Contentious topics in the management of severe acute pancreatitis

Introduction

Acute pancreatitis results from an intense inflammatory reaction resulting most commonly from excessive alcoholism or the presence of gall stones. It runs a relatively mild course in most patients and responds rapidly to supportive therapy including adequate pain relief, intravenous fluids, and oral intake when feasible. However, the severe form of the disease occurs in 20-30% of patients, characterized by organ failures, and leads to a protracted and often complicated clinical course.¹ The management of the critically ill patient with severe acute pancreatitis (SAP) has evolved over the years; however, several contentious issues remain, especially in the high-risk group of patients. 

Classification of severity

Although the revised Atlanta Classification is widely accepted, no single classification system has been demonstrated to accurately predict the development of organ failures, infected necrosis, or other important clinical outcomes in SAP. According to this classification, mild acute pancreatitis is defined as uncomplicated pancreatitis without organ failures. The presence of organ failure for a period of less than 48 h or local complications represents moderately severe acute pancreatitis. SAP is defined as the presence of organ failure for more than 48 h. The APACHE II score was shown to have a high sensitivity for the prediction of necrosis, organ failures, and the requirement for ICU admission.² In the real world, severity scoring systems may be of limited value in predicting clinical outcomes. Furthermore, the decision for focused care in the ICU is largely based on the current clinical situation, and not on predicted outcomes. 

Therapeutic modalities 

Intravenous fluids

Extensive third space fluid sequestration can lead to hypovolemia in SAP. Hypovolemia can result in global circulatory impairment and provoke organ failures; besides, it can also compromise microcirculatory flow within the pancreas and trigger pancreatic and peripancreatic necrosis. However, high-volume fluid resuscitation may be detrimental and lead to fluid overload, pulmonary edema, and abdominal compartment syndrome (ACS). Aggressive resuscitation with 10 to 15 ml/kg/h within the first 72 h of disease onset was associated with increased requirement for ventilator support, development of ACS, sepsis, and higher mortality as compared to a modest resuscitative strategy of 5 to 10 ml/kg/h. The choice of crystalloid fluid between normal saline and Ringer’s lactate is widely debated in the critically ill, with no definitive conclusions. A recent randomized controlled trial (RCT) of 40 patients suggested a lower inflammatory response based on the SIRS criteria and C-reactive protein levels at 24, 48, and 72 h using Ringer’s lactate compared to normal saline as the resuscitation fluid in patients with SAP.³

Nutritional support 

Patients with SAP require nutritional support for an extended period, usually, for 6–8 weeks. Total parenteral nutrition was recommended previously, based on the presumption that enteral feeding may stimulate pancreatic and intestinal secretions, worsening the inflammatory process. However, withholding enteral feeds leads to gut mucosal atrophy, translocation of bacteria from the intestines, and endotoxin release. This may lead to an increased propensity for infection within the necrotic pancreas. In a meta-analysis of 381 patients from eight RCTs, enteral nutrition was associated with lower mortality, a lower incidence of infectious complications, reduced organ failures, and less requirement for surgical intervention compared to parenteral nutrition. Most patients may be fed by the nasogastric route. Enteral nutrition is well usually well-tolerated by the nasogastric route with no recurrence of pain or feeding intolerance in patients with SAP. A recent meta-analysis revealed no difference in the delivery of 75% of nutritional targets with nasogastric compared to nasojejunal feeding; the requirement for total parenteral nutrition was also no different.⁴

Prophylactic antibiotics

Antibiotic therapy is not indicated in acute pancreatitis in the absence of infection. Prophylactic antibiotic therapy does not prevent infection in sterile necrosis; besides, it does not influence the incidence of organ failures, mortality, and duration of stay in hospital.⁵ Infection of the necrotic pancreatic or peripancreatic tissues generally occurs after 10 days of disease onset. Appropriate antibiotic therapy is indicated in the presence of pancreatic or non-pancreatic infections. Infection of pancreatic or peripancreatic collections is strongly suggested by the presence of gas on a contrast-enhanced CT scan, or by positive culture from fine-needle aspiration (FNA). FNA and culture, though recommended, has a low sensitivity for the diagnosis of infection, and generally not utilized by most physicians.⁶ Carbapenems, fluoroquinolones, and metronidazole achieve high concentrations in infected pancreatic tissue and are generally recommended. Fungal infections are common in patients with infected necrosis and pseudocyst formation. Prolonged therapy with multiple broad-spectrum antibiotics predisposes to fungal infections in SAP. 

The role of endoscopic retrograde cholangiopancreatography in SAP

Gall stones may obstruct the sphincter of Oddi impeding biliary drainage; this results in back pressure within the pancreatic duct and stimulates enzyme release, with the potential to worsen the inflammatory response. Endoscopic retrograde cholangiopancreatography (ERCP) directed sphincterotomy and stone extraction is appropriate within 24–48 h of disease onset in patients with cholangitis or in the presence of unrelieved biliary obstruction. Although a mortality benefit has not been demonstrated in patients who undergo early ERCP, it may lead to a more rapid recovery and reduced hospital stay.⁷

Triglyceride lowering therapies

Hypertriglyceridemia is the third commonest cause of acute pancreatitis worldwide; an appropriate treatment plan is crucial. Specific therapy in the acute phase includes insulin, heparin, high volumehemofiltration, and plasmapheresis with albumin replacement. Treatment should be continued aiming for serum triglyceride levels of <500 mg/dl. Oral lipid-lowering therapy with fibrates is recommended when oral intake is feasible.

Abdominal compartment syndrome

The intra-abdominal pressure (IAP) may rise in SAP due to aggressive fluid resuscitation, leaky capillaries, pancreatic and peripancreatic edema, hemorrhage, necrosis, and generalized ileus. Measurement of IAP is important, as clinical assessment is often fallacious. Bladder pressure is well established as the surrogate of IAP and transduced at the point of intersection between the midaxillary line and the iliac crest. Abdominal compartment syndrome is diagnosed when there is a sustained rise in IAP over 20 mm Hg or an abdominal perfusion pressure (mean arterial pressure-intra-abdominal pressure) below 60 mm Hg accompanied by the onset of new organ failure. The kidneys are often initially affected, followed by circulatory and respiratory impairment. It is crucial to recognize ACS early and initiate measures to reduce IAP. These include using a judicious resuscitative strategy, abdominal fluid drainage, and evacuation of intraluminal contents. Administration of intravenous diuretics and fluid removal by continuous renal replacement therapies may also help reduce IAP. 

Interventional strategies 

Intervention is often required in the presence of infected pancreatic or peripancreatic necrosis. Interventional strategies have undergone a paradigm shift in recent years; minimally invasive surgical and endoscopic approaches have largely supplanted the traditional open approach. Drainage or necrosectomy may not be required in a minority of patients with infected necrosis if they remain clinically stable on antibiotic therapy.⁸ The first step in patients who require intervention is either endoscopic transluminal drainage (ETD) or CT or ultrasound-guided percutaneous drainage, usually through the retroperitoneal route. This is followed by endoscopic or minimally invasive surgical necrosectomy as appropriate. A minimally invasive approach has not been shown to reduce mortality compared to open necrosectomy in RCTs. However, a recent pooled analysis of 1980 patients from 15 study cohorts showed reduced overall mortality with endoscopic and minimally invasive surgical compared to open necrosectomy. Following propensity score matching and risk stratification, the mortality benefit was evident in the high and very high-risk category of patients.⁹ Endoscopic ultrasonography is currently preferred for transluminal drainage as collections can be directly visualized and drained regardless of the presence of a visible gastric bulge. Color doppler allows visualization and avoidance of blood vessels, adding to safety. Forward-viewing endoscopes allow irrigation and debridement of necrotic material using a combination of balloons, snares, nets, and other accessories.¹⁰

Centrally located and lesser sac collections may be drained through the endoscopic route; however, collections in the flanks, and deep pelvic collections may require image-guided percutaneous catheter drainage. This may later be followed up later by sinus tract endoscopy or video-assisted retroperitoneal debridement. A step-up approach to necrotizing SAP is depicted in Fig 1. An open surgical approach may be required in case of perforated viscus, to relieve refractory ACS, if ischemic bowel is suspected, or with failure of a step-up approach. 

The bottom line 

• SAP often leads to a complicated clinical course and carries significant mortality.
• Although several severity classifications have been described, they have limited value in predicting hardcore clinical outcomes. 
• A judicious approach to fluid resuscitation with crystalloids is warranted in the early phase of resuscitation; Ringer’s lactate solution may be preferable to normal saline as the resuscitation fluid.
• Enteral nutrition within the first 48 h of disease onset may help to preserve the integrity of the gut mucosa and reduce the incidence of infective complications.
• Prophylactic antibiotic use is not beneficial in SAP; in contrast, it may lead to overgrowth with resistant organisms. 
• ERCP and sphincterotomy within the first 48 h may be appropriate in patients with gall stone-related pancreatitis. 
• Contrary to the traditional open approach, a minimally invasive step-up strategy with endoscopic and percutaneous drainage as the first step is currently preferred. This may be followed later by minimally invasive surgical or endoscopic necrosectomy as appropriate.  

References

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2.         Kumar AH, Griwan MS. A comparison of APACHE II, BISAP, Ranson’s score and modified CTSI in predicting the severity of acute pancreatitis based on the 2012 revised Atlanta Classification. Gastroenterol Rep. 2018;6(2):127. doi:10.1093/gastro/gox029

3.         al de-ME et. Fluid resuscitation with lactated Ringer’s solution vs normal saline in acute pancreatitis: A triple-blind, randomized, controlled trial. – PubMed – NCBI. https://www.ncbi.nlm.nih.gov/pubmed/29435315. Accessed September 5, 2019.

4.         Yi F, Ge L, Zhao J, et al. Meta-analysis: Total Parenteral Nutrition Versus Total Enteral Nutrition in Predicted Severe Acute Pancreatitis. Intern Med. 2012;51(6):523-530. doi:10.2169/internalmedicine.51.6685

5.         Lim CLL, Lee W, Liew YX, Tang SSL, Chlebicki MP, Kwa AL-H. Role of Antibiotic Prophylaxis in Necrotizing Pancreatitis: A Meta-Analysis. J Gastrointest Surg. 2015;19(3):480-491. doi:10.1007/s11605-014-2662-6

6.         Grinsven J van, Brunschot S van, Bakker OJ, et al. Diagnostic strategy and timing of intervention in infected necrotizing pancreatitis: an international expert survey and case vignette study. HPB. 2016;18(1):49-56. doi:10.1016/j.hpb.2015.07.003

7.         Vege SS, DiMagno MJ, Forsmark CE, Martel M, Barkun AN. Initial Medical Treatment of Acute Pancreatitis: American Gastroenterological Association Institute Technical Review. Gastroenterology. 2018;154(4):1103-1139. doi:10.1053/j.gastro.2018.01.031

8.         Runzi M, Niebel W, Goebell H, Gerken G, Layer P. Severe acute pancreatitis: nonsurgical treatment of infected necroses.Pancreas. 2005;30(3):195-199.

9.         van Brunschot S, Hollemans RA, Bakker OJ, et al. Minimally invasive and endoscopic versus open necrosectomy for necrotising pancreatitis: a pooled analysis of individual data for 1980 patients. Gut. 2018;67(4):697-706. doi:10.1136/gutjnl-2016-313341

10.       Arvanitakis M, Dumonceau J-M, Albert J, et al. Endoscopic management of acute necrotizing pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) evidence-based multidisciplinary guidelines. Endoscopy. 2018;50(5):524-546. doi:10.1055/a-0588-5365