Somatostatina Em Fistulas 12

META-ANALYSIS

A meta-Analysis of Outcomes Following Use of Somatostatin andIts Analogues for the Management of Enterocutaneous Fistulas

Goher Rahbour, B Med Sci, MBChB, MRCS, Muhammed R. Siddiqui, MBChB, MRCS,Mohammad Rehan Ullah, B Med Sci, MB ChB, Simon M. Gabe, MD, MSc, BSc, MBBS, FRCP,

Janindra Warusavitarne, B Med, FRACS, PhD, and Carolynne J. Vaizey, MD, FRCS (Gen), FCS (SA)

Objective: Several randomized control trials (RCTs) have compared somato-statin and its analogues versus a control group in patients with enterocutaneousfistulas (ECF). This study meta-analyzes the literature and establishes whetherit shows a beneficial effect on ECF closure.Methods: We searched MEDLINE, EMBASE, CINAHL, Cochrane, andPubMed databases according to PRISMA guidelines. Seventy-nine articleswere screened. Nine RCTs met the inclusion criteria. Statistical analyses wereperformed using Review Manager 5.1.Results: Somatostatin analogues versus control

Number of fistula closed: A significant number of ECF closed in thesomatostatin analogue group compared to control group, P = 0.002.

Time to closure: ECF closed significantly faster with somatostatin ana-logues compared to controls, P < 0.0001.

Mortality: No significant difference between somatostatin analogues andcontrols, P = 0.68.

Somatostatin versus controlNumber of fistula closed: A significant number of ECF closed with so-

matostatin as compared to control, P = 0.04.Time to closure: ECF closed significantly faster with somatostatin than

controls, P < 0.00001.Mortality: No significant difference between somatostatin and controls,

P = 0.63Conclusions: Somatostatin and octreotide increase the likelihood of fistulaclosure. Both are beneficial in reducing the time to fistula closure. Neitherhas an effect on mortality. The risk ratio (RR) for somatostatin was higherthan the RR for analogues. This may suggest that somatostatin could be betterthan analogues in relation to the number of fistulas closed and time to closure.Further studies are required to corroborate these apparent findings.

Keywords: enterocutaneous, fistula, meta-analysis, octreotide, somatostatin

(Ann Surg 2012;00: 1–9)

S omatostatin was discovered in 19721 and is a naturally occurringpeptide hormone. It has an inhibitory effect on gastrointestinal

secretion.2 Somatostatin has been found in the pancreas, stomach,intestinal mucosa, and mesenteric neurones. It is used in the man-agement of upper gastrointestinal hemorrhage, secretory diarrhea,dumping syndrome, and peptide-secreting neuro endocrine tumorsbecause of its antisecretory action.3

As the plasma half-life is 1 to 2 minutes, it must be adminis-tered by continuous intravenous infusion. Somatostatin reduces thesecretion of a range of gastrointestinal hormones, including gastrin

From the St Mark’s Hospital and Academic Institute, Colorectal Surgery andLennard-Jones Intestinal Failure Unit, Watford Road, Harrow, Middlesex, UK.

Disclosure: The authors declare no conflicts of interest.Reprints: Goher Rahbour, B Med Sci, MBChB, MRCS, St Mark’s Hospital

and Academic Institute, Colorectal Surgery and Lennard-Jones IntestinalFailure Unit, Watford Road, Harrow, Middlesex HA1 3UJ, UK. E-mail:[email protected].

Copyright C© 2012 by Lippincott Williams & WilkinsISSN: 0003-4932/12/00000-0001DOI: 10.1097/SLA.0b013e318260aa26

and cholecystokinin, which in turn reduce gastric and pancreatic se-cretions. In addition, somatostatin reduces splanchnic blood flow,reduces the rate of gastric emptying, and inhibits gallbladder contrac-tion. As a result of the short half-life, a number of synthetic analogueshave been developed, and of these, octreotide is used most commonlyin the treatment of gastrointestinal fistula.4 Its significantly longerhalf-life allows it to be given by intermittent subcutaneous injection(usually 3 times daily). Despite the similarities, the receptor bindingproperties of somatostatin and octreotide are not identical and theiractions may not be equivalent.4

Enterocutaneous fistulas (ECF) are abnormal communicationsbetween the gastrointestinal tract and the skin. Although rare, they areassociated with considerable morbidity and mortality. Death relatedto ECF remains disproportionately high when compared with othersurgical conditions. Mortality rates for ECF have been reported torange from 6% to 33%.4–8

Fistula formation can result in a number of serious or debilitat-ing complications, varying from disturbance of fluid and electrolytebalance to sepsis and even death. The patient will almost alwayssuffer from severe discomfort and pain. They may also have psy-chological problems, which include anxiety over the course of theirdisease, and a poor body image due to the malodorous drainage fluid.9

Postoperative fistula formation often results in prolonged hospitaliza-tion, patient disability, and enormous cost.

Both somatostatin and octreotide have been described as ef-fective treatments for ECF in adults, with few short-term side effects(diarrhea, flushing, and abdominal pain). Accelerating spontaneousECF closure reduces the period of parenteral nutrition requirementand the morbidity inherent to long-lasting conservative treatment.There is also the potential benefit of reducing patient’s discomfort,shortening the length of hospital stay and of cutting the cost of ECFtreatment. Some authors argue that high cost, equivocal therapeuticeffect on underlying diseases, painful injections, and the potentialfor long-term side-effects make the use of somatostatin and its ana-logues controversial.3 Although there are data suggesting reducedtime to fistula closure, there is little evidence of increased probabilityof spontaneous closure.4

There have been several randomized control trials (RCTs) andstudies9–20 comparing somatostatin and somatostatin analogues ver-sus standard medical therapy or a placebo (control group) in patientswith ECF. The objective of this study is to undertake a meta-analysisof the published literature to assess the efficacy of somatostatin andsomatostatin analogues in the treatment of ECF.

METHODSAll comparative studies investigating the use of somatostatin

and somatostatin analogues in the management of ECF were identi-fied. Articles were dated between January 1987 and March 2011. Wesearched the MEDLINE, EMBASE, and CINAHL available throughthe National Library of Health Web site, the Cochrane library, andPubMed databases available online. The text words “somatostatin,”“octreotide,” and “analogues” were used in combination with the

Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Annals of Surgery � Volume 00, Number 00, 2012 www.annalsofsurgery.com | 1

mailto:[email protected].

Rahbour et al Annals of Surgery � Volume 00, Number 00, 2012

medical subject headings “enterocutaneous” and “fistula.” Irrelevantarticles and reviews evident from the titles and abstracts were ex-cluded. Relevant articles referenced in these publications were ob-tained and the “related article” function was used to widen the results.No language restriction was applied and trials on patients of any ageor sex were included. All abstracts, comparative studies, non-RCTs,and citations were searched comprehensively. A flow chart of the liter-ature search according to PRISMA guidelines21 is shown in Figure 1.Seventy-nine articles were screened for relevance. On further scrutiny,9 RCTs were found to have useful data for this meta-analysis.

Each article was critically reviewed by 2 researchers using adouble extraction method for eligibility in our review. This was per-formed independently, and conflicts, if any, were resolved before finalanalysis. A third researcher confirmed the data extraction. Outcomemeasures were chosen on the basis of whether they were common tothe included articles.

Statistical analyses were performed using Review Manager5.1 (RevMan; Cochrane Collaboration, Copenhagen, Denmark).22

A value of P < 0.05 was chosen as the significance level for out-come measures. For continuous data (time to closure of fistula), theInverse-Variance method was used for the combination of standard-ized mean differences. Binary data (number of fistula closed andmortality) were summarized as risk ratios (RRs) and combined usingthe Mantel-Haenszel method. In each case, a heterogeneity test wascarried out to see whether the fixed effects model was appropriate.

In a sensitivity analysis, 1 was added to each cell frequency for trialsin which no event occurred, according to the method recommendedby Deeks et al.23 Where standard deviations were not reported, thesewere estimated from either ranges or P values. Forest plots were usedfor the graphical display.

RESULTSThirteen full-text articles were retrieved from the electronic

databases and assessed for eligibility. Four trials10,15,18,24 were ex-cluded and their reasons are explained in Table 1. Nine RCTs com-paring somatostatin and somatostatin analogues for use in the man-agement of ECF were included in our study according to our criteria.

Characteristics of trials comparing somatostatin analogues (oc-treotide and lanreotide) with the control or placebo are given inTable 2. Characteristics of trials comparing somatostatin with thecontrol or placebo are given in Table 3. Leondros et al14 compared 3groups in the study—somatostatin, octreotide, and control. Charac-teristics and outcomes of this study were separated into both of therelevant tables accordingly. There were 141 patients in the somato-statin analogue group and 147 in the control or placebo group. Whencomparing somatostatin with the control or placebo, there were 82and 85 patients in each group, respectively.

The outcome variables extracted are shown in Tables 4 and5. The methodological quality of the included trials is explainedcomprehensively in Tables 625,26 and 7.27

FIGURE 1. Flow chart—Literature review fol-lowing PRISMA guidelines.


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Annals of Surgery � Volume 00, Number 00, 2012 Management of Enterocutaneous Fistulas

TABLE 1. Excluded Trials

Trial Reason for exclusion

Perez and Acosta10 Somatostatin used in 19 patients compared with 50 historical cases. Non-RCT.Sitges-Serra et al18 Series of 27 patients treated with octreotide after having received parenteral nutrition for a mean of 25 days. Non-RCT.Kusuhara et al24 Reduction of the effluent volume in high-output ileostomy patients by a somatostatin analogue octreotide. Not related to ECF.Nubiola-Calonge et al15 Blind evaluation crossover trial. Patients randomized to 2 days of octreotide followed by 2 days on placebo or vice versa, after

which all patients were treated with octreotide. Inadequate length of study arms before randomization.

TABLE 2. Characteristics of Trials: Somatostatin Analogues (Octreotide and Lanreotide) Versus Control

Trial Type N Type Control ProtocolOctreotide Protocol(lanreotide if stated) Population Characteristics

Gayral et al9 ControlLanreotide

5354

ProspectiveRCT

30 mg placebo IMat first visit

30 mg lanreotide IM(prolonged release)at first visit.Subsequenttreatmentdependent onresponse of at least50% reduction infistula vol.

Male 32 (60.4%), female 21 (39.6%). Mean age(SD) 59 (14.4). Pancreatic 35 (66%),duodenum 12 (22.6%), small bowel 6(11.3%). Mean fistula vol (SD) / 24 hr: 333.4(225.0)

Male 27 (50%), female 27 (50%). Mean age(SD): 54.8 (15.6). Pancreatic 36 (66.7%),duodenum 6 (11.1%), small bowel 12(22.2%). Mean fistula vol (SD) / 24 hr: 340.4(200.0)

Leandros et al14 Control 15 ProspectiveRCT

Standard medicaltherapy

100 μg SC tds (Untilfistula closure)

Male/female 10/5. Mean age (SD) 72 (13).Enteric 14, pancreatic 1. Low output 10, highoutput (>500 mL / 24 hr) 5

Octreotide 17 Male/female 9/8. Mean age 70 (SD 11.1).Enteric 12, pancreatic 5. Low output 8, highoutput 9

Somatostatin 19 Male/female 12/7. Mean age 61.5 (SD 16.9), P< 0.05. Enteric 12, pancreatic 7. Low output9, high output 10

Jamil et al13 Control 17 ProspectiveRCT


Sandostatin(octreotide) 100 μgSC tds (Until fistulaclosure)

55% male, age range 14–68, mean 39 yrs. 45%female, age range 19–56, mean 34 yrs. ECF:52% ileum, 18% jejunum, 12% colon, 9%biliary tree / pancreas, 6% duodenum, 3%appendix. Low output ECF ( 500 mL / 24 hr)12.12% & 9.10%, respectivelyOctreotide 16

Hernandez-Arandaet al11

Control 45 ProspectiveRCT


100 μg SC tds (Untilfistula closure)

Male/female 27/26 at start. Mean age 51 ± 17yrs. Oesophagus 9, gastric 7, duodenal 9,intestinal 28. ECF 500 mL / 24 hrs = 47

Octreotide 40 Male/female 28/18 at start. Mean age 49 ± 22yrs. Oesophagus 2, gastric 3, duodenal 13,intestinal 28. ECF 500 mL / 24 hrs = 37

Sancho et al16 Control 17 ProspectiveRCT

Standard medicaltherapy +Placebo: saline

100 μg tds SC for 20days

Male/female 8/9. Age 65 yrs (58–73). Stomach1, pancreas 2, duodenum 5, jejunum 4,ileum 5

Octreotide 14 Male/female 11/3. Age 64 yrs (58–70).Pancreas 3, duodenum 6, jejunum 1, ileum 4

Scott et al17 Control 8 ProspectiveRCT

12 days placebo:acetate bufferedsaline SC

100 μg tds SC for 12days

Male/female 2/6. Mean age 66.7 (range 33–78).Duodenal 4, small bowel 4

Octreotide 11 Male/female 5/6. Mean age 57.5 yrs (range22–67). 2 gastric, 2 pancreatic, 7 small bowel

tds indicates three times per day.

Somatostatin Analogues Versus ControlNumber of Fistula Closed

Six studies9,11,13,14,16,17 contributed to a summative outcome.There was no significant heterogeneity among trials (Q = 9.38, df =5 (P = 0.09); I2 = 47%). The number of ECF closed was significantlygreater in the somatostatin analogue group (n = 100/152) compared

with the control group (n = 77/155) [fixed effects model: RR = 1.36,95% CI (1.12, 1.63), z = 3.17, P = 0.002; Fig. 2].

Time to ClosureFive trials9,11,13,14,16 reported on time to closure. There was no

significant heterogeneity among the trials [Q = 3.52, df = 4 (P =0.47); I2 = 0%]. ECF were significantly more likely to close faster


C© 2012 Lippincott Williams & Wilkins www.annalsofsurgery.com | 3


TABLE 3. Characteristics of Trials: Somatostatin Versus Control

Trial Type N TypeControlProtocol Somatostatin Protocol Population Characteristics

Leandros et al14 Control 15 Prospective RCT Standardmedicaltherapy

Continuous intravenousinfusion at 6000 IU/day(Until fistula closure)

Male/Female 10/5. Mean age (SD) 72(13). Enteric 14, pancreatic 1. Lowoutput 10, high output (>500 mL / 24hr) 5

Somatostatin 19 Male/female 12/7. Mean age (SD) 61.5(16.9), P < 0.05. Enteric 12, pancreatic7. Low output 9, high output 10

Isenmann et al12 Control 20 Prospective RCT Standardmedicaltherapy

Continuous intravenousinfusion at 250 μg/hr.(Until fistula closure)

Mean age 59.9. Pancreas 9, duodenum 9,bile duct 2. Output average: 373.3 mL /24 hr.

Somatostatin 25 Mean age 56. Pancreas 11, duodenum 12,bile duct 2. Output average: 303.8 mL /24 hr.

Torres et al20 Control 20 Prospective RCT Standardmedicaltherapy

TPN for 48–72 hrs. followedby somatostatin continuousintravenous infusion at 250μg/hr. for 20 days. Infusionstopped if fistulaunproductive for 48 hrs.

Male/female 10/10. Mean age 49.5(37–78). Fistula output: 202.5 mL /24hr. Pancreas 3, duodenum 2, jejunum 4,ileum 9, ileocolic 2

Somatostatin 20 Male/female 16/4. Mean age 61.9 (36–74)P < 0.05. Fistula output: 369.7 mL / 24hr, P < 0.05. Pancreas 4, duodenum 3,jejunum 3, ileum 9, ileocolic 1

Spiliotis et al19 Control 30 Prospectivetreatment groupcompared withretrospectivegroup

Standardmedicaltherapy

Continuous intravenousinfusion at 250 μg/hr.(Until fistula closure)

Male/female 18/12. Mean age 63.5 (range22–84 yrs). Gastro duodenal 10, smallbowel 9, biliary 4, pancreatic 7

Somatostatin 18 Male/female 10/8. Mean age 59.3 (range26–74). Gastro duodenal 6, small bowel6, biliary 2, pancreatic 4

TABLE 4. Outcomes: Somatostatin Analogues (Octreotide and Lanreotide) Versus Control

Study Type N Closure n Time to closure (days) Mortality rate (%)

Gayral et al9 Control 53 20 Median 26 0 (0)Lanreotide 54 35 (P = 0.006) Median 17 (assume P = 0.06) 0 (0)

Leandros et al14 Control 15 4 Median 18 (SD 5.3) 2 (13.3) P > 0.05Octreotide 17 11 Median 16.5 (SD 16.6) 0 (0)

Jamil et al13 Control 17 14 Mean 17.7 2 (12) P > 0.05Octreotide 16 15 Mean 14 (assume P = 0.06) 3 (19)

Hernandez-Aranda et al11 Control 45 30 27 14 (31%)Octreotide 40 30 18 (P = 0.002) 10 (25%) P > 0.05

Sancho et al16 Control 17 6 Mean 12 (SD 7) 2 (12%)Octreotide 14 8 Mean 7 (SD 3) P = 0.16 2 (14%)

Scott et al17 Control 8 3 — —Octreotide 11 1 (P > 0.05) — —

TABLE 5. Outcomes: Somatostatin Versus Control

Study Type N Closure n Time to closure (days) Mortality rate (%)

Leandros et al14 Control 15 4 Median 18 (SD 5.3) 2 (13.3) P > 0.05Somatostatin 19 16 (P = 0.007) Median 10.5 (SD 7.5) 0 (0)

Isenmann et al12 Control 20 3 / 16 19 —Somatostatin 25 14 / 18 13 —

Torres et al20 Control 20 3 / 16 19 0 (0)Somatostatin 20 17 / 20 13 (Assume P = 0.06) 0 (0)

Spiliotis et al19 Control 30 20 27.4 3 (10)Somatostatin 18 14 (P > 0.05) 18.2 (P < 0.01) 1 (5.5)




TABLE 6. Modified Quality Score for RCTs (Jaddad et al & Chalmers et al)

Quality variablesGayralet al9

Leondroset al14 Jamil et al

Hernandez-Arandaet al11

Sanchoet al16

Scottet al17

Isenmannet al12

Torreset al20

Was the study described asrandomized such as using the wordsrandomly, random, andrandomization? [0,1]

1 1 1 1 1 1 1 1

Was randomization described andappropriate? [−1,0,1]

1 1 1 1 1 1 1 1

Was the study described as doubleblind? [0,1]

1 0 0 0 1 1 0 0

Was method of blinding appropriate?[−1,0,1]

1 0 0 0 1 1 0 1

Was there a description ofwithdrawals and dropouts? [0,1]

1 1 1 1 1 1 1 1

Inclusion criteria 1 1 1 1 1 1 1 1Exclusion criteria 1 0 1 1 1 1 1 1Study period given 1 1 1 1 1 1 1Appropriate statistical analysis 1 1 1 1 1 1 1 1Hard end points 1 1 1 1 1 1 1 1Sample size calculation 1 0 0 0 1 0 0 0Baseline comparable 1 1 1 1 1 1 1 1Any missing post op data 1 1 1 1 1 1 1 1Allocation concealment 1 0 0 0 1 1 0 0Analysis by intention to treat 1 1 1 1 1 1 0 0Score 15 10 10 11 15 14 10 11

Score Max 15; Poor = 1–5; Fair = 6–10; Good = 11–15.

TABLE 7. Methodological Qualities of Retrospective Studies Included in the Trial. Adapted From theScottish Intercollegiate Guidelines Network and Rangel et al27

Quality variables Spiliotis et al19

Inclusion criteria 1Exclusion criteria 0Demographics comparable 1Can the number of participating centers be determined 1Can the number of clinicians who participated be determined 0Can the reader determine where the authors are on the learning curve for the reported investigative procedure 1Is the technique adequately described 1Is there any way that they have tried to standardize the technique 1Is the age and range given for patients 1Do authors address whether there is any missing data 1Were patients in each group treated along similar timelines 1Dropout rates stated 1Outcomes clearly defined 1Blind comparators 0Analysis by intention to treat 1Score 12

Total 15; Less than 6—Poor quality; 6–10—Fair quality; 11 or more—Good quality.

with somatostatin analogues (n = 141) compared with the control(n = 147) group [fixed effects model: SMD = −0.51, 95% CI (−0.75,−0.28), z = 4.27, P < 0.0001; Fig. 3].

MortalityFive studies9,11,13,14,16 reported on mortality. There was no sig-

nificant heterogeneity among the trials [Q = 1.03, df = 4 (P = 0.90);I2 = 0%]. No significant difference was highlighted between ana-logues (n = 17/141) and controls (n = 21/147) [fixed effects model:RR = 0.89, 95% CI (0.50, 1.56), z = 0.41, P = 0.68; Fig. 4].

Somatostatin Versus ControlNumber of Fistula Closed

Four studies12,14,19,20 contributed to a summative outcome.There was significant heterogeneity among trials [τ 2 = 0.84; Q =19.07, df = 3 (P = 0.0003); I2 = 84%]; therefore, the fixed effectsmodel was inappropriate. There was a significant difference with agreater number of ECF closed with the use of somatostatin (n =61/82) as compared with control group (n = 30/85) [random ef-fects model: RR = 2.79, 95% CI (1.03, 7.56), z = 2.02, P = 0.04;Fig. 5].




FIGURE 2. Forest plot—Somatostatin analogues versus control. Outcome—Number of ECF closed.

FIGURE 3. Forest plot—Somatostatin analogues versus control. Outcome—Time to closure.

FIGURE 4. Forest plot—Somatostatin analogues versus control. Outcome—Mortality.

FIGURE 5. Forest plot—Somatostatin versus control. Outcome—Number of ECF closed.

Time to ClosureFour trials12,14,19,20 reported on time to closure. There was no

significant heterogeneity among the trials [Q = 1.06, df = 3 (P =0.79); I2 = 0%]. There was a significant difference, with ECF morelikely to close faster with somatostatin (n = 82) than with controls (n= 85) [fixed effects model: SMD = −0.79, 95% CI (−1.11, −0.47),z = 4.86, P < 0.00001; Fig. 6].

MortalityFour studies12,14,19,20 reported on mortality. There was no sig-

nificant heterogeneity among the trials [Q = 0.12, df = 3 (P = 0.99);

I2 = 0%]. No significant difference was highlighted between somato-statin (n = 4/82) and controls (n = 6/85) [fixed effects model: RR =0.73, 95% CI (0.21, 2.59), z = 0.48, P = 0.63; Fig. 7].

Fistula OutputOf the 9 RCTs, fistula output reduction was not recorded in 3

trials.11,12,14 Torres et al20 recorded a significant reduction in numberof days (P < 0.05 and P < 0.01, respectively) in the somatostatingroup when compared with the control group for a 50% or 75% re-duction in output volume, respectively. Spiliotis et al19 records thatthe somatostatin group had a 50% reduction in fistula volume in 3




FIGURE 7. Forest plot—Somatostatin versus control. Outcome—Mortality.

FIGURE 6. Forest plot—Somatostatin versus control. Outcome—Time to closure.

days, in comparison with 1 week in the control group. This is com-mented to be a significant difference. Jamil et al13 recorded time forfistulous secretions to cease at 7, 14, 21, and 28 days when comparingoctreotide to the control group. No significant difference was notedin the reduction of secretions. Sancho et al16 recorded no significantdifference in fistula output at 24, 48, or 72 hours between octreotideand the control group. Scott et al17 recorded fistula losses during 12days of placebo and octreotide injections. They noted no advantagein reduction in fistula losses. Gayral et al9 showed a significant (P =0.005) mean reduction in fistula output at 72 hours of 45.1% in thelanreotide group versus 8.9% in the control group.

DISCUSSIONSomatostatin receptors comprise a family of 5 heptahelical

membrane proteins encoded by 5 related genes that map to sepa-rate chromosomes.28 The clinically used somatostatin analogues, oc-treotide and lanreotide, act primarily by only binding to somatostatinreceptor 2,29 and this may contribute to a comparatively less effectiveoutcome.

Octreotide has a much longer half-life (approximately 90 min-utes, compared with 1–2 minutes for somatostatin). Because it isabsorbed poorly from the gut, it is administered parenterally (subcu-taneously, intramuscularly, or intravenously). The pharmacokineticand pharmacodynamic differences between somatostatin and its ana-logues require continuous infusion with somatostatin and the par-enteral route for analogues.

In this meta-analysis, we have evaluated the effect of somato-statin and its analogues as an effective treatment for fistula closure.Somatostatin was shown to be associated with an increased numberof fistulas closed and a reduced time to closure when compared withanalogues.

All trials comparing somatostatin with the control favored so-matostatin. All but one trial,17 comparing somatostatin analogues withthe control, favored somatostatin analogues. In comparing somato-statin analogues with the control, there was a significant differencein only one study9 for fistula closure. Gayral et al9 recorded a signifi-cant difference (P = 0.006) with the use of the long acting analogue,lanreotide in fistula closure versus the control.

The study by Scott et al17 was the only trial where the num-ber of fistula closed was better in the control group rather than thesomatostatin analogue group. This is highlighted in the Forest PlotFigure 2. This anomalous result may be explained by the reducedduration of use of octreotide (12 days) when compared with otherstudies. Most of the studies use octreotide 3 times per day as a sub-cutaneous injection11,13,14,16,17 but a continuous infusion may be moreeffective as demonstrated in the study using lanreotide (half-life:2 hours)9,30 where a significant increased rate of fistula closure wasobserved. Further research with continuous infusion of somatostatinanalogues may be useful to evaluate this.

Somatostatin analogues are often thought to be effective at aclinical level, as fistula output will often decrease as they are intro-duced. This study has not been able to analyze the effect on fistulaoutput because of the variation in reporting this between the stud-ies. There was wide variability in the methodology to record fistulaoutput. Pooling of data was not possible, and hence a summativecomparison was excluded from the meta-analysis.

It can be noted from the trials where fistula output was recordedthat both trials using somatostatin19,20 showed a significant benefit infistula output reduction. However, we are unable to elucidate whetherthis has an effect on closure rates.

The 3 trials using octreotide13,16,17 showed no significant ben-efit in fistula output reduction and closure rates. In contrast, the longacting analogue, lanreotide, had both significant benefit in fistulaoutput reduction and number of fistula closed.

Some authors have reported that enteral elemental diets mayreduce fistula output as much as parenteral nutrition4,31 without theassociated complications of central line sepsis, thrombosis, or pneu-mothorax, and hence adherence to a short bowel regime is the mosteffective way of decreasing fistula output. This is also relevant whenconsidering the use of somatostatin, as it is believed to induce intesti-nal atrophy.

Common adverse effects of treatment with somatostatin ana-logues include nausea, abdominal cramps, loose stools, mild steat-orrhea (presumably resulting from transient inhibition of pancreaticexocrine secretion and malabsorption of fat), and flatulence. Thesesymptoms start within hours of the first subcutaneous injection, are




dose-dependent, and usually subside spontaneously within the firstfew weeks of treatment.32

In particular, there is the risk of developing gallstones in pa-tients undergoing therapy with somatostatin analogues. Rates ap-proaching 50% have been reported when used in treating patientswith metastatic gut neuro endocrine tumours or malignant islet celltumors.33

Data on complications including catheter, abdominal, urinarysepsis, pneumothorax, pneumonia, wound, or skin problems werelimited. Torres et al20 reported a greater complication rate within thesomatostatin study group (68.75%, 11/16 patients) than the controlgroup (35%, 7/20 patients). This was a significant difference. Isen-mann et al12 and Leondros et al14 noted no significant difference incomplications between the study groups. Jamil et al13 had a 50% lesscomplication rate in the somatostatin group when compared with thecontrol group.

There was a wide variability in population characteristics in allthe studies analyzed. Torres et al20 had a significant difference in themean ages between the comparison groups and fistula output beforethe commencement of the trial. Leondros et al14 showed a significantdifference in mean age within the somatostatin group as opposed tothe octreotide and control groups. There was wide variability in thelocation of fistula as well as the criteria used to define low or highoutput fistula in all studies (Table 2). All studies except 117 statedtime to closure.

In 511,13,14,16,17 of the 6 RCTs that compared octreotide to stan-dard medical therapy, a dose of 100 μg subcutaneous injection 3times per day was used, for a range of durations. When comparingsomatostatin with the control, 3 of the 4 studies12,14,19 used a con-tinuous somatostatin intravenous infusion dose of 250 μg per hour,for varying durations. Reviewing “time to closure” for each of thesestudies, the current literature supports the use of either octreotide 100μg subcutaneous injection 3 times daily or somatostatin intravenousinfusion dose of 250 μg per hour for a minimum period of 2 weeks.The study of Sancho et al16 was the only trial to comment on whentreatment should be commenced in relation to the duration of an ECF.Their inclusion criteria included all patients with postoperative ECFof less than 8 days’ duration with a daily output greater than 50 mL.

Our meta-analysis is limited because of several studies havingsmall numbers of patients recruited. There is further limitation dueto the wide variability in study designs, which has been reflectedin patient characteristics and study protocol. There is also a lack ofclear definitions relating to the recording of study outcomes: fistulaclosure, time of fistula closure, fistula output reduction, complicationrate, and mortality. There was no significant heterogeneity exceptfor when comparing somatostatin with the control for the number offistulas closed. This may relate to the study of Spiliotis et al19 having ahigher number of patients in the control group than any other studies.

CONCLUSIONSOur meta-analysis suggests that somatostatin and octreotide

increase the likelihood of fistula closure. Both are beneficial in re-ducing the time to fistula closure. Neither has a significant effect onmortality when compared with standard medical treatment. The bestresults were after the use of somatostatin or long acting somatostatinanalogue, lanreotide.

The RR for somatostatin was higher than the RR for analogues.This may suggest that somatostatin is more effective than analoguesin relation to the number of fistulas closed and time until closure.Further studies are required comparing these 2 agents to corroboratethese findings.

Recommendation is for a large RCT with adequate patientnumbers or a multicenter trial with well-defined criteria and agreedparameters between the participating centers. If a clear option is

identified, this would benefit an already surgically challenging groupof patients associated with a high morbidity and mortality where it isdeemed standard medical treatment has failed.

ACKNOWLEDGMENTSG.R., M.S., J.W., and C.V. conceived and designed the study.

G.R., M.S., and M.U. reviewed the literature and performed the sta-tistical analysis. G.R. and M.U. drafted the manuscript. G.R., M.S.,S.G., J.W., and C.V. interpreted the analysis, contributed, edited, andrevised the manuscript. G.R. is also using data from the study for hisMD (Res) research thesis for Imperial College London. All authorscontributed to and approved the final manuscript.

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