Effect of intraoperative secretin on operative outcomes in pancreatic resection: A randomized controlled trial.

BACKGROUND: Objectives: We performed a randomized, double-blind, placebo-controlled trial to determine if using Secretin intra-operatively to identify leaks and subsequently target operative intervention would decrease the frequency of clinically significant post-operative pancreatic fistula formation. METHODS: Patients undergoing pancreaticoduodenectomy or distal pancreatectomy were randomized to receive intra-operative Secretin or placebo intra-operatively following the completed pancreaticojejunostomy or closure of the cut remnant stump. If a potential leak was identified, targeted therapy with directed suture placement was performed. RESULTS: 170 patients were randomized; 83 receiving placebo and 87 receiving Secretin. The rate of clinically significant fistula formation was 3% (3/87) in the Secretin group and 6% (5/83) in the placebo group (p = 0.489). The rate of biochemical leak was 29% (25/87) in the Secretin group and 19% (16/83) in the placebo group (p = 0.157). There were no Grade C post-operative fistula in either group. Of the 9% of patients in the Secretin group who had a targeted intra-operative intervention, none developed a clinically significant fistula. Adverse events were similar between groups. CONCLUSIONS: Compared to placebo, intra-operative Secretin administration was not associated with an overall reduction in clinically significant pancreatic fistula formation. However, patients with an intra-operative leak identified by Secretin may benefit from intervention (clinicaltrials.gov: NCT02160808).

A phase II trial of human secretin infusion for refractory type B pain in chronic pancreatitis.

OBJECTIVE: We aimed to determine if intravenous synthetic human secretin (sHS) improves refractory type B pain in patients with chronic pancreatitis (CP). METHODS: In a phase II dose escalation trial, patients with CP received sHS of varying doses (0.05-0.8 µg/kg) for 3 days. The primary outcomes were changes in the visual analogue pain score (VAS), short form (SF)-36, and opiate use from baseline at 30 days after infusion. RESULTS: Twelve patients (mean age, 42 years, 6 men) were included. Mean pain scores (VAS) were 5.79, 4.80, 4.72, and 4.90, at baseline, day 4, day 10, and day 30, respectively (P = 0.25, 0.19, and 0.27 when compared with baseline, respectively). Daily opiate use (oral morphine equivalents) decreased throughout the study from a baseline value of 136 to 111 mg on day 4 (P = 0.52) and to 104 mg on day 30 (P = 0.34). In subgroup analysis, women had the most improvement (VAS baseline, 5.42 vs. VAS day 30, 3.67; P = 0.07; baseline morphine equivalents, 107 mg vs. 84 mg; P = 0.21). CONCLUSIONS: In patients, especially women, with refractory type B pain from CP, intravenous sHS administration demonstrated a trend toward improvement in self-reported pain and opiate use at 30 days after infusion, although statistical significance was not achieved (clinicaltrials.gov registration number NCT01265875).

Pancreatic duct compliance after secretin stimulation: a novel endoscopic ultrasound diagnostic tool for chronic pancreatitis.

OBJECTIVES: Endoscopic ultrasound (EUS) evaluation of pancreatic duct compliance after secretin stimulation (sEUS) along with EUS morphologic examination (EUS) and duodenal fluid [HCO3] measurement (endoscopic pancreatic function test, ePFT) in 1 endoscopic session has not been reported as a means of evaluating for chronic pancreatitis (CP). We evaluated the feasibility of the combined examination and compared EUS measurements of pancreatic ductal compliance with duodenal fluid [HCO3] for diagnosing CP. METHODS: The study is a prospective case series of patients with suspected CP who underwent a combined EUS, sEUS, and ePFT examination in 1 endoscopic session. The main outcome measures were the feasibility of performing the combination examination and the correlation between ductal compliance and ePFT. RESULTS: All examinations were completed in 1 endoscopic session, and there were no complications in 35 patients. Although there was a trend toward less change from baseline head and body ductal diameter in patients with CP, only the percent change from baseline in the tail was significant (CP 144.3% vs healthy patients 240.9%, P < 0.01). Regression analysis demonstrated fair correlation between maximum change in ductal diameter and duodenal fluid [HCO3] (r = 0.27). CONCLUSIONS: Combined EUS, sEUS, and ePFTs are feasible and safe, with preliminary results demonstrating a positive correlation between pancreatic ductal compliance and duodenal fluid [HCO3].

Intravenous synthetic secretin reduces the incidence of pancreatitis induced by endoscopic retrograde cholangiopancreatography.

OBJECTIVES: This study aimed to evaluate whether synthetic secretin is effective in reducing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. METHODS: This is a single academic medical center, prospective, randomized, double-blind, placebo-controlled trial using secretin (dose of 16 µg) administered intravenously immediately before ERCP. Patients were evaluated for the primary outcome of post-ERCP pancreatitis as diagnosed by a single investigator. RESULTS: A total of 1100 patients were screened, of whom 869 were randomly assigned to receive secretin (n = 426) or placebo (n = 443) before ERCP and were evaluated after the procedure for efficacy of secretin. The incidence of pancreatitis in the secretin group compared with the placebo group was 36 (8.7%) of 413 patients versus 65 (15.1%) of 431 patients, respectively, P = 0.004. In the subgroup analysis, secretin was highly protective against post-ERCP pancreatitis for patients undergoing biliary sphincterotomy (6/129 vs 32/142, P < 0.001), patients undergoing cannulation of the common bile duct (26/339 vs 56/342, P < 0.001), and patients not undergoing pancreatic sphincterotomy (26/388 vs 57/403, P = 0.001). Analysis of the interaction between these groups reveals that the primary effect of secretin prophylaxis was prevention of post-ERCP pancreatitis in patients undergoing biliary sphincterotomy. CONCLUSIONS: Synthetic secretin reduces the risk of post-ERCP pancreatitis, particularly in patients in undergoing biliary sphincterotomy.

Evaluation of duct-cell and acinar-cell function and endosonographic abnormalities in patients with suspected chronic pancreatitis.

BACKGROUND & AIMS: Endoscopic ultrasound (EUS) detects mild and severe structural abnormalities of the pancreas that correlate with fibrosis. Direct pancreatic function tests (PFTs) detect mild exocrine insufficiency associated with early fibrosis. The primary aim of this study was to compare EUS structural criteria with duct-cell and acinar-cell function. METHODS: Fifty patients evaluated for chronic pancreatitis underwent combined EUS and secretin endoscopic PFTs (ePFT) on day 1 and CCK ePFT on day 2. EUS images were videotaped and interpreted by consensus of 3 blinded expert reviewers. RESULTS: There were inverse correlations of EUS consensus score with both duct-cell bicarbonate secretion (R = -0.71, P < .001) and acinar-cell lipase secretion (R = -0.52, P < .001). With secretin ePFT as reference standard, EUS (>or=4 criteria) showed a sensitivity of 71% (95% confidence interval [CI], 53%-89%) and specificity of 92% (95% CI, 75%-99%). With CCK ePFT as reference standard, EUS had a sensitivity of 63% (95% CI, 43%-82%) and specificity of 85% (95% CI, 71%-98%). Main duct dilation, irregularity, calcifications, and visible side-branches were most predictive of exocrine insufficiency (positive predictive value >80% for both acinar- and duct-cell insufficiency). CONCLUSIONS: Acinar- and duct-cell function decreases as EUS structural abnormalities increase. EUS has fair sensitivity and very good specificity compared with secretin and CCK functional reference standards.

A prospective crossover study comparing secretin-stimulated endoscopic and Dreiling tube pancreatic function testing in patients evaluated for chronic pancreatitis.

BACKGROUND: Direct pancreatic function tests (PFT) are conventionally performed with use of double-lumen "Dreiling" collection tubes. We have developed an endoscopic collection method (ePFT) that eases the performance of these tests. OBJECTIVE: Our aim was to compare the bicarbonate results obtained from the secretin ePFT and Dreiling PFT methods in patients evaluated for chronic pancreatitis. DESIGN: A prospective crossover design was used to compare the PFT methods. SETTING: Tertiary care referral center. PATIENTS AND INTERVENTIONS: Twenty-four patients undergoing an evaluation for chronic pancreatitis underwent the secretin-stimulated ePFT and Dreiling PFT methods on separate days. MAIN OUTCOME MEASUREMENTS: Duodenal fluid bicarbonate concentrations and estimated bicarbonate outputs were compared. RESULTS: The mean difference in peak bicarbonate concentration (Dreiling PFT minus ePFT) was 7 mEq/L (SD 20) and not statistically significant (P = .11). A good correlation in peak bicarbonate concentrations (r = 0.74, 95% CI, 0.48-0.88) and estimated bicarbonate output (r = 0.78, 95% CI, 0.54-0.90) was observed between the two PFT methods. LIMITATION: The sensitivities and specificities of the secretin ePFT and Dreiling PFT could not be compared because of the lack of a histologic gold standard. CONCLUSION: The secretin ePFT yields results similar to those of the Dreiling PFT in patients evaluated for chronic pancreatitis.

Comparison of endoscopic ultrasound chronic pancreatitis criteria to the endoscopic secretin-stimulated pancreatic function test.

Endosonography (EUS) has emerged as a major diagnostic tool in pancreatic imaging. Direct tests of pancreatic function are considered the most sensitive and accurate method to establish a diagnosis of chronic pancreatitis (CP), particularly when imaging studies are inconclusive. The aim of this study was to compare current EUS CP criteria with our newly described, purely endoscopic, secretin-stimulated pancreatic function test (ePFT). Fifty-six patients (25 male, mean age = 44 years) who were referred for evaluation/treatment of chronic abdominal pain with or without CP underwent both EUS and ePFT. The EUS protocol included the following: (1) EUS images were obtained in a standardized fashion from both gastric and duodenal stations, and (2) EUS images were scored independently by one of three therapeutic endoscopists for 0--9 parenchymal/ductal criteria as follows: 0-3 = normal, 4-5 = equivocal, >/=6 = definite CP. Endoscopic pancreatic function test (ePFT) protocol included the following: (1) upper endoscopy, (2) intravenous synthetic porcine secretin (0.2 mcg/kg, ChiRhoClin, Inc.) after test dose, (3) duodenal fluid aspirated every 15 min for 1 h, and (4) autoanalyzed for [HCO3] cutpoint of 80 mEq/L. According to EUS, 33 were normal, 13 equivocal, and 10 definite for CP. The mean peak [HCO3 -] range (in mEq/L) for each group was normal CP (83.7, range = 58-118), equivocal CP (68, range = 30-88), and definite CP (56, range=19-84). Using a peak [HCO3 -] of

A randomized crossover study of secretin-stimulated endoscopic and dreiling tube pancreatic function test methods in healthy subjects.

OBJECTIVES: We have developed an endoscopic method of secretin endoscopic pancreatic function testing (ePFT) to simplify duodenal fluid collection. Validation of the ePFT requires a direct comparison to the traditional PFT using a Dreiling tube (DT). Our aim was to compare bicarbonate concentrations [HCO3-] obtained by the ePFT and DT methods in healthy subjects (HS). METHODS: HS were randomized to either DT or ePFT, then crossed over to the other test after a minimum 1-wk washout. An age/weight-based sedation bolus was used for each test. DT protocol: Endoscopic placement of a DT was confirmed by fluoroscopy. After a baseline 15-min collection and administration of IV synthetic secretin, fluid was continuously collected in 15-min aliquots for an hour. ePFT protocol: Endoscopy was performed using a 6-mm endoscope. After gastric aspiration and discard and IV secretin, duodenal aspirates were obtained every 15-min for an hour. Fluid specimens were auto-analyzed for [HCO3-]. RESULTS: Twelve HS were enrolled (6F, mean age 37 yr). The difference in [HCO3-] between the two methods was not significant at the 0-, 30-, 45-, or 60-min collections. An excellent correlation in peak [HCO3-] was observed (R2 = 0.84, p < 0.001). Using a peak [HCO3-] cutpoint 80 mEq/L, there was 100% agreement between the methods; using cutpoint 90 mEq/L, there was 83% agreement. CONCLUSIONS: The accuracy of the ePFT is similar to DT: There were minimal differences in [HCO3-] at each of the timed collections and at peak. There is an excellent correlation in peak [HCO3-] and high level of diagnostic agreement between the tests.

The effect of moderate sedation on exocrine pancreas function in normal healthy subjects: a prospective, randomized, cross-over trial using the synthetic porcine secretin stimulated Endoscopic Pancreatic Function Test (ePFT).

BACKGROUND: We have developed a purely endoscopic collection method for the assessment of pancreatic secretory function (ePFT). The pancreatic secretory effects of sedation medications utilized during endoscopic procedures are not completely known. AIMS: To study the effect of moderate sedation on the exocrine pancreas gland in a prospective, randomized trial. METHODS: Healthy volunteers were randomized by computers to one of two treatments (A-no sedation, B-sedation) in period 1 and crossed-over to the other treatment in period 2 with a minimal washout interval of 7 days. Sedation dosage was standardized for each patient based on age, gender and weight from a previously published dosing nomogram. Synthetic porcine secretin (ChiRhoClin, Inc., Burtonsville, Maryland) was used as the pancreatic stimulant. Duodenal fluid samples were aspirated via the endoscope every 5 min for 1 h and sent on ice to our hospital laboratory for the measurement of pancreatic secretory electrolyte concentrations by autoanalyzer. RESULTS: A total of 17 healthy volunteers were enrolled. Sixteen subjects (8 males and 8 females) completed the randomized prospective trial. Median intravenous meperidine and midazolam sedation dose was 62.5 mg and 2.5 mg, respectively. Maximum pancreatic juice flow occurred during the early phase of secretion and maximum bicarbonate concentration occurred during the late phase of secretion. Analysis of the electrolyte composition of the endoscopically collected duodenal drainage fluid revealed a constant cation concentration for both sodium and potassium over the 1 h collection period. The anions, chloride and bicarbonate, exhibited a reciprocal relationship identical to that seen in traditional gastroduodenal tube collection studies. There was no statistical difference observed between the sedation and no sedation groups. The estimated total bicarbonate output (area under curve, AUC) for the sedated and non-sedated groups were 5,017 meq + 724 (range 3,663-6,173) and 5,364 meq +/- 583 (range 4,323-6563) respectively (p= 0.0656). The mean peak bicarbonate concentrations for sedated (n = 8) versus non-sedated (n = 8) groups were 103 +/- 11 meq/L (range 78-125) and 106 +/- 11 meq/L (range 87-138), respectively (p= 0.1346). There was excellent correlation of peak bicarbonate concentrations when sedation and no sedation groups were compared (r= 0.744, p < 0.05; Spearman rank correlation). There were no episodes of pancreatitis. CONCLUSIONS: (a) Moderate sedation used for upper endoscopy does not effect the clinical diagnostic parameters (peak bicarbonate concentration or total bicarbonate output) utilized to diagnose pancreatic insufficiency. (b) Analysis of duodenal drainage fluid collected endoscopically after synthetic secretin stimulation produces an identical pancreatic secretory curve described with traditional gastroduodenal tube collection methods.

Use of capillary electrophoresis in drug quality assessment of synthetic porcine secretin.

The purity profile for porcine secretin attributable to contamination by equilibrium products such as aspartoyl(3) secretin has been shown to be dependent on the pH of the analytical system. Capillary zone electrophoresis (CZE) methods have been developed for the efficient separation of synthetic porcine secretin, its equilibrium products and other impurities in aqueous solutions at both acidic and alkaline pH. These conditions are more representative of those used for the reconstitution and administration of porcine secretin, and good results cannot be achieved using HPLC due to poor peak shape above pH 5.8. The influence of various CZE operational parameters was systematically examined. The methods were validated for accuracy, precision, linearity, LOD and LOQ. A comparative evaluation of the stability of test solutions was determined using CZE and HPLC over a range of pH values. HPLC and CZE methods produced similar results at low pH.

Electrolyte composition of endoscopically collected duodenal drainage fluid after synthetic porcine secretin stimulation in healthy subjects.

BACKGROUND: Traditional pancreatic function tests are sensitive for the diagnosis of pancreatic exocrine insufficiency but are cumbersome and difficult to perform. A sedationless endoscopic pancreatic function test that has the potential for wide clinical application was developed by us, but data on the results of this method in healthy subjects are lacking. This study analyzed endoscopically collected duodenal fluid from healthy subjects after synthetic porcine secretin stimulation. METHODS: Healthy subjects underwent the sedationless endoscopic pancreatic function test. After secretin stimulation, duodenal aspirates were obtained every 5 minutes for 1 hour. The collected fluid was analyzed for electrolyte concentrations. RESULTS: Sixteen healthy subjects (8 women, 8 men; median age 34.5 years) underwent the endoscopic pancreatic function test. The concentrations of the sodium ([Na+]) and potassium ([K+]) cations remained constant, similar to normal concentrations in plasma (median [Na+], 155 mEq/L; median [K+], 4.3 mEq/L). The concentrations of the bicarbonate ([HCO 3 - ]) and chloride anions increased and decreased, respectively, in an inverse and reciprocal manner, similar to the previously characterized "secretory curve." The median peak [HCO 3 - ] was 108 mEq/L IQR: 99-110). By the 20-minute collection, the [HCO 3 - ] was greater than 80 mEq/L for 94% (15/16) of subjects, the historic cut point for [HCO 3 - ] in studies based on traditional methods of pancreatic function testing. CONCLUSIONS: Endoscopic collection of pancreatic fluid reproduces the anion-cation secretory curve described by prior studies of pancreatic secretory physiology based on traditional collection methods.

A new synthetic porcine secretin for facilitation of cannulation of the dorsal pancreatic duct at ERCP in patients with pancreas divisum: a multicenter, randomized, double-blind comparative study.

BACKGROUND: Secretin, a 27 amino acid polypeptide released in response to duodenal luminal acidification, stimulates secretion of water and bicarbonate from pancreatic ductal cells. To date the only secretin available for clinical use has been a biologically derived compound extracted from porcine duodenums. Although used to facilitate pancreatic duct cannulation, secretin has not been approved for this indication. In this study, a new synthetic porcine secretin with an identical amino acid composition was compared with saline solution for the facilitation of minor papilla cannulation in patients with pancreas divisum. METHODS: A multicenter, prospective, randomized, placebo-controlled, double-blind, comparative trial was conducted at 4 centers with expertise in pancreaticobiliary endoscopy. Patients with pancreas divisum in whom minor papilla cannulation initially was unsuccessful were enrolled. Either saline solution (placebo) or synthetic porcine secretin was administered. If the minor papilla orifice and/or pancreatic juice flow was noted, cannulation was attempted and success or failure was documented (phase 1), as well as the time taken for successful cannulation. If cannulation was unsuccessful, no juice flow was noted, or the orifice was not seen, the alternate agent was administered (phase 2). RESULTS: Twenty-nine patients (7 men, 22 women; mean age 51 years, range 21-76 years) were enrolled. In phase 1, cannulation was achieved in 1 of 13 patients (7.7%) after the placebo was given and in 13 of 16 patients (81.3%) after synthetic porcine secretin was given (p < 0.0001). In phase 2, cannulation was achieved in 12 of 12 patients (100%) after synthetic porcine secretin was given and in 0 of 3 patients (0%) after the placebo was given (p = 0.0022). Overall, cannulation was successful in 25 of 28 patients (89.3%) who received synthetic porcine secretin and in 1 of 16 (6.3%) who received the placebo (p < 0.0001). Mean time to cannulation was significantly greater for the placebo than for the synthetic porcine secretin (4.75 min vs. 2.63 min; p = 0.0001). No adverse events directly attributable to synthetic porcine secretin administration were documented. CONCLUSIONS: This study confirmed the use and safety of synthetic porcine secretin in facilitating cannulation of the minor papilla in patients with pancreas divisum in whom cannulation was difficult. Use of this agent has the potential to further increase the cannulation success rate in this group of patients.