Severe Acute Pancreatitis

This chapter deals with the management of acute pancreatitis so severe that it requires ICU level care. It is not your average Sunday Morning Pancreatitis. The college loves this condition, and it is well represented among the past papers. Specifically, the following questions have required an indepth understanding of this condition:

Specific issues which have been asked about, and which the candidates need to be familiar with. These issues form the headings for the subsections of this chapter, to simplify revision. As far as pulished literature goes, the time-poor candidate may safely limit their reading to Maheshwari & Subramanian (2016) from Critical Care Clinics.

Differential diagnosis of acute abdomen

Question 23 from the first paper of 2009 offered the candidates an obese hypoxic woman in a state of shock, with a history of abdominal pain and vomiting. They also gave them a high lipase, making pancreatitis the most likely explanation. But what if they didn't? Differentials for an acute shocked abdomen include the following easily remembered list:

Vascular causes:

  • acute mesenteric vasculitis
  • mesenteric ischaemia, embolic or otherwise

Infectious causes: sepsis from any origin, but more likely the gut,

  • biliary sepsis
  • colitis

Neoplastic causes

  • perforated colorectal mass
  • SIRS due to a systemic cytokine release, due to lymphoma or leukaemia

Drug-induced causes

  • Drug-induced pancreatitis or hepatitis

Autoimmune causes eg. inflammatory bowel disease with perforation

Traumatic causes eg. Boerhaave's syndrome due to excessive vomiting

Endocrinological cause of abdo pain and SIRS, eg. pacreatitis due to any number of causes

Causes of pancreatitis

Toxic:

  • Alcohol (36%)
  • Azathioprine
  • Tetracyclines
  • Metronidazole
  • Pentamidine
  • Nitrofurantoin
  • Methyldopa
  • Ranitidine
  • Thiazides
  • Frusemide
  • Valproate
  • Scorpion venom
  • Organophosphates
  • Methanol

Obstructive/mechanical:

  • Gall stones (38%)
  • Biliary tract disease
  • ERCP
  • Trauma
  • Penetrating duodenal ulcer

Infectious

  • HIV
  • EBV
  • Mumps
  • Mycoplasma
  • legionella
  • Campylobacter
  • Ascaris

Ischaemic

  • Atheroma (eg. post IABP insertion)
  • Shock states

Miscellaneous:

  • Hyperlipidaemia
  • Hypercalcemia
  • Ketoacidosis
  • End-stage renal failure
  • Pregnancy
  • Vasculitis (eg. SLE)

All clever bullshit aside, 70% of the time its either gallstones or alcoholism.

However, the College expects us to be able to generate a torrential stream of differential aetiologies for pancreatitis, and this is not a complete waste of time, because one of these days one will encounter a pancreatitis caused by something very rare and weird.

LITFL offers a nice mnemonic for these aetiologies: I GET SMASHED

  • Idiopathic
  • Gall stones
  • Ethanol
  • Trauma
  • Steroids
  • Mumps and other viruses (EBV, CMV, HIV)
  • Autoimmune diseases (SLE, polyarteritis nodosa, pregnancy)
  • Scorpion stings
  • Hypercalcaemia, hyperlipidaemia, hypothermia, hypotension (ischemia)
  • ERCP, emboli
  • Drugs

Causes of hypotension in pancreatitis

  • "Third space losses" due to capillary leak, particularly sequestration in the abdomen
  • Systemic inflammatory response due to cytokine release
  • Gastrointestinal losses due to vomiting, diarrhoea, decreased oral intake, and gastric bleeding
  • Retroperitoeal hematoma (maybe from a ruptured splenic artery aneurysm)
  • Decreased preload due to abdominal compartment syndrome
  • Cardiac output decrease due to acidosis and SIRS-associated cardiomyopathy

Causes of hypoxia in pancreatitis

  • ARDS due to systemic cytokine release
  • Pleural effusions due to third space fluid mobilisation and aggressive fluid resuscitation
  • Pulmonary oedema (decreased cardiac contractility, capillary leak, fluid resuscitation)
  • Aspiration pneumonia (decreased level of consciousness, history of vomiting)

Ranson's criteria for predicting mortality from pancreatitis

We have had these since 1974. I found a simple breakdown in the ANZ Journal of Surgery.

On admission
Age > 55 yrs
WCC > 16,000
LDH > 600 U/I
AST > 120 U/I
Glucose > 10 mmol/L

Within 48 hours
Haematocrit fall > 10%
Urea rise > 0.9 mmol/L
Calcium < 2 mmol/L
pO2 < 60mmHg
Base deficit > 4
Fluid sequestration > 6 L

You get one point for each criteria met. The mortality from pancreatitis by these criteria, according to the score generated, are as follows:

< 3  =  1%
3-4  =  15%
5-6  =  40%
> 6  =  100%

Thus, if you are an elderly person who has rocked up to ED hyperglycaemic, with a high WCC, high LDH, deranged LFTs, acidosis, hypoxia and hypocalcemia - you are not going to do well.

Of course, since Ranson's days, we have improved our management somewhat, and these days mortality from severe acute pancreatitis in the ICU is closer to 15%. From this, one may be tempted to reach the conclusion that the Ranson criteria are no longer worth very much as a predictor of survival.

Investigations for severe acute pancreatitis

  • EUC/CMP: low total calcium, renal failure,
  • Arterial blood gas: ionised calcium, metabolic acidosis
  • Amylase and lipase
  • LFTs  in the event the common bile duct is obstructed, and to screen for complications of alcoholism.
  • Abdominal CT with contrast is the king. An inflamed pancreas will not absorb contrast. and, an obstructing stone may be obvious.
  • Triglycerides to exclude that cause of pancreatitis

Treatments which we know are ineffective

Octreotide:

Several trials have been analysied; there does not appear to be any benefit.

Protease inhibitors:

Aprotinin and gabexate mesilate were supposed to decrease pancreatic "autodigestion" by inhibiting the pancreatic proteases. Turns out, they dont work.

Prophylactic antibiotics

About 50% of these people will get their pancreatic pseudocyst infected with various organisms.

In the 1990s, people believed in prophylactic antibiotics because small-scale trials demonstrated a benefit. However, a recent review suggests that there does not appear to be any benefit, even on the basis of studies which were not adequately powered to detect a subtle benefit. This review, it must be added, excluded the cases of severe necrotising pancreatitis, so the hardcore proponents of antibiotic therapy still recommend prophylaxis.

If your pseudocyst is infected, or if you are a firm believer in hosing your patients with antibiotics, then it seems you need carbapenems, because their penetration into pancreatic tissue tends to be the best.

Treatments which are supported by weak evidence

Corticosteroids

Like in all shock states of critical illness, there is perhaps a role here for "stress dose" steroids. In the absence of actual evidence, this is still a hypothesis with some merit.

Anti-fungals

The more severe your pancreatic necrosis, the more likely you are to get it colonised with a fungus. Thus, there may be a role for antifungal drugs here, at least in the opinion of some people, as a means of delaying surgery. Others may argue that the surgery should be delayed as long as possible anyway, and by that stage one does not wish to be colonised by a species which has been selected for resistance to routine antifungal drugs.

Enteral nutrition for severe acute pancreatitis

In short, TPN either does nothing to improve mortality, or is associated with increased mortality.

The 2009 Canadian Guidelines mention 3 meta-analysis studies, which all show a mortality benefit with early eneteral nutrition. This is thought to be the result of a decreased SIRS response, which in turn is due to diminished bacterial translocation from the healthier gut.

Oh's Manual quotes the International consensus guidelines for nutrition therapy in pancreatitis, which suggest a few simple rules. These have been modified slightly with the addition of whatever the college examiners wrote in their model answer to Question 16 from the second paper of 2017.

  • For mild or moderate pancreatitis:
    • Fast for the first 3-4 days? Oh's Manual suggests that these patients need no feeding whatsoever until the disease settles (i.e. for 5-7 days), but the 2017 college answer recommends immediate feeding. The college quote a study ("NEJM 2014") to support their answer, which presumably is the PYTHON trial by Bakker et al (2014). This was an RCT which compared immediate enteral feeding with oral diet initiated 72 hours after presentation, which is not exactly "commence at admission or within 24 hours" ​​​​​.​
    • Advance to normal oral diet before 72 hours. Bakker et al (2014) found that enteral nutrition is no better than oral.
    • No need to rush enteral nutrition. Only progress to enteral nutrition of the patient is not tolerating oral diet after 5-7 days
    • Avoid TPN. Only progress to TPN if enteral nutrition has been trialled and is clearly not tolerated. The college mention another study ("Cochrane 2010") to support their aversion to TPN,  presumably referring to the meta-analysis by Al-Omran et al (2010). After pruning the evidence tree the authors found only two trials to analyse, with a total of 70 patients. They were forced to conclude that the data were insufficient for any firm recommendation, but that the trend was in the direction of better outcomes with enteral nutrition. This vaguely reflects "reduced mortality and other end-points (including infective, MOF)" which is what the college examiners said about it.
  • For severe pancreatitis:
    • EN is preferable to PN (ASPEN and ESPEN agree on this)
    • EN should be started early.
    • Tube position does not matter (gastric vs jejunal). The college refer to "2 small metaanalyses" in support of their assertion, presumably referring to Chang et al (2013)  with 157 patients and Petrov et al (2008) with 92 patients.  Neither found any benefit in jejunal feeding unless you've got clearly demonstrated impaired gastric emptying. 
    • Elemental feeds are preferred (ASPEN)
    • Nutritional requirements should be:
      • 25-35 kcal/kg of total body weight per day
      • 1.2 to 1.5g/kg of protein
      • 3-6g/kg of carbohydrate
      • go easy on the lipids (up to 2g/kg)
    • When to use parentral nutrition? These guidelines are much less prescriptive than previous statements. "when EN is contraindicated or not well tolerated", they say.

Systemic antibiotics for severe acute pancreatitis

A part of Question 16 from the second paper of 2017 and the whole 10-mark lot of Question 1 from the first paper of 2016 asked the candidates to discuss this issue.   The college answer to the latter question was quite good, and is used to create the summary below. In brief, there is no role for prophylactic antibiotics in severe acute pancreatitis, and one may briefly conclude this issue by saying that clinically significant extrapancreatic infections should still be treated with antibiotics (as you normally would), as well as any infected pancreatic material (which has been proven to be infected).  However, in order for future generations to have a prefabricated answer in their pocket, the issue will be critically evaluated below.

Potential uses of antibiotics in pancreatitis

  • Prophylaxis to prevent infection of the necrotic pancreas
  • Prophylaxis to prevent infection of the pancreatic pseudocyst
  • Treatment of infected pancreatic necrosis
  • Coincidental use of these antibiotics to treat an unrelated extrapancreatic infection

Coincidental treatment of extrapancreatic infection

  • The college answer to Question 1 from the first paper of 2016 mentions that up to 20% of these patients go on to develop extrapancreatic infections which require antibiotics. This is probably not based on the 2014 systematic review by Brown et al, who found that the incidence of infectious complication  was 32% (95% CI 23–41%), with the commonest being respiratory infection (9.2%) and bacteraemia (8.4%).
  • There is some risk that the pancreatic necrosis will get infected by haematogenous spread: "Half of bacterial cultures of pancreatic necrosis are of non-enteric origin".
  • However, Brown et al did not find any association between the presence of extrapancreatic infection and severity or mortality of the pancreatitis. From this, we can infer that we need not be "extra-aggressive" in managing these infections; no additional measures need to take place apart from the  antibiotic and source control measures which would routinely be used.

Treatment of infected pancreatic necrosis

  • "Pancreatic necrosis" is defined as an non-enhancing area of the pancreas no less than 3cm in diameter, or no less than 30% of the pancreatic volume on a contrast-enhanced CT.
  • About 20% of the patients go on to develop necrosis, and about 8-12% of patients go on to develop infected necrosis (Mike Larvin, 2008)
  • Infection of the pancreatic necrosis tends to be confirmed late (19-21 days following onset).
  • Survivors from early organ system failure may still die if pancreatic necrosis later becomes infected.
  • Organ system failure tends to be worse and mortality tends to be high (in one series, six of the eight patients had died).
  • Confirmation of the diagnosis is invasive, i.e. by samples and culture. Pros (Banks, 2005) and cons (Pappas, 2005) of aspiration have been offered, and they are equally valid points of view.
  • If the patient is haemodynamically unstable and the infected pancreas is held responsible, CT-guided or gastroscopic drainage offers both a diagnosis (confirming infection) and souirce control.
  • If infection is confirmed by gram stain, the best choice of antibiotics is probably meropenem.

Arguments for the use of prophylactic antibiotics in severe pancreatitis

  • Pancreatic necrosis promotes the development of a nutrient-rich medium for bacterial growth
  • The decomposing pancreatic tissue is difficult to access surgically, and represents a source of infection which cannot be easily controlled (hence, one must rely on antibiotics)
  • The pancreatitis patient will be constantly febrile and with raised inflammatory markers, which makes the diagnosis of sepsis more difficult.
  • Sepsis is a major cause of death in severe pancreatitis
  • Non-pancreatic infection plays a major role in this mortality (so, its not just "for the pancreas").
  • Everybody gives antibiotics, it appears to be standard practice in spite of the published guidelines. In their compliance survey, Baltatziz et al (2016) found antibiotic prophylaxis was used in 44-88% of the units

Counterarguments to the wanton abuse of antibiotics

  • Penetration into the collection will be poor.
  • If you use antibiotics to treat a presumed non-pancreatic source of sepsis, then those antibiotics will likely have poor penetration into the area of pancreatic necrosis. If, instead, you intentionally choose antibiotics which penetrate well, then likely you are over-treating the extrapancreatic source (i.e. meropenem ends up beign used where ceftriaxone would have sufficed).
  • Infection of the collection typically occurs after day 10; fever prior to this will usually be aseptic SIRS.
  • The use of antibiotics will promote the overgrowth of resistant organisms, and select for species which will subsequently be more difficult to eradicate.

Evidence

  • To quote a recent publication, "the highest quality studies (rigorous blinding, placebo protocols, inclusion only of severe disease, detailed patient flow descriptions) uniformly fail to show benefit for prophylaxis" (Parent et al, 2016)
  • The most recent meta-analysis (Jafri et al, 2009) found no improvement in mortality, risk of pancreatic pseudocyst infection or need for surgical intervention. The risk of extrapancreatic infection, however, did improve (an absolute risk reduction of 15%, NNT =7).
  • The Cochrane analysis referred to by the college in Question 1 from the first paper of 2016 is Villatoro et al (2010), whose conclusion was also "no benefit". Of the literature available at the time, the authors were able to identify seven heterogeneous studies (with 404 patients). There were various trends towards improved mortality (with β-lactams) and decreased pancreatic infection (with imipenem), but these trends did not reach statistical significance. As well, "the incidence of non-pancreatic infections was non-significantly different (21% versus 32.5%), as was the incidence of overall infections (34.4% versus 52.8%), and operative treatment rates". None of the included studies were adequately powered.

Antibiotic choice (if you felt compelled to give them)

  • All antibiotics penetrate the necrotic tissue, but most end up not achieving MIC (Bassi et al, 1994).
  • Drugs which achieve a high concentration in pancreatic tissue :
    • Imipenem (and thus also meropenem)
    • Metronidazole
    • Fluoroquinolones (specifically, pefloxacin)
  • Drugs which are known to penetrate poorly:
    • Aminoglycosides
    • Beta-lactams

Guidelines and "own practice"

  • This practice is not supported by the American College of Gastroenterology guidelines (2013)
  • Antibiotics should not be routinely given to patients with severe acute pancreatitis
  • Clinical evidence of sepsis (including sepsis fo other origin, eg. urinary or pulmonary) should be promptly treated with appropriate antibiotics (not pancreas-specific antibiotics)
  • It may be possible to sample the collection by CT-guided aspiration; if the Gram-stain is positive this will be the deciding factor

A generic approach to the management of acute severe pancreatitis

  • Airway:
    • intubation may be required; aspiration may be a major risk
  • Breathing:
    • mechanical ventilation with PEEP titrated to permit recruitment of collapsed lung bases
    • As ARDS develops, tidal volumes may nee to be reduced and lung-protective ventilation may need to be adopted, with permissive hypercapnea
  • Circulation:
    • Initial stages of resuscitation will likely consist of fluids only
    • The SIRS response may lead to cardiovascular collapse; given that metabolic acidosis and SIRS-associated cardiomyopathy may also be present, inotropes as well as vasopressors will likely be required
  • Pain control:
    • this will be vitally important in the non-intubated patient, in order to maintain VQ matching by continuing deep breathing
  • Electrolytes- particularly calcium - must be carefully monitored
  • Fluid balance management neesd to be careful, and dialysis may be required
  • Feeds via the NG tube may be commenced; there does not appear to be any evidence that "pancreatic rest" is in any way beneficial. The necrotic pancreas is not going to be responsive to the normal secretory stimuli, and the
  • Coagulation factors need to be corrected, and careful surveillance of the abdominal vessels must occur, as the splenic artery has a tendency to form aneurysms and bleed everywhere
  • Antibiotics are probably not indicated
  • ERCP to manage the cause of CBD obstruction should take place at the earliest opportunity, as indicated. if there is no ERCP-amenable cause, surgical drainage of the necrotic pseudocyst may take place as soonas the pseudocyst has formed a sufficiently distinct "wall".
  • An alternative to surgical cyst drainage is endoscopic ultrasound-guided drainage, which may be a better option for the frail patient.

The role of ERCP in pancreatitis

This came up as a minor 20% part of Question 16 from the second paper of 2017.

  • ERCP specifically:
    • Diagnostic use:
      • To establish that there are gall stones in the common bile duct
      • To determine that the sphincter of Oddi is dysfunctional
      • To investigate pancreatic duct stenosis
      • To get biopsy samples of a neoplasm
      • To investigate any sort of anastomosis
      • To perform intra-ductal ultrasound
    • Therapeutic use:
      • Sphincterotomy, for stenosis or sphincter dysfunction
      • Stone extraction or fragmentation
      • Placement of a pancreatic duct or common bile duct stent
  • Endoscopy more generally adds a few strategies:
    • Placement of nasojejunal tubes
    • Transgastric drainage of pancreatic pseudocysts

 

References

Oh's Intensive Care manual: Chapter   43  (pp. 495)  Severe  acute  pancreatitis by Duncan  LA  Wyncoll

Wang, Guo-Jun, et al. "Acute pancreatitis: etiology and common pathogenesis." World J Gastroenterol 15.12 (2009): 1427-1430.

Cappell, Mitchell S. "Acute pancreatitis: etiology, clinical presentation, diagnosis, and therapy." Medical Clinics of North America 92.4 (2008): 889-923.

Ranson, J. H., et al. "Prognostic signs and the role of operative management in acute pancreatitis." Surgery, gynecology & obstetrics 139.1 (1974): 69-81.

Ziada, Susan, Jonathan Field, and Gerben BJM Keijzers. "Outcome of severe pancreatitis." Australian Critical Care 22.1 (2009): 48. - presented HERE as a brief summary

Heinrich, Stefan, et al. "Evidence-based treatment of acute pancreatitis: a look at established paradigms." Annals of surgery 243.2 (2006): 154-168.

Pederzoli, Paolo, et al. "A randomized multicenter clinical trial of antibiotic prophylaxis of septic complications in acute necrotizing pancreatitis with imipenem." Surgery, gynecology & obstetrics 176.5 (1993): 480-483.

Wilmer, Alexander. "ICU management of severe acute pancreatitis." European journal of internal medicine 15.5 (2004): 274-280.

Villatoro, Eduardo, Mubashir Mulla, and Mike Larvin. "Antibiotic therapy for prophylaxis against infection of pancreatic necrosis in acute pancreatitis."Cochrane Database Syst Rev 5.5 (2010).

De Waele, Jan, et al. "Relative adrenal insufficiency in patients with severe acute pancreatitis." Critical Care 11.Suppl 2 (2007): P401.

Eggimann, Philippe, Saurabh Jamdar, and Ajith K. Siriwardena. "Pro/con debate: antifungal prophylaxis is important to prevent fungal infection in patients with acute necrotizing pancreatitis receiving broad-spectrum antibiotics." Crit Care 10.5 (2006): 229.

Mirtallo, Jay M., et al. "International consensus guidelines for nutrition therapy in pancreatitis." Journal of Parenteral and Enteral Nutrition 36.3 (2012): 284-291.

Maheshwari, Rahul, and Ram M. Subramanian. "Severe Acute Pancreatitis and Necrotizing Pancreatitis." Critical care clinics 32.2 (2016): 279-290.

Baltatzis, Minas, et al. "Antibiotic use in acute pancreatitis: Global overview of compliance with international guidelines." Pancreatology (2016).

Parent, Brodie, and E. Patchen Dellinger. "Antibiotic Prophylaxis for Acute Necrotizing Pancreatitis." Difficult Decisions in Hepatobiliary and Pancreatic Surgery. Springer International Publishing, 2016. 433-449.

Tenner, Scott, et al. "American College of Gastroenterology guideline: management of acute pancreatitis." The American journal of gastroenterology 108.9 (2013): 1400-1415.

Jiang, Kun, et al. "Present and future of prophylactic antibiotics for severe acute pancreatitis." World J Gastroenterol 18.3 (2012): 279-84.

Jafri, Nadim S., et al. "Antibiotic prophylaxis is not protective in severe acute pancreatitis: a systematic review and meta-analysis." The American Journal of Surgery 197.6 (2009): 806-813.

Bassi, C., et al. "Behavior of antibiotics during human necrotizing pancreatitis." Antimicrobial agents and chemotherapy 38.4 (1994): 830-836.

Brown, Lisa A., et al. "A systematic review of the extra-pancreatic infectious complications in acute pancreatitis." Pancreatology 14.6 (2014): 436-443.

Larvin, Mike. "Management of infected pancreatic necrosis." Current gastroenterology reports 10.2 (2008): 107-114.

Banks, Peter A. "Pro: computerized tomographic fine needle aspiration (CT-FNA) is valuable in the management of infected pancreatic necrosis." The American journal of gastroenterology 100.11 (2005): 2371.

Pappas, Theodore N. "Con: computerized tomographic aspiration of infected pancreatic necrosis: the opinion against its routine use." The American journal of gastroenterology 100.11 (2005): 2373.

Villatoro, Eduardo, Mubashir Mulla, and Mike Larvin. "Antibiotic therapy for prophylaxis against infection of pancreatic necrosis in acute pancreatitis." The Cochrane Library (2010).

Bakker, Olaf J., et al. "Early versus on-demand nasoenteric tube feeding in acute pancreatitis." New England Journal of Medicine 371.21 (2014): 1983-1993.