View of A modern approach to the intensive treatment of patients with severe acute pancreatitis

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Department of

Anaesthetics and Surgical Intensive Care, Division of Surgery, University Medical Centre Ljubljana, Ljubljana, Slovenia

Correspondence/

Korespondenca:

Tomislav Mirkovič, e:

tommirkovic63@gmail.

com Key words:

severe acute pancreatitis;

pancreatic necrosis;

infection; inflammation;

multiorgan failure; ARDS;

protective ventilation;

intraabdominal hypertension; parenteral nutrition; enteral nutrition;

epidural analgesia;

minimal invasive operative procedures

Ključne besede:

hud akutni pankreatitis;

nekroza trebušne slinavke; okužba; vnetje;

odpoved organov; ARDS;

zaščitno predihavanje;

znotrajtrebušna

hipertenzija; parenteralna prehrana; enteralna prehrana; epiduralna analgezija; minimalno invazivni kirurški postopki en

10.6016/ZdravVestn.2886 doi

25.1.2018 date-received

16.10.2018 date-accepted

Microbiology and immunology Mikrobiologija in imunologija discipline

Professional article Strokovni članek article-type

A modern approach to the intensive treatment

of patients with severe acute pancreatitis Sodobni pristop k intenzivnemu zdravljenju bolnikov s hudim akutnim pankreatitisom

article-title A modern approach to the intensive treatment

of patients with severe acute pancreatitis Sodobni pristop k intenzivnemu zdravljenju bolnikov s hudim akutnim pankreatitisom

alt-title severe acute pancreatitis, pancreatic necrosis,

infection, inflammation, multiorgan failure, ARDS, protective ventilation, intraabdominal hipertension, parenteral nutrition, enteral nutrition, epidural analgesia, minimal invasive operative procedures

hud akutni pankreatitis, pankreatična nekroza, okužba, vnetje, odpoved organov, ARDS, protek- tivno predihavanje, intraabdominalna hipertenzija, parenteralna prehrana, enteralna prehrana, epiduralna analgezija, minimalno invazivni operativni postopki

kwd-group

The authors declare that there are no conflicts

of interest present. Avtorji so izjavili, da ne obstajajo nobeni

konkurenčni interesi. conflict

year volume first month last month first page last page

2019 88 7 8 385 402

name surname aff email

Tomislav Mirkovič 1 tommirkovic63@gmail.com

name surname aff

eng slo aff-id

Department of Anaesthetics and Surgical Intensive Care, Division of Surgery, University Medical Centre Ljubljana, Ljubljana, Slovenia

Klinični oddelek za

anesteziologijo in intenzivno terapijo operativnih strok, Kirurška klinika, Univerzitetni klinični center Ljubljana, Ljubljana, Slovenija

1

A modern approach to the intensive

treatment of patients with severe acute pancreatitis

Sodobni pristop k intenzivnemu zdravljenju bolnikov s hudim akutnim pankreatitisom

Tomislav Mirkovič

Abstract

Severe acute pancreatitis (SAP) is an acute inflammatory disorder of the pancreas which is associated with significant morbidity and mortality. The main characteristic of the disease is severe systemic inflammation which can be complicated by multiorgan failure and infection of pancreatic necrosis. Repeated assessment of the severity of SAP, based on clinical signs, intensive care monitoring, blood tests and imaging tools should be performed to determine the optimal way of treatment for each patient. Infectious complications in SAP are considerable problem and have an impact on outcome in patients who survived the first inflammatory hit of the disease. The diagnosis of infected pancreatic necrosis is often challenging. At this moment, the only rational indication for antibiotic treatment is documented infection. If the patient’s condition allows, enteral nutrition should be implemented, otherwise pareneteral or combined nutrition is advised.

Surgical treatment of SAP is nowadays delayed and includes minimally invasive techniques. The intensive care of SAP patients is oriented towards supportive treatment and prevention of complications.

Izvleček

Hud akutni pankreatitis (HAP) je akutna vnetna bolezen trebušne slinavke, ki je še vedno pov- ezana z visoko obolevnostjo in smrtnostjo. Glavna značilnost bolezni je hud sistemski vnetni odgovor organizma, ki velikokrat vodi v odpoved več organskih sistemov. Za oceno optimalnega načina zdravljenja je potreben individualni pristop, ki temelji na pozornem spremljanju kliničnih znakov, intenzivnem monitoriranju ter krvnih in slikovnih preiskavah. Infekcijski zapleti dodat- no otežijo potek bolezni in pomembno vplivajo na večjo smrtnost pri bolnikih, ki so preživeli prvo vnetno fazo bolezni. Diagnosticiranje okužene nekroze trebušne slinavke je pogosto težav- na naloga. Edina jasna indikacija za protimikrobno zdravljenje HAP je dokazana okužena nekroza trebušne slinavke. Če stanje bolnika omogoča, se ta hrani enteralno, v nasprotnem primeru pa parenteralno oziroma kombinirano. Sodobno kirurško zdravljenje HAP temelji na odloženih kirurških posegih, ki naj vključujejo različne minimalno invazivne tehnike. Intenzivno zdravljenje bolnikov s HAP obsega podporno zdravljenje ter preprečevanje zapletov.

Cite as/Citirajte kot: Mirkovič T. A modern approach to the intensive treatment of patients with severe acute pancreatitis. Zdrav Vestn. 2019;88(7–8):385–402.

DOI: https://doi.org/10.6016/ZdravVestn.2886

Slovenian Medical

Journal

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1 Introduction

Severe acute pancreatitis (SAP) is a dangerous acute inflammatory disorder of the pancreas which is associated with significant morbidity and mortality. Accord- ing to the data from some studies, mortality rate due to SAP can exceed 80% (1).

Between 2015 and 2018, 35 patients with SAP were treated at the Department of Anaesthetics and Surgical Intensive Care, Division of Surgery (University Medical Centre Ljubljana). During early stages it is characteristic that patients suffer from systemic inflammatory response syndrome (SIRS), which can cause multiorgan dysfunction syndrome (MODS), and result in multiorgan failure, (MOF). In later stages the disorder can cause complications with pancreatic infection, the pancreatic necrosis and sepsis. Decades ago the basic therapy for SAP was surgical, but in the past few decades the approach has changed. The reason for these changes was in numerous reports that point to a higher survival rate for patients who were treated with less invasive procedures or who were operated at a later stage (1,2,3).

2 Definitions and severity levels of AP

When talking about therapy for SAP, it bares first to divide pancreatitis by the severity of the disorder. The level of acute pancreatitis (AP) can be assessed based on two classifications; the so-called revised Atlantic classification (Table 1) and the

Received: 25. 1. 2018 Accepted: 16. 10. 2018

determinant-based severity classification (DBSC) (Table 2) (1).

Theoretically the second one has a better prediction value with regard to ex- pected mortality. However, the downside of DBSC is that it requires the assessment of the potential presence of necrosis, which can only be done using a comput- ed tomography (CT) scan with a contrast, which is often not yet required in the first couple of days. The morphological classification of AP includes three basic forms, which progress one into another: a), b) necrotizing, and c) haemorrhagic pancreatitis. Edematous pancreatitis is generally clinically mild, while the severities of the disorders with necrosis or haemorrhaging have dire clinical outlooks and frequent complications (1).

3 Aetiology

AP is most frequently caused by devel- opments in the gall bladder (biliary aetiology) or from alcohol abuse (alcoholic aetiology). In a lesser percentage AP is the result of closures of the pancreatic ducts or the ampulla of Vater, duodenum disorders, injuries, infections (AIDS), blood supply disorders, hyperparathyroidism, hyperlipidaemia, diabetic coma, pregnancy, allergies and autoimmune disorders, medication and toxins, hereditary factors, reactions to procedures (e.g. ERCP and ERP) (4).

Table 1: Revised Atlantic division of AP.

Mild AP Moderate AP Strong AP

both criteria one or another criteria Failure of the organ

system Absent temporary

(< 48h) permanent

(> 48h) Local and systemic

complications Absent present (usually present – not

required for the division)

Table 2: The division is based on determinants – DBSC.

Determinant Mild AP Moderate AP Strong AP Critical AP

both criteria one or another

criteria Any measurement both criteria Local no necrosis sterile necrosis infected necrosis infected necrosis

Systemic no organ

dysfunction temporary (< 48h)

organ dysfunction permanent (> 48h)

organ dysfunction permanent (> 48h) organ dysfunction

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4 Pathogenesis

The pathogenesis of AP is only partial- ly explained. Under normal conditions the parenchymal acinus cells of the pancreas have well secured inactive proteolytic enzymes (functional protein) in the zymo- gen granule. In the inactive form they are maintained by numerous safety mechanisms that prevent automatic activation of these enzymes (α-1-antitrypsin). When this defence fails, the triggering factors ac- tivate small amounts of trypsinogen in the ducts of the pancreas, which is followed by a rapid chain reaction with the activation of phospholipases A2, collagenase, elas- tase, chymotrypsin, and kallikreins. This is followed by damage to the structural lipo- proteins of the cell membranes, then au- to-digestion of acinar cells, vein structures and fat, which additionally releases and activates large amounts of proteases and lipases. This results in necrosis of smaller and larger lobules and the lipolysis (stea- tonecrosis). The inflammation process can easily spread across the anatomical bor- ders of the pancreas, as it does not have its own fascia (Figure 1) (5).

In the event of a blockage to the duct from the pancreas and the biliary ducts, the components of bile also participate in the pathogenesis of pancreatitis, as shown in Figure 2 (5).

A product of the proteolysis are va- soactive amines that are toxic for remote organs (heart, lungs, kidneys), and are responsible for the onset of clinical signs, characteristic of SIRS (hypotension, tachy- cardia, fever) (Figure 3) (6).

5 Identification and treatment of the dysfunction of organ systems

5.1 Cardiovascular system

Generally patients with SAP are hemo- dynamically unstable, which means that a patient has to be monitored and treated from the onset of the disorder (1,6).

A precise and focused clinical examination is not reliable enough, but it does allow for a more correct and rational use of the most precise and often more invasive methods of hemodynamic monitoring.

The objective of detailed haemodynamic monitoring is to assess artery pressure and ascertain whether it is sufficient, to assess the blood flow and ascertain whether it is sufficient, to assess cardiac filling volume and the cardiac function, as SIRS, which is present since the onset of SAP, affects all of the above parameters of the cardiovascular system. The basic objective of treating hemodynamic instability is ensuring sufficient oxygen transfer and normal operation of the organs. A focused clinical examination should be enhanced with laboratory blood analysis, ultrasound examination (UE) of the heart and by using the more invasive methods of hemodynamic monitoring that aim to ascertain the operation of the heart, the status of liquids, the flow and whether it is sufficient.

Clinical assessment is used to assess blood pressure (central and peripheral pulses are possible when the blood pressure is at least 50 mmHg), how the right determinant-based severity classification

(DBSC) (Table 2) (1).

Theoretically the second one has a better prediction value with regard to ex- pected mortality. However, the downside of DBSC is that it requires the assessment of the potential presence of necrosis, which can only be done using a comput- ed tomography (CT) scan with a contrast, which is often not yet required in the first couple of days. The morphological classification of AP includes three basic forms, which progress one into another: a), b) necrotizing, and c) haemorrhagic pancreatitis. Edematous pancreatitis is generally clinically mild, while the severities of the disorders with necrosis or haemorrhaging have dire clinical outlooks and frequent complications (1).

3 Aetiology

AP is most frequently caused by devel- opments in the gall bladder (biliary aetiology) or from alcohol abuse (alcoholic aetiology). In a lesser percentage AP is the result of closures of the pancreatic ducts or the ampulla of Vater, duodenum disorders, injuries, infections (AIDS), blood supply disorders, hyperparathyroidism, hyperlipidaemia, diabetic coma, pregnancy, allergies and autoimmune disorders, medication and toxins, hereditary factors, reactions to procedures (e.g. ERCP and ERP) (4).

Table 1: Revised Atlantic division of AP.

Mild AP Moderate AP Strong AP

both criteria one or another criteria Failure of the organ

system Absent temporary

(< 48h) permanent

(> 48h) Local and systemic

complications Absent present (usually present – not

required for the division)

Table 2: The division is based on determinants – DBSC.

Determinant Mild AP Moderate AP Strong AP Critical AP

both criteria one or another

criteria Any measurement both criteria Local no necrosis sterile necrosis infected necrosis infected necrosis

Systemic no organ

dysfunction temporary (< 48h)

organ dysfunction permanent (> 48h)

organ dysfunction permanent (> 48h) organ dysfunction

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chamber fills up (by observing the pulsa- tion of the internal jugular veins we can assess the central venal pressure (CVP) – a poor indicator of responsiveness to liquids), how the left chamber fills with blood (it is not clinically yet possible to measure pressure in the left pre-chamber reliably – we can find a congestion in the lungs or the presence of the third heart sound, which both point to high blood pressure, however, this method has proven to be unreliable with critically ill patients), the sufficiency of the blood flow (flow through the skin – temperature and the colour of

the skin, capillary filling up, flow through the central nervous system – disturbances of the consciousness; flow through the kidneys – assessment of hourly diuresis, cardiac output – disturbances to the heart rate and/or stenocardia). With additional laboratory and biochemical analyses of the arterial and venal blood we can get a more detailed insight into oxygen delivery (DO₂), i.e. haemoglobin concentrations, PaO₂ and SaO₂ in the superior vena cava – ScvO₂; a potential insight into the aetiology of the haemodynamic instability – low Hb (anaemia, bleeding), increased troponin and/or proBNP (heart failure), increased inflammation markers (sepsis); and to the effect on various organs or organ systems (nitrogen retention, liver tests, blood coagulation tests, etc.) (7). Ev- ery patient with suspected haemodynamic instability is also given an EKG (objective overview of possible heart palpitations or ischemia of the heart muscle), and a ra- diography image of the chest organs (objective overview of possible signs of heart failure or increased permeability of the al- veolocapillary membrane) (7).

When we establish a patient has haemodynamic instability (clinical signs, hypotension, increased lactate, lower values of ScvO₂), we have to select the tests that will allow us to better determine the patient’s conditions. Selecting the method of haemodynamic monitoring depends on the patient’s condition, available equip- ment, knowledge and skills of the staff in the department. Regardless of the method we have to find the answers to the following questions after a detailed haemodynamic assessment:

1. What is the arterial pressure, and is it sufficient?

2. What is the blood flow, and is it sufficient?

3. What is the cardiac function?

4. What is the cardiac filling volume, and is it sufficient?

Ad 1. The lowest value of arterial pressure that supports sufficient blood supply Figure 1: Causal factor and the pathogenesis of AP (summed up from

Creutzfeld and Lankisch).

Figure 2: Effect of the gall on the pancreas (summed up from Creutzfeld and Lankisch).

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to the organs must be determined for each individual patient. With haemodynam- ically unstable patients we recommend continuous invasive monitoring in the peripheral or central artery (8).

Ad 2. Global blood flow is the cardiac output (CO) in a minute which can be measured fairly easily using several methods. Usually we begin with the estimate of the blood flow with an ultrasound of the heart, however, this does not support continuous measurement. Among the bedside methods intensive care units most frequently apply the thermodilution method and the pulse waveform analysis method.

Thermodilution is the most frequent bedside method for measuring CO. With regard to the position of the measuring catheter we separate them into pulmonary thermodilution (pulmonary artery – Swan-Ganz – catheterization, PAC), where we inject a bolus of cold fluid into the central vein, while blood temperature is monitored in the pulmonary artery; and

the transpulmonary thermodilution (e.g.

PiCCO™, VolumeView™), where we inject a bolus of cold fluid into the central vein, so that it travels through the right heart and the pulmonary circulation to the left heart, while the temperature is monitored in one of the major arteries. In a similar way CO is also measured by the LiDCO™

system, except that it uses lithium instead of thermodilution. This CO measurement method requires invasive procedures – catheterization of the right heart (PAC) or catheterization of the central vein and one of the major arteries (PiCCO™, Vol- umeView™), while LiDCO™ technology also permits cannulation of the minor peripheral artery. Various methods have been developed to assess stroke volume (SV) using the analysis of the artery pulse waveform, of which the most important ones are the Windkessel model and the Fourier transform, which take into account resistance, capacity, impedance and the inertia of the venal system. This way we can fairly reliably assess or calculate the SV. We require a quality artery signal, which depends on the actual SV, the me- chanic characteristics of the artery system, the location of the measurement (central/

peripheral artery) and the measurement’s accuracy. The SV calculated using this method is the actual SV. The PiCCO™ and EV1000™ systems measure CO this way between beats. Both require occasional calibration with transpulmonary thermodilution. Some systems (e.g. Flotrack Vig- ileo, LiDCO rapid, etc.) measure CO con- tinuously by analysing the arterial pulse waveform, and do not require calibration.

This method of measuring CO is less invasive, as it requires only the peripheral arterial line (10).

Ad 3 The cardiac function is also indi- rectly expressed by the measured cardiac output in a minute, however, the dimen- sions of heart chambers, the functions of both ventricles, heart valves and the peri- cardium can only be assessed by taking an ultrasound. It is also important to as- the skin, capillary filling up, flow through

the central nervous system – disturbances of the consciousness; flow through the kidneys – assessment of hourly diuresis, cardiac output – disturbances to the heart rate and/or stenocardia). With additional laboratory and biochemical analyses of the arterial and venal blood we can get a more detailed insight into oxygen delivery (DO₂), i.e. haemoglobin concentrations, PaO₂ and SaO₂ in the superior vena cava – ScvO₂; a potential insight into the aetiology of the haemodynamic instability – low Hb (anaemia, bleeding), increased troponin and/or proBNP (heart failure), increased inflammation markers (sepsis); and to the effect on various organs or organ systems (nitrogen retention, liver tests, blood coagulation tests, etc.) (7). Ev- ery patient with suspected haemodynamic instability is also given an EKG (objective overview of possible heart palpitations or ischemia of the heart muscle), and a ra- diography image of the chest organs (objective overview of possible signs of heart failure or increased permeability of the al- veolocapillary membrane) (7).

When we establish a patient has haemodynamic instability (clinical signs, hypotension, increased lactate, lower values of ScvO₂), we have to select the tests that will allow us to better determine the patient’s conditions. Selecting the method of haemodynamic monitoring depends on the patient’s condition, available equip- ment, knowledge and skills of the staff in the department. Regardless of the method we have to find the answers to the following questions after a detailed haemodynamic assessment:

1. What is the arterial pressure, and is it sufficient?

2. What is the blood flow, and is it sufficient?

3. What is the cardiac function?

4. What is the cardiac filling volume, and is it sufficient?

Ad 1. The lowest value of arterial pressure that supports sufficient blood supply Figure 1: Causal factor and the pathogenesis of AP (summed up from

Creutzfeld and Lankisch).

Figure 2: Effect of the gall on the pancreas (summed up from Creutzfeld and Lankisch).

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certain whether the heart retains enough cardiac output only due to higher filling pressure (heart failure) (7).

Ad 4 Most systems that support measuring cardiac filling volume (PiCCO™, EV1000™, LiDCO™), also make it possible to set numerous volume and pressure indicators of cardiac filling, both dynamic (stroke volume variability, SVV, pulse pressure variability, PPV) and static (global end-diastolic volume, GEDV and intra- thoracic blood volume, ITBV).

With this method of monitoring a haemodynamic unstable patient, we can ob- tain good data for how much volume a patient requires, and whether the patient requires additional inotrope and/or vaso- active support for maintaining a satisfactory filling volume. The objective of treating a haemodynamic unstable patient is to normalize their oxygen transfer as soon as possible (the golden hour rule). Insuffi- cient fluid or fluid overload can additionally accelerate the process of organ failure, which has a high correlation with early mortality (10,11,12). Fluid overload used to be practised, but is no longer accept- able due to numerous negative effects and consequential complications (increased intra-abdominal hypertension – IAH, hy- perchloremic acidosis, ARDS). Consid- ering the data from randomized control studies, a conservative fluid therapy is correlated with lower mortality rate (OR 0.4) and lower occurrence of organ failure (OR 0.69) compared to the more liberal approach of supplying fluids (3). We can use dynamic filling parameters, such as SVV and PPV, for assistance, as they are better indicators of right heart filling than the static parameters, and which are constant- ly calculated using the above techniques, when the patients are mechanically ventilated and have rhythmic cardiac activity (10,14,15). The International Association of Pancreatology (IAP) and American Pancreatic Association (APA) recommend the use of balanced electrolyte infusions.

The results of some studies show that the

Figure 3: Pathophysiology of acute pancreatitis.

Legend: IL-1, IL-6, IL-8, IL-10, IL-11 – interleukins, NO – nitrous monoxide, PAF – platelets activation factor, SIRS – systemic inflammatory response syndrome, ARDS – acute respiratory distress syndrome.

use of colloid solutions is related to increased mortality rate among SAP patients (16-18).

5.2 Ventilation

Acute respiratory distress syndrome (ARDS) with SAP is most commonly a combination of the hypoxemic and hypercapnic respiratory failure. Hypoxemia is the result of a damage to the capillary endothelium, and in the case of aspiration, also to the alveolar epithelium, which leads to the development of ARDS. These changes are the pathophysiological basis for the onset of a discrepancy between ventilation and perfusion for lowering the diffusion capacity of oxygen and for the onset of a right-left intrapulmonary shunt.

On the other hand, the onset of ileus, ascites and tympanites of the gut is increased by intra-abdominal pressure (IAP), which together with pleural effusions lowers the lung compliance. All of this increases the breathing effort, leading to exhaustion of muscles of respiration and the onset of hypercapnic respiratory failure. Patients with SAP suffer severe pain, and consequently using strong opioid pain killers can cause a depression of the respiratory centre and can consequently worsen the hypercapnia in ARDS. With mild forms of AP the patient can be helped with non-invasive ventilation, however, only in the case of hypoxemic ARDS, while for patients with SAP the ventilation support is mostly invasive and completely based on algorithms that were based on protective ventilation. All the approaches generally used with patients with ARDS for setting the parameters for protective ventilation (see below) can also be used with patients with ARDS resulting from SAP. Turning the patient to the stomach can be relative- ly contraindicative if they have high IAP or after stomach surgery, therefore treatment is continued using only continuous monitoring of the negative pressure – vacuum assisted closure (VAC) therapy. The

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primary goal of mechanical ventilation of an ARDS patient is to ensure appropriate exchange of gases and lower the risk for ventilatory induced lung injury (VILI).

Both pharmacological (muscle relaxation using neuro-muscular blocking agents, NMBA, inhalation vasodilators, cortico- steroids), and non-pharmacological strategies (lung recruitment manoeuvre, positive end expiratory pressure, PEEPa) are used to achieve this goal, as well as setting the respiratory volume, targeted O₂ and CO₂ with protected ventilation strategy, turning the patient on the stomach and the assistance of the extracorporeal membrane oxygenation (ECMO).

Gravity is the main reason for the col- laboration of the dorsal part of the pulmonary parenchyma in a patient with ARDS. This occurrence is even more expressed with extrapulmonary ARDS, such as with SAP, where a raised diaphragm squeezes the lungs even more because of the increased IAP. IAH has a major effect on both the lungs and the complete respiratory system, as well as other peripheral

organs. With increased permeability of the pulmonary capillaries, which is already present at ARDS, IAH can further increase damage to the lungs and the oe- dema, decreasing pulmonary drainage and increasing the pressure in the chest cavity. This can lead to the onset of atelectasis of the lungs and the closure of the small respiratory pathways, and can worsen the mechanics of respiration and gas exchange. Between each breathing cy- cle the pulmonary tissue in these areas is opened during breathing in, and collapses during breathing out, leading to the onset of atelectotrauma. Talmor et al described the protocol for setting positive pressure at the end of the positive end-expiratory pressure (PEEP) by using the trans-pul- monal pressure (P_TP). P_TP is the difference between the pressure in the airflow pathways (P_DP) and the pressure in the oesophagus (P_ESO) and must have a positive value when breathing out is concluded in order to stop the collapse of the pulmonary tissue and the start of the atelectasis in the back side of the lungs (21). The pressure in certain whether the heart retains enough

cardiac output only due to higher filling pressure (heart failure) (7).

Ad 4 Most systems that support measuring cardiac filling volume (PiCCO™, EV1000™, LiDCO™), also make it possible to set numerous volume and pressure indicators of cardiac filling, both dynamic (stroke volume variability, SVV, pulse pressure variability, PPV) and static (global end-diastolic volume, GEDV and intra- thoracic blood volume, ITBV).

With this method of monitoring a haemodynamic unstable patient, we can ob- tain good data for how much volume a patient requires, and whether the patient requires additional inotrope and/or vaso- active support for maintaining a satisfactory filling volume. The objective of treating a haemodynamic unstable patient is to normalize their oxygen transfer as soon as possible (the golden hour rule). Insuffi- cient fluid or fluid overload can additionally accelerate the process of organ failure, which has a high correlation with early mortality (10,11,12). Fluid overload used to be practised, but is no longer accept- able due to numerous negative effects and consequential complications (increased intra-abdominal hypertension – IAH, hy- perchloremic acidosis, ARDS). Consid- ering the data from randomized control studies, a conservative fluid therapy is correlated with lower mortality rate (OR 0.4) and lower occurrence of organ failure (OR 0.69) compared to the more liberal approach of supplying fluids (3). We can use dynamic filling parameters, such as SVV and PPV, for assistance, as they are better indicators of right heart filling than the static parameters, and which are constant- ly calculated using the above techniques, when the patients are mechanically ventilated and have rhythmic cardiac activity (10,14,15). The International Association of Pancreatology (IAP) and American Pancreatic Association (APA) recommend the use of balanced electrolyte infusions.

The results of some studies show that the

Figure 3: Pathophysiology of acute pancreatitis.

Legend: IL-1, IL-6, IL-8, IL-10, IL-11 – interleukins, NO – nitrous monoxide, PAF – platelets activation factor, SIRS – systemic inflammatory response syndrome, ARDS – acute respiratory distress syndrome.

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the oesophagus is usually measured at the heart level and mirrors the pressure in the surrounding pulmonary tissue. The pressure in the oesophagus is not the same as the pressure in the pleural cave, however, the pressure values are very well reflected in the changes to the pressure in the pleural cavity. This Talmore study PEEP was set by having P_TP with a positive value at the end of the blow-out, improves oxygenation, lung compliance, respiratory system compliance, and the cumulative survival when compared to the conventional protocol, which was based on using the AR- DS.net tables for PaO₂/ FiO₂ (22). At the moment there is no sufficient data nor any randomized studies on how to treat AR- DS patients with IAH, even though a few good recommendations were made. The optimally set parameters of the ventilation of patients with ARDS and IAH should include the following:

1. measuring intra-abdominal pressure and the pressure in the oesophagus and hemodynamic monitoring;

2. setting parameters for ventilation with a protective breathing volume by using recruitment manoeuvres and setting the PEEP values to achieve the best compliance of the respiratory system or the lungs.

3. deep sedation with neuromuscular pa- ralysis or without with severe ARDS;

4. opening the stomach with patients who show the signs of the abdominal compartment syndrome (ACS) (23,25).

5.3 Intra-abdominal hypertension (IAH)

The occurrence rate of IAH with SAP is between 60% and 85%, therefore measuring intra-abdominal pressure is recommended for every patient with SAP who is admitted into the intensive care unit (24,25). The main reasons for the onset of IAH are the process of infection in the retroperitoneal space, the onset of ascites and the development of ileus. The World

society for abdominal compartment syndrome – WSACS describes the 4 stages of IAH as follows (25):

1st stage: IAP of 12–15 mmHg;

2nd stage: IAP 16–20 mmHg;

3rd stage: IAP 21–25 mmHg;

4th stage: IAP above 25 mmHg.

Normal activity of abdominal organs requires abdominal perfusion pressure (APP) of 60 mmHg or above. APP is the difference between the mean artery pressure (MAP) and the intra-abdominal pressure (IAP) (APP = MAP–IAP). Ab- dominal compartment syndrome (ACS) occurs when IAP is above 20 mmHg with APP ≤ 60 mmHg, and along with both of these factors, at least one abdominal organ must be failing, most frequently the kidneys (25). The second important factor is the speed of IAH onset. With acute development ACS can occur with lower IAP and APP values and in within just a few hours. When IAH develops over a few weeks or months (with pregnancy or obesity), ACS does not occur. Patients with SAP should have their IAP measured every 5 to 6 hours. In day-to-day practice IAP is measured using additional pressure converters connected to the urine catheter. An alternative approach is inserting an additional “balloon catheter” in the stomach or inserting a NutriVent™ probe. This probe measures pressure in the oesophagus (P_ESO), which is needed to calculate the transpulmonary pressure P_TP and gastric pressure (P_GA), which represents intra-abdominal pressure (26). By using non-surgical techniques we have to maintain IAP

≤ 15 mmHG, APP ≥ 60 mmHg, and make sure there are no signs of abdominal organ failure.

Non-surgical techniques are:

1. Improving abdominal wall compliance:

• sufficient analgesia and/or sedation,

• tilting the body by no more than 20 °,

• using the Trendelenburg position (if possible),

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• using NMBA.

2. Removing the content from intra-abdominal cavities:

• gastric and/or intestinal decompression by inserting a gastric (NGS) or intestinal tube,

• using prokinetic agents,

• using enema,

• decreasing or forgoing enteral feeding,

• colonoscope decompression of the large intestine,

• inserting urine catheter.

3. Optimizing fluid treatment:

• limiting the amount of absorbed liquids,

• giving diuretic to haemodynamic stable patients,

• in the event of a oliguric or anuria ALO supplemental therapy with hae- modialysis is needed.

4. Optimization of the system and regional blood flow:

• constant haemodynamic monitoring for the optimization of the volume burden and using inotropic or vasoac- tive drugs for optimum oxygen transfer;• optimum ventilation (see chapter 5.2).

Surgical procedures with decompression have to be undertaken with the onset of the secondary ACS, where IAT is above 20 mmHg in spite of non-surgical therapy, and there are signs of abdominal organ failure. Surgical laparostomy should be performed as a median laparotomy, or preferably as transverse bilateral laparotomy (27,28). Currently three different techniques are used for temporal laparotomy:

a) skin closure technique; b) fascia closure technique; c) vacuum-assisted closure technique (VAC).

5.4 Monitoring the infection

More than 80% of fatalities among SAP patients are the result of a secondary infection to the pancreas and/or necrosis

near the pancreas (29). The main source of these infections are intestinal micro- biota, which enter/invade the pancreatic tissue from the hyper-permeable intestines during the systemic infection. The most frequent pathogens are E.Coli (26%), Pseudomonas spp. (16%), Staphylococcus spp. (15%), Klebsiella spp. (10%), Prote- us spp. (10%), Streptococcus spp. (4%), Enterococcus spp. and anaerobic bacteria (16%). As a rule the fungal superinfection occurs later in the development of the disease, usually within a few weeks or even months after the infection (16).

At the moment we do not have sufficient data on the efficiency of prophylactic antibiotic treatment (30). In the summary article by Villatora et al., which took into account 7 randomised studies on 404 patients, they did not find any visible differences in mortality between patients who received prophylactic antibiotics and those who received placebo (8.4% versus 14.4%, NS). There were also no differences in the number of infected necrosis between both groups (19.7% versus 24.4%, NS). They did prove that the group with antibiotic protection had a statistically significantly lower share of total infections (37.5% versus 51.9%). There were also no differences between the groups in the need for surgical therapy and the frequency of fungal infections. When patient groups were compared by antibiotic groups they received, they found that when using a combination of fluoroquinolones with metronidazole there were no differences in mortality rates, the frequency of pancreatic necrosis infections and the frequency of total infections. In patients who received protective antibiotic treatment with imipenem there was a statistically significant lower frequency of pancreatic necrosis infections, however, this did not have a significant impact on survival rates. Consequently the authors find that there is currently not enough quality data on the use of antibiotics in acute pancreatitis for prophylaxis (31). In 2012 another meta-analysis was

(10)

published, which included 622 patients with SAP from 11 randomised studies.

This study did also not confirm a positive effect of prophylactic antibiotic use on survival rates. It was estimated that 1,429 patients would have to have been treated in order to prevent one death (32). Wittau et al. reached similar conclusions, when they included 14 randomised studies with 841 patients in their meta-analysis. They found that mortality, frequency of pancreatic necrosis infections, frequency of nonpancreatic infections and the number of surgical measures are comparable between the group of patients who were receiving antibiotic protection and the control group (30). In a prospective randomized study Maraví-Poma et al. proved a 3-fold increase of occurrence of local and systemic fungal infections in patients with acute pancreatitis who have been receiving antibiotic protection for a longer period of time (33). Excessive use of antibiotics is also tied to the onset of antibiotic-related diarrhoea or diarrhoea caused by Clostridium difficile and a selection of bacteria resistant to numerous antibiotics.

Considering all this data we can assume that poor efficiency of antibiotic prophylaxis and its unwanted effects supersede the positive ones, therefore prophylaxis is not used routinely (34). Antibiotics are only used when there is a serious indication of an infection or a proven infection (16). In the first 7 to 10 days antibiotics are not prescribed for treating complications related to the acute pancreatitis, but for treating other infections, such as cholangitis, infections related to venal catheters, bacteraemia, infections to the urinary system or pneumonia. Clinically speaking it is very difficult to differentiate between a sterile and an infected necrosis. We con- sider the infection of pancreatic necrosis and surrounding tissue when we have a patient whose clinical picture is not in remission after 7–10 days or if they have SIRS. With such a patient it makes sense to conduct a CT-guided needle aspiration

to collect infectious material, and then begin antibiotic therapy. We speak of infected pancreatic necrosis when we prove the presence of bacteria in the aspirate or when inclusions of air are visible on CT in necrotic areas. If a percutaneous drainage is planned to treat local procedures, a CT-guided aspirate puncture is not required separately. Antibiotic therapy is often combined with surgical therapy.

At the moment there is not enough quality data to allow for solid recommendations regarding types of experienced antibiotic therapy of infected pancreatic necrosis. More studies are focused on the analysis of antibiotics entering the pancreatic tissue. Imipenem and ertapenem are good at permeating the tissue of the pancreas, where they achieve concentrations above the minimum inhibition con- centration for the most frequent infection agents with acute pancreatitis (35,36).

Similar data is available also for moxiflox- acin (37). When the effectiveness of these antibiotics against bacteria that were often isolated from pancreatic necrosis (E. coli, Enterobacter cloacae, Enterococcus faecalis and Bacteroides fragilis) was compared in vitro on the model of acute pancreatitis, it was discovered that all three antibiotics are similarly effective, however that moxi- floxacin is more effective against E. cloa- cae, E. faecalis and anaerobic bacteria in mixed cultures. Ertapenem was ineffective against enterococcus (38). Detailed data on therapy duration is not yet available.

Most authors recommend therapy be continued for at least 14 days after the remov- al of the source of infection (16,34,39).

Mortality rates of patients with SAP and an infected necrosis of the pancreas are up to 30%. In most cases, up to 80%, it is the result of septic complications.

When we have patients with infected pancreatic necrosis and multi-organ failure, who were treated without additional surgical procedures, the mortality rate nears 100% (40). Including surgical treatment lowers the mortality rate. Dutch research-

(11)

ers showed that the survival rate is better with those patients where the levelled surgical approach was used (percutaneous drainage or endoscopic transluminal drainage, followed by a minimally invasive retroperitoneal necrosectomy) than with those patients where open necrosectomy was performed. If possible, it is sensible to postpone surgical procedures at least until the 4th week after the onset of a characteristic clinical picture in order to have a limitation of necrosis with granular tissue or fascia (41). Pancreatic abscesses occur late in the course of the disease; for most a percutaneous drainage in combination with antibiotic treatment suffices. If we cannot achieve clinical improvement and the abscess remains, surgical drainage is required. When SAP is connected with cholangitis, an endoscopic retrograde cholangiopancreatography (ERCP) is obligatory, while for other biliary pancreatitis types there is not enough data to determine an appropriate period when ERCP should be performed (16).

The most frequent complications related to the infections that occur after surgical necrosectomy are additional infections of the remaining pancreatic tissue and other frequent hospital infections (e.g. pneumonia related to mechanical ventilation, infections, related to central catheters, etc.).

Behraman et al. described the occurrence of postoperative pancreatic infection with patients who had elective resection of the necrosis of the pancreas. Among these the polymicrobial infections were only noticed in 55% of the patients. Long-term use of vancomycin leads to vancomycin-resistant enterococcus.

5.5 Nutrition

The debate on appropriate and optimum nutrition for treating SAP has been going on for decades. The so-called bowl-at-rest strategy was conventionally introduced in SAP therapy more than 30 years ago, and is outdated now (43-45).

Regardless, dietary restrictions worsen the patient’s undernourishment due to the imbalance between the lower food intake and the higher nutritional requirements during the course of the disease, which further leads towards increased catab- olism, bacterial translocations (46) and even death (47). Evidence from clinical studies has shown that parenteral nutrition (PN) blocks the stimulation of the pancreas, while enteral nutrition (EN) has many other advantages. It is, however, difficult to predict in day-to-day practice whether patients with SAP will handle EN well (48). By introducing additional nutritional supplements they attempted to provide additional immunoregulatory and antioxidative effects. It was proven that probiotics and prebiotics help stabilize disturbances in the intestinal wall. Regardless, there is no solid proof that probiotics lower the mortality rate in those critically ill (49,50). Immunonutrients (e.g. glutamine and omega-3 fatty acids) were added into parenteral and enteral formulas because of the immunosuppressive and infectious na- ture of the disease itself in order to mod- ulate immunity functions, lower the excessive infection response and re-establish homeostasis in tissues and organs (51,52).

Additives with antioxidative properties, such as glutamine and vitamin C, also provide additional beneficiary effects on the course of the disease (53). In the meta-analysis by Yao- H. et al. which compared PN with EN on SAP patients, EN was correlated with a significant decrease of total mortality rate (risk ratio (RR) = 0.36, 95% confidence interval (CI) 0.20–

0.65, P = 0,001) and a lower multi-organ failure rate (RR = 0.39, 95% CI 0.21–0.73, P = 0,003). The analysis is concluded with the finding that EN should be the primary nutrition method for critically ill SAP patients (54). If the patient cannot cope with oral feeding, which is most common with SAP, they should be receive enteral nutrition through a nasogastric or nasojejunal feeding tube. PN should be decreased be-

(12)

cause of risk of infection and other related complications. Only if the enteral path is not available or the patient is responding poorly to it, should PN be introduced. In general nutritional support has a major significance in clinical treatment of SAP, even though the optimum feeding time remains uncertain. As the current assessment system is not yet completed, it is difficult to predict nutritional tolerance with SAP patients. Different nutritional supplements in combination with PN, EN and the current clinical possibilities are an interesting topic for further research, and could lead to new promising results (55).

Another meta-analysis compared early (during the first 48 hours – EEN) and late (after 48 hours – LEN) enteral nutrition.

The authors concluded that for SAP patients EEN is more significant than LEN.

However, more studies should be done in this field in order to confirm these result with greater certainty (56). Nutritional instructions for a SAP patient are also included in the EPSEN guidelines (57):

1. energy 25–35 kcal/kg BM/day;

2. 1.2–1.5 g protein/kg BM/day;

3. 3–6 g carbohydrates/kg BM/day in order to achieve a blood glucose concen- tration of between 6 an 10 mmol/L;

4. up to 2 g of lipids/kg BM/day, until blood triglyceride level below 12 mmol/L is achieved

5.6 Monitoring the pain

Pain is the main sign of acute pancreatitis, and one of the main reasons for ad- mitting patients into various hospital de- partments (58-60). At the moment there are no major studies on the pharmacol- ogy of monitoring the pain in acute pancreatitis, which is somewhat surprising, as pain is an important symptom in the development of the disease. There is also no sufficient evidence of the effectiveness of various pharmacological substances that are used for treating various types of acute pancreatitis. The most frequent-

ly used substances and techniques for treating acute pancreatitis: a) nonsteroidal anti-inflammatory drugs (NSAID); b) var- ious opioid substances; and c) epidural an- aesthesia which is becoming increasingly popular according to recent studies. For intravenous pain relief the currently recommended treatment is a multimodal approach for treating severe pain in SAP as a combination of opioid substances (fentanyl, sufentanil, piritramide, etc.), NSAID and paracetamol, except when they are contraindicated in these combinations.

This is especially true for renal insufficien- cy, when opioid substances or their active metabolites accumulate.

As regard to pain relief using NSAID for acute pancreatitis, literature is full of contradictions. On the one side there are various reports on the possibility that NDAID can even cause acute pancreatitis (61-64). On the other side NSAID was used for preventing acute pancreatitis caused by ERCP. In the meta-analysis conducted by Pezzilli R et al. authors strove to answer the following questions:

can NSAIDs cause acute pancreatitis or is their prophylactic use capable of preventing acute pancreatitis from ERCP, and whether these drugs are capable of reliev- ing pain in acute pancreatitis. They came to several conclusions:

• by using NSAID there is a level of risk for the onset of acute pancreatitis, therefore it appears in clinical practice that naproxen is the primary analgesic, as it has the lowest possibility for the onset of acute pancreatitis;

• both diclophenac and indometacin can significantly reduce the risk for the onset of acute pancreatitis after ERCP, resulting in bigger clinical and economic benefits;

• it should be noted: NSAID can provide a satisfactory level of pain relief to patients with AP (66).

However, further clinical studies are required to determine the best NSAID to be used in clinical practice.

(13)

Next case is using diclophenac. This drug is mostly used for pain relief in acute pancreatitis. It is useful in preventing pancreatitis after ERCP, but it is believed to be the main drug from the NSAID group responsible for causing acute pancreatitis in the general population (65,66).

With SAP severe pain is always present.

There is a large selection of drugs for pain relief. Strong analgesics from the group of opioid analgesics are also additionally used. Analgesics are often supplied to the patient through infusion fluids or through the epidural catheter. Sometimes a patient can adjust their own analgesic dosage, and this is also why such an approach to therapy is called patient-controlled analgesia – PCA. With this method the chance of overdosing an individual drug is less likely.

Opioids seem a suitable choice for treating the severe pain in SAP. Com- pared to other analgesics they can lower the need for additional analgesia. There is currently no difference regarding risk for pancreatitis complications or clinically serious undesirable events between opioids and other types of analgesia. The recently published meta-analysis on AP included at least 5 randomised studies and a total of 227 patients (aged between 23 and 76, of whom 65% were men) (67). The following opioids were included in the study:

buprenorphine (intravenously or intramuscularly), pethidine (intramuscularly), pentazocine (intravenously), fentanyl (transdermally) and morphine (subcutaneously). Buprenorphine is a non-narcotic analgesic with better effects than procaine, and unlike procaine it does not worsen AP, as it does not cause the sphincter of Oddi dysfunction (68). Buprenorphine has similar analgesic effects as pethidine.

One randomised study, which compared subcutaneously injected morphine and intravenously injected metamizole, did not report on any significant decrease in pain intensity (primary result) (RR 0.50, 95%

CI from 0.19 to 1.33) (68). These studies compared analgesia among opioid agents

and nonopioid agents. After excluding one study in which opioids were used with a continuous intravenous infusion, the number of patients who required additional analgesia (RR 0.53, 95% CI from 0.3 to 0.93). Only one study did not mark a difference in the need for additional analgesics among patients who received buprenorphine or pethidine (RR 0.82, 95% CI from 0.61 to 1.10). None of the tested drugs caused any additional complications related to pancreatitis, nor were there any serious clinical or life-threaten- ing events. There were also no differences found between treatment with opioids and non-opioids, or between a the types of unwanted events (nausea, vomiting and sleepiness after sedation). All of studies noted a total of one death using procaine (68). One randomised study which compared pethidine with intramuscularly injected buprenorphine, reported on in- significant differences with an additional analgesic, undesired events and survival rates. The second randomised research, which compared fentanyl with placebo, did not find any difference in undesired events.

Epidural anaesthesia (EA) is frequent- ly used to trigger analgesia during operation, as well as for pain relief on patients with SAP (69). Experimental studies also showed a specially favourable effect of EA on SAP patients, which was attributed to blocking the sympathetic nerve, which causes a redistribution of the splanchnic blood flow with increased blood flow in- to the parts of the pancreas that otherwise have none (70,71).

The first randomised study on the use of EA for treating acute pancreatitis showed that there were no additional complications that would be related to the epidural procedure itself, nor any infection related to epidural catheters or haemodynamic complications in the mean duration of 5.7 days that epidural anaesthesia lasted (72).

Authors showed a significant improvement to the blood flow through the pan-

(14)

creas, which was also noted in 13 (43%) of the 30 measurements in the EA group, and in 27 measurements in the control group.

In the EA group none of the patients developed a clinical sepsis, one patient required intubation, while in the control group a total of six patients required intubation because of an acute respiratory distress (7.7% were intubated versus 27.3%, i.e. P

= 0.22). Also the use of antibiotics was not much different between the groups (81.5%

of patients in the EA group, and 68.2% in the control group, P = 0,689), and the duration of the therapy did not differ either.

During hospitalization the EA group developed 9 cases of local and regional complications and 10 cases of systemic complications compared to the control group which included 12 cases of local and regional and 13 systemic complications. The assessment using the VAS scale showed an improvement in subjective pain in the first 12 days in the EA group compared to the control group, with significant difference on the day EA was performed and for the following 10 days. Results for the mean value of pain on the scale of 1 to 10 were at 6.5 versus 7.31, P = 0.57 before random- ization; after EA they were 1.6 versus 3.5, P = 0.02; on the first day 0.57 versus 2, P

= 0.06; on the 5th day 1.86 versus 1.38, P

= 0.69; on the 10th day 0.2 versus 2.33, P

= 0,034; on the 12th day 0 versus 2.8, P = 0,071. The conclusion of the study was that EA is a safe procedure which significantly increases the blood flow in the pancreas, resulting in fewer necrosis being developed, pointing to the trend of improving clinical issues with SAP patients (72).

5.7 Preventing deep vein thrombosis

All SAP patients are recommended to undergo prophylaxis of the deep vein thrombosis (6). Increase of the procoagu- lating infected mediators, the venal path, shrinking of various veins in this area and the mass effect because of an infected

pancreas can contribute to the creation of a thrombosis of the spleen and/or portal vein, which occurs in about 20% of the patients during ongoing treatment. Once diagnosis is confirmed, therapy with heparin can begin. Standard nonfractional heparin has an advantage over low-molecule heparin, as dosing is both simple, it has pre- dictable kinetics and an available antidote, which comes into effect especially because of the numerously repeated surgical procedures (73).

5.8 Surgical treatment

Endoscopic necrozectomy. Endoscopic transgastric resection (ETR) was recently added to the list for treating pancreatic necrosis. Compared to the open surgery the randomized study has proven that with ETR there are fewer joined major complications (20% versus 80%) and that there are fewer cases of fistula on the pancreas (10% versus 70%), and that only a small minority of patients, who were treated with ETC, are moved into ETI after the procedure (2). Even though these results are very promising, the true role of ETR in the broad range of patients with severe AP should be defined in more detail. This treatment has especially long duration and requires a lot of procedures for drainage and debridement.

Minimally invasive surgery. Minimally invasive retroperitoneal necrosectomy of the pancreas was recently introduced as a method for treating SAP in order to avoid the trans-peritoneal approach (1,41). After the introduction of the percutaneous abscess drainage under the CT monitoring, this drain is used as a guide for the retroperitoneal endoscopic approach. Even though this technique has its limitations, several studies have already published ex- cellent results on select patients. This minimally invasive approach is also the second part of the advanced approach introduced by the Dutch working group for acute pancreatitis (37). This method uses an ac-

(15)

tive technique if the necrosis is accessible for retroperitoneal approach, such as e.g.

necrosis of the head of the pancreas (74).

Surgical open approach. Studies have shown a high rate of morbidity and mortality after an open surgical approach, and therefore it is not recommended in all cases, when the patient’s condition even allows it. Surgical treatment is most often required with infected necrosis, however they should be limited. The most frequent complications with an open surgical approach are the pancreatic fistula and the damage to the intestines.

Until now there have been no randomised studies – except for PANTHER – that would compare different surgical approaches, therefore also the retrospective analysis from this field is lacking, i.e. there are still no well-founded conclusions (1,3).

With patients operated using a minimum invasive technique the risk for organ failure was significantly lower [OR 0.16, with

90% confidence interval (CI) 0.06–0.39]

(1).

6 Conclusion

For intensive medicine SAP is still a difficult clinical condition with frequent complications and a high mortality rate.

The main pathophysiological mechanisms that affect the final score, are the uncon- trolled systemic infection response which begins already in the early stage, and the infection of the necrosis of the pancreas during the later stages of the disease.

Pre- and postoperative patient’s monitoring using SAP must include also intensive monitoring and a timely therapy for the decrease of the failure of different organ systems. Timely recognition and therapy of possible complications, especially infections, does make this severe disease more tolerable.

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