Severe Acute Pancreatitis: Optimal Management Strategies for Improved Patient Outcomes

Although there are no effective pharmacological treatments, advances have been made in understanding the risk factors and specific therapeutic steps in patients with acute pancreatitis.

The importance of smoking alone and combined with alcohol abuse in increasing the risk of pancreatitis in adults, blood triglyceride concentrations during pancreatitis, and genetic risks in children is more appreciated .

It is necessary to convey this information to patients in order to reduce the risk of recurrence of acute pancreatitis.

Updates to the Atlanta classification define three degrees of severity of acute pancreatitis—mild, moderate, and severe.

There are new methods of dynamic measurements of severity that can be used to make decisions during the course of the disease.

Several randomized controlled trials (RCTs) evaluated the use of antibiotics, peritoneal lavage, and drugs to treat complications and limit the severity of acute pancreatitis.

Recently, cohort studies and RCTs have provided moderate evidence supporting a stepwise approach to invasive techniques to address local complications of severe acute pancreatitis, including pancreatic fluid collections and pancreatic necrosis.

These advances provide a platform for future improvements, including the development of treatments that take into account the cause of the pancreatitis episode, its severity, and its dynamic activity.

Systematic reviews, meta-analyses, RCTs and international guidelines on the topic between 1980 and April 2019 were searched in PubMed.

The annual incidence of acute pancreatitis in the US is 13-45 cases per 100,000 people. Gallstones and alcohol abuse are the key causative factors of acute pancreatitis.

The proportions are equal for women and men, but alcohol abuse is more frequently associated with acute pancreatitis in men, while gallstones are more frequently associated with acute pancreatitis in women.

In addition to gallstones, women are more likely to have acute pancreatitis due to complications of endoscopic retrograde cholangiopancreatography (ERCP) or autoimmune causes, and they are also more likely to have idiopathic acute pancreatitis.

The diagnosis of acute pancreatitis is less common in children than in adults and most pediatric cases are due to genetic influences with mutations in key digestive enzymes and genes in the cystic fibrosis mutation family. Recent data show that smoking is a risk factor for acute pancreatitis, which adds to the risk of pancreatitis induced by alcohol abuse.

Moderate alcohol consumption rarely causes pancreatitis and on the contrary can be protective, as long as it is not associated with smoking. Other recent works show associations between diet and the incidence of pancreatitis.

For example, increased consumption of saturated fat and cholesterol is positively associated with the incidence of gallstone pancreatitis, while increased fiber consumption is negatively associated with all forms of pancreatitis.

Vitamin D intake is negatively associated with gallstone pancreatitis, and coffee consumption protects against non-gallstone pancreatitis.

A retrospective demographic study with 3,967,859 patients showed that patients taking statins had a large reduction in the incidence of acute pancreatitis. The mechanisms of this favorable effect still remain to be determined.

Gallstones that migrate out of the gallbladder and cause temporary obstruction of the pancreatic duct and expose the pancreas to bile components are the most common cause of acute pancreatitis .

The second most common cause is alcohol abuse . To cause pancreatitis, it is necessary to consume a significant amount of alcohol over a long period of time (at least four to five drinks per day for more than five years).

Smoking along with alcohol consumption is common . Recent studies indicate that smoking is an independent risk factor for pancreatitis (acute, relapsing, and chronic) in addition to alcohol abuse.

Pancreatitis due to increased triglycerides is the third cause of acute pancreatitis. A systematic review of retrospective case-control studies and case series studies with 1979 patients estimated that 15-20% of those with triglyceride concentrations greater than 1000 mg/dl) suffered from pancreatitis.

A retrospective study of 2,519 patients found that the clinical course of those with increased triglycerides was more severe , with a higher incidence of persistent multiple organ failure than in those without hypertriglyceridemia.

Recent studies show greater severity of pancreatitis also in patients with mild (150-199 mg/dl) and moderate (200-999 mg/dl) increases in triglycerides measured during an episode. These studies suggest that the metabolic effect of pancreatitis associated with increased circulating concentrations of triglycerides favors the severity of pancreatitis.

Drug -associated pancreatitis is less common (less than 5% of cases). Medications associated with acute pancreatitis are azathioprine, 6-mercaptopurine, didanosine, valproic acid, angiotensin-converting enzyme inhibitors, and mesalamine.

Regarding the importance of glucagon -like peptide 1 receptor agonists as causes of pancreatitis . used for the treatment of diabetes, more extensive research indicates that the increased incidence in these cases is probably due to diabetes , which multiplies the risk of acute pancreatitis by two or three, and not to treatment with these drugs.

As already noted, most cases of acute, recurrent, and chronic pancreatitis in children are associated with mutations in several genes. Only a minority of adult patients suffer from pancreatitis due to genetic alterations. The recent report of a genetic mutation in claudin-2 that may increase the effect of drinking alcohol on susceptibility to pancreatitis is important.

When it is not possible to identify the cause of pancreatitis, the possibility of a malignant tumor must be taken into account, which can occasionally manifest as acute pancreatitis, especially in patients over 50 years of age.

Additionally, mucinous material from pancreatic cysts, such as intraductal mucinous pancreatic neoplasms, can obstruct the flow of pancreatic fluid and lead to pancreatitis. In cases of unknown cause, especially with a recurrent episode, imaging studies of the pancreas, including endoscopic ultrasound and testing for genetic abnormalities, should be performed.

It is of great importance to identify the cause of an episode of pancreatitis in order to counsel patients to prevent recurrences and possible progression to chronic pancreatitis. Likewise, it is necessary to suspend drugs that could cause acute pancreatitis in order to prevent recurrences.

It is also important to reveal the genetic factors underlying recurrent episodes of acute pancreatitis, in order to inform the patient about the importance of avoiding factors such as alcohol abuse, smoking, certain drugs, and hypertriglyceridemia, which may cause the risk of recurrent episodes. .

The diagnosis of acute pancreatitis requires the presence of two of the three features of the disease: abdominal pain, blood amylase or lipase concentrations at least three times the upper limit of normal, and data from abdominal imaging studies that match the diagnosis.

Multiple validated methods have been created to predict the severity of the course of acute pancreatitis. These methods use further measurements of physiological responses (cardiopulmonary function and kidney function), laboratory studies that reflect damage to extrapancreatic organs (liver enzymes), and imaging studies of the pancreas, with and without contrast.

Some use a single laboratory study such as C-reactive protein, urea or procalcitonin in the blood.

The most reliable of these methods are scoring systems . One or more of these methods can be used to plan the initial level of care and interventions necessary to treat patients during the course of their illness.

An episode of acute pancreatitis can also be described by grading its severity.

A limitation of these methods is that they do not provide the real-time measurements of disease activity necessary for an organic disease with fluctuations in its activity. Some patients may have signs of relatively mild illness but quickly progress to severe, life-threatening illness.

A group of international specialists recently created the Pancreatitis Activity Scoring System + (PASS), a scoring system that uses clinical analyzes obtained to provide dynamic measurements of disease activity over the entire spectrum of disease severity and throughout the duration of the disease. duration of this.

This measurement system is the sum of five important clinically weighted parameters (organ failure, systemic inflammatory response, pain, pain medication, and solid food intolerance) that is calculated continuously during an episode of pancreatitis.

Recently, in a prospective study of the PASS for its validation, in which 439 patients participated, it was found that in addition to predicting the severity of the pancreatitis episode through the initial scores, the dynamic score was associated with local complications such as pseudocysts and necrosis. and with the duration of hospitalization and rehospitalization after discharge.

• The course of an episode of acute pancreatitis can be defined by prediction models, severity classification, and dynamic activity.
   
• Prognosis and dynamic activity measurements are used to assign a level of care and interventions during the initial phases of the disease .
   
• Measurement of dynamic activity is necessary for adjustments in the level of care and interventions during the course of the episode.

The disease classification system provides the overall report of an episode, which can be used to characterize the episode for clinical care and research purposes.

Patients with severe acute pancreatitis have hypovolemia and may suffer from hypotension secondary to a systemic inflammatory response.

They may need several liters of fluid resuscitation to maintain organ function. Oliguria, decreased cardiac output, and hypotension are common during severe acute pancreatitis and require intensive monitoring.

Two studies suggest that lactated Ringer ’s solution decreases the systemic inflammatory response in patients with acute pancreatitis. The International Association of Pancreatology and American Pancreatic Association guidelines recommend lactated Ringer’s for the initial phase of resuscitation.

Fluid resuscitation should be initially evaluated with noninvasive monitoring that monitors heart rate, blood pressure, and urine output.

A study of 200 patients suggested those with severe acute pancreatitis treated with invasive monitoring to achieve a central venous pressure of 8-12 mm Hg and mixed venous oxygen saturation of at least 70% needed fewer days of ventilation and hospitalization, suffered from less organ failure and had lower mortality rates.

The need for fluids may be considerable and the amount administered intravenously should be sufficient to normalize clinical and biochemical perfusion parameters (heart rate, blood pressure, central venous pressure, urine output, uremia, and hematocrit).

Targeted treatment with intravenous fluids at a rate of 5-10 ml/kg/h should be used until resuscitation objectives are achieved.

• Ultrasound can show evidence of pancreatic and peripancreatic edema or edema or fluid collections, but is less effective in visualizing the pancreas because of the overlying intestine. Ultrasound can determine if gallstones are present and assess the likelihood of common bile duct stones if the bile duct is dilated.
   
• Computed tomography ( CT) is indicated for initial evaluation if the diagnosis is uncertain, to confirm severity when severe acute pancreatitis is suspected or if initial treatment fails or in case of clinical deterioration. CT can also be used to evaluate complications of pancreatitis such as necrosis, infection, pseudocyst, and hemorrhage.
   
• MRI and magnetic resonance cholangiopancreatography are useful in defining the anatomy of the pancreatic and bile ducts and identifying the cause of pancreatitis, including choledocholithiasis, but are less useful in the initial treatment of this disease.

A meta-analysis of six RCTs involving 329 patients found no evidence to support the use of prophylactic antibiotics.

The only advantage was the significant reduction in hospitalization. A second meta-analysis confirmed the same.

However, a meta-analysis of seven randomized studies with 404 participants reported decreased pancreatic infection in the case of pancreatic necrosis in patients treated prophylactically with imipenem.

However, antibiotic prophylaxis is not recommended to prevent infection in patients with severe acute pancreatitis.

Some evidence supports the concept of selective oral decontamination to prevent infection. In a study of 102 patients with severe acute pancreatitis, mortality and the incidence of Gram-negative infection were significantly decreased in the selective decontamination group, which was treated with an oral paste containing colistin, amphotericin, and norfloxacin. More studies are necessary to confirm these results.

Probiotics are not recommended in severe acute pancreatitis.

Nutritional support improves outcomes and limits complications in patients with severe acute pancreatitis.

This was confirmed in a meta-analysis of five RCTs with 202 patients who had a lower risk of infectious complications, pancreatic infections and mortality.

A meta-analysis of eight studies and 348 participants found that enteral feeding was superior to parenteral feeding in terms of complications and mortality. Another meta-analysis of 20 RCTs with 1070 patients found that no special type of enteral feeding improved outcomes.

A randomized Dutch study (PYTHON study) of 208 patients found that early enteral feeding (within 24 hours) did not decrease infection or death rates.

Enteral feeding can support the intestinal mucosal barrier and reduce bacterial translocation and through this decrease the risk of infected peripancreatic necrosis and other serious outcomes of acute pancreatitis.

The following drugs were studied:

> Octreotide is a peptide that inhibits exocrine secretion from the pancreas. Since trypsinogen and other enzymes initiate and propagate pancreatitis, octreotide would theoretically improve the course of severe acute pancreatitis. The evidence is weak on the effects of octreotide or the analogue somatostatin in reducing the incidence of organ failure, but not necrosis with infection or mortality.

> Antioxidants and vitamin C After several studies, the treatment of severe acute pancreatitis with antioxidants is not recommended.

> Pentoxifylline is a phosphodiesterase inhibitor that reduces tumor necrosis factor and leukotrienes, dampening inflammation, in addition to other effects. In a small RCT, 28 patients with severe acute pancreatitis were randomized to receive pentoxifylline or placebo. The pentoxifylline group had fewer days in the intensive care unit and in the hospital (P<0.05). Although not significant, none of the treatment group suffered new necrosis or organ failure, while two patients in the placebo group suffered progressive necrosis and three manifested organ failure.

> Lexipafant is a potent platelet-activating factor antagonist that was studied in 286 patients with severe acute pancreatitis. A small decrease in organ failure score was found in the treated group (P=0.023), but lexipafant had no other beneficial effects. 

> Gabexate mesylate, a protease inhibitor, was studied in 223 patients with no differences in mortality found between the group treated with this drug and the group receiving placebo.

Until now, no drug has been found to improve outcomes in patients with severe acute pancreatitis.

Peritoneal lavage was used in patients with severe acute pancreatitis and intraperitoneal fluid, theorizing that it removes toxins and various metabolites from the peritoneal cavity, minimizing systemic absorption and the effect on the systemic inflammatory response and organ failure. However, a systematic review of 10 RCTs with 469 patients found that peritoneal lavage made no significant difference in the risk of mortality or complications.

Patients with severe acute biliary pancreatitis may benefit from early endoscopic sphincterectomy and stone removal, according to four randomized studies. A prospective multicenter study of 153 patients reported that patients with cholestasis who underwent ERCP had fewer complications than those who did not receive this intervention. (25% v 54%, P=0.02).

Severe acute pancreatitis with biliary obstruction or cholangitis may improve with sphincterectomy after early resuscitation.

The American Gastroenterological Association is against urgent ERCP (<24 hours) in patients with acute biliary pancreatitis and without cholangitis.

The International Association of Pancreatology and the American Pancreatic Association recommend urgent ERCP in acute pancreatitis in patients with acute cholangitis.

In patients with mild biliary pancreatitis that resolves in two or three days, cholecystectomy should be performed during the same hospitalization, since the incidence of recurrent pancreatitis can be up to 60-80% in the following months.

On the other hand, patients with a severe episode of biliary pancreatitis should undergo cholecystectomy after resolution of pancreatitis and subsequent local complications.

Bile duct stones do not usually require surgical intervention, as endoscopic approaches are effective, but laparoscopic or open exploration of the common bile duct may be used.

> Acute accumulation of pancreatic fluid

Acute pancreatic fluid collection is a collection of homogeneous fluid adjacent to the pancreas associated with pancreatitis, without evidence of pancreatic necrosis. This term applies to a buildup within the first four weeks after the onset of pancreatitis. These fluid collections rarely become infected and most resolve spontaneously.

> Pseudocysts

Pseudocysts are encapsulated collections of fluid, with an inflammatory wall. They generally occur more than four weeks after the onset of severe acute pancreatitis. Many pseudocysts resolve spontaneously.

The size of the pseudocyst is not a reason for intervention, although some evidence suggests that cysts larger than 5 cm are less likely to resolve. As long as the pseudocyst is asymptomatic, observation and follow-up with contrast-enhanced CT or MRI are sufficient to confirm resolution.

When the pseudocyst is symptomatic, patients may experience pain, variable episodes of gastric or duodenal obstruction, weight loss, or biliary obstruction.

In these cases, the pseudocyst can be drained using various techniques, with the endoscopic route being the most accepted.

Pancreatic necrosis is classified into acute necrotic collection and encapsulated necrosis.

In recent decades, the trend has predominated to replace surgical debridement with a less aggressive treatment characterized by percutaneous drainage followed, when necessary, by minimally invasive approaches, such as video-assisted retroperitoneal debridement, surgical laparoscopic debridement, endoscopic drainage. transgastric and any combination of these modalities.

Case series indicated that sterile necrosis can resolve without intervention. Endoscopic techniques are used for symptomatic or infected pancreatic necrosis.

A systematic review of 10 retrospective reports and one RCT with 384 patients found that percutaneous drainage was sufficient as definitive treatment in 56% of patients with necrotizing pancreatitis.

Several controlled studies such as PANTER (PAncreatitis, Necrosectomy versus sTEp up approach ), PENGUIN ( Pancreatitis Endoscopic Transgastric vs Primary Necrosectomy in Patients with Infected Pancreatic Necrosis ) and others, showed that the rate of pancreatic fistulas and hospital stay were lower in the groups that received endoscopic treatment.

Hemorrhage and vascular emergence are rare, but potentially life-threatening in the presence of severe acute pancreatitis. The hemorrhage is caused by erosion of the splenic or gastroduodenal arteries or some other abdominal vessel close to the pancreas.

The diagnosis is made by arteriography or CT , in the presence of signs of hypovolemia and a decreasing hematocrit. The limited experience available suggests that arteriography with embolization or stent placement is the first-line treatment and if it fails, surgery is attempted.

The following table summarizes the International Association of Pancreatology/American Pancreatic Association (IAP/APA) guidelines ; the American Gastroenterological Association (AGA) and the American Society of

Gastrointestinal Endoscopy (ASGE)

There are several studies in development for the treatment of patients with acute pancreatitis.

• One of them reconsiders fluid replacement and compares the administration of saline with lactated Ringer’s. The primary endpoint is the change in the prevalence of early systemic inflammatory response syndrome using the PASS score to determine the severity of pancreatitis.
   
• Another study evaluates the administration of dabigatran, an anticoagulant that is also a strong trypsin inhibitor, which is activated in pancreatitis and contributes to the pathophysiology of the disease.
   
• Another study underway is the administration of infliximab in these patients. Infliximab is a monoclonal antibody that blocks tumor necrosis factor alpha (TNF-a), which plays an important role in the pathogenesis and severity of acute pancreatitis.
• Another study compares early percutaneous drainage of acute sterile collections with standard treatment.

The results of these works will be reported in 2020.