Purpose of review To review the changing insights in the pathophysiology and management of acute pancreatitis.

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1 REVIEW C URRENT OPINION Acute pancreatitis Jan J. De Waele Purpose of review To review the changing insights in the pathophysiology and management of acute pancreatitis. Recent findings The outdated 1992 Atlanta classification has been replaced by two new classifications, both of which acknowledge the role of organ dysfunction in determining the outcome of acute pancreatitis, and both of which have introduced a new category of moderate pancreatitis. The new classifications will allow fewer patients to be classified as severe, which better reflects the risk of dying of the disease. Intra-abdominal hypertension has emerged as a relevant issue, and strategies to lower intra-abdominal pressure may often be required. Antibiotic prophylaxis has been discontinued for some time, but aggressive fluid resuscitation is also being questioned, and the role of surgery is further reduced as percutaneous drainage of collections has shown to reduce the need for more surgical interventions. If needed, surgery should be as conservative as possible, with minimally invasive strategies preferable. Newer techniques such as endoscopic transgastric drainage are being developed, but their exact role has yet to be defined. Summary Management of severe acute pancreatitis is changing fundamentally. Less is more is the new paradigm in acute pancreatitis less antibiotics, less fluids, less surgery, which should eventually lead to less morbidity and mortality. Keywords acute pancreatitis, fluid resuscitation, intra-abdominal hypertension, organ failure, pancreatic necrosis INTRODUCTION Acute pancreatitis is an acute inflammation of the pancreas that is self-limiting in most cases, and only a minority of patients, estimated around 15%, develops a more serious form of the disease. Despite improvements in our knowledge of the disease and critical care support, severe acute pancreatitis still carries a considerable mortality rate. In recent years, much of what was once standard therapy has become obsolete, as research found several treatment strategies such as aggressive fluid resuscitation, prophylactic antibiotics and early debridement for patients who do not improve, to be associated with worse rather than improved outcome. In this review, we will discuss the proposed new classification of acute pancreatitis and the above-mentioned changes in the management of these severely ill patients. ACUTE PANCREATITIS: DESCRIPTION AND CLASSIFICATION Classification of acute pancreatitis is essential when studying the disease, in order to compare studies as well as for appropriate patient selection for inclusion in these clinical studies. In 1992, a panel of experts convened in Atlanta, which resulted in the so-called Atlanta criteria that have been used in clinical research. Although these may have been valid at the time of development, the criteria received a lot of criticism in recent years. The 1992 criteria discriminated mild and severe pancreatitis based on local and systemic criteria, but the definitions used were no longer up to date, and in recent years, several publications used additional criteria to define severe acute pancreatitis. Notably, the definitions used to describe organ dysfunction were outdated and it was considered that the definitions did no longer reflect current knowledge. This led two groups of experts to independently Ghent University Hospital, Department of Critical Care Medicine, Ghent, Belgium Correspondence to Jan J. De Waele, MD, PhD, Department of Critical Care Medicine, Ghent University Hospital, De Pintelaan 185, 9000 Gent, Belgium. Tel: ; fax: ; Jan.DeWaele@UGent.be Curr Opin Crit Care 2014, 20: DOI: /MCC ß 2014 Wolters Kluwer Health Lippincott Williams Wilkins

2 Gastrointestinal system KEY POINTS Classification of acute pancreatitis has been revised and now better reflects the risk of mortality; two new classifications have recently been introduced, but it is unclear if either of them is superior. Aggressive fluid resuscitation, traditionally considered an important element of critical care interventions, has been linked to worse outcome. Judicious use of fluids is warranted while ongoing studies further investigate this issue. Patients admitted with severe acute pancreatitis are at risk of intra-abdominal hypertension; therefore IAP monitoring is warranted, and preventive measures as well as therapeutic interventions should be considered when IAP increases. There is no role for prophylactic antibiotics. When an intervention, usually for infected pancreatitis, is needed, a more conservative strategy including percutaneous drainage is advisable. Only when this fails, surgical intervention is warranted. develop new classifications of acute pancreatitis, which were published almost simultaneously in December 2012 [1 ] and January 2013 [2 ]. Both groups introduced a category of intermediate severity ( moderate pancreatitis), recognized the importance of persistent organ failure (compared to transient organ failure), and used more appropriated classification of organ dysfunction. The revised Atlanta criteria defined three degrees of pancreatitis and the determinant-based classification has four severity classes. The three-stage Atlanta definition added an intermediate-severity category, moderate pancreatitis, which is characterized by either transient organ dysfunction (i.e. less than 48 h), local complications without organ dysfunction or exacerbation of comorbidities (Table 1) [2 ]. In this classification, persistent organ dysfunction based on the modified Marshall score, usually accompanied by local complications, is the hallmark of severe acute pancreatitis. The modified Marshall score was preferred over other scoring systems as it can be calculated also for patients not in an ICU, for example the general ward or emergency room. Apart from a new set of definitions, the terminology of the different local complications was also revised. A complete review is beyond the scope of this article, but we refer to a number of excellent reviews on this issue [3 ]. Important to know is that hemorrhagic pancreatitis, pancreatic phlegmon and pancreatic abscess are no longer used. Important new concepts are acute necrotic collection and walled off necrosis, both describing the same process but at different moments in time, with the first usually occurring in the first 4 weeks and the latter being the end result of the first. The second classification system that was recently introduced, the determinant-based severity classification (DBSC), is based on the concept that the determinants of outcome should be used to classify acute pancreatitis [1 ]. Two important determinants were defined, one systemic determinant (distant organ failure) and one local determinant (necrosis of pancreatic or peripancreatic tissue). On the basis of these considerations, a four-level classification is described (Table 2) also with a category of moderate pancreatitis and, in addition to that, a new category of critical acute pancreatitis. Theoretically, the above classification has the advantage of better reflecting the risk of mortality and also recognizes the (limited) role of transient organ failure. A score of 2 or more on the Sequential Organ Failure Assessment score is used to describe organ dysfunction for the cardiovascular, respiratory and renal system. A downside is that the score heavily depends on the demonstration of local complications, implying the need for a contrastenhanced abdominal computed tomography (CT) scan, which is mostly not needed or sometimes not possible in the first days. It is unclear which classification will prove superior; a recent study comparing the two classification systems found no significant differences in predicting outcome between the two [4]. From a practical point of view, the DBSC seems more attractive for critical care physicians as these scores are Table 1. Revised Atlanta classification Mild Moderate Severe Both criteria present One or two criteria present Organ failure Absent Transient only (<48 h) Persistent (>48 h) Local or systemic complications Absent Present (Usually present not required for classification) Data from [2 ] Volume 20 Number 2 April 2014

3 Acute pancreatitis De Waele well known and often available from the patient data management system. DETERMINANTS OF MORTALITY For a long time, infection has been considered the most important risk factor for adverse outcome, but recent literature has studied the role of organ dysfunction in detail. Petrov et al. [5] analyzed the available literature and found in a meta-analysis that both have comparable impact on outcome, but the combination of both has the highest impact. Recent studies confirm this importance of organ dysfunction. Guo et al. [6] reviewed 447 patients treated between 2009 and Overall mortality was 13%, and several characteristics were associated with worse outcome, such as age, bacteremia and pancreatic necrosis; persistent organ failure was found to be a major determinant of mortality [odds ratio (OR) 16.72]. The role of timing of surgery has been again found to be relevant in a study by Busquets et al. [7]. These authors found that early surgery, advanced age, and sterility of tissue cultures were associated with mortality. PREDICTION IN ACUTE PANCREATITIS Predicting severity of pancreatitis is a desirable goal, but the search for the ultimate predictor is still ongoing. A number of recent studies have further explored old and new predictors. Bollen et al. [8] found clinical scoring systems to be as reliable as radiological scoring systems, implying that early imaging to predict the severity of pancreatitis is not necessary. Of note, the recently proposed Bedside Index of Severity in Pancreatitis (BISAP) score [8] performed the poorest in this study, suggesting that scoring systems perform differently, depending on the population and setting, and that the concept of a universal scoring system may be elusive. Whereas the debate on the role of new biomarkers such as procalcitonin continues [9 ], Cardoso et al. [10] reported on the value of C-reactive protein (CRP) in a large cohort of acute pancreatitis patients. They found that the CRP level at 48 h after hospital admission had good discriminative power for the development of pancreatic infection and in-hospital mortality (area under the receiver operating curve of 0.77 and 0.79, respectively). Despite the delay of 48 h, CRP could be a valuable parameter as these two complications do not occur early in the course of the disease, and clinical features rather than lab values determine early management and disposition. Another simple predictor that was investigated in a large population was blood urea nitrogen (BUN). Wu et al. [11] found in a cohort that an elevated BUN (>20 mg/dl) at admission and any rise in BUN level during admission was associated with a 4.6 and 4.3-fold increase in mortality, respectively. These predictors performed comparable to other scoring systems [e.g. the Acute Physiology and Chronic Health Evaluation (APACHE) II score] but of course are simpler and can be used already at admission. FLUID RESUSCITATION As in other areas of critical care medicine, fluid resuscitation has come under scrutiny in severe acute pancreatitis patients as well [12 14]. Liberal or aggressive fluid resuscitation has always been one of the mainstays of therapy, but this has been questioned recently. It is assumed that fluid resuscitation could affect the pancreatic microcirculation, and fluid overload could further impair pancreatic tissue perfusion, leading to necrosis of the pancreas. A number of studies have demonstrated that a less aggressive fluid resuscitation strategy does not lead to worse outcome, and conversely that administration of large volumes of fluid resuscitation is associated with worse outcome [15,16]. Another study found the volume of fluid that is sequestrated in the first 48 h to be variable, and identified age, alcohol-induced pancreatitis, hematocrit, glucose, and systemic inflammatory response syndrome in the emergency room to be associated with increased fluid sequestration [17]. Whether this helps to identify patients who may need less fluids, however, remains unclear. Table 2. Determinant-based severity classification Determinant Mild Moderate abstract Severe Critical Both criteria present One or two criteria present Either one criterion Both criteria present Local No necrosis Sterile necrosis Infected necrosis Infected necrosis Systemic No organ dysfunction Transient (>48 h) organ dysfunction Persistent (>48 h) organ dysfunction Persistent (>48 h) organ dysfunction Data from [1 ] ß 2014 Wolters Kluwer Health Lippincott Williams Wilkins 191

4 Gastrointestinal system The most marked conclusion of a recent systematic review on this topic was that the evidence on which an aggressive fluid therapy approach is based is very limited [18]. The authors also concluded that recent randomized studies of moderate quality found that a nonaggressive fluid resuscitation strategy is associated with a lower risk of organ dysfunction (OR 0.69) and lower risk of mortality (OR 0.40). When discussing fluid resuscitation, resuscitation endpoints are of critical importance. This has been poorly investigated in acute pancreatitis, with most studies focusing on conventional hemodynamics [19]. Wu et al. [20] used BUN as a resuscitation endpoint, but could not demonstrate this to be a superior strategy. A recent animal study found that stroke volume variation led to improved survival [21], but this has as yet to be confirmed in humans. This review could not find a particular resuscitation goal that was associated with improved outcome; this area clearly needs more research. The choice of fluid resuscitation may be equally important. Wu et al. [20] found lactated Ringer s to be superior to normal saline. Remarkably, a number of small studies have suggested that resuscitation with hydroxyethyl starches (HES) [22] or a combination of HES and crystalloids [23] results in lower use of mechanical ventilation and lower organ failure, respectively. Recent studies describing increased harm with the use of starches have of course changed the discussion and starches can no longer be recommended as resuscitation fluid in these critically ill patients. At this point, adopting a more restrictive early fluid resuscitation strategy seems prudent, but an appropriate resuscitation endpoint cannot be recommended. Balanced crystalloid solutions are a good choice for early fluid resuscitation. ANTIBIOTIC USE IN ACUTE PANCREATITIS The impact of infection in patients with severe acute pancreatitis has triggered an interest in administration of antibiotic prophylaxis, which has been applied on a large scale in the 1980s and 1990s, after a number of small unblinded studies had suggested a beneficial effect of this approach [24]. Two large randomized controlled trials (RCTs), however, could not replicate these findings, and since the publication of these two studies in 2004 [25] and 2007 [26], no new compelling evidence has been published in support of prophylaxis. Antibiotics should therefore be reserved for patients with established infections only. When infection occurs, it is typically late in the course of the disease. In a large cohort study in the Netherlands, pancreatic infection developed after a median of 26 days [27]. Typically, these infections are often caused by nosocomial pathogens, and empirical antibiotics should cover enteric organisms (Gram-positive as well as Gram-negative aerobic and anaerobic microorganisms, and fungi), as translocation is presumably the route of infection of the pancreatic necrosis. Previous exposure to antibiotics may select for multidrug-resistant microorganisms [28]. Antibiotics should be used cautiously in patients with severe acute pancreatitis, as the course of the disease is often protracted, and multiple courses of antibiotics may be necessary once infection develops. Unnecessary and prolonged antibiotic use will further enhance development of antibiotic resistance. Source control in pancreatitis is equally important, and it should be remembered that administration of antibiotics without source control [e.g. through percutaneous drainage (PCD) of infected collections] is ineffective. The role of surgery has evolved significantly in recent years and is further discussed below. FUNGAL INFECTIONS IN SEVERE ACUTE PANCREATITIS There have been multiple studies reporting variable incidences of fungal infection [29]. Also, the effect on mortality was different and conclusions about the pathogenic role of fungi in this setting are difficult to make. Fungal infections, usually with Candida species, however, remain frequent and carry a high mortality rate. A recent study suggested that the Candida Colonization Index score was a good and (in this study the) sole predictor of subsequent infection [30]. It should be noted that all scoring systems evaluated in the study did have a low positive predictive value. Doubts remain about the efficacy of antifungal prophylaxis in patients with pancreatitis; further research is, however, needed to fully elucidate the role of antifungal prophylaxis [31]. INTRA-ABDOMINAL HYPERTENSION AND ABDOMINAL COMPARTMENT SYNDROME Patients with severe acute pancreatitis and organ failure are at high risk of suffering from intraabdominal hypertension (IAH); the incidence of IAH in this population is very high with incidences varying from 60 to 85% [13]. In a recent metaanalysis, acute pancreatitis was listed as one of the risk factors, but it was also evident that many other factors for IAH are typically present in IAH [32 ]. Specifically, multiple factors contribute to IAH in Volume 20 Number 2 April 2014

5 Acute pancreatitis De Waele this setting and both characteristics of primary (i.e. an intra-abdominal cause) and secondary (due to fluid overload and edema) IAH are present [13]. Obviously the inflammatory process in the retroperitoneum increases the intra-abdominal volume, which can be further increased due to the development of ascites or ileus with increased intraluminal content. Vigorous fluid resuscitation which can amount to l per day may further accelerate the development of abdominal compartment syndrome (ACS), which is the end product of IAH and characterized by severe organ dysfunction, with respiratory, cardiovascular and renal dysfunction most pronounced. In this context, Zhao et al. [23] found that using a resuscitation protocol with only normal saline, patients had higher intra-abdominal pressure (IAP) and ACS more often, compared to patients treated with a combination of colloids and crystalloids. Given the pathophysiology of IAH in pancreatitis, several nonoperative measures are available to reduce the IAP in pancreatitis patients. The 2012 World Society of the Abdominal Compartment Syndrome recommendations review in detail these options. Nasogastric tube placement to reduce IAP in patients with gastric distension due to gastric outlet obstruction and PCD in patients with ascites are just a few options [33 ]. In a RCT, a restrictive fluid resuscitation approach was associated with lower IAP and lower incidence of ACS [34]. When conservative measures fail and IAH is considered to be an important contributor to organ dysfunction, surgical decompression may be considered. There is ample evidence that decompressive laparotomy is effective in reducing IAP as several studies have reported marked decreases in IAP [35], but the effect on organ dysfunction is variable and comparative studies are lacking. A well conducted animal study simulating IAH in acute pancreatitis found significantly decreased morbidity and mortality after early decompression [36]. Mentula et al. [37] reported that early decompression (within the first 2 days) was most effective with patients decompressed late having a high mortality rate. Other single-institution experiences have been reported in the past years [38], but it is difficult to draw firm conclusions. Mortality remains high after abdominal decompression and complications are significant [35]. In practice, IAP measurement in patients admitted to the ICU is mandatory to monitor the trend and avoid deterioration or the development of ACS when possible. If IAH develops, nonoperative measures should be applied, and in most cases, significant decrease in IAP will be possible. Decompressive laparotomy should be reserved for selected cases. LOCAL MANAGEMENT OF PANCREATIC NECROSIS Operative management of acute pancreatitis has evolved significantly in recent years [39], and a number of recent studies confirm earlier findings that a less aggressive approach appears to be associated with improved outcome. In the discussion below, we will only focus on the treatment of pancreatic necrosis, not fluid collections or pseudocyst, as these do not typically pose problems in critically ill patients. The principles of surgical management in this context are listed below. (1) Transfer to an experienced center that has access to interventional radiology, endoscopy, and surgery (2) Delineate well defined indications for intervention (3) Start with PCD as the first-line strategy (4) Use the least invasive procedure possible (endoscopy and minimally invasive surgery) (5) Do not delay intervention when indicated (6) Avoid early surgery if possible (7) Be patient Pancreatic necrosis as such is not an indication for an intervention other than fine needle aspiration to document the presence of infection in pancreatic or peripancreatic necrosis [40]. Samples should be sent to the lab for direct examination and culture. Direct examination may direct empirical treatment and culture eventually may allow directed therapy. In this way, apart from establishing the diagnosis of infected necrosis which warrants antibiotic therapy, fine needle aspiration also allows the identification of the causative microorganism(s). There are two important reasons to sample the necrosis: firstly it allows de-escalation after most often broad-spectrum empirical antibiotics, and secondly it may detect antibiotic-resistant isolates, a common finding in pancreatic necrosis [28]. Percutaneous drainage PCD for fluid collections in severe acute pancreatitis was described first in 1998 and has been increasingly used [41]. The Dutch Collaborative Pancreatitis Study Group randomized 88 patients to either open surgery or a step-up approach of PCD with minimally invasive surgery for failures [the PAncreatitis, Necrosectomy versus step up approach (PANTER) study] and found that PCD indeed avoided surgery in a significant group of patients, and that the minimally invasive approach had fewer major complications compared to open surgery [42] ß 2014 Wolters Kluwer Health Lippincott Williams Wilkins 193

6 Gastrointestinal system More recent investigations confirm these findings. Using a strategy of primary PCD in a broad population of severe acute pancreatitis patients, Babu et al. [43] found that PCD resulted in sepsis reversal in almost two-thirds of the patients, and avoided open necrosectomy despite the presence of infection in the majority of the patients undergoing PCD, in about half of them. They found that severity of disease at the first PCD, as expressed by the APACHE II score, and the number of bacteria isolated, were predictive of the need for subsequent surgery. As in other studies, outcome was primarily determined by severity of illness; factors associated with mortality included the APACHE II score at the first intervention, as well as the number of bacteria isolated and gallstone disease. Endoscopic necrosectomy Endoscopic transgastric necrosectomy was recently added to the armentarium in the treatment of pancreatic necrosis [44]. Compared to open surgery, a small RCT found that endoscopic necrosectomy was associated with fewer major complications (20 vs. 80%) and pancreatic fistula (10 vs. 70%) [45 ]; only a minority of these patients was admitted to the ICU at the moment of intervention. Although promising, the exact role of this intervention in a broader population of acute pancreatitis patients remains to be determined. The intervention is time-consuming and requires multiple procedures to drain the collections and remove tissue necrosis. Minimally invasive surgery Minimally invasive retroperitoneal pancreatic necrosectomy was introduced recently and avoids a transperitoneal approach [46]. After insertion of a percutaneous drain under CT guidance, this drain is used as a guide to debride the retroperitoneum using a retroperitoneal endoscopic approach. Although this technique has its limitations, several studies have reported excellent results in selected patients [47]. This minimally invasive approach was also the second part of the step-up approach as investigated by the Dutch Acute Pancreatitis Collaborative Group. It is an attractive technique, if indeed the necrosis is amenable for a retroperitoneal approach in some cases, such as necrosis of the head or extensive collections, this may be more challenging. Open surgery Several studies have reported high morbidity and mortality rates with open surgery [48], and whenever possible, open procedures in pancreatitis need to be avoided. Complications are frequent, including pancreatic fistula, bowel injury, and incisional hernia [42]. Except for the PANTER study [42], no randomized studies comparing different surgical approaches, however, exist, and all retrospective analyses suffer from selection bias. A recent systematic review could not draw a conclusion due to the limited and heterogeneous studies [49]; the effect on major outcomes in this analysis was unclear, but the effect on organ dysfunction, with clearly lower risk [OR 0.16, 90% confidence interval (CI) ] in patients managed using minimally invasive techniques, was a clear advantage. Restricting indications and an overall minimally invasive approach to control the source of infection, however, seem reasonable, given the high morbidity and mortality associated with open surgery. CONCLUSION Our knowledge regarding the pathophysiology and management of the severe forms of acute pancreatitis has changed dramatically over the past years. The updated classification has yet to prove its virtues, but is now based on a more sound rationale and may help to identify patients at the highest risk of mortality who may be better candidates for interventional studies. Strategies once taken for granted, such as antibiotic prophylaxis, have been abandoned, but also liberal fluid resuscitation and aggressive most often open surgery is now being questioned. Restrictive early fluid resuscitation and less invasive interventions such as PCD have emerged as valid options. In severe acute pancreatitis, less seems to be more. Acknowledgements None. Conflicts of interest Disclosures: Jan De Waele is current President of the World Society of the Abdominal Comparment Syndrome and has served as a consultant for KCI, Smith Nephew, Bayer, and AstraZeneca. REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1. Dellinger EP, Forsmark CE, Layer P, et al. Determinant-based classification of acute pancreatitis severity: an international multidisciplinary consultation. Ann Surg 2012; 256: First of two new classifications for acute pancreatitis with concise review of the rationale Volume 20 Number 2 April 2014

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