severe acute pancreatitis

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DIGESTIVE DISEASES - RESEARCH AND CLINICAL DEVELOPMENTS

ACUTE PANCREATITIS HEALTH EFFECTS, CLINICAL ASPECTS AND EMERGING THERAPIES

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DIGESTIVE DISEASES - RESEARCH AND CLINICAL DEVELOPMENTS

ACUTE PANCREATITIS HEALTH EFFECTS, CLINICAL ASPECTS AND EMERGING THERAPIES

SHANE COPELAND EDITOR

New York


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Published by Nova Science Publishers, Inc. † New York


CONTENTS Preface

vii

Chapter 1

Acute Pancreatitis in Childhood Gilles Duvoisin and Chee Yee Ooi

Chapter 2

Walled-Off Pancreatic Necrosis V. Arteaga Peralta, A. A. Medina Velasco, R. de la Plaza Llamas, J. M. Ramia Angel and J. D. Gonzales Aguilar

Chapter 3

Ocular Manifestations of Acute Pancreatitis: Purtscher’s Retinopathy Edward Chu

1 33

55

Chapter 4

Impact of Obesity to Severity of Acute Pancreatitis Jana Katuchova

71

Chapter 5

Severe Acute Pancreatitis: Since the Classical Alejandra Guillermina Miranda-Díaz, José Manuel Hermosillo-Sandoval and Carlos Alberto Gutiérrez-Martínez

79

Chapter 6

Management of Acute Biliary Pancreatitis Vincenzo Neri

Chapter 7

Radiology of Acute Pancreatitis and Its Complications Kamil Zeleňák and Martin Števík


109

143

vi

Contents

Chapter 8

Antibiotics in Acute Pancreatitis José Ramón Oliver Guillén, Ana Palomares Cano, María Beltrán Martos, Mario Serradilla Martín and Alejandro Serrablo

Chapter 9

Beneficial Effect and Underlying Mechanism of Shenmai injection on Acute Experimental Pancreatitis Qiang Yan, Wei Wu, Xing Yao, Guolei Zhang, Mingjie Zhang, Feng Cen and Xu Sun

Index

175

195

211


PREFACE Acute pancreatitis (AP) is the inflammatory process secondary to damage of the pancreatic acinar cells. AP is one of the most common diseases of the gastrointestinal tract, leading to significant emotional, physical, and financial burden for society. The diagnosis of acute pancreatitis is often established by clinical symptoms and laboratory testing. Chapter One of this book reviews the clinical characteristics of acute pancreatitis in children based on the clinically based diagnostic criteria for childhood pancreatitis, which until recently was not available. Chapter Two presents an update on the current state of walled-off pancreatic necrosis. Chapter Three provides a review of Purtscher's Retinopathy. Chapter Four examines the impact of obesity on the severity of AP. Chapter Five discusses several advances in the management of AP, from classical methods to more advances options. Chapter Six discusses management of acute biliary pancreatitis. Chapter Seven reviews radiology of AP and the complications associated with it. Chapter Eight studies the use of antibiotics in AP. The final chapter explores the therapeutic effect of Shenmai injection (SMI) on acute experimental pancreatitis and underlying mechanisms.



In: Acute Pancreatitis Editor: Shane Copeland

ISBN: 978-1-63485-229-6 © 2016 Nova Science Publishers, Inc.

Chapter 1

ACUTE PANCREATITIS IN CHILDHOOD Gilles Duvoisin1,2 and Chee Yee Ooi2,3, 1

Department of Paediatrics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland 2 Department of Gastroenterology, Sydney Children’s Hospital, Randwick, NSW, Australia 3 Discipline of Paediatrics, School of Women’s and Children’s Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia

ABSTRACT Acute pancreatitis (AP) in children is increasingly recognized to be a challenge for affected patients and their families, their treating physicians and surgeons, and the health care system. An increase in incidence of paediatric AP has been reported. The incidence of paediatric AP was estimated at 3.6 to 13.2 per 100,000 per children per year, which is within the range of incidence reported for adult AP. Genetic contributions to the development of pancreatitis, especially in acute recurrent and chronic pancreatitis, are now increasingly recognised. This chapter will review the clinical characteristics of acute pancreatitis in children based on the clinically based diagnostic criteria for childhood pancreatitis, which until recently was not available. The 

Corresponding author: Dr (Keith) C. Y. Ooi, Discipline of Paediatrics, School of Women’s and, University of New South Wales, Australia. Email: [email protected].


2

Gilles Duvoisin and Chee Yee Ooi diagnostic criteria are based on symptoms, biochemical and imaging evidence of pancreatitis, with two of the three criteria required to diagnose AP. Although abdominal pain is the most common clinical manifestation, it may be absent in up to one third of paediatric patients. The diagnostic yield and concordances for serum pancreatic enzymes and imaging for the diagnosis of paediatric AP will be discussed. There is currently no consensus on the definition for the severity of AP in children. However, there are now predictors of severity for AP that has been developed and validated in children. The management of AP remains driven by adult studies and recommendations. Treatment is directed at the underlying aetiology as well as supportive measures. Early fluid resuscitation and early enteral feeding has been recent additions to the limited armamentarium available in AP. Its application in children with AP is promising but lacking in evidence. Potential future therapies in AP that may apply to children will also be discussed.

1. INTRODUCTION The pancreas is a transversely oriented retroperitoneal organ. Although it does not have well-defined anatomic divisions, surroundings vessels and ligaments delineate the organ into a head, body, and tail. The pancreas has dichotomous roles: endocrine and exocrine. Regarding the exocrine portion of the pancreas, ductal cells form the tubules that secrete bicarbonate and fluid to help flush pancreatic enzymes produced by the acinar cells into the duodenum. Acute pancreatitis is an inflammatory disorder of the pancreas. The alterations cause oedema by microvascular leakage, necrosis of fat by lipase, an acute inflammatory reaction, proteolytic destruction of pancreatic parenchyma, and destruction of the blood vessels leading to intestinal haemorrhage. Its severity may vary from a mild disease, self-remitting to a fulminant, life-threatening process. Acute pancreatitis in children is a well recognised disease. Acute pancreatitis may present with a wide-range of clinical presentations in childhood from gastrointestinal symptoms of nausea, vomiting and abdominal pain to non-specific manifestations such as irritability, fever and tachycardia. In recent years, there has been a rise in the incidence and admission rates for acute pancreatitis in children [1, 2]. Despite this, paediatric acute pancreatitis has been a relatively poorly studied condition compared to the adult form. The understanding and the management of this condition is predominantly based on a historical approaches and extrapolated from the adult perspective. However, there are significant differences between the


Acute Pancreatitis in Childhood

3

paediatric and the adult form of acute pancreatitis regarding the aetiology, the clinical presentation, the severity and its complications [3]. For this reason, further studies are required to enhance the specific knowledge related to paediatric acute pancreatitis. This chapter will review the clinical characteristics of acute pancreatitis in children based on the diagnostic criteria for childhood pancreatitis, which until recently was not available. The diagnostic criteria are based on symptoms, biochemical and imaging evidence of pancreatitis, with two of the three criteria required to diagnose acute pancreatitis. In addition, we will describe the burden of paediatric acute pancreatitis as well as its aetiology. Furthermore, we will summarise the recommendation of its management and how the complications can be documented and addressed. Finally, we will discuss emerging therapies.

2. BURDEN OF DISEASE: INCIDENCE AND LENGTH OF HOSPITALISATION 2.1. Incidence In adults, acute pancreatitis is on the rise and has become the leading gastrointestinal cause of hospitalization in the US [4]. Similarly, acute pancreatitis in children has become an increasingly recognized disease. Several single centres around the world have reported the incidence of acute pancreatitis. A rise in the admission rates of children with acute pancreatitis had been described [5, 6]. In addition, retrospective studies in Melbourne, Australia and in Pittsburgh, US, which took into account the catchment population, described an incidence of 3.6 per 100,000 children from 0 to 15 years old/year and 13.2 per 100,000 children/year, respectively [2, 7]. In comparison, the incidence reported in adults with acute pancreatitis range from 4.8 to 38 per 100,000/year. What are the reasons for this increase of incidence of acute pancreatitis in children? Undoubtedly, the answer is complex and likely multifactorial. There are several hypotheses. Firstly, there may be an absolute increase in the case of acute pancreatitis leading to this observation. Nevertheless, as far as we are aware, none of the causes responsible for acute pancreatitis in children has shown a specific upwards trend. Secondly, the increase of incidence may be related to a referral bias, as the catchment population is not fully considered in


4

Gilles Duvoisin and Chee Yee Ooi

the majority of the studies. For instance, an increased number of patients may have been directly referred to the tertiary care centre by their clinician, instead of their community hospitals [8]. The incidence may be biased if theses cases are reported without adding the population of these areas to the catchment population of the tertiary care centre. Thirdly, it was documented than an increased awareness of acute pancreatitis in children has lead to an increased testing for amylase and lipase. Simultaneously, it was associated with an increase of the reports of episode of acute pancreatitis [2]. It was postulated that this effect was responsible for 94% of the change in all the admissions.

2.2. Length of Hospitalisation The length of hospitalisation for an episode of acute pancreatitis varies regarding the severity of its manifestation and the underlying condition. If the episode is non-complicated, the median length of stay was reported from 5 days (IQR 3-10) to 8 days and the average length between 15 and 24 days [6, 8, 9]. The length of stay of children less than 2 years old with acute pancreatitis was significantly longer when compared with the group of 3-10 years and 11-20 years. In adults, in comparison, it was described that the length of stay for a mild acute pancreatitis was between 3 to 5 days [4].

3. PATHOPHYSIOLOGY Since the observation by Chiari in 1886, the paradigm of acute pancreatitis has been described as the autodigestion of the pancreas triggered by premature auto-activation of trypsin. Physiologically, trypsin, a serine protease, is activated by the enterokinase produced by the brush border of the duodenum. In acute pancreatitis, the early pathogenesis possibly includes a pathologic cytoplasmic calcium response to a pancreatic insult (e.g., drug induced pancreatitis, bile acids metabolite, ethanol, etc.) [10]. This dysregulation may lead to a premature intrapancreatic activation of trypsinogen to trypsin [11, 12]. Trypsin then induces a cascade of activation of other protease leading to further insult to the pancreas. Nevertheless, recent studies suggest that a multifaceted paradigm should be considered, composed of several paralleled independent pathway contributing to the pancreatic injury [13]. The zymogen activation pathways and the inflammatory pathway are beginning to be clarified, both pathways are



5

thought to be sufficient to trigger acute pancreatitis [10]. However, their link is still debatable. Regarding the inflammatory pathway, proinflammatory cytokines such as tumour necrosis factor  (TNF) and interleukin-1 (IL-1) may contribute to the activation of a key transcriptional factor: nuclear factor B (NF B). Recently, a novel protein kinase C (PKC), presenting several isoforms, has been suggested to mediate the activation of NF B [14]. The relative contribution of the zymogen activation pathway and the inflammatory pathway is one of the central interrogation in the pathophysiology of acute pancreatitis at present and further studies are required to specify their interactions. As a result of this complexity and the expected common pathophysiologic pathway between the adult and the paediatric form of acute pancreatitis, a complete description of the pathophysiology of acute pancreatitis goes beyond the scope of this chapter.

4. AETIOLOGY Defining the aetiology of an episode of acute pancreatitis is a complex question. However, the cause should be determined for several important reasons. Firstly, some aetiologies may require a specific treatment such as biliary acute pancreatitis and these interventions should not be delayed. Secondly, some patients may have susceptibility for recurrent episodes (e.g., genetic mutations) and patients may benefit from assessing subsequent modifiable risk factors (e.g., alcohol or tobacco smoke exposure) to prevent or limit further episodes. Finally, clinicians should be able to discuss the prognosis/natural history with the patients and their family and knowing the aetiology is crucial in this setting. Various studies have been performed to identify the aetiology of acute pancreatitis; however most of them are based on adult populations [15, 16]. In adult pancreatitis, gallstones and alcohol predominate as aetiological factors and account for up to 70% of cases. In children, the aetiology of acute pancreatitis is more diverse and alcohol ingestion is rarely reported as a cause of pancreatitis in children. The true frequency of the various aetiological factors in paediatric acute pancreatitis remains unclear. The vast majority of published studies are retrospective in nature and have various limitations. First, the diagnosis of paediatric acute pancreatitis proposed by the INSPPIRE consortium is not unanimously used in the literature due to its recent publication [17]. To the


6


same extent, the nomenclature of the causes is not shared among the studies. Secondly, a bias may be related to the clinicians’ knowledge and expertise. Finally, the extent of the investigations is debatable and may be responsible for the heterogeneity of the so-called “idiopathic” acute pancreatitis. In 2013, Bai et al. performed a literature review of the aetiology of paediatric acute pancreatitis [5-7, 9, 18-26]. Bai and colleagues reported that the most frequent causes for paediatric acute pancreatitis are: biliary disease, medications, idiopathic, multisystem diseases and trauma. Infections, hereditary pancreatitis and metabolic diseases are less common causes of acute pancreatitis in children.

4.1. Biliary Disease Biliary disease, which includes gallstones, biliary sludge, as well as other structural anomalies of the biliary and/or pancreatic tree such as choledochal cyst account for 10-30% of the aetiology of paediatric acute pancreatitis. Simplistically, these causes are associated with obstructed or reduced outflow of pancreatic secretions. In contrary to the adult form, the presence of pancreatic tumour is rare. The management of biliary disease causing acute pancreatitis differs from the other causes of acute pancreatitis in that it may improve and/or future episodes may be preventable with specific intervention. For these reasons, Coffey et al. developed a simple clinical tool to predict biliary aetiology for acute pancreatitis in children. The “biliary pancreatitis triad” of (a) serum gamma-glutamyl transpeptidase ≥40 U/l, (b) alanine aminotransferase ≥150 U/l and (c) lipase ≥15 x upper limit of normal, performed within 48h of presentation, was reported to be significantly associated with the presence of an underlying biliary cause. When two of the three items were met, the “biliary pancreatitis triad” was predictive of an underlying biliary cause with a sensitivity of 89% and a specificity of 95% (OR 150.4, p < 0.001). Among children who did not fulfil at least two of the three items, the negative predictive value reached 98%, i.e., a biliary cause was unlikely to be responsible for acute pancreatitis. This simple tool, established in a retrospective study, requires validation from larger multicentre prospective studies [27].



7

4.2. Medications Although medications have been reported to contribute up to 25% of acute pancreatitis in children, the true extent of medication-induced pancreatitis is difficult to study and the relevant paediatric literature is sparse. Published cases have frequently consisted of single case reports lacking adequate documentation including whether the diagnostic criteria for acute pancreatitis was fulfilled and if a sufficiently comprehensive range of investigations were performed to rule out more common causes of pancreatitis such as biliary or anatomic. In addition, most reported cases lacked a re-challenge of the suspected medication. The suspect medication(s) may indeed be the cause of the pancreatitis (idiosyncratic reaction or dose-related), be a co-factor or a bystander. The most common medication implicated in paediatric acute pancreatitis include valproic acid, L-asparaginase, prednisone, and azathioprine or 6-mercaptopurine. Different mechanisms have been postulated to explain how drugs may trigger acute pancreatitis. Valproic acid-induced acute pancreatitis, for instance, is an example of a dose-related side effect [28]. Idiosyncratic reactions, likely mediated by direct immunological effects, has been speculated to be the cause for azathioprine-related acute pancreatitis [29]. Several authors have proposed classification systems to categorise and link medication risk for acute pancreatitis in adults. Karch et al. [30] proposed that classification should be based on the temporal relation between the medication exposure and the manifestation of acute pancreatitis. Three parameters should be examined: the time between the exposure of the medication and the presentation of the acute pancreatitis, the resolution of the episode following the discontinuation of the medication, and finally, the recurrence of pancreatitis if the exposure of the medication was repeated [30]. More recently Trivedi et al., proposed a classification for medication-induced pancreatitis based on the number of cases reported in the literature and the presence of a positive rechallenge [31]. In addition to this concept, Badalov et al. highlighted the role of the latency of effect, which refers to a time-frame from the introduction of the medication to the onset of pancreatitis [32]. The latency can vary from less than 24 hours to greater than 30 days. In 2015, the INSPPIRE consortium reported a summary of these recommendations and proposed the need to gather detailed information regarding any suspected medication as part of the initial work up: onset of use, dosing, duration of use before onset of acute pancreatitis [33].


8


4.3. Idiopathic Despite the increased recognition of the various causes of acute pancreatitis (including genetic and metabolic causes), the aetiology of acute pancreatitis may remain elusive in 13% to 34% of cases [34]. However, it has been reported that in infants, aetiologies are more frequently determined. Park et al. [8], in a retrospective study, documented the aetiology of acute pancreatitis in children and according to age. In children less than 2 years old, an underlying aetiology was identified for all episodes of acute pancreatitis.

4.4. Multisystem Diseases Multisystem diseases that affect adults with acute pancreatitis differ from children. Accounting for one third of the aetiology of acute pancreatitis in children, systemic diseases include a variety of conditions such as sepsis, haemolytic uraemic syndrome and systemic lupus erythematous [34]. As multisystem diseases require a complex management with often several treatments, the concomitant medications used should be considered as possible contributing factors as described in section 4.2.

4.5. Trauma Trauma has been reported as a cause of acute pancreatitis in 9% to 40% of episodes [7, 22, 26]. Blunt trauma is the most common injury in children. In contrast to adults, penetrating trauma are rare in children. Despite its relative protection in the retroperitoneal space, blows to the epigastrium in motor vehicle accidents, sport injuries, bicycle handlebar, falls and child abuse might lead to its injury due compression forces on the pancreas against the vertebral column [35]. The contusion of the pancreas involves rupture of minor or major components of the ducts. The released pancreatic enzymes, which become in the contact with the parenchyma, may trigger an inflammatory cascade. It is important for clinicians to recognise that pancreatic injury is rarely a solitary injury and a coexistent injury to another abdominal organ is found in 90% of cases [36].



9

4.6. Infections Infections have been reported to be linked with acute pancreatitis in less than 10% of children. However, it is a challenge to determine whether the identified infectious agent was indeed the cause of the pancreatitis, a co-factor, an “innocent bystander.” The most frequent infectious agents described in the literature include viruses (mumps virus, hepatitis A virus, rotavirus, hepatitis E virus, varicella-zoster virus, adenovirus and coxsackie B4) and bacteria (Mycoplasma pneumonia, Moraxella catarrhalis). The presenting symptoms and clinical signs should conduct to specific investigations; therefore, the list is non exhaustive. Even if most of the cases are caused by viruses, specific treatment for bacterial pancreatitis might improve the outcome of the episode.

4.7. Genetic Genetic causes account for about 3% of patients with acute pancreatitis [6, 21]. However, the prevalence of an underlying genetic predisposition to developing pancreatitis varies depending on whether the study cohort involves only children with the first episode of acute pancreatitis or children with acute recurrent pancreatitis and chronic pancreatitis. To complicate matters further, genetic factors may be present in isolation or identified together with other genetic or non-genetic risk factors. In addition, interpretation of genetic tests results can be complicated, with identification of mutations or variants not necessarily indicative of being disease-causing. Genetic counselling is recommended when genetic testing is undertaken. Various genetic mutations have now been identified as causative/ predisposing factors for pancreatitis. Here, we briefly discuss the three most commonly identified mutations. The cationic trypsinogen (PRSS1) and pancreatic secretory trypsin inhibitor (SPINK1) genes are well-recognized mutations. Their role in the pathophysiology of acute pancreatitis demonstrate how mutations affect the auto-regulatory and homeostatic pathways, predisposing affected individuals to the development of pancreatitis. Mutations in the PRSS1 gene promotes trypsinogen activation (i.e., mutation leads to a gain of function), increasing the risk of episode of acute pancreatitis. In contrast, SPINK1 acts as a defence mechanism against premature activation of trypsin in the pancreas. Mutations that reduce its activity (i.e., mutation leads to a loss of function) is associated with an increased risk of acute pancreatitis. The cystic fibrosis transmembrane conductance regulator (CFTR)


10


gene plays a complex role by flushing ductal proteins released from the acinus into the duodenum, as well as regulating the intraluminal pH through bicarbonate secretion.

4.8. Metabolic Metabolic diseases were seen in 5% to 6% of patients with acute pancreatitis [6, 7, 21, 22, 24]. This is a heterogeneous group of diseases which may contribute to acute pancreatitis in children differently, either as a predisposing factor or an absolute risk factor. Unlike some of the other causes, metabolic conditions may be modifiable or correctable. Hence, its identification may reduce the risk of future episodes. A detailed review of the most frequent metabolic risk factors, namely hypertryglyceridemia, hypercalcemia and chronic renal failure, was recently described [33]. Hypertryglyceridemia above 1000 mg/dl (88.6 mol/l) was described as an absolute risk for pancreatitis. If the child presented elevated levels of serum tryglyceride of 500 to 1000 mg/dl (44.3-88.6 mol/l), it was suggested that this represented a predisposing factor. Even though the underlying mechanisms are not fully understood, two hypothesis have been postulated [37, 38]. Firstly, pancreatic microcirculation may be altered by the hyperviscosity from chylomicrons, leading to ischemia. Secondly, free fatty acids, resulting from the transformation of triglyceride within the pancreas, may directly induce injury in the acinus and capillaries. Primary hyperparathyroidism should be suspected in the setting of mild persistent hypercalcemia (above 10.7 mg/dl or 2.675 mmol/l) and further investigations to evaluate the underlying cause is recommended [33]. The regulation of intra-acinar calcium is crucial as the level of calcium influences the activation/inactivation of trypsin. For example, high serum levels of calcium promotes activation of trypsinogen and prevent trypsin inactivation. As hypercalcemia can be easily identified and management, it should be included in the diagnostic evaluation of acute pancreatitis. Acute pancreatitis has been reported in adults with chronic renal failure. The pathogenic mechanisms of acute pancreatitis in chronic renal failure remain unclear but is likely multifactorial and related to systemic vascular disease, medications, hyperparathyroidism and hyperlipidemia. To confound matters, in the setting of chronic renal failure, there is delayed clearance of amylase and lipase which may make the diagnosis of acute pancreatitis challenging if based solely on serum pancreatic enzyme levels [39, 40]. The



11

association between chronic renal failure in children and acute pancreatitis in children deserves further study.

4.9. Special Considerations in Acute Recurrent Pancreatitis As eluded above (4.7), the frequencies of the various aetiologies differ depending on whether the individual has had recurrent episodes of pancreatitis or a single event only. In the setting of acute recurrent pancreatitis, the two most common aetiological factors were identified to be genetic (48%) and anatomic anomalies (30%) (41 [accepted]). As such, investigations to evaluate for these factors should be considered in children who present with more than one episode of acute pancreatitis.

5. DEFINITIONS AND DIAGNOSIS 5.1. Definitions With the primary aim of standardising the reporting of paediatric acute pancreatitis, as well as to encourage communication with the different specialists (namely: surgeons, radiologists and paediatricians) using the same “language,” a shared definition of acute pancreatitis was required. However, until 2012, no uniform terminology had been described in the literature to define acute pancreatitis in children. For this reason, The International Study Group of Paediatric Pancreatitis: In Search for a Cure (INSPPIRE) consortium worked to establish recommendations for the diagnosis of acute pancreatitis, acute recurrent pancreatitis and chronic pancreatitis. These definitions were based on expert opinions gathered through the prism of adult studies due to the sparse paediatric literature. The work was mainly based on the revision of the Atlanta classification [41]. The results of the consortium proposed that paediatric acute pancreatitis, acute recurrent pancreatitis and chronic pancreatitis should be defined accordingly (Table 1).

5.2. Diagnosis Having a standardised definition of acute pancreatitis is crucial not only to provide specific criteria for the purposes of making a diagnosis but also to


12


enable future evaluation and research studies on the same condition using the same criteria. However, the three main components of the definition/ diagnostic criteria are worthy of discussion. Table 1. Definitions of acute, acute recurrent and chronic pancreatitis [17] Acute Pancreatitis At least 2 of the 3 items: a) Abdominal pain suggestive of, or compatible with acute pancreatitis b) Serum amylase and/or lipase activity at least ≥3 times upper limits of normal laboratory range c) Imaging findings characteristic of, or compatible with acute pancreatitis Acute Recurrent Pancreatitis At least 2 episodes of acute pancreatitis (as defined above), along with:  Complete resolution of pain (1 month pain-free interval the diagnoses of acute pancreatitis) OR  Complete normalization of serum pancreatic enzyme levels (amylase and lipase), before the subsequent of acute pancreatitis is diagnosed, along with a complete resolution of pain syndrome, irrespective of a specific time interval between episodes of acute pancreatitis. Chronic pancreatitis At least one of the following 4: a) Abdominal pain consistent with pancreatic origin and imaging findings1 suggestive of chronic pancreatic damage. b) Evidence of exocrine pancreatic insufficiency2 and and imaging findings1 suggestive of chronic pancreatitis damage c) Evidence of endocrine pancreatic insufficiency3 and imaging findings1 suggestive of chronic pancreatic damage d) Surgical or pancreatic biopsy specimen with histologic findings consistent with chronic pancreatitis Note: 1 Imaging findings suggestive of chronic pancreatitis/pancreatic damages include: 1) Ductal changes: irregular contour of the pancreatic ducts; intraductal filling defects; calculi; stricture or dilatation; 2) Parenchymal changes: generalized or focal enlargement, irregular contour, cavities, calcifications, heterogeneous echotexture. Imaging modalities may include ultrasound (US), contrast-enhanced computerized tomography (CT), Magnetic resonance imaging/Magnetic resonance cholangiopancreatography (MRI/MRCP), endoscopic ultrasonography (EUS) and endoscopic retrograde cholangiopancreatography (ERCP). 2 Exocrine pancreatic insufficiency (Not tested during an episode of acute pancreatitis). 1) Fecalelastase-1 monoclonal assay 4 weeks Fluid collection

±

Acute peripancreatic fluid collection (APFC)

Pancreatic pseudocyst (PPC)

±

Acute necrotic collection (ANC)

Walled-off necrosis (WON)

This classification can be summarised in Table 3. The most commonly used imaging modalities include abdominal ultrasound (US), contrast-enhanced computerized tomography (CT), magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), endoscopic ultrasonography (EUS) [6, 21, 22]. Ultrasound is the most commonly used imaging test in children, most likely due to its easy access, and lack of radiation and requirement for general anaesthesia. It was reportedly used in 50% to 79% of patients [6, 8, 21, 22]. It allows assessment of two major findings of acute pancreatitis, which are an increase pancreatic size and decreased pancreatic echogenicity, indicating oedema. In addition, it can identify complication of acute pancreatitis and its vascular component (venous thrombosis or pseudoaneurysm formation). US may be helpful for evaluating the biliary tree/gallbladder [47, 48]. Furthermore, it can identify other causes of acute abdominal pain such as appendicitis, intussusception or volvulus. Its overall sensitivity was reported from 25% up to 67% [6, 8, 21, 46, 49]. However, US has its limitations as it is operator dependant and its accuracy can be reduced by the overlying bowel gas and overweight children. Contrast-enhanced computer tomography (CT) is not recommended on initial presentation, unless the diagnosis is uncertain [44]. Its sensitivity was documented from 50 to 74%, which is superior to abdominal US to diagnose acute pancreatitis [6, 8, 18, 21, 46]. The main role for CT imaging is to assess the severity of acute pancreatitis and its complications, such as pancreatic necrosis. Despite this, CT is less commonly performed (35 to 46% of cases) compared to abdominal US [6, 8, 21, 22]. This is in part due to physicians, especially paediatrician, being hesitant in exposing children to radiation [50]. With MRI and MRCP, it is possible to investigate the aetiology of acute pancreatitis without exposing the child to any radiation or iodine contrast agent. However, depending of the age and maturity of the child, it may have to be performed under general anaesthesia. The efficacy of MRI is comparable to



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CT, and on the other hand, MRCP showed good correlation with endoscopic retrograde cholangiography or direct cholangiography for assessing the pancreaticobiliary system, particularly for anatomic anomalies. However, CT is more sensitive to diagnosis pancreatic pseudocyst (PPC) and is the modality of choice for traumatic pancreatitis [51]. The other limitations of the MRCP are related to the respiratory motion artefacts and low signal-to-noise ratio leading to dark and grainy images. Small calibre pancreaticobiliary duct may not be seen and nearby fluid-filled organs such the stomach or fluid collections might overlap the pancreatic duct, affecting its visibility. In addition, secretinenhanced MRCP, based on the principle that secretin stimulates pancreatic exocrine secretion, was postulated to increase the visualization of the pancreatic duct. In contrast to the majority of adult studies showing a benefit in using the secretin-enhanced MRCP, the only study in paediatric patients [52] did not report any significant improvement in the image quality in children. Endoscopic ultrasonography (EUS) can be used for diagnosis and therapeutic interventions and requires general anaesthesia. There is relatively little literature regarding its use in paediatrics. Several case series have described the procedure in children [53-55]. In 2009, Attila et al. [53] reported 40 interventions; ten of them were for pancreatitis. Recently, in 2015, Sheers et al. [55] described 52 procedures, among them 20 had pancreatitis. Both of the groups reported that the procedure was technically feasible and safe in children above 3 years (more than 15 kg). EUS is suggested to have a better capacity for visualizing common bile duct stones compared to US. However, additional studies are needed to establish the role of EUS in the management of acute pancreatitis.

5.2.5. Combination and Comparison of Serum Pancreatic Enzymes and Imaging Tests Using a retrospective cohort of children with acute pancreatitis, Coffey et al. [46] evaluated the diagnostic yield of serum pancreatic enzymes (amylase, lipase; >3 upper limit of normal) and imaging tests (US, CT). It was reported that lipase (93%) and CT (67%) had the highest diagnostic yield followed by amylase and US with 54% and 27% respectively. Furthermore, the diagnostic yield of combination of tests of at least one serum pancreatic enzyme level and one imaging test surpassed the use of any single test or the combination of serum amylase and lipase. In approximately half (55%) of all cases of acute pancreatitis associated with abnormal serum pancreatic enzyme levels (amylase or lipase), imaging tests (US or CT) were normal. In contrary, only


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5% of children with acute pancreatitis with abnormal imaging tests had normal serum pancreatic enzyme levels. In addition, there was poor agreement between the different tests. For example, when serum lipase was performed in association with an US, the tests agreed with each other (for a diagnosis of acute pancreatitis) in only 26% of cases. These findings suggest that if a test is negative in the context of a high probability of acute pancreatitis, clinician should not restrain to perform additional tests with a superior diagnostic yield.

6. MANAGEMENT AND INVESTIGATION The management of paediatric acute pancreatitis is complex and complicated by the multiple possible aetiologies, no/limited specific treatments and often unpredictable complications. Historically, the management was mainly based on adult practices which aimed to provide supportive care and limit pancreatic stimulation. There has recently been great interest in the management of adult acute pancreatitis, which has led to several modifications of treatment guidelines, with particular interests in early enteral feeding and early fluid resuscitation [44, 56, 57]. However, this is lacking in children and multicentre prospective studies are required to validate these interventions in children.

6.1. Severity The severity of acute pancreatitis varies and may range from a mild, selflimited disease to a severe multisystem disorder that can lead to death. For this reasons, it is crucial to establish, in the initial phase of the disease, the likelihood of a severe episode. This may lead to allocate better resource such as paediatric intensive care unit and to initiate appropriate treatment as early as possible. Before discussing predictive tools, a question should be considered: “What features characterise severe acute pancreatitis?” In the adult literature, the revised Atlanta classification in 2012 described the terminology and classification of severity of adult pancreatitis [41]. The terminology is important and includes transient organ failure (less than 48 hours), persistent organ failure (more than 48 hours), and local and systemic complications. The modified Marshall scoring system is used to describe organ dysfunction [58].



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Acute pancreatitis can be stratified into three categories: mild, moderately severe and severe pancreatitis. Firstly, mild acute pancreatitis is characterised by the absence of organ failure and local or systemic complication. Then, moderately severe acute pancreatitis is defined by the presence of either transient organ failure, local complication or systemic complications. Finally, severe acute pancreatitis is characterized by persistent organ failure (single or multiple) and usually have one or more local or systemic complications. It is worth considering that acute pancreatitis is a dynamic evolving condition. Consensus to establish classification of disease severity for children is required. The next question that has to be addressed: “Can the severity of the disease be predicted?”. Prognosis systems have been proposed and validated in adult acute pancreatitis: Ranson criteria [59, 60], Glasgow [61], modified Glasgow [62] and the Acute Physiology and Chronic Health Evaluation II Score (APACHEII) [63]. DeBanto et al. [20] developed a scoring system for the severity of paediatric acute pancreatitis. Nevertheless, subsequent studies suggested that the DeBanto scoring system may not be superior to the previous adult-based system. Recently, Coffey et al. [27] proposed an early predictor of severe paediatric acute pancreatitis. Children with serum lipase ≥7 times the upper limit of normal, within the 24 hours of presentation, were significantly more likely to develop a severe episode (OR 7.1, P < 0.001). A sensitivity of 85% and high negative predictive value of 89% were described, emphasising its utility to rule out severe paediatric acute pancreatitis.

6.2. Early Aggressive Intravenous Fluid Resuscitation In the management of adult acute pancreatitis, early fluid resuscitation has become widely supported [56, 57, 64]. Patients with acute pancreatitis may encounter hypovolaemia due to vomiting, reduced oral intake, third spacing of fluids and increased respiratory losses. In addition, oedema and microangiopathic effects can, in turn, decrease pancreatic blood flow and increased the cellular damages and necrosis [65]. Early aggressive intravenous hydration has been described to support micro- and macro-circulation, being most beneficial during the first 24-48 h. This was associated with a reduction in frequency of multi-organ failure [66] and mortality [67]. In 2013, The International Association of Pancreatology (IAP) and the American Pancreatic Association (APA) established recommendations [57] regarding the type of fluid and the rate of infusion. Both recommended the use of Ringer’s lactate


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for the initial fluid resuscitation [68]. The infusion rate should be between 5 to 10 ml/kg/h and should be used until resuscitation goals are reached, underlying the importance of not over-resuscitating. The same year, the American College of Gastroenterology published their recommendations [56]. Isotonic crystalloid solutions have also been advised for the initial management of acute pancreatitis, and Ringer’s lactate being the preferred solution. They propose a perfusion rate of 250-500 ml/h which is slightly bellow the recommendation of the IAP-APA previously described. However, no such recommendations have been established for the management of paediatric acute pancreatitis. Especially as children have a different proportions of fluid compartments and often less comorbidities than adults (e.g., congestive heart disease, chronic renal failure). Szabo et al. [69] evaluated whether the recommendations for treatment of acute pancreatitis in adults impact the outcome of paediatric acute pancreatitis. There was no statistical difference in the length of stay if the children received 1.5 to 2 times the maintenance IV fluid volume (Dextrose 5% Normal saline) in comparison of normal rate of infusion with Dextrose 5% and ½ Normal saline. Further studies are required to assess which IV fluid should be used in paediatric acute pancreatitis, the rate of infusion and which are the best markers to assess the hemodynamic state of children.

6.3. Gut Rest and Early Feeding The traditional approach of treatment with fasting (or “gut rest”) supported by intravenous fluids was based on the premise that this would minimise the activity or stimulation of an already inflamed pancreas. However, over the last decade, there is accumulating evidence that early enteral feeding of patients with acute pancreatitis may be beneficial. In a randomised controlled trial of fasting vs. immediate oral full diet in adult patients with mild acute pancreatitis, there were no differences in pain, and serum amylase and CRP levels but early feeding resulted in shorter hospital stay (4 vs. 6 days) [70]. In addition, Moreas et al. demonstrated that adults can start on a full solid diet without a need of a liquid or soft diet [71]. In a separate study of adults with severe acute pancreatitis, enteral nutrition within 48 hours after admission was associated with decreased mortality, infections and multi-organ failure [72]. Meta-analyses of adult acute pancreatitis studies have demonstrated that enteral nutrition within 48 hours of admission results in lower rates of multi-organ failure, less systemic infections and lower



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mortality compared to parenteral nutrition; these benefits were lost if enteral nutrition was commenced 48 hours after admission [73]. It has been suggested that enteral nutrition may better maintain integrity and function of intestinal mucosa and reduce gut-origin sepsis [74]. Mode of delivery of enteral nutrition has been previously assessed in adults with AP. Historically, nasojejunal feeds were felt to be safer than oral or nasogastric (NG) feeds in the setting of acute pancreatitis by avoiding the cephalic and gastric phases of pancreatic stimulation. However, nasojejunal feeding requires tube insertion under radiographic or endoscopic guidance, which exposes the child to radiation or general anaesthesia respectively. Furthermore, recent studies in adult acute pancreatitis suggest that oral or NG feeding with a low fat diet was safe and well-tolerated compared to nasojejunal feeding [75-78]. A group in Cincinnati, US [79] reported, in a retrospective study of 38 admissions with mild pancreatitis, that children may start feeds on admission, without increasing pain or the length of stay. The same group [69] reviewed 201 admissions before and after the implementation of adult-based recommendations. Their data suggest that early enteral nutrition may improve the outcome of paediatric acute pancreatitis (length of stay, rate of severe acute pancreatitis, and rate of transfer to intensive care unit). The group receiving enteral nutrition had a shorter length of stay, a reduced rate of severe acute pancreatitis and a reduced transfer rate to intensive care unit. Randomized controlled trials are needed to assess the administration of enteral feeding in children. A summary of these concepts is presented in Figure 1.

6.4. Other The management of acute pancreatitis should include pain control, treatment of the underlying condition and management of complications. Due to the sparse paediatric data on the treatment of specific aetiology and complications in paediatric acute pancreatitis, the management has been inferred from adult recommendations. In addition, in the recent review by Husain et al. [33], treatment recommendations regarding hyperlipidemia, hypercalemia, chronic renal failure, smoking exposure and medications were discussed. For biliary acute pancreatitis, in a case series examining the timing of cholecystectomy, Lin et


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al. [80] reported that early performance of cholecystectomy is safe. However, larger, prospective and controlled studies are required.

Figure 1. Early enteral feeding and early aggressive intravenous fluid resuscitation, illustrated concept.



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CONCLUSION Acute pancreatitis in children is a challenging clinical entity which incidence is approaching adult acute pancreatitis. In addition, as children are not “small adults,” this chapter tried to underline the specificity of this disease: clinical presentation, variety of aetiology, management. One of the most challenging aspects in studying this disease has been the relatively small number of affected children in each centre, necessitating the establishment of multicentre prospective studies to enhance our current understanding, in general. The search continues for a specific and effective treatment for acute pancreatitis. Novel therapies have been used in animal experiments, such as anti-secretory agents, protease inhibitors, probiotics, anti-inflammatory agents, anti-oxidants, and anti-TNF-α agents. Recently, in predicted severe acute pancreatitis in adults, pentoxifylline, a competitive nonselective phosphodiesterase inhibitor and reported modulator of TNF-α activity, was investigated in a randomized controlled double-blind trial [81]. There are many unanswered questions regarding the nutritional management of paediatric acute pancreatitis also, including “Which patients will benefit most from enteral feeding?”, “When can early enteral feeding start?”, and “Which enteral route is the optimal route?”. The knowledge of patients with genetic susceptibilities to pancreatitis is increasing and novel genetic mutations are expected to be discovered. However, for the majority of genetic cause of pancreatitis, this has not translated to specific therapies based on the underlying genetic mutation to date. Nonetheless, there is optimism that this will change in the future. For instance, alipogene tiparvovec [82, 83], the first gene therapy to be approved anywhere in the world, is an adeno-associated virus serotype 1-based gene therapy for adult patients with familial lipoprotein lipase (LPL) deficiency (LPLD) who suffer from severe or multiple attacks of acute pancreatitis (despite dietary interventions). The majority of LPLD cases are only diagnosed in adulthood. Additionally, therapies that specifically target the basic defect in the CFTR protein are also now available. Small molecules that either increase the number or the opening time (‘open probability’) of CFTR channels on the cell surface have now been identified and successfully trialled in patients with cystic fibrosis [84, 85]. The effects of these therapies on CFTR-related pancreatitis is unknown, including whether they increase or decrease the risks of developing acute pancreatitis [86, 87].


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BIOGRAPHICAL SKETCHES Name: (Keith) Chee Y. Ooi Affiliation: Discipline of Paediatrics, School of Women’s and Children’s Health, Faculty of Medicine, University of New South Wales, and Department of Gastroenterology, Sydney Children’s Hospital Randwick, Sydney, Australia



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Education: MBBS, Dip Paed, FRACP, PhD Address: Sydney Children’s Hospital Randwick, High Street, Randwick NSW 2031, Australia Research and Professional Experience: Dr Ooi is a Clinical Academic at the School of Women’s and Children’s Health, Medicine at University of New South Wales, Australia and a Paediatric Gastroenterologist at Sydney Children’s Hospitals Network. Dr Ooi’s area of interest and expertise is in pancreatic diseases in childhood, and in the spectrum of diseases related to defects in the CFTR gene, in particular genotype and phenotype correlations in CFTR-related pancreatitis.. Publications and Awards: https://research.unsw.edu.au/people/dr-keithooi

Name: Gilles Duvoisin Affiliation: Department of Gastroenterology, Sydney Children’s Hospital Randwick, Sydney, Australia Department of Paediatrics (Département Médico-Chirurgical de Pédiatrie), Lausanne University Hospital (CHUV), Lausanne, Switzerland Date of Birth: October 10th Education: MBBS (equivalent), Dip Paed (equivalent), MD, Master of advance studies in Health Organisation. Address: Sydney Children’s Hospital, High Street, Randwick NSW 2031 Australia Research and Professional Experience: Dr Duvoisin is the Fellow of Gastroenterology at the Sydney Children’s Hospital, Sydney, Australia. Dr Duvoisin areas of interest are general gastroenterology and paediatric pancreatitis. Dr Duvoisin is conducting several international multicentric studies in the field of Paediatric Gastroenterology. Dr Duvoisin obtained his MD in studying the field of risks of early-onset neonatal sepsis and the use of IV antibiotics.





Chapter 2

WALLED-OFF PANCREATIC NECROSIS V. Arteaga Peralta1, MD, PhD, A. A. Medina Velasco1, MD, R. de la Plaza Llamas1, MD, J. M. Ramia Angel1,*, MD, PhD, FACS, FRCS and J. D. Gonzales Aguilar1, MD 1

Hepato-Pancreato-Biliary Surgical Unit, Department of Surgery, Hospital Universitario de Guadalajara, Guadalajara, Spain

ABSTRACT The term “walled-off pancreatic necrosis” (WOPN) refers to the presence of a variable amount of necrotic tissue encapsulated within a wall of reactive tissue four weeks after acute pancreatitis. The diagnosis is based on radiological evidence of a well-defined wall around an intraor extra-pancreatic collection in a patient with a history of pancreatitis or pancreatic trauma, always including some necrotic tissue inside. Initial management is medical observation. Therapeutic action in patients WOPN is only recommended in the case of infection or in sterile WOPN causing clinical symptoms. The best treatment of WOPN is not clearly defined. WOPN patients should be treated by a multidisciplinary team. Several therapeutic options are available, including percutaneous **

E-mail: [email protected], Tlf: 0034-616292056.


34 V. Arteaga Peralta, A. A. Medina Velasco, R. de la Plaza Llamas et al. drainage, endoscopic drainage, transluminal endoscopic necrosectomy or retroperitoneal video-assisted surgery when necessary. Open surgery is reserved for patients who do not meet the criteria for endoscopic or percutaneous treatment, for complications of endoscopic or laparoscopic treatment, or when such treatments have failed. In this chapter we review the literature and present an update on the current state of WOPN.

WALLED-OFF PANCREATIC NECROSIS The term “walled-off pancreatic necrosis” (WOPN) was first used in 2005 to define a mixed solid-liquid collection with an appearance similar to a pancreatic pseudocyst, occurring four weeks after a severe acute pancreatitis [1-3]. We conducted an exhaustive review of the literature on the epidemiological, clinical, diagnostic and therapeutic aspects of WOPN. An unlimited PubMed search (updated on December 15, 2015) was performed using the following search strategy: (Walled off necrosis) OR (Walled off pancreatic necrosis) OR (WOPN). One hundred and sixty-four results were obtained, of which 26 were studied.

DEFINITION OF WOPN The Atlanta Classification for Acute Pancreatitis (AP) [4] was created in 1992, in an attempt to standardize and classify AP according to its severity and complications. This classification did not include WOPN. With time, some authors found that a subgroup of patients diagnosed with pancreatic pseudocyst had poor clinical outcomes for reasons that were unclear, and began to postulate the existence of a distinct entity. Today, we know that certain patients who were diagnosed with pseudocysts in fact had WOPN and therefore received inadequate treatment [5]. A review of the Atlanta Classification (6) was begun in 2007. It was completed after an international consensus meeting and published in the journal Gut in January 2013 [2, 7]. According to the revised classification, inflammatory accumulations of pancreatic fluid include acute peripancreatic fluid collections, pseudocysts, acute necrotic collections and WOPN [2, 7-9]. In this classification the WOPN is defined as an encapsulated collection of pancreatic necrosis that may


Walled-Off Pancreatic Necrosis

35

contain liquids and solids (with or without loculation) and develops after four weeks of the start of the AP, and can be located at either intra- or extrapancreatic levels [2].

PATHOLOGY The evolution of AP and the reasons for the subsequent formation of WOPN or pseudocyst remain unclear. The evolution and natural history of WOPN have not been definitively established [10, 11]. Several hypotheses have been put forward, proposing that the pathophysiology of WOPN depends on its location and on the pathological background. All authors agree that it is the result of a severe, intense inflammatory process [5, 9, 10, 12, 13]. According to location: 



Extra-pancreatic onset: AP with necrosis of peripancreatic tissue may progress to the liquefaction and subsequent organization and evolution of a walled-off accumulation of fluid that may communicate with the pancreatic duct [12]. Intra-pancreatic onset: A collection of walled-off fluid may result from parenchymal necrosis, which can lead to complete ductal disruption and leakage of pancreatic fluid [12].

According to pathological background: 



In chronic pancreatitis: A walled-off pancreatic fluid accumulation may be induced by an acute exacerbation of pancreatitis or by progressive ductal obstruction. The resulting increase in intraductal pressure can then induce ductal leakage, with the accumulation of a collection of peripancreatic liquid [5, 12]. In trauma: blunt or penetrating pancreatic trauma (including iatrogenic injury, such as pancreatic surgery) can directly alter the pancreatic duct and lead to the formation of a walled-off fluid collection [5-10].


36 V. Arteaga Peralta, A. A. Medina Velasco, R. de la Plaza Llamas et al.

EPIDEMIOLOGY In the literature, no significant differences in the frequency of WOPN formation have been reported between men and women [1, 14]. WOPN occurs in 1-9% of cases of necrotizing AP [1, 15-17]. Acute biliary pancreatitis is the most common cause of WOPN, representing 50-70% of cases. Other less common causes are alcohol abuse and idiopathic AP [1, 15, 18-19]. It is estimated that chronic pancreatitis may be the cause of WOPN in between 4% and 16% of cases [1, 20, 21]. The most common sites are the body and tail of the pancreas (80-92% of cases), and the spread to paracolic gutters is frequent [1, 18, 19]. The mean size is between 11 and 17 cm [1, 18, 19].

CLINICAL FEATURES After the first episode of AP around half of WOPN patients are asymptomatic, while the other half report symptoms such as abdominal pain, malaise, relapsing or recurrent pancreatitis, feeding intolerance or weight loss [1, 20]. These symptoms are mainly due to the mass effect created by the WOPN which produces abdominal pain, duodenal or biliary obstruction, fistula formation in adjacent viscera, pancreatic ascites and pleural effusion due to the disruption of the pancreatic duct, with fistula in the abdomen or chest, vascular occlusion or erosion/digestion of a vessel inside or adjacent to the WOPN which may cause pancreaticus hemosuccus [12]. The WOPN may also develop a spontaneous infection.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS OF WOPN WOPN consists of a variable amount of necrotic tissue encapsulated in a reactive tissue wall four weeks after AP. Radiological images show a welldefined wall around the intra- or extra-pancreatic collection in a patient with a history of pancreatitis or pancreatic trauma [11, 12]. The correct categorization of WOPN is the vital first step in the management of the condition. Differentiation from pseudocyst (on the grounds of the solid content in collections) is clinically relevant because each condition has its own prognosis and requires specific treatment strategies. Pseudocysts



37

usually have a better prognosis than WOPN and, if necessary, are easier to drain via endoscopy [5, 7]. Currently, computed tomography (CT) is considered the gold standard in the evaluation of AP images, not just because of its effectiveness but because of its speed and wide availability [7]. Intravenous iodinated contrast should be used to define the criteria and the therapeutic approach to WOPN, bearing in mind that the morphological changes provide guidance for treatment [7, 12]. On CT, the WOPN appears as a heterogeneous collection (mixture of fat, liquid and solid) generally without gas [1, 22, 23], with varying degrees of loculation and a well-defined capsule (Figure 1) [11, 12]. The presence of gas within a WOPN collection does not always indicate infection: it may be due to a stomach or duodenum fistula, in which case the collection may be sterile. When WOPN fistulizes to the colon there is always WOPN infection [1]. The accuracy of CT for the differential diagnosis between WOPN and pseudocyst is around 80% [1, 22].

Figure 1. CT: WOPN: mixed solid- liquid collection.

In some cases the use of magnetic resonance imaging (MRI) or ultrasound (US) may be required to confirm the diagnosis, since the presence of necrotic tissue may produce a variable attenuation on CT [24]. MRI is superior to CT for characterizing collections of pancreatic/peripancreatic liquid, and is an alternative to CT in situations in which the use of iodinated contrast is contraindicated. It also offers the advantage of avoiding ionizing radiation [5, 7, 25]. However, MRI has drawbacks of its own in the clinical setting: it takes


38 V. Arteaga Peralta, A. A. Medina Velasco, R. de la Plaza Llamas et al. more time, requires patient cooperation (e.g., immobility during prolonged periods or apnea), and is more expensive [7]. Some authors suggest that MRI can determine the need for necrosectomy or other interventions, because it allows the identification of solid waste inside a necrotic collection [5]. This is particularly relevant because the CT with contrast cannot reliably detect necrotic debris after an endoscopic or surgical procedure [5]. In addition, MRI cholangiopancreatography is highly sensitive for detecting cholelithiasis and for assisting in the selection of patients who may require endoscopic cholangiopancreatography [7]. Assessment of ductal pancreatic disease in all patients with WOPN is vital. If the transmural resolution of the collection is not accompanied by a correct diagnosis and treatment of the underlying ductal pathology, the risk of recurrence is high [11, 26]. Ductal disruption or stenosis must be ruled out. Currently, the least invasive technique for assessing the integrity of the pancreatic duct is secretin-enhanced pancreatic MRI [11]. Alternative diagnoses should be considered if the clinical history is not compatible with WOPN (i.e., acute and chronic pancreatitis, trauma, surgery), especially if radiological images presented intracystic septa and no signs of inflammation [12]. Among the conditions that may resemble WOPN are certain cystic neoplasms of the pancreas, cystic degeneration of a solid pancreatic tumor and rare non-neoplastic pancreatic cysts (e.g., retention cysts) [12]. When diagnosis is doubtful, it may be necessary to take a sample of fluid from the cyst [27], by ultrasound CT or endoscopy punction, and measure tumor markers (carcinoembryonal antigen –CEA- and carbohydrate antigen 19-9) and amylase. If there is communication with the pancreatic ductal system, the amylase level in the cyst fluid will be raised. WOPN has high amylase and low CEA, whereas intraductal papillary mucinous neoplasm and mucinous cystadenoma present high CEA and low amylase [5, 11-25, 27, 28]. If infection is suspected, Gram stain and culture [12] are recommended.

MANAGEMENT OF WOPN The latest Atlanta classification (mentioned above in the Definition of WOPN section) provides a detailed definition of the condition, but indications and guidelines for its management remain unclear. At present the literature is scarce and of little value, probably because WOPN is a recently defined entity. The discussions focus on the need to define the timing, duration and type of



39

treatment [1, 16, 21]. Several factors influence the choice of the initial approach for the treatment of pancreatic collections, such as the duration of the collection, anatomical factors, previous surgeries, and the state and the integrity of the pancreatic duct [11]. Thus, the ideal approach in the treatment of WOPN is unclear at present and in many cases a combination of different techniques is recommended if the decision is taken to intervene [11]. In around 70% of patients with necrotizing pancreatitis, the necrosis remains sterile. The vast majority of sterile pancreatic necrotic collections can be treated conservatively, and most of the collections resolve spontaneously [3, 29, 30]. However, there is no absolute time frame and intervention is based upon the severity of clinical symptoms and degree of organization. Several treatment options are available: percutaneous drainage, endoscopic drainage, laparoscopic drainage, surgical necrosectomy and combinations of techniques [1, 20, 21, 23]. WOPN was initially believed to be less amenable to endoscopic or percutaneous treatment because of non-viable solid components. More recently, there has been a paradigm shift in the management of WOPN toward less invasive approaches [18]. The goal of these techniques is to provide minimal access necrosectomy with success rates equivalent to those of open necrosectomy [18]. Intervention in patients with sterile WOPN is only indicated if they present clinical deterioration despite appropriate treatment, in the form of obstructive symptoms (constant abdominal pain, persistent vomiting, intestinal or biliary obstruction) due to the mass effect of the WOPN. In case of persistent symptoms such as pain and failure to thrive, intervention is more controversial and current guidelines suggest that it should be considered some eight weeks after onset [3, 23, 29, 30]. In severe cases, WOPN may fistulize into adjacent anatomical areas, compress or erode blood vessels, or cause portal vein thrombosis [1, 11, 23] and in these situations intervention is indicated. Splenic vein thrombosis is seen in 40% of cases [16]. Infected WOPN is almost always an indication for intervention [31]. Infection is suspected on the grounds of clinical criteria (sepsis), analytical criteria (increased acute phase reactants and positive blood cultures) and radiology results [1, 8, 29]. Fine needle aspiration to demonstrate infection is rarely necessary; in addition, it delays the intervention and may give rise to false negatives and secondary infection [29, 32, 33]. WOPN infection is suspected if gas is detected on CT [8, 29], although fistulization must be ruled out and so confirmation with positive cultures is necessary [1]. A third of patients have infected WOPN, sometimes due to percutaneous drainage or endoscopy treatment. There is no clear correlation between the symptoms and


40 V. Arteaga Peralta, A. A. Medina Velasco, R. de la Plaza Llamas et al. WOPN infection. The most commonly isolated bacteria in WOPN are E. coli, K. pneumoniae, E. faecalis and S. aureus [1, 14, 16]. Despite the enthusiasm surrounding new developments and minimally invasive techniques, we must not forget that conservative treatment with antibiotics can also produce satisfactory results in selected, clinically stable patients [27]. Therefore, since there is little evidence of results and treatments for WOPN, all the decisions regarding whether and when to operate should be discussed by a multidisciplinary team. Local experience and the location of the collection are probably the most important factors in determining the choice of approach.

THERAPEUTIC OPTIONS IN WOPN “Wait and See” “Wait and see” is an option in WOPN patients with minimal or no symptoms and without evidence of complications [12]. Peripancreatic fluid collections occur frequently in acute and chronic pancreatitis; fortunately, over 50% will resolve spontaneously and so watchful waiting is a good initial decision [3, 27, 29, 30].

Drainage Drainage is currently one of most widely used treatments. There are several options: percutaneous drainage, endoscopic drainage alone, endoscopic ultrasound-guided (ED-US) drainage, laparoscopic drainage and combinations. It is unclear which of these techniques should be offered to patients as initial therapy; no randomized controlled trials have been performed to date [12]. All these treatments present disadvantages. Surgical drainage is the most invasive approach, percutaneous drainage requires the maintenance of a prolonged external drainage with possible formation of an external pancreatic fistula, and endoscopic drainage often requires multiple procedures in order to function adequately [34]. At present, there is no single fully effective treatment.



41

Percutaneous Drainage Percutaneous drainage (PD) can be used as initial or complementary treatment. PD is not usually effective as definitive treatment [12, 23] although it is occasionally useful if the patient presents clinical, analytical and radiological improvement [31]. It can also be used as a bridging technique to decompress retroperitoneal fluid collections or if the intention is to continue with other more invasive treatments or to allow the stabilization of patients with sepsis before surgical debridement [12, 20, 21, 23, 32, 33, 35]. The main indications for PD are as a first step combined with endoscopic procedures and puncture in order to rule out infection [1, 15, 21]. Incomplete percutaneous drainage of the WOPN and the infection may lead to complications [12]. PD is likely to be more successful in patients without pancreatic duct pathology, since in patients with this condition it may predispose to a pancreaticocutaneous fistula [36]. The solid component of WOPN limits the management of patients with PD, and so the resolution rate is low [18, 21]. Percutaneous therapy alone has a worse success rate and prolonged length of stay, more complications, greater need for surgery and higher mortality compared with combined therapy [1, 23]. PD is only effective if multiple large drains are used with frequent upsizing, removal of solid debris, and aggressive irrigation. Endoscopic Drainage Endoscopic drainage (ED) of WOPN is one of the most frequently used therapeutic approaches. Among its multiple advantages, it uses the puncture route with the shortest distance between the gastrointestinal tract and the wall of the WOPN [8]. At experienced centers, virtually all pancreatic fluid collections in contact with the stomach or duodenum are treated through an endoscopic approach; surgical drainage procedures are reserved for unsuccessful ED attempts, recurrence of collections after ED, or when the criteria for ED or PD are not met [12]. ED is usually performed (with or without endoscopic necrosectomy) when the collection is technically accessible and when there is no evidence of hemorrhage [12]. The choice of a transpapillary or transmural approach depends on the size of the collection, its relationship with the pancreatic duct, its location, and underlying disease [11]. ED should be performed in patients under deep sedation or general anesthesia. The use of broad-spectrum antibiotics is recommended in those who were not previously receiving antibiotics for suspected infection. All procedures are performed with


42 V. Arteaga Peralta, A. A. Medina Velasco, R. de la Plaza Llamas et al. insufflation of carbon dioxide (CO2) since fatal gas embolism has been reported after ED [29]. ED is contraindicated in encapsulated collections located more than 1 cm from the gastrointestinal tract [11], and the presence of neovascularization due to portal hypertension is considered a relative contraindication [11, 37]. Factors that make ED more difficult to perform are:  



Abundant pancreatic necrosis in the collection to be drained [12]; this means that therapy with ED alone is insufficient to treat WOPN [38]. Peripancreatic necrosis extending into the paracolic gutter due to the lack of continuity with the central necrosis. Size alone is not considered a risk factor for failure [20, 39]. Currently it is debated whether the presence of a pseudoaneurysm in the WOPN is a contraindication for drainage. Some authors consider that if it is previously embolized, ED can be performed [11, 12].

In 1992, Grimm et al. first described endoscopic ultrasound-guided drainage (ED-US). Since then, conventional endoscopy has been shown to be inferior to ED-US in numerous studies and has been rendered obsolete for drainage of pancreatic collections [11, 37]. ED of pancreatic pseudocysts is simpler and more effective than draining of WOPN [11, 35]. The use of EDUS allows a better study of collections and may lead to a modification of management in 5%-9% of cases, either by providing an alternative diagnosis or by achieving resolution of the collection [11]. In ED-US, as we have stated, the puncture route is the shortest distance between the gastrointestinal tract and the cyst wall. The route can be chosen under US guidance, that is, under direct vision to facilitate the process [8, 40]. But it is essential that the puncture is in contact with the WOPN. The transgastric route is the most frequent access (73%-85%), but the duodenal route [1, 15, 18, 19] is also used. ED-US is safer than a simple endoscopic drainage because the cysts can be punctured after checking the absence of blood vessels with Doppler flow in the puncture area [8, 29]. This is especially useful in cases in which the WOPN presents associated portal hypertension with obstruction of the portal vein or splenic vein with secondary collateral circulation around the stomach. ED-US also allows direct endoscopic access inside the collection in order to perform debridement. Between three and six sessions may be needed to achieve complete debridement, which is inconvenient for patients [1, 12, 15, 16, 18, 23]. The response rate of infected WOPN to ED-US alone is currently reported to be roughly 40-50% [8].



43

ED-US presents complication rates between 1% and 18% [35], severe morbidity in 10-26% of cases (the most common being bleeding and perforation), mortality of 2.7% and the need for laparotomy in 0-23% [1, 15, 16, 19, 20, 21, 35]. Several devices have been used to improve the drainage of the necrotic content. WOPN drainage with plastic prostheses such as the ones used in treating pseudocysts may be insufficient, due to their small internal diameter [8]. Therefore, fully covered self-expanding metal stents combined with an axial stent with an internal pigtail are being used more and more frequently, achieving a success rate of 87.8% and an adverse event rate of 9.5% (Figure 2) [38]. The self-expanding metal stent with an inner diameter of 1 cm has a lower rate of occlusion and needs only a single insertion of the stent due to its large diameter, thus offering clear advantages over conventional stents. Some authors insert a double pigtail stent through the metal stent to prevent migration [27]. One of the criticisms of metal stents is their displacement when the cyst size decreases, which may cause the stent to touch the cyst wall and lead to bleeding [8]. Other technical options used to improve WOPN emptying are the placement of a single pigtail stent along with a nasocystic tube to allow irrigation of the cavity, an approach that has obtained good clinical outcomes [12, 23, 38], and percutaneous drainage of the WOPN without emptying, followed by ED using the standard technique for treating pseudocysts (double pigtail stents) or coated stents. In this way, the percutaneous route with large drains is used to irrigate the WOPN, while the stents allow necrotic debris to pass into the gastric cavity [12, 23]. In cases of multiloculated cysts, even without contact between the cavities, Mukai et al. described an efficient method called transluminal single gateway transcystic multiple drainages (SGTMD) for cases with sub-cavities located away from the gastrointestinal tract [8], although currently drainage with multiple internal passages is preferred [5, 19]. Another modification in these patients is the use of multiple transluminal stents in order to increase drainage in multiseptated necrotic collections. This can be done either by creating several transluminal pathways if the collections do not seem to communicate with each other, or by placing multiple double pigtail stents and a nasocystic catheter in different subcavities via the same route.


44 V. Arteaga Peralta, A. A. Medina Velasco, R. de la Plaza Llamas et al. This method has proved superior to the conventional technique with a single stent and can be combined with direct necrosectomy. In some cases, it may avoid the need for endoscopic debridement or open surgery [8, 27, 29, 37]. A potential complication whenever any type of stent is used is the possibility of migration, which has an incidence of between 1% and 2% [19]. External migration merely requires repetition of the procedure, but internal migration of the stent represents a serious complication and a major therapeutic challenge. It is advisable to remove the stent as early as possible to avoid closure of the previously created fistula [11].

Figure 2. CT: WOPN treated by endoscopic ultrasound guided drainage (prosthesis and pigtail).

Endoscopic Transluminal Necrosectomy Currently, it is very difficult to predict the cases of WOPN that can be managed efficiently and safely without necrosectomy. In cases of large anfractuous collections with considerable amounts of necrosis, necrosectomy is generally required in order to induce the healing process. Necrosectomy is usually performed when the initial endoscopic drainage has not been effective [11]. Classically, necrosectomy was performed by surgery, but in 2000 Seifert described a new concept termed endoscopic transluminal necrosectomy (ETN), developed as a minimally invasive alternative to surgical treatment [41]. ETN requires the creation of a large caliber transmural orifice between the gastric or duodenal area and the lumen of the cyst to allow passage of a standard endoscope into the cystic cavity and thus remove the pancreatic necrosis through the communication made. ETN has proved more effective for



45

WOPN than simple ED [1, 15, 18], and is successful in around 90% of cases, compared with 50% when standard ED is used [1, 15, 18, 19, 20]. Conventional endoscopic snares and dormia baskets can be used to carefully extract necrotic debris from the stomach or duodenum. An average of four repeated endoscopic sessions are needed to completely mobilize the necrotic tissue. Complications such as perforation (4%) and bleeding (18%) may occur during ETN [27, 29, 42]. In the GEPARD study, a multicenter study of ETN after acute pancreatitis with long-term follow-up, a procedurerelated adverse event rate of 26% was observed, with a mortality rate of 2.1% [5, 28]. It is recommended that ETN be performed two or three days after first draining in order to evaluate the adhesion of the cyst wall to the stomach wall, since performance of necrosectomy after drainage increases the risk of the stent migrating into the peritoneal cavity and causing a perforation. If clinical findings improve with drainage alone there is no need for necrosectomy, and the most common complication of ETN (bleeding caused by balloon dilatation of the fistula) is avoided. The delay in dilatation reduces the risk of bleeding [8, 29]. A retrospective multicenter study published in 2011 of 104 symptomatic patients with WOPN treated with ETN recorded successful resolution in 95 of 104 patients (91%), with a mean resolution time of 4.1 months. BMI> 32 was a risk factor for failure of the procedure. The team concluded that ETN is effective for treating WOPN and has an acceptable safety profile [15, 18]. A systematic review published in 2014 also showed ETN to be a safe and effective minimally invasive treatment; over 80% of patients were successfully treated with endoscopic management and rates of mortality and complications were 6% and 36% respectively. However, most of the studies included were retrospective and the methodological quality was moderate to low [42]. Another meta-analysis and systematic review conducted in 2014 also aimed to assess the value of ETN for treating WOPN. In the pooled analysis, ETN emerged as an efficient procedure with a successful resolution rate of 81.8% and a mean of four procedures per patient. Significant complications such as bleeding, perforation of organs and sepsis were reported in 21.3% of cases. Mean hospital stay after ETN was 32.85 days. Despite the success rate mentioned above, surgery could not be avoided in 13%. It appears that the sickest patients were the ones who most frequently needed surgery. One limitation of this review, as the authors acknowledged, was that most studies included were retrospective case series with small sample sizes. There were also significant technical differences between the studies [39].


46 V. Arteaga Peralta, A. A. Medina Velasco, R. de la Plaza Llamas et al. ETN is considered successful when the fever and inflammatory response recede. Endoscopic examination shows complete removal of necrotic tissue and good exposure of granulation tissue. By contrast, in cases where it is difficult to control the infection even with necrosectomy, ETN is unlikely to be sufficient [8]. It has been suggested that infection after ETN is due to the occlusion of the stent caused by solid debris and subsequent bacterial colonization.

Surgery Necrosectomy via laparotomy has been the standard treatment of infected necrosis for decades. The classical approach is to reach the pancreas located in the retroperitoneum via a laparotomy, and to remove the necrotic tissue by blunt dissection. The aim is to preserve as much viable pancreatic tissue as possible, thereby minimizing the risk of postoperative bleeding or pancreatic fistula. Several surgical techniques have been applied to perform necroscopy: open surgery, closed surgery, planned reoperation or continuous postoperative lavage [1, 16, 20, 21, 31]. However, the complication rate (25-55%) and mortality (5-14%) are high [8, 23]. Initially, these were the necrosectomy techniques applied in WOPN, but today techniques similar to the ones performed via endoscopic approaches are gaining ground. For example, open surgical drainage can be accomplished via cyst gastrostomy, cystenterostomy (direct drainage or via a Roux limb) or in selected cases by resection [12]. Open surgery is reserved for those patients who do not meet the criteria for percutaneous or endoscopic treatment [35], with complications of endoscopic and/or laparoscopic treatment, or in cases in which these treatments have failed [1, 20, 21]. In a bid to reduce the morbidity and mortality rates recorded with laparotomy, several minimally invasive approaches have been developed. For example, laparoscopic necrosectomy is progressively replacing classical necrosectomy for both AP and WOPN. Laparoscopic approaches for necrosectomy can be classified according to the access route (transperitoneal, retroperitoneal or transgastric) [1, 12, 35] and the equipment used (endoscopy, laparoscopy or nephroscopy). Minimally invasive surgical necrosectomy is technically feasible and the results are acceptable [1, 16, 43]. The main stumbling block of the laparoscopic approach is the possibility of incomplete or unsuccessful drainage [1, 21].



47

The most commonly used technique is a hybrid approach known as videoassisted retroperitoneal debridement (VARD). First, the collection is drained percutaneously. Then, via a 5 cm subcostal incision in the left side near the exit point of the PD, the drainage is followed closely towards the collection. After opening the collection and removing the liquid and solid debris, a 0degree laparoscopic camera is introduced into the necrotic cavity. The camera is inserted through a single laparoscopic port, which is placed directly through the incision. Carbon dioxide is infused through the percutaneous drain to inflate the cavity. After surgery, continuous lavage is started using two largediameter drains. This technique allows vigorous debridement of the necrotic cavity and usually requires only a single procedure [8, 31]. The PANTER (Patients with acute necrotizing pancreatitis) study of 88 patients compared primary necrosectomy by laparotomy vs the step-up approach (percutaneous drainage and VARD if required). The study found a significantly lower rate of the composite endpoint of major morbidity or death in the step-up group (40% vs 69%; p = 0.006). New-onset multiple organ failure was also significantly less frequent in the step-up group (12% vs 40%; p = 0.002) [30, 31]. The PENGUIN (Pancreatitis endoscopic transgastric vs Primary necrosectomy in patients with Infected Pancreatic Necrosis) trial in 2012 compared endoscopic necrosectomy vs surgical necrosectomy (VARD and laparotomy) in 20 patients (ten in each arm). The points evaluated were the pro-inflammatory response after the procedure, as measured by IL-6 levels, the clinical endpoints such as major complications (new onset of multiple organ failure, intra-abdominal bleeding, enterocutaneous fistula, or pancreatic fistula) or death. The study found that ETN reduces IL-6 levels compared with surgical necrosectomy (p = 0.004). The clinical endpoint occurred less frequently after endoscopic necrosectomy (20% vs 80% in the surgical necrosectomy). Endoscopic necrosectomy did not cause new onset multiple organ failure (0% vs 50%), and reduced the rate of pancreatic fistula (10% vs 70%) [44]. A multicenter randomized controlled trial (the TENSION trial) is currently underway comparing the endoscopic approach (ETN) and minimally invasive surgical approach after performing PD in both cases. The variables studied are deaths, major complications, hospital stay and associated costs in patients with infected necrotizing pancreatitis [45]. At the time of writing, neither method has demonstrated superiority. Although these studies are specific to AP rather than to WOPN, we feel that they are likely to establish the bases for future therapeutic approaches.


48 V. Arteaga Peralta, A. A. Medina Velasco, R. de la Plaza Llamas et al.

FOLLOW-UP The presence of a multidisciplinary medical team is essential in the treatment of WOPN. Only a multidisciplinary team including a surgeon, gastroenterologist, radiologist and intensivist can provide proper care at all stages of the disease. Hospitals lacking a team of this kind should promptly transfer the patient to another facility [31]. Patients with WOPN can be best treated applying a multimodal approach and follow-up, including a combination of ETN, PD and VARD when necessary. Several authors recommend radiological monitoring with CT or MRI repeated every three to six months, or sooner if the patient develops symptoms such as abdominal pain, chills, jaundice, early satiety, or fever [12].

THE FUTURE Some authors suggest that the amount of necrosis is a major predictor of successful outcome for the drainage of a pancreatic collection, and classify these collections according to the percentage of necrotic waste in their composition or as indicated by radiological images [35]. They propose a classification system according to the necrotic intracystic component: less than 20%, between 20% and 50%, and more than 50%. For collections with 48 h. In SAP local and systemic complications are present (accumulation of peripancreatic fluid, and sterile or infected pancreatic and peripancreatic necrosis). Early diagnosis should be managed aggressively in order to prevent multiple, lethal, organ failure. There are many options to support the precise diagnosis, from the classical methods, to more advanced methods among them advances in imaging through tomographic slices, with or without contrast, and magnetic resonance imaging. In the actual management of SAP, vigorous administration of fluids continues to predominate. Early artificial enteral nutrition and the administration of select antibiotics help of infected AP. Nevertheless, some interesting alternative treatments are emerging that could offer better results in selected patients than traditional ones: analgesia and peridural anesthesia. Drotrecogin alpha (activated), through its anti-thrombotic, antiinflammatory and pro-fibrinolytic properties, is capable of reducing mortality in SAP and severe sepsis. The recombinant human soluble thrombomodulin emerges as an alternative in the prevention and development of walled-off pancreatic necrosis in SAP. Among emerging surgical therapies is the management of sterile or infected pancreatic necrosis. Peritoneal lavage of different types continues to be a useful tool. The approach to pancreatic necrosis through the minimally invasive or video-assisted ‘Step up’ approach emerges as an attractive, viable alternative. The bio-technological system of vacuum-assisted closure (VAC) as an aid to programmed open necrosectomy, seems to offer additional benefits, and the combination of Drotrecogin alpha (activated) plus VAC could offer even better results in decreasing mortality and hospital stays in SAP. However, all the methodological and therapeutic advances in SAP have no significant impact in reducing mortality of patients affected.

Keywords: acute pancreatitis, severe acute pancreatitis, drotrecogin alpha activated, vacuum-assisted closure system

INTRODUCTION Acute pancreatitis (AP) is the inflammatory process secondary to damage of the pancreatic acinar cells characterized by activation of the pancreatic


Severe Acute Pancreatitis: Since the Classical

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enzymes, which causes auto-digestion of the pancreatic parenchyma [1]. In all cases of AP, the triggered cause in 60-80% in developed countries is attributed to biliary illnesses or alcohol abuse. The incidence of idiopathic pancreatitis emerges as an etiology more and more frequently, seemingly due to the increase in rates of morbid obesity [1, 2], Although the incidence of AP continues to increase, the mortality rate remains the same [3]. Males and females are similarly affected despite alcohol abuse being more common in men and biliary illnesses more common in women [4]. The Atlanta classification describes AP as mild, moderate, and severe [5]. 





Mild presentation (Interstitial edematous pancreatitis) is 80-90% more frequent, is self-limited, and resolves without serious complications in about one week [3]. It is characterized by the absence of pancreatic or peripancreatic necrosis and mortality is rare [6]. In moderate AP, there are local complications (collection of peripancreatic fluid, peripancreatic necrosis) or systemic complications (exacerbation of the pre-existing illness), and organ failure is transient 48 h, with presence of local and systemic complications; accumulation of peripancreatic fluid, pancreatic and peripancreatic necrosis (sterile or infected); and pseudocysts and necrosis (sterile or infected) can appear. SAP has a mortality rate from 5-35% [7]. Early diagnosis and classification of its severity should be managed aggressively in order to prevent lethal multiple organ failure (MOF) [8]. The development of infected necrosis indicates severity and is considered the primary cause of death [9].

Acute pancreatitis has a biphasic clinical course. The first 1-2 weeks after the onset of symptoms are characterized by the appearance of the systemic inflammatory response syndrome (SIRS). The SIRS is a direct result of serious systemic inflammation, seemingly unrelated to the infection. Among complications, infections with bacteremia are frequently associated with the use of mechanical ventilators [10]. Early organ failure presents approximately 2 days after hospitalization and affects all the organs, but can be present from the outset. Fatal cases of AP are related to MOF and if infected necrosis occurs about 43% of patients die. After 1-2 weeks evolution, SAP presents with the


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compensatory anti-inflammatory response syndrome (CARS), which is related to infection and infected necrosis [11]. The patient’s response to management can vary depending on the seriousness of the AP; and there can improvement with treatment measures or they can present with early onset MOF with deterioration about 3-4 weeks after its onset, due to infected necrosis. With early organ failure that does not improve after 2-3 weeks of intensive therapy, or with the appearance of gas bubbles, it is recommended to confirm or discard infection in order to determine the need for antibiotic therapy or some type of interventional procedure [12].

COMPLICATIONS OF SAP Infected Necrotic Pancreatitis Infection in pancreatic and peripancreatic necrosis is unusual during the first week after the episode of necrotizing pancreatitis demonstrating a greater increase in peripancreatic fat. It is speculated that the infection occurs when there are focal air bubbles in the pancreas and/or peripancreatic tissues [13]. Infection of the pancreatic necrosis occurs early (20 mmHg with signs of MOF. While the optimal treatment strategy for abdominal compartmental syndrome is still not well-defined, percutaneous drainage could be useful as an initial step in the presence of free intraabdominal fluid. If this does not lead to immediate clinical improvement or if liquid is not present on the left side, the next recommended step is the performance of decompressive laparotomy. The majority of authors advise against exploring the pancreas during decompression of the compartmental syndrome, because it is too early to remove the necrosis safely, and there is the risk of infecting the developing, yet likely still sterile at that stage, necrosis. An interesting alternative after decompressive laparotomy, could be the application of the vacuum-assisted closure system (VAC) with exchanges every 48-72 h [18]. Figure 1A

Figure 1. Severe Acute Pancreatitis. 1A) Vacuum-assisted closure system (VAC) applied to a patient with SAP with compartmental syndrome. 1B) and 1C) Observation of removal of necrotic pancreatic tissue. Previously, the purulent necrotic peripancreatic material was drained. 1D) and 1E) Show the application of the VAC system; and 1F) Time lapse in the management with the VAC system.


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Walled-Off Pancreatic Necrosis (WOPN) Severe acute pancreatitis can complicate with WOPN in its late phase (minimum of 4 weeks after onset of the illness) [19]. Because the morphological changes occur late in the course of necrotizing AP, WOPN consists of a circumscribed area that contains the remains of parts of the pancreas and necrotic fluid, stemming from some necrotic area. The translation of the term originally proposed in the English language can cause initial controversy; however, the radiological concept includes defined, welldemonstrated changes that are described by the term ‘muralled-off pancreatic necrosis’ that stems from the expression ‘In wall-off,’ which means building a mural around a determined space; in this case in pancreas [20].

Pancreatic Pseudocysts Defined as a round collection or ovoid form, circumscribed and homogenous, with liquid rich in amylase, which develops late in the course of AP (About 4 weeks after the initial event), and does not contain any sign of necrosis or solid material within it. They are surrounded by a capsule of nonepithelialized granular tissue, and are found in intra or extra-pancreatic spaces [36]. Pseudocysts consist of the natural development of collections of peripancreatic fluid, which persist for >4 weeks and occur in 10-20% of patients. The term ‘pseudocyst’ is used for the majority of cases of collections of extra-pancreatic fluids. Visualization of the walls of the pseudocyst (Capsule) in images is possible depending on the wall’s thickness, and the observation of a circumscribed accumulation of fluid should always be seen. Pseudocysts can disappear spontaneously or develop complications such as bleeding and infection. ‘Pancreatic abscess’ is the term adopted by the Atlanta classification that is actually no longer in use and should be replaced by ‘infected pseudocyst’ [21].

METHODS Initial clinical manifestations of AP are based on intense abdominal pain, serum amylase or lipase ≥3 times higher than normal and after 72-96 h of evolution, and findings of AP on computed tomography (CT) with the presence of relevant morphological changes. It is recommended that the group



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of patients with a high risk of suffering SAP benefit from aggressive fluid replacement, broad vigilance for the timely detection of organ failure, timely adequate administration of antibiotics, and specific therapeutic procedures such as endoscopic sphincterotomy and interventional radiology [22].

Clinical Evaluation There are diverse methods to evaluate for AP. Individual parameters such as age, presence of pleural effusion, obesity; levels of blood urea nitrogen, creatinine, hematocrit; C-reactive protein and procalcitonin, have been described [23]. There are also multiple parameters that evaluate severity of the pancreatic and systemic damage, among which are found: the Ranson’s criteria, the SIRS, the Glasgow scale, and the Acute Physiology and Chronic Health Evaluation II (APACHE II). Liver enzymes can be elevated; in particular the alanine aminotransferase (ALT), where levels >150 IU/L tend to be a substitute marker for pancreatitis due to gallstones, with a positive predictive value of 95%. Findings of AST >100 U/L also seem to be useful [24]. The Bedside Index of Severity in Acute Pancreatitis (BISAP score) is the newest predictive scoring system and is a reliable tool to identify AP patients who have a high risk of unfavorable outcomes, in comparison with the classical Ranson’s criteria and the APACHE II classification system. The BISAP index was proposed as a simple, precise method to early identify patients with high risk of hospital mortality [25, 26]. It primarily evaluates levels of blood urea nitrogen >25 mg/dL, impairment of mental state, the development of SIRS, age >60 years, and the presence of pleural effusion. The BISAP score is 95% specific but 51% sensitive in predicting mortality due to SAP [27, 28]. The prognostic utility of the different clinical and radiological scoring systems in AP is compatible with the BISAP score because it has the highest accuracy to predict premature MOF and mortality [29, 30].

Ranson’s Criteria In the ‘Seventies’ of the past century Ranson’s criteria was designed. This classification system, upon hospitalization, evaluates: age >55 years, white blood cell count >16,000/mm3, blood glucose >200 mg/100 mL; serum lactic dehydrogenase >350 IU/L, and AST >250 IU/100 mL; and, after the first 48 h:


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hematocrit 5 mg/100 mL, serum calcium 4 mq/dL, and ~>6000 mL of fluid requirements [31]. Recently, a retrospective analysis was published on 21 patients with SAP, where the Ranson’s score had a global sensitivity of 75%, a specificity of 77%, a positive predictive value (PPV) of 49%, and a negative predictive value (NPV) of 91%; outstanding in the high rate of false positives that SAP doesn’t have [32]. For the APACHE II classification, an 81% sensitivity, 65.7% specificity, PPV of 26.2%, and NPV of 95.8% were reported [22]. It must be emphasized that a definitive consensus does not exist on which scoring system should be used. Recent norms suggest that existing scoring systems have limited value because they all have a good NPV but a low PPV. Nonetheless, it is recommended to complete the evaluation on all patients with pancreatitis and to stratify or categorize them as high or low risk, since the majority of scoring systems require 48 h for the exact score, and the systems based in CT are also inaccurate in the early phase of the illness because the necrosis becomes evident 48 h after the onset of the symptomatology [33]. Table 1 shows the sensitivity, specificity, and the positive and negative predictive values of some evaluation systems. Table 1. Evaluation Methods in Severe Acute Pancreatitis. Shows the sensitivity, specificity, positive predictive value, and negative predictive value in SAP. The data were obtained from various bibliographic references, the majority of which are found in the primary text Sensitivity

Specificity

Ranson ALT

75%

77%

CT MR BISAP APACHE II

87% 83% 51% 81%

100% [34] 91% [50] 91% [20, 21] 65.7%

Predictive value (+) 49% 95% Gallstones [17]

40.48% 26.2%

CTSI

Predictive value (-) 91% [25]

96.23% 95.8% [26]

100% Pancreatic 100% Pancreatic necrosis necrosis CRP 86% 87% 75% 93% ALT: alanine-aminotransferase; CT: Computed Tomography; MR: Magnetic Resonance; BISAP: Bedside index for severity in acute pancreatitis; APACHE-II, Acute physiology and chronic health evaluation-II, CTSI: Computed tomography severity index; CRP: C-reactive protein, measured after 24 h.



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Ultrasound Ultrasound is the imaging method that is most relevant at the affliction’s onset to detect sediment or gallstones in the gallbladder or common bile duct. The diagnosis of biliary pancreatitis is based in the formation of images, but can also be made in absence of them when the common bile duct is >10 mm in patients >75 years of age. When the cause of AP cannot be determined, ultrasound or endoscopic echography is recommended as a first-line to evaluate occult microlithiasis in 57% of cases, neoplasia, or chronic pancreatitis [34].

Endoscopic Retrograde Cholangeo-Pancreatography (ERCP) with Sphincterotomy Is the endoscopic procedure recommended in the case of lithiasic illness, which can reveal sediment or gallstones in the gallbladder or the common bile duct. Patients with biliary pancreatitis who present with cholangitis or stones in the bile duct should be subjected to ERCP within the first 24 h from the onset of pancreatitis. However, the evidence reported in a recent meta-analysis did not demonstrate any benefit from ERCP in the evolution of SAP [35].

Radiological Classification Systems The diagnosis and classification of AP is aided by CT or magnetic resonance (MR), ideally performed 72 h after the appearance of symptoms, with the objective of achieving the most accurate classification of the pancreatic necrosis. Extension of the necrosis correlates well with the incidence of infected necrosis, MOF, need for debridement, morbidity, and mortality. Characteristics of the CT images in AP include diffuse or focal amplification of the pancreas, the peripancreatic fat, thickening of the peripancreatic fascia, and the presence of fluids [36]. Normal assessment of the pancreas by CT is classified because it is surrounded by fat in the transverse section. It has a homogeneous attenuation and is identified by its relationship to the superior mesenteric artery and the duodenum [37]. Normal pancreatic parenchyma have ~50-80 Hounsfield Units (HU) [38]. Computed tomography has an 87% sensitivity and 100% specificity in the detection of pancreatic necrosis [39]. The role that CT plays in predicting SAP has been


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evaluated by different methods such as the Balthazar score categorized by grades: a) Grade A, normal; Grade B, enlargement of the pancreas; Grade C, peripancreatic inflammation; Grade D, accumulation of fluid; and Grade E, ≥2 fluid collections with or without gas bubbles [40]. This assessment system is based on size, shape, and density of the pancreatic anomalies and of the peripancreatic tissue, to predict severity of the AP [41]. In 1990, Balthazar validated the severity of AP with the Computed Tomography Severity Index (CTSI). This system combines the initial classification system (1985) with the presence and extension of pancreatic necrosis. This severity index has more prognostic accuracy than the previous scoring method, but it has some limitations since the score does not incorporate organ failure, additional complications of the pancreatic parenchyma or vascular/peripancreatic vascular complications, and correlation with the final outcome. CT alone should be used for the initial assessment if doubts exist regarding the clinical diagnosis or normal level of lipase/amylase. Doubt in the clinical diagnosis can be due to the pain not being typical, or if some alternative diagnosis (suspected intestinal perforation or ischemia) should be excluded [42, 43, 44]. The Modified Computed Tomography Severity Index (MCTSI) developed by Mortele, et al., [45] is a system that is easy to calculate and reproduce, and correlates more widely with the appearance of infection, MOF, the necessity for percutaneous surgical intervention, duration of hospital stay, and mortality, than the CTSI [46]. The MCTSI, apart from being more accurate than the CTSI, has a stronger statistical correlation than the clinical outcome [47]. The Contrast Enhanced Computed Tomography index (CECT) is considered the gold standard in imaging modality for evaluating patients with AP [48]. The role in the formation of images is not only for diagnosing AP, but demonstrates the presence and extension of pancreatic necrosis and complications. The ideal time to obtain the CECT is 48-72 h after the appearance of the acute attack, since the possibilities of finding necrotizing pancreatitis increases [49]. The ideal moment to repeat CT imaging is indicated when the clinical picture changes significantly, which can occur with the appearance of fever, decrease in hematocrit, or signs of sepsis. The CT is an indispensible complement to guide the needle and place a catheter in the bed of the pancreas, as well as monitoring the success of treatment in patients who have been subjected to percutaneous intervention, endoscopy, or surgery [50]. On the other hand, the usefulness of the Extra-pancreatic Inflammation on Computed Tomography (EPIC) index and the Renal Rim Sign is unclear because these scoring systems have not been compared to the conventional radiological scoring systems such as the CTSI, CECT, and the MCTSI [51].



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Magnetic Resonance Magnetic resonance (MR) is often reserved for the detection of choledocholithiasis not seen on CT, and to outline the anatomy of the pancreatic duct. Although CT continues to be ideal for pancreatic necrosis in the majority of institutions, some groups prefer MR [52]. The advantages of MR are that it doesn’t produce ionizing radiation and it has a grand capacity to show the bile ducts in high resolution, which makes it ideal for pregnant patients. MR is recommended in patients with poor renal function who should not receive contrast mediums (typically with GFR 20 litres intravenously in the first 24 h [64]. Fluid replenishment in SAP is meant to replace blood volume deficiency, stabilize capillary permeability, maintain the intestinal wall function, and moderate the inflammatory response [65]. The success of this therapy is related to improving perfusion of the pancreas [66]. Since hypovolemia is an early trait of AP, the type of solution recommended for initial fluid management has been theme for debate for many years. However, fluid replacement without restrictions should be avoided because it can be damaging. Current recommendations don’t specify a precise strategy for the administration of fluids in AP [67].

Analgesia Since pain in AP is intense, opioids are widely used; although there is some uncertainty about secondary effects through the induction of spasms to the ampulla of Vater that cause additional pain. Epidural anaesthesia is the most effective pain control method, and it has a beneficial effect on the course of the illness in improving pancreatic microcirculation and tissue oxygenation [68]. However, its use is limited when there are coagulation disturbances and systemic inflammation [69].

Somatostatin Somatostatin is a peptide hormone primarily produced in the gastrointestinal tract that has an inhibitory effect on gastric emptying, intestinal motility, and intestinal blood flow. Also, somatostatin strongly inhibits the production of pancreatic enzymes (Fundamental basis of its use in AP). The analogue of somatostatin is octreotide [70]. Despite the fact that there have been clinical and experimental trials with somatostatin and octreotide, the results have not shown any effect on the course of the illness, seemingly


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because the majority of clinical trials include few patients with SAP [71]. Still, the biggest and best study performed is a randomized, multi-centric, prospective study from Germany, with 302 patients with moderate to SAP from 32 hospitals (Where octreotide or placebo were administered), which had results that showed no significant differences with respect to mortality [72].

Corticosteroids Corticosteroids are potent anti-inflammatories used in diverse inflammatory illnesses. It must be considered that there are reports of cases where AP is caused by an adverse effect of steroids, without a definitive, wellestablished relationship [73]. Circulating pro-inflammatory cytokines take on a predominant role in the progression of SAP on activating the vascular endothelium, the migration of leukocytes, and increasing the systemic capillary permeability [74]. Inhibition of the pro-inflammatory cytokines through the use of corticosteroids could be beneficial in reducing hospital stay, the need for surgical intervention, and mortality rate. The actual effects of corticosteroids are still unclear and these should be investigated in welldesigned studies with adequate time, size, and follow-up [75].

Prophylactic Antibiotics The role of antibiotics is determined by the presence of infected necrosis. The use of prophylactic antibiotics has not been demonstrated to offer beneficial effects in the prevention of infection in pancreatic necrosis, although this strategy is still widely used in clinical practice. In nearly all trials published systematic problems exist. Prospective, randomized controlled trials with the exact definition of the illness that justifies the use of antibiotics are required. Infections of the pancreas are diagnosed by fine-needle aspiration (FNA) guided by imaging and through the cultivation of samples obtained through open surgical intervention [15].

Meropenem Meropenem 1g is administered by intravenous infusion over 15-30 min, every 8 h. The infusion bottles and drip regulators should be opaque in color.



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A minimum administration for 7 days up to a maximum of 21 days is recommended. The recommended duration is 14 days. Additional well-carriedout studies that explore the benefits of antibiotic prophylaxis in SAP are required; taking into account the adverse effects, variable duration, and if the outcome of the infection is related to the etiology [76].

Drotrecogin Alpha (Activated) Drotecogin alpha (activated), also known as Xigris, is an analogue of the glycoprotein of the endogenous human protein C; is produced by recombinant DNA technology, has 55 kDa of molecular weight, has anti-thrombotic, antiinflammatory, and fibrinolytic properties; and is capable of reducing mortality in SAP and severe sepsis. Plasma concentration levels are 28 ± 9 L/h, and it has a kinetic biphasic elimination (rapid phase of 13 min and slow of 1.6 h); and an infusion of 12-30 mg/kg/h is recommended to maintain stable plasma concentrations 2 h after the onset of infusion. The mechanism by which Drotrecogin alpha (activated) improves survival in patients with SAP or sepsis has not yet been entirely determined [77]. This recombinant human protein C has been the object of controversy since 2001, when it became the first biological agent approved for the treatment of severe sepsis and septic shock. The PROWESS study demonstrated an absolute reduction of 6.1% in mortality at 28 days. This medication was taken off of the market in 2011 despite observational trials having consistently demonstrated a benefit on mortality. In an observational study published in 2013, where 6 patients with SAP were subjected to open necrosectomy for infected pancreatitis every 48 h, plus the VAC system, plus Drotrecogin alpha (activated) with an infusion of 12-30 µg/Kg/h and a stable plasma concentration 2 h after the onset of the infusion; an improvement in survival was found in 83.4% compared to 70.9% when they were subjected to open necrosectomy plus VAC; or 37.5% when only open necrosectomy was performed [78]. Even though it was a study that included a small sample size, the results were uplifting. And, in the case that the product would be available it would be convenient to perform controlled clinical trials. However, in another study with 6 patients, it was reported that treatment with Drotecogin alpha (activated) did not alter the course of the systemic inflammation in SAP [79].


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Recombinant Human Soluble Thrombomodulin In 2013, a phase III clinical trial reported using recombinant human soluble thrombomodulin (rhTM) to treat patients with disseminated intravascular coagulation and severe sepsis. The authors state that treatment with rhTM can be associated with reduction in hospital mortality in mechanically ventilated adult patients with disseminated intravascular coagulation caused by sepsis [80]. In another retrospective study, the authors investigated the efficacy of rhTM in preventing the development of WONP in patients with SAP, where they report that it can prevent the progression from pancreatic necrosis from ischemia to WONP [81]. However, some reports indicate that rhTM is not effective in actual clinical practice, and others mention that the administration of rhTM is significantly associated with the reduction of mortality in high-risk patients [82]. Also, in a systematic review it’s mentioned that the probability of finding beneficial effects is related to an increase in baseline risk [83].

SURGICAL TREATMENT In the management of mild biliary pancreatitis, laparoscopic cholecystectomy is recommended during the initial hospitalization. A delay of >4 weeks is associated with recurrent biliary pancreatitis or other complications. The interventional therapy should be guided by the individual characteristics of each patient, available resources, and the principle of the minimally invasive approach [84].

Peritoneal Lavage The name ‘pancreatic abscess’ has been given to the collection of intraabdominal purulent material that generates after a case of AP [85]. In SAP sterile or infected pancreatic necrosis is produced. The treatment for pancreatic necrosis has evolved considerably with respect to the moment of intervention and to the development of treatment alternatives from traditional open necrosectomy. The traditional surgical approach to infected pancreatic necrosis is open necrosectomy with the aim of draining all the infected compartments and completely eliminating all of the necrotic tissue with the placement of drains for continuous postoperative lavage, closed or with



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marsupialization. At times, repeat laparotomy is periodically required to assure complete debridement [86]. The fundamental disadvantage of open necrosectomy is its association to increased mortality and increase in perioperative mortality >50% [87].

Management with the ‘Step-Up’ Approach Among alternatives in the management of SAP suspension of the surgical intervention as a strategy to facilitate necrosectomy and improve prognostics, is recommended. In the presence of infected necrosis, it is recommended to start with the minimally invasive ‘Step-up’ approach. The first step in the ‘Step-up’ approach includes endoscopic or trans-gastric percutaneous drainage. The preferred approach is through the left retroperitoneum. In the case that another approach is later required, the minimally invasive retroperitoneal necrosectomy is recommended. If after 72 h there is no cumulative clinical improvement or the drainage of liquid proves to be inadequate, another drainage procedure is recommended. If this is not possible, or if there is no clinical improvement after another 72 h, videoassisted retroperitoneal debridement (VARD) with post-operative lavage is recommended [88]. The benefits to the ‘Step-up’ approach are the avoidance, when possible, of the open abdomen approach and its associated complications that cause greater morbidity and mortality [89]. A decrease in the appearance of diabetes mellitus and incisional hernias are also made relevant by this method [90]. The ‘Step-up’ approach contributes to economic benefits that can be substantial in decreasing number of days in hospital (including days spent in ICU). Despite these aforementioned benefits, complications or death are reported in 40% of patients [91].

Open Surgical Debridement When the least invasive method fails or when it’s not considered possible, then open debridement can be necessary. Traditional open necrosectomy can be performed by way of the gastro-colic ligament or the transverse mesocolon, including directly through the stomach. When early open debridement is performed, pancreatic necrosis is associated with high morbidity and mortality; thus, it is recommended to wait the longest amount of time possible of 3-6 weeks. This recommended time permits the demarcation of the necrosis


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of the pancreas from viable tissue, which permits the removal of the necrosis with little to no bleeding [92]. The open abdomen with early debridement approach is recommended when there is hemorrhagic pancreatitis or intestinal ischemia with forthcoming mortality of 100% [86].

Vacuum-Assisted Closure System (VAC) The VAC system consists of a biocompatible material that is placed in the abdominal cavity (permeable polyurethane sponge, adhesive plastic film, and impermeable plastic for a hermetic seal) connected to a sub-atmospheric suction pump (between 50-150 mmHg), continuous or intermittent, that provides continuous cleansing of the involved area and accelerates healing [93]. The usefulness of the VAC system after necrosectomy permits the gentle suction of the whole abdominal cavity including the pancreatic bed, and occasionally it is recommended for programmed postoperative lavage. After percutaneous drainage secondary to necrosectomy, controlled pancreatic fistula can present, which will close with conservative treatment [94]. In a recent study, the authors report that in open necrosectomy programmed every 48 h plus placement of the VAC system, in 24 patients with SAP and infected pancreatic necrosis, they found that the combination was beneficial for improving survival (70.9%) and the membrane fluidity in erythrocytes; compared to 16 patients who were subjected only to open necrosectomy programmed every 48 h, with a survival of 37.5%; although, the programmed open necrosectomy was effective in decreasing elimination of the products of peroxidation [95]. Figures 1B, 1C depict images of the removal of necrotic pancreas through the open abdomen approach. Figures 1D, 1E, and 1F show the placement of the VAC system in SAP with infected pancreatic necrosis. Shown, as well, is the evolution in time in patients managed with the open abdomen approach for SAP with infected pancreatic necrosis. In conclusion, AP represents a wide range of clinical manifestations and presentations. It also includes different diagnostic approaches and some recent treatment alternatives for patients with AP. The management of SAP can be excellent if all of the clinical parameters to identify sensitive populations who could benefit from the different types of management, and considering the individual characteristics of each patient, are controlled.



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intervention in necrotizing pancreatitis. Arch Surg., 2007, 142(12), 1194-1201. [93] Wondberg, D; Larusson, HJ; Metzger, U; Platz, A; Zingg, U. Treatment of the open abdomen with the commercially available vacuum-assisted closure system in patients with abdominal sepsis. World Journal of Surgery., 2008, 32(12), 2724-2729. Doi:10.1007/s00268-008-9762-y. [94] Abdo, A; Jani, N; Cunningham, SC. Pancreatic duct disruption and nonoperative management: the SEALANTS approach. Hepatobiliary Pancreat Dis Int., 2013, 12(3), 239-243. [95] Miranda-Díaz, AG; Hermosillo-Sandoval, JM; Gutiérrez-Martínez, CA; Rodríguez-Carrizalez, AD; Román-Pintos, LM; Cardona-Muñoz, EG; Pacheco-Moisés, FP; Arias-Carvajal, O. Effect of necrosectomy and vacuum-assisted closure (VAC) on mitochondrial function and oxidative stress markers in severe acute pancreatitis. Rev Esp Enferm Dig., 2014, 106(8), 505-514.

BIOGRAPHICAL SKETCH Name: Alejandra Guillermina Miranda Díaz Affiliation: Department Of Physiology, University Health Sciences Centre, University of Guadalajara (Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara), Guadalajara, Jalisco, México Education: MD, FACS, Master in Sc, PhD Address: Avenida La Paz 2758, Arcos Sur, CP 44150, Guadalajara, Jalisco México Research and Professional Experience: General Surgeon, Profesor and Investigator, Department Of Physiology, University Health Sciences Centre, University of Guadalajara (Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara), Guadalajara, Jalisco, México Professional Appointments: Avenida La Paz 2758, Arcos Sur, CP 44150, Guadalajara, Jalisco México Honors: Publications Last 3 Years:  The effect of ubiquinone and combined antioxidant therapy on oxidative stress markers in non-proliferative diabetic retinopathy: A phase IIa, randomized, double-blind, and placebo-controlled study.


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Effects of Ezetimibe/Simvastatin and Rosuvastatin on Oxidative Stress in Diabetic Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. The antioxidant effect of ubiquinone and combined therapy on mitochondrial function in blood cells in non-proliferative diabetic retinopathy: A randomized, double-blind, phase IIa, placebocontrolled study. Toll-like receptor-1 and receptor-2 and Beta-defensin in postcholecystectomy bile duct injury. Effect of necrosectomy and vacuum-assisted closure (VAC) on mitochondrial function and oxidative stress markers in severe acute pancreatitis. Effect of rosuvastatin on diabetic polyneuropathy: a randomized, double-blind, placebo-controlled Phase IIa study. Effect of botulinum toxin type A in lateral abdominal wall muscles thickness and length of patients with midline incisional hernia secondary to open abdomen management. Oxidants, antioxidants and mitochondrial function in non-proliferative diabetic retinopathy. The effect of ubiquinone in diabetic polyneuropathy: a randomized double-blind placebo-controlled study.





Chapter 6

MANAGEMENT OF ACUTE BILIARY PANCREATITIS Vincenzo Neri, Professor, Dr Med General Surgery, University of Foggia, Italy

ABSTRACT Acute pancreatitis is a complex gastrointestinal disease with various etiology, most frequent biliary and alcoholic (70-80%). Biliary lithiasis can be considered the most common cause of acute pancreatitis. The complete diagnostic study should be necessary because etiologic assessment can be a guide for surgery in the therapeutic program. The very diversified territorial distribution of the various clinical and etiological forms of pancreatitis generated uncertainties. In fact in our experience we can assume the prevalence of biliary etiology with the pathogenesis based on obstacle in the papillary patency. The etiological assessment can be a guide in the therapeutic programmes. The biliary etiology at the initial assessment has been defined by the evaluation of liver function tests and cholestasis exams and by the research, on abdominal US, of gallbladder lithiasis, and/or gallstones, sludge, microlithiasis in the common bile duct. The following diagnostic tools, MRCP and/or endoscopic US confirmed the biliary origin of pancreatitis. Acute pancreatitis in the majority of patients (70-80%) present with a mild-moderate disease that need only fluid rehydratation and abdominal pain control. On the contrary 20-30% shows a severe curse. Severe acute pancreatitis can be seen a biphasic disease: first phase (1-2 weeks) characterized by early toxic-enzymatic action and evolution in SIRS-


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Vincenzo Neri MODS; the later phase (3-4 weeks) with septic complications of pancreatic-peripancreatic fluid necrotic gatherings. Based on this criteria therapeutic program usually develops in 2 phases. In the severe forms the therapeutic program has the purpose to control and treat, by intensive care, the impairment of the general conditions. In particular in the acute biliary pancreatitis the control of papillary patency and its treatment with ERCP/ES within 3-4 days is the cornerstone of therapeutic program, based on the confirmation of papillary obstacle by US/MRCP or if is present cholestasis or cholangitis. For the treatment of further evolution of necrotizing pancreatitis there are some specific surgical decisions based on the following questions:    

How long the control and observation of not complicated fluidnecrotic gatherings may be prolonged? How to differentiate infected pancreatic necrosis from those sterile? In some patients with infected necrosis may be delayed the surgical treatment? Which is the best surgical approach and its time for the treatment of the fluid necrotic complicated gatherings?

The surgical procedures showed a progressive evolution to miniinvasivity: percutaneous drainage, endoscopic drainage, necrosectomy with minimally invasive step-up approach, endoscopic transluminal necrosectomy (ETN), videoassisted retroperitoneal debridment (VARD). About the surgical time there is almost unanimous consensus to delay the intervention until the fluid necrotic collections are encapsulated (walled off necrosis). In conclusion in severe, moderate severe, recurrent acute pancreatitis with cholestasis-cholangitis, or instrumental confirmation (US/MRCP) of papillary or CDB obstacle is indicated the therapeutic ERCP/ES within 34 days. In septic necrotic collections the role of the surgery should be limited to percutaneous drainage (that in most cases could reduce the needs for surgery). If major surgical interventions are required, these should be more conservative as possible and preferred minimally invasive approaches.

Keywords: acute biliary pancreatitis, ERCP/ES, pancreatic gatherings

INTRODUCTION Acute pancreatitis (AP) is an inflammatory disease of the pancreas with systemic response to auto-digestion of the glandular and peri-pancreatic tissue.


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The disease is characterized by different degree of severity from a mild edematous – interstitial inflammation, as a self – limiting disease, to a severe type with local necrotizing inflammation and systemic complications as systemic inflammatory response syndrome (SIRS) and organ failure. AP is one of the most common gastrointestinal diseases. Annual incidence worldwide is 4, 9 – 73 cases per 100.000 people/year with an increase in the annual incidence in many countries [1]. The data from England, Denmark, US report the incidence of AP from 4, 8 to 24, 2 cases per population of 100.000 [2]. There is certainly an increase due to better clinical and diagnostic knowledge of the disease, at the same time with real increase of pancreatitis. The incidence of Acute biliary pancreatitis (ABP) per year has been reported by different communications between 4, 9 to 80 cases per 100.000 people and also has been increasing over the past two decades [3].

PATHOPHYSIOLOGY AP is an inflammatory disease characterized by various degrees of pancreatic and peripancreatic tissues damage varying from edema, inflammation, parenchymal cells injury, necrosis. AP develops from autodigestion processes of the gland accomplished by enzymes that have been inappropriately activated in the gland. Trypsin first and the activation of other pancreatic proenymes follows (proelastase, chemotrypinogen, ecc…). The enzymes activation in the pancreatic parenchyma, that is the pancreatic acini, is the basic and initial process of pancreatitis of all etiology. The first consideration is about the sequence of cell events. Normally digestive pancreatic enzymes are secreted by acinar cells as inactive proenzymes into pancreatic ductal system and subsequently into duodenum where the activation [4] takes place of trypsinogen to active trypsin by enterokinase and low duodenal pH. Many theories has been proposed for explanation of pathophysiology of AP. The most likely sequence of events indicates the alteration of exocytosis (the discarge of pancreatic enzymes in the acinar lumen), the block of secrection of newly synthetized enzymes, the formation of condensing vacuolis (fusion of newly synthetized zymogens and lysosome with hydrolases). Finally the contact between lisosomal hydrolases and pancreatic


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enzymes allows the intracellular activation of trypsin and other pancreatic proenzymes [5].

ETIOLOGY Etiologic factors of AP are various and with different frequence and geographic distribution. Most frequent causes are biliary obstruction and alcohol consumption that are confirmed in almost 80% of patients; the remaining 20% comprises pancreatitis with various etiologies. In summary the etiologies of AP can be subdivided:  





genetic causes  hereditary pancreatitis; obstructive causes:  biliary pancreatitis: gallstones/papillary stenosis;  tumours;  pancreas divisum; metabolic causes:  alcohol;  hypercalcemia;  hyperlipidemia; drugs.

In this presentation our attention should be focused on biliary causes. The pathologic sequences of acute biliary pancreatitis (ABP) can be hypotized: the gallstones passage through the duodenal papilla or subsequent papillary edema causes obstruction at the ampulla also temporary, damaging the biliary flow with the bile reflux into the pancreatic duct leading the start of the pancreatitis [6, 7, 8, 9]. The hypothesis has been proposed in the past [10] and so far always shown but there are some details not well classified: the confluence in a common duct in the ampulla of biliary and pancreatic ducts is frequently but not always present (70 – 85%) [11]; moreover the stones impacted at the ampulla have been reported in less than 5% of the patients with AP [12]. Probably the papillary obstruction should be in most cases temporary due to the passage of biliary sludge, small stones (3 x upper limit of normal. Serum amylase increases at the onset of the disease and decreases in a few days (3-5 days); on the contrary the lipase tends to remain elevated for longer. The increase level of serum amylase has not correlation with severity of pancreatitis. Several laboratory tests contribute to define biliary etiology of pancreatitis: first of all the liver function tests (AST, ALT, ALP, yGT, bilirubin), fasting serum calcium and lipid profile.


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In particular among liver function tests ALT had a positive predictive value of 95% in diagnosis of acute gallstone pancreatitis [15]. The imaging exams play the central role in the etiological assessment of pancreatitis. At the first level abdominal US may demostrate gallbladder lithiasis and/or gallstones, sludge, microlithiasis, etc. in the common bile duct (CBD) or also a dilatation of the CBD (>8mm) and impacted CBD stone. Nevertheless van Santvoort [16] and our privious report [17] demonstrated that CBD dilation >8mm had poor sensitivity, specificity, PPV, NPV. On the contrary the association of increased liver function tests and gallbladder stone on US reach a sensitivity of 97% and specificity of 100% in the diagnosis of ABP. At the second level of imaging exams there are contrast enhanced CT and MRI. Both these instrumental exams have double diagnostic role: the assessment of pancreatic parenchima damage, involvement of pancreatic tissue, presence of fluid-necrotic collections and on the other hand the detection of bile stones, CBD dilatation, that is to recognize biliary origin of pancreatitis.

EVOLUTION OF ABP AP in the majority of patients (70-80%) occurs as a mild-moderate disease; on the contrary 20-30% shows a severe course. Moreover within the severe forms, approximately in 20% of the cases, development of persistent organ failure and/or of infected pancreatic collections necessitates the definition of the most severe forms, identified as critical, early severe acute pancreatitis [18, 19]. The clinical appearance of the critical forms shows a very severe disease with early hypoxaemia, progressive multiple organ dysfunction, compromised computed tomography severity index (CTSI), increased incidences of necrosis, infection, and sometime abdominal compartment syndrome (ACS). In summary the critical forms of pancreatitis are characterized by a short course and very high mortality rate, to 40% [20, 21]. Severe acute pancreatitis can be seen as a biphasic disease, with the first phase –first two weeks- characterized by early toxic–enzymatic injury, SIRS and a late phase –third and fourth week- characterized by septic complications of necrotic tissue and of pancripancreatic fluid necrotic collections.



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The first phase of pancreatitis can develop in most cases with disease quickly responsive to intensive care based on aggressive rehydratation. On the contrary several cases can quickly evolve into SIRS and multi organ dysfunction syndrome (MODS). The most relevant clinical feature of AP is the progress and worsen from local disease to general involvement. The key of this evolution is the tissue response of the pancreas acinars cell necrosis. Locally the phlogosis directs the actviation of macrophages and attraction of activated polymorphonuclear cells. SIRS can develops from the passage of inflammatory mediators (pro-anti inflammatory mediators released from the splanchnic area) to systemic compartments by lymphatic system, portal vein, and general circulation. Vascular alterations cause gut barrier failure with bacterial translocation and endotoxin diffusion. The final results are distant MODS and generally later infection of fluid-necrotic pancreatic-peripancreatic gatherings [22, 23, 24, 25, 26, 27, 28, 29, 30]. Revised Atlanta Criteria [19] indicate that peripancreatic necrosis can be a risk factor for worsening of severe acute pancreatitis and some data from the literature suggest that it may occurs also with minimal pancreatic necrosis [31]. Visceral fat lypolisis in peripancreatic necrosis, as peripancreatic fluidnecrotic collections causes lipotoxicity of unsatured fatty acids (UFAs) that are elevated in biliary severe acute pancreatitis with high level of unsatured triglicerides (UTGs). The increased UFAs cause organ failure including acute lung injury, renal tubular toxicity, renal failure and hypocalcaemia [32, 33, 34]. Peripancreatic necrotic gatherings with “production” of UFAs cause MODS and consiquently increased mortality, converting mild/moderate acute pancreatitis in severe or early severe pancreatitis indipendent of pancreatic necrosis, underlining that the mild onset of the disease can develops in the severe form [35].

EARLY ASSESSMENT OF ABP The severity of ABP at the onset varies from mild forms, with no systemic or local complication, moderate forms with morphologic, local evidence of disease and systemic complications such organ failure but with quick resolution (within 48 hours) and finally severe forms with persistent organ


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failure [19]. Mild panreatitis has generally favorable evolution without mortality risk; in the moderate forms there is minimal risk of mortality. Finally in the severe forms the risk of mortality increase to 15-40% with the general involvement as SIRS and MODS [36]. The severity of pancreatitis has been assessed by several scoring system [20]. Table 1.

CRP (> 150mg/L at 24 and 48h) TAP Urinary Trypsinogen Activation Peptide (increased at admission and after 12h) Procalcitonin (> 160 fmol/mL at admission)  infected pancreatic necrosis marker  altered permeability of gut barrier marker Hct (at admission and after 24h) cut off: 43% M – 39% F Hyperglycemia (>125mg/dL)  pancreatic necrosis index  complication index

Unifactorial markers of severity most recurrent in the literature Sensibility Specificity VPP VPN Accuracy 57-94.1% 60-90% 36-90% 75-95.7% 76-80%

References [37, 38, 3948]

58-100%

73-89.7%

3978.6%

85-96.3%

---

[37, 46-52]

67-100%

20-89%

5564.7%

82.6-93%

85%

[40, 53-60]

61-74%

38-45%

24-37%

61-97%

---

[61-64]

83-100%

49%

28%

92-100%

---

[63, 65-67]



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Table 2.

Sensibility 33-83% 33-83% 18%

Multifactorial bioclinic scores Specificity VPP VPN 79-98% 45-83% 86-95% 79-98% 45-83% 86-95% 98% -----

Ranson Glasgow BALI (after 48h) BUN > 25mg/dL Age > 65y LDH > 300U/L IL6 > 300pg/dL APACHE II 52-62% 77-86% 46-57% >7 APACHE II 50-75% 69-72.4% 20-52.9% >9 Simplified 71.4% 75.5% --prognostic tests  Lypasemia  Calcemia  Glycemia  WBC MOSS/OF Correlation with outcome / indirect index of severity Simplified acute physiology score Predictive model for the final result  Age  High creatinine in 72h  mechanical ventilation  chronic impairment Renal and respiratory failure

Accuracy 78-89% 78-89% ---

84-88%

---

87.589% ---

---

References [68, 69 , 70, 71-82]

---

Predictive factors of severity, except clinical evaluation, may be divided into direct and indirect. The direct factors are morphologic based on anatomical compromission of the pancreas and assessed by imaging exams (US, CT, MRI). The indirect methods can be subdivided in monofactorial and multifactorial. The first (monofactorial) can make the prognostic assessment by means of single laboratory marker. These consist of several hematic, urinary biochemical data that can be early detector of systemic inflammatory response and multiorgan failure. In the Table 1 we report the monofactorial


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markers more reported in the literature. Into these markers are reliabe and very early CRP, TAP (urniary trypsinogen activation peptide), procalcitonin. The multifactorial prognostic scoring systems consist of Ranson and Glasgow scores, specific for the pancreatitis and APACHE II score which is not specific. In the Table 2 had shown the multifactorial severity scoring system most employed in the practice. Should be useful the distinction between the single factors or the multifactorial scores that are reliable only at the onset of pancreatitis attack or on the contrary active and effective late after 24-48 hours from the onset when the general impairment has already made. The new scoring systems meet the need to assess severity of disease within the first 24h. The Harmless Acute pancreatitis score [83], aims to identify the mild/moderate pancreatitis. On the other hand there is the Bedside index of Severity in Acute pancreatitis (BISAP) [84] based on the evaluation of 5 criteria: blood urea nitrogen (BUN) > 25mg/dL, age >60 years, impaired mental status, SIRS and pleural effusion. For BISAP a score of > 2 is associated with a 10 fold increase in mortality risk. Beside mono – multifactorial scores there is the morphological/pathological evaluation of the pancreas and peripancreatic tissues by imaging exams: US, TC, MRI. The imaging exams are very important for the pathological definition of pancreatitis, and prognostic – therapeutic evaluation, but are not useful for early assessment of severity because the complete evolution of the pancreatic and peripancreatic damage generally can develop within 24-48 hours [85, 86, 87]. The US provides guidance informations, nevertehless the CT represents a valuable method to identify the degree of pancreatic impairment. CT images obtained within 72 h of onset allow the use of CTSI and modified CT severity index (MCTSI) with Balthazar scoring for grading of acute pancreatitis and points for necrosis. The classification is based on morphological and functional feature: local or diffuse enlargement of the pancreas, pancreatic gland abnormalities, peripancreatic inflammation with pancreatic and peripancreatic fluid collections and areas of non-enhanced parenchyma (that is necrotic). The imaging evaluation should be integrated and completed always within 24-72h by CT assessment of pancreatic size index (PSI), extra pancreatic inflammation on CT index score (EPIC) and extra-pancreatic score (EP) [88]. There are valuable differences between clinical and laboratory prognostic scoring systems and radiologic prognostic scoring systems. The first should detect early the severe evolution of the disease providing the prognostic evaluation. On the other hand imaging exams as CT or MRI have certainly a diagnostic role and provide a prognostic



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evaluation but also are very useful for detecting degree of pancreatic and peripancreatic damage and complications and finally they guide the indications for surgery and interventional procedures. Bollen and coll [89]. compared CTSI, MCTSI with APACHE II index. They showed any significant differences between MCTSI and CTSI in evaluating the severity of AP. Clinical scoring systems correlate with organ failure and mortality whereas radiologic scoring systems diagnose carefully the severity of pancreatitis and better define the need for surgical procedure. In summary the evaluation of severity of AP should employ several detector following the onset and development of acute attack. At the admission can be useful BUN, hematocrit, procalcitonin, chest x ray; at 24 – 48h, BISAP, Ranson, Glasgow score, APACHE II; after the 48h MCTSI and CTSI. MRI provides images and pathological data overlappable to CT.

THERAPEUTIC APPROACH OF ABP The therapeutic program of ABP should follow the evolution of the disease. The first approach, usually based on medical treatment, is overlappable for pancreatitis of any etiology. The various differences in the early therapeutic approach are conditioned by the clinical feature of the pancreatic attack. Acute pancreatitis can develop with a wide range of disease, ranging from mild form to a severe or early severe, rapidly progressive illness. Mild acute pancreatitis usually is a self limiting form developing only pancreatic and/or peripancreatic oedema without change of the enhancement of pancreatic parenchyma on contrast enhanced CT (CECT). The medical treatment includes as main measure the intravenous fluid replacement; in summary it is usually conservative. The aims of the treatment of mild moderate ABP are the following: control of pain, fluid electrolyte replacement, nutrition, removal of the persistent papillary obstacle. In the first phase at the onset the severe and early severe forms of ABP can show a clinical picture with local and/or systemic complications. The clinical severity corresponds to degree of pancreas impairment assessed with Balthazar score. Usually this score ranges between 5 to 8. The major morbidity is linked to simple organ dysfunction or worse, to MODS, with hypoxaemia. It can also manifest pancreatic sepsis and ACS; the latter require urgent surgical intervention. These formes require management


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in intensive care. In early severe formes there is a great compromission of general conditions by early toxic – enzymatic injury and high rate of early mortality (more than 10%). The later phase of the disease (third and fourth week) is characterized by septic complications of pancreatic or peripancreatic fluid – necrotic collections. In the severe forms the therapeutic approach is more complex with early fluide resuscitation for the correction of hypovolemia [90]. Hypovolemia is due, over the all, to third space extravasation, secondly to vomiting, respiratory losses, and diaphoresis. The specific purpose of the correction of hypovolemia is to avoid the decrease of macro/microcirculation and sequently the cascade of events leading to pancreatic necrosis [91]. The early fluid administration is the first line therapeutic approach and should be adequate in the severe forms of the disease to reach the beneficial effects. The fluid resuscitation with lactated Ringer’s solution showed more resolutive effects on development of severe acute pancreatitis based on major balancement of pH with reduction in the SIRS evolution and levels of CRP. Attentif care should be raccomended on early fluid administration: we should be carefully consider the need of aggressive fluid therapy at the onset because it can be detrimental in the patients without fluid depletion or with chronic cardiovascular comorbidities. The pain control can be accomplished, following the severity of the pain, by administration of non-steroidal, antinflammatory drugs (NSAIDs) as a first line, and then opioids. The pharmacological control of the pain should be considered a very important object in the treatment of AP. In the therapeutic program of AP the bowel rest is the most debatable mesaure. This therapeutic choice is still present in the clinical practice, (but not with defined diffusion) and also reported in the literature [92]. The pathophisiology of severe acute pancreatitis proves that risk of pancreatic and peripancreatic fluid necrotic collections contamination comes from bacterial translocation. The bacterial translocation is due to failure of integrity of gut barrier based on morphological changes in the gut associated with fasting, bacterial overgrowth, motility changes, immunosoppression. Several studies show that enteral nutrition in the severe acute pancreatitis (such as parenteral nutrition), should be used with the improvement of severity evolution and clinical outcome of the disease [93]. The great variety of acute pancreatitis in severit grade, type of complications and patients comorbidities makes difficult the choice between enteral or parenteral nutrition. In summary Italian guidelines recommend using enteral nutrition rather than parenteral nutrition in severe acute pancreatitis or



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alternatively one could use no nutrition in some patients in case of diagnostic doubt, ACS ecc… [94] The use of antibiotics in ABP is still under discussion. There are two relevant points in this topic: first point quite defined is the treatment of an infection already present that requires only the choice of the antibiotics. On the other hand the prophilactic use of antibiotics is not well defined. In the evolution of severe acute pancreatitis the main aim of the propylactic use of antibiotics is to avoid the contaminations of the fluidnecrotic pancreatic or peripancreatic collections. Therefore the antibiotics employed should have well defined antimicrobial activity such as penetration rate, persistence and therapeutic concentrations rate in the necrotic area. Study of several years ago had suggested the use of pefloxacin and metronidazol or, to varying degrees, imipenem and mezocillin [95]. In conclusion the prophilactic uses of antibiotics in AP should b initiated at the admission, because half of infective complications occur in the first few days after the onset and should be continued for 14 days [96, 97]. In the medical specific therapeutic approach of AP there are three drugs largely employed: antiproteases, somatostatin and octreotide. The use of antiproteases shows results highly debatable [98]. Somatostatin and octreotide develop positive action of inhibition of pancreatic secrection but they are also splanchnic vasoconstrictors with hypoperfusion of the pancreas that can promote pancreatic necrosis. Therefore its employment is controversial [99]. In summary the therapeutic approach of ABP usually develops in two phases following the evolution of the disease. In mild-moderate forms at the onset of the disease (first phase) the treatment includes simple fluid rehydratation and control of abdominal pain. In the severe forms, at first phase, the therapeutic approach consists of intensive care, initial fluid, aggressive resuscitation, low dose steroides, anticoagulatory agents for antiinflammatory properties, correction of hypoxaemia, enteral nutrition to preserve the intestinal integrity and antibiotic prophylaxis. In conclusion in this first phase of severe forms the central purpose is to control and treat, by intensive care support, the damage of the general conditions and possible organ failure [100]. In the ABP the control of papillary patency and, if necessary, its treatment with endoscopic retrograde cholangiopancreatography/endoscopic sphyncterotomy (ERCP/ES), can be considered the cornerstone of therapeutic program based on the confirmation by instrumental exams (US, MRCP) of papillary obstacle (stones, sludge, papillary sclerosis, ecc…) or, if it is present,


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cholestasis or cholangitis. ERCP/ES can assure papillary flow and CBD cleaning if lithiasis obstacle, sludge, microlithiasis are present. Following this general considerations on the pathophysiology of acute biliary pancreatitis, the therapeutic use of ERCP/ES is based on several data to be evaluated: a.

Confirmation of papillary obstacle, persistent or transient, generally due to biliary lithiasis. b. Indication of procedure: wich patients (with ABP) should be submitted to ES c. Timing of the procedure d. Complications. Biliary etiology of pancreatitis can be established at the onset with first level etiological assessment by the research, on abdominal US, of gallbladder lithiasis, and/or gallstones, sludge, microlithiasis in the CBD or also a dilatation of CBD (>8 mm) besides with liver function tests/cholestasis indexes, fasting serum calcium and lipid profile. The second level diagnostic study, that is MRCP and/or endoscopic US usually should confirm the biliary origin of pancreatitis in majority of patients. In very few patients the etiology of pancreatitis remain unexplained [101]. More complex is the answer to the following question: which patients should be submitted to ERCP/ES? The choice of the patients for ERCP/ES and its timing in ABP are nowadays still controversial despite many years since its introduction in the therapeutic program. There are many studies in the literature about this topic. Some of these are now “historic”: Neoptolemos [102], Fan [103], Nowak [104], Folsch [105]. Recent systematic review have been published [106, 107, 108]. The conclusion of these studies agree on some points:  

Early ERCP/ES has not advantage for patients with mild pancreatitis and is not indicated; Early ERCP/ES may be indicated in patients with severe disease, biliary obstruction or cholangitis.

Also in one review [108] early ERCP/ES may reduce complications in patients with predicted severe pancreatitis.



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Tse F et al. published a cochrane database Systematic Review. Their conclusions are that early ERCP/ES does not significatly nodify mortality, local and systematic complications [109]. However early ERCP/ES should be recomended for patients with severe or moderate pancreatitis with co-existing papillary obstruction (laboratory – instrumental dimonstration) or cholangitis. In conclusion this therapeutic procedure can be proposed in all patients with severe, early severe acute biliary pancreatitis and recurrent pancreatitis and also in several patients with moderate or moderate – severe disease. Obviously all these patients should achieve laboratoristic, strumental (US or MRCP), confirmation of a papillary or CBD lithiasis obstacle, sometime complicated by angiocholithis. The timing of ERCP/ES after identification of patients should be choiced within the first 48 – 72 hous from the onset of pancreatic attack. Finally ERCP/ES in patients with severe acute pancreatitis, severe impairment of general conditions and requirement of intensive care and assisted ventilation can be high risk procedure. This therapeutic choice is very difficult and without worldwide consent. Complicatons of ERCP/ES are not unusual. They include post-procedural pancreatitis, perforations, bleeding, infections. Some data from the literature show that the incidence rate of these complications ranges about 10%. The complications with major morbidity reach 1, 5% and mortality less than 0, 5% [110, 111]. More recent data show that the majority of events are of mild-to-moderate severity; but on the other hand the overall complication rate not diminiuished [112]. In all patients with pancreatitis with biliary pathogenesis, submitted to ERCP/ES or not, it is necessary to perform lapaoscopic cholecystectomy in the same hospital stay to complete the gallstone treatment. The timing of laparoscopic cholecystectomy is connetted with acute pancreatitis evolution because it is preferable to wait for the stabilization and improvement of the general conditions and of phlogistic impairment of pancreatic and peripancreatic tissue. An algorithm of ERCP/ES employment in ABP is shown in Figure 1. The pathological basis of therapeutic perspectives in severe acute biliary pancreatitis are linked on grade of impairment of pancreatic parenchyma and peripancreatic tissues. The advanced phase of severe acute pancreatitis is characterized by a counteractive anti-inflammatory response syndrome (CARS), with the risk of infected necrosis and worsening of organ failure.


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Figure 1. ERCP/ES in Acute Biliary pancreatitis.

Severe acute pancreatitis in its late phase can have some evolutions: amelioration of early organ failure after intensive care but infection of peripancreatic necrotic tissues causes worsening of general conditions in the second, late phase of disease; or uninterrupted serious conditions without improvement between the first phase of early organ failure and the infected necrosis in the following third – fourth weeks. Also persistent organ failure requires control of collections infection -fine nidle aspiration bacteriology (FNAB), gas bubbles on CECT-; in these latter cases interventional procedures should be employed [113]. The prevalence of necrotizing forms is 15-20%, that are characterized by hypoperfusion of the parenchyma on a CECT (Balthazar score) [89]. The necroting process involves the gland parenchyma and peripancreatic tissues with very variable extension. The extensive interstitial oedema is associated with pancreatic and peripancreatic necrosis in a short period of 48 – 72 hours after the onset of acute attack. These inflammatory, necrotic tissues give rise to acute fluid collections with an amount of devitalized tissue. The further evolution of these fluid gatherings is characterized by demarcation between viable and necrotic tissue and the limit is set with a wall of granulation tissue. The management of these pancreatic and peripancreatic fluid – necrotic collections and their complications is the longest and most debated therapeutic problem. This therapeutic program includes some specific surgical decision based on the following questions:



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a.

How long the control and observation of not complicated fluidnecrotic gatherings may be prolonged? b. How to differentiate infected pancreatic necrosis from those sterile? c. In some patients with infected necrosis may be delayed the surgical treatment? d. Which is the best treatment of the fluid – necrotic complicated gatherings? The therapeutic program should follow the evolution of ABP. In the early toxic phase (first two weeks), besides the control and treatment of papillary and CBD lithiasic obstacle by ERCP/ES, to obtain the normal biliary and pancreatic papillary flow and CBD cleaning, the central therapeutic purpose is to improve the severe involvement of general conditions, to avoid the start of the dreaded SIRS and minimizing the mortality from MODS. Therefore in this phase all surgical procedures should be avoided. The following phase from the third/fourth weeks is characterized by the fluid necrotic collections with or without septic complications, such as infected pancreatic necrosis. a.

How long the control and observation of not complicated fluidnecrotic gatherings may be prolonged? If not complicated the gatherings may be submitted to conservative procedure also for several weeks (four/eight weeks). The pathological conclusion of persisiting peripancreatic fluid collection generally greater than 5 cm can be acute postnecrotic pseudocyst. In the asyntomatic gatherings surgical manoeuvres and percutaneous drainage should be avoided because the risk of secondary infections [114]. In selected patients with persistent severe impairment of general conditions and organ failure interventional procedures can be indicated also for sterile fluid – necrotic collections [115]. b. How to differentiate infected pancreatic necrosis from those sterile? The first step is the control of clinical and laboratory signs of sepsis. The suspicious of infection may be based on the demonstration by CECT of gas bubbles into the gatherings. Only if there is doubt of infections in necrotic collections, the FNAB should be performed, because of a potential risk of secondary infections [116]. c. In some patients with infected necrosis may be delayed the surgical treatment?


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Vincenzo Neri In the general assessment, surgical procedures are indicated in patients with fluid – necrotic septic gatherings because to avoid the impairment of general conditions by sepsis. Septic complication of pancreatic and peripancreatic necrotizing tissues can occur in the first phase of the disease and causes the true pancreatic abscess with further worsening of the general conditions. In this case the drainage of the infected collection should be mandatory by percutaneous or endoscopic or open approach [117]. Therefore with worldwide antimicrobic therapy, in patients without compromission of general conditions may be to delay the surgical procedure for some weeks when the collection has become walled off [118, 119]. Surgery in the first phase of the disease (first two weeks from the onset) has a very high mortality rate (75%), generally because of necrosectomy for infected collections, but if delayed later than four weeks from the onset the mortality decrease to 5% [120]. The better results in the surgical treatment of fluid – necroting pancreatic – peripancreatic gatherings are connected to a suitable time interval –between the onset of disease and intervention- for encapsulation of collection and the recovery of general conditions of patients. d. Which is the best treatment of the fluid – necrotic complicated gatherings? The treatment of pancreatic – peripancreatic necrotic gatherings in the last decade is oriented, with a progressive evolution, toward minimally invasive surgical procedures. There are no, in these therapeutic programs, indications and surgical procedures unanimously standardized and employed. In the past has been proposed and used for infected necrotic collections, the open necrosectomy with complete debridment, necrosectomy, retroperitoneal lavage system and drains in the lesser sac. The mortality was 25% [121]. Other open procedures have been also proposed: closed packing intervention with mortality 11% and open abdomen strategy with planned relaparotomy with high mortality 70% [122, 115]. Lately necrosectomy by a mininvasive procedures are getting popular: percutaneous minimally invasive retroperitoneal necrosectomy, videoassisted retroperitoneal debridement (VARS) (with removing some pieces of less adherent necrosis and reducing the risk of bleeding and the remnant necrotic tissue can be resorbed), necrosectomy with minimally invasive step-up approach, endoscopic transluminal necrosectomy (ETN), percutanoeus drainage [123, 124,



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125, 136]. The comparison between open necrosectomy and step-up approach with percutaneous or transgastric drainage and drain-guided necrosectomy, showed for the latter minor complications [127]. In summary under the procedures minimally invasive could be revalued the simple percutaneous drainage of septic necrotic collections. We should keep in mind that it can be a first step of therapeutic program, with a real possibility that the necrotic tissue can be resorbed; it also if the drainage of the collection is incomplete, it should be possible to perform a complete necrosectomy. Recent data from the literature showed the high number of patients treated with percutaneous drainage (22 – 55%) and the technical success rate of 99% [123]. In conclusion it is not clear the best procedure for the treatment of septic necrotic pancreatic collections. No single approach can be right and suitable for all patients. The procedures for drainage of collections and/or debridement of septic – necrotic tissue among the several therapeutic choices proposed should be tailored based on patient presentation and anatomy [128]. Open necrosectomy ramains the last option after the failure of less invasive procedures. Algorithm of management of pancreatic – peripancreatic fluid – necrotic collections is shown in Figure 2.

Figure 2. Management of pancreatic – peripancreatic gatherings.


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Fluid – necrotic pancreatic – peripancreatic collections not infected may have a dual evolutions: resorption of collections and resolution of disease or the collection forms the acute postnecrotic pseudocyst. Two factors influence these trends, the size of gatherings and time. Necrotizing pancreatic gatherings not complicated can develop a complete separation of the tissues with liquid content and a fibrous wall (acute postnecrotic pseudocyst). The evolution of a lesion with a fibrous wall can be complete in many weeks (12-16 weeks). Small cysts lesser than 5-6cm can show a spontaneous resorption in many months without clinical appearance. The incidence of acute postnecrotic pseudocysts is low, at 5-16% [129]. Pseudocysts larger than 6 – 7cm, or symptomatic, or persistent over many months require surgical treatment. The choice of the procedures should be guided by a fundamental pathological characteristic: the connection with pancreatic ducts. If the connection is present should be avoided simple percutaneous US/CT guided drainage because the risk of persistent leakage of pancreatic juice from the drain, infection and the possible repeated changes of drain. The procedures to be proposed are surgical with open or minimally invasive approach (laparoscopic, endoscopic): always pseudocystodigestive prolonged connection such as anastomosis or fistulas [130]. The choice of the digestive tract for the surgical drainage is based on the site of the development of the pseudocyst: lesser sac, epiploic foramen, infracolic compartment, ecc… Intestinal organs usually employed for the anastomosis are stomach, duodenum, small intestine: pseudocystojejunostomy, pseudocystogastrostomy, pseudocystoduodenostomy [131].

CONCLUSION In the past twenty years many important advances have been made in the management of ABP. In severe, moderate – severe, recurrent acute pancreatitis with cholestasis – cholangitis or with instrumental confirmation (US – MRCP) of papillary – CBD obstacle is indicated the therapeutic ERCP/ES within 72 hours. The interventional procedures in the treatment of severe acute pancreatitis require a radical revision. In septic necrotic collections the role of the surgery should be limited to percutaneous drainage, that in most cases could reduce the need for surgery. If major surgical interventions are required, these should be more conservative as possible and preferred minimally invasive approaches.



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ACKNOWLEDGMENT I’m very grateful to the doctors Libero Luca Giambavicchio and Francesco Lapolla for their valuable assistance in the typographical transcription of the manuscript.

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BIOGRAPHICAL SKETCH Vincenzo Neri, Prof Dr Med General Surgery, University of Foggia, Italy Full Professor of General Surgery, University of Foggia, Italy V. G. Murat 46, Bari (71023) Italy Research and Professional Experience: Director of the Division of General Surgery (1997- today) Director of Residency School of General Surgery, Policlinic University of Foggia (2008-today) Assistant Professor from 1974 to 1982 (University of Bari – Italy). Associate Professor from 1982-2001 (University of Bari – Italy). He obtained the Diploma of “Maitrise Universitaire en Pedagogie des Sciences de la Santé” on the Université Paris-Nord Bobigny.


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Into ERASMUS-Program 2010-2011 he developed in the University of Gent (BE) a seminare on “Cystic tumours of the pancreas.” He was the President of the Course of Degree of Medicine and Surgery, University of Foggia from 1996 to 2002. He was Director of Department of Surgical Sciences, University of Foggia, from 2002 to 2008. Research’s interest: Hepatobiliarypancreatic Surgery. Publications Last Three Years: Laparoscopic Treatment of Hepatic Cysts: A 10-Years Single Institution Experience. Nicola Tartaglia · Alessandra Lascia · Pasquale Cianci · Alberto Fersini · Vincenzo Lizzi · Antonio Ambrosi · Vincenzo Neri. British Journal of Medicine and Medical Research 12(3): 1-10, 2016, Article no. BJMMR.22140 ISSN: 2231-0614, NLM ID: 101570965. Spleen assessment after laparoscopic transperitoneal left adrenalectomy: preliminary results. Cianci P, Fersini A, Tartaglia N, Altamura A, Lizzi V, Stoppino LP, Macarini L, Ambrosi A, Neri V. Surg Endosc. 2015 Jul 3. Voluminous omental inflammatory myofibroblastic tumor in an elderly man: a case report and literature review. Cianci P, Ambrosi A, Fersini A, Tartaglia N, Lizzi V, Sanguedolce F, Parafioriti A, Neri V. Case Rep Surg. 2015;2015:873758. doi: 10.1155/2015/873758. Epub 2015 Jan 22. Laparoscopic cholecystectomy: evaluation of liver function tests. Neri V, Ambrosi A, Fersini A, Tartaglia N, Cianci P, Lapolla F, Forlano I. Ann Ital Chir. 2014 Sep-Oct; 85(5): 431-7. Defining a therapeutic program for recurrent acute pancreatitis patients with unknown etiology. Neri V, Lapolla F, Di Lascia A, Giambavicchio LL. Clin Med Insights Gastroenterol. 2014 Jan 5; 7: 1-7. doi: 10.4137/CGast.S13531. eCollection 2014. Multiple skeletal muscle metastases from colon carcinoma preceded by paraneoplastic dermatomyositis. Landriscina M, Gerardi AM, Fersini A, Modoni S, Stoppino LP, Macarini L, Sanguedolce F, Bufo P, Neri V. Case Rep Med. 2013;2013:392609. doi: 10.1155/2013/392609. Epub 2013 Jul 24. Common bile duct lithiasis: therapeutic approach. Neri V, Ambrosi A, Fersini A, Tartaglia N, Lapolla F. Ann Ital Chir. 2013 Jul-Aug; 84(4): 405-10. Review.



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Severe acute pancreatitis: clinical forms of different gravity. Neri V, Ambrosi A, Fersini A, Tartaglia N, Lapolla F, Forlano I. Ann Ital Chir. 2013 JanFeb; 84(1):47-53.





Chapter 7

RADIOLOGY OF ACUTE PANCREATITIS AND ITS COMPLICATIONS Kamil Zeleňák1 , MD, PhD, and Martin Števík2, MD, PhD *

1

Jessenius Faculty of Medicine and University Hospital, Kollárova 2 Martin, Slovakia 2 University Hospital Kollárova 2, Martin, Slovakia

ABSTRACT Acute pancreatitis (AP) is one of the most common diseases of the gastrointestinal tract, leading to significant emotional, physical, and financial burden for society. The diagnosis of acute pancreatitis is often established by clinical symptoms and laboratory testing. The latest revised Atlanta classification of acute pancreatitis was in 2012. This international consensus provides clear definitions to classify acute pancreatitis using easily identified clinical and radiologic criteria. This classification differentiates the two types of acute pancreatitis, namely interstitial oedematous pancreatitis and necrotizing pancreatitis, and defines the morphology seen on imaging of pancreatic and peripancreatic collections that arise as complications of acute pancreatitis. Severity is classified as mild, moderate or severe. Local complications are peripancreatic fluid collection, pancreatic and peripancreatic sterile or infected necrosis, pseudocyst and walled-off necrosis.

*

Corresponding Author address: Email: [email protected].


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Kamil Zeleňák and Martin Števík Imaging techniques commonly used for the diagnosis and severity assessment of AP include abdominal ultrasound, contrast-enhanced computed tomography (CECT), and magnetic resonance imaging (MRI). CECT provides over 90% sensitivity and specificity for the diagnosis of acute pancreatitis, which is why, together with MRI, it should be reserved for patients in whom the diagnosis is unclear or who fail to improve clinically. Computed tomography (CT) and MRI are comparable in the early assessment of AP. Magnetic resonance imaging is useful for patients with a contrast allergy and renal insufficiency. Alongside treatment with drugs, supportive and surgical treatment, interventional radiology has a unique place in indicated cases. Infected pancreatic necrosis remains the most important indication for intervention, to prevent the development of sepsis, and thus it is the most common cause of death in acute pancreatitis. Haemorrhagic complications are usually manifestations of the progress of severe pancreatitis. Endovascular therapy remains the firstline option for known arterial bleeding and visceral pseudoaneurysms.

Keywords: acute pancreatitis, scoring system, pancreatic peripancreatic collection, bleeding, visceral pseudoaneurysm

necrosis,

INTRODUCTION Acute pancreatitis (AP) is a common medical condition with extensive morbidity and mortality. Approximately 5% of patients with AP will die [23]. Gallstones and alcohol misuse are the main risk factors for acute pancreatitis [33]. The incidence of acute pancreatitis varies between 4.9 and 73.4 cases per 100,000 worldwide. Acute pancreatitis is a sudden onset, primarily noninfectious inflammatory disease of the pancreas. It is caused by inappropriate intracellular activation of proteolytic enzymes and subsequent autodigestion of the pancreatic parenchyma and surrounding tissues [20]. Even with increasing proportion of patients with severe AP, there has been a significant decrease in organ failure adjusted mortality due to AP suggesting improved management over years [1]. In accordance with the revised Atlanta classification, acute pancreatitis can be diagnosed if at least two of the following three criteria are fulfilled: abdominal pain (acute onset of persistent and severe epigastric pain, often radiating to the back); serum lipase (or amylase) activity at least three times the upper limit of normal; or characteristic findings of acute pancreatitis on


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contrast-enhanced CT or, less often, MRI or transabdominal ultrasonography [10].

CLASSIFICATION The classification has prognostic and therapeutic implications. It has two major roles. Staging the severity of the inflammatory process and detecting complications, especially the identification and quantification of parenchymal and peripancreatic necrosis. The diagnosis of acute pancreatitis is often established by clinical symptoms and laboratory testing. Stratification of patients with acute pancreatitis depends on the power of the initial attack. Rapid assessment of the likelihood of severe course is important to start an adequate treatment because any delay is burdened by significant increases in morbidity and mortality [2, 48]. The clinical prognostic indicators mention the Ranson score, which takes into account the biochemical parameters at the admission and during the first 48 hours of illness. Severe acute pancreatitis fulfils three or more of Ranson’s criteria [39]. The first established radiological score was noted by Balthazar in 1985 [7]. The changes were described on a non-contrast enhanced computed tomography scan looking for fluid collection and the degree of inflammatory changes in the tissue, not for the evaluation of pancreatic necrosis. Five years later, the Balthazar score was expanded by the computed tomography severity index (CTSI) [8]. This combines the two computed tomography prognostic indicators, i.e., the extent of necrosis and acute inflammatory process. Another version of the CTSI designed by Mortelé (modified CTSI) [36], adds parameters such as peripancreatic or vascular changes and gastrointestinal involvement. A comparison of both classifications is shown in (Table 1). Both the CTSI and modified CTSI systems were able to predict the need for interventions with greater accuracy than clinical systems [15]. The problem of radiological scoring systems based on the extent of necrosis is the low resolution of the contrast computed tomography examinations in the early days of the disease, which is crucial for the initiation of therapy. The scores of De Waele et al. [20] includes the peripancreatic inflammatory conditions and the extent of ascites, pleural effusion and others. The advantage of this is that for these to be detected it is not necessary to apply a contrast medium, they can be differentiated in the early days of the disease. With a sensitivity of 100% and a specificity of 70.8% it is possible, 24


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hours after admission, to predict severe acute pancreatitis with scores of 4 or more [20, 43]. Table 1. Comparison of computed tomography severity index (CTSI) – according to Balthazar [8] and Mortelé [36]

Pancreatic inflammation Normal pancreas Enlargement of the pancreas Peripancreatic inflammation One acute peripancreatitic fluid collection Two or more acute peripancreatitic fluid collection Extra pancreatic complications Pancreatic necrosis None Less than 30% 30-50% More than 50% CTSI Score Grade Mild pancreatitis Moderate pancreatitis Severe pancreatitis

Balthazar CTSI Points Grade 0 A 1 B 2 C 3 D 4

Mortelé CTSI Points 0 2 2

E 2

0 2 4 6

0 2 4

0-3 4-6 7-10

0-2 4-6 8-10

The Atlanta classification of acute pancreatitis was most recently revised in 2012 [10]. This international consensus provides clear definitions to classify acute pancreatitis using easily identified clinical and radiologic criteria. On admission it is important to identify patients with potentially severe acute pancreatitis who require aggressive early treatment. The most common latest the Atlanta classification (as revised in 2012) has several aspects: Depending on the severity of clinical manifestations and from the morphological point of view acute pancreatitis is divided into three grades: mild acute pancreatitis, moderately severe acute pancreatitis and severe acute pancreatitis [9]. Mild acute pancreatitis (Figure 1) is without organ failure and the absence of local or systemic complications. Patients with mild acute



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pancreatitis usually do not require pancreatic imaging. The diagnosis is based on clinical and laboratory findings.

Figure 1. Axial CT image of acute interstitial oedematous pancreatitis in a 47 year-old man. The image shows homogeneous enhancement of an enlarged pancreatic parenchyma (asterisk) without necrosis and mild peripancreatic fat stranding (arrows). Grade C (Balthazar), modified CTSI 2 - mild acute pancreatitis.

Figure 2. Axial CT image of acute necrotizing pancreatitis (peripancreatic necrosis alone) in a 79-year-old man. CT shows normal enhancing pancreas (asterisk)


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surrounded by heterogeneous acute necrotic collections (arrows) with fluid and nonliquid (fat) densities, suggestive of peripancreatic necrosis alone. This collection can be observed in the left anterior pararenal space and the root of the transverse mesocolon. Grade D (Balthazar), modified CTSI 4 - moderate acute pancreatitis.

Moderately severe acute pancreatitis is characterized by the presence of transient organ failure or local or systemic complications in the absence of persistent organ dysfunction lasting less than 48 hours (Figure 2). Severe acute pancreatitis is characterized by persistent organ failure, dysfunction lasting more than 48 hours (Figure 3).

Figure 3. Axial CT image. Acute necrotizing pancreatitis (pancreas gland and peripancreatic necrosis) in a 47-year-old man. (A) The enlargement of the pancreatic head and a poorly contrasted area (indicated by the white asterix) were observed. CT reveals perfusion defect of approximately 50% at the head and body of the pancreas (white asterisk) with preserved enhancement of tail white arrow), surrounded by heterogeneous acute necrotic collections (black arrow). Significant fat necrosis can be observed in the lesser sac, both anterior and posterior pararenal space and transverse mesocolon (arrows). A large amount of ascites (AS) was observed. Walled-off necrosis in right posterior pararenal compartment (black asterix). Grade E (Balthazar), 30% to 50% parenchymal necrosis; modified CTSI 8, severe acute pancreatitis.



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(B) Follow-up CT examination 26 days later. After operation without walled-off necrosis in right posterior pararenal compartment, but progression of walled-off necrosis in peripancreatic compartment was observed (>4 weeks) (white asterix) and pancreatic necrosis (black asterix). CT depicts well-defined heterogeneous fully encapsulated collection (white asterix). This was diagnosed as walled-off necrosis (WON).

In terms of time, acute pancreatitis is divided into early (less than one week) and late stages (over one week). Morphologically there are two types of acute pancreatitis, interstitial or oedematous pancreatitis (mild level) and acute haemorrhagic necrotizing pancreatitis (severe stage) [21]. Necrosis of pancreatic parenchyma or peripancreatic tissues occurs in 1015% of patients. It is characterized by a protracted clinical course, a high incidence of local complications, and a high mortality rate. There are three subtypes of necrotizing pancreatitis: 1. Necrosis of both pancreatic parenchyma and peripancreatic tissues (most common); 2. Necrosis of only extrapancreatic tissue without necrosis of pancreatic parenchyma (less common); 3. Necrosis of pancreatic parenchyma without surrounding necrosis of peripancreatic tissue (very rare) [47].

Revised Definitions of Morphological Feature of Acute Pancreatitis Interstitial oedematous pancreatitis: Acute inflammation of the pancreatic parenchyma and peripancreatic tissues, but without recognizable tissue necrosis. CECT criteria: pancreatic parenchyma enhancement by intravenous contrast agent. No findings of peripancreatic necrosis. Necrotizing pancreatitis: Inflammation associated with pancreatic parenchymal necrosis and/or peripancreatic necrosis. CECT criteria: lack of pancreatic parenchymal enhancement by intravenous contrast agent and/or presence of findings of peripancreatitic necrosis (ANC and WON).

Atlanta Classification of Fluid Collections The 2012 revised Atlanta classification discerns four types of peripancreatic fluid collections in acute pancreatitis depending on the content, degree of encapsulation and time (Table 2).


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Content: Fluid only in acute peripancreatic fluid collection (APFC) and pseudocyst. Mixture of fluid and necrotic material in acute necrotic collection (ANC) and walled-off-necrosis. Degree of encapsulation: None or partial wall in APFC and ANC. Complete encapsulation in pseudocyst and WON. Time: Within 4 weeks: APFC and ANC. After 4 weeks: pseudocysts and WON. It takes about 4 weeks for a capsule to form. On CT, the discrimination between an APFC and ANC may be difficult, especially in the first weeks and the term ‘indeterminate peripancreatic collections’ can be used. All these collections may remain sterile or become infected. Infection is rare during the first week. Table 2. Revised Atlanta classification for imaging [21] Pancreatitis Less than 4 weeks Interstitial oedematous pancreatitis Necrotizing pancreatitis

Collection

Infection

APFC

+/- infection

PNPFC Parenchymal necrosis Peripancreatitis necrosis Mixed necrosis

More than 4 weeks Interstitial oedematous Pseudocyst pancreatitis Necrotizing pancreatitis WOPN APFC – acute peripancreatitic fluid collection. PNPFC – post-necrotic pancreatic fluid collection. WOPN – walled-off pancreatic necrosis.

+/- infection

+/- infection +/- infection

1. APFC (Acute Peripancreatic Fluid Collection) Peripancreatic fluid associated with interstitial oedematous pancreatitis with no associated peripancreatic necrosis. This term applies only to areas with peripancreatic fluid seen within the first 4 weeks after onset of interstitial oedematous pancreatitis without the features of a pseudocyst. CECT criteria: occurs in the setting of interstitial oedematous pancreatitis. Homogeneous collection with fluid density. Confined by normal peripancreatic fascial planes. No definable wall encapsulating the collection. Adjacent to pancreas (no intrapancreatic extension).



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2. Pancreatic Pseudocyst An encapsulated collection of fluid with a well-defined inflammatory wall usually outside the pancreas with minimal or no necrosis. This entity usually occurs more than 4 weeks after the onset of interstitial oedematous pancreatitis. CECT criteria: well circumscribed usually round or oval. Homogeneous fluid density. No non-liquid component. Well-defined wall, which is completely encapsulated. Maturation usually requires more than 4 weeks after onset of acute pancreatitis, occuring after interstitial oedematous pancreatitis. 3. ANC (Acute Necrotic Collection) A collection containing variable amounts of both fluid and necrosis associated with necrotizing pancreatitis, the necrosis can involve the pancreatic parenchyma and/or the peripancreatic tissues. CECT criteria: occurs only in the setting of acute necrotizing pancreatitis. Heterogeneous and nonliquid density of varying degrees in different locations (some appear homogeneous early in their course). No definable wall encapsulating the collection. Location could be intrapancreatic and/or extrapancreatic. 4. WON (Walled-Off Necrosis) A mature encapsulated collection of pancreatic and/or peripancreatic necrosis that has developed a well-defined inflammatory wall. WON usually occurs more than 4 weeks after onset of necrotizing pancreatitis. CECT criteria: heterogeneous with liquid and non-liquid density with varying degrees of loculations (some may appear homogeneous). Well-defined wall, which is completely encapsulated. Location could be intrapancreatic and/or extrapancreatic. Maturation usually requires 4 weeks after onset of acute necrotizing pancreatitis [10].

OVERVIEW OF IMAGING TECHNIQUES Imaging techniques commonly used for the diagnosis and severity assessment of AP include abdominal ultrasound, contrast-enhanced CT, and magnetic resonance imaging [17]. Plain film of the abdomen is a non-specific examination. Clinical suspicion of acute pancreatitis should be confirmed by checking for elevated pancreatic enzyme levels in the blood serum, in the urine, or


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peritoneal fluid, although the increase is not specific. However, abdominal symptomatology accompanied by three times elevated amylase is very likely in the diagnosis of acute pancreatitis. In the diagnosis of severe acute pancreatitis imaging methods are essential [13]. Plain film. When acute pancreatitis is suspected, chest and abdominal Xray examinations should be performed to check for the presence of any abnormal findings caused by acute pancreatitis. Abdominal X-ray examinations in acute pancreatitis visualize ileus, localized sentinel loop signs in the left upper abdomen, enlarged duodenal loops and gas collections, colon cutoff signs in the right colon, retroperitoneal gas collection, calcified gallstones, and pancreatolithiasis [32]. Abdominal ultrasonography. The pancreas may appear completely normal in mild cases of acute pancreatitis. Because of the increased amount of gas in the intestine (paralytic ileus) in the early stage of the disease, ultrasound is not useful for the early detection of acute pancreatitis. Ultrasound’s role is to detect gallstones after the first episode of AP [5]. In the first line, ultrasound is used to exclude biliary aetiology, and then in distinguishing fluid and semisolid local complications (Figure 4). The advantage of ultrasound is its simplicity and the fact that it is a non-invasive examination. More definitive findings include a diffusely enlarged gland and reduced parenchymal echogenicity. Focal enlargement of the pancreatic head and body may also be seen. In severe form the area of peripancreatic fluid collections or intrapancreatic localization of liquid compositions may be evidence of necrosis. The spleen can be used as an acoustic window to image the pancreatic tail. The Doppler technique should be used to assess vascular complications of acute pancreatitis, such as venous thrombosis and pseudoaneurysm formation. A pseudoaneurysm has turbulent arterial flow within the mass. Complications of acute pancreatitis may be identified. Peripancreatic free fluid collections look like ill-defined anechoic collections. The fluid collections may demonstrate internal echoes/debris or septations if haemorrhage or a superimposed infection has occurred. Pseudocysts look like well-defined round or oval anechoic fluid collections with through transmission. Infected and non-infected pseudocysts are indistinguishable from each other sonographically. Ultrasonography is often used to monitor the resolution of pancreatic pseudocysts. A pancreatic abscess may appear as a complex cystic structure with internal debris, septations and, possibly, echogenic gas bubbles [16].



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CEUS (contrast enhanced ultrasound) has been proven to be an accurate method for evaluating the presence and extent of necrosis in acute pancreatitis [4]. EUS (endosonography) allows to accurately predict the severity and risk of mortality in nearly 90% of cases with AP [3]. Computed tomography. Computed tomography scan with contrast medium is considered the gold standard in the diagnosis of local involvement, especially of pancreatic necrosis. An early CT scan is only recommended when the diagnosis is uncertain, or in case of suspected early complications, such as bowel perforation or ischaemia. Typical CT findings in acute pancreatitis include focal or diffuse enlargement of the pancreas, heterogeneous enhancement of the gland due to oedema or necrosis, irregular or shaggy contour of the pancreatic margins, blurring of peripancreatic fat planes with streaky soft tissue stranding densities, thickening of fascial planes, and the presence of intraperitoneal or retroperitoneal fluid collections (Figure 5).

Figure 4. Axial ultrasound image of interstitial oedematous pancreatitis in a 10 yearold boy. The image shows homogeneous pancreatic parenchyma without necrosis (asterisk) and hypoechoic peripancreatic fat stranding (arrow). VL – lienal vein; Ao – aorta.


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Figure 5. Axial CT image of interstitial oedematous pancreatitis in a 49-year-old man. The image shows homogeneous enhancement of the pancreatic parenchyma without necrosis (asterisk) and mild peripancreatic fat stranding (arrow).

Fluid collections are most commonly found in the peripancreatic and anterior pararenal spaces. They can extend from the mediastinum down to the pelvis. Clavien et al. reported a 92% sensitivity and 100% specificity in diagnosing acute pancreatitis via CECT [19]. Balthazar et al. reported an overall accuracy of 80–90% in the detection of pancreatic necrosis [8]. The Atlanta classification defined pancreatic necrosis as a deposit of the pancreatic tissue, the density of which does not exceed 50 Hounsfield units (HU) and covers at least 30% of the pancreatic tissue and an area of more than 3 centimetres in diameter [29]. An early CT may be misleading regarding the morphologic severity of the pancreatitis, because it may underestimate the presence and amount of necrosis. Necrosis of peripancreatic tissue can be very difficult to diagnose, but is suspected when the collection is inhomogeneous, i.e., there are various densities on CT. Necrosis is stabilized within 96 hours after the onset of symptoms, and can therefore contrast CT findings within the first 24 hours can give a false negative and be underestimated. A pancreatic abscess can manifest as a thick-walled low-attenuation fluid collection with gas bubbles or a poorly defined fluid collection with mixed densities/attenuation. Gas bubbles are not specific for infection. A suspected pancreatic abscess requires needle aspiration because it cannot be ruled out on the basis of CT morphology. Necrotic pancreatic tissue is not enhanced after the administration of intravenous contrast. Normal unenhanced pancreas has CT attenuation measuring 30–50 HU and after intravenous contrast, the pancreas should display attenuation measuring 100–150 HU [8].



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Early detection of infection in acute pancreatitis affects the choice of treatment and clinical outcome. Positron emission tomography-computed tomography (PET/CT) is useful in detecting infection in pancreatic or peripancreatic fluid collections in patients with AP [14, 40]. Local complications of acute pancreatitis can be recognized using CECT [29], such as necrosis, infected necrosis (difficult to differentiate from aseptic necrosis, often only by the presence of bubbles of gas), abscesses (collection density of over 10 HU), pseudocysts, haemorrhage (hyperdense fluid collection retroperitoneal or peripancreatic tissue) (Figure 6). A pseudocyst appears as an oval or round water density collection with a thin or thick wall, which may be enhanced. Venous thrombosis can be identified through a failure of the peripancreatic vein (splenic vein, portal vein) to enhance or as an intraluminal filling defect. Associated gastric varices may be identified. A pseudoaneurysm usually appears as a well-defined round structure with a contrast-enhancement pattern similar to that of the aorta and other arteries. Haemorrhage appears as a high-attenuation fluid collections. Active bleeding is seen as contrast extravasation [16].

Figure 6. (Continued).



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Figure 6. (Continued).



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Figure 6. Serial axial CT scans (A−E). Acute necrotizing pancreatitis (pancreas gland and peripancreatic necrosis) in a 28-year-old man. Typical sequence of events in a case of central gland necrosis, pseudocyst formation and walled-off necrosis. Collections (white arrows) in lesser sac and left anterior and posterior pararenal compartment. Grade E, less than 30% parenchymal necrosis; modified CTSI 8 − severe acute pancreatitis. (A) Initial CT shows perfusion defects of the body of the pancreas (asterix), indicating parenchymal necrosis with a fluid collection extending into the left pararenal compartment (arrows) and the root of the transverse mesocolon. The fluid collection lacks a well-defined wall. Acute peripancreatic fluid collection (4 weeks) (arrows). (A) CT depicts welldefined heterogeneous collection (arrows) with primarily fluid density and scattered areas of fat density and fully encapsulated collection, indicative of necrosis of peripancreatic tissues. This was diagnosed as walled-off necrosis (WON). The patient suffered from fever despite antibiotic treatment. This heterogeneous and fully encapsulated collection (arrows) was classified as pancreatic necrosis, pseudocyst, or even pancreatic abscess (all may have a similar appearance on CT). (D) Follow-up axial CT scan. Three months after the acute attack a persistent heterogeneous collection is observed (arrows). Drainage operation – pseudocystostomi (arrow) was performed between WON and stomach, which is partially diminished in size.


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Kamil Zeleňák and Martin Števík (E) Follow-up CT 4 months later shows a recurrent collection. The patient developed fever and elevated white blood cell count, suggestive of infected collection. CT shows extensive necrosis (30−50%) and an encapsulated heterogeneous collection (arrows) with liquid and non-liquid (fat) densities (small arrows), as well as impacted gas bubbles (arrowheads), indicative of infected necrosis. At surgery, infected necrosis was debrided and pus was drained.

Indications for Use of CT in Patients with Acute Pancreatitis An initial CT scan is indicated in patients in cases where there is doubt about the clinical diagnosis (best at least 48 hours after onset of symptoms): in patients with clinical signs of severe pancreatitis; in patients who do not show adequate improvement within 72 hours of initiation of the conservative medical treatment; in patients who develop a sudden change in clinical status (fever, pain, decreasing hematocrit, hypotension, etc.) after initial improvement, suggesting complications. Follow-up CT scan should be obtained after 7 to 10 days and/or before hospital discharge in all patients with a grade D or E pancreatitis (CTSI score of 3−10) to exclude clinically silent complications; in patients with no or inadequate clinical improvement or deterioration under treatment; in patients with grade A−C pancreatitis (CTSI 0−2) only when complications are suspected [41]. Magnetic resonance image is preferred for patients where the CT is contraindicated. The morphologic changes of acute pancreatitis are similar on CT and MRI. The pancreas may be enlarged focally (usually the pancreatic head) or diffusely. An MRI is superior to CT in differentiating between fluid and solid necrotic debris (Figures 7, 8). Magnetic resonance imaging has a better resolution of solid material within fluid collections, and provides a better identification of local complications. Magnetic resonance cholangiopancreatography (MRCP) is also helpful in the diagnosis of choledocholithiasis and pancreas divisum. Magnetic resonance imaging may also be better than CT in detecting areas of sterile pancreatic necrosis in what appear to be simple pseudocysts on CT. Acute inflammatory changes appear as strands of low signal intensity in the surrounding peripancreatic fat. Complications of acute pancreatitis can also be identified. Haemorrhage is characterized by T1 shortening or high signal intensity on T1-weighted images (WI) with fat suppression. Peripancreatic fluid collection, pseudocyst, and abscess are recognized by their high signal



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intensity on T2-weighted images. Devascularized or necrotic portions of the pancreas fail to enhance on dynamic gadolinium-enhanced images [42]. The T1−WI is present variable decrease in the intensity signal in case of acute pancreatitis and hyperintensity of haemorrhage. If the collections show homogeneous high signal intensity on a fat-suppressed T2−weighted MRI image, they contain clear fluid (i.e., pseudocysts). If a T2−weighted MRI sequence shows that the collection has a low signal intensity, most likely this is necrotic fat tissue (i.e., sterile necrosis or walled-off necrosis). The necrosis and pseudocyst are without enhancement in T1−WI [16]. Diffusion-weighted magnetic resonance imaging (DW-MRI) can be used as a non-invasive technique for the detection of infection in acute pancreatitis-associated collections [28].

Figure 7. Axial MR T1−weighted fat suppressed image of acute interstitial oedematous pancreatitis in a 56-year-old woman. The image shows homogeneous signal of the pancreatic parenchyma (asterisk) without necrosis and mild peripancreatic fat stranding (white arrow). Fluid collection can be observed in the left anterior pararenal space (black arrow). Grade D (Balthazar), modified CTSI 3 - mild acute pancreatitis.


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Figure 8. Axial MR T1−weighted fat suppressed image of acute necrotizing pancreatitis (peripancreatic necrosis alone) in a 28-year-old woman. MR shows normal pancreas (asterisk), tail is surrounded by heterogeneous acute necrotic collections (arrows) with hyperintense signal due to a high level of protein, suggestive of peripancreatic necrosis alone. This collection can be observed in the left anterior pararenal space and the root of the transverse mesocolon. Grade D (Balthazar), modified CTSI 4 − moderate acute pancreatitis.

ANGIOGRAPHY AND INTERVENTIONAL RADIOLOGY Vascular complications of acute pancreatitis result from the proteolytic effects of the pancreatic enzymes that cause the erosion of blood vessels, which often results in pseudoaneurysm (PSA) formation. The splenic artery, followed by the pancreaticoduodenal and gastroduodenal arteries, are most commonly affected. The bleeding point is identified by noting free contrast extravasation [27]. Haemorrhagic complications are usually manifestations of the progress of severe pancreatitis [50]. It is recommended that all pseudoaneurysms be repaired [24]. Endovascular therapy remains the first-line option for known arterial bleeding (preferably in a patient with a stable haemodynamic status) and is considered a safe and effective modality to treat visceral pseudoaneurysms. Metallic coil embolization is preferable distal and proximal to the site of arterial extravasation (the so-called sandwich technique), thereby preventing backflow from the collateral circulation [25, 26]. A PSA with narrow neck can be embolized selectively (Figures 9−13).



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Figure 9. Contrast-enhanced CT – coronal reconstruction: pseudoaneurysm of inferior pancreaticoduodenal artery.

Endovascular techniques utilized include coiling, covered stent exclusion, thrombin injection, gel-foam injection, gluing, plug deployment, particle injection, and polyvinyl alcohol injection. Transabdominal coiling and thrombin injection under ultrasound or fluoroscopic guidance have also been employed [22]. The endovascular approach to pancreatitis-associated pseudoaneurysms depends on the location and morphology of the pseudoaneurysm [29]. In cases where the configuration of the pseudoaneurysm neck is suboptimal or where there is a high risk of non-target embolization, a covered stent can be placed to exclude the pseudoaneurysm from the circulation. Stent-graft implantation is usually limited to straight and proximal segments of visceral arteries. Liquid embolic material (Onyx) has also been used for treatment of haemorrhage caused by pancreatitis [50].


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Figure 10. CTA (CT angiography) – VRT (volume rendering technique) confirmed pseudoaneurysm of inferior pancreaticoduodenal artery.

Image-guided intervention has an important role in the management of late complications of acute pancreatitis which significantly add to the degree of morbidity. Image-guided drainage procedures have been found to be an effective alternative to surgical debridement in patients with pancreatitisassociated complications [37]. Indications for drainage include: symptomatic collections which are exerting mass effect, causing pain or have become infected [46]. Pseudocysts larger than 5 centimetres that have been present for longer than six weeks, are unlikely to resolve spontaneously [34]. According to a recent study, compared with percutaneous drainage, endoscopic drainage of symptomatic pancreatic fluid collections was associated with higher rates of treatment success, and lower rates of reintervention, including surgery and shorter lengths of hospital stay [30].

Endoscopic Retrograde Cholangiopancreatography Because of its risks this is not indicated in mild biliary acute pancreatitis. In contrast, an absolute indication is acute biliary pancreatitis and cholangitis. An MRCP is preferred to view an anatomy and abnormalities of the biliary tract and pancreatic duct.



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Figure 11. Angiography of superior mesenteric artery: pseudoaneurysm of inferior pancreaticoduodenal artery before embolization.

Figure 12. Angiography of superior mesenteric artery: pseudoaneurysm of inferior pancreaticoduodenal artery after embolization.



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Figure 13. 5-year follow-up magnetic resonance – T1−WI fat-suppressed technique: complete occlusion of treated PSA without recanalization. Implanted coils are hypointense (arrow).

COMPLICATIONS OF ACUTE PANCREATITIS In addition to systemic complications, such as respiratory, cardiac, renal failure and other biochemical and coagulation disorders, other local complications may also occur in acute pancreatitis. Local complications are classified by their content of pure fluid, and those containing a proportion of solid content. Distinction is made between an acute collection which does not have a demarcated and clearly defined wall and a collection bounded by inflammatory granulation and fibrotic wall. Another complication could be haemorrhage, formation of pseudoaneurysm and venous thrombosis. Radiological description should include the presence or absence of local complications [35].

Fluid Collections Acute pancreatic fluid collection (APFC): collections of enzyme-rich pancreatic juice develop around the pancreas as a result of interstitial pancreatitis without necrosis in the first 4 weeks of illness. Most of them



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remain sterile and gradually disappear spontaneously in 50% of cases. Location may by intrapancreatic, anterior pararenal space, lesser sac or anywhere in the abdomen, in solid organs or in the chest. Pseudocyst: not reabsorbed APFC inflammatory circumscribed wall after 4 weeks of onset of the disease arises rupture of the pancreatic duct and therefore has a high amylose content. It may arise in terrain of interstitial as well as necrotic acute pancreatitis. Pseudocysts present as rounded, wellencapsulated fluid collections of varying attenuation (0−25 HU). There is contrast encement in the cyst wall, septations are uncommon. Most frequently pseudocysts are located close to the pancreas, but may also be found in the liver, spleen or mediastinum. Some of them will require a catheter or surgical drainage [18].

Solid, Semi-Solid Locoregional Complications The Atlantic revised classification distinguishes between acute necrotic collection and walled-off necrosis. They develop in the field of necrotic acute pancreatitis 4 or more weeks after the onset of the disease [49]. Acute necrotizing collection − necrotic material includes pancreatic and/or peripancreatic materials and variable amounts of liquid material. Walled-off necrosis − necrotic collection of the pancreatic and / or peripancreatic tissue, with the radiologically clearly marked wall. The infection – abscess (most often from the gastrointestinal tract) occurs in one-third of cases with severe acute pancreatitis. Diagnosis is either radiological, gas bubbles in the peripancreatic region or by fine needle aspiration (FNA) of the necrotic material [38]. Thrombosis splenic and the portal vein and spleen lesions − their consequence is prehepatic portal hypertension. Spleen lesions include fluid collections inside the spleen, pseudocysts, vascular injury, infarction or haemorrhage. Haemorrhage - occurs due to erosion of blood vessels (pancreatic duodenal artery, splenic artery branch) by extravasation of proteolytic enzyme. CT occasionally shows a circumscribed peripancreatic fluid collection of high attenuation of more than 60 HU. Possible treatment could be embolization. Pseudoaneurysm – autodigestion of arterial walls by pancreatic enzyme, mass is lined by fibrous tissue and communicates with parent artery (Figure 14).


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Extrapancreatic complications could be ileus, bowel ischaemia, gastroparesis, pseudoaneurysm, cholecystitis, fluidothorax or ascites.

Figure 14. Axial (A) and coronal (B) CT image of interstitial oedematous pancreatitis in a 52-year-old man. CT shows normal enhancement of the pancreas (asterix) with a fluid collection extending into both anterior pararenal compartment and the root of the transverse mesocolon (white arrows). Acute peripancreatic fluid collection ( 4 weeks after onset of NP [2, 6]. WON can be differentiated from pancreatic pseudocyst (PPC) using CT contrast level and MRI. PPC are homogeneous, well circumscribed and liquid collections seen > 4 weeks after onset of interstitial oedematous pancreatitis [3, 5, 6]. The content of collections might be difficult to be differentiated using CT; MRI may enable the diagnosis. Fatty necrosis presents higher signals in T1enhanced imaging and mildly lower signals in T2-enhanced imaging compared with fluid [4, 5].

Necrosis (-) Necrosis (+)

APFC (sterile) APFC (infected) ANC (sterile) ANC (infected)

4 weeks after onset of pancreatitis PPC (sterile) PPC (infected) WON (sterile) WON (infected)

APFC: acute peripancreatic fluid collection. ANC: acute necrotic collection. PPC: pancreatic pseudocyst. WON: walled-off necrosis.


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Pancreatic and peripancreatic necrosis, ANC and WON can remain sterile or become infected. Infected necrosis is rare during the first week [2].

Phases of AP Two different phases have been identified according to two peaks of mortality: a.

Early (within 1 week), characterized by the systemic inflammatory response syndrome (SIRS) and/ or organ failure. b. Late (> 1 week), characterized by persistence of systemic signs of inflammation or by local complications. The SIRS appeared in the early phase may be followed by a compensatory anti-inflammatory response syndrome (CARS) that may contribute to an increased risk of infection. The presence and duration of organ failure is the main determinant of severity in both phases.

Severity of AP Several scoring systems have been proposed and are used at clinical sites for severity assessments of AP: Ranson (1974) [7], APACHE-II (1989) [8], Panc 3 score (2007) [9], POP (Pancreatitis Outcome Prediction, 2007) [10], BiSAP (Bed-side for Severity in Acute Pancreatitis, 2008) [11], JSS (Japanese Severity Score, 2008) [12], HAPS (Harmless Acute Pancreatitis Score, 2009) [13] and revised Atlanta classification and definitions (2012) [2], among others. It is recommended to make a severity assessment immediately after diagnosis and repeated over time; re-evaluations should be made 24 hours, 48 hours and 7 days after admission to the hospital [2, 3]. Following the latest revised Atlanta definitions [2], three new severity grades were shaped: mild, moderately severe and severe AP. a.

In mild AP there’s neither organ failure or local or systemic complications. Pancreatic imaging is not usually required, and


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mortality is very rare. Antibiotic prophylaxis is not recommended, as seen later. b. In moderately severe AP there is transient organ failure (resolves within 48 hours) or local or systemic complications in the absence of persistent organ failure. Prolonged specialist care may be required. Mortality is far less than that of severe AP. c. Finally, severe AP is characterised by persistent organ failure. It may be single or multiple. One or more local complications are usually presented. Severe AP in the first few days associates a high risk of death (36-50%) [14]; infection of necrosis associates an extremely high mortality.

3. INCIDENCE A large increase in the incidence of AP and a smaller increase in the incidence of chronic pancreatitis have been reported in population studies. Nowadays, the annual incidence of AP ranges from 13 to 45/100,000 population [15], with an overall prevalence rate of 49.4 per 100,000 population [16]. It’s one of the most frequent causes of acute gastrointestinal, liver, and pancreatic diseases requiring hospitalization, rising the third leading position in US in 2012 (275,170 admissions). It was also the 12th most common cause of the emergency department visit (330,561 visits) and the 15th cause of death (2,844 patients as underlying cause of death) from gastrointestinal, liver, and pancreatic diseases. In other words, that means a crude mortality rate of 0.9%, [17], even though it can raise up to 50% in infected pancreatic necrosis as said before [14].

4. ETIOLOGY The identification of the etiology is important for the management during the early phase of the disease. Although there is no specific therapy for acute pancreatitis, the causing factor must be investigated and eliminated if identified [18].


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Acquired Conditions a.

Gallstone disease. Gallstone-induced pancreatitis is caused by duct obstruction. This is produced as a consequence of an impacted stone that obstructs the main pancreatic duct at the level of papilla of Vater, or because of transient papillary edema or papillary orifice relaxation following the passage of stones, that can obstruct the pancreatic juice flow or favor duodenopancreatic reflux. Transient ampullary obstruction may allow bile to reflux into the pancreas, even if the pressure in the main pancreatic duct in normal conditions is generally higher than in the common bile duct. Bile reflux into the pancreatic ductal system is facilitated if there is a common channel at biliopancreatic junction. The common channel theory has been confirmed in 1993 by Hernández and Lerch [19]. These studies documented the presence of amylase in the bile collected by a T-tube inserted into the common bile duct, suggesting there might be a functional channel between the two ductal systems. The gallstone disease may also be manifested only by: 1) microlithiasis (stones less that 2 mm of diameter), that can be seen or suspected mainly at endoscopic ultrasound or endoscopic retrograde cholangio-pancreatography (ERCP); 2) gallbladder sludge, which can only be visualized by endoscopic ultrasound; and 3) calcium carbonate, cholesterol monohydrate and calcium bilirubinate crystals [20]. b. Alcohol-induced AP. Alcohol abuse is the second most frequent cause of AP [21]. Typically occurs in people who have consumed large amounts of alcohol for at least 5-10 years. In most countries, the proportions of alcohol-attributable mortality from pancreatitis fall within the range between 40 and 80% [22]. Alcohol intake causes a transient stimulation of exocrine pancreatic secretion by increasing the synthesis and secretion of digestive and lysosomal enzymes in pancreatic acinar cells. Ethanol has been proven not to cause AP itself but sensitizes the pancreas to disease. It appears that the pancreas has developed protective mechanisms that can partially compensate for ethanol-induced cellular damage. Further defining the mechanisms of ethanol-induced pancreatic injury may help define these protective mechanisms. It is hoped that this strategy will lead to the development of therapeutic targets that will prevent or reduce the severity of alcoholic pancreatitis [23].


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Sphincter of oddi dysfunction (SOD). Is another common cause of AP. SOD comprises two clinical entities: 1) SO increased basal pressure, which refers to a structural alteration of the sphincter, as consequence of a long-lasting inflammatory process with subsequent fibrosis (stenosis); and 2) SO dyskinesia, referring to a transient primary motor abnormality characterized mainly by sphincter hypertone. SOD has been classified under three headings on the basis of clinical and morphological parameters and may involve either the biliary or the pancreatic segment of the sphincter [20]. d. Post – ERCP. Pancreatitis is the most common complication of ERCP and carries a high morbidity and mortality. Asymptomatic hyperamylasaemia occurs in 35%-70% of patients after the procedure [21]. Risk is particularly high in young women with SOD. Metaanalyses have helped screen for promising modalities of prophylaxis. At present, evidence is emerging that pancreatic stenting of patients with SOD and rectally administered nonsteroidal anti-inflammatory drugs in a large unselected trial reduce the risk of post-procedure pancreatitis. A recent meta-analysis have demonstrated that rectally administered indomethacin, just before or after ERCP is associated with significantly lower rate of pancreatitis compared with placebo [24]. In another retrospective study analyzing 900 cases of patients who underwent ERCP, AP developed in 3,7% of the cases [25]. e. Metabolic causes. Like hypertriglyceridemia and hypercalcemia. There are many causes of hypercalcemia, but the majority of patients who develop acute recurrent pancreatitis have hyperparathyroidism. The diagnosis may be missed if calcium levels are not measured during each attack. Typically, serum triglycerides have to exceed 1,000 mg/dL to precipitate an attack of AP [19]. f. Postraumatic AP. The typical clinical triad of pancreatic trauma is upper abdominal pain, leukocytosis, and elevated serum amylase level, that may be absent in adults during the first 24 hours and even for several days [27]. Pancreatic trauma is difficult to recognize because of coexisting injuries and the central retroperitoneal location, presenting higher mortality rates than observed in injuries to other intra-abdominal organs. In a patient with an isolated pancreatic injury, even ductal transection may be initially asymptomatic or have only minor signs. g. Other acquired conditions. Benign and malignant tumors of the papilla of Vater or pancreatico-biliary junction, organic strictures of


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José R. O. Guillén, Ana P. Cano, María B.Martos et al. the main pancreatic duct, and cystic neoplasms, including mucinous ductal ectasia. Neoplastic strictures are found to induce AP in about 5% of cases [19, 21]. Choledochocele is a congenital or acquired condition in which the intramural segment of the common bile duct is dilated and herniates into the duodenal lumen. AP may develop when the cystic dilation or bile duct sludge or stones obstruct the pancreatic juice outflow. Ampullary choledochal cysts can develop when there is SOD [19].

Many infectious agents are associated with AP, but no microorganism has ever been identified within the pancreas [21]. Smoking has long been thought to play a role in the induction of AP, but it was only recently that large prospective studies have proved that cigarette smoking is an independent risk factor and could be dose-dependent [27]. For a number of substances there is general agreement on some relation with AP, and a recent review by the Midwest Multicenter Pancreatic Study Group [28] listed the following as medications for which a strong association with AP is documented: alphamethyldopa, azathioprine, cimetidine, cytosine arabinoside, corticosteroids, estrogens, furosemide, isoniazid, mercaptopurine, metronidazole, pentamidine, procainamide, sulfamethazole, sulindac, tetracycline, trimethroprim/sulfamethoxazole and valproic acid. Another causes of drug induced AP are azathioprine, mesalazine/sulfasalazine, 2-3dideoxyinosine (ddI), hydrochlorothiazide, and rifampicin [29].

Anatomical Variants Pancreas divisum is the most common variant of pancreatic ductal anatomy, occurring in up to 7% of autopsy series [21]. The dorsal duct of the pancreas can drain through the major papilla via a communicating branch of the ventral duct. However, this communication is generally narrow and may be inadequate for draining the pancreatic secretion. The inability of minor papilla to adapt the outflow of pancreatic juice when the gland is stimulated leads to ductal hypertension that in some individuals may cause either recurrent pain, elevation of amylase or AP. Dilatation of the dorsal duct confirms the presence of some obstruction at the level of minor papilla and suggests a positive outcome after sphincterotomy or stenting. Annular pancreas is a rare anatomical condition that may be associated with duodenal or biliary obstructive symptoms, as the consequence of the



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entrapment of duodenum and common bile duct by the annular growth of the gland. About one third of patients with annular pancreas also have pancreas divisum, so it is not clear whether recurrent pancreatitis depends on the annular variant or on the pancreas divisum. The presence of a common pancreatico-biliary channel abnormally long without sphincters separating the biliary and pancreatic ducts is a condition that facilitates free reflux of bile and pancreatic juice into the alternative duct. This abnormality of the pancreaticobiliary junction is easily diagnosed by magnetic resonance cholangiopancreatography or ERCP. Choledochal cysts and sigmoid configuration of the main pancreatic duct are other anatomical causes of AP [20].

Autoinmune Pancreatitis This is an autoinmune disorder caused by an infiltration of immune cells into pancreatic tissue. The pancreas of a patient with autoinmune pancreatitis is infiltrated by immune cells like cluster of differentiation CD 4-positive, T cells, and granulocytes in type 2 or IgG4-producing plasma cells and Blymphocyte antigen CD20 in type 1. It can be divided into a) Type 1: more frequent on adults, usually male, presenting elevated serum IgG4 levels, with a high relapse rate and associated with lymphadenophaty, thyroiditis or hypothyroidism, breast inflammatory pseudotumor or mastitis, chronic gastritis, ampulla of Vater pseudotumor, sclerosing cholangitis and others extra-pancreatic lessions; and b) Type 2: more frequent on children, regardless of gender, presenting normal serum IgG4 levels, with normal relapse rate and associated with inflammatory bowel disease. This type of AP responds to steroid therapy successfully [30].

Genetic Causes a.

CFTR - gene mutations. This condition represents the most common inherited disease of the exocrine pancreas. Exocrine pancreatic insufficiency with no inflammatory changes is the most common finding; AP may be the only clinical sign in some patients. CFTR mutation plays its role in intraluminal pH regulation from bicarbonate secretion and the flushing of ductal proteins [31]. Those with less severe mutations in the CFTR gene risk developing pancreatitis, which is estimated to be 40 to 80 times that in the general population.


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José R. O. Guillén, Ana P. Cano, María B.Martos et al. Heterozygotes for CFTR mutations are generally healthy but still have a 3 to 4-fold risk over the general population for pancreatitis [20]. b. PRSS1 - gene mutations. Mutations in the cationic trypsinogen gene have been found in patients with hereditary pancreatitis. In this autosomal dominant disorder the pancreas is unable to protect itself by premature or excessive trypsin activation in the gland; the lack of this protective mechanism against premature activation of trypsin predisposes individuals to recurrent bouts of pancreatitis in childhood and frequent progression to chronic pancreatitis [20]. c. SPINK1 - gene mutations. SPINK1 polymorphisms are common in the general population (~2%) and are significantly associated with pancreatitis [32]. SPINK1 has a protective action in the pancreas since it serves as an inhibitor of trypsin and plays a role in the prevention of premature activation of zymogen that is catalyzed by trypsin within the pancreatic duct system or the acinar tissue. These mutations have been estimated to raise the risk for pancreatitis [20], but the results of several studies are divergent depending on the geography [31].

5. MORTALITY Mild form of AP accounts for 80% of the cases; 95% of deceased patients for AP comes from the remaining 20% [33]. Although the mortality rate of severe AP has decreased in recent years, it is still around 20 to 25% [34]. Advanced age has been considered an independent prognostic factor for mortality in AP [34]. The presence of complications such as infected pancreatic necrosis in the aged population is associated with a mortality rate of up to 50% [35, 36]. Mortality rate has two peaks, early mortality (within the first six days of hospitalization) and late mortality (after the sixth day). The former is usually caused by a SIRS through shock and multiple organ failure, effect of the circulating pancreatic enzymes and activated inflammatory mediators (cytokines, interleukins, prostaglandins, etc.). SIRS can evolve independently of the original injury and its management consists in the treatment of the damages caused by systemic inflammation. Late mortality is generally caused by local complications (necrosis infections or peripancreatic collections infections) or distant complications (pneumonia, septicemia). For some authors, late mortality has decreased because of better antibiotic treatment and nutritional support and learned surgical decisions, while others guess that mortality rate has not changed but moved from early to late peak.



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Infection is widely accepted as the main reason for death in AP, mainly infected pancreatic necrosis, although older patients and those with comorbidities present high mortality attributed to others causes. The rate of infection correlates with the extent of necrosis and, therefore, with the severity of the disease. This infection has an enormous impact in mortality, multiplying it by 4 to 15 times. In general, infections are involved in 80% of deaths caused by AP. Mortality in patients without necrosis is nearly 0%, with sterile necrosis is between 0 and 11%, and with infected necrosis reaches 40% [1].

6. ANTIBIOTIC PROPHYLAXIS Antibiotic prophylaxis is the setting of pancreatic necrosis refers to the use of antibiotics to avoid infection in severe AP [1]. This issue has remained controversial for the lasts four decades. The most important questions raised are about antibiotic indications, antibiotic selection and length of treatment. Available studies are not conclusive although some have shown benefit from antibiotic prophylaxis. These last studies used different antibiotic drugs, different selection criteria, and different length of treatment. Also, definitions of severe disease varied between trials although in each the aim was to deliver antimicrobial prophylaxis to patients with severe AP and evidence of pancreatic necrosis. Combinations of the number observed in these studies suggests that there may be a significant reduction in complications and deaths in patients with predicted severe AP treated with prophylactic antibiotics, but this ignores the major inconsistences within and between these trials. When there is less than 30% of pancreatic necrosis, the risk of infection of necrosis and peripancreatic tissue is very low, so that the onset of antibiotic prophylaxis is recommended when there is evidence from imaging test (CT) of more than 30% of pancreatic necrosis, according to the American Gastroenterology Association [37]. In the beginning is also accepted after surgical necrosectomy, even without microbiological diagnosis to confirm the infection [38]. The basis of antibiotic prophylaxis in severe pancreatitis is to avoid infection and all the problems arising from it (major complications and death) [39, 40], since the infection of pancreatic necrosis is a major determinant in the prognosis of the patient [41]. Several prospective studies using broadspectrum antibiotic with good distribution in pancreatic tissue, exhibit a significant decrease in the range of infected necrosis, sepsis and mortality compared with the group of patients not receiving prophylaxis [42-44].


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Early trials show preference for use in severe pancreatitis grade, without finding evidence of benefit in mild pancreatitis [45]. In recent studies, it is established that the indication for initiating antibiotics must be based on the clinical judgment of the physician [46]. In the main studies treatment duration ranges from 7 to 14 days, because of longer treatments increases the prevalence of fungal infection. If there is no evidence of infection after this period, treatment is finished; on the other side, if we have evidence of infection for cultures, antibiotics based on the antibiogram are mandatory [38]. The monobacterial infection occurs in about 55-60% of cases of infected necrosis, the rest is multibacterial (Table 1). Abscesses are usually mainly multibacterial [47]. Fungal infection is increasing, caused in most cases by Candida. The major risk factors for the appearance of this type of infectious agent is the use of broad-spectrum antibiotics, prolonged hospitalization and surgical and / or endoscopic procedures. Both for prophylaxis and treatment, the antibiotic chosen must be one with good broad-spectrum diffusion in pancreatic tissue and also covers flora involved in infected necrosis. In published studies they have used different types of antibiotics, although the two groups have mainly been used carbapenems, quinolones, metronidazole and high dose cephalosporines. Some authors state that imipenem is the only antibiotic showing a significant decrease in infection of pancreatic necrosis [48, 49]. Table 1. Etiologic agents in infected AP Etiologic agents Gram-negative bacilii

Etiologic agents Other gram-negative bacilii Gram-positive cocci

Anaerobius Yeast

Escherichia coli Klebsiella spp Enterobacter spp Proteus spp Psuedomonas spp Staphylococcus aureus Enterococcus spp

Percentage 25-25% 10-25% 3-7% 8-10% Percentage 11-16% 14-15% 4-7% 6-16% 36%



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The problems arising from use are increasing the prevalence of fungal infection [38, 50, 51], and increasing the resistance and adverse effects associated with antibiotic. The role of antifungal prophylaxis, despite being debated in the last 15 years, is not well defined [38, 51-53]. So far there are no randomized studies on fungal prophylactic therapy in acute pancreatitis. In conclusion, we can say that there is no evidence or consensus to support the use of prophylactic antibiotics [49, 54-64]. They are not recommended by international guidelines for the treatment of AP [65-67]. In particular, the Working Group IAP / APA Guidelines Acute Pancreatitis of 2013, the use of intravenous antibiotic is not recomemended as prophylaxis for the prevention of infectious complications in AP with a degree of strong recommendation, grade I. Some of these authors believe in the existence of subgroups of patients who could benefit from using them, but more studies are needed to determine them [68]. Since 1993, there have been 11 prospective, randomized trials with proper study design, participants, and outcome measures that evaluated the use of prophylactic antibiotics in severe AP [55]. From this meta-analysis, the number needed to treat was 1,429 for one patient to benefit. Based on the current literature, the use of prophylactic antibiotics to prevent infection in patients with sterile necrosis (even predicted as having severe disease) is not recommended.

7. ANTIBIOTIC TREATMENT Three questions arise when we have to select an empirical treatment: which one is more adequate for bacterial flora and bacterial resistance in our hospital? When we must begin the treatment? For how long we keep the drug without clinical or microbiological demonstration? Antibiotic treatment only starts after confirmation of infected necrosis [67, 69, 70], based on the patient's clinical and imaging tests [51] that move fine needle aspiration as the gold standard for the confirmation of infection. Thus, the following clinical situations would be clear indication of the beginning of antibiotic treatment: a. Sepsis or SIRS. b. Multi-organ failure.


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Extrapancreatic infection: pneumonia, intrabadominal infection, urinary tract infection, sepsis of unknown focus, cholangitis, catheteracquired infections, bacteriemia, positive bronchoalveolar lavage. d. After pancreatitis surgery to prevent persistent systemic sepsis [71, 72]. Fever, tachycardia, tachypnea, and leukocytosis associated with SIRS that may occur early in the course of AP may be indistinguishable from sepsis syndrome. When an infection is suspected, antibiotics should be given while the source of the infection is being investigated [65]. However, once blood and other cultures are found to be negative and no source of infection is identifed, antibiotics should be discontinued. It is necessary an antibiotic that covers the most common agents involved and with good distribution within the pancreatic tissue. Büchler [73] studied the concentrations of antibiotic in blood and pancreatic tissue finding high concentrations with the use of ciprofloxacin, ofloxacin and imipenem. Imipenem is the most widely used antibiotic in clinical routine [49, 68, 74, 75]. Also in the choice of treatment should be taken into account flora and resistance of our own hospital. Therefore, the antibiotic selected should be one broad spectrum, starting with a carbapenem [55, 56]. Tigecycline is an antibiotic used for intra-abdominal infections caused by gram-positive, gram negative and anaerobius. It has proved its good penetration into pancreatic tissue. Some studies described the possibility of their use causing pancreatitis [76, 77] However, in 2014 a study concluded that pancreatitis associated with use of this antibiotic is rare (below 1 was published %), although it is a phenomenon that is still little studied [78]. Due to the high resistance of hospital flora to carbapenems, tigecycline should consider as an alternative in such cases [79]. The duration of treatment should not be more than 14 days without laboratory confirmation of infection. In summary, antibiotic treatment using carbapenems and quinolones is indicated on demand in patients with severe AP and multiorgan failure at admission and in those with hemodynamic shock. Antibiotics are also useful with biliary AP, clinically acute cholecystitis and/or cholangitis, bacteriemia, positive bronchoalveolar lavage, and urinary tract infection. Antibiotics of choice are imipenem, meropenem or tigecycline in patients allergic to betalactams. Fluconazole must be given if surgery is performed, if fungal isolation in blood, drained fluids or tissue is obtained or when clinical improvement is followed by the complications described in the treatment on demand.



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[68] Khan A, Khan S. Antibiotics in acute necrotizing pancreatitis – perspective of a developing country. J Pak Med Assoc 2010; 60:121–6. [69] Vlada AC, Schmit B, Perry A, Trevino JG, Behrns KE, Hughes SJ. Failure to follow evidence-based best practice guidelines in the treatment of severe acute pancreatitis. HPB 2013; 15:822–7.  [70] Bakker OJ, Issa Y, van Santvoort HC, Besselink MG, Schepers NJ, Bruno MJ, et al. Treatment options for acute pancreatitis. Nat Rev Gastroenterol Hepatol 2014; 11:462-9. [71] Isenmann R, Rünzi M, Kron M, Kahl S, Kraus D, Jung N, et al. Prophylactic antibiotic treatment in patients with predicted severe acute pancreatitis:a placebo-controlled, doublé-blind trial. Gastroenterology 2004; 126:997-1004. [72] Dellinger EP1, Tellado JM, Soto NE, Ashley SW, Barie PS, Dugernier T, et al. Early antibiotic treatment for severe acute necrotizing pancreatitis: a radomized, doublé-blind, placebo-controlled study. Ann Surg 2007; 245:674-83. [73] Büchler M, Malfertheiner P, Friess H, Isenmann R, Vanek E, Grimm H, et al. Human pancreatic tissue concentration of bactericidal antibiotics. Gastroenterology 1992; 103:1902-8. [74] Gumaste V. Prophylactic antibiotic therapy in the management of acute pancreatitis. J Clin Gastroenterol 2000;31:6–10. [75] Laws HL, Kent RB 3rd. Acute pancreatitis: management of complicating infection. Am Surg 2000; 66:145–52. [76] Mascarello M, Papa G, Arnez ZM, Luzzati R. Acute necrotizing pancreatitis related to tigecycline. J Antimicrob Chemother 2012; 67(5):1296–7. [77] Marot JC, Jonckheere S, Munyentwali H, Belkhir L, Vandercam B, Yombi JC. Tigecycline-induced acute pancreatitis: about two cases and review of the literature. Acta Clin Belg 2012; 67(3):229–32. [78] McGovern PC1, Wible M, Korth-Bradley JM, Quintana A. Pancreatitis in tigecycline Phase 3 and 4 clinical studies. J Antimicrob Chemother 2014; 69(3):773–8. [79] Deshpande P1, Rodrigues C, Shetty A, Kapadia F, Hedge A, Soman R. New Delhi Metallo-b lactamase (NDM-1) in Enterobacteriaceae: Treatment options with Carbapenems Compromised. J Assoc Physicians India 2010; 58:147–9.




Chapter 9

BENEFICIAL EFFECT AND UNDERLYING MECHANISM OF SHENMAI INJECTION ON ACUTE EXPERIMENTAL PANCREATITIS Qiang Yan, Wei Wu, Xing Yao, Guolei Zhang, Mingjie Zhang, Feng Cen and Xu Sun Department of general surgery, Zhejiang University Huzhou hospital, Huzhou, Zhejiang Province, China

ABSTRACT Aim: To explore the therapeutic effect of Shenmai injection (SMI) on acute experimental pancreatitis and underlying mechanisms. Methods: After induction of acute pancreatitis model with caerulein in rat, sixty Sprague-Dawley rats were randomized into a SMI (5 ml/kg/d) group (n = 30) and control (5 ml/kg/d saline) group (n = 30). The expression of serum amylase, vascular endothelial growth factor (VEGR), angiogenetic factor (AF), platelet activating factor (PAF) was measured at d1 (day 1), d3, d5, d7 respectively after the pancreatitis. Moreover, half of the rats in each group were executed respectively at d7 and d14 to assess nuclear factor kappa B (NF-κB), positive expression of CD31 and microvascular density (MVD) of pancreatic tissue. 

Correspondence: Qiang YAN, M.D., Department of general surgery, Zhejiang University Huzhou hospital, Zhejiang, China. Tel: +8613957288699, Fax: +8657220213129, E-mail: [email protected].


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Qiang Yan, Wei Wu, Xing Yao et al. Results: Expression of serum amylase in SMI group at d3, d5, d7 was significantly lower than the counterparts in control (P < 0.05) while the PAF was downregulated at d5 and d7 in SMI group (P < 0.05). Conversely, the levels of VEGR and AF at 5d and 7d were significantly higher in SMI group (P < 0.05). With respect to the biopsy result, while the mRNA expression and protein concentration of NF-κB were significantly lower in SMI group at d7 and d14, positive expression of CD31 and microvascular density were significantly higher in SMI group (P < 0.05). Conclusion: Treatment with SMI, a traditional Chinese medicine, in experimental pancreatitis rats, would attenuate inflammatory reaction, promote angiogenesis and consequently improve microcirculation. This may partially explain the beneficial effect of SMI in acute pancreatitis.

Keywords: acute microcirculation

pancreatitis,

Shenmai

injection,

inflammation,

INTRODUCTION Acute pancreatitis is one of the most common reasons for acute abdomen. The severe acute pancreatitis is the most severe category of pancreatitis, and is responsible for the high mortality of pancreatitis by leading to necrosis of pancreas, sequential activation of cytokines and consequently systemic inflammatory reaction syndrome and eventually to multiple organ dysfunction [1]. Despite dozens of trials have been done in the past years, the exact pathology for pancreatitis has not been elucidated. Recently, researchers demonstrated that microangiopathy in the early phase of acute pancreatitis was associated with the severity of the pancreatitis and the level of elevated serum amylase [2, 3]. The Shenmai injection (SMI), a traditional Chinese medicine with ginsenoside as the major and active ingredient, has been shown to inhibit the expression and release of endothelin-1 [4], to inhibit the platelet aggregation [5] and synthesis of thromboxane [6], while facilitate the production of the prostacyclin. Pharmacologically, therefore, the SMI may improve microcirculation in patients with acute pancreatitis, yet few empirical data are available about this. We sought to answer this question by examining the cytokines level and pancreatic biopsy in experimental pancreatitis rats treated with SMI and saline respectively.


Beneficial Effect and Underlying Mechanism …

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MATERIALS AND METHODS Chemicals, Animal Model and Study Design Shenmai injection is extracted from two traditional Chinese herbs, red ginseng and radix ophiopogonis, with ginsenoside Rg1, ginsenoside Re and ginsenoside Rb1 as its major and active ingredients. SMI was purchased from Chia Tai Qingchunbao Pharmaceutical Co., Ltd. (Hangzhou, China). The appraisal of SMI was provided by the State Food and Drug Administration (WS3-B-3428-98-2010Z) according to the State pharmaceutical standards. This study was approved by the Ethical Committee on Animal Experiments of the Zhejiang University. Male Sprague-Dawley rats (weighing 200 ± 50g) were kept at a constant room temperature (25°C) with light–dark cycles of 12h and were allowed free access to water ad libitum. After 1 week of acclimatization, rats were made to fast overnight before the induction of acute pancreatitis. As previously described, seven intraperitoneal injections of caerulein (50 μg/kg/h) were applied consecutively at 1h intervals. Rats were randomly divided into caerulein + NS (normal saline) pancreatitis group (Control, n = 30), and caerulein + SMI group (SMI group, n = 30). 5ml/kg/d of SMI or isovolumic NS were infused per day for study and control groups respectively through osmotic pumps since the last injection of caerulein. Caudal vein blood sample taken at d1, d3, d5, d7 respectively were centrifuged at 15,000 rpm under 4°C and then stored in a −80°C fridge for next analysis. Half of the rats in each group were sacrificed at d7 and d14 after the last injection of caerulein for pancreas samples collection.

Measurement of Amylase, Vascular Endothelial Growth-Factor (VEGR), Angiogenetic Factor (AF) and Platelet Activating Factor (PAF) Serum amylase was measured with ELISA method. Similarly, the VEGR, AF and PAF were detected using a commercial enzyme-linked immunosorbent assay kits (Jingma biotech, Shanghai, China), according to the manufacturers' protocols.


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RNA and Western Blot Assay for the Expression of NF-κB Total RNA was extracted from biopsied pancreas using guanidine isothiocyanate based Trizol reagent (Generay Corporation, Shanghai, China) according to the manufacturer's specifications. Superscript III reverse transcriptase (RT) (Fermentas Corporation, Canada) was used to reverse transcribes 5 μg of total RNA. The primer sequences used for fluorescence quantitative PCR were: Forward Primer 5'-ACGGGGAAGGTCTGAATGC3', Reverse Primer 5'-GGTGTCGTCCCATCGTAGGT-3'. Gene ID of the target gene in the Genbank was 81736, and a 223-bp product was expected in the reaction. Results were analyzed using BIO-RAD CFX Manager. On the other hand, total 50 mg of pancreas was homogenized in RIPA buffer (containing 1 μM phenylmethanesulfonyl fluoride) and then centrifuged (15000 × g, 5 min). Supernatants were collected and proteins were separated via an 8% SDS-PAGE (80 V, 30 min for concentrating gel; 120 V, 60 min for separating gel). Proteins were then transferred to a cellulose acetate membrane, blocked with 5% non-fat milk in buffer (20 mM Tris HCl, pH 7.4, 135 mM NaCl, 0.1% Tween) (2 h, at room temperature). Membranes were then incubated overnight (at 4°C) with the primary antibodies: mouse anti-NFκB (p65) or rabbit anti-histone H1 (P13) (1:1000), followed by the secondary antibodies: anti-mouse or anti-rabbit (1:1000), respectively (1 h, at room temperature). Immunoreactive proteins were detected using an enhanced chemiluminescence detection system. Autoradiographic images were analyzed using Quantity One software.

Immunohistochemistry and Assessment of Microvascular Density (MVD) Immunohistochemical staining for CD31 was performed by the streptoavidin–biotin method. The 4-μm thick sections were stained with an automated system. Briefly, the slides were deparaffinized, and endogenous peroxidase activity was blocked by incubation with 3% H2O2 (10min). Antigenic sites were revealed by applying citrate buffer in a pressure cooker (120°C for 3min). To minimize nonspecific background staining, the sections were then preincubated with milk (30min). Then, a mouse monoclonal antibody against CD31 (JC70; 1/50 dilution; Santa, USA) was added at room temperature for 30 minutes. The optimal working dilutions were defined on the basis of a titration experiment. Negative controls for each tissue section



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were prepared by omitting the primary antibody. After washing three times with trisphosphate buffered saline (TBS), sections were incubated with biotinylated rabbit antigoat immunoglobulin G for 15 minutes. They were then washed three times with TBS, treated with streptavidin–peroxidase reagent for 15 minutes, and then washed with TBS three times again. Finally, immunoreactivity was developed with diaminobenzidine for 10 minutes, followed by haematoxylin counterstaining. Sections were then dehydrated, mounted and examined. CD31- containing cells were identified by the presence of a brownish yellow chromogen. Endothelial cells of the pancreas were immunostained with the endothelial cell marker CD31. Five equal areas of high vascularization were photographed with a magnification of 250. The number of vessels with CD31 immunostained was counted. Immunoreactive cell groups clearly distinguishable from the background were counted as one vessel. CD31positive cell groups without an evident lumen were considered as undifferentiated vessels and included in our analysis. MVD was assessed with the reference to the previous method by Weidner [7]. Areas with the highest CD31-defined microvascular density (vascular hot spots) were selected with a Leica DMD 108 digital microimaging device. Vascular hot spots were identified at a low optical power using ×4 and ×10 objectives. Five areas of high vascularization were photographed to assess the microvascular density respectively. The average number of the five areas was counted as the MVD of the sample. Measurements were performed using the Image Pro-Plus 6.0 Image Analysis System (Media-Cybernetics). Any artifacts occurring in the samples were removed manually.

Statistical Analysis Descriptive data were reported as either mean ± SD, or number and percentage. With respect to the differences between the groups, categorical variables were compared using chi-square analysis. Continuous variables were compared using Independent Sample T test for normally distributed data. Statistical analysis was performed, using SPSS 15.0 (Chicago, Ill, USA). Significance was defined as a P value < 0.05.


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RESULTS The average weight for the rats in the control and SMI group were comparable, at 210.5 g and 213.8 g respectively. No mortality was observed in both groups during the induction and treatment of acute pancreatitis.

Downregulation of Serum Amylase Expression after SMI Administration Serum amylase, as a routine Lab index for pancreatitis, is helpful to access the diagnosis and prognosis. The expression levels of serum enzyme at d1, d3, d5, and d7 were detected and the trends were shown in Table 1. The serum enzyme expression at d1 between two groups showed no significant differences. Although the trends were decreasing in both groups from the 1st day to 7th day, amylase of SMI group at d3, d5 and d7 were significantly lower than counterparts in control (P < 0.01 and P < 0.05 respectively). Though amylase is not strictly related to the severity of pancreas, SMI downregulated the level of serum amylase and attenuated progressive pancreas damage in caerulein-induced pancreatitis. Table 1. Change of serum amylase, PAF, VEGF and AF in the two groups Group

Number

Amylase (IU/L) SMI Control PAF SMI Control VEGF SMI Control AF SMI Control

30 30

Days post induction of pancreatitis 1d 3d 5d 7716 ± 197 5368 ± 185** 4568 ± 158* 7658 ± 202 7532 ± 235 5056 ± 198

30 30

39.34 ± 6.39 39.12 ± 6.42

30.63 ± 5.04** 37.07 ± 6.33

30 30

105.19 ± 12.43 106.70 ± 15.62

30 30

1356 ± 58 1340 ± 55

119.46 ± 15.63** 110.44 ± 18.36 1522 ± 42** 1351 ± 65

25.30 ± 4.76** 36.06 ± 5.57 139.78 ± 24.30** 118.51 ± 21.70 1820 ± 65** 1402 ± 42

*

7d 3025 ± 175* 4528 ± 210

20.64 ± 3.56** 33.26 ± 4.87 193.37 ± 22.66* 127.07 ± 20.16 2018 ± 78** 1428 ± 51

P < 0.05, **P < 0.01, vs control, PAF: platelet activating factor, VEGF: vascular endothelial growth factor, AF: angiogenesis factor, SMI: Shenmai injection.



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PAF and NF-B Decreased after SMI Treatment According to the Lab test results, we observed that much less amylase was released to serum from pancreas after ginsenoside treatment and hypothesized it results from the alleviated inflammatory reaction. PAF was detected in serum via ELISA, and similar with the trend of amylase, the PAF expression decreased gradually after the induction of pancreatitis. Moreover, the PAF of SMI group at d3, d5 and d7 were significantly lower than counterparts in control (P < 0.01) (Table 1). In addition to PAF, a significantly lower mRNA and protein level of NF-B was expressed at d7 and d14 (both P < 0.05 respectively) (Table 2, Figure 1) in pancreas tissue in SMI group via real-time quantitative PCR, compared with control group. PAF and NF-B are inflammation-related factors. Then the hypothesis was confirmed that SMI attenuated the inflammation of acute pancreatitis and alleviated the progressive damage and promoted the recovery of pathological pancreas. Table 2. Comparison of NF-κB and CD31 expression between the two groups Group

Number

NF-κB 30 SMI 30 Control CD31 positive 30 expression SMI 30 Control * P < 0.05, **P < 0.01, vs control.

7d

Days post induction of pancreatitis 14d

0.83±0.03* 1.00±0.06

0.44±0.02* 0.76±0.05

6.41±1.14** 3.62±0.89

9.03±2.55** 3.22±1.92

Figure 1. NF-κB activity and β-actin expression of the pancreas by Western blot Test.


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Figure 2. Mean MVD of the pancreas at d7 and d14 for the two groups. A) pancreas collected at d7 of the SMI group; B) pancreas collected at d14 of the SMI group; C) pancreas collected at d7 of the control group; D) pancreas collected at d14 of the control group; E) pancreas at the time of induction of pancreatitis.

SMI Promoted Angiogenesis and Improved Microcirculation Differing from PAF and NF-B, VEGF and AF increased steadily with the pancreatitis. Interestingly, both VEGF and AF of SMI group at d3, d5 and d7 were significantly higher than those in control (P < 0.05) (Table 1). Both VEGF and AF are associated with angiogenesis and establishment of microcirculation. CD31, involved in angiogenesis, was expressed significantly higher in SMI group both at d7 and d14 (P < 0.01 respectively) (Table 2). Besides, the mean rate of MVD as assessed by CD31 was higher in SMI group compared to control in IHC assay (Figure 2). Thus, SMI promoted



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angiogenesis during the recovery of acute pancreatitis, improved microcirculation establishment and finally alleviated the inflammation reaction and improved the prognosis.

DISCUSSION Studies have demonstrated that the occurrence of acute pancreatitis was associated with pancreatic self-digestion of trypsin, microcirculation disturbance, destruction of the pancreatic duct barrier, oxygen free radicals, inflammatory mediators and a variety of cytokines. However, cytokine network and immune dysfunction maybe the main reasons to precipitate the rapid progress of pancreatitis from local lesions to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction [8]. Although to suppress trypsinogen activation was believed to be the primary treatment for patients with acute pancreatitis or severe acute pancreatitis in the past years, ways to improve microcirculation had currently been adopted to mitigate cell damage and necrosis and consequently improve or prevent general microcirculatory disturbance and multiple organ dysfunction given that microcirculation dysfunction had been one of the main mechanism for the pancreatitis [9]. AF is a large family of polypeptide which can promote angiogenesis under physiological and pathological conditions, accelerate blood vessel maturation, and maintenance of vascular stability. However, the VEGF is a purified class of angiogenic factors. VEGF is a secretary protein and has been shown to only stimulate endothelial cells and it can induce and promote angiogenesis in vivo. PAF, a biologically active phospholipid, is expressed by blood cells, platelets, endothelial cells, lung, liver, kidney, and other cell types. The factor was then activated by binding the specific receptor in the target cell membrane. A large of studies [10, 11] had demonstrated the association between the PAF and the pathogenesis of pancreatitis. Potential mechanisms including: 1) PAF is able to directly modulate microvascular permeability and increase venular permeability. Increased capillary permeability permits sequestration of macromolecules and fluid, which causes a deficiency of circulating blood volume and microcirculatory disorders. Consequently, prolonged local hypoxia or anoxia, and necrosis ensued. 2) PAF promotes the activation and adhesion of platelets and may cause microthrombi formation, which can also lead to the deterioration of pancreatic microcirculation and pancreatic necrosis. 3) PAF is shown to be involved in adhesion, chemotaxis, degranulation and,


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even the whole procedure of activation of leukocytes. Besides, it can amplify inflammatory response. As a result, large amounts of oxygen free radicals were released to the circulation and subsequently disintegrate the lysosome, which then causes the cell damage and death. 4) Activation of phospholipase A2 by PAF and mutual positive feedback further aggravates tissue injury. All the above indicated that the higher the PAF is in the pancreatitis, the more severe the disease is. SMI, a Chinese traditional prescription mainly consisting of two herbal components, Radix ginseng Rubra and Radix ophiopogonis, is extensively being used in China as a microcirculation protector because SMI has been shown to protect endothelial cells and increase the vasodilators released, which consequently dilate the vessels and amply the blood flow. Moreover, SMI has been documented to activate the adrenal system and enhance the ability of reticulo-endothelial system to scavenge various pathological materials. As a result, the blood flows to vital organs like heart, liver, brain were increased and the microcirculation was increased. In this study, both VEGF and AF of SMI group at d3, d5 and d7 were significantly higher than those in control (P < 0.05). This means the SMI treatment after caerulein-induced pancreatitis may promote the angiogenesis and attenuate inflammatory response. By contrast, PAF of amylase of SMI group at d3, d5 and d7 were significantly lower than counterparts in control, i.e., the inflammatory response of pancreatitis was greatly mitigated after administration of SMI. The “excessive leukocyte activation” theory has attracted increasing attentions for the occurrence of pancreatitis with more studies focused on the pathogenesis of acute pancreatitis. Nevertheless, cytokines played a vital role in the excessive leukocyte activation and the progress into systemic inflammatory response syndrome. NF–κB is a multi-directional regulatory protein, responsible for cytokine production and cell survival. It may modulate gene expression in various other situations that signal rapid gene expression and plays an important role in the immune regulation, inflammation, stress response and apoptosis. Activated NF–κB could translocate from cytoplasm to nucleus rapidly and bind to the κB domain of promoter or enhancer of the target genes. This consequently regulate the transcription of factors including cytokines such as TNF-α, IL-1β, IL-2 and IL-6, chemokines such as IL-8, macrophage chemotactic peptides, adhesion molecules like E-selectin, growth factors like IL-3, immunoglobulin light chain class I major hisocompatibility complex. Therefore, the NF–κB if of paramount importance in the regulation of inflammatory immune response given all the above factors would involve in the inflammatory response [12, 13]. However, excessive activation of NF–κB



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would enhance general immune response, which resulted in the tissue damage and organ dysfunction. Telek and colleagues [14] demonstrated that the activation of NF–κB was associated with early acinar oxidative stress and consequently tissue damage in pancreatitis model. Further study by Hietaranta et al., [15] shown that NF–κB activation per se is required for the inflammatory exacerbation and extra-pancreatic organ injury such as acute respiratory distress syndrome in the developing phase. Given the essential role of reactive oxygen species in the activation of NF–κB, the antioxidants could thereby used as NF–κB inhibitors. Coincidently, Kim et al., [16] revealed that antioxidants such as N-acetylcysteine might be useful antiinflammatory agents in acute pancreatitis mode by inhibiting oxidant-mediated activation of NF–κB and decreasing cytokine production. The main ingredients for ShenMai Injection are ginseng saponin, Radix saponins, flavonoids and trace Radix ginseng polysaccharides and polysaccharides and have been shown to have a wide variety of biological activities including immunomodulatory effect, antioxidant, anti-inflammatory, and anti-tumor activity. As shown in this study, the SMI significantly decreased the expression of NF–κB at d7 and d14 compared to the control. This implies the antioxidant effect of SMI may mitigate the inflammation and enhance the survival. CD31, also known as platelet-endothelial cell adhesion molecule (PECAM-1) is a member of the immunoglobulin gene superfamily. As a main adhesive molecule of vascular endothelial cells, CD31 is mainly expressed in endothelial cells, platelets, monocytes, neutrophils, naive CD8 + T cells and NK cells [17]. As a new marker of microvessels, CD31 is superior to other markers of endothelial cells to identify the vessels [18]. Thus, the CD31 could be used as specific markers to differentiate the endothelial cells and quantitative evaluation of the role of angiogenic factors played in the process of angiogenesis [19]. MVD is a useful and common marker to reflect angiogenesis. Given the CD31 is a main marker of vascular endothelial cells, it plays an important role in angiogenesis and is expressed in both mature and non-mature blood vessels. CD31 are expressed in the cytoplasm of endothelial cells and brown staining, hence the MVD count and CD31 immunohistochemical analysis could accurately reflect the number of microvessels [20]. In our study, more positive CD 31 were expressed in the SMI group at d7 and d14 and so did mean MVD assessed by CD31 positive staining. We hypothesized that the SMI may enhance CD31 positive expression, increase MVD and prompt angiogenesis. Microcirculation was consequently improved and this may attenuate the acute pancreatitis.


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In summary, SMI could promote angiogenesis and improve microcirculation. Consequently, the inflammatory mediators were reduced and inhibited, and the injury to pancreatic acinar cells was then greatly alleviated. Hence, the SMI may be beneficial in the treatment of acute pancreatitis.

CONFLICTS OF INTEREST None declared.

FUNDING This study was partially supported by the Clinical Scientific Research of project funds in Zhejiang Province Medical Association (No. 2009 zyc35)

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Qiang Yan, Wei Wu, Xing Yao et al. adhesion molecule-1 (CD31) in vascular endothelial cells. J Biol Chem, 2005. 280(12): p. 11185-91.

BIOGRAPHICAL SKETCH Name: Qiang Yan Affiliation: Zhejiang University Huzhou hospital Education: 09/1988-07/1993 Zhejiang Medical University, China. Bachelor of Medicine. 09/2007-11/2013 Zhejiang University medical school, China. MD, PhD Address: #198 Hongqi Road, Huzhou, Zhejiang 313000, China. Research and Professional Experience: Dr. Qiang Yan joined the Department of Surgery in Zhejiang University Huzhou Hospital in 1997, became the Director of the Division of HPB Surgery in 2009 and Chairman of the Department of Surgery in 2015. Taking the special training at Department of HPB and Minimally invasive Surgery Universität Regensburg Germany in 2009 and Stanford University USA in 2012, Dr. Yan has special experience in advanced laparoscopic liver and pancreatic surgery. Professional Appointments: Chairman and Professor of Department of Surgery and Director of Division of Hepatobiliary and pancreatic surgery, Zhejiang University Huzhou hospital Member of Gastrointestinal Physicians Branch of World endoscopy Doctors Association, Member of Chinese college of Surgeons, Chinese Medical Doctor Association, Member of the standing committee, College of Surgeons, Zhejiang Medical Doctor Association Member of division of Enteral parenteral nutrition, Chinese Medical Association Zhejiang Branch. Invited reviewer of journal of Medicine of Johns Hopkins Hospital, Member of editor board of some Chinese medical journals. Honors: 2005, awarded the third prize of science and technology progress, Huzhou City, Zhejiang Province, China. 2006, awarded the third prize of medical science and technology progress, Zhejiang Province, China. 2009, awarded the Youth Science and Technology Award of Huzhou City



209

2013, awarded the third prize of medical science and technology progress, Zhejiang Province, China. Publications Last 3 Years: 1.

2. 3.

4.

5.

6. 7. 8.

9.

10.

11. 12. 13.

The management of injuries of choledocbo-pancreatico-duodenal junction in Biliary operation. J Surg Con Prac, 2015, 20(3): 199-204. (In Chinese). Effects of timing of enteral nutrition in the severe acute pancreatitis. Chin J Dig Surg, 2015, 14(5): 390-4. (In Chinese). The impact of antiviral therapy on postoperative intrahepatic recurrence of hepatitis B related hepatocellular carcinoma, Chin J Hepatobiliary Surg, 2015, 21(2)91-5. (In Chinese). Augmented miR-10b expression associated with depressed expression of its target gene KLF4 involved in gastric carcinoma. International journal of clinical and experimental pathology 2015, 8(5):5071-9. Clinical application value of laparoscopic intraoperative cholangiography in laparoscopic cholecystectomy. Chin J Prim Pharm, 2015, 22(7):996-8. (In Chinese). Therapeutic effect of Shenmai injection on acute pancreatitis and mechanism, Chin J Pancreatol, 2014, 14(4): 255-8. (In Chinese). Clinical application value of laparoscopic treatment of mesenteric cyst. Zh J J Traumatic. 2014, 19(6): 919-20. (In Chinese). Three Points on Laparoscope Operation to Gallbladder Neck Incarceration Stone. Journal of Zhejiang University of Traditional Chinese Medicine, 2013, 37(11): 1319-21. (In Chinese). Efficacy of postoperative antiviral combined transcatheter arterial chemoembolization therapy in prevention of hepatitis B-related hepatocellular. Chinese medical journal, 2013, 126(5) 855-9. The Associated Ion between the VDR Gene Polymorphisms and Susceptibility to Hepatocellular Carcinoma and the Clinicopathological Features in Subjects Infected with HBV. Biomed Res Int, 2013, 953-74. Prevention and Control System of Hypokalemia in Fast Recovery After Abdominal Surgery. Current Therapeutic Research, 2013(3), 74:68–73. Novel functional proteins interact with midkine in hepatic cancer cells. HBPD INT 2012, 11(3):272-7. Expression of FHIT, FN and PTEN in hepatocellular carcinomas. Chin J Gen Surg, 2012, 27(2):487-90. (In Chinese).


210 14.

15.

Qiang Yan, Wei Wu, Xing Yao et al. Clinicopathological and prognostic significance of epithelial mesenchymal transition-related protein expression in intrahepatic cholangiocarcinoma. OncoTargets and Therapy 2012, 5(10):255-61. Effects of combined enteral nutrition support on hemorrheologic parameters and the level of inflammatory factors in rabbits with severe acute pancreatitis. Zhonghua yi xue za zhi, 2011, 91(28):2006-10. (In Chinese).


INDEX A Abdominal ultrasonography, 152 abuse, 59, 63, 81, 178 access, 16, 39, 42, 46, 138, 195, 198 acid, 7, 78, 180 acute biliary pancreatitis, ERCP/ES, pancreatic gatherings, 110 acute lung injury, 115, 131 acute pancreatitis, vii, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 23, 24, 25, 26, 27, 28, 29, 30, 33, 34, 45, 49, 50, 51, 55, 56, 57, 58, 59, 60, 61, 63, 65, 66, 67, 68, 71, 72, 74, 75, 76, 77, 78, 79, 80, 81, 84, 86, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 109, 110, 114, 115, 118, 119, 120, 121, 123, 124, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 140, 141, 143, 144, 145, 146, 147, 148, 149, 151, 152, 153, 154, 156, acute respiratory distress syndrome, 203 ADC, 89, 102 adenocarcinoma, 56, 68, 167 adhesion, 45, 201, 202, 203, 205, 206 adipose tissue, 13, 73, 77 adults, 3, 4, 7, 8, 10, 13, 20, 21, 23, 30, 179, 181 adverse effects, 93, 185

aetiology, 2, 3, 5, 6, 8, 16, 21, 23, 25, 97, 129, 152 aggregation, 64, 66, 67 alanine aminotransferase, 6, 85 alcohol abuse, 36, 57, 58, 59, 61, 81 alcohol consumption, 61, 112 alcoholism, 56, 58, 61 algorithm, 48, 123, 135, 187 ALT, 85, 86, 113, 114 ampulla, 91, 112, 113, 181 amylase, 4, 10, 12, 13, 14, 15, 17, 20, 26, 38, 57, 58, 59, 74, 84, 88, 113, 144, 151, 174, 178, 179, 180, 193, 194, 195, 198, 199, 202 anatomy, 52, 62, 67, 89, 127, 161, 180 ANC (Acute Necrotic Collection), 15, 149, 150, 151, 156, 175, 176 angiogenesis, 194, 198, 200, 201, 203, 204, 205 Angiogenetic Factor (AF), 24, 26, 29, 97, 105, 137, 171, 193, 194, 195, 198, 199, 200, 201 angiography, 57, 58, 59, 61, 66, 161 antibiotic, 82, 93, 98, 121, 136, 157, 173, 174, 182, 183, 184, 185, 186, 189, 190, 191, 192 anti-inflammatories, 92 anti-inflammatory agents, 23 anti-inflammatory drugs, 179 antioxidant, 106, 107, 131, 203 APA, 19, 28, 49, 100, 102, 185, 191


212

Index

APFC (Acute Peripancreatic Fluid Collection), 15, 149, 150, 163, 164, 175 arteries, 56, 57, 62, 63, 154, 159, 160 arterioles, 57, 58, 61, 62, 63, 65 artery, 58, 62, 63, 66, 87, 159, 160, 161, 162, 164, 169, 170 ascites, 36, 145, 148, 165, 166, 205 aspiration, 39, 92, 124, 138, 154, 164, 185 assessment, 16, 49, 87, 97, 99, 100, 102, 109, 113, 114, 117, 118, 122, 126, 133, 135, 140, 143, 144, 145, 151, 168, 171, 176 asymptomatic, 36, 179 Atlanta classification, 11, 38, 49, 71, 72, 76, 79, 81, 84, 90, 97, 100, 146, 150, 154, 168, 187 autoimmune disease, 56, 205

B bacteria, 9, 40, 90 Balthazar, 88, 100, 101, 118, 119, 124, 135, 145, 146, 147, 148, 154, 158, 159, 165, 168 beneficial effect, 91, 92, 94, 120, 194 benefits, 21, 80, 93, 95 bicarbonate, 2, 10, 181 bilateral, 55, 58, 59, 60, 61, 63, 65, 82 bile, 4, 87, 89, 107, 112, 113, 114, 141, 178, 180, 181 bile duct, 87, 89, 107, 141, 178, 180 biliary obstruction, 36, 39, 112, 122 biliary tract, 161, 166 biological activities, 203 biopsy, 12, 194 bleeding, 43, 45, 46, 47, 72, 84, 96, 99, 123, 126, 144, 155, 159, 166 blood, 2, 19, 39, 42, 59, 61, 62, 85, 91, 107, 118, 134, 151, 159, 164, 186, 195, 201, 203 blood flow, 19, 91, 202 blood urea nitrogen, 85, 86, 118 blood vessels, 2, 39, 42, 159, 164, 203 body mass index (BMI), 45, 71, 73, 75 bone, 56, 60, 66

bowel, 14, 16, 113, 120, 153, 165

C calcium, 4, 10, 86, 113, 122, 178, 179, 204 capillary, 57, 61, 62, 91, 92, 201 capsule, 37, 84, 149 carcinoma, 140, 207 catheter, 43, 52, 88, 138, 164, 171, 186 CBD, 114, 122, 123, 125, 128 central retinal artery occlusion, 57, 58 CEUS (contrast enhanced ultrasound), 152 childhood, vii, 1, 2, 3, 24, 25, 27, 31, 182 children, vii, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 23, 24, 25, 26, 27, 181 China, 193, 195, 196, 202, 206, 207 cholangiography, 17, 207 cholangitis, 87, 110, 122, 123, 128, 161, 181, 186 cholecystectomy, 21, 123, 129, 140, 167 cholecystitis, 165, 186 choledocholithiasis, 89, 158 cholestasis, 109, 110, 122, 128 chronic renal failure, 10, 20, 21, 68 circulation, 14, 19, 42, 55, 57, 63, 115, 159, 160, 202 classical methods, vii, 80 classification, 7, 11, 15, 16, 18, 28, 34, 38, 48, 49, 71, 72, 76, 79, 81, 84, 85, 87, 90, 97, 100, 105, 118, 130, 143, 145, 146, 149, 150, 154, 164, 167, 168, 169, 176, 187 clinical diagnosis, 88, 157 clinical presentation, 2, 3, 23, 72 clinical symptoms, vii, 33, 39, 143, 145 clinical trials, 90, 92, 93 closure, 44, 80, 83, 104, 106, 107 cluster of differentiation, 181 CO2, 42 coil embolization, 159, 170 colic, 95, 113 collateral, 42, 159 colon, 37, 140, 152, 166


213

Index common bile duct, 17, 87, 109, 114, 130, 178, 180, 181 communication, 11, 38, 44, 167, 180 compartment syndrome, 98, 114, 166 complement, 55, 56, 62, 64, 65, 66, 67, 88, 132 complications, vii, 3, 15, 16, 18, 21, 34, 40, 41, 45, 46, 47, 56, 71, 72, 74, 75, 76, 77, 80, 81, 84, 88, 94, 95, 98, 110, 111, 114, 115, 119, 120, 121, 122, 123, 124, 125, 127, 130, 134, 137, 138, 143, 144, 145, 146, 148, 149, 152, 153, 154, 157, 158, 159, 161, 163, 165, 166, 167, 169, 170, 176, 177, 182, 183, 185, 186, 187, 190 Complications of Acute Pancreatitis, 163 composition, 48, 78 compression, 8, 60, 67, 99 computed tomography, 37, 58, 84, 114, 134, 143, 145, 146, 154, 167, 168, 169, 174 Computed tomography, 86, 87, 100, 101, 132, 134, 144, 152 configuration, 160, 181 consensus, 2, 19, 34, 49, 76, 83, 86, 98, 100, 110, 130, 143, 146, 168, 174, 185, 187 contamination, 120, 190 control group, 195, 199, 200 controlled trials, 21, 40, 92, 104, 137, 191 controversial, 39, 121, 122, 183 coronary arteries, 204 correlation, 17, 39, 88, 101, 113, 130 corticosteroids, 92, 180 cotton, 57, 58, 59, 60, 61, 62 coworkers, 73, 74 creatinine, 85, 117 CRP, 20, 73, 86, 116, 118, 120, 132, 134 CT scan, 27, 100, 152, 156, 157, 166, 167 CTA, 161 cyst, 6, 38, 42, 43, 44, 45, 46, 99, 164, 207 cystic fibrosis, 9, 23, 30 cytokines, 5, 72, 73, 74, 90, 92, 131, 182, 194, 201, 202 cytoplasm, 202, 203

D debridement, 42, 44, 47, 50, 51, 87, 95, 105, 126, 127, 139 defects, 12, 31, 156 deficiency, 23, 30, 91, 201 destruction, 2, 131, 201 detection, 85, 87, 89, 114, 135, 152, 154, 158, 170, 196 diabetic retinopathy, 106, 107 diagnostic criteria, vii, 1, 3, 7, 12, 113, 170 differential diagnosis, 37, 167 diffusion, 89, 102, 115, 120, 170, 184 Diffusion-weighted magnetic resonance imaging (DW-MRI), 158 digestion, 36, 81, 110, 201 dilation, 55, 114, 180 diseases, vii, 6, 8, 10, 31, 76, 111, 143, 177 disorder, 2, 15, 18, 181, 182 displacement, 43, 82 disseminated intravascular coagulation, 94, 104 distribution, 73, 77, 109, 112, 183, 186 DNase, 205 double-blind trial, 23, 28 drainage, 34, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 50, 51, 52, 53, 83, 95, 96, 105, 110, 125, 126, 127, 128, 138, 161, 164, 166, 170, 171, 172 drugs, 7, 112, 120, 121, 144, 166, 183 duodenum, 2, 4, 10, 37, 41, 45, 87, 111, 128, 181 DWI, 89 DW-MRI, 158

E E. coli, 40 edema, 111, 112, 113, 174, 178 electrolyte, 89, 119 ELISA, 195, 199 ELISA method, 195 embolization, 55, 56, 68, 159, 160, 162, 164, 170, 172


214

Index

emergency, 58, 177 encapsulation, 126, 149 endocrine, 2, 12 Endoscopic Retrograde Cholangiopancreatography, 12, 121, 137, 161 endoscopy, 27, 28, 37, 38, 39, 42, 46, 49, 88, 206 endothelial cells, 201, 203, 206 endothelial dysfunction, 204 Endovascular therapy, 144, 159 end-stage renal disease, 26 England, 29, 52, 111 enlargement, 12, 88, 118, 148, 152, 153, 174 enterokinase, 4, 111 enzyme, 10, 12, 13, 17, 151, 163, 164, 195, 198 enzyme-linked immunosorbent assay, 195 enzymes, 2, 8, 13, 15, 17, 27, 81, 85, 91, 111, 159, 178, 182 epidemiology, 65, 129, 188 epithelium, 56, 57 erosion, 36, 159, 164 etiology, 56, 81, 93, 109, 111, 113, 119, 122, 137, 140, 177, 188 EUS (endosonography), 12, 16, 17, 27, 50, 53, 152, 168 evidence, 2, 3, 20, 26, 28, 33, 40, 41, 49, 61, 62, 64, 71, 73, 87, 100, 102, 115, 152, 173, 179, 183, 184, 185, 191, 192 evolution, 35, 81, 84, 87, 96, 109, 110, 113, 115, 116, 118, 119, 120, 121, 123, 124, 125, 126, 128, 173, 174 examinations, 145, 151 exclusion, 25, 160 exposure, 5, 7, 21, 46, 131 extravasation, 120, 155, 159, 164

F false negative, 39, 154 familial lipoprotein lipase deficiency, 30 fasting, 20, 90, 113, 120, 122

fat, 2, 37, 56, 68, 73, 74, 77, 78, 82, 87, 115, 131, 147, 148, 153, 156, 157, 158, 159, 163, 174, 196 fatty acids, 10, 74, 75, 115, 131 fever, 2, 46, 48, 58, 61, 88, 157 fibrinolytic, 80, 93 fibrosis, 30, 179 flame, 55, 58, 61 flora, 184, 185, 186 fluid, 2, 15, 17, 18, 19, 20, 22, 28, 34, 35, 38, 40, 41, 50, 51, 52, 53, 75, 80, 81, 83, 84, 85, 86, 88, 91, 103, 109, 110, 114, 115, 118, 119, 120, 121, 124, 125, 126, 127, 138, 139, 143, 145, 146, 147, 149, 150, 151, 152, 153, 154, 156, 157, 158, 161, 163, 164, 165, 166, 169, 170, 175, 201 fluorescence, 57, 196 Food and Drug Administration, 195 formation, 16, 35, 36, 40, 87, 88, 111, 152, 156, 159, 163, 201 founding, 76 free radicals, 131, 201, 202 fungal infection, 184, 185, 190

G gallbladder, 16, 87, 109, 114, 122, 129, 178 gallstones, 5, 6, 25, 27, 85, 87, 109, 112, 114, 122, 129, 134, 137, 152 gastroenterologist, 30, 48 gastrointestinal involvement, 145 gastrointestinal tract, vii, 41, 42, 43, 82, 143, 164 gel, 160, 196 gene therapy, 23, 30 general anaesthesia, 16, 17, 21 genes, 9, 189, 202 genetic mutations, 5, 9, 23 Germany, 92, 206 ginseng, 195, 202, 203 gland, 14, 111, 118, 124, 148, 152, 153, 156, 180, 181, 182 glucose, 12, 74, 85, 134 grades, 88, 146, 176


Index gravity, 130, 141 Great Britain, 27, 172 guidance, 21, 37, 42, 118, 160 guidelines, 18, 28, 38, 39, 49, 76, 98, 100, 101, 102, 120, 131, 170, 172, 185, 187, 191, 192

H HBV, 207 healing, 44, 96 health, 1, 86, 135 hematocrit, 85, 86, 88, 119, 133, 134, 157 hemolytic uremic syndrome, 56, 68 hemorrhage, 41, 56, 57 hepatitis, 9, 207 hepatocellular carcinoma, 207 history, 5, 33, 35, 36, 38, 50, 57, 58, 59, 61, 65, 113, 130 HIV, 14, 66 hospitalization, 3, 29, 58, 61, 81, 85, 90, 94, 177, 182, 184 human, 27, 28, 74, 78, 80, 93, 94, 104, 130, 131, 188 hypercalcemia, 10, 112, 179 hyperlipidemia, 10, 21, 112 hyperparathyroidism, 10, 179 hypertension, 82, 98, 113, 180 hypothesis, 10, 112, 113, 199 hypovolemia, 72, 91, 120 hypoxia, 82, 201

I ideal, 39, 88, 89, 166 identification, 9, 10, 38, 123, 145, 158, 177, 189 idiopathic, 6, 36, 81, 97, 102 IL-8, 202 image(s), 17, 36, 37, 38, 48, 84, 87, 96, 118, 119, 147, 148, 152, 153, 157, 158, 159, 165, 166, 196 Imaging techniques, 143, 151 immune function, 102

215

immune regulation, 202 immune response, 90, 202 immunity, 77, 131 immunoglobulin, 197, 202, 203 immunosuppression, 90, 103 in vitro, 63, 66 in vivo, 201 incidence, 1, 2, 3, 23, 24, 44, 72, 81, 82, 87, 97, 111, 123, 128, 144, 149, 177, 189 incidence of acute pancreatitis, 3, 24, 144 incisional hernia, 95, 107 India, 68, 192 individual characteristics, 94, 96 individuals, 9, 60, 64, 102, 180, 182 induction, 74, 90, 91, 180, 193, 195, 198, 199, 200 infants, 8, 13, 24, 25 infarction, 14, 164 infection, 33, 36, 37, 38, 39, 41, 46, 72, 74, 77, 81, 82, 84, 88, 93, 97, 114, 115, 121, 124, 125, 128, 138, 150, 152, 154, 158, 164, 166, 170, 171, 173, 176, 177, 183, 184, 185, 186, 190, 192 infectious agents, 9, 180 inflammation, 15, 29, 38, 63, 64, 77, 81, 88, 91, 93, 99, 111, 118, 131, 146, 149, 169, 176, 182, 194, 199, 201, 202, 205 inflammatory bowel disease, 181 inflammatory disease, 14, 110, 111, 144 inflammatory mediators, 72, 73, 115, 182, 201, 204 ingredients, 195, 203 inhibition, 74, 121, 204 inhibitor, 9, 23, 73, 74, 113, 136, 182 initiation, 145, 157 injury(ies), 4, 8, 10, 26, 35, 55, 63, 64, 72, 73, 74, 103, 107, 111, 113, 114, 120, 164, 178, 179, 182, 202, 203, 204, 207 integrity, 21, 38, 39, 89, 120, 121 intensive care unit, 18, 21, 135 intervention, 6, 39, 51, 64, 88, 94, 100, 101, 105, 110, 126, 135, 144, 161, 166, 168, 170, 187 intestinal perforation, 88 intravenous fluids, 20, 89


216

Index

ionizing radiation, 37, 89 ischemia, 10, 57, 58, 59, 61, 62, 74, 88, 94, 96 isolation, 9, 170, 186 Italy, 109, 139

L laboratory tests, 113, 132 laparoscopic cholecystectomy, 94, 123, 137, 207 laparotomy, 43, 46, 47, 83, 95 lead, 4, 8, 18, 35, 41, 42, 43, 55, 65, 74, 82, 178, 201 leakage, 2, 35, 57, 61, 128 lesions, 66, 102, 164, 201 leukocytes, 13, 92, 131, 169, 202 leukocytosis, 179, 186 lipases, 74, 77 Liquid embolic material (Onyx), 160 liver, 109, 113, 114, 122, 140, 164, 166, 177, 201, 206 liver function tests, 109, 113, 114, 122, 140 lumen, 44, 48, 111, 180, 197 lymphoma, 167

M magnetic resonance (MR), 12, 16, 27, 37, 80, 87, 89, 101, 102, 143, 144, 157, 158 163, 169, 170, 174, 181 Magnetic resonance cholangiopancreatography (MRCP), 158 magnetic resonance imaging, 16, 37, 80, 101, 143, 151, 158, 169, 170, 174 majority, 4, 5, 15, 17, 23, 39, 83, 84, 86, 89, 92, 109, 114, 122, 123, 179 malignant tumors, 179 management, vii, 2, 3, 6, 8, 10, 17, 18, 19, 20, 21, 23, 24, 25, 26, 28, 33, 36, 38, 39, 41, 42, 45, 48, 49, 50, 51, 52, 64, 76, 80, 82, 83, 90, 94, 95, 96, 97, 100, 102, 103, 105, 106, 107, 119, 124, 127, 128, 129, 134, 136, 137, 138, 139, 144, 161, 168,

169, 170, 171, 172, 177, 182, 187, 188, 190, 191, 192, 207 measurements, 13, 66, 71, 73 mechanical ventilation, 117 mechanical ventilator, 81 mediastinum, 154, 164 medical, 25, 33, 48, 61, 119, 121, 129, 144, 157, 189, 206, 207 medical science, 206, 207 medication, 7, 93 mellitus, 12, 95 meta-analysis, 29, 45, 77, 87, 99, 102, 103, 104, 130, 136, 179, 185, 189, 190, 191 Metabolic, 10, 14, 26, 179 methylprednisolone, 64, 65 microcirculation, 10, 28, 58, 91, 103, 120, 194, 200, 201, 204 migration, 43, 44, 92, 131 molecules, 23, 89, 202, 205 monoclonal antibody, 196 morbidity, 28, 43, 46, 47, 71, 72, 81, 83, 87, 95, 97, 119, 123, 138, 144, 145, 161, 179 morphology, 143, 154, 160 mortality, 19, 20, 28, 29, 41, 43, 45, 46, 71, 72, 74, 75, 76, 77, 80, 81, 82, 83, 85, 87, 90, 92, 93, 94, 95, 97, 99, 114, 115, 116, 118, 119, 120, 123, 125, 126, 131, 135, 138, 144, 145, 149, 152, 167, 171, 173, 176, 177, 178, 179, 182, 183, 187, 188, 189, 190, 191, 194, 198 mortality rate, 45, 46, 75, 81, 82, 92, 114, 126, 149, 173, 177, 179, 182 mortality risk, 116, 118 MRCP, 12, 16, 109, 110, 121, 122, 123, 128, 161 MRI, 12, 16, 37, 38, 48, 102, 114, 117, 118, 119, 143, 144, 157, 158, 174, 175, 187 mRNA, 194, 199 mutation, 9, 23, 30, 113, 181, 182, 189

N NaCl, 196 nausea, 2, 13, 61, 90, 113


217

Index necrosis, vii, 2, 5, 15, 16, 19, 29, 33, 34, 35, 39, 42, 44, 46, 48, 49, 50, 51, 52, 53, 72, 74, 75, 77, 80, 81, 82, 83, 84, 86, 87, 89, 90, 92, 94, 95, 96, 97, 98, 101, 104, 105, 110, 111, 114, 115, 116, 118, 120, 121, 123, 124, 125, 126, 131, 132, 133, 138, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 156, 157, 158, 159, 163, 164, 166, 168, 171, 173, 174, 175, 176, 177, 182, 183, 184, 185, 189, 190, 191, 194, 201 neovascularization, 42 nephritic syndrome, 68 New South Wales, 1, 30, 31 NK cells, 203 non-Hodgkin’s lymphoma, 167 North America, 100 NSAIDs, 120 nutrition, 20, 21, 27, 29, 30, 80, 89, 90, 102, 119, 120, 121, 206, 207, 208

O obesity, vii, 71, 73, 74, 75, 76, 77, 78, 81, 85 obstruction, 14, 35, 42, 112, 113, 123, 129, 166, 178, 180, 188 occlusion, 43, 46, 57, 58, 62, 63, 65, 163 oedema, 2, 16, 19, 119, 124, 153 oleic acid, 75, 131 opioids, 91, 120 optic nerve, 57, 58, 62 organ, 2, 8, 18, 19, 20, 28, 47, 56, 67, 72, 73, 74, 78, 80, 81, 82, 85, 88, 89, 91, 97, 99, 100, 102, 111, 114, 115, 119, 121, 123, 124, 125, 134, 135, 144, 146, 148, 176, 177, 182, 185, 189, 194, 201, 203 organs, 13, 17, 45, 81, 102, 128, 164, 179, 202 overweight, 16, 73 oxidative stress, 106, 107, 203, 205 oxygen, 131, 201, 202

P paediatric patients, 2, 17 PAF, 193, 194, 195, 198, 199, 200, 201 pain, 2, 12, 13, 16, 20, 21, 36, 39, 48, 58, 59, 60, 61, 84, 88, 89, 90, 91, 109, 113, 119, 120, 121, 144, 157, 161, 174, 179, 180 pallor, 56, 57, 58, 62 pancreas, 2, 4, 8, 9, 10, 13, 15, 20, 25, 36, 38, 46, 74, 82, 83, 84, 87, 90, 91, 92, 96, 100, 110, 112, 115, 117, 118, 119, 121, 136, 138, 140, 144, 146, 147, 148, 150, 152, 153, 154, 156, 157, 158, 159, 163, 164, 165, 167, 168, 169, 171, 175, 178, 180, 181, 182, 194, 195, 196, 197, 198, 199, 200, 205 pancreatic acinar cell, vii, 24, 79, 80, 178, 204, 205 pancreatic cancer, 100, 188 pancreatic insufficiency, 12, 181 Pancreatic Pseudocyst, 84, 150 pancreatitis, vii, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 23, 24, 25, 26, 27, 28, 29, 30, 31, 33, 34, 35, 36, 38, 39, 40, 45, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 63, 65, 66, 67, 68, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 84, 85, 86, 87, 88, 93, 94, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 109, 110, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 124, 128, 129, 130, 131, 132, 133, parenchyma, 2, 8, 15, 75, 81, 87, 111, 118, 119, 123, 124, 144, 147, 149, 151, 153, 158, 174, 175 pathogenesis, 4, 73, 109, 123, 188, 190, 201, 202 pathology, 38, 41, 62, 168, 194, 207 pathophysiological, 130 pathophysiology, 5, 9, 35, 63, 111, 113, 122 pathway(s), 4, 5, 9, 43, 205 PCR, 196, 199 peptide(s), 91, 118, 132, 133, 134, 202, 205 perforation, 43, 45, 167


218

Index

perfusion, 20, 57, 61, 89, 91, 148, 156 peritoneal cavity, 45, 156 peritoneal lavage, 97, 100 permeability, 91, 92, 116, 201 pH, 10, 111, 120, 181, 196 pharmacological treatment, 90 physiology, 86, 117, 135 placebo, 92, 98, 106, 107, 179, 192 Plain film., 151 Platelet Activating Factor (PAF), 193, 195, 198 platelet aggregation, 194 platelets, 60, 201, 203 pleural effusion, 36, 82, 85, 118, 145 PM, 26, 68, 105, 171 pneumonia, 9, 182, 186 population, 3, 97, 99, 111, 130, 135, 177, 181, 182, 187, 188 portal hypertension, 42, 164 portal vein, 39, 42, 115, 154, 164 Positron emission tomography-computed tomography (PET/CT), 154, 169, 171 potential benefits, 64, 129 prevention, 29, 80, 92, 182, 185, 207 probability, 18, 23, 94 prognosis, 5, 36, 56, 67, 101, 135, 168, 169, 183, 198, 201 pro-inflammatory, 47, 92 project, 167, 204 prophylactic, 82, 92, 129, 183, 185, 191 prophylaxis, 93, 98, 104, 121, 136, 173, 174, 177, 179, 183, 184, 185, 190, 191 protease inhibitors, 23 protective mechanisms, 178 protein kinase C, 5 proteins, 10, 131, 181, 196, 207 proteolytic enzyme, 144, 164 PSA, 159, 163 pseudoaneurysm, 16, 42, 144, 152, 154, 159, 160, 161, 162, 163, 165, 169 pseudocyst, 15, 17, 34, 35, 36, 37, 49, 51, 52, 53, 72, 84, 125, 128, 143, 149, 150, 154, 156, 157, 158, 175 PTEN, 207 pulmonary arteries, 204

R radiation, 13, 16, 21, 27 Ranson score, 135, 145 RCP, 12 receptor, 107, 131, 133, 201, 205 recognition, 8, 167 recombinant DNA, 93 recommendations, iv, 2, 7, 11, 19, 20, 21, 48, 91 recovery, 29, 56, 61, 63, 64, 65, 102, 126, 199, 201 recurrence, 7, 38, 41, 167, 207 renal failure, 10, 26, 56, 89, 115, 163 requirement, 16, 86, 123 resistance, 185, 186 resolution, 7, 12, 38, 41, 42, 45, 56, 58, 59, 60, 62, 89, 115, 128, 145, 152, 158 resources, 51, 94 respiratory failure, 117 response, 4, 42, 46, 47, 73, 74, 76, 81, 82, 91, 110, 115, 117, 123, 130, 131, 173, 174, 176, 188, 201, 202, 204 retina, 57, 62 retinal ischemia, 57, 58, 61 retinopathy, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68 reverse transcriptase, 196 revised Atlanta classification, 15, 18, 76, 143, 149, 176 risk, 5, 7, 9, 10, 23, 31, 30, 38, 42, 45, 46, 60, 64, 72, 74, 75, 76, 77, 78, 83, 85, 90, 91, 94, 102, 115, 116, 120, 123, 125, 126, 128, 129, 137, 144, 152, 160, 161, 176, 177, 179, 180, 181, 182, 183, 184, 188 risk factors, 5, 9, 10, 72, 144, 184, 188 RNA, 196 room temperature, 195, 196

S safety, 26, 30, 45, 67


219

Index SAP, 72, 73, 74, 75, 80, 81, 82, 83, 85, 86, 87, 89, 90, 91, 92, 93, 94, 95, 96 SDS-PAGE, 196 secretin, 17, 27, 38 secretion, 10, 17, 90, 178, 180, 181 sensitivity, 6, 15, 16, 19, 86, 87, 89, 114, 144, 145, 154 sepsis, 8, 21, 39, 41, 45, 80, 88, 93, 94, 104, 106, 119, 125, 126, 144, 166, 183, 186, 189 serum, 2, 6, 10, 12, 13, 14, 15, 17, 18, 19, 20, 27, 57, 59, 74, 84, 85, 90, 113, 122, 132, 134, 144, 151, 174, 179, 181, 193, 194, 198, 199 severe, 18, 19, 20, 21, 23, 28, 29, 30, 34, 35, 39, 43, 58, 59, 67, 71, 72, 74, 75, 77, 78, 80, 81, 82, 93, 94, 97, 98, 101, 102, 103, 104, 106, 107, 109, 110, 111, 114, 115, 116, 118, 119, 120, 121, 122, 123, 125, 128, 131, 132, 133, 134, 135, 136, 143, 144, 145, 146, 148, 149, 151, 152, 156, 157, 159, 164, 167, 171, 173, 174, 176, 177, 181, 182, 183, 184, 185, 186, 187, 189, 190, 191, 192, 194, 201, 202, 205, 207, 208 Shenmai injection, vi, vii, 193, 194, 195, 198, 207 signs, 9, 28, 38, 57, 58, 63, 83, 88, 100, 125, 152, 157, 171, 176, 179, 187 sludge, 6, 109, 112, 114, 121, 122, 178, 180 smoking, 21, 189 society, vii, 143 solution, 20, 29, 91, 103, 120 spleen, 138, 152, 164 Sprague-Dawley rats, 193, 195 stabilization, 41, 64, 123 state(s), vii, 20, 34, 39, 67, 73, 94, 184 stenosis, 38, 112, 113, 179 stent, 43, 44, 45, 46, 48, 160 Stent-graft, 160 sterile, 33, 37, 39, 52, 80, 81, 83, 94, 110, 125, 138, 143, 150, 158, 164, 171, 173, 175, 176, 183, 185 steroids, 64, 92 stimulation, 18, 20, 21, 178, 205

stomach, 13, 17, 37, 41, 42, 45, 95, 128, 157, 166, 167 stratification, 135, 188 stress, 131, 202, 205 structure, 152, 154 success rate, 39, 41, 43, 45, 127 Sun, vi, 99, 102, 135, 187, 193 surgical debridement, 41, 161, 166 surgical intervention, 88, 92, 95, 106, 110, 119, 128 survival, 93, 96, 103, 190, 202 symptoms, 2, 3, 9, 13, 36, 39, 40, 48, 58, 60, 61, 81, 87, 154, 157, 167, 180 syndrome, 8, 12, 56, 67, 72, 81, 82, 83, 111, 115, 123, 176, 186, 194, 201, 202 synthesis, 178, 194

T T cells, 181, 203 tachycardia, 2, 113, 186 tachypnea, 113, 186 TAP, 116, 118 target, 23, 160, 196, 201, 202, 207 techniques, 39, 40, 46, 89, 143, 151, 160 technology, 93, 206, 207 testing, vii, 4, 143, 145 therapeutic approaches, 41, 47 therapeutic effect, vii, 193 therapy, 23, 28, 30, 40, 41, 42, 51, 64, 82, 91, 94, 103, 106, 107, 120, 126, 144, 145, 159, 166, 168, 177, 181, 185, 190, 192, 207 thrombocytopenic purpura, 56, 68 thrombomodulin, 80, 94, 104 thrombosis, 16, 39, 152, 154, 163, 204 tissue, 15, 33, 35, 36, 37, 45, 46, 62, 73, 74, 75, 77, 78, 83, 84, 88, 89, 91, 94, 96, 110, 114, 115, 123, 124, 126, 127, 145, 149, 153, 154, 158, 164, 174, 181, 182, 183, 184, 186, 192, 193, 196, 199, 202, 203 TNF, 5, 23, 73, 202 TNF-α, 23, 202 toddlers, 13, 24, 25


220

Index

tones, 17, 130 total parenteral nutrition, 102, 136 transcatheter, 170, 172, 207 transcription, 129, 202 translocation, 29, 90, 115, 120, 131 trauma, 6, 8, 14, 33, 35, 36, 38, 56, 58, 64, 65, 179, 188 treatment, 5, 9, 18, 20, 21, 23, 26, 33, 34, 36, 37, 38, 39, 40, 41, 44, 45, 46, 48, 49, 50, 51, 52, 56, 60, 64, 65, 68, 76, 77, 82, 83, 88, 90, 91, 93, 94, 96, 98, 103, 110, 119, 120, 121, 123, 125, 126, 127, 128, 136, 137, 138, 144, 145, 146, 154, 157, 160, 161, 164, 166, 173, 174, 182, 183, 184, 185, 186, 188, 190, 192, 198, 199, 201, 202, 204, 207 trial, 20, 29, 30, 47, 53, 54, 94, 103, 104, 136, 137, 138, 139, 179, 190, 192 triglycerides, 179 trypsin, 4, 9, 10, 24, 63, 111, 112, 113, 182, 201 tumor, 38, 99, 132, 140, 203, 205 tumor necrosis factor, 132 tumours, 112, 140

U ultrasonography, 12, 16, 17, 51, 102, 144, 152, 174 ultrasound, 12, 16, 28, 37, 38, 40, 42, 44, 48, 49, 53, 58, 87, 143, 151, 152, 153, 160, 168, 169, 178 underlying mechanisms, vii, 10, 193

United States (USA), 24, 129, 188, 196, 197, 206 urinary tract infection, 186 urine, 133, 151

V vacuum, 80, 83, 104, 106, 107 validation, 6, 48 Vascular Endothelial Growth-Factor (VEGR), 193, 194, 195, 198 vascular occlusion, 36, 68 vasculature, 57, 62 VEGF, 198, 200, 201, 205 vein, 39, 42, 153, 154, 195 vessels, 2, 62, 63, 67, 197, 202, 203 vision, 42, 56, 57, 58, 59, 60, 61, 63, 64, 65 visual acuity, 56, 57, 60, 61, 63, 65 vomiting, 2, 13, 19, 39, 58, 60, 61, 90, 113, 120

W water, 89, 154, 195 white blood cell count, 85, 157 WON (Walled-Off Necrosis), 15, 148, 149, 151, 157, 175, 176 wool, 57, 58, 59, 60, 61, 62 worldwide, 76, 111, 123, 126, 144

Y yield, 2, 17, 18, 27
