Acute Pancreatitis: Recognizing the Cardinal Symptoms

According to the Revised Atlanta Classification (CAR), to make the diagnosis of acute pancreatitis (AP), the patient must meet at least 2 of the following 3 criteria: typical abdominal pain (epigastralgia of acute onset, often radiating to the back ), increased serum lipase or amylase, at least 3 times the upper limit of normal, and characteristic imaging findings of BP.

The cardinal symptom of AP is acute epigastric pain, of sudden onset. It is an abdominal pain that usually radiates to the back. Nausea and vomiting are very common.

For more than 7 decades, the most used tests for the diagnosis of AP were serum amylase and/or lipase . The 2 main sources of serum amylase are the pancreas and salivary glands. Specific isoforms of pancreatic amylase can be measured in the blood. To rule out the influence of salivary amylase, some laboratories only determine these isoforms.

Its serum activity begins to increase within 6 hours after the onset of BP, reaches a maximum within 48 hours and normalizes within 5-7 days. Lipase comes almost exclusively from the pancreas, so it is considered more specific for BP. It rises after 4 to 8 hours, peaks at 24 hours, and remains elevated longer than amylase (8-14 days).

As for urinary markers , you can measure amylase or use a rapid reagent strip for the trypsinogen-2 test. Both have good sensitivity and specificity. However, the trisinogen-2 dipstick test has limited availability.

Urinary markers may be more useful when there is a high diagnostic suspicion of AP and amylase or lipase levels are normal, for example, in cases of hypertriglyceridemia. It is highlighted that there is no evidence that one analytical test is more accurate than others. Repeated measurements of pancreatic enzyme levels in blood or urine are not useful in predicting the severity or monitoring the course of the disease.

Other causes of inflammation and acute abdominal pain are associated with increased amylasemia or lipasemia, including: acute cholecystitis, cholangitis, perforation, acute mesenteric ischemia or gynecological problems. Inflammatory diarrhea and diabetic ketoacidosis are other causes of acute increases in pancreatic enzymes in the blood and urine. These alternative diagnoses are often associated with atypical signs or symptoms. In this context, images are needed.

Images are needed for 3 purposes:

1. Make the differential diagnosis at the beginning of the disease, if the signs or symptoms are atypical.
    
2. Diagnose local complications of BP.
    
3. Determine the etiology of AP.

> Differential diagnosis

Imaging is not needed to diagnose BP in patients with typical features and elevated blood amylase or lipase levels greater than 3 times the upper limit of normal.

In cases of atypical signs or symptoms (eg, high fever, chills, peritoneal signs, diarrhea, central or lower quadrant pain), contrast-enhanced computed tomography (CCT) is particularly useful to confirm BP. However, abdominal ultrasound has greater sensitivity and specificity for the diagnosis of acute cholecystitis compared to CBT.

> Diagnosis of local complications

During hospitalization, contrast-enhanced CT and abdominal MRI are used to evaluate the severity of pancreatitis, detecting the presence of local complications. Imaging should not be performed before the first 72 hours as it may underestimate the severity of AP. They are indicated when local complications are suspected (predicted severe illness, persistent pain, persistent systemic inflammatory response syndrome (SIRS), inability to resume oral feeding or early satiety, presence of an abdominal mass, etc.).

As a first step to correctly guide the etiological study of BP, it is essential to have a good clinical history, a complete blood test, including liver and lipid profiles, as well as the level of calcemia, and an abdominal ultrasound. It is recommended to determine the levels of triglycerides and calcium in the blood , since they allow us to arrive at the etiology, since alcohol is a cause of hypertriglyceridemia, and necrosis may be associated with hypocalcemia.  

Endoscopic ultrasound is particularly useful when the etiology remains unknown after the first step. On the other hand, MRI or endoscopic ultrasound can be used to rule out choledocholithiasis in gallstone-related BP.

Approximately two-thirds of patients with AP have a mild course of the disease, with rapid recovery.

However, one third suffers disease progression, with the development of local complications and/or organ failure (OI).

The 2 phases evident in moderate to severe AP are: the early phase, during the first week, and the late phase, starting from the first week. In the first, the release of proinflammatory agents due to local pancreatic and peripancreatic tissue damage can result in the development of SIRS.

Uncontrolled inflammation is associated with OI. The development of local complications (collections, necrosis) is related to fluid sequestration during the initial phase, but, more importantly, it has consequences in the late phase, in which these local complications may be associated with symptoms and infection. .

There are 2 types of PA:

1. Interstitial
2. Necrotizing

In interstitial AP , the pancreas is enlarged due to inflammatory edema. Some patients with interstitial AP may develop acute peripancreatic fluid collections (CALP), which are early (<4 weeks), homogeneous (without necrotic remains), without defined wall collections. Most of those collections are reabsorbed. Collections that persist >4 weeks develop a defined wall and are called pseudocysts .

Necrotizing AP is characterized by the presence of pancreatic or peripancreatic necrosis. In the first 4 weeks, these collections have no defined wall and are called acute necrotic collections . These collections are heterogeneous due to the presence of liquid and necrotic waste inside. Persistence of the acute necrotic collection for >4 weeks results in the development of a defined wall, termed walled necrosis . Peripancreatic necrosis is particularly associated with worse outcomes.

In PA, OI is defined, according to the CAR, by the modified Marshall score, namely: respiratory (PaO2/FiO2 300); renal (serum creatinine 1.9 mg/dl) and/or cardiovascular (systolic blood pressure <90 mmHg, not sensitive to fluid resuscitation). 

OI can be transient (up to 48 hours) or persistent (>48 hours) and single or multiple (if more than one system is affected). Any OI increases morbidity and mortality, but the risk of mortality is much higher in persistent OI and/or multiple OI (almost 50% mortality in both types of OI, according to prospective data).

The CAR, published in 2021, updated the 1993 Atlanta Classification. Based on the history of AP complications, this classification defines 3 categories : mild, moderately severe, and severe.

1. The mild category , which includes patients without local or systemic complications, or without OI, results in low morbidity and zero mortality.
    
2. Moderately severe AP is characterized by local and/or systemic complications (exacerbation of preexisting comorbidities), and/or transient OI, and is associated with greater orbidity and low mortality.
    
3. Finally, the severe category is defined by persistent OI, related to maximum morbidity and a high risk of mortality. Older age, obesity, comorbidities, increased blood urea nitrogen and/or increased hematocrit, presence of SIRS (particularly if it lasts >2 days) are more likely to cause adverse outcomes.

Several scores (APACHE-II, BISAP, Ranson) have been developed to achieve greater precision, but in general, all are associated with a high negative predictive value and a low positive predictive value.

The pillars of early management of BP are:

> Fluid resuscitation . Hypovolemia is common in PA for several reasons. First, because it is associated with greater vascular permeability, with extravasation of fluids to the tissues (vascular leak syndrome). Together with local complications and paralytic ileus, it produces fluid sequestration.

On the other hand, there is greater fluid loss due to vomiting, sweating (due to increased body temperature), tachypnea associated with SIRS, and decreased oral fluid intake. It can result in severe hypovolemia affecting organ perfusion, which can be counteracted by adequate fluid resuscitation.

However, aggressive fluid resuscitation in patients without hypovolemia can cause pulmonary edema and increased intra-abdominal pressure, consequently creating an abdominal compartment syndrome.

 • Volume . The optimal rate of volume in PA is controversial, and the few available trials have provided conflicting results. In 2009 and 2010, two randomized clinical trials in severe AP showed that patients assigned to aggressive fluid delivery had worse outcomes (greater morbidity and mortality).

A recent randomized controlled trial (RCT) in patients with mild AP compared the outcomes of aggressive fluid resuscitation using lactated Ringer’s solution. The primary outcome was “clinical improvement within 36 hours,” with decreased hematocrit, blood urea nitrogen, and creatinine, decreased pain, and tolerance to oral diet. Patients undergoing intensive fluid resuscitation showed a higher rate of that primary outcome.

The definition of "clinical improvement" has been criticized for being too reliant on hemodilution, which is not a direct marker of good disease outcome, and it is clear that patients receiving intensive fluid resuscitation have more rapid hemodilution. Well-designed RCTs are required, as the evidence on which guideline recommendations are based is weak.

The International Association of Pancreatology, the American Association of Pancreas, and the American Gastroenterological Association recommend goal-directed therapy with fluid resuscitation (these recommendations are based on low-quality evidence).

 • Type of fluids . In AP, lactated Ringer’s solution is recommended, since it is associated with a decrease in inflammation. In open-label, triple-blind trials, with 40 patients each, this solution was found to decrease the rate of SIRS and blood levels of C-reactive protein, compared to normal saline. Therefore, specialized scientific societies recommend Lactated Ringer’s Solution as a resuscitation fluid in PA. However, SIRS and CRP are surrogate markers of severity, and new trials are required that focus on the most important clinical outcomes, such as OI, local complications, or mortality.

> Oral feedback and nutritional support

Activated intrapancreatic trypsin is a key step in the pathophysiology of AP. Because food stimulates the secretion of trypsinogen, the inactive precursor of trypsin, "pancreatic rest" was previously believed to give better results (patients continued oral fasting until complete recovery, with or without parenteral nutrition). However, several subsequent studies have disqualified that belief.

 • Nutrition in mild BP . RCTs have shown that in mild AP, early oral refeeding is safe and results in a shorter hospital stay. On the other hand, it is not necessary to start with clear liquids to progressively reach the intake of solid foods. Initiation of refeeding with a completely solid diet is well tolerated and also results in a shorter hospital stay.

 • Nutrition in moderate to severe acute pancreatitis . In a multicenter RCT of patients with predicted severe AP, early nasojejunal feeding within 24 hours did not show better results, compared with on-demand enteral nutrition (used only in patients who do not tolerate oral diet on day 4).

Therefore, in moderate to severe BP, oral refeeding can be attempted, reserving tube feeding for patients who do not tolerate oral diet after 3-4 days. In patients who cannot tolerate oral feeding, nutritional support with enteral nutrition is clearly superior to total parenteral nutrition. A decrease in infectious complications and the need for surgical interventions has been demonstrated, comparing OI and mortality between enteral nutrition and total parenteral nutrition.

Therefore, in this context, BP guidelines strongly recommend enteral nutrition. Regarding the enteral feeding route, several trials found no difference between nasojejunal tube feeding or nasogastric tube feeding in terms of mortality, need for surgery or abdominal pain. However, in the presence of gastric outlet obstruction, the nasojejunal tube is preferred.

> Antibiotics

Antibiotic treatment in AP is not recommended unless there is a confirmed or highly suspected pancreatic necrosis infection or other infection.

The first open RCTs showed a benefit of prophylactic antibiotics for the prevention of pancreatic necrosis infection. However, these studies had methodological flaws. Consequently, current AP guidelines do not recommend antibiotic prophylaxis in AP8.

> Endoscopic Retrograde Cholangiopancreatography (ERCP)

A meta-analysis of RCTs comparing ERCP versus conservative BP management showed no benefits from early ERCP in the absence of acute cholangitis. The latter is the only widely accepted indication for urgent exploration of the biliary tree.

Similar to the case of antibiotic prophylaxis, previous studies suggested that ERCP performed within 24 to 72 hours reduces biliary complications, sepsis, and hospital stay. However, these benefits were not confirmed in subsequent well-designed studies. The early publication of a Dutch RCT addressing this issue is awaited. Although some preliminary reports suggested that early ERCP is not associated with better outcomes.

> Analgesia

Although some RCTs have compared different analgesics in BP, most of them only included a few patients and have low methodological quality. There is no firm consensus on which drug and which route of administration is preferable in AP. A systematic review concluded that opioids could reduce the need for supplemental analgesics without increasing adverse effects.

Classic non-steroidal anti-inflammatory drugs (NSAIDs) and metamizole can be used as analgesics in BP, although their adverse effects must be considered (gastrointestinal damage and renal failure with NSAIDs and neutropenia with metamizole).

Epidural analgesia may be an alternative for patients with severe pain.

The patient whose history was presented here had SIRS at the time of presentation. Blood tests showed increased blood amylase levels of 3,500 IU/l (upper limit of normal: 100 IU/l) and hematocrit 51%.

The patient required aggressive fluid resuscitation to maintain adequate urine output (>0.5 mL/kg/h), but oral feeding was effectively initiated on day 3.

An abdominal ultrasound showed cholelithiasis . On day 4, a CT scan was performed, which showed an acute collection of peripancreatic fluid.

A follow-up outpatient ultrasound showed resorption of the collection, so cholecystectomy was performed on day 30. Although several RCTs have clarified the treatment of late complications, there are still many unanswered questions about the initial management of AP.

Future studies should address specific medications aimed at improving inflammation at an early stage, and establish the optimal volume and type of fluids for resuscitation, the function of nutritional support (pathways, different composition of nutritional supplements), new forms of prevent infection by pancreatic necrosis (selective intestinal decontamination) and analgesic drugs.