INFLUENCE OF ETIOLOGY AND MORPHOLOGICAL CHANGES ON TREATMENT OPTIMIZATION IN SEVERE ACUTE PANCREATITIS

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LITHUANIAN UNIVERSITY OF HEALTH SCIENCES MEDICAL ACADEMY

Povilas Ignatavičius

INFLUENCE OF ETIOLOGY AND

MORPHOLOGICAL CHANGES ON

TREATMENT OPTIMIZATION IN

SEVERE ACUTE PANCREATITIS

Doctoral Dissertation Biomedical Sciences,

Medicine (06B)

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Dissertation has been prepared at the Department of Surgery of Medical Academy of Lithuanian University of Health Sciences during the period of 2014–2019.

Scientific Supervisor:

Prof. Habil. Dr. Juozas Pundzius (Lithuanian University of Health Sciences, Biomedical Sciences, Medicine – 06B).

Dissertation is defended at the Medical Research Council of the Lithuanian University of Health Sciences:

Chairperson

Prof. Habil. Dr. Virgilijus Ulozas (Lithuanian University of Health Sciences, Biomedical Sciences, Medicine – 06B).

Members:

Prof. Dr. Jūratė Kondrackienė (Lithuanian University of Health Sciences, Biomedical Sciences, Medicine – 06B);

Prof. Dr. Juozas Kupčinskas (Lithuanian University of Health Sciences, Biomedical Sciences, Medicine – 06B);

Prof. Dr. Tomas Poškus (Vilnius University, Biomedical Sciences, Medicine – 06B);

Prof. Dr. Aldis Pukitis (University of Latvia, Biomedical Sciences, Medicine – 06B).

Dissertation will be defended at the open session of the Medical Research Council of Lithuanian University of Health Sciences on May 9th_{, 2019 at} 2 p. m., in the Great Auditorium at the Hospital of Lithuanian University of Health Sciences Kauno Klinikos.

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LIETUVOS SVEIKATOS MOKSLŲ UNIVERSITETAS MEDICINOS AKADEMIJA

Povilas Ignatavičius

ETIOLOGIJOS IR MORFOLOGINIŲ

PAKITIMŲ ĮTAKA SUNKIU ŪMINIU

PANKREATITU SERGANČIŲJŲ

GYDYMO OPTIMIZAVIMUI

Daktaro disertacija Biomedicinos mokslai, medicina (06B) Kaunas, 2019

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Disertacija rengta 2014–2019 metais Lietuvos sveikatos mokslų universitete Medicinos akademijos Chirurgijos klinikoje.

Mokslinis vadovas:

Prof. habil. dr. Juozas Pundzius (Lietuvos sveikatos mokslų universitetas, biomedicinos mokslai, medicina – 06B).

Disertacija ginama Lietuvos sveikatos mokslų universiteto medicinos mokslo krypties taryboje:

Pirmininkas:

prof. habil. dr. Virgilijus Ulozas (Lietuvos sveikatos mokslų universite-tas, biomedicinos mokslai, medicina – 06B).

Nariai:

prof. dr. Jūratė Kondrackienė (Lietuvos sveikatos mokslų universitetas, biomedicinos mokslai, medicina – 06B);

prof. dr. Juozas Kupčinskas (Lietuvos sveikatos mokslų universitetas, biomedicinos mokslai, medicina – 06B);

prof. dr. Tomas Poškus (Vilniaus universitetas, biomedicinos mokslai, medicina – 06B);

prof. dr. Aldis Pukitis (Latvijos universitetas, biomedicinos mokslai, medicina – 06B).

Disertacija bus ginama viešame medicinos mokslo krypties tarybos posėdyje 2019 m. gegužės 9 d. 14 val. Lietuvos sveikatos mokslų universiteto ligoninės Kauno klinikų Didžiojoje auditorijoje.

Disertacijos gynimo vietos adresas: Eivenių g. 2, LT-50161 Kaunas, Lietuva.

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Skiriu savo seneliui Doc.Vytautui Aleksai

Dedicated to my grandfather Assoc. Prof. Vytautas Aleksa

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ABBREVIATIONS

AP – Acute pancreatitis

SAP – Severe acute pancreatitis

RAC – Revised Atlanta 2012 Classification of Acute Pancreatitis

CT – Computed tomography

CECT – Contrast-enhanced computed tomography ABP – Acute biliary pancreatitis

AAP – Alcohol-induced acute pancreatitis WHO – World Health Organization

ERCP – Endoscopic retrograde cholangiopancreatography

US – Ultrasound

MRI – Magnetic resonance imaging

NSAID – Nonsteroidal anti-inflammatory drugs SIRS – Systemic inflammatory response syndrome RCT – Randomized controlled trial

FNA – Fine needle aspiration UGD – Ultrasound guided drainage CRP – C-reactive protein

ICU – Intensive care unit

MODS – Multiple organ dysfunction syndrome

BISAP – Bedside Index for the Severity in Acute Pancreatitis APACHE II – Acute Physiology and Chronic Health Evaluation II CTSI – Computed tomography severity index

IAP – International Association of Pancreatology APA – American Pancreatic Association

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INTRODUCTION

Over the last decades, acute pancreatitis (AP) remains one of the most extensively investigated therapeutic problems with a hardly improvable course. The incidence of the first attack of AP has increased in past decades, and varies from 4.9 to 200 cases per million inhabitants [1, 2]. In 80% of AP patients, pancreatic injury is mild or moderate and self-limiting, requiring only brief hospitalization to recover without complications. About 25% of patients with AP develop severe acute pancreatitis (SAP), which is strongly associated with organ failure and local complications such as pancreatic or extrapancreatic necrosis and formation of walled-off necrosis or pseudocysts. Infected pancreatic necrosis is observed in 30%–70% of SAP patients [3–5]. The extent and infection of pancreatic necrosis directly correlates with morbidity and mortality [6, 7]. Length of hospital stay, and intensive care unit (ICU) stay is long in these patients. Therefore, the management of patients diagnosed with SAP is associated with high treatment costs and costs due to loss of production, reaching up to €28,200 per person [8]. Due to considerable improvements in the diagnosis and management of these patients, overall mortality of the disease has decreased, but still ranges between 15% and 25%. The extent of pancreatic necrosis as well as the presence of secondary bacterial infections have been identified as major determinants of lethal outcomes after the third week, representing the most common cause of late mortality [9]. Secondary infection of pancreatic necrosis increases the mortality rate by up to 35% [5, 10].

According to the literature, gallstones and alcohol consumption are the most common (>80%) etiological factors of AP. However, the effect of these factors on the disease’s course and outcomes is still not fully understood [2, 11, 12]. Cultural and traditional differences impact on the prevalence of these etiological factors across different countries. Several studies have reported higher incidence of acute biliary pancreatitis (ABP) in southern countries. Contrarily, alcohol-induced acute pancreatitis (AAP) is more often diagnosed in northern countries [5, 13]. Other etiologic factors such as drugs, hyper-triglyceridemia, viruses and idiopathic causes are also reported [14]. Acute pancreatitis encompasses a wide spectrum of disease severity from a brief, self-limited presentation, to a fulminant progression, to multi-organ failure and death [15]. In response to the need for a comprehensive classification system in the treatment of AP, the 1992 Atlanta Classification of AP was established. The 1992 Atlanta Classification of AP identified two categories of the disease, “mild” and “severe”, and recommended the clinical treatment for each type [6, 16–18]. However, a subgroup of AP patients who fell in

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between the two severity categories were often observed to have relatively good outcomes and positive responses to less aggressive treatment protocols than those with the severe disease, thus calling for the revision of the existing classification system. In 2012 the Atlanta Classification of AP was revised by adding a third category defined as “moderately severe” [4].

The aim of the study

The aim of the study was to evaluate the significance of etiology, morphological changes (pancreatic and extrapancreatic necrosis) and the Revised Atlanta 2012 Classification of Acute Pancreatitis in early identifi-cation of patients with severe acute pancreatitis.

The objectives of the study

1. To compare the clinical course (development of pancreatic necrosis and secondary infection, the need for surgical interventions) and outcomes of biliary and alcohol-induced acute pancreatitis

2. To assess the impact of etiology on the presence and location of pancreatic necrosis in patients with acute pancreatitis

3. To evaluate the effectiveness of the Atlanta 2012 Classification of Acute Pancreatitis criteria for computed tomography assessment in distingui-shing different morphological types of acute pancreatitis

4. To assess the effectiveness of the Atlanta 2012 Classification of Acute Pancreatitis in allocating patients diagnosed with acute pancreatitis to the different categories (mild, moderately severe, severe) and to assess the difference in outcomes

Novelty of the study

Annual incidences of AP and mortality rates remain high and, together with distribution into different severity categories, differs between different countries. The wide variation in incidence reflects different factors such as population differences in culture, tradition and lifestyle, different etiology (alcohol abuse, biliary stones, hypertriglyceridemia, etc.), and variations in clinical assessment tools.

The influence of etiological factors on the course and outcomes of AP is not yet fully understood [11]. The dominant (>80%) etiological factors of AP are gallstones and alcohol consumption [2, 12]. Prevalence of these two main etiologic factors in AP varies considerably between different countries,

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reflecting differences in culture, tradition and lifestyle. Predominance of ABP has been reported in southern countries, on the contrary a similar frequency or predominance of AAP has been observed in northern ones [5, 13]. Other etiologic factors such as drugs, hypertriglyceridemia, viruses and idiopathic causes are also reported [14]. To answer the question of the importance of different etiologic factors our study compares the clinical course and outcomes of AP induced by two main etiologic factors – alcohol consumption and biliary stones.

The Revised Atlanta 2012 Classification of AP (RAC) distinguishes two morphological types of acute pancreatitis – interstitial edematous and necro-tizing AP [4]. Necronecro-tizing AP is more severe form and can be followed by local and/or systemic complications. Necrotizing AP can present to different extents and in different locations (pancreatic head, neck, body, tail or extrapancreatic necrosis). The data on the importance of the location of the necrosis is controversial. However it could affect the clinical course of the disease and management options [19, 20]. As mentioned before, two main etiologic factors inducing AP are alcohol abuse and gallstones. The pathoge-nic mechanisms of inflammatory process of both etiologic factors are differ-ent [14]. It might be considered that differdiffer-ent etiologic factors lead to differdiffer-ent morphological changes in the pancreas. However, the data on this topic is also controversial [21–24]. Therefore, in the second multicenter study we assessed the impact of etiology on the presence and location of pancreatic necrosis in patients with AP.

However, etiologic factors alone are not sufficient to classify AP. In 2013 the RAC was published [4, 16]. The Revised Atlanta 2012 Classification of AP distinguishes three disease severity categories (mild, moderately severe, severe). However, the main focal point of these classifications are the different morphological types of AP. Interstitial edematous pancreatitis and necrotizing pancreatitis (pancreatic parenchymal necrosis, extrapancreatic necrosis, combined necrosis) are identified according to the computed tomography (CT) evaluation criteria. It was previously shown that different morphological types of AP have different clinical courses and outcomes [4, 19, 20]. The Revised Atlanta 2012 Classification of AP was published a few years ago, however there is still not enough data on its effectiveness and advantages in distinguishing different morphological types of AP.

A subgroup of AP patients who fell in between the two Atlanta 1992 classifications of AP severity categories (mild and severe) were often obser-ved to have relatively good outcomes and respond positively to less aggres-sive treatment protocols than those with the severe disease. As mentioned above the Atlanta 2012 Classification of AP was revised by adding a third category defined as “moderately severe” AP. To the best of our knowledge

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no previous studies have focused on the complications, mortality and outcomes of patients with moderately severe AP. This raises the question of whether patients of different severity categories should receive the same aggressive treatment and expensive interventions. Our fourth study answers the question of the outcomes and clinical course of different severity categories of AP and assesses the effectiveness of RAC in allocating patients diagnosed with AP to different categories.

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1. REVIEW OF THE LITERATURE

1.1. Acute pancreatitis

Acute pancreatitis is an acute inflammation of the pancreas and surround-ing fatty tissue. The incidence of the first attack of AP is rissurround-ing worldwide and varies from 4.9 to 200 cases per million inhabitants [1, 2, 25]. In the United States the number of patients discharged with a diagnosis of AP increased from 164,776 in 1997 to 275,170 in 2012. With the rising incidence of the disease, the healthcare cost for its treatment is also continuously increasing. In the United States the mean treatment cost per patient diagnosed with AP increased from $15,433 in 1997 to $33,744 in 2012 [26]. In Sweden the extrapolated annual financial burden for AP reaches up to ∼ €38,500,000. Depending on the severity of the disease the treatment cost per patient varies

from €5,100 to €28,200 [8].

In about 80% of patients’ pancreatic injury is mild, without organ failure and pancreatic necrosis. The mortality rate in these patients does not exceed 1%. On the contrary, in patients with SAP and infected pancreatic necrosis, the mortality rate reaches 15%–35% (Fig. 1.1.1) [10].

Fig. 1.1.1. Incidence and mortality rates of acute pancreatitis

In 80% of cases acute pancreatitis is mild without organ failure and pancreatic necrosis. In 20% of cases severe disease is diagnosed. The mortality rate does not exceed 1% in mild disease. In severe acute pancreatitis the mortality rate varies from 13% in case of sterile necrosis to 15–35% in case of infected necrosis (van Dijk SM, et al., 2017) [10]

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1.2. Etiology of acute pancreatitis

Alcohol abuse and gallstones are two main etiological factors of AP identified as the possible cause of the disease in 70%–80% of patients [12, 14, 27, 28]. Prevalence of these two main etiologic factors in AP varies consi-derably among different countries, reflecting differences in culture, tradition and lifestyle. Predominance of biliary pancreatitis has been reported in southern countries, on the contrary a similar frequency or predominance of alcoholic pancreatitis has been observed in northern ones [13, 29, 30].

Gallstones as an etiological factor of AP are identified in about 40% of cases. Migrating stones might cause not only the obstruction of the main hepatic duct but also they might obstruct the pancreatic duct [1, 31]. Usually the obstruction is transient and mostly the gallstones migrate rapidly [29]. The role of gallstones in the etiology of AP is supported by several studies sho-wing the positive effect of endoscopic sphincterotomy on the rate of attacks of ABP [32, 33]. However the risk of ABP is less than 2% in asymptomatic patients with gallstones [34]. Experimental studies in animals identified several changes in the pancreas and biliary tract after obstruction by gallsto-nes. The most important changes are acinar cell necrosis, pancreatic edema and increased pancreatic juice secretion containing increased concentration of bile acids, and reduced activity of sphincter of Oddi [35, 36]. However, the exact mechanisms of how these changes are induced by the gallstones are not fully understood. Small size (≤5 mm) and high number (≥20), along with a wide cystic duct (>5 mm) are identified as possible risk factors of ABP [37, 38]. Increased level of circulating cholecystokinin, reflux of infected bile into the pancreatic duct, peculiarity of bile and pancreatic duct anatomy (wide common bile duct, wide angle between the bile duct and pancreatic duct), mutations in the pancreatic enzymes encoding genes (SPINK1, ABCB4) are identified also as possible factors in the pathogenesis of ABP [29, 39–42].

In 2%–5% of heavy alcohol drinkers alcohol-induced AP will be diagnosed during their lifetime, making alcohol the second most common cause of the disease [31, 34]. Neither the type of alcohol nor its amount, nor the increase of alcohol consumption in the population is associated with the increased prevalence of AAP [43, 44]. In experimental studies no association between alcohol feeding and AAP was found [45]. However, the association between incidence of AP and prolonged alcohol abuse was showed in several studies [43, 46, 47]. While the direct toxicity on the pancreas is well known, other cofactors are no less important. Several mechanisms by which alcohol induces AP are reported in the literature. Alcohol-induced changes to the

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tine) are responsible for the pancreatic duct obstruction, acinar cells dysfunc-tion and fibrosis [48]. Intracellular activadysfunc-tion of digestive enzymes due to alcohol metabolism is also reported. During the oxidative (generation of acetaldehyde) and non-oxidative (formation of free fatty acid ethyl esters) pathways several toxic metabolites are produced and pancreatic stellate cells are activated, leading to pancreatic cell injury, inflammation and death [14, 49]. All these mechanism lead to a described hypothesis of alcohol-induced pancreatic stress and sensitization to AAP [27].

All other etiological factors are much less frequent. Drug-induced AP is reported in less than 5% of patients. Although 525 drugs are identified by World Health Organization (WHO) as being capable of inducing AP, causality was proven for only 31 drugs (mesalamine, valproic acid, didano-sine, azathioprine, 6-mercaptopurine and etc.) [50, 51]. The diagnosis of drug-induced AP is difficult and mostly based on the incidence of taking one of the listed drugs before or at the onset of symptoms of AP [52].

In 3%–5% patients who have undergone endoscopic retrograde cholan-giopancreatography (ERCP) AP is diagnosed as postprocedural complication. Several risk factors for ERCP-associated AP are identified: Sphincter of Oddi dysfunction, female sex, pancreatic injection, precut sphincterotomy [53]. Direct injury to the pancreas and bile duct obstruction during other surgical procedures (e.g. splenectomy, distal gastrectomy) might be also complicated by AP [27].

Hyperlipidemia-induced AP (in patients with diagnosed familial hyper-lipoproteinemia of type 1, 4 and 5) is diagnosed in 2%–5% of patients [31]. Fasting triglyceride level of more than 1000 mg/dl is an identified risk factor. In most cases of this type AP serum amylase level does not increase [54]. In some cases, secondary factors (alcohol abuse, medication, diabetes and etc.) responsible for hyperlipidemia might be identified. However, the exact mechanism of the development of hyperlipidemia-induced AP is not fully understood. The goal of diet and lipid-lowering drugs to prevent AP should be a triglyceride level of below 1000 mg/dl [55].

Autoimmune causes, blunt and penetrating abdominal trauma, infection (mumps virus, Coxsackie virus, mycoplasma), hyperparathyroidism, pancreas divisum (congenital pancreatic anomaly) have been also identified as possible causes of AP. The incidence of AP induced by each of these factors is less than 1% [27, 56, 57].

More commonly AP is induced by multiple factors and it is difficult to name a sole cause. In a growing number of cases it is not possible at all to identify the main etiological factor and the diagnosis of idiopathic AP is made.

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1.3. Diagnosis and classification

In 1992, at the three-day International Symposium on Acute Pancreatitis in Atlanta, USA, a clinically based classification system for AP was built. The classification system distinguished two forms of severity of the disease – mild and severe AP. Acute fluid collection, pancreatic necrosis, acute pseudo-cyst and pancreatic abscess were determined as complications of AP [16]. Since then the Atlanta Classification of AP has remained the most widely used classification system for AP. However, improved diagnostic modalities, better understanding of the disease and complications, not uniformly used terminology led to the revision of the classification system [58]. The need for revision was indicated by several retrospective and prospective studies. These studies identified patients with local complications of AP, but without organ failure. According to the Atlanta Classification of AP these patients were classified as severe. However, the outcomes were more similar to the patients with mild AP [17, 59, 60]. This was seen as an acknowledgment for the need of an additional severity category.

Twenty years after the first classification system, the revised Atlanta Classification of AP was published in 2013 [4]. The third severity group of “moderately severe” acute pancreatitis was added. The revision was led by international working group which performed web-based consultations with 11 national and international societies. After multiple steps, the final consen-sus was reached.

According to the RAC the diagnosis of AP is based on the following criteria: (1) abdominal pain (persistent, severe pain in epigastric region, often radiating to the back), (2) serum lipase (amylase) activity at least three times greater than the upper limit of normal, (3) characteristic findings on contrast-enhanced computed tomography (CECT). At least two of the three criteria are needed to confirm the diagnosis [4]. In some cases transabdominal ultrasound (US) or magnetic resonance imaging (MRI) might be used for the assessment of the pancreas and extrapancreatic tissue [61, 62]. If the first two criteria are met the CECT is postponed for several days, when morphological changes of the pancreas and peripancreatic tissue are better identified [63, 64]. According to the CECT assessment interstitial edematous and necrotizing AP (Fig. 1.3.1) are identified.

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Fig. 1.3.1. Pancreatic necrosis (30%–50%) in the head and body of

pancreas in a 54-year-old patient (Axial CECT)

Isolated parenchymal necrosis, isolated necrosis of extrapancreatic tissues and combined necrosis of pancreatic parenchyma and extrapancreatic tissues can be distinguished. However, it was shown that several days (48– 72 hours) are needed to see the signs of impaired tissue perfusion and necrosis on CECT [65–68]. Therefore, early CECT should be performed only if the diagnosis of AP is doubtful and other possible causes of the abdominal pain are suspected. Several years ago, a new entity, “extrapancreatic necrosis” (Fig. 1.3.2) was introduced. This is defined as necrosis of the fat surrounding the pancreas without pancreatic tissue necrosis. Several studies showed better prognosis of extrapancreatic necrosis alone and recommended regarding it as separate morphological entity of AP. The term is now widely accepted by pancreatologists around the world [19, 20, 69].

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Fig.1.3.2. Extrapancreatic necrosis in a 49-year-old patient (Axial CECT)

In the majority of patients with AP pancreatic and/or extrapancreatic necrosis remains sterile during the course of the disease. However, in some patients it becomes infected and is associated with high mortality (15%–35%) and severe complications. Generally infection occurs after the first week of the disease [10, 70, 71]. Infection might be suspected if the clinical status of the patient is worsening, if there are signs of infection on CECT (extraluminal gas in necrotic tissue) and/or if a fine needle aspiration (FNA) culture tests are positive for bacteria.

Two phases of AP can be distinguished. The early phase generally lasts for one week and is rarely associated with pancreatic necrosis and local complications. The disease severity during the first phase is determined ac-cording to the duration of organ failure. “Transient” (<48 h) and “persistent” (>48 h) organ failure is identified [4, 17, 72]. Interstitial edematous AP mostly resolves within the first phase. Contrarily, the second phase can last for several weeks or months and is associated with signs of systemic inflam-mation and local and systemic (exacerbation of other comorbidities) compli-cations. The second phase is characteristic for moderately severe and severe AP. As the extent and type of local complications might determine the outcomes of the disease, it’s important to correctly identify them. According to the RAC four types of local complications are identified: acute peripan-creatic fluid collection, panperipan-creatic pseudocyst, acute necrotic collection and walled-off necrosis. Gastric outlet dysfunction, splenic and portal vein thrombosis, and colonic necrosis might also be distinguished [4]. Acute peripancreatic fluid collection is defined as a collection without a

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defined wall, which resolves spontaneously and is characteristic for intersti-tial edematous AP. If the fluid collection persists for more than 4 weeks and a well-defined wall can be identified on CECT, diagnosis of pancreatic pseudocyst (Fig. 1.3.3) might be determined [73–75].

Fig. 1.3.3. A 57-year-old patient with a pancreatic pseudocyst

and liver steatosis (Axial CECT)

43 days after the onset of acute pancreatitis.

Acute necrotic collection is characteristic for necrotic AP and is present during the first 4 weeks of the disease. On CECT fluid collection with variable amount of necrotic tissue is identified. It may be diagnosed together with all morphological types of AP: pancreatic necrosis, extrapancreatic necrosis or combined necrosis. The radiological signs of a well-defined wall around the fluid collection with necrotic tissue in it and a duration exceeding 4 weeks are characteristic for walled-off necrosis (Fig. 1.3.4). Both acute necrotic collection and walled-off necrosis may become infected during the course of the disease [4, 74–76].

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Fig. 1.3.4. Walled-off necrosis in a 45-year-old patient (Axial CECT)

To ascertain severity radiological evaluation is not sufficient. Therefore, according to the RAC, three organ systems should be evaluated to determine possible organ failure. Organ dysfunction is assessed according to the modified Marshall scoring system (Table 1.3.1) [4, 77].

Table 1.3.1. Modified Marshall scoring system for organ dysfunction (Banks

PA, et al., 2012) [4]

Organ system Score

0 1 2 3 4

Respiratory (PaO2/FiO2) >400 301–400 201–300 101–200 ≤101

Renal (serum creatinine,

µmol/l) ≤134 134–169 170–310 311–439 >439 Cardiovascular (systolic blood

pressure, mmHg) >90 <90, fluid responsive <90, not fluid responsive pH<7.3 <90, pH<7.2 <90, FiO2 (%) for non-ventilated patients according to supplemental oxygen (l/min): 21 – Room

air, 25 – 2, 30 – 4, 40 – 6–8, 50 – 9–10; A score of 2 or more points is needed to identify organ failure.

Accurate severity assessment is mandatory for early identification of most severe patients with a need of transfer to ICU and aggressive treatment. Reassessment during the course of the disease is needed to avoid the possible failure of missing timely recognition of clinical status worsening. Nonethe-less, the severity grading is beneficial for clinicians at secondary care settings not to postpone the transfer of patients to tertiary centers. According to the organ failure (“transient” (<48 h) and “persistent” (>48 h)) and presence of

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local or systemic complications according to the RAC, patients with AP are distinguished into 3 severity grades (Table 1.3.2) [4, 16].

Table 1.3.2. Grades of severity (Banks PA, et al., 2012) [4]

Mild No organ failure

No local or systemic complications Low mortality Resolves during the first phase Moderately

severe Transient organ failure (<48 h) and/or Local or systemic complications May resolve without intervention May require prolonged care Mortality lower than that of severe Severe Persistent organ failure (>48 h)

Single organ failure Multiple organ failure

High mortality

Radiological, endoscopic and/or surgical intervention may be needed The slightly different classification “Determinant-Based Classification of Acute Pancreatitis Severity” is based on local (absent, sterile, or infected peri-/pancreatic necrosis) and systemic (absent, transient or persistent organ failure) determinants. Regarding the presence or absence of the above-mentioned determinants, four severity categories are distinguished (Table 1.3.3) [78].

Table 1.3.3. Determinant-Based Classification of Acute Pancreatitis Severity

(Dellinger EP, et al., 2012) [78]

Mild acute pancreatitis No peri-/pancreatic necrosis No organ failure

Moderate acute pancreatitis Sterile peri-/pancreatic necrosis and/or Transient organ failure

Severe acute pancreatitis Infected peri-/pancreatic necrosis or Persistent organ failure

Critical acute pancreatitis Infected peri-/pancreatic necrosis and Persistent organ failure

Several studies have compared and analyzed both RAC and Determi-nant-Based classifications. However, no significant differences were found. If some studies showed a positive effect in differentiating patients when the fourth severity category “Critical AP” was added, then others concluded that RAC is better in correctly selecting patients [79–82].

1.4. Severity prediction

Severe acute pancreatitis is associated with a high risk of local compli-cations, increased need for interventions and high mortality. If in patients with mild AP mortality rate does not exceed 1%, in patients with severe AP and

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infected pancreatic necrosis it can be as high as 15%–35% [10]. Therefore, early identification and prediction of patients having a high risk of developing severe AP is the first step in the management. Over the last decades multiple scoring systems have been proposed and used: Ranson score, Computed tomography severity index (CTSI), Bedside Index for Severity in Acute Pancreatitis (BISAP), Acute Physiology and Chronic Health Evaluation II (APACHE II), Systemic Inflammatory Response Syndrome (SIRS) criteria, modified Glasgow/Imrie Criteria etc. [10]. However, the majority of these scores have a high false positive rate and are inaccurate at predicting severe AP. Many published comparison studies showed similar results for all the scoring systems [83–88]. Nevertheless, some recent comparative studies show a positive predictive value of the BISAP scoring system [89, 90]. Not only are complex scoring systems continuously assessed, but the value of single biochemical markers has also been also studied. Such studies on single biochemical markers and their combinations showed a positive prognostic effect of routine clinical tests such as C-reactive protein (CRP), leukocyte count, neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) [91–93]. As none of these routine clinical tests is regarded as a gold standard, many studies are performed to investigate the possible prognostic value of various cytokines and their combination. Regardless of some positive findings (interleukin 6, hepatocyte growth factor, resistin, growth differentia-tion factor-15, pentraxin 3) none of these and other cytokines are used as a predictive markers in daily practice [94–96].

According to the evidence-based guidelines for the management of AP (International Association of Pancreatology/American Pancreatic Associa-tion (IAP/APA)), SIRS is recommended as a predicAssocia-tion score [97]. SIRS is defined if two or more of the following criteria are present: (1) body tempe-rature <36° or >38°, (2) heart rate >90/min, (3) respiratory rate >20/min, (4) white blood cell count < 4×109_{/L or >12×10}9_{/L (or >10% bands) [98]. Several} studies showed an association between presence of SIRS and persistent organ failure [72, 99, 100]. As described previously, duration of the organ failure is one the main factors when distinguishing different severity grades of AP.

1.5. Management of acute pancreatitis

Management of AP should start as early as possible. As there is no specific curative treatment, it’s main goal in the early phase of the disease is adequate pain management and fluid resuscitation. Severe abdominal pain in the epigastric region is the first symptom and the main complaint of patients with AP. Various analgesics in different dosage can be used for pain

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management. However, it is only in mild AP that nonsteroidal anti-inflam-matory drugs (NSAIDs) might be sufficient. In case of severe necrotizing pancreatitis administration of opioids might be needed [10, 101]. Adequate use of opioids can reduce the need for additional analgesics, without increasing the rate of adverse events [102, 103]. However, a recent systematic review and meta-analysis of eight randomized controlled trials analyzed the effectiveness of different parenteral analgesics for pain management in AP. No significant superiority of any of the included drugs was proven [104]. To avoid the overuse of analgesics, pain management protocols should be used. The modified WHO analgesia ladder after Vargas-Schaffer and Stephan Schorn starts with the first step when NSAIDs are administered and ends with the fourth step when epidural analgesia might be indicated (Fig. 1.5.1) [101, 105].

Fig. 1.5.1. Stepwise pain management protocol of acute pancreatitis

NSAIDs, opioids, interventional treatment (epidural analgesia) or the combination of various analgesics at different pain management steps are used (Vargas-Schaffer G,

et al., 2010 and Shorn S, et al., 2015) [105]

Acute pancreatitis is associated with inflammation of the pancreas and surrounding tissue followed by SIRS. These reactions lead to the changes of fluid distribution and may cause hypovolemia followed by hypoperfusion and organ failure in moderately severe or severe AP. To avoid possible deterio-ration of the disease, adequate fluid resuscitation must be started early. As the effectiveness of colloids is questionable, crystalloids are the most used type of fluids [10]. According to IAP/APA evidence-based guidelines for the management of AP, fluid resuscitation should be started with Ringer’s

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lactate [106]. This recommendation recently was confirmed in a triple-blind, randomized controlled trial (RCT). When comparing to normal saline Ringer’s solution showed anti-inflammatory effects in patients with AP [107]. For many years’ aggressive fluid therapy for the management of AP was favored. The results of recent RCT’s are contradictory. In a study of 60 patients diagnosed with mild AP aggressive fluid therapy (20 ml/kg bolus followed by 3 ml/kg/h) was associated with better clinical improvement without any signs of fluid overload [108]. However, at the end of 2017 a published critical review of the seven RCT’s found a possible positive effect of aggressive infusion only at the very early stage of the disease. Aggressive and rapid infusion of fluids was associated with increased morbidity and mortality in the later stage [109]. Therefore IAP/APA propose goal-directed fluid therapy (5–10 ml/kg/h). The positive response of the fluid therapy is based on the following criteria: (1) heart rate <120/min, (2) mean arterial pressure between 65 and 85 mmHg, (3) urinary output of >0.5 ml/kg/h, (4) hematocrit level between 35% and 44% [106]. Fluid resuscitation is most important in the first 24 hours and should not cause fluid overload which could lead to higher risk of abdominal compartment syndrome, sepsis and death [31, 110].

With an onset of acute abdominal pain most patients stop eating and drinking. Nausea followed by vomiting also impact the clinical status of the patient. Experimental and clinical studies have shown significant effect of disturbance of intestinal motility on bacterial overgrowth and translocation followed by infected pancreatic necrosis [111–113]. Therefore, in patients with predicted mild AP an oral diet can be started as soon as abdominal pain decreases and level of inflammatory markers starts decreasing [106]. If moderately severe or severe AP is predicted enteral tube feeding is the prima-ry option, which helps to increase intestinal motility and decrease bacterial translocation. Effectiveness of enteral tube feeding in reducing mortality, rate of multiple organ failure, and systemic infections was confirmed by several systematic reviews [114, 115]. Either nasogastric or nasojejunal tube feeding can be chosen without any risk of higher number of complications [10]. Parenteral nutrition might be needed as a second-line choice if other feeding methods are ineffective [106]

As discussed previously, gallstones as an etiological factor of AP are identified in about 40% of cases. Usually the obstruction is transient and mostly the gallstones migrate rapidly [29]. Therefore, if mild acute pancrea-titis is predicted, in most cases the benefits of early ERCP do not outweigh possible complications. Contrarily, if ABP with concomitant cholangitis is diagnosed, urgent (<24 hours) ERCP is indicated. If performed early, ERCP significantly reduces mortality, rate of local and systemic complications [10,

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106, 116]. The effectiveness and timing of ERCP in case of AP with common bile duct obstruction without cholangitis is controversial. As well designed and large RCTs addressing this issue are lacking, IAP/APA states that ERCP is probably indicated in patients with common bile duct obstruction. The exact timing of intervention is still unclear, and it could be reasonable to wait for 24–48 hours [106]. These questions might be answered by the ongoing multicenter RCT “Early biliary decompression versus conservative treatment in acute biliary pancreatitis (APEC trial)” [117]. To prevent the recurrence of biliary AP, cholecystectomy is indicated. However, the recommendations for the timing of surgical intervention differ between mild and severe AP. In a multicenter RCT (266 patients) same-admission cholecystectomy was asso-ciated with reduced rate of gallstone-related complications and lower treat-ment costs when compared with interval cholecystectomy in patients with mild ABP [118, 119]. In patients with SAP cholecystectomy should be delayed until the patient has recovered or at least for 6 weeks [106].

In case of infected pancreatic necrosis mortality reaches up to 15%–35% [10]. Therefore, diagnosed or suspected infected pancreatic necrosis is the main indication for antibacterial treatment. However, for many years there has been ongoing discussion as to whether antibiotic prophylaxis might reduce the rate of infected pancreatic and/or extrapancreatic necrosis. It has been shown than antibiotic prophylaxis might reduce or postpone the need for surgical interventions [120]. However, recent reviews and meta-analysis failed to show the reduction of infection rate when antibiotic prophylaxis is routinely given. As many unanswered questions regarding indications and type of antibiotic prophylaxis still remain, more and better designed RCT’s are needed [121,122]. If infection of pancreatic and/or extrapancreatic necro-sis is diagnosed or suspected, broad-spectrum antibiotics with the ability to penetrate the pancreatic tissue, according to the local protocol, should be given. If the clinical status of the patient does not improve for several weeks but there are no clinical and radiological signs of infection, FNA should be performed. A positive culture might indicate the administration of more spe-cific antibiotics [10, 106].

Despite antibacterial treatment most patients with infected necrotizing pancreatitis will need an intervention. According to the protocol and accessi-bility radiological, endoscopical or surgical intervention might be performed. According to the guidelines intervention preferably is performed after walled-off necrosis (>4 weeks after onset of AP) has formed [4, 106, 123]. The minimally invasive step-up approach in treating patients with infected necrotizing pancreatitis is a standard of care. Ultrasound or CT guided percutaneous catheter or endoscopic transgastric/transduodenal drainage is followed by necrosectomy only if the first step is ineffective. Widely accepted

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RCT has showed the reduced rate of mortality and major complications when comparing to open necrosectomy [124]. The reduction of death rates when performing minimally invasive surgical and endoscopic necrosectomy was confirmed in a large pooled analysis of 1980 patients [125]. Necrosectomy might be performed either endoscopically or surgically. A multicenter, rando-mized, superiority trial in Netherlands did not prove the superiority (reduction or mortality and major complications) of endoscopic treatment over a surgical step-up approach [126].

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2. METHODS

2.1. Ethics

The study was approved by the Kaunas Regional Biomedical Research Ethics Committee (No. BE-2-47 and P1-113/2005). All the patients provided written informed consent. For the multicenter part of the study approval of the local medical ethical committee was obtained at each study center.

2.2. Design of the study

The study consists of two parts. For the comparison of clinical course and outcomes of biliary and alcohol-induced AP and for the assessment of the effectiveness of RAC in allocating patients diagnosed with AP to different categories (mild, moderately severe, severe) two studies at the Lithuanian University of Health Sciences were performed. To assess the impact of etiology on the presence and location of pancreatic necrosis and to evaluate the effectiveness of RAC criteria for CT assessment in distinguishing different morphological types of AP, two multicenter studies were performed. The following European Centers participated in the multicenter studies: (1) Institution of Clinical Sciences Malmö, Lund University, Malmö, Sweden; (2) St. Antonius Hospital, Nieuwegein, The Netherlands; (3) Hospital del Mar, Barcelona, Spain; (4) University Hospital for Emergency Medicine “Pirogov”, Sofia, Bulgaria; (5) Lithuanian University of Health Sciences, Kaunas, Lithuania; (6) East Tallinn Central Hospital, Tallinn, Estonia; (7) Helsinki University Central Hospital, Helsinki, Finland.

2.3. Patients

Patients >18 years diagnosed with a first episode of AP were included in the study. The diagnosis of AP was established according to the following criteria: (1) abdominal pain (persistent, severe pain in epigastric region, often radiating to the back), (2) serum amylase activity at least three times greater than the upper limit of normal, (3) characteristic findings on CECT. At least two of the three criteria were needed to confirm the diagnosis.

For the first part of the study performed at the Lithuanian University of Health Sciences, patients were identified and recruited at the Department of Surgery. Data was prospectively collected and entered into a specially designed database.

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In the study comparing the clinical course and outcomes of biliary and induced SAP 81 patients with biliary (37 patients) and alcohol-induced (44 patients) SAP were included. Diagnosis of biliary SAP was based on the following criteria: (1) gallbladder and/or bile duct stones on abdominal US or CT, (2) elevated levels of serum bilirubin and liver enzymes, (3) no history of recent alcohol intake. Respectively patients with a history of recent alcohol intake, no gallbladder and/or bile duct stones on abdominal US and/or CT were included in the group of alcohol-induced SAP. The complete process of patient selection and follow-up is described in the publication of Barauskas

et al. [127].

One hundred three patients were included in the study assessing the effectiveness of the RAC in allocating patients diagnosed with AP to different categories: mild (no organ failure, no local or systemic complications), moderately severe (transient organ failure of less than 48 hours), and severe (persistent organ failure of more than 48 hours). The complete process of patient selection and follow-up is described in the publication of Ignatavicius

et al. [128].

For the second part of the study each participating center included 50 patients diagnosed with AP in whom CECT was performed at least once. All CECTs performed within three months of the date of admission were reviewed by a local radiologist and a specially designed radiology score sheet was filled out (Appendix A). All CECTs were also coded and reviewed by the central expert radiologist. The same radiology score sheet (Appendix A) was filled out. Patients with insufficient CECT quality, radiological signs of chronic pancreatitis and patients with previous pancreas-related invasive interventions were excluded from the analysis. Clinical data was collected and entered into a specially designed database. In the final analysis 285 patients, on whom 388 CECTs were performed, were included. The complete process of patient selection and follow-up is described in the publication of

Sternby et al. [5].

To assess the impact of etiology on the presence and location of pancreatic necrosis in patients with AP, post-hoc analysis of the previously described multicenter cohort was performed. One hundred five patients with biliary AP, 102 patients with alcohol-induced AP and 78 patients with idiopathic AP were analyzed. Presence, extent and location of pancreatic and/or extrapancreatic necrosis were established on the CECT.

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2.4. Statistical analysis

Statistical analysis was performed using IBM SPSS, version 22 (IBM Corp., Armonk, New York, USA). Data were expressed as median (range) or mean ± standard deviation. The independent Student, Mann–Whitney U, and Pearson linear regression tests were used as appropriate. Differences among three or more groups were evaluated using the nonparametric one-way ANOVA test. For the multicenter studies sample size calculations were performed (variables with 2, 3 and 4 categories). For the assessment of inter-observer agreement between the local and the expert radiologist Cohens kappa test was used. When calculating sample size, Cohens kappa values of >0.40 (moderate agreement) and >0.60 (substantial agreement) were used [129]. A sample size of 360 CECTs was calculated. However, we assumed that some patients would have more than one CECT performed during the first three months of the disease. Therefore, each center included a total of 50 patients. The following agreement levels were defined: 0.00–0.20 – slight, 0.21–0.40 – fair, 0.41–0.60 – moderate, 0.61–0.80 – substantial, 0.81–1.00 – almost perfect. In the study analyzing the impact of etiology on the presence and location of pancreatic necrosis in patients with AP a Kruskal–Wallis test was used for ordinal analysis of severity category and percentage of parenchymal necrosis. Significance was accepted at P<0.05.

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3. RESULTS

3.1. Biliary and alcohol-induced severe acute pancreatitis

Analysis in the first study revealed that alcohol-induced SAP is more characteristic for younger men (males 95.4%). Contrarily in elderly woman biliary SAP is more often diagnosed (males 27%) (P = 0.003). There were no significant differences either in prognostic scoring systems, nor in systemic complication (single or multiple organ dysfunction). Thirty-six (81.8%) patients in the alcohol-induced SAP group and 30 (81.1%) patients in the biliary SAP group were investigated for infection of peri-/pancreatic necrosis. It was more frequently diagnosed in patients with alcohol-induced SAP (24; 66.7% vs. 14; 46.6%). However, statistical significance was not found (Table 3.1.1).

Table 3.1.1. Patients’ characteristics and comparison of primary endpoints

in alcohol-induced and biliary SAP groups

Alcohol-induced SAP Biliary SAP P

Gender Male 42 (95.4%) Male 10 (27%) 0.003

Age 40.9±12.5 (21–82) 61.4±16.3 (20–82) 0.001

Severity score (at admission) APACHE II

MODS 6.19±4.4 (0–15) 1.62±2.5 (0–10) 7.64±2.9 (1–14) 1±1.3 (0–5) 0.112 0.202

Patient’s at ICU 27 (61.4%) 18 (48.7%) 0.578

Length of stay (days) In-hospital ICU 48 (16–240) 8.4 (1–59) 34 (8–110) 14 (1–68) 0.021 0.512 Complications MODS Pulmonary dysfunction Renal dysfunction Cardiac dysfunction Pneumonia Sepsis IPN 12 (27.3%) 8 (18.2%) 4 (9.1%) 1 (2.3%) 6 (13.6%) 3 (6.8%) 24 (66.7%) 4 (10.8%) 4 (10.8%) 2 (5.4%) 6 (16.2%) 3 (8.1%) 3 (8.1%) 14 (46.6%) 0.169 0.539 0.687 0.055 0.726 1.000 0.428 Mortality 11 (25.0%) 5 (13.5%) 0.409 n 44 37

ICU – Intensive care unit; MODS – Multiple organ dysfunction syndrome; SAP – Severe acute pancreatitis, APACHE II – Acute Physiology and Chronic Health Evaluation II; IPN – Infected pancreatic necrosis.

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Frequency and timing of interventions (FNA, US guided drainage, open necrosectomy) was similar in both groups. However, five patients in the alcohol-induced SAP group were diagnosed with abdominal compartment syndrome (intraabdominal pressure – 23.5 mmHg, range 20–27.2 mmHg) and decompressing subcutaneous fasciotomy was performed. Despite significant effect of the procedure (intraabdominal pressure – 14.2 mmHg, range 12– 16 mmHg, P<0.001), three of the five patients died (Table 3.1.2).

Table 3.1.2. Performed interventional procedures

Alcohol-induced SAP Biliary SAP P

FNA Day 17 (38.6%) 16 (6–25) 16 (43.2%) 16 (8–29) 0.838 1.000 UGD Day 8 (18.2%) 20 (3–47) 5 (13.5%) 21 (3–37) 0.767 0.898 Necrosectomy Day 42 (15–210) 22 (50.0%) 9 (24.3%) 29 (3–55) 0.135 0.654 Fasciotomy 5 (11.4%) 0 (0%) 0.067

FNA – Ultrasound-guided fine needle aspiration; UGD – Ultrasound-guided drainage; SAP – Severe acute pancreatitis.

In 41 (93.2%) patients with alcohol-induced SAP and in 31 (83.8%) patients with biliary SAP, CECT performed within the first 7 days revealed pancreatic necrosis exceeding 30% in 24 (58.5%) and 16 (51.6%) patients respectively. In alcohol-induced SAP there was a direct positive correlation between the extent of pancreatic necrosis and mortality rate (R>0.5; P = 0.01) (Fig. 3.1.1).

Fig. 3.1.1. The extent of pancreatic necrosis, as defined by CECT,

and lethal outcomes are demonstrated (%)

The extent of pancreatic necrosis directly correlates with mortality rate in alcohol-induced SAP group patients (R = 0.5; P = 0.01)

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The subgroup (pancreatic necrosis exceeding 30%) analysis did not find any significant differences between alcohol-induced SAP and biliary SAP, when comparing in-hospital stay, rate of necrosectomies, incidence of infected peri-/pancreatic necrosis and mortality.

In the entire patient cohort 136 specimens for bacterial analysis were taken. The number of isolated bacterial strands was higher in patients with alcohol-induced SAP (168 vs. 68). In these patients the prevalence of

Entero-bacteriaceae, Staphylococcaceae, Streptococcaceae, CoryneEntero-bacteriaceae,

and Pseudomonadaceae families was higher when comparing to patients with biliary SAP. In contrast, in patients with biliary SAP fungal infection (Candida spp.) was more often diagnosed (19.1% vs. 4.2%, P = 0.002) (Table 3.1.3). Analysis of antibacterial resistance showed no differences between the two groups.

Table 3.1.3. Analysis of isolated bacterial strands from specimens of patients

with alcohol-induced and biliary SAP

Alcohol-induced SAP Biliary SAP P

Microorganisms (n) 168 68 Enterobacteriaceae Escherichia coli Citrobacter spp. Proteus spp. Klebsiella spp. Enterobacter spp. Other 80 (47.6%) 29 (17.3%) 9 (5.4%) 22 (13.1%) 7 (4.2%) 4 (2.4%) 9 (5.4%) 24 (35.3%) 11 (16.2%) 3 (4.4%) 2 (2.9%) 6 (8.8%) 2 (2.9%) 0 (0%) 0.292 1.000 1.000 0.03 0.215 1.000 0.066 Enterococcaceae 29 (17.2%) 13 (19.1%) 0.854 Staphylococcaceae Staphylococcus aureus Coagulase-negative staphylococci 20 (11.9%) 9 (5.4%) 11 (6.6%) 7 (10.3%) 0 (0%) 7 (10.3%) 0.826 0.066 0.423 Streptococcaceae 8 (4.8%) 6 (8.8%) 0.365 Candida spp. 7 (4.2%) 13 (19.1%) 0.002 Corynebacterium spp. 8 (4.8%) 2 (2.9%) 0.729 Pseudomonas spp., Acinetobacter spp. 16 (9.5%) 3 (4.4%) 0.293

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3.2. Impact of etiology on the presence and location of necrosis The second study on the impact of etiology confirmed that patients with alcohol-induced pancreatitis are more often male, significantly younger and have fewer concomitant diseases (diabetes mellitus, chronic renal failure, coronary artery disease). Alcohol-induced AP was diagnosed in 102 (36%) patients, ABP diagnosed in 105 (37%) patients. Seventy-eight (27%) patients had AP of other etiologies. Necrotizing pancreatitis was confirmed by CECT in 159 (56%) patients (Table 3.2.1).

Table 3.2.1. Patient characteristics by aetiology

Biliary Alcohol Other P

Number of patients 105 102 78

Age [median (range)] 68 (18–92) 46 (22–86) 62 (18–92) 0.000

Male 34 (32%) 83 (81%) 42 (54%) 0.000

BMI [median (range)] 28 (21–45) 28 (19–43) 27 (18–50) 0.251 Comorbidity

Chronic renal failure Diabetes mellitus Chronic lung disease Coronary artery disease

4 (4%) 14 (14%) 4 (4%) 24 (23%) 1 (1%) 6 (6%) 7 (7%) 7 (7%) 2 (3%) 14 (18%) 6 (8%) 21 (27%) 0.014 0.040 0.171 0.001 BMI – Body mass index.

Further analysis revealed that in the alcohol-induced AP group pancreatic necrosis with a higher incidence of pancreatic tail necrosis was more often seen. However, these results are not statistically significant (P>0.05). Likewise, no significant differences were found between both etiologies when comparing the distribution and location of pancreatic and extrapancreatic necrosis and presence of collections. Rates of organ failure, severity catego-ries according to RAC, CRP values and presence of SIRS were also compar-able (Tcompar-able 3.2.2).

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Table 3.2.2. Outcome comparison by aetiology

Biliary Alcohol Other P

Number of patients 105 102 78 Necrotising pancreatitis 53 (50%) 60 (59%) 46 (59%) 0.664 Extrapancreatic necrosisa _{53 (51%)} _{59 (59%)} _{44 (56%)} _0.752 Pancreatic necrosisb _{20 (19%)} _{30 (29%)} _{15 (19%)} _0.140 Parenchymal necrosis (%) None < 30 30–50 >50 85 (81%) 10 (9%) 4 (4%) 6 (6%) 72 (71%) 23 (22%) 4 (4%) 3 (3%) 63 (81%) 8 (10%) 4 (5%) 3 (4%) 0.149 Necrosis-locationc Head Neck Body Tail 11 (11%) 15 (14%) 13 (12%) 11 (11%) 11 (11%) 9 (9%) 11 (11%) 21 (21%) 8 (10%) 10 (13%) 10 (13%) 8 (10%) 0.993 0.461 0.902 0.059 Presence of collections 67 (64%) 79 (78%) 58 (74%) 0.097 SIRS at the time of admission 22 (21%) 26 (26%) 21 (27%) 0.850 CRP at admission [median (range)] 9 (0–416) 31 (0–455) 15 (0–477) 0.178 Highest CRP [median (range)] 283 (3–553) 284 (0–520) 277 (0–519) 0.588 RAC

Mild/Moderate/Severe (%) 45/47/8 29/61/10 38/45/17 0.050 Systemic complications 76 (73%) 84 (82%) 74 (77%) 0.427 Organ failure (%)

Non/transient/persistent 84/9/7 80/9/11 72/13/15 0.304

a_{With or without parenchymal necrosis;}b_{With or without extrapancreatic necrosis;}c_{One or}

more locations could be necrotic at the same time; SIRS – Systemic inflammatory response syndrome; CRP – C-reactive protein; RAC – Revised Atlanta 2012 Classification of AP.

3.3. Evaluation of Revised Atlanta 2012 Classification of AP criteria In a multicenter setting 301 patients were included at six participating centers. Sixteen patients were excluded due to signs of chronic pancreatitis on CECT and insufficient quality of some CECTs. In the final analysis we included 285 patients. Baseline characteristics of patients in each center and all centers combined are presented in the publication by Sternby et al. [5]. In total 405 CECTs were collected. Due to the abovementioned reasons 17 CECTs were excluded, leaving 388 CECTs for the interobserver evaluation. Characteristics of included CECTs are presented in the publication by Sternby

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Analysis of interobserver agreement showed evident differences of Cohens kappa value between centers. Kappa value varied from 0.024 to 1.00. Substantial agreement was on the following categories: “Necrosis – Neck” (0.618), “Necrosis – Body” (0.628), “Necrosis – Tail” (0.617), presence of “Collections” (0.756), “Location of Collections” (0.633), presence of “Wall” (0.675), presence of “Intraluminal Gas/fluid Level” (0.764). In all other categories moderate or fair agreement was reached (Table 3.3.1).

Table 3.3.1. Center-independent and center-dependent Cohens kappa values

Category _centersAll Center _B Center _C Center _D Center _E Center _F Center _G Type of pancreatitis 0.370 0.317 0.342 0.309 0.098b_0.838a_0.360 Parenchymal Necrosis 0.539 0.380 0.319b_{0.609 0.731}a_{0.663 0.465} Necrosis – Head 0.516 0.669 0.345 0.323b_1.00a_{0.660 0.646} Necrosis – Neck 0.618 0.922a_{0.577 0.822 0.660 0.364 0.236}b Necrosis – Body 0.628 0.766 0.611 0.687 0.873a_0.392b_0.570 Necrosis – Tail 0.617 0.451 0.626 0.687 0.409b_0.806a_0.532 Extrapancreatic necrosis 0.326 0.321 0.504 0.293 0.120 0.877a_0.024b Collections 0.756 0.780 0.750 0.624b_0.864a_{0.827 0.625} Location of collections 0.633 0.728 0.761a_{0.508 0.694 0.604 0.439}b Characteristics of collections 0.408 0.397 0.485 0.293 0.305 0.744a 0.251b Wall 0.675 0.638 0.638 0.588 0.777a_{0.726 0.632}b

Intraluminal gas/fluid level 0.764 0.774 0.671b_{0.764 0.887}a_{0.837 0.675}

Collection – most

appropriate term 0.356 0.385 0.480 0.136 0.218b 0.673a 0.261

a_{Highest kappa value for center B to G for each category.}b_{Lowest kappa value for center B}

to G for each category.

The lowest agreement level (0.326) was observed when evaluating extrapancreatic necrosis. The expert radiologist identified extrapancreatic necrosis on CECTs significantly more often than local radiologists (59% vs. 33%, P<0.0001). Subgroup analysis (combined necrosis, isolated extrapan-creatic necrosis) revealed that both local and expert radiologist identified combined necrosis with a similar degree of accuracy. However, the central expert radiologist identified isolated extrapancreatic necrosis three times more often than local radiologists (36% vs. 11%) (Table 3.3.2).

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Table 3.3.2. Comparison of rates of extrapancreatic necrosis identified by

local radiologist and central expert

Total number of EXPN Combined necrosis Isolated EXPN Local rad Central exp Local rad Central exp Local rad Central exp Yes 126 (33%) 230 (59%) 85 (22%) 92 (24%) 41 (11%) 138 (36%) No 245 (63%) 110 (28%) 303 (78%) 296 (76%) 347 (89%) 250 (64%) Ind. 17 (4%) 48 (12%)

Local rad – Local radiologists; Central exp – Central expert radiologist; EXPN – extrapan-creatic necrosis; Combined necrosis – extrapanextrapan-creatic necrosis with parenchymal necrosis; Isolated EXPN – extrapancreatic necrosis without parenchymal necrosis; Ind. – indeter-minate.

To assess the possible significance of isolated extrapancreatic necrosis on clinical outcomes (organ failure, mortality), correlation analysis was performed. The results showed statistically significant better correlation between morphological findings on CECT and clinical outcome when isolated extrapancreatic necrosis is identified by a central expert radiologist (Table 3.3.3).

Table 3.3.3. Correlation of isolated extrapancreatic necrosis with clinical

outcome

Local radiologist Central expert P

Cases (n) 41 138 0.0001 Organ failure Persistent Transient 4 (9.7%) 4 (9.7%) 24 (17.4%) 20 (14.5%) 0.0001 0.0001 Mortality 1 (2.4%) 7 (5.1%) 0.025 Intervention 12 (29.3%) 26 (18.8%) 0.001 CRP (mg/L) 298 318 >0.05 SIRS 9 (22.0%) 38 (27.5%) 0.0001

CRP – C-reactive protein; SIRS – Systemic inflammatory response syndrome. 3.4. Allocation of patients according to Revised Atlanta 2012

Classification of AP

Analysis of the data of 103 patients showed that 56 (54.4%) patients were diagnosed with mild AP and 47 (45.6%) patients with severe AP according to the Atlanta 1992 Classification of AP. According to the RAC 49 (47.6%) patients had mild AP, 27 (26.2%) patients had moderately severe and 27

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(26.2%) patients had severe AP. The complete patient characteristics are presented in the publication by Ignatavicius et al. [128].

A comparison of the Atlanta 1992 and the Revised Atlanta 2012 Classi-fication of AP showed that the majority of patients classified as mild accor-ding to Atlanta 1992 Classification of AP stayed in the same group after reclassification. However, half of the patients from the severe AP group moved to the moderately severe AP group (27 (26.2%)) (Fig. 3.4.1).

Fig. 3.4.1. Distribution of patients between the Atlanta 1992 and

Revised Atlanta 2012 Classification of Acute Pancreatitis

Majority (20) of patients with moderately severe AP according to Revised Atlanta 2012 Classification of AP matched to being severe cases according to Atlanta 1992 Classification of AP. Both groups of patients diagnosed with mild and severe AP

according to Revised Atlanta 2012 Classification of AP matched the groups identically to Atlanta 1992 Classification of AP

A subgroup analysis of patients diagnosed with SAP according to Atlanta 1992 and Atlanta 2012 Classifications of AP revealed no statistically significant difference in ICU admission rate, rate of US guided drainage, rate of infected necrosis or incidence of death (Table 3.4.1).

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Table 3.4.1. Comparison of severe AP group outcomes

Atlanta 1992 Atlanta 2012 P

ICU admission (n) 5 6 0.32

US drainage (n) 5 4 0.71

Infected necrosis (n) 12 11 0.19

Deaths (n) 13 13 0.75

ICU – intensive care unit; US drainage – Ultrasound guided drainage; Atlanta 1992 – Atlanta 1992 Classification of Acute Pancreatitis; Atlanta 2012 – Atlanta 2012 Classification of Acute Pancreatitis.

A comparison of patients with mild and severe AP according to the Atlanta 1992 Classification of AP showed significantly higher rates of sepsis, US guided and open surgical interventions and deaths in the SAP group (P<0.05). APACHE II and MODS scores were also higher (Table 3.4.2.).

Table 3.4.2. Comparison of mild and severe acute pancreatitis (Atlanta 1992

Classification of Acute Pancreatitis)

Mild Severe P Male 29 (51.8%) 25 (53.2%) 1.000 Necrosis Sterile Infected 55 (98.2%) 1 (1.8%) 41 (87.2%) 6 (12.8%) 0.343 0.054 Sepsis 0 (0%) 6 (12.8%) 0.011 Interventions FNA UGD Necrosectomy 1 (1.8%) 1 (1.8%) 0 (0%) 12 (25.5%) 5 (10.6%) 6 (12.7%) 0.002 0.101 0.011 APACHE II, mean± SD 3.51±1.94 11.48±4.79 <0.001

MODS, mean±SD 1.17±1.28 4.29±3.38 <0.001

Deaths 0 (0%) 13 (27.7%) <0.001

FNA – Fine needle aspiration; UGD – Ultrasound guided drainage; APACHE II – Acute Physiology and Chronic Health Evaluation II; MODS – Multiple organ dysfunction syndrome.

The same comparison of patients with moderately severe and severe AP according to RAC, revealed significantly lower rates of sepsis, open necro-sectomies, ICU admissions and deaths in the moderately severe AP group (P<0.05). APACHE II and MODS scores were significantly higher in the severe AP group (Table 3.4.3).

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Table 3.4.3. Comparison of moderately severe and severe acute pancreatitis

(Revised Atlanta 2012 Classification of Acute Pancreatitis)

Moderately severe Severe P

Male 15 (55.6%) 16 (59.3%) 1.000 Necrosis Sterile Infected 26 (96.3%) 1 (3.7%) 22 (81.5%) 5 (18.5%) 0.696 0.201 Sepsis 0 (0%) 6 (22.2%) 0.028 Interventions FNA UGD Necrosectomy 2 (7.4%) 1 (3.7%) 0 (0%) 10 (37.0%) 4 (14.8%) 6 (22.2%) 0.053 0.356 0.028

APACHE II, mean±SD 7.7±3.07 13,2±5.43 0.002

MODS, mean±SD 2.9±1.78 5.2±3.90 <0.001

ICU admission 5 (18.5%) 24 (88.9%) 0.004

Deaths 0 (0%) 13 (27.7%) 0.001

FNA – Fine needle aspiration; UGD – Ultrasound guided drainage; APACHE II – Acute Physiology and Chronic Health Evaluation II; MODS – Multiple organ dysfunction syndrome; ICU – Intensive care unit.

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4. DISCUSSION

4.1. Impact of etiology on the clinical course of acute pancreatitis It is well known that the main etiological factors of AP vary across different regions. Gallstones as an etiological factor are more often diagnosed in the southern part of Europe and alcohol in eastern and northern Europe. The link between age, sex and etiological factors is also known. In both our studies on the etiology of AP we confirmed previously observed tendency that alcohol-induced AP is characteristic for younger male patients. Contrarily, biliary AP is more characteristic for older female patients [1, 2, 44]. We also observed different demographic characteristics, clinical course and outcome in alcohol-induced and biliary SAP.

The data on the clinical course differences of biliary and alcohol-induced AP is conflicting. Cho et al. demonstrated a significantly higher number of patients classified as moderately severe and severe in alcohol-induced AP patients [21]. Other investigators showed a higher risk of mortality and infection in biliary AP [130]. In our single center study, we saw a higher rate of MODS, pulmonary and renal dysfunction in patients with alcohol-induced SAP. In contrast, an increased rate of cardiac dysfunction in patients with biliary SAP was observed. In a multicenter setting we also confirmed a higher rate of comorbidities (chronic renal failure, diabetes mellitus, coronary artery disease) in patients with biliary AP. However, this increase might be linked to the older age of patients with biliary SAP in both single center and multicenter settings.

In recent years a higher mortality rate in patients with alcohol-induced AP was found in several studies [21, 131]. A significant difference was confirmed especially by larger studies like that of Kim et al. in a South Korean population [132] and by Omdal et al. in a Norwegian population [133]. In our single center study, we also showed a higher mortality rate in patients with alcohol-induced SAP (25.0% vs. 13.5%). We may speculate that due to relatively small number of study participants, we were not able to show a statistically significant difference. However, a twofold increase in mortality rate might be clinically relevant. Better early and late outcomes, such as lower rate of pancreatic necrosis or other lethal outcomes, were reported in patients with biliary AP by several studies [134–137]. When analyzing the correlation between the extent of pancreatic necrosis and mortality in alcohol-induced SAP, our data corroborates the data from previous studies, showing a positive correlation (R>0.5, P = 0.01) [71, 130]. In our single center study, we were unable to show any association between etiology of AP and the extent or

INFLUENCE OF ETIOLOGY AND MORPHOLOGICAL CHANGES ON TREATMENT OPTIMIZATION IN SEVERE ACUTE PANCREATITIS

Povilas Ignatavičius