Aggressive fluid hydration plus non-steroidal anti-inflammatory drugs versus non-steroidal anti-inflammatory drugs alone for post-endoscopic retrograde cholangiopancreatography pancreatitis (FLUYT): a multicentre, open-label, randomised, controlled trial.

BACKGROUND: Pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). Prophylactic rectal administration of non-steroidal anti-inflammatory drugs (NSAIDs) is considered as standard of care to reduce the risk of post-ERCP pancreatitis. It has been suggested that aggressive hydration might further reduce this risk. Guidelines already recommend aggressive hydration in patients who are unable to receive rectal NSAIDs, although it is laborious and time consuming. We aimed to evaluate the added value of aggressive hydration in patients receiving prophylactic rectal NSAIDs. METHODS: FLUYT, a multicentre, open-label, randomised, controlled trial done across 22 Dutch hospitals, included patients aged between 18 and 85 years with moderate to high risk of post-ERCP pancreatitis. Patients were randomly assigned (1:1) by a web-based module with varying block sizes to a combination of aggressive hydration and rectal NSAIDs (100 mg diclofenac or indomethacin; aggressive hydration group) or rectal NSAIDs (100 mg diclofenac or indomethacin) alone (control group). Randomisation was stratified according to treatment centre. Aggressive hydration comprised 20 mL/kg intravenous Ringer's lactate solution within 60 min from the start of ERCP, followed by 3 mL/kg per h for 8 h. The control group received normal intravenous saline with a maximum of 1·5 mL/kg per h and 3 L per 24 h. The primary endpoint was post-ERCP pancreatitis and was analysed on a modified intention-to-treat basis (including all patients who underwent randomisation and an ERCP and for whom data regarding the primary outcome were available). The trial is registered with the ISRCTN registry, ISRCTN13659155. FINDINGS: Between June 5, 2015, and June 6, 2019, 826 patients were randomly assigned, of whom 388 in the aggressive hydration group and 425 in the control group were included in the modified intention-to-treat analysis. Post-ERCP pancreatitis occurred in 30 (8%) patients in the aggressive hydration group and in 39 (9%) patients in the control group (relative risk 0·84, 95% CI 0·53-1·33, p=0·53). There were no differences in serious adverse events, including hydration-related complications (relative risk 0·99, 95% CI 0·59-1·64; p=1·00), ERCP-related complications (0·90, 0·62-1·31; p=0·62), intensive care unit admission (0·37, 0·07-1·80; p=0·22), and 30-day mortality (0·95, 0·50-1·83; p=1·00). INTERPRETATION: Aggressive periprocedural hydration did not reduce the incidence of post-ERCP pancreatitis in patients with moderate to high risk of developing this complication who routinely received prophylactic rectal NSAIDs. Therefore, the burden of laborious and time-consuming aggressive periprocedural hydration to further reduce the risk of post-ERCP pancreatitis is not justified. FUNDING: Netherlands Organisation for Health Research and Development and Radboud University Medical Center.

Vegetable, fruit and nitrate intake in relation to the risk of Barrett's oesophagus in a large Dutch cohort.

There are few epidemiological data on the dietary risk factors of Barrett's oesophagus, a precursor of oesophageal adenocarcinoma. The present study investigated the association between vegetable, fruit and nitrate intake and Barrett's oesophagus risk in a large prospective cohort. The Netherlands Cohort Study recruited 120,852 individuals aged 55-69 years in 1986. Vegetable and fruit intake was assessed using a 150-item FFQ, and nitrate intake from dietary sources and drinking water was determined. After 16.3 years of follow-up, 433 cases (241 men and 192 women) of Barrett's oesophagus with specialised intestinal metaplasia and 3717 subcohort members were analysed in a case-cohort design using Cox proportional hazards models while adjusting for potential confounders. Men exhibited a lower risk of Barrett's oesophagus in the highest v. the lowest quintile of total (multivariable-adjusted hazard ratio (HR): 0.66, 95% CI 0.43, 1.01), raw (HR 0.63, 95% CI 0.40, 0.99), raw leafy (HR 0.55, 95% CI 0.36, 0.86) and Brassica (HR 0.64, 95% CI 0.41, 1.00) vegetable intake. No association was found for other vegetable groups and fruits. No significant associations were found between vegetable and fruit intake and Barrett's oesophagus risk among women. Total nitrate intake was inversely associated with Barrett's disease risk in men (HR 0.50, 95% CI 0.25, 0.99) and positively associated with it in women (HR 3.77, 95% CI 1.68, 8.45) (P for interaction = 0.04). These results suggest that vegetable intake may contribute to the prevention of Barrett's oesophagus. The possible differential effect in men and women should be evaluated further.

[Transfusions in the acutely bleeding patient: the borders between too little too late and too much too early]. / Transfusie bij de acuut bloedende patiënt: de grens tussen 'te weinig te laat' en 'te veel te vroeg'.

A restrictive regime regarding the initiation of blood transfusions was found to be safe in a Spanish study that included 921 patients with upper gastrointestinal bleeding. Survival after 6 weeks was higher (95 vs. 91%) in the restrictive group (Hb 4.3 mmol/l) than in the liberal group (Hb 5.6 mmol/l). The restrictive regimen was found favourable in patients with cirrhosis (class Child-Pugh A and B). In the Netherlands, guidelines prescribe the use of the 4-5-6 rule for initiating blood transfusions, depending on comorbidity (according to ASA classification) for patients who are haemodynamically stable and an aggressive regime when unstable. Starting blood transfusions can be lifesaving and must not be withheld in those who are haemodynamically unstable, but when stable, nuance is needed. In conclusion, the right balance needs to be found between too little too late and too much too early.

Meat consumption and the risk of Barrett's esophagus in a large Dutch cohort.

BACKGROUND: Increasing meat intake and its possible role in the development of esophageal adenocarcinoma raises the question whether meat consumption is associated with the premalignant lesion, Barrett's esophagus. METHODS: Associations between the risk of Barrett's esophagus and meat consumption, intake of N-nitrosodimethylamine, nitrite, and heme iron were examined in the Netherlands Cohort Study among 120,852 subjects aged 55 to 69 years in 1986. Exposure was measured on the basis of a 150-item food frequency questionnaire. After 16.3 years of follow-up, 447 Barrett's esophagus cases with specialized intestinal metaplasia and 3,919 subcohort members were analyzed in a case-cohort design. RESULTS: There was no association of any of the examined exposures with Barrett's risk in men or women. Results were similar in age-adjusted and fully adjusted models and in models excluding the first two years of follow-up. CONCLUSIONS: Our results do not support a role of meat consumption and N-nitrosation related factors in the development of Barrett's esophagus. IMPACT: The possible causal association between red meat intake and esophageal adenocarcinoma is unlikely to be mediated by mechanisms through the development of Barrett's esophagus.

Percutaneous radiofrequency ablation of the splanchnic nerves in patients with chronic pancreatitis: results of single and repeated procedures in 11 patients.

BACKGROUND: Pain is a major problem for chronic pancreatitis (CP) patients. Unfortunately, medical therapy often fails. Endoscopic and surgical treatments are invasive, and results vary. Percutaneous radiofrequency ablation of the splanchnic nerves (RFSN) is a relatively new and minimally invasive procedure for treatment of intractable pain in CP patients. MATERIALS AND METHODS: We retrospectively evaluated 18 RFSN procedures in 11 CP patients, all refractory to analgesics. Five patients underwent a second procedure; two patients underwent a third procedure. NRS pain scores were assessed. Complications, analgesics usage, and length of the pain-free period were recorded. RESULTS: Radiofrequency ablation of the splanchnic nerves was effective in 15/18 interventions. The mean NRS pain score decreased from 7.7 ± 1.0 to 2.8 ± 2.7 (P ≤ 0.001). The pain-free period lasted for a median period of 45 weeks. The effect of repeated interventions was comparable to the initial procedure. One transient side effect was reported. Four patients reported significantly reduced analgesic usage; 4 patients completely stopped their pain medication. CONCLUSION: Radiofrequency ablation of the splanchnic nerves is a minimally invasive, effective procedure for pain relief. After the effect has subsided, RFSN can be successfully repeated. RFSN might become an alternative treatment in a selected group of CP patients. A larger, randomized trial is justified to substantiate these findings.

26. Pain in chronic pancreatitis.

Chronic pancreatitis is defined as a progressive inflammatory response of the pancreas that has lead to irreversible morphological changes of the parenchyma (fibrosis, loss of acini and islets of Langerhans, and formation of pancreatic stones) as well as of the pancreatic duct (stenosis and pancreatic stones). Pain is one of the most important symptoms of chronic pancreatitis. The pathogenesis of this pain can only partly be explained and it is therefore often difficult to treat this symptom. The management of pain induced by chronic pancreatitis starts with lifestyle changes and analgesics. For the pharmacological management, the three-step ladder of the World Health Organization extended with the use of co-analgesics is followed. Interventional pain management may consist of radiofrequency treatment of the nervi splanchnici, spinal cord stimulation, endoscopic stenting or stone extraction possibly in combination with lithotripsy, and surgery. To date, there are no randomized controlled trials supporting the efficacy of radiofrequency and spinal cord stimulation. The large published series reports justify a recommendation to consider these treatment options. Radiofrequency treatment, being less invasive than spinal cord stimulation, could be tested prior to considering spinal cord stimulation. There are several other treatment possibilities such as endoscopic or surgical treatment, pancreatic enzyme supplementation and administration of octreotide and antioxidants. All may have a role in the management of pain induced by chronic pancreatitis.

Total cancer incidence and overall mortality are not increased among patients with Barrett's esophagus.

BACKGROUND & AIMS: Barrett's esophagus (BE) increases risk for esophageal adenocarcinoma, but it is not clear how it affects risk for other cancers or overall mortality. We analyzed data from a population-based cohort of subjects with BE. METHODS: The Netherlands Cohort Study was initiated in 1986 and included 120,852 participants (55-69 years old at baseline). Until December 2002, 626 incident cases of BE (excluding nonintestinal metaplasia) were identified by record linkage with the nationwide Pathology Registry. This cohort was followed for a median period of 5.7 years; data on cancer and mortality were obtained from record linkage to the Netherlands Cancer Registry and Statistics Netherlands. The expected number of cases was calculated using national cancer incidence and mortality data. RESULTS: In the BE cohort, 13 individuals developed esophageal cancer and 5 developed gastric cancer. The ratio of observed:expected (O:E) incidence of esophageal and gastric cancer was 10.0 (95% confidence interval [CI], 5.3-17.1) and 1.8 (95% CI, 0.6-4.2), respectively. Total cancer incidence (excluding esophageal and gastric cancer) increased in the BE cohort, although not by a statistically significant amount (O:E, 1.3; 95% CI, 1.0-1.6). Of cancer subtypes, incidences of small intestinal and pancreatic cancer increased in subjects with BE, but not by a statistically significant amount, after exclusion of data from the first 6 months of follow-up. During the follow-up period, 225 individuals with BE died. Mortality from all causes (excluding esophageal and gastric cancer) was not increased among subjects with BE (O:E, 1.0; 95% CI, 0.9-1.2), nor was mortality from specific causes of death. CONCLUSIONS: The incidence of esophageal cancer was increased in a population-based cohort of subjects with BE. However, when esophageal and gastric cancers were excluded, total cancer incidence and overall mortality were not increased among subjects with BE.

A prospective cohort study on overweight, smoking, alcohol consumption, and risk of Barrett's esophagus.

BACKGROUND: Barrett's esophagus (BE) is a precursor lesion of esophageal adenocarcinoma. Besides gastroesophageal reflux, possible risk factors for BE include overweight, cigarette smoking, and alcohol consumption. Our objective was to study these associations by using prospective data. METHODS: The prospective Netherlands Cohort Study, initiated in 1986, consists of 120,852 men and women, aged 55 to 69 years at baseline. At baseline, all subjects completed a questionnaire on dietary habits and lifestyle. After 16.3 years of follow-up, 370 BE cases with specialized intestinal metaplasia and 3,866 subcohort members were available for case-cohort analysis. Cox proportional hazards models were used to calculate incidence rate ratios (RR) and 95% CIs. RESULTS: Body mass index (BMI) at baseline was associated with risk of BE in women [multivariable adjusted RR per 1 kg/m(2), 1.07 (1.03-1.11)] but not in men [RR per 1 kg/m(2), 0.99 (0.93-1.05)]. The association in women was not specifically due to abdominal overweight. Former cigarette smokers were at increased risk of BE (RR = 1.33, 95% CI: 1.00-1.77), but current smokers were not. Smoking duration showed a positive association with BE risk (P(trend) = 0.03). For alcohol consumption, the RR per 10 g ethanol/d was 0.95 (0.87-1.03). CONCLUSIONS: Increased BMI was a risk factor for BE in women but not in men. Several aspects of cigarette smoking were positively associated with BE risk. Alcohol consumption was not associated with an increased risk of BE. IMPACT: Future research should focus on risk factors both for development and for progression of BE to esophageal adenocarcinoma.

Toenail selenium status and the risk of Barrett's esophagus: the Netherlands Cohort Study.

OBJECTIVE: To investigate the association between selenium and the risk of Barrett's esophagus (BE), the precursor lesion of esophageal adenocarcinoma. METHODS: Data from the prospective Netherlands Cohort Study were used. This cohort study was initiated in 1986, when 120,852 subjects aged 55-69 years completed a questionnaire on dietary habits and lifestyle, and provided toenail clippings for the determination of baseline selenium status. After 16.3 years of follow-up, 253 BE cases (identified through linkage with the nationwide Dutch pathology registry) and 2,039 subcohort members were available for case-cohort analysis. Cox proportional hazards models were used to calculate incidence rate ratios (RR). RESULTS: The multivariable-adjusted RR for the highest versus the lowest quartile of toenail selenium was 1.06 (95% CI 0.71-1.57). No dose-response trend was seen (p trend = 0.99). No association was found in subgroups defined by sex, smoking status, body mass index (BMI), or intake of antioxidants. For BE cases that later progressed to high-grade dysplasia or adenocarcinoma, the RR for a selenium level above the median vs. below the median was 0.64 (95% CI 0.24-1.76). CONCLUSIONS: In this large prospective cohort study, we found no evidence of an association between selenium and risk of BE.

Ursodeoxycholic acid exerts no beneficial effect in patients with symptomatic gallstones awaiting cholecystectomy.

Ursodeoxycholic acid (UDCA) and impaired gallbladder motility purportedly reduce biliary pain and acute cholecystitis in patients with gallstones. However, the effect of UDCA in this setting has not been studied prospectively. This issue is important, as in several countries (including the Netherlands) scheduling problems result in long waiting periods for elective cholecystectomy. We conducted a randomized, double-blind, placebo-controlled trial on effects of UDCA in 177 highly symptomatic patients with gallstones scheduled for cholecystectomy. Patients were stratified for colic number in the preceding year (<3: 32 patients; > or =3: 145 patients). Baseline postprandial gallbladder motility was measured by ultrasound in 126 consenting patients. Twenty-three patients (26%) receiving UDCA and 29 (33%) receiving placebo remained colic-free during the waiting period (89 +/- 4; median [range]: 75[4-365] days) before cholecystectomy (P = .3). Number of colics, non-severe biliary pain, and analgesics intake were comparable. A low number of prior colics was associated with a higher likelihood of remaining colic-free (59% vs. 23%, P < .001), without effects on the risk of complications. In patients evaluated for gallbladder motility, 57% were weak and 43% were strong contractors (minimal gallbladder volume > respectively < or = 6 mL). Likelihood to remain colic-free was comparable in strong and weak contractors (31% vs. 33%). In weak contractors, UDCA decreased likelihood to remain colic-free (21% vs. 47%, P = .02). In the placebo group, 3 preoperative and 2 post-cholecystectomy complications occurred. In contrast, all 4 complications in the UDCA group occurred after cholecystectomy. In conclusion, UDCA does not reduce biliary symptoms in highly symptomatic patients. Early cholecystectomy is warranted in patients with symptomatic gallstones.

Wait-and-see policy or laparoscopic cholecystectomy after endoscopic sphincterotomy for bile-duct stones: a randomised trial.

BACKGROUND: Patients who undergo endoscopic sphincterotomy for common bile-duct stones, who have residual gallbladder stones, are referred for laparoscopic cholecystectomy. However, only 10% of patients who do not have this operation are reported to develop recurrent biliary symptoms. We aimed to assess whether a wait-and-see policy is justified. METHODS: We did a prospective, randomised, multicentre trial in 120 patients (age 18-80 years) who underwent endoscopic sphincterotomy and stone extraction, with proven gallbladder stones. Patients were randomly allocated to wait and see (n=64) or laparoscopic cholecystectomy (56). Primary outcome was recurrence of at least one biliary event during 2-year follow-up, and secondary outcomes were complications of cholecystectomy and quality of life. Analysis was by intention to treat. FINDINGS: 12 patients were lost to follow-up immediately. Of 59 patients allocated to wait and see, 27 (47%) had recurrent biliary symptoms compared with one (2%) of 49 patients after laparoscopic cholecystectomy (relative risk 22.42, 95% CI 3.16-159.14, p<0.0001). 22 (81%) of 27 patients underwent cholecystectomy, mainly for biliary pain (n=13) or acute cholecystitis (7). Conversion rate to open surgery was 55% in patients allocated to wait and see who underwent cholecystectomy compared with 23% in those who were allocated laparoscopic cholecystectomy (p=0.0104). Morbidity was 32% versus 14% (p=0.1048), and median hospital stay was 9 versus 7 days. Quality of life returned to normal within 3 months after either treatment policy. INTERPRETATION: A wait-and-see policy after endoscopic sphincterotomy in combined cholecystodocholithiasis cannot be recommended as standard treatment, since 47% of expectantly managed patients developed at least one recurrent biliary event and 37% needed cholecystectomy. No major biliary complications arose, but conversion rate was high.