Piperacillin-Tazobactam Compared With Cefoxitin as Antimicrobial Prophylaxis for Pancreatoduodenectomy: A Randomized Clinical Trial.

Importance: Despite improvements in perioperative mortality, the incidence of postoperative surgical site infection (SSI) remains high after pancreatoduodenectomy. The effect of broad-spectrum antimicrobial surgical prophylaxis in reducing SSI is poorly understood. Objective: To define the effect of broad-spectrum perioperative antimicrobial prophylaxis on postoperative SSI incidence compared with standard care antibiotics. Design, Setting, and Participants: Pragmatic, open-label, multicenter, randomized phase 3 clinical trial at 26 hospitals across the US and Canada. Participants were enrolled between November 2017 and August 2021, with follow-up through December 2021. Adults undergoing open pancreatoduodenectomy for any indication were eligible. Individuals were excluded if they had allergies to study medications, active infections, chronic steroid use, significant kidney dysfunction, or were pregnant or breastfeeding. Participants were block randomized in a 1:1 ratio and stratified by the presence of a preoperative biliary stent. Participants, investigators, and statisticians analyzing trial data were unblinded to treatment assignment. Intervention: The intervention group received piperacillin-tazobactam (3.375 or 4 g intravenously) as perioperative antimicrobial prophylaxis, while the control group received cefoxitin (2 g intravenously; standard care). Main Outcomes and Measures: The primary outcome was development of postoperative SSI within 30 days. Secondary end points included 30-day mortality, development of clinically relevant postoperative pancreatic fistula, and sepsis. All data were collected as part of the American College of Surgeons National Surgical Quality Improvement Program. Results: The trial was terminated at an interim analysis on the basis of a predefined stopping rule. Of 778 participants (378 in the piperacillin-tazobactam group [median age, 66.8 y; 233 {61.6%} men] and 400 in the cefoxitin group [median age, 68.0 y; 223 {55.8%} men]), the percentage with SSI at 30 days was lower in the perioperative piperacillin-tazobactam vs cefoxitin group (19.8% vs 32.8%; absolute difference, -13.0% [95% CI, -19.1% to -6.9%]; P < .001). Participants treated with piperacillin-tazobactam, vs cefoxitin, had lower rates of postoperative sepsis (4.2% vs 7.5%; difference, -3.3% [95% CI, -6.6% to 0.0%]; P = .02) and clinically relevant postoperative pancreatic fistula (12.7% vs 19.0%; difference, -6.3% [95% CI, -11.4% to -1.2%]; P = .03). Mortality rates at 30 days were 1.3% (5/378) among participants treated with piperacillin-tazobactam and 2.5% (10/400) among those receiving cefoxitin (difference, -1.2% [95% CI, -3.1% to 0.7%]; P = .32). Conclusions and Relevance: In participants undergoing open pancreatoduodenectomy, use of piperacillin-tazobactam as perioperative prophylaxis reduced postoperative SSI, pancreatic fistula, and multiple downstream sequelae of SSI. The findings support the use of piperacillin-tazobactam as standard care for open pancreatoduodenectomy. Trial Registration: ClinicalTrials.gov Identifier: NCT03269994.

[Novel Treatment Strategy Using Trafermin® Consisting of bFGF for Intractable Pancreatic Fistula-A Case Report].

Pancreatic fistula is one of the most critical complication following distal pancreatectomy. We report here a successfully treated case with intractable pancreatic fistula using Trafermin® consisting of basic fibroblast growth factor(bFGF). A 60- year-old man underwent laparoscopic distal pancreatectomy. After surgery, pancreatic fistula was occurred. Pancreatic fistula persisted for 3 months despite of several conservative treatments. After obtaining informed consent, we started to inject 50µg/day of Trafermin® through a drainage tube into the dehiscence of pancreas. Consequently, pancreatic fistula was successfully closed within a week. This technique could be one of the treatment choices for intractable pancreatic fistula following distal pancreatectomy.

A randomised, multicentre trial of somatostatin to prevent clinically relevant postoperative pancreatic fistula in intermediate-risk patients after pancreaticoduodenectomy.

BACKGROUND: Prophylactic somatostatin to reduce the incidence of clinically relevant postoperative pancreatic fistula after pancreaticoduodenectomy remains controversial. We assessed the preventive efficacy of somatostatin on clinically relevant postoperative pancreatic fistula in intermediate-risk patients who underwent pancreaticoduodenectomy at pancreatic centres in China. METHODS: In this multicentre, prospective, randomised controlled trial, we used the updated postoperative pancreatic fistula classification criteria and cases were confirmed by an independent data monitoring committee to improve comparability between centres. The primary endpoint was the rate of clinically relevant postoperative pancreatic fistula within 30 days after pancreaticoduodenectomy. RESULTS: Eligible patients (randomised, n = 205; final analysis, n = 199) were randomised to receive postoperative intravenous somatostatin (250 µg/h over 120 h; n = 99) or conventional therapy (n = 100). The primary endpoint was significantly lower in the somatostatin vs control group (n = 13 vs n = 25; 13% vs 25%, P = 0.032). There were no significant differences for biochemical leak (P = 0.289), biliary fistula (P = 0.986), abdominal infection (P = 0.829), chylous fistula (P = 0.748), late postoperative haemorrhage (P = 0.237), mean length of hospital stay (P = 0.512), medical costs (P = 0.917), reoperation rate (P > 0.99), or 30 days' readmission rate (P = 0.361). The somatostatin group had a higher rate of delayed gastric emptying vs control (n = 33 vs n = 21; 33% vs 21%, P = 0.050). CONCLUSIONS: Prophylactic somatostatin treatment reduced clinically relevant postoperative pancreatic fistula in intermediate-risk patients after pancreaticoduodenectomy. TRIAL REGISTRATION: NCT03349424.

Impact of Neoadjuvant Chemotherapy Among Patients with Pancreatic Fistula After Gastrectomy for Advanced Gastric Cancer.

BACKGROUND: Neoadjuvant chemotherapy (NAC) has been widely adopted for patients with advanced gastric cancer; however, the safety of gastrectomy with D2 lymphadenectomy followed by NAC has not yet been evaluated. We retrospectively analyzed the influence of NAC on morbidity and mortality after gastrectomy in patients with advanced gastric cancer. PATIENTS AND METHODS: A series of 364 patients with advanced gastric cancer who underwent gastrectomy without pancreatectomy between January 2008 and December 2010 at eight hospitals registered to the Yokohama Clinical Oncology Group were studied retrospectively. There were 330 patients who underwent surgical treatment immediately after diagnosis (surgery alone group) and 34 patients (NAC group) who first received NAC and then underwent surgical resection. RESULTS: Although there were no significant differences in the morbidity rate between the two groups, postoperative pancreatic fistula was more often observed in NAC patients than in patients of the group treated with surgery alone [5 cases (14.7%) vs. 11 cases (3.3%); p=0.011]. In the univariate analysis, NAC (p=0.029), bursectomy (p<0.001) and operative bleeding (≥300 ml, p=0.002), were significantly correlated with postoperative pancreatic fistula, and NAC [odds ratio (OR)=4.901, 95% confidence interval (CI)=1.455-16.67; p=0.010] and bursectomy (OR=11.2, 95% CI=3.460-37.04; p<0.001) were independent risk factors for postoperative pancreatic fistula by multivariate analysis. The incidence of postoperative pancreatic fistula was 40.0% among patients who underwent gastrectomy with bursectomy followed by NAC. CONCLUSION: The incidence of pancreatic fistula in patients treated with NAC and bursectomy was significantly higher than that in other patients. Bursectomy may be discouraged for the prevention of pancreatic fistula from gastrectomy following NAC.

[Impact of octreotide on pancreatic fistula after pancreaticoduodenectomy: a prospective study].

OBJECTIVE: To investigate the effect of utilizing octreotide during perioperative period on pancreatic fistula after pancreaticoduodenectomy (PD). METHODS: Three hundreds and six patients admitted from January 2010 to October 2014, who prepared to undergo pancreaticoduodenectomy (PD) were randomly divided into octreotide group (147 cases) and control group (159 cases). In octreotide group, octreotide was used in subcutaneous injection instantly after PD, each 8 hours until postoperative 10(th) day, and patients in control group were injected with the same volume of saline. Differences of pancreatic fistula (Grade A, Grade B, Grade C), hospitalization days and treatment cost were compared. χ(2) test, t-test and Fisher exact test were used to analyzed to the data, respectively. RESULTS: No statistical significance (P>0.05) between two groups in the incidence of pancreatic fistula after PD (Grade A: 8.8% vs. 10.2%, Grade B: 2.7% vs. 4.4%, Grade C: 0.7% vs. 1.3%; χ(2)=0.197, 0.700, 0.288; P=0.657, 0.403, 0.591), the length of hospitalization((12.1±1.2)days vs. (13.0±1.2)days)(t=1.711, P=0.104) and treatment cost (79 700±6 700 vs. 77 600±5 200)(t=1.378, P=0.185). When accompanied with high risk factors, such as soft texture of pancreas, pancreatic duct size less than 3 mm, BMI≥25 kg/m(2) and diabetes, compared with control group, octreotide group had the lower incidence rate of pancreatic fistula and clinical correlative pancreatic fistula(all P<0.05) after PD. CONCLUSIONS: Generally, octreotide makes no contribution to reduce the incidence of pancreatic fistula after PD. However, for patients who is accompanied with high risk factors, such as soft texture of pancreas, pancreatic duct size less than 3 mm, BMI≥25 kg/m(2) and diabetes, octreotide can effectively prevent pancreatic fistula after PD.

[Possibilities of treatment of external pancreatic fistula].

Evaluation of the efficacy of sekretoliticeskoj therapy with synthetic analogue of somatostatin, a short-acting oktreotid (group 1) and extended oktreotid-depo (group 2) in 24 patients with external pancreatic fistulas after destructive pancreatitis. Results of clinical studies have shown that against the backdrop of an analogue of somatostatin-depo true healing and purulent-necrotic pancreatic external fistula occurs in less time: average 19 ± 1.8, and 16.2 ± 1.2 day observations, respectively.

[Somatostatin and the digestive system. Clinical experiences]. / A szomatosztatin és az emésztorendszer. Klinikai tapasztalatok.

The effect of somatostatin on the gastrointestinal tract is complex; it inhibits the release of gastrointestinal hormones, the exocrine function of the stomach, pancreas and bile, decreases motility and influences absorption as well. Based on these diverse effects there was an increased expectation towards the success of somatostatin therapy in various gastrointestinal disorders. The preconditions for somatostatin treatment was created by the development of long acting somatostatin analogues (octreotide, lanreotide). During the last twenty-five years large trials clarified the role of somatostatin analogues in the treatment of various gastrointestinal diseases. This study summarizes shortly these results. Somatostatin analogue treatment could be effective in various pathological conditions of the gastrointestinal tract, however, this therapeutic modality became a part of the clinical routine only in neuroendocrine tumours and adjuvant treatment of oesophageal variceal bleeding and pancreatic fistulas.

[A case of pancreatic and duodenal fistula after total gastrectomy successfully treated with coagulation factor XIII].

Pancreatic fistula( PF) is a challenging postoperative complication. We report a case of PF following gastrectomy successfully treated using intravenous coagulation factor XIII( FXIII).A 78-year-old man with early gastric cancer underwent total gastrectomy with Roux-en-Y reconstruction. PF developed postoperatively, following which, leakage from the duodenal stump was observed. Percutaneous drainage and re-operative surgery were performed. A somatostatin analogue, antibiotic drugs, and gabexate mesilate were administrated along with nutritional support. The pancreatic and duodenal fistula had been producing duodenal juice for over 30 days since the re-operative surgery. As suspected, reduced FXIII activity was confirmed in the patient. After administering FXIII for 5 days, the amount of duodenal juice from the fistula markedly reduced, and the fistula closed immediately afterwards. The results of our study suggest that administration of FXIII could be a reasonable and effective treatment for patients with pancreatic or/and enterocutaneous fistula who are resistant to standard treatments.

[Best time to administer coagulation factor XIII( Fibrogammin P) for postoperative intractable pancreatic fistula following gastrectomy for gastric cancer].

BACKGROUND: Coagulation factor XIII( Fibrogammin P, F XIII) has been used to treat postoperative pancreatic fistulas following gastrectomy for gastric cancer in Japan. However, little is known about the best timing to start this treatment for early recovery. This study was designed to examine the appropriate time to start Fibrogammin P treatment for pancreatic fistulas, based on nutritional and inflammatory parameters. METHOD: We retrospectively examined 27 consecutive patients with Grade B or C pancreatic fistulas as defined by the International Study Group of Pancreatic Fistula( ISGPF) classification who underwent gastrectomy at our institute between 1997 and 2011. We analyzed data on total protein( TP), albumin (Alb), C-reactive protein( CRP), and hemoglobin( Hb) concentrations and white blood cell( WBC) and lymphocyte counts. We used this information to determine laboratory cut-off values that indicate the most advantageous time to start the administration of Fibrogammin P in order to achieve early recovery within 2 weeks. RESULT: When Fibrogammin P administration was based on more than 2 cut-off values such as Alb>2.6 g/dL and Hb>9.0 g/dL and WBC<9,000/µL (p= 0.1563), early cure of pancreatic fistulas was achieved. CONCLUSION: The use of nutritional and inflammatory parameter values to determine the best time to administer Fibrogammin P may shorten the treatment period.

[Efficacy of octreotide in the treatment of chyle fistulas associated with pancreatic disease]. / Eficacia del octreótido en el tratamiento de la fístula quilosa asociada a enfermedades pancreáticas.

INTRODUCTION: A chyle fistula is an uncommon complication following abdominal and pancreatic surgery, particularly in the retroperitoneal compartment. It can also appear as a complication of a severe acute pancreatitis. Medical treatment is the initial approach, but resolution is often slow. Somatostatin or octreotide can help in accelerating the resolution of fistulae. PATIENTS AND METHODS: Patients developing a chyle fistula (output > 100ml/24h, normal amylase levels and triglyceride concentrations above 110mg/dl) associated with pancreatic disorders were treated with oral intake restriction and parenteral nutrition, followed by subcutaneous octreotide 0.1mg/8h. RESULTS: Four female patients from 55 to 80 years old, underwent pancreatic surgery or presented with an acute pancreatitis, were treated. Chyle fistulae ranging from 100 to 2,000ml/24h were treated with octreotide, being resolved within five to seven days. No recurrence has been found in a 2 to 4 years follow up. CONCLUSIONS: We have found that chyle fistula medical treatment is often related to a slow resolution, somatostatin or octreotide administration dramatically reduces its duration. Other previously reported studies have also shown that the quick onset of such treatment can accelerate the whole process, leading to a shorter recovery and lower hospital costs.

Systematic review and meta-analysis of somatostatin analogues for the treatment of pancreatic fistula.

BACKGROUND: Somatostatin analogues are used for the treatment of pancreatic fistula, with the aim of achieving fistula closure or reduction of output. METHOD: MEDLINE, Embase and Cochrane databases were searched systematically for relevant articles followed by hand-searching of reference lists. Data on patient recruitment, intervention and outcome were extracted and meta-analysis performed where reasonable. RESULTS: Seven randomized clinical trials met the inclusion criteria and included a total of 297 patients with fistulas of the gastrointestinal tract; of these, 102 patients had fistulas of pancreatic origin. Pooling of closure rates showed no significant difference between patients treated with somatostatin analogues compared with controls: odds ratio 1·52 (95 per cent confidence interval 0·88 to 2·61). Owing to inconsistent descriptions, pooling of results was not possible for other endpoints, such as time to fistula closure. CONCLUSION: There is no solid evidence that somatostatin analogues result in a higher closure rate of pancreatic fistula compared with other treatments.

[Novel treatment strategy using Trafermin® consisting of bFGF for intractable pancreatic fistula following gastrectomy for gastric cancer-a case report with literature reviews].

Despite recent perioperative technological advances in gastric cancer, intractable pancreatic fistula is still a major critical complication following gastrectomy and should be specifically targeted in the effort to improve postoperative outcomes. We preliminary report here a successfully treated case with intractable pancreatic fistula using Trafermin® consisting of basic fibroblast growth factor (bFGF). A 67-year-old man underwent laparoscopic proximal gastrectomy with radical lymphadenectomy for early proximal gastric cancer (pT1bN0M0). After surgery, pancreatic fistula was occurred. Pancreatic fistula persisted for three months despite of surgical and several conservative treatments. After obtaining informed consent, we started to inject 50 µg/day of Trafermin® through a drainage tube into the dehiscence of pancreas. Consequently, pancreatic fistula was successfully closed within three weeks. Our novel treatment technique is simple, rapid and not costly. If informed consent was obtained from patients with low risk of recurrences, this technique should be recommended as one of the treatment choices for intractable pancreatic fistula following curative gastrectomy for gastric cancer.

Postoperative pancreatic fistula after cytoreductive surgery and perioperative intraperitoneal chemotherapy: incidence, risk factors, management, and clinical sequelae.

BACKGROUND: Cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC) has improved survival in selected patients with peritoneal carcinomatosis. This study evaluates the morbidity of postoperative pancreatic fistula (PF) within the context of CRS and PIC. METHODS: Two hundred seventy-one consecutive CRS and PIC procedures were evaluated. Diagnosis and classification of postoperative PF were performed according to the international study group on PF criteria. The associations between 8 clinical and 20 treatment-related factors with postoperative PF were determined by univariate and multivariate analysis. The management and clinical sequelae of postoperative PF were discussed. RESULTS: Seventeen patients (6.3%) developed postoperative PF. None of these patients died during their in-hospital stay. Multivariate analysis identified three independent risk factors for PF: transfusion of >or=6 units of blood (P = 0.029), operation duration of >or=9 h (P = 0.035), and splenectomy (P = 0.020). Conservative management of PF was instituted in all 17 patients and was successful in 16 (94%). The overall time to PF closure was 26 (standard deviation 16) days after diagnosis. Although PF did not contribute to procedure-related mortality, it was associated with increased length of hospital stay (P < 0.001). CONCLUSIONS: CRS and PIC presented an acceptable rate of PF that did not increase the procedure-related mortality. However, PF was associated with longer hospital stay. Most patients with PF were treated conservatively and did not require surgical intervention.

Randomized, placebo-controlled, double-blind study of the efficacy of lanreotide 30 mg PR in the treatment of pancreatic and enterocutaneous fistulae.

OBJECTIVE: Continuous intravenous infusion of somatostatin improves the natural course of digestive fistulae. Lanreotide 30 mg PR is a synthetic analogue of somatostatin with pharmacological activity extending to at least 10 days after intramuscular administration. Its effectiveness was assessed in patients with simple externalized digestive fistulae in a randomized, doubleblind, placebo-controlled study. METHODS: Patients demonstrating a reduction of at least 50% of fistula output within 72 hours after a first double-blind intramuscular injection of lanreotide or placebo were considered to be responders (primary end point) and continued the double-blind treatment to a maximum of 6 injections at 10-day intervals. Other endpoints included fistula closure rate and time to closure. Blind was lifted for nonresponders, and those initially on placebo were then treated with open-label lanreotide. RESULTS: Following the first double-blind injection, 35 of 54 patients (64.8%) on lanreotide were responders versus 20 of 53 (37.7%) on placebo, ie, a 3.1 times higher response likelihood on lanreotide compared with placebo (P = 0.006). Group mean reduction of fistula output at 72 hours was 45.1% and 8.9%, respectively (P = 0.005). Lanreotide compared with placebo had no effect on closure rate which averaged 77% but median time to fistula closure was shorter on lanreotide, based on Kaplan-Meier analysis, although no statistical significance was achieved. CONCLUSION: Compared with placebo, intramuscular lanreotide 30 mg PR significantly decreases digestive fistulae output at Day 3 and shortens time to fistula closure by 9 days. ClinicalTrials.gov registration number: NCT00729313.

[Application of somatulin in the treatment of complications after operations on the pancreatic gland].

The results of treatment of 32 patients with complications, occurring after operations on pancreatic gland, ended by the external pancreatic fistula formation, in the complex of their treatment Somatulin, somatostatin analogue of prolonged action, were studied. Application of the treatment tactics proposed have permitted to achieve the fistula closure in all the patients without the operative intervention. The terms of the pancreatic fistula closure after Somatulin injection had constituted 5-20 days, (11.1 +/- 0.7) days at average.

[The splanchnic blood flow indices in the patients, suffering external pancreatic fistula, and their dynamics under the influence of sandostatin and somatulin according to the ultrasonographic duplex scanning data].

Hemodynamical effects of the somatostatin analogues were studied in the patients with external pancreatic fistula. There were examined 29 patients, using ultrasonographic duplex scanning, for investigation of the blood flow indices in a. mesenterica superior, truncus coeliacus and its branches, v. lienalis, v. portae and pancreatic intraorgan arteries. Initial indices of splanchnic blood flow were compared with such while administration of octreotide. The main splanchnic blood flow indices in patients, suffering external pancreatic fistula, did not differ from that in controls, the lowering of the pulsation and resistance indices was noted as well as enhancement of the vessels quantity in pancreatic surgical margin. Under the influence of somatostatin the quantity of visualized vessels had reduced, the pulsation and resistance indices increased, the blood flow velocity along a. mesenterica superior, a. lienalis and pancreatic intraorgan arteries lowered, causing reduction of the blood flow linear and volumetric velocity along v. mesenterica superior and vv. intrapancreatici. Inhibitory action of the preparation on splanchnic blood flow was maximal in terms from 6 till 24 h after its infusion and had lowered step by step during all the follow-up period.

Pancreaticopleural fistula visualized by computed tomography scan combined with pancreatography.

CONTEXT: We report a case of a pancreaticopleural fistula which was clearly demonstrated by computed tomography (CT) scan following pancreatography and which was successfully treated with endoscopic nasopancreatic drainage combined with octreotide. CASE REPORT: A 52-year-old male was admitted to our hospital for additionally evaluation of bilateral pleural effusion. The pleural fluid amylase level was markedly elevated. Endoscopic retrograde pancreatography showed a cyst in the body of the pancreas and extravasation of contrast medium extending cranially from the cyst. The disease was treated successfully with endoscopic nasopancreatic drainage combined with the administration of octreotide. A pancreaticopleural fistulous route was clearly demonstrated by CT scan following pancreatography through the nasopancreatic drainage tube. CONCLUSIONS: A CT scan following pancreatography was useful in demonstrating a pancreaticopleural fistulous route.