Efficacy of octreotide in postoperative alimentary tract fistulas

Transcription

1 ORIGINAL ARTICLE Osman B. Belim 1*, Ojas Mody 1 1 Associate Professor, Department of Emergency Medicine, Medical College, Baroda ABSTRACT BACKGROUND: With the passage of time, there has been changing pattern of incidence and mortality of enterocutaneous fistulae. The earliest record of enterocutaneous fistulae appears in the The old testament of judges written by Samuel between 1043 BC and 1004 BC. It is the account of eglon, who sustained an acute post- traumatic enterocutaneous fistula. Celsus described the first reported attempt at surgical repair of a colocutaneous fistula: it can be sutured, not with any certain assurance. In 18th century, john hunter advocated a conservative approach to fistula after he noted that fistulae occasionally close spontaneously: In such cases nothing to be done but dressing the wound superficially, and when the contents of the wounded viscus becomes less, we may hope for cure , antibiotics were introduced in the management of entero cutaneous fistulae. During , there was rapid improvement inparasurgical care, perfection of antibiotics, some introduction of nutritional support. They also discovered that greater the fistula output, the greater the morbidity and Even in more contemporary times, where parasurgical care is improved. Enterocutaneous fistulae still have 6% to 20% mortality. In addition to sepsis, malnutrition and electrolyte disturbance contributes to morbidity and mortality now accounting for 5% to 30% fistulae death. MATERIALS AND METHODS: A prospective randomized randomized controlled trial was conducted at department of surgery; Sir Sayajirao General Hospital and Medical College Baroda from August 2011 to December 2012 A total of 37 patients were enrolled in the study,19 patients in octreotide group A and 18 patients in group B who were not givenoctreotide. Average age of patients in group A was 41 years and in group B was 40 years. Majority of patients weremale in both groups. Causes of fistula in both groups being postoperative in 90% cases in group A and 100% cases in group B with majority of fistula arising from small bowel (21 casesout of 37 patients). RESULTS: Results showed that there was significant difference in closure time in two groups with closure time in group A beings 19 days as compared to 30 days in group B (P=0.0442).Majority of patients in both the groups had sepsis as major complication with mortality occurring much higher ingroup B as 44% compared to 21 % in group A. CONCLUSION: The present study demonstrated that regardless of fistula type, the introduction of octreotide in standard treatment of enterocutaneous fistula optimized treatment efficacy by reducing fistula output, accelerating spontaneous fistula closure rate, reducing fistula closure time and decreasing fistula related mortality. Keywords: Fistula, octreotide, alimentarytract, morbidity, mortality INTRODUCTION Enterocutaneous fistula is an abnormal communication between epithelial lined lumen of GI tract and epithelium of an adjacent viscous or skin 1,2. Fistula management has been challenging to physician. Management of external digestive tract fistula (EDTF) and biliary-pancreatic fistulas has been associated with high morbidity rates upto to 65% and morbidity rates of upto 40%. Although the causality of these high mortality rate is multifactorial, it is generally emphasized that mortality rate is higher in patients with underlying infections, malnutrition and high-output fistulas. *Corresponding Author Dr. Osman B. Belim Associate Professor, Department of Emergency Medicine, Govt. Medical College, Baroda (Gujarat-India) drbelim@yahoo.co.in Nonetheless, in patients diagnosed with EDTF, a high morbidity, prolonged hospitalization and high mortality rate has been reported. The role of nutrition support in decreasing the number of deaths caused by enterocutaneous fistulas still remains controversial. It seems that conservative treatment with only succeeds in closing 60-75% of fistulas 1. Octreotide (OC) as an adjuvant therapy to standard fistula management has been reported to decrease fistula output. However its role in shortening fistula closure time still remains to be proven. We compared disease outcomes of 19 patients with EDTF treated with octreotide 3 during period august 2011 to December 2012 with that of 18 patients treated with conventional treatment was applied as routine method. The objectives of this study were the following: To study the demographics and etiology of fistulas, to study effects of octreotide of fistula output 4, to study effects of octreotide on 82 Int J Res Med. 2014; 3(1);82-86 e ISSN: p ISSN:

2 fistula closure and to study mortality, morbidity, complications and duration of hospital stay of patients enrolled in study. MATERIALS AND METHODS Hospital records were prospectively reviewed at the academic department of surgery of our hospital, from august 2011 to December Selection of cases were done from various surgical units. The study comprised of 19 cases and 18 control forming a total of 37 patients. Inclusion criteria and exclusion criteria for patients in study are described below: Inclusion Criteria: 1. All patients with gastric, duodenal, pancreatic, small and large bowel fistulas within 7 days of fistula onset without any abscess or distal obstruction. 2. Fistula output higher than 150 ml/day. Exclusion Criteria: 1. Intraabdominal sepsis 2. Intraabdominal foreign body 3. Complete discontinuity 4. Spontaneous fistula (crohn s, malignancy, radiation enteritis). 5. Epitheliazed track 6. Gross early anastomotic leak(1000ml/48 hours) Randomization: Eligible patients were randomly assigned within 7 days of fistula onset to either placebo or octreotide by drawing of consecutively numbered drug packages that contained either treatment 5. In all cases the patient, surgeon in charge and investigator were blinded. At 1 month after the last patient had been discharged from hospital the sealed envelopes were opened by the head of the study and two investigators. Patient records were then accordingly labelled before any statisticalanalysis was carried out. End point of Study: (1) Primary end point: fistula output reduction. (2) Secondary end point: fistula closure defined as 2 or more successive days with no fistula output during the treatment period. High output fistulas were defined as those that drained over 500 ml per 24 hours. Total of 37 patients were included in the study, out of which 18 (group B) recieved standard therapy which include nasogastric suction, antibiotics according to surgeon s discretion, intravenous supportive measures (ivglucose, crystalloid solutions and electrolytes). Fistula output and clinical and laboratory manifestations of infection were recorded. Nutritional support was administered by adequate oral intake or by tube feedingwith high calorie liquefied diets. 19 patients in group A received octreotide (100 microgram in 100 ml NS iv 8 hourly) as an adjunct to standard treatment. In group A, supportive measures, control of sepsis, control of fistula effluent were also included. All the patients were given gms of nitrogen and kcal daily via a peripheral vein. In all patients with gastrointestinal and biliary fistulas, octreotide was started one or two days after fistula onset. Routine laboratory tests were performed as needed in order tomonitor metabolic effects of fistula, as well preventhyperglycemia related to OC administration. Fistulas that closed without any operative intervention were Considered to be those that spontaneously closed. Some of these required some surgical procedures, such as exploratory laparotomy and drainage of fistula related abscess. Fistula output was recorded on daily basis (millilitres per day), while reduction of fistula output (mean[±sem]) and time for fistula healing (mean[±sem]) was also evaluated. Data management. Data collected at participating institutions were sent to the study coordinator's office for review. Data were double entered into a computer database for verification and checked routinely for outliers and erroneous values. Completion and correction procedures were carried out before the code was revealed. Statistical Analysis: The necessary sample size was estimated on the basis that considering shortage of duration of study of one and half years and considering fistula patients to be less, so minimum of patients required to conduct a study were taken that is 15 each group. Comparison of discrete variables between placebo and octreotide arms was made by x2 and Fisher's exact test as necessary. Comparison between means of continuous variables of each group was carried out with Student's t test. Linear regression coefficients were calculated to assess the relationship between numerical variables. Test statistics for comparisons were regarded as significantat P<0.05 (all P values are two-tailed). Results after treatment are given as mean (s.d.). RESULTS Patients clinical and demographics are shown in table 1 Table 1: Demographic characteristics of patients with external digestive tract Fistulas Characteristic Group A Group B No. of patients Gender (M/F) 14/5 14/4 Mean age (years) years years The patients in the study belonged to range of 41.78±12.35 years in group A with youngest being 25 years and eldest being 70 years. Patients in control group B had mean age of 40.05±15.02 years with youngest being 6 years and eldest being 60 years. There was a preponderance of male patients in both groups with 73% male patients in group A and 77%male patients in group B. Fistulas etiology, location and output are shown in table 2,3, and 4. 90% fistulas in group A were postoperative with rest being traumatic while in group B all fistula 83 Int J Res Med. 2014; 3(1);82-86 e ISSN: p ISSN:

3 patients were postoperative which is illustrated in table 2. Table 2: Causes of external digestive tract fistula in two group patients. Causes of fistula Group A No.% Group B No.% Postoperative 17(89.47) 18(100) Traumatic 2(10.53) - Table 3: External digestive tract fistula origin in the two groups of patients Fistula origin Group A Group B Stomach 1 3 Duodenum 2 1 Small intestine Colon 4 2 Biliary tree 1 1 Pancreas 1 - Total Majority of patients in both group had fistula arising from small bowel, that is 10 out of 19 patients in group A and 11 out of 18 patients in group B. Rest of fistula in study arose from colon, stomach, with 1 patient in each group had biliary fistula. Table 4: External digestive tract fistula in two group of patients Type of Fistula output Group A Group B Low output (<500ml/24h) 09(47.37%) 09(50%) High output (<500ml/24h) 10(52.63%) 09(50%) According to output both the group had similarity with nearly 50% Patients in both groups were high output and 50% being low output. Majority of patients in both groups that is 10 out 0f 19 in group A and 12 out 18 in group B had perforation repair failure as cause of fistula, While two patients in group A were found to have malignancy after biopsy confirmation who were previously had report suggestive of benign disease, while in one patient in group A cause was pancreatic in origin while in group B next most common cause after perforation was found to be duodenum in origin. Table 5: Primary disease that caused external digestive tract fistula. Primary disease Group A Group B Cancer 2 - Duodenum 2 4 Trauma 2 - Extra hepatic 1 1 biliary tree disease Diverticulitis 1 - Pancreas 1 - Perforation Miscellaneous - 1 The introduction of OC resulted in a rapid and significant decrease in fistula output. This dramatic fistula output reduction was noted in hours after OC administration especially in high output fistulas. Fistula output was not influenced by the time of treatment initiation or fistula anatomical site. Eleven (57%) patients in group A and eleven (61%) patients in group B had been exclusively treated conservatively. Two (18%) patients in group A and four patients (36%) patients in group B, failed initial conservative management and underwent a primary surgical fistula repair (table 6). Table 6: Definite treatment of external digestive tract fistula in two group of Patients. Definite treatment Group A Group B Conservative 11(57.89%) 11(61.11%) Operative 08(42.11%) 07(38.89%) The incidence of spontaneous fistula closure was decreased from (42 %) (08 /19 patients in group A to (33 %) (06 /18 patients) in group B On applying x2 test, x2= Degree of Freedom = 1 P = which is >0.05 this is not statistically significant at 95% confidence interval. The mean closure time for fistulas that closed spontaneously was decreased from (19.5 ±15.8) days for group A as compared to (29.66 ± 13.66) days for group B fistulas (p<0.05)(table 7). On applying T test, t = Degree of Freedom= 35 P = which is <0.05 which is statistically significant at 95% confidence interval. Table 7: Fistula outcome in both group with external digestive tract fistula. Fistula output Group A No.% Group B No.% Spontaneous closure 08(42) 06(33) 50% reduction in output 03(16) 00 75% reduction in output 02(11) 02(11) Surgical closure failure 02(25) 03(43) after surgical repair Deaths after conservative 02(18) 03(27) treatment Deaths after surgical treatment 01(12) 03(43) Closure time days days Table 8: Complications during treatment of external digestive tract fistulas. Type of Group A complications Total no of patients with complications Sepsis Pneumonitis Urinary infections Malnutrition Electrolyte disturbances Group B Anemia Ventilator support Renal failure Mortality No fistulas of group A and B had relapse after initial conservative treatment. Surgical treatment had failed to repair enterocutaneous fistula in a 2 gastric fistula and duodenal fistula in group B patient and a billiary fistula in a case of periampuullary mass and ileal fistula in small bowel volvulus in group A patient % reduction in fistula output was achieved in almost thirty percent of cases in group A as compared to ten percent cases in group B. Morbidity assessment in both groups showed that complications were much more frequent in group B patients who were treated with standard therapy (table 8). Sepsis had been the most frequent serious complication that led to conservative and surgical failures as well as 84 Int J Res Med. 2014; 3(1);82-86 e ISSN: p ISSN:

4 morbidity and mortality. The introduction of OC significantly reduced metabolic and waterelectrolyte abnormalities in group A compared to group B (21 % vs 44 %, p<0.05). In group A, 14 out of 19 patients had some or other complications. With majority that is 9 out of 14 having sepsis, second major complication being malnutrition. In group B, majority of paients were having complication of sepsis that is 11 out of 17 patients, with second commom complication being electrolyte disturbances followed by anemia and malnutrition. One patient from both group had renal failure as complication. Three patients in group A and seven patients in group B died. In group B, mortality rate was approximating 40% which was very high as compared to group A which was about 16%. On applying Odd s ratio OR = 2.46 Therefore mortality in group B was 2.5 times higher than group A. In group B, one patient died from metabolic disturbances other patients died from intraabdominal sepsis and from respiratory complications. In group A, one patient died from sepsis and other two from pneumonitis and renal failure complication. Hospital stay in group A patients was 36.78±15.79 days and that in group B was 38.7±15.5 days and there was no statistical significance as hospital stay in both groups were similar. On applying t Test, t = Degree of Freedom = 35 P = which is >0.05. So, this value is not statistically significant at 95% confidence interval. DISCUSSION Gastrointestinal cutaneous fistulas still remain a serious problem of current surgical practice. The predominant cause of death in patients with EDTF have been and still remain malnutrition, electrolyte abnormalities and sepsis. This is especially true in patients with high output duodenal or jejunal fistulas in whom mortality rates remains approximately 35%. Although the reported rates of spontaneous closure tends to increase, the morbidity rates still remains high. A recent placebo-controlled trial showed that octreotide reduces small bowel fistula output and initial experience suggested that the drug did not increase the incidence of spontaneous closure of postoperative enterocutaneous fistula but shortened the spontaneous closure time once the fistula was stabilized, sepsis controlled and the patient treated with parenteral nutrition for a mean of 3 weeks after fistula onset 6. Experience with somatostatin and its analogues in the management of postoperative enterocutaneous fistula suggests that the timing of administration influences the clinical course. Octreotide did not influence clinical outcome of patients with postoperative enterocutaneous fistula and the results of previous study do not support administration of octreotide within 8 days of onset of such a fistula. This finding does not conflict with previously reported resultsof a blind, cross-over, randomized trial in patients with well established fistula, no sepsis and a stable output treated with parenteral nutrition for at least 7 days, in which the reduction of fistula output 48 hrs after octreotide administration was of the order of 60 per cent. In a subsequent open prospective study, 27 patients with postoperative fistula who had already received parenteral nutrition for a mean of 25 days were treated with octreotide. The spontaneous closure rate was 78 percent and the reduction in output achieved by octreotide averaged 55 per cent at 48 hrs, In contrast with previous reports, patients in my trial had fistulas of recent onset and had not previously received parenteral nutrition. This may have obscured the potential benefit of octreotide in a more stable clinical setting and emphasizes the critical importance of the timing of octreotide administration in the treatment of postoperative enterocutaneous fistula. Besides, it has been shown by the majority of studies that octreotide or somatostatin reduces the closure time and the period of hospitalization and it improves the quality of life of patients with gastrointestinal tract fistulae. No important side effects with OC treatment were observed in our study, as reported. Scott el at conducted a prospective randomized double-blind study to evaluateoctreotide in the treatment of postoperative enterocutaneous fistula. The study evaluated 19 patients with at least 7 days of fistula output who were randomized to receive octreotide 100 mcg subcutaneously every 8 hours for 12 days or placebo. Eleven patients were randomized to receive octreotide and 9 patients received placebo. About half the patients in the study had upper gastrointestinal fistula. Median fistula losses were not statistically different between the two treatment groups (252 to 550 ml/day in the octreotide group and 202 to 400 ml/day in the placebo group). One patient in the treatment group had fistula closure and 3 patients in the placebo group had fistula closure, which was not statistically different. (Class I). Sancho et al conducted a randomized doubleblind placebo-controlled trial to evaluate early administration of octreotide in the treatment of postoperativeenterocutaneous fistula. The study evaluated 36 patients who were also started on total parenteral nutrition, and randomized them to receive octreotide 100mcg every 8 hours for 20 days or placebo. Fourteen patients were randomized to receive octreotide and 17 received placebo. There was no difference in the reduction of output at 24, 48 and 72 hours. The closure rate in the octreotide group was 57% and in the placebo group was 35%, which was not statistically different. There was also 85 Int J Res Med. 2014; 3(1);82-86 e ISSN: p ISSN:

5 no difference in the time to closure between the two groups (Class I). In a study conducted by col rajanchaudhary 9/17 patients (52%) the fistulae arose from the proximal small gut (duodenum and jejunum) and in the remaining 48% from the ileum. Octreotide was used in 11/17 patients (64%). Enteral nutrition was used in 9/17 patients (52%) while re-feed from the proximal gut fistulae was used in 4/9 patients (44%) to maintain the nutrition of the patients. Only one fistula (6%) closed spontaneously. There were 2 deaths (12%) in this study. 14/17 patients (82%) required surgical intervention at some stage for successful closure of intestinal fistula. Aggressive surgical treatment with judicious use of octreotide, nutritional support, stoma care and control of sepsis significantly improves the outcome of small intestinal fistulae 7. In this study it was shown that the main advantage of OC introduction was the rapid decrease fistula output leading to hastening of fistula closure. In group A the mean fistula closure time was (19.5±15.8) days and it was significantly shorter compared to standard treatment in group B which was (29.66±13.66) days [p<0.05]. Total parenteral nutrition has been historically associated with fistula spontaneous closure times of 30 to 50 days while OC use has been reported to reduce digestive fistula activity in fewer than 16 days occasionally within 24 hours. Two prospective placebocontrolled trials did not show any improvement in fistula closure rate using OC and TPN versus monotherapy. Another study had also failed to also failed to demonstrate significant improvement in the long term outcome of complicated fistulas using OC therapy. According to that study prolonged therapy failed to affect the outcome parameters studied, particularly fistula duration, spontaneous closure rate, and length of hospitalization. Our study demonstrated that in good hands the OC therapy is safe and effective and leads to significantly improved outcomes for patients with postoperative external digestive tract fistulas 8. So, OC succeeded in closing of eight (fourty two percent) fistulas in this unselected randomized prospective study. Besides it has been shown by majority of studies that octreotide reduces the closure time and period of hospitalization and it improves the quality of life of patients with gastrointestinal tract fistulae 9. No important side effects with OC treatment were observed in our study, as reported. This was in contrast with other studies, reporting thatoctreotide might have contributed to cardiac morbidity in patients with pancreatic fistulas. By reducing the volume and enzymatic content of gastrointestinal fistulas, OC facilitated the management of fluid and electrolyte abnormalities, metabolic and nutritional disorders. OC succeeded in reducing morbidity in group A and this outcome was statistically significant (p<0.05). In addition, there was no evidence of increased septic complications. Better results were also obtained with surgical fistula repair in patients of group A and this may be attributed to improvement of nutritional status with TPN in postoperative period. Studies however do not support the opinion of prophylactic octreotide, as there is no convincing evidence for its efficacy so far. REFERENCES 1. N. Xeropotamos, D. Nastos, V. Nousias, K.H. Katsanos1, D. Christodoulou1, E.V. Tsianos1, A.M. Kappas: Octreotide plus Total Parenteral Nutrition in Patients with External Digestive Tract Fistulas. An Evaluation of our Experience annals of gastroenterology2005, 18(4): Dixon C.F. and Deuterman J.L. (1938). Management of external intestinal fistula. JAMA, Di Constanzo J, Can N, Martin J. Somatostatin in persistent gastrointestinal fistula treated by total parenteral nutrition.lancet1982; ii: (Letter). 4. Amy R Evanson, Josef E. Fischer,GautamShrikhande. Maingot sabd. Op. 11th edition vol. 1: J. J. Sancho, J. Di costanzo*, P. Nubiola, A. Larradt, A. Beguiristains, F. Roquetas, G. Franch, A. Oliva, J. M. Gubern and A. Sitgesserra. Randomized double-blind placebocontrolled trial of early octreotide in patients with postoperative enterocutaneous fistula, British Journal of Surgery 1995, 82, The Challenge of Enterocutaneous Fistulae Col Rajan Chaudhry. MJAFI 2004; 60 : Rich A.J. and Sainsbury JRC. Somatostatin in gastrointestinal fistulae. Lancet 1986; i: 1381(Letter). 8. Nubiola-Calonee P. Badia JM. Sancho J. Gil MJ. Seeura M. Sitges-Serra AT Blind evaluation of the 'effect of octreotide (SMS ), a somatostatin analogue, on small bowel fistula output. Lancet 1987; ii: Torres A, Landa J, Moreno-Azcoitia M et al. Somatostatin and its analogue in the management of gastrointestinal fistulae. Arch Surg1992; 86 Int J Res Med. 2014; 3(1);82-86 e ISSN: p ISSN: