Core Topics in General & Emergency Surgery: Companion to Specialist Surgical Practice (41 page)
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Authors: Simon Paterson-Brown MBBS MPhil MS FRCS
In those patients with severe acute pancreatitis the systemic inflammatory response may be maintained by intestinal dysfunction, leading to bacterial translocation from the intestinal lumen. Intestinal dysfunction may in part be a consequence of the nil-by-mouth regimen, leading to a loss of luminal nutrition in the intestine. The provision of enteral nutrition aims to ameliorate intestinal dysfunction, thereby reducing the systemic inflammatory response and improving outcome.
This hypothesis was assessed in a randomised study of 32 patients with acute pancreatitis who received either early enteral nutrition through an endoscopically placed feeding tube, or parenteral nutrition following central or peripheral venous cannulation.
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Enteral nutrition appeared to be well tolerated, with no patients developing a significant complication from the study intervention. Importantly, enteral nutrition was able to supply a similar caloric intake to parenteral nutrition. However, the patients in the study had relatively mild disease and thus no significant differences in clinical outcome were observed, although enteral nutrition was associated with a significant reduction in the cost of patient care.
A similar study that randomised 34 patients with acute pancreatitis to receive, in addition to standard therapy, either early enteral nutrition or parenteral nutrition demonstrated that the introduction of early enteral nutrition was associated with a significant reduction in CRP and APACHE II scores.
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Furthermore, in those receiving parenteral nutrition, serum anti-endotoxin IgM antibody levels increased, whereas they remained unchanged in those receiving enteral nutrition.
In contrast to the previous two studies, all patients in the randomised controlled trial reported by Kalfarentzos et al.
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had prognostically severe disease. In total, 38 patients were randomised to receive either enteral nutrition or parenteral nutrition. Enteral nutrition was delivered distal to the ligament of Treitz through a radiologically placed feeding tube. Even in this population of patients with severe disease, enteral nutrition was well tolerated, with the protein and caloric intake equalling that administered to the patients receiving parenteral nutrition. This ability to provide adequate nutrition via the enteral route appeared to translate into a clinical benefit. In those patients receiving enteral nutrition there were significantly fewer complications and a significant reduction in the number of infectious episodes. Further, the cost of nutritional support in the enteral feeding group was one-third of that in the parenteral nutrition group.
A slightly different study randomised 27 patients with prognostically severe acute pancreatitis to either enteral nutrition or standard care, where parenteral nutrition was not instituted from the outset.
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Although no major complications arose from the provision of enteral nutrition, it was not possible to meet full nutritional requirements. In contrast to previous studies, enteral nutrition did not appear to affect markers of the inflammatory response (IL-6, tumour necrosis factor receptors and CRP). Moreover, the institution of enteral nutrition was associated with a significant deterioration in gut barrier function.
A large study from China
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randomised 96 patients with severe pancreatitis to parenteral nutrition versus nasojejunal feeding. Measures of inflammation including CRP and IL-6 decreased earlier with enteral nutrition, as did APACHE II scores. Furthermore, mucosal permeability was improved, as inferred by urine endotoxin levels.
In an attempt to determine the efficacy of both enteral nutrition and antibiotic prophylaxis, Olah et al.
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undertook a two-phase study. In the first phase, patients within 72 hours of the onset of prognostically severe acute pancreatitis were ‘randomised’ to either parenteral nutrition or enteral nutrition delivered by a nasojejunal feeding tube. In this phase of the study there was no significant difference in the rates of septic complications between the two treatment groups. The second phase of the study was a prospective cohort study, with all patients being given enteral nutrition and imipenem with prophylactic intent, with subsequent comparison of outcome measures obtained in phase 2 with those obtained in phase 1. Following their analysis, the authors of this study stated that the combination of enteral nutrition and antibiotic prophylaxis significantly reduced the rate of septic complications and the requirement for surgical intervention when compared with parenteral nutrition. However, the results of the study have to be interpreted with caution. The initial phase of the study was not truly ‘randomised’, with patients being allocated to treatment groups according to date of birth, whereas the second phase involved comparison of historical cohorts. Both of these flaws may have resulted in bias.
Another small study randomised 17 patients with prognostically severe acute pancreatitis (APACHE II score = 6) to either enteral nutrition through a nasojejunal tube (
n
= 8) or parenteral nutrition (
n =
9).
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Not surprisingly, given the small numbers enrolled in the trial, there was no significant difference in morbidity between the two treatment groups, although the use of enteral nutrition was associated with an earlier institution of normal diet and resumption of normal bowel opening.
The interpretation of the results of all the published trials assessing the role of enteral nutrition and the subsequent translation of these into evidence-based clinical practice is difficult. Firstly, all the trials have insufficient power to determine the effects of enteral nutrition on the most relevant outcome measures of morbidity and mortality. The conclusions of two meta-analyses, one of which reported on six studies
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and the other on two of the six studies,
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were contradictory. In one, enteral nutrition was favoured;
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in the other, the interpretation was that there were insufficient data upon which to make firm judgments.
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Secondly, all the randomised trials to date have delivered enteral nutrition through a nasojejunal feeding tube requiring either radiological or endoscopic placement. However, a prospective observational study has reported that successful nasogastric feeding can be achieved in patients with severe acute pancreatitis.
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Early nasogastric and nasojejunal feeding appear equivalent in patients with objectively graded severe acute pancreatitis.
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Thirdly, other than the trial conducted by Powell et al.,
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enteral nutrition was compared with early parenteral nutrition. In general, it is not standard practice to commence parenteral nutrition in patients immediately following admission with acute pancreatitis. Furthermore, it is possible that the observed ‘benefits’ from the institution of enteral nutrition, as compared with parenteral nutrition, are in fact due to the induction of deleterious effects by parenteral nutrition. It has been demonstrated that a nil-by-mouth regimen and the institution of parenteral nutrition in normal volunteers is associated with an increased inflammatory response following a stimulus,
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and malnourished patients have an impairment of intestinal function and increased markers of the acute-phase response. Furthermore, the use of parenteral nutrition in acute pancreatitis is associated with a significant increase in line sepsis when compared with standard management.
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The Dutch PYTHON multicentre trial
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plans to recruit 208 patients with predicted severe acute pancreatitis and randomise to a very early (< 24 h) start of enteral nutrition versus introducing oral diet and enteral nutrition if necessary at around 72 hours after admission. The 3-year trial is designed to determine whether very early feeding reduces the combined end-point of mortality or infections.
Although there is no definitive evidence demonstrating that early enteral nutrition improves outcome in severe acute pancreatitis, all published studies demonstrate that enteral nutrition is feasible, safe and does not exacerbate the disease process. Further trials are required to determine the impact of early enteral nutrition in predicted severe acute pancreatitis on infectious complications and disease outcome.
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Probiotic therapy:
The use of probiotic therapy in acute pancreatitis is based on the hypothesis that colonisation of the proximal gastrointestinal tract by pathogenic bacteria is a precursor to the development of infected pancreatic necrosis. Probiotic therapy therefore aims to establish colonisation of the gastrointestinal tract by non-pathogenic bacteria, thereby reducing the risk of infective complications. This hypothesis was tested by randomising 45 patients with acute pancreatitis, 32 of whom had severe disease, to receive either live
Lactobacillus plantarum
(
n
= 22) or killed
Lactobacillus plantarum
(
n
= 23) delivered via a nasojejunal feeding tube, along with oat fibre as a bacterial substrate.
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All patients received a standard enteral nutrition formula in addition to the live or killed
L
.
plantarum.
Within this trial, probiotic therapy appeared to reduce the risk of developing either infected pancreatic necrosis or abscess. One patient who received live
L
.
plantarum
developed pancreatic infection compared with seven patients in the control group (
P
= 0.023).
The controversial PROPATRIA trial, a multicentre randomised, double-blind, placebo-controlled trial, recruited 298 patients with predicted severe acute pancreatitis (Acute Physiology and Chronic Health Evaluation (APACHE II) score ≥ 8, Imrie score ≥ 3 or CRP > 150 mg/L) within 72 hours of onset of symptoms to receive a multispecies probiotic preparation (
n
= 153) or placebo (
n
= 145), via the enteral route twice daily for 28 days. An unexpected more than doubling in mortality in the treatment arm was reported.
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This trial provoked extensive discussion regarding its design, execution, analysis and safety monitoring.
Anticytokine therapy:
With increased understanding of the pathogenetic mechanisms in acute pancreatitis, it is hoped that novel therapies will be developed that can perturb these mechanisms and improve outcome. Indeed, a large number of agents that either antagonise the proinflammatory response or augment the anti-inflammatory response have been demonstrated to ameliorate disease severity in animal models of acute pancreatitis. However, it should be noted that in these studies the agent is usually administered before or immediately after the induction of acute pancreatitis, a scenario that does not translate to the clinical situation. One such agent to undergo clinical trials was lexipafant, a high-affinity platelet-activating factor receptor antagonist, which acts as a general down-regulator of the proinflammatory cytokine response. On the basis of encouraging results from initial trials, a large multicentre trial recruiting 1500 patients was undertaken. Although the trial results have not been formally reported, it is widely known that there was no improvement in mortality following the use of lexipafant, and that the manufacturers are now no longer pursuing this drug as a treatment for severe acute pancreatitis.
It is expected that further drugs that perturb the pathogenetic mechanisms of acute pancreatitis will be developed and will undergo clinical trials.
Current UK guidelines provide targets for mortality rates in acute pancreatitis.
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These guidelines state that overall mortality should be less than 10% of patients admitted with acute pancreatitis, with a mortality rate less than 30% in those with prognostically severe disease. Certainly, epidemiological data published in 1999 suggested that there had been a significant reduction in mortality rates between 1984 and 1995.
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