Case Study, Chapter 50, Assessment and Management of Patients with Biliary Disorders

World J Gastrointest Pathophysiol. 2014 Aug 15; 5(3): 158–168.

Abstract

Acute pancreatitis (AP) is a potentially life-threatening disease with a wide spectrum of severity. The overall mortality of AP is approximately 5%. According to the revised Atlanta classification system, AP can be classified as mild, moderate, or severe. Severe AP often takes a clinical course with two phases, an early and a late phase, which should both be considered separately. In this review article, we first discuss general aspects of AP, including incidence, pathophysiology, etiology, and grading of severity, then focus on the assessment of patients with suspected AP, including diagnosis and risk stratification, followed by the management of AP during the early phase, with special emphasis on fluid therapy, pain management, nutrition, and antibiotic prophylaxis.

Keywords: Acute pancreatitis, Incidence, Pathophysiology, Etiology, Severity, Risk stratification, Fluid therapy, Pain management, Nutrition, Antibiotic prophylaxis

Core tip: Acute pancreatitis is a frequent and potentially life-threatening disease. Therapy is currently mostly symptomatic with fluid resuscitation, pain management, and early oral feeding. Vigorous fluid resuscitation remains a cornerstone of early management of acute pancreatitis. Cross-sectional imaging during the early phase of evaluation has not been associated with improvement in outcome. There is no role for prophylactic antibiotics in the management of the early phase of acute pancreatitis (AP). Enteral nutrition in AP can reduce mortality, systemic infections, and multiorgan dysfunction compared to parenteral nutrition. Immediate endoscopic retrograde cholangiography is indicated only in patients with biliary pancreatitis with common bile duct obstruction and cholangitis.

INTRODUCTION

Acute pancreatitis (AP) is a potentially life-threatening disease with a wide spectrum of severity. The reported incidence of acute pancreatitis differs depending on geographic location and ranges from 14.7/100000 person years in the Netherlands to 45.1/100000 person years in Japan[1,2]. However, most studies show an incidence between 30 and 45/100000 person years[2-7]. Many studies report an increase in incidence over the last few decades[2,3,8], however, it is a matter of debate whether this represents a real increase in incidence due to increasing biliary AP in an increasingly obese population or whether this rise in incidence is due to improved diagnostic capabilities, a higher level of suspicion of this disease, or an overestimation of retrospective studies using administrative diagnostic codes[9-11]. In 2009, AP was the most common principal gastrointestinal diagnosis at discharge in the Unite States with estimated inpatient costs of $2.6 billion per year. Furthermore, it was the 14th most common cause of death with a crude rate of 1.0 per 100000 inhabitants[12]. The overall mortality of AP is about 5% and can reach up to 20%-30% in patients with severe AP and infected necrosis[13,14]. While there seems to be an increase in incidence, several studies have reported a decrease in mortality. Again, this could be a real decrease due to an earlier diagnosis and better therapeutic options or it may also be due to an improved sensitivity of diagnostic modalities, leading to an increase in the diagnosis of mild forms of pancreatitis[15].

In this review article, we first discuss general aspects of AP, including pathophysiology, etiology, and grading of severity, then focus on the assessment of patients with suspected AP, including diagnosis and risk stratification, followed by the management of AP during the early phase with special emphasis on fluid therapy, pain management, nutrition, and antibiotic prophylaxis.

PATHOPHYSIOLOGY

The pathophysiology of AP with multi organ failure (MOF) is poorly understood. Researchers have long hypothesized that AP results from premature activation of digestive enzymes within the pancreas, a process referred to as autodigestion. Indeed, inherited mutations in genes encoding for digestive enzymes have been found in patients with a hereditary form of pancreatitis[16]. However, affected patients develop chronic, rather than acute pancreatitis. Therefore, in recent years, a novel concept has evolved, suggesting that systemic complications during AP result from uncontrolled activation of the inflammatory cascade. As indicated above, severe AP is associated with a significant mortality. Thus, early identification of severe forms of AP is crucial for outcome. In an attempt to identify surrogate parameters as predictors for severe AP, several association studies linking cytokines and chemokines with AP severity have been conducted[17]. Among these, serum levels of interleukin (IL)-6 and the IL-6-dependent acute phase protein, C-reactive protein (CRP) were identified as the most reliable predictors for severe AP[18,19]. Recent results from basic research have established that IL-6 or CRP are not only relevant markers to predict the severity of AP, but that the cytokine IL-6 also has a substantial pathophysiological impact on the course of the disease[19]. While excessive stimulation of the inflammatory cascade [hyper-inflammatory state, systemic inflammatory response syndrome (SIRS)] accounts for early systemic complications, paralysis of the inflammatory response, also termed compensatory anti-inflammatory response syndrome (CARS), contributes to local complications and sepsis associated with the late phase of the disease. Although these definitions are largely non-specific, they are undeniably useful in the clinical and research setting. Among the agents contributing to this anti-inflammatory response, IL-10 may be of importance. In fact, the protective role of IL-10 in experimental studies in animal models has been well documented[20]. Thus, the hypo-inflammatory status of CARS might facilitate superinfections that lead to extensive necrosis and/or septic complications. This interplay of these two contrasting phenomena requires an individualized therapeutic approach[20-22].

ETIOLOGY

The identification of the etiology of AP is crucial for the management during the early phase of the disease and also for the prevention of recurrence of AP. Although there is no specific therapy for AP, the causing factor, e.g., choledocholithiasis in biliary AP, must be investigated and eliminated if identified. The most common causes of AP are gallstones and prolonged heavy use of alcohol, which together account for about 60%-80% of all cases. The incidence of biliary etiology differs considerably between different geographic regions. For example, there is a clear predominance for biliary AP over alcoholic AP in Greece (71.4% vs 6.0%) whereas the opposite is the case for Finland (6.3% vs 79.3%)[23,24]. The regional differences in frequency of biliary and alcoholic etiology are shown in Figure ​1[6,7,23-31].

Regional differences in frequency of biliary (black) and alcoholic (gray) etiology of acute pancreatitis.

Other causes of AP include ERCP (0.4% to 11%[32,33]), idiosyncratic reactions to drugs (0.1% to 2%)[34], hypertriglyceridemia (1.1%-3.8%)[6,23,35], anatomic alterations[36], genetic predispositions[37], and other rare causes[38,39]. Despite a thorough clinical workup, 10%-25% of all cases remain idiopathic[6,11,23,33].

NATURAL COURSE OF ACUTE PANCREATITIS

The severity of AP can be subclinical, mild without organ dysfunction, or can be severe. Patients with mild disease often improve spontaneously and heal within a few days. However, patients with severe disease may develop life-threatening local and/or systemic complications. According to the revised Atlanta classification system, AP can be classified as mild, moderate, or severe[40]. However, it is important to remember that AP is a rapidly evolving, dynamic condition in which the severity may change rapidly during the course of the disease[40]. Severe AP often takes a clinical course with two phases, an early and a late one, which should both be considered separately[40].

The early phase, which usually lasts for about one week, is characterized by a complex inflammatory reaction. The course of AP starts with a systemic proinflammatory phase systemic inflammatory response syndrome (SIRS), followed by a mixed inflammatory response syndrome mixed antagonist response syndrome (MARS), and finally leads to a phase with a suppressed inflammatory response compensatory anti-inflammatory response syndrome (CARS)[41-43]. In the phase of CARS, the immune system is downregulated and the chance of an infection of pancreatic and peripancreatic necrotic tissue rises. This is likely the reason why infections usually do not occur earlier than at the end of the first week[44]. During the stage of CARS pathogens can migrate unopposed from the intestinal lumen into necrotic tissue in and around the damaged pancreas. At that point, the clinical course of AP moves towards the second phase, including SIRS, sepsis, local and systemic complications, persistent organ failure, and possibly death. The model of the two-phase course is shown in Figure ​2.

Two-phase course of severe acute pancreatitis. CARS: Compensatory anti-inflammatory response syndrome; MARS: Mixed anti-inflammatory response syndrome; SIRS: Systemic inflammatory response syndrome.

Efforts must be made to predict the severity of the disease as early as possible in order to know whether a patient diagnosed with AP can be treated as an outpatient, has to be admitted to a regular ward, to an intermediate care facility, or even to the intensive care unit. While it is generally recognized how important the prediction of severity of the disease is for the management of the individual patient, it is also recognized that such prediction is very difficult. Underestimation of the severity could be harmful for the patient, while overestimation could lead to unnecessary costs and a waste of resources. Therefore, the assessment and prediction of the severity is crucial for the management of the disease. A lot of research has been done over the last few decades trying to identify new tools to accurately predict the severity of pancreatitis, yet no gold standard for such prediction of the course of AP has been identified. An ideal predictor should be fast and easy to obtain, widely available, economical, and associated with a high sensitivity and specificity. Even though there are several clinical scores with a high sensitivity, specificity, positive, and/or negative predictive value, many of them are complicated to asses or can predict severity only after 48 h of admission to the hospital, which effectively means more than 72 h after the onset of disease[45]. This might be too late, as early aggressive fluid resuscitation is a cornerstone of AP therapy.

ASSESSMENT

Diagnosis

The diagnosis of AP can be made if ≥ 2 of the following three criteria are fulfilled: (1) abdominal pain characteristic of acute pancreatitis; (2) elevation of serum lipase or amylase activity > 3-fold of the upper limit of the reference interval; and (3) characteristic signs of pancreatitis on computed tomography (CT) imaging.

The first step in the diagnosis of AP should be a thorough clinical history. The pain caused by AP is typically dull, located in the epigastrium, may radiate into the back, and is usually severe, leading to hospital admission and often necessitating opioid therapy[45,46]. Furthermore, AP often causes nausea and vomiting. Known cholecystolithiasis and/or colics, alcohol excess within 48 h before the onset of pain, new medications, and the character of the pain should be evaluated. The second step of pancreatitis diagnosis is based on clinical chemistry. The measurement of serum lipase activity is generally thought to be more sensitive and specific than that of serum amylase activity and there is no additional value in simultaneous measurement of serum lipase and amylase activities[14,47]. Also, the degree of the elevation of serum pancreatic enzyme activities does not correlate with the severity of the disease, although, some studies would suggest such a correlation between serum enzyme activity and severity[6,45]. Only in patients with characteristic epigastric pain, but serum enzyme activities below 3-fold of the upper limit of the reference interval, a CT scan should be considered to rule out other differential diagnoses or to confirm AP. Apart from that, a CT in the early phase of AP is not recommended by current practice guidelines[14,48,49].

Risk stratification

Risk factors: Obesity favors the development of local and systemic complications in patients with AP[50]. Since assessment for obesity is simple and free it should be assessed in every patient. The same applies for age, as patients 55 years or older are at increased risk for severe disease[14].

Scoring systems: Several single parameters and more or less complex scoring systems for the prediction of the severity of AP have been developed and clinically evaluated and all of them have been shown to be associated with advantages and disadvantages. The HAPScore (harmless acute pancreatitis score) was developed to identify patients with mild AP who can be treated as outpatients. Patients without rebound tenderness and/or guarding, a normal hematocrit, and a normal serum creatinine concentration have a high probability (positive predictive value: 98%-98.7%) to have a harmless course of the disease[51,52].

One of the oldest and probably best known and heavily used scores to predict a severe course of pancreatitis was developed in the early 70ties by John Ranson and colleagues[53]. The Ranson score is based on the presence or absence of simple parameters and is assessed differently at the time of admission (5 parameters; possible scores: 0-5) and 48 h later (6 parameters; possible scores: 0-6; Table ​1).

Table 1

Prognostic criteria of Ranson

Although a score ≥ 3 has a high sensitivity and specificity regarding a severe course of pancreatitis (83.9% and 78.0%, respectively) and a negative predictive value of 94.5%, the severity can be predicted no earlier than 48 h after admission[25,54]. A modification of the Ranson score by Clemens Imrie and colleagues (Imrie score or Glasgow score) was first reported in 1978 and is still widely used and has a similar accuracy as the Ranson score[25,55].

Currently, the score with the highest sensitivity regarding prediction of a severe course is the Acute Physiology And Chronic Health Evaluation (APACHE) II score[14,56]. Originally developed to predict mortality in intensive care patients, a value ≥ 8 of the APACHE II score predicts a severe course of AP with a sensitivity of 65%-83%, specificity of 77%-91%, positive predictive value (PPV) of 23%-69%, and negative predictive value (NPV) of 86%-99%[54,57]. However, the determination of an APACHE II score in a clinical patient is complex and time-consuming as it utilizes more than 15 parameters, which limits the clinical value of this score.

A score that was developed and validated more recently in almost 18000 patients, is the BISAP (Bedside Index of Severity in Acute Pancreatitis) score[58]. The main advantage of the BISAP score is its simplicity. One point each is given for blood urea nitrogen (BUN) > 8.9 mmol/L, impaired mental status (Glasgow Coma Scale < 15), presence of SIRS, age > 60 years, and pleural effusion (Table ​2). A score ≥ 3 is predictive for a severe course (observed mortality of > 5%; Table ​2) with a sensitivity of 83% and a PPV of 76.9%[58-60]. One disadvantage of the BISAP score is, that this score cannot easily distinguish patients with transient and persistent organ failure and therefore may overestimate severity and preclude differentiation between moderate and severe AP.

Table 2

Bedside index of severity in acute pancreatitis score and observed mortality by bedside index of severity in acute pancreatitis score score

In summary, there is currently no ideal predictor of severity of AP. All prognostic factors and scores show a good NPV, but suffer from a low PPV. Thus, the main value of severity assessment is to exclude a large number of patients with a low risk of mortality[57].

In addition to the laboratory/clinical scoring systems described above there are scoring systems based on imaging results to assess and predict the severity of AP. A CT scan for diagnostic purposes and severity assessment has been-and probably still is - standard practice in many centers[61]. The Balthazar score, developed in 1985, categorizes patients with AP into 5 groups (A-E) according to pancreatic and peripancreatic changes diagnosed by CT (Table ​3)[62]. In 1990, Balthazar et al[63] modified this score, including assessment of the extent of pancreatic necrosis and named this score Computed Tomography Severity Index (CTSI) (Table ​4). The CTSI is probably the most frequently used imaging score to assess severity in patients with AP and a score ≥ 4 has a negative predictive value of 94%-97% and a positive predictive value 53%-69% regarding the clinical severity of disease[61,64].

Table 3

Balthazar score

Table 4

Computed tomography severity index

In addition to the Balthazar score and the CTSI, several other scores, e.g., pancreatic size index (PSI), mesenteric edema and peritoneal fluid (MOP) score, extrapancreatic (EP) score, extrapancreatic inflammation on CT (EPIC) score, modified CTSI (MCTSI), and MR severity index (MRSI) have been developed and evaluated[61,65]. However, none of these imaging scores were shown to be superior to clinical scoring systems. Thus, a CT on admission to predict severity of AP cannot be recommended at the current time[61].

In addition to laboratory/clinical and imaging scoring systems, single parameters have been evaluated to assess and predict severity.

A lot of research has been done evaluating hematocrit as an indicator for hemoconcentration. The first prospective cohort study showed a high NPV for a hematocrit ≥ 44 % (93% on admission and 97% 24 h later) but a poor PPV (26% and 27%, respectively) regarding organ failure in AP[66]. Similar results were obtained by several other studies focusing on the usefulness of hematocrit to predict a severe course of AP, organ failure, pancreatic necrosis, or death[67,68]. Due to its high negative predictive value, its low cost, and the ease of measurement, the hematocrit has value in predicting a non-severe course of AP.

The disruption of water balance can lead to hypoperfusion and a disturbance of pancreatic microcirculation[69], which in turn correlates with the severity of AP[70,71]. Understanding the water balance and the resulting changes in laboratory tests can help to predict severity and outcome of AP. In addition to hematocrit, other parameters, that mirror intravascular volume depletion, can also be helpful.

Serum creatinine has been identified as a predictor for pancreatic necrosis. Also, more recently, an estimated glomerular filtration rate (GFR) < 90 mL/min per 1.73 m2 on admission has been shown to predict pancreatic necrosis with a sensitivity, specificity, PPV, and NPV of 78.1%, 71%, 64%, and 83%, respectively[72,73]. While only one study has described GFR as a predictor of severity, BUN has been evaluated for many years and has been shown to be a good predictor for severity in AP in several large studies. A rise in BUN > 1.8 mmol/L after 48 h had already been included in the Ranson score 40 some years ago, is one of the 4 parameters used in the BISAP score, and has also been shown to have a high predictive value as a single parameter[74,75].

Besides parameters focusing on water balance and microcirculation, laboratory parameters suggesting the presence of an inflammatory process have been used as a predictor of severity. The most intensively studied parameter is CRP. In one study, a serum CRP concentration of 150 mg/L or greater predicted severe AP at 36 h after admission with a sensitivity, specificity, PPV, and NPV of 86%, 87%, 75%, and 93%, respectively[76]. However, the prediction of severity was only possible more than 24 h after admission, which, on average, is about 50 h after the onset of pain[45]. Also, several other studies showed a high predictive value of CRP during the course of AP in regards to severity, but a very low predictive value on admission[77,78].

Procalcitonin appears to be a valuable tool to discriminate between sterile and infected necrosis within the first days of AP[79,80]. However, data on the ability to predict the course of AP are not consistent. On one hand, a multicenter study from the United Kingdom found a significant difference of procalcitonin concentrations measured within 48 h of the onset of symptoms in patients with mild and severe AP and showed an accuracy of 94% in predicting death[81]. In a study from Slovakia, the PPV for predicting a fatal outcome reached 75% when a cut-off value of 5 ng/mL was used[82]. A third study evaluating procalcitonin showed an accuracy of 76% and a PPV of 75% for predicting a severe course of pancreatitis[83]. On the other hand, two studies reported that procalcitonin is not useful in predicting the severity of AP upon admission[79,84]. However, the time point for determination of procalcitonin concentrations, the assays used, and the cut-off values applied were different for all studies. Finally, measurement of procalcitonin is not widely available and is expensive.

A blood glucose concentration < 6.9 mmol/L on admission has a high negative predictive value (92%) for pancreatic necrosis and also can serve as a predictor for severity[85,86]. Blood glucose is easy, fast, and inexpensive to determine and widely available and therefore should be included in the risk stratification.

In summary, there is no single marker that can adequately predict the severity of AP, but there are several scoring systems that can be used to assess and predict the severity of AP. However, these scoring systems must be applied at the correct time, the correct place, and in the correct patient. Also, it is important to observe patients carefully and reassess severity frequently as the disease course can change rapidly at any given time.

MANAGEMENT

Patients diagnosed with mild AP (according to the HAPScore) and no other risk factors can be treated as outpatients. In contrast, patients with any of the above-mentioned risk factors should be considered for admission to the hospital for close monitoring and timely reassessment of disease severity. In contrast, patients with a Ranson score ≥ 3, a BISAP score ≥ 3, an APACHE-II score ≥ 8, or patients with apparent organ failure should be transferred to an advanced medical care ward or facility.

Therapy

Fluid therapy: Despite a lot of research, there is no pharmacological treatment of AP[87]. Thus, fluid resuscitation, analgesia, supportive care, and management of the local and systemic complications are the key elements of the management of patients with acute pancreatitis. One of the most important components of therapy of AP is early intravenous fluid resuscitation[88]. In fact, the decrease in mortality observed over the last decade might be due to the prevention of pancreatic necrosis by maintenance of microcirculation due to more aggressive fluid resuscitation[89]. Two studies have shown a decrease in mortality by early and aggressive fluid resuscitation[90,91]. However, data on the amount of fluid needed to prevent necrosis or to improve outcome are contradictory and the volume must be adjusted to the patient’s age, weight, and pre-existing renal and/or cardiac conditions[92]. The importance of starting fluid resuscitation as early as possible and in fact already in the emergency room was shown by two retrospective studies[90,91]. However, the optimal type of fluid is still a matter of debate. Studies comparing isotonic saline and lactated Ringer’s solution and crystalloid vs colloid solutions, respectively, showed no differences between both groups regarding clinical outcome as determined by the frequency of pancreatic necrosis, length of hospital stay, or mortality[93,94]. Also, the optimal therapeutic goal of fluid resuscitation is not yet clear. A goal-directed fluid resuscitation algorithm based on changes in BUN measurements, as a mirror of renal function, showed no improvement in outcome in patients with AP[93]. Nonetheless, blood pressure, respiratory function, urine output, and-where appropriate-intraabdominal pressure should be closely monitored. One study showed a less severe course of post-ERCP pancreatitis when patients were treated according to a fluid resuscitation protocol based on vital signs and hematocrit[95]. While questions on the type of fluid, the optimal rate of administration, and the therapeutic goal to reach remain unanswered[96], the time-point appears to be very important - the earlier, the better[90,91].

Causative therapy: Elimination of any potential risk factor is another important approach to AP therapy. In case of suspected alcohol- or drug-induced AP, the intake of the causing agent must be stopped immediately. In case of biliary AP, the indication to perform an endoscopic retrograde cholangiography (ERC) and removal of stones within the bile duct depends on the degree of obstruction of the common bile duct and the presence of cholangitis. Biliary pancreatitis and cholangitis are clear indications for ERC and ERC should be performed as early as possible[49,97,98]. Immediate ERC is indicated in patients with biliary pancreatitis with common bile duct obstruction and cholangitis, arguable in patients with predicted severe pancreatitis but without cholangitis, and not indicated in predicted mild pancreatitis without cholangitis[49].

After biliary pancreatitis, cholecystectomy is recommended within the same hospital stay for mild pancreatitis or after an interval of 6 wk following an episode of severe pancreatitis[49].

Pain management: Given that most patients with AP suffer from severe pain, adequate analgesia is very important. In mild cases, non-opioid drugs might be satisfying, but in many cases, especially severe AP, parenterally administered narcotic agents are warranted and most patients will require the use of opioids to control the pain[99,100]. In contrast to historical reports, there is no evidence or a recommendation for restrictions on the type of pain medications being used[14].

Nutrition: For many years, resting the pancreas by giving the patient nothing per os was an important part of therapy. Nowadays, there is wide agreement that total oral abstinence from food combined with total parenteral nutrition is not beneficial to patients with severe AP, but may in fact be detrimental. A recent meta-analysis showed a statistically significant association of early enteral nutrition and reductions in systemic infections, pancreatic infections, length of hospital stay, and mortality[101]. Also, in patients with severe AP, enteral nutrition was significantly superior to total parenteral nutrition regarding mortality, infectious complications, and organ failure[102]. Gut barrier function is compromised in patients with acute pancreatitis, likely leading to bacterial translocation and potentially causing infected necrosis or even sepsis[103,104]. Because enteral feeding stabilizes gut barrier function, thereby reducing bacterial translocation, it is important early during the course of AP[14,105].

Therefore, whenever possible, i.e., when dissipating pain allows the patient to eat and infectious parameters do not continue to rise, oral food intake should be initiated as early as possible[49]. If oral food intake is not possible and the patient needs nutritional support, enteral tube feeding is preferred over total parenteral nutrition. However, the composition of an optimal diet has not yet been evaluated.

Antibiotic prophylaxis: There also has been a change regarding prophylactic antibiotic therapy in patients with AP. While in the 90ties, prophylactic antibiotics where thought to improve the outcome in patients with AP, there is no emerging evidence that prophylactic antibiotics reduce infectious complications or mortality[106-108]. Today, there is no clear evidence that supports antibiotic prophylaxis as a routine treatment in patients with severe AP[109-111]. Prophylactic antibiotics may reduce pancreatic infection in special subgroups of patients, but further well-designed and adequately-powered studies are needed to definitively answer the clinical usefulness of antibiotic prophylaxis in these patients[108]. Therefore, antibiotic prophylaxis is currently not recommended by international guidelines for the treatment of acute pancreatitis[14,49].

CONCLUSION

Acute pancreatitis is a frequent and potentially life-threatening disease. Numerous clinical prognostic scoring systems have been developed, and yet tools to discriminate between mild, moderate, and severe AP early during the course of the disease are not well advanced. Therapy is currently mostly symptomatic with fluid resuscitation, pain management, and early oral feeding. However, most of these therapeutic approaches are not well-defined. Vigorous fluid resuscitation remains a cornerstone of early management of acute pancreatitis. Cross-sectional imaging during the early phase of evaluation has not been associated with improvement in outcome. There is no role for prophylactic antibiotics in the management of the early phase of AP. Enteral nutrition in AP can reduce mortality, systemic infections, and multiorgan dysfunction compared to parenteral nutrition. Immediate ERC is indicated only in patients with biliary pancreatitis with common bile duct obstruction and cholangitis. These developments have contributed to an improved outcome for patients with acute pancreatitis, but further studies are still required to tackle the high mortality in this disease.

Footnotes

P- Reviewer: Bradley EL, Goral V, Pezzilli R, Sakata N S- Editor: Ji FF L- Editor: A E- Editor: Lu YJ

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