcomes of PN and EN in Summary: Adult literature supports early EN to reduce patients with AP report that the use of EN in severe acute pancrea- AP complications and improving survival. Pediatric literature titis (SAP) or predicted SAP results in significantly lower rates of supports early EN in mild AP cases, and small case report in complications (124–132). A recent meta-analysis demonstrated severe AP. superiority of EN compared with PN with a lower incidence of Recommendation 2di: Except in the presence of direct infection and multiorgan failure, resulting in lower mortality rates contraindications to use the gut, children with mild acute and a shorter hospital stay (133). Since full EN may not always pancreatitis may benefit from early (within 48–72 hours of feasible during AP because of increase in pain or feeding intoler- presentation) oral/EN to decrease LOS and decrease risk of ance, some, however, have advocated a role for a combination of organ dysfunction. EN and PN. In 1 study that randomized 100 patients to receive PN 22/24 U 92% agreement with recommendation alone versus PN in combination of EN or EN alone, sepsis, intra- Voting results: Strongly agree ¼ 17; agree ¼ 5; neutral ¼ 1; abdominal infection, and length of hospitalization declined when disagree ¼ 0; strongly disagree ¼ 1. EN was included in the management (134). The routes of EN described have included gastric and jejunal. Recommendation 2dii: Parenteral nutrition (PN) should Two small studies found no difference in outcomes between be considered in cases where EN is not possible for a prolonged nasogastric and nasojejunal fed groups (135,136). A meta-analysis period (longer than 5–7 days) such as in ileus, complex fistulae, of 10 RCTs showed no differences in outcomes between groups abdominal compartment syndrome, to reduce the catabolic receiving (semi)elemental and polymeric formulas (137). state of the body. Enteral nutrition should commence as soon No guidelines have been published relating to nutritional as feasible, with a combination of EN and PN being superior to support of children with AP. A recent study by Abu-El-Haija et al sole PN. (138) demonstrated the feasibility of establishing enteral feeds in 22/24 U 92% agreement with recommendation pediatric AP, without complicating the course or affecting the pain Voting results: Strongly agree ¼ 15 agree ¼ 7; neutral ¼ 1; scores of AP. From the same center, a retrospective study showed disagree ¼ 0; strongly disagree ¼ 1. that a combination of early enteral feeds in addition to greater than Recommendation 2diii: In cases of pancreatic laceration, 1.5 times maintenance IV fluids were associated with a shorter fracture, or duct disruption, it is unclear whether oral/enteral LOS and milder illness compared with those who remained nil per feedings may be detrimental in the acute phase. This must be os for 48 hours and had lower rates of IV fluids than 1.5 times further studied. maintenance (72). Two children with severe AP are reported who 21/24 U 88% agreement with recommendation were treated successfully with nasojejunal feedings in a PICU Voting results: Strongly agree ¼ 13; agree ¼ 8; neutral ¼ 2; and switched to oral feeding when discharged to the general disagree ¼ 0; strongly disagree ¼ 0; no vote ¼ 1. ward (139). 2e. Use of Antibiotics in Pediatric Acute Parenteral Nutrition Pancreatitis Parental nutrition provides the required calories and nutrients The rationale for consideration of antibiotics in the manage- to compensate for a catabolic state. Concern that PN could further ment of AP relates to the concern for bacterial infection from stimulate the pancreas and result in exaggeration of the autodiges- translocated intestinal microbiota. Antibiotics are not recom- tive process has not been supported by the literature (140,141). Data mended for use in adult mild AP (69). indicate that infusion of protein does not stimulate pancreatic In the management of adult severe AP, antibiotics have been secretions (142). When comparing different PN formulations, PN studied to prevent and manage infections. Imipenem and/or third enhanced with glutamine has been reported to reduce overall generation cephalosporins have been most often used historically in complication rates, as well as reduce LOS (143–147). The admin- an attempt to reduce morbidity and mortality. This prophylactic istration of IV glucose also does not appear to stimulate pancreas approach is controversial, with prior studies suggesting benefit secretion (148,149). Infusion of glucose in critically ill patients may (157–159), whereas other studies did not demonstrate benefit from be useful to provide an easily accessible energy source during a routine use (160) in the absence of documented infection. Prophylac- catabolic state and counteract gluconeogenesis from protein break- tic antibiotics have been used in the setting of sterile necrotizing down. But glucose infusion must be monitored, as it may predispose pancreatitis to prevent infected necrotizing pancreatitis (161,162), to hyperglycemia (150), as an inflamed pancreas may not mount an particularly imipenem (162). Systematic reviews do not, however, appropriate insulin response. support a benefit regarding mortality, for infections not involving the Hypertriglyceridemia is associated with severe AP (151– pancreas, or for the reduction of surgical interventions in adults (161). 154), but the mechanism leading to SAP is not clear (155). More recent meta-analyses support the use of antibiotics for infected Insufficient data exist to recommend or to discourage the use of necrotizing pancreatitis but not for sterile necrosis (163–165). Current parenteral lipids in AP. adult AP recommendations are to use antibiotics only for infected With respect to the timing of PN in AP, where the measured necrosis, or in patients with necrotizing pancreatitis who are hospi- outcome was mortality, data suggest that early PN is significantly talized and not improving clinically without antibiotic use (69). more beneficial than bowel rest in adult severe AP (121). In all cases Infected necrosis should be suspected if the patient’s clinical status where EN is not possible for a prolonged time, such as in ileus, is worsening with fevers, or with presence of gas within collections on complex fistulae, and abdominal compartment syndrome, PN has imaging. In certain situations aspiration of the fluid by an endoscopic- been advocated. In contrast, a recent study advocated for delaying guided technique or via interventional radiology and establishment of initiation of PN to 7 days in critically ill children due to increased appropriate drainage may be needed to guide management (8). For risk of infection, and increased complication rates when PN was necrotizing pancreatitis, antibiotics known to penetrate necrotic tissue initiated within the first 24 hours of ICU stay. Early EN was allowed are recommended, such as carbapenems, quinolones, and metronida- in both groups. The presence or percentage of AP patients specifi- zole, as antibiotic use in this setting has been demonstrated to delay cally was, however, not specified in that report (156). surgical interventions and decrease morbidity and mortality (31).

166 www.jpgn.org

Documented infections originating outside the pancreas Recommendations 2f: Anti-proteases cannot be recom- should be treated as indicated. mended in the management of acute pancreatitis in children at No studies have been published on the use of antibiotics in this time. the management of AP in children. 24/24 U 100% agreement with recommendation Summary: Antibiotics should not be used in the man- Voting results: Strongly agree ¼ 17; agree ¼ 7; neutral ¼ 0; agement of AP, except in the presence of documented infected disagree ¼ 0; strongly disagree ¼ 0. necrosis, or in patients with necrotizing pancreatitis who are hospitalized and not improving clinically without antibiotic 2g. Use of Antioxidants in Pediatric Acute use. Antibiotics known to penetrate necrotic tissue should be used in management of infected pancreatic necrosis as these Pancreatitis may delay surgical intervention and decrease morbidity and Oxidative stress contributes to injury in AP, through forma- mortality. tion of oxygen free radicals that cause damage to the lipid pancre- Recommendations 2ei: Prophylactic antibiotics are not atic cell membrane, depolarization of the mitochondrial membrane, empirically recommended in severe acute pancreatitis. and induction of DNA fragmentation (173). This contributes to 23/24 U 96% agreement with recommendation edema, generation of pain and may also be involved with the Voting results: Strongly agree ¼ 20; agree ¼ 3; neutral ¼ 1; process of necrosis. Antioxidants have thus been hypothesized to disagree ¼ 0; strongly disagree ¼ 0. be of potential benefit as adjunct management in AP by preventing Recommendation 2eii: Antibiotic use is indicated only in the formation of free radicals or scavenging existing oxygen cases of documented infected necrosis in acute pancreatitis. free radicals. 16/24 U 67% agreement with recommendation. Recom- The agents most studied have been antioxidant vitamins mendation not supported. This was identified as an area of (ascorbic acid, a-tocopherol, b-carotene), inorganic antioxidants particular controversy requiring further study. (selenium) and glutamine. Two partially overlapping meta-analyses published in 2015 utilize different methodologies to assess Voting results: Strongly agree ¼ 10; agree ¼ 6; neutral ¼ 2; benefit of antioxidants in acute pancreatitis, 1 reviewing 11 and disagree ¼ 4; strongly disagree ¼ 0; no vote ¼ 2. other 12 adults randomized controlled trials (168,169). Pederzoli et al (168), found that antioxidants reduce the number of AP 2f. Use of Protease inhibitors in Pediatric Acute complications and shortened LOS, with glutamine reducing com- Pancreatitis plications and mortality rates. Ino et al, reported that antioxidant therapy shortens LOS, and decreases serum C-reactive protein, but As AP is hypothesized to be a necroinflammatory process only after 10 days (169). begun through the acute, and inappropriate, activation of the A significant limitation of published data of antioxidants in protease trypsin and pancreatic zymogens within the parenchyma, adult AP is that trials have included the entire spectrum of mild to investigators have been keenly interested in blocking this inflam- severe AP. In addition to this, different combinations of antiox- matory process to limit extent of injury. idants and timing of delivery have been utilized in trials. Large The 2 main compounds described in the literature to inhibit this randomized studies lack standardization of specific antioxidants as enzyme activation include the serine protease inhibitor gabexate well as timing and duration of treatment. mesilate and the trypsin inhibitor aprotinin. In 1993, Pederzoli No data exist on antioxidant use in AP in the pediatric et al (166) reported results of a randomized, double-blind multicenter population. clinical trial on use of gabexate mesilate versus aprotinin in AP Summary: Pediatric data regarding the use of antioxi- therapy. In this study, gabexate mesilate appeared more favorable to dants in AP is lacking Adult publications display significant aprotinin for the period 24 to 72 hours, but importantly, a placebo heterogeneity with respect to composition, timing, and duration control arm is missing. Timing of treatment and mode of delivery of therapy. Despite potential benefits described in the adult seem to be key factors in efficacy (166,167). Ino et al studied the series, evidence is insufficient to support their use in pediatrics efficacy of continuous regional artery infusion CRAI with gabexate at this time. mesilate and antibiotics for severe AP via a small prospective study involving 9 patients receiving CRAI for 3 to 5 days and 9 others Recommendation 2 g: Antioxidants should not be consid- receiving systemic protease inhibitor therapy and antibiotics. ered standard therapy in the management of pediatric acute pancreatitis. Abdominal pain and SIRS disappeared quicker, LOS was signifi- U cantly shorter in the CRAI group (167). CRAI of anti-proteases and 22/24 92% agreement with recommendation. antibiotics has been reported to reduce C-reactive protein and Voting results: Strongly agree ¼ 15; agree ¼ 7; neutral ¼ 1; APACHE II scores when initiated within 72 hours of onset of illness disagree ¼ 0; strongly disagree ¼ 1. (168), an approach described in pediatric patients as well (169). A 2007 review by Kitagawa and Hayakawa found no evi- 2h. Role of Probiotics in Pediatric Acute dence to justify the routine use of anti-proteases in AP, and although Pancreatitis the use of continuous IV high-dose protease inhibitors and antibiotics may be effective in preventing the exacerbation of severe Up to third of adult patients may develop severe AP, AP, cost-effectiveness studies were necessary. Of importance, these characterized by SIRS, organ failure and an increased risk of compounds are not Food and Drug Administration (FDA)-approved infection (174). In patients with infected peri-pancreatic and pan- in the United States (170–172). creatic necrosis, the risk of mortality is significantly increased. Summary: Certain adult studies support use of anti- Reduction of gut permeability and bacterial overgrowth during AP proteases in the management of severe AP, but no definite is hypothesized to decrease the risk of infected pancreatic necrosis recommendations have ever been made for their use. Studies and thereby decrease the risk of mortality (175,176). are not randomized with placebo controls and only a few cases The World Health Organization defines probiotics as ‘‘live are described in pediatric patients. microbes which, when administered in adequate amounts, confer a www.jpgn.org 167

Copyright © ESPGHAN and NASPGHAN. All rights reserved. Abu-El-Haija et al JPGN Volume 66, Number 1, January 2018 health benefit to their host’’. Probiotics have been shown to play a of the ampulla (195,196). But in general, the role of esophagogas- role in maintaining gut microflora balance, inhibiting the growth of troduodenoscopy in AP is limited. harmful bacteria, and enhancing immune function (177). Of impor- No studies evaluate indications or benefits of esophagogas- tance, published studies have utilized different compositions and troduodenoscopy in pediatric AP. dosing regimens of probiotic bacteria. Summary: The role of endoscopy in the acute care of Muftuoglu et al (177) demonstrated that lactobacillus aci- children with AP is unclear. The potential for primary extra- dophilus and bifidobacterium lactis decrease the severity of histo- pancreatic diseases resulting in the development of AP requires logical damage in an experimental pancreatitis model. Early small thoughtful consideration. adult clinic trials suggested a beneficial role for probiotics in the Recommendation 2i: Esophagogastroduodenoscopy is management of AP. Olah et al (178) randomized 45 patients to 9 not considered a standard diagnostic tool in pediatric acute receive either 10 live or heat killed lactobacillus plantarum twice pancreatitis at this time. Indication for its use should be deter- daily together with enteral feeds. They found a statistically signifi- mined on a case-by-case basis. cant lower risk of infected pancreatic necrosis in the study group 24/24 U 100% agreement with recommendation compared with control groups. Subsequently, the PROPATRIA study, a double-blinded, Voting results: Strongly agree ¼ 18; agree ¼ 6; neutral ¼ 0; placebo-controlled randomized, multicenter study on the role of disagree ¼ 0; strongly disagree ¼ 0. probiotics in preventing infectious complications in AP) consisting of 298 adult patients with predicted severe AP, however, demon- 2j. Role of Endoscopic Retrograde strated a significantly higher risk of mortality in the multispecies Cholangiopancreatography in Pediatric Acute probiotic group (179,180). Two small randomized trials since Pancreatitis completed did not demonstrate an increase in mortality (181,182), but the impact of the adverse findings of the PROPA- The role for ERCP in AP has evolved with technological TRIA study has led to generalized caution in use of probiotics in improvements in the diagnostic capabilities of MRI/MRCP and adult AP. with increasing pediatric experience with EUS. With the availabil- No pediatric study has examined the role of probiotics in ity of these latter diagnostic tools for pancreatic disorders, ERCP is children with AP. increasingly being used primarily for therapeutic interventions or Summary: Subsequent to small case series suggesting a for unclear diagnoses following MRCP or EUS. ERCP is safe in potential benefit of probiotics in adult AP, a large randomized children with the most common complication being mild post- study demonstrated increased mortality in a probiotic group. ERCP pancreatitis, occurring at rates similar to those in adults No pediatric studies have been published. (3%–10%) when being done by experienced endoscopists (197– 205). Biliary obstruction and CP are the most common indications Recommendation 2 h: Probiotics cannot be recom- for ERCP in children. In pediatric AP, ERCP has a limited role, mended in the management of pediatric acute pancreatitis at performed almost exclusively for biliary pancreatitis secondary to this time. Highest-quality published adult evidence suggests choledocholithiasis or sludge. ERCP for choledocholithiasis with- they may not only be of no benefit, but increase mortality. out pancreatitis is safe and effective (206,207), but no specific U 23/24 96% agreement with recommendation recommendations exist in pediatrics about the timing of ERCP in Voting results: Strongly agree ¼ 14; agree ¼ 9; neutral ¼ 1; choledocholithiasis or acute biliary pancreatitis. In adults, a large disagree ¼ 0; strongly disagree ¼ 0. meta-analysis and the IAP evidence-based guidelines for management of acute biliary pancreatitis have recommended ERCP within 48 hours of symptomatic onset if patient has obstructive jaundice 2i. Role of Endoscopy in Pediatric Acute and/or cholangitis. Otherwise, ERCP can be done electively for Pancreatitis uncomplicated choledocholithiasis and in other cases of biliary pancreatitis, regardless of severity (208,209). Various causes of duodenal mucosal inflammation have been Less common indications for ERCP in AP are pancreatic ductal linked to increased risk of AP. Celiac disease pancreatic-associated stones, strictures, pseudocyst drainage, and pancreatic duct leaks manifestations include endocrine and exocrine insufficiency, acute (210). Pancreatic ductal stones and strictures are typically features and CP, malnutrition, papillary stenosis secondary to duodenitis, or of acute recurrent or CP, thus are relatively uncommon indications for immunological disturbances and have all been hypothesized to be ERCP in AP. In rare circumstances when ductal obstruction prevents implicated mechanistically (183–185). Gallstone disease has been resolution of pancreatitis, therapeutic ERCP can be performed. Pan- found in up to 34% of Crohn patients and may manifest as AP (186). creatic pseudocysts in children can occur from acute or CP, but the AIP and primary sclerosing cholangitis (187) can also be found in majority occurs following blunt trauma. Pancreatic pseudocysts, are patients with inflammatory bowel disease presenting with AP homogenous collection of pancreatic fluid enclosed by fibrous or (188–190). Although IgG4 elevation is seen in Type I AIP in adult granulation tissue but lacking an epithelial lining (15,211), and can patients, pediatric patients with AIP present commonly without develop from fluid collections persisting greater than 4 weeks (212). IgG4 elevation, where biopsies from the duodenum or gastroduo- ERCP can be used to assess communication of the pseudocyst with denal inflammatory lesions can be helpful in the diagnosis pancreatic duct, where a transpapillary stent can be placed for drain- (191,192). Acute and CP have been uncommonly reported as age. Otherwise, endoscopic cystagastrostomy (213–215) and EUS- manifestations or associations of Helicobacter pylori infection guided drainage (216) are safe and effective ways to drain pancreatic (193,194). Exceedingly rare though possible causes of pancreatitis pseudocysts inchildren and maybe considered basedon the location of in children are tumors involving the ampulla or peri-ampullary the pseudocyst. Pancreatic duct injury and leak can also occur region of the duodenum. Such lesions may be first identified by from trauma. Early endoscopic or surgical intervention may help to radiographic imaging, but can also be found at the time of endo- minimize ongoing morbidity from a ductal leak, as ERCP provides a scopic assessment. From available case reports, the mechanism by rapid and more definitive method to delineate the location and extent which these patients develop recurrent pancreatitis is not fully of injury than MRCP or CT and also provides the opportunity for understood, but is likely related to tumor obstruction at the level therapeutic stent placement across the injury (217,218).

168 www.jpgn.org

Summary: The role of ERCP in acute pancreatitis pri- 2l. Role of Surgery/Surgical Consultation marily relates to therapeutic management of biliary pancreati- in Pediatric Acute Pancreatitis tis secondary to choledocholithiasis or sludge. Adult literature suggests the performance of ERCP within 48 hours of symp- Surgical interventions are not part of the algorithm in the tomatic onset if patient has obstructive jaundice and/or cho- management of a typical episode of AP. Publications relate to adult langitis. Less common indications for ERCP in acute experience. An early indication for surgery includes management of pancreatitis are pancreatic ductal stones, strictures, pseudocyst abdominal compartment syndrome. Management of pancreatic drainage, and pancreatic duct leaks or ductal lacerations. necrosis with early necrosectomy within first 72 hours has, how- Recommendations 2ji and 2jii: (2ji) The role of ERCP is ever, been shown to lead to increased morbidity and mortality limited in acute pancreatitis and depends on local expertise. compared with those delayed at least to beyond 12 days (224). (2jii) ERCP is indicated in management of acute pancreatitis Guidelines by the International Association of Pancreatology from related to choledocholithiasis causing biliary pancreatitis, and 2002 suggest that delaying necrosectomy surgery for at least 3 to for pancreatic duct pathologies such as ductal stones or ductal 4 weeks after onset of disease leads to lower morbidity and leaks. mortality (209). The 2013 ACG guidelines on the management 24/24 U 100% agreement with recommendation of adult AP have commented on consideration of surgery in the Voting results: Strongly agree ¼ 21; agree ¼ 3; neutral ¼ 0; context of gallstone pancreatitis, debridement of necrosis (infected disagree ¼ 0; strongly disagree ¼ 0. vs sterile), and minimally invasive management of pancreatic necrosis (32). Recommendations included early cholecystectomy 2k. Role of Endoscopic Ultrasonography during the same hospitalization for a mild attack of gallstone in Pediatric Acute Pancreatitis pancreatitis, and discussion between gastroenterology and surgery for timing of cholecystectomy versus other therapeutic options in EUS has been utilized to help determine the etiology of AP. cases of severe AP, especially with necrosis. For patients with EUS not only comprehensively evaluates the pancreatic paren- persisting clinical instability and deterioration in the context of chyma and duct, but also the hepato-biliary anatomy. Biliary pancreatic necrosis, drainage may be necessary to improve patient disease such as choledocholithiasis can be evaluated with EUS status and limit morbidity and mortality. The ACG guidelines especially when transabdominal ultrasound does not visualize the propose that debridement of necrosis should be delayed whenever distal common bile duct. EUS can also determine the presence of possible, ideally to beyond 4 weeks from presentation, to allow microlithiasis in the gallbladder that many times is not visualized on inflammatory reactions to be better organized. Even in need of transabdominal ultrasound or CT scan. Microlithiasis can lead to necrosectomy, less invasive methods including percutaneous radio- AP, and is treatable with cholecystectomy (219). Although logic, or endoscopic drainage/debridement shouldbe considered extremely rare in children, pancreatic tumors, which could be along with laparoscopic surgical management as options to be due to pancreatic neoplasm or AIP can present with AP and be favored above open surgery (32). further evaluated with EUS with the possibility of pancreatic tissue The 2015 pancreatitis of biliary origin, optimal timing of sampling (220,221). cholecystectomy (PONCHO) trial involving 266 inpatients ran- The therapeutic role of EUS in AP is mostly limited for the domized to interval cholecystectomy or same-admission cholecys- treatment of complications of AP, namely pancreatic fluid collec- tectomy also supported that same-admission cholecystectomy tions or WON. EUS has been shown to be useful in the management reduced the rate of recurrent gallstone-related complications in of pancreatic fluid collections/or necrosis secondary to severe AP. adult patients with mild gallstone pancreatitis with extremely Spontaneous resolution of pseudocysts is believed to occur more low risk of cholecystectomy-related complications (225). commonly in children than adults, especially if < 5 cm in size In cases of severe abdominal trauma requiring emergent (expert opinion). Thus, most collections of any type can be managed laparotomy (including motor vehicle accidents), injury to the conservatively and therapeutic intervention is not necessary in the pancreas should be sought, including those involving the pancreatic acute setting except with evidence of infection (222). If maturation duct. The severity of pancreatic trauma may be graded according to occurs (typically after 4–6 weeks), self-resolution is less likely, and the American Association for the Surgery of Trauma Pancreas the patient may, however, need endoscopic drainage. Other indica- Injury Scale, wherein 5 grades of injury may be assigned (226). tions for EUS intervention and drainage include large size when Higher-grade injuries to the pancreas from trauma typically also causing clinical symptoms, suspected infected collections or per- include associated duodenal injuries. Those with milder blunt grade sistent symptoms from the pseudocyst. EUS-guided drainage and I and II injuries may be managed nonoperatively. In cases of the creation of a cystgastrostomy has been demonstrated to be as pancreatic trauma, a multidisciplinary approach involving the effective and safe as surgical cystgastrostomy and has been shown medical/gastroenterology and surgical teams is indicated. to be successful even in children (223). The pediatric literature regarding the indications for surgery is Summary: Based on adult literature, EUS may be useful much more limited. With regard to biliary pancreatitis, a retrospective to determine the etiology of acute pancreatitis, which may case series of 19 children admitted with biliary pancreatitis reported 9 include diagnosis of distal common bile duct stones, pancreatic children undergoing early cholecystectomy with no adverse events, masses, or AIP. Its role for therapy is mostly limited for the and 4 of 10 children that had delayed surgery experiencing adverse treatment of complications of acute pancreatitis, namely pan- clinical events (including recurrence of pancreatitis) (227). creatic fluid collections or WON secondary to severe AP. Summary: Indications for acute surgical intervention in Recommendation 2k: EUS is not considered a standard AP indications include abdominal trauma where patient insta- diagnostic tool in pediatric acute pancreatitis at this time. bility and/or search for associated injury to other organs is Indication for its use should be determined on a case-by-case occurring. In the context of biliary pancreatitis, cholecystec- basis. tomy has been shown to not only be safe, but prevent recur- 24/24 U 100% agreement with recommendation rences if occurring within the index hospitalization. Adult Voting results: Strongly agree ¼ 18; agree ¼ 6; neutral ¼ 0; literature suggests that early intervention in pancreatic necrosis disagree ¼ 0; strongly disagree ¼ 0. leads to increased morbidity and mortality, and hence www.jpgn.org 169

Copyright © ESPGHAN and NASPGHAN. All rights reserved. Abu-El-Haija et al JPGN Volume 66, Number 1, January 2018 debridement of pancreatic necrosis causing patient instability or pseudocysts. Overall pediatric patients with acute pancreatitis should preferably be delayed at least 4 weeks from presentation have a good prognosis with extremely low rate of mortality, but up and ideally performed by endoscopic or percutaneous means. to 15–35% rate of recurrence is reported. Recommendation 2li: Cholecystectomy safely can and Recommendation 3: Children with acute pancreatitis should be performed before discharge in cases of mild uncom- should receive close follow-up by a health care provider to plicated acute biliary pancreatitis. identify early or late complications, or recurrence. 22/24 U 92% agreement with recommendation 24/24 U 100% agreement with recommendation Voting results: Strongly agree ¼ 16; agree ¼ 6; neutral ¼ 1; Voting results: Strongly agree ¼ 18; agree ¼ 6; neutral ¼ 0; disagree ¼ 1; strongly disagree ¼ 0. disagree ¼ 0; strongly disagree ¼ 0. Recommendation 2lii: In the management of acute necrotic collections, interventions should be avoided and 4. SUMMARY OF RECOMMENDATIONS delayed, even for infected necrosis, as outcomes are superior Please refer to Table 1 for a summary of the above recom- with delayed (>4 weeks) approach. mendations for the management of pediatric AP accepted by at least 21/24 U 88% agreement with recommendation 75% of the voting group. Only 1 recommendation, relating to Voting results: Strongly agree ¼ 15; agree ¼ 6; neutral ¼ 2; antibiotic use in documented infected necrosis (Recommendation disagree ¼ 1; strongly disagree ¼ 0. 2eii) did not reach sufficient level of agreement to be accepted, with Recommendation 2liii: When drainage or necrosectomy only 16/24 (67%) voters agreeing with the statement, and 2 voters is necessary, nonsurgical approaches including endoscopic being ‘‘neutral,’’ 4 voters disagreeing, and 2 voters abstaining. As (EUS, and ERCP-assisted) or percutaneous methods are pre- voting was conducted in an anonymous fashion without requesting ferred over open necrosectomy or open pseudocyst drainage. explanation for voting category selected, the reason for the dis- 24/24 U 100% agreement with recommendation agreement cannot be confirmed. This topic had, however, been debated at the October 2016 face-to-face meeting, with certain Voting results: Strongly agree ¼ 15; agree ¼ 9; neutral ¼ 0; members advocating for antibiotic prophylaxis for severe pancrea- disagree ¼ 0; strongly disagree ¼ 0. titis episodes involving pancreatic necrosis without necessarily 3. OUTCOMES OF PEDIATRIC ACUTE infected necrosis. PANCREATITIS 5. FUTURE DIRECTIONS Overall outcomes in AP in children are favorable compared to The differences in etiologies leadingtoadultversuspediat- adults. The average length of hospitalization for children with AP ric AP, the differences in physiology between children and adults, averages 2.8 to 8 days, although infants/toddlers tend to be admitted and the increased coexistence of extrapancreatic illnesses in many for a longer period (average 19.5 days) (12,15,72,228,229). Early adult patients would be anticipated to lead to different outcomes in initiation of EN and aggressive fluid resuscitation has been linked to children versus adults with AP. Findings from AP studies in adult shorter hospital stay, fewer ICU admissions, and decreased rates of patients thus cannot be justified as appropriate surrogate for severe AP compared with patients who are kept nil per os (72). These managing children with AP. A 2014 manuscript by Abu-El-Haija findings appear generally in line with most adult studies (230), but et al (4) highlighted areas in need of research within the realm may not have been applied to pediatric patients until recently. Higher of management of pediatric AP. Areas of note included the need mortality in pediatric AP is associated with systemic disease but is for robust studies that are prospectively designed to answer low overall and is less than 5% in most cohorts, even including ICU fundamental questions on optimizing imaging modalities, pain admissions (15,29,231,232). medications, rehydration strategies, route and timing of EN, Early-onset complications in AP include multiorgan dys- surgical interventions, and prognostication scores in pediatric function or shock (15). Acute peripancreatic fluid collections are pancreatitis. seen in the acute phase of pancreatitis and tend to resolve sponta- This current review of the available literature in pediatric AP neously. The frequency of pseudocyst formation ranges from 8% to highlights the ongoing lack of high-quality research focusing on 41% in children with pancreatitis, and higher rates are seen in pediatric AP in the great majority of spheres mentioned above. patients who present with pancreatitis related to abdominal trauma Some limited evidence has been published regarding fluid manage- (15,211,233). Pseudocysts are often asymptomatic and can be ment and early introduction of EN in children with AP, and managed conservatively or become larger and cause abdominal prognostication of severity in pediatric AP. Recommendations on pain, vomiting, or fever. They can also become infected in 10% to monitoring patients with AP relate to the care of sick children in 15% of cases (234). Another late-onset complication relates to general, and are not specific to AP. Pain management similarly has pancreatic necrosis. Necrosis can manifest firstly as an acute not focused on children with AP. Other than 1 retrospective case necrotic collection and then mature to WON (8). Management series on biliary pancreatitis timing of cholecystectomy, surgical options for drainage of pseudocysts and WON collections include recommendations remain extrapolations from adult literature. endoscopic (transpapillary or transmural) drainage, percutaneous Extremely few studies are published on use of protease inhibitors. catheter drainage, or open/laparoscopic surgery. The modality Experience with ERCP and EUS in pediatric AP remains limited. chosen depends on size, location, anatomy and the risks/benefits No pediatric AP-specific data are published regarding use of of the procedure, although percutaneous and EUS-guided transgas- antibiotics, antioxidants, or probiotics. The lack of agreement on trointestinal drainage is now becoming more widely accepted (235). proposed recommendation 2eii relating to limiting use of antibiotics Approximately 15% to 35% of children with acute pancrea- to only cases of documented infected pancreatic necrosis supports titis will have another bout of pancreatitis. Pediatric ARP is the need for further systematic research on use of antibiotics for AP. associated with pancreatico-biliary anomalies, AIP, metabolic dis- Certain authors stated monitoring recommendations were not suf- orders, and hereditary pancreatitis (15). ficiently aggressive, leading to ‘‘neutral’’ votes cast. The authors Summary: Children need to be followed during their wish to highlight the importance and necessity of supporting course of AP for local and systemic complications that may include pediatric-specific research in the field of AP in all areas of organ dysfunction, acute fluid collections and subsequently WON management detailed within this manuscript.

170 www.jpgn.org

TABLE 1. Summary recommendations for management of acute pancreatitis in children

Topic Recommendation

Diagnosis AP Diagnosis of pediatric AP should be as per previously published INSPPIRE criteria. Diagnosis of AP in pediatric patients requires at least 2 of the following: (1) abdominal pain compatible with AP, (2) serum amylase and/or lipase values 3 times upper limits of normal, (3) imaging findings consistent with AP Initial imaging may be accomplished via transabdominal ultrasonography, with other imaging (CT, MRI) reserved for more complicated cases tailored to suspected etiology Based on most frequent etiologies and those for which therapeutic options exist, first attack of AP testing should include liver enzymes (ALT, AST, GGT, ALP, bilirubin), triglyceride level, and calcium level Fluid resuscitation Children with AP should be initially resuscitated with crystalloids, either with LR or NS in the acute setting. Based on assessment of hydration status/hemodynamic status, if evidence of hemodynamic compromise, a bolus of 10 to 20 mL/kg is recommended Children with diagnosis of AP should be provided 1.5 to 2 times maintenance IV fluids with monitoring of urine output over the next 24 to 48 hours Monitoring In patients admitted to an inpatient ward, vitals should be obtained at least every 4 hours during the first 48 hours of admission and during periods of aggressive hydration to monitor oxygen saturation, blood pressure and respiratory rate. Frequency to be adjusted based on clinical status. Abnormalities of vital signs should prompt specialist assessment BUN, creatinine and urine output should be monitored routinely during the first 48 hours as marker of appropriate fluid management and to screen for AKI. Abnormalities should prompt nephrology assessment Pain management IV morphine or other opioid should be used for acute pancreatitis pain not responding to acetaminophen or NSAIDs Acute pain specialist services should ideally be consulted in cases of more severe pain to optimize pain management Nutrition Except in the presence of direct contraindications to use the gut, children with mild AP may benefit from early (within 48–72 hours of presentation) oral/enteral nutrition (EN) to decrease LOS and decrease risk of organ dysfunction Parenteral nutrition (PN) should be considered in cases when EN is not possible for a prolonged period (longer than 5–7 days) such as in ileus, complex fistulae, abdominal compartment syndrome, to reduce the catabolic state of the body. Enteral nutrition should commence as soon as feasible, with a combination of EN and PN being superior to sole PN. In cases of pancreatic laceration, fracture, or duct disruption, it is unclear whether oral/enteral feedings may be detrimental in the acute phase. This must be further studied. Antibiotics Prophylactic antibiotics are not empirically recommended in severe AP Antibiotic use is indicated only in cases of documented infected necrosis in AP Proteases Anti-proteases cannot be recommended in the management of acute pancreatitis in children at this time Antioxidants Antioxidants should not be considered standard therapy in the management of pediatric AP Probiotics Probiotics cannot be recommended in the management of pediatric AP at this time. Highest-quality published adult evidence suggests they may be not only of no benefit, but increase mortality Endoscopy Esophago-gastroduodenoscopy is not considered a standard diagnostic tool in pediatric AP at this time. Indication for its use should be determined on a case-by-case basis ERCP The role of ERCP is limited in AP and depends on local expertise. ERCP is indicated in management of AP related to choledocholithiasis causing biliary pancreatitis, and for pancreatic duct pathologies such as ductal stones or ductal leaks EUS EUS is not considered a standard diagnostic tool in pediatric AP at this time. Indication for its use should be determined on a case- by-case basis Surgery Cholecystectomy safely can and should be performed before discharge in cases of mild uncomplicated acute biliary pancreatitis In the management of acute necrotic collections, interventions should be avoided and delayed, even for infected necrosis, as outcomes are superior with delayed (>4 weeks) approach When drainage or necrosectomy is necessary, non-surgical approaches including endoscopic (EUS, and ERCP-assisted) or percutaneous methods are preferred over open necrosectomy or open pseudocyst drainage Outcomes/surveillance Children with AP should receive close follow-up by a health care provider to identify early or late complications, or recurrence

AKI ¼ acute kidney injury; ALP ¼ alkaline phosphatase; ALT ¼ alanine aminotransferase; AP ¼ acute pancreatitis; AST ¼ aspartate aminotransferase; BUN ¼ blood urea nitrogen; CT ¼ computed tomography; ERCP ¼ Endoscopic Retrograde Cholangiopancreatography; EUS ¼ endoscopic ultrasonography; GGT ¼ gamma-glutamyl transferase; INSPPIRE ¼ INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE; IV ¼ intravenous; LOS ¼ length of stay; MRI ¼ magnetic resonance imaging. 6. CONCLUDING REMARKS Acknowledgments: The authors wish to thank Ms Melissa Due to the increased incidence of pediatric acute pan- Davis, intake coordinator at Cincinnati Children’s Hospital creatitis in recent years, pediatric specialists must be aware of Medical Center for summarizing the second round of voting the literature regarding its management. This clinical report results. We also wish to thank the NASPGHAN Council for their reviews published evidence and provides recommendations for review of the manuscript. optimal management of AP in children, drawing upon adult literature, the limited pediatric studies and expert opinion in REFERENCES areas where pediatric data are lacking. To optimize pediatric 1. Lopez MJ. The changing incidence of acute pancreatitis in children: a AP outcomes, it will be critical to revisit these topics single-institution perspective. J Pediatr 2002;140:622–4. again in the near future when more pediatric focused, prospective 2. Morinville VD, Barmada MM, Lowe ME. Increasing incidence of acute studies in all aspects of pancreatitis management become pancreatitis at an American pediatric tertiary care center: is greater available. awareness among physicians responsible? Pancreas 2010;39:5–8. www.jpgn.org 171

3. Lowe M, Morinville V. Acute pancreatitis in children. The Pancreas: 29. Szabo FK, Hornung L, Oparaji JA, et al. A prognostic tool to predict An Integrated Textbook of Basic Science, Medicine and Surgery. severe acute pancreatitis in pediatrics. Pancreatology 2016;16: Malden, Massachusetts: Blackwell Publishing; 2008:184–92. 358–64. 4. Abu-El-Haija M, Lin TK, Palermo J. Update to the management of 30. Abu El-Haija M, Kumar S, Szabo F, et al. Classification of acute pediatric acute pancreatitis: highlighting areas in need of research. pancreatitis in the pediatric population: clinical report from J Pediatr Gastroenterol Nutr 2014;58:689–93. the NASPGHAN Pancreas Committee. J Pediatr Nutr 2017;64: 5. Parniczky A, Czako L, Dubravcsik Z, et al. Pediatric pancreatitis. 984–90. Evidence based management guidelines of the Hungarian Pancreatic 31. Lankisch PG, Burchard-Reckert S, Lehnick D. Underestimation of Study Group. Orv Hetil 2015;156:308–25. acute pancreatitis: patients with only a small increase in amylase/lipase 6. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging levels can also have or develop severe acute pancreatitis. Gut consensus on rating quality of evidence and strength of recommenda- 1999;44:542–4. tions. BMJ 2008;336:924–6. 32. Tenner S, Baillie J, DeWitt J, et al. American College of Gastroenter- 7. Nydegger A, Heine RG, Ranuh R, et al. Changing incidence of acute ology guideline: management of acute pancreatitis. Am J Gastroenter- pancreatitis: 10-year experience at the Royal Children’s Hospital, ol 2013;108:1400–1516. Melbourne. J Gastroenterol Hepatol 2007;22:1313–6. 33. Ventrucci M, Pezzilli R, Naldoni P, et al. Serum pancreatic enzyme 8. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute behavior during the course of acute pancreatitis. Pancreas pancreatitis—2012: revision of the Atlanta classification and defini- 1987;2:506–9. tions by international consensus. Gut 2013;62:102–11. 34. Gumaste VV, Roditis N, Mehta D, et al. Serum lipase levels in 9. Morinville VD, Husain SZ, Bai H, et al. Definitions of pediatric nonpancreatic abdominal pain versus acute pancreatitis. Am J Gastro- pancreatitis and survey of present clinical practices. J Pediatr Gastro- enterol 1993;88:2051–5. enterol Nutr 2012;55:261–5. 35. Hemingway DM, Johnson I, Tuffnell DJ, et al. The value of immu- 10. Morinville VD, Lowe ME, Ahuja M, et al. Design and implementation noreactive lipase in acute pancreatitis. Ann R Coll Surg Engl of insppire (International Study Group of Pediatric Pancreatitis: in 1988;70:195–6. Search for a Cure). J Pediatr Gastroenterol Nutr 2014;59:360–4. 36. Pezzilli R, Billi P, Barakat B, et al. Clinical value of serum pancreatic 11. Kandula L, Lowe ME. Etiology and outcome of acute pancreatitis in enzymes in acute alcohol intoxication and acute alcoholic pancreatitis. infants and toddlers. J Pediatr 2008;152:106–1010. Ital J Gastroenterol Hepatol 1997;29:174–8. 12. Park AJ, Latif SU, Ahmad MU, et al. A comparison of presentation and 37. Ventrucci M, Pezzilli R, Gullo L, et al. Role of serum pancreatic management trends in acute pancreatitis between infants/toddlers and enzyme assays in diagnosis of pancreatic disease. Dig Dis Sci older children. J Pediatr Gastroenterol Nutr 2010;51:167–70. 1989;34:39–45. 13. Kandula L, Lowe ME. Etiology and outcome of acute pancreatitis in 38. Frank B, Gottlieb K. Amylase normal, lipase elevated: is it pancrea- infants and toddlers. J Pediatr 2008;152:106–1010 e1. titis? A case series and review of the literature. Am J Gastroenterol 14. Park A, Latif SU, Shah AU, et al. Changing referral trends of acute 1999;94:463–9. pancreatitis in children: a 12-year single-center analysis. J Pediatr 39. Yadav D, Agarwal N, Pitchumoni CS. A critical evaluation of labora- Gastroenterol Nutr 2009;49:316–22. tory tests in acute pancreatitis. Am J Gastroenterol 2002;97:1309–18. 15. Bai HX, Lowe ME, Husain SZ. What have we learned about acute 40. Clavien PA, Robert J, Meyer P, et al. Acute pancreatitis and normoa- pancreatitis in children? J Pediatr Gastroenterol Nutr 2011;52: mylasemia. Not an uncommon combination. Ann Surg 1989;210: 262–70. 614–20. 16. Werlin SL, Kugathasan S, Frautschy BC. Pancreatitis in children. 41. Fallat RW, Vester JW, Glueck CJ. Suppression of amylase activity by J Pediatr Gastroenterol Nutr 2003;37:591–5. hypertriglyceridemia. JAMA 1973;225:1331–4. 17. Morinville VD, Lowe ME, Ahuja M, et al. Design and implementation 42. Yadav D, Pitchumoni CS. Issues in hyperlipidemic pancreatitis. J Clin of INSPPIRE. J Pediatr Gastroenterol Nutr 2014;59:360–4. Gastroenterol 2003;36:54–62. 18. Sanchez-Ramirez CA, Larrosa-Haro A, Flores-Martinez S, et al. Acute 43. Carrere J, Estevenon JP, Guy-Crotte O, et al. Physiologically elevated and recurrent pancreatitis in children: etiological factors. Acta Pae- concentration of serum trypsin-like immunoreactivity in newborns. diatr 2007;96:534–7. Comparison with lipase. Biol Neonate 1986;49:113–20. 19. Fujishiro J, Masumoto K, Urita Y, et al. Pancreatic complications in 44. Cleghorn G, Durie P, Benjamin L, et al. The ontogeny of serum pediatric choledochal cysts. J Pediatr Surg 2013;48:1897–902. immunoreactive pancreatic lipase and cationic trypsinogen in the 20. Nitsche C, Maertin S, Scheiber J, et al. Drug-induced pancreatitis. premature human infant. Biol Neonate 1988;53:10–6. Curr Gastroenterol Rep 2012;14:131–8. 45. Lippi G, Valentino M, Cervellin G. Laboratory diagnosis of acute 21. Spanier BW, Tuynman HA, van der Hulst RW, et al. Acute pancreatitis pancreatitis: in search of the Holy Grail. Crit Rev Clin Lab Sci and concomitant use of pancreatitis-associated drugs. Am J Gastro- 2012;49:18–31. enterol 2011;106:2183–8. 46. Clifford SM, Bunker AM, Jacobsen JR, et al. Age and gender specific 22. Trivedi CD, Pitchumoni CS. Drug-induced pancreatitis: an update. pediatric reference intervals for aldolase, amylase, ceruloplasmin, J Clin Gastroenterol 2005;39:709–16. creatine kinase, pancreatic amylase, prealbumin, and uric acid. Clin 23. Berney T, Belli D, Bugmann P, et al. Influence of severe underlying Chim Acta 2011;412:788–90. pathology and hypovolemic shock on the development of acute 47. Skude G. Sources of the serum isoamylases and their normal range of pancreatitis in children. J Pediatr Surg 1996;31:1256–61. variation with age. Scand J Gastroenterol 1975;10:577–84. 24. Coffey MJ, Nightingale S, Ooi CY. Serum lipase as an early predictor 48. Quiros JA, Marcin JP, Kuppermann N, et al. Elevated serum amylase of severity in pediatric acute pancreatitis. J Pediatr Gastroenterol Nutr and lipase in pediatric diabetic ketoacidosis. Pediatr Crit Care Med 2013;56:602–8. 2008;9:418–22. 25. Robert JH, Frossard JL, Mermillod B, et al. Early prediction of acute 49. Keating JP, Lowe ME. Persistent hyperlipasemia caused by macro- pancreatitis: prospective study comparing computed tomography lipase in an adolescent. J Pediatr 2002;141:129–31. scans, Ranson, Glascow, Acute Physiology and Chronic Health Eva- 50. Al-Bahrani AZ, Ammori BJ. Clinical laboratory assessment of acute luation II scores, and various serum markers. World J Surg pancreatitis. Clin Chim Acta 2005;362:26–48. 2002;26:612–9. 51. Meher S, Mishra TS, Sasmal PK, et al. Role of biomarkers in diagnosis 26. Debanto JR, Goday PS, Pedroso MR, et al. Acute pancreatitis in and prognostic evaluation of acute pancreatitis. J Biomark 2015;2015: children. Am J Gastroenterol 2002;97:1726–31. 519534. 27. Balthazar EJ, Ranson JH, Naidich DP, et al. Acute pancreatitis: 52. Koutroumpakis E, Wu BU, Bakker OJ, et al. Admission hematocrit and prognostic value of CT. Radiology 1985;156:767–72. rise in blood urea nitrogen at 24 h outperform other laboratory markers 28. Suzuki M, Saito N, Naritaka N, et al. Scoring system for the in predicting persistent organ failure and pancreatic necrosis in acute prediction of severe acute pancreatitis in children. Pediatr Int pancreatitis: a post hoc analysis of three large prospective databases. 2015;57:113–8. Am J Gastroenterol 2015;110:1707–16.

172 www.jpgn.org

53. Kumar S, Ooi CY,Werlin S, et al. Risk factors associated with pediatric 78. Weitz G, Woitalla J, Wellhoner P, et al. Detrimental effect of high acute recurrent and chronic pancreatitis: lessons from INSPPIRE. volume fluid administration in acute pancreatitis - a retrospective JAMA Pediatr 2016;170:562–9. analysis of 391 patients. Pancreatology 2014;14:478–83. 54. Husain SZ, Morinville V, Pohl J, et al. Toxic-metabolic risk factors in 79. Whitcomb DC. Clinical practice. Acute pancreatitis. N Engl J Med pediatric pancreatitis: recommendations for diagnosis, management, 2006;354:2142–50. and future research. J Pediatr Gastroenterol Nutr 2016;62:609–17. 80. Aggarwal A, Manrai M, Kochhar R. Fluid resuscitation in acute 55. Gariepy CE, Heyman MB, Lowe ME, et al. Causal evaluation of acute pancreatitis. World J Gastroenterol 2014;20:18092–103. recurrent and chronic pancreatitis in children: consensus from the 81. Nasr JY, Papachristou GI. Early fluid resuscitation in acute pancrea- INSPPIRE Group. J Pediatr Gastroenterol Nutr 2017;64:95–103. titis: a lot more than just fluids. Clin Gastroenterol Hepatol 56. Scheers I, Palermo JJ, Freedman S, et al. Autoimmune pancreatitis in 2011;9:633–4. children: characteristic features, diagnosis, and management. Am J 82. Mentula P, Leppaniemi A. Position paper: timely interventions in Gastroenterol 2017. severe acute pancreatitis are crucial for survival. World J Emerg Surg 57. Baker ME, Nelson RC, Rosen MP, et al. ACR Appropriateness 2014;9:15. Criteria(R) acute pancreatitis. Ultrasound Q 2014;30:267–73. 83. Ranson JH. Etiological and prognostic factors in human acute pan- 58. Barral M, Taouli B, Guiu B, et al. Diffusion-weighted MR imaging of creatitis: a review. Am J Gastroenterol 1982;77:633–8. the pancreas: current status and recommendations. Radiology 84. Blamey SL, Imrie CW, O’Neill J, et al. Prognostic factors in acute 2015;274:45–63. pancreatitis. Gut 1984;25:1340–6. 59. Zhao K, Adam SZ, Keswani RN, et al. Acute pancreatitis: revised 85. Malangoni MA, Martin AS. Outcome of severe acute pancreatitis. Am atlanta classification and the role of cross-sectional imaging. AJR Am J J Surg 2005;189:273–7. Roentgenol 2015;205:W32–41. 86. Wu BU, Johannes RS, Sun X, et al. The early prediction of mortality 60. Lautz TB, Turkel G, Radhakrishnan J, et al. Utility of the computed in acute pancreatitis: a large population-based study. Gut 2008;57: tomography severity index (Balthazar score) in children with acute 1698–703. pancreatitis. J Pediatr Surg 2012;47:1185–91. 87. Lautz TB, Chin AC, Radhakrishnan J. Acute pancreatitis in children: 61. O’Neill E, Hammond N, Miller FH. MR imaging of the pancreas. spectrum of disease and predictors of severity. J Pediatr Surg Radiol Clin North Am 2014;52:757–77. 2011;46:1144–9. 62. Tirkes T, Sandrasegaran K, Sanyal R, et al. Secretin-enhanced MR 88. Akbarshahi H, Rosendahl AH, Westergren-Thorsson G, et al. Acute cholangiopancreatography: spectrum of findings. Radiographics lung injury in acute pancreatitis—awaiting the big leap. Respir Med 2013;33:1889–906. 2012;106:1199–210. 63. Trout AT, Podberesky DJ, Serai SD, et al. Does secretin add value in 89. Lai SW, Lin CL, Liao KF. Atrial fibrillation associated with acute pediatric magnetic resonance cholangiopancreatography? Pediatr pancreatitis: a retrospective cohort study in Taiwan. J Hepatobiliary Radiol 2013;43:479–86. Pancreat Sci 2016;23:242–7. 64. Lin TK, Troendle DM, Wallihan DB, et al. Specialized imaging and 90. Bastian A, Arendt T, Stoffregen C, et al. Cardiac tamponade—a rare procedures in pediatric pancreatology: a North American Society for complication in acute pancreatitis. Z Gastroenterol 1997;35:477–80. Pediatric Gastroenterology, Hepatology, and Nutrition Clinical Report. 91. Veron Esquivel D, Aello G, Batiz F, et al. Cardiac tamponade, an J Pediatr Gastroenterol Nutr 2017;64:472–84. unusual complication of acute pancreatitis. BMJ Case Rep 2016; 65. Gardner TB, Vege SS, Pearson RK, et al. Fluid resuscitation in acute 2016:bcr2016214460. pancreatitis. Clin Gastroenterol Hepatol 2008;6:1070–6. 92. Petit JS, Pintault A, Rio C, et al. Tamponade a rare cause of shock in 66. Banks PA, Freeman ML. Gastroenterology PPCotACo Practice patients with pancreatitis: difficulty of diagnostic in patients with guidelines in acute pancreatitis. Am J Gastroenterol 2006;101: positive pressure ventilation. Ann Fr Anesth Reanim 2013;32:e167–9. 2379–400. 93. Pastor CM, Matthay MA, Frossard JL. Pancreatitis-associated acute 67. Forsmark CE, Baillie J. AGA Institute Clinical Practice and Econom- lung injury: new insights. Chest 2003;124:2341–51. ics Committee. AGA Institute technical review on acute pancreatitis 94. Wang G, Zhang J, Xu C, et al. Inhibition of SOCs attenuates acute lung Gastroenterology 2007;132:2022–44. injury induced by severe acute pancreatitis in rats and PMVECs injury 68. Pezzilli R, Zerbi A, Di Carlo V, et al. Practical guidelines for acute induced by lipopolysaccharide. Inflammation 2016;39:1049–58. pancreatitis. Pancreatology 2010;10:523–35. 95. Malledant Y, Malbrain ML, Reuter DA. What’s new in the manage- 69. Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA ment of severe acute pancreatitis? Intensive Care Med 2015;41: evidence-based guidelines for the management of acute pancreatitis. 1957–60. Pancreatology 2013;13(4 suppl 2):e1–5. 96. He ZJ, Alho H, Harmoinen A, et al. Extrapancreatic multiorgan injury 70. Wu BU, Hwang JQ, Gardner TH, et al. Lactated Ringer’s solution in a severe sublethal acute pancreatitis model. Int J Surg Investig reduces systemic inflammation compared with saline in patients 1999;1:177–84. with acute pancreatitis. Clin Gastroenterol Hepatol 2011;9:710–7e1. 97. Janisch NH, Gardner TB. Advances in management of acute pancrea- 71. Lipinski M, Rydzewska-Rosolowska A, Rydzewski A, et al. Fluid titis. Gastroenterol Clin North Am 2016;45:1–8. resuscitation in acute pancreatitis: normal saline or lactated Ringer’s 98. Zhou J, Li Y, Tang Y, et al. Effect of acute kidney injury on mortality solution? World J Gastroenterol 2015;21:9367–72. and hospital stay in patient with severe acute pancreatitis. Nephrology 72. Szabo FK, Fei L, Cruz LA, et al. Early enteral nutrition and aggressive (Carlton) 2015;20:485–91. fluid resuscitation are associated with improved clinical outcomes in 99. Pupelis G, Plaudis H, Zeiza K, et al. Early continuous veno-venous acute pancreatitis. J Pediatr 2015;167:397–402e1. haemofiltration in the management of severe acute pancreatitis com- 73. Mayerle J, Hlouschek V, Lerch MM. Current management of plicated with intra-abdominal hypertension: retrospective review of acute pancreatitis. Nat Clin Pract Gastroenterol Hepatol 2005;2: 10 years’ experience. Ann Intensive Care 2012;2(Suppl 1):S21. 473–83. 100. Glasbrenner B, Adler G. Pathophysiology of acute pancreatitis. 74. Gardner TB, Vege SS, Chari ST, et al. Faster rate of initial fluid Hepatogastroenterology 1993;40:517–21. resuscitation in severe acute pancreatitis diminishes in-hospital mor- 101. Liddle RA, Nathan JD. Neurogenic inflammation and pancreatitis. tality. Pancreatology 2009;9:770–6. Pancreatology 2004;4:551–9. 75. Wall I, Badalov N, Baradarian R, et al. Decreased mortality in acute 102. Morinville VD, Husain SZ, Bai H, et al. Definitions of pediatric pancreatitis related to early aggressive hydration. Pancreas 2011;40: pancreatitis and survey of current clinical practices: report from 547–50. INSPPIRE (International Study Group Of Pediatric Pancreatitis: In 76. Mao EQ, Tang YQ, Fei J, et al. Fluid therapy for severe acute Search For A Cure). J Pediatr Gastroenterol Nutr 2012;55:261–5. pancreatitis in acute response stage. Chin Med J (Engl) 2009;122: 103. Helm JF, Venu RP, Geenen JE, et al. Effects of morphine on the human 169–73. sphincter of Oddi. Gut 1988;29:1402–7. 77. de-Madaria E, Soler-Sala G, Sanchez-Paya J, et al. Influence of fluid 104. Peiro´ AM, Martıńez J, Martıńez E, et al. Efficacy and tolerance of therapy on the prognosis of acute pancreatitis: a prospective cohort metamizole versus morphine for acute pancreatitis pain. Pancreatol- study. Am J Gastroenterol 2011;106:1843–50. ogy 2008;8:25–9. www.jpgn.org 173

105. Isenhower HL, Mueller BA. Selection of narcotic analgesics for 129. McClave SA, Greene LM, Snider HL, et al. Comparison of the safety pain associated with pancreatitis. Am J Health Syst Pharm 1998;55: of early enteral vs parenteral nutrition in mild acute pancreatitis. JPEN 480–6. J Parenter Enteral Nutr 1997;21:14–20. 106. Thompson DR. Narcotic analgesic effects on the sphincter of Oddi: a 130. Olah A, Pardavi G, Belagyi T, et al. Early nasojejunal feeding in acute review of the data and therapeutic implications in treating pancreatitis. pancreatitis is associated with a lower complication rate. Nutrition Am J Gastroenterol 2001;96:1266–72. 2002;18:259–62. 107. Basurto Ona X, Rigau Comas D, Urrutia G. Opioids for acute 131. Petrov MS, Kukosh MV, Emelyanov NV. A randomized controlled pancreatitis pain. Cochrane Database Syst Rev 2013;(7):CD009179. trial of enteral versus parenteral feeding in patients with predicted 108. Akshintala VS, Hutfless SM, Colantuoni E, et al. Systematic review severe acute pancreatitis shows a significant reduction in mortality and with network meta-analysis: pharmacological prophylaxis against in infected pancreatic complications with total enteral nutrition. Dig post-ERCP pancreatitis. Aliment Pharmacol Ther 2013;38:1325–37. Surg 2006;23:336–44. 109. Pezzilli R, Morselli-Labate AM, Corinaldesi R. NSAIDs and acute 132. Windsor AC, Kanwar S, Li AG, et al. Compared with parenteral pancreatitis: a systematic review. Pharmaceuticals (Basel) 2010;3: nutrition, enteral feeding attenuates the acute phase response and 558–71. improves disease severity in acute pancreatitis. Gut 1998;42:431–5. 110. Ebbehoj N, Friis J, Svendsen LB, et al. Indomethacin treatment of 133. Yi F, Ge L, Zhao J, et al. Meta-analysis: total parenteral nutrition versus acute pancreatitis. A controlled double-blind trial. Scand J Gastro- total enteral nutrition in predicted severe acute pancreatitis. Intern Med enterol 1985;20:798–800. 2012;51:523–30. 111. Layer P, Bronisch HJ, Henniges UM, et al. Effects of systemic 134. Sun B, Gao Y, Xu J, et al. Role of individually staged nutritional administration of a local anesthetic on pain in acute pancreatitis: a support in the management of severe acute pancreatitis. Hepatobiliary randomized clinical trial. Pancreas 2011;40:673–9. Pancreat Dis Int 2004;3:458–63. 112. Sadowski SM, Andres A, Morel P, et al. Epidural anesthesia improves 135. Eatock FC, Chong P, Menezes N, et al. A randomized study of early pancreatic perfusion and decreases the severity of acute pancreatitis. nasogastric versus nasojejunal feeding in severe acute pancreatitis. Am World J Gastroenterol 2015;21:12448–56. J Gastroenterol 2005;100:432–9. 113. Bernhardt A, Kortgen A, Niesel H, et al. Using epidural anesthesia in 136. Kumar A, Singh N, Prakash S, et al. Early enteral nutrition in severe patients with acute pancreatitis—prospective study of 121 patients. acute pancreatitis: a prospective randomized controlled trial com- Anaesthesiol Reanim 2002;27:16–22. paring nasojejunal and nasogastric routes. J Clin Gastroenterol 114. Houben CH, Ade-Ajayi N, Patel S, et al. Traumatic pancreatic duct 2006;40:431–4. injury in children: minimally invasive approach to management. J 137. Olah A, Romics L Jr. Evidence-based use of enteral nutrition in acute Pediatr Surg 2007;42:629–35. pancreatitis. Langenbecks Arch Surg 2010;395:309–16. 115. Al-Omran M, Albalawi ZH, Tashkandi MF, et al. Enteral versus 138. Abu-El-Haija M, Wilhelm R, Heinzman C, et al. Early enteral nutrition parenteral nutrition for acute pancreatitis. Cochrane Database Syst in children with acute pancreatitis. J Pediatr Gastroenterol Nutr Rev 2010;(1):CD002837. 2016;62:453–6. 116. Leach SD, Modlin IM, Scheele GA, et al. Intracellular activation of 139. Carreazo NY, Ugarte K, Bada C. When should we start oral intake in digestive zymogens in rat pancreatic acini. Stimulation by high doses children with severe acute pancreatitis? Evid Based Med 2008;13:4–5. of cholecystokinin. J Clin Invest 1991;87:362–6. 140. Niederau C, Niederau M, Luthen R, et al. Pancreatic exocrine secretion 117. Halangk W, Lerch MM. Early events in acute pancreatitis. Clin Lab in acute experimental pancreatitis. Gastroenterology 1990;99:1120–7. Med 2005;25:1–15. 141. Fan BG, Salehi A, Sternby B, et al. Total parenteral nutrition influences 118. Mirtallo JM, Forbes A, McClave SA, et al. International consensus both endocrine and exocrine function of rat pancreas. Pancreas guidelines for nutrition therapy in pancreatitis. JPEN J Parenter 1997;15:147–53. Enteral Nutr 2012;36:284–91. 142. Variyam EP, Fuller RK, Brown FM, et al. Effect of parenteral amino 119. Lodewijkx PJ, Besselink MG, Witteman BJ, et al. Nutrition in acute acids on human pancreatic exocrine secretion. Dig Dis Sci 1985;30: pancreatitis: a critical review. Expert Rev Gastroenterol Hepatol 541–6. 2016;10:571–80. 143. Ockenga J, Borchert K, Rifai K, et al. Effect of glutamine-enriched 120. Bakker OJ, van Brunschot S, van Santvoort HC, et al. Early versus on- total parenteral nutrition in patients with acute pancreatitis. Clin Nutr demand nasoenteric tube feeding in acute pancreatitis. N Engl J Med 2002;21:409–16. 2014;371:1983–93. 144. de Beaux AC, O’Riordain MG, Ross JA, et al. Glutamine-supplemen- 121. Petrov MS, Pylypchuk RD, Emelyanov NV. Systematic review: nutri- ted total parenteral nutrition reduces blood mononuclear cell inter- tional support in acute pancreatitis. Aliment Pharmacol Ther leukin-8 release in severe acute pancreatitis. Nutrition 1998;14:261–5. 2008;28:704–12. 145. Zhao G, Wang CY, Wang F, et al. Clinical study on nutrition support in 122. Grant JP. Nutritional support in acute and chronic pancreatitis. Surg patients with severe acute pancreatitis. World J Gastroenterol Clin North Am 2011;91:805–820; viii. 2003;9:2105–8. 123. Marik PE. What is the best way to feed patients with pancreatitis? Curr 146. McClave SA, Chang WK, Dhaliwal R, et al. Nutrition support in acute Opin Crit Care 2009;15:131–8. pancreatitis: a systematic review of the literature. JPEN J Parenter 124. Abou-Assi S, Craig K, O’Keefe SJ. Hypocaloric jejunal feeding Enteral Nutr 2006;30:143–56. is better than total parenteral nutrition in acute pancreatitis: results 147. Sahin H, Mercanligil SM, Inanc N, et al. Effects of glutamine-enriched of a randomized comparative study. Am J Gastroenterol 2002;97: total parenteral nutrition on acute pancreatitis. Eur J Clin Nutr 2255–62. 2007;61:1429–34. 125. Eckerwall GE, Axelsson JB, Andersson RG. Early nasogastric feeding 148. Klein E, Shnebaum S, Ben-Ari G, et al. Effects of total parenteral in predicted severe acute pancreatitis: a clinical, randomized study. nutrition on exocrine pancreatic secretion. Am J Gastroenterol Ann Surg 2006;244:959–65. 1983;78:31–3. 126. Gupta R, Patel K, Calder PC, et al. A randomised clinical trial to assess 149. Lam WF, Masclee AA, de Boer SY, et al. Effect of acute hypergly- the effect of total enteral and total parenteral nutritional support on cemia on basal and cholecystokinin stimulated exocrine pancreatic metabolic, inflammatory and oxidative markers in patients with pre- secretion in humans. Life Sci 1997;60:2183–90. dicted severe acute pancreatitis (APACHE II > or ¼ 6). Pancreatology 150. Fan BG, Andren-Sandberg A. Acute pancreatitis. N Am J Med Sci 2003;3:406–13. 2010;2:211–4. 127. Kalfarentzos F, Kehagias J, Mead N, et al. Enteral nutrition is superior 151. Rollan A, Guzman S, Pimentel F, et al. Catabolism of chylomicron to parenteral nutrition in severe acute pancreatitis: results of a rando- remnants in patients with previous acute pancreatitis. Gastroenterol- mized prospective trial. Br J Surg 1997;84:1665–9. ogy 1990;98:1649–54. 128. Louie BE, Noseworthy T, Hailey D, et al. 2004 MacLean-Mueller prize 152. Guzman S, Nervi F, Llanos O, et al. Impaired lipid clearance in patients enteral or parenteral nutrition for severe pancreatitis: a randomized with previous acute pancreatitis. Gut 1985;26:888–91. controlled trial and health technology assessment. Can J Surg 153. Buch A, Buch J, Carlsen A, et al. Hyperlipidemia and pancreatitis. 2005;48:298–306. World J Surg 1980;4:307–14.

174 www.jpgn.org

154. Dominguez-Munoz JE, Malfertheiner P, Ditschuneit HH, et al. Hy- 179. Bongaerts GP, Severijnen RS. A reassessment of the PROPATRIA perlipidemia in acute pancreatitis. Relationship with etiology, onset, study and its implications for probiotic therapy. Nat Biotechnol and severity of the disease. Int J Pancreatol 1991;10:261–7. 2016;34:55–63. 155. Searles GE, Ooi TC. Underrecognition of chylomicronemia as a cause 180. Besselink MG, van Santvoort HC, Buskens E, et al. Probiotic pro- of acute pancreatitis. CMAJ 1992;147:1806–8. phylaxis in predicted severe acute pancreatitis: a randomised, double- 156. Fivez T, Kerklaan D, Mesotten D, et al. Early versus late parenteral blind, placebo-controlled trial. Lancet 2008;371:651–9. nutrition in critically ill children. N Engl J Med 2016;374:1111–22. 181. Gou S, Yang Z, Liu T, et al. Use of probiotics in the treatment of severe 157. Delcenserie R, Yzet T, Ducroix JP. Prophylactic antibiotics in treat- acute pancreatitis: a systematic review and meta-analysis of rando- ment of severe acute alcoholic pancreatitis. Pancreas 1996;13: mized controlled trials. Crit Care 2014;18:R57. 198–201. 182. Sun S, Yang K, He X, et al. Probiotics in patients with severe acute 158. Nordback I, Sand J, Saaristo R, et al. Early treatment with antibiotics pancreatitis: a meta-analysis. Langenbecks Arch Surg 2009;394: reduces the need for surgery in acute necrotizing pancreatitis—a 171–7. single-center randomized study. J Gastrointest Surg 2001;5:113–8. 183. Freeman HJ, Kim YS, Sleisenger MH. Protein digestion and absorp- 159. Sainio V, Kemppainen E, Puolakkainen P, et al. Early antibiotic tion in man. Normal mechanisms and protein-energy malnutrition. Am treatment in acute necrotising pancreatitis. Lancet 1995;346: J Med 1979;67:1030–6. 663–7. 184. Freeman HJ. Pancreatic endocrine and exocrine changes in celiac 160. Isenmann R, Runzi M, Kron M, et al. Prophylactic antibiotic treatment disease. World J Gastroenterol 2007;13:6344–6. in patients with predicted severe acute pancreatitis: a placebo-con- 185. Fernanez LB, De Paula A, Prizont R, et al. Exocrine pancreas trolled, double-blind trial. Gastroenterology 2004;126:997–1004. insufficiency secondary to glutenenteropathy. Am J Gastroenterol 161. Yao L, Huang X, Li Y, et al. Prophylactic antibiotics reduce pancreatic 1970;53:564–9. necrosis in acute necrotizing pancreatitis: a meta-analysis of rando- 186. Lankisch PG, Apte M, Banks PA. Acute pancreatitis. Lancet 2015;386: mized trials. Dig Surg 2010;27:442–9. 85–96. 162. Villatoro E, Mulla M, Larvin M. Antibiotic therapy for prophylaxis 187. Boonstra K, Weersma RK, van Erpecum KJ, et al. Population-based against infection of pancreatic necrosis in acute pancreatitis. Cochrane epidemiology, malignancy risk, and outcome of primary sclerosing Database Syst Rev 2010;(5):CD002941. cholangitis. Hepatology 2013;58:2045–55. 163. Arlt A, Erhart W, Schafmayer C, et al. Antibiosis of necrotizing 188. Kamisawa T, Egawa N, Nakajima H. Autoimmune pancreatitis is a pancreatitis. Viszeralmedizin 2014;30:318–24. systemic autoimmune disease. Am J Gastroenterol 2003;98:2811–2. 164. Wittau M, Mayer B, Scheele J, et al. Systematic review and meta- 189. Pitchumoni CS, Rubin A, Das K. Pancreatitis in inflammatory bowel analysis of antibiotic prophylaxis in severe acute pancreatitis. Scand J diseases. J Clin Gastroenterol 2010;44:246–53. Gastroenterol 2011;46:261–70. 190. Roque Ramos L, DiMaio CJ, Sachar DB, et al. Autoimmune pan- 165. Bai Y, Gao J, Zou DW, et al. Prophylactic antibiotics cannot reduce creatitis and inflammatory bowel disease: case series and review of the infected pancreatic necrosis and mortality in acute necrotizing pan- literature. Dig Liver Dis 2016;48:893–8. creatitis: evidence from a meta-analysis of randomized controlled 191. Hirano K, Fukushima N, Tada M, et al. Diagnostic utility of biopsy trials. Am J Gastroenterol 2008;103:104–10. specimens for autoimmune pancreatitis. J Gastroenterol 2009; 166. Pederzoli P, Cavallini G, Falconi M, et al. Gabexate mesilate vs 44:765–73. aprotinin in human acute pancreatitis (GA.ME.P.A.). A prospective, 192. Shinji A, Sano K, Hamano H, et al. Autoimmune pancreatitis is closely randomized, double-blind multicenter study. Int J Pancreatol associated with gastric ulcer presenting with abundant IgG4-bearing 1993;14:117–24. plasma cell infiltration. Gastrointest Endosc 2004;59:506–11. 167. Ino Y, Arita Y, Akashi T, et al. Continuous regional arterial infusion 193. Lee KM, Paik CN, Chung WC, et al. Association between acute therapy with gabexate mesilate for severe acute pancreatitis. World J pancreatitis and peptic ulcer disease. World J Gastroenterol 2011;17: Gastroenterol 2008;14:6382–7. 1058–62. 168. Takeda K, Yamauchi J, Shibuya K, et al. Benefit of continuous 194. Manes G, Balzano A, Vaira D. Helicobacter pylori and pancreatic regional arterial infusion of protease inhibitor and antibiotic in the disease. JOP 2003;4:111–6. management of acute necrotizing pancreatitis. Pancreatology 2001;1: 195. Lytras D, Kalaitzakis E, Hatfield AR, et al. Recurrent acute pancreatitis 668–73. as primary manifestation of gangliocytic paraganglioma of the am- 169. Fukushima H, Fukushima T, Suzuki R, et al. Continuous regional pulla. Pancreas 2011;40:985–6. arterial infusion effective for children with acute necrotizing pancrea- 196. Asimakopoulou NI, Papakonstantinou PE, Lasithiotakis KG, et al. titis even under neutropenia. Pediatr Int 2013;55:e11–3. Recurrent episodes of acute pancreatitis due to duodenal gangliocytic 170. Kitagawa M, Hayakawa T. Antiproteases in the treatment of acute paraganglioma: report of a case. JOP 2014;15:201–5. pancreatitis. JOP 2007;8(4 suppl):518–25. 197. Cheng CL, Fogel EL, Sherman S, et al. Diagnostic and therapeutic 171. Keck T, Balcom JH, Antoniu BA, et al. Regional effects of nafamostat, endoscopic retrograde cholangiopancreatography in children: a large a novel potent protease and complement inhibitor, on severe necrotiz- series report. J Pediatr Gastroenterol Nutr 2005;41:445–53. ing pancreatitis. Surgery 2001;130:175–81. 198. Enestvedt BK, Tofani C, Lee DY, et al. Endoscopic retrograde cho- 172. Seta T, Noguchi Y,Shikata S, et al. Treatment of acute pancreatitis with langiopancreatography in the pediatric population is safe and effica- protease inhibitors administered through intravenous infusion: an cious. J Pediatr Gastroenterol Nutr 2013;57:649–54. updated systematic review and meta-analysis. BMC Gastroenterol 199. Giefer MJ, Kozarek RA. Technical outcomes and complications of 2014;14:102. pediatric ERCP. Surg Endosc 2015;29:3543–50. 173. Inoue S, Kawanishi S. Oxidative DNA damage induced by simulta- 200. Limketkai BN, Chandrasekhara V, Kalloo AN, et al. Comparison of neous generation of nitric oxide and superoxide. FEBS Lett performance and safety of endoscopic retrograde cholangiopancrea- 1995;371:86–8. tography across pediatric age groups. Dig Dis Sci 2013;58:2653–60. 174. Hegazi RA, DeWitt T. Enteral nutrition and immune modulation of 201. Paris C, Bejjani J, Beaunoyer M, et al. Endoscopic retrograde cho- acute pancreatitis. World J Gastroenterol 2014;20:16101–5. langiopancreatography is useful and safe in children. J Pediatr Surg 175. Capurso G, Zerboni G, Signoretti M, et al. Role of the gut barrier in 2010;45:938–42. acute pancreatitis. J Clin Gastroenterol 2012;46(suppl):S46–51. 202. Pfau PR, Chelimsky GG, Kinnard MF, et al. Endoscopic retrograde 176. Liu H, Li W, Wang X, et al. Early gut mucosal dysfunction in patients cholangiopancreatography in children and adolescents. J Pediatr with acute pancreatitis. Pancreas 2008;36:192–6. Gastroenterol Nutr 2002;35:619–23. 177. Muftuoglu MA, Isikgor S, Tosun S, et al. Effects of probiotics on the 203. Vegting IL, Tabbers MM, Taminiau JA, et al. Is endoscopic retrograde severity of experimental acute pancreatitis. Eur J Clin Nutr cholangiopancreatography valuable and safe in children of all ages? J 2006;60:464–8. Pediatr Gastroenterol Nutr 2009;48:66–71. 178. Olah A, Belagyi T, Issekutz A, et al. Randomized clinical trial of 204. Woods KE, Willingham FF. Endoscopic retrograde cholangiopancrea- specific lactobacillus and fibre supplement to early enteral nutrition in tography associated pancreatitis: a 15-year review. World J Gastro- patients with acute pancreatitis. Br J Surg 2002;89:1103–7. intest Endosc 2010;2:165–78. www.jpgn.org 175

205. Usatin D, Fernandes M, Allen IE, et al. Complications of endoscopic 219. Ardengh JC, Malheiros CA, Rahal F, et al. Microlithiasis of the retrograde cholangiopancreatography in pediatric patients; a gallbladder: role of endoscopic ultrasonography in patients with idio- systematic literature review and meta-analysis. J Pediatr 2016;179:1 pathic acute pancreatitis. Rev Assoc Med Bras 19922010;56:27–31. 160–5e3. 220. Inoue D, Gabata T, Matsui O, et al. Autoimmune pancreatitis with 206. Troendle DM, Barth BA. ERCP can be safely and effectively per- multifocal mass lesions. Radiat Med 2006;24:587–91. formed by a pediatric gastroenterologist for choledocholithiasis in a 221. Friedlander J, Quiros JA, Morgan T, et al. Diagnosis of autoimmune pediatric facility. J Pediatr Gastroenterol Nutr 2013;57:655–8. pancreatitis vs neoplasms in children with pancreatic mass and biliary 207. Fishman DS, Chumpitazi BP, Raijman I, et al. Endoscopic retrograde obstruction. Clin Gastroenterol Hepatol 2012;10:1051–5e1. cholangiography for pediatric choledocholithiasis: assessing the need 222. Yachha SK, Chetri K, Saraswat VA, et al. Management of childhood for endoscopic intervention. World J Gastrointest Endosc 2016;8: pancreatic disorders: a multidisciplinary approach. J Pediatr Gastro- 425–32. enterol Nutr 2003;36:206–12. 208. Tse F, Yuan Y. Early routine endoscopic retrograde cholangiopancrea- 223. Ramesh J, Bang JY, Trevino J, et al. Endoscopic ultrasound-guided tography strategy versus early conservative management strategy drainage of pancreatic fluid collections in children. J Pediatr Gastro- in acute gallstone pancreatitis. Cochrane Database Syst Rev enterol Nutr 2013;56:30–5. 2012;(5):CD009779. 224. Mier J, Leon EL, Castillo A, et al. Early versus late necrosectomy in 209. Uhl W, Warshaw A, Imrie C, et al. IAP guidelines for the surgical severe necrotizing pancreatitis. Am J Surg 1997;173:71–5. management of acute pancreatitis. Pancreatology 2002;2:565–73. 225. da Costa DW, Bouwense SA, Schepers NJ, et al. Same-admission 210. Agarwal J, Nageshwar Reddy D, Talukdar R, et al. ERCP in the versus interval cholecystectomy for mild gallstone pancreatitis management of pancreatic diseases in children. Gastrointest Endosc (PONCHO): a multicentre randomised controlled trial. Lancet 2014;79:271–8. 2015;386:1261–8. 211. Bolia R, Srivastava A, Yachha SK, et al. Prevalence, natural 226. Moore EE, Cogbill TH, Malangoni MA, et al. Organ injury scaling, II: history, and outcome of acute fluid collection and pseudocyst in Pancreas, duodenum, small bowel, colon, and rectum. J Trauma children with acute pancreatitis. J Pediatr Gastroenterol Nutr 1990;30:1427–9. 2015;61:451–5. 227. Lin TK, Palermo JJ, Nathan JD, et al. Timing of cholecystectomy in 212. Restrepo R, Hagerott HE, Kulkarni S, et al. Acute pancreatitis in children with biliary pancreatitis. J Pediatr Gastroenterol Nutr pediatric patients: demographics, etiology, and diagnostic imaging. 2016;62:118–21. AJR Am J Roentgenol 2016;206:632–44. 228. Kandula L, Lowe ME. Etiology and outcome of acute pancreatitis in 213. Haluszka O, Campbell A, Horvath K. Endoscopic management of infants and toddlers. J Pediatr 2008;152:106–1010.e1. pancreatic pseudocyst in children. Gastrointest Endosc 2002;55: 229. Pant C, Deshpande A, Olyaee M, et al. Epidemiology of acute 128–31. pancreatitis in hospitalized children in the United States from 214. Sharma SS, Maharshi S. Endoscopic management of pancreatic pseu- 2000–2009. PLoS One 2014;9:e95552. docyst in children-a long-term follow-up. J Pediatr Surg 2008;43: 230. Kumar S, Gariepy CE. Nutrition and acute pancreatitis: review of the 1636–9. literature and pediatric perspectives. Curr Gastroenterol Rep 215. Makin E, Harrison PM, Patel S, et al. Pancreatic pseudocysts in 2013;15:338. children: treatment by endoscopic cyst gastrostomy. J Pediatr Gastro- 231. Chang YJ, Chao HC, Kong MS, et al. Acute pancreatitis in children. enterol Nutr 2012;55:556–8. Acta Paediatr 2011;100:740–4. 216. Jazrawi SF, Barth BA, Sreenarasimhaiah J. Efficacy of endoscopic 232. Goday PS, Wakeham M, Kuhn EM, et al. Acute pancreatitis in the ultrasound-guided drainage of pancreatic pseudocysts in a pediatric pediatric intensive care unit. J Pediatr Gastroenterol Nutr population. Dig Dis Sci 2011;56:902–8. 2015;61:108–12. 217. Canty TG Sr, Weinman D. Treatment of pancreatic duct disruption 233. Benifla M, Weizman Z. Acute pancreatitis in childhood: analysis of in children by an endoscopically placed stent. J Pediatr Surg literature data. J Clin Gastroenterol 2003;37:169–72. 2001;36:345–8. 234. Boerma D, van Gulik TM, Obertop H, et al. Internal drainage of infected 218. Keil R, Drabek J, Lochmannova J, et al. What is the role of pancreatic pseudocysts: safe or sorry? Dig Surg 1999;16:501–5. endoscopic retrograde cholangiopancreatography in assessing trau- 235. Mukai S, Itoi T, Moriyasu F. Interventional endoscopy for the treat- matic rupture of the pancreatic in children? Scand J Gastroenterol ment of pancreatic pseudocyst and walled-off necrosis (with videos). 2016;51:218–24. J Hepatobiliary Pancreat Sci 2014;21:E75–85.

176 www.jpgn.org