MANAGEMENT OF SEVERE ACUTE PANCREATITIS IN INTENSIVE CARE UNIT: A LITERATURE REVIEW

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MANAGEMENT OF SEVERE ACUTE PANCREATITIS IN

INTENSIVE CARE UNIT: A LITERATURE REVIEW

A thesis submitted in partial fulfilment for the degree of Master of Medicine

Author: Behzad Hashim Bashir, MF Supervisor: Vidas Pilvinis, MD, PhD

KAUNAS

2020

LITHUANIAN UNIVERSITY OF HEALTH SCIENCES

FACULTY OF MEDICINE

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TABLE OF CONTENTS

3 3.1.1 Intensive care unit ... 21 3.1.2 Pulmonary management ... 21 3.1.3 Fluid resuscitation support ... 22 3.1.4 Nutritional support ... 23 3.1.5 Use of antibiotics in SAP ... 25 3.1.6 Management of pain ... 26 3.2 Management of complications ... 27 3.2.1 Acute compartment syndrome ... 27 3.2.2 Necrotising pancreatitis ... 29 3.2.3 Surgical technique ... 29 4.0 DISCUSSION ... 31 5.0 CONCLUSION ... 33 6.0 REFERENCES ... 34

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SUMMARY

Author: Behzad Hashim Bashir

Scientific supervisor: Dr. Vidas Pilvinis, MD, PhD

Research title: Management of severe acute pancreatitis in intensive care unit: a literature

review

Aim: To establish the methods management of patients suffering from severe acute pancreatitis

(SAP) in the intensive care unit (ICU).

Objectives:

The objectives of this thesis are to be met by systematically analysing the available literature regarding SAP. The objectives are as follows:

1. To determine effective initial management strategies of SAP in the ICU in terms of;

pulmonary interventions, fluid resuscitation, nutrition, antibiotics and pain treatment.

2. Management of complications in the ICU, such as acute compartment syndrome (ACS)

and necrotising pancreatitis (NP).

Methodology: The investigation was a systematic literature review; database was utilised to

extract articles. Keywords were searched and cross-matched against other key terms.

Result: The findings in this review indicate that in the event of SAP within the ICU, the most

important intervention is likely to be fluid resuscitation which is closely followed by pulmonary management. Additionally, nutritional support, pain management and interventions for complications are also critical. Moreover, antibiotics are no longer recommended for prophylaxis, however, in the case of NP need surgical intervention in many cases. In case of ACS evacuation of content and optimizing treatment is recommended.

Conclusion: In SAP no curative treatment exists, instead the treatment is directed to support

organ dysfunction. Critical points are to correct fluid balance with fluid resuscitation and pulmonary management with oxygen according to the state of patient. The management of SAP has been shifted from a past that involved aggressive approaches such as early surgical interventions, liberal antibiotics usage and aggressive fluid resuscitation to now follow a more restricted and conservative methodology. Enteral nutrition, antibiotics management of infections and pain are also critical areas that increase patient survival.

For the management of ACS giving fluids diligently and when the abdominal pressure is increased a step by step approach is necessary to decrease the pressure. The end goal is to correct fluid state and space occupying lesions in the abdomen. It is highly recommended that

5 patients with NP wait at least 4 weeks for the necrosis to be walled of for surgical removal. A collaboration with surgical department is necessary for successful intervention

ACKNOWLEDGMENT

I would like to thank my supervisor prof Vidas Pilvinis with his guidance and

help.

CONFLICT OF INTREST

No conflict of interest to report

SOURCED OF FUNDING

There are no provisional sources of funding.

ETHICAL COMMITTEE CLEARANCE

No ethical committee clearance was needed.

TERMS

SEVERE ACUTE PANCREATITIS, INFECTIVE NECROTIZING PANCREATITIS, ACUTE COMPARTMENT SYNDROME, INTRA-ABDOMINAL HYPERTENSION, ACUTE RESPIRATORY DISTRESS SYNDROME, WALLED OF NECROSIS, ACUTE NECROTIC COLLECTION.

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ABBREVIATIONS

ACS Abdominal compartment syndrome ANC Acute necrotic collections

APACHE II Acute physiology and chronic health evaluation II APFC Acute peri-pancreatic fluid collections

ARDS Acute respiratory distress syndrome

BISAP Bedside index of severity in acute pancreatitis ERCP Endoscopic cholangiopancreatography ICU Intensive care unit

IAH Intra-abdominal hypertension IAP Intra-abdominal pressure IPN Infected pancreatic necrosis SAP Severe acute pancreatitis RAC Revised Atlanta Classification NP Necrotizing pancreatitis

MRCP Magnetic Resonance cholangiopancreatography MODS Multiple organ dysfunction syndrome

NPPV Non-invasive positive pressure ventilation SIRS Systemic inflammatory response syndrome WON Walled off necrosis

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INTRODUCTION

Acute pancreatitis is a prevalent inflammatory condition of the pancreas and is the leading gastrointestinal cause of hospitalisation in the United States of America USA. In a study in 2014, hospitals in the USA indicated acute pancreatitis to be among the 3rd _{most common} diagnoses with an approximate incidence of up to 30 cases per 100,000 per year [1]. The socioeconomic burden of AP in the USA is also significant, with the annual cost of acute pancreatitis estimated to be around $2.6 billion dollars per year [2]. Disease severity is variable, wherein mild disease warrants conservative management while severe or complicated conditions are associated with high levels of mortality. Severe acute pancreatitis (SAP) involves multiple organs in the disease process with both local and systemic involvement, and management in the intensive care unit (ICU) is often critical for patient survival.

As aforementioned, the majority of AP cases are mild, however 20-30 % are classified as SAP and require emergency care in the ICU. Among these patients with SAP, the mortality rate is around 20% and when infected it can increase up to 30%. There are two major etiological forms of AP, gallstone AP accounts for 40-70 % and alcohol induced make up 25-35 % [2].

Historically, the management of AP has always been largely invasive however, in recent times there has been significant evidence suggesting that treatment should be more inclined towards supportive and conservative methods of care [3]. In many cases a multidisciplinary approach is necessary in management, and this includes an interventional radiologist, gastroenterologists and surgeons. This approach is designed to find the etiology of the presenting AP and in the later stages, both resolve and treat any complications that may arise.

When it comes to finding an appropriate treatment strategy there are several plans which can be followed and these include; prophylactic antibiotic therapy, nutritional support and fluid resuscitation. Even though these methods of management are currently in use, they are still under debate.

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AIMS AND OBJECTIVES

Aim:

The aim is to establish the methods of management of patients suffering from SAP in the ICU.

Objectives:

The objectives of this thesis are to be met by systematically analysing the available literature regarding SAP. The objectives are as follows:

1. To determine effective initial management strategies of severe in the ICU in terms of;

pulmonary interventions, fluid resuscitation, nutrition, antibiotic therapy and pain control.

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1.0 LITERATURE REVIEW

1.0 Background

SAP is a clinically severe form of AP that involves multiple organ systems and can be potentially life threatening. Pancreatitis is generally an inflammatory process wherein the pancreatic enzymes self-digest the pancreas. The gland may sometimes heal itself without the development of significant problems and such cases are referred to as AP [6]. Intermittent recurrences of pancreatitis contribute to the functional and morphological loss of the gland and such instances are chronic pancreatitis. Both variants are a common presentation in the emergency department and intensive care unit, and it is imperative to identify acute clinical findings as soon as possible to achieve optimal results [7]. The causative factors for males are predominantly alcohol-related while for females it is associated with gallstones[8]. At present, there is no curative method and the main strategy for management is through patient surveillance and organ-system support[9].

1.0.1 Pathophysiology

The exact causative origin of AP is currently unknown and much of the active research in this regard is on the molecular level. There are a number of hypotheses, all of which ultimately indicate that AP is a consequence of the activation of proteolytic enzymes which leads to both the breakdown of junctional barrier proteins between acinar cells and the leakage of pancreatic enzymes into interstitial space which causes the autodigestion and of acinar cells[10]. The most common etiology of AP is the formation of gallstones which causes from 40-70% of all cases; to a lesser extent alcohol consumption is another causative factor which can lead to alcohol-induced AP. The pathophysiological mechanism of gallstone AP has been well documented [11][12–14]. It is inferred that in cases of gallstone AP the sphincter of Oddi is obstructed and consequently pancreatic enzymes accumulate and eventually result in acinar cell destruction [15]. This is dissimilar to the alcohol-induced AP, where there is a limited understanding of the underlying mechanism[2]. Nevertheless, there is some evidence suggesting that it may cause contractions of the sphincter of Oddi [3]. Other studies provide evidence suggesting that there may be a genetic component to alcohol-induced AP, implicating certain genes to predisposing patients to an increased risk of developing the disease [11]. There are a number of other etiological factors, including but not limited to: autoimmune disorders, drug-induced, caused by ERCP, idiopathic and hypertriglyceridemia [12]. Smoking is also an associated risk factor for AP, since it has been linked to non-gallstone AP in some studies [13].

10 Systemic inflammatory response syndrome (SIRS) is a typical finding characteristic to AP due to acinar cell death. The acinar cell death and pancreatic damage releases the activated pancreatic enzymes which stimulates local inflammatory response mechanisms. This in turn activates the systemic inflammatory response by releasing pro-inflammatory cytokines [19,20].

1.1 Classification

The classification of AP can be approached either temporally, based on severity or morphologically. According to the Revised Atlanta classification (RAC) which was established in 2012, temporally AP is classified as either early phase or late phase [21]. With regards to severity, the disease process is classified based on morphologic or clinical findings; it can be mild, moderate or severe. In mild AP, there is no organ failure nor is it associated with any local or systemic complications. This is in contrast to moderate AP where there exists transient organ failure less than 48h with or without local complications. SAP is naturally the most critical and it is characterised by persistent organ failure longer than 48h. In accordance to the RAC, morphologically AP can be divided into either interstitial oedematous pancreatitis or necrotising pancreatitis.

1.1.1 Biphasic course of AP

The natural course of AP is biphasic and as stated previously it is divided into the early and late phase[22]. Early phase (weeks 1-2) is characterised by SIRS due to inflammatory mediators being released as a result of pancreatic injury. If the pro-inflammatory response is severe enough it can lead to the failure of multiple organ systems [21,22]. As such, only clinical parameters associated to SIRS are necessary and relevant when determining the treatment strategy.

The late phase is after 1-2 weeks of pathology and the course of the disease leads to a transition from a pro-inflammatory to an anti-inflammatory response[22]. Due to this immunosuppressive response and failure of the intestinal barrier, patients become exposed to the risk of intestinal flora translocating and causing a secondary infection in pancreatic or peripancreatic tissue and fluid collections. This process is believed to be the cause of infected necrotising pancreatitis and can eventually lead to sepsis[21–23]. Patient mortality is thus also biphasic; early mortality being the consequence of severe SIRS with multiple organ failure; and late mortality is a product of the spread of infection as well as the resultant sepsis. Tactics

11 of treatment in this phase are determined by the morphological revelations indicated by clinical parameters and radiological findings. Figure 1 indicates the biphasic course of AP below[22,23].

1.1.2 Severity-based classification

In the context of AP, it is critical to clearly define the severity of the disease since potentially severe cases necessitate aggressive treatment while milder forms may be suitably handled in specialist care. The RAC establishes 3 degrees of severity ranging from: mild AP, moderately severe pancreatitis and SAP [21]. In mild AP, patients characteristically lack any evidence of organ failure as well as local or systemic complications. Dissimilarly, moderately severe acute pancreatitis is characterised by organ failure that resolves within 48h (transient organ failure) with/without local or systemic complications. SAP is characteristically the most severe with either single or multiple organ failure that persists for greater than 48h (persistent organ failure). SAP will typically also have local and systemic complications [7,21]. These stratifications of organ failure mentioned are defined according to the Modified Marshall scoring scheme which defines them as failure of the cardiovascular, respiratory and renal organ systems [7,11,21].

Figure 1. Phases of severe acute pancreatitis [22] [Zerem E.]

12 1.1.3 Morphological classification

This classification of AP is based upon the morphological characteristics of the complications that arise; interstitial edematous pancreatitis which can be either acute peripancreatic fluid collections (APFC) or pseudocysts; and necrotising pancreatitis which can be either acute necrotic collections (ANC) or walled-off necrosis (WON) [21]. Interstitial edematous pancreatitis is characterized by pancreatic and peri-pancreatic inflammation without signs of necrosis on CT and typically has a clinical course that is mild. In usual circumstances this clinical form of AP achieves resolution after around one week of conservative management [8]. Necrotizing pancreatitis affects pancreatic and peri-pancreatic tissue. This type develops over several days, therefore, CT assessment to verify necrosis can be considered usually after one week of symptom development [7]. Pancreatic necrosis can become infected, and in such instances, it is associated with increased rates of mortality and morbidity[21].

The local complications of the disease are these morphological changes which include the APFC, pseudocyst, ANC and WON while systemic complications are typically an exacerbation of comorbidities such as heart or lung disease [11]. APFC usually remains sterile and treatment is not indicated since it resolves spontaneously (<4 weeks). Pseudocyst is a fluid filled collection that appears due to disruption of the pancreatic duct without necrosis, after 4 weeks of formation [6]. ANC are collections of necrotic tissue and fluids that develop within the first 4 weeks. It can be distinguished from APFC (APFC is a non-necrotic collection) by CT only after one week [24]. WON starts after four weeks and are defined as mature pancreatic and/or peri-pancreatic necrotic tissues that are encapsulated within well-defined walls. MRI/endoscopic ultrasound is often required to make distinctions from pancreatic [21].

1.2 Diagnostic considerations 1.2.1 Clinical manifestations

The main symptom of AP is pain, and it is most commonly located centrally in the epigastric region with radiation to the back. In most circumstances it is moderate to severe pain which starts gradually, increases over several hours which then reaches a plateau and maintenance threshold for several days [1,10]. The symptomatic pain is commonly associated with additional symptoms of nausea and vomiting. If the patient presents with cholangitis, then fever is also a part of the clinical presentation. Symptoms that indicate SAP include the worsening of pain after the plateau phase, as well as mental status changes and the reactions of the

13 cardiovascular and respiratory system, with hypotension and hypoxia respectively [25]. Cullen’s and Grey Turner's signs are ecchymosis in the flanks and around the epigastrium that can be found in physical examination.

Other clinical findings that are related to AP are fever and in minority case jaundice. Cardiovascular exam might show increased heart rate and decreased blood pressure. Patients presenting with SAP can show signs of cardiovascular instability. Other presenting symptoms in SAP can be lethargy, sweating and pale [10].

1.2.2 Laboratory diagnosis

There are several enzymes that are released from the pancreas into the systemic circulation. The main enzymes are lipase, amylase and trypsin. In the case of AP, amylase levels increase within the first day of injury and reaches its maximum after 48h, after which it slowly decreases over several days to one week, eventually normalizing again. In the case of lipase, it increases in about 3-6 h, reaching its peak levels after 24 h and it remains elevated for 1-2 weeks. Trypsin, on the other hand, is elevated for about 3 days. To make a diagnosis the serum amylase is required to be three times above the normal limit [4].

Amylase and lipase have only diagnostic value and no value for following the progress of disease [26]. Amylase is the most common marker that is used. A prospective study that included 476 patients with abdominal pain and elevated serum amylase/lipase, indicated that 154 patients (32%) had AP. Hofmeyr et al, indicated that the sensitivity of lipase was 91% while amylase was 62 %. Specificity was 92% for lipase and 93% for amylase [27].

Trypsinogen is zymogen of trypsin that is also released into the circulation and elevated for 3 days after which it is cleared via the kidneys and can thus be used as a rapid bedside test. In a study Andersen AM et al including 75 patients admitted with severe cases of AP, the sensitivity was found to be 87% and specificity was 97% [19].

1.2.3 Imaging

To verify diagnosis of severity, form and etiology of AP imaging test are an essential part of workup. The first imaging modality of choice is right upper abdominal ultrasound (US) on admission or within 48h [28]. Computed tomography (CT) has a sensitivity and specificity of 90% when making the diagnosis of AP [29]. CT scans are usually unnecessary because the

14 majority of patients fulfil the criteria from the clinical presentation, laboratory investigation and US. Contrast enhanced CT (CECT)/Magnetic resonance imaging (MRI) is recommended when the symptoms of fever, nausea and pain persist as well as for assessment of complications [3].

CECT should be avoided in mild forms of AP; they are usually reserved for SAP when suspecting complications and also when there is a need during treatment strategies. The main concern with CECT in SAP is the risk of acute kidney injury due to contrast induced nephrotoxicity. A meta-analysis from 2018 with more than 100,000 patients found no significant links between using contrast and acute kidney injury (AKI) [30].

In a study by McPherson SJ et al in the United Kingdom, 518 cases of severe forms of AP (ICU admission, death from AP, inpatient stay for more than 4 days) were reviewed and it was found that for diagnosis only 12% of (50/518) of cases required CT or MRI in order to make the diagnosis, and these were in cases where there was no characteristic abdominal pain or elevated enzymes, according to the criteria. But more importantly CT is used to classify severity, complications and determine the type of AP which aids in planning further management of the patient. In cases of pancreatic necrosis, CECT was done in almost ⅔ of patients in contrast to MRI. In this study they also indicate that CT scans were used responsibly i.e. in only 3% of the cases was it used too many times and in another 3 % the number of CT scans were too few. MRI can be used in patients with contrast allergy, kidney disease and pregnancy to reduce the risk of AKI [24].

Magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound (EUS) endoscopic cholangiopancreatography (ERCP) are diagnostic tools that can be used in cases where US does not shows signs of biliary obstruction and liver enzymes are within the normal ranges [24]. ERCP should be used with caution as diagnostic method because in some case ERCP can be used in patients without cholangitis and therefore no impact on treatment. EUS has better results excluding small bile stones (<5mm) but less available and more operator dependent, and MRCP is less invasive [24].

1.2.4 Diagnostic criteria

Due to the inflammatory process of AP, there are several ways of identifying the pathology. The patient's presenting symptoms and general status are important indications for diagnosis

15 and, sometimes, even for estimating the severity [31]. In terms of symptoms, AP is closely associated with a characteristic abdominal pain which presents in most cases as a direct indication of the disease [21]. With a more instrumental approach, laboratory tests can be utilised to establish the diagnosis; the finding of pancreatic enzymes in the systemic circulation is a significant discovery which assists in the confirmation of AP. Another crucial element of objective testing includes radiological investigations. Imaging studies through CECT provides another diagnostic tool that can be used. In order to confirm the diagnosis, symptomatic abdominal pain, elevated pancreatic enzymes and a CECT showing signs of AP, are important. However, only two of the three are needed to satisfy the diagnostic criteria of AP [21].

1.3 Management

This section reviews the management strategies currently employed when handling SAP patients in the ICU. Further information and analyses of data regarding each strategy is provided in the results and discussion sections.

1.3.1 Pulmonary management

Acute lung injury is a typical cause for mortality in SAP. Additionally, SAP has a tendency to involve other thoracic structures including the pleura, thoracic vasculature and the mediastinum [34]. These manifestations are an important cause for morbidity and hence their management is among the priorities in the treatment strategy. Respiratory failure is a common outcome from severe patient hypoxia and the development of SIRS. The patient becomes hypoxic due to the associated decrease in tidal volume. Typically, depending on the extent of respiratory dysfunction, mechanical ventilation, oxygen therapy, nasogastric decompression and even non-invasive ventilation are all good options. Oxygen therapy is usually performed by giving patients additional oxygen through a nasal cannula that may be clipped to the nose or breathing mask. High-flow nasal oxygen is delivered at approximately 90% to enables the patient to maintain adequate levels of oxygen saturation [4].

Ventilation support is either non-invasive or invasive; in the former patient ventilator interfaces such as facial masks ensure adequate ventilation while in the latter ventilatory support is provided via an endotracheal or tracheostomy tube. Positive pressure ventilation through a mask is among the main routes of providing ventilatory support non-invasively. In patients it is shown to reduce hypoxia and decrease symptoms of dyspnoea and the respiratory rate, while increasing the tidal volume [4]. In cases of pleural effusion ultrasound-guided drainage is a

16 frequently employed practice. Analgesic interventions as well as early physiotherapy has been linked to preventing atelectasis related complications as well [35].

1.3.2 Cardiovascular management

One of the most important interventions is fluid treatment due to hypovolemia when a SAP patient is presented to the emergency room. SAP is closely related to third-space fluid loss, which has a causal relationship with hypoperfusion, the consequential splanchnic vasoconstriction and the ultimately decreased blood flow to the pancreas [36]. Hypovolemia also leads to poor perfusion to other organs which can leave the patient far more susceptible to multi-organ failure and/or death in those patients with SIRS [36,37]..

The literature supports an approach to fluid resuscitation that is balanced and given in the right time [23,37,38]. The benefit of fluid reduction is that it improves microcirculation and stops the progression of the disease. Due to their retention within the intravascular space, colloids have the ability to exert oncotic forces which maintains the intravascular volume [39]. Crystalloids on the other hand, are able to replenish fluid that has been lost from the intravascular space. The preferred type of fluid is Ringer acetate due to its benefits of anti-inflammatory effect and availability [40]. It is believed that a timely and meticulous approach to fluid resuscitation reduces mortality and improves patient outcomes. The monitoring of fluid resuscitation can be bedside assessed such ash measurement of blood pressure, heart rate and urinary output. Another way of control to hemodynamic is to have laboratory data such as haematocrit our blood urea level [41].

Even if patients are receiving fluid resuscitation, patients can remain hypotensive and, in such cases, intravenous vasopressors are incredibly useful. Vasopressors constrict blood vessels and increase the mean arterial pressure and thus improve perfusion pressure [42]. Guidelines indicate norepinephrine as the first-line agent in distributive shock. Furthermore, additional agents such as epinephrine, dobutamine or vasopressin may be considered depending on the severity of the situation [42].

1.3.3 Nutrition

Nutrition is a basic treatment plan and needs to be corrected when managing SAP in ICU. The question that rises regarding nutrition is the consistency of nutrition, routes such as total parenteral, nasogastric (NG), naso-jejunal (NJ) [45]. Also, nutritional supplements such as

17 vitamin C, probiotics and omega 3 fats have been used in clinical settings. However, there is not strong evidence of its efficacy when it comes to probiotics as an example. Sharma et al divided patient into a group receiving probiotic and second placebo, and in the result it showed no effect on gut permeability or other factors [46]. Another study by Asrani et al concluded that there may be advantages to glutamine supplementation in case of total parenteral nutrition because of reduction of mortality and infection [47]. Despite this, in a study from 2015 Oldani et al found that there is no significant benefit to giving glutamine to critically ill patients [48].

1.3.4 Management of infection

The exact mechanism of infection of acute pancreatitis is still not understood fully, but the main theories is the translocation of colon bacteria to the pancreas, via lymphatics, hematogenous or transmurally. The main pathogens present in infected pancreas are from colon, and in inflamed pancreas with reduced capacity to clear microbes creates a susceptible environment for infection [49]. Common microbes are gram negative (E. coli), gram positive (Enterococcus) and anaerobic bacteria. Prevalence of primary fungal infections have been reported in up to 17 % of cases and secondary infections up to 32 % [50].

There has been debate about preventive measures such as prophylaxis of antibiotics in many years but there is no clear recommendation from the scientific community. The main reason is that there appears to be significant uncertainty from studies [54]. What is clearer, is that whenever the clinicals suspect infection of pancreas a prompt regimen of antibiotic according to local guidelines is necessary. Numerous articles surmise that although antibiotics are prescribed in SAP patients who have developed pancreatic or extra pancreatic infections, as a prophylactic adjunct it does not decrease mortality nor secondary infection [4,55,56]. Antibiotics may only be administered when the infection markers are identified [15,57]. Excessive use of antibiotics also bears with it the risk of resistance which can be associated toa prolonged hospital stay and a poorer outcome

When using antibiotics for IPN two criteria must be fulfilled, an antibiotic that is broad spectrum and that has a good penetration into the pancreas [51]. In a study by Büchler M et al that included 15 patients with SAP that received Piperacillin/Tazobactam 4,5g every 8 h concluded that the antibiotic had very good penetration in the pancreas, necrosis with a mean concentration of 120 mg/kg in the tissue [52]. Piperacillin/tazobactam is not as problematic with bacterial resistance and has shown better cost-effectiveness. The efficacy factor of each

18 antibiotic is shown in table 1 and it can be seen that Imipenem and Ciprofloxacin are the best to use. Notably, they have been linked with resistance and should be used with caution [53].

1.3.5 Pain management

For the pain management, the analgesics that can be used are according to guidelines of pain and no specific therapy have been established for SAP. Opioids that are administered intravenously or subcutaneously have shown no side effects related to pancreatitis and are safe to use [43]. If the patient is not treated with good pain control it can lead to cardiovascular instability therefore swift pain management is of interest.

The WHO addresses management of pain in patients with 5 recommendations for correct analgesic use and proposes a 4-step analgesic ladder with regards to treating pain. The 5 recommendations include; oral administration whenever possible; analgesic administration at regular intervals, respecting the medications duration of effectiveness; analgesic prescribed according to pain intensity, confirmed via a measurable intensity scale (Visual analogue scale/numerical rating scale); dosing adapted to individual needs; and analgesics prescribed with a constant concern to detail, to ensure that maximum pain relief is achieved at not detrimental cost to the patient [44].

Table 1. Efficacy factors for different antibiotics in pancreatic tissues [53] [Büchler M, Malfertheiner P, Friess H, Isenmann R, Vanek E, Grimm H, et al.]

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2.0 METHODOLOGY

In order to achieve the objectives outlined in this investigation, we screened the PubMed database using the Advanced Search Builder. The search consisted of three parts, one regarding the terms referring to SAP, cross-matched with another regarding the terms referring to ICU or intensive care unit, cross matched with another term referring to management or treatment. The search yielded 1331 results. Moreover, other filters were also incorporated in the interest of maintaining relevancy and also so that the investigation reflected current attitudes and approaches in ICU management. Mainly papers published within the last decade (2010-2020) were utilised, and preference was given to articles written in English. After establishing all of these criteria, 43 articles remained eligible for use. Figure 3 below is a broad schematic of the methodological process.

Assessment of eligibility:

The articles were deemed suitable based on objectively reviewing the title and abstract and selection was made if the paper satisfied eligibility criteria. Irrelevant and outdated studies were thus excluded, and other common reasons included but were not limited to: the small sample size, investigations that were not performed in the ICU, inaccessible due to fees.

Inclusion criteria:

Inclusion criteria were employed in order to further eliminate irrelevant studies and these included the date of publication, wherein only papers published from the last 30 years were used (more than 70% of the cited research remained within the last 10 years). Other inclusion criteria determining eligibility to be within the literature review are English language, topic relevance, peer-reviewed status, had both quantitative and qualitative implications, and that they were conducted on humans. Disregard was given to age, gender and the race of

participants.

Exclusion criteria:

The exclusion of articles was predominantly based upon the following factors: inappropriate/incomprehensible language, outdated or obsolete research, articles focused on milder forms of pancreatitis, management was not within the ICU and if the investigation was conducted upon animals or in vitro.

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sdfsfdA

After the initial search that yielded 1331 results, 1233 articles were excluded based on title and the articles being old and 98 articles were identified.

33 articles were excluded after abstract review

40 articles were included after full text review

z

Figure 2. Schematic of the selection process

1331 results yielded in PubMed

98 articles reviewed from PubMed

1233 excluded

33 excluded

65 articles distilled for full text

review 25 articles excluded

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3.0 RESULTS

3.1.1 Intensive care unit

In cases of SAP with organ dysfunction, the main treatment is supportive organ management that only can be provided by ICUs with specialized care. In international multidisciplinary conferences it was the jury’s recommendation that there should be two main objectives of treatment, first is supportive and second is to avoid potential complications that may occur in SAP [58].

Initial management of SAP includes supporting the basic organ systems. This conservative approach prioritises each system by making the following provisions; pulmonary system with oxygen therapy; cardiovascular system with fluid correction; pain control through analgesia; and gastrointestinal management with nutrition. For every patient a strategy consisting of these parameters is typically included.

3.1.2 Pulmonary management

Respiratory abnormalities are a common development in cases of SAP, and patients usually develop these features after fluid resuscitation [21]. It will typically present as acute respiratory distress syndrome (ARDS) as well as through decreased thoracic compliance, bilateral infiltrates, and pulmonary hypertension[59]. It is paramount that patients suffering from SAP are closely monitored in order to recognise early features of organ failure.

One of the most common causes of organ failure, secondary to SAP is respiratory insufficiency, and consequently it remains a common cause of death in SAP [60]. To administer oxygen is one of the most essential parts of treatment and it should be started as soon as possible. Oxygen support with high flow or continuous positive airway pressure (CPAP) should be part of the respiratory system support. Mechanical ventilation with intubation cannot be excluded and should be an option. A study done by Zhao et al where the objectives were to find out the efficacy of non-invasive positive-pressure ventilation (NPPV) in cases of patient with AP and ARDS and it was concluded that NPPV could be considered [59,61]. The study showed effective results on heart rate, systolic pressure, respiratory rate and oxygen saturation [59,61]. It is notable however, that NPPV can be poorly tolerated in a number of patients because of abdominal distension and reduced functional residual capacity. When comparing the outcomes of patients that were successfully treated with NPPV versus patients that required intubation,

22 the incidence of pancreatic necrosis (P = 0.000) and altered consciousness (P = 0.000) were higher among patient that were intubated, but other complication such as sepsis and infected necrosis was comparable (P > 0.05) [61]

Ibadov RA et al did a retrospective investigation of 67 SAP patients treated in the ICU from 2008-2017 conclusively determined that pancreatitis associated ARDS is a leading cause for multiple organ dysfunction and mortality in patients [60]. The study observed the development of ARDS in 36 patients (53.7%), from which patient mortality was 44.5% [60]. It was therefore evident that ARDS is closely associated with patient death and further indicates that an early recognition of the pulmonary complication is critical and allows for early application of ventilatory support and consequently, restoring oxygenation achieving more positive outcomes[59,60].

3.1.3 Fluid resuscitation support

Fluid resuscitation is essential part of treatment of SAP, mainly because of the effect of the inflammatory process that affects the microcirculation. Microthrombi, vascular spasms and edema diminish the perfusion to organs and therefore it is crucial to start treatment with fluids as soon as possible to improve circulation [31]. Gardner et al studied 45 patients with identifiable SAP and they were divided into two groups according to the fluid given in time and after admission. Patients that received more than third of their cumulative 72h fluid within the first day had lower mortality rates and shorter hospital stays compared to patients who received less than third of their cumulative fluid within the first day. (0 vs 18%, p < 0.04 and 35 vs 43%, p = 0.31 respectively) [37,62].

Parameter Recommendation

Fluid resuscitation necessary

The earlier the resuscitation, the better outcome.

Type of fluid Crystalloids: Among crystalloids, Ringer’s better than normal saline. Amount of fluid Total fluid in first 24H, between 3 and 4 L, not to exceed 4L.

Rate of infusion Initial bolus 1000 ml over one hour followed by 3 ml/kg per hour

Table 2. Recommendations for fluid replacement in predicted severe or SAP [62]

[Aggarwal A, Manrai M, Kochhar R.]

23 The recommendations that were published in guidelines recommends crystalloids, however colloids could be considered patients with very low haematocrit or albumin levels. There are no comprehensive studies on the types of crystalloids, however ringer acetate seems to be preferred over normal saline. The amount and rate of infusion fluid, monitoring and duration of resuscitation is presented in table 2 above [62].

A study performed by Mao E, et al. compared what they referred to as aggressive fluid resuscitation (10-15 ml/kg/h) with controlled resuscitation (5-10 ml/kg/h), used APACHE II to see the effect and arrived at the conclusion that 5-10 ml/kg/h had better prognosis when using APACHE II [63]. Survival rate was higher with controlled resuscitation compared to aggressive resuscitation (90% vs 69%, P < 0.05).

De-Madaria et al studied 247 participants with AP were divided into three groups to see the effect of the amounts of fluid; the first group received < 3.1 L, second group 3.1-4.1 L, and the third group > 4.1 L during the first day. The group that improved the most, in terms of local complications and organ failures, was the group of patients that received fluid amounts between 3.1-4.1 L. The worst outcomes were for the patients that received more than 4.1L [64].

Sharma et al sought to identify the difference between routes of administration of fluid i.e. naso-jejunal versus intravenous route. 49 patients were included in the study and it indicated no difference between the two group in terms of organ failure (66 vs. 68%), pancreatic necrosis (69 vs 76%) and mortality (16 vs. 8) (P > 0.05) [65].

3.1.4 Nutritional support

For many decades the nutritional approach to SAP was total parenteral nutrition, with the idea that giving nutrition would stimulate pancreatic enzyme secretion which would further aggravate the patient’s condition [20]. But the approach to rest the pancreas by giving total

(200 ml/h] for 24-48 h

Monitoring Urine output 0,5 ml/kg/h, haematocrit = 25-35 %, drop in BUN. Duration of

24 parenteral nutrition (TPN) has shown no benefits in multiple studies. A study from Sweden done by Eckerwall GE et al with 50 participants with SAP showed no difference between TPN and enteral nutrition (EN) nutrition in terms of intestinal or systemic inflammation markers, and EN showed greater benefit with lower glucose levels [87]. The respiratory complication was 10 in EN group and 52 in TPN group (P = 0.04). Total complication was also lower in EN group compared to TPN group (25 vs. 52, P = 0.04).

In a study done by Petrov et al concluded that infection complications and mortality rates were significantly lower in patients receiving enteral versus parenteral nutrition [88]. The infectious complication showed (P <0.001), pancreatic infections (P =0.02), and mortality (P = 0.03) among patient receiving EN compared to TPN.

For the last decade the trend has been to move from TPN and instead introduce enteral nutrition. The topic of discussion has mainly been regarding when to start and whether naso-jejunal EN (NJ EN) is better than nasogastric EN (NG EN). The principle of enteral nutrition is that during AP the natural gut barrier is compromised with increased permeability due to damaged tight junctions and epithelial disruption. This is hypothesised to be the cause of bacterial and toxin translocation via the lymphatic and hematogenous pathway causing secondary infection, sepsis and multiple organ failure [57]. Therefore, it has been suggested that EN should be started as soon as possible. Bakker et al compared early EN (<24h) versus late oral nutrition (>72h) and saw no difference in mortality (11 vs. 7 %, P = 0.33) and infection rate (25 vs. 26, P = 0.87) between the two groups [89].

In a study done by Li J-Y et al investigated early EN (<48h) and concluded that EN reduces mortality (P = 0.05) and infection complication (P = 0.05) in SAP [90]. Early enteral nutrition also has some associated risks, it should for example be avoided in patients that are hemodynamically stable due to the risk of mesenteric ischaemia that is not occlusive. Most of the guidelines have recommended to start enteral nutrition less than 48 from admission and no laboratory markers are needed in order to start as long as the patient is hemodynamically stable [60].

It has been presumed that NJ EN is safer than nasogastric NG EN because of associated aspiration risks and it is thought to be better for the gut barrier. But a meta-analysis by Chang et al has shown no superiority of NJ EN compared to NG EN in terms of toleration (P = 0.20)

25 and complication such as aspiration (P = 0.25), diarrhoea (P = 0.43) and exacerbation of pain (P = 0.90) [91]. In many cases nasogastric tube is preferred due to the higher skills required in order to insert the naso-jejunal tube.

3.1.5 Use of antibiotics in SAP

One of the older strategies of treatment was by giving patients with SAP and no concomitant bacterial infection, prophylactic antibiotics in order to prevent infected necrotizing AP and sepsis [22]. But recent trials have shown no significant reduction with systemic complication, necrotizing pancreatitis or mortality [68]. Dellinger et al enrolled 50 patients in one group that received Meropenem and the other group of 50 persons were placed into a placebo group. This study concluded in the results of the study that giving antibiotic prophylaxis is not recommended [69]. In the group of meropenem infection developed in 9 of 50 patients and in placebo group 6 of 50 (P =0.401).Mortality rate in Meropenem group was 20 % vs 18 % in placebo (P=0.799). Surgery was needed in 26 % in meropenem group vs 20 % in placebo group (P=0.476) [69].

When diagnosing infected pancreatic necrosis (IPN), antibiotics are recommended and well established in their ability to prevent further extra-pancreatic infection and sepsis due to increased association with organ failure and mortality rates [70].

CT guided fine needle aspiration (FNA) has been a part of routine examinations in order to confirm infection and also for determining the type of bacteria and give pathogen-specific antibiotics. But in most recent guidelines the recommendation to use FNA has been loosened and its utility in determining infections is no longer as strong a criterion as it was before [4]. A multidisciplinary conference on IPN suggested that CT-FNA may be performed by clinicians but are reserved for only diagnostic purposes that can be done for patients that do not respond to antibiotics and have laboratory data such as leukocytosis despite antibiotic treatment [71].

There are several methods to confirm infectious pancreatitis. Procalcitonin (PCT) is valuable not only in predicting the severity but also in diagnosing infections of the pancreas. Rau BM et al included 96 patients with SAP to investigate PCT levels. CRP and PCT were compared and it showed that patients with an infected pancreas had significantly increased PCT compared to CRP and it is the single best biochemical test for evaluation of an infected pancreas [72]. PCT level of 3,5ng/ml or more on two successive days was better to CRP

26 430mg/L or more for the assessment of infected necrosis with multiple organ dysfunction syndrome (MODS), with a sensitivity and specificity of 93% and 88% for PCT and 40% and 100% for CRP (P < 0.01) [72].

Van Baal MC et al divided patients into three groups based on their peri-operative status; group 1 with the clinical signs of infection (fever, leucocytosis, elevated CRP), group 2 with gas on CT and group 3 with FNA positive before intervention [73]. In the clinical group, 80% of patients were confirmed to have an infection while in the imaging group this was 94 %, and from the FNA group 86% had infection (P = 0.07). The day of intervention for INP (median 27 days) or mortality rates (18 %) was not different between the groups (P = 0.39) [73]. Another negative aspect with FNA is that it has been reported to have false negative results [73].

3.1.6 Management of pain

Pain is the main symptom of SAP and ideally it should be addressed within 24 hours from coming into the hospital for the quality of the patient’s life. Pain creates extreme discomfort for the patient and increases sympathetic activity and it even impairs oxygenation since there is also pain-associated restriction of abdominal wall movements[20]. There are no specific recommendation or restriction for pain management of SAP due to limited clinical trials. However, the best guidelines are to adhere to WHO peri-operative pain management. Most of the patients will require management through parenteral analgesics such as opioids. Hydromorphone is the opioid of preference over fentanyl and morphine in non-intubated patients [4]. Previously, morphine was thought to aggravate AP by inducing contraction of the sphincter of Oddi, thus increasing and causing dysfunction. This notion has since been dismissed as there is insufficient data or evidence [20].

Epidural analgesia with local anaesthetics is also often considered in cases of severe pain. A study by Sadowski SM et al suggested that epidural analgesia is not only effective at improving pain scores (VAS), but also capable of increasing pancreatic arterial perfusion when measured by CECT of patient with SAP [66]. They divided patient into group 1 epidural (n=13) and group 2 control (n=22) and saw that the pain score (0-10) before randomization was 6,55 vs 7,31 (P = 0.57). On the fifth day after epidural analgesia was given the pain score was 0,57 vs 2 (P < 0.06). Vascular perfusion was improved in 13 of 30 measurements in epidural group and

27 2 of 27 in control group. The difference among perfusion improvement measurements (n=15) and rest of the cases was statically significant (P = 0.0025) [66].

Layer et al investigation from 2011 also indicated that systemic administration of local anaesthetic improves pain and accelerates clinical recovery [67]. In this study, 44 patients were examined on their response to procaine 2g/24h or a placebo for 72h in a double-blind manner. Pain severity and the clinical course of the disease were monitored at regular 24h intervals. When compared to the placebo, 75% of the patients receiving procaine reported overall pain reduction, and a staggering 80% had faster recovery (P = 0.012) [67]. After 72 hour the pain score (0-100) was reduced both procaine group and in placebo group. However median decrement was significantly greater with procaine (-62) than with placebo (-39) (P = 0.025) [67].

NSAIDs are typically used in conjunction with stronger analgesics as per the analgesic ladder. However, NSAIDs should not be administered in cases of AKI. There is no evidence of higher mortality or morbidity due to the use of opioids as analgesics [4]. Patient-controlled analgesia should be applied as much as possible [20].

3.2 Management of complications 3.2.1 Acute compartment syndrome

There are several mechanisms behind the abdominal compartment syndrome (ACS) and intra-abdominal hypertension (IAH). In SAP it is common that pancreas is increased in size and has fluid collections which affects the IAH. Paralytic ileus will lead to mechanical obstruction of duodenum which will cause enlargement of gastric cavity and subsequently add on intra-abdominal volume. Over-fluid resuscitation will cause increased hydrostatic pressure, infection of pancreas and necrosis also contributing to IAH due to capillary leakage, and the development of ascites is another cause [74]. IAH is defined as >12h mmHg and ACS as > 20 mmHg [66]. Incidence of IAH among SAP has been reported to be up to 60%, and incidence of ACS was 27% in one study and the mortality rate of patients with both SAP and ACS was as high as 75 % in that study [75,76].

The updated recommendations on the management of abdominal compartment syndrome (ACS) can be separated into approaches towards evacuating intraluminal contents; evacuating

28 intra-abdominal space occupying lesions; improving abdominal wall compliance; optimising fluid administration and systemic/regional perfusion [77]. Within each approach there are step by step guidelines on management all of which are dependent on the severity of the patient’s condition [77]. In order to evacuate intra-luminal contents, the first step includes the insertion of a NG and/or rectal tube and initiation of gastro-/colo- prokinetic agents (Grade 2D). The second step is to reduce enteral nutrition, and if necessary, to avoid it completely.

Removal of space occupying lesions begins by identification through abdominal ultrasound examinations. Subsequently, a CT can be utilised, and once lesions are well visualised, catheter drainage or surgical removal are the methods of choice; choice will depend on extent and severity of lesions [77]. The approach to improve abdominal compliance involves prescribing suitable levels of analgesia and neuromuscular blockade to the patient. Repositioning the patient and the removal of constrictive dressings are also equally appropriate approaches to optimising abdominal compliance.

Fluid resuscitation must be handled meticulously, since excessive fluid resuscitation can easily lead to fluid overload and consequently lead to an increased risk of ACS. Resuscitation using hypertonic fluids or colloids must be considered [77]. If the patient is stable, excess fluid may be removed via diuresis and on the other hand, if the patient is deteriorating haemodialysis or ultrafiltration ought to be considered. Optimisation of perfusion is achieved through goal-directed fluid resuscitation and efficient haemodynamic monitoring to guide resuscitation [77].

Zhao-Xi Sun et al enrolled patients into two groups, group 1 received combined indwelling of catheter celiac drainage and intra-abdominal pressure monitoring and routine treatment, and a control group (group2). The incidence of cysts was reduced in group 1 (P = 0.01) as well as mortality but was not statically significant [32]. Neuromuscular blockade may also have a significant effect of IAH reduction. De Laet et al showed a 4 mmHg decrease in intra-abdominal pressure (IAP) by 4 mmHg (from 18 mmHg at baseline to 14mmHg) after 30min of administering I/V cisatracurium 0.15 mg/kg compared to control group (P = 0.01) [39].

The most common surgical management of SAP with ACS is with midline laparotomy but other methods such as subcutaneous linea alba fasciotomy and bilateral subcostal incisions are used [77]. Mentula et al in their retrospective study (consisting of 26 patients with SAP and ACS) recommended, based on mortality rate, that the appropriate time of surgical

29 decompressive management is when conservative treatment is failing, and the patients have MODS with IAH more than 25 mmhg after 4 days [33]. In the same study the IAH decreased from 31.5 to 16 and interestingly all nine patients who had surgical decompression after day 5 died but only 2 of 17 patients died if the decompression was done within first 4 days. This suggests that early surgical decompression is associated with a significantly reduced rate of mortality in patients with SAP.

3.2.2 Necrotising pancreatitis

For a successful surgical intervention, it is important for the infected necrosis to be walled off for best results. Diagnosis of infected necrosis has been discussed above. According to the Revised Atlanta classification, walled off necrosis is defined as an encapsulated necrotic mass after 4 weeks [21]. The correlation between mortality rate and timing have been shown in several studies in which early intervention is associated with a mortality rate that is higher compared to late intervention (4 weeks) [78]. Besselink MG et al showed that mortality rate was better in all patients (with organ failure or without organ failure) that underwent operation after the 30th _{day from admission (P=0.001) compared to group that had operation before 30}th day.

In case of sterile necrosis, the time for intervention is prolonged up to 4-8 weeks. If there is any evidence of outlet obstruction caused by the WON and if symptoms persist after 8 weeks and/or disconnected duct syndrome is present, then intervention should be considered [79].

3.2.3 Surgical technique

For many decades open abdomen was the procedure of choice but that tradition has changed now to more minimally invasive approaches [71]. The different approaches will be not be discussed here in depth but they include; percutaneous, endoscopic, laparoscopic, drainages and open abdomen [80].

For the support of minimally invasive approaches, van Santvoort HC et al did a study that included 88 patients divided into open abdomen and step-up approach (percutaneous followed by) showed that major complication and mortality was 69 % for open abdomen group and 40 % of minimally invasive group (P = 0.006), and multiple organ failure was almost 4 times less in step up approach [9,81]. However, in the study mortality rate were comparable between the two groups (16 and 38 %, P = 0.70)

30 Van Brunschot S et al compared endoscopic step up approach (transluminal drainage followed by endoscopic necrosectomy) to surgical step up (percutaneous drainage followed by VARD if necessary). Mortality did not differ between the two groups 9 patients (18%) in the endoscopy group vs 6 (13%) patients in the surgery group (P = 0.50) [82]. Thus, the results showed that mortality and major complication rates were the same, but hospital stay and fistula showed lower rates for endoscopic step up approach [82].

31

4.0 DISCUSSION

An essential part of the management of SAP patients is that they should be placed in the ICU, for this reason the guidelines have tried to come up with criteria that justify admission into the ICU, but these guidelines lack a clear recommendation. Two issues are related to this question, the first is intensive care units are not homogenous departments, rather different types exist, depending if it is University hospital, Regional hospital or Primary hospital. The other issue is that to determine persistent organ failure in SAP, it takes 48 hours. The question thus arises, should all patients with transient organ failure be admitted into ICU, or only those with persistent organ failure?

The data suggest that the most important action in uncomplicated SAP is fluid therapy. In previous times the fluid resuscitation has been too liberal with large quantities leading to complications such as abdominal compartment syndrome and patients with chronic heart failure having fluid overload with the consequence of pulmonary edema and a risk of intubation. Studies that have been analysed in this thesis indicate that fluid resuscitation within 24 hours significantly reduces mortality and therefore, it appears that initial aggressive resuscitation is as important as the total amount of fluid given. The small sample size of the articles and also the fact that many studies are retrospective studies, indicates that it would be of interest to make new prospective studies in this field [37,85,86].

Alternatives agents such as pentoxifylline which a phosphodiesterase inhibitor that reduces leukotrienes and act as anti-inflammatory can be used. Vegge SS et al studied patients with SAP, and in the investigation it has shown that patients, total of 28, receiving pentoxifylline had a shorter stay in both ICU and hospitals in general (P < 0.05) [83]. Another agent that has been studied is octreotide which inhibits the secretion of pancreatic enzymes. However, in several trials there has been no real evidence of its efficacy [40]. Moggia E et al concluded in a Cochrane study that there is no evidence for pharmacological management resulting in mortality reduction [84].

Even if there are not many studies on the type of fluid, the general consensus is that in most cases Ringer Acetate is preferred over other types. Not only because of the small number of studies about anti-inflammatory effect in case of SAP, but also due to its relatively low cost and availability. It is a safe option to give Ringer’s as initial therapy as well as during maintenance.

32 Maybe the most controversial question is with regards to antibiotic usage as prophylaxis. The bulk of studies about prophylaxis shows that there are no evidence of reducing morbidity and mortality with antibiotics in severe acute pancreatitis [3]. It is possible to argue that in cases of sterile necrotizing pancreatitis which may develop into infected necrotizing pancreatitis, it could be useful. However, Dellinger et al showed no benefits in his study that was designed with most ill patients and very few flaws in the study [52].

As there is no good evidence supporting the use of antibiotic prophylaxis, clinicians should abstain from its use, due to its minimally therapeutic effect and weigh-in concerns over side effects and global antibiotic resistance issues.

An essential part of recovery from SAP is to restore gut barrier, mainly in order to prevent infections. The data suggests that starting enteral nutrition as soon as possible results in good prognosis. Historically, the mainstream nutritional approach was to let patients be in a fasted state, believing that it would protect the gut barrier but as with the prophylactic use of antibiotics, in recent times the recommendations have changed to start enteral nutrition.

It seems that the route of enteral nutrition is not so significant; it can either be nasogastric or naso-jejunal. The potential risks of aspiration in case of nasogastric was not supported in the data as described in the results. What is more important is when exactly to start the nutrition. The current understanding is that enteral nutrition can started as soon as possible after fluid resuscitation and stabilisation due to risk of mesenteric ischemia.

ACS is a complication that can further cause deterioration of gut barrier with increased permeability to an already vulnerable mucosa. What is clear that several strategies can be used to normalize the pressure, and in a step way fashion from conservative to surgical intervention can be applied. The data from Al-Bahrani et al ACS and IAP is a good predictor of mortality as well as ICU stay. The exact mechanism and reason of it is still not understood, De Waele considers that with IAP there is hypoperfusion to the tissue leading to necrosis of the pancreas..

As discussed previously, SAP is divided into two critical phases, the first one which develops within 2 weeks that results in organ dysfunction and failure causing the first mortality peak, and therefore giving the supportive treatment is the best approach. During the second critical phase where complications and infections occur, a multidisciplinary approach that involves interventional radiologists and surgeons with critical care in the centre a method for reducing mortality.

33

5.0 CONCLUSION

In SAP no curative treatment exists, instead the treatment is directed to support organ dysfunction. Critical points are to correct fluid balance with fluid resuscitation and pulmonary management with oxygen according to the state of patient. The management of SAP has been shifted from a past that involved aggressive approaches such as early surgical interventions, liberal antibiotics usage and aggressive fluid resuscitation to now follow a more restricted and conservative methodology. Enteral nutrition, antibiotics management of infections and pain are also critical areas that increase patient survival.

For the management of ACS giving fluids diligently and when the abdominal pressure is increased a step by step approach is necessary to decrease the pressure. The end goal is to correct fluid state and space occupying lesions in the abdomen. It is highly recommended that patients with infective necrotizing pancreatic wait at least 4 weeks for the necrosis to be walled of for surgical removal. A collaboration with surgical department is necessary for successful intervention.

34

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