1Surgery Department, University Hospital Therezinha de Jesus, Faculty of Medical Sciences and Health Juiz de Fora (SUPREMA) - Brazil
2Emergency Surgery Unit, Maggiore Hospital Regional Emergency Surgery and Trauma Center, Bologna Local Health District, Bologna, Italy
3Emergency Surgery Unit, Macerata University, Macerata, Italy
4Intensive Care Unit, Maggiore Hospital, Bologna Local Health District, Bologna, Italy
5Internal Medicine, Pancreas Unit, DIMEC. Policlinico Sant'Orsola, Bologna, Italy
6Gastroenterology, DIMEC, Policlinico Sant'Orsola, Bologna, Italy
7Surgery Department, Hospital Governador Israel Pinheiro (HGIP – IPSEMG), Belo Horizonte, Minas Gerais, Brazil
Received June 14th, 2017 - Accepted August 30th, 2017
Pancreas; Pancreatitis; surgery
AP acute pancreatitis; ERCP endoscopic retrograde cholangio-pancreatography
The manuscript makes a comprehensive review of the most important aspects involved in the management of severe acute pancreatitis (AP). It was also based on the most current evidence-findings, which were summaries in a concise and objective way. In addition, it could be used as a reference to decision-making at the emergency room and follows the principle of goal-direct therapy. It could be also used as a protocol in many acute care unit (ACU) and surgical team in different scenarios.
In addition, the manuscript has an educational proposal, since it approaches the subject in academic form for easy assimilation. By means of a mnemonic method using the acronym “PANCREAS” = Perfusion, Analgesia, Nutrition, Clinical assessment, Radiological assessment, ERCP, Antibiotics, and Surgery. Therefore, the purpose of this review design is innovative, because each letter is associated a fundamental step in the management of severe AP. At same time, it is a guide that highlights the attendance priorities and how such attitudes should be orderly implemented .
P = PERFUSION
The goals of fluid resuscitation in severe AP are: to maintain perfusion of pancreatic microcirculation and to prevent systemic hypovolemia caused by capillary leakage syndrome, which results in increased third space loss and decrease of intravascular volume . There is still no agreement on infusion regimens, total volume, type of fluid and duration of treatment, but serum creatinine, azotemia hematocrit are indicator severe dehydration and more severe disease [3, 4].
In addition, their levels can be used as a guide to fluid restoration [5, 6, 7]. The target-goal therapy should maintain the central venous pressure (CVP) = 12 - 15 mmHg, urinary output from 0.5 to 1 ml/kg/h and the collapsibility index of the inferior vena cava (>48%, predicted fluid repost = sensitivity of 84% and a specificity of 90%) [1, 8]. In cases of pancreatitis-associated shock, vasoactive agents as well as invasive hemodynamic monitoring to guide the therapeutic are indicated .
There is evidence of early and dynamic rehydration (12-24 h of symptoms onset), is most important approach in severe acute pancreatitis. The crystalloids solutions have been recommended (200 to 500 ml)/h, or (5 to 10 ml)/kg/h. In severe forms about 2500 to 4000 ml/24 h of fluid infusion are necessary until the outlined parameter should be reached . Furthermore, it is suggested that the use of Ringer’s lactate results in a significant reduction of systemic inflammation in relation to the use of saline solution .
A = ANALGESY
Abdominal pain is often the predominant symptom in patients with acute pancreatitis. In addition, uncontrolled pain may contribute to hemodynamic instability. The pain should be managed in an aggressive way. Systemic and combined pharmacological treatment is considered of first choice and the opioid has proved to be effective and safe. Moreover, it is recommended a multimodal treatment of pain associated with early mobilization [12, 13].
The Epidural Analgesia for Pancreatitis (EPIPAN) trial is a prospective randomized multicentricity study, which included 148 in two arms. It compared the application of epidural analgesia containing a mixed solution of ropivacaine (2 mg/mL) and sufentanil (0.5 μg/mL), in continuous infusion rate of 5–15 mL/hour (six to nine thoracic vertebra), for at least 72 hours, plus standard care analgesia (opioid plus non-opioid drugs ± other adjuvant drugs) versus standard of care analgesia only. The study proved that epidural analgesia is superior to standard care alone in patients with AP in the ACU and its use may become standard of care in selected centers .
N = NUTRITION
The idea “to put the pancreas at rest” in acute pancreatitis is an old paradigm that should be abandoned. According to the “autodigestion” theory in shock, the pancreatic enzymes are nowadays important subtracts, which breakdown of the intestinal mucosal barrier. These aspects highlight the need for precocity of enteral/ parenteral nutrition to prevent bacterial translocation and changes in intestinal microbiota towards a sustained proinflammatory status [15, 16, 17].
A systematic Cochrane review has compared enteral nutritional (EN) to parenteral nutrition (PN) in the set of severe AP. The authors found that EN reduces relative risk of death, multiple organ failure, systemic infection and operative interventions. So, EN should be considered the standard of care and should be given in different situations, including complications [17, 18, 19]. The only contraindication to EN is prolonged a dynamic ileus, however, even if this case, the European Society for Parenteral and Enteral Nutrition, recommend combining PN with a small content diet (10-30 ml/h) in continuous gut perfusion .
The nasogastric tube has demonstrated to be safe and useful as well as the nasojejunal tube. Current studies have showed that there were no differences in terms of mortality, tracheal aspiration, diarrhea, exacerbation of pain and meeting energy balance between them [20, 21, 22]. The start period of enteral nutrition in severe AP is crucial and should not be postponed. Many studies have demonstrated the benefits of EN versus PN only when the EN was introduced within the first 48 hours of the onset of the symptoms . In addition, the Italian Association for the Study of the Pancreas, recommends starting the EN within 24-48 hours after the patient’s admission . Others, state that early nasoenteric feeding is not superior on demand strategy, after attempting an oral diet at 72 hours. The tube should be introduced if oral feeding is not tolerated over the ensuing 2 to 3 days .
Regarding to total caloric value, it has been recommended (25-35 kcal/kg/day) with (1.2-1.5 g/kg of protein/day). The carbohydrates and lipid supplies should be 3-6 g/kg/day and up to 2 g/kg/day respectively. Moreover, the glycemic rate should not exceed 10 mmol/l (180 mg/dl) and the triglycerides 3-4 mmol/l (266 mg/dl) respectively .
A small peptide or peptide-based formulas and medium chain triglyceride oil (MCT) are the macro elements of choice, nevertheless, the standard formula could be an option if well tolerated [19, 26]. The use of glutamine supplementation (except in PN, when inevitable), is not support as routine approach. In addition, the immunenutrition, prebiotics or probiotics is not advised by largescale . Therefore, a prompt and adequate nutritional therapy may reduce the morbidity, hospital stay, costs and mortality in patients suffering from severe AP.
C = CLINICAL
The simple laboratory confirmation at admission of elevated BUN value or its subsequent rise in the next 24 hours of hospitalization is an independent risk for mortality . Also, interleukin-6 level seems an acceptable predictor of severe acute pancreatitis with sensitivities from 81.0 to 83.6% and specificities from 75.6 to 85.3% and should be employed in the first 72 hours .
However, according to international consensus, which took place in Atlanta 2013, a practical and reproducible aspect in acute pancreatic diagnosis is to recognize its severity based on clinical features. Therefore, the disease should be stratified in mild, moderate and severe pancreatitis, taking in account the presence organ dysfunction and if it lasts more than 48 h; despite resuscitative maneuver in ACU (severe pancreatitis). On the other hand, severe forms courses with locoregional complications (peripancreatic fluid collections or pseudocysts and pancreatic or peripancreatic necrosis, sterile or infected . The mortality of the disease can reach 30%, especially in patients who evolve with persistent organ failure and infected pancreatic necrosis (“critical” pancreatitis) .
R = RADIOLOGY
At least two of following criteria are necessary for AP diagnose: typical pain and/or lipase amylase levels 3 times bigger than plasma concentration and characteristic imaging findings on computed tomography (CT) or magnetic resonance (MR) . According to Japanese guidelines in a suspect attack of AP an ultrasonography and magnetic resonance image (MRI) should be requested, because it are more useful than computed tomography (CT) in diagnosing bile duct stones causing pancreatitis and hemorrhagic necrotizing pancreatitis. Contrast-enhanced CT is useful for the diagnosis of active hemorrhage and thrombosis associated with AP .
However, contrast-enhanced CT scan should be considered invaluable as an initial AP diagnostic criterion. It should be used in the third or fourth day of onset of symptoms as prognostic indicator, because in the initial phase of the disease it is very difficult the complete evaluation of the extension and the pancreas and peripancreatic fluid collection and/or necrosis .
Severe AP, according to recent published Japanese severity score, was present when the prognostic contrastenhanced CT score was >2. It is based on accumulated points acquired with progressive extrapancreatic inflammation: pararenal space = 0, root of mesocolon = 1, beyond lower pole of kidney = 2. In addition, take in account the compromised hypoenhanced segments of pancreas (head, body, and tail). One segment or peripancreatic = 0 point, two segments = 1 point, entire 2 segments or more = 2. The total score was graded accordingly: grade 1 = score 0 or 1; grade 2 = score 2; grade 3 = score 3 or more .
E = ENDOSCOPY
The use of various predictors is unreliable in selecting patients with persistent stones for endoscopic retrograde cholangiopancreatography (ERCP), On the other hand, when AP is associated with acute cholangitis, the indication of early (within 72 h) ERCP with sphincterotomy is well established . Moreover, if the patient with AP course without signs of cholangitis, the American guidelines suggest performing endoscopic ultrasound (EUS) or magnetic resonance. Magnetic resonance cholangiopancreatography (MRCP) prior to ERCP depending on the local availability even if EUS is more accurate in the detection of small stones from the gallbladder and signs of stone passage in the CBD .
There is no clear consensus on the indications and timing of sphincterotomy in severe attacks of AP without cholangitis. ERCP should be performed early (within 24–48 h) in patients with acute gallstone pancreatitis associated with bile duct obstruction or cholangitis. In unstable patients with severe acute gallstone pancreatitis and associated bile duct obstruction or cholangitis, placement of a percutaneous transhepatic gallbladder drainage tube should be considered if ERCP is not safely feasible [31,36]. In addition, EUS is pointed out as the technique of choice in drainage of pancreatic fluid collection or pancreatic walled off necrosis. The timing for intervention must be chosen accurately and it is better to postpone the drainage unless infected necrosis is suspected [37, 38].
EUS-guided infection necrosis diagnosis and intervention has become an important tool for management of pancreatic fluid collections (PFCs) and now days are considered the option of first choice for most patients in centers of excellence. Two endoscopic procedures were described to manage the infected “walled-off necrosis” (WON): direct endoscopic necrosectomy (DEN) and lumen apposing metal stenting (LAMS). The first one, despite temporizing patient recovery and treat the infected necrosis, the associated morbidity and mortality are very high. On the other hand, the second one represents a significant promise for improve and simplify the management of these collections .
A = ANTIBIOTICS
Infectious complications are common causes of morbidity and mortality in patients with AP. The controversy over using antibiotics should be focused on pancreatic necrosis. In fact, if compared with patients with sterile pancreatic necrosis, patients with infected necrosis have a higher mortality rate . Although early unblinded trials suggested that administration of antibiotics may prevent infectious complications in patients with sterile necrosis [41, 42], other, better-designed trials have failed to confirm the advantage of antibiotic prophylaxis in acute pancreatitis [43, 44, 45].
Therefore, guidelines do not recommend antibiotic prophylaxis in patients with acute pancreatitis  and antibiotic treatment on demand should be the best option, avoiding excessive treatment and selection of antibiotic resistance. The only rational indication for antibiotics is documented pancreatic infection. Antibiotics should be always given to treat patients with infected necrosis.
Although diagnosis of infection in acute pancreatitis patients may be difficult based on clinical parameters, infected necrosis should be considered in patients with pancreatic necrosis who deteriorate or fail to improve after 7–10 days of hospitalization. Empiric antibiotic regimen should be always given in these patients. After empirical antibiotic therapy, a targeted antibiotic treatment can be based on the results of the cultures from the necrosis. A CT-guided fine needle aspiration (FNA) for Gram stain and culture can guide clinicians in choosing an appropriate individualized antibiotic regimen .
Appropriate spectrum and adequate tissue levels at the site of infection are the main aspects that should be considered when selecting an appropriate antibiotic agent. Two factors should drive the clinicians in choosing the antibiotics: the microbiologic flora and the penetration of the antibiotic agent in the necrotic pancreatic tissue. The spectrum of empirical antibiotic regimen should include both aerobic and anaerobic Gram-negative and Gram-positive microorganisms. The bacteria most frequently found are E. coli, Enterococcus, Staphylococcus aureus, Staphylococcus epidermidis, Klebsiella pneumonia, Pseudomonas sp and Streptococcus sp [47, 48].
Pancreatic penetration is good for fluoroquinolones, carbapenems, Ceftazidime, Cefepime, Metronidazole and Piperacillin-tazobactam . When there is no or minimal residual infection left after a source control procedure, a 7-10 days period of antibiotic therapy may be sufficient, basing on the patient’s condition improves. Also, candida infections may be often present in these patients, and antifungal therapy should be based on the previous exposure to antifungal agents, colonization status of the patient, and severity of illness. Fluconazole remains the most widely used agent for antifungal treatment. When the patient has already been exposed to fluconazole or is colonized with non-albicans candida or when the patient is hemodynamically unstable, therapy with echinocandins is suggested .
S = SURGERY
Generally, the treatment for AP is a medical supportive therapy. However, serious complications may affect the patients, ranging from 10% to 30% . During the early phase of the AP, surgery is rarely indicated and the main reasons for a laparotomy are an ongoing abdominal compartment syndrome, which is not responsive to medical management, and intestinal perforation. In case of intra-abdominal bleeding, angiography with embolization is the first choice; surgery should be recommended in case of failure .
Interventional strategy, such as endoscopic drainage or minimally invasive or open necrosectomy, should be delayed, when it’s possible, at least 4 weeks after the symptoms onset, to colliquate the necrotic tissue and to allow collection to become WON. Thus, interventional strategy is indicated in case of suspected or confirmed infected necrosis, ongoing clinical deterioration with organ failure despite maximum medical support, in case of persistent symptoms of gastric, intestinal or biliary obstruction deriving from mass effect. When an interventional approach is indicated, the dogma is represented by “3Ds” (Delay, Drain, Debride), which summarizes the contemporary strategy for the management of patients with necrotizing AP .
The preferred method is a minimally invasive stepup approach, which consists in gradually more invasive procedure when the previous fails . Many minimally invasive techniques are available to drain and debride infected necrotic pancreatic tissue. Percutaneous catheter or endoscopic drainage should be the first choice, indicated in case of infection of acute necrotic collections or walled-off necrosis . The next step involves minimally invasive surgical debridement, such as minimal access retroperitoneal pancreatic necrosectomy (MARPN) or video assisted retroperitoneal debridement (VARD), which are the two minimally invasive techniques for surgical necrosectomy . However, there isn’t any strong evidence that support which is the best choice between VARD and MARPN; differences are small; thus, they are interchangeable .
Transperitoneal laparoscopic necrosectomy and drainage should be considered as alternative procedure to MARPN or VARD, especially if the necrotic area is limited to the lesser sac  or when intraabdominal distant collections require minimally invasive drainage but they are multiple and interloop and they cannot be reached percutaneously. These minimally invasive strategies aim to reduce mortality and morbidity, which classically affect patients with severe AP, undergoing to more aggressive approach, such as open necrosectomy. Therefore, the open necrosectomy, which represents the classic procedure, remains as the last step and it’s indicated after the failure of the minimally invasive approaches. However, traditional surgery is associated with high morbidity and mortality and it should be considered only as last resort. Cholecystectomy should be performed during the index admission in patients who have mild acute pancreatitis and delayed until clinical resolution in patients who have severe acute pancreatitis .
The best surgical strategy is multimodal and tailored on the clinical conditions of the patients and on the surgical expertise; a step-up approach should be considered, starting with the less invasive procedure and considering more aggressivetechniques in case of ongoing patient worsening.
All authors of this manuscript thank the Drs. Abdul Khaliq, Usha Dutta, Rakesh Kochhar, Kartar Singh, responsible for the “brain idea” and the first summarized publication in Journal of Pancreas (JOP), 2010.
Carlos Augusto Gomes, Salomone Di Saverio, Massimo Sartelli - Study concept, writing the paper, final decision to publish, data collection. Edoardo Segallini, Nicola Cilloni, Angelina Adduci, Claudia Della Casa, Raffaele Pezzilli, Nico Pagano, Felipe Couto Gomes and Camila Couto Gomes - Study concept, data collection, writing the paper, final decision to publish.
There are no relevant conflicts of interest to report for any author.
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