- Study protocol
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One-layer versus two-layer duct-to-mucosa pancreaticojejunostomy after pancreaticoduodenectomy: study protocol for a randomized controlled trial
© Pan et al. 2016
- Received: 10 September 2015
- Accepted: 21 July 2016
- Published: 17 August 2016
Although various pancreaticojejunal duct-to-mucosa anastomosis methods have been developed to reduce the postoperative risks of pancreaticoduodenectomy, pancreatic fistula remains the most serious complication with a high incident rate. The aim of this study is to compare the safety and effectiveness of one-layer and two-layer duct-to-mucosa pancreaticojejunostomy in patients undergoing pancreaticoduodenectomy.
In this study, adult patients who sign consent forms will be recruited and scheduled for elective pancreaticoduodenectomy. One hundred and fourteen patients will be included and randomized before pancreaticojejunal reconstruction and after resection of the lesion from the pancreatic or periampullary region. The primary efficacy endpoint is the incident rate of postoperative pancreatic fistula. Statistical analysis will be based on the intention-to-treat population. Patients will be followed up for 3 months by monitoring for complications and other adverse events.
This prospective, single-center, randomized, single-blinded, two-group parallel trial is designed to compare one-layer with two-layer duct-to-mucosa anastomosis for pancreaticojejunal anastomosis during elective pancreaticoduodenectomy.
Clinical Trials.gov: NCT02511951. Registered on 29 July 2015.
- Postoperative pancreatic fistula
To date, pancreaticoduodenectomy (PD) has been regarded as the only potentially curative treatment for pancreatic head and periampullary tumors, including tumors in the ampullary region, distal biliary duct, and periampullary duodenum . A retrospective study in which 1000 cases were recruited over the past three decades showed that PD has become an effective treatment to reduce hospital mortality . Mortality has been reduced to less than 5 %, but the morbidity remains at 30–50 % [2, 3]. Postoperative pancreatic fistula (POPF) is one of the most frequent and ominous complications after PD, and its occurrence reportedly ranges from 2–40 % [4, 5]. Severe POPF prolongs hospital stay and requires the use of specific treatments, such as the use of antibiotics, nutritional support, endoscopy, interventional radiology, and/or reoperation, etc. . POPF risk is increased by many factors including pancreatic texture, main pancreatic duct diameter, and pancreaticojejunal (PJ) anastomotic technique [7–9]. Among these factors, only anastomotic technique can be improved. According to the International Study Group of Pancreatic Surgery (ISGPS) definition, POPF exists if the drainage of any measurable volume of fluid containing amylase exceeds three times the normal serum value on or after postoperative day (POD) 3 .
Several anastomotic surgical techniques have been developed to reduce the incidence of pancreatic fistula in recent decades, including the duct-to-mucosa method, pancreaticogastrostomy, Peng’s binding method, and the “end-to-end” or “end-to-side” invaginated method. Among these techniques, the conventional duct-to-mucosa method remains the most popular anastomosis due to its advantages. The size of the pancreatic remnant is not limited; moreover, the jejunal lumen and pancreatic remnant lead to easier anastomosis [11–14].
Compared with two-layer duct-to-mucosa anastomosis, the novel one-layer duct-to-mucosa PJ anastomosis method has been reported to be efficient at reducing POPF occurrence [15, 16]. However, the two cited retrospective studies might lead to selection bias. Because this evidence is insufficient, we will conduct a randomized controlled trial to verify the superiority of one-layer duct-to-mucosa PJ anastomosis after PD over the two-layer technique.
The aim of this study is to compare the effect of two duct-to-mucosa PJ anastomotic methods for PD by assessing factors that are related to mortality or morbidity, including postoperative pancreatic fistula rate, biliary leakage, postpancreatectomy hemorrhage, and anastomosis time.
Age 18–80 years
Provision of informed consent.
Patients with any severe cardiopulmonary disease: American Society of Anesthesiologists (ASA) classification or ejection fraction below 30 % that might prolong the postoperative hospital stay
Previous pancreatic operation
Immunodeficiency, such as that observed under HIV
Patients can withdraw from the trial at their own request or at the request of their legal representative at any time. Patients may be removed if, in the investigator’s opinion, continuation of the trail could be detrimental to the patient’s well-being or if a PD is not performed due to technical unresectability, metastatic disease, or other reasons. Every withdrawal will be recorded in the clinical report forms (CRFs) and in the patient’s medical case records. All examinations scheduled for the final trial day will be performed on all patients and documented. All data will be analyzed according to the intention-to-treat (ITT) principle .
Ethics, study registration, and consent
The final protocol has been approved by the Ethics Committee of the Second Affiliated Hospital of Anhui Medical University (approval number: KY201502). The trial protocol has also been registered in the protocol registration system at ClinicalTrials.gov (identifier: NCT02511951). All patients will be scheduled only after comprehensive information concerning the nature, scope, and possible consequences of the clinical trial has been provided to them in an understandable way by the investigator. Written informed consent for the study will be obtained from each patient before the operation. The study procedure, benefits, risks, and data management will be clarified in detail during the preoperative conversation.
One-layer duct-to-mucosa PJ anastomosis
Two-layer duct-to-mucosa PJ anastomosis
Primary and secondary endpoints
The primary efficacy endpoint of the trial will be the POPF occurrence rate. POPF is defined by the International Study Group of Pancreatic Fistula (ISGPF) as any measurable volume of drain fluid that contains three times higher amylase content than the normal upper serum value, on or after POD 3. Amylase will be assessed on PODs 1, 3, 5, and 7. Three grades of POPF are determined according to clinical severity: A, B, and C .
Definition of secondary endpoints
Definition and assessment of outcomes
Time from beginning to end of PJ anastomosis
Death due to any cause until 90 days after the operation and the reason
Postoperative complications will be recorded until 90 days after operation. The severity of complications will be graded according to the Clavien-Dindo classification 
Postoperative hospital stay
Time from day of operation until discharge (days)
Evidence of blood loss from drains and/or nasogastric tube, based on ultrasonography, as defined by ISGPS 
Bilirubin concentration in the drain fluid at least three times the serum bilirubin concentration as defined by International Study Group of Liver Surgery 
Delayed gastric emptying
Failure to resume solid diet with prolonged need for nasogastric tube as defined by ISGPS 
Intra-abdominal fluid collection
Collection of fluid measuring ≥3 cm associated with clinical or laboratory abnormalities
Surgical site infection associated with laparotomy that develops during the initial hospital stay
Presence of a new infiltrate on chest X-ray, as well as following: body temperature >38 °C, abnormal elevation of white blood cells, or positive sputum, and requiring antibiotic treatment
Dehiscence of abnormal closure with need for resuture of the laparotomy during the initial hospital stay
Complication grades according to the Clavien-Dindo classication schemea
Any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic, and radiological intervention
Requiring pharmacological treatment with drugs other than those allowed for grade I complications
Requiring surgical, endoscopic, or radiological intervention
Intervention not under general anesthesia
Intervention under general anesthesia
Life-threatening complication. Requiring intensive care unit management
Single organ dysfunction
Death of patient
Type of trial
This is a prospective, randomized, interventional, and patient-blinded, single-center trial comparing two parallel groups.
To achieve intervention groups with comparable known and unknown risk factors, randomization will be performed. The randomization number will be generated using computer-generated random numbers with an allocation ratio of 1:1 (an equal probability of assignment to either group). All patients will be randomized using consecutively numbered opaque envelopes that will have been sealed by the investigators. The envelopes will be opened before PJ reconstruction and after resection of the lesion from the pancreatic or periampullary region.
Patients and outcome observers will be blinded with respect to the trial intervention. Blinding of the surgeons and people involved in the operation is not feasible due to the nature of the interventions.
Data management and quality assurance
Flow chart of the trial
Day of surgery
Past medical history
The two-sided null hypothesis for the primary endpoint measurement states that both study interventions will lead to a similar POPF occurrence rate; the alternative hypothesis is that one intervention will perform better than the other. The null hypothesis will be tested by analyzing the covariance while adjusting for pancreatic texture (soft or hard) and main pancreatic duct diameter (<3 mm or ≥3 mm). A binary logistic regression will be applied to compare the POPF occurrence rates between the groups after adjusting for other factors. Background characteristics and surgical outcome measures will be compared using chi-squared or Fisher’s exact tests for categorical data and two-tailed t tests or nonparametric Mann–Whitney U tests for continuous variables. Categorical data will be presented as frequencies and group percentages, and continuous variables will be expressed as the means and standard deviations. The homogeneity of two groups will be described by comparison of the demographic data and baseline values. All analyses will be performed on an ITT basis . For the ITT analysis, the data will be processed for all trial patients in their randomized groups. A P value < 0.05 will be considered statistically significant. All statistical calculations will be performed using SPSS10.0 (SPSS, Chicago, IL, USA).
Currently, pancreaticoduodenectomy is a routine operation, and postoperative mortality is less than 5 % [2, 3]. POPF is among the most frequently encountered complications that contribute to a high postoperative mortality. Debate regarding the preferred surgical technique for PJ anastomosis has continued for decades. Many retrospective studies have suggested that the POPF occurrence rate is reduced by using a one-layer rather than a two-layer duct-to-mucosa PJ anastomosis [15, 16]. However, more reliable evidence should be accumulated to address the advantages and disadvantages of both techniques. In this way, the most beneficial technique can be selected for individual patients. Therefore, the factors affecting the success of one-layer versus two-layer duct-to-mucosa PJ anastomosis should be evaluated in this randomized controlled trial to minimize the POPF rates associated with PD.
The trail is currently recruiting patients. All patients should be recruited by December 2018.
CRF, clinical report form; ISGLS, International Study Group of Liver Surgery; ISGPF, International Study Group of Pancreatic Fistula; ISGPS, International Study Group of Pancreatic Surgery; POPF, postoperative pancreatic fistula; WBC, white blood cell
We thank QiaoHong Yang of the Department of Epidemiology and Health Statistfics, Anhui Medical University, Hefei, for planning the statistical analyses. We are indebted to all patients who support this scientific research without personal benefit. No funding has supported this project.
SBP and WG conceived the study, drafted the manuscript, and revised the manuscript. XPG and HCZ conceived the study and critically revised the manuscript. DCZ and HH calculated the sample size. JMC and FBL drafted the manuscript. GBW and KX drafted the study protocol. SXX and YJZ revised the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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