Intervention Protocol

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Somatostatin analogues for treatment of enterocutaneous fistula

  1. Philip Stevens1,*,
  2. Sorrel Burden2,
  3. Raymond Delicata3,
  4. Gordon Carlson4,
  5. Simon Lal5

Editorial Group: Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group

Published Online: 30 APR 2013

DOI: 10.1002/14651858.CD010489


How to Cite

Stevens P, Burden S, Delicata R, Carlson G, Lal S. Somatostatin analogues for treatment of enterocutaneous fistula (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD010489. DOI: 10.1002/14651858.CD010489.

Author Information

  1. 1

    Salford Royal NHS Foundation Trust, Surgery, Salford, UK

  2. 2

    University of Manchester, School of Nursing, Midwifery and Social Work, Manchester, UK

  3. 3

    Gwent Healthcare NHS Healthboard ? Nevill Hall Hospital, General Surgery, Abergavenny, UK

  4. 4

    Salford Royal NHS Foundation Trust, General Surgery, Salford, UK

  5. 5

    Salford Royal Foundation Trust, Intestinal Failure Unit, Salford, UK

*Philip Stevens, Surgery, Salford Royal NHS Foundation Trust, Stott Lane, Salford, M6 8HD, UK. Stevens_P1@hotmail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 30 APR 2013

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Contributions of authors
  7. Declarations of interest
  8. Sources of support
 

Description of the condition

Gastrointestinal fistulas are the most common cause of severe acute intestinal failure (Carlson 2003; Carlson 2010). Seventy-five to 85 per cent of fistulas arise as a complication of surgical treatment, either due to inadvertent serosal injury or anastomotic leakage (Berry 1996; Falconi 2001). Fistulas are associated with considerable morbidity and mortality (Mastboom 1989; Berry 1996; Falconi 2001; Buchler 2002; Adkins 2004; Lloyd 2006). The  majority occur in the small intestine (Soeters 1979). Almost half follow surgery where no bowel resection has occurred, but bowel has been injured and repaired (Van Der Krabben 2000).

Fistulas are described as simple or complex, the latter indicating the presence of multiple fistula tracks, an associated abscess cavity or involvement of other organs. Over the last 30 years the eradication of sepsis, improved wound and skin care, safe nutritional support and appropriate timing of surgical intervention have reduced mortality with enterocutaneous fistulas (ECF) from 65% to less than 10% (Martinez 1998; Martinez 2008; Datta 2010; Martinez 2012). However, mortality from enteroatmospheric fistulas (EAF - fistulas within an open abdomen) has remained as high as 10% ( Sitges-Serra 1982; Mastboom 1989; Adkins 2004; Connolly 2008; Yuan 2011).

EAF do not heal without surgical intervention (Dubose 2010), whilst ECF with an intact abdominal wall have a spontaneous closure rate ranging from 50 to 80% (Sitges-Serra 1982; LaBerge 1992). Low fistula output is associated with a greater likelihood of spontaneous closure (Martinez 2008; Mawdsely 2008), although earlier closure rather than increased spontaneous closure rates have been reported by other authors (LaBerge 1992). Once sepsis has been treated, nutritional status restored and distal obstruction excluded, management is therefore focused on reduction of fistula output.

Output can be modified by slowing gastrointestinal transit with loperamide and codeine, optimisation of luminal absorption with oral rehydration salts, and reduction of enteric secretions with proton pump inhibitors (Edmunds 1960; Schwartz 1989; Kuvshinoff 1993; Berry 1994; Campos 1999). However, care of these patients is often long and costly (Fagniez 1999) and there is no evidence that reduction in fistula output from high to low volume loss actually increases the chance of spontaneous closure (Lloyd 2006). Fistula output is itself intimately related to the underlying anatomy of the fistula track. Proximal small bowel defects give rise to caustic effluent, a factor that may explain the poor healing of high-output fistulas regardless of the absolute volume of effluent produced (Martinez 2008). Complex fistulas may arise from multiple levels of the gastrointestinal tract. Complex fistulas are often associated with intra-abdominal abscess formation, and are less likely to close spontaneously than simple fistulous tracks (Martinez 2008).

 

Description of the intervention

Somatostatin is an endogenous hormone which has the effect of reducing enteric secretion and motility (Haffejee 2004; Lloyd 2006), increasing water and electrolyte absorption and inhibiting pancreatic exocrine secretion (Raptis 1978; Tulassay 1998). Given the apparently low incidence of adverse events, including diarrhoea, flushing, abdominal pain, cholelithiasis and insulin resistance (Jost 1984; Mulvihill 1986; Gorden 1989); some authors advocate somatostatin or its analogues for the management of ECF (Hesse 2002). The short half-life of somatostatin, however, necessitates continuous intravenous infusion for prolonged periods (Pederzoli 1986), making the use of longer-acting somatostatin analogues (e.g. octreotide or lanreotide) more appealing.

Octreotide (Sandostatin; Novartis Pharmaceuticals, Basle, Switzerland) and lanreotide (Somatuline; Ipsen, Paris, France) are synthetic octapeptides with greater potency and a longer half-life than somatostatin (e.g. a single injection of lanreotide lasts from 10 to 14 days) making them more appealing for ease of administration (Sheppard 1979; Bauer 1982; Kohler 1986; Kutz 1986; Heron 1993; Johnson 1994) with a low incidence of adverse events (Lamberts1996; Bornschein 2009). The somatostatin analogues vapreotide (Octastatin; Sanvar, New Orleans, USA) and pasireotide (SOM230; Novartis Pharmaceuticals, Basel, Switzerland), the latter of which acts on multiple somatostatin receptors (SSTRs) such as SSTR-1, SSTR-2, SSTR-3 and SSTR-5, have not been evaluated for the treatment of ECF (Lesche 2009).

 

How the intervention might work

It is postulated that somatostatin could expedite spontaneous fistula closure both by reducing fluid volume and output. This is based on the observation that low fistula output is associated with a greater probability of spontaneous closure (Bauer 1982; Kohler 1986; Miller 1993; Beglinger 1999; Gonzalez-Pinto 2002; Gouillat 2002; Lloyd 2006; Mawdsely 2008), or earlier closure (LaBerge 1992), and that enzymatic content of pancreatic secretions is reduced by administration of somatostatin analogues (Jenkins 1995). Such treatment may reduce the length of hospital stay or decrease the number of patients who eventually require operative fistula management.

Somatostatin analogues have largely replaced somatostatin in clinical practice. Octreotide and lanreotide are, however, not necessarily equivalent in biological effect to native somatostatin. Both have a poor affinity for somatostatin receptors, binding mostly to SSTR-2 and SSTR-5 (Lesche 2009). Several biological responses of SSTRs have been identified that display absolute or relative subtype selectivity. These include growth hormone secretion (SSTR-2 and SSTR-5), insulin secretion (SSTR-5), glucagon secretion (SSTR-2), and immune responses (SSTR-2) (Patel 1999). Human gastric and colonic tissues contain predominantly SSTR-1 or SSTR-4, but the receptor subtypes in human small bowel are not known. Other factors may also impair the clinical efficacy of somatostatin analogues. Whilst intermittent dosing schedules may be more practical than a continuous infusion, down-regulation of SSTR expression may limit treatment efficacy with either prolonged administration or intermittent dosing schedules. Furthermore, rebound increase in secretions between bolus doses may also impair the efficacy of octreotide (Londong, 1989; Lamberts 1990; Miller 1993; Friess 1994; Jenkins 1995; Lamberts1996; Hesse 2002).

 

Why it is important to do this review

Meta-analyses have demonstrated prophylactic somatostatin analogue use in pancreatic surgery led to a significant reduction in the incidence of pancreatic fistulae following elective resection (Alghamdi 2007; Koti 2010). Another study suggested these drugs may be beneficial for the treatment of established fistula, although heterogeneity of data limited firm conclusions (Li-Ling 2001). However, other reviews concluded that although somatostatin analogues reduced fistula output, they did not seem to significantly improve spontaneous fistula closure rate (Martineau 1996). Data on somatostatin analogue use for the treatment of enterocutaneous non-pancreatic fistula, however, are less clear than for pancreatic fistula and recommendations are conflicting (Haffejee 2004; Lloyd 2006).

A search of the literature available on MEDLINE and EMBASE for this subject was undertaken by Stevens 2011. Twenty-seven studies were identified, 17 were excluded on methodological grounds (Nubiola 1989; Spiliotis 1990; Niv 1991; Paran 1991; Boike 1992; Borison 1992; Castañón-González 1992; Sitges-Serra 1993; Gerardo 1994; Lindsetmo 1994; Pérez 1994; Sleth 1994; Paran 1995; Alvarez 2000; Alivizatos 2002; Lavy 2003; Xeropotamos 2005). The ten remaining prospective studies included in the meta-analysis (di Costanzo 1987; Nubiola-Calonge 1987; Torres 1992; Scott 1993; Isenmann 1994; Sancho 1995; Hernandez-Aranda 1996; Jamil 2004; Leandros 2004; Gayral 2009) reported treatment outcomes for ECF in 462 patients (mean sample size 46, range 14 to 107). Only one of these studies excluded pancreatic or biliary fistula, although the only reported outcome was fistula output, with no reference to spontaneous closure, mortality or healing rates (Nubiola-Calonge 1987). Stevens 2011 concluded that somatostatin and octreotide improved fistula closure time but only somatostatin improved spontaneous closure rate. A subsequent meta-analysis (Coughlin 2012) identified the same studies but results for all ten studies were pooled without regard to pharmacodynamic idiosyncrasies between the individual somatostatin analogues, which may have led to an inflated estimate of the efficacy of somatostatin analogues compared to the earlier analysis (Stevens 2011). Another meta-analysis (Rahbour 2012) drew similar conclusions to Stevens 2011 with regard to time to closure and total closure rates, again with somatostatin appearing to be more effective than somatostatin analogues. However, none of the published meta-analyses excluded pancreatic fistulae and the latter Rahbour 2012 meta-analysis included fewer studies and did not exclude retrospective analyses.

There is therefore no clear evidence of benefit from the use of somatostatin or its analogues for the treatment of ECF. It is important therefore, to critically evaluate the literature with regard to the level of evidence and any newly published data which may add to the body of evidence regarding the efficacy of somatostatin or its analogues used to treat small bowel ECF.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Contributions of authors
  7. Declarations of interest
  8. Sources of support

The objectives of this review are to assess the efficacy and safety of somatostatin and somatostatin analogues for the treatment of ECF and EAF.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Contributions of authors
  7. Declarations of interest
  8. Sources of support
 

Criteria for considering studies for this review

 

Types of studies

This review will include randomised controlled trials, quasi-randomised clinical trials and cohort studies.   

 

Types of participants

Participants will be adult patients (> 18 years) with established enterocutaneous or enteroatmospheric fistulae of any cause.

 

Types of interventions

Studies of treatment with somatostatin or somatostatin analogues (octreotide, lanreotide, vapreotide, pasireotide), compared with standard medical management of enteric fistulas will be considered for inclusion.

 

Types of outcome measures

 

Primary outcomes

The primary outcomes will include:

1. The proportion of patients with spontaneous fistula closure, as defined by cessation of fistula output for a period of two weeks;

2. The proportion of patients who require surgery to facilitate fistula closure; and

3. Time to spontaneous, surgical and all cause fistula closures.

For each study population, the relative risk of spontaneous fistula closure will be determined as well as the relative risk for the need for operative fistula management and the relative risk for closure by either spontaneous or operative intervention. Time to fistula closure will be recorded as the number of days from initiation of somatostatin or somatostatin analogue or randomisation to control group to the point defined by study authors as reaching their definition of fistula closure. This will be reported as the mean difference in days (between somatostatin analogue treated versus control populations).

 

Secondary outcomes

Secondary outcomes will include:

1. Volume of fistula output per day (standardised by length of proximal small bowel where possible) during treatment with somatostatin or somatostatin analogues;

2. All-cause mortality at 30 days, 90 days and 12 months;

3. Effect on quality of life at 30 days, 90 days and 12 months;

4. Proportion of patients requiring parenteral nutritional support at 30 days, 90 days and 12 months;

5. Proportion of patients with adverse events and serious adverse events at 30 days, 90 days and 12 months;

6. Proportion of patients with sepsis at 30 days, 90 days and 12 months;

7. Proportion of patients with jaundice or biliary calculi at 30 days, 90 days and 12 months; and

8. Proportion of patients with gastrointestinal obstruction or ischaemia at 30 days, 90 days and 12 months.

Volume of fistula output will be reported as the percentage change in daily fistula volume loss for day 1 and day 7 of somatostatin analogues use as compared to the pre-treatment reported fistula loss. If outcome measures cannot be reported in standardised definitions, data will not be meta-analysed and may only be reported as descriptive of the primary study outcome measures. Mortality data will be recorded as the relative risk of all deaths occurring within the study populations at 30 days, 60 days and at 1 year. Where possible, subgroup analyses for ECF will be compared for outcome from enteroatmospheric fistulae (defined as any fistula opening from the gastrointestinal tract into an open abdominal wound). Prior meta-analyses (Stevens 2011, Coughlin 2012, Rahbour 2012) did not report quality of life as an outcome measure. Where quality of life or patient-related outcome measures are considered, these will be reported qualitatively. It is not expected that there will be sufficient, homogenous quality of life data to enable meta-analysis to be performed for this outcome.

 

Search methods for identification of studies

 

Electronic searches

The following electronic databases will be searched with no restriction on language or publication status (e.g. in press articles): The Specialised Trials Register of the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group, and the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (2013), AMED (1985 to 2013), MEDLINE (1966 to 2013), EMBASE (1980 to 2013), Cinahl (1982 to 2013), and the British Nursing Index (1984 to 2013). Conference proceedings including Digestive Disease Week (DDW), the Association of Surgeons of Great Britain and Ireland (ASGBI), and the United European Gastroenterology Week (UEGW), and the Conference Proceedings Citation Index - Social Science and Humanities (CPCI-SSH) published in the last 10 years will be searched to identify studies published only in abstract form.

The following search strategy will be utilized for this review, using text and keyword/MESH terms for each database:

(somatostatin) or (octreotide) or (lanreotide) or (vapreotide) or (pasireotide) or (somatostatin analogue) or (SMS) and (fistula) or (enterocutaneous) or (enteroatmospheric)

From the list of references obtained, retrospective studies will be excluded and all studies with prospective methodology, or those for which it is not clear which methodology was employed, will be obtained in full to clarify suitability according to types of studies as specified in the selection criteria. All studies comparing somatostatin or a somatostatin-analogue with standard medical management for treatment of ECF and EAF will be included.

 

Searching other resources

Reference lists of identified publications will be searched for additional studies not identified on review of the electronic search results. On-going trials will be searched through the national research register, the web-sites www.controlled-trials.com and clinicaltrials.gov. Grey literature will be searched through the SIGLE database.

All searches will be performed independently by two of the authors (PS and SB) according to the a priori defined search strategy. Where discrepancy is evident between the two authors, further evaluation of suitability for inclusion will be dealt with by the senior author (SL).

 

Data collection and analysis

 

Selection of studies

Two authors (PS and SB) will independently review the abstracts of potentially relevant studies to determine if they meet the pre-specified inclusion criteria and full publications will be obtained where necessary. Any disagreement between authors will be resolved by consensus and if necessary by consultation with the third author (SL).

 

Data extraction and management

A standardised data extraction sheet will be developed to record data on: methodological quality (as described for Cochrane methodology by Higgins 2011), study setting, participants (age and sex; how diagnosis and gastrointestinal anatomy was confirmed or obstruction excluded; inclusion and exclusion criteria), interventions (choice of somatostatin analogue, dose used, duration of administration, route of administration, regimen of control intervention), outcome measures, attrition, intention to treat analysis, duration of follow-up and the type and number of any reported adverse events.

Other medical treatments used, prior to implementation of somatostatin analogue treatment, will be recorded both to consider intra-study confounders and inter-study confounders in terms of medical management of fistulae. Factors evaluated will be: measurement of oral intake (calorific and fluid intake or nil by mouth regimens), proton-pump inhibitors or anti-histamine use, non-steroidal drugs, antimotility agents (loperamide, codeine or other opiates) and oral rehydration solutions (dioralyte, St Mark's or WHO solutions and concentrations prescribed).

 

Assessment of risk of bias in included studies

The Cochrane risk of bias tool (Higgins 2011) will be used to assess the quality of randomised controlled trials. Factors to be assessed include: sequence generation; allocation sequence concealment; blinding; incomplete outcome data; selective outcome reporting; and other potential sources of bias. Items will be rated as low risk of bias, high risk of bias, or unclear (or unknown) risk of bias. Disagreements will be resolved by consensus between SL and GLC. Study authors will be contacted when insufficient information was provided to determine the risk of bias. The methodological quality of cohort and case control studies will be assessed using the Newcastle-Ottawa Scale (Wells 2013).

We will use the GRADE criteria to evaluate the overall quality of evidence for the primary outcomes and selected secondary outcomes (Atkins 2004; Guyatt 2008; Schünemann 2011). Randomized trials start as high quality evidence, but may be downgraded due to: (1) risk of bias, (2) indirectness of evidence, (3) unexplained heterogeneity, (4) sparse data, and (5) publication bias. The overall quality of evidence for each outcome will be determined after considering each of these elements, and categorized as high quality (i.e. further research is very unlikely to change our confidence in the estimate of effect); moderate quality (i.e. further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate); low quality (i.e. further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate); or very low quality (i.e. we are very uncertain about the estimate).

 

Measures of treatment effect

The relative risk (RR) with 95% confidence intervals (95% CI) will be calculated for each dichotomous outcome. The number needed to treat (NNT) and risk difference (RD) will be calculated where appropriate. For continuous variables, the weighted mean difference (WMD) or standardised mean difference (SMD) with 95% CI will be calculated.

 

Unit of analysis issues

In most cases, the number of observations in the analyses will match the number of participants that were randomised. For a parallel group design, a single measurement for each outcome from each participant will be collected and analysed. We will also consider if groups of individuals were randomised together to the same intervention (cluster randomisation), or if individuals undergo more than one intervention (i.e. cross-over trial) or if there are multiple observations for the same outcome.

 

Dealing with missing data

Where possible, original investigators will be contacted to request missing data. Where data are assumed to be missing at random, an available case analysis will be used, such that only available data will be analysed. This will be presented along with an intention to treat analysis. Data that are not missing at random will be assumed to have a particular value, imputed from the mean or from regression analyses. Sensitivity analyses will be performed to assess how sensitive results are to reasonable changes in the assumptions that are made. Sensitivity analyses will be used to compare studies with differing median small bowel length for the outcome volume of fistula output per day.

 

Assessment of heterogeneity

Clinical homogeneity of included studies will be assessed by reviewing the study populations, interventions, comparison groups and outcome measures used. Heterogeneity will be assessed using the Chi2 test (a P value of 0.10 will be regarded as statistically significant). The l2 statistic will be used to estimate the degree of heterogeneity. This measure describes the percentage of total variation across studies that results from heterogeneity rather than chance. A value of 25% is considered to indicate low heterogeneity, 50% moderate heterogeneity and 75% high heterogeneity (Higgins 2003).

In the event of high levels of heterogeneity, the data extraction will be checked to ensure accuracy of data entry. If discrepancies are identified the analysis will be repeated and if high levels of heterogeneity remain, a meta-analysis will not be performed on that data. Where heterogeneity prohibits pooling, data will be presented as a qualitative outcomes. Where moderate heterogeneity is identified, meta-analysis will be undertaken using a random-effects model. Where heterogeneity is low or not evident, a fixed-effect model will be used.

Sources of heterogeneity will be investigated using a graphic display. The log RR and its 95% CI will be calculated and plotted for each trial. These plots will be examined to identify any possible outliers as well as to explore any trends in outcome due to differences in methodology, patient population or treatment regimens. Sub-group analyses will be performed to investigate heterogeneity.

 

Assessment of reporting biases

Potential publication bias will be investigated using a funnel plot or other corrective analytical methods (Egger 1997). A linear regression approach to measure funnel plot asymmetry or the natural logarithm scale of the odds ratio will be used.

 

Data synthesis

Data will be analysed using Review Manager (RevMan 5.0.25). Data from individual trials will be combined for meta-analysis if the interventions, patient groups and outcomes are sufficiently similar (to be determined by consensus). Data will not be pooled for meta-analysis if a high degree of heterogeneity is detected (i.e. l2 > 75%). A fixed-effect model will be used to pool data in the absence of heterogeneity. A random-effects model will be used if significant heterogeneity is detected. The pooled RR and 95% CI will be calculated for dichotomous outcomes. For continuous outcomes the pooled WMD or SMD and 95% CI will be calculated as appropriate.

 

Subgroup analysis and investigation of heterogeneity

Subgroup analyses will be performed by anatomical fistula site (duodenal, jejunal or ileal), non-neoplastic aetiologies (ischaemia, Crohn's and surgical complications) and dosage of somatostatin or somatostatin analogues. Where appreciable heterogeneity is present, studies will be examined for causes of heterogeneity. An attempt will be made to explain any heterogeneity on the basis of patient’s clinical characteristics and interventions of the included studies.

 

Sensitivity analysis

A sensitivity analysis will be carried out to determine if the findings from the primary analysis are changed by removing different trials from the analysis (e.g. quasi-randomised clinical trials, cohort studies, abstract publications, high risk of bias studies). This will be done by varying the inclusion criteria and repeating the analysis with the new data set. If a sufficient number of randomised trials are identified, a sensitivity analysis to explore the influence of trial quality on effect estimates will be performed. Sensitivity analyses will be conducted where studies report differing baseline demographics with regard to either age distribution or patient gender. The definitions of 'standard medical therapy' for comparator groups used in each study will be recorded and sensitivity analyses performed between groups where differences are evident.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Contributions of authors
  7. Declarations of interest
  8. Sources of support

Funding for the IBD/FBD Review Group (September 1, 2010 - August 31, 2015) has been provided by the Canadian Institutes of Health Research (CIHR) Knowledge Translation Branch (CON - 105529) and the CIHR Institutes of Nutrition, Metabolism and Diabetes (INMD); and Infection and Immunity (III) and the Ontario Ministry of Health and Long Term Care (HLTC3968FL-2010-2235).

Miss Ila Stewart has provided support for the IBD/FBD Review Group through the Olive Stewart Fund.

 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Contributions of authors
  7. Declarations of interest
  8. Sources of support

P Stevens - primary author: production of written report of the study, production of the study protocol and one of the authors responsible for the literature search and data extraction

S Burden - second author responsible for the literature search and data extraction

R Delicata - additional surgical advisor, independent internal reviewer of data handling and analyses

G Carlson - senior surgical advisor and internal reviewer of statistical methodology and contextual interpretation of fistula management

S Lal - senior author: supervision of final article and quality assurance of Cochrane methodology and statistical analyses

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Contributions of authors
  7. Declarations of interest
  8. Sources of support

The authors have no conflicts of interest to declare.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Contributions of authors
  7. Declarations of interest
  8. Sources of support
 

Internal sources

  • Salford Royal NHS Foundation Trust, UK.
    None - base institution of primary and senior authors

 

External sources

  • No external sources of support, Not specified.

References

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
  10. Additional references
Adkins 2004
Alghamdi 2007
  • Alghamdi AA, Jawas AM, Hart RS. Use of octreotide for the prevention of pancreatic fistula after elective pancreatic surgery: a systematic review and meta-analysis. Canadian Journal of Surgery 2007;50:459-66.
Alivizatos 2002
  • Alivizatos V, Felekis D, Zorbalas A. Evaluation of the effectiveness of octreotide in the conservative treatment of postoperative enterocutaneous fistulas. Hepatogastroenterology 2002;49:1010-2.
Alvarez 2000
  • Alvarez C, McFadden MD, Reber HA. Complicated enterocutaneous fistulas: Failure of octreotide to improve healing. World Journal of Surgery 2000;24:533-8.
Atkins 2004
  • Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, et al. Grading quality of evidence and strength of recommendations. BMJ 2004;328(7454):1490.
Bauer 1982
  • Bauer W, Briner U, Doepfner W, Haller R, Huguenin R, Marbach P, et al. SMS 201-995: a very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sciences 1982;31:1133-40.
Beglinger 1999
Berry 1994
  • Berry SM, Fischer JE. Enterocutaneous fistulas. Current Problems in Surgery 1994;31(6):469-566.
Berry 1996
Boike 1992
Borison 1992
Bornschein 2009
  • Bornschein J, Drozdov I, Malfertheiner P. Octreotide LAR. Safety and tolerability issues. Expert Opinion on Drug Safety Issues 2009;8:755-68.
Buchler 2002
  • Buchler MW. Gastrointestinal fistulae. Gut 2002;49(Suppl IV):iv1.
Campos 1999
  • Campos AC, Andrade DF, Campos GM, Matias JE, Coelho JC. Multivariate model to determine prognostic factors in gastrointestinal fistulas. Journal of the American College of Surgeons 1999;188:483-90.
Carlson 2003
Carlson 2010
Castañón-González 1992
  • Castañón-González JA, Miranda Ruíz R, Arías E, Fuentes Pintado E, Zárate Treviño A. The somatostatin analog SMA (201-995) as adjuvant treatment in patients with external fistulae of the digestive system. Gaceta Médica de México 1992;138(3):285-8.
Connolly 2008
  • Connolly PT, Teubner A, Lees NP, Anderson ID, Scott NA, Carlson GL. Outcome of reconstructive surgery for intestinal fistula in the open abdomen. Annals of Surgery 2008;247(3):440-4.
Coughlin 2012
  • Coughlin S, Roth L, Lurati G, Faulharber M. Somatostatin analogues for the treatment of enterocutaneous fistulas: a systematic review and meta-analysis. World Journal of Surgery 2012;36(5):1016-29.
Datta 2010
  • Datta V, Engledow A, Chan S, Forbes A, Cohen CR, Windsor A. The management of enterocutaneous fistula in a regional unit in the United kingdom: a prospective study. Diseases of the Colon and Rectum 2010;53(2):192-9.
di Costanzo 1987
  • di Costanzo J, Cano N, Martin J, Richieri JP, Mercier R, Lafille C, et al. Treatment of external gastrointestinal fistulas by a combination of total parenteral nutrition and somatostatin. Journal of Parenteral and Enteral Nutrition 1987;11:465-70.
Dubose 2010
  • Dubose JJ, Lundy JB. Enterocutaneous fistulas in the setting of trauma and critical illness. Clinics in Colon and Rectal Surgery 2010;23(3):182-9.
Edmunds 1960
  • Edmunds LH Jr, Williams GM, Welch CE. External fistulas arising from the gastro-intestinal tract. Annals of Surgery 1960;152:445-71.
Egger 1997
  • Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by simple graphical test. BMJ 1997;316(7109):629-34.
Fagniez 1999
Falconi 2001
Friess 1994
  • Friess H, Bordihn K, Ebert M, Malfertheiner P, Kemmer T, Dennler HJ, et al. Inhibition of pancreatic secretion under long-term octreotide treatment in humans. Digestion 1994;55(Suppl 1):10-5.
Gayral 2009
  • Gayral F, Campion JP, Regimbeau JM, Blumberg J, Maisonobe P, Topart P, et al. Randomized, placebo-controlled, double-blind study of the efficacy of lanreotide 30 mg PR in the treatment of pancreatic and enterocutaneous fistulae. Annals of Surgery 2009;250:872-7.
Gerardo 1994
  • Gerardo PD, Bernardo AM. Gastrointestinal fistulas. Treatment with a somatostatin analogue (SMS 201–995). G.E.N. 1994;48:209-18.
Gonzalez-Pinto 2002
  • Gonzalez-Pinto I, Gonzalez EM. Optimising the treatment of upper gastrointestinal fistulae. Gut 2002;49(Suppl IV):iv21-8.
Gorden 1989
  • Gorden P, Comi RJ, Maton PN, Go VL. Somatostatin and somatostatin analogue (SMS 201-995) in treatment of hormone-secreting tumours of the pituitary and gastrointestinal tract and non-neoplastic diseases of the gut. Annals of Internal Medicine 1989;110:35-50.
Gouillat 2002
  • Gouillat C, Gigot JF. Pancreatic surgical complications, the case for prophylaxis. Gut 2002;49(Suppl IV):iv32-9.
Guyatt 2008
  • Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336(7650):924-6.
Haffejee 2004
Hernandez-Aranda 1996
  • Hernandez-Aranda JC, Gallo-Chico B, Flores-Ramirez LA, Avalos-Huante R, Mago-Vazquez FJ, Ramirez-Barba EJ. Treatment of enterocutaneous fistula with or without octreotide and parenteral nutrition. Nutrición Hospitalaria 1996;11:226-9.
Heron 1993
  • Heron I, Thomas F, Dero M, Gancel A, Ruiz JM, Schatz B, et al. Pharmacokinetics and efficacy of a long-acting formulation of the new somatostatin analog BIM 23014 in patients with acromegaly. Journal of Clinical Endocrinology and Metabolism 1993;76:721-7.
Hesse 2002
  • Hesse U, Ysebaert D, de Hemptinne B. Role of somatostatin-14 and its analogues in the management of gastrointestinal fistulae: clinical data. Gut 2002;49(Suppl IV):iv11-20.
Higgins 2003
Higgins 2011
  • Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Isenmann 1994
  • Isenmann R, Schielke DJ, Morl FK, Wunsch N, Vestweber KH, Doertenbach JH, et al. Adjuvant therapy with somatostatin iv in postoperative fistulae of the pancreas, gall bladder and small intestine. A multicentre randomised study. Aktuelle Chirurgie 1994;29:96-9.
Jamil 2004
  • Jamil M, Ahmed U, Sobia H. Role of somatostatin analogues in the management of enterocutaneous fistulae. Journal of the College of Physicians and Surgeons of Pakistan 2004;14:237-40.
Jenkins 1995
  • Jenkins SA, Nott DM, Baxter JN. Fluctuations in the secretion of pancreatic enzymes between consecutive doses of octreotide: implications for the management of fistulae. European Journal of Gastroenterology and Hepatology 1995;7:255-8.
Johnson 1994
  • Johnson MR, Chowdrey HS, Thomas F, Grint C, Lightman SL. Pharmacokinetics and efficacy of the long-acting somatostatin analogue somatuline in acromegaly. European Journal of Endocinology 1994;130:229-34.
Jost 1984
Kohler 1986
  • Kohler E, Beglinger C, Dettwiler S, Whitehouse I, Gyr K. Effect of a new somatostatin analogue on pancreatic function in healthy volunteers. Pancreas 1986;1:154-9.
Koti 2010
Kutz 1986
Kuvshinoff 1993
  • Kuvshinoff BW, Brodish RJ, McFadden DW, Fischer JE. Serum transferrin as a prognostic indicator of spontaneous closure and mortality in gastrointestinal cutaneous fistulas. Annals of Surgery 1993;217:615-23.
LaBerge 1992
  • LaBerge JM, Kerlan RK Jr, Gordon RL, Ring EJ. Nonoperative treatment of enteric fistulas: results in 53 patients. JVIR: Journal of vascular and Interventional Radiology 1992;3(2):353-7.
Lamberts 1990
  • Lamberts SW, Hofland LJ, van Koetsveld PM, Reubi JC, Bruining HA, Bakker WH, et al. Parallel in vivo and in vitro detection of functional somatostatin receptors in human endocrine pancreatic tumours:consequences with regard to diagnosis, localization, and therapy. Journal of Clinical Endocrinology and Metabolism 1990;71:566-74.
Lamberts1996
  • Lamberts SW, Van der Lely AJ, de Herder WW, Hofland LJ. Octreotide. New England Journal of Medicine 1996;334:246-54.
Lavy 2003
Leandros 2004
  • Leandros E, Antonakis PT, Albanopoulos K, Dervenis C, Konstadoulakis MM. Somatostatin versus octreotide in the treatment of patients with gastrointestinal and pancreatic fistulas. Canadian Journal of Gastroenterology 2004;18:303-6.
Lesche 2009
  • Lesche S, Lehmann D, Nagel F, Schmid HA, Schulz S. Differential effects of octreotide and pasireotide on somatostatin receptor internalization and trafficking in vitro. Journal of Clinical Endocinology and Metabolism 2009;94:654-61.
Li-Ling 2001
  • Li-Ling J, Irving M. Somatostatin and octreotide in the prevention of postoperative pancreatic complications and the treatment of enterocutaneous pancreatic fistulas: a systematic review of randomized controlled trials. British Journal of Surgery 2001;88:190-9.
Lindsetmo 1994
  • Lindsetmo RO, Revhaug A. Treatment of hypersecretory ileostomy, gastrostomy and fistula of the small intestine with the somatostatin analog octreotide. Tidsskrift for den Norske Laegeforening 94;114(24):2829-30.
Lloyd 2006
Londong, 1989
  • Londong W, Angerer M, Kutz K, Landgraf R, Londong V. Diminishing efficacy of octreotide (SMS 201-995) on gastric functions of healthy subjects during one-week administration. Gastroenterology 1989;96:713-22.
Martineau 1996
Martinez 1998
  • Martinez D, Zibari G, Aultman D, McMillan R, Mancini MC, Rush BM, et al. The outcome of intestinal fistulae: the Louisiana State University Medical Center--Shreveport experience. The American Surgeon 1998;64(3):252-4.
Martinez 2008
  • Martinez JL, Luque-de-Leon E, Mier J, Blanco-Benavides R, Robledo F. Systematic management of postoperative enterocutaneous fistulas: factors related to outcomes. World Journal of Surgery 2008;32(3):436-43.
Martinez 2012
  • Martinez JL, Luque-de-León E, Ballinas-Oseguera G, Mendez JD, Juárez-Oropeza MA, Román-Ramos R. Factors predictive of recurrence and mortality after surgical repair of enterocutaneous fistula. Journal of Gastrointestal Surgery 2012;16(1):156-63.
Mastboom 1989
  • Mastboom WJ, Kuypers HH, Schoots FJ, Wobbes T. Small-bowel perforation complicating the open treatment of generalized peritonitis. Archives of Surgery 1989;124(6):689-92.
Mawdsely 2008
Miller 1993
Mulvihill 1986
Niv 1991
  • Niv Y, Hadari A, Asaf V, Oren M. Closure of postoperative anastomotic fistulas with a somatostatin analogue. Harefuah 1991;120(11):647-8.
Nubiola 1989
  • Nubiola P, Badia JM, Martinez-Rodenas F, Gil MJ, Segura M, Sancho J, et al. Treatment of 27 postoperative enterocutaneous fistulas with the long half-life somatostatin analogue SMS 201-995. Annals of Surgery 1989;210(1):56-8.
Nubiola-Calonge 1987
  • Nubiola-Calonge P, Badia JM, Sancho J, Gil MJ, Segura M, Sitges-Serra A. Blind evaluation of the effect of Octreotide (SMS 201-995), a somatostatin analogue, on small-bowel fistula output. Lancet 1987;2:672-4.
Paran 1991
  • Paran H, Neufeld D, Epstein T, Bendahan J, Freund U. Use of somatostatin analogue for intestinal and pancreatic fistulas. Harefuah 1991;120(4):185-6.
Paran 1995
  • Paran H, Neufeld D, Kaplan O, Klausner J, Freund U. Octreotide for treatment of postoperative alimentary tract fistulas. World Journal of Surgery 1995;19(3):430-3.
Patel 1999
Pederzoli 1986
  • Pederzoli P, Bassi C, Falconi M. Conservative treatment of external pancreatic fistulas with parenteral nutrition alone or in combination with continuous intravenous infusion of somatostatin, glucagon or calcitonin. Surgery, Gynecoloogy and Obstetrics 1986;163:428-32.
Pérez 1994
  • Pérez GD, Acosta BM. Gastrointestinal fistulas. Treatment with a somatostatin analogue (SMS 201–995). G.E.N. 1994;48:209-18.
Rahbour 2012
  • Rahbour G, Siddiqui MR, Ullah MR, Gabe SM, Warusavitarne J, Vaizey CJ. A meta-analysis of outcomes following use of somatostatin and its analogues for the management of enterocutaneous fistulas. Annals of Surgery 2012;256(6):946-54.
Raptis 1978
Sancho 1995
  • Sancho JJ, Di Costanzo J, Nubiola P, Larrad A, Beguiristain A, Roqueta F, et al. Randomized double-blind placebo-controlled trial of early octreotide in patients withpostoperative enterocutaneous fistula. British Journal of Surgery 1995;82:638-41.
Schwartz 1989
  • Schwartz RW, Barker DE, Griffen WOJ, Ross CB, Strodel WE. Gastrointestinal disconnection and the treatment of intra-abdominal sepsis. American Surgeon 1989;55:50-4.
Schünemann 2011
  • Schünemann HJ, Oxman AD, Vist GE, Higgins JPT, Deeks JJ, Glasziou P, et al. Chapter 12: Interpreting results and drawing conclusions. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Scott 1993
  • Scott NA, Finnegan S, Irving MH. Octreotide and postoperative enterocutaneous fistulae: a controlled prospective study. Acta Gastro-enteroligca Belgica 1993;56:266-70.
Sheppard 1979
  • Sheppard M, Shapiro B, Pimstone B, Kronheim S, Berelowitz M, Gregory M. Metabolic clearance and plasma half-disappearance time of exogenous somatostatin in man. Journal of Clinical Endocrinology and Metabolism 1979;48:50-3.
Sitges-Serra 1982
Sitges-Serra 1993
  • Sitges-Serra A, Guirao X, Pereira JA, Nubiola P. Treatment of gastrointestinal fistulas with Sandostatin. Digestion 1993;54 Suppl 1:38-40.
Sleth 1994
  • Sleth JC, Andraos Y, Borie F, Dumay R, Legroux P. Value of octreotide in the treatment of postoperative enterocutaneous fistula. Annales Françaises d’Anesthèsie et de Rèanimation 1994;12(5):738-40.
Soeters 1979
Spiliotis 1990
  • Spiliotis J, Vagenas K, Panagopoulos K, Kalfarentzos F. Treatment of enterocutaneous fistulas with TPN and somatostatin, compared with patients who received TPN only. British Journal of Clinical Practice 1990;44:616-8.
Stevens 2011
  • Stevens P, Foulkes R, Hartford-Beynon J, Delicata RJ. Systematic review and meta-analysis of the role of somatostatin analogues in the treatment of non-pancreatic enterocutaneous fistulae. European Journal of Gastroenterology and Hepatology 2011;23(10):912-22.
Torres 1992
  • Torres AJ, Landa JI, Arguello JM, Silecchia G, Hernandez-Merlo F, Jover JM, et al. Somatostatin in the management of gastrointestinal fistulas. Archives of Surgery 1992;127:97-100.
Tulassay 1998
Van Der Krabben 2000
Wells 2013
  • Wells GA Shea B, O'Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. www.ohri.ca/programs/clinical_epidemiology/oxford.asp (accessed 20 March 2013)..
Xeropotamos 2005
  • Xeropotamos N, Nastos D, Nousias KH, Christodoulou D, Tsianos EV, Kappas AM. Octreotide plus total parenteral nutrition in patients with external digestive tract fistulas – an evaluation of our experience. Annals of Gastroenterology 2005;18:427-33.
Yuan 2011
  • Yuan Y, Ren J, Gu G, Chen J, Li J. Early enteral nutrition improves outcomes of open abdomen in gastrointestinal fistula patients complicated with severe sepsis. Nutrition in Clinical Practice 2011;26(6):688-94.