A Single Center Prospective Randomized Trial of Complete vs. Postoperative Nasogastric Tube Omission in Pancreaticoduodenectomied Patients
A Single Center Prospective Randomized Trial of Complete vs. Postoperative Nasogastric Tube Omission in Pancreaticoduodenectomied Patients
Enhanced recovery after surgery (ERAS) programs recommend early removal of a nasogastric tube ( NGT) after operation has been suggested in elective major abdominal surgery, such as colorectal3, gastric4, and hepatic surgery5. However, in spite of immediate removal after operation, NGT is still worldwide routinely inserted before major abdominal surgery. The rationale to insert NGT before operation include prevention of aspiration pneumonia during anesthesia and use for decompression of the distended stomach induced by mask bagging during anesthesia induction. However, the risk of aspiration pneumonia during intubation is so low that even American Society of Anesthesiology (ASA) guidelines for preoperative fasting guideline suggest continuing a clear carbohydrate supplement drink up to 2 hours prior to operation for decreasing the fasting period.6 Indeed, musk bagging during anesthesia occasionally will distend the stomach with air to a great extent to make the operation difficult. Besides, for anatomic reasons, the insertion of NGTs into anesthetized and intubated patients during operation for decompression of distended stomach can be very challenging.7 Therefore, in spite, distended stomach occur only occasionally and insertion of a NGT into conscious patients cause a lot of discomfort, most centers adopt policy to insert it before operation. But, it is not necessary to insert a NGT during operation for decompression of distended stomach. Instead, investigators developed a novelty method to decompress distended stomach intraoperatively by thick needler suction. With this new technique, 578 PDs have been successfully performed with complete omission of NGT (CONGT)8 and none of them needed the intraoperative insertion of NGT for decompression of encountered distended stomach. Based on the excellent results of previous study, investigators further propose a prospective randomized trial to compare complete versus postoperative omission of nasogastric tube in pancreaticoduodenectomied patients.
The complete omission of NGT (CONGT) study will be a prospective, single-center randomized controlled trial with 2 groups comparing rate of postoperative complications between pancreaticoduodenectomied patients with complete (CONGT) or traditional postoperative omission of NGT (PONGTR). Key inclusion criteria will be patients between 20 and 75 years of age requiring PD for benign or malignant disease of the biliopancreatic confluence and without symptoms or signs of intestinal obstruction (such as vomiting, presence of nasogastric tube). The primary end point will be the occurrence of a Clavien-Dindo classification grade II or higher postoperative complication. The secondary outcomes will be occurrence of pulmonary complications; occurrence of delayed gastric emptying; occurrence of pancreatic fistula; occurrence of biliary fistula or hemorrhage; the need for surgical reintervention; NGT reinsertion rate; 90-day mortality rate; length of hospital stay; and the readmission rate until 90 days after surgery.
216 patients will be required to have 80 per cent power to test the non-inferiority of CONGT compared with PONGT, with a non-inferiority margin of 20 per cent. Assuming a 10 per cent dropout rate, the final planned sample size will be 240 patients. Analyses will be conducted with the intent-to-treat population.
As the most destructive abdominal surgery, PD should be the last type of abdominal surgical procedure performed with CONGT because of associated highest rate of delayed gastric emptying. Therefore, positive results of this study could be implied to millions of patients undergoing abdominal surgery and avoid their NGT-insertion-associated discomfort.
Routine use of nasogastric tubes (NGT) during abdominal surgery, historically intended to hasten bowel function return, prevent pulmonary complications, and reduce risks like anastomotic leakage, has been found largely ineffective.1 Early removal or selective use of NGT (postoperative omission of NGT, [PONGT]) is considered safer and leads to better outcomes including shorter hospital stay and less pulmonary complications.2 Therefore Enhanced recovery after surgery (ERAS) programs recommend early removal of an NGT has been suggested after major abdominal surgery, such as colorectal3, gastric4, and hepatic surgery5. However, in spite of immediate removal after surgery, NGT is still worldwide routinely inserted before abdominal surgery. The rationales to use preoperative NGT include 1. prevention of aspiration pneumonia during anesthesia and 2. use for decompression of the distended stomach induced by mask bagging during anesthesia induction. However, the risk of aspiration during anesthesia is so low that American Society of Anesthesiology (ASA) guidelines for preoperative fasting even suggest continuing a clear carbohydrate supplement drink up to 2 hours prior to operation for decreasing the fasting period.6 Musk bagging during anesthesia occasionally will distend the stomach with air to a great extent to make the operation difficult. Besides, for anatomic reasons, the insertion of NGTs into anesthetized and in tubated patients during operation for decompression of distended stomach can be very challenging.7 Therefore, most centers adopt policy to insert the NGT before operation. However, insertion of a NGT before operation into patients with clear consciousness causes a lot of discomfort. But, as shown in investigators' previous report8, instead of NGT, the distended stomach encountered during operation could be alternately decompressed through thick needle suction. In that case, the preoperative insertion of NGT could also be avoided. Therefore, the NGT could be omitted throughout the whole perioperative course of abdominal surgery, i.e. complete omission of NGT (CONGT).
Pancreaticoduodenectomy (PD) is the most destructive abdominal surgery with highest rate of postoperative complications. 9-11 Notably, among the common PD-related complications, delayed gastric emptying (DGE) remains the most common complication associated with the need for NGT placement, and its prevalence rate ranges from 3.2% to 59.0%. 12, 13 Nevertheless, more and more centers14-18 also adopt policy of removal of NGT immediate after PD (PONGT). But again, NGT is still widely used before and during PD. Theoretically, PD should be the last type of abdominal surgical procedure performed with complete omission of NGT because of associated highest rate of delayed gastric emptying. However, as shown ininvestigators' recent report, 578 PDs have been safely performed with complete omission of NGT.8 None of them needed the intraoperative insertion of NGT to decompress distended stomach. Moreover, there was significant less pulmonary complication in patients operated with CONGT compared to those operated with NGT omission only after operation. Based on the excellent results of previous study, investigators further propose a single center prospective randomized trial to compare complete versus postoperative omission of nasogastric tube in pancreaticoduodenectomied patients.
Study Design and Participants： The complete omission of NGT (CONGT) study will be a prospective, single-center RCT with 2 groups (PD performed with CONGT or PONGT) comparing rate of occurrence of postoperative complications (trial protocol in Supplement 1). The study will be performed in accordance with good clinical practice guidelines and the principles of the Declaration of Helsinki.19 This study will follow the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. The study protocol will be approved by Ethics Committee of National Taiwan University Hospital. Written informed consent will be obtained from all patients in accordance with the Declaration of Helsinki. No one will receive compensation or be offered any incentive for participating in this study. All patients scheduled for PD at the National Taiwan University Hospital will be screened and assessed for CONGT trial eligibility. Key inclusion criteria will be patients between 20 and 75 years of age requiring PD for benign or malignant disease of the biliopancreatic confluence and without symptoms or signs of intestinal obstruction (such as vomiting, presence of nasogastric tube). Key exclusion criteria will be previous gastric or esophageal surgery, severe comorbidities, such as end-stage kidney disease (creatinine clearance, <15 mL/min/1.73m2; to convert to mL/s/m2, multiply by 0.0167), documented chronic respiratory disease, heart failure (New York Heart Association class III or higher), pregnancy, nursing mothers, and persons under legal protection (guardianship).
Surgery All PD procedures will be performed by senior pancreatic surgeons (YWT, CHW) via laparotomy. A standard lymph node dissection will be performed, including the right lateral and superior aspect of the mesenteric superior artery and a paraaortic lymph node picking under the left renal vein in case of pancreatic head carcinoma. All reconstruction procedures will be standardized with pancreatojejunostomy and antecolic gastrojejunal or duodenojejunal anastomosis. Pancreatojejunostomy will be performed by an end-to-side one-layer pancreaticojejunostomy with a trans-anastomotic internal stent in the pancreatic duct using a suitable pediatric feeding tube as previously described.20 Vascular (vein or artery) resection will be performed when necessary. Three 7-mm Jackson-Pratt® drains will routinely be placed after all anastomoses [pancre- aticojejunal (PJ) reconstruction, hepaticojejunostomy (HJ) reconstruction, and antecolic gastro- /duodenojejunal reconstruction in sequential order)]. One will be placed near the PJ, another near the HJ, and the other at the left retroperitoneal cavity to precisely define the postoperative pancreatic fistula according to the International Study Group of Pancreatic Fistula (ISGPF) classification.21 Anesthesia will be administered according to the routine institution protocol used at the National Taiwan University Hospital. General anesthesia will be induced with administration of intravenous (IV) propofol, sufentanil citrate, and cisatracurium and maintained with either sevoflurane or desflurane. Continuous IV ketamine hydrochloride will be administered intraoperatively at antihyperalgesic doses. Self-paid epidural with ropivacaine hydrochloride for 24 to 48 hours will be given at patients' choice. Postoperative nausea and vomiting prevention was ensured with administration of IV dexamethasone sodium phosphate, 8 mg, during induction of anesthesia and then with IV droperidol or IV ondansetron hydrochloride according to the Apfel score.22 For antibiotic prophylaxis, IV cefmetazole sodium, 2 g, will be administered during induction of anesthesia and followed by administration of 1 g IV every 3 hours during surgery.
Management of NGT Included patients will be randomized into CONGT and PONGT groups in 1 : 1 ratio. Patients in the PONGT group will have a 14- French NGT inserted before the operation and removed at completion of operation at operating room. In contrast, for patients in CONGT group, no NGT tube will be inserted before or during operation. Distended stomach encountered during operation will be decompressed by preoperatively-placed NGT in PONGT and by thick needle suction in CONGT group patients. Patients in both groups will be allowed to drink 300-500 mL of liquids on postoperative day 1, and afterwards a soft diet will be given for 2 days. If this well tolerated, increasing amounts of solid food will be given. The NGT will be reinserted if the patient later vomits a volume of more than 300 mL or more than one occasion. Reinserted tubes will be removed if the reflux is less than 200 mL per 24 h, and oral feeding (initially with a liquid diet) will be tried again.
Postoperative Care Postoperative analgesia will be multimodal and include administration of paracetamol, celebrex, or epidural analgesia with ropivacaine for 24 to 48 hours and morphine patient-controlled analgesia as rescue analgesia. Mobilization will be begun as soon as possible (usually the next day after operation). Drainage tubes will be removed in the absence of hemorrhage or postoperative pancreatic fistula on day 4 or 5 after surgery, depending on the amylase level.
Outcomes Members of the surgical staff, not involved in the trial, will record postoperative complications. The postoperative course of each patient will be closely monitored. The day of passage of flatus and oral food intake, and length of hospital stay will be recorded. Mortality, abdominal complications, pulmonary complications (pneumonia, atelectasis), postoperative fever, nausea, and vomiting, tube reinsertion, discomfort from the tube (ear pain, nasal soreness, painful swallowing), and duration of reinserted NGT will be noted. According to the recommendation by the International Study Group of Pancreatic Surgery (ISGPS)12, gastroparesis will be defined as the need for the need to reinsert the NGT for persistent vomiting after surgery. The severity of gastroparesis will be classified by the ISGPS definition12 as grade A: NGT required for 4-7 days or reinsertion after postoperative day (POD) 3 or inability to tolerate solid oral intake by POD 7; grade B: NGT required for 8-14 days or inability to tolerate solid oral intake by POD 14; grade C: NGT required for >14 days or inability to tolerate solid food by POD 21. Again, according to the International Study Group definition, postoperative pancreatic fistula will be defined as output via an operatively placed drain (or a subsequently placed percutaneous drain) of any measurable volume of drain fluid on or after POD 3, with an amylase content greater than three times the upper normal serum value.21 Postoperative bleeding will also be graded using ISGPS definitions.23 All infectious complications will be proven by microbiological analysis and positive fluid The primary end point will be the occurrence of a Clavien-Dindo classification grade II or higher postoperative complication (range I to V, with higher scores indicating more severe complication).24 The secondary outcomes will be occurrence of pulmonary complications (including atelectasis, pleural effusion, and pneumonitis); occurrence of delayed gastric emptying (based on the International Study Group on Pancreatic Surgery guidelines as A, B, or C, with increasing clinical severity12); occurrence of pancreatic fistula (classified according to the ISGPF classification as A, B, or C, with increasing clinical severity21); occurrence of biliary fistula or hemorrhage; the need for surgical reintervention; NGT reinsertion rate (time and causes); 90-day mortality rate; length of hospital stay; and the readmission rate until 90 days after surgery. Patients will be followed up until 90 days after surgery (on days 30 and 90) using standardized case report forms completed by local study coordinators and then verified by an independent clinical research associate as stated in the protocol. Preoperative data will be collected by the investigator or by an independent clinical research associate as stated in the protocol (trial protocol in Supplement 1). Data will be collected from case report forms and entered an electronic database, with data accuracy double checked. Medical records and case report forms will be reviewed to resolve missing or implausible data.
Reinsertion of NGT and Safety Patient safety will be monitored by a board that could stop the study if adverse events occurred or more than 8 of the first 10 patients required NGT replacement. To avoid bias, surgery will be performed only by 2 senior surgeons (Y.W.T., C.H.W.) with substantial experience in pancreatic resection, including PD.
Statistical Analysis
Sample size estimation:
Given a one-sided α level of 2.5 per cent and assuming a rate of 54 per cent for complication of Clavien-Dindo classification grade II or higher, based on authors' pilot data,17 216 patients will be required to have 80 per cent power to test the non-inferiority of CONGT compared with PONGT, with a non-inferiority margin of 20 per cent. This non-inferiority margin is based on a previous study15 and the pilot data, which showed that the rate of complications of Clavien-Dindo classification grade II or higher with complete and postoperative omission of NGT in pancreaticoduodenectomied patients were approximately 38.2 and 53.8 per cent respectively. The non-inferiority margin will be set at 20 per cent to avoid loss of more than half of the benefit of PONGT over CONGT. Assuming a 10 per cent dropout rate, the final planned sample size will be 240 patients. Analyses will be conducted with the intent-to-treat population (Figure 1 Flowchart). A randomization list will be produced randomly with a block size of two.
The primary end point will be compared between the 2 groups with the χ2 test. Secondary end points will be compared with t tests or Mann-Whitney tests as appropriate for continuous variables, and with χ2 tests or Fisher exact tests as appropriate for qualitative variables. For primary and secondary outcomes, risk ratios with 95% Cis will be calculated for qualitative variables. Qualitative variables will be expressed as number of observations (percentages), and continuous variables will be expressed as mean (SD) values or as median values with interquartile ranges (IQRs). Patients who do not reach experiment end points (such as those with unplanned readmission or diet tolerance), owing to early postoperative death, will be excluded from the analysis (detailed in the respective tables). Investigators will also conduct an exploratory analysis to identify risk factors for NGT reinsertion in the CONG group to identify risk factors that could help better identify patients who would or would not need an NGT before and during surgery. All analyses were 2-sided, and the threshold for statistical significance will be set at P < .05. Analyses will be performed with R statistical software, version 3.6.3 (The R Project for Statistical Computing).
Inclusion Criteria:
Exclusion Criteria:
ywtien5106@ntu.edu.tw0972651427