|PRACTICE CHANGING CONTINUING EDUCATION: HEPATOPANCREATOBILIARY SURGICAL PRACTICE
|Year : 2014 | Volume
| Issue : 2 | Page : 93-99
Selective digestive decontamination in severe acute pancreatitis
Leong Tiong1, Ryan Jalleh1, Savio George Barreto2
1 Department of Surgery, Modbury Hospital, Modbury, Australia
2 Department of Surgery, Modbury Hospital, Modbury, Australia; Department of Gastrointestinal Surgery, Gastrointestinal Oncology and Bariatric Surgery, Institute of Digestive and Hepatobiliary Sciences, Medanta, The Medicity, Gurgaon, Haryana, India
|Date of Web Publication||31-Jul-2014|
Dr. Savio George Barreto
GI Surgery, GI Oncology and Bariatric Surgery Medanta Institute of Digestive and Hepatobiliary Sciences Medanta, The Medicity, Sector 38, Gurgaon - 122 001, Haryana, India
Source of Support: None, Conflict of Interest: None
Background: Infected pancreatic necrosis is associated with the risk of considerable morbidity and mortality. Preventing the development of infection in pancreatic necrosis may help reduce the poor outcomes in patients with severe acute pancreatitis (SAP). Aim : The aim of the current review was to determine the benefit of selective digestive decontamination (SDD) in improving outcomes in SAP. Materials and Methods: A systematic literature search was conducted using MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Cochrane Methodology Register, Database of Abstracts of Reviews of Effects and Health Technology Assessment, until June 2011 without any restrictions. Papers reporting on experimental animal studies and clinical studies on patients with acute pancreatitis (AP) who were treated with SDD, either alone or in combination with intravenous antibiotic and antifungals in comparison with other interventions, antibiotics, or placebo, were eligible for inclusion. Outcome data collected were duration and regimen of SDD used, short- and long-term morbidity and mortality rates, length of hospital stay, incidence and rates of bacterial/fungal infection. Results: A total of 53 articles were identified from the literature search of which 10 (7 animals, 3 humans) were eligible for inclusion in this systematic review. There was only one randomized controlled trial among the human studies. Most studies used a combination of SDD and intravenous antibiotics precluding a clear interpretation of the individual benefit of SDD. Although SDD significantly reduced pancreatic infection rates, its benefit on patient survival is unclear. Conclusion: Although SDD significantly reduced pancreatic infection rates and overall survival in experimental animal models, in human studies this benefit is not clearly appreciated owing to the confounding effects of concurrently administered intravenous antibiotics. Hence, further controlled studies are needed to determine the benefit of SDD in AP in humans.
Keywords: Antibiotic prophylaxis, infection, pancreas
|How to cite this article:|
Tiong L, Jalleh R, Barreto SG. Selective digestive decontamination in severe acute pancreatitis. Astrocyte 2014;1:93-9
| Introduction|| |
Acute pancreatitis (AP), an inflammatory disease of the pancreas, is associated with a high morbidity and even the risk of mortality. , While most cases of AP run a mild clinical course, infection of pancreatic necroses as seen in severe acute pancreatitis (SAP) plays an important role in the dismal outcome linked to the disease.  While scoring systems such as the Imrie and the Apache II provide a useful guide in classifying patients at admission into those who are more likely to have a mild, as opposed to a severe disease, these systems lack sensitivity.  Moreover, they do not provide clues as to which patients with SAP and pancreatic necrosis will develop an infection of the pancreatic necrosum.
The role of parenteral antibiotics has been investigated extensively in SAP with studies looking at tissue penetration of the drugs. , A recent Cochrane systematic review has concluded that there is no role for prophylactic parenteral antibiotic therapy in SAP with necrosis, except for intravenous imipenem, which significantly reduced the infection rates.  Besides, antibiotics are associated with an innate risk of fungal superinfection. , Acknowledging this and the fact that once infection does set in, the outcomes are worsened, which dictates the need to develop a treatment strategy that will prevent infection of the pancreatic necrosum. However, such a preventative strategy should not add to the morbidity of the patient.
Infection of the pancreatic necrosum is usually due to translocation of Gram-negative organisms from the digestive tract. ,,, This led to the hypothesis that prophylactic reduction of the bacterial load in the digestive tract (selective digestive decontamination [SDD]) may reduce the incidence, and therefore the morbidity, of infected pancreatic necrosis.
SDD involves the administration of enteral antibiotics, which are poorly absorbed from the digestive tract, therefore minimizing systemic toxicity. The role of SDD in SAP has been studied in animal models as well as in humans. In some instances, parenteral antibiotics were also administered for systemic antibacterial benefits, and antifungals were used to counter the risk of fungal super-infection.
This systematic review examines the evidence in the literature with an aim to determining if there is a role for SDD in the prevention of pancreatic infection in SAP, and in reducing the morbidity and mortality associated with the disease.
| Materials and Methods|| |
A literature search was conducted using MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Cochrane Methodology Register, Database of Abstracts of Reviews of Effects and Health Technology Assessment, as per the search terms given in [Table 1] until June 2011 without any restrictions.
Inclusion criteria for articles included in this review were as follows: (1) Participants - subjects (humans or animals) with AP. (2) Intervention - SDD, either by itself or in combination with other intervention, for example, parenteral antibiotics. (3) Comparative interventions - any other intervention except SDD. (4) Outcomes data - duration and regimen of SDD used, short- and long-term morbidity and mortality rates, length of hospital stay, incidence and rates of bacterial/fungal infection. (5) Types of study - randomized controlled trials (RCTs), quasi-RCTs, nonrandomized comparative studies, large case series, and experimental animal studies were included in this review. In addition, meeting abstracts and each article's bibliography identified above were cross-referenced for relevant publications. (6) Exclusion criteria - meta-analyses, review articles, letters/comments and editorials were excluded. Methodological qualities of all RCTs were assessed using both the Cochrane Collaboration's tool for assessing risk of bias  and the Jadad scoring system. 
Abstracts of citations identified from the literature search were independently assessed by two authors (LT, RJ) for eligibility for inclusion in this systematic review, and the relevant data extracted into a prespecified spreadsheet. Any disagreement was resolved by discussion with the third author (SGB).
| Results|| |
A total of 53 articles were identified from the literature search of which 10 (7 animals, 3 humans) were eligible for inclusion in this systematic review [Figure 1]. Six of the experimental animal studies used a murine model while one employed a canine model. There was only one RCT  among the human studies, which has a Jadad score of 2 [Table 2]. The other two were comparative case series. , The outcome data of the animal and human studies are shown in [Table 3] and [Table 4], respectively.
|Table 3: Animal Studies Using SDD Alone or in Combination in Acute Pancreatitis|
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|Table 4: Human Studies Exploring the Role of SDD Alone, or in Combination|
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Various combinations of antibiotics were used against both Gram-positive organisms (tetracyclines, aztreonam, bacitracin, and macrolides), and Gram-negative organisms (aminoglycosides, polymyxin B and E, and cephalosporins). The data from the animal studies suggested that SDD significantly reduced infection rates and improved short-term survival rates when given before, or at the onset, of SAP. ,,,,, If given after the onset of SAP, SDD alone was found to have no benefit compared with placebo in reducing infection rates or mortality.  An intravenous antibiotic (cefotaxime) was used to provide systemic antibacterial effect in addition to oral SDD. 
Four of seven articles reported improved short-term survival after SDD for SAP. ,,, Two articles reported no statistically significant differences in short-term survival between the SDD and placebo groups. , Fritz et al. did not report survival data.
No morbidity data were available from the animal studies.
Four studies found significant reduction of the pancreatic tissue infection rates in the SDD groups compared with controls. ,,, Foitzik et al. noted that SDD (oral polymyxin E, oral tobramycin, oral amphotericin B, and intravenous cefotaxime) significantly reduced pancreatic infection rates after SAP compared with placebo. A similar benefit could also be achieved using intravenous imipenem only. SDD using polymyxin E and amikacin significantly reduced bacterial (both Gram-positive and negative) translocation to the pancreas compared with placebo.  The addition of amphotericin B significantly reduced fungal translocation to the pancreas. SDD (gentamicin, bacitracin, and neomycin) significantly reduced infection rates of the pancreas (11.8% vs. 52.9%, P = 0.01), mesenteric lymph nodes (LN) (18% vs. 59%, P = 0.01) and the liver (6% vs. 47%, P = 0.008) compared with placebo.  There were no differences in the infection rates in the spleen or the peritoneum between the two groups. Fritz et al.  found that SDD of the small and large bowel, as well as the small bowel alone, significantly reduced bacterial translocation into mesenteric lymph nodes and the pancreas. Three articles had no data on infection rates. ,,
The antibiotics against Gram-negative organisms were the ones most commonly used in SDD (aminoglycoside and polymyxin B and E). Amphotericin B was usually included as a prophylaxis against fungal super-infection. Intravenous antibiotics were used in two of the studies. , Luiten et al. included intravenous cefotaxime as part of their SDD regimen, whereas Sawa et al. administered intravenous imipenem to all their patients in both the SDD and control groups.
None of the human studies noted any significant reduction in mortality rate when SDD was compared with standard treatment for SAP. ,, Luiten et al. found that the 90-day mortality rate was 22% in the SDD group versus 35% in the control group (P = 0.19). Sub-group analyses showed that the difference in mortality rate reached significance only when adjusted for the Imrie and the Balthazar score (P = 0.048).
SDD was found to reduce the number of laparotomies (performed upon confirmation of infected pancreatic necrosis) required per patient (0.9 vs. 3.1, P < 0.05).  However, there were no significant differences in the length of hospital stay  or the incidence of organ dysfunction. 
Two of the three studies reported significantly lower infection rates in the SDD groups compared with control. , In the RCT by Luiten et al., SDD reduced the rates of overall pancreatic infection (18% vs. 38%, P = 0.03) as well as Gram-negative pancreatic infection (8% vs. 33%, P < 0.003) compared with control. One study showed no significant differences in pancreatic infection rates between the SDD and control groups. 
| Discussion|| |
The rationale behind SDD is to prevent infection of the pancreatic necrosum in SAP, which is associated with high morbidity and mortality rates. This review shows that although SDD significantly reduced pancreatic infection rates, its benefit on patient survival is unclear. Only four of the seven animal studies reported significant improvement in short-term survival in the SDD groups. However, most of the animal studies were designed to investigate the routes of bacterial translocation and infection rates rather specifically targeting survival as an end-point.
In contrast, all three of the human studies showed no survival benefit ,, when SDD was compared with standard treatment. From sub-group analyses, the authors reported that SDD could improve survival if given to patients with SAP and an Imrie score ≥3, regardless of their Balthazar score.  A potential bias here was the inclusion of intravenous cefotaxime into the SDD regimen, which made it impossible to determine how much of the survival benefit was due to SDD alone, rather than to the administration of intravenous cefotaxime. Besides, the small number of patients included in the study and the short duration of follow-up could be another confounding factor. The authors concluded that SDD reduced mortality among patients with SAP because of a significant reduction in the development of gram-negative infection of pancreatic necrosis. They also found that SDD was not useful for patients in whom Gram-negative pancreatic infection already existed or developed during SDD administration.
Experiments in animal models have shown that SDD given before the onset of SAP reduced pancreatic infection rates significantly.  If given after the onset of SAP, SDD per se had no significant benefit compared with placebo, in which case an intravenous antibiotic (cefotaxime) was required in addition to SDD to reduce the rate of pancreatic infection.  These findings suggested that injury to the intestinal mucosa occurs early in SAP and therefore SDD needs to be given early, preferably before or at the onset of SAP, to prevent translocation of bacteria to the pancreatic tissues.
In the clinical setting, it is not always easy to predict which patients will develop SAP, and this makes it difficult to prescribe SDD appropriately. All three human studies in this review started SDD at different time points after the diagnosis of SAP, and included intravenous antibiotics as well as part of their SDD regimen. McClelland et al. and Luiten et al. reported significantly lower overall infection rates in the SDD and intravenous antibiotics group. In the study by Sawa et al.,  both the SDD and the control groups received intravenous imipenem, and this might explain the lack of significant differences in organ dysfunction, infected pancreatic necrosis, or mortality rate between the two groups in this study.
Data from the human studies suggested that SDD has to be started as soon as the diagnosis of SAP was made for optimum benefits.  In the RCT by Luiten et al., SDD was administered until "no significant infection risks exist".  The lack of data on the optimal duration of SDD means that each case needs to be treated individually based on clinical judgement.
Imipenem may have an important role in the management of SAP. In the study by Foitzik et al.,  intravenous imipenem alone was found to be as good as SDD and intravenous cefotaxime in reducing pancreatic infection. Imipenem, a broad spectrum antibiotic, was found to penetrate pancreatic tissues very well,  which explains its effectiveness in reducing pancreatic infection in SAP.
In conclusion, this review shows that SDD significantly reduced pancreatic infection (especially Gram-negative organisms) rates if given early, preferably before the onset of SAP in experimental animal models. While studies exploring the role of SDD in humans have shown SDD to reduce infection rates and the number of laparotomies performed, the actual benefit of SDD alone is unclear. This could be attributed to two main reasons; first it was difficult to predict which patient would develop SAP to warrant prophylactic SDD therapy and second, the inclusion of intravenous antibiotics as part of the SDD regimen and sometimes in the control group as well in the human studies introduced a potential bias in the results. There is no data to indicate the ideal duration of prescription of SDD. Future research should investigate whether prophylactic SDD alone has any benefit in SAP compared with intravenous antibiotics, and if so, provide an optimum duration of treatment.
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[Table 1], [Table 2], [Table 3], [Table 4]